US 20160O81976A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0081976 A1 Bromley (43) Pub. Date: Mar. 24, 2016

(54) FORMULATIONS OF WATER-SOLUBLE A6II 45/06 (2006.01) DERVATIVES OF VITAMIN E AND SOFT A63L/22 (2006.01) GEL COMPOSITIONS, CONCENTRATES A61E36/324 (2006.01) AND POWDERS CONTAINING SAME A61E36/85 (2006.01) (71) Applicant: VIRUN, INC., Walnut, CA (US) A647/48 (2006.01) O O A613 L/437 (2006.01) (72) Inventor: Philip J. Bromley, Fullerton, CA (US) (52) U.S. Cl. (21) Appl. No.: 14/866,808 CPC ...... A61 K3I/355 (2013.01); A61K47/48215 (2013.01); A61 K3I/09 (2013.01); A61 K (22) Filed: Sep. 25, 2015 31/202 (2013.01); A61K 31/437 (2013.01); Related U.S. Application Data A6 IK3I/122 (2013.01); A61K 36/324 (2013.01); A61K 36/185 (2013.01); A61 K (63) Continuation of application No. PCT/US2015/ 45/06 (2013.01) 051097, filed on Sep. 18, 2015, Continuation of appli cation No. PCT/US2015/051083, filed on Sep. 18, 2015. (57) ABSTRACT (60) Provisional application No. 62/052,433, filed on Sep. RA's prcity, application N. R Provided herein are compositions that contain water-soluble ed. On Sep. 1S, prov1s1onal application No. itamin E derivati ixtu iti has toco 62/052,435, filed on Sep. 18, 2014, provisional appli- N 1 N. 1Ve t t E. aS f cation No. 62/052,450, filed on Sep. 18, 2014. pheryl polyethylene glycol Succinate ( ), analogS, TPGS homologs and TPGS derivatives. The water-soluble Publication Classification Vitamin E mixtures contain mixtures of dimers and mono (51) Int. Cl mers of the vitamin E derivative. Provided are products con A. 6iK I/355 (2006.01) taining the water-soluble vitamin E derivative mixtures, A6 IK3I/09 (2006.01) including capsules, soft gel compositions, pre-gel composi A6 IK3I/202 (2006.01) tions, emulsions and powders. US 2016/008 1976 A1 Mar. 24, 2016

FORMULATIONS OF WATER-SOLUBLE tion Ser. No. 61/852,243, filed Mar. 15, 2013, entitled “FOR DERVATIVES OF VITAMIN E AND SOFT MULATIONS OF PEG-DERIVATIVES OF VITAMIN E GEL COMPOSITIONS, CONCENTRATES AND COMPOSITIONS CONTAINING SAME, to Philip AND POWDERS CONTAINING SAME Bromley, and International PCT Application No. PCT/ US2014/25006, filed Mar. 12, 2014, published as WO 2014/ RELATED APPLICATIONS 151109 on Sep. 25, 2014, entitled “FORMULATIONS OF 0001. This application is a continuation of PCT/US2015/ WATER-SOLUBLE DERIVATIVES OF VITAMIN E AND 051097, filed Sep. 18, 2015, entitled “PRE-SPRAY EMUL COMPOSITIONS CONTAINING SAME, which also SIONS AND POWDERS CONTAINING NON-POLAR claims priority to U.S. Provisional Application Ser. No. COMPOUNDS.” to Philip Bromley, which claims the benefit 61/852,243, filed Mar. 15, 2013, entitled “FORMULATIONS of priority to U.S. Provisional Application Ser. No. 62/052, OF PEG-DERIVATIVES OF VITAMINE AND COMPOSI 433, filed Sep. 18, 2014, entitled “PRE-SPRAY EMUL TIONS CONTAINING SAME and to U.S. Provisional SIONS AND POWDERS CONTAINING NON-POLAR Application Ser. No. 61/863,732, filed Aug. 8, 2013, entitled COMPOUNDS,” to Philip J. Bromley, and to U.S. Provi FORMULATIONS OF WATER-SOLUBLE DERIVA sional Application Ser. No. 62/052,450, filed Sep. 18, 2014, TIVES OF VITAMIN E AND COMPOSITIONS CON entitled “FORMULATIONS OF WATER-SOLUBLE TAINING SAME, each to Philip Bromley. DERIVATIVES OF VITAMINE AND SOFT GEL COMPO 0006. The subject matter of each of the above-referenced SITIONS, CONCENTRATES AND POWDERS CON applications is incorporated by reference in its entirety. TAINING SAME, to Philip J. Bromley. 0002 This application also is a continuation of PCT/ FIELD OF THE INVENTION US2015/051083, filed Sep. 18, 2015, entitled “SOFT GEL 0007 Provided herein are compositions that contain COMPOSITIONS AND PRE-GEL CONCENTRATES to water-soluble vitamin E derivative mixtures (compositions), Philip J. Bromley, which also claims the benefit of priority to such as tocopheryl polyethylene glycol succinate (TPGS), U.S. Provisional Application Ser. No. 62/052,435, filed Sep. TPGS analogs, TPGS homologs and TPGS derivatives. The 18, 2014, entitled “SOFT GEL COMPOSITIONS AND water-soluble vitamin E mixtures contain mixtures of dimers PRE-GEL CONCENTRATES. to Philip J. Bromley, and to and monomers of the vitamin E derivative. Also provided are U.S. Provisional Application Ser. No. 62/052.450, filed Sep. products containing the water-soluble vitamin E derivative 18, 2014, entitled “FORMULATIONS OF WATER mixtures, including soft gel compositions, pre-gel concen SOLUBLE DERIVATIVES OF VITAMIN E AND SOFT trates, capsules and soft gels compositions that contain the GEL COMPOSITIONS, CONCENTRATES AND POW pre-gel concentrates, and powders, and methods for prepar DERS CONTAINING SAME to Philip J. Bromley. ing the products. Methods for preparing the products are 0003. This application is related to U.S. application Ser. provided. No. 14/866,717, filed the same day herewith, entitled “PRE SPRAY EMULSIONS AND POWDERS CONTAINING BACKGROUND NON-POLAR COMPOUNDS.” to Philip J. Bromley. U.S. application Ser. No. 14/866,717 also claims priority to U.S. 0008. Non-polar ingredients and compounds are not eas Provisional Application Ser. No. 62/052,433, filed Sep. 18, ily dissolved in aqueous solutions, such as water or other 2014, entitled “PRE-SPRAY EMULSIONS AND POW polar solvents. A number of non-polar ingredients and com DERS CONTAINING NON-POLAR COMPOUNDS to pounds are used in compositions for human ingestion. These Philip J. Bromley, and to U.S. Provisional Application Ser. include, for example, pharmaceuticals, nutraceuticals and/or No. 62/052,450, filed Sep. 18, 2014, entitled “FORMULA dietary Supplements. Exemplary of non-polar ingredients are TIONS OF WATER-SOLUBLE DERIVATIVES OF VITA Vitamins and minerals, fatty acids, and other non-polar com MIN E AND SOFT GEL COMPOSITIONS, CONCEN pounds, non-polar bioactive agents and non-polar ingredi TRATES AND POWDERS CONTAINING SAME to ents. Because of poor water Solubility, inclusion of non-polar Philip J. Bromley. ingredients and compounds in products for human consump 0004. This application also is related to U.S. application tion, for example, in Supplements, foods and beverages, can Ser. No. 14/866,724, filed the same day herewith, entitled be problematic, and the amount of non-polar ingredient that SOFT GEL COMPOSITIONS AND PRE-GEL CONCEN can be included is limited. TRATES.” to Philip J. Bromley. U.S. application Ser. No. 0009 Water-soluble forms of vitamin E, such as TPGS 14/866,724 also claims priority to U.S. Provisional Applica (D-O-tocopheryl polyethylene glycol Succinate), in particular tion Ser. No. 62/052,435, filed Sep. 18, 2014, entitled “SOFT TPGS 1000 (D-C-tocopheryl polyethylene glycol 1000 suc GEL COMPOSITIONS AND PRE-GEL CONCEN cinate), have been approved by the FDA as vitamin E nutri TRATES.” to Philip J. Bromley, and to U.S. Provisional tional supplements. TPGS is a stable, tasteless and odorless Application Ser. No. 62/052,450, filed Sep. 18, 2014, entitled source of readily bioavailable vitamin E that does not hydro FORMULATIONS OF WATER-SOLUBLE DERIVA lyze under normal conditions. TPGS, TPGS homologs, TPGS TIVES OF VITAMIN E AND SOFT GEL COMPOSI analogs and TPGS derivatives also are used as Surfactants, TIONS, CONCENTRATES AND POWDERS CONTAIN and have been used to prepare stabilized formulations of food, ING SAME, to Philip J. Bromley. beverage, pharmaceutical or nutraceutical products contain 0005. This application also is related to U.S. patent appli ing non-polar compounds. TPGS (and homologs, analogs and cation Ser. No. 14/207,310, filed Mar. 12, 2014, published as derivatives) has been used as a solubilizing agent for Such US-2014-0271593-A1 on Sep. 18, 2014, entitled “FORMU stabilized formulations, such as water-soluble formulations LATIONS OF WATER-SOLUBLE DERIVATIVES OF that contain water-insoluble non-polar compounds, such as VITAMIN E AND COMPOSITIONS CONTAINING drugs, vitamins, or other biologically active compounds, Such SAME.” which claims priority to U.S. Provisional Applica as natural and non-natural omega-fatty acids. Thus, TPGS US 2016/008 1976 A1 Mar. 24, 2016

possesses the dual function of providing additional dietary of the dimer form of the vitamin E derivative product. One Vitamin E and providing stabilization to a formulation. advantageous property of the higher dimer-containing water 0010 Available products containing non-polar com soluble vitamin E derivative compositions is that, when pounds, particularly products for human consumption, Such diluted into foods and beverages, the resulting products have as food and beverage products containing non-polar com greater clarity and stability than products produced by addi pounds, and methods for formulating Such products, are lim tion of the same concentrates, except that the concentrates ited. In addition, the amount, or concentration, of non-polar containa water-soluble vitamin Ederivative composition that compounds in available food and beverage products is limited contains less than 13% dimer. due to the display of undesirable organoleptic properties 0014 Generally, vitamin E derivative compositions have when the amount of non-polar compound is increased. Thus, been prepared to contain as much monomer form as possible there is a need to develop products for human consumption, and contain dimer only as an undesired byproduct in low Such as food and beverage products, that contain non-polar concentration. The water-soluble vitamin E derivative mix compounds and methods for making the products. There is an tures (compositions) provided herein can be used as the PEG additional need to develop products for human consumption, derivative of vitamin E, such as TPGS, in addition to or in Such as food and beverage products, that contain a higher place of another Surfactant, such as a polysorbate, in any amount of non-polar compound than is offered in available composition or formulation that contains a PEG derivative of food and beverage products. There also is a need to develop vitamin E, such as TPGS. products for human consumption, Such as food and beverage 0015 The water-soluble vitamin E derivative mixtures products, that retain their organoleptic properties when they (compositions) described and used herein are manufactured contain a higher amount of non-polar compound. Accord to contain higher amounts of the dimer form and, conse ingly, it is among the objects herein to provide food and quently, lower amounts of the monomer form of the vitamin beverage products containing non-polar compounds, in par E derivative. For example, aqueous beverages that contain ticular, food and beverage products containing more non these higher dimer content water-soluble vitamin Ederivative polar compounds than available products that retain desirable mixtures (compositions) have substantially greater clarity; organoleptic properties, and methods for making the prod typically they are about 2-fold less turbid when measured uctS. with a nephelometer in Nephelometric Turbidity Units (NTU5), compared to the same beverages and concentrates SUMMARY that differ only in the water-soluble vitamin E derivative 0011 Provided herein are compositions that contain composition that is used. Amounts and particulars of the water-soluble vitamin E derivative mixtures (compositions) compositions and the concentrates and resulting liquid dilu and a non-polar ingredient and optionally, additional ingre tion compositions. Such as aqueous beverages, are described dients. The water-soluble vitamin E derivative mixtures herein. Reference is made to the description and claims set (compositions) contain a relatively high percentage. Such as forth below. at least 13%, typically greater than 25%, 29%, 35%, 45%, 0016 Previously, water-soluble vitamin E derivative com 48%, 49%, 50%, 51%, 52%, or 53%, up to 60-65%, of the positions have been prepared to have as high as possible dimer form of the vitamin E derivative, generally a PEG monomer concentration and typically have at least 87% or derivative of vitamin E. The remainder of the water-soluble more monomer. It is shown herein that the water-soluble vitamin E derivative composition is the monomerform with a Vitamin E derivative mixtures (compositions) that contain small percentage, less than 5%, 4%. 3%, 2%, 1% of contami high amounts of dimer impart advantageous properties to nants, such as higher order polymers and reagents, such as compositions that contain the water-soluble vitamin Ederiva vitamin E. Previously, water-soluble vitamin E derivative tive composition. Hence, provided herein are compositions compositions have been prepared to have as high as possible that contain a water-soluble vitamin E derivative mixture monomer concentration and typically have at least 87% or (composition) and a non-polar ingredient, Such as polyun OOOC. saturated fatty acids, coenzyme Q10 compounds, phytoster 0012. It is shown herein that the water-soluble vitamin E ols, non-polar Small molecules, drugs, vitamins and other derivative mixtures (compositions) that contain the high nutraceuticals, and other such compounds. dimer-containing compositions impart advantageous proper 0017 Provided herein are compositions that include con ties to compositions that contain the water-soluble vitamin E centrates and liquid dilution compositions produced from the derivative composition. Hence, provided herein are compo concentrates, compositions for direct consumption, and dilu sitions that contain a water-soluble vitamin Ederivative com tions of the concentrates, such as beverages, that contain position and a non-polar ingredient, Such as polyunsaturated water-soluble vitamin E derivative mixtures (compositions) fatty acids, coenzyme Q10 compounds, phytosterols, non and a non-polar ingredient and optionally, additional ingre polar Small molecule drugs, vitamins and other nutraceuticals dients. The water-soluble vitamin E derivative mixtures and other Such compounds. (compositions) contain a relatively high percentage, at least 0013 Hence provided herein are compositions which can 13%, typically greater than 25%, 29%, 35%, 45%, 48%, 49%, be used as concentrates for providing soluble forms of non 50%, 51%, 52%. 53%, up to 60-65%, of the dimerform of the polar compounds for dilution into aqueous beverages and vitamin Ederivative, generally a PEG derivative of vitamin E. other foods and beverages, or can be formulated for direct The remainder of the water-soluble vitamin Ederivative com consumption. The compositions, referred to herein as con position is the monomer form and a small percentage, less centrates (although they can be formulated not only for dilu than 5%, 4%. 3%, 2%, or 1% of contaminants, such as higher tion, but for direct consumption), that contain a non-polar order polymers and reagents, such as vitamin E. compound and a water-soluble vitamin E derivative compo 0018. These high dimer-containing water-soluble vitamin sition that contains at least 13%, typically, at least 20%, 25%, E derivative compositions (mixtures) are employed for the 29%, 30%, 40%, 45%, 50% or more, typically up to 60-65%, preparation of compositions that contain the water-soluble US 2016/008 1976 A1 Mar. 24, 2016

Vitamin E mixtures and one or more non-polar ingredients, 50% and 69%, 55% and 60%, 55% and 65%, 55% and 70%, Such as fatty acids, vitamins, phytosterols, other nutraceuti 55% and 75%, 60% and 65%, 60% and 70%, 60% and 75%, cals, drugs, and bioactive components. The water-soluble 65% and 70%. 65% and 75%, or 70% and 75%, by weight, of Vitamin E derivative mixtures (compositions) contain a high the water-soluble vitamin E derivative mixture or is or is at percentage, greater than or at least 13%, by weight, of the least or at least about 13%, 14%, 15%, 16%, 17%, 18%, 19%, dimer form of the vitamin E derivative, and the remainder is 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, predominantly the monomerform, with up to 5% other com 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, ponents, such as trace amounts of reagents, other forms of 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, Vitamin E, and other minor contaminants. Thus, the water 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, soluble vitamin E derivative mixture (composition) provides 60%, 61%. 62%, 63%, 64%. 65%, 66%, 67%, 68%, 69%, a mixture of the dimer form and monomer form of the water 70%, 71%, 72%, 73% or 74%, up to 75%, by weight, of the soluble vitamin E derivative and contains a relatively high water-soluble vitamin E derivative mixture. concentration of dimer form. These mixtures (or composi 0020. The monomer is present in the high dimer-contain tions) also are referred to as high dimer-containing vitamin E ing water-soluble derivatives of vitamin E mixtures in an derivative mixtures, because they are manufactured to be a amount from between or between about 25% and 30%, 25% mixture of forms, with greater than 13%, typically greater and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% than 20%, dimer form. This mixture has advantageous prop and 55%, 25% and 60%, 25% and 65%, 30% and 35%, 30% erties, particularly compared to the same derivative of Vita and 40%, 30% and 45%, 30% and 50%, 30% and 55%, 30% min E that has been used that contains much lower concen and 60%, 30% and 65%, 30% and 69%, 35% and 40%, 35% trations of dimer, if any, and at least 87% monomerform. The and 45%, 35% and 50%, 35% and 55%, 35% and 60%, 35% high dimer-containing water-soluble derivatives of vitamin E and 65%, 35% and 69%, 40% and 45%, 40% and 50%, 40% mixtures are employed to Solubilize non-polar ingredients. and 55%, 40% and 60%, 40% and 65%, 40% and 69%, 45% Thus, provided are compositions that contain high dimer and 50%, 45% and 55%, 45% and 60%, 45% and 65%, 45% containing water-soluble derivatives of vitamin E mixtures and 69%, 50% and 55%, 50% and 60%, 50% and 65%, 50% and a non-polar compound. In particular, the compositions, and 69%, 55% and 60%, 55% and 65%, 55% and 69%, 60% which include compositions for direct consumption and con and 65%, 60% and 69%, or 65% and 69%, by weight, of the centrates, including nanoemulsion concentrates, contain: a water-soluble vitamin E derivative mixture or is or is at least water-soluble vitamin E derivative mixture (composition) in about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, an amount of from between 1% to 99%, inclusive, by weight, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, of the resulting composition, where the water-soluble vitamin 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, E derivative mixture contains at least 13 wt % water-soluble 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, vitamin E derivative dimer and up to 87 wt % monomer; and 64%. 65%, 66%, 67%, 68%, up to and including 69%, by a non-polar compound other than the water-soluble vitamin E weight, of the water-soluble vitamin E derivative mixture. derivative mixture. In some embodiments, the water-soluble 0021. In the high dimer-containing water-soluble deriva vitamin E derivative mixture contains at least 20%, 25% or tives of vitamin E mixtures, the monomer comprises between 29%, by weight, vitamin E derivative dimer, or the water or between about 35% and 65%, inclusive, by weight, of the soluble vitamin E derivative mixture contains up to 75%, water-soluble vitamin E derivative mixture and the dimer 70%, 69%, 62%, 55%, 50%, 45%, 40%, 35% dimer or 29%- comprises between or between about 25% and 65%, by 69%, inclusive, of dimer; and/or contains less than 70%. 65%, weight, of the water-soluble vitamin E derivative mixture, or 63%. 62%, 61%, 55%, 50%, 48%, by weight, of the vitamin the dimer comprises between or between about 29% and 61% E derivative monomer in the water-soluble vitamin E deriva or 62%, by weight, of the water-soluble vitamin E derivative tive mixture. In some embodiments, the amount of dimer is mixture, and the monomer and dimer comprise at least 70%, greater than 29% and the total amount of dimer and monomer by weight, of the water-soluble vitamin E mixture in the in the water-soluble vitamin E derivative mixture is greater composition. than 95%, 96%, 97%, 98%, or 99%. 0022. The water-soluble vitamin E derivative is any suit 0019. The dimer form of the water-soluble vitamin E able derivative of vitamin E that renders it more soluble than derivative is present in an amount between or between about in its absence, and can result in mixtures of dimers and mono 13% and 15%, 13% and 20%, 13% and 25%, 13% and 30%, mers. Exemplary of Such derivatives are polyalkylene glycol 13% and 35%, 13% and 40%, 13% and 45%, 13% and 50%, derivatives of vitamin E, such as, but not limited to, polyeth 13% and 55%, 13% and 60%, 13% and 65%, 13% and 70%, ylene glycol (PEG) derivatives of vitamin E. PEG derivatives 13% and 75%, 20% and 25%, 20% and 30%, 20% and 35%, include those in which the PEG derivative of vitamin Econ 20% and 40%, 20% and 45%, 20% and 50%, 20% and 55%, tains a PEG moiety having a molecular weight between or 20% and 60%, 20% and 65%, 20% and 70%, 20% and 75%, between about 100 Da and 20,000 Da, inclusive, including 25% and 30%, 25% and 35%, 25% and 40%, 25% and 45%, between 200 Da and 10,000 Da, 200 Da and 8000 Da, 200 Da 25% and 50%, 25% and 55%, 25% and 60%, 25% and 65%, and 6000 Da, 200 Da and 5000 Da, 200 Da and 3000 Da, 200 25% and 70%, 25% and 75%, 30% and 35%, 30% and 40%, Da and 1000 Da, 200 Da and 800 Da, 200 Da and 600 Da, 200 30% and 45%, 30% and 50%, 29% and 52%, 30% and 55%, Da and 400 Da, 400 Da and 20,000 Da, 400 Da and 10,000 30% and 60%, 30% and 65%, 30% and 70%, 30% and 75%, Da, 400 Da and 8000 Da, 400 Da and 6000 Da, 400 Da and 35% and 40%, 35% and 45%, 35% and 50%, 35% and 55%, 5000 Da, 400 Da and 3000 Da, 400 Da and 1000 Da, 400 Da 35% and 60%, 35% and 65%, 35% and 70%, 35% and 75%, and 800 Da, 400 Da and 600 Da, 600 Da and 20,000 Da, 600 40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%, Da and 10,000 Da, 600 Da and 8000 Da, 600 Da and 6000 Da, 40% and 65%, 40% and 70%, 40% and 75%, 45% and 50%, 600 Da and 5000 Da, 600 Da and 3000 Da, 600 Da and 1000 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%, Da, 600 Da and 800 Da, 800 Da and 20,000 Da, 800 Da and 45% and 75%, 50% and 55%, 50% and 60%, 50% and 65%, 10,000 Da, 800 Da and 8000 Da, 800 Da and 6000 Da, 800 Da US 2016/008 1976 A1 Mar. 24, 2016

and 5000 Da, 800 Da and 3000 Da, 800 Da and 1000 Da, 1000 non-polar compounds that contain PUFAs, such as fish oil, Da and 20,000 Da, 1000 Da and 10,000 Da, 1000 Da and 8000 algae (algal) oil, flaxseed oil, borage oil, saw palmetto extract, Da, 1000 Da and 6000 Da, 1000 Da and 5000 Da, 1000 Da safflower oil, coconut oil, soybean oil and conjugated linoleic and 3000 Da, 3000 Da and 20,000 Da, 3000 Da and 10,000 acid (CLA)-containing compounds. These include omega-3 Da, 3000 Da and 8000 Da, 3000 Da and 6000 Da, 3000 Da fatty acids, omega-6 fatty acids, omega-9 fatty acids and and 5000 Da, 5000 Da and 20,000 Da, 5000 Da and 10,000 conjugated fatty acids, such as, but not limited to, docosa Da, 5000 Da and 8000 Da, 5000 Da and 6000 Da, 6000 Da hexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha and 20,000 Da, 6000 Da and 10,000 Da, 6000 Da and 8000 linolenic acid (ALA), gamma-linolenic acid (GLA), conju Da, 8000 Da and 20,000 Da, 8000 Da and 10,000 Da or 10000 gated linoleic acid (CLA) and oleic acid compounds. Among Da and 20,000 Da, or has a molecular weight of at least 100, these are coenzyme Q10; an oil-soluble vitamin that is 200, 238, 300, 400, 500, 600, 750, 800, 1000, 1200, 1500, selected from among vitamin B12, vitamin D3, vitamin A 2000, 2500, 3000, 3400, 3500, 4000, 6000, 8000, 10,000, palmitate, vitamin E, vitamin B1, vitamin B3, vitamin B5, 12,000, 14,000, 16,000, or 18,000, up to and including 20,000 vitamin B6, vitamin C and mixtures thereof, a carotenoid Da. containing compound that is selected from amonglycopene, 0023. Among the PEG derivatives of vitamin E are, for lutein, Zeaxanthin and mixtures of lutein and Zeaxanthin; and example, tocopheryl polyethylene glycol Succinate, toco a micronutrient-containing compound that is selected from pheryl polyethylene glycol sebacate, tocopheryl polyethyl among yerba mate, ginkgo biloba and ginseng. ene glycol dodecanodioate, tocopheryl polyethylene glycol 0027. The concentration of non-polar compound in the Suberate, tocopheryl polyethylene glycol azelaate, toco composition depends upon the particular compound and pheryl polyethylene glycol citraconate, tocopheryl polyeth desired dosage or amount to be administered and also ylene glycol methylcitraconate, tocopheryl polyethylene gly whether the composition is intended for direct administration col itaconate, tocopheryl polyethylene glycol maleate, or is a concentrate for dilution or consumption in a capsule. tocopheryl polyethylene glycol glutarate, tocopheryl poly Hence, the concentration of non-polar compound can be ethylene glycol glutaconate, tocopheryl polyethylene glycol present in an amount from 0.1%-99%, by weight, of the fumarate, tocopheryl polyethylene glycol phthalate, tocot composition, such as 0.5% or 1% to 75%, by weight, of the rienol polyethylene glycol Succinate, tocotrienol polyethyl composition, or, for example, 0.1% to 10%, 1% to 5%, 5% to ene glycol sebacate, tocotrienol polyethylene glycol dode 10%, 5% to 12%, 5% to 15%, 5% to 20%, 5% to 25%, 10% to canodioate, tocotrienol polyethylene glycol Suberate, 14%, 10% to 12%, 10% to 15%, 10% to 20%, 10% to 25%, tocotrienol polyethylene glycol azelaate, tocotrienol polyeth 5% to 30%, 1% to 30% or 1% to 15%, inclusive, by weight, of ylene glycol citraconate, tocotrienol polyethylene glycol the composition. methylcitraconate, tocotrienol polyethylene glycolitaconate, 0028. Other ingredients in the compositions include a pre tocotrienol polyethylene glycol maleate, tocotrienol polyeth servative in an amount Sufficient to preserve the composition. ylene glycol glutarate, tocotrienol polyethylene glycol gluta The preservative, for example, can contain benzyl alcohol. conate, tocotrienol polyethylene glycol fumarate and tocot 0029. The compositions can also include a non-polar sol rienol polyethylene glycol phthalate. vent that dissolves the non-polar compound and is different 0024. In some embodiments the vitamin E derivative is therefrom and is present in an amount Sufficient to dissolve selected from among tocopheryl polyethylene glycol Succi the non-polar compound. Exemplary non-polar solvents nate (TPGS), tocopheryl sebacate polyethylene glycol and include, for example, a vitamin E oil, a flaxseed oil, an oat oil other TPGS analogs and TPGS homologs, tocopheryl dode and mixtures thereof. canodioate polyethylene glycol, tocopheryl Suberate polyeth 0030 The compositions can include a polar solvent, such ylene glycol, tocopheryl azelaate polyethylene glycol, toco as a polar protic solvent. Exemplary polar solvents include pheryl citraconate polyethylene glycol, tocopheryl water and consumable alcohols and mixtures thereof. Such as, methylcitraconate polyethylene glycol, tocopheryl itaconate but not limited to, water, glycerin, propylene glycol, ethylene polyethylene glycol, tocopheryl maleate polyethylene glycol, glycol, tetraethylene glycol, triethylene glycol and trimethyl tocopheryl glutarate polyethylene glycol, tocopheryl gluta ene glycol. The amount of polar solvent depends upon the conate polyethylene glycol and tocopheryl phthalate polyeth particular composition and whether it is a concentrate or for ylene glycol. Exemplary of TPGS, is D-O-tocopheryl polyeth direct consumption. Hence, the concentration can be, for ylene glycol succinate (TPGS). example, from more than 0.5% or 1% to 95%, by weight, of 0025. In addition to the high dimer-containing water the composition, such as from 45% to 80%, or 60% to 80%, soluble derivatives of vitamin E mixtures, the compositions by weight, of the composition. provided herein contain an additional ingredient, which typi 0031. The compositions also can contain a co-surfactant cally is a bioactive ingredient. Such as a drug, vitamin or present in an amount Sufficient to increase stability of the nutraceutical. Generally, such ingredients are non-polar composition compared to the absence of a co-surfactant. Co ingredients and are rendered soluble by the high dimer-con Surfactants for use with the high dimer-containing water taining water-soluble derivatives of vitamin E mixture. As soluble vitamin E derivative mixtures include, for example, a provided and shown herein, the high dimer-containing water phospholipid, Such as phosphatidylcholine, a Sucrose fatty soluble derivatives of vitamin E mixtures are more effective acid ester, a polysorbate and a polysorbate analog. than vitamin E derivative compositions that contain high 0032. The compositions also can include an emulsion sta amounts of monomer and low amounts, if any, of dimer. bilizer, Such as a modified Starch and gum mixture. These 0026. Among the non-polar ingredients are those that are include, for example, one or more of a blend of Xanthan gum, or contain a non-polar compound, such as, but not limited to, guar gum and sodium alginate; modified gum acacia; and polyunsaturated fatty acids (PUFA), coenzyme Q, phytoster ester gum. ols, resveratrol, carotenoids, micronutrients, alpha lipoic acid 0033. The compositions include other optional ingredi and oil-soluble vitamins. Exemplary of such compounds are ents, such as a pH adjuster, present to adjust the pH of the US 2016/008 1976 A1 Mar. 24, 2016 composition to between 2.0 and 4.0. Typically, the pH 0037 Another exemplary composition contains: a water adjuster is present in an amount of less than 1% by weight. soluble vitamin E derivative mixture, present in an amount Exemplary pH adjusters include citric acid and phosphoric from 5% to 95%, by weight, of the composition, where the acid. Other ingredients include a flavor or flavoring agent water-soluble vitamin E derivative mixture comprises from and/or Sweeteners, particularly in the compositions for direct 25 wt % to 69 wt % water-soluble vitamin E monomer and administration. Flavors can be imparted by beverage bases as from 13 wt % to 75 wt % water-soluble vitamin E dimer; a well as flavoring agents. non-polar compound other than the water-soluble vitamin E derivative mixture, present in an amount from 1% to 75%, by 0034. The amount of the water-soluble vitamin E deriva weight, of the composition; a preservative, present in an tive mixture is from 16% to 30%, inclusive, or is 1% to 95%, amount Sufficient to preserve the composition; a polar Sol inclusive, or is 10% to 40%, inclusive, or 10% to 50%, inclu vent, present in an amount from 45% to 80%, by weight, of sive, or 15% to 25%, inclusive, by weight, of the composition, the composition; and a pH adjuster, present in an amount or is at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, sufficient to adjust the pH of the composition to between 2.0 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, and 4.0. 80%, 85%, 90%, or 95%, inclusive, by weight, of the com position, such as greater than 1%. 2%. 3%, 4%. 5%, 10%, 0038. The compositions provided herein can be concen 15% or 20% or about 20%, greater than 30% or about 30%, trates or can be for direct consumption. Among those for between 30% or about 30% and 55% or about 55%, between direct consumption are dilution compositions, such as bever 16% and 30%, between 30% or about 30% and 50% or about age compositions, into which any of the concentrates provide 50%, between 30% or about 30% and 45% or about 45%, or herein have been diluted. Also included are the pre-gel com at least 10%, 12%, 15%, 17%, 20%, 22%, 24%, 27%, 30%, positions and Soft gel compositions that contain a surfactant 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, and non-polar ingredient(s) for direct consumption. 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 0039. The compositions provided herein also can contain 51%, 52%. 53%, 54% or 55%, up to at least 60%. 65%, 70%, additional ingredients such as Sweeteners, stabilizers, pH 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%, all by adjusters and antifoaming agents. Sweeteners include any weight, of the composition. For example, for concentrates, known to those of skill in the art, including, but not limited to, the vitamin E derivative mixture can be present in an amount Sucralose. Sucrose, lactose, fructose, an acesulfame salt, of about at least 15%, or 15% to 30%, at least 40% or about aspartame, saccharin, Stevia, Stevioside and Xylitol. Stabiliz 40%, 50% or about 50%, or greater than 60% or about 60%, ers include, but are not limited to, carbonates, bicarbonates, greater than 65% or about 65%, for example, greater than acids and antioxidants. The carbonates, bicarbonates, acids 70% or about 70%, for example, a starting concentration and antioxidants can be included in the compositions for within the concentration range of between 50% or about 50% direct consumption, as they stabilize the compositions as and 95% or about 95%, between 60% or about 60% and 95% consumed and packaged. Such compositions also are pack or about 95%, between 65% or about 65% and 90% or about aged in a sealed container, which can contain nitrogen to 90%, for example, between 69% or about 69% and 90% or displace oxygen from the sealed container. Such composi about 90%, between 69% or about 69% and 89% or about tions include, but are not limited to, juice, water, sports drinks 89%, for example, at least 65%, 66%, 67%, 68%, 69%, and sodas. 69.5%, 69.9%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 0040 Also provided are emulsion compositions that can 78%, 79%, 79.5%, 79.9%, 80%, 81%, 82%, 83%, 84%, 85%, be used to form dry powders. Also provided are soft gel 86%, 87%, 88%. 89%, 89.5%, 89.9%, or 90%, by weight, of compositions that contain a non-polar ingredient, a high the composition. dimer-containing water-soluble vitamin E derivative mixture (composition), such as a the PEG derivative of vitamin E 0035 Exemplary compositions, particularly concentrates, composition, Such as a high dimer-containing TPGS compo include a composition that contains a water-soluble vitamin E sition, and a relatively high concentration, Such as greater derivative mixture present in an amount from 5% to 95%, by than 1%, typically greater than 7%, 10%, 15%, of a non weight, of the composition, wherein the water-soluble vita aqueous solvent, such as an alkyl alcohol. Such as benzyl min E derivative mixture comprises from 25 wt % to 69 wt % alcohol, in an amount greater than 1% and up to 25%, are water-soluble vitamin E monomer and from 13 wt % to 75 wt provided. The claims set forth below directed to each of these % water-soluble vitamin E dimer; a non-polar compound compositions are herein incorporated by reference. Also, other than the water-soluble vitamin E derivative mixture, incorporated by reference are the subject matter, and all present in an amount from 1% to 75%, by weight, of the claims in U.S. Provisional Application Ser. No. 62/052,435, composition; and a preservative, present in an amount Suffi filed Sep. 18, 2014, entitled “SOFT GEL COMPOSITIONS cient to preserve the composition. AND PRE-GEL CONCENTRATES” to Philip J. Bromley, 0036) Another composition contains: a water-soluble vita and U.S. Provisional Application Ser. No. 62/052,433, filed min E derivative mixture present in an amount from 5% to Sep. 18, 2014, entitled “PRE-SPRAY EMULSIONS AND 95%, by weight, of the composition, where the water-soluble POWDERS CONTAINING NON-POLAR COMPOUNDS vitamin Ederivative mixture comprises from 25 wt % to 69 wit to Philip J. Bromley. It is understood that for purposes herein, % water-soluble vitamin E monomer and from 13 wt % to 75 the water-soluble vitamin E derivative compositions in the wt % water-soluble vitamin E dimer; a non-polar compound incorporated claims are the high dimer-containing composi other than the water-soluble vitamin E derivative mixture, tions as described herein. present in an amount from 1% to 75%, by weight, of the 0041) Provided are powders and pre-spray emulsions. The composition; a preservative, present in an amount Sufficient pre-spray emulsions comprise the ingredients of the powders to preserve the composition; and a non-polar solvent that plus a polar solvent. The capsules, tablets and soft gel cap differs from the non-polar compound and is present in an Sules are for administering to a Subject to provide a non-polar amount Sufficient to dissolve the non-polar compound. ingredient or compound to the Subject, Such as for Supple US 2016/008 1976 A1 Mar. 24, 2016

mentation to provide a nutrient or nutraceutical or a bioactive 0060) 1. Reaction mixture compound for treating or lowering the risk of a disease. The 0061 a. Vitamin E succinate powders, which are soluble, can be introduced into a beverage 0062) b. Polyethylene glycol of choice to provide the non-polar ingredient or compound or 0063 c. Catalyst sprinkled on food. 0064 d. Solvent 0042 Exemplary of the non-polar ingredients in all of the 0065 e. Exemplary reaction mixtures compositions provided herein are the following: omega-3 0.066 2. Exemplary methods EPA and DHA; resveratrol; sesamin; curcumin; Boswellia 0067 a. Preparation of a crude water-soluble vita (Boswellic acids); lipoic acid, such as alpha lipoic acids, min E derivative mixture capsaicinoids; POQ, carotenoids. Such as astaxanthin, Zeax 0068 b. Processing the reaction mixture to obtain anthin; lutein, beta carotene, and lycopene; and Vitamins, a crude water-soluble vitamin E derivative mixture Such as vitamin A, vitamin D and vitamin E complexes; 0069 c. Purification of the crude water-soluble vitamin K1 and vitamin Kas MK7. vitamin E derivative mixture to obtain a purified 0043 Methods for preparing the compositions, particu high dimer-containing water-soluble vitamin E larly those that are concentrates, are provided. These methods derivative mixture include steps of: (a) mixing and heating initial ingredients in 0070 D. Products containing high dimer-containing a vessel, where the initial ingredient(s) comprise: a water water-soluble vitamin E derivative mixtures soluble vitamin E derivative mixture present in an amount 0071 1. Exemplary ingredients and exemplary con from 5% to 95%, by weight, of the concentrate; and the centration ranges water-soluble vitamin E derivative mixture comprises from 0072 a. Water-soluble vitamin E derivatives 25 wt % to 69 wt % water-soluble vitamin E monomer and 0073 b. Non-polar ingredients from 13 wt % to 75 wt % water-soluble vitamin E dimer; and (0074) i. Polyunsaturated fatty acid (PUFA)-con then (b) adding one or more additional ingredients to the taining ingredients vessel, where the one or more additional ingredients com (a) Omega-3 fatty acid compounds prise: a non-polar compound at an amount from 1% to 75%, (1) DHA/EPA by weight, of the concentrate; and then (c) homogenizing the Fish oils ingredients; and (d) cooling the mixed ingredients, whereby, (ii) Algae oil for compositions with high levels of vitamin Ederivatives, the (2) Flax seed oil—omega 3 (ALA) mixed ingredients become waxy in consistency, and lower (b) Omega-6 compounds levels form an emulsion, thereby generating the composition. (c) Saw palmetto extract 0044) Methods for preparing a beverage, soft gel, and (d) Conjugated linoleic acid (CLA) other compositions for direct consumption containing non ii. Coenzyme Q compounds polar ingredients also are provided. The beverages are pre iii. Phytochemical-containing non-polar ingre pared by adding the composition provided herein, such as a dients nanoemulsion concentrate, to a beverage base. The concen (a) Phytosterols trate is added at a predetermined concentration to produce a (b) Resveratrol beverage Supplemented with the non-polar ingredient in the iv. Carotenoid-containing compounds concentrate at an effective or intended concentration. The (a) Carotenes beverage base comprises the other components of the result (b) Xanthophylls ing beverage, including, but not limited to, water, juice, Soda, V. Micronutrient-containing compounds a sports drink and/or a nutritional drink. Soft gel composi (a) Vitamins tions are prepared by introducing a pre-gel composition into (b) Alpha-lipoic acid (thioctic acid) vi Boswellia extracts a soft gel shell or capsule. vii. Alkaloids viii. Cannabinoids DETAILED DESCRIPTION ix. Hops-containing compounds Outline X. Antioxidants 0075 c. Non-polar solvents 0045 A. Definitions 0076 d. Preservatives and sterilizers 0046 B. Water-soluble vitamin E derivatives 0077 e. Polar solvents 0047 l. Vitamin E 0078 f. Co-surfactants (emulsifiers) 0048 2. Polyalkylene glycol derivatives of vitamin E (0079 i. Phospholipids 0049 a. Tocopherols and tocotrienols 0080 ii. Sugar-derived surfactants 0050 b. Linkers 0081 iii. PEG-derived surfactants 0051 c. PEG moieties I0082 iv. Sucrose fatty acid ester surfactants 0.052 d. Surfactant properties 0083 g. Emulsion stabilizers (co-emulsifiers) 0053. 3. Tocopheryl polyalkylene glycol derivatives 0084 h. Flavors 0054 a. Uses I0085 i. pH adjusters 0055) i. Nutritional supplement I0086 j. Soluble fibers 0056 ii. Surfactant 0087 k. Additional ingredients 0057 4. Synthesis I0088 i. Additional non-polar compounds 0058 5. Water-soluble vitamin Ederivative mixtures 0089 ii. Stabilizers (compositions) (a) Bicarbonates or carbonates 0059 C. Methods for making water-soluble vitamin E (b) Acids derivatives (c) Antioxidants US 2016/008 1976 A1 Mar. 24, 2016

0090 2. Concentrates (a) Pre-emulsion concentrates 0091 a. Pre-emulsion concentrates (b) Surfactants 0092 i. Formulating the pre-emulsion concen (1) Sucrose fatty acid ester surfactants trates (c) Stabilizers 0093. ii. Exemplary ingredients and typical con (1) Bicarbonates and carbonates centration ranges (2) Ingestible acids 0094) b. Liquid nanoemulsion concentrates (3) Antioxidants 0.095 i. Formulating the liquid nanoemulsion (d) Polar solvents COncentrates (e) Binders 0.096 c. Liquid dilution compositions containing (1) Co-surfactants (emulsifiers) the concentrates (1) Phospholipids 0097 d. Evaluation of the concentrates and liquid (2) PEG-derived surfactants (g) Emulsion stabilizers (co-emulsifiers) dilution compositions (h) pH adjusters 0.098 i. Clarity 0.125 b. Powder compositions containing non-po (a) Empirical evaluation lar ingredients (b) Particle size or number of particles 0.126 i. Formulating the powder compositions (c) Turbidity measurement 0127 ii. Ingredients and concentration ranges 0099 ii. Stability 0.128 E. Exemplary methods for preparing products 0100 iii. Advantageous characteristics of com containing high dimer-containing water-soluble vitamin positions for human consumption E derivative mixtures 0101 iv. Safety I0129. 1. Equipment employed in the methods 0102 v. Oral bioavailability 0130 a. Scales 0.103 e. Selecting a formulation and modifying 0131 b. Purifiers formulations (0132 c. Vessels 0104 3. Soft gel and pre-gel compositions contain 0.133 d. Mixers ing non-polaringredients and the high dimer-contain 0134 e. Heating/cooling apparatuses ing PEG derivative of vitamin E mixture 0135 f. Transfer devices 0105 a. Non-aqueous pre-gel compositions con 013.6 g. Evaluation equipment taining non-polar ingredients 0.137 2. General methods for producing the compo 0106 i. Non-polar ingredients sitions 0107 ii. Surfactants (high dimer-containing 0138 a. Water phase ingredients water-soluble vitamin E derivative mixtures) 0139 b. Water phase production 0.108 iii. Non-aqueous solvents 0140 c. Oil phase ingredients 0141 d. Oil phase production 0109 iv. Co-surfactants (emulsifiers) 0142. e. Combining phases (a) Phospholipids 0143 f. Cooling (b) Sugar-derived surfactants 0144 g. Filtration, additions, evaluation and pack (c) PEG-derived surfactants aging (d) Sucrose fatty acid ester surfactants 0145 h. Cleaning the equipment 0110 V. Emulsion stabilizers (co-emulsifiers) 0146) i. Clarity 0111 vi. Flavors 0147 3. General methods for preparing aqueous pre 0112 vii. pH adjusters gel concentrates (compositions that are introduced 0113 viii. Soluble fibers into or formulated in Soft gel shells or capsules) 0114 ix. Stabilizers 0148 a. Ingredients 0149 b. Production of the non-aqueous pre-gel (a) Bicarbonates or carbonates COncentrates (b) Acids 0150 c. Transfer and/or packaging (c) Antioxidants 0151. 4. Exemplary methods for preparing pre-spray 0115 b. Formulating the non-aqueous pre-gel con emulsions and powders centrates containing non-polar ingredients 0152 a. General methods for producing the emul 0116 c. Soft gel compositions containing non-po sions and powders lar ingredients 0153 b. Drying the emulsions to produce powders 0117 i. Capsules 0154 c. Storing the powders 0118 d. Formulating the soft gel compositions 0155 d. Filtration, additions, evaluation and pack 0119 e. Ingredients and concentration ranges aging 0120 f. Exemplary dosages and administration of 0156 F. Examples the Soft gel compositions I0121 4. Powders and pre-spray emulsions A. DEFINITIONS 0.122 a. Pre-spray emulsions containing non-polar 0157. Unless defined otherwise, all technical and scien ingredients tific terms used herein have the same meaning as is commonly I0123 i. Formulating the pre-spray emulsions understood by one of skill in the art to which the invention(s) 0.124 ii. Exemplary ingredients and typical con belong. All patents, patent applications, published applica centration ranges tions and publications, Genbank sequences, databases, web US 2016/008 1976 A1 Mar. 24, 2016 sites and other published materials referred to throughout the 0162 AS manufactured, the high dimer-containing mix entire disclosure herein, unless noted otherwise, are incorpo tures can include other forms and unreacted components, rated by reference in their entirety. In the event that there are hence the total amount of dimer and monomer do not neces a plurality of definitions for terms herein, those in this section sarily total 100%, by weight, of the composition. It is shown prevail. Where reference is made to a URL or other such herein that inclusion of at least 13%, 20%, 25%, 29%, or more identifier or address, it is understood that such identifiers can of the dimer form, and some monomer form, about less than change and particular information on the internet can come 87%, 69%, 65%, 60%, 55%, or 50% of the monomer with at and go, but equivalent information can be found by searching least 13% dimer, confers advantageous properties on these the internet. Reference thereto evidences the availability and water-soluble vitamin E derivative mixtures (compositions) public dissemination of Such information. not possessed by Such compositions that contain lower 0158. As used herein, “vitamin E' refers to any naturally amounts of the dimer form. occurring or synthetic form of vitamin E, for example, toco 0163 Examples of water-soluble vitamin Ederivatives are pherols and tocotrienols, and can refer to a single form of the those formed by covalently attaching a vitamin E moiety, e.g., compound or a mixture of forms. a tocopherol or tocotrienol, to a hydrophilic moiety, for example, an alkylene glycol, Such as a polyethylene glycol 0159. As used herein, “water-soluble vitamin E derivative (PEG) moiety, via a linker. The compositions as provided composition.” “water-soluble vitamin E derivative.” “water herein are manufactured so that the resulting water-soluble soluble vitamin E derivative surfactant,” “water-soluble vita Vitamin E derivative mixtures (compositions) include a mix min E surfactant, and “water-soluble derivative of vitamin E ture of monomers and dimers of the water-soluble vitamin E mixture, which are be used interchangeably, refer to compo derivatives, and contain a Substantial amount (compared to sitions that contain mixtures of water-soluble forms of vita prior art preparations), i.e., 13% to 95%, inclusive, such as at min E (vitamin E derivatized with moieties, such as polyalky least 13%, 20%, 25%, or 29%, up to as much as 75%, 80%, lene glycol that increase the water solubility of the water 85%, 90%. 95%, by weight, of the dimer form and generally insoluble vitamin E). The mixtures contain dimers and less than 70%, 65%, 63%, 62%, 61% or 60%, or less of the monomers of the vitamin E derivatives. The water-soluble monomer form. Water-soluble vitamin E derivative mixtures Vitamin E derivative mixtures (compositions) include Vitamin (compositions) include, for example, polyalkylene glycol E (natural or synthetic forms of vitamin E). Such as toco derivatives of tocopherol, e.g., polyethylene glycol (PEG) pherol derivatives and tocotrienol derivatives. Derivatives of derivatives oftocopherol, and polyalkylene glycol derivatives vitamin E, such as polyethylene glycol (PEG)-derivatives oftocotrienol, e.g., polyethylene glycol (PEG) derivatives of previously produced, are manufactured to contain as much tocotrienol. The water-soluble vitamin E derivatives can monomer form as possible, and to contain minimal amounts include, for example, vitamin ETPGS (D-C-tocopheryl poly of any dimer form (see, e.g., Christiansen et al. (2011) J. ethylene glycol succinate), TPGS analogs, TPGS homologs Pharm. Sci. 100(5):1773-1782). and TPGS derivatives. 0160. In contrast, the high dimer-containing vitamin E 0164. As used herein, “tocopherol and “tocotrienol refer derivative mixtures, such as PEG derivative of vitamin E to any naturally occurring or synthetic form of vitamin E, and compositions (also referred to herein as high dimer PEG can refer to a single compound or a mixture of tocopherols derivatives of vitamin E mixtures or high dimer-containing and tocotrienols. Examples of tocopherols include, for PEG derivatives of vitamin E mixtures) employed herein, are example, C-tocopherol, D-O-tocopherol, B-tocopherol, Y-to manufactured to contain dimer forms. The mixtures copherol and 8-tocopherol. Examples oftocotrienols include, described herein contain at least 13%, particularly at least or for example, C-tocotrienol, B-tocotrienol, Y-tocotrienol and at least about 20%, 25%, 29%, or more, dimer form of the Ö-tocotrienol. water-soluble vitamin E derivative. In particular, the water (0165. As used herein, a “PEG derivative of vitamin E' or soluble vitamin E derivative mixtures (compositions) are “vitamin E-PEG conjugate' or “vitamin E-PEG derivative.” manufactured to contain between or between about 13 wt % is a compound containing one or more vitamin E moieties and about or up to 95%, 90%, 85%, 80%, or 75 wt %, par (e.g., a tocopherol or tocotrienol) joined by a covalent bond, ticularly at least 29% to 75% or 80%, inclusive, of the water for example, an ester, ether, amide or thioester bond, to one or soluble vitamin Edimer. In general, the high dimer-contain more polyethylene glycol (PEG) moieties, via a linker, such ing derivatives, such as PEG derivatives of vitamin E as a dicarboxylic or tricarboxylic acid. Exemplary of PEG mixtures, such as a high dimer-containing TPGS composi derivatives of vitamin E are D-C-tocopheryl polyethylene gly tion, contain 30%-60%, particularly 35%-52%, dimer, and col succinate (TPGS), TPGS analogs, TPGS homologs and the remainder is the monomer form and is present in less than TPGS derivatives. 5%, generally 3%, 2%, or 1%, and other trace components, 0166 As used herein, “tocopheryl polyethylene glycol Such as unreacted reagents, such as vitamin E and the hydro succinate.” “TPGS.” “tocopheryl polyethylene glycol succi philic derivatizing moiety. nate surfactant” and “TPGS surfactant” refer to tocopheryl 0161 In general, the mixtures herein contain at least 13% polyethylene glycol conjugates that are formed by covalently of the dimer form and up to 87% monomerform, particularly joining tocopherol Succinate, an ester formed through esteri at least 25% of the dimer form and up to 70% of the monomer fication of tocopherol and Succinic acid, to a polyethylene form, such as between or between about 25 wt % and 69%, glycol (PEG) moiety via an esterification reaction. The PEG inclusive, of the monomer. Hence, the water-soluble vitamin moiety of the TPGS surfactant can be any PEG moiety, for E derivative mixtures (compositions) (high dimer-containing example, a PEG moiety with a molecular weight of between compositions) contain a substantial amount (i.e., 13% or orbetween about 200 Dato 20,000 Da or about 20,000 Da, for more, particularly 25%, 29%, 35%, 48%, 52%, or more) of example, PEG moieties having a molecular weight of or about the dimer form compared to commercially available forms 200, 300, 400, 500, 600, 800, 1000, 3000, 5000, 6000, 8000, that are manufactured to provide the monomer form. 10,000, 20,000 Da, or more; or PEG analogs, including, for US 2016/008 1976 A1 Mar. 24, 2016 example, PEG-NHS (N-hydroxysuccinimide), PEG-alde the oil and water phase of the emulsion, providing stability. hyde, PEG-SH, PEG-NH. PEG-COH, and branched PEGs. Typically, the nanoemulsions of the provided liquid dilution 0167 As used herein, “TPGS monomer' is a single vita compositions contain micelles that contain one or more Sur min E moiety, i.e., D-O-tocopherol, covalently joined to a factants surrounding a non-polar ingredient which is dis water-soluble moiety. Such as a polyethylene glycol, through persed in the water phase. Exemplary of the provided emul a succinate linker. “TPGS monomer can also refer to TPGS sions are the provided liquid nanoemulsion concentrates and analogs, homologs or derivatives, including any other water liquid dilution compositions and flavored shots, made by Soluble vitamin E derivatives described herein. A “TPGS diluting the concentrates, typically in an aqueous medium. In dimer' is made up of two vitamin E moieties, i.e., D-O-toco general, emulsions (e.g., oil-in-water emulsions) are colloidal pherol, covalently joined to a water-soluble moiety, such as a dispersions of two immiscible liquids (e.g., oil and an aque polyethylene glycol, through one or more Succinate linkers ous liquid, such as water) that contain a continuous and a (shown below). “TPGS dimer' can also refer to TPGS ana dispersed phase. Emulsions can be used to disperse non-polar logs, homologs or derivatives, including any other water compounds in aqueous liquids. In an oil-in-water emulsion, soluble vitamin E derivatives described herein. The esterifi the dispersed phase is an oil phase and the continuous phase cation reaction between the vitamin E moiety, for example, is an aqueous (e.g., water) phase. D-O-tocopheryl Succinate, and PEG results in a highly com (0171 As used herein, a "nanoemulsion' is an emulsion in plex crude product that contains a mixture of TPGS mono which the dispersed droplets, for example, the micelles, have mer, unreacted PEG, unreacted vitamin E (e.g., D-O-toco a diameter (particle size) of less than 1000 nm or less than pheryl succinate), catalyst, and TPGS dimer, formed when a about 1000 nm, typically, less than 500 nm or less than about second molecule of the vitamin E moiety reacts with the 500 nm, typically less than 300 nm or less than about 300 nm, terminal hydroxyl group of a PEG moiety already conjugated for example, less than 250 nm or less than about 250 nm, for to TPGS monomer via a linker. For purposes herein, mixtures example, less than or less than about 200 nm, for example, are produced by performing the reaction under conditions less than or less than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, that result in higher amounts of the TPGS dimer being pro 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, duced as compared to prior art preparations. In addition, the 36, 37,38, 39, 40, 41,42, 43,44, 45,46, 47,48, 49, 50, 60, 70, TPGS dimer can be purified and the amounts increased. The 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or water-soluble vitamin E derivative mixtures (compositions) 200 nm. Exemplary of nanoemulsions are the provided liquid where the vitamin E derivative is TPGS, as described herein, nanoemulsion concentrates and the liquid dilution composi contain a mixture of TPGS monomer and TPGS dimer, and tions, for example, the aqueous liquid dilution compositions contain more than 12%, but generally at least 20%, 25%, containing the diluted concentrates. 29%, 35%, or more, TPGS dimer, up to as much as 95% or 0172. As used herein, “surfactant refers to synthetic and about 95% TPGS dimer, but typically up to about 75%. The naturally occurring amphiphilic molecules that have hydro remainder of the composition contains the TPGS monomer phobic portion(s) and hydrophilic portion(s). Due to their and can contain unreacted Starting materials and catalyst. amphiphilic (amphipathic) nature, Surfactants typically can Similarly, water-soluble vitamin E derivative mixtures (com reduce the surface tension between two immiscible liquids, positions) containing vitamin E derivatives other than TPGS for example, the oil and water phases in an emulsion, stabi contain mixtures of dimer and monomer. lizing the emulsion. Surfactants can be characterized based 0168 As used herein, a “concentrate' is a composition on their relative hydrophobicity and/or hydrophilicity. For that comprises the water-soluble high dimer-containing vita example, relatively lipophilic Surfactants are more soluble in min E derivative mixture and/or the non-polar ingredient that fats, oils and waxes, and typically have HLB values less than is or contains a non-polar compound(s) in higher than single or about 10, while relatively hydrophilic surfactants are more dosage concentrations so that the concentrate compositions soluble in aqueous compositions, for example, water, and are diluted for ingestion. typically have HLB values greater than or about 10. Rela 0169. As used herein, "colloid” refers to a mixture con tively amphiphilic surfactants are soluble in oil- and water taining two phases, a dispersed phase and a continuous phase, based liquids and typically have HLB values close to 10 or with the dispersed phase containing particles (droplets) dis about 10. tributed throughout the continuous phase. Colloidal mixtures (0173 As used herein, “co-surfactant” is used to refer to a include aerosols, foams, and dispersions, for example, emul Surfactant that is used in the provided compositions in com sions, for example, nanoemulsions. A liquid colloid, for bination with the primary Surfactant, for example, the water example, a nanoemulsion, can have a similar appearance, for soluble vitamin E derivative mixtures (compositions) example, similar clarity, to a solution in which there is no described herein, for example, to improve the emulsification dispersed phase. of the provided compositions and/or compounds, for 0170 As used herein, "emulsion” refers to a colloidal example, to emulsify the ingredients. In one example, the dispersion of two immiscible liquids, for example, an oil and provided compositions can contain at least one surfactant and water (or other aqueous liquid, e.g., a polar solvent), one of at least one co-surfactant. Typically, the co-surfactant repre which is part of a continuous phase and the other of which is sents a lower percent, by weight (w/w), of the provided com part of a dispersed phase. The provided liquid dilution com positions, compared to the Surfactant. Thus, the provided positions include emulsions, typically oil-in-water compositions typically have a lower concentration of the nanoemulsions (which include any oil-soluble phase dis co-Surfactant(s) than of the Surfactant. persed in any aqueous phase, also called the water phase), in 0.174 As used herein, “HLB” refers to a value that is used which the oil phase is the dispersed phase and the water phase to index and describe a surfactant according to its relative is the continuous phase. Emulsions typically are stabilized by hydrophobicity/hydrophilicity, relative to other surfactants. one or more surfactants and/or co-surfactants and/or emul A surfactants HLB value is an indication of the molecular sion stabilizers. Surfactants form an interfacial film between balance of the hydrophobic and hydrophilic portions of the US 2016/008 1976 A1 Mar. 24, 2016

Surfactant, which is an amphipathic molecule. Each Surfac identical biological and/or chemical activity. For example, tant and mixture of Surfactants (and/or co-surfactants) has an the analog can be more hydrophilic or it can have altered HLB value that is a numerical representation of the relative reactivity as compared to the parent compound. The analog weight percent of hydrophobic and hydrophilic portions of can mimic the chemical and/or biological activity of the par the surfactant molecule(s). HLB values are derived from a ent compound (i.e., it can have similar or identical activity), semi-empirical formula. The relative weight percentages of or, in some cases, can have increased or decreased activity. the hydrophobic and hydrophilic groups are indicative of The analog can be a naturally or non-naturally occurring (e.g., Surfactant properties, including the molecular structure, for synthetic) variant of the original compound. Other types of example, the types of aggregates the Surfactants form and the analogs include isomers (e.g., enantiomers, diastereomers) solubility of the surfactant. See, for example, Griffin (1949).J. and other types of chiral variants of a compound, as well as Soc. Cos. Chem. 1:311. Surfactant HLB values range from structural isomers. The analog can be a branched or cyclic 1-45, while the range for non-ionic Surfactants typically is variant of a linear compound. For example, a linear com from 1-20. The more lipophilic a surfactant is, the lower its pound can have an analog that is branched or otherwise Sub HLB value. Conversely, the more hydrophilic a surfactant is, stituted to impart certain advantageous properties (e.g., the higher its HLB value. improved hydrophobicity or bioavailability). Exemplary of 0.175. As used herein, “micelle” refers to aggregates the analogs used in the provided compositions and methods formed by surfactants that typically form when a surfactant is are TPGS analogs, which can be formed using the methods present in an aqueous composition, typically when the Sur provided herein and can be used in place of TPGS in the factant is used at a concentration above the critical micelle provided compositions. concentration (CMC). In micelles, the hydrophilic portions of the Surfactant molecules contact the aqueous or the water 0177. As used herein, “tocopheryl polyethylene glycol phase, while the hydrophobic portions form the core of the succinate analog or “TPGS analog refers to compounds, micelle, which can encapsulate non-polar ingredient(s), for other than TPGS, that are similar to a parent TPGS com example, the non-polar ingredients in the provided concen pound, but differ slightly in composition, for example, by the trates. Typically, the Surfactants in the provided concentrates variation, addition or removal of an atom, one or more units form micelles containing the non-polar ingredient at their (e.g., methylene units, —(CH), ), or one or more func center in the aqueous liquid dilution compositions. Typically, tional groups. TPGS analogs include vitamin E-derived sur the micelles in the provided concentrates have a particle size factants, e.g., tocopheryls and tocotrienols, including PEG of about 1000 nm, typically less than or less than about 500 derivatives of vitamin E, including vitamin E PEG monomers nm, typically less than 300 or less than about 300 nm, for and dimers, such as, but not limited to, tocopheryl polyethyl example, less than 250 nm or less than about 250 nm, for ene glycol sebacate (PTS), tocopheryl polyethylene glycol example, less than 200 nm or less than about 200 nm, for dodecanodioate (PTD), tocopheryl polyethylene glycol sub example, less than or less than about 5, 10, 11, 12, 13, 14, 15, erate (PTSr), tocopheryl polyethylene glycol azelaate 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, (PTAZ), and polyoxyethanyl tocotrienyl sebacate (PTrienS), 33,34,35,36, 37,38, 39, 40, 41, 42, 43,44, 45,46, 47, 48,49, as well as other PEG derivatives of vitamin E. The composi 50, 60, 70, 80,90, 100, 110, 120, 130, 140, 150, 160, 170, 180, tions provided herein include at least 13%, typically more 190, or 200 nm. than 29%, such as 29%-55%, dimer form in the composition, 0176). As used herein, “analog refers to a chemical com with the rest of the composition the monomer form or small pound that is structurally similar to another compound (re amounts of other forms and trace contaminants. ferred to as a parent compound), but differs slightly in com 0.178 Exemplary of TPGS analogs are compounds having position, for example, due to the variation, addition or the formula shown in Formula II:

Formula II

O R R-kN------) t

O R a ---3 R3 removal of an atom, one or more units (e.g., methylene units, where R, R2 and Rs each independently is hydrogen (H) or —(CH), ) or one or more functional groups. The analog methyl (CH); R is H, CH or the portion marked 'A'; each can have different chemical or physical properties compared dashed line (-----) is independently a single or double bond; in with the original compound and/or can have improved bio is an integer from 1 to 5000; m and q each independently are logical and/or chemical activity. Alternatively, the analog can 0 or 1; and p is an integer from 1 to 20. have similar oridentical chemical orphysical properties com (0179. As used herein, “TPGS 1000 analogs' are com pared with the original compound and/or can have similar or pounds other than TPGS 1000 that are similar to a parent US 2016/008 1976 A1 Mar. 24, 2016

TPGS 1000 compound due to the addition or removal of an able odor, taste and/or appearance, or the lack of an undesir atom, one or more units (e.g., methylene units—(CH), ), able odor, taste and/or appearance. Undesirable organoleptic or one or more functional groups. TPGS 1000 analogs properties include the presence of for example, an undesir include, but are not limited to, TPGS compounds having one able taste, odor or appearance attribute, such as the presence or more PEG moieties that vary in chain length and molecular of an “off-taste' or “off-odor.” for example a fishy, grassy, weight compared to TPGS 1000, including, for example, metal or iron, sharp or tingling taste or odor, or the presence TPGS compounds having PEG moieties having a molecular of an undesirable appearance attribute. Such as separation or weight between or about between 200 Da to 20,000 Da or precipitation. In one example, the provided beverage compo about 20,000 Da, for example, PEG moieties having a sitions retain the same or about the same taste, odor and/or molecular weight of or about 200, 300, 400, 500, 600, 800, appearance as the same beverage composition that does not 1000, 3000, 5000, 6000, 8000, 10,000, 20,000 Da, or more. Also exemplary of TPGS 1000 analogs are TPGS compounds contain the provided concentrates, that is, the provided bev including PEG analogs, e.g., PEG-NHS, PEG-aldehyde, erage compositions retain organoleptic properties desirable PEG-SH, PEG-NH, PEG-COH, and branched PEGs. Also for consumption by an average human Subject. Desirable and exemplary of TPGS 1000 analogs are any TPGS analogs, e.g., undesirable organoleptic properties can be measured by a vitamin E-derived surfactants, including PEG derivatives of variety of methods known to those skilled in the art, includ Vitamin E, including, but not limited to, tocopheryl polyeth ing, for example, organoleptic evaluation methods by which ylene glycol sebacate (PTS), tocopheryl polyethylene glycol undesirable properties are detectable by sight, taste and/or dodecanodioate (PTD), tocopheryl polyethylene glycol sub Smell and chemical tests, as well as by chemical analytical erate (PTSr), tocopheryl polyethylene glycol azelaate (PTAZ) methods. For example, the provided beverage compositions and polyoxyethanyltocotrienyl sebacate (PTrienS), as well as retain the same or about the same organoleptic properties as other PEG derivatives of vitamin E. the same beverage composition that does not contain the 0180. As used herein, “homolog” refers to an analog that provided concentrates over a period of time, for example, at differs from the parent compound only by the presence or least or over 1, 2, 3, 4, 5, 6, or more days, at least or over 1, 2, absence of a simple unit, Such as a methylene unit, or some 3, 4, or more weeks, at least or over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, multiple of such units, e.g., -(CH), . Typically, a 11, 12, or more months, or at least or over 1, 2, 3, 4, or more homolog has similar chemical and physical properties as the years. parent compound. Exemplary of the homologs used in the 0184. In one example, the compositions retain the same or provided compositions and methods are TPGS homologs. about the same taste as the same beverage composition that 0181. As used herein, “TPGS homologs are analogs of does not contain the provided concentrate or powder. In one TPGS that differ from a TPGS parent compound only by the example, the provided beverage compositions retain the same presence or absence of a simple unit, such as a methylene unit, or about the same odoras the same beverage composition that or some multiple of such units, e.g., -(CH) . Typically, does not contain the provided concentrates. In one example, suitable TPGS homologs have similar surfactant properties the provided beverage compositions retain the same or about compared to the parent compound (TPGS), for example, the same appearance as the same beverage composition that similar HLB values, for example, HLB values between 12 or does not contain the provided concentrates. In one example, about 12 and 20 or about 20. Exemplary of TPGS homologs the beverage compositions retain the same organoleptic prop are tocopheryl polyethylene glycol sebacate (PTS), toco erties at room temperature, for example, at 25°C. or at about pheryl polyethylene glycol dodecanodioate (PTD), toco 25°C. In another example, the compositions retain the same pheryl polyethylene glycol suberate (PTSr), tocopheryl poly organoleptic properties at between 19°C. or about 19°C. and ethylene glycol azelaate (PTAZ). Exemplary of TPGS 25° C. or about 25°C. In another example, the beverage homologs are compounds having the formula in Formula I compositions retain the same organoleptic properties at (above), where neither of the dashed lines represent a double elevated temperatures, for example, at 40°C. or at about 40° bond and where, when mand q both are 0, and p is greater than C. In another example, the compositions retain the same 1 organoleptic properties at refrigerated temperatures, for 0182. As used herein, “TPGS 1000 homologs are analogs example, at 4°C. or at about 4°C., or at frozen temperatures, of TPGS 1000 that differ from a TPGS1000 parent compound for example, at -20°C. or at about -20°C. Typically, retain only by the presence or absence of a simple unit, such as a ing the same or about the same organoleptic properties means methylene unit, or some multiple of such units, e.g., -(CH2) that the shelf-life of beverage compositions that contain the . Suitable TPGS 1000 homologs have similar surfactant provided concentrates is the same or about the same or longer properties compared to the parent compound (TPGS 1000), than the beverage compositions not containing the provided for example, similar HLB values, for example, HLB values concentrates. Any or all of the above organoleptic properties, between 12 or about 12 and 20 or about 20, such as 13-18. particularly the desirable organoleptic properties, are retained TPGS 1000 homologs include TPGS 1000 homologs with for the shelf-life of the beverage composition that does not slight variations in the length of the PEG chain moiety. contain the provided concentrates under conditions in which 0183. As used herein, “organoleptic properties’ refers to the beverage composition is normally stored. Generally, bev sensory attributes of a food or beverage, in particular the erage compositions remain free from organoleptic changes beverage compositions and powder provided herein. Those of for at least 6 months, unless the beverage composition that skill in the art understand Such properties and they can be does not contain the provided concentrates has a shorter shelf quantitated if needed. Organoleptic properties include, but life. The beverage composition retains its desired organolep are not limited to, taste, odor and/or appearance. “Desirable' tic properties for this period of time. or “advantageous' organoleptic properties include those 0185. As used herein, "retaining the organoleptic proper organoleptic properties of a food or beverage composition for ties' refers to retention of these properties upon storage for a consumption by an average human Subject, Such as a desir recited period of time, typically at room temperature. US 2016/008 1976 A1 Mar. 24, 2016

0186. As used herein, “shelf life” refers to a time period (0191 As used herein, “clear can be used to describe the within which the provided compositions retain desirable compositions provided herein, for example, the aqueous liq organoleptic properties, for example, the ability of the pro uid dilution compositions containing the diluted nanoemul vided compositions to retain desirable organoleptic proper sion concentrates and/or the nanoemulsion concentrates ties for a period of time, for example, for at least or more than themselves. In one example, a clear liquid is one that does not 1, 2, 3, 4, or more weeks, typically at least or more than 1, 2, appear cloudy by empirical observation, Such as to the naked 3,4,5,6,7,8,9, 10, 11, 12, or more months, or at least or more eye, and/or does not contain particles or crystals that are than 1, 2, 3, 4, or more years. In one example, the composi visible to the naked eye, or that does not exhibit “ringing.” In tions retain desirable organoleptic properties if they exhibit another example, a clear liquid is one that has a low or rela one or more of these described characteristics, over time, tively low turbidity value, for example an NTU value, that is when kept at a particular temperature. In one example, the less than or equal to a desired NTU value. For example, a compositions retain desirable organoleptic properties at room liquid is described as clear that has an NTU value of less than temperature, for example, 25°C. or about 25°C. In another or about 80. For example, a liquid can be clear and have an example, the compositions retain desirable organoleptic NTU value of less than or about 30. In another example, a properties at between 19°C. and 25°C. In another example, clear liquid is one that has a small or relatively small average the compositions retain desirable organoleptic properties at particle size, for example, less than or about 1000 nm. For refrigerated temperatures, for example, 4°C. or about 4°C., example, a liquid can be described as clear and have an or at frozen temperatures, for example, at -20° C. or about average particle size of less than or about 200 nm. In another -20°C. In another example, the compositions retain desirable example, clarity is expressed relatively. For example, it can be organoleptic properties at elevated temperatures, for desired that a particular composition is equally as clear, about example, at 40°C. or at about 40°C. as clear, or more clear than another liquid (as measured 0187. As used herein, “particle size' and “average particle empirically, or by measuring turbidity value or particle size). size refer synonymously to the average diameter of particles For example, clarity can be assessed relative to another aque in a provided liquid, for example, the droplet diameter or ous liquid dilution composition, for example, a beverage. In micelle diameter in an emulsion. Particle size diameter can be one example, a liquid is clear if it is similar in appearance to expressed in terms of a unit of length, for example, nanom another clear liquid, for example, a beverage, for example, eters (nm). Alternatively, information about particles in con water. In another example, it can be desired that a composi centrates and liquid dilution compositions can be expressed tion has a particle size that is less than or equal to another in terms of particle density, for example, ppm (parts per liquid, for example, a beverage. In another example, it can be million), or percent solids, in the compositions. desired that a composition has a turbidity value that is less 0188 As used herein, “visible particles' are particles, for than or equal to another liquid, for example, a beverage. In example, in a liquid. Such as an emulsion, that are visible another example, it can be desired that a composition appears when viewing the liquid with the naked eye (i.e., without more clear or as clear as another liquid, for example, a bev magnification). For example, the visible particles can be par erage, for example, by having no more visible particles, no ticles that are observed by the artisan formulating the com more crystal formation and/or no more cloudiness than the positions, for example, the concentrates or the aqueous liquid other liquid. In one example, the provided compositions are dilution compositions containing the diluted concentrates. In clear. In another example, they are relatively clear or as clear one example, the provided compositions contain no visible as or about as clear as another liquid, for example, a beverage particles. In another example, the compositions contain few that does not contain the non-polar ingredient or liquid visible particles, for example, no more visible particles than nanoemulsion composition. another liquid, for example, a beverage. The presence of 0.192 As used herein, “ringing refers to the formation of visible particles and the number of visible particles is deter a whitish or opaque ring around a container containing a mined by empirical observation. liquid, for example, an aqueous liquid, for example a bever 0189 As used herein, “turbidity” is a measure of the age, for example, a liquid dilution composition containing an cloudiness or haziness of a liquid, caused by particles in emulsion or nanoemulsion. Typically, the ring forms around Suspension in the liquid. Turbidity can be measured optically, the perimeter of the container, typically at the surface level of for example, using a nephelometer, an instrument with a light the liquid in the container, for example, at the neck of the and a detector. The nephelometer measures turbidity by container. Ringing can occur over time and, if it occurs over a detecting scattered light resulting from exposure of the liquid short period of time, can be a sign of instability. Ringing to an incident light. The amount of scattered light correlates to typically is undesirable, particularly in the case of a liquid for the amount of particulate matter in the liquid. For example, a human consumption, for example, a beverage. Typically, the beam of light passes through a sample with low turbidity with provided concentrates and liquid dilution compositions do little disturbance. Other methods for measuring turbidity are not exhibit ringing or are stable, without ringing, for a period well known and can be used with the provided methods and of time, for example, days, weeks, months or years. compositions. The units of a turbidity value measured with a 0193 As used herein, “stability” refers to a desirable prop nephelometer are Nephelometric Turbidity Units (NTU). For erty of the provided concentrates and liquid dilution compo purposes herein, the compositions provided herein typically sitions, for example, the ability of the provided concentrates have low turbidity, for example, a turbidity value (NTU) of and liquid dilution compositions to remain free from one or less than or about 80. For example, the compositions provided more changes over a period of time, for example, at least or herein can have a turbidity value (NTU) of less than or about longer than 1 day, 1 week, 1 month, 1 year, or more. For 3O. example, a concentrate or liquid dilution composition can be 0190. As used herein, a “turbid liquid” is one that is thick described as stable if it is formulated such that it remains free or opaque with visible particles in Suspension, for example, a from oxidation or Substantial oxidation over time, remains liquid that is cloudy or muddy in appearance. clear over time, remains safe and/or desirable for human US 2016/008 1976 A1 Mar. 24, 2016

consumption over time, has a lack of precipitates forming 0201 As used herein, “polar solvent refers to a solvent over time, has a lack of ringing over time, and/or does not that is readily miscible with water and other polar solvents. exhibit any visible phase separation over a period of time. For Polar solvents are well-known and can be assessed by mea example, the concentrates and liquid dilution compositions Suring any parameter known to those of skill in the art, includ can be described as stable if they exhibit one or more of these ing dielectric constant, polarity index and dipole moment described characteristics, over time, when kept at a particular (see, e.g., Przybitek (1980) “High Purity Solvent Guide.” temperature, for example, room temperature, e.g., at or about Burdick and Jackson Laboratories, Inc.). For example, polar 25° C., slightly below room temperature, e.g., between or Solvents generally have high dielectric constants, such as between about 19° C. and 25°C., at refrigerated tempera greater than or about 15, generally have high polarity indices, tures, e.g., at or about 4°C., or at frozen temperatures, e.g., at typically greater than or about 3, and generally large dipole or about -20°C. or lower. moments, for example, greater than or about 1.4 Debye. Polar 0194 As used herein, “phase separation” refers to the Solvents include polar protic solvents and polar aprotic Sol physical separation of a homogenous emulsion, for example, VentS. the separation of the oil and water phases of an emulsion, into 0202 As used herein, a “polar protic solvent' is a polar two separate visible heterogeneous layers. Solvent containing a hydrogenatom attached to an electrone 0195 As used herein, “stabilize” means to increase the gative atom, Such that the hydrogen has a proton-like charac stability of one of the provided compositions. ter and/or the bond between the hydrogen and electronegative 0196. As used herein, “room temperature' and “ambient atom is polarized. Exemplary polar protic solvents include, temperature are used to describe a temperature that is com but are not limited to, water, alcohols, including monohydric, mon in one or more enclosed spaces in which human beings dihydric and trihydric alcohols, including, but not limited to, typically are or reside. Room temperature can vary, but gen methanol, ethanol, glycerin and propylene glycol. erally refers to temperatures between or between about 19°C. 0203 As used herein, "monohydric alcohols' are alcohols and 25°C. When a composition is stored at room temperature, that contain a single hydroxyl group including, but not limited it should be understood it is generally kept at a temperature to, methanol, ethanol, propanol, isopropanol, n-butanol and within this range or about within this range. t-butanol. 0.197 As used herein, “refrigerated temperature' refers to 0204 As used herein, “dihydric alcohols' are alcohols a temperature that is common in a refrigerator, for example, a that contain two hydroxyl groups. Exemplary dihydric alco household or restaurant refrigerator, for example, a tempera hols include, but are not limited to, glycols, e.g., propylene ture that is cooler than room temperature, but typically a few glycol, ethylene glycol, tetraethylene glycol, triethylene gly degrees above the freezing point of water. Typically, refrig col and trimethylene glycol. erated temperatures are between or between about 0°C. and 0205 As used herein, "trihydric alcohols' are alcohols 10°C., for example, at or about 4°C. When a composition is that contain three hydroxyl groups. Exemplary trihydric alco stored at a refrigerated temperature, it should be understood hols include, but are not limited to, glycerin, butane-1,2,3- that it is kept at a temperature common to household or triol, pentane-1,3,5-triol and 2-amino-2-hydroxymethyl-pro industrial refrigerators. pane-1,3-diol. 0198 As used herein, "frozen temperature” refers to a 0206. As used herein, “non-polar.” “lipophilic' and “lipid temperature around or below the freezing point of water, e.g., soluble' synonymously refer to compounds and/or ingredi a temperature commonly used in a household freezer, for ents, for example, non-polar compounds and non-polar ingre example, 0°F. or about 0° F., or -19° C. or about -19° C. or dients, which have greater Solubility in organic solvents (e.g., -20°C. or about -20°C., or colder. ethanol, methanol, ethyl ether, acetone and benzene), fats and (0199. As used herein, “hydrophilic” and “polar refer syn oils than in aqueous liquids, for example, water. Non-polar onymously to ingredients and/or compounds having greater ingredients include drugs, hormones, vitamins, nutrients and solubility in aqueous liquids, for example, water, than in fats, other lipophilic compounds. Typically, non-polar ingredients oils and/or organic solvents (e.g., methanol, ethanol, ethyl are poorly water-soluble, for example, water insoluble or ether, acetone and benzene). compounds having low water solubility. Exemplary non-po 0200. As used herein, a “solvent' is an ingredient that can lar ingredients include ingredients that contain one or more be used to dissolve another ingredient. Solvents include polar non-polar compounds, for example, lipid-soluble drugs, hor and non-polar solvents. Non-polar solvents include oils and mones, essential fatty acids, for example, polyunsaturated other non-polar ingredients that dissolve non-polar com fatty acids (PUFA), for example, omega-3 and omega-6 fatty pounds. Typically, the non-polar solvent included in the con acids, vitamins, nutrients, nutraceuticals, minerals and other centrates or liquid dilution compositions provided herein is compounds. Additional exemplary non-polar ingredients are an oil that is in addition to the non-polar ingredient. The described herein. The provided compositions can be formu non-polar solvent typically is not the non-polar ingredient lated with any non-polar ingredient, for example, any non itself, i.e., is distinct from the non-polaringredient. More than polar ingredient that is or contains a non-polar compound. one non-polar solvent can be used. Certain compounds, for 0207 As used herein, “non-polar compound” refers to a example, flaxseed oil and safflower oil, can be non-polar compound that contains an active component or is active Such Solvents and non-polar ingredients. Typically, the non-polar that, when administered to a Subject, for example, a human, Solvent contains one or more oils, typically oils other than the induces or is proposed to induce a desired response, Such as non-polar ingredient or oil(s) not contained in the non-polar altering body function at the cellular, tissue, organ or other ingredient. Exemplary non-polar solvents include, but are not level, and/or altering the cosmetic appearance or other prop limited to, oils (in addition to the non-polar ingredient), for erty, or a compound that is ingested in order to achieve a example, vitamin E oil, flaxseed oil, CLA, borage oil, rice desired effect. Non-polar compounds include any synthetic or branoil, D-limonene, canola oil, corn oil, MCT oil and oat oil. natural non-polar ingredient or compound, including a phar Other oils also can be used. maceutical, drug, therapeutic, nutritional Supplement, herb, US 2016/008 1976 A1 Mar. 24, 2016 hormone or other ingredient. Non-polar compounds can heated to higher temperatures, such as to 125° F. or about include the non-polar compounds listed herein, as well as 125° F., or to 50° C. or about 50° C. or to 60° C. or about 60° other pharmaceutically acceptable or food-grade active C derivatives of the non-polar compounds, for example, salts, 0213. As used herein, “waxy' is used to describe compo esters, amides, prodrugs, active metabolites, isomers, frag sitions and materials, typically oil-soluble compositions or ments and analogs. Non-polar compounds can include com materials, that are similar in consistency to one or more pounds proven to have a desired effect and also compounds waxes. Pre-emulsion concentrates, particularly those with thought to produce Such effects, for example, compounds higher concentrations (greater than 25% or 30%) of the water typically ingested for nutritional Supplementation purposes. soluble vitamin E derivative composition described herein The non-polar compound can be contained in a non-polar have a waxy consistency at room temperature. Compositions ingredient or is the non-polar ingredient. and compounds having waxy consistencies typically have 0208. As used herein, a “subject' includes an animal, typi melting points or melting ranges above ambient temperature cally a mammal, typically a human. (e.g., above room temperature, for example, above 25°C. or 0209. As used herein, an “additive' includes anything that about 25° C.), meaning they are either solid or semi-solid one can add to a food, beverage, or other human consumable (i.e., not liquid) at room temperature. Typically, waxy com to enhance one or more of its nutritional, pharmaceutical, positions are of relatively low viscosity a little above their dietary, health, nutraceutical, health benefit, energy-provid liquefying point. Exemplary of waxes that have waxy consis ing, treating, holistic, or other properties. For example, the tencies are natural waxes, including waxes of vegetal origin, additives can be oil-based additives (e.g., non-polar ingredi Such as purcellin, shea butter, cocoa butter, Japan wax, ents), Such as nutraceuticals; pharmaceuticals; vitamins, for esparto grass wax, cork wax, Guaruma wax, rice shoot wax, example, oil-soluble vitamins, e.g., vitamin D. Vitamin E and Ouricury wax, montan wax, Sunflower wax, Sugar cane wax, Vitamin A; minerals; fatty acids, such as essential fatty acids, carnauba wax, candelilla wax, lanolin; fruit-derived waxes, for example, polyunsaturated fatty acids, e.g., omega-3 fatty Such as orange wax, lemon wax, grapefruit wax and bayberry acids and omega-6 fatty acids, such as alpha-linolenic acid wax, waxes of animal origin, Such as beeswax, Woolwax, (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid spermateci and bear fat, shellac wax: mineral waxes such as (EPA), gamma-linolenic acid (GLA), CLA, saw palmetto ceresine and oZokerite waxes; and synthetic waxes, including extract, flaxseed oil, fish oil and algae oil. phytosterols; coen petroleum-based waxes such as paraffin, petrolatum, micro Zymes, such as coenzyme Q10; and any other oil-based addi wax, polyalkylene and polyethyleneglycol waxes, e.g. poly tives. ethylene wax, waxes based on chlorinated naphthalenes, such 0210. As used herein, “water insoluble” refers to a com as “Halowax”: synthetic hydrocarbon waxes. pound that does not dissolve when the compound is mixed 0214. As used herein, “liquid concentrate” and “liquid with water, for example, when mixed with water at room nanoemulsion concentrate' are used synonymously to refer temperature, for example, between or between about 25°C. to the provided compositions that contain the water-soluble and 50° C. vitamin E derivative mixtures (compositions) described 0211. As used herein, “low water solubility” refers to a herein, i.e., water-soluble vitamin E derivative mixtures compound that has a solubility in water of less than or about (compositions) that contain a mixture of monomers and 30 mg/mL, for example, when mixed with water at room dimers of the water-soluble vitamin Ederivatives, and contain temperature, such as between or between about 25° C. and a Substantial amount (compared to prior art preparations), i.e., 50° C. As used herein, “poorly water-soluble' can be used to 13% to 95%, inclusive, such as least 13%, 20%, 25%, 29%, up refer to compounds, for example, non-polar compounds, that to as much as 75%, 80%, 85%, 90%. 95%, by weight, of the are water insoluble or have low water solubility. dimer form and generally less than 70%. 65%, 63%. 62%, 0212. As used herein, “pre-emulsion concentrate' is used 61% or 60% or less of the monomer form; one or more to refer to the provided compositions that contain the water non-polar ingredients that are or contain one or more non soluble vitamin E derivative mixtures (compositions) polar compounds; a polar solvent; and optionally, additional described herein, i.e., water-soluble vitamin Ederivative mix ingredients. The liquid concentrates are liquid at room tem tures (compositions) that contain a mixture of monomers and perature, for example, at a temperature of at or about 25°C. or dimers of the water-soluble vitamin Ederivatives, and contain between or between about 25° C. and 50° C., and can be a Substantial amount (compared to prior art preparations), i.e., diluted in aqueous media, for example, in water, to form the 13% to 95%, inclusive, such as at least 13%, 20%, 25%, 29%, provided aqueous liquid dilution compositions. Typically, the up to as much as 75%, 80%, 85%, 90%, or 95%, by weight, of liquid concentrate is an emulsion that has a particle (droplet) the dimer form and generally less than 70%. 65%, 63%. 62%, size (or can be diluted to form an aqueous liquid dilution 61% or 60%, or less of the monomer form; and one or more composition having a particle size) that is less than or about non-polar ingredients that are or contain non-polar com 1000 nm. For example, the particle size can be less than or pounds and can be diluted in aqueous media, for example, in about 200 nm. water, to form the provided aqueous liquid dilution compo 0215. As used herein, “aqueous liquid dilution composi sitions. The pre-emulsion concentrates can additionally tion.” “liquid dilution composition.” “dilution composition include other ingredients, such as preservatives or non-polar and “liquid dilution” are used synonymously to refer to a Solvents. The pre-emulsion concentrates typically do not con composition that contains one or more of the provided con tain any polar solvent, such as water. Typically, the pre-emul centrates (i.e., the pre-emulsion concentrates or liquid sion concentrates are semi-solid compositions, which typi nanoemulsion concentrates provided herein) diluted in a liq cally have a waxy consistency, for example, the consistency uid, for example, an aqueous medium, e.g., water. For of a Substance Such as wax, for example, a lip balm, at room example, the concentrate forms the dispersion phase within temperature, for example, at 25° C. or about 25° C., and the aqueous liquid, which is an emulsion (e.g., nanoemul become liquid at higher temperatures, for example when sion). The liquid dilution compositions are typically bever US 2016/008 1976 A1 Mar. 24, 2016 ages Suitable for human consumption. Exemplary of liquid rowan, gooseberry, pomegranate, persimmon, mango, rhu dilution compositions are aqueous compositions that contain barb, papaya, litchi, lemon, orange, lime, tangerine, manda the concentrates provided herein, for example, waters, rin and grapefruit juices, or any combination thereof. Exem sauces, Soups, Syrups, Soda, juice, e.g., fruit juice, milk, cof plary beverage compositions provided herein include fee, tea, nutritional beverages, sports drinks, energy drinks, combinations of juices or flavors that impart peach mango, vitamin-fortified beverages, flavored waters and any other peach, citrus, pomegranate blueberry, tropical berry, cherry beverage containing the diluted concentrates. It is not neces chocolate, Vanilla, cherry Vanilla, chocolate blueberry, choco sary that the aqueous liquid dilution compositions be com late caramel, cucumber, green tea, honey-dew melon, pine pletely aqueous. For example, the aqueous liquid dilution apple papaya, peach nectarine, raspberry lemonade, grape, compositions can be primarily aqueous and can contain an orange tangerine, orange, lime and mixed berry flavors. aqueous portion, for example, an aqueous continuous phase, 0220. As used herein, “oil phase' refers to the portion (or as well as an additional portion, for example, a dispersion phase) of a composition, such as the concentrates and liquid phase, Such as a lipophilic dispersion phase. Typically, the dilution compositions provided herein, that contains one or lipophilic dispersion phase contains one or more lipophilic more lipophilic ingredients and/or amphiphilic ingredients substances, for example, the water-soluble vitamin E deriva (oil phase ingredients) and is, in general, the lipid-soluble tive mixtures (compositions) described herein and one or phase. In the provided emulsion compositions (e.g., the more non-polar ingredients, for example, non-polar ingredi nanoemulsion concentrates and the dilution compositions), ents that are or contain non-polar compounds. the oil phase typically represents the dispersion phase. "Oil 0216. As used herein, a “beverage composition” or “bev phase also can be used to refer to the liquid containing the oil erage product” refers to a composition, typically an aqueous phase ingredients that is generated, typically in an oil phase ingestible composition, that contains one or more of the pro vessel, while carrying out the methods for making the liquid vided concentrates, one or more stabilizers, and a beverage nanoemulsion concentrates. For example, “oil phase' can base that contains a polar solvent, such as water, a juice, a refer to the mixture of the components (oil phase ingredients) juice concentrate, a fruit juice extract or a fruit flavor. Typi that are combined, mixed and heated, for example, in the oil cally, beverage compositions provided herein are provided phase vessel (e.g., tank), prior to mixing with the water phase. for direct ingestion, that is they are directly consumed by a “Oil phase' can refer to the oil phase mixture that is formed Subject, e.g., a human. Beverage compositions can be formed after all the ingredients are dissolved; alternatively, it can by dissolving the pre-emulsion concentrates and liquid refer to the forming mixture, for example, as it is being nanoemulsion concentrates provided herein in an aqueous mixed/heated. liquid, e.g., water, to form an aqueous liquid dilution compo 0221. As used herein, “oil phase ingredient(s) refers to sition. the components of the provided concentrates and liquid dilu 0217. As used herein, “food and beverage product” refers tion compositions that are included in the oil phase in the to a product that is Suitable for human consumption. For provided methods for making the concentrates and liquid example, “food and beverage product' can refer to a pre dilution compositions. Typical oil phase ingredients include emulsion concentrate or liquid nanoemulsion concentrate the water-soluble vitamin E derivative mixtures (composi that is dissolved in a solvent, typically an aqueous solvent, tions); non-polar ingredients, e.g., non-polar ingredients that e.g., water, to form a liquid dilution composition, i.e., bever are or contain non-polar compounds; co-surfactants; oils, age composition or beverage product. "Food and beverage Such as non-polar solvents; preservatives; and emulsion sta product' can also refer to the final product that is suitable for bilizers. Other lipophilic and/or amphiphilic ingredients can human consumption, Such as the liquid dilution composition, be included in the oil phase. i.e., beverage composition or beverage product. 0222. As used herein, “water phase' is used to refer to the 0218. As used herein, a “beverage base' refers to an aque portion (or phase) of a composition, such as the concentrates ous composition to which one or more non-polar ingredients and liquid dilution compositions provided herein, that con can be added. A beverage base includes, but is not limited to, tains one or more hydrophilic ingredients and/or amphiphilic an aqueous composition that contains one or more of a polar ingredients (water phase ingredients) and is, in general, the Solvent, typically water, a juice, Such as a fruit juice, a fruit water-soluble phase. Typically, in the provided emulsion juice concentrate, a fruit juice extract, a fruit flavor, a soda, a compositions, for example, the nanoemulsion concentrates flavored soda, a carbonated water, a carbonated juice and any and the dilution compositions, the water phase is the continu combination thereof. The concentrates and/or powders pro ous phase. “Water phase' also is used to refer to the liquid vided herein a can be introduced into a beverage base (or containing the water phase ingredients that is generated while beverage or other food). carrying out the methods for making the liquid nanoemulsion 0219. As used herein, a “fruit juice.” “fruit juice concen concentrates. For example, “water phase' can refer to the trate.” “fruit juice extract” or “fruit flavor” refer to fruit-based mixture of the components (water phase ingredients) that are juices and flavors that impart taste or smell to the provided combined, mixed and heated, for example, in the water phase beverage compositions (products). Any juice or fruit flavor tank, prior to mixing with the oil phase. “Water phase' can can be added to the provided beverage compositions, includ refer to the water phase mixture that is formed after all the ing, but not limited to, plum, prune, date, currant, fig, grape, ingredients are dissolved; alternatively, “water phase' can raisin, cranberry, pineapple, peach, nectarine, banana, apple, refer to the forming mixture, for example, as it is being pear, guava, apricot, Saskatoonberry, blueberry, plainsberry, mixed/heated. prairie berry, mulberry, elderberry, Barbados cherry (acerola 0223) As used herein, “water phase ingredient(s) refers to cherry), choke cherry, chocolate, Vanilla, caramel, coconut, the components of the provided concentrates and liquid dilu olive, raspberry, strawberry, huckleberry, loganberry, dew tion compositions that are included in the water phase (e.g., berry, boysenberry, kiwi, cherry, blackberry, honey dew, added to the water phase vessel) in the provided methods for green tea, cucumber, quince, buckthorn, passion fruit, sloe, making the concentrates and liquid dilution compositions. US 2016/008 1976 A1 Mar. 24, 2016

Typical water phase ingredients include, but are not limited gammalinolenic acid (DGLA) (20:3 (p6); eicosadienoic acid to, polar solvents, typically polar protic solvents. Such as (20:2006); arachidonic acid (AA) (20:4()6); docosadienoic water and alcohols, typically alcohols having more than one acid (22:2006); adrenic acid (22:4(O6); and docosapentaenoic hydroxy group Such as dihydroxy and trihydroxy alcohols, acid (22:5(O6). Exemplary of non-polar ingredients contain e.g., glycerol and propylene glycol; co-surfactants; preserva ing omega-6 fatty acids are ingredients containing GLA, for tives; and emulsion stabilizers. Other hydrophilic and/or example, borage oil. Also exemplary of omega-6-containing amphiphilic ingredients can be included in the water phase. non-polar ingredients are compounds containing conjugated 0224. As used herein, an “initial concentrate' is a concen fatty acids, for example, conjugated linoleic acid (CLA) and trate (e.g., pre-emulsion concentrate and/or liquid nanoemul compounds containing saw palmetto extract. sion concentrate) that is made in the provided methods of 0230. As used herein, “algae oil” refers to any oil derived formulating the provided concentrates, typically by selecting from marine dinoflagellates in, for example, microalgae, for ingredients, for example, the water-soluble vitamin E deriva example, Crypthecodinium sp. particularly, Crypthecod tives provided herein, non-polar ingredient(s), polar solvent, inium cohnii. Algae oil can be used as a non-polar ingredient, and, optionally, other ingredients, and selecting starting con for example, as a non-polar ingredient that contains a non centrations of the ingredients from an appropriate concentra polar compound, in the provided concentrates and liquid dilu tion range as described herein. tion compositions. The algae oil typically contains DHA. The 0225. As used herein, “fatty acid refers to straight-chain algae oil can be a source of EPA. hydrocarbon molecules with a carboxyl ( COOH) group at 0231. As used herein, “fish oil” refers to any oil derived one end of the chain. from any fish, typically a cold water fish, for example, from 0226. As used herein, "polyunsaturated fatty acid and fish tissue. Such as from frozen fish tissue, for example, from “PUFA are used synonymously to refer to fatty acids that cod liver. Fish oil can be used as a non-polar ingredient, for contain more than one carbon-carbon double bonds in the example, as a non-polar ingredient that contains a non-polar carbon chain of the fatty acid. PUFAs, particularly essential compound, in the provided concentrates and liquid dilution fatty acids, are useful as dietary Supplements. compositions. The fish oil typically contains DHA. The fish 0227. As used herein, “essential fatty acids” are PUFAs oil can also contain EPA. For example, the fish oil can contain that mammals, including humans, cannot synthesize using a mixture of DHA and EPA. any known chemical pathway. Thus, essential fatty acids must 0232. As used herein, “preservative' and “preservativer' be obtained from diet or by supplementation. Exemplary of are used synonymously to refer to ingredients that can essential PUFA fatty acids are the omega-3 (c)3: n-3) fatty improve the stability of the provided concentrates and liquid acids and omega-6 (c)-6; n-6) fatty acids. dilution compositions. Preservatives, particularly food and 0228. As used herein, “omega-3 (c)3: n-3) fatty acids” and beverage preservatives, are well known. Any known preser “omega-3 fatty acids' are used synonymously to describe Vative can be used in the provided concentrates and liquid methylene-interrupted polyenes which have two or more cis dilution compositions. Exemplary of the preservatives that double bonds separated by a single methylene group, in can be used in the provided concentrates and liquid dilution which the first double bond appears at the third carbon from compositions are oil-soluble preservatives, such as benzyl the last (()) carbon. Omega-3 fatty acids are used as dietary alcohol, benzyl benzoate, methyl paraben, propyl paraben, Supplements, for example, for disease treatment and preven antioxidants, for example, Vitamin E, vitaminA palmitate and tion. The provided concentrates and liquid dilution composi beta carotene. Typically, a preservative is selected that is safe tions can contain non-polar ingredients that include at least for human consumption, for example, in foods and beverages, one omega-3 fatty acid. Exemplary of omega-3 fatty acids are for example, a GRAS certified and/or Kosher-certified pre alpha-linolenic acid (O-linolenic acid; ALA) (18:3c)3) (a servative, for example, benzyl alcohol. short-chain fatty acid); stearidonic acid (18:4(O3) (a short 0233. As used herein, an “antioxidant’ refers to a stabi chain fatty acid); eicosapentaenoic acid (EPA) (20:5c)3); lizer or one component of a stabilizing system that acts as an docosahexaenoic acid (DHA) (22:6c)3); eicosatetraenoic antioxidant, and that, when added to a beverage composition acid (24:4(O3); docosapentaenoic acid (DPA, clupanodonic in combination with the other required components (i.e., acid acid) (22:5c)3); 16:3 (03:24:5 (03 and nisinic acid (24:6c)3). and/or bicarbonate or carbonate) yields beverage composi Longer chain omega-3 fatty acids can be synthesized from tions that retain one or more desired organoleptic properties, ALA (the short-chain omega-3 fatty acid). Exemplary of Such as, but not limited to, the taste, Smell, odor and/or non-polar ingredients containing omega-3 fatty acids are appearance, of the beverage composition over time. Typi non-polar ingredients containing DHA and/or EPA, for cally, antioxidants are food-approved, e.g., edible antioxi example, containing fish oil, krill oil and/or algae oil, for dants, for example, antioxidants that are safe and/or approved example, microalgae oil, and non-polar ingredients contain for human consumption. Exemplary antioxidants include, but ing alpha-linolenic acid (ALA), for example, containing flax are not limited to, ascorbic acid, vitamin C, ascorbate and seed oil. coenzyme Q-containing compounds, including, but not lim 0229. As used herein, “omega-6 (co-6; n-6) fatty acids' ited to, coenzyme Q10. and "omega-6 fatty acids' are used synonymously to describe 0234. As used herein, an “acid' or "ingestible acid refers methylene-interrupted polyenes which have two or more cis to a stabilizer or one component of a stabilizing system that, double bonds separated by a single methylene group, in when added to a beverage composition in combination with which the first double bond appears at the sixth carbon from the other components (i.e., antioxidant and/or bicarbonate or the last (()) carbon. The provided concentrates and liquid carbonate), yields beverage compositions that retain one or dilution compositions can contain non-polar ingredients that more desired organoleptic properties, such as, but not limited include at least one omega-6 fatty acid. Exemplary of to, the taste, Smell, odor and/or appearance of the beverage omega-6 fatty acids are linoleic acid (18:2006) (a short-chain composition over time. Typically, the acids are food-ap fatty acid); gamma-linolenic acid (GLA) (18:3c)6); dihomo proved, e.g., edible acids or ingestible acids, for example, US 2016/008 1976 A1 Mar. 24, 2016

acids that are safe and/or approved for human consumption. 0241. As used herein, “G.R.A.S. and “GRAS are used Exemplary acids include, but are not limited to, citric acid, synonymously to refer to compounds, compositions and phosphoric acid, adipic acid, ascorbic acid, lactic acid, malic ingredients that are “Generally Regarded as Safe” by the acid, fumaric acid, gluconic acid. Succinic acid, tartaric acid USDA and FDA for use as additives, for example, in foods, and maleic acid. beverages and/or other Substance for human consumption, 0235. As used herein, a “bicarbonate' or “carbonate' Such as any Substance that meets the criteria of sections 201(s) refers to a stabilizer or one component of a stabilizing system and 409 of the U.S. Federal Food, Drug and Cosmetic Act. that, when added to a beverage composition in combination Typically, the compositions, concentrates and liquid dilution with the other components (i.e., the acid and/or antioxidant) compositions provided herein are GRAS certified. yields beverage compositions that retain one or more desired 0242. As used herein, “kosher' is used to refer to sub organoleptic properties, such as, but not limited to, the taste, stances that conform to Jewish Kosher dietary laws, for Smell, odor and/or appearance of the beverage composition example, Substances that do not contain ingredients derived over time. Typically, bicarbonates or carbonates are food from non-kosher animals or do not contain ingredients that approved, e.g., edible bicarbonates or carbonates, for were not made following kosher procedures. Typically, the example, bicarbonates or carbonates that are safe and/or compositions, concentrates and liquid dilution compositions approved for human consumption. Exemplary bicarbonates provided herein are Kosher-certified. include, but are not limited to, potassium bicarbonate and 0243 As used herein, “vessel” refers to any container, for Sodium bicarbonate. Exemplary carbonates include, but are example, any tank, pot, vial, flask, cylinder or beaker that can not limited to, potassium carbonate, Sodium carbonate, cal be used to contain the ingredients and/or phases of the pro cium carbonate, magnesium carbonate and Zinc carbonate. vided concentrates and liquid dilution compositions during 0236. As used herein, “carbonation” or “carbonated” the methods for making the concentrates and liquid dilution refers to carbon dioxide dissolved in liquid, such as a bever compositions. The vessel can be a tank that is used to mix age base, including water. A liquid, or beverage, can be car and/or heat one or more ingredients and/or phases of the bonated by direct addition of carbon dioxide to the liquid or composition, for example, the water phase tanks and oil phase beverage. tanks, such as during the provided scaled-up methods. The oil and the water phases can be mixed and heated in separate 0237 As used herein, "emulsion stabilizer” refers to com tanks before combining the phases to form an emulsion. The pounds that can be used to stabilize and/or emulsify and/or tank can be a packaging or holding tank, which holds the change the viscosity of the provided concentrates and aque provided compositions after forming the compositions, for ous compositions containing the diluted concentrates. For example, the emulsions. A number of tanks are available for example, the emulsion stabilizer can increase the Viscosity of mixing ingredients. Typically, the tanks are cleaned, for the liquid concentrate. One or more emulsion stabilizers can example, rinsed, soaped and/or sanitized according to known be added, for example, during formulation after evaluation of procedures prior to use and between uses. The tanks can be an initial concentrate, particularly if the oil and water phases equipped with one or more mixers, for example, a standard of the initial concentrate (or the aqueous liquid dilution com mixer and/or homogenizer, which are used to mix the ingre position resulting from dilution of the initial concentrate) dients added to the tank. The tank can be equipped with a appear to be separating. Addition of the emulsion stabilizer heating and/or cooling device. For example, the tank can be a can prevent separation of the oil and water phases. water-jacketed tank. The temperature of the water-jacketed 0238. As used herein, a “pH adjuster' is any compound, tank is controlled through the water-jacket, for example, to typically an acid or a base, that is capable of changing the pH heat the contents, for example, while mixing. of the provided concentrates and liquid dilution composi 0244 As used herein, a “water phase vessel” refers to a tions, for example, to reduce the pH of the concentrates or vessel used to mix and/or heat the water phase ingredients to liquid dilution composition or to increase the pH of the con generate the water phase of the provided compositions. The centrates or liquid dilution composition, typically without water phase vessel can be a tank. The tank can be a water altering other properties of the concentrates and liquid dilu jacketed tank, which is a tank equipped with a water jacket tion composition, or without Substantially altering other that can be used to heat the contents of the tank. properties. pH adjusters are well known. Exemplary of the pH 0245. As used herein, an “oil phase vessel” refers to a adjusters are acids, for example, citric acid and phosphoric vessel used to mix and/or heat the oil phase ingredients to acid, and bases. generate the oil phase of the provided compositions. The oil 0239. As used herein, “flavor” is any ingredient that phase vessel can be an oil phase tank. The tank can be a changes, typically improves, the taste and/or Smell of the water-jacketed tank. provided concentrates and liquid dilution compositions, for 0246. As used herein, “transfer device' refers to any example, the beverages. equipment, combination of equipment and/or system that can 0240. As used herein, “natural' is used to refer to a com be used to transfer liquid, for example, from one tank to position, concentrate or liquid dilution composition, and/or another tank, in the provided methods for making the con ingredients in the composition, concentrate or liquid dilution centrates and liquid dilution compositions. Exemplary of the composition, that can be found in nature and is not solely transfer devices is a transfer pump and appropriate fittings, man-made. For example, benzyl alcohol is a natural preser for example, sanitary fittings, ball valves and transfer hoses, Vative. Similarly, tocopheryl polyethylene glycol is a natural for example, food grade hoses. surfactant. The natural composition/ingredient can be GRAS 0247. As used herein a “mixer' is any piece of equipment and/or Kosher-certified. Typically, the provided composi or combination of equipment that can be used to mix ingre tions, concentrates and liquid dilution compositions are natu dients in the provided methods for making the concentrates ral, semi-natural and/or contain one or more natural ingredi and liquid dilution compositions, for example, standard mix entS. ers and homogenizers (shears). For example, mixers can be US 2016/008 1976 A1 Mar. 24, 2016 used to mix the ingredients of the water phase and the oil Similarly, “not less than' and “NLT refer to a quantity that is phase and/or to mix the additional ingredients. greater than or equal to the listed quantity. 0248. As used herein, “standard mixers' are mixers that 0255 As used herein, the singular forms “a” “an and are used to combine a group of ingredients, for example, the “the include plural referents unless the context clearly dic oil phase ingredients or the water phase ingredients, or to mix tates otherwise. Thus, for example, reference to a composi one or more ingredients with a liquid, for example, with an tion containing 'a non-polar ingredient includes composi emulsion, for example, to mix additional ingredients with the tions with one or more non-polar ingredients. emulsion. Standard mixers can be any mixers that move the 0256 AS used herein, ranges and amounts can be material, for example, the ingredients, during heating, for expressed as “about a particular value or range. About also example, to promote dissolving of the ingredients. includes the exact amount. Hence, “about 5 grams' means 0249. As used herein, “homogenizer and “shear are “about 5 grams” and also “5 grams. It also is understood that used to refer to mixers that typically have high shear, which ranges expressed herein include whole numbers within the can be used, for example, to form an emulsion, for example, ranges and fractions thereof. For example, a range of between to emulsify the water phase and the oil phase, in the provided 5 grams and 20 grams includes whole number values such as methods. The homogenizers typically are capable of high 5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 grams, shear mixing, which emulsifies the phases. and fractions within the range including, but not limited to, 0250) As used herein, a “cooling apparatus is any piece of 5.25, 6.72, 8.5 and 11.95 grams. equipment or combination of equipment that can be used with 0257. As used herein, “optional or “optionally’ means the provided methods to cool the compositions and phases that the Subsequently described eventor circumstance does or and ingredients thereof, for example, during mixing and/or does not occur and that the description includes instances homogenizing, for example, to chill the mixture while emul where said event or circumstance occurs and instances where Sifying the oil and water phases. Exemplary of the cooling it does not. For example, a reaction mixture that "optionally apparatuses are coolers (chillers), for example, recirculating includes a catalyst” means that the reaction mixture contains coolers which can be attached, for example, to the tanks used a catalyst or it does not contain a catalyst. in the provided methods, for example, remotely or by a tank 0258 As used herein, "consisting essentially of means mounted in the cooler, to recirculate fluid from the tank, containing the following list of ingredient(s), and not includ through the chiller and back to the tank, in order to rapidly ing any additional non-polar ingredient that is or contains a cool and maintain the temperature of the mixture during non-polar compound other than those listed. mixing. Typically, the cooling apparatus can be used to cool 0259. As used herein, a softgel shell is an oral dosage form the liquid to between or about between 25°C. and 45°C., for for administration of pharmaceuticals and nutraceuticals, example, to at or about 25, 26, 27, 28, 29, 30, 31, 32,33, 34, similar to capsules. Softgel shells area combination of gelatin 35, 36, 37,38, 39, 40, 41, 42, 43, 44 or 45° C. or gelatin alternative, water, opacifier and a plasticizer to lend 0251. As used herein, “rapid cooling refers to a process flexibility, such as glycerin and/or sorbitol. by which a composition, for example, a liquid composition, 0260. As used herein, a softgel composition refers to a soft for example, a forming emulsion, is cooled to a desired tem gel shell that contains the non-aqueous pre-gel compositions perature, for example, between or between about 25°C. and provided herein. 45° C., in less than or less than about 2 hours, typically less 0261. As used herein, a “concentrate.” particularly a “pre than or less than aboutl hour, for example, less than or less gel concentrate' is a composition that generally is formulated than about 30 minutes, such as 15 minutes. for dilution, rather than direct ingestion, or for direct inges 0252. As used herein, “w/w,”“by weight,” “% by weight.” tion in a Small quantity. Such as in a capsule. For purposes “wt %' and “weight percent” are used synonymously to herein, a “pre-gel concentrate refers to a composition that is express the ratio of the mass of one component of a compo formulated as a composition for dilution, but also is provided sition compared to the mass of the entire composition. For in capsules, such as Soft gels, for direct ingestion, where a example, when the amount of a particular ingredient repre single capsule provides a single dosage or a fractional dosage. sents 1%, by weight (w/w), of a concentrate, the mass of that 0262. As used herein, a “pre-gel concentrate” refers to a ingredient is 1% of the mass of the entire concentrate. Simi composition that contains in a particular Volume to be encap larly, when the amount of an ingredient is 50% (w/w) of the Sulated, contains a single dosage or fractional dosage of a concentrate, the mass of that ingredient is 50% of the entire composition containing non-polar ingredients. mass of the concentrate. Similarly, when a composition and/ 0263. As used herein, fractional dosage refers to an or a compound contains 10%, by weight, of an ingredient, the amount that is less that a full dosage so that, when provided as mass of the ingredient is 10% of the total mass of the com a capsule, a plurality of capsules will be required to provide a position or compound. When a composition contains 10 wt % single dosage. Typically, a fractional dosage is at least 20%, of an ingredient, the mass of that ingredient is 10% of the 25%, 50% of a full dosage. mass of the entire composition. When only a concentration, 0264. As used herein, “stability” of compositions, such as amount, or percentage (without units) is listed, it is to be the pre-gel emulsions and concentrates and soft gels to understood that the concentration or percentage is a concen remain free from one or more deleterious changes over a tration or percentage by weight. period of time, for example, at least or longer than 1 day, 1 0253) Similarly, as used herein “v/v and “volume per week, 1 month, 1 year, or more. For example, a concentrate or cent are used synonymously to express the ratio of the Vol softgel can be described as stable if it is formulated such that ume of one component of a composition to the Volume of the it remains free from oxidation or substantial oxidation over entire composition. time, remains clear over time, remains safe and/or desirable 0254. As used herein, “not more than and “NMT refer to for human consumption over time, does not form precipitates a quantity that is less than or equal to the listed quantity. and remains free of microbial or other contamination. US 2016/008 1976 A1 Mar. 24, 2016

0265. As used herein, “non-aqueous solvent refers to any 0270 Provided herein is a water-soluble vitamin E deriva liquid other than water in which non-polar ingredients or tive mixture, such as a PEG derivative of vitamin E mixture, compounds can be dissolved. Typically, a non-aqueous sol Such as a TPGS mixture, that is a high dimer-containing vent is solvent that is not soluble in water or is partially mixture (as described herein) of the water-soluble vitamin E soluble in water has no or only partial solubility in water. For derivative. These high dimer-containing water-soluble vita purposes herein, the non-aqueous solvent is acceptable for min E derivative mixtures can be used in any composition in human consumption. Benzyl alcohol is exemplary of Such which a water-soluble vitamin E derivative is included. As Solvents. described herein, these include the Soft-gel compositions, the 0266. As used herein, “excipients”, refer to any substance pre-gel compositions and the powders and pre-spray emul needed to formulate the composition to a desired form. For sions. Also included are compositions described, for example, Suitable excipients include but are not limited to, example, in U.S. application Ser. No. 14/207.310, and Inter diluents or fillers, binders or granulating agents or adhesives, national PCT Application No. PCT/US14/25006, now pub disintegrants, lubricants, antiadherants, glidants, wetting lished as US-2014-0271593-A1 and WO 2014/151109, agents, dissolution retardants or enhancers, adsorbents, buff respectively, that include concentrates, e.g., the pre-emulsion ers, chelating agents, preservatives, colors, flavors and Sweet concentrates and liquid nanoemulsion concentrates, that con eners. Typical excipients include, but are not limited to, tain one or more non-polar ingredients that are or contain one starch, pregelatinized starch, maltodextrin, monohydrous or more non-polar compound. dextrose, alginic acid, Sorbitol and mannitol. In general, the 0271 Water-soluble vitamin E derivatives can be formed excipient should be selected from non-toxic excipients (IIG, by covalently attaching the vitamin E moiety, a hydrophobic Inactive Ingredient Guide, or GRAS, Generally Regarded as moiety, to another moiety, Such as a hydrophilic moiety, for safe, Handbook of Pharmaceutical Excipients). example, a polyalkylene glycol moiety, e.g., a polyethylene 0267 As used herein, a binder is an excipient added to a glycol (PEG) moiety, via a linker. For example, the vitamin E composition to aid formation of a powder when the compo derivative compositions can include, but are not limited to, sition is dried. Non-limiting examples of suitable binders polyalkylene glycol derivatives of tocopherol, e.g., polyeth include, but are not limited to, acacia, dextrin, starch, povi ylene glycol (PEG) derivatives of tocopherol, and polyalky done, carboxymethylcellulose, guar gum, glucose, hydrox lene glycol derivatives of tocotrienol, e.g., polyethylene gly ypropyl methylcellulose, methylcellulose, polymethacry col (PEG) derivatives of tocotrienol, and any other lates, maltodextrin, hydroxyethyl cellulose, whey, derivatized water-soluble form of vitamin E, such as those disaccharides, sucrose, lactose, polysaccharides and their described in U.S. Pub. No. 2011-0184194. The water-soluble derivatives such as starches, cellulose or modified cellulose vitamin E derivatives include, for example, vitamin E TPGS Such as microcrystalline cellulose and cellulose ethers such as (D-O-tocopheryl polyethylene glycol Succinate), TPGS ana hydroxypropyl cellulose, Sugar alcohols such as Xylitol, Sor logs, TPGS homologs and TPGS derivatives. bitol or maltitol, protein, gelatins and synthetic polymers, 0272 Polyethylene glycol derivatives of vitamin E, such such as polyvinylpyrrolidone (PVP) or polyethylene glycol as vitamin ETPGS (D-O-tocopheryl polyethylene glycol suc (PEG). cinate), are known. Compositions of PEG derivatives of vita 0268. As used herein, stabilizers refer to additives that aid min E, for example, TPGS compositions, typically contain a in retaining retain organoleptic properties. These include, but mixture of monomers and dimers, where a monomer is a are not limited to carbonate, bicarbonate and/or CO. Addi single vitamin E molecule covalently joined to a water tional components, such as ingestible acids and antioxidants, soluble moiety, such as a polyethylene glycol, through a Such as, for example, ascorbic acid, ascorbate or a coenzyme linker, where the water-soluble moiety, e.g., PEG, has a free, Q-containing compound. improve organoleptic properties unreacted, terminal reactive group, e.g., a free terminal hydroxyl group. A dimer is made up of two vitamin E mol ecules covalently joined to a water-soluble moiety. Such as a B. WATER-SOLUBLEVITAMINEDERIVATIVES polyethylene glycol, through one or more linkers, where both 0269 Provided herein are concentrates, compositions and ends of the water-soluble moiety, e.g., both terminal hydroxyl beverage compositions, such as liquid dilution compositions groups of a PEG moiety, have reacted with a linker that is and aqueous beverages, Soft gel compositions and powders, joined to a vitamin E molecule so that there are no free that provide non-polar compounds and contain water-soluble terminal reactive groups, e.g., hydroxyl groups. For example, Vitamin E derivative mixtures (compositions). Such as water the monomer and dimer are formed during the esterification soluble tocopherol-derived compositions and tocotrienol-de reaction between the acid moiety of vitamin E Succinate and rived compositions. The water-soluble vitamin E derivative the terminal hydroxyl groups of a polyethylene glycol to mixtures (compositions) contain a relatively high concentra produce TPGS. Known TPGS compositions contain prima tion, as described herein, of the dimer form of the water rily TPGS monomer, e.g., between 70 wt % and 87 wt %, or soluble vitamin Ederivative. This composition is employed in higher, TPGS monomer. The monomer has been considered the preparation of the compositions provided herein, includ the effective component and the dimer considered to be a ing the powders, softgels, concentrates, emulsions, beverage byproduct, thus the amounts of dimer are minimal, e.g., less compositions and concentrates that contain non-polar ingre than 12 wt %. dients, such as nutritional Supplements, including water-in 0273. In contrast, the water-soluble vitamin E derivative soluble vitamins, fatty acids, phytosterols, coenzyme Q and mixtures (compositions) employed in the concentrates and other Such compounds, for addition to foods, particularly compositions provided herein are prepared so that they con aqueous beverages. Also provided are compositions that con tain significantly more dimer, i.e., more than 12%, particu tain the water-soluble vitamin E derivative mixtures (compo larly at least 20%, 25%, 29%, or more, generally between sitions) with a non-polar ingredient and other optional ingre about 29-55%, 35%-55%, or more such as up to 75%, 80%, dients for direct consumption without dilution. 85%, 90% or 95% dimer, and contain some monomer, i.e., US 2016/008 1976 A1 Mar. 24, 2016 20 less than 70 wt % monomer. For example, described herein tion as well as amounts of the non-polar ingredient that pro are TPGS compositions that contain less TPGS monomer, vide a dosage or effective amount upon consumption of a i.e., less than 70 wt % TPGS monomer, and more TPGS single serving, Such as 1-10 mL. dimer, i.e., more than 12 wt % TPGS dimer, such as at least 0278. The food and beverage products provided herein 20%, 25%, 29%, or more, up to 75%, 80%, 85%,90% or 95% that contain the water-soluble vitamin E derivative mixtures dimer. with concentrations of dimer that are greater than 12%, par 0274 PEG derivatives oftocopherols or tocotrienols, e.g., ticularly at least 20%, 25%, 29% and higher, contain non TPGS, are water-soluble and can be added to products for polar ingredients, for example, non-polar ingredients that are mulated for human consumption, Such as food and beverage poorly water-soluble (e.g., have low water solubility or are products, in particular aqueous food and beverage products, water-insoluble), that are or contain one or more non-polar and for delivery of nutritional Supplements and drugs that compounds. The use of the water-soluble vitamin Ederivative have little or no solubility in aqueous compositions. They mixtures (compositions) that contain less monomer, i.e., less have been used, for example, to increase bioavailability of than 70 wt % monomer, and more dimer, i.e., more than 12 wit Vitamin E and/or to act as a Surfactant for other water-in % dimer, thanknown water-soluble vitamin Ederivative mix soluble compounds, for example, non-polar compounds. tures with higher concentrations of monomer and lower con 0275. The concentrates, powders, softgels, and foods and centrations of dimer, in aqueous food and beverage products beverages provided herein contain the water-soluble vitamin allows for the addition of higher amounts (i.e., concentra E derivative mixtures (compositions) that have the higher tions) of non-polar ingredients as compared to available food concentrations of dimer, such as TPGS compositions contain and beverage products without sacrificing clarity and Stability ing, for example, less monomer, i.e., less than 70 wt %, and of the resulting product. Thus, described herein are water more dimer, i.e., more than 12 wt %. soluble vitamin E derivative mixtures (compositions). Such as 0276. It is shown herein that the water-soluble vitamin E TPGS compositions, that can be added to food and beverage derivative mixtures (compositions) described herein have products that allow for the addition of higher concentrations advantageous properties compared to Vitamin E derivative of non-polar ingredients that result in food and beverage compositions that contain higher concentrations (i.e., greater products that retain desirable organoleptic properties. than 70%) monomer. In particular, the vitamin E derivative 0279 1. Vitamin E compositions provided herein contain at least about 13%, 0280 Vitamin E refers to a group of eight water-insoluble typically more, dimer form of the vitamin E derivative than compounds that include tocopherols and tocotrienols. Both previous preparations, in which the amount of monomerform Structures are similar, containing a chromal ring and a 16-car is maximized. It is shown herein that the vitamin E derivative bon side chain. The 16-carbon side chain of the tocopherols is compositions that contain more dimer form are more effec saturated, while the side chain of the tocotrienols is unsatur tive in solubilizing non-polar additives (non-polar com ated, with double bonds at the 3', 7 and 11" positions. Each pounds) in aqueous compositions than compositions that con tocopherol and tocotrienol exists in the C. B. Y and ö forms, tain the monomer form and very little dimer form, and result differentiated by the number and position of methyl groups on in compositions and concentrates that produce liquid dilution the ring (labeled R, R and Rs), as shown below. compositions, such as aqueous beverages, that are more clear and stable than comparable compositions produced from con centrates that contain low amounts of dimer and higher amounts of monomer. In addition, the higher dimer-contain ing water-soluble vitamin E derivative mixtures (composi tions) described herein permit dissolution of higher concen trations of non-polar ingredients while retaining the clarity and stability of the resulting foods and beverages. As shown herein, higher concentrations of non-polar ingredients can be Tocopherol dissolved, resulting in beverages of greater clarity than bev erages containing water-soluble vitamin E derivative mix tures (compositions) that contain lower concentrations of dimer. In addition, across all ranges of concentrations of non-polar ingredients, the resulting beverages are signifi cantly more clear (see Examples below). Thus, provided herein are products formulated for human consumption, for example, food and beverage products, such as aqueous food Tocotrienol and beverage products, that contain the water-soluble vitamin E derivative mixtures (compositions) described herein and one or more non-polar ingredients that are or contain one or more non-polar compounds, and methods for producing Such products. Form R R2 R 0277. The concentrates containing the water-soluble vita C. Me Me Me min E derivative mixtures (compositions) described herein B Me H Me can be used in aqueous compositions, for example, aqueous y H Me Me food and beverage products for human consumption. In some 8 H H Me instances, the concentrates can be formulated for direct administration or direct consumption. Those compositions (0281 Vitamin E is an important natural antioxidant and contain lower amounts of the vitamin E derivative composi has been shown to have anti-inflammatory and anti-carcino US 2016/008 1976 A1 Mar. 24, 2016 genic activity (Yang et al. (2010) Ann. N.Y. Acad. Sci. 1203: conjugate that contains an carboxylic acid can be activated to 29-34; Ju et al. (2010) Carcinogenesis 31(4):533-542; Lietal. the corresponding acid halide and reacted with a PEG-SH (2011) Cancer Prev. Res. (Phila.) 4(3):404-413). The most derivative to form a thioester bond between the tocopherol common and biologically active form of vitamin E is C.-toco linker conjugate and the PEG molecule. pherol, and is the form often referred to as vitamin E. Since tocopherols, including C-tocopherol, cannot be synthesized 0286 a. Tocopherols and Tocotrienols in humans and animals, they must be obtained from dietary 0287. The tocopherols used to make the water-soluble Sources. Alpha-tocopherol, the main component of vitamin E vitamin E derivative mixtures described herein can be any in the American diet, is most commonly found in wheat germ, natural or synthetic vitamin Etocopherol, including, but not nuts and vegetable and plant oils, such as oils from Soybean, limited to, alpha-tocopherols, beta-tocopherols, gamma-to corn, sesame, cottonseed, Sunflower and almond. copherols and delta tocopherols, either in pure form or in a 0282) 2. Polyalkylene Glycol Derivatives of Vitamin E heterogeneous mixture of more than one form. Exemplary 0283. The water-soluble vitamin E derivatives described tocopherols are d-C-tocopherols and dl-C-tocopherols. To herein (e.g., water-soluble tocopherols or water-soluble make the vitamin E-PEG derivative, the tocopherol typically tocotrienols) can include polyalkylene glycol derivatives of is esterified with a linker, for example, a dicarboxylic acid, to vitamin E, such as polyethylene glycol (PEG) derivatives of formatocopherol ester, which then isjoined to a PEG moiety. vitamin E, for example, PEG derivatives of tocopherols or 0288 The tocotrienols used to make the water-soluble tocotrienols. Suitable PEG derivatives of vitamin E can con vitamin E derivative mixtures described herein can be any tain one or more tocopherol or tocotrienol, attached to one or natural or synthetic vitamin Etocotrienol, including, but not more PEG moiety via a linker, for example, a dicarboxylic limited to, alpha-tocotrienols, beta-tocotrienols, gamma-to acid linker. Exemplary dicarboxylic acid linkers include Suc cotrienols and delta tocotrienols, either in pure form or in a cinic acid and Succinic anhydride. An exemplary water heterogeneous mixture of more than one form. Mixtures of soluble vitamin E derivative is shown schematically below: tocopherols and tocotrienols are contemplated for use in the described methods and compositions. A tocotrienol can be esterified with a linker, such as a dicarboxylic acid, before joining with a PEG moiety to form a vitamin E-PEG deriva tive. 0289 b. Linkers where the line between the PEG and the linker, and the line between the linker and the vitamin E moiety, each indepen 0290 Typically, the water-soluble vitamin E derivatives dently represent a covalent bond, for example, a covalent described herein include a vitamin E moiety, e.g., a toco bond that forms an ester, ether, amide or thioester. pherol or tocotrienol, attached to a PEG moiety through a 0284 Typically, the vitamin E-PEG derivatives are made linker. The linker can be any linker that is capable of forming by covalently attaching the PEG moiety, such as by esterifi a covalent bond with both the vitamin E moiety and the PEG cation, to a vitamin E-linker conjugate (e.g., a tocopherol moiety. For example, the linker can be any linker capable of linker conjugate). The vitamin E-linker conjugate can be forming more than one covalent bond such as an ester bond, formed through esterification of the hydroxyl group of the an amide bond, an ether bond, a thioether bond, or any com Vitamin E moiety with a carboxylic acid group of a linker, bination thereof. In some embodiments, the linker is capable Such as a dicarboxylic acid linker. In one example, the vitamin of forming more than one ester bond, for example, the linker E-linker conjugate can be a tocopherol-linker conjugate. Such can be a dicarboxylic acid or dicarboxylic acid derivative. as a tocopherol ester, for example, tocopherol Succinate. The Exemplary dicarboxylic acids and derivatives useful as link esterification reaction can be performed by any of a number of ers in the water-soluble vitamin E derivatives described known methods, including those described in U.S. Pat. Nos. herein include Succinic acid, Succinic anhydride, Sebacic 2,680,749; 4,665,204; 3,538,119; and 6,632,443. The result acid, dodecanedioic acid, Suberic acid (i.e., octanedioic acid), ing vitamin E-linker conjugate can then be attached to a PEG aZelaic acid, citraconic acid, methylcitraconic acid, itaconic moiety by another esterification reaction, for example, acid, maleic acid, glutaric acid, glutaconic acid, fumaric acid between a carboxylic acid group of the vitamin E-linker con and phthalic acid. Accordingly, exemplary of the vitamin jugate and a hydroxyl group of the PEG moiety, to form a E-linker conjugates (i.e., tocopherol ortocotrienol attached to vitamin E-PEG derivative. a linker through an ester bond) that can be furtheresterified to 0285 PEG derivatives of a tocopherol-linker or tocot form the vitamin E-PEG derivatives (i.e., water-soluble vita rienol-linker conjugate can be made by any other method min E derivatives) described herein are tocopheryl succinate, known to those of skill in the art. Various methods known in tocopheryl sebacate, tocopheryl dodecanodioate, tocopheryl the art for producing PEG derivatives can be used to attach a Suberate, tocopheryl azelaate, tocopheryl citraconate, toco PEG molecule to tocopherol-linker or tocotrienol-linker pheryl methylcitraconate, tocopheryl itaconate, tocopheryl compounds. For example, a tocopherol-linker conjugate can maleate, tocopheryl glutarate, tocopheryl glutaconate, toco form a covalent bond to the PEG molecule viaanamide, ether pheryl fumarate, tocopheryl phthalate, tocotrienol Succinate, orthioether bond. For example, a tocopherol-linker conjugate tocotrienol sebacate, tocotrienol dodecanodioate, tocotrienol that contains an amine group can be reacted with a PEG-NHS Suberate, tocotrienol azelaate, tocotrienol citraconate, tocot (N-hydroxysuccinimide) derivative to form an amide bond rienol methylcitraconate, tocotrienol itaconate, tocotrienol between the tocopherol-linker conjugate and the PEG mol maleate, tocotrienol glutarate, tocotrienol glutaconate, tocot ecule. A tocopherol-linker conjugate that contains an amine rienol fumarate and tocotrienol phthalate. group can be reacted with a PEG-aldehyde derivative to form 0291. In other embodiments, the linker can be any com an amide bond between the tocopherol-linker conjugate and pound capable of forming more than one covalent bond, for the PEG molecule. In another example, a tocopherol-linker example, a Succinate ester, Such as N-hydroxySuccinimide; US 2016/008 1976 A1 Mar. 24, 2016 22 an amino acid, Such as glycine, alanine, 5-aminopentanoic natural Surfactants, for example, Surfactants that are G.R.A.S. acid or 8-aminooctanoic acid; or an amino alcohol. Such as certified (generally recognized as safe) by the FDA and/or ethanolamine. Kosher certified. 0292 c. PEG Moieties 0298 Typically, Surfactants aggregate in aqueous liquids, 0293. The polyalkylene moiety used to produce the water such as water, to form micelles. The hydrophilic portion(s) of soluble vitamin E derivatives described herein can be any the surfactant molecules are oriented toward the outside of the polyalkylene moiety. Exemplary of a polyalkylene moiety is micelle, in contact with the aqueous medium, while the a polyethylene glycol (PEG) moiety. The PEG moiety used in hydrophobic portion(s) of the surfactant molecules are ori the vitamin E derivatives described herein can be any of a ented toward the center of the micelle. Surfactants also are plurality of known PEG moieties. Exemplary of suitable PEG capable of forming “inverse micelles, which form in lipo moieties are PEG moieties having varying chain lengths and philic medium, the hydrophobic tails being in contact with the varying molecular weights, such as, for example, PEG 200, lipophilic medium and the hydrophilic heads facing the cen PEG 500, PEG 1000 and PEG 20,000, where the molecular ter of the inverse micelle. Typically, however, the water weight of the PEG moiety is 200 Da, 500 Da, 1000 Da and soluble vitamin E derivatives described herein are surfactants 20,000 Da, respectively. Typically, the number following that form micelles in aqueous medium, for example, in aque “PEG' indicates the molecular weight, in daltons (Da), of the ous liquids, Such as water. PEG moiety. The PEG moiety of the water-soluble vitamin E 0299. The water-soluble vitamin E derivatives described derivatives described herein typically has a molecular weight herein can be represented by an HLB (hydrophilic-lipophilic of between or about between 200 Da to 20,000 Da, for balance) value. Generally, HLB is a value derived from a example, between or about between 200 Dato 20,000 Da,200 semi-empirical formula, which is used to index surfactants Da to 10,000 Da, 200 Da to 8000 Da, 200 Da to 6000 Da, 200 according to their relative hydrophobicity/hydrophilicity. An Da to 5000 Da, 200 Da to 3000 Da, 200 Da to 1000 Da, 200 HLB value is a numerical representation of the relative rep Da to 800 Da, 200 Dato 600 Da, 200 Da to 400 Da, 400 Da to resentation of hydrophilic groups and hydrophobic groups in 20,000 Da, 400 Da to 10,000 Da, 400 Da to 8000 Da, 400 Da a Surfactant or mixture of Surfactants. The weight percent of to 6000 Da, 400 Da to 5000 Da, 400 Da to 3000 Da, 400 Da these respective groups indicates properties of the molecular to 1000 Da, 400 Da to 800 Da, 400 Da to 600 Da, 600 Da to structure. See, for example, Griffin (1949).J. Soc. Cos. Chem. 20,000 Da, 600 Da to 10,000 Da, 600 Da to 8000 Da, 600 Da 1:311. Surfactant HLB values range from 1-45, while the to 6000 Da, 600 Da to 5000 Da, 600 Da to 3000 Da, 600 Da range for non-ionic Surfactants typically is from 1-20. The to 1000 Da, 600 Da to 800 Da, 800 Da to 20,000 Da, 800 Da more lipophilic a surfactant is, the lower its HLB value. to 10,000 Da, 800 Da to 8000 Da, 800 Da to 6000 Da, 800 Da Conversely, the more hydrophilica Surfactantis, the higher its to 5000 Da, 800 Da to 3000 Da, 800 Da to 1000 Da, 1000 Da HLB value. Lipophilic surfactants have greater solubility in to 20,000 Da, 1000 Da to 10,000 Da, 1000 Da to 8000 Da, oil and lipophilic Substances, while hydrophilic Surfactants 1000 Da to 6000 Da, 1000 Da to 5000 Da, 1000 Da to 3000 dissolve more easily in aqueous liquids. In general, Surfac Da, 3000 Da to 20,000 Da, 3000 Da to 10,000 Da, 3000 Da to tants with HLB values greater than 10 or greater than about 10 8000 Da, 3000 Da to 6000 Da, 3000 Da to 5000 Da, 5000 Da are called “hydrophilic surfactants.” while surfactants having to 20,000 Da, 5000 Da to 10,000 Da, 5000 Da to 8000 Da, HLB values less than 10 or less than about 10 are referred to 5000 Da to 6000 Da, 6000 Da to 20,000 Da, 6000 Da to as “hydrophobic surfactants.” It should be appreciated that 10,000 Da, 6000 Da to 8000 Da, 8000 Da to 20,000 Da, 8000 HLB values for a given Surfactant can vary, depending upon Da to 10,000 Da, or 10000 Da to 20,000 Da. For example, the the empirical method used to determine the value. Thus, HLB PEG moiety of the water-soluble vitamin E derivatives values of Surfactants provide a rough guide for formulating described herein can have a molecular weight of 200, 300, compositions based on relative hydrophobicity/hydrophilic 400, 500, 600, 800, 1000, 3000, 5000, 6000, 8000, 10,000, ity. For example, a Surfactant typically is selected from 20,000 Da or more. among Surfactants having HLB values within a particular range of the Surfactant or co-surfactant that can be used to 0294 Other known PEG analogs also can be used in the guide formulations. The water-soluble vitamin E derivatives water-soluble vitamin E derivatives described herein. The described herein, such as the polyalkylene glycol derivatives PEG moieties can be selected from among any reactive PEG of vitamin E with greater than 12%, 20%, 25%, or 29% dimer, moiety, including, but not limited to, PEG-OH, PEG-NHS, are surfactants in which the vitamin E moiety represents the PEG-aldehyde, PEG-SH, PEG-NH. PEG-COH, and hydrophobic region of the Surfactant and is attached, via a branched PEG moieties. linker, to a polyalkylene glycol moiety, Such as a polyethylene 0295 Exemplary of a water-soluble vitamin E derivative glycol (PEG) moiety, that provides the hydrophilic portion of having a PEG moiety with a molecular weight of 1000 Da is the surfactant. The water-soluble vitamin E derivative mix TPGS 1000 (i.e., D-O-tocopheryl polyethylene glycol succi tures (compositions) described herein contain more than nate 1000). 12%, such as at least 20%, 25% and 29%, up to 95%, 90%, 85%, 80%, or 75% of the dimer form of the water-soluble 0296 d. Surfactant Properties vitamin E derivative, such as PEG derivatives of vitamin E. 0297. The water-soluble vitamin E derivative mixtures Exemplary of the water-soluble vitamin Ederivatives that can (compositions) described herein, for example, the polyalky be used as Surfactants are tocopherol-derived surfactants, lene glycol derivatives of vitamin E described herein, are including polyalkylene glycol derivatives oftocopherol, typi Surfactants. Surfactants are molecules that contain hydropho cally polyethylene glycol (PEG) derivatives of tocopherol, bic and hydrophilic portions. For example, the hydrophobic such as tocopheryl polyethylene glycol succinate (TPGS), portion can be a hydrophobic tail and the hydrophilic portion TPGS analogs, TPGS homologs and TPGS derivatives and can be a hydrophilic head of the surfactant molecule. The tocotrienol-derived surfactants, including polyalkylene gly water-soluble vitamin E derivatives described herein can be col derivatives of tocotrienol, typically polyethylene glycol US 2016/008 1976 A1 Mar. 24, 2016

(PEG) derivatives oftocotrienol. These are prepared as com soluble vitamin E derivatives that can be prepared in compo positions containing the higher levels of dimers as described sitions with the higher levels of dimer as described herein. herein. (0303. 3. Tocopheryl Polyalkylene Glycol Derivatives 0300 Exemplary of vitamin E derivatives that can be pre 0304. In its natural water-insoluble state, vitamin E, e.g., pared for use herein are tocopheryl polyalkylene glycol tocopherol or tocotrienol, is easily absorbed and used in derivatives, such as tocopheryl polyethylene glycol deriva humans and animals. Processing of foods and feeds by indus tives. These include tocopheryl polyethylene glycol Succinate try for long-term storage can promote accelerated degrada (TPGS), tocopheryl sebacate polyethylene glycol, tocopheryl tion of the effective vitamin E content. To compensate for the dodecanodioate polyethylene glycol, tocopheryl Suberate loss of natural vitamin E from food sources, nutritional polyethylene glycol, tocopheryl azelaate polyethylene gly supplements of natural or synthetic fat-soluble vitamin E col, tocopheryl citraconate polyethylene glycol, tocopheryl have been developed. Not all humans and animals can suffi methylcitraconate polyethylene glycol, tocopheryl itaconate ciently absorb the supplements though. To address this prob polyethylene glycol, tocopheryl maleate polyethylene glycol, lem, water-soluble vitamin Ederivatives have been developed tocopheryl glutarate polyethylene glycol, tocopheryl gluta that are an excellent source of vitamin E (i.e., maintain a high conate polyethylene glycol and tocopheryl phthalate polyeth degree of vitamin E biological activity) in humans with ylene glycol, TPGS analogs and TPGS homologs. Othertoco impaired vitamin E absorption, for example, in humans with pheryl polyethylene glycol derivatives, such as those malabsorption syndromes (Traber et al. (1986) Am. J. Clin. prepared as described in U.S. Pub. No. 2011-0184194, can be Nutr. 44:914-923). Water-soluble vitamin E derivatives have used in the compositions, including softgels, powders, con been developed for this purpose. Tocopheryl polyethylene centrates and food and beverage compositions described glycol derivatives, such as those listed above, are employed to herein. These derivatives are prepared as described herein or produce the water-soluble vitamin E derivative mixtures using other methods such that the resulting compositions (compositions) with higher levels of dimer as described contain greater than 12%, such as at least 20%, 25% and 29%, herein. The water-soluble vitamin E derivative D-O-toco up to 95%, 90%, 85%, 80%, or 75% of the dimer form of the pheryl polyethylene glycol succinate (TPGS) is exemplary of Vitamin E derivative. Concentrates and beverage composi the tocopheryl polyethylene glycol derivatives. tions containing Such compounds have advantageous proper (0305 TPGS contains a hydrophilic (i.e., water-soluble) ties shown herein. polyethylene glycol (PEG) chain and a lipophilic (i.e., water 0301 The water-soluble vitamin E derivatives described insoluble) C-tocopherol head. The amphiphilic structure of herein typically have an HLB value between or about between TPGS, shown below, renders it much more water-soluble than 12 and about 20, for example, 12, 13, 14, 15, 16, 17, 18, 19, traditional vitamin E, allowing TPGS to form a micellar solu 20, or about 12, about 13, about 14, about 15, about 16, about tion at low concentrations (0.04-0.06 mmol/L) that can be 17, about 18, about 19 or about 20. Exemplary of water absorbed by humans and animals in the absence of bile salts.

hydrophilic portion -N- --- O N -- - hydrophobic portion

TPGS soluble vitamin E derivatives that can be used as surfactants 0306 a. Uses are the water-soluble vitamin E derivatives described herein. For example, the water-soluble vitamin E derivatives (0307 i. Nutritional Supplement described herein, such as polyalkylene glycol derivatives of (0308 TPGS has been approved by the FDA as a water vitamin E, have an HLB value of between or about between soluble vitamin E nutritional supplement. It is a GRAS (Gen 12 and about 20. Exemplary of a water-soluble vitamin E erally Regarded As Safe)-listed supplement that can be taken derivate having an HLB value between or about between 12 orally at long-term doses of 13.4-16.8 mg/kg/day or up to 100 and about 20 is tocopheryl polyethylene glycol Succinate mg/kg/day for people with impaired uptake. In the body, (TPGS), such as the TPGS compositions described herein. TPGS undergoes enzymatic cleavage to deliver the lipophilic TPGS typically has an HLB value of between or about antioxidant C.-tocopherol (vitamin E) to cell membranes. Cel between 12 and 14 or about 13. lular enzymatic hydrolysis by cytoplasmic esterases liberates 0302) The following discussion describes properties and free C-tocopherol, which then localizes in the cell membrane, preparations of the vitamin Ederivative D-C-tocopheryl poly and through free radical quenching, protects the membrane ethylene glycol succinate (TPGS) as exemplary of the water from lipid peroxidation and damage. US 2016/008 1976 A1 Mar. 24, 2016 24

0309 ii. Surfactant lipophilic balance, value. The HLB value is a numerical rep 0310 TPGS also is used as a non-ionic surfactant and resentation of the molecular balance of the hydrophobic and emulsifier. Non-ionic Surface-active agents are used in oral hydrophilic portions of the surfactant, relative to other sur formulations to enhance the bioavailability of water-in factants. HLB values are derived from a semi-empirical for soluble pharmaceuticals, such as drugs, vitamins, or other mula, where the relative weight percentages of the hydropho biologically active compounds. TPGS is an effective absorp bic and hydrophilic groups are indicative of Surfactant tion and bioavailability enhancer, and has been approved for properties, such as the types of aggregates the Surfactant use as a drug solubilizer in oral, parenteral, topical, nasal, and forms, and the solubility of the surfactant (Griffin (1949) J. rectal/vaginal therapies (see, e.g., Constantinides etal. (2006) Soc. Cosmet. Chem. 1:311-326). Surfactant HLB values Pharm. Res. 23(2):243-255: Varma et al. (2005) Eur. J. range from 1-45, where the range for non-ionic Surfactants Pharm. Sci. 25(4-5):445-453) and as a solubilizer for inhala typically is from 1-20. The more lipophilica surfactant is, the tion drug delivery (Fulzele et al. (2006) 23(9):2094-2106). lower its HLB value. Conversely, the more hydrophilic a TPGS improves the bioavailability of such water-insoluble surfactant is, the higher its HLB value. The exact HLB value drugs as the HIV protease inhibitor amprenavir (Yu et al. for a given Surfactant can vary, however, depending on the (1999) Pharm. Res. 16:1812-1817: Brouwers et al. (2006) J. empirical method used to determine the value. Values have Pharm. Sci. 95:372-383), the non-nucleoside reverse tran been determined for a number of Surfactants (see, e.g., U.S. scriptase inhibitor UC 781 (Goddeeris et al. (2008) Eur, J. Pat. No. 6,267.985). TPGS is a non-ionic surfactant that, as Pharm. Sci. 35:104-113), cyclosporin (Sokol et al. (1991) reported, has an HLB value of approximately 13. Lancet 338:212-215), paclitaxel (Zhao et al. (2010).J. Pharm. 4. Synthesis Sci. 99(8):3552-3560), estradiol (Sheu et al. (2003) J. Con 0313 trolled Release 88:355-368), and fat-soluble vitamins such as 0314 Scheme 1 shows the synthesis of an exemplary vitamin D (Argao et al. (1992) Ped. Res. 31(2):146-150). water-soluble vitamin E derivative, TPGS, but any vitamin E 0311 TPGS acts as a surfactant due to its hydrophilic moiety, i.e., any tocopherol or tocotrienol, can be used as the polyethylene glycol (PEG) chain and its hydrophobic C-to starting material and reacted with any linker, Such as those copherol portion. Surfactants aggregate and form micelles in described herein, that is capable of reacting with a polyalky aqueous mediums such that the hydrophilic portion(s) of the lene glycol moiety to form a monomerform and dimer form surfactant molecules are oriented toward the outside of the of a water-soluble vitamin E derivative. As shown in Scheme micelle, in contact with the aqueous medium, while the 1 below, TPGS can be prepared by reacting vitamin E with hydrophobic portion(s) of the surfactant molecules are ori Succinic anhydride or Succinic acid to obtain vitamin E Suc ented toward the center of the micelle. In the softgels, pow cinate, i.e., D-O-tocopheryl Succinate, followed by esterifica ders, food and beverage products provided herein, TPGS can tion with a polyethylene glycol molecule, to obtain TPGS act as a Surfactant by forming micelles in an aqueous medium, (see U.S. Pat. No. 2,680,749). TPGS analogs varying in PEG such as water, where the hydrophilic portion of TPGS, i.e., the chain length (e.g., TPGS 200, 238, 400, 600, 2000, 3400, polyethylene glycol (PEG) moiety, is oriented toward the 3500, 4000 and 6000) have been synthesized, but the most outside of the micelle, in contact with the aqueous medium, widely used form of TPGS is TPGS 1000, which incorporates while the hydrophobic portion of TPGS, i.e., the vitamin E PEG 1000, a polyethylene glycol molecule with a molecular moiety, is oriented toward the center of the micelle, in contact weight of approximately 1,000 Daltons (Collinot et al. (2006) with the non-polar compound(s), which are thus contained in J. Controlled Release 1 11:35-40). TPGS 1000 is a pale yel the center of the micelle. low, waxy Solid Substance that is amphipathic and hydro 0312 The hydrophobic/hydrophilic character of a surfac philic, with a molecular weight of approximately 1,513 Dal tant can be described in terms of an HLB, or hydrophilic tOnS.

Scheme 1

OH

Succinic Succinic Vitamin E anhydride acid US 2016/008 1976 A1 Mar. 24, 2016 25

-continued OH

Vitamin E succinate (D-alpha-tocopheryl Succinate) HO(CH2CH2O).H polyethylene glycol n = 200 to 20,000

TPGS monomer (D-alpha-tocopheryl polyethylene glycol Succinate monomer)

TPGS dimer (D-alpha-tocopheryl polyethylene glycol Succinate dimer)

0315 TPGS compositions, as generally prepared, such as nate. For example, commercially available TPGS, such as the commercially available TPGS 1000, are mixtures that contain TPGS 1000 available from Eastman Chemical Company primarily TPGS monomer (between 70% and 87% or more) (Kingsport, Tenn.), contains primarily TPGS monomer and a lesser amount of TPGS dimer (less than 12%). The (-86% or more) and a small amount of TPGS dimer (-11% or monomer is considered the effective component in TPGS, less) (Christiansen et al. (2011) J. Pharm. Sci. 100(5):1773 while the dimer is viewed as a byproduct of the esterification 1782). TPGS synthesized according to standard methods, for reaction between polyethylene glycol and vitamin E Succi example, the method described in U.S. Pat. No. 2,680,749, US 2016/008 1976 A1 Mar. 24, 2016 26 results in a TPGS composition that is composed primarily of and between or between about 13 wt % and 95 wt % dimer, TPGS monomer (70-87%) and a small amount of TPGS such as water-soluble vitamin E derivative mixtures (compo dimer (<12%) (US Pharmacopeia 23 (1998) Supp. 9:4712; sitions) containing between or about between 40 wt % and 60 Scientific Panel of the European Food Safety Authority wt % monomer and between or about between 25 wt % and 60 (2007) EFSA.J. 490:1-20). Because the separation of TPGS wt % dimer, such as 29% to 55%, 35% to 50% or 30% to 45%, monomer and TPGS dimer is difficult and because TPGS dimer. Advantageous properties are exhibited by composi monomer is considered the effective component of TPGS, tions that contain at least these amounts. TPGS compositions containing primarily TPGS dimer have 0318. In the water-soluble vitamin E derivative mixtures not been developed (Kong et al. (2011) J. Chromatography A (compositions) described herein, the total amount of mono 1218:8664-8671). TPGS dimer, shown below, is usually con meras a percentage (%), by weight, of the composition (wt sidered an unwanted byproduct of the esterification reaction %) can be, e.g., between or between about 25 wt % and 69 wit between PEG and vitamin E succinate, formed due to the % monomer, inclusive, such as between or between about equal reactivity of both terminal hydroxyl groups of the PEG 25% and 30%, 25% and 35%, 25% and 40%, 25% and 45%, moiety. 25% and 50%, 25% and 55%, 25% and 60%, 25% and 65%,

O

TPGS monomer

O

TPGS dimer

0316 5. Water-Soluble Vitamin E Derivative Mixtures 25% and 69%, 30% and 35%, 30% and 40%, 30% and 45%, (Compositions) 30% and 50%, 30% and 55%, 30% and 60%, 30% and 65%, 0317 Described herein are water-soluble vitamin E 30% and 69%, 35% and 40%, 35% and 45%, 35% and 50%, derivative mixtures (compositions), for example, TPGS com 35% and 55%, 35% and 60%, 35% and 65%, 35% and 69%, positions, that contain varying amounts of monomer and 40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%, dimer, particularly compositions that contain less monomer 40% and 65%, 40% and 69%, 45% and 50%, 45% and 55%, than is found in typical, known water-soluble vitamin E 45% and 60%, 45% and 65%, 45% and 69%, 50% and 55%, derivative mixtures (compositions), for example, less than 70 50% and 60%, 50% and 65%, 50% and 69%, 55% and 60%, wt % monomer, and more dimer, i.e., greater than 12 wt % 55% and 65%, 55% and 69%, 60% and 65%, 60% and 69%, dimer, than in typical, known water-soluble vitamin Ederiva and 65% and 69% monomer, by weight, of the composition. tive mixtures (compositions), for example, known TPGS Generally, the compositions contain less than 69 wt % mono compositions. For example, the water-soluble vitamin E mer. For example, the water-soluble vitamin E derivative derivative mixtures (compositions) described herein can con mixtures (compositions) described herein contain at least or tain between or between about 25 wt % and 69 wt % monomer about at least 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, US 2016/008 1976 A1 Mar. 24, 2016 27

41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, greater than 12 wt % dimer allow for the addition of a higher 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, concentration of non-polar ingredients when used in the com 61%. 62%, 63%, 64%, 65%, 66%, 67%, 68%, but less than positions provided herein, including the powders, soft gel 69% (wt %), total monomer. compositions, aqueous food and beverage products as com 0319. In the water-soluble vitamin E derivative mixtures pared to available aqueous food and beverage products, while (compositions) described herein, the total amount of dimeras maintaining clarity and Stability, for example, exhibiting a percentage (%), by weight, of the composition (wt %) can decreased turbidity values. be, e.g., between or between about 13 wt % and 95 wt % 0321 Exemplary of the compositions described herein are dimer, inclusive, such as between or between about 13% and TPGS compositions containing less than 70 wt % TPGS 20%, 13% and 25%, 13% and 30%, 13% and 35%, 13% and monomer and more than 12 wt % TPGS dimer, such as 40%, 13% and 45%, 13% and 50%, 13% and 55%, 13% and compositions containing between or about between 25 wt % 60%, 13% and 65%, 13% and 70%, 13% and 75%, 13% and and 69 wt % TPGS monomer and between or about between 80%, 13% and 85%, 13% and 90%, 13% and 95%, 20% and 13 wt % and 95 wt % TPGS dimer, such as TPGS composi 25%, 20% and 30%, 20% and 35%, 20% and 40%, 20% and tions containing between or about between 40 wt % and 60 wt 45%, 20% and 50%, 20% and 55%, 20% and 60%, 20% and % TPGS monomer and between or about between 25 wt % 65%, 20% and 70%, 20% and 75%, 20% and 80%, 20% and and 60 wt % TPGS dimer, are described herein. The compo 85%, 20% and 90%, 20% and 95%, 25% and 30%, 25% and sitions described herein containing less than 70 wt % TPGS 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and monomer and greater than 12 wt % TPGS dimer exhibit 55%, 25% and 60%, 25% and 65%, 25% and 70%, 25% and decreased turbidity values when dissolved, for example, 75%, 25% and 80%, 25% and 85%, 25% and 90%, 25% and when dissolved in water, as compared to typical, known 95%, 30% and 35%, 30% and 40%, 30% and 45%, 30% and TPGS compositions, i.e., TPGS compositions that contain 50%, 30% and 55%, 30% and 60%, 30% and 65%, 30% and more than 70 wt % TPGS monomer and less than 12 wt % 70%, 30% and 75%, 30% and 80%, 30% and 85%, 30% and TPGS dimer. The TPGS compositions described herein allow 90%, 30% and 95%, 35% and 40%, 35% and 45%, 35% and for the addition of a higher concentration of non-polar ingre 50%, 35% and 55%, 35% and 60%, 35% and 65%, 35% and dients when used in aqueous food and beverage products as 70%, 35% and 75%, 35% and 80%, 35% and 85%, 35% and compared to available aqueous food and beverage products, 90%, 35% and 95%, 40% and 45%, 40% and 50%, 40% and while maintaining clarity and stability, for example, exhibit 55%, 40% and 60%, 40% and 65%, 40% and 70%, 40% and ing decreased turbidity values. 75%, 40% and 80%, 40% and 85%, 40% and 90%, 40% and 0322 The water-soluble vitamin E derivative mixtures 95%, 45% and 50%, 45% and 55%, 45% and 60%, 45% and (compositions), e.g., TPGS compositions, described herein 65%, 45% and 70%, 45% and 75%, 45% and 80%, 45% and contain a mixture of monomer and dimer, e.g., a mixture of 85%, 45% and 90%, 45% and 95%, 50% and 55%, 50% and TPGS monomer and TPGS dimer. The monomer, for 60%, 50% and 65%, 50% and 70%, 50% and 75%, 50% and example, a TPGS monomer, can be present in an amount that 80%, 50% and 85%, 50% and 90%, 50% and 95%, 55% and is less than what is typically found in known water-soluble 60%, 55% and 65%, 55% and 70%, 55% and 75%, 55% and Vitamin E derivative mixtures (compositions), e.g., known 80%, 55% and 85%, 55% and 90%, 55% and 95%, 60% and TPGS compositions, i.e., less than 70 wt % monomer. The 65%, 60% and 70%, 60% and 75%, 60% and 80%, 60% and dimer, for example, a TPGS dimer, can be present in an 85%, 60% and 90%, 60% and 95%, 65% and 70%. 65% and amount that is greater than what is typically found in known 75%, 65% and 80%, 65% and 85%, 65% and 90%. 65% and water-soluble vitamin E derivative mixtures (compositions), 95%, 70% to 75%, 70% and 80%, 70% and 85%, 70% and e.g., known TPGS compositions, i.e., greater than 12 wt % 90%, 70% and 95%, 75% and 80%, 75% and 85%, 75% and dimer. The water-soluble vitamin Ederivative mixtures (com 90%, 75% and 95%, 80% and 85%, 80% and 90%, 80% and positions), such as the TPGS compositions, described herein 95%, 85% and 90%, 85% and 95% and 90% and 95% dimer, can also contain other components, such as, for example, by weight, of the composition. Generally, the compositions unreacted PEG, unreacted vitamin E. e.g., D-O-tocopheryl contain less than 95 wt % dimer. For example, the water Succinate, and one or more catalysts. soluble vitamin E derivative mixtures (compositions) 0323 Methods for preparing the water-soluble vitamin E described herein contain at least or about at least 13%, 15%, derivative mixtures (compositions), such as the TPGS com 20%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, positions described herein, are described herein, for example, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, methods of preparing water-soluble vitamin E derivative 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, compositions. Such as TPGS compositions, that contain less 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, than 70 wt % TPGS monomer and more than 12 wt % TPGS 64%. 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, dimer. Existing methods for preparing derivatives of vitamin 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, E can be employed, except that the methods are modified to 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, produce higher concentrations of the dimer form by modify 94%, but less than 95% (wt %) total dimer. ing reaction conditions. Such modifications can be deter 0320. The compositions described herein containing less mined empirically if needed. Such as by varying reaction than 70 wt % monomer and greater than 12 wt % dimer parameters, such as time, temperature and reactant concen exhibit decreased turbidity values when dissolved in an aque trations, to identify conditions that favor higher levels of ous solution, for example, when dissolved in water, as com dimer production. pared to typical, known water-soluble vitamin E derivative 0324. The water-soluble vitamin E derivative mixtures mixtures (compositions), i.e., water-soluble vitamin Ederiva e.g., TPGS monomer-dimer mixtures, prepared according to tive mixtures (compositions) that contain more than 70 wt % the methods, can contain between or about between 25 wt % monomer and less than 12 wt % dimer. The compositions and 69 wt % monomer, for example, at or about 25, 26, 27, 28. described herein containing less than 70 wt % monomer and 29, 30, 31, 32,33,34, 35,36, 37,38, 39, 40, 41,42, 43,44, 45, US 2016/008 1976 A1 Mar. 24, 2016 28

46,47, 48,49, 50, 51, 52,53,54, 55,56, 57,58, 59, 60, 61, 62, and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% 63, 64, 65, 66, 67, 68 or 69 wt % monomer and between or and 50%, 15% and 55%, 15% and 60%, 15% and 65%, 15% about between 13 wt % and 95 wt % dimer, for example, at or and 70%, 20% and 25%, 20% and 30%, 20% and 35%, 20% about 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 40%, 20% and 45%, 20% and 50%, 20% and 55%, 20% 28, 29, 30, 31, 32,33, 34,35,36, 37,38, 39, 40, 41,42, 43,44, and 60%, 20% and 65%, 20% and 70%, 20% and 75%, 25% 45, 46,47, 48,49, 50, 51, 52,53,54, 55,56, 57,58, 59, 60, 61, and 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% 62,63,64, 65,66, 67,68, 69,70, 71,72, 73,74, 75,76, 77,78, and 50%, 25% and 55%, 25% and 60%, 25% and 65%, 25% 89, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90,91, 92,93, 94 or and 70%, 25% and 75%, 30% and 35%, 30% and 40%, 30% 95 wt % dimer. and 45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% 0325 Exemplary of the water-soluble vitamin Ederivative and 65%, 30% and 70%, 30% and 75%, 35% and 40%, 35% mixtures (compositions) described herein that contain a mix and 45%, 35% and 50%, 35% and 55%, 35% and 60%, 35% ture of monomerand dimer, for example, TPGS compositions and 65%, 35% and 70%, 35% and 75%, 40% and 45%, 40% that contain a mixture of TPGS monomer and TPGS dimer, and 50%, 40% and 55%, 40% and 60%, 40% and 65%, 40% are compositions that contain between or about between 25 and 70%, 40% and 75%, 45% and 50%, 45% and 55%, 45% wt % and 69 wt % monomer and between or about between 13 and 60%, 45% and 65%, 45% and 70%, 45% and 75%, 50% wt % and 95 wt %, such as 29% to 55%, dimer. For example, and 55%, 50% and 60%, 50% and 65%, 50% and 69%, 55% the water-soluble vitamin Ederivative mixtures can contain at and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 60% or about at least 39.35 wt % monomer and at or about at least and 65%, 60% and 70%, 60% and 75%, 65% and 70%, 65% 35.56 wt % dimer; at or about 40.39 wt % monomer and at or and 75% and 70% and 75% non-polar ingredient, by weight, about 54.90 wt % dimer; at or about 40.95 wt % monomerand of the food or beverage product. Generally, the products con at or about 53.15 wt % dimer; at or about 42.76 wt % mono tain less than 75 wt % non-polar ingredient. For example, the merandator about 51.10 wt % dimer; at or about 43.52 wt % food and beverage products containing the water-soluble monomerandator about 49.80 wt % dimer; at or about 43.90 Vitamin E derivative mixture, including the concentrates, pro wt % monomer and at or about 53.90 wt % dimer; at or about vided herein contain at least or about at least 1%. 5%, 10%, 52.92 wt % monomer and at or about 33.70 wt % dimer; at or 15%, 20%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, about 55.88wt % monomerandator about 29.27 wt % dimer; 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, at or about 57.70 wt % monomer and at or about 40.40 wt % 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, dimer; at or about 60.00 wt % monomer and at or about 38.10 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, wt % dimer; and at or about 70.90 wt % monomer and at or 63%, 64%. 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, about 28.65 wt % dimer. Thus, described herein are water 73%, 74%, but less than 75% (wt %) total non-polar ingredi soluble vitamin Ederivative mixtures (compositions). Such as ent. TPGS compositions, that contain less monomer, i.e., less than 70 wt % monomer, such as between 25 wt % and 69 wt % C. METHODS FOR MAKING WATER-SOLUBLE monomer, and more dimer, i.e., more than 12 wt % dimer, VITAMINEDERIVATIVES such as between 13 wt % and 95% dimer, than typical com 0328. The water-soluble vitamin E derivative mixtures mercial TPGS compositions. (compositions) with higher amounts of dimer can be prepared 0326. The concentrates containing water-soluble vitamin by modification of methods that compositions with higher E derivative mixtures, such as tocopheryl polyalkylene glycol amounts of monomer and lower amounts of dimer are pre derivative compositions, including TPGS compositions, pared by, appropriately varying reaction conditions to favor described herein, allow for the solubilization of higher increased dimer formation. Alternatively, standard known amounts of non-polar ingredients, such as non-polar ingredi methods can be employed and the dimers purified or partially ents that are or contain non-polar compounds, in foods and purified and added to compositions to increase the percentage beverages, particularly aqueous beverages to which the con of dimer to a desired level. centrate is added. Provided herein are powders, softgel com 0329. For example, for production of compositions with positions, pre-gel compositions, pre-emulsion concentrates, higher amounts of TPGS dimer, the methods employ the use liquid nanoemulsion concentrates and liquid dilution compo of vitamin E Succinate, e.g., D-C-tocopheryl Succinate, as a sitions, capsules, tablets and beverage compositions that con starting material. Methods that use vitamin E, e.g., tocopherol tain the high dimer-containing water-soluble vitamin E or tocotrienol, and Succinic acid or Succinic anhydride as the derivative mixtures (compositions) described herein. starting materials (to synthesize vitamin E Succinate) also can 0327. For example, these concentrates allow for the addi be used to prepare the water-soluble vitamin E derivative tion of non-polar ingredients that are or contain non-polar mixtures (compositions) described herein. The methods can compounds to products Suitable for human consumption in be adapted for production of any desired water-soluble vita amounts between or between about 1 wt % and 75 wt %, such min E derivative composition that contains the higher as between or between about 1% and 5%, 1% and 10%, 1% amounts of dimer. and 15%, 1% and 20%, 1% and 25%, 1% and 30%, 1% and 0330. As noted, these water-soluble vitamin E derivative 35%, 1% and 40%, 1% and 45%, 1% and 50%, 1% and 55%, mixtures (compositions) exhibit decreased turbidity values as 1% and 60%, 1% and 65%, 1% and 70%, 1% and 75%, 5% compared to known water-soluble vitamin E derivative mix and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and tures (compositions). Such as known TPGS compositions, 30%, 5% and 35%, 5% and 40%, 5% and 45%, 5% and 50%, when dissolved, such as, for example, when dissolved in 5% and 55%, 5% and 60%, 5% and 65%, 5% and 70%, 5% water or other aqueous beverages. Thus, the described meth and 75%, 10% and 15%, 10% and 20%, 10% and 25%, 10% ods are advantageous over existing prior art methods of pre and 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% paring TPGS compositions that exhibit high turbidity values, and 50%, 10% and 55%, 10% and 60%, 10% and 65%, 10% e.g., higher than 80 NTUs, when dissolved, such as when and 70%, 10% and 75%, 15% and 20%, 15% and 25%, 15% dissolved in water. US 2016/008 1976 A1 Mar. 24, 2016 29

0331 Water-soluble vitamin Ederivatives, such as TPGS, 0337. In the methods, the total amount of vitamin E suc can be prepared by esterifying vitamin E Succinate, for cinate in the reaction mixture as a percentage (%), by weight, example, D-O-tocopheryl acid Succinate, with polyethylene of the reaction mixture (wt %) can be, e.g., from at or about glycol. The resulting vitamin ETPGS has a chemical formula 0.1% to at or about 15%, such as 0.1% to 1%, 0.1% to 3%, of COHs (CH2CH2O), where “n” represents the number 0.1% to 5%, 0.1% to 10%, 0.1% to 15%, 0.5% to 1%, 0.5% to of polyethylene oxide moieties attached to the acid group of 3%, 0.5% to 5%, 0.5% to 10%, 0.5% to 15%, 1% to 3%, 1% the vitamin E Succinate. In an exemplary embodiment, the to 5%, 1% to 10%, 1% to 15%, 3% to 5%, 3% to 10%, 3% to method includes preparing a crude water-soluble vitamin E, 15%. 5% to 10%, 5% to 15%, or 10% to 15%, by weight, of e.g., TPGS, composition by first preparing a reaction mixture the reaction mixture. Generally, the reaction mixtures contain containing vitamin E Succinate, a polyethylene glycol (PEG), less than 15 wt % vitamin E succinate. For example, the and optionally, a catalyst, in a solvent, and heating the reac reaction mixtures described herein contain up to at or about tion mixture to an elevated temperature to produce a crude 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, water-soluble vitamin E, e.g., TPGS, composition containing 13%, 14% or 15% vitamin E succinate. Generally, the reac less TPGS monomer and more TPGS dimer than what is tion mixtures described herein contain less than 15% (wt %) typically found in known TPGS compositions, i.e., less than total vitamin E Succinate. 70 wt %TPGS monomer and more than 12 wt %TPGS dimer. 0338 b. Polyethylene Glycol The crude water-soluble vitamin E, e.g., TPGS, composition 0339. In the methods, the reaction mixtures include any then can be purified and concentrated to obtain a purified polyethylene glycol that can react with the acid moiety of water-soluble vitamin E, e.g., TPGS, composition containing Vitamin E Succinate to form an ester. The polyethylene glycol less TPGS monomer and more TPGS dimer than what is can include, for example, any polyethylene glycol that gives typically found in known TPGS compositions, i.e., less than the desired molecular weight of the water-soluble vitamin E 70 wt %TPGS monomer and more than 12 wt %TPGS dimer. compound, the desired polyethylene glycol chain length of Any purification process known in the art can be used to the water-soluble vitamin E compound or the desired amount purify the reaction product. of water-soluble vitamin E water-solubility. The polyethylene 0332 1. Reaction Mixture glycol in the reaction mixtures of the methods can include, for 0333. The methods include preparing a crude water example, any polyethylene glycol that is capable of forming soluble vitamin E derivative mixture, such as a crude TPGS an ester when reacted with vitamin E Succinate to produce a composition, by esterifying vitamin E Succinate with poly vitamin E derivative that is water-soluble. For example, the ethylene glycol in a solvent. The esterification procedure can polyethylene glycol can include PEG-OH, PEG-SH, PEG be promoted by a catalyst, for example, an esterification NH and branched PEGs. Typically, the polyethylene glycol catalyst. In the methods, the crude composition can be pre is PEG-OH. The resulting water-soluble vitamin E product, pared from a reaction mixture containing vitamin E Succinate, for example, TPGS, formed by the reaction between vitamin a polyethylene glycol (PEG), a solvent, and optionally, a E. Succinate and a polyethylene glycol contains at least poly catalyst. The components of the reaction mixture can be ethylene glycol esters of vitamin E Succinate. The esters can added in any order. In an exemplary embodiment, the poly be a mixture of esters, such as a mixture of TPGS monomer ethylene glycol is dissolved in the solvent before the addition and TPGS dimer. of vitamin E Succinate and the catalyst. 0340. The polyethylene glycols in the reaction mixtures of 0334. The methods produce a crude water-soluble vitamin the methods can be any molecular weight, for example, any E derivative mixture, such as a crude TPGS composition, that molecular weight that renders vitamin E Succinate water contains less TPGS monomer and more TPGS dimer than soluble after esterification with the polyethylene glycol (i.e., what is typically found in known TPGS compositions, i.e., the resulting TPGS is water-soluble). Such polyethylene gly less than 70 wt % TPGS monomer and more than 12 wt % cols are known in the art and can be purchased from Suppliers TPGS dimer. In some instances, the crude TPGS composition such as Sigma-Aldrich (St. Louis, Mo.), Fisher Scientific contains between or between about 25 wt % and 69 wt % (Fair Lawn, N.J.), and VWR International (Radnor, Pa.). The TPGS monomer and between or between about 13 wt % and polyethylene glycol can be added to the reaction mixture by 95 wt %TPGS dimer, such as between or between about 40 wit any method suitable for transferring the PEG to the reaction % and 60 wt % TPGS monomer and between or between mixture. For example, the PEG can be transferred to the about 25 wt % and 60 wt % TPGS dimer. reaction mixture in molten form. 0335) a. Vitamin E Succinate 0341 Suitable polyethylene glycols for use in the methods 0336. The reaction mixtures of the methods contain vita include polyethylene glycols having an average molecular min ESuccinate, for example, D-C-tocopheryl Succinate. Vita weight ranging from between or between about 100 Daltons min E Succinate can be purchased from Suppliers such as (Da) and 20,000 Da. For example, the average molecular Sigma-Aldrich (St. Louis, Mo.), Parchem (New Rochelle, weight can be between or between about 200 Da and 10,000 N.Y.), Fisher Scientific (Fair Lawn, N.J.), and VWR Interna Da, or 400 Da and 5,000 Da, or 500 Da and 1500 Da, or 750 tional (Radnor, Pa.), or can be synthesized according to meth Da and 1200 Da, or 1000 Da and 2,500 Da. Generally, the ods known to those of skill in the art. Typically, vitamin E molecular weight of the polyethylene glycol is less than Succinate can be synthesized by reacting vitamin E (i.e., 20,000 Da. For example, the average molecular weight of the D-O-tocopherol) with Succinic anhydride in a solvent (e.g., polyethylene glycol used in the reaction mixtures described toluene) in the presence of a base (e.g., triethylamine) (see, herein can be or can be about 100, 200, 238, 300, 400, 500, for example, U.S. Patent Pub. Nos. 2011/0130562 and 2011/ 600, 750, 800, 1000, 1200, 1500, 2000, 2500, 3000, 3400, 0184194; Lipshutz et al. (2011) J. Org. Chem. 76(11):4379 3500, 4000, 6000, 8000, 10,000, or 12,000 Da, but less than 4391; Gelo-Pujic et al. (2008) Int. J. Cosmet. Sci. 30(3):195 20,000 Da. 204; and Vraka et al. (2006) Bioorg. Med. Chem. 14(8):2684 0342 Exemplary polyethylene glycols include PEG 100 2696). (where 100 represents the PEG chain molecular weight), PEG US 2016/008 1976 A1 Mar. 24, 2016 30

200, PEG 238, PEG 300, PEG 400, PEG 500, PEG 600, PEG 0349 Suitable solvents used in the methods include sol 750, PEG 800, PEG 1000, PEG 1200, PEG 1500, PEG 2000, vents that are inert to the reaction and are aprotic, for example, PEG 2500, PEG 3000, PEG 3400, PEG 3500, PEG 4000, Solvents that lack an acidic hydrogen, Such as toluene, PEG 6000, PEG 8000, PEG 10,000, PEG 12,000 or PEG xylenes, ethers such as tetrahydrofuran (THF), diethyl ether 20,000. Any other suitable polyethylene glycol known to and dioxane, ethyl acetate, acetone, dimethylformamide those of skill in the art also can be used in the methods. In (DMF), N,N-dimethylacetamide, acetonitrile, methyl ethyl Some embodiments described herein, the polyethylene glycol ketone (MEK), methyl isobutyl ketone (MIBK), dimethyl is PEG 1 OOO. sulfoxide (DMSO), ethyleneglycol dimethylether, hexanes, 0343. In the methods, the total amount of PEG in the cyclohexane, pentane, cyclopentane and any combination reaction mixture as a percentage (%), by weight, of the reac thereof. An exemplary Solvent used in the reaction mixtures tion mixture (wt %) can be, e.g., from at or about 1% to at or of the methods is toluene. about 50%, such as 1% to 5%, 5% to 10%, 5% to 15%, 5% to 0350. In the reaction mixtures of the methods, the total 20%, 5% to 25%, 5% to 30%, 5% to 35%, 5% to 40%, 5% to amount of Solvent as a percentage (%), by weight, of the 45%, 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, reaction mixture (wt %) can be, e.g., from at or about 60% to 10% to 35%, 10% to 40%, 10% to 45%, 10% to 50%, 15% to at or about 95%, such as 60% to 65%, 60% to 70%, 60% to 20%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to 40%, 75%, 60% to 80%, 60% to 85%, 60% to 90%, 60% to 95%, 15% to 45%, 15% to 50%, 20% to 25%, 20% to 30%, 20% to 65% to 70%, 65% to 75%, 65% to 80%, 65% to 85%, 65% to 40%, 20% to 50%, 25% to 50%, or 30% to 50%, by weight, of 90%. 65% to 95%, 70% to 75%, 70% to 80%, 70% to 85%, the reaction mixture. Generally, the reaction mixtures contain 70% to 90%, 70% to 95%, 75% to 80%, 75% to 85%, 75% to less than 50 wt % PEG For example, the reaction mixtures 90%, 75% to 95%, 80% to 85%, 80% to 90%, 80% to 95%, described herein contain at least or about at least 1%, 2%,3%, 85% to 90%, 85% to 95% and 90% to 95%, by weight, of the 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, reaction mixture. Generally, the reaction mixtures contain 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, less than 95 wt % solvent. For example, the reaction mixtures 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, can contain at least or about at least 60%, 65%, 70%, 75%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 80%, 85%, 90%, but less than 95% (wt %) total solvent. 46%, 47%, 48%, 49%, but less than 50% (wt %) total PEG. 0351). e. Exemplary Reaction Mixtures 0344 c. Catalyst 0352 Exemplary reaction mixtures that can be used in the 0345 The reaction mixtures of the methods can optionally methods to ultimately produce a water-soluble vitamin E contain a catalyst. Suitable catalysts include those catalysts derivative mixture, for example, a TPGS composition, that that can be used to promote the esterification reaction contains less TPGS monomer and more TPGS dimer than between the PEG and the acid moiety of vitamin E succinate. what is typically manufactured, i.e., less than 70 wt % TPGS Exemplary catalysts include acidic catalysts, such as p-tolu monomer and more than 12 wt %TPGS dimer, are described. enesulfonic acid, oxalic acid, hydrochloric acid, tricholora They are exemplified with TPGS, but similar reaction mix cetic acid, and any other known catalyst that can promote tures can be prepared and reactions performed to produce esterification. tocopherol sebacate polyethylene glycol, tocopherol dode 0346. In the reaction mixtures of the methods, the total canodioate polyethylene glycol, tocopherol Suberate polyeth amount of catalyst, as a percentage (%), by weight, of the ylene glycol, tocopherol azelaate polyethylene glycol, toco reaction mixture (wt %) can be, e.g., from at or about 0% to at pherol citraconate polyethylene glycol, tocopherol or about 15%, such as 0.01% to 0.05%, 0.01% to 0.1%, 0.01% methylcitraconate polyethylene glycol, tocopherol itaconate to 0.5%, 0.01% to 0.75%, 0.01% to 1%, 0.01% to 3%, 0.01% polyethylene glycol, tocopherol maleate polyethylene glycol, to 5%, 0.01% to 10%, 0.01% to 15%, 0.01% to 0.5%, 0.01% tocopherol glutarate polyethylene glycol, tocopherol gluta to 0.75%, 0.01% to 1%, 0.01% to 3%, 0.01% to 5%, 0.01% to conate polyethylene glycol and tocopherol phthalate polyeth 10%, 0.01% to 15%, 0.05% to 0.1%, 0.05% to 0.5%, 0.05% to ylene glycol, TPGS analogs and TPGS homologs. 0.75%, 0.05% to 1%, 0.05% to 3%, 0.05% to 5%, 0.05% to 0353. The reaction mixtures exemplified herein include 10%, 0.05% to 15%, 0.05% to 0.5%, 0.05% to 0.75%, 0.05% Vitamin E Succinate, a polyethylene glycol, a solvent, and to 1%, 0.05% to 3%, 0.05% to 5%, 0.05% to 10%, 0.05% to optionally, a catalyst. Exemplary of Such reaction mixtures 15%, 0.1% to 0.5%, 0.1% to 0.75%, 0.1% to 1%, 0.1% to 3%, contain from at or about 0.1 wt % to at or about 15 wt % of 0.1% to 5%, 0.1% to 10%, 0.1% to 15%, 0.5% to 0.75%, 0.5% Vitamin E Succinate; a polyethylene glycol, in an amount to 1%, 0.5% to 3%, 0.5% to 5%, 0.5% to 10%, 0.5% to 15%, from at or about 1 wt % to at or about 50 wt %; a catalyst, in 1% to 3%, 1% to 5%, 1% to 10%, 1% to 15%, 3% to 5%, 3% an amount from at or about 0.01 wt % to at or about 15 wt %; to 10%, 3% to 15%. 5% to 10%, 5% to 15%, 10% to 15%, by and from at or about 60% to at or about 95% of a solvent. weight, of the reaction mixture. Generally, the reaction mix 0354. In some embodiments, the polyethylene glycol can tures contain less than 15 wt % catalyst. For example, the be a polyethylene glycol with a molecular weight of around reaction mixtures described herein can contain up to at or 1000 Da, for example, PEG 1000. For example, the exem about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, plary reaction mixtures described herein can contain from at 12%, 13%, 14% or 15% catalyst, based on the weight of the or about 0.1 wt % to at or about 15 wt % of vitamin E reaction mixture. succinate; from at or about 1 wt % to at or about 50 wt % of 0347 d. Solvent a polyethylene glycol, for example, PEG 1000; from at or 0348. The reaction mixtures of the methods include a sol about 0.01 wt % to at or about 15 wt % of a catalyst, for vent or combination of solvents. Suitable solvents include example, p-toluenesulfonic acid; and from at or about 60% to those that do not prevent the esterification reaction between at or about 95% of a solvent, for example, toluene. the PEG and acid moiety of vitamin E succinate from taking 0355 2. Exemplary Methods place. For example, the solvent or combination of solvents 0356. The methods include preparing a reaction mixture can be aprotic solvents. containing vitamin E Succinate, a polyethylene glycol and US 2016/008 1976 A1 Mar. 24, 2016

optionally, a catalyst, in a solvent; heating the reaction mix can be at least at or about 1 hour, at least at or about 1.5 hours, ture to a temperature equal to or higher than the boiling point at least at or about 2 hours, at least at or about 2.5 hours, at of the solvent to form a crude water-soluble vitamin Ederiva least at or about 3 hours, at least at or about 3.5 hours, at least tive mixture; processing the reaction mixture to obtain the at or about 4 hours, at least at or about 4.5 hours, at least at or crude water-soluble vitamin E derivative mixture; and puri about 5 hours, at least at or about 5.5 hours, at leastator about fying the crude water-soluble vitamin E derivative mixture to 6 hours, or at least at or about 6.5 hours, or longer, before obtain a purified water-soluble vitamin E derivative mixture. cooling. In particular, the methods use the exemplary reaction mix 0361. After the elevated temperature has been maintained tures described above. The methods to synthesize water for the desired amount of time, e.g., the amount of time soluble vitamin E derivative mixtures described herein result required to produce the desired amounts of TPGS monomer in water-soluble vitamin Ederivative mixtures, such as TPGS and TPGS dimer, the reaction mixture can be cooled to a compositions, that are less turbid than known water-soluble temperature lower than the elevated temperature. For Vitamin E derivative mixtures, i.e., known compositions that example, the reaction mixture can be cooled to room tem contain more than 70% TPGS monomer and less than 12% perature, i.e., at or about 20°C., after heating at an elevated TPGS dimer, when diluted in an aqueous medium, e.g., water. temperature for the desired amount of time. The reaction 0357 The following methods are exemplary only and pro mixture can be heated to at least or about at least 110° C. for vide a platform from which adjustments can be made. It is a total time of about 6.5 hours before cooling, e.g., to room understood that changes can be made to the steps of the temperature (i.e., at or about 20° C.), depending on the Sub method and to the reaction components while retaining some strates, solvent and formation of the crude water-soluble vita if not all of the desirable properties of the method. Further min E derivative mixture, for example, a crude TPGS com changes can be made by adding or altering steps or compo position, resulting in the desired amounts of TPGS monomer nents of each step. For example, the order in which the steps and TPGS dimer. One of skill in the art can perform the are performed can be changed. methods and, if necessary, empirically determine the appro 0358 a. Preparation of a Crude Water-Soluble Vitamin E priate reaction duration to produce the desired ratio of dimer Derivative Mixture to monomer, based on the formation of the desired amounts of 0359 Exemplary of the methods is preparation of a high TPGS monomer and TPGS dimer. dimer-containing mixture of TPGS. The methods can be 0362. In the methods, the reaction mixture can be heated employed to produce high dimer-containing mixtures of any from room temperature (i.e., at or about 20°C.) to an elevated vitamin Ederivative, including PEG derivatives of vitamin E. temperature of at least at or about 30°C., 40°C., 50° C., 60° Exemplary of the methods is a method of preparing a crude C., 70° C., 80° C., 90° C., 100° C. 1050 C. 110° C. 115° C., water-soluble vitamin E derivative mixture, for example, a 120° C. 125° C., 130° C., 140° C. 150° C., 1550 C., 160° C., crude TPGS composition, by providing a reaction mixture 1650 C. 170° C. 1759 C., 180° C., 1859 C., 190° C., 1950 C., containing vitamin E Succinate, e.g. D-C-tocopheryl Succi 200° C. 2050 C., 210°C., 2150 C., 220° C., 225° C. 23.0°C., nate, a polyethylene glycol, e.g., PEG 1000, a catalyst, e.g., 235° C. 240° C. 245° C. 250° C. 2550 C., 260° C. 265 C., p-toluenesulfonic acid, and a solvent, e.g., toluene, heating 270° C., 275° C., 280° C., 285°C.,290° C., 295 C., 300° C., the reaction mixture to a temperature of at least or about at or higher. The reaction mixture can be maintained at a tem least 110° C. and maintaining the elevated temperature for a perature elevated from room temperature for at least at or period of up to at or about 6.5 hours before cooling, for about 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, example, to room temperature, i.e., at or about 20° C., and 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or washing the reaction mixture with an aqueous solution of a longer before cooling. In an exemplary method, the reaction weak base, e.g., a 10% aqueous solution of sodium bicarbon mixture can be maintained at an elevated temperature for up ate. to at or about 6.5 hours before cooling, e.g., to room tempera 0360. A crude water-soluble vitamin E derivative mixture ture, i.e., at or about 20°C. The particular conditions depend is prepared by providing a reaction mixture containing Vita upon the particular vitamin E derivative and the amount of min E Succinate, a polyethylene glycol and optionally, a cata monomer and dimer desired. lyst, in a solvent and heating the reaction mixture from room 0363. The amount of time that the reaction mixture is temperature, i.e., at or about 20°C., to an elevated tempera maintained at the temperature elevated from room tempera ture, and maintaining the elevated temperature for a period of ture, for example, between or about between 30°C. and 300° time until a crude water-soluble vitamin Ederivative mixture, C. Such as the boiling point of the solvent in the reaction for example, a crude TPGS composition, is formed that con mixture, can be determined by monitoring the progress of tains the desired amounts of TPGS monomer and TPGS reaction during heating. For example, the reaction mixture dimer. The elevated temperature can be any temperature in can be monitored during heating to determine the amounts of the range of from 30°C. to about 300° C., generally between TPGS monomer and TPGS dimer present in the reaction 80° C. and 250° C., such as between 100° C. and 200°C. The mixture. The heating can then be terminated when the desired elevated temperature can be, for example, the boiling point of amounts of TPGS monomerandTPGS dimer are formed. The the solvent in the reaction mixture. A typical heating schedule monitoring can be done by any method of monitoring a reac can be heating the reaction mixture to a temperature of at least tion known to those of skill in the art, Such as by chromatog or about at least 110°C. with stirring, and once achieved, the raphy, spectroscopy or spectrometry. For example, the reac elevated temperature, e.g., at least or about at least 110°C., is tion can be monitored by thin layer chromatography (TLC), maintained for a total time of up to at or about 6.5 hours with high performance liquid chromatography (HPLC), infrared stirring. Other heating temperatures and times can be used spectroscopy (IR). Fourier transform infrared spectroscopy depending on the Substrates, solvent and formation of the (FTIR), mass spectrometry (MS), nuclear magnetic reso desired crude water-soluble vitamin Ederivative mixture. For nance (NMR) spectroscopy, or any combination thereof. In example, the total time the elevated temperature is maintained Some embodiments of the methods, the reaction progress is US 2016/008 1976 A1 Mar. 24, 2016 32 monitored by TLC. In other embodiments, the reaction E derivative mixture from the reaction mixture. For example, progress is monitored by HPLC. In yet other embodiments, the reaction mixture can be further processed by treating the the reaction progress is monitored by both TLC and HPLC. reaction mixture with an adsorbent, such as activated charcoal One of skill in the art, if necessary, can determine particular (i.e., activated carbon). Activated charcoal can be used as a parameters empirically, Such as appropriate reaction dura decolorizer and to remove impurities by chemical adsorption. tion, based on monitoring the formation of the desired Any activated charcoal knownto those of skill in the art can be amounts of vitamin Ederivative monomer and dimer, such as used to treat the reaction mixture. Such activated charcoal is TPGS monomer and TPGS dimer. available from commercial Sources under Such trade names as 0364. The reaction mixture of the methods can be heated Calgon-Type CPG(R), Type PCB(R, Type SGL(R), Type CAL(R), to an elevated temperature under an inert gas atmosphere, and Type OL(R). Such as a nitrogen gas or argon gas atmosphere, or under air. 0368. Further processing of the reaction mixture, for The reaction mixture of the methods can be heated to an example, treating the reaction mixture with activated char elevated temperature at atmospheric pressure or at an elevated coal, can take place for a period of time of from at or about 0.5 pressure, i.e., a pressure higher than atmospheric pressure. hours to at or about 5 hours, or longer if required. For The elevated pressure can be achieved, e.g., by performing example, treating the reaction mixture with activated charcoal the reaction in a closed vessel or in a vented vessel. can take place for at least or about at least 0.5 hours, 1 hour, 0365. The progress of the reaction can be terminated after 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, or longer. The heating for the desired amount of time, for example, up to at further processing, for example, treating the reaction mixture or about 6.5 hours, by cooling the reaction mixture, for with activated charcoal, can be done at any temperature of example, to room temperature, i.e., at or about 20° C. After from at or about room temperature, i.e., at or about 20°C., to cooling. Such as cooling to room temperature, i.e., at or about a temperature elevated from room temperature. For example, 20°C., the reaction mixture can be washed with an aqueous the temperature of the process, e.g., activated charcoal treat Solution. The aqueous Solution can be an aqueous Solution of ment, can beat or about 20°C., 30°C., 40°C., 50° C., 55°C., base. Such as a weak base, i.e., bases that do not fully ionize 60° C., 70° C., 80°C.,90° C., or 100° C., or any temperature in an aqueous solution. Suitable weak bases include, for between 20° C. and 100° C., such as between or about example, carbonates orbicarbonates, e.g., Sodium carbonate, between 55° C. and 60°C. The treatment temperatures and Sodium bicarbonate, potassium carbonate and potassium times can be varied depending on the reaction mixture, the bicarbonate; amines, ammonias or ammoniums, e.g., methyl Solvent, and the impurities present in the reaction mixture. In amine, methyl ethylamine, dimethylamine, aniline, ammo an exemplary process, such as an activated charcoal treatment nia, trimethyl ammonia and ammonium hydroxide; and pyri process, the reaction mixture can be treated, e.g., with activate dine. For example, the aqueous solution of base can be an charcoal, for at least or about at least 1 hour at a temperature aqueous Solution of Sodium bicarbonate. Suitable aqueous of between or about between 55° C. and 60°C., before cool Solutions of the weak base include solutions that contain, e.g., 1ng 1% to 20% weak base, such as at least or about 1%, 1.5%, 2%, 0369. In the methods, the reaction mixture can be filtered 2.5%, 3%, 3.5%, 4%, 4.5%. 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, and washed after cooling, Such as cooling to room tempera 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, ture, i.e., at or about 20°C., after further processing. Such as 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, after treating the reaction mixture with activated charcoal. 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, or more, weak base. The reaction mixture can be filtered and washed, for example, For example, the aqueous Solution can be an aqueous solution to remove the activated charcoal from the reaction mixture. containing at or about 10% sodium bicarbonate. After the For example, the reaction mixture can be filtered through a aqueous solution of a weak base has been added to the reac filter aid, such as diatomaceous earth. Suitable filter aids for tion mixture, the aqueous solution can be separated from the use in the methods include, for example, those sold under the reaction mixture, Such as by allowing the reaction mixture trademark Celite(R), such as those sold under the trademark and aqueous solution of weak base to separate into layers, and Hyflo. R. After filtering through a filter aid, such as diatoma removed. In some embodiments, the reaction mixture and ceous earth, the reaction mixture can be washed, for example, aqueous Solution of weak base can be stirred for a period of with the same solvent used in the reaction mixture. In an time before separating. For example, the reaction mixture and exemplary embodiment, after further processing, e.g., treat aqueous solution can be stirred for 1 minute, 2 minutes, 3 ment with activated charcoal, and cooling, e.g., to room tem minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 min perature, i.e., at or about 20° C., the reaction mixture is utes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, or more, filtered through diatomaceous earth, e.g., Hyflo R filter aid, before allowing the reaction mixture and aqueous Solution of and washed with solvent, e.g., toluene. weak base to separate into layers. 0370. In the methods, the reaction mixture can be further 0366 b. Processing the Reaction Mixture to Obtain a processed in order to isolate the crude water-soluble vitamin Crude Water-Soluble Vitamin E Derivative Mixture E derivative mixture from the reaction mixture. For example, 0367. After preparing the reaction mixture, the reaction the reaction mixture can be further processed by removing the mixture can be further processed in order to obtain a crude Solvent from the reaction mixture, i.e., concentrating the reac water-soluble vitamin E mixture, for example, a crude TPGS tion mixture, in order to obtain a crude water-soluble vitamin composition that contains less TPGS monomer, i.e., less than Ederivative mixture. Any method of removing a solvent from 70 wt %, and more TPGS dimer, i.e., more than 12 wt %, than a reaction mixture known to those of skill in the art can be known water-soluble vitamin E derivative mixtures. The fur used, including, for example, vacuum distillation, rotary ther processing can be performed to remove impurities from evaporation and filtration. Removing the solvent from the the reaction mixture before obtaining the crude water-soluble reaction mixture can be done at any temperature, for example vitamin E derivative mixture. The further processing can be at room temperature, i.e., 20°C., or at a temperature elevated performed in order to isolate the crude water-soluble vitamin from room temperature. For example, the Solvent can be US 2016/008 1976 A1 Mar. 24, 2016

removed at a temperature of at or about 20°C., 30°C., 40°C., 0374. The purification process, i.e., the wash, can be per 50° C., 55° C., 60° C., 70° C., 80° C., or 90° C., but below or formed by dissolving the crude water-soluble vitamin E about below 100° C., such as below or about below 60°C. In derivative mixture in a first solvent, for example, an organic an exemplary embodiment, the Solvent can be removed from Solvent, Such as a polar organic solvent. The polar organic the reaction mixture by distillation, e.g., vacuum distillation, solvent can be any solvent that can dissolve the crude water at a temperature elevated from room temperature, i.e., at or soluble vitamin E derivative mixture, such as a polar protic about 20° C., but below or about below 60° C. Solvent, for example, an alcohol, e.g., methanol, ethanol, 0371. Further processing of the reaction mixture of the propanol or butanol. In the methods, the amount of first sol methods can include further processing by treating the reac vent, e.g., polar organic Solvent, used to dissolve the crude tion mixture to remove impurities from the reaction mixture, water-soluble vitamin E derivative mixture can be based on Such as by treating the reaction mixture with activated char the ratio of the volume of the first solvent to the volume of the coal. Further processing of the reaction mixture of the meth crude water-soluble vitamin Ederivative mixture. The ratio of ods can include further processing by removing the solvent the volume of the first solvent to the volume of the crude from the reaction mixture. Such as by removing the solvent by water-soluble vitamin E derivative mixture can range from vacuum distillation. The further processing can include treat 0.1:1 to 10:1. In some embodiments, the ratio of the volume ing the reaction mixture with activated charcoal or removing of the first solvent to the volume of the crude TPGS compo the solvent from the reaction mixture or both. In an exemplary sition is or is about 0.1:1, 0.2:1, 0.25:1, 0.3:1, 0.4:1, 0.45:1, method, the further processing of the reaction mixture 0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1:1, 1.2:1, 1.25:1, includes removing the impurities from the reaction mixture, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.75:1, 1.8:1, 19:1, 2:1, 2.5:1, e.g., treating the reaction mixture with activated charcoal, and 3:1, 3.5:1, 3.6:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, removing the solvent from the reaction mixture, e.g., remov 8:1, 8.5:1, 9:1,9.5:1, or 10:1 or more. For example, the ratio ing the Solvent by vacuum distillation, in order to obtain a of the volume of the first solvent to the volume of the crude crude water-soluble vitamin E derivative mixture, for water-soluble vitamin E derivative mixture can be 2:1. example, a crude TPGS composition, containing less TPGS 0375. The wash can be performed using a second solvent, monomer, i.e., less than 70 wt %, and more TPGS dimer, i.e., for example, an organic solvent, that is not miscible with the more than 12 wt %, than in known TPGS compositions. first solvent, i.e., the solvent used to dissolve the crude water 0372 c. Purification of the Crude Water-Soluble Vitamin soluble vitamin E derivative mixture. The second solvent can E. Derivative Mixture to Obtain a Purified High Dimer-Con be any solvent that is not miscible with the first solvent, for taining Water-Soluble Vitamin E Derivative Mixture example, any solvent that is not miscible with a polar protic 0373 The crude water-soluble vitamin E derivative mix Solvent such as an alcohol. Suitable organic solvents that can ture obtained after further processing can be further purified be used as a second solvent include non-polar organic Sol in order to obtain a purified high dimer-containing water vents, such as hydrocarbons, e.g., alkanes and cycloalkanes, soluble vitamin E derivative mixture. For example, the puri Such as hexane and cyclohexane; halogenated hydrocarbons, fied water-soluble vitamin E derivative mixture can be a PEG e.g., chloroform and dichloromethane; ethers, e.g., diethyl derivative of vitamin E, such as TPGS, PTS, PTD and other ether; and aromatics, e.g., benzene and toluene. In the meth TPGS analogs and PEG derivatives of vitamin E, mixture. ods, the amount of second solvent, e.g., a non-polar organic The mixture contains less TPGS monomer, i.e., less than 70 solvent immiscible with the first solvent, used to wash the wt %, and more TPGS dimer, i.e., more than 12, 19, 24, 29 wit crude water-soluble vitamin Ederivative mixture dissolved in % dimer. The purification process removes impurities from the first solvent can be based on the ratio of the volume of the the crude water-soluble vitamin E derivative mixture, such as second solvent to the volume of the crude water-soluble vita impurities that were not removed by further processing of the min E derivative mixture. The ratio of the volume of the reaction mixture. For example, the crude water-soluble vita second solvent to the volume of the crude water-soluble vita min Ederivative mixture can be purified by performing one or min E derivative mixture can range from 0.1:1 to 10:1. In more wash, i.e., extraction, steps. The wash can be performed some embodiments, the ratio of the volume of second solvent using more than one solvent, such as more than one organic to the volume of crude water-soluble vitamin E derivative Solvent, for example, two organic solvents that are not mis mixture is or is about 0.1:1, 0.2:1, 0.25:1, 0.3:1, 0.4:1, 0.45:1, cible with each other. For example, in the methods, the crude 0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1:1, 1.2:1, 1.25:1, water-soluble vitamin E derivative mixture can be dissolved 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.75:1, 1.8:1, 19:1, 2:1, 2.5:1, in a first solvent, for example, a polar solvent, such as an 3:1, 3.5:1, 3.6:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, alcohol, and can be washed with a second solvent, for 8:1, 8.5:1, 9:1,9.5:1, or 10:1 or more. For example, the ratio example, a non-polar solvent, such as a hydrocarbon Solvent of the volume of the second solvent to the volume of the crude that is not miscible with the first solvent. The purification water-soluble vitamin E derivative mixture can be 3:1. process, e.g., the wash, can be performed one time, two times, 0376. The purification process of the methods, for three times, four times, or more, depending on the desired example, a wash with organic solvent, can be performed one purity level of the water-soluble vitamin E derivative mixture or more times on the crude water-soluble vitamin Ederivative and the amount of impurities present. For example, the puri mixture, for example, two times, three times, four times, or fication process, e.g., the wash, can be performed one or more more. The wash can be performed while stirring. In an exem times on the crude water-soluble vitamin E derivative mix plary method, the crude water-soluble vitamin E derivative ture, e.g., after the crude water-soluble vitamin E derivative mixture can be dissolved in a first solvent, for example, a mixture is obtained after processing. In an exemplary method, protic polar organic solvent, e.g., an alcohol, and washed the purification process can be performed three or more times three or more times with a second solvent, for example, a on the crude water-soluble vitamin E derivative mixture after non-polar organic solvent not miscible in the first solvent, the further processing is complete. e.g., a hydrocarbon. US 2016/008 1976 A1 Mar. 24, 2016 34

0377 Exemplary of the methods is a method of purifying of from at or about room temperature, i.e., at or about 20°C., a crude water-soluble vitamin E derivative mixture by per to a temperature elevated from room temperature. For formingapurification process, such as a wash with an organic example, the temperature of the purification process, e.g., Solvent, e.g., by dissolving the crude water-soluble vitamin E activated charcoal treatment, can beator about 20°C.,30°C., derivative mixture in methanol and washing with cyclohex 40° C., 50° C., 550 C, 60° C., 70° C., 80° C. 90° C., or 100° ane, and repeating the wash with the cyclohexane three or C., or any temperature between 20° C. and 100° C., such as more times. between or about between 55° C. and 60° C. The treatment 0378. The crude water-soluble vitamin E derivative mix temperatures and times can be varied depending on the nature ture can be further purified in order to obtain a purified water of the crude water-soluble vitamin E derivative mixture, the soluble vitamin E derivative mixture, for example, a purified solvent, and the impurities present in the crude water-soluble TPGS composition. The purified water-soluble vitamin E Vitamin E derivative mixture. In an exemplary purification derivative mixture can be a purified TPGS composition that process, such as an activated charcoal treatment process, the contains less TPGS monomer, i.e., less than 70 wt %, and crude water-soluble vitamin E derivative mixture can be more TPGS dimer, i.e., more than 12 wt %, thanknown TPGS treated, e.g., with activate charcoal, for at least or about at compositions. The further purification can be performed to least 1 hour at a temperature of between or about between 55° remove impurities from the crude water-soluble vitamin E C. and 60° C., before cooling. derivative mixture. The further purification can be performed 0381. In the methods, the crude water-soluble vitamin E in order to isolate the purified water-soluble vitamin Ederiva derivative mixture can be filtered and washed after cooling, tive mixture from the first solvent. For example, the crude Such as cooling to room temperature, i.e., at or about 20°C., water-soluble vitamin E derivative mixture can be further after further purification, such as after treating the crude purified by treating the crude water-soluble vitamin E deriva water-soluble vitamin E derivative mixture with activated tive mixture with an adsorbent, such as activated charcoal charcoal. The crude water-soluble vitamin E derivative mix (i.e., activated carbon). Activated charcoal can be used as a ture, for example, the crude water-soluble vitamin E deriva decolorizer and to remove impurities by chemical adsorption. tive mixture dissolved in a solvent, can be filtered and Any activated charcoal known to those of skill in the art can be washed, for example, to remove the activated charcoal from used to treat the crude water-soluble vitamin E derivative the crude water-soluble vitamin E derivative mixture. For mixture. Such activated charcoal is available from commer example, the crude water-soluble vitamin E derivative mix cial sources under Such trade names as Calgon-Type CPG(R), ture, for example, the crude water-soluble vitamin E deriva Type PCB(R, Type SGL(R), Type CAL(R), and Type OL(R). tive mixture dissolved in a solvent, can be filtered through a 0379 Further purification of the crude water-soluble vita filter aid, such as diatomaceous earth. Suitable filter aids for min E derivative mixture, for example, treating the crude use in the methods include, for example, those sold under the water-soluble vitamin E derivative mixture with activated trademarks Celite(R) and Hyflo.R. After filtering through a charcoal, can take place for a period of time of from at or filter aid, such as diatomaceous earth, the crude TPGS com about 0.5 hours to at or about 5 hours, or longer if required. position can be washed, for example, with the same solvent The crude water-soluble vitamin E derivative mixture to be used to dissolve the crude water-soluble vitamin E derivative treated can be dissolved in a solvent, for example, the first mixture, e.g., the first solvent. In an exemplary embodiment, solvent used in the wash described above. Additional solvent after further purification, e.g., treatment with activated char can be added, for example, the same solvent used to dissolve coal, and cooling, e.g., to room temperature, i.e., at or about the crude water-soluble vitamin E derivative mixture during 20°C., the crude water-soluble vitamin E derivative mixture the wash, e.g., a polar protic organic solvent. In the methods, is filtered through diatomaceous earth, e.g., Hyflo R filter aid the amount of additional Solvent, e.g., polar protic organic and washed with solvent, e.g., methanol. solvent, added to the crude water-soluble vitamin Ederivative 0382. In the methods, the crude water-soluble vitamin E mixture can be based on the ratio of the total volume of the derivative mixture can be further purified in order to isolate Solvent, e.g., the first solvent, Such as a polar protic organic the purified water-soluble vitamin E derivative mixture from solvent, plus the additional solvent, to the volume of the crude the solvent, e.g., the first solvent. For example, the crude water-soluble vitamin E derivative mixture. The ratio of the water-soluble vitamin E derivative mixture can be further total volume of the first solvent plus the additional solvent to purified by removing the solvent from the water-soluble vita the volume of the crude TPGS composition can range from min E derivative mixture dissolved in solvent, i.e., concen 0.1:1 to 10:1. In some embodiments, the ratio of the volume trating the crude water-soluble vitamin E derivative mixture, of total solvent to the volume of crude water-soluble vitamin in order to obtain a purified water-soluble vitamin E deriva E derivative mixture is or is about 0.1:1, 0.2:1, 0.25:1, 0.3:1, tive mixture. Any method of removing a solvent from a com 0.4:1, 0.45:1, 0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1:1, position known to those of skill in the art can be used, includ 1.2:1, 1.25:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.75:1, 1.8:1, ing, for example, vacuum distillation, rotary evaporation and 1.9:1, 2:1, 2.5:1, 3:1, 3.5:1, 3.6:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, filtration. Removing the solvent from the water-soluble vita 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, or 10:1 or more. For min E derivative mixture can be done at any temperature, for example, the ratio of the total volume of the first solvent plus example at room temperature, i.e., 20°C., or at a temperature additional solvent to the volume of the crude water-soluble elevated from room temperature. For example, the solvent vitamin E derivative mixture can be 5:1. can be removed at a temperature of at or about 20°C., 30°C., 0380. In the methods, further purification, such as treating 40° C., 50° C., 55° C., 60° C., 70° C., 80° C., or 90° C., but the reaction mixture with, for example, activated charcoal, below or about below 100° C., such as below or about below can take place for at least or about at least 0.5 hours, 1 hour, 60° C. In an exemplary embodiment, the solvent can be 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, or longer. The removed from the crude water-soluble vitamin E derivative further purification, for example, treating the reaction mix mixture by distillation, e.g., vacuum distillation, at a tempera ture with activated charcoal, can be done at any temperature ture elevated from room temperature, i.e., at or about 20°C., US 2016/008 1976 A1 Mar. 24, 2016

but below or about below 60° C. After removing the solvent, between 25 wt % and 69 wt % monomer, for example, at or the purified water-soluble vitamin Ederivative mixture can be about 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 36, 37,38, 39, dried by any method of drying known to those of skill in the 40, 41,42, 43,44, 45,46,47, 48,49, 50, 51, 52,53,54, 55,56, art. Suitable methods of drying include drying under an inert 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 or 69 wt % gas, for example, nitrogen or argon, or drying under Vacuum, monomer and between or about between 13 wt % and 95 wt or any combination thereof. % dimer, for example, at or about 13, 14, 15, 16, 17, 18, 19. 0383. In exemplary embodiments of the methods, further 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 36, purification of the crude water-soluble vitamin E derivative 37,38,39, 40, 41, 42, 43,44, 45,46, 47, 48,49, 50, 51, 52,53, mixture produced by the methods can include further purifi 54, 55,56, 57,58, 59, 60, 61, 62,63, 64, 65,66, 67,68, 69,70, cation by treating the crude water-soluble vitamin E deriva 71, 72,73,74, 75,76, 77,78, 79,80, 81, 82,83, 84,85, 86, 87, tive mixture to remove impurities from the reaction mixture, 88, 89,90,91, 92,93, 94 or 95 wt % dimer. such as by treating the crude water-soluble vitamin E deriva 0385. These methods are described with reference to tive mixture with activated charcoal. Further purification of TPGS and can be adapted to produce any higher dimer the crude water-soluble vitamin E derivative mixture pro containing water-soluble vitamin E derivative composition. duced by the methods can include further purification by Other methods to produce compositions with the desired removing the solvent from the crude water-soluble vitamin E dimer or dimer and monomer concentrations can be derivative mixture, for example, a crude water-soluble vita employed, including purifying dimer from standard prepara min E derivative mixture dissolved in a solvent, such as by tions and adding the dimer back to a standard preparation to removing the solvent by vacuum distillation. The further puri increase its concentration. The resulting compositions are fication can include treating the crude water-soluble vitamin employed in the concentrates and dilution compositions E derivative mixture with activated charcoal or removing the described herein. solvent from the crude water-soluble vitamin E derivative mixture or both. In an exemplary method, the further purifi D. PRODUCTS CONTAINING HIGH cation of the crude water-soluble vitamin E derivative mix DIMER-CONTAINING WATER-SOLUBLE ture includes removing the impurities from the crude water VITAMINEDERIVATIVE MIXTURES soluble vitamin E derivative mixture, e.g., treating the crude 0386 Provided herein are products containing the high water-soluble vitamin E derivative mixture with activated dimer-containing water-soluble vitamin E mixtures. These charcoal, and removing the solvent from the crude water include, for example, products for human consumption, Such soluble vitamin E derivative mixture, e.g., removing the sol as food and beverage products, in particular aqueous food and vent by vacuum distillation, in order to obtain a purified beverage products, and soft gel capsules containing emul water-soluble vitamin E derivative mixture, for example, a sions for direct consumption, as well as methods for making purified TPGS composition. The purified TPGS composition the products. In particular, provided are pre-emulsion con can contain less TPGS monomer, i.e., less than 70 wt %, and centrates, pre-gel concentrates, liquid nanoemulsion concen more TPGS dimer, i.e., more than 12 wt %, than in known trates, Soft gel compositions (capsules), and liquid dilution TPGS compositions. (beverage) compositions containing the concentrates, and 0384 The methods yield a purified water-soluble vitamin other beverage compositions that contain the water-soluble E derivative mixture, such as a purified TPGS composition, vitamin E derivative mixtures (compositions) as described with the desired amount of dimer (greater than 12%) that can herein. Also provided are compositions for direct consump be used in any application where water-soluble vitamin E tion in that the water-soluble vitamin Ederivative mixture and derivative mixtures are used. Such as in food, beverage, phar other ingredients are present in amounts for direct ingestion. maceutical or nutraceutical products for human consumption, The water-soluble vitamin E derivative mixture is typically and particularly to prepare concentrates that contain the present in an amount of less than 10%, generally in an amount water-soluble vitamin E derivative composition and a non of about 1%-5%. polar ingredient(s) and other optional ingredients. For 0387. The compositions provided herein that contain the example, the methods produce a purified water-soluble vita water-soluble vitamin E derivative mixtures described herein min E derivative mixture, such as a purified TPGS composi can contain non-polar ingredients. Non-polar ingredients are tion, for example, a TPGS composition that contains less poorly water-soluble (e.g., have low water solubility or are TPGS monomer, i.e., less than 70 wt %, and more TPGS water-insoluble). Thus, it generally can be difficult to formu dimer, i.e., more than 12 wt %, than in known TPGS compo late non-polar ingredients into products for human consump sitions, that can be used in products for human consumption, tion, particularly aqueous products, for example, food and for example, food and beverage products, particularly aque beverage compositions. Poor water solubility of non-polar ous food and beverage products, and any other application in ingredients also can contribute to their poor bioavailability. which a water-soluble vitamin E derivative mixture can be Improved methods and compositions for formulating food added. Exemplary purified water-soluble vitamin E deriva and beverage products containing non-polar ingredients are tive mixtures (compositions) that can be prepared following provided herein. The products containing the water-soluble the methods are those that containless than 70 wt % monomer vitamin E derivative mixtures described herein can contain and more than 12 wt % dimer, Such as such as compositions higher concentrations of non-polar ingredients as compared containing between or about between 25 wt % and 69 wt % to available food and beverage products. The products con monomer and between or about between 13 wt % and 95 wt taining the water-soluble vitamin Ederivative mixtures (com % dimer, such as compositions containing between or about positions) can solubilize higher amounts of non-polar ingre between 40 wt % and 60 wt % monomerand between or about dients than in products containing such water-soluble vitamin between 25 wt % to 60 wt % dimer. For example, the methods E with lower concentrations (i.e., less than 13%, 29%, 35%, can be followed to obtain water-soluble vitamin E derivative 52%) of dimers. These resulting products retain desirable mixtures (compositions) that contain between or about organoleptic properties, such as clarity (i.e., low turbidity). US 2016/008 1976 A1 Mar. 24, 2016 36

The products provided herein can contain high amounts of compounds. The liquid dilution compositions that are pro non-polaringredient, such as non-polaringredients that are or duced are clear or remain clear. contain non-polar compounds, for example, between or 0389. The water-soluble vitamin E derivative mixtures between about 1 wt % and 75 wt % non-polar ingredient, such (compositions) provided herein can be formulated with non as between or between about 1% and 5%, 1% and 10%, 1% polar ingredients that are or contain non-polar compounds or and 15%, 1% and 20%, 1% and 25%, 1% and 30%, 1% and other ingredients to form a composition for direct consump 35%, 1% and 40%, 1% and 45%, 1% and 50%, 1% and 55%, tion, such as a beverage composition. These compositions can 1% and 60%, 1% and 65%, 1% and 70%, 1% and 75%, 5% beformulated in a variety of volumes and sizes, including, but and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and not limited to, a single-serving shot and a multi-serving com 30%, 5% and 35%, 5% and 40%, 5% and 45%, 5% and 50%, position. The beverage compositions that are produced are 5% and 55%, 5% and 60%, 5% and 65%, 5% and 70%, 5% clear and typically remain clear. and 75%, 10% and 15%, 10% and 20%, 10% and 25%, 10% 0390 Concentrates and compositions for direct consump and 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% tion that contain the water-soluble vitamin E derivative mix and 50%, 10% and 55%, 10% and 60%, 10% and 65%, 10% tures (compositions) described herein and a non-polar com and 70%, 10% and 75%, 15% and 20%, 15% and 25%, 15% ponent are provided. The concentrates contain from 99% or and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% more of the water-soluble vitamin E derivative composition and 50%, 15% and 55%, 15% and 60%, 15% and 65%, 15% with the remainder as a non-polar ingredient, to as little as and 70%, 20% and 25%, 20% and 30%, 20% and 35%, 20% 1%, typically 5%, of the water-soluble vitamin E derivative and 40%, 20% and 45%, 20% and 50%, 20% and 55%, 20% composition. The compositions for direct consumption con and 60%, 20% and 65%, 20% and 70%, 20% and 75%, 25% tain from 50% or more of the water-soluble vitamin E deriva and 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% tive composition to as little as 0.1%, typically 1.5%, of the and 50%, 25% and 55%, 25% and 60%, 25% and 65%, 25% water-soluble vitamin E derivative composition. Further and 70%, 25% and 75%, 30% and 35%, 30% and 40%, 30% description and examples are provided below. The concen and 45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% trates and compositions for direct consumption can contain and 65%, 30% and 70%, 30% and 75%, 35% and 40%, 35% additional optional ingredients, including polar solvents, and 45%, 35% and 50%, 35% and 55%, 35% and 60%, 35% Such as water and/or alcohol. and 65%, 35% and 70%, 35% and 75%, 40% and 45%, 40% 0391) Depending upon the amount of water-soluble and 50%, 40% and 55%, 40% and 60%, 40% and 65%, 40% derivative of vitamin E, the concentrates are waxy or creamy and 70%, 40% and 75%, 45% and 50%, 45% and 55%, 45% (semi-solids) or liquids, including emulsions, depending and 60%, 45% and 65%, 45% and 70%, 45% and 75%, 50% upon the particular components and amounts thereof. The and 55%, 50% and 60%, 50% and 65%, 50% and 69%, 55% concentrates are added to foods, particularly beverages, and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 60% including aqueous beverages, that contain desired amounts of and 65%, 60% and 70%, 60% and 75%, 65% and 70%. 65% the non-polar ingredients, by adding an appropriate amount and 75% and 70% and 75%, by weight, of the food or bever of an appropriate concentrate to the beverage. For example, age product. The products that contain the water-soluble vita the concentrate can be dissolved and diluted to form a liquid min E derivative mixtures and high amounts of non-polar dilution composition. Alternatively, the water-soluble vita ingredient retain desirable organoleptic properties, such as min E derivative mixtures (compositions) can be formulated remaining free from turbidity. For example, the products pro directly into a beverage composition. For example, the water vided herein can contain up to twice the amount of non-polar soluble vitamin E derivative mixtures (compositions) can be ingredient as available products that contain known TPGS added to the beverage composition without formulating a compositions and retain the same level of turbidity. Products concentrate. The resulting food/beverage compositions retain that contain known TPGS compositions, such as products that desirable organoleptic properties, such as improved clarity contain TPGS compositions made up of mostly monomer (e.g., Small particle size, low turbidity), stability (e.g., lack of (e.g., 70% or greater) and a small amount of dimer (e.g., 12% separation), taste and Smell. Food and beverage compositions or less), and a high amount of non-polar ingredient, e.g., up to that retain desirable organoleptic properties are needed. The 75 wt % non-polar ingredient, exhibit higher turbidity levels, emulsions provided herein address those needs among others. for example, a two-fold higher turbidity level, as compared to 0392 Among the compositions for direct consumption the products provided herein that contain the TPGS compo and concentrates described herein are concentrates that are sitions provided herein and the same amount of non-polar semi-solid waxes and emulsions, where the concentrates and ingredient, e.g., up to 75 wt % non-polar ingredient. compositions for direct consumption also contain a polar 0388. The water-soluble vitamin E derivative mixtures solvent, such as water or alcohol. The emulsions provided (compositions) provided herein can be formulated with non herein contain the water-soluble vitamin E derivative mix polar ingredients that are or contain non-polar compounds to tures described herein. form a pre-emulsion concentrate. The water-soluble vitamin 0393. It is shown herein that the water-soluble vitamin E E derivate compositions described herein can be formulated derivative mixtures (high dimer-containing) described herein with non-polar ingredients that are or contain non-polar com permit higher amounts of non-polar ingredients to be dis pounds and additional ingredients, such as a polar solvent, to persed in an aqueous liquid than compositions containing form liquid nanoemulsion concentrates. The liquid water-soluble vitamin E derivative mixtures with low dimer nanoemulsion concentrates that contain the water-soluble amounts. For example, oil-in-water emulsions are provided vitamin E derivative mixtures (compositions) described that contain water-soluble vitamin E derivative mixtures and herein and the non-polar ingredients can be diluted to form non-polaringredients dispersed in an aqueous liquid that have liquid dilution compositions that contain the water-soluble desirable properties, including improved clarity, stability, vitamin E derivative mixtures (compositions) described smell and taste. The provided emulsions (and methods for herein and non-polar ingredients that are or contain non-polar making the emulsions) can be used to formulate any non US 2016/008 1976 A1 Mar. 24, 2016 37 polar ingredient in an aqueous composition, including the derivative mixtures are employed (typically greater than 25% non-polar ingredients (e.g., non-polar ingredients that are or or about 25%), particularly without any liquid components, contain non-polar compounds) described herein and other the compositions are waxy. Where lower concentrations are known non-polar compounds and ingredients. Typically, the used, the compositions can be more liquid; where polar sol provided compositions containing the water-soluble vitamin vents and or other polar ingredients are included, the concen Ederivatives are emulsions. Typically, the provided emulsion trates are emulsions. All can be used as vehicles for solubi compositions are oil-in-water nanoemulsions that contain the lizing desired non-polar ingredients in food and beverages. non-polar ingredients dispersed in aqueous liquid. 0399. Each of the provided concentrates, e.g., pre-emul 0394 The provided emulsion compositions can be further sion concentrates and liquid nanoemulsion concentrates, and stabilized by inclusion of one or more co-surfactants and/or semi-solids, and beverage compositions, e.g., liquid dilution emulsion stabilizers in addition to the water-soluble vitamin compositions and single-serving shots, contain at least one Ederivatives described herein. Surfactants forman interfacial surfactant that is a water-soluble vitamin Ederivative mixture film in the emulsion between the oil and water phase, provid described herein, for example, the TPGS, TPGS analogs, ing stability. Typically, the nanoemulsions of the provided TPGS homologs and TPGS derivative mixtures described compositions contain micelles in which one or more Surfac herein. The surfactant typically has an HLB value of between tants Surround the non-polar compound. The micelles are 12 or about 12 and 20 or about 20, for example, 12, 13, 14, 15, dispersed in the water phase. 16, 17, 18, 19 or 20, or about 12, about 13, about 14, about 15, 0395. The provided emulsion compositions include liquid about 16, about 17, about 18, about 19, or about 20, typically nanoemulsion concentrates containing the water-soluble between at or about 12 and at or about 14. For example, Vitamin E derivatives described herein and non-polar ingre TPGS, such as the TPGS described herein, has an HLB value dients, which can be diluted to provide non-polar ingredients of about 12 to 14, generally about 13. in aqueous compositions, such as beverage products. The 0400 For compositions that are to be diluted, the water liquid nanoemulsion concentrates can be diluted into a soluble vitamin E derivative mixture, e.g., TPGS, is typically medium, for example, an aqueous medium, to form a liquid present in an amount as a percentage (%), by weight, of the dilution composition (e.g., an aqueous liquid dilution com concentrate (wt %), e.g., from at or about 20% to at or about position) containing the non-polar ingredients. Also exem 90%, such as 20% to 25%, 20% to 30%, 20% to 35%, 20% to plary of the provided compositions are the liquid dilution 40%, 20% to 45%, 20% to 50%, 20% to 55%, 20% to 60%, compositions (e.g., aqueous liquid dilution compositions) 20% to 65%, 20% to 70%, 20% to 75%, 20% to 80%, 20% to made by diluting the liquid nanoemulsion concentrates in the 85%, 20% to 90%, 25% to 30%, 25% to 35%, 25% to 40%, medium, that remain clear. 25% to 45%, 25% to 50%, 25% to 55%, 25% to 60%, 25% to 0396 The emulsion compositions and food and beverage 65%, 25% to 70%, 25% to 75%, 25% to 80%, 25% to 85%, products provided herein can contain any non-polar ingredi 25% to 90%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to ent or compound. The non-polar ingredients typically are 50%, 30% to 55%, 30% to 60%, 30% to 65%, 30% to 70%, non-polar compounds, for example, pharmaceuticals, nutra 30% to 75%, 30% to 80%, 30% to 85%, 30% to 90%, 35% to ceuticals, vitamins and minerals. The non-polar ingredients 40%, 35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, include, but are not limited to, polyunsaturated fatty acid 35% to 65%, 35% to 70%, 35% to 75%, 35% to 80%, 35% to (PUFA)-containing compounds, such as omega-3-containing 85%, 35% to 90%, 40% to 45%, 40% to 50%, 40% to 55%, ingredients, for example, compounds containing ALA, DHA 40% to 60%, 40% to 65%, 40% to 70%, 40% to 75%, 40% to and/or EPA, e.g., oils derived from fish and microalgae, krill 80%, 40% to 85%, 40% to 90%, 45% to 50%, 45% to 55%, and/or flaxseed extract, and omega-6-containing non-polar 45% to 60%, 45% to 65%, 45% to 70%, 45% to 75%, 45% to compounds, for example, gamma-linolenic acid (GLA)-con 80%, 45% to 85%, 45% to 90%, 50% to 55%, 50% to 60%, taining compounds, e.g., borage oil; saw palmetto oil-con 50% to 65%, 50% to 70%, 50% to 75%, 50% to 80%, 50% to taining compounds; conjugated fatty acid containing-ingre 85%, 50% to 90%, 55% to 60%, 55% to 65%, 55% to 70%, dients, for example, conjugated linoleic acid (CLA)- 55% to 75%, 55% to 80%, 55% to 85%, 55% to 90%, 60% to containing compounds; coenzyme Q-containing ingredients, 65%, 60% to 70%, 60% to 75%, 60% to 80%, 60% to 85%, for example, coenzyme Q10 (coO10), e.g., oxidized coQ10 60% to 90%. 65% to 70%, 65% to 75%, 65% to 80%, 65% to (ubidecarenone)-containing compounds; and compounds 85%, 65% to 90%, 70% to 75%, 70% to 80%, 75% to 85%, containing phytosterols (plant sterols). Additional exemplary 75% to 90%, 80% to 85%, 80% to 90%, or 85% to 90%, by non-polar ingredients and other compounds are described weight, of the concentrate. Exemplary concentrations of the herein. Any non-polar compound or ingredient can be used in water-soluble vitamin Ederivative mixture, e.g., TPGS, in the the provided emulsion compositions and food and beverage pre-emulsion concentrate are at or about 20%, 25%, 30%, products provided herein. 35%, 40%, 45%, 49.5%, 50%, 55%, 60%, 65%, 68%, 69.5%, 0397 1. Exemplary Ingredients and Exemplary Concen 70%, 75%, 79.5%, 80%, 85%, 89.5% and 90% (wt %) of the tration Ranges concentrate. The concentrates can contain lower amounts of 0398. The following sections describe ingredients used in the water-soluble vitamin E derivative mixture, and the com the provided pre-emulsion concentrates and liquid nanoemul positions for direct consumption contain lower amounts, such sion concentrates or otherforms of concentrates and beverage as 1%-15%, generally 1%-5%. compositions. As noted, the form of the resulting composition 04.01 Each of the provided compositions, e.g., pre-emul containing the high dimer-containing water-soluble vitamin sion concentrates and liquid nanoemulsion concentrates, fur E derivative mixture depends upon the concentration ranges ther contains a non-polar ingredient including, but not limited and types of ingredients. Concentrates typically are intended to, the exemplary non-polar ingredients described herein for dilution prior to consumption, and, thus, contain non below. Typically, the non-polar ingredient is or contains one polaringredients in higher than single dosage concentrations. or more non-polar compounds, for example, an oil-based Where high concentration of the water-soluble vitamin E non-polar ingredient, Such as a polyunsaturated fatty acid US 2016/008 1976 A1 Mar. 24, 2016

(PUFA), a coenzyme Q or a phytochemical. The concentrates D-limonene or lemon oil; a co-surfactant, for example, a provided herein can contain one non-polar ingredient or more phospholipid, e.g., phosphatidylcholine, or a Sucrose fatty than one non-polar ingredient, such as two, three, four, five or acid ester Surfactant. more non-polar ingredients. The concentrates provided 04.05 The appropriate concentration ranges for the addi herein can contain higher amounts (i.e., concentrations) of tional ingredients are described in individual sections below. non-polaringredients than can available concentrates, such as Typically, the concentration of the additional ingredients up to at or about 75 wt % non-polar ingredient. depends, in part, on the concentrations of the non-polar ingre 0402 For formulating the concentrates, the total amount dient and the water-soluble vitamin E derivative surfactant. of non-polar ingredient(s) that is or contains one or more Typically, the concentrations of these ingredients (surfactant non-polar compounds is typically present in a total amount as and non-polar ingredient) are the focus of the formulating a percentage (%), by weight, of the concentrate (wt %), e.g., methods. For example, when it is determined that modifica from at or about 1% to at or about 75 wt %, such as between tions to ingredient concentrations in the initial concentrate or between about 1% and 5%, 1% and 10%, 1% and 15%, 1% should be made, it typically is the concentrations of one or and 20%, 1% and 25%, 1% and 30%, 1% and 35%, 1% and more of these ingredients that are adjusted. 40%, 1% and 45%, 1% and 50%, 1% and 55%, 1% and 60%, 0406. In one example, it can be desirable to add one or 1% and 65%, 1% and 70%, 1% and 75%, 5% and 10%, 5% more of the additional ingredients after evaluation of the and 15%, 5% and 20%, 5% and 25%, 5% and 30%, 5% and initial concentrate, for example, in order to improve the con 35%, 5% and 40%, 5% and 45%, 5% and 50%, 5% and 55%, centrate with respect to one or more desired properties. 5% and 60%, 5% and 65%, 5% and 70%, 5% and 75%, 10% 04.07 a. Water-Soluble Vitamin E Derivatives and 15%, 10% and 20%, 10% and 25%, 10% and 30%, 10% 0408. The compositions for direct consumption, the pre and 35%, 10% and 40%, 10% and 45%, 10% and 50%, 10% emulsion concentrates and liquid nanoemulsion concentrates and 55%, 10% and 60%, 10% and 65%, 10% and 70%, 10% provided herein, contain the high dimer-containing water and 75%, 15% and 20%, 15% and 25%, 15% and 30%, 15% soluble vitamin E derivative mixtures described herein, for and 35%, 15% and 40%, 15% and 45%, 15% and 50%, 15% example, the TPGS compounds noted above, including and 55%, 15% and 60%, 15% and 65%, 15% and 70%, 20% TPGS, TPGS homologs, TPGS analogs and TPGS deriva and 25%, 20% and 30%, 20% and 35%, 20% and 40%, 20% tives and other vitamin E derivatives. The water-soluble vita and 45%, 20% and 50%, 20% and 55%, 20% and 60%, 20% min E derivative mixtures can act as Surfactants. The water and 65%, 20% and 70%, 20% and 75%, 25% and 30%, 25% soluble vitamin E derivative mixtures can be any of the high and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% dimer-containing water-soluble vitamin E derivative mix and 55%, 25% and 60%, 25% and 65%, 25% and 70%, 25% tures described herein, for example, tocopherol-derived com and 75%, 30% and 35%, 30% and 40%, 30% and 45%, 30% positions and tocotrienol-derived compositions, including, and 50%, 30% and 55%, 30% and 60%, 30% and 65%, 30% but not limited to, polyalkylene glycol derivatives of toco and 70%, 30% and 75%, 35% and 40%, 35% and 45%, 35% pherol, e.g., polyethylene glycol (PEG) derivatives of toco and 50%, 35% and 55%, 35% and 60%, 35% and 65%, 35% pherol, such as vitamin E TPGS (D-O-tocopheryl polyethyl and 70%, 35% and 75%, 40% and 45%, 40% and 50%, 40% ene glycol Succinate), and polyalkylene glycol derivatives of and 55%, 40% and 60%, 40% and 65%, 40% and 70%, 40% tocotrienol, e.g., polyethylene glycol (PEG) derivatives of and 75%, 45% and 50%, 45% and 55%, 45% and 60%, 45% tocotrienol. The high dimer-containing water-soluble vitamin and 65%, 45% and 70%, 45% and 75%, 50% and 55%, 50% E derivative mixtures (compositions), e.g., compositions of and 60%, 50% and 65%, 50% and 69%, 55% and 60%, 55% TPGS, TPGS analogs, TPGS homologs or TPGS derivatives, and 65%, 55% and 70%, 55% and 75%, 60% and 65%, 60% containless water-soluble vitamin Ederivative monomer, i.e., and 70%, 60% and 75%, 65% and 70%. 65% and 75%, or less than 70 wt %, and more water-soluble vitamin E deriva 70% to 75% non-polar ingredient, by weight, of the concen tive dimer, i.e., more than 12 wt %, than in known water trate. Exemplary concentrations of the total amount of non soluble vitamin E derivative mixtures (compositions). polar ingredient(s) in the concentrate is at or about 5%, 10%, 04.09. In the concentrates provided herein, e.g., the pre 12.5%, 15%, 15.5%, 16.7%, 20%, 22%, 25%, 30%, 31.5%, emulsion concentrates, pre-gel concentrates and liquid 35%, 40%, 45.5% and 50% (wt %) of the concentrate. nanoemulsion concentrates, the water-soluble vitamin E derivatives can act as Surfactants by aggregating in aqueous 0403. The concentrates, e.g., the pre-emulsion concen liquids, Such as water, to form micelles, which contain the trates and liquid nanoemulsion concentrates, can further con non-polar ingredient(s). The hydrophilic portion(s) of the tain additional ingredients, for example, preservatives and/or surfactant molecules are oriented toward the outside of the non-polar solvents. In some examples, the preservative is a micelle, in contact with the aqueous medium, while the natural preservative. Such as benzyl alcohol. In some hydrophobic portion(s) of the surfactant molecules are ori examples, the non-polar solvent is an oil, other than the non ented toward the center of the micelle, in contact with the polar ingredient, for example, Vitamin E oil, flaxseed oil or non-polar ingredient(s), which is contained in the center of rice bran oil. the micelle. Properties of the provided food and beverage 04.04 The liquid nanoemulsion concentrates additionally products, for example, the particle size of the concentrates contain at least one polar solvent. Exemplary polar solvents and desirable properties related to the particle size, are influ include water, propylene glycol and glycerin (glycerol). One enced by the choice of surfactant(s) and the relative amount or more, typically more than one, additional ingredients can (concentration) of surfactant. For example, the HLB of the be added to the liquid nanoemulsion concentrate. Exemplary Surfactant(s) can affect particle size, clarity, taste, Smell, crys of other additional ingredients that can be added to the liquid tal formation and other properties of the provided food and concentrates include emulsion stabilizers, for example, a beverage products. Similarly, the concentration of the Surfac blend of gums; a pH adjuster, for example, citric acid or tant compared with the concentration(s) of other ingredients, phosphoric acid; one or more flavoring agents, for example, particularly compared with the concentration of the polar US 2016/008 1976 A1 Mar. 24, 2016 39

Solvent(s) and the concentration of the non-polar ingredient acid (DHA) (22:6c)3); eicosatetraenoic acid (24:4(O3); (s), can affect various desirable properties, for example, the docosapentaenoic acid (DPA, clupanodonic acid) (22:503); ability to disperse or dissolve in aqueous media, e.g., to form 16:3 (03:24:5 (03 and/or nisinic acid (24:6c)3), e.g., fish oil, a clear aqueous liquid dilution composition or pleasant taste algae oil, krill oil, canola oil, flaxseed oil, soybean oil and and/or smell. The water-soluble vitamin E derivative mix walnut oil; compounds containing short-chain omega-3 fatty tures (compositions) described herein can be used to increase acids, for example, alpha-linolenic acid (O-linolenic acid; the amount of non-polar ingredient that can be added to a ALA; 18:3c)3) and stearidonic acid (18:4c)3), esters of an concentrate. Such as the concentrates provided herein, with omega-3 fatty acid and glycerol, for example, monoglycer out sacrificing the various desirable properties of the food and ides, diglycerides and triglycerides, esters of omega-3 fatty beverage products containing the concentrate, such as par acid and a primary alcohol, for example, fatty acid methyl ticle size, clarity, taste, Smell, crystal formation and other esters and fatty acid esters, precursors of omega-3 fatty acid desirable properties of food and beverage products. oils, for example, EPA precursor, DHA precursor, derivatives 0410. The water-soluble vitamin E derivative mixtures Such as polyglycolized derivatives or polyoxyethylene described herein and others known to those of skill in the art derivatives, oils containing the omega-3 fatty acids, for and used in the concentrates provided herein, e.g., the pre example, fish oil (marine oil), e.g., highly purified fish oil emulsion concentrates and liquid nanoemulsion concen concentrates, perilla oil, krill oil, and algae oil, e.g., microal trates, typically have an HLB value between or about between gae oil; compounds containing omega-6 fatty acids, such as 12 and 20, for example, at least 12, 13, 14, 15, 16, 17, 18, 19, compounds containing linoleic acid (18:2006) (a short-chain up to 20, about 12, about 13, about 14, about 15, about 16, fatty acid); gamma-linolenic acid (GLA; 18:3(O6); dihomo about 17, about 18, about 19 or about 20. Typically, the gamma linolenic acid (DGLA; 20:3(O6), eicosadienoic acid water-soluble vitamin E derivative is a natural surfactant, for (20:2006); arachidonic acid (AA; 20:4(O6); docosadienoic example, a surfactant that is GRAS (generally recognized as acid (22:2006); adrenic acid (22:4(O6); and/or docosapen safe) certified by the FDA and/or Kosher certified, for taenoic acid (22:5c)6), for example, borage oil, corn oil, cot example, TPGS, such as the TPGS derivative mixtures tonseed oil, grapeseed oil, peanut oil, primrose oil, e.g., described herein. In one example, the water-soluble vitamin E evening primrose (Oenothera biennis) oil, blackcurrant seed derivative mixture used in the provided concentrates is a oil, hemp seed oil, spirulina extract, Safflower oil, sesame oil, polyalkylene glycol derivative of vitamin E, for example, a coconut oil and soybean oil; polyethylene glycol derivative of vitamin E, e.g., TPGS. 0416 other fatty acids, Such as triglycerides, including TPGS has an HLB value of or about 13. medium chain triglycerides, polar lipids, for example, ether 0411. At room temperature, TPGS typically is a waxy lipids, phosphoric acid, choline, fatty acids, glycerol, gly low-melting solid. TPGS can be heated prior to use, for colipids, triglycerides, and phospholipids (e.g., phosphatidyl example, to at least the melting temperature, such as between choline (lecithin), phosphatidylethanolamine, and phosphati or about between 37° C. and 41° C. or about 41° C. and the dylinositol); saw palmetto extract; ethyl linoleate; herb oils, desired amount is poured out. Alternatively, TPGS can be for example, garlic oils and scordinin; short-chain Saturated added as a waxy Solid to a vessel and heated with the heating fatty acids (4:0-10:0), lauric acid (12:0), myristic acid (14:0). apparatus. pentadecanoic acid (15:0), palmitic acid (16:0), palmitoleic 0412 b. Non-Polar Ingredients acid (16:1 ()7), heptadecanoic acid (17:0), stearic acid (18:0), 0413 All of the compositions described and provided oleic acid (18:1 ()9), and arachidic acid (20:0); herein includea water-soluble vitamin E derivative, such as a 0417 micronutrients, such as vitamins, minerals, co-fac PEG derivative of vitamin E, such as a TPGS, that is a high tors, for example, coenzyme Q10 (coQ10, also called dimer-containing mixture (as described herein) of the water ubiquinone), ubiquinol, tumeric extract (cucuminoids), saw soluble vitamin E derivative. The compositions all include a palmetto lipid extract (saw palmetto oil), echinacea extract, non-polar ingredient or mixture thereof. The non-polar ingre hawthornberry extract, ginseng extract, lipoic acid (thioctic dient is or contains a non-polar compound. Such as a non acid), ascorbyl palmitate, kava extract, St. John's Wort (hy polar bioactive compound, for example, a nutritional Supple pericum, Klamath weed, goat weed), extract of quercitin, ment or a drug. The non-polar ingredients include, but are not dihydroepiandrosterone, and indol-3-carbinol: limited to, drugs, hormones, vitamins, nutrients and other 0418 carotenoids, including hydrocarbons and oxygen lipophilic compounds. Exemplary non-polar ingredients are ated, alcoholic derivatives of hydrocarbons, for example, beta listed herein below. The provided methods and compositions carotene, mixed carotenoid complex, lutein, lycopene, Zeax can be used to dilute (e.g., dissolve? disperse) any non-polar anthin, cryptoxanthin, for example, beta-crytoxanthin, beta ingredient in aqueous medium, Such as water. carotene, astaxanthin, bixin, canthaxanthin, capsanthin, cap 0414. The non-polar ingredient is not a water-soluble vita Sorubin, apo-carotenal, beta-12'-apo-carotenal, “Carotene’ min Ederivative. Exemplary of non-polaringredients that can (mixture of alpha- and beta-carotene), gamma carotene, ciol be used in the provided pre-emulsion concentrates and liquid erythrin, and esters of hydroxyl- or carboxyl-containing nanoemulsion concentrates are: members thereof 0415 non-polar ingredients containing essential fatty 0419 fat-soluble vitamins, for example, vitamins A, D, E acids, such as polyunsaturated fatty acids (PUFAs), for and K, and corresponding pro-Vitamins and vitamin deriva example, gamma-linolenic acid (GLA), e.g., borage oil and tives. Such as esters, with an action resembling that of vitamin evening primrose (Oenothera biennis) oil, blackcurrant seed A, D, E or K, for example, retinol (vitamin A) and pharma oil, hemp seed oil and spirulina extract; compounds contain ceutically acceptable derivatives thereof. Such as palmitate ing omega-3 fatty acids, such as natural and synthetic ester of retinol and other esters of retinol, calciferol (vitamin omega-3 fatty acids, for example, compounds containing D) and its pharmaceutically acceptable derivatives thereof omega-3 polyunsaturated long-chain fatty acids, including and precursors of vitamin D. d-alpha tocopherol (vitamin E) eicosapentaenoic acid (EPA) (20:5c)3); docosahexaenoic and derivatives thereof, including pharmaceutical derivatives US 2016/008 1976 A1 Mar. 24, 2016 40 thereof, for example, tocotrienols, d-alpha tocopherol acetate from diet or by supplementation (U.S. Pat. No. 6,870,077; and other esters of d-alpha tocopherol, and ascorbyl palmi Covington (2004) American Family Physician tate, a fat-soluble version of vitamin C: 70(1):133-140). The essential PUFAs are the omega-3 (c)3: 0420 phytochemicals, including phytoestrogens, for n-3) fatty acids and the omega-6 (c)-6; n-6) fatty acids. example, genistein and daidzein, such as isoflavones, e.g., Soy Omega-3 and omega-6 fatty acids are methylene interrupted isoflavones, flavonoids, phytoalexins, for example, resvera polyenes which have two or more cis double bonds separated trol (3,5,4'-trihydroxy stilbene), red clover extract, and phy by a single methylene group. Exemplary of omega-3 fatty tosterols; acids are alpha-linolenic acid (O-linolenic acid; ALA; 0421 lipid-soluble drugs, including natural and synthetic 18:3c)3) (a short-chain fatty acid); stearidonic acid (18:4c03) forms of immunosuppressive drugs, such as cyclosporin, pro (a short-chain fatty acid), eicosapentaenoic acid (EPA; tease inhibitors such as ritonavir, macrollide antibiotics and oil 20:5c)3); docosahexaenoic acid (DHA; 22:6c)3); eicosatet soluble anesthetics such as propofol, natural and synthetic raenoic acid (24:4(O3); docosapentaenoic acid (DPA; clupan forms of steroidal hormones, for example, estrogens, estradi odonic acid; 22:5c)3); 16:3 (03:24:5 (03 and nisinic acid ols, progesterone, testosterone, cortisone, phytoestrogens, (24:603). Longer chain omega-3 fatty acids can be synthe dehydroepiandrosterone (DHEA), growth hormones and sized from ALA (the short-chain omega-3 fatty acid). Exem other hormones; and oil-soluble acids and alcohols, for plary of omega-6 fatty acids are linoleic acid (18:2006) (a example, tartaric acid, lactylic acid, butylated hydroxyani short-chain fatty acid); gamma-linolenic acid (GLA; sole, butylated hydroxytoluene, lignin, Sterols, polyphenolic 18:3c)6); dihomo gamma linolenic acid (DGLA; 20:3()6); compounds, ory Zanol, cholesterol, phytosterols, flavonoids, eicosadienoic acid (20:2006); arachidonic acid (AA; 20:4(O6); Such as quercetin and resveratrol, and diallyl disulfides. docosadienoic acid (22:2006); adrenic acid (22:4(O6); and 0422 i. Polyunsaturated Fatty Acid (PUFA)-Containing docosapentaenoic acid (22:5c)6). Ingredients 0427. While the longer chain omega-3 and omega-6 essen 0423 Exemplary of the non-polar ingredients contained in tial fatty acids can be synthesized from ALA (the short-chain the concentrates, e.g., pre-emulsion concentrates and liquid omega-3 fatty acid) and linolenic acid (LA), respectively, nanoemulsion concentrates, are ingredients containing fatty evidence Suggests that conversion of these short chain fatty acids, for example, non-polar ingredients containing the non acids in humans is slow. Thus, a major source of long chain polar compounds polyunsaturated fatty acids (PUFAs). Fatty essential PUFAs is dietary (see, e.g., Ross et al. (2007) Lipids acids are straight-chain hydrocarbon molecules with a car in Health and Disease 6:21 and Lands (1992) FASEB J. boxyl (COOH) group at one end of the chain. PUFAs are fatty 6(8):2530). Dietary supplements containing PUFAs, particu acids that contain more than one carbon-carbon double bonds larly essential PUFAs, are desirable for protection against in the carbon chain of the fatty acid. PUFAs, particularly cardiovascular disease, inflammation and mental illnesses essential fatty acids, are useful as dietary Supplements. (see, e.g., Ross et al. (2007) Lipids in Health and Disease 0424 Different nomenclature is used to describe fatty acid 6:21; Lands (1992) FASEB J. 6(8):2530; and U.S. Pat. No. molecules. Lipid nomenclature, for example, 18:3 ()-3, indi 6,870.077). Evidence suggests that essential fatty acids, par cates the carbon chain length, number of double bonds and ticularly EPA and DHA, in the form of food and nutritional the position along the carbon chain of the first carbon-carbon Supplements, play a role in preventing a number of disease double bond in a fatty acid. Using this nomenclature, each states, including cardiovascular diseases, inflammation, men carbon along the chain is labeled according to its position tal health and behavioral diseases and disorders (see, e.g., relative to one end of the chain. For example, the first carbon Ross et al. (2007) Lipids in Health and Disease 6:21; Lands away from the carboxylate end is named C, the second is (1992) FASEB J. 6(8):2530; U.S. Pat. No. 6,870,077; and named f, and so forth. The last carbon in the molecule (fur Covington (2004) American Family Physician thest from the carboxy group) always is labeled () (or omega, 70(1):133-140). or n). The number of carbons and the number of double bonds 0428 Omega-9 fatty acids are non-essential PUFAs. are listed first in the lipid name of a fatty acid, separated by a Exemplary of omega-9 fatty acids are oleic acid (which is colon. For example, the name “18:3” indicates that the mol monounsaturated) (18:1 ()9); eicosenoic acid (20:1 (09); ecule has eighteen (18) carbons and three (3) double bonds. mead acid (20:3 (09): erucic acid (22:1 ()9); and nervonic acid Following these numbers, the position at which the first (24:1 (09). Conjugated fatty acids are PUFAs with two or double bond appears, relative to the last (()) carbon, is listed. more conjugated double bonds. For example, the nomenclature, 18:3 c)-3 (or 18:3 omega-3: 0429 Conjugated fatty acids can be used as nutritional or 18:3 n-3), describes a fatty acid with eighteen (18) carbons Supplements. Exemplary of conjugated fatty acids are conju and three (3) double bonds, the first of which occurs at the gated linoleic acid (CLA), for example, 18:2 (p7, 18:2 (06: third carbon away from the omega carbon. conjugated linolenic acid, for example, 18:3 (D6, 18:305; and 0425. Alternatively, chemical nomenclature can be used. other conjugated fatty acids, for example, 18:3 (p3, 18:4c)3, The chemical name of a fatty acid describes the position of and 20:5 (06. each double bond. In the chemical naming, the carbons are 0430 (a) Omega-3 Fatty Acid Compounds numbered, beginning with 1, starting with the carbon that is 0431 Exemplary of the PUFA-containing non-polar part of the carboxy (COOH) group. Thus, with this number ingredients that can be used in the provided concentrates, e.g., ing system, the C. carbon is labeled “2. The chemical name of pre-emulsion concentrates and liquid nano emulsion concen the fatty acid lists the first carbon (from the COOH end) to trates, are non-polar ingredients that contain one or more of participate in each double bond. the non-polar compound omega-3 (c)3: n-3) fatty acids, for 0426 Certain PUFAs are called essential fatty acids example, ingredients containing DHA and/or EPA fatty acids, because they are required for biological processes and mam for example, marine oils, e.g., fish oil, krill oil and algae oil; mals, including humans, cannot synthesize them using any and compounds containing ALA fatty acids, for example, flax known chemical pathway, and therefore must obtain them seed oil. US 2016/008 1976 A1 Mar. 24, 2016

0432 Typically, oils and aqueous compositions contain sources, for example, fish oils available from Jedwards Inter ing long-chain polyunsaturated fatty acids (PUFA) are sus national, Inc., any of which can be used with the provided ceptible to oxidation, making them unstable and giving them compositions. an unpleasant taste. The ingredients and relative concentra 0437 Fish oils typically are extracted from fish tissue, for tions thereof, as well as the methods for making the concen example, frozen fish tissue. For example, the fish oil can be a trates, contribute to desirable properties of DHA/EPA-con tasteless fish oil, for example, a cod liver oil, which has been taining concentrates. For example, the ingredients and isolated from fish, for example, from cod liver, and then methods used to make the concentrates provided herein mini refined and deodorized, or in some other way treated so its mize the “fishy' odor and/or taste of DHA/EPA compositions taste becomes neutral, such as described in International Pub and increase their stability over time. For example, the com lication NOS. WO OO/23545 and WO 2004/0983.11. In one pounds in the concentrates can have low oxidation, contrib example, these fish oils are isolated from frozen fish tissue by uting to these desirable properties. a process that minimizes oxidation. Exemplary of Such a 0433 (1) DHA/EPA tasteless fish oil is a fish oil sold under the trademark Denom 0434 Exemplary of non-polar ingredients that contain one egaTM 100 (Borregaard Ingredients, Sarpsborg, Norway; dis or more omega-3 fatty acids, which can be used in the pro tributed by Denomega Nutritional Oils AS, Boulder, Colo.). vided concentrates, e.g., pre-emulsion concentrates and liq Typically, the tasteless fish oil, for example, cod liver oil, uid nanoemulsion concentrates, are ingredients containing contains between or about between 25% and 35% omega-3 DHA and/or EPA, for example, marine oil, e.g., fish oil, krill fatty acids, for example, 34% omega-3 fatty acids. In one oil and algae oil. Any oil containing DHA and/or EPA can be example, the fish oil, for example, the DenomegaTM 100 oil, used. In one example, the non-polar ingredient contains contains 13% or about 13% DHA and 13% or about 13% between 10% or about 10% and 40% or about 40% DHA. In EPA. another example, the non-polar ingredient contains between 0438 Also exemplary of the fish oils that can be included 25% or about 25% and 45% or about 45% DHA. In another in the provided concentrates are fish oils containing high example, the non-polar ingredient contains at least 60% or amounts of omega-3 fatty acids, for example, high amounts of about 60%, by weight (w/w), DHA, for example, at least 65% DHA. One example of such a fish oil contains at least or about or about 65%, at least 70% or about 70%, at least 75% or at least 85% DHA, typically greater than 85% DHA, and at about 75%, at least 80% or about 80%, at least 85% or about least or about at least 90% omega-3 fatty acids, typically 85%, or at least 90% or about 90%, by weight (w/w), DHA. In greater than 90% omega-3 fatty acids. In another example, the another example, the non-polar ingredient contains between fish oil can contain 98% PUFA, 89% omega-3 fatty acids, 5% or about 5% and 15% or about 15% EPA, for example, 5, about 70% DHA, about 10% EPA, 8.9% omega-6 fatty acids 6,7,8,9, 10, 11, 12, 13, 14 or 15%, by weight (w/w), EPA. In and 0.7% omega-9 fatty acids. another example, the non-polar ingredient comprises not 0439 Exemplary of a fish oil containing high amounts of more than 10% or about 10% EPA or less than 10% or about omega-3 fatty acids that can be used as the non-polar ingre 10%, EPA. In another example, the non-polar ingredient con dient in the provided concentrates is an omega-3 fish oil EE tains DHA and EPA, for example, DHA representing at least (O3C Nutraceuticals; supplied by Jedwards International 20% or about 20%, by weight, of the non-polar ingredient and Inc., Quincy, Mass.), which contains 89% omega-3 fatty EPA representing not more than 13% or about 13% of the acids, 8.9% omega-6 fatty acids, 0.7% omega-9 fatty acids, non-polar ingredient, for example, not more than 10% or 0.1% saturated fatty acids, 1.0% monounsaturated fatty acids, about 10%, by weight, of the non-polar ingredient. In another 74.5% docosahexanoic (DHA) fatty acids, 9.3% eicosapen example, the non-polar ingredient contains DHA, represent taenoic (EPA) fatty acids and 98% polyunsaturated fatty acids ing at least 35% or about 35% of the non-polar ingredient and (PUFA). This fish oil also contains 0.1% (16:0) palmitic acid, EPA representing not more than 13% or about 13% of the 0.1% (16:1 ()7) palmitoleic acid, 0.1% (18:0) stearic acid, non-polar ingredient, for example, not more than 10% or 0.6% (18:1 (09) oleic acid, 0.1% (18:1 (07) oleic acid, 0.3% about 10% of the non-polar ingredient. In another example, (18:2 (p6) linoleic acid, 0.2% (18:3 (03) linolenic acid, 0.2% the non-polar ingredient contains DHA and EPA, for (18:4 (03) octadecatetraenoic acid, 0.1% (20:1 (09) eicosanoic example, DHA representing at least 70% or about 70% of the acid, 0.1% (20:2 ()6) eicosadienoic acid, 0.2% (20:3 (D6) non-polar ingredient and EPA representing not more than eicosatrienoic acid, 2.4% (20:4 (06) arachidonic acid, 0.6% 13% or about 13% of the non-polar ingredient, for example, (20:4 (O3) arachidonic acid, 0.1% (22:1 () 11) erucic acid, not more than 10% or about 10% of the non-polar ingredient. 0.6% (21:5 (03) uncosapentaenoic acid, 0.5% (22:4 (06) doco In one example, the non-polar ingredient contains DHA and satetraenoic acid, 5.4% (22:5 (06) docosapentaenoic acid, EPA, for example, the total of DHA and EPA represents at 3.6% (22:5 (03) docosapentaenoic acid and 0.9% other fatty least 30% or about 30% of the non-polar ingredient. In acids. another example, the non-polar ingredient contains DHA and 0440 Also exemplary of a fish oil containing high EPA, for example, the total of DHA and EPA represents at amounts of omega-3 fatty acids that can be used in the pro least 61% or about 61% of the non-polar ingredient. vided concentrates is Omega Concentrate 85 DHA TG Ultra 0435 (i) Fish Oils (O3C Nutraceuticals AS, Oslo, Norway), which contains 0436 Exemplary of the PUFA-containing non-polar greater than 85% DHA (C22:6n-3) and greater than 90% total ingredients that can be used in the provided concentrates, e.g. omega-3 fatty acids and is isolated from fatty fish species in pre-emulsion concentrates and liquid nanoemulsion concen the Eugraulidae, Clupeidae and Scombridae families. This trates, are oils derived from fish which contain DHA, EPA or fish oil is produced by purifying and concentrating the oils both DHA and EPA. Particularly, cold water marine fish are a from these fish with gentle technologies to increase the con known source of omega-3 fatty acids (U.S. Pat. No. 4,670. centration of omega-3 fatty acid DHA. Any fish oil containing 285). Suitable fish oils containing DHA, EPA or both DHA DHA and/or EPA can be used as the non-polar ingredient in and EPA can be obtained from any of a number of commercial the provided compositions. Also exemplary of the fish oils are US 2016/008 1976 A1 Mar. 24, 2016 42 other fish oils made by O3C Nutraceuticals, AS and other fish at least 70% triglycerides, which contain about 20-35% DHA oils Supplied by Jedwards International, Inc. and lack EPA, isolated from Crypthecodinium cohnii, in one 0441 Any fish oil containing DHA and/or EPA can be example containing more than 70% triglycerides, having used as the non-polar ingredient in the provided concentrates. 15-20% myristic acid; 20-25% palmitic acid; 10-15% oleic Exemplary of the fish oils that can be included in the provided acid; 30-40% DHA; and 0-10% other triglycerides. U.S. Pat. compositions is EternatM OmegasourceTM Oil (supplied by No. 5,711,983 describes, interalia, single cell edible oils (and Hormel Foods Specialty Products Division, Austin, Minn.), methods for making the oils) containing at least 70% triglyc which contains at least 30% omega-3 fatty acids (DHA, EPA erides, which contain about 20-35% DHA and lack EPA, and ALA), is odorless, virtually free of cholesterol and bland isolated from Crypthecodinium cohnii, in one example, con in flavor. This fish oil contains about 28% DHA and EPA, taining more than 70% triglycerides, having 15-20% myristic typically 17% EPA and 11% DHA, and additionally contains acid; 20-25% palmitic acid; 10-15% oleic acid; 30-40% 4.5% omega-6 fatty acids. Also exemplary of the fish oils that DHA; and 0-10% other triglycerides. can be included in the provided compositions are Omega 30 0445 Also exemplary of suitable microalgae oils are those TG Food Grade (Non-GMO) MEG-3TM Fish Oil (supplied by disclosed, for example, in U.S. Pat. No. 6,977,166 and U.S. Ocean Nutrition Canada, Dartmouth, Nova Scotia, Canada), Publication No. US 2004/0072330. Any oil derived from a kosher fish oil which contains about 30% DHA/EPA and dinoflagellate, for example, microalgae, which contains Marinol C-38 (supplied by Lipid Nutrition B.V., Channahon, DHA, and optionally EPA, is suitable as an algae oil for use Ill.), which contains about 52% omega-3 fatty acids, includ with the provided compositions, for example, V-Pure algae ing at least 38% DHA/EPA, more specifically includes about oil (Water4Life, Switzerland), which contains EPA and 22% EPA and 14% DHA. Also exemplary of fish oils are DHA, and Martek DHATM-S (supplied by Martek Bio Marinol D-40 (supplied by Lipid Nutrition B.V., Channahon, sciences Corporation, Columbia, Md.), derived from the Ill.), which contains about 40% DHA and 7% EPA; omega-3 marine alga Schizochytrium sp., containing not less than 35% fish oil 70TG that is 61% by weight DHA/EPA; fish oils sold DHA and 16.1% (22:5 (p6) docosapentaenoic acid, 1.3% by GC Rieber Oils (Kristiansund, Norway) that contain 30% (20:5 (03) eicosapentaenoic acid, 0.6% (20:4 (06) arachidonic or 65% DHA. ONCTG fish oil sold by Ocean Nutrition acid, 1.6% (18:2 (06) linoleic acid, 16.9% (18:1 (09) oleic acid Canada (Dartmouth, Nova Scotia); OmevitalTM 30% MP and 19.8% other fatty acids. Gold, a fish oil that contains 30% DHA/EPA (Cognis, Mon 0446 (2) Flax Seed Oil Omega 3 (ALA) heim am Rhein, North Rhine-Westphalia, Germany); and a 0447. Also exemplary of the omega-3 containing non fish oil containing 60% DHA (sold by FINALLC, Cincinnati, polar ingredients used in the provided concentrates, e.g., pre Ohio). Also exemplary of the fish oils are krill oils, such as emulsion concentrates and liquid nanoemulsion concen those made according to International Publication No. WO trates, is flaxseed oil (linseed oil). Flaxseed oils, which are 2007/080515. good sources of omega-3 fatty acids, particularly alpha-lino 0442 (ii) Algae Oil lenic acid, have been used as nutritional Supplements. Flax 0443 Also exemplary of non-polar ingredients containing seed oils are produced by pressing the flaxseed and refining omega-3 PUFAs, particularly DHA (and optionally EPA), the oil from the flaxseeds. Exemplary of flaxseed oil that can that can be used as the non-polar ingredient in the provided be used as the non-polar ingredient in the provided composi concentrates, e.g., pre-emulsion concentrates and liquid tions is flaxseed oil derived from Linum usitatissimum L. nanoemulsion concentrates, are oils derived from microor Exemplary of flaxseed oils suitable for use in the concentrates ganisms, for example, oils derived from marine dinoflagel provided herein include flaxseed oil supplied by Sanmark lates, such as microalgae, e.g., Crypthecodinium sp. particu LLC (Greensboro, N.C.; Sanmark Limited, Dalian, Liaoning larly Crypthecodinium cohnii. Microalgae oils, like fish oils, Province, China), which contains not less than (NLT) 50% are an excellent Source of omega-3 fatty acids, particularly C18:3 alpha-linolenic acid, and further contains other fatty DHA (U.S. Pat. Nos. 5,397,591; 5,407,957; 5.492,938; and acids, for example, 3-8% C16:0 palmitic acid, 2-8% C18:0 5,711,983). Exemplary of oils derived from microalgae are stearic acid, 11-24% C18:1 oleic acid, 11-24% C18:2 linoleic the oils disclosed in (and oils made according to the methods acid and 0-3% other fatty acids. Also exemplary of suitable described in) U.S. Pat. Nos. 5,397,591; 5,407,957;5.492,938; flaxseed oil is a flaxseed oil containing 6% palmitic acid, and 5,711,983 and U.S. Publication No. 2007/0166411, 2.5% stearic acid, 0.5% arachidic acid, 19% oleic acid, 24.1% including DHASCOR) and DHASCO-S(R) (Martek Bio linoleic acid, 47.4% linolenic acid, and 0.5% other fatty acids. Sciences Corporation). The fatty acid composition of flaxseed oil can vary. Any 0444) For example, U.S. Pat. No. 5,397,591 describes, flaxseed oil can be used as the non-polar ingredient in the interalia, single-cell edible oils (algae oils) (and methods for provided compositions. For example, the flaxseed oil can making the oils), which contain at least 70% triglycerides, contain at least or about at least 50%, at least or about at least which contain about 20-35% DHA and lack EPA, isolated 65%, or at least or about at least 70% alpha-linolenic acid. from Crypthecodinium cohnii, preferably containing more Exemplary of a flaxseed containing greater than 65% lino than 70% triglycerides, having 15-20% myristic acid; lenic acid content (of total fatty acid content), for example, 20-25% palmitic acid; 10-15% oleic acid; 30-40% DHA; and 70-80% or 70-75%, is the flaxseed described in U.S. Pat. No. 0-10% other triglycerides. U.S. Pat. No. 5,407,957 describes, 6,870,077. interalia, algae oils (and methods for making the oils) derived 0448 (b) Omega-6 Compounds from Crypthecodinium cohnii, preferably containing greater 0449 Also exemplary of the non-polar ingredients used in than about 90% triglycerides, at least 35% DHA, by weight the provided concentrates, e.g., pre-emulsion concentrates (w/w), in one example, having 15-20% myristic acid; 20-25% and liquid nanoemulsion concentrates, are ingredients con palmitic acid; 10-15% oleic acid; 40-45% DHA; and 0-5% taining omega-6 PUFAs, for example, gamma-linolenic acid other oils. U.S. Pat. No. 5.492.938 describes, interalia, single (GLA), for example, borage oil and evening primrose cell edible oils (and methods for making the oils) containing (Oenothera biennis) oil, blackcurrant seed oil, hemp seed oil, US 2016/008 1976 A1 Mar. 24, 2016 fungal oil and spirulina extract. Any oil containing omega-6 tional Supplements. Exemplary of the non-polar ingredients fatty acids can be used in the provided compositions. Exem containing conjugated fatty acids are compounds containing plary of the omega-6 containing non-polar ingredients are conjugated linoleic acid (CLA), for example, 18:2 (p7 and ingredients containing GLA, for example, borage oil. GLA is 18:2 (06; conjugated linolenic acid, for example, 18:3c)6 and an omega-6 PUFA, which primarily is derived from vegetable 18:3c)5; and other conjugated fatty acids, for example, 18:3 oils, for example, evening primrose (Oenothera biennis) oil, ()3, 18:4 (03 and 20:5 ()6. CLA refers to a family of linoleic blackcurrant seed oil, hemp seed oil, and spirulina extract. acid isomers found primarily in meat and dairy products of GLA has been used as a nutritional Supplement. It has been ruminants. Typically, the CLA compounds contain a mixture proposed that GLA has a role in treating various chronic of different CLA isomers, for example, C18:2 CLA c9, t11, diseases and in particular that it has anti-inflammatory effects CLAt 10, c12 and other CLA isomers. Exemplary of the CLA (Fan and Chapkin (1998).J. Nutr. 128(9): 141 1-1414). In one that can be used as a non-polar ingredient in the provided example, the non-polar ingredient contains at least or about at compositions is CLA (70%) commercially available from least 22 wt % of GLA, for example, 22, 23, 24, 25, 26, 27, 28. Sanmark, LTD (Dalian, Liaoning Province, China; product 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60 wt % or code 01.057-A80). This CLA is a clear white to pale yellow oil more, by weight, of GLA. and has the following fatty acid composition: NMT (not more 0450 Borage (Borago officinalis), also known as “star than) 9.0% C16:0 palmitic acid, NMT 4.0% stearic acid, flower, is an herb with seeds containing high amounts of NMT 15.0% C18:1 oleic acid, NMT 3.0% C18:2 linoleic GLA. Exemplary of borage oils that can be used as a non acid, NLT (not less than) 80% C18:2 CLA (including the polar ingredient in the provided compositions are borage oils following isomers: NLT 37.5% C18:2 CLA c9, t11, 37.5% supplied by Sanmark LLC (Greensboro, N.C.; Sanmark Lim C18:2 CLA t10, c12, and NMT 5.0% other CLA isomers): ited, Dalian, Liaoning Province, China), derived by pressing and NMT 5.0% other fatty acids. Another exemplary CLA and isolating oil from the seeds of Borago officinalis L. This compound is a CLA that contains 74.5% CLA (Clarinol R. oil contains not less than (NLT) 22% C18:3 gamma-linolenic CLA, Stepan Lipid Nutrition, Maywood, N.J.). Other CLA acid (GLA), between 9 and 12% C16:0 palmitic acid, containing compounds can be used. between 3% and 5% C18:0 stearic acid, between 15% and 0455 ii. Coenzyme Q Compounds 20% C18:1 oleic acid, between 35% and 42% C18:2 linoleic 0456 Exemplary of the non-polar ingredients are ingredi acid, between 3% and 5% C20:1 ocosenoic acid, between 1% ents that are or contain the non-polar compound coenzyme Q. and 4% C22:1 docosenoic acid and between 0% and 4% other for example, coenzyme Q10 (also called coO10, ubiquinone, fatty acids. Other borage oils can be used. Other GLA-con ubidecarenone, ubiquinol and vitamin Q10). Coenzyme Q taining oils also can be used as the non-polar ingredient. compounds are benzoquinone compounds containing isopre 0451 (c) Saw Palmetto Extract nyl units. The number of isoprenyl units in each of the differ 0452. Also exemplary of the non-polar ingredients used in ent CoQ species is indicated with a number following CoQ. the provided concentrates, e.g., pre-emulsion concentrates For example, coO10 contains 10 isoprenyl units. Coenzyme and liquid nanoemulsion concentrates, is saw palmetto Q10 is a predominant coenzyme Q species. extract, a lipophilic extract of the ripe berries of the American 0457 Coenzyme Q can exist in two different forms: an dwarf palm (also called Serenoa repens or Sabal serrulata), oxidized formanda reduced form. When the oxidized form of which has been used to treat genitourinary and other diseases a coenzyme Q species is reduced by one equivalent, it and to enhance sperm production, breast size and libido, as a becomes a ubisemiquinone, denoted QH, which contains a mild diuretic, a nerve sedative, an expectorant and a digestive free radical on one of the oxygens in the benzene ring of the tract tonic, and particularly to treat benign prostate hyperpla benzoquinone. Both oxidized and reduced coenzyme Q-con sia (BHP) (Ernst (2002) Acad. Clin. 136:42-53; and Gordon taining compounds can be used as non-polar ingredients in and Shaughnessy (2003) Comp. Alt. Med. 76(6):1281-1283). the provided compositions. Saw palmetto extract is commercially available from a num 0458 Exemplary of the coenzyme Q-containing non-po ber of Sources. Any saw palmetto lipid extract can be used in lar ingredients that can be used in the provided concentrates, the provided concentrates. Exemplary of the saw palmetto e.g., pre-emulsion concentrates and liquid nanoemulsion extract that can be used in the provided concentrates is Saw concentrates, are non-polar ingredients containing coenzyme Palmetto, Lipophilic Extract, commercially available from Q10 (also called coO10, ubiquinone, ubidecarenone, Natural Medicinals, Inc. (Felda, Fla.). This saw palmetto ubiquinol and vitamin Q10), a benzoquinone compound that lipophilic extract is carbon dioxide extracted and, in one contains 10 isoprenoid units. The "Q” in the name refers to example, contains 85.9% total fatty acids, including 0.8% quinone and the 10 refers to the number of isoprenoid units. caproic acid, 2% caprylic acid, 2.4% capric acid, 27.% lauric CoQ10 typically refers to the oxidized form of coO10, which acid, 10.3% myristic acid, 8.1% palmitic acid, 0.2% palmi also is referred to as ubidecarenone, as opposed to the reduced toleic acid, 2% stearic acid, 26.7% oleic acid, 4.9% linoleic form of coO10. Both the reduced and oxidized forms of acid, 0.7% linolenic acid, 0.42% phytosterols, including coQ10 are exemplary of the coenzyme Q species that can be 0.42% beta sitosterol, 0.09% campesterol, 0.03% stigmas used as non-polar ingredients in the provided concentrates. terol; and 0.2% moisture. Other sources of saw palmetto 0459 CoQ10 has electron-transferability and is present in extract can be used. cellular membranes, such as those of the endoplasmic reticu 0453 (d) Conjugated Linoleic Acid (CLA) lum, peroxisomes, lysosomes, vesicles and the mitochondria. 0454. Also exemplary of the PUFA non-polar ingredients A decrease in natural coQ10 synthesis has been observed in that can be used in the provided concentrates, e.g., pre-emul sick and elderly people. Because of this observation and its sion concentrates and liquid nanoemulsion concentrates, are potent antioxidant properties, coO10 is used as a dietary non-polaringredients containing conjugated fatty acids. Con Supplement and a treatment for diseases Such as cancer and jugated fatty acids are PUFAs with two or more conjugated heart disease. CoQ10, however, exhibits relatively poor bio double bonds. Conjugated fatty acids can be used as nutri availability. US 2016/008 1976 A1 Mar. 24, 2016 44

0460 CoQ10 containing compounds are available com be used as non-polar ingredients in the provided composi mercially. Any coQ10 compound or reduced coO10 com tions are compounds containing plant Sterols, for example, pound can be used with the provided concentrates, e.g., pre the compound sold under the name Cardio AidTM, distributed emulsion concentrates and liquid nanoemulsion by B&D Nutrition and manufactured by ADMNatural Health concentrates. Exemplary of the coO10 compounds that can be and Nutrition, Decatur, Ill. This compound contains kosher, used are coenzyme Q10 compounds containing greater than pareve, and halal plant sterols that are produced under current 98% or greater than about 98% ubidecarenone, for example, food GMPs. The sterols are PCR negative and the material is the compound sold under the name Kaneka Q10TM (USP derived from genetically modified organisms (GMOs). This Ubidecarenone) by Kaneka Nutrients, L.P. (Pasadena, Tex.). phytosterol compound contains a minimum of 95% plant The compound sold under the name Kaneka Q10TM is fer sterols, which can include up to 5 plant Sterols. The com mented entirely from yeast and is identical to the body's own pound can contain, for example, 40-58% beta sitosterol, coQ10 and free from the cis isomer found in some syntheti 20-30% campesterol, 14-22% stigmasterol. 0-6% brassicas cally produced coQ10 compounds. Any coO10 compound terol and 0.5% sitostanol. The compound further can contain can be used in the provided concentrates. tocopherols, for example, 0-15 mg/g tocopherols. The com 0461) iii. Phytochemical-Containing Non-Polar Ingredi pound is tested and is negative for microorganisms. Such as ents Salmonella, E. coli and Staphylococcus aureus. 0462 Exemplary of the non-polar ingredients that are or 0468 (b) Resveratrol contain non-polar compounds in the provided compositions 0469 Exemplary of the phytochemical-containing com are phytochemical-containing compounds, for example, phy pounds used as non-polar ingredients in the provided compo tosterols (plant sterols), phytoestrogens, for example, sitions is resveratrol. Resveratrol, or trans-resveratrol (trans genistein and daidzein, flavonoids, for example, isoflavones, 3.5,4'-trihydroxy stilbene), is a phytoalexin that is naturally for example, soy isoflavones, phytoalexins, for example, res produced by several plants, such as the Japanese knotweed, Veratrol (trans-3.5,4'-trihydroxystilbene) and red clover and also is found in the skin and seeds of grapes, numerous eXtract. berries, including mulberry, blueberries, bilberries and cran 0463 Typically, phytochemical-containing ingredients berries, and in peanuts. This polyphenolic compound can act are added to the compositions in amounts such that when as an antioxidant and additionally aid in cancer prevention diluted in a beverage, one serving of the beverage provides and reduction of cardiovascular disease. between at or about 0.5 and at or about 10 mg. typically, 0470 Any resveratrol-containing compound can be used between at or about 1 and at or about 10 mg, between at or as a non-polar ingredient in the provided compositions. about 1 and at or about 5 mg, for example, at or about 0.5, at Exemplary of the resveratrol-containing compounds that can or about 1, at or about 2, at or about 3, at or about 4, at or about be used as non-polar ingredients in the provided composi 5 mg, at or about 6 mg, at or about 7 mg, at or about 8 mg, at tions are compounds containing trans-resveratrol, for or about 9 mg or at or about 10 mg phytochemical-containing example the compounds sold under the name ReserveNa compound, for example phytochemical-containing com tureTM, sold by Jiaherb, Shaanxi, China. This compound con pound, per serving of the beverage. Such as for example, 8 tains trans-resveratrol from the botanical Source Polygonum ounces of a beverage. cuspidatum (Japanese knotweed). This resveratrol compound 0464 (a) Phytosterols contains a minimum of 98.5% trans resveratrol and does not 0465 Exemplary of the phytochemical-containing com contain emodin. The compound is tested and is negative for pounds that contain non-polar ingredients in the provided microorganisms, such as Salmonella, E. coli, yeast and mold. compositions are phytosterols (plant sterols). Plant sterols are 0471 iv. Carotenoid-Containing Compounds structurally similar to cholesterol and have been found to 0472. Exemplary of the non-polar ingredients that are or reduce the absorption of dietary cholesterol, which can affect contain non-polar compounds and are use in the provided the levels of serum cholesterol. According to the U.S. Food compositions are carotenoid-containing ingredient, for and Drug Administration (FDA), two servings per day, each example, carotenoids, including hydrocarbons (carotenes) containing 0.4 grams of plant sterols, for a total daily intake of and oxygenated, alcoholic derivatives of hydrocarbons (Xan at least 0.8 grams, as part of a diet low in Saturated fat and thophylls), for example, beta carotene, mixed carotenoids cholesterol, is reported to reduce the risk of heart disease. complex, lutein, Zeaxanthin, cryptoxanthin, for example, Thus, plant sterols are used in nutritional Supplements. beta-crytoxanthin, lycopene, beta carotene, mixed caro 0466 Phytosterol non-polar ingredients are typically tenoids complex, astaxanthin, bixin, canthaxanthin, capsan added to the compositions in amounts such that when diluted thin, capsorubin, apo-carotenal, beta-12'-apo-carotenal, in a beverage, one serving of the beverage provides between "carotene' (mixture of alpha and beta-carotene), gamma at or about 100 and at or about 1000 mg. typically between at carotene, ciolerythrin and esters of hydroxyl- or carboxyl or about 100 and at or about 500 mg, between at or about 100 containing members thereof. Carotenoids are efficient free and at or about 800 mg, between at or about 300 and at or radical scavengers, or anti-oxidants, and are capable of about 500 mg, between at or about 300 and at or about 800 enhancing the vertebrate immune system. mg, between at or about 500 and at or about 1000 mg, for 0473. Typically, carotenoid-containing compounds are example, at or about 100, at or about 200, at or about 300, at used in the provided compositions within a concentration or about 400, at or about 500, at or about 600, at or about 700, range of between 0% or about 0% and 10% or about 10%, at or about 800, at or about 900 or at or about 1000 mg typically between 0% or about 0% and 5% or about 5%, for phytosterols, per serving of the beverage. Such as for example, at or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% example, 8 ounces of a beverage. or 10%, w/w, of the beverage composition. 0467. Any phytosterol-containing compound can be used 0474 (a) Carotenes as a non-polar ingredient in the provided compositions. 0475 Exemplary of the carotenoid-containing com Exemplary of the phytosterol-containing compounds that can pounds used as non-polar ingredients in the provided bever US 2016/008 1976 A1 Mar. 24, 2016

age compositions are carotenes, for example, alpha-carotene, Ingredients, Inc., Fullerton, Calif.; vitamin B12: Vitamin B1; beta-carotene and lycopene. Any carotene-containing com vitamin B3; vitamin B5; and vitamin B6. pound can be used as a non-polar ingredient in the provided compositions. Exemplary of the carotene-containing com 0483 Typically, vitamin non-polar ingredients are pounds that can be used as non-polar ingredients in the pro included in the provided compositions within a concentration vided compositions is lycopene, sold by Zhejiang Medicine range of between 0.0001% or about 0.0001% and 1% or about CO., LTD, Xinchang Pharmaceutical Factory, Xinchang, 1%, more typically between at or about 0.001% and at or China, a purple or red crystalline powder containing not less about 0.1%, for example, at or about 0.0001%, 0.0005%, than 70% all E-lycopene, not more than 23% 5-Z-lycopene 0.0008%, 0.0009%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.5% or and not more than 9% related substances. 1%, W/w, of the beverage composition. Vitamin non-polar 0476 (b) Xanthophylls ingredients are typically added to the beverage compositions 0477 Exemplary of the carotenoid-containing com in amounts such that one serving of the beverage provides an pounds used in the provided compositions are Xanthophylls, amount of the vitamin that corresponds to the dietary refer for example, neoxanthin, violaxanthin, C- and B-cryptoxan ence intakes. For example, Vitamin A is added such that a thins, lutein and Zeaxanthin. Xanthophylls, or phylloxan serving of the beverage provides between at or about 10 to at thins, are oxygen containing carotenoids that are typically or about 2000 micrograms (mcg), for example, between at or yellow pigments. Any carotene-containing compound can be about 20 to at or about 900mcg, more typically between at or used as a non-polar ingredient in the provided compositions. about 40 to at or about 400 mcg of vitamin A per serving, for Exemplary of the carotene-containing compounds that can be example, between at or about 40 and at or about 200 mcg, or used as non-polar ingredients in the provided compositions between at or about 100 and at or about 400 mcg, or between are lutein and zeaxanthin, sold under the name Xanmax(R-80 at or about 100 and at or about 300 mcg per serving. For (Lutein crystals), by Katra Phytochem (India) Private Lim example, the beverage composition can contain 40 or about ited, Bangalore, India, containing 80% lutein and 4.5% zeax 40, 50 or about 50, 60 or about 60, 70 or about 70, 80 or about anthin. 80, 90 or about 90, 100 or about 100, 110 or about 110, 120 or 0478 v. Micronutrient-Containing Compounds about 120, 130 or about 130, 140 or about 140, 150 or about 0479. Exemplary of the non-polar ingredients that are or 150, 200 or about 200, 250 or about 250, 300 or about 300, contain non-polar compounds that are used in the provided 350 or about 350, or 400 or about 400 mcg vitamin Aper compositions are micronutrient-containing ingredients, for serving. In another example, Vitamin D3 is added such that a example, vitamins, including vitamins A, B, C, D, E and K, serving of the beverage composition provides between at or and corresponding provitamins and vitamin derivatives with about 100 to at or about 2000 International Units (IU), for an action resembling that of vitamin A, B, C, D, E or K, and example, between at or about 100 to at or about 1000 IU, more alpha lipoic acid (thioctic acid), yerba mate, ginseng and typically, between at or about 400 and at or about 800 IU, per ginkgo biloba. serving, for example between at or about 400 and at or about 0480 (a) Vitamins 600 or between at or about 500 and at or about 800, or 0481 Exemplary of the vitamins used as non-polar ingre between at or about 600 and at or about 800 IU per serving. dients in the provided compositions are fat-soluble vitamins, For example, the beverage composition can contain 400 or for example, Vitamins A, B, C, D, E and K, and corresponding about 400, 450 or about 450, 500 or about 500, 550 or about provitamins and vitamin derivatives, such as esters with an 550, 600 or about 600, 650 or about 650, 700 or about 700, action resembling that of vitamin A, B, C, D, E or K, for 750 or about 750 or 800 or about 800 IU vitamin D3 per example, retinol (vitamin A) and pharmaceutically accept serving. In another example, vitamin B12 is added such that able derivatives thereof, for example, palmitate ester of ret a serving of the beverage composition provides between at or inol and otheresters of retinol, for example, Vitamin A palmi about 1 and 12 mcg, such as 1 or about 1, 2 or about 2, 2.4 or tate; B vitamins, for example, thiamin (vitamin B1). about 2.4, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid 6, 8 or about 8, 10 or about 10 or 12 or about 12 mcg vitamin (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), B12 per serving. In another example, vitamin B1 is added folic acid or folate (vitamin B9), and cyanocobalamin, cobal Such that a serving of the beverage composition provides amin, or reduced forms of cobalamin (vitamin B12); calcif between at or about 0.2 and 1.4 mg, such as 0.2 or about 0.2, erol (vitamin D) and its pharmaceutically acceptable deriva 0.3 or about 0.3, 0.4 or about 0.4,0.5 or about 0.5,0.6 or about tives thereof, for example, for example, cholecalciferol 0.6,0.7 or about 0.7, 0.8 or about 0.8, 0.9 or about 0.9, 1.0 or (vitamin D3), and precursors of vitamin D; d-alpha toco about 1.0, 1.1 or about 1.1, 1.2 or about 1.2, 1.3 or about 1.3 pherol (vitamin E) and derivatives thereof, including pharma or 1.4 or about 1.4 mg vitamin B1 per serving. In another ceutical derivatives thereof, for example, tocotrienols, d-al example, vitamin B3 is added such that a serving of the phatocopherol acetate and otheresters of d-alpha tocopherol; beverage composition provides between at or about 2 and 18 and ascorbyl palmitate, a fat-soluble version of vitamin C. mg, such as 2 or about 2, 3 or about 3, 4 or about 4, 5 or about 0482 Any vitamin can be used as a non-polar ingredient in 5, 6 or about 6, 7 or about 7, 8 or about 8, 9 or about 9, 10 or the provided compositions. Exemplary of the vitamins that about 10, 11 or about 11, 12 or about 12, 13 or about 13, 14 or can be used as non-polar ingredients in the provided compo about 14, 15 or about 15, 16 or about 16, 17 or about 17 or 18 sitions are vitaminA palmitate, for example, vitaminA palmi or about 18 mg vitamin B3 per serving. In another example, tate containing 1.7 mIU/g, produced by DSM Nutritional vitamin B5 is added such that a serving of the beverage Products, Inc., Belvidere, N.J., and distributed through composition provides between at or about 1.7 and 7 mg. Such Stauber Performance Ingredients, Inc., Fullerton, Calif.; Vita as 1.7 or about 1.7, 1.8 or about 1.8, 1.9 or about 1.9, 2 or min D3, for example, vitamin D3 in corn oil, containing about about 2, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about 6 1 mIU/g, produced by DSM Nutritional Products, Inc., Bel or 7 or about 7 mg vitamin B5 per serving. In another videre, N.J., and distributed through Stauber Performance example, vitamin B6 is added Such that a serving of the US 2016/008 1976 A1 Mar. 24, 2016 46 beverage composition provides between at or about 0.1 and 6%, between at or about 0.1% and at or about 5%, between at 2.0 mg, such as 0.1 or about 0.1, 0.2 or about 0.2,0.3 or about or about 0.1% and at or about 4%, between at or about 0.1% 0.3, 0.4 or about 0.4, 0.5 or about 0.5,0.6 or about 0.6,0.7 or and at or about 3%, between at or about 0.1% and at or about about 0.7, 0.8 or about 0.8, 0.9 or about 0.9, 1.0 or about 1.0, 2%, between at or about 0.1% and at or about 1%, between at 1.1 or about 1.1, 1.2 or about 1.2, 1.3 or about 1.3, 1.4 or about or about 0.5% and at or about 7%, between at or about 0.5% 1.4, 1.5 or about 1.5, 1.6 or about 1.6, 1.7 or about 1.7, 1.8 or and at or about 6%, between at or about 0.5% and at or about about 1.8, 1.9 or about 1.9 or 2.0 or about 2.0 mg vitamin B6 5%, between at or about 0.5% and at or about 4%, between at per serving. or about 0.5% and at or about 3%, between at or about 0.5% 0484 (b) Alpha-Lipoic Acid (Thioctic Acid) and at or about 2%, between at or about 0.5% and at or about 0485 The alpha lipoic acid non-polar ingredients include 1%, betweenator about 1% and at or about 7%, betweenator the alpha-lipoic acids sold by NutriChem Resources Com about 1% and at or about 6%, between at or about 1% and at pany (Walnut, Calif.) and Zhejiang Medicines & Health Prod or about 5%, between at or about 1% and at or about 4%, ucts Import & Export Co., Ltd (Hangzhou, China) and other between at or about 1% and at or about 3%, between at or alpha-lipoic acids. Typically, alpha-lipoic acid is used in the about 1% and at or about 2%, between at or about 2% and at provided compositions within a concentration range of or about 7%, between at or about 2% and at or about 5%, between 0% or about 0% and 10% or about 10%, typically between at or about 2% and at or about 4%, between at or between 0% or about 0% and 5% or about 5%, for example, about 3% and at or about 7%, between at or about 3% and at at or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, or about 5%, between at or about 4% and at or about 7%, W/w, of the beverage composition. between at or about 6% and at or about 7%, between at or 0486 vi. Boswellia Extracts about 5% and at or about 7%, or between at or about 5% and 0487 Exemplary of non-polar ingredients included in the at or about 6%, by weight, of the beverage composition. In compositions herein are non-polar ingredients containing Some examples, the amount of alkaloid used in the provided extracts of a Boswellia plant or a boswellic acid or derivative beverage compositions is less than 7% or about 7%, typically thereof. Extracts of the Boswellia family of plants, including, less than 5% or about 5%, for example at or about 0.01%. for example, Boswellia Serrata, exhibit anti-inflammatory, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, anti-arthritic and anti-ulcerogenic activity (see, e.g., U.S. Pat. 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, No. 6,589.516). Extracts derived from Boswellia plants and 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, Suitable for use in the pre-gel concentrates provided herein 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, include extracts derived from Boswellia Carteni, Boswellia 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, Frereana, Boswellia Bhau-daiaina, Boswellia Serrata, and 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, Boswellia Thurifera. The extracts derived from Boswellia 4.7%, 4.8%, 4.9%, 5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, plants can be gums, oleo-gums, resins, essential oils and 5.7%, 5.8%, 5.9%, 6%, 6.2%, 6.5%, 6.7%, or 7%, by weight, residues, or mixtures thereof. A typical extract of a Boswellia of the beverage composition. plant suitable for use herein includes at least one boswellic 0491. The alkaloid-containing non-polar ingredients acid, for example, acetyl-11-keto-B-boswellic acid (AKBA). include caffeine that is added in the form of caffeine anhy Exemplary of a Boswellia extract-containing compound that drous, such as the Caffeine Anhydrous powder (white, crys can be used as the non-polar ingredient in the provided pre talline powder), sold by Pacific Rainbow International, Inc., gel concentrates is sold under the trademark ApresFLEXR, City of Industry, CA, which is a white crystalline powder which is a formulation that includes a Boswellia Serrata containing caffeine anhydrous. The amount of alkaloid, e.g., extract that contains acetyl-11-keto-B-boswellic acid caffeine, in the composition can be between at or about 0% (AKBA), sold by PLT Health Solutions, Morristown, N.J. and at or about 50%, by weight, of the composition, and 0488 vii. Alkaloids typically is between at or about 0% and at or about 25%, such 0489 Exemplary of non-polar ingredients in the provided as at or about 0% and at or about 10%, or between at or about pre-gel concentrates are non-polar ingredients that are or 0% and at or about 5%, e.g., at or about 0%, 0.01%, 0.015%, containan alkaloid, for example, any edible or food-approved 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.05%, 0.06%, alkaloid. Exemplary suitable alkaloids include, but are not 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, limited to, caffeine, Synephrine, and Y-aminobutyric acid 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1% 1.5%, 2%, 2.5%, 3%, (GABA) derivatives, e.g., 4-amino-3-phenylbutyric acid (i.e., 3.5%, 4%, 4.5%. 5%, 6%, 7%, 8%, 9%, or 10%, such as phenibut). Other exemplary non-polar ingredients containing between at or about 0% and at or about 3%, by weight, of the alkaloids include herbal extracts, medicinal extracts and com composition, e.g., between at or about 0% and 2%, e.g., at or pounds from plants and drugs. Suitable alkaloids for inclu about 2%, by weight, of the composition, or is less than 5%, sion in the provided pre-gel concentrates are a matter of by weight, of the composition, e.g., at or about 5.4.3, 2 or 1%, design choice and well within the skill of the skilled artisan. by weight, of the composition, or less. In one example, the 0490 The amount of alkaloid depends upon the desired or composition contains at or about 2%, by weight, caffeine. In intended dosage and the particular compound. For example, another example, the composition contains between at or the amount of alkaloid, e.g., caffeine, included in the provided about 1 mg and at or about 500 mg caffeine per mL or per beverage compositions is typically between or between about serving, Such as a 4 mL serving of the composition, e.g., at or 0.01% and 10%, by weight, of the composition, for example, about 200, 150, 125, 100, 80, 75, 50 or 25 milligrams (mg) between at or about 0.01% and 9%, between at or about caffeine per serving of the composition, e.g., per 4 mL of the 0.01% and at or about 8%, between at or about 0.01% and at composition. or about 7%, between at or about 0.01% and at or about 6%, 0492. Other exemplary ingredients including alkaloids between at or about 0.01% and at or about 5%, between at or include herbal extracts, medicinal extracts and compounds about 0.01% and at or about 4%, between at or about 0.1% from plants and drugs. Example 10 below describes addi and at or about 3%, between at or about 0.1% and at or about tional exemplary non-polar ingredients. US 2016/008 1976 A1 Mar. 24, 2016 47

0493 viii. Cannabinoids 2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl-7,7- 0494 Cannabinoids and cannabinoid-containing com dimethyl-4-bicyclo3.1.1]hept-3-enylmethanol): pounds are exemplary of non-polar ingredients that can be rimonabant (AcompliaTM; 5-(4-chlorophenyl)-1-(2,4- included the compositions provided herein. Cannabinoids dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole include phytocannabinoids (found in the Cannabis sativa 3-carboxamide); taranabant (MK-0364; N-(2S,3S)-4-(4- plant and some other plants), endocannabinoids (produced chlorophenyl)-3-(3-cyanophenyl)-2-butanyl-2-methyl-2- naturally in the body by humans and animals), and synthetic 5-(trifluoromethyl)-2-pyridinyloxypropanamide); cannabinoids. Cannabinoids that can be included in the pre levonantradol (I(6S,6aR.9R, 10aR)-9-hydroxy-6-methyl-3- gel concentrates provided herein can be natural cannabinoids, (2R)-5-phenylpentan-2-yl)oxy-5,6,6a,7,8,9,10,10a-octahy synthetic cannabinoids, semi-synthetic cannabinoids, or mix drophenanthridin-1-yl)acetate); WIN55212-2 ((R)-(+)-2,3- tures thereof. Actual or potential therapeutic applications for dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo 1,2,3- cannabinoids include the treatment of multiple Sclerosis and de-1,4-benzoxazin-6-yl)-1-napthalenylmethanone); HU other forms of muscular spasm, migraine headache, glau 331 (3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex coma, asthma, inflammation, insomnia, high blood pressure, 2-en-1-yl-5-pentyl-1,4-benzoquinone); and any other com nausea and Vomiting, and the stimulation of appetite. Other pound having a cannabinoid-based structure or that produces potential therapeutic applications include the use of cannab effects similar to those of cannabinoids that is manufactured inoids as oxytoxic, anxiolytic, anti-convulsive, anti-depres using chemical means. sive, anti-psychotic, and anti-cancer agents. 0498 ix. Hops-Containing Compounds 0495 Exemplary phytocannabinoids derived from the 0499 Exemplary of non-polar ingredients that can be Cannabis sativa plant (commonly known as marijuana) are included in the provided compositions are ingredients that the terpenophenolic compounds A-tetrahydrocannabinol contain hops (Humulus lupulus L.), including ingredients (THC), A-tetrahydrocannabinol (A-THC) and other com isolated or derived from hops, such as extracts of hops cones, pounds structurally related to THC, cannabidiol (CBD), can for example, hops oils, hops resins or hops resin derivatives, nabigerol (CBG), cannabichromene (CBC), cannabinol hops acids or hops acid derivatives, or mixtures thereof. Hops (CBN), cannabicyclo (CBL), cannabivarin (CBV), tetrahy oils include, but are not limited to, humulene, beta-caryophyl drocannabivarin (THCV), cannabidivarin (CBDV), canna lene, mycrene, farnescene, gamma-cadinene, alpha-selinene, bielsoin (CBE), cannabicitran (CBT), cannabinodiol and alpha-cadinene. Hops contain alpha-acids, such as humu (CBDL), cannabichromevarin (CBCV), cannabigerovarin lone (C-lupulic acid), cohumulone, adhumulone, hulupone, (CBGV), cannabigerol monoethyl ether (CBGM), and mix and isoprehumulone, and beta-acids, such as lupulone, colu tures and derivatives thereof, for example, nabiximols (Sa pulone, adlupulone, tetrahydroisohumulone, and hexahydro tiveXR), a mixture of THC and CBD. Suitable phytocannab colupulone. Both alpha- and beta-acids have demonstrated inoids also include those derived from plants other than antibacterial, antioxidant, and antiinflammatory properties. Cannabis sativa, Such as, for example, lipophilic alkamides An exemplary non-polar ingredient containing hops is sold (alkylamides) derived from Echinacea plants, and other can under the trademark PerluxanTM, and that is a compound nabinoids derived from plants including, but not limited to, containing a Supercritical extract of hops cones that includes Echinacea purpurea, Echinacea angustifolia, Echinacea pal a minimum of 30% alpha-acids (including humulone, cohu lida, Acmela oleracea, Helichrysum umbraculigerum, and mulone, adhumulone, iso-cohumulone and iso-adhumulone) Radula marginate plants. and 10% beta-acids (including lupulone and colupulone), 0496 Endogenous cannabinoids are lipid-like substances such as sold by Pharmachem Laboratories, Kearny, N.J. produced in the brain and peripheral tissues that bind to and 0500 x. Antioxidants activate cannabinoid receptors present in the cell membrane, 0501) Exemplary of non-polar ingredients that can be including, but not limited to, arachidonate acid-based lipids included in the compositions provided herein are ingredients Such as anandamide (N-arachidonoylethanolamide, AEA), that contain an antioxidant or have antioxidant properties, for 2-arachidonoylglycerol (2-AG), noladin ether (2-arachidonyl example, a molecule that is capable of inhibiting the oxida glyceryl ether), N-arachidonoyl dopamine (NADA), and tion of other molecules. Antioxidants include molecules that Virodhamine (OAE). Scavenge free radicals. Suitable antioxidants include those 0497 Synthetic cannabinoids are among the cannabinoids that are used as ingredients in dietary Supplements. The anti that can be included as non-polar ingredients. Synthetic can oxidant can be a natural antioxidant or a synthetic antioxi nabinoids include any compound having a cannabinoid-like dant. structure or that produces effects similar to those of cannab 0502. Examples of antioxidants include, but are not lim inoids that is manufactured using chemical means, including, ited to hormones, carotenoids, carotenoid terpenoids, non for example, synthetic A-THC; dronabinol (MarinolR; carotenoid terpenoids, flavonoids, flavonoid polyphenolics (6aR-trans)-6a, 7.8.10a-tetrahydro-6,6,9-trimethyl-3-pentyl (e.g., bioflavonoids), flavonols, flavones, phenols, polyphe 6H-dibenzob.dpyran-1-ol): nabilone (CesametTM; (+)- nols, esters of phenols, esters of polyphenols, nonflavonoid trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1- phenolics, isothiocyanates, vitamins and vitamin cofactors, hydroxy-6-6-dimethyl-9H-dibenzob.dpyran-9-one); Such as VitaminA, Vitamin C, Vitamin E. Vitamin Ephosphate dexanabinol (6aS,10aS)-9-(hydroxymethyl)-6,6-dimethyl and ubiquinone (ubidecarenone, coenzyme Q, coenzyme 3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzoc Q10), ubiquinol, pyrroloquinoline quinone (POO), ascorbic chromen-1-ol); ajulemic acid (ResunabM; (6aR, 10aR)-3-(1, acid, citric acid, rosemary oil, minerals, such as mineral sele 1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6.6- nium and manganese, melatonin, C-carotene, B-carotene, dimethyl-6H-dibenzo(b.d)pyran-9-carboxylic acid); lycopene, lutein, Zeanthin, crypoxanthin, resveratrol, cannabinor ((E)-4-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicy eugenol, quercetin, catechin, gossypol, hesperetin, curcumin, clo3.1.1 heptan-2-yl)-3-hydroxy-5-(2-methyloctan-2-yl) turmeric, turmeric/curcumin blend, ferulic acid, thymol. phenoxy)-4-oxobut-2-enoic acid); HU 308 ((1R,2R,5R)-2- hydroxytyrosol, thyme, olive oil, lipoic acid, including alpha US 2016/008 1976 A1 Mar. 24, 2016 48 lipoic acid, glutathione, oxalic acid, tocopherol, tocopherol Liaoning Province, China), which contains not less than derived compounds, di-alpha-tocopheryl phosphate, tocot (NLT) 50% C18:3 alpha-linolenic acid. rienols, butylated hydroxyanisole, butylated hydroxytoluene, 0506. When present in the pre-emulsion concentrates pro ethylenediaminetetraacetic acid, tert-butylhydroquinone, vided herein, the non-polar solvent typically represents less acetic acid, pectin, Zeaxanthin, astaxanthin, canthaxanthin, than or about 50%, by weight (w/w), of the pre-emulsion saponins, limonoids, kaempferol, myricetin, isorhamnetin, concentrate, for example, less than or about 45%, 40%, 35%, proanthocyanidins, quercetin, rutin, luteolin, apigenin, 30%, 25%, 20%, 15%, 10%, 5% or less, by weight (w/w), of tangeritin, naringenin, eriodictyol, flavan-3-ols (e.g., antho the concentrate. cyanadins), gallocatechins, epicatechin and its gallate forms, 0507 When present in the liquid nanoemulsion concen epigallocatechin and its gallate forms, theaflavin and its gal trates provided herein, the non-polar solvent typically repre late forms, thearubigins, isoflavone phytoestrogens, sents less than or about 15%, by weight (w/w), of the pre genistein, daidzein, glycitein, anythocyanins, delphinidin, emulsion concentrate, for example, less than or about 15%, malvidin, pelargonidin, peonidin, and hops (Humulus lupulus 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%. 5%, 4%, 3%, L.)-containing compounds. In one example, the antioxidant 2%, 1% or less, by weight (w/w), of the concentrate. includes ubiquinol. In another example, the antioxidant 0508 d. Preservatives and Sterilizers includes alpha-lipoic acid. In another example, the antioxi 0509. The concentrates, e.g., pre-emulsion concentrates dant includes pyrroloquinoline quinone (POO). In yet or liquid nanoemulsion concentrates, provided herein can another example, the antioxidant includes a turmeric/cur further contain one or more preservatives (or preservativers) cumin composition. and/or sterilizers. The preservative or sterilizer can be 0503) Any non-polar ingredient that is an antioxidant or included to improve the stability of the concentrate and the has antioxidant properties can be included in the provided compositions made by diluting the concentrate, over time. compositions. Exemplary of an antioxidant that can be used Preservatives can be added to preserve the ingredients, for in the provided compositions is alpha-lipoic acid, for example, in order to prevent oxidation of the ingredients, for example, the alpha-lipoic acids sold by NutriChem Resources example, the non-polaringredients, for example, the omega-3 Company (Walnut, Calif.) and Zhejiang Medicines & Health containing compounds, for example, the DHA. Preservatives, Products Import & Export Co., Ltd (Hangzhou, China), and particularly food and beverage preservatives, are well known. any other alpha-lipoic acid. Another exemplary antioxidant Any known preservative can be used in the provided concen that can be used in the provided compositions is pyrrolo trates. Exemplary of the preservatives that can be used in the quinoline quinone (POO), such as PureQQ, sold by Nascent provided concentrates are oil soluble preservatives, for Health Science (Allentown, N.J.). Exemplary of a non-polar example, benzyl alcohol, benzyl benzoate, methyl paraben, ingredient that contains antioxidants that can be included in propyl paraben, and antioxidants, for example, Vitamin E, the provided compositions is a turmeric/curcumin composi Vitamin A palmitate and beta carotene. Typically, a preserva tion, for example, the turmeric/curcumin composition that is tive is selected that is safe for human consumption, for 95% curcumin, sold by Siddharth International, Mumbai, example, in foods and beverages, for example, a GRAS cer India. tified and/or Kosher-certified preservative, for example, ben Zyl alcohol. 0504 c. Non-Polar Solvents 0510. The preservative typically represents less than 1%, 0505. The pre-emulsion concentrates and liquid less than about 1%, 1% or about 1%, by weight (w/w), of the nanoemulsion concentrates provided herein can further con pre-emulsion concentrate or liquid concentrate or between tain a non-polar solvent, for example, an oil. The non-polar 0.1% or about 0.1% and 1% or about 1%, by weight (w/w), of Solvent can be included in the composition in addition to the the concentrate, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, non-polar ingredient and can be used to dissolve the non 0.6%, 0.7%, 0.725%, 0.75%, 0.8%, 0.9%, 1%, about 0.1%, polar ingredient. For example, the solvent can be an oil that about 0.2%, about 0.3%, about 0.4%, about 0.5%, about does not contain the non-polar ingredient. When a non-polar 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, by Solvent is included in the concentrates, it typically is used to weight (W/w), of the concentrate. dissolve the non-polar ingredient before mixing with the 0511 e. Polar Solvents other ingredients, for example, before mixing with the other 0512. The liquid nanoemulsion concentrates and the liq oil phase ingredients. For example, use of a non-polar solvent uid dilution compositions (i.e., beverages), further include can reduce the crystal size and/or increase the clarity of the polar solvents. Polar solvents are well known in the art. The aqueous liquid dilution composition containing the diluted polarity of a solvent generally indicates which compounds concentrate. Exemplary of non-polar solvents that can be are soluble in the solvent, and with which other solvents/ used in the provided concentrates are oils (in addition to the liquids the solvent is miscible. Generally speaking, polar non-polar ingredients that are or contain non-polar com compounds are more readily solubilized in water and other pounds) such as Vitamin E oil, flaxseed oil, CLA, borage oil, polar solvents than are non-polar ingredients. Polar solvents rice bran oil, D-limonene, canola oil, corn oil, MCT oil and are more likely to be miscible with water and other polar oat oil. Other oils also can be used. Exemplary of a non-polar Solvents and liquids. solvent suitable for use in the concentrates provided herein 0513. The polarity of a solvent can be assessed by mea includes vitamin E oil, such as the vitamin E oil sold by ADM Suring a number of different parameters according to well Natural Health and Nutrition under the name NovatolTM 5-67 known methods (see, e.g., Przybitek, “High Purity Solvent Vitamin E (D-alpha-tocopherol; product code 410217; Deca Guide. Burdick and Jackson Laboratories, Inc., 1980), such tur, Ill.), which contains at least 67.2% tocopherol and as by determining a property of the solvent, such as the approximately 32.8% soybean oil. Another exemplary oil dielectric constant, the dipole moment or the polarity index. includes a flaxseed oil solvent, such as the flaxseed oil from For example, polar solvents generally have high dielectric Sanmark LLC (Greensboro, N.C.; Sanmark Limited, Dalian, constants, typically dielectric constants greater than at or US 2016/008 1976 A1 Mar. 24, 2016 49 about 15 (see, e.g., Lowery et al., “Mechanism and Theory in dielectric constants of solvents, see, for example, Landolt Organic Chemistry.” Harper Collins Publishers, 3rd ed., Bornstein, New Series IV/17, “Static Dielectric Constants of 1987, p. 177), such as at or about 15, 16, 17, 18, 19, 20, 21, 22, Pure Liquids and Binary Liquid Mixtures.” Springer, 2008: 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 40, 45, 50,55, and “CRC Handbook of Chemistry and Physics.” Lide, ed., 60, 65, 70, 75, 80 85,90 or greater than 90. For example, the 82nd edition, CRC Press, 2001; for dipole moment of sol dielectric constant of water is at or about 80.10 at 20° C. Polar vents, see, for example, “CRC Handbook of Chemistry and Solvents generally have high polarity indices, typically Physics.” Lide, ed., 82nd edition, CRC Press, 2001; and for greater than at or about 3 (see, e.g., Snyder, "Classification of polarity indices of solvents, see, for example, Snyder, "Clas the solvent properties of common liquids” (1974) J. Chro sification of the solvent properties of common liquids. J. matog. A 92:223-230), such as at or about 3, 4, 5, 6, 7, 8 or 9 Chromatography A. 92:223-230, 1974). or greater than 9. Polar solvents generally have large dipole moments, typically greater thanator about 1.4 Debye, Such as 0517. When present, such as in the liquid nanoemulsion at or about 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2.2.3, 2.4, 2.5, concentrates, the amount of the polar solvent typically is 2.6, 3.0, 3.5, 4 or greater than 4 Debye (see, e.g., “CRC present in a high concentration, for example, the total amount Handbook of Chemistry and Physics. Lide, ed., 82nd edi of polar solvent as a percentage (%), by weight, of the liquid tion, CRC Press, 2001, p. 15(14)-15(18)). Other methods of concentrate (wt %) can be, e.g., from at or about 45% to at or assessing solvent polarity are known in the art, including, but about 80%, such as 45% to 50%, 45% to 55%, 45% to 60%, not limited to, the Kosower Zscale (Kosower, “An introduc 45% to 65%, 45% to 70%, 45% to 75%, 50% to 55%, 50% to tion to physical organic chemistry.” Wiley, 1969, p. 293), the 60%, 50% to 65%, 50% to 70%, 50% to 75%, 50% to 80%, donor number and donor acceptor scale (Gutmann, "Solvent 55% to 60%, 55% to 65%, 55% to 70%, 55% to 75%, 55% to effects on the reactivities of organometallic compounds' 80%, 60% to 65%, 60% to 70%, 60% to 75%, 60% to 80%, (1976) Coord. Chem. Rev. 18:225-255), and the Hildebrand 65% to 70%, 65% to 75%, 65% to 80%, 70% to 75%, 70% to solubility parameters (see, e.g., Giddings et al., "High pres 80% and 75% to 80%, by weight, of the liquid concentrate. Sure gas chromatography of nonvolatile species. Compressed Exemplary concentrations of the polar solvent in the liquid gas is used to cause migration of intractable solutes' (1968) nanoemulsion concentrate are at or about 50%, 52%, 55%, Science 162:67-73). 58%. 60%, 62%. 65%, 68%, 70%, 72% and 76% (w/w) of the 0514 Polar solvents include polar protic solvents and COncentrate. polar aprotic solvents. A polar protic solvent (e.g., water, 0518. In the provided methods for making the liquid methanol, ethanol) contains a hydrogen atom attached to an nanoemulsion concentrates, the polar solvent is added to the electronegative atom, such that the hydrogen has a proton water phase. In one example, the polar solvent is water, e.g., like character and/or the bond between the hydrogen and purified water, Such as water that is purified prior to adding it electronegative atom is polarized. Polar aprotic solvents, on to the concentrate formula, for example, by charcoal filter, ion the other hand (e.g., acetone, acetonitrile), generally do not exchange, reverse osmosis, UV sterilization and/or filtering contain positively polarized hydrogen atoms. using a filter, for example, a 50-100 micron filter. Typically, 0515. The polar solvents in the provided compositions when a filter is used, it is an endpoint ofuse filter, which filters typically are polar protic solvents, including, but not limited the water before it reaches the tank in the provided process. to, water, alcohols, such as dihydric alcohols which contain Alternatively, previously filtered water can be added to the two hydroxyl groups (for example, glycols, e.g., propylene COncentrates. glycol, ethylene glycol, tetraethylene glycol, triethylene gly 0519 f. Co-Surfactants (Emulsifiers) col, trimethylene glycol), trihydric alcohols which contain three hydroxyl groups (e.g., glycerin, butane-1,2,3-triol, pen 0520. The concentrates, e.g., pre-emulsion concentrates tane-1,3,5-triol, 2-amino-2-hydroxymethyl-propane-1,3- and liquid nanoemulsion concentrates, can further contain diol), monohydric alcohols (e.g., methanol, ethanol, pro one or more co-surfactants (emulsifiers). For example, a co panol, isopropanol, n-butanol and t-butanol) and other surfactant can be included to improve emulsification of the alcohols; and acids, such as acetic acid and formic acid. Other non-polar ingredient and/or the stability of the composition, polar solvents include, but are not limited to, acetone, aceto for example, by preventing or slowing oxidation of the non nitrile, butyl acetate, dimethylformamide, dimethyl sulfox polar ingredient. Exemplary of a co-surfactant that can be ide, dioxane, ethyl acetate, tetrahydrofuran and hexameth used in the provided concentrates is a phospholipid, for ylphosphoric triamide. Typically, the polar solventis water, or example, phosphatidylcholine. Other exemplary co-surfac is an alcohol that typically contains two or more hydroxyl tants include non-ionic Surfactants, such as Sugar-derived groups, such as a trihydric or dihydric alcohol. Such as, but not Surfactants, including fatty acid esters of Sugars and Sugar limited to, glycerol and propylene glycol. The polar solvents derivatives, and PEG-derived surfactants, such as PEG further include low molecular weight polyethylene glycols derivatives of sterols, PEG derivatives of fat-soluble vitamins (PEGs), such as PEGs having a molecular weight not more and PEG-sorbitan fatty acid esters. than at or about 600 kDa, such as between or about between 0521. When present, such as in the liquid nanoemulsion 200 kDa and 600 kDa, typically not more thanator about 400 concentrates, the amount of the co-surfactant typically is kDa, for example, not more than 200 kDa. present in a concentration less than or less than about 10%, 0516. In one example, the polar solvent has a dielectric typically less than or less than about 5%, for example, the constant greater than at or about 15, and typically between at total amount of co-surfactant as a percentage (%), by weight, or about 20 and at or about 80, such as at or about 80.1. In of the liquid concentrate (wt %) can be, e.g., less than or less another example, the polar solvent has a polarity index than about 10%, such as less than or about 5%, 4.5%, 4%, between at or about 3 and at or about 9. In another example, 3.5%, 3.15%, 3%, 2.5%, 2%, 1.75%, 1.5%, 1.25%, 1%, the dipole moment of the polar solvent is between 1.5 and 3. 0.75%, 0.5%, 0.25%, 0.15% or less, by weight, of the liquid and typically betweenator about 1.8 and 2.8, such as 1.85 (for COncentrate. US 2016/008 1976 A1 Mar. 24, 2016 50

0522 i. Phospholipids 4,710,567; 4,898,935; 4,996,309: 4,995,911; 5,011,922 and 0523 Exemplary of the co-surfactants that can be used in 5,017,697 and International Patent Pub. No. WO 2007/ the provided compositions are phospholipids. Phospholipids 082149), typically in an esterification reaction as described in are amphipathic lipid-like molecules, typically containing a U.S. Pub. No. 2012-001 6026. hydrophobic portion at one end of the molecule and a hydro 0530 Because sucrose contains eight hydroxy (OH) philic portion at the other end of the molecule. A number of groups, the esterification reaction can join the Sucrose mol phospholipids can be used as ingredients in the provided ecule to one fatty acid molecule, or can join it to a plurality of compositions, for example, lecithin, including phosphatidyl fatty acid molecules, producing different degrees of esterifi choline (PC), phosphatidylethanolamine (PE), dis cation, e.g., mono-, di-, tri- and poly- (up to octa-) fatty acid tearoylphosphatidylcholine (DSPC), phosphatidylserine esters, but primarily mono-, di- and/or tri-esters. The degree (PS), phosphatidylglycerol (PG), phosphatidic acid (PA), of esterification can depend on conditions of esterification. phosphatidylinositol (PI), sphingomyelin (SPM) or a combi The esterification reaction can be carried out with a single nation thereof. Typically, the phospholipid is phosphatidyl type of fatty acid, or a plurality of fatty acids, Such as fatty choline (PC), which sometimes is referred to by the general acids with varying carbon chain lengths, branched and linear name “lecithin.” Exemplary of the phospholipids that can be fatty acids, and/or saturated or unsaturated fatty acids. The used as co-surfactants in the provided compositions are the esterification reaction with a single fatty acid can produce a phospholipids sold by Lipoid, LLC (Newark, N.J.), for single ester, and typically forms more than one ester, such as example, Purified Egg Lecithins, Purified Soybean Lecithins, mono- di-, tri- and/or poly-esters, formed from one reaction. Hydrogenated Egg and Soybean Lecithins, Egg Phospholip The relative amounts of mono- di- tri- and/or poly-esters can ids. Soybean Phospholipids, Hydrogenated Egg and Soybean depend on reaction conditions. Phospholipids, Synthetic Phospholipids, PEG-ylated Phos 0531. The fatty acid in the sucrose fatty acid ester can be pholipids and phospholipid blends. Exemplary of the phos any fatty acid, and can contain between 4 and 28 carbon phatidylcholine that can be used as a co-surfactant in the atoms, typically between 8 and 28 carbon atoms, and typi provided compositions is the phosphatidylcholine composi cally between 8 and 25 carbon atoms, such as between 8 and tion sold by Lipoid, LLC, under the name Lipoid S100, which 18 carbonatoms, such as 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and is derived from soy extract and contains greater than or 18 carbon atoms. The fatty acid can be synthetic or naturally greater than about 95% phosphatidylcholine. occurring, and include linear and branched fatty acids. The 0524 ii. Sugar-Derived Surfactants fatty acids include, but are not limited to, myristic acid, palm 0525 Exemplary sugar-derived surfactants include, but itic acid, Stearic acid, oleic acid, caproic acid, capric (or are not limited to, Sugar fatty acid esters including fatty acid decanoic) acid, lauric acid, caprylic acid and pelargonic (or esters of sucrose, glucose, maltose and other Sugars, esterified nonanoic) acid. to fatty acids of varying lengths (e.g., containing a varying 0532. Thus, the sucrose fatty acid ester surfactants include numbers of carbons). The fatty acids typically have carbon Sucrose monoesters, diesters, triesters and polyesters, and chains between 8 and 28 carbons in length, and typically mixtures thereof, and typically contain Sucrose monoesters. between 8 and 20, or between 8 and 18 or between 12 and 18, The Sucrose fatty acid ester Surfactants include single fatty Such as, but not limited to, Stearic acid (18 carbons), oleic acid acid esters and also include homogeneous mixtures of (18 carbons), palmitic acid (16 carbons), myristic acid (14 Sucrose esters, containing members with different lengths of carbons) and lauric acid (12 carbons). Typically, the Sugar fatty acid carbon chain and/or members with different ester Surfactants are Sucrose ester Surfactants, typically degrees of esterification. For example, the Sucrose fatty acid Sucrose fatty acid ester Surfactants. ester Surfactants include mixtures of monoesters, diesters, 0526 iii. PEG-Derived Surfactants triesters, and/or polyesters. The Sugarester Surfactants further 0527 Exemplary PEG-derived surfactants include, but are include Sucrose fatty acid ester analogs and homologs and not limited to, PEG derivatives of sterols, e.g., a cholesterolor mixtures thereof. a sitosterol (including, for example, any of the PEG deriva 0533. In general, sucrose fatty acid esters, including mix tives disclosed in U.S. Pat. No. 6,632.443); PEG derivatives tures of Sucrose fatty acid esters, can have varying HLB offat-soluble vitamins, for example, some forms of vitamin A values, such as HLB values ranging from at or about 1 to at or (e.g., retinol) or vitamin D (e.g., vitamin D1-D5); and PEG about 20. The HLB value of the sucrose fatty acid ester Sorbitan fatty acid esters, such as polysorbates, including generally depends on the degree of esterification (e.g., the polyoxyethylene (20) sorbitan monooleate (also called average degree of esterification in a mixture of different polysorbate 80) and analogs (e.g., homologs) of polysorbate esters). Typically, the lower the degree of esterification (e.g., 80, such as, for example, polysorbate 20 (polyoxyethylene average degree), the higher the HLB value of the sucrose fatty (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene acid ester or mixture thereof. Exemplary Sucrose esters (20) sorbitan monopalmitate) and polysorbate 60 (polyoxy include sucrose distearate (HLB-3), sucrose distearate/ ethylene (20) Sorbitan monostearate); and Stearic acid deriva monostearate (HLB 12), sucrose dipalmitate (HLB=7.4), tives, including, for example, polyethylene glycol 400 dis Sucrose monostearate (HLB-15). Sucrose monopalmitate tearate (PEG 400DS), such as the PEG 400 DS sold by Stepan (HLB-10), sucrose monolaurate (HLB 15). Typically, the Lipid Nutrition (Maywood, N.J.). Sucrose fatty acid ester Surfactants in the provided concen 0528 iv. Sucrose Fatty Acid Ester Surfactants trates have an HLB value of between at or about 13 and at or 0529 Sucrose fatty acid ester (SFAE) surfactants contain about 20, such as at or about 13, 14, 15, 16, 17, 18, 19, or 20, one or more Sucrose fatty acid esters, which are non-ionic and typically between at or about 13 and at or about 18, such Surfactants that contain Sucrose in the hydrophilic portions as, but not limited to, HLB values of at or about 15, 16 and 17, and fatty acids in the hydrophobic portions. The sucrose fatty Such as, for example, Sucrose ester Surfactants including acid esters can be made by well-known methods (see, for Sucrose monopalmitate. Sucrose monolaurate and Sucrose example, U.S. Pat. Nos. 3,480,616; 3,644,333; 3,714,144: mono Stearate. US 2016/008 1976 A1 Mar. 24, 2016

0534. The sugar ester surfactants include sucrose ester than gum, guar gum and Sodium alginate. Exemplary of Such blends, for example. Sucrose ester mixtures containing a an emulsion stabilizer includes the emulsion stabilizer sold specified amount (e.g., percent, by weight) of Sucrose under the brand name SALADIZER(R), available from TIC monoesters. Exemplary Surfactants include Sucrose ester Gums, Inc. (Belcamp, Md.). Other gums can be included in mixtures having at least at or about 50%, by weight (w/w), the emulsion stabilizer, for example, gum acacia, ester gums monoester, such as at least or about at least 50, 51, 52, 53, 54, and Sugar beet pectin. Exemplary emulsion stabilizers 55,56, 57,58, 59, 60, 61, 62,63, 64, 65, 66, 67,68, 69,70, 71, include modified food starches. These include the modified 72, 73,74, 75,76, 77,78, 79,80, 81,82, 83, 84,85, 86, 87,88, gum acacia sold under the name Tic Pretested R Ticamulsion 89,90,91, 92,93, 94, 95, 96, 97,98, 99 or 100%, by weight A-2010 Powder, available from TIC Gums, Inc. (Belcamp, (w/w), sucrose monoesters, and typically at least at or about Md.). Other exemplary emulsion stabilizers containing an 60%, by weight, or at least at or about 70%, by weight (w/w), ester gum are, for example, the emulsion stabilizer sold under monoesterS. the name Tic Pretested(R) Ester Gum 8BG, available from TIC 0535 The sucrose fatty acid ester surfactants include Gums, Inc. (Belcamp, Md.) or Ester Gum 8BG, available Sucrose fatty acid monoesters, such as Sucrose monocapry from Hercules/Pinova (Brunswick, Ga.). Others sold by late. Sucrose monodecanoate. Sucrose monolaurate. Sucrose Ingredion, Inc (Westchester, Ill.) under the trademarks CAP monomyristate. Sucrose monopalmitate. Sucrose monostear SULR, FIRMTEXR, THERMFLOR), THERMTEXR, and ate, Sucrose monopelargonate. Sucrose monoundecanoate, TEXTRAR) and others, can be included in the compositions Sucrose monotridecanoate, Sucrose monopentadecanoate and provided herein. Other blends of similar gums can also be Sucrose monoheptadecanoate. The Sucrose fatty acid esters used as emulsion stabilizers. further include mixtures containing varying percentages of 0540. The emulsion stabilizer can be added to the water monoesters, diesters, triesters and polyesters, such as, but not phase, the oil phase, or both the water and the oil phase, limited to, a mixture having at or about 72% monoesters, 23% during formation of the liquid concentrates and composi diesters, 5% triesters and 0 polyesters; a mixture having at or tions. In one example, the emulsion stabilizer is added to the about 61% monoesters, 30% diesters, 7% triesters, and 2% water phase at a concentration, such that it represents less polyesters; and a mixture having at or about 52% monoesters, than 1% or about 1% w/w of the liquid concentrate. In another 36% diesters, 10% triesters and 2% polyesters. example, the emulsion stabilizer is added for a final concen 0536 The sucrose fatty acid ester surfactants include tration of greater than 1%, such as at or about 1.5% w/w of the sucrose fatty acid esters sold under the trade name DK liquid concentrate. In one example, the emulsion stabilizer is Ester R, produced by Dai-Ichi Kogyo Seiyaku Co., Ltd of added to the water phase for a final concentration of between Japan (which, in some examples, can be produced according 0.1% or about 0.1% and 1% or about 1%, for example, 0.1%, to the methods described in U.S. Pat. Nos. 4,898,935; 4,996, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 309: 4,995,911; 5,011,922 and 5,017,697), and distributed 0.2%, 0.25%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, through Montello Inc., Tulsa, Okla., such as the F-160 and 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.5%, 0.6%, 0.7%, F-140 grade esters sold under the trade name DK Ester(R), and 0.8%, 0.9% or 1% w/w of the liquid concentrate. In one Sucrose esters sold under the trade name SURFHOPER SE example, the emulsion stabilizer is added to the oil phase Such PHARMA, by Mitsubishi-Kagaku Foods Corporation, dis that it represents less than 0.1% or about 0.1%, for example, tributed by Mitsubishi Chemical Performance Polymers, Inc. between 0.01% or about 0.01% and 0.1% or about 0.1%, for These sucrose fatty acid esters are mixtures of esters with example, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, different degrees of esterification. The sucrose fatty acid 0.061%, 0.062%, 0.063%, 0.0635%, 0.07%, 0.08%, 0.09% or esters further include Ryoto sugar esters, which are food 0.1%, by weight (w/w), of the concentrate. In one example, grade esters sold by Mitsubishi-Kagaku Foods Corporation, the emulsion stabilizer is added to the water phase and the oil distributed by Mitsubishi Chemical Performance Polymers, phase, for example, at a concentration within the oil and water Inc. Other exemplary Sucrose fatty acid ester Surfactants are phase concentration ranges listed above. In one Such described in Youan et al. (2003) AAPS PharmaSci 5(2): example, the emulsion stabilizer represents less than 1%, for Article 22 (1-9) and in Okamoto et al. (2005) Biol. Pharm. example, between 0.01% or about 0.01% and 1% or about 1% Bull. 28(9): 1689-1694. (w/w), emulsion stabilizer, for example, 0.01%, 0.02%, 0537 g. Emulsion Stabilizers (Co-Emulsifiers) 0.03%, 0.04%, 0.05%, 0.06%, 0.061%, 0.062%, 0.063%, 0538. The provided liquid concentrates can further con 0.0635%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.13%, tain one or more emulsion stabilizers (co-emulsifiers), which 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.25%, can be used to stabilize the liquid nanoemulsion concentrate 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, and/or the aqueous compositions containing the diluted con 0.38%, 0.39%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%, centrates. For example, the emulsion stabilizer can increase by weight (w/w), of the liquid concentrate. The emulsion the viscosity of the liquid concentrate. One or more emulsion stabilizer, such as Ticamulsion, can be added in higher con stabilizers can be added, for example, during formulation centrations, including 5%, 10%, 15%, 18%, 20%, or 25%, by after evaluation of an initial concentrate, particularly if the oil weight, or more. and water phases of the initial concentrate (or the aqueous (0541 h. Flavors liquid dilution composition resulting from dilution of the 0542. The liquid nanoemulsion concentrates and compo initial concentrate) appear to be separating. Addition of the sitions provided herein can further contain one or more fla emulsion stabilizer can prevent separation of the oil and water Vors or flavoring agents, for example, any compound that can phases. add flavor to the concentrate and/or to the aqueous liquid 0539 Exemplary of an emulsion stabilizer that can be dilution composition containing the diluted concentrate, for used in the provided compositions is a composition contain example, the food or beverage product containing the con ing a blend of gums, for example, gums used as emulsifying centrate. Several flavors are well known. Any flavor can be agents, for example, a blend containing one or more of Xan added to the concentrates, for example, any flavor sold by US 2016/008 1976 A1 Mar. 24, 2016 52

Mission Flavors (Foothill Ranch, CA). Exemplary of flavors Soft gels and powders and pre-spray emulsions, provided that can be used are fruit flavors, such as guava, kiwi, peach, herein additionally can contain further ingredients. For mango, papaya, pineapple, banana, Strawberry, raspberry, example, compositions provided herein can contain one or blueberry, orange, grapefruit, tangerine, lemon, lime and more stabilizers (i.e., stabilizing system). The beverage com lemon-lime; cola flavors, tea flavors, coffee flavors, chocolate positions can additionally contain Sweeteners. The composi flavors, dairy flavors, root beer and birch beer flavors, methyl tions provided herein also can contain, for example, pH salicylate (wintergreen oil, Sweet birch oil), citrus oils and adjusters and/or antifoaming agents. other flavors. Typically, the flavors are safe and/or desirable 0550 i. Additional Non-Polar Compounds for human consumption, for example, GRAS or Kosher-cer 0551. The compositions provided herein can contain one tified flavors. An exemplary flavoring agent that can be used or more additional non-polar compounds. The compositions, in the concentrates and compositions provided herein are for example, the compositions for direct consumption, Such lemon oil, for example lemon oil sold by Mission Flavors as the Soft gels and powders and pre-spray emulsions, can (Foothill Ranch, CA), and D-limonene, for example, 99% contain a non-polar ingredient that is a non-polar compound GRAS certified D-Limonene, sold by Florida Chemical or can contain an additional non-polar compound or both. (Winter Haven, Fla.). The flavor can be added, using the Suitable additional non-polar compounds include any com provided methods, to the nanoemulsion concentrates after pound that can induce, promote or enhance one or more combining the oil and water phases. Alternatively, flavor(s) effects, such as upon delivery to a Subject or upon adminis can be added to the water and/or oil phase directly. tration to a sample, for example, sympathomimetic effects, (0543 i. pH Adjusters stimulatory effects, vasoconstriction, decongestion (e.g., 0544 One or more pH adjusters can be added to the pro bronchial or nasal decongestion), increased energy, endur vided liquid nanoemulsion concentrates, typically to the ance, mood-enhancement, appetite Suppression and/or emulsion that is formed after combining the water and oil weight loss. The additional non-polar compounds include, phases according to the provided methods. In particular, the but are not limited to, alkaloids, e.g., caffeine, Synephrine, pH adjuster can be used in compositions containing water. and Y-aminobutyric acid (GABA) derivatives, e.g., 4-amino Alternatively, the pH adjuster can be added, at an appropriate 3-phenylbutyric acid (i.e., phenibut), plant extracts, particu concentration to achieve a desired pH, to the oil phase and/or larly those with medicinal and herbal effects, and any com the water phase. Typically, the pH adjuster is added to adjust bination thereof (such as those described above in section the pH of the concentrate to within a range of 2.0 or about 2.0 D.1.b.Vii.). Typically, the additional non-polar compounds to 4.0 or about 4.0. One or more of a plurality of pH adjusting are food-approved, i.e., edible or ingestible, non-polar com agents can be used. Typically, the pH adjusting agent is safe pounds, for example, non-polar compounds that are safe and/ for human consumption, for example, GRAS certified. The or approved for human consumption. pH adjuster can be citric acid. An exemplary pH adjuster 0552. In general, the compositions provided herein con suitable for use with the concentrates provided herein tain at least one non-polar ingredient, i.e., at least one non includes the citric acid sold by Mitsubishi Chemical (Dublin, polar ingredient containing non-polar compound, or an addi Ohio). Another exemplary pH adjuster is phosphoric acid, tional non-polar ingredient. Typically, when included in a such as Food Grade 80%. Phosphoric Acid, sold by Univar. beverage composition, the total amount of additional non 0545 Typically, the concentration of pH adjuster added to polar compound included in the provided beverage composi the provided liquid concentrates is less than 5% or about 5%, tion is less than 30% or about 30%, typically less than 20% or for example, less than or about 4%, 3.5%. 3%, 2.5%, 2%, about 20%, for example, less than 30%, 25%, 20%, 15%, 1.5%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 10%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1% or less, by weight, of the liquid concentrate. 0.1%, by weight, of the beverage composition. (0546 j. Soluble Fibers 0553 ii. Stabilizers 0547. The liquid nanoemulsion concentrates provided 0554. The compositions provided herein contain one or herein can contain soluble fiber. Soluble fibers include any more stabilizers, or a stabilizing system. Stabilizers include soluble dietary fiber that can be readily fermented in the any compound used to stabilize the non-polar ingredients in colon, typically a plant based dietary fiber, for example, a the beverage compositions. The stabilizer or stabilizing sys soluble fiber from legumes, vegetables, such as broccoli and tem can aid in retaining one or more desirable properties of carrots, root vegetables, such as potatoes, Sweet potatoes and the compositions, for example the appearance, taste or odor. onions, oats, rye, chia, barley and fruits, such as prunes, The compositions provided herein containing non-polar plums, berries, bananas, apples and pears. Typically, soluble ingredients and a stabilizer or stabilizing system can retain dietary fiber contains non-starch polysaccharides, such as one or more desirable properties of the beverage composition arabinoxylans, cellulose, dextrans, inulin, beta-glucans, for a period of time after formulation, such as at or about 1, 2, fructo-oligosaccharides, oligosaccharides and polysaccha 3, 4, 5, 6, or 7 days, at or about 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or rides. Soluble fibers include, but are not limited to, fructo 36 weeks, at or about 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 36 oligosaccharides, for example, inulins, for example, inulins months, or at or about 1, 2, 3, or 4 years. The stabilizers found in chicory, Jerusalem artichoke, dahlia, garlic, leeks include, but are not limited to, carbonates and bicarbonates, and onions, fructans and water-soluble Soybean fiber. Exem acids, antioxidants, and any combination thereof. Typically plary of a soluble fiber is an inulin, for example, Oliggo-Fiber the stabilizers or stabilizing system are food-approved, i.e., Instant Inulin (FibrulineR Instant) (supplied by Cosucra edible or ingestible, stabilizers, for example, stabilizers that Groupe Warcoing SA, Belgium, sold by Gillco Products, San are safe and/or approved for human consumption. Marcos, CA), containing chicory inulin. 0555. In general, the beverage compositions contain more 0548 k. Additional Ingredients than one stabilizer. Typically, the total amount of stabilizers 0549. The compositions, e.g., liquid dilution composi included in the provided beverage compositions is less than tions and compositions for direct consumption, such as the 20% or about 20%, typically less than 10% or about 10%, for US 2016/008 1976 A1 Mar. 24, 2016

example, less than 20%, 15%, 10%, 5%, 4.5%, 4%, 3.5%, the pH of the composition. The acid can be, for example, an 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the edible, ingestible or food-approved acid. Exemplary of suit beverage composition. able acids for use in the provided beverage compositions are 0556 (a) Bicarbonates or Carbonates citric acid, phosphoric acid, adipic acid, ascorbic acid, lactic 0557 Exemplary of a stabilizer used in the provided bev acid, malic acid, fumaric acid, gluconic acid, Succinic acid, erage compositions is a bicarbonate or carbonate, for tartaric acid, maleic acid, and any combination thereof. In one example, any edible or food-approved bicarbonate or carbon example, the acid is citric acid. ate. Examples of suitable bicarbonates and carbonates 0561 Typically, the amount of acid added to the provided include Sodium bicarbonate, potassium bicarbonate, sodium beverage compositions is between or between about 0.01% carbonate, potassium carbonate, calcium carbonate, magne and 5%, by weight, of the composition, for example, between sium carbonate, Zinc carbonate, and any combination thereof. at or about 0.01% and at or about 4%, between at or about In some examples, the carbonate orbicarbonate is a carbon 0.01% and at or about 3%, between at or about 0.01% and at ated beverage, such as a soda, flavored soda, carbonated water or about 2%, between at or about 0.01% and at or about 1%, or carbonated juice. Alternatively, the beverage can be car between at or about 0.1% and at or about 5%, between at or bonated by the addition of carbon dioxide. Selection of suit about 0.1% and at or about 4%, between at or about 0.1% and able bicarbonates and carbonates for use in the provided at or about 3%, between at or about 0.1% and at or about 2%, beverage compositions is within the skill of the skilled arti between at or about 0.1% and at or about 1%, between at or Sail about 0.5% and at or about 5%, between at or about 0.5% and 0558 Typically, the amount of bicarbonate or carbonate at or about 4%, between at or about 0.5% and at or about 3%, used in the provided beverage compositions is between or between at or about 0.5% and at or about 2%, between at or between about 0.01% and 7%, by weight, of the composition, about 0.5% and at or about 1%, betweenator about 1% and at for example, between at or about 0.01% and at or about 6%, or about 5%, between at or about 1% and at or about 4%, between at or about 0.01% and at or about 5%, between at or between at or about 1% and at or about 3%, between at or about 0.01% and at or about 4%, between at or about 0.01% about 1% and at or about 2%, between at or about 2% and at and at or about 3%, betweenator about 0.01% and at or about or about 5%, between at or about 2% and at or about 4%, 2%, between at or about 0.01% and at or about 1%, between between at or about 2% and at or about 3%, between at or at or about 0.1%andator about 7%, betweenator about 0.1% about 3% and at or about 5%, between at or about 3% and at and at or about 6%, between at or about 0.1% and at or about or about 4%, or between at or about 4% and at or about 5%, by 5%, between at or about 0.1% and at or about 4%, between at weight, of the beverage composition. In some examples, the or about 0.1% and at or about 3%, between at or about 0.1% amount of acid added to the provided beverage compositions and at or about 2%, between at or about 0.1% and at or about is less than 5% or about 5%, typically less than 4% or about 1%, between at or about 0.5% and at or about 7%, between at 4%, for example, at or about 0.01%, 0.02%, 0.03%, 0.04%, or about 0.5% and at or about 6%, between at or about 0.5% 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, and at or about 5%, between at or about 0.5% and at or about 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 4%, between at or about 0.5% and at or about 3%, between at 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, or about 0.5% and at or about 2%, between at or about 0.5% 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, and at or about 1%, between at or about 1% and at or about 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 7%, betweenator about 1% and at or about 6%, between at or 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9% or about 1% and at or about 5%, between at or about 1% and at 5%, by weight, of the beverage composition. or about 4%, between at or about 1% and at or about 3%, 0562 (c) Antioxidants between at or about 1% and at or about 2%, between at or 0563. In one example, the stabilizer used in the beverage about 2% and at or about 7%, between at or about 2% and at compositions contain an antioxidant, for example, a molecule or about 5%, between at or about 2% and at or about 4%, that is capable of inhibiting the oxidation of other molecules. between at or about 3% and at or about 7%, between at or Antioxidants include molecules that scavenge free radicals. about 3% and at or about 5%, between at or about 4% and at Suitable antioxidants include those that are used as ingredi or about 7%, between at or about 6% and at or about 7%, ents in dietary Supplements. The antioxidant can be a natural between at or about 5% and at or about 7%, or between at or antioxidant or a synthetic antioxidant. about 5% and at or about 6%, by weight, of the beverage 0564) Examples of antioxidants include, but are not lim composition. In some examples, the amount of bicarbonate or ited to hormones, carotenoids, carotenoid terpenoids, non carbonate used in the provided beverage compositions is less carotenoid terpenoids, flavonoids, flavonoid polyphenolics than 7% or about 7%, typically less than 5% or about 5%, for (e.g., bioflavonoids), flavonols, flavones, phenols, polyphe example at or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, nols, esters of phenols, esters of polyphenols, nonflavonoid 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, phenolics, isothiocyanates, vitamins and vitamin cofactors, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, Such as VitaminA, Vitamin C, Vitamin E. Vitamin Ephosphate 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, and ubiquinone (ubidecarenone, coenzyme Q, coenzyme 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, Q10), ascorbic acid, citric acid, rosemary oil, minerals, such 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, as mineral selenium and manganese, melatonin, C-carotene, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%, B-carotene, lycopene, lutein, Zeanthin, crypoxanthin, res 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.2%, Veratrol, eugenol, quercetin, catechin, gossypol, hesperetin, 6.5%, 6.7%, or 7%, by weight, of the beverage composition. curcumin, ferulic acid, thymol, hydroxytyrosol, tumeric, 0559) (b) Acids thyme, olive oil, lipoic acid, glutathione, gulamine, Oxalic 0560. In one example, the stabilizer used in the beverage acid, tocopherol-derived compounds, di-alpha-tocopheryl compositions contains one or more acids, for example, any phosphate, tocotrienols, butylated hydroxyanisole, butylated compound added to the beverage composition that can lower hydroxytoluene, ethylenediaminetetraacetic acid, tert-butyl US 2016/008 1976 A1 Mar. 24, 2016 54 hydroquinone, acetic acid, pectin, tocotrienol, tocopherol, provided liquid dilution compositions containing the water coenzyme Q10 (coC10), Zeaxanthin, astaxanthin, canthaxan soluble vitamin E derivative mixtures (compositions) and thin, Saponins, limonoids, kaempferol, myricetin, isorhamne non-polaringredients. The pre-emulsion concentrates are for tin, proanthocyanidins, quercetin, rutin, luteolin, apigenin, mulated Such that dilution of the concentrates, for example, in tangeritin, hesperetin, naringenin, eriodictyol, flavan-3-ols aqueous media, yields a composition having one or more (e.g., anthocyanadins), gallocatechins, epicatechin and its desirable properties, for example, clarity; safety; taste; Smell; gallate forms, epigallocatechin and its gallate forms theafla stability, for example, lack of phase separation, "ringing vin and its gallate forms, thearubigins, isoflavone phytoestro and/or precipitation over time; and/or bioavailability. In one gens, genistein, daidZein, glycitein, anythocyanins, cyanid example, the desirable property is the ability of the provided ing, delphinidin, malvidin, pelargonidin and peonidin. In one pre-emulsion concentrates to yield a clear or partially clear example, the antioxidant is vitamin C. In another example, aqueous liquid dilution composition when it is diluted into the antioxidant is a coenzyme Q-containing compounds, Such aqueous medium, for example, a beverage such as water. In as ubiquinone (ubidecarenone, coenzyme Q, coenzyme another example, the desirable property relates to the safety Q10). of the pre-emulsion concentrates and/or the desirability of the 0565 Typically, the amount of antioxidant added to the pre-emulsion concentrates for human consumption, for provided beverage compositions is betweenator about 0.01% example, in foods and beverages. In another example, it can and at or about 3%, for example, between at or about 0.01% be desirable that the pre-emulsion concentrate contains less and at or about 2.5%, between at or about 0.01% and at or than or equal to a particular concentration of one or more about 2%, between at or about 0.01% and at or about 1.5%, ingredients. In another example, it can be desirable that the between at or about 0.01% and at or about 1%, between at or pre-emulsion concentrate contains greater than or equal to a about 0.01% and at or about 0.5%, between at or about 0.05% particular concentration of one or more ingredients. and at or about 3%, betweenator about 0.05% and at or about 2.5%, betweenator about 0.05% andator about 2%, between 0570. In addition to the non-polar ingredients, the pre at or about 0.05% and at or about 1.5%, between at or about emulsion concentrates contain at least one surfactant, such as 0.05% and at or about 1%, between at or about 0.05% and at the water-soluble vitamin E derivative mixtures (composi or about 0.5%, between at or about 0.1% and at or about 3%, tions) described herein. Typically, the surfactant has an HLB between at or about 0.1% and at or about 2.5%, between at or value between 12 or about 12 and 20 or about 20, for example, about 0.1% and at or about 2%, between at or about 0.1% and 12, 13, 14, 15, 16, 17, 18, 19, or 20, about 12, about 13, about at or about 1.5%, between at or about 0.1% and at or about 14, about 15, about 16, about 17, about 18, about 19, or about 1%, between at or about 0.1% and at or about 0.5%, between 20. Exemplary of suitable surfactants are tocopherol polyeth at or about 0.5% andator about 3%, betweenator about 0.5% ylene glycol succinate (TPGS), such as the TPGS, TPGS and at or about 2.5%, betweenator about 0.5% andator about analogs, TPGS homologs and TPGS derivatives described 2%, between at or about 0.5% and at or about 1.5%, between herein, and other Surfactants having similar properties to at or about 0.5% and at or about 1%, between at or about 1% TPGS, for example, other surfactants having HLB values and at or about 3%, between at or about 1% and at or about between 12 or about 12 and 20 or about 20. Typically, the 2.5%, between at or about 1% and at or about 2%, between at Surfactant is a natural Surfactant, for example, a Surfactant or about 1% and at or about 1.5%, between at or about 1.5% that is GRAS (generally recognized as safe)-certified by the and at or about 3%, between at or about 1.5% and at or about FDA and/or Kosher certified, for example, TPGS. 2.5%, between at or about 1.5% and at or about 2%, between 0571 Typically, the pre-emulsion concentrates further at or about 2% and at or about 3%, betweenator about 2% and contain one or more additional ingredients. Exemplary of at or about 2.5%, between at or about 2.5% and at or about additional ingredients that can be included in the pre-emul 3%, by weight, of the beverage composition. In some sion compositions are preservatives, solvents, co-surfactants, examples, the amount of antioxidant added to the provided emulsion-stabilizers, additional non-polar ingredients, and beverage compositions is less than 5% or about 5%, typically flavoring agents, as described herein. less than 3% or about 2%, for example, at or about 0.01%. 0572 Typically, the pre-emulsion concentrates are formu 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, lated Such that, when diluted into an aqueous medium (e.g., 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, water), they yield a dilution composition that is a nanoemul 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, Sion, in which the non-polar ingredient(s) are present in 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, micelles. These micelles, containing the non-polar ingredient 2.8%, 2.9% or 3.0%, by weight, of the beverage composition. surrounded by the one or more surfactants, facilitate the dis 0566 2. Concentrates persion of the non-polar ingredient among the polar solvent 0567 a. Pre-Emulsion Concentrates (s) of the aqueous medium in the dilution compositions. Typi 0568 Exemplary of the provided compositions are pre cally, the pre-emulsion concentrates are formulated Such that emulsion concentrates containing one or more non-polar the micelles in the dilution composition have a small or rela ingredients. The pre-emulsion concentrates can be semi-solid tively small particle size, for example, less than 1000 or about compositions, typically having a waxy or creamy consis 1000 nm, less than 500 or about 500 nm, typically less than tency, for example, the consistency of a Substance Such as 300 or about 300 nm, typically less than 250 or about 250 nm, wax, for example, a lip balm, at room temperature, for typically less than 200 or about 200 nm, for example, 0, 1, 2, example, at 25° C. or about 25° C., and become liquid at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, higher temperatures, for example, when heated to higher 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45,50, 55, 60, 65,70, temperatures, such as to 125° F. or about 125° F., or to 50° C. 75, 80, 85,90, 95, 100, 125, 150 or 200 nm. Smaller particle or about 50° C. or to 60° C. or about 60° C. size correlates with increased clarity of the dilution compo 0569. The pre-emulsion concentrates can be diluted into sitions that results from diluting the pre-emulsion concen aqueous media, using the provided methods, to form the trates. For example, a liquid with a smaller particle size can be US 2016/008 1976 A1 Mar. 24, 2016 more clear than a liquid with a larger particle size. Small ous representative concentrations within an appropriate con particle size also can contribute to other desirable properties, centration range for one or more particular ingredients. for example, stability. 0573. A number of parameters of the pre-emulsion con 0579. In a typical example, the initial pre-emulsion con centrates, including ingredients, their relative concentrations, centrate is made by including at least one surfactant, such as and methods for making the pre-emulsion concentrates, the water-soluble vitamin E derivative mixtures (composi affect the particle size of the liquid dilution compositions tions) described herein, having an HLB value between 12 or made by diluting the pre-emulsion concentrates. By exten about 12 and 20 or about 20, typically a tocopheryl polyeth Sion, these parameters of the pre-emulsion concentrates also ylene glycol succinate (TPGS) surfactant. affect the desirable properties of the dilution compositions, 0580. In one example, the starting concentration of the for example, the clarity of the dilution compositions. In par surfactant, for example, a water-soluble vitamin E derivative ticular, the nature of the surfactant, particularly the HLB of mixture described herein, e.g., TPGS, is greater than 50% or the Surfactant, and the relative concentrations of the Surfac about 50%, typically greater than 60% or about 60%, typi tant and the non-polar ingredient in the pre-emulsion concen cally greater than 65% or about 65%, for example, greater trates, contribute to small particle size and clarity of the than 70% or about 70%, for example, a starting concentration dilution compositions. Typically, several of these parameters within the concentration range of between 50% or about 50% and properties relate to one another. For example, several of and 95% or about 95%, between 60% or about 60% and 95% the parameters contribute to the particle size, typically small or about 95%, typically between 65% or about 65% and 90% particle size. Particle size contributes directly to clarity of the or about 90%, for example, between 69% or about 69% and aqueous liquid dilution compositions containing the pre 90% or about 90%, for example, between 69% or about 69% emulsion concentrates. Particle size also can relate to other and 89% or about 89%, for example, 65, 66, 67,68, 69, 69.5, properties, for example, stability, lack of “ringing and/or 69.9, 70, 71,72, 73,74, 75,76, 77,78, 79, 79.5, 79.9, 80, 81, precipitate formation of the aqueous liquid dilution compo 82, 83, 84,85, 86, 87, 88,89, 89.5, 89.9, or 90%, by weight, sitions containing the pre-emulsion concentrates. of the pre-emulsion concentrate. 0574. Accordingly, properties of the ingredients and their 0581. In another example, the starting concentration of the relative concentrations in the pre-emulsion concentrates are surfactant, for example, a water-soluble vitamin E derivative important for the ability of the pre-emulsion concentrate to mixture described herein, e.g., TPGS, is greater than 20% or yield desirable dilution compositions. Determining the about 20%, typically greater than 30% or about 30%, for appropriate ingredients, and relative concentrations thereof, example, between 30% or about 30% and 55% or about 55%, that yield dilution compositions having desirable properties is for example, between 30% or about 30% and 50% or about carried out using the provided methods for formulating the 50%, for example, between 30% or about 30% and 45% or pre-emulsion concentrates. about 45%, for example, 30, 31, 32,33, 34,35,36, 37,38,39. 0575 i. Formulating the Pre-Emulsion Concentrates 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 0576. Using the provided formulation methods, the pre 55%, by weight, of the pre-emulsion concentrate. This emulsion concentrates are formulated by selecting ingredi example is typically used for pre-emulsion concentrates ents and concentration ratios of the ingredients that yield where the non-polar ingredient includes a phytosterol. compositions having one or more desired properties. When formulating the pre-emulsion concentrates, selected ingredi 0582. Also, in this typical example, the initial pre-emul ents and starting concentrations are used to make initial pre sion concentrate further includes at least one non-polar ingre emulsion concentrates, which typically are diluted, evaluated dient (e.g., non-polaringredient that is or contains a non-polar and modified, if necessary. compound). In one example, the starting concentration of the 0577 As a first step informulating the provided pre-emul non-polar ingredient (e.g., non-polar ingredient that is or sion concentrates, one or more initial pre-emulsion concen contains a non-polar compound), or the total of all of the one trates are made and evaluated for desired properties. For this or more non-polar ingredients, is chosen from within a con step, ingredients are selected, for example, from one or more centration range of between 5% or about 5% and 35% or of the lists of ingredients provided below. A starting concen about 35%, typically between 10% or about 10% and 30% or tration (weight percentage) of each selected ingredient is about 30%, for example, between 10% or about 10% and 20% selected from within an appropriate concentration range for or about 20%, or between 20% or about 20% and 30% or that ingredient or category of ingredient. For example, a start about 30%, for example, 5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, ing Surfactant concentration, Such as a water-soluble vitamin 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%, by E derivative, e.g., TPGS, is selected from within an appropri weight, of the pre-emulsion concentrate. ate Surfactant concentration range. In some cases, the initial 0583. In another example, the starting concentration of the pre-emulsion concentrate is formulated based on the ingredi non-polar ingredient (e.g., non-polar ingredient that is or ents, and concentrations thereof, of an existing pre-emulsion contains a non-polar compound), or the total of all of the one concentrate having one or more desired properties. or more non-polar ingredients, is chosen from within a con 0578. The initial pre-emulsion concentrate(s) is then centration range of between 1% or about 1% and 50% or made, using the methods for making the pre-emulsion con about 50%. In this example, which typically is used when centrates provided below, adding each ingredient at its start using more than one non-polar ingredient, the total concen ing concentration at the appropriate step. In one example, tration of the non-polar ingredients is chosen from within a more than one initial pre-emulsion concentrate is made. For concentration range of between 30% or about 30% and 55% example, multiple initial pre-emulsion concentrates, each or about 55%, for example between 40% or about 40% and having a different concentration of one or more ingredients, 50% or about 50%, by weight, of the composition. Exemplary can be made and compared. For example, multiple initial of starting concentrations for individual non-polar ingredi pre-emulsion concentrates can be made in order to test Vari ents used in this example are between 1% and 50%, for US 2016/008 1976 A1 Mar. 24, 2016 56 example, 1%, 10.5%, 34%, or 45%, by weight, of the pre compound, for example, an oil-based non-polar compound, emulsion concentrate, and other concentrations within the for example, a polyunsaturated fatty acid (PUFA), a coen range. Zyme Q, or a phytochemical. 0584. In one example, the initial pre-emulsion concentrate 0589. In one example, for formulating the initial pre-emul further includes other ingredients, for example, preservative sion concentrates, the starting concentration of the non-polar (s), for example, benzyl alcohol; co-surfactant(s), for ingredient, or the total of all the non-polar ingredients, typi example, a phospholipid, e.g., phosphatidylcholine; a non cally is chosen from within a concentration range of between polar solvent, for example, an oil, and/or an emulsion stabi 5% or about 5% and 35% or about 35%, typically between lizer. Typically, a polar solvent, e.g., water, is not added as an 10% or about 10% and 30% or about 30%, for example, ingredient to the pre-emulsion concentrate. between 10% or about 10% and 20% or about 20%, or 0585. After making the initial pre-emulsion concentrate between 20% or about 20% and 30% or about 30%, for (S), the pre-emulsion concentrate(s) is evaluated for one or example, 5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, more desired properties, for example, the ability to form 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%, by weight, of the dilution compositions (e.g., clear dilution compositions or pre-emulsion concentrate. In another example, the starting dilution compositions having a particular turbidity value, par concentration of the non-polar ingredient (e.g., non-polar ticle size or other property). The ability to form dilution ingredient that is or contains a non-polar compound), or the compositions having one or more properties is assessed by total of all the non-polar ingredients, is chosen from within a diluting the pre-emulsion concentrate in aqueous medium, concentration range of between 1% or about 1% and 50% or for example, diluting the pre-emulsion composition in the about 50%. In this example, which typically is used when aqueous medium at a dilution factor of between 1:10 or about using more than one non-polar ingredient, the total concen 1:10 and 1:1000 or about 1:1000 or more, typically between tration of the non-polar ingredients is chosen from within a 1:10 or about 1:10 and 1:500 or about 1:500 or more, for concentration range of between 30% or about 30% and 55% example, diluted not more than 1:10 or about 1:10, 1:20 or or about 55%, for example between 40% or about 40% and about 1:20, 1:25 or about 1:25, 1:50 or about 1:50, 1:100 or 50% or about 50%, by weight, of the concentrate. Exemplary about 1:100, 1:200 or about 1:200, 1:250 or about 1:250, of starting concentrations for individual non-polar ingredi 1:300 or about 1:300, 1:400 or about 1:400, 1:500 or about ents used in this example are between 1% and 50%, for 1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, example, 1%, 10.5%, 34% or 45%, by weight, of the concen 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, trate, and other concentrations within the range. 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, 0590. In addition to the non-polar ingredient, the pre 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, emulsion concentrates contain at least one surfactant that is 1:300, 1:350, 1:400, 1:450, 1:500, or more. In one example, the water-soluble vitamin E derivative mixture described the dilution is carried out by including one or more drops of herein, such as TPGS. The surfactant has an HLB value of the heated pre-emulsion concentrate in the aqueous medium, between 12 or about 12 and 20 or about 20, for example, 12, for example, in 25 mL or more of the aqueous medium. 13, 14, 15, 16, 17, 18, 19 or 20. Exemplary of suitable sur 0586. After evaluation, the ingredients, and/or concentra factants are the water-soluble vitamin E derivative mixtures tions thereof, can be adjusted in order to generate the desired (compositions) described herein, such as TPGS, TPGS ana properties in the final pre-emulsion concentrate. Typically, logs, TPGS homologs and TPGS derivatives and other sur the concentration of the non-polar ingredient and/or the Sur factants having similar properties, for example, any Surfac factant, for example, a water-soluble vitamin E derivative tant having an HLB value between 12 or about 12 and 20 or composition, e.g., TPGS, is the concentration that is adjusted about 20, where vitamin Ederivative is provided as a mixture after evaluating the initial pre-emulsion concentrate. Simi of dimer and monomer with at least 13% percent dimer, larly, when formulating multiple initial pre-emulsion concen typically at least 29%, 35%, or 50% dimer, and the remainder trates, one or more of the non-polar ingredients and the Sur monomer and about or no more than 10%, 5%, 4%, 3%, 2%, factant are varied among the multiple initial pre-emulsion or 1% other minor contaminants, impurities or higher forms concentrates. In some cases, following evaluation, it can be of polymer. Surfactants, HLB values and methods for deter determined that additional ingredients (not included in the mining HLB values are well known. initial formulation) are needed or desirable for achieving the 0591. In one example, the starting concentration of water desired properties of a particular pre-emulsion concentrate. soluble vitamin E derivative mixtures (compositions) This process can be repeated until a pre-emulsion concentrate described herein, e.g., TPGS, is greater than 50% or about having the desired property or properties is generated. 50%, typically greater than 60% or about 60%, typically 0587 ii. Exemplary Ingredients and Typical Concentra greater than 65% or about 65%, for example, greater than tion Ranges 70% or about 70%, for example, a starting concentration 0588. Each of the provided pre-emulsion concentrates and within the concentration range of between 50% or about 50% other compositions contains at least one non-polaringredient, and 95% or about 95%, between 60% or about 60% and 95% for example, a non-polar ingredient that is or contains one or or about 95%, typically between 65% or about 65% and 90% more non-polar compounds, and a Surfactant, for example, or about 90%, for example, between 69% or about 69% and the water-soluble vitamin E derivative mixtures (composi 90% or about 90%, for example, between 69% or about 69% tions) described herein, e.g., mixtures of monomers and and 89% or about 89%, for example, 65, 66, 67,68, 69, 69.5, dimers of TPGS. Any non-polar ingredient that is or contains 69.9, 70, 71,72, 73,74, 75,76, 77,78, 79, 79.5, 79.9, 80, 81, one or more non-polar compounds can beformulated with the 82, 83, 84,85, 86, 87, 88,89, 89.5, 89.9, or 90%, by weight, provided methods and pre-emulsion concentrates. Several of the pre-emulsion concentrate. exemplary non-polar ingredients that can be incorporated 0592. In another example, the starting concentration of the into the provided concentrates are described herein below. surfactant, for example, the water-soluble vitamin E deriva Typically, the non-polar ingredient is or contains a non-polar tive mixtures (compositions) described herein, e.g., TPGS, is US 2016/008 1976 A1 Mar. 24, 2016 57 greater than 20% or about 20%, typically greater than 30% or concentration of one or more ingredients. In another example, about 30%, for example, between 30% or about 30% and 55% it can be desirable that the liquid concentrate contains greater or about 55%, for example, between 30% or about 30% and than or equal to a particular concentration of one or more 50% or about 50%, for example, between 30% or about 30% ingredients. and 45% or about 45%, for example, 30, 31, 32,33,34,35,36, 0598. In addition to the water-soluble vitamin E derivative 37,38,39, 40, 41, 42, 43,44, 45,46, 47, 48,49, 50, 51, 52,53, mixtures described herein and non-polar ingredients, the liq 54, or 55%, by weight, of the pre-emulsion concentrate. This uid concentrates further contain a polar solvent. Such as water example is typically used for pre-emulsion concentrates (e.g., filtered water), or any other edible aqueous liquid (e.g., where the non-polar ingredient includes a phytosterol. propylene glycol or glycerin), or combination thereof. Typi 0593. One or more, typically more than one, additional cally, the liquid concentrates contain a high amount of the ingredients can be added to the initial pre-emulsion concen polar solvent, for example, between or between about 50% trate. For example, the pre-emulsion concentrates typically and about 80%, by weight (w/w), of the liquid concentrate, contain at least one preservative, typically a natural preserva typically between or between about 50% and about 79%, by tive, for example, benzyl alcohol. Exemplary of other addi weight, of the liquid concentrate. tional ingredients that can be added to the pre-emulsion con 0599 Typically, the liquid concentrates further contain centrates, including the initial pre-emulsion concentrates, are one or more additional ingredients. Exemplary of additional emulsion stabilizers, for example, a blend of gums; a non ingredients that can be included in the liquid concentrates are polar solvent for the non-polar ingredient, for example, an oil preservatives, non-polar solvents, co-surfactants, emulsion other than the non-polar ingredient, e.g., vitamin E oil or flax stabilizers, pH adjusters, additional non-polar ingredients seed oil; a pH adjuster, for example, citric acid orphosphoric and flavoring agents. acid; one or more flavoring agents, for example, D-limonene 0600 The non-polar ingredients in the liquid concentrates or lemon oil; a co-surfactant, for example, a phospholipid, and dilution compositions provided herein are contained in e.g., phosphatidylcholine. micelles. These micelles, containing the non-polar ingredi 0594. The appropriate concentration ranges for the addi ents Surrounded by the one or more Surfactants, allow disper tional ingredients are described in individual sections below. sion of the non-polar ingredients among polar solvents, for Typically, the concentration of the additional ingredients example, when the liquid concentrates are diluted to form depends, in part, on the concentrations of the non-polar ingre aqueous liquid dilution compositions. The micelles contain dient and/or of the surfactant. Typically, the concentrations of ing the non-polar ingredients typically have a small or rela these three ingredients are the focus of the formulating meth tively small particle size, for example, less than or less than ods. For example, when it is determined that modifications to about 1000 nm, less than or less than about 500 nm, less than ingredient concentrations in the initial pre-emulsion concen or less than about 300 nm, less than or less than about 200 nm, trate should be made, it typically is the concentration of one or for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, more of these two ingredients, i.e., the non-polar ingredient 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, and/or surfactant, that is/are adjusted. 50,55, 60, 65,70, 75,80, 85,90, 95, 100, 125, 150 or 200 nm. 0595. In one example, it can be desirable to add one or Smaller particle size correlates with clarity of the aqueous more of the additional ingredients after evaluation of the liquid dilution compositions containing the diluted liquid initial pre-emulsion concentrate, for example, in order to concentrates. For example, a liquid with a smaller particle improve the pre-emulsion concentrate with respect to one or size can be more clear than a liquid with a larger particle size. more desired properties. Small particle size also can contribute to other desirable prop 0596 b. Liquid Nanoemulsion Concentrates erties, for example, stability. 0597 Provided herein are liquid nanoemulsion concen 0601. A number of factors, including ingredients, their trates (also called “liquid concentrates') containing the relative concentrations, and methods for making the liquid water-soluble vitamin Ederivative mixtures described herein, concentrates, affect the particle size of the compositions, and one or more non-polar ingredients that are or contain one or other desirable properties of the compositions, such as clarity. more non-polar compounds, and a polar solvent. The liquid In particular, the nature of the Surfactant, particularly the concentrates, which include emulsions, can be diluted into HLB of the surfactant, and the relative concentrations of polar aqueous medium to form aqueous liquid dilution composi Solvent (e.g., water), Surfactant and the non-polar ingredient tions containing the water-soluble vitamin E derivative mix contribute to Small particle size and clarity of the aqueous tures described herein and non-polar ingredients that are or liquid dilution compositions. Typically, several of these contain non-polar compounds. The liquid concentrates are parameters and properties are related to one another. For formulated based on one or more desirable properties, such as example, several of the parameters contribute to the particle clarity; safety; taste; Smell; Stability, for example, lack of size, typically small particle size, of the compositions. Par phase separation, “ringing and/or precipitation over time; ticle size contributes directly to clarity of the aqueous liquid and/or bioavailability of the concentrate and/or the aqueous dilution compositions containing the liquid concentrates. Par liquid dilution compositions containing the concentrate. In ticle size also can relate to other properties, for example, one example, the desirable property is the ability of the pro stability, lack of “ringing and/or precipitate formation of the vided concentrate to yield a clear or partially clear aqueous aqueous liquid dilution compositions containing the liquid liquid dilution composition when it is diluted into aqueous COncentrates. medium, e.g., water, Such as in a beverage product. In another 0602. Accordingly, properties of the ingredients and their example, the desirable property relates to the safety of the relative concentrations in the liquid concentrates are impor concentrates and/or the desirability of the liquid concentrates tant for the ability of the concentrate to yield desirable dilu for human consumption, for example, in food and beverage tion compositions. Provided are methods for formulating the products. In another example, it can be desirable that the liquid nanoemulsion concentrates. Determining the appropri liquid concentrate contains less than or equal to a particular ate ingredients, and relative concentrations thereof, that yield US 2016/008 1976 A1 Mar. 24, 2016

dilution compositions having desirable properties is per 1:10, 1:20 or about 1:20, 1:25 or about 1:25, 1:50 or about formed using provided methods for formulating the liquid 1:50, 1:100 or about 1:100, 1:200 or about 1:200, 1:250 or COncentrates. about 1:250, 1:300 or about 1:300, 1:400 or about 1:400, 0603 i. Formulating the Liquid Nanoemulsion Concen 1:500 or about 1:500, for example, 1:10, 1:20, 1:25, 1:30, trates 1:35, 1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 0604. In the provided formulation methods, the liquid con 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, centrates are formulated by selecting ingredients and 1:190, 1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, amounts of the ingredients that yield compositions having 1:270, 1:280, 1:290, 1:300, 1:350, 1:400, 1:450, 1:500 or one or more desired properties. When formulating the liquid more, or according to other dilutions provided herein. concentrates, selected ingredients and starting amounts (con 0609. After evaluation, the ingredients and/or amounts centrations) are used to make initial liquid concentrates, (concentrations) thereof can be adjusted in order to generate which are evaluated and modified, if necessary. the desired properties in the final liquid concentrate. Typi 0605 As a first step in formulating the provided liquid cally, the concentrations of the non-polar ingredient, the Sur concentrates, one or more initial concentrates are made and factant, e.g., water-soluble vitamin E derivative mixture, and/ evaluated for desired properties. For this step, ingredients are or the polar solvent are the concentrations that are adjusted selected, for example, from among the ingredients described after evaluating the initial liquid concentrate. Similarly, when herein. The ingredients generally include Surfactants, for formulating multiple initial liquid concentrates, one or more example, the water-soluble vitamin E derivatives described of the non-polar ingredients, Surfactant, e.g., water-soluble herein, e.g., TPGS, polar solvents, non-polar ingredients, and Vitamin E derivative, and polar solvent concentrations are other ingredients. A starting concentration (weight percent varied among the multiple initial liquid concentrates. In some age) of each selected ingredient is selected from within the cases, following evaluation, it can be determined that addi appropriate range for that ingredient or category of ingredi tional ingredients (not included in the initial formulation) are ent, for example, the appropriate concentration range for the needed or desirable for achieving the desired properties of a Surfactant. In some cases, the initial liquid concentrate is particular concentrate. This process can be repeated until a formulated based on the ingredients and amounts (concentra liquid concentrate having the desired property or properties is tion) thereof of an existing liquid concentrate having one or generated. more desired properties. 0610 c. Liquid Dilution Compositions Containing the 0606. The initial liquid concentrate is made, for example, Concentrates using the methods for making the liquid concentrates, pro 0611. Among the products provided herein are liquid dilu vided below, adding each ingredient at its starting concentra tion compositions, typically aqueous liquid dilution compo tion at the appropriate step. More than one initial liquid con sitions (i.e., beverages), containing the described concen centrate, e.g., multiple initial liquid concentrates, each having trates containing the water-soluble vitamin E derivative a different concentration of one or more ingredients, can be mixtures (compositions) described herein and non-polar made and compared. For example, multiple initial liquid con ingredients. The aqueous liquid dilution compositions are centrates can be produced to test various representative con made by diluting the provided liquid nanoemulsion concen centrations within an appropriate concentration range for one trates into aqueous media, for example, beverages, for or more particular ingredients. example, water, flavored water, Soda, milk, juices, including 0607. In a typical example, the initial liquid concentrate is fruit juices, sauces, syrups, soups, sports drinks, nutritional made by including at least one surfactant, for example, a beverages, energy drinks, vitamin-fortified beverages, or any water-soluble vitamin E derivative described herein, e.g., beverage. Any beverage can be prepared or modified using the TPGS, that has an HLB value of between or about between 12 water-soluble vitamin E derivative mixtures (compositions) and 20, at a starting concentration within the concentration described herein and other water-soluble vitamin Ederivative range of between or about between 5 wt % and 35 wt % of the mixtures (compositions), for example, see U.S. Pub. No. liquid concentrate; at least one non-polar ingredient, at a 2008-0254188 and U.S. Pat. No. 6,045,826. starting concentration within the concentration range of 0612. In one example, the aqueous liquid dilution compo between or about between 1 wt % and 30 wt % of the liquid sition contains between 0.05 grams (g) or about 0.05 g and 10 concentrate; and a polar solvent, at a starting concentration of g or about 10 g, typically between 0.05 g and 5 g, of the between or about between 40 wt % and 85 wt % of the liquid concentrate per 8 fluid ounces or about 8 fluid ounces, at least concentrate. In one example, the initial liquid concentrate 8 fluid ounces or at least about 8 fluid ounces, or less than 8 further includes otheringredients, for example, preservatives, fluid ounces or less than about 8 fluid ounces, or per serving co-emulsifiers, pH adjusters and/or other ingredients as size, of the aqueous medium, for example, 0.05 g, 0.06g, 0.07 described herein. g, 0.08 g., 0.09 g, 0.1 g, 0.2g, 0.3 g, 0.4g, 0.5g, 0.6 g., 0.7 g. 0608. After making an initial liquid concentrate, the liquid 0.8 g. 0.9 g, 1 g, 2g, 3 g, 4 g. 5 g. 6 g. 7 g.8 g. 9 g, or 10g of concentrate can be evaluated for one or more desired proper the concentrate per 8 fluid ounces, about 8 fluid ounces, or at ties, for example, the ability to form dilution compositions least 8 fluid ounces or at least about 8 fluid ounces of the (e.g., clear dilution compositions or dilution compositions aqueous medium, for example 8, 9, 10, 11, 12, 13, 14, 15, 16, having a particular turbidity value, particle size or other prop 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 100, 200 or more fluid erty). The ability to form dilution compositions having one or ounces, of aqueous medium. more properties can be assessed by diluting the liquid con 0613. In another example, the aqueous liquid dilution centrate in an aqueous medium, Such as water. For example, composition contains between 1 mL or about 1 mL and 10 mL the liquid concentrate can be diluted in an aqueous medium at or about 10 mL of the concentrate, for example, 1 mL, 2 mL. a dilution factor of between or about between 1:10 and 1:1000 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10 mL of the or more, typically between or about between 1:10 and 1:500 concentrate, per 8 fluid ounces, about 8 fluid ounces, at least or more, for example, diluted not more than 1:10 or about 8 fluid ounces or at least about 8 fluid ounces, or less than 8 US 2016/008 1976 A1 Mar. 24, 2016 59 fluid ounces or less than about 8 fluid ounces, or per serving concentrates, e.g., the pre-emulsion concentrates and/or the size, of the aqueous medium, for example 8, 9, 10, 11, 12, 13, liquid nanoemulsion concentrates, can be diluted into an 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 100, 200 or aqueous medium, for example, water or another polar Sol more fluid ounces, of aqueous medium. vent, at a dilution factor of between or about between 1:10 and 0614. In another example, the aqueous liquid dilution 1:1000, typically between or about between 1:10 and 1:500, composition contains at least 10 mg or about 10 mg. typically for example, diluted at least or about 1:10, at least or about at least 25 mg or about 25 mg. typically at least 35 mg. of the 1:20, at least or about 1:25, at least or about 1:50, at least or non-polar ingredient, for example, a non-polaringredient that about 1:100, at least or about 1:200, at least or about 1:250, at is or contains the non-polar ingredient, per 8 fluid ounces or least or about 1:300, at least or about 1:400, or at least or about about 8 fluid ounces, at least 8 fluid ounces or at least about 8 1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, fluid ounces of the aqueous medium, or less than 8 ounces or 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, less than about 8 ounces, or per serving size, of the aqueous 1: 130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, medium; for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 20, 21, 22, 23, 25, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 40, 1:300, 1:350, 1:400, 1:450, or 1:500, or any other dilution, 45, 50,55, 60, 65,70, 75, 80, 85,90, 95, 100, 110, 120, 130, such as others provided herein. Typically, clarity of the result 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, ing aqueous liquid dilution composition containing the 260, 270, 280,290, 300, 325, 350,375, 400, 425, 450, 475, diluted initial concentrate is evaluated using one or more 500, 550, 600, 700, 800, 900, 1000, 1500, 2000 mg, or more, approaches. Additionally, other properties can be evaluated, of the non-polar ingredient per at least 8 fluid ounces or at for example, smell and/or taste properties of the liquid. For least about 8 fluid ounces of aqueous medium. In another example, when the non-polar ingredient is a polyunsaturated example, the aqueous liquid dilution composition contains fatty acid (PUFA), particularly fish oil or algae oil, the aque the concentrate diluted at a dilution factor of between 1:10 or ous liquid dilution composition can be evaluated empirically about 1:10 and 1:1000 or about 1:1000 or more, typically for a “fishy' smell. between 1:10 or about 1:10 and 1:500 or about 1:500 or more, 0619 i. Clarity for example, diluted not more than 1:10 or about 1:10, 1:20 or 0620. Dilution of the provided concentrates, e.g., the pre about 1:20, 1:25 or about 1:25, 1:50 or about 1:50, 1:100 or emulsion concentrates and/or the liquid nanoemulsion con about 1:100, 1:200 or about 1:200, 1:250 or about 1:250, centrates, in aqueous media can yield clear liquids. The clar 1:300 or about 1:300, 1:400 or about 1:400, 1:500 or about ity of the resulting aqueous liquid dilution composition 1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, containing the initial concentrate can be evaluated by one or 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, more of a plurality of approaches, such as by empirical obser 1: 130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210, Vation, by measuring particle size and/or by measuring the 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, turbidity value of the liquid. 1:300, 1:350, 1:400, 1:450, or 1:500, or more. In another 0621 For example, the concentrates, e.g., the pre-emul example, the aqueous liquid dilution compositions contain sion concentrates and/or the liquid nanoemulsion concen the liquid concentrate diluted to any amount. In another trates, can be diluted to form clear liquids (or liquids that are example, the dilution is less than 1:10 or about 1:10. equal in clarity to known liquids), by adding between or about 0615 Properties of the provided concentrates that are between 0.05 grams (g) and 10g of the concentrate. Such as diluted into the aqueous medium contribute to various prop between or about between 0.05 g and 5 g, for example, about erties of the provided resulting aqueous liquid dilution com 0.05 g, 0.06g, 0.07 g., 0.08 g., 0.09 g, 0.1 g, 0.2g, 0.3 g 0.4g, positions, for example, clarity; desirability for human con 0.5g, 0.6 g. 0.7g, 0.8 g. 0.9 g, 1 g, 2g, 3 g, 4 g., 5 g. 6 g. 7 g. Sumption, for example, pleasant taste, and/or Smell, for 8 g, 9 g, or 10 g of the concentrate, to aqueous medium, for example, lack of “fishy' taste/smell, lack of “ringing and example, to at least or about at least 8 fluid ounces, such as at lack of crystal formation; stability, for example, lack of oxi least or about at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, dation, “ringing and/or precipitation over time; and safety 20, 25, 30, 35, 40, 45, 50, 100, or 200, or more fluid ounces of for human consumption. As described herein, the liquid con aqueous medium, e.g., water, to form a clear aqueous liquid centrates are formulated according to the desired properties dilution composition that contains the concentrate that con of the aqueous liquid dilution compositions containing the tains the water-soluble vitamin E derivative composition and COncentrates. non-polar ingredient. The concentrates can be diluted to form 0616 d. Evaluation of the Concentrates and Liquid Dilu clear aqueous liquid dilution compositions by adding tion Compositions between or about between 1 mL and 10 mL of the concentrate, 0617 The formulation methods can further include analy for example, about 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 sis of the initial concentrates, e.g., the pre-emulsion concen mL, 8 mL, 9 mL or 10 mL of the concentrate to at least or trates and/or the liquid nanoemulsion concentrates, based on about at least 8 fluid ounces of aqueous medium, for example one or more desired properties, for example, properties of an at least or about at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, aqueous liquid dilution composition containing the diluted 19, 20, 25, 30,35, 40, 45,50, 100, or 200, or more fluid ounces concentrate Such as clarity, color, Smell, taste, Safety, stability, of aqueous medium, e.g., water, to form a clearaqueous liquid “ringing or forming of precipitates and/or the presence of dilution composition that contains the concentrate that con crystals. For example, the methods typically include analyZ tains the water-soluble vitamin E derivative composition and ing the ability of the initial concentrate to form a clear liquid non-polar ingredient. upon dilution in an aqueous medium, Such as by analysis of 0622. The provided concentrates, e.g., the pre-emulsion the clarity/turbidity of the resulting aqueous liquid dilution concentrates and/or the liquid nanoemulsion concentrates, composition containing the initial concentrate. can be formulated using any non-polar ingredient for dilution 0618. For evaluation of properties of the initial concen in an aqueous medium. The concentrate can be diluted in an trates in an aqueous liquid dilution composition, the initial aqueous medium, Such as water, to form a clear aqueous US 2016/008 1976 A1 Mar. 24, 2016 60 liquid dilution composition at a dilution factor of between or 0626 (a) Empirical Evaluation about between 1:10 and 1:1000, such as between or about 0627 The relative clarity/turbidity of the aqueous liquid between 1:10 and 1:500, for example, when diluted not more dilution composition containing the diluted concentrate, e.g., than 1:10 or about 1:10, 1:20 or about 1:20, 1:25 or about the pre-emulsion concentrates and/or the liquid nanoemul 1:25, 1:50 or about 1:50, 1:100 or about 1:100, 1:200 or about sion concentrates, can be assessed qualitatively by observa 1:200, 1:250 or about 1:250, 1:300 or about 1:300, 1:400 or tion. For example, a liquid can be considered clear if it does about 1:400, 1:500 or about 1:500, for example, 1:10, 1:20, not have a cloudy appearance and/or if no particles are visible 1:25, 1:30, 1:35, 1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, when looking at the liquid with the naked eye. Clarity can be 1:90, 1:100, 1:110, 1:120, 1: 130, 1:140, 1:150, 1:160, 1:170, assessed empirically by comparison to other liquids, for 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250, example, water, fruit juice, Soda and/or milk. For example, it can be desirable that the liquid is as clear or about as clear as 1:260, 1:270, 1:280, 1:290, 1:300, 1:350, 1:400, 1:450, 1:500 water or another liquid, for example a beverage. For example, or more. The clear liquid can beformed at dilutions less dilute the liquid (containing the concentrate diluted in an aqueous than 1:10 of the concentrate. Typically, the clarity of the liquid medium, for example, a beverage product) can be as clear or is maintained with increasing dilutions, for example, to infin about as clear as the same aqueous medium not containing the 1ty. concentrate. In some cases, the aqueous liquid dilution com 0623 Clarity of the aqueous liquid dilution composition position is as clear or about as clear as water or another liquid, containing the diluted concentrate, e.g., the pre-emulsion for example a beverage. In some examples, there is no Sub concentrates and/or the liquid nanoemulsion concentrates, stantial difference, for example, no observable difference, can be evaluated using one or more of a plurality of between the aqueous liquid dilution composition containing approaches, for example, qualitatively. Such as by empirical the concentrate and the same aqueous medium without the evaluation, or quantitatively. Such as by measuring particle concentrate. A clear liquid is not necessarily colorless, for size and/or by measuring the turbidity value of the liquid. In example, a yellow liquid that contains no visible particles or one example, the aqueous liquid dilution compositions are cloudiness can be considered clear. In another example, the clear aqueous liquid dilution compositions or non-turbid liquid is clear or partially clear or Substantially clear if no aqueous liquid dilution compositions, for example, as deter crystals are visible and/or if no “ringing is observed on the mined, as described below, empirically or by measuring tur container containing the liquid. bidity and/or particle size. In another example, the aqueous (0628 (b) Particle Size or Number of Particles liquid dilution compositions are not clear, or not completely 0629. Alternatively, the clarity of the aqueous liquid dilu clear. The liquid dilution compositions can be more or less tion composition containing the diluted concentrate, e.g., the clear, or have the same clarity as another liquid, for example, pre-emulsion concentrates and/or the liquid nanoemulsion an aqueous liquid dilution composition made according to the concentrates, can be assessed by measuring the particle size provided methods or a beverage, for example, a beverage that and/or number of particles of the liquid. Methods for measur does not contain the diluted concentrate. ing particle size are known and any method for measuring particle size that can measure particle sizes in the appropriate 0624 For example, a particular quantitative or qualitative ranges as described below, can be used. clarity value can be desired. The emulsions and compositions 0630 Particle size can be analyzed by commercial ser provided herein, as well as the aqueous liquid dilution com vices, for example, from Delta Analytical Instruments, Inc., positions provided herein, are more clear than the same com Such as by using a light-scattering analyzer, for example, a positions made with a corresponding low dimer-containing dynamic light scattering analyzer, e.g., the Horiba RLB-550, water-soluble vitamin E derivative composition. An aqueous which can measure particle sizes within a range of 0.001 liquid dilution composition containing the concentrate microns to 6 microns and uses a Fourier-transform/iterative diluted in a beverage product can be as clear or about as clear deconvolution technique for reporting data and can measure as the same beverage containing no concentrate. The evalua sample concentrations from ppm to 40% solids; the Horiba R. tion can be done qualitatively, for example by empirical LA-920, which is a laser light-scattering instrument having observation, or quantitatively, for example, by calculating an He—Ne laser and a tungsten lamp and can determine particle size and/or turbidity value (NTU) for the liquid(s). particle sizes from 0.02 microns to 2000 microns using Mie 0625 Properties of the liquid concentrates can affect the theory; or other analyzers known to those of skill in the art, for clarity of the liquid. A number of parameters can vary the example, analyzers available from Delta Analytical Instru clarity of the liquids, for example, the relative concentration ments, Inc. of Surfactant, non-polar ingredient and/or water, the type of 0631 Alternatively, the particle size can be measured non-polar ingredient; the concentration of excipient(s) in the microscopically, for example, by viewing the liquid under a particular non-polar ingredient; and the purity of the non microscope, for example, at 640x magnification. With this polar ingredient, for example, whether it has been standard method, particle size can be quantified by comparing to a ized to a high purity, or whether it is an extract or a filtered measuring device, for example, a ruler, which is visible when extract. For example, an aqueous liquid dilution composition viewing the liquid under the microscope. If any particles are made by diluting a concentrate containing a non-polar ingre observable at this magnification, they are measured by com dient that contains lecithin, for example a high amount of parison to the measuring device. At a magnification of 640x. lecithin, can be less clear than one made with a concentrate for example, any particle that is about or greater than 25 nm is containing a non-polar ingredient that does not contain leci visible, while particle sizes smaller than 25 nm typically are thin. In another example, a liquid concentrate containing a not visible. non-polar ingredient that is a filtered extract can produce a 0632 Typically, it is desired that the aqueous liquid dilu clearer aqueous liquid dilution composition when diluted tion compositions have a particle size less than or about less than a concentrate containing a crude extract. than 200 nm, for example, 5, 10, 11, 12, 13, 14, 15, 16, 17, 18. US 2016/008 1976 A1 Mar. 24, 2016

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 0638. In one example, the clear aqueous liquid dilution 36, 37,38, 39, 40, 41,42, 43,44, 45,46, 47,48, 49, 50, 60, 70, composition has a turbidity value (NTU) less than or about 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 80, such as less than or about 70, less than or about 60, less 200 nm. Typically, it is desired that the aqueous liquid dilution than or about 50, less than or about 40, less than or about 30, compositions have a particle size less than or about less than less than or about 29, less than or about 28, less than or about 100 nm, less than or about less than 50 nm, or less than or 27, less than or about 26, less than or about 25, less than or about less than 25 nm. Typically, the particle size of the about 24, less than or about 23, less than or about 22, less than aqueous liquid dilution composition containing the concen or about 21, less than or about 20, less than or about 19, less trate is between or about between 5 nm and 200 nm, or than or about 18, less than or about 17, less than or about 16, between 5 nm or about 5 nm and 50 nm or about 50 nm. less than or about 15, less than or about 14, less than or about 0633 Typically, the particle size of the provided aqueous 13, less than or about 12, less than or about 11, less than or liquid dilution composition containing the liquid concentrate, about 10, less than or about 9, less than or about 8, less than or which contains the non-polar ingredient, is Smaller than the about 7, less than or about 6, less than or about 5, less than or particle size of a liquid containing the non-polar ingredient about 4, less than or about 3, less than or about 2, less than or (not formulated in a liquid concentrate). about 1, or about 0. In another example, the turbidity value of 0634 (c) Turbidity Measurement the aqueous liquid dilution composition is less than or about 0635 Clarity of the liquid dilution composition can be 80, for example, 80, 70, 60, 50, 40, 30, 25, 20, 15, or 10, or analyzed by taking optical turbidity measurements, which less. indicate the level of cloudiness or haziness of a liquid, corre 0639 ii. Stability lating to the size and number of particles in Suspension in a 0640 Typically, the provided aqueous liquid dilution liquid. For example, turbidity can be measured optically, to compositions containing the concentrates are stable, for get a value indicating the cloudiness or haziness of the liquid, example, free from one or more changes overa period of time, which correlates with particles in Suspension in the liquid. for example, 1 or more days, 1 or more weeks, 1 or more The units of a turbidity value measured with a nephelometer months, or one or more years, for example, 1, 2, 3, 4, 5, 6, 7 are expressed as Nephelometric Turbidity Units (NTU). The or more days, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks, 1, 2, more clear a particular liquid, the lower its turbidity (i.e., 3,4,5,6,7,8,9, 10, 11, 12 or more months or 1,2,3,4 or more NTU) value. years. 0636 Turbidity can be measured optically, for example, 0641. In one example, the liquid dilution compositions are using a nephelometer, an instrument with a light and a detec stable because they are free from oxidation or substantial tor. The nephelometer measures turbidity by detecting scat oxidation over time. In another example, they are stable tered light resulting from exposure of the liquid to an incident because they remain clear over time. In another example, the light. The amount of Scattered light correlates to the amount stable compositions remain safe and/or desirable for human of particulate matter in the liquid. For example, a beam of consumption over time. In one example, stability refers to the light passes through a sample with low turbidity with little lack of precipitates forming in the compositions over the disturbance. Other methods for measuring turbidity are well period of time. In a related example, the compositions are known and can be used with the provided methods and com stable because they do not exhibit “ringing.” formation of a positions. whitish or opaque ring around the perimeter of the container 0637. The aqueous liquid dilution composition containing holding the liquid, typically at the Surface of the liquid. Ring a diluted concentrate, e.g., the pre-emulsion concentrates ing typically is undesirable, particularly in the case of a liquid and/or the liquid nanoemulsion concentrates, has low turbid for human consumption, for example, a beverage. ity, for example, a turbidity value (NTU) less than or about 80, 0642. In another example, the liquid dilution composition such as less than or about 70, less than or about 60, less than is stable if it does not exhibit any visible phase separation over or about 50, less than or about 40, less than or about 30, less a period of time, for example, after 24 hours, after one week than or about 29, less than or about 28, less than or about 27, or after one month. In one example, the compositions are less than or about 26, less than or about 25, less than or about stable if they exhibit one or more of these described charac 24, less than or about 23, less than or about 22, less than or teristics, over time, when kept at a particular temperature. In about 21, less than or about 20, less than or about 19, less than one example, the liquid dilution compositions remain stable or about 18, less than or about 17, less than or about 16, less at room temperature, for example, 25°C. or about 25°C. In than or about 15, less than or about 14, less than or about 13, another example, the liquid dilution compositions remain less than or about 12, less than or about 11, less than or about stable at between 19°C. and 25°C. In another example, the 10, less than or about 9, less than or about 8, less than or about liquid dilution compositions remain stable at refrigerated 7, less than or about 6, less than or about 5, less than or about temperatures, for example, 4°C. or about 4°C., or at frozen 4, less than or about 3, less than or about 2, less than or about temperatures, for example, at -20°C. or about -20°C. 1, or about 0. For example, the turbidity value of the aqueous 0643 Stability refers to a desirable property of the pro liquid dilution compositions provided herein typically is less vided liquid dilution compositions, for example, the ability of than or about 80, for example, 80, 70, 60, 50, 40, 30, 25, 20, the provided liquid dilution compositions to remain free from 15, 10, 5, 4, 3, 2, 1 or less. The turbidity depends upon the one or more changes over a period of time, for example, 1 or components of the compositions and amounts thereof. In all more days, 1 or more weeks, 1 or more months, or one or more instances, a composition provided herein that contains a high years, for example, 1, 2, 3, 4, 5, 6, 7 or more days, 1, 2, 3, 4, dimer-containing form of a water-soluble derivative of vita 5, 6, 7, 8, 9, 10 or more weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, min E. Such as a high dimer-containing TPGS composition, is 12 or more months or 1, 2, 3, 4 or more years. In one example, less turbid than the same composition that contains a low the liquid dilution composition is stable if it is formulated dimer-containing composition of the same water-soluble Such that it remains free from oxidation or Substantial oxida derivative of vitamin E. tion over time. In another example, the stable liquid dilution US 2016/008 1976 A1 Mar. 24, 2016 62 compositions remain clear over time. In another example, the Typically, non-polar ingredients in liquids having Small par stable liquid dilution compositions remain safe and/or desir ticle sizes are better absorbed than those with larger particle able for human consumption over time. In one example, sta sizes. bility refers to the lack of precipitates forming in the liquid 0652 e. Selecting a Formulation and Modifying Formu dilution compositions over the period of time. In a related lations example, stability refers to the lack of “ringing over the 0653. After evaluating a concentrate, e.g., a pre-emulsion period of time. In another example, the liquid dilution com concentrate and/or a liquid nanoemulsion concentrate, or a position is stable if it does not exhibit any visible phase liquiddilution composition, either a particular formula can be separation over a period of time, for example, after 24 hours, chosen or one or more modifications can be made to the initial after one week or after one month. In one example, the liquid concentrate formula based on the results of the evaluation. dilution compositions are stable if they exhibit one or more of When an initial concentrate does not display one or more these described characteristics, over time, when kept at a desired properties, e.g., to the desired extent, based on the particular temperature. evaluation, the concentration of one or more ingredients can 0644. In one example, the liquid dilution compositions are be adjusted and another initial concentrate made. The process stable at room temperature, for example, 25°C. or about 25° can be repeated until a concentrate with the desired properties C. In another example, the liquid dilution compositions is made. For modification of the initial concentrate, the remain stable at between 19° C. and 25° C. In another amount of the polar solvent (in the liquid nanoemulsion con example, the liquid dilution compositions remain stable at centrates), Surfactant, e.g., water-soluble vitamin E deriva refrigerated temperatures, for example, 4°C. or about 4°C., tive, and/or non-polar ingredient can be adjusted, for or at frozen temperature, for example, at -20° C. or about example, by adjusting the concentration within the appropri -20° C. ate concentration range. Additional ingredients also can be 0645 iii. Advantageous Characteristics of Compositions chosen. For example, modification of the initial concentrates for Human Consumption can involve the addition of one or more additional ingredi ents. For example, if evaluation reveals that the oil and water 0646 A variety of properties of the concentrates and liquid phases of the concentrate or aqueous liquid dilution compo dilution compositions can contribute to its desirability as a sition containing the diluted concentrate are separating, an consumable product. For example, taste, Smell, clarity, color, emulsion stabilizer can be added to the formulation. In crystal formation, precipitation and “ringing.” are properties another example, a co-surfactant can be added to help emul of interest. Sify the components of the concentrate. In another example, 0647. In one example, the liquid dilution composition has the phase (oil phase or water phase), to which a particular a pleasant taste and/or Smell, for example, due to one or more ingredient is added, can be modified. For example, the for flavors added to the concentrate and/or to the aqueous mulation can be modified to change whether an ingredient is medium. In another example, the liquid dilution composition added to the oil phase or the water phase. containing the concentrate is free from an unpleasant taste or 0654 When evaluation of the initial concentrate, e.g., the Smell, for example, a “fishy' taste or Smell. In one example, pre-emulsion concentrates and/or the liquid nanoemulsion the liquid dilution composition Smells or tastes less unpleas concentrates, reveals that it has the desired properties, no ant, for example, less fishy, compared to another aqueous modifications are made. In this example, the formula of the liquid dilution composition. In another example, the aqueous initial concentrate is used for making the concentrate. When liquid dilution composition does not have crystals or has two or more initial concentrates are made, for example, with fewer crystals compared with another aqueous liquid dilution increasing concentrations of an ingredient, the formula of one composition. In another example, the aqueous liquid dilution of the initial concentrates can be chosen. Which formula is composition is desirable because it does not exhibit ringing. chosen can be based on which formula has the most desirable 0648 iv. Safety properties. Alternatively, desirable properties can be bal 0649. Typically, the aqueous liquid dilution compositions anced with relative amounts of ingredients. For example, a containing the concentrates are safe for human consumption, formulation that contains the lowest or the highest concentra for example, containing only ingredients approved by the tion of a particular ingredient, but still provides a concentrate FDA for human consumption, for example GRAS-certified that yields a clear liquid upon dilution in an aqueous medium, ingredients. In one example, one or more of the ingredients, for example, when formulating a liquid dilution composition, for example, all the ingredients, are Kosher-certified. Safety can be selected. of the liquid dilution compositions also relates to stability 0655 Modifications can be effected even if the initial con over time. Lack of or minimum oxidation of the liquid dilu centrate, e.g., the pre-emulsion concentrates and/or the liquid tion compositions over time can contribute to the safety of the nanoemulsion concentrates, possesses the desired properties. compositions. For example, upon determining that a particular concentrate formulation results in desired properties, the concentration of 0650 v. Oral Bioavailability one or more ingredients can be varied to determine whether 0651. In one example, the non-polar ingredients, for the same properties can be achieved if a higher or lower example, the non-polar ingredients that are or contain non concentration of the ingredient is included. For example, the polar compounds, contained in the aqueous liquid dilution lowest concentration of surfactant that can be used, while still compositions exhibit a high or relatively high bioavailability, generating a concentrate with a desired property, for example, for example, a bioavailability that is higher than a liquid the ability to form a clear liquid upon dilution in an aqueous containing the non-polar ingredient alone (i.e., not formu medium, can be determined. In another example, the highest lated in the liquid concentrate). Bioavailability relates to the concentration of the non-polar ingredient that can be incor ability of the body to absorb the non-polar ingredient into a porated into a concentrate, while still maintaining the desired particular space, tissue cell and/or cellular compartment. property, for example, the ability of the concentrate to form a US 2016/008 1976 A1 Mar. 24, 2016

clear liquid upon dilution in an aqueous medium, can be aqueous solvent, and a PEG derivative of vitamin E, such as determined. In another example, one or more additional TPGS, in an amount that is about or at 5% to 65%, by weight, ingredients can be added after making an initial concentrate of the pre-gel concentrate. Additional optional ingredients, with desirable properties, for example, flavoring agents and/ Such as other Surfactants, emulsifiers, and co-solvents, in or pH adjusting agents. amounts totaling less than 5% or less than about 5% can be 0656 3. Soft Gel and Pre-Gel Compositions Containing included. Non-Polar Ingredients and the High Dimer-Containing PEG 0662 By virtue of the high concentration of the non-polar Derivative of Vitamin E Mixture ingredients, and also the Surfactant, the pre-gel concentrates 0657 Methods and compositions for formulating compo as provided herein can be waxy, having the consistency of a sitions containing non-polar ingredients are provided herein. Substance Such as wax, for example, a lip balm, or a semi Provided herein are soft gel compositions containing a non solidat room temperature, for example, at 25°C. or about 25° aqueous pre-gel concentrate in a shell or coating that is Suit C., and become liquid at higher temperatures, for example able for human consumption, and methods for preparing the when heated to higher temperatures, such as to 125° F. or compositions. The Soft gel compositions containing a non about 125°F., or to 50° C. or about 50° C. or to 60°C. or about aqueous pre-gel concentrate contain one or more non-polar 60° C., or the concentrates can be liquid. Whether the pre-gel ingredients, a Surfactant, and a high amount (greater than 2%, concentrate is waxy (i.e., semi-solid) or a liquid depends upon 3%. 5%, 6%, 7%, 10%, up to 20%) of non-aqueous solvent. the particular components and amounts thereof. The pre-gel compositions also are provided. By virtue of the 0663 The pre-gel concentrates are then introduced into or ingredients, including the high amount of non-aqueous sol formulated with materials, such as gelatins and/or gelatin vent, the pre-gel compositions exhibit advantageous proper replacements and other ingredients to form softgel capsules. ties, such as, for example, the formulation of the ingredients Each capsule is designed for oral administration and typically results in stable pre-gel concentrates that do not form precipi contains an amount of the pre-gel composition Sufficient to tates and exhibit enhanced bioavailability of the non-polar provide a single dosage or fractional amount of the non-polar ingredients, for example, when consumed. ingredients or non-polar compounds. 0658. In particular, the non-aqueous pre-gel concentrates 0664) i. Non-Polar Ingredients provided herein contain non-polar ingredients that are or 0665. The non-aqueous pre-gel concentrates provided contain non-polar compounds and/or mixtures of non-polar herein contain one or more non-polar ingredients that are or compounds, at least one surfactant, and one or more non contain one or more non-polar compounds. Non-polar ingre aqueous solvents. The pre-gel concentrates are encapsulated dients include any lipophilic or lipid-soluble compound that by enclosing the pre-gel concentrates in a desired coating or has greater solubility in organic solvents (e.g., benzyl alcohol, shell to form the soft gel compositions provided herein. The benzylbenzoate, d-limonene, ethanol, methanol, ethyl ether, pre-gel concentrates contain from 40% to as much as 90% of acetone, and benzene) and in fats and oils, than in polar the non-polar ingredient, by weight, of the concentrate and Solvents, for example, water. Typically, the non-polar ingre between 5% and 20% non-aqueous solvent, and the remain dients are poorly water-soluble, for example, water insoluble, der is/are surfactant(s), such as a PEG derivative of vitamin E, or are compounds that have low water solubility. The non particularly TPGS. The resulting compositions do not contain polar ingredients include, but are not limited to, drugs, hor precipitated non-polar ingredients or compounds. The com mones, vitamins, nutrients and other lipophilic compounds. positions described herein, in particular, the Soft-gel compo Exemplary non-polar ingredients are listed herein below. The sitions and pre-gel compositions, contain high concentrations non-polar ingredient differs from the Surfactant, e.g., poly of non-polar ingredients and have enhanced bioavailability, alkylene glycol derivative of vitamin E, for example, the for example, after human consumption. Further description non-polar ingredient is not a polyalkylene glycol Vitamin E and examples of the pre-gel concentrates and soft gel com derivative. positions are provided below. 0666. The non-polar ingredients are included in the pre 0659 For purposes herein, the pre-gel compositions gel concentrate in an amount from about or at 30% to 90%, include a non-aqueous solvent that also can be a preservative. typically 35% to 85% or 40% to 90%, inclusive, or 45%-90%, Exemplary of Such solvents is benzyl alcohol, in an amount 40%-85%, or 40%-75%, all inclusive by weight of the com that is significantly higher than the amount at which it is position. The amount included depends upon the particular effective as an anti-microbial preservative. Hence, the com ingredient and desired dosage. positions provided herein generally do not require additional 0667 The non-polar ingredients are any non-polar ingre preservatives. dients of interest, and include all described above (see, sec 0660 a. Non-Aqueous Pre-Gel Compositions Containing tion D1, which is incorporated here) and elsewhere herein. Non-Polar Ingredients 0668 ii. Surfactants (High Dimer-Containing Water 0661 Non-aqueous pre-gel compositions (also referred to Soluble Vitamin E Derivative Mixtures) as concentrates) that contain non-polar ingredients, a Surfac 0669. In addition to the one or more non-polar ingredients, tant(s), and one or more non-aqueous solvents are provided. each of the provided pre-gel concentrates contains at least one The pre-gel concentrates are formulated by selecting ingre Surfactant selected from among the high dimer-containing dients and concentrations of the ingredients as described water-soluble vitamin E derivatives provided and described herein that yield non-aqueous pre-gel concentrates having herein. In particular, the pre-gel concentrations contain a high one or more desired properties, for example, pre-gel concen dimer-containing PEG derivative of vitamin E composition, trates that do not contain any precipitated non-polar ingredi such as a higher dimer TPGS composition as described ents or compounds. The pre-gel concentrates contain high herein. The pre-gel concentrates contain from about or at 5% concentrations of the non-polaringredients ranging from at or to 50%, by weight, such as least 5%, 6%, 7%, 8%, 9%, 10%, about 30%-90% by weight of the pre-gel concentrate, from or 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% of about more than 5% to about or 20% by weight of the non the vitamin E derivative. US 2016/008 1976 A1 Mar. 24, 2016 64

0670) iii. Non-Aqueous Solvents d-limonene that is 99% GRAS-certified, sold by Florida 0671 The pre-gel concentrates provided herein contain at Chemical, Winter Haven, Fla.; and any other non-aqueous least one non-aqueous solvent, for example, any pharmaceu solvent that is insoluble or has only partial solubility in water. tically acceptable solvent that is non-aqueous that can dis 0674) iv. Co-Surfactants (Emulsifiers) Solve the non-polar ingredients provided herein. The non 0675. The concentrates, e.g., pre-emulsion concentrates aqueous solvent, such as, but is not limited to, benzyl alcohol, and liquid nanoemulsion concentrates, can further contain is included in the composition in a high amount, e.g., between one or more co-surfactants (emulsifiers). For example, a co 5% or about 5% and 20% or about 20%, such as, 5-15%, surfactant can be included to improve emulsification of the 10%-15%. 5%-10%, at least 5%, 6%, 7%, 8%, 9%, 10%, non-polar ingredient and/or the stability of the composition, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, up for example, by preventing or slowing oxidation of the non to about or 20% or 25%. The non-aqueous solvent dissolves polar ingredient. Exemplary of a co-surfactant that can be the non-polar ingredients. The non-aqueous solvent is one used in the provided concentrates is a phospholipid, for that dissolves the non-polar ingredients and is different than example, phosphatidylcholine. Other exemplary co-surfac or does not contain the non-polar ingredient. The non-aque tants include non-ionic Surfactants, such as Sugar-derived ous solvent prevents the non-polar ingredients from precipi Surfactants, including fatty acid esters of Sugars and Sugar tating out of the concentrate. The use of these higher amounts derivatives, and PEG-derived surfactants, such as PEG of non-aqueous solvent has been found herein to provide derivatives of sterols, PEG derivatives of fat-soluble vitamins advantageous properties, for example, in the pre-gel concen and PEG-sorbitan fatty acid esters. trates and the Softgel compositions provided herein, when the 0676. When present, the amount of the co-surfactant typi Soft gel compositions contain a pre-gel concentrate contain cally is present in a concentration less than or less than about ing non-polar ingredients and a Surfactant along with high 10%, typically less than or less than about 5%, for example, amounts of non-aqueous solvent. For example, the concen the total amount of co-surfactant as a percentage (%), by trates and soft gels do not contain precipitated non-polar weight, of the liquid concentrate (wt %) can be, e.g., less than ingredients and provide enhanced bioavailability of the non or less than about 10%, such as less than or about 5%, 4.5%, polar ingredients in the soft gel compositions, for example, 4%, 3.5%, 3.15%, 3%, 2.5%, 2%, 1.75%, 1.5%, 1.25%, 1%, after consumption. 0.75%, 0.5%, 0.25%, 0.15% or less, by weight, of the liquid 0672. The one or more non-aqueous solvents included in COncentrate. the pre-gel concentrates are typically insoluble or only partial 0677 (a) Phospholipids soluble in water. For example, the non-aqueous solvents can 0678 Exemplary of the co-surfactants that can be used in include, but are not limited to, alkanes, e.g., hydrocarbons and the provided compositions are phospholipids. Phospholipids cyclic hydrocarbons, e.g., d-limonene; aromatic compounds, are amphipathic lipid-like molecules, typically containing a Such as aromatic alcohols, ethers and esters, e.g., benzyl hydrophobic portion at one end of the molecule and a hydro alcohol and benzyl benzoate; haloalkanes, ethers, esters and philic portion at the other end of the molecule. A number of ketones; organic solvents of natural origin, Such as natural phospholipids can be used as ingredients in the provided hydrocarbons, for example, cyclic hydrocarbons, e.g., terpe compositions, for example, lecithin, including phosphatidyl nes, for example, d-limonene, alpha-pinene, beta-pinene, choline (PC), phosphatidylethanolamine (PE), dis myrcene, linalol, citronellol, geraniol, menthol, citral, cit tearoylphosphatidylcholine (DSPC), phosphatidylserine ronellal, or oxidized organic derivatives, in particular ethers, (PS), phosphatidylglycerol (PG), phosphatidic acid (PA), aldehydes, alcohols and esters; lactams, e.g., N-methyl pyr phosphatidylinositol (PI), sphingomyelin (SPM) or a combi rolidone (NMP); alkylene glycols, e.g., propylene glycol and nation thereof. Typically, the phospholipid is phosphatidyl polyethylene glycol (e.g., PEG300, PEG400); dimethyl sul choline (PC), which sometimes is referred to by the general foxide; dimethyl acetamide: 2-pyrrolidone; C2-C6 alkanols: name “lecithin.” Exemplary of the phospholipids that can be 2-ethoxyethanol; alkyl esters such as 2-ethoxyethyl acetate, used as co-surfactants in the provided compositions are the methyl acetate, ethyl acetate, ethylene glycol diethyl ether, or phospholipids sold by Lipoid, LLC (Newark, N.J.), for ethylene glycol dimethylether: (S)-(–)-ethyl lactate; acetone: example, Purified Egg Lecithins, Purified Soybean Lecithins, glycerol; alkyl ketones Such as methylethyl ketone or dim Hydrogenated Egg and Soybean Lecithins, Egg Phospholip ethyl Sulfone; tetrahydrofuran; cyclic alkyl amides Such as ids. Soybean Phospholipids, Hydrogenated Egg and Soybean caprolactam, decylmethylsulfoxide; oleic acid; aromatic Phospholipids, Synthetic Phospholipids, PEG-ylated Phos amines such as N,N-diethyl-m-toluamide: 1-dodecylazacy pholipids and phospholipid blends. Exemplary of the phos cloheptan-2-one; natural products, such as oils, including phatidylcholine that can be used as a co-surfactant in the olive oils and fatty acids, which can be saturated or non provided compositions is the phosphatidylcholine composi saturated; and acyl glycerols. The pre-gel concentrates pro tion sold by Lipoid, LLC, under the name Lipoid S100, which vided herein can contain one non-aqueous solvent or more is derived from soy extract and contains greater than or than one non-aqueous solvent, for example, two, three, or greater than about 95% phosphatidylcholine. more non-aqueous solvents. 0679 (b) Sugar-Derived Surfactants 0673 Typically, the non-aqueous solvent is an alcohol, an 0680 Exemplary sugar-derived surfactants include, but alcohol derivative, and/or a hydrocarbon that has little or no are not limited to, Sugar fatty acid esters including fatty acid solubility in water. Exemplary of non-aqueous solvents that esters of sucrose, glucose, maltose and other Sugars, esterified can be included in the pre-gel concentrates are alcohols, for to fatty acids of varying lengths (e.g., containing a varying example, aromatic alcohols, e.g., benzyl alcohol. Such as the numbers of carbons). The fatty acids typically have carbon benzyl alcohol sold by Sigma Aldrich (St. Louis, Mo.); alco chains between 8 and 28 carbons in length, and typically hol derivatives, for example, ester derivatives of alcohols, between 8 and 20, or between 8 and 18 or between 12 and 18, Such as aromatic esters, e.g., benzylbenzoate, hydrocarbons, Such as, but not limited to, Stearic acid (18 carbons), oleic acid for example, cyclic hydrocarbons, e.g., d-limonene. Such as (18 carbons), palmitic acid (16 carbons), myristic acid (14 US 2016/008 1976 A1 Mar. 24, 2016

carbons) and lauric acid (12 carbons). Typically, the Sugar fatty acid carbon chain and/or members with different ester Surfactants are Sucrose ester Surfactants, typically degrees of esterification. For example, the Sucrose fatty acid Sucrose fatty acid ester Surfactants. ester Surfactants include mixtures of monoesters, diesters, 0681 (c) PEG-Derived Surfactants triesters, and/or polyesters. The Sugarester Surfactants further 0682 Exemplary PEG-derived surfactants include, but are include Sucrose fatty acid ester analogs and homologs and not limited to, PEG derivatives of sterols, e.g., a cholesterolor mixtures thereof. a sitosterol (including, for example, any of the PEG deriva 0688. In general. Sucrose fatty acid esters, including mix tives disclosed in U.S. Pat. No. 6,632.443); PEG derivatives tures of Sucrose fatty acid esters, can have varying HLB offat-soluble vitamins, for example, some forms of vitamin A values, such as HLB values ranging from at or about 1 to at or (e.g., retinol) or vitamin D (e.g., vitamin D1-D5); and PEG about 20. The HLB value of the sucrose fatty acid ester Sorbitan fatty acid esters, such as polysorbates, including generally depends on the degree of esterification (e.g., the polyoxyethylene (20) sorbitan monooleate (also called average degree of esterification in a mixture of different polysorbate 80) and analogs (e.g., homologs) of polysorbate esters). Typically, the lower the degree of esterification (e.g., 80, such as, for example, polysorbate 20 (polyoxyethylene average degree), the higher the HLB value of the sucrose fatty (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene acid ester or mixture thereof. Exemplary Sucrose esters (20) sorbitan monopalmitate) and polysorbate 60 (polyoxy include sucrose distearate (HLB-3), sucrose distearate/ ethylene (20) Sorbitan monostearate); and Stearic acid deriva monostearate (HLB 12), sucrose dipalmitate (HLB=7.4), tives, including, for example, polyethylene glycol 400 dis Sucrose monostearate (HLB-15). Sucrose monopalmitate tearate (PEG 400DS), such as the PEG 400 DS sold by Stepan (HLB-10), sucrose monolaurate (HLB 15). Typically, the Lipid Nutrition (Maywood, N.J.). Sucrose fatty acid ester Surfactants in the provided concen 0683 (d) Sucrose Fatty Acid Ester Surfactants trates have an HLB value of between at or about 13 and at or 0684 Sucrose fatty acid ester (SFAE) surfactants contain about 20, such as at or about 13, 14, 15, 16, 17, 18, 19, or 20, one or more Sucrose fatty acid esters, which are non-ionic and typically between at or about 13 and at or about 18, such Surfactants that contain Sucrose in the hydrophilic portions as, but not limited to, HLB values of at or about 15, 16 and 17, and fatty acids in the hydrophobic portions. The sucrose fatty Such as, for example, Sucrose ester Surfactants including acid esters can be made by well-known methods (see, for Sucrose monopalmitate. Sucrose monolaurate and Sucrose example, U.S. Pat. Nos. 3,480,616; 3,644,333; 3,714,144: mono Stearate. 4,710,567; 4,898,935; 4,996,309: 4,995,911; 5,011,922 and 0689. The sugar ester surfactants include sucrose ester 5,017,697 and International Patent Pub. No. WO 2007/ blends, for example, Sucrose ester mixtures containing a 082149), typically in an esterification reaction as described in specified amount (e.g., percent, by weight) of Sucrose U.S. Pub. No. 2012-0016026. monoesters. Exemplary Surfactants include Sucrose ester 0685. Because sucrose contains eight hydroxy (OH) mixtures having at least at or about 50%, by weight (w/w), groups, the esterification reaction can join the Sucrose mol monoester, such as at least or about at least 50, 51, 52, 53, 54, ecule to one fatty acid molecule, or can join it to a plurality of 55, 56, 57,58, 59, 60, 61, 62,63, 64, 65, 66, 67,68, 69,70, 71, fatty acid molecules, producing different degrees of esterifi 72, 73,74, 75,76, 77,78, 79,80, 81,82, 83, 84,85, 86, 87,88, cation, e.g., mono-, di-, tri- and poly- (up to octa-) fatty acid 89, 90,91, 92,93, 94, 95, 96, 97,98, 99 or 100%, by weight esters, but primarily mono-, di- and/or tri-esters. The degree (w/w), sucrose monoesters, and typically at least at or about of esterification can depend on conditions of esterification. 60%, by weight, or at least at or about 70%, by weight (w/w), The esterification reaction can be carried out with a single monoesterS. type of fatty acid, or a plurality of fatty acids, Such as fatty 0690. The sucrose fatty acid ester surfactants include acids with varying carbon chain lengths, branched and linear Sucrose fatty acid monoesters, such as Sucrose monocapry fatty acids, and/or saturated or unsaturated fatty acids. The late. Sucrose monodecanoate. Sucrose monolaurate. Sucrose esterification reaction with a single fatty acid can produce a monomyristate. Sucrose monopalmitate. Sucrose monostear single ester, and typically forms more than one ester, such as ate, Sucrose monopelargonate. Sucrose monoundecanoate, mono- di-, tri- and/or poly-esters, formed from one reaction. Sucrose monotridecanoate, Sucrose monopentadecanoate and The relative amounts of mono- di- tri- and/or poly-esters can Sucrose monoheptadecanoate. The Sucrose fatty acid esters depend on reaction conditions. further include mixtures containing varying percentages of 0686. The fatty acid in the sucrose fatty acid ester can be monoesters, diesters, triesters and polyesters, such as, but not any fatty acid, and can contain between 4 and 28 carbon limited to, a mixture having at or about 72% monoesters, 23% atoms, typically between 8 and 28 carbon atoms, and typi diesters, 5% triesters and 0 polyesters; a mixture having at or cally between 8 and 25 carbon atoms, such as between 8 and about 61% monoesters, 30% diesters, 7% triesters, and 2% 18 carbonatoms, such as 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and polyesters; and a mixture having at or about 52% monoesters, 18 carbon atoms. The fatty acid can be synthetic or naturally 36% diesters, 10% triesters and 2% polyesters. occurring, and include linear and branched fatty acids. The 0691. The sucrose fatty acid ester surfactants include fatty acids include, but are not limited to, myristic acid, palm sucrose fatty acid esters sold under the trade name DK itic acid, Stearic acid, oleic acid, caproic acid, capric (or Ester(R), produced by Dai-Ichi Kogyo Seiyaku Co., Ltd of decanoic) acid, lauric acid, caprylic acid and pelargonic (or Japan (which, in Some examples, can be produced according nonanoic) acid. to the methods described in U.S. Pat. Nos. 4,898,935; 4,996, 0687 Thus, the sucrose fatty acid ester surfactants include 309: 4,995,911; 5,011,922 and 5,017,697), and distributed Sucrose monoesters, diesters, triesters and polyesters, and through Montello Inc., Tulsa, Okla., such as the F-160 and mixtures thereof, and typically contain Sucrose monoesters. F-140 grade esters sold under the trade name DK Ester R, and The Sucrose fatty acid ester Surfactants include single fatty Sucrose esters sold under the trade name SURFHOPER SE acid esters and also include homogeneous mixtures of PHARMA, by Mitsubishi-Kagaku Foods Corporation, dis Sucrose esters, containing members with different lengths of tributed by Mitsubishi Chemical Performance Polymers, Inc. US 2016/008 1976 A1 Mar. 24, 2016 66

These sucrose fatty acid esters are mixtures of esters with can be added in higher concentrations, including 5%, 10%, different degrees of esterification. The sucrose fatty acid 15%, 18%, 20%, or 25%, by weight, or more. esters further include Ryoto sugar esters, which are food 0696 vi. Flavors grade esters sold by Mitsubishi-Kagaku Foods Corporation, 0697 The compositions provided herein can further con distributed by Mitsubishi Chemical Performance Polymers, tain one or more flavors or flavoring agents, for example, any Inc. Other exemplary Sucrose fatty acid ester Surfactants are compound that can add flavor to the concentrate and/or to the described in Youan et al. (2003) AAPS PharmaSci 5(2): aqueous liquid dilution composition containing the diluted Article 22 (1-9) and in Okamoto et al. (2005) Biol. Pharm. concentrate, for example, the food or beverage product con Bull. 28(9): 1689-1694. taining the concentrate. Several flavors are well known. Any (0692 v. Emulsion Stabilizers (Co-Emulsifiers) flavor can be added to the concentrates, for example, any 0693. The compositions can further contain one or more flavor sold by Mission Flavors (Foothill Ranch, CA). Exem emulsion stabilizers (co-emulsifiers), which can be used to plary of flavors that can be used are fruit flavors, such as stabilize the liquid nanoemulsion concentrate and/or the guava, kiwi, peach, mango, papaya, pineapple, banana, aqueous compositions containing the diluted concentrates. Strawberry, raspberry, blueberry, orange, grapefruit, tanger For example, the emulsion stabilizer can increase the Viscos ine, lemon, lime and lemon-lime; cola flavors, tea flavors, ity of the liquid concentrate. One or more emulsion stabilizers coffee flavors, chocolate flavors, dairy flavors, root beer and can be added, for example, during formulation after evalua birch beer flavors, methyl salicylate (wintergreen oil, sweet tion of an initial concentrate, particularly if the oil and water birch oil), citrus oils and other flavors. Typically, the flavors phases of the initial concentrate (or the aqueous liquid dilu are safe and/or desirable for human consumption, for tion composition resulting from dilution of the initial concen example, GRAS or Kosher-certified flavors. An exemplary trate) appear to be separating. Addition of the emulsion sta flavoring agent that can be used in the concentrates and com bilizer can prevent separation of the oil and water phases. positions provided herein are lemon oil, for example lemon 0694 Exemplary of an emulsion stabilizer that can oil sold by Mission Flavors (Foothill Ranch, CA), and D-li included in the provided compositions is a composition con monene, for example, 99% GRAS certified D-Limonene, taining a blend of gums, for example, gums used as emulsi sold by Florida Chemical (Winter Haven, Fla.). The flavor can fying agents, for example, a blend containing one or more of be added, using the provided methods, to the nanoemulsion Xanthan gum, guar gum and sodium alginate. Exemplary of concentrates after combining the oil and water phases. Alter such an emulsion stabilizer includes the emulsion stabilizer natively, flavor(s) can be added to the water and/or oil phase sold under the brand name SALADIZER(R), available from directly. TIC Gums, Inc. (Belcamp, Md.). Other gums can be included (0698 vii. pH Adjusters in the emulsion stabilizer, for example, gum acacia, ester 0699. One or more pH adjusters can be added to the com gums and Sugar beet pectin. Exemplary emulsion stabilizers positions at an appropriate concentration to achieve a desired include modified food starches. These include the modified pH One or more of a plurality of pH adjusting agents can be gum acacia sold under the name Tic Pretested(R) Ticamulsion used. The pH adjusting agent is safe for human consumption, A-2010 Powder, available from TIC Gums, Inc. (Belcamp, for example, GRAS certified. The pH adjuster can be citric Md.). Other exemplary emulsion stabilizers containing an acid. An exemplary pH adjuster includes the citric acid sold ester gum are, for example, the emulsion stabilizer sold under by Mitsubishi Chemical (Dublin, Ohio). Another exemplary the name Tic Pretested(R) Ester Gum 8BG, available from TIC pH adjuster is phosphoric acid, such as Food Grade 80% Gums, Inc. (Belcamp, Md.) or Ester Gum 8BG, available Phosphoric Acid, sold by Univar. from Hercules/Pinova (Brunswick, Ga.). Others sold by (0700 viii. Soluble Fibers Ingredion, Inc (Westchester, Ill.) under the trademarks CAP 0701. The compositions provided herein can contain SULR, FIRMTEXR, THERMFLOR), THERMTEXR, and soluble fiber. Soluble fibers include any soluble dietary fiber TEXTRAR) and others, can be included in the compositions that can be readily fermented in the colon, typically a plant provided herein. Other blends of similar gums can also be based dietary fiber, for example, a soluble fiber from legumes, used as emulsion stabilizers. Vegetables, such as broccoli and carrots, root vegetables. Such 0695. In another example, the emulsion stabilizer is added as potatoes, Sweet potatoes and onions, oats, rye, chia, barley for a final concentration of greater than 1%. Such as at or about and fruits, such as prunes, plums, berries, bananas, apples and 1.5% w/w of the liquid concentrate. In one example, the pears. Typically, soluble dietary fiber contains non-starch emulsion stabilizer is added to the water phase for a final polysaccharides, such as arabinoxylans, cellulose, dextrans, concentration of between 0.1% or about 0.1% and 1% or inulin, beta-glucans, fructo-oligosaccharides, oligosaccha about 1%, for example, 0.1%, 0.12%, 0.13%, 0.14%, 0.15%, rides and polysaccharides. Soluble fibers include, but are not 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.25%, 0.3%, 0.31%, limited to, fructo-oligosaccharides, for example, inulins, for 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, example, inulins found in chicory, Jerusalem artichoke, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% w/w of the dahlia, garlic, leeks and onions, fructans and water-soluble composition. In one such example, the emulsion stabilizer soybean fiber. Exemplary of a soluble fiber is an inulin, for represents less than 1%, for example, between 0.01% or about example, Oliggo-Fiber Instant Inulin (FibrulineR Instant; 0.01% and 1% or about 1% (w/w), emulsion stabilizer, for supplied by Cosucra-Groupe Warcoing SA, Belgium, sold by example, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, Gillco Products, San Marcos, CA), containing chicory inulin. 0.061%, 0.062%, 0.063%, 0.0635%, 0.07%, 0.08%, 0.09%, 0702 ix. Stabilizers 0.1%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0703. The compositions provided herein contain one or 0.19%, 0.2%, 0.25%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, more stabilizers, or a stabilizing system. Stabilizers include 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.5%, 0.6%, any compound used to stabilize the non-polar ingredients in 0.7%, 0.8%, 0.9% or 1%, by weight (w/w), of the liquid the beverage compositions. The stabilizer or stabilizing sys concentrate. The emulsion stabilizer, Such as Ticamulsion, tem can aid in retaining one or more desirable properties of US 2016/008 1976 A1 Mar. 24, 2016 67 the compositions, for example the appearance, taste or odor. about 5% and at or about 6%, by weight, of the beverage The compositions provided herein containing non-polar composition. In some examples, the amount of bicarbonate or ingredients and a stabilizer or stabilizing system can retain carbonate used in the provided beverage compositions is less one or more desirable properties of the beverage composition than 7% or about 7%, typically less than 5% or about 5%, for for a period of time after formulation, such as at or about 1, 2, example at or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 3, 4, 5, 6, or 7 days, at or about 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 36 weeks, at or about 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 36 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, months, or at or about 1, 2, 3, or 4 years. The stabilizers 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, include, but are not limited to, carbonates and bicarbonates, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, acids, antioxidants, and any combination thereof. Typically 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, the stabilizers or stabilizing system are food-approved, i.e., 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%, edible or ingestible, stabilizers, for example, stabilizers that 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.2%, are safe and/or approved for human consumption. 6.5%, 6.7%, or 7%, by weight, of the beverage composition. 0704. In general, the beverage compositions contain more 0708 (b) Acids than one stabilizer. Typically, the total amount of stabilizers 0709. In one example, the stabilizer included in the com included in the provided beverage compositions is less than positions contains one or more acids, for example, any com 20% or about 20%, typically less than 10% or about 10%, for pound added to the beverage composition that can lower the example, less than 20%, 15%, 10%, 5%, 4.5%, 4%, 3.5%, pH of the composition. The acid can be, for example, an 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the edible, ingestible or food-approved acid. Exemplary of suit beverage composition. able acids for use in the provided beverage compositions are (0705 (a) Bicarbonates or Carbonates citric acid, phosphoric acid, adipic acid, ascorbic acid, lactic 0706 Exemplary of a stabilizer used in the provided bev acid, malic acid, fumaric acid, gluconic acid, Succinic acid, erage compositions is a bicarbonate or carbonate, for tartaric acid, maleic acid, and any combination thereof. In one example, any edible or food-approved bicarbonate or carbon example, the acid is citric acid. ate. Examples of suitable bicarbonates and carbonates 0710 Typically, the amount of acid added to the provided include Sodium bicarbonate, potassium bicarbonate, sodium beverage compositions is between or between about 0.01% carbonate, potassium carbonate, calcium carbonate, magne and 5%, by weight, of the composition, for example, between sium carbonate, Zinc carbonate, and any combination thereof. at or about 0.01% and at or about 4%, between at or about In some examples, the carbonate orbicarbonate is a carbon 0.01% and at or about 3%, between at or about 0.01% and at ated beverage, such as a soda, flavored soda, carbonated water or about 2%, between at or about 0.01% and at or about 1%, or carbonated juice. Alternatively, the beverage can be car between at or about 0.1% and at or about 5%, between at or bonated by the addition of carbon dioxide. Selection of suit about 0.1% and at or about 4%, between at or about 0.1% and able bicarbonates and carbonates for use in the provided at or about 3%, between at or about 0.1% and at or about 2%, beverage compositions is within the skill of the skilled arti between at or about 0.1% and at or about 1%, between at or Sail about 0.5% and at or about 5%, between at or about 0.5% and 0707. Typically, the amount of bicarbonate or carbonate at or about 4%, between at or about 0.5% and at or about 3%, used in the provided beverage compositions is between or between at or about 0.5% and at or about 2%, between at or between about 0.01% and 7%, by weight, of the composition, about 0.5% and at or about 1%, betweenator about 1% and at for example, between at or about 0.01% and at or about 6%, or about 5%, between at or about 1% and at or about 4%, between at or about 0.01% and at or about 5%, between at or between at or about 1% and at or about 3%, between at or about 0.01% and at or about 4%, between at or about 0.01% about 1% and at or about 2%, between at or about 2% and at and at or about 3%, betweenator about 0.01% and at or about or about 5%, between at or about 2% and at or about 4%, 2%, between at or about 0.01% and at or about 1%, between between at or about 2% and at or about 3%, between at or at or about 0.1%andator about 7%, betweenator about 0.1% about 3% and at or about 5%, between at or about 3% and at and at or about 6%, between at or about 0.1% and at or about or about 4%, or between at or about 4% and at or about 5%, by 5%, between at or about 0.1% and at or about 4%, between at weight, of the beverage composition. In some examples, the or about 0.1% and at or about 3%, between at or about 0.1% amount of acid added to the provided beverage compositions and at or about 2%, between at or about 0.1% and at or about is less than 5% or about 5%, typically less than 4% or about 1%, between at or about 0.5% and at or about 7%, between at 4%, for example, at or about 0.01%, 0.02%, 0.03%, 0.04%, or about 0.5% and at or about 6%, between at or about 0.5% 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, and at or about 5%, between at or about 0.5% and at or about 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 4%, between at or about 0.5% and at or about 3%, between at 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, or about 0.5% and at or about 2%, between at or about 0.5% 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, and at or about 1%, between at or about 1% and at or about 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 7%, betweenator about 1% and at or about 6%, between at or 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9% or about 1% and at or about 5%, between at or about 1% and at 5%, by weight, of the beverage composition. or about 4%, between at or about 1% and at or about 3%, 0711 (c) Antioxidants between at or about 1% and at or about 2%, between at or 0712. In one example, the stabilizer contains an antioxi about 2% and at or about 7%, between at or about 2% and at dant, for example, a molecule that is capable of inhibiting the or about 5%, between at or about 2% and at or about 4%, oxidation of other molecules. Antioxidants include molecules between at or about 3% and at or about 7%, between at or that Scavenge free radicals. Suitable antioxidants include about 3% and at or about 5%, between at or about 4% and at those that are used as ingredients in dietary Supplements. The or about 7%, between at or about 6% and at or about 7%, antioxidant can be a natural antioxidant or a synthetic anti between at or about 5% and at or about 7%, or between at or oxidant. US 2016/008 1976 A1 Mar. 24, 2016

0713 Examples of antioxidants include, but are not lim 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, ited to hormones, carotenoids, carotenoid terpenoids, non 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, carotenoid terpenoids, flavonoids, flavonoid polyphenolics 2.8%, (e.g., bioflavonoids), flavonols, flavones, phenols, polyphe 0715 b. Formulating the Non-Aqueous Pre-Gel Concen nols, esters of phenols, esters of polyphenols, nonflavonoid trates Containing Non-Polar Ingredients phenolics, isothiocyanates, vitamins and vitamin cofactors, 0716. The non-aqueous pre-gel concentrates contain one Such as VitaminA, Vitamin C, Vitamin E. Vitamin E phosphate or more non-polar ingredients; at least one surfactant, for and ubiquinone (ubidecarenone, coenzyme Q, coenzyme example, a polyethylene glycol derivative of vitamin E, e.g., Q10), ascorbic acid, citric acid, rosemary oil, minerals, such TPGS, and one or more non-aqueous solvents, for example, as mineral selenium and manganese, melatonin, C-carotene, solvents that have little or no solubility in water, for example, B-carotene, lycopene, lutein, Zeanthin, crypoxanthin, res an alcohol, ester, or hydrocarbon, or mixtures thereof. Veratrol, eugenol, quercetin, catechin, gossypol, hesperetin, 0717. As a first step in formulating the provided pre-gel curcumin, ferulic acid, thymol, hydroxytyrosol, tumeric, concentrates, one or more initial pre-gel concentrates are thyme, olive oil, lipoic acid, glutathione, gulamine, oxalic made and evaluated for desired properties. For this step, acid, tocopherol-derived compounds, di-alpha-tocopheryl ingredients are selected, for example, from one or more of the phosphate, tocotrienols, butylated hydroxyanisole, butylated lists of ingredients provided below. A starting concentration hydroxytoluene, ethylenediaminetetraacetic acid, tert-butyl (weight percentage) of each selected ingredient is selected hydroquinone, acetic acid, pectin, tocotrienol, tocopherol, from within an appropriate concentration range for that ingre coenzyme Q10 (coC10), Zeaxanthin, astaxanthin, canthaxan dient or category of ingredient. For example, a starting Sur thin, Saponins, limonoids, kaempferol, myricetin, isorhamne factant concentration, such as a polyethylene glycol derivate tin, proanthocyanidins, quercetin, rutin, luteolin, apigenin, of vitamin E, e.g., TPGS, is selected from within an appro tangeritin, hesperetin, naringenin, eriodictyol, flavan-3-ols priate surfactant concentration range. In some cases, the ini (e.g., anthocyanadins), gallocatechins, epicatechin and its tial pre-gel concentrate is formulated based on the ingredi gallate forms, epigallocatechin and its gallate forms theafla ents, and concentrations thereof, of an existing pre-gel vin and its gallate forms, thearubigins, isoflavone phytoestro concentrate, having one or more desired properties. gens, genistein, daidZein, glycitein, anythocyanins, cyanid 0718 The initial pre-gel concentrate(s) is then made, ing, delphinidin, malvidin, pelargonidin and peonidin. In one using the methods for making described below, adding each example, the antioxidant is vitamin C. In another example, ingredient at its starting concentration at the appropriate step. the antioxidant is a coenzyme Q-containing compounds, such In one example, more than one initial pre-gel concentrate is as ubiquinone (ubidecarenone, coenzyme Q, coenzyme made. For example, multiple initial pre-gel concentrates, Q10). each having a different concentration of one or more ingre 0714 Typically, the amount of antioxidant added to the dients, can be made and compared. For example, multiple compositions is between at or about 0.01% and at or about initial pre-gel concentrates can be made in order to test Vari 3%, for example, between at or about 0.01% and at or about ous representative concentrations within an appropriate con 2.5%, betweenator about 0.01% andator about 2%, between centration range for one or more particular ingredient. at or about 0.01% and at or about 1.5%, between at or about 0719 Each of the provided non-aqueous pre-gel concen 0.01% and at or about 1%, between at or about 0.01% and at trates contains at least one non-polar ingredient, typically or about 0.5%, between at or about 0.05% and at or about 3%, more than one non-polar ingredient, for example, non-polar between at or about 0.05% and at or about 2.5%, between at ingredients the contain one or more non-polar compounds. or about 0.05%andator about 2%, between at or about 0.05% Any non-polaringredient that contains one or more non-polar and at or about 1.5%, between at or about 0.05% and at or compounds can beformulated with the provided methods and about 1%, between at or about 0.05% and at or about 0.5%, pre-gel concentrates. Several exemplary non-polar ingredi between at or about 0.1% and at or about 3%, between at or ents that can be incorporated into the provided concentrates about 0.1% and at or about 2.5%, between at or about 0.1% are described herein below. Typically, the non-polar ingredi and at or about 2%, between at or about 0.1% and at or about ent is or contains a non-polar compound, for example, an 1.5%, between at or about 0.1% and at or about 1%, between oil-based ingredient, for example, a polyunsaturated fatty at or about 0.1% and at or about 0.5%, between at or about acid (PUFA), a coenzyme Q, or a vitamin. 0.5% and at or about 3%, between at or about 0.5% and at or 0720. The non-aqueous pre-gel concentrates provided about 2.5%, between at or about 0.5% and at or about 2%, herein contain high amounts of non-polar ingredients, for between at or about 0.5% and at or about 1.5%, between at or example, between or between about 30% or 35% or 40 wt % about 0.5% and at or about 1%, betweenator about 1% and at and 90 wt % non-polar ingredient, such as between or or about 3%, between at or about 1% and at or about 2.5%, between about 40% and 45%, 40% and 50%, 40% and 55%, between at or about 1% and at or about 2%, between at or 40% and 60%, 40% and 65%, 40% and 70%, 40% and 75%, about 1% and at or about 1.5%, between at or about 1.5% and 40% and 80%, 40% and 85%, 40% and 90%, 45% and 50%, at or about 3%, between at or about 1.5% and at or about 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%, 2.5%, between at or about 1.5% and at or about 2%, between 45% and 75%, 45% and 80%, 45% and 85%, 45% and 90%, at or about 2% and at or about 3%, betweenator about 2% and 50% and 55%, 50% and 60%, 50% and 65%, 50% and 70%, at or about 2.5%, between at or about 2.5% and at or about 50% and 75%, 50% and 80%, 50% and 85%, 50% and 90%, 3%, by weight, of the beverage composition. In some 55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, examples, the amount of antioxidant added to the provided 55% and 80%, 55% and 85%, 55% and 90%, 60% and 65%, beverage compositions is less than 5% or about 5%, typically 60% and 70%, 60% and 75%, 60% and 80%, 60% and 85%, less than 3% or about 2%, for example, at or about 0.01%. 60% and 90%. 65% and 70%, 65% and 75%, 65% and 80%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 65% and 85%, 65% and 90%, 70% and 75%, 70% and 80%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 70% and 85%, 70% and 90%, 75% and 80%, 75% and 85%, US 2016/008 1976 A1 Mar. 24, 2016 69

75% and 90%, 80% and 85%, 80% and 90%, and 85% and compositions, for example, the bioavailability of the non 90%, by weight of the pre-gel concentrate. The pre-gel con polar ingredients in the Soft gel composition after consump centrates that contain high amounts of non-polar ingredients tion, for example, human consumption. In particular, the and high amounts of non-aqueous solvent exhibit desirable nature of the surfactant, particularly the HLB of the surfac properties, for example, the non-polar ingredients remain in tant, and the non-aqueous solvent, and the relative concentra Solution in the non-aqueous solvent and do not precipitate tions of the Surfactant, non-aqueous solvent, and non-polar Out ingredients in the pre-gel concentrates, contribute to the 0721. In addition to the non-polar ingredients, the non desirable properties of the pre-gel concentrates and thus, the aqueous pre-gel concentrates contain at least one Surfactant, softgel compositions. for example, a polyethylene glycol derivate of vitamin E. 0725. Accordingly, properties of the ingredients and their Typically, the surfactant has an HLB value between 12 or relative concentrations in the pre-gel concentrates are impor about 12 and 20 or about 20, for example, 12, 13, 14, 15, 16, tant for the ability of the pre-gel concentrates to yield desir 17, 18, 19, 20, about 12, about 13, about 14, about 15, about able soft gel compositions. Selecting the appropriate ingre 16, about 17, about 18, about 19 or about 20. Exemplary of dients and relative concentrations thereof, within the ranges Surfactants are those described above, including polyethylene described herein, produce pre-gel concentrates that can be glycol derivatives of vitamin E described herein, such as introduced into gel capsules to yield soft gel compositions tocopherol polyethylene glycol succinate (TPGS), such as the having desirable properties. TPGS, TPGS analogs, TPGS homologs and TPGS deriva 0726 c. Soft Gel Compositions Containing Non-Polar tives described herein, and other Surfactants having similar Ingredients properties to TPGS, for example, other surfactants having 0727 i. Capsules HLB values between 12 or about 12 and 20 or about 20. 0728. The pre-gel concentrates are introduced into softgel Typically, the Surfactant is a natural Surfactant, for example, a capsules to produce the softgels provided. The soft gelcom Surfactant that is GRAS (generally recognized as safe)-certi positions contain a non-aqueous pre-gel concentrate within a fied by the FDA and/or Kosher certified, for example, TPGS. shell or coating, typically, a gel or similar capsule. The non 0722. In the non-aqueous pre-gel concentrates provided aqueous pre-gel concentrates described herein that contain herein, the concentration of the Surfactant, for example, the non-polar ingredients, a Surfactant, and non-aqueous solvent, polyethylene glycol derivative of vitamin E, e.g., TPGS, is are encapsulated in a coating or shell. Such as a gel coating, to greater than 5% or about 5%, typically greater than 10% or form the softgel compositions provided herein. The resulting about 10%, typically greater than 20% or about 20%, for soft gel compositions provided herein display advantageous example, greater than 25% or about 25%, for example, a properties. Such as enhanced bioavailability of the non-polar concentration within the concentration range of between 5% ingredients, for example, after the Soft gel has been con or about 5% and 40% or about 40%, between 10% or about Sumed. Methods for encapsulating non-aqueous pre-gelcom 10% and 40% or about 40%, typically between 20% or about positions are well known, and include encapsulation into 20% and 40% or about 40%, for example, between 25% or gelatin shells, or into shells composed of alternative materials about 25% and 40% or about 40%, for example, at least, 20, or combinations of materials are knownto those of skill in the 21, 22, 23, 24, 25, 26, 27, 28, 28.25, 28.4, 29, 30, 31, 32, 33, art. Numerous vendors and companies provide Such services 34, 34.6, 35,36, 37,38, 39, or 40%, by weight, of the pre-gel and compositions. The Soft gels containing the non-aqueous COncentrate. pre-gel concentrates containing the non-polar ingredients 0723. The pre-gel concentrates contain one or more non provide more bioavailable product compared to tablets or aqueous solvents, such as solvents that are insoluble or only powders. When consumed, the soft gel coating dissolves, partial soluble in water. Typically, the non-aqueous solvent is releasing the contents. an alcohol, a hydrocarbon, and/or an ester that has little or no 0729 Materials for encapsulation are well known. Cap solubility in water. Exemplary of non-aqueous solvents that Sules generally include a high proportion of gelatin (or a can be included in the pre-gel concentrates are aromatic alco gelatin Substitute) and additional ingredients, for example a hols, including, but are not limited to, benzyl alcohol, cyclic plasticizer, to make the gel Soft and pliable. Examples of the hydrocarbons, e.g., d-limonene, aromatic esters, e.g., benzyl capsular materials include, but are not limited to, natural or benzoate, and any non-aqueous solvent that is insoluble or synthetic gelatin, pectin, casein, collagen, protein, modified has only partial solubility in water. Typically, an aqueous starch, polyvinyl pyrrolidone, acrylic, natural or synthetic Solvent, e.g., water, is not added as an ingredient to the pre-gel polymers, cellulose derivatives (such as, but not limited to, concentrate. In the pre-gel concentrates provided herein, the hydroxypropyl methylcellulose (HPMC)), and combinations concentration of the non-aqueous solvent, or the total of all of thereof, optionally with one or more plasticizers and/or water. the one or more non-aqueous solvents, is chosen from within In some examples, soft gel capsules are made to accommo a concentration range of between 5% or about 5% and 20% or date vegetarian or vegan lifestyles. For Such applications, about 20%, for example, at least 5, 6, 7, 7.5,8,9, 10, 10.6, 11, alternative animal-free capsules. Such as capsules made from 12, 13, 14, 15, 15.4, 16, 17, 18, 19, or 20%, by weight, of the seaweed extract and gluten free starch without modified Sug pre-gel concentrate. ars, can be used. Capsular materials also optionally include 0724. A number of parameters of the pre-gel concentrates, one or more preservatives, coloring and opacifying agents including ingredients, their relative concentrations, and such as titanium dioxide to decrease the clarity of the shell of methods for making the pre-gel concentrates, affect the desir the soft gel capsule, flavorings and Sweeteners, Sugars, gas able properties of the concentrate, for example, the ability of troresistant Substances, fillers, binders, lubricants, disinte the non-polar ingredients to remain in Solution and not pre grates, or combinations thereof. In some embodiments, addi cipitate when a high concentration of non-polar ingredient is tional coatings on the capsules, such as immediate release present. By extension, these parameters of the pre-gel con coatings, protective coatings, enteric or delayed release coat centrates also affect the desirable properties of the soft gel ings, Sustained release coatings, barrier coatings, and combi US 2016/008 1976 A1 Mar. 24, 2016 70 nations thereof can be placed upon the Soft gel coating. Fla semi-fluid matrix Such as, for example, the Volume occupied Vors and up to 5% sucrose are added in certain examples in by a concentrate containing non-polar ingredients. For order to increase palatability of the softgel prior to ingestion. example, an oblong or oval capsule that is 4.0 minims in size In another example, in cases of decreased bioavailability of can contain 0.246 mL of material, for example, a concentrate the non-aqueous pre-gel concentrates containing non-polar containing non-polar ingredients. In another example, an ingredients, additional coatings can be added to the Soft gel oblong or oval capsule that is 8.0 minims in size can contain that increase delivery of the non-polar ingredients. 0.493 mL of material, for example, a concentrate containing 0730 Methods of manufacturing soft capsules are well non-polar ingredients. Capsule sizes are designated by con known to the skilled artisan. Exemplary processes for manu vention as (000), (00), (0), (1), (2), (3), (4), and (5), with a facture of soft capsules include, but are not limited to, the larger number corresponding to a smaller size. For example, plate process, the rotary die process, the reciprocating die one teaspoon can fill approximately seven size “0” capsules process, the bubble process, and the continuous process and about five size “00 capsules. Size “00 capsules are (Ebert (1978), “Soft Elastic Gelatin Capsules: A Unique Dos generally the largest size utilized for human consumption. age Form.” Pharm. Tech. 1(5); Reich (2004), “Chapter 11: Softgels can contain, for example, at least 30, 40, 50, 60, 70. Formulation and physical properties of soft capsules. Phar 80, 90. 100, 150, 200,300, 400, 500, 600, 800 or 1000 mg of maceutical Capsules, 2d Ed., Pharmaceutical Press, 201-212: the pre-gel composition. Dosage amount depends upon the Gullapalli, R. P. (2010) “Soft Gelatin Capsules (Softgels).J. non-polar components, a daily dosage thereofand the number Pharm. Sci. 99(10):4107-4146). Soft gel capsules can be of softgels to be consumed per day. The softgel composition made using standard rotary die encapsulation technology, can provide a single dose or a fractional dose. detailed in Stanley's Chapter 13 of “The Theory and Practice 0734 The soft capsules can be manufactured, for of Industrial Chemistry’ (Lachman, Lieberman, and Kanig, example, according to the conventional methods listed above Copyright Lea & Febiger, 1970) and in U.S. Patent Publica with the addition of a printed item on the capsule. Examples tion No. 2012/0301546 and U.S. Pat. Nos. 6,769,226 and of printed items include, but are not limited to, bandings, 7.213,511). Capsules can be manufactured and then hermeti brandings, designations, identifications, images, and other cally sealed to form a one-piece hermetically sealed gelatin printed items, and are exerted by methods well known in the shellencasing the concentrate containing the non-polaringre art (see, e.g., U.S. Pat. Nos. 2,449,139; 2,623,494; 2,703,047: dients. Capsules also can be manufactured according to meth 2,688,775; 3,124,840:3.203,347; 3,333,031; and 5,246,635). ods to create seamless capsules (see, e.g., U.S. Pat. Nos. A softgel capsule, for example, a softgelatin capsule, that has 5,478.508, 5,882,680 and 4,780.316). been manufactured in accordance with conventional methods 0731. The capsules, for example, a gelatin capsule, can be an be characterized by several properties of the capsule, manufactured in accord with conventional methods, for including, but not limited to, Bloom strength and hardness. example, as a two-piece hard gelatin capsule, sealed or The Bloom test measures the strength of the gel capsule in unsealed, typically in standard shape and various standard which the majority is composed of gelatin, by determining the sizes or as a soft gelatin capsule that is a one-piece hermeti weight (in grams) of a probe that is needed to deflect the cally sealed gelatin shell. The shape and size of the capsules Surface of the gel 4 mm without puncturing the Surface of the can vary in accordance with the method of preparation and the gel. Results of the Bloom test are expressed in Bloom units planned use of the capsule. Capsule shapes can be tailored to and generally vary between 30-300 Bloom. The specific pro the requirements of specific products, including, but not lim cedure of characterization by the Bloom method are well ited to, tube-shaped topical disposable capsules, aplicaps for known to the skilled artisan. In other instances, the strength of ophthalmic preparations, Suppositories, or an oral dosage the capsule wall is measured by an alternative device that form. Additional capsule shapes include, but are not limited assesses the elasticity, integrity and/or strength of the gel to, round, oval, tubular, oblong, twist off, or a non-standard capsule, including seam strength. The optimal range for a shape (e.g., a fish, tree, star, heart, or bear), and are preferably characteristic softgel, such as the softgel capsules described oblong. In some embodiments, non-standard shapes can be herewith, is 150-250. In addition to Bloom strength, softgel used. The size of the capsule used will vary in accordance capsules can also be characterized by their hardness. The with the volume of the fill composition, for example the hardness of a soft gel capsule is largely determined by the Volume of a pre-gel concentrate containing non-polar ingre ratio of the plasticizer component to gelatin. Following the dients, such as the non-aqueous pre-gel concentrates contain drying process during capsule manufacturing, a Bareiss ing non-polar ingredients described herein, that are intended Hardness tester, or an equivalent device, is used to measure to be contained therein. the hardness of the soft gel capsule. Measures of soft gel 0732. The soft gel capsules are filled with non-aqueous capsule integrity are essential for quality control prior to pre-gel concentrates provided herein. Compositions for packaging; moreover, measurements that fall within accept encapsulation by Soft gel. Such as compositions containing able ranges, such as values known to the skilled artisan, are non-polar ingredients, can be formulated in any conventional used to predict and prevent failure during packaging. manner by adding a selected amount of the concentrate, into 0735. Soft gel capsules, such as the softgel capsules con an acceptable soft gel capsule. Such as a soft gelatin capsule. taining the non-aqueous pre-gel concentrates containing non 0733 Soft gel capsule fill volume typically depends upon polar ingredients provided herein, can be packaged in con the density of the encapsulated material, the particular ingre tainers, for example packaging for the Soft gels can include, dients and dosages desired of non-polar components thereof but is not limited to, plastic or glass or metal containers, or desired. A single-body soft gelatin capsule, for example, in blister cards. Soft gel packaging can provide enhanced pro oval, oblong or other shapes, typically is provided, for tection against various insults, including, but not limited to, example, in sizes from 3 to 22 US minims (1 US minim being humidity, oxygen, light, and other toxicities. Plastic contain equal to 0.0616 mL or about /60 of a fluid dram (about one ers can be made of any suitable plastic materials including, for drop)). A minim is a unit of Volume occupied by a fluid or example, high density polyethylene, polypropylene, and US 2016/008 1976 A1 Mar. 24, 2016 polyethylene terephthalate, and can also include an integrated 0740. A number of parameters of the pre-gel concentrates, or separate desiccant and/or oxygen absorber. Glass bottles including ingredients, their relative concentrations, and can be colored glass, induction sealed, and have a plastic or methods for making the pre-gel concentrates, affect the abil metallid. In some embodiments, the packaging of softgels in ity of the non-polar ingredients to remain in Solution and not bottles can include bottles that are opaque, tamper-resistant, precipitate when a high concentration of non-polaringredient or tamper-evident. In some embodiments, the bottles contain is present. By extension, these parameters of the pre-gel con Sufficient desiccant material to protect the Soft gels from centrates also affect the advantageous properties of the soft damage from increased water or humidity where the desic gel compositions, for example, the bioavailability of the non cant can be integrated into the container, separate, or as a film. polar ingredients in the softgel composition upon consump 0736. In some examples, the soft gels composition are tion, for example, human consumption. packaged in containers. Containers used for packaging soft 0741. Thus, the pre-gel concentrates are formulated such gels, such as the soft gels containing non-aqueous pre-gel that after encapsulation, the resulting soft gel composition concentrates containing non-polar ingredients provided displays one or more advantageous properties, for example, herein, can be filled with any number of softgel capsules. For lack of phase separation and/or precipitation over time, and/ example, a container can contain, for example, 10, 20, 30, 40, or enhanced bioavailability of the non-polar ingredients. In 50, 60, 70,80,90, 100,500, 1000, or more than 1000, softgel one example, the advantageous property is the ability of the capsules, such as the soft gel capsules containing the non provided pre-gel concentrates to yield soft gel compositions aqueous pre-gel concentrates containing non-polar ingredi that have a lack of precipitation of the non-polar ingredients ents provided herein. In other examples, the Soft gel compo when encapsulated, for example, in a coating or shell. In sitions are packaged in blister cards. Blister cards used for another example, the advantageous property relates to the packaging soft gels, such as the Soft gels containing non ability of pre-gel concentrates to be encapsulated for human aqueous pre-gel concentrates containing non-polar ingredi consumption, for example, in a consumable shell or coating. ents provided herein, can contain any number of Soft gel In another example, it can be advantageous that the pre-gel tablets, e.g., ablister card can hold 3, 5, 10, 20, 30, 40, 50, 60, concentrate contains less than or equal to a particular concen 70, 80.90, 100, or more than 100 softgel capsules, such as the tration of one or more ingredients. In another example, it can softgel capsules containing the non-aqueous pre-gel concen be advantageous that the pre-gel concentrates contains trates containing non-polar ingredients provided herein. Blis greater than or equal to a particular concentration of one or ter cards can, for example, contain a foil backing as a barrier. more ingredients. Blister cards or packaging can include, for example, triplex 0742 e. Ingredients and Concentration Ranges blister film of different types, such as standard and high 0743 Each of the provided softgel compositions contains barrier films, including, for example, triplex Flexafarm Sbc a pre-gel concentrate encapsulated in a shell or coating, Such (e.g., PVC 250 my+PE 25 my+PVDC 150 g/md sbc grade) as a gelatin shell or coating. The pre-gel concentrates, and and Aquaba-PVC (e.g., PVC 250 my+AQUABA 160 g/md), thus, the encapsulated softgel compositions provided herein, Aclar, Alu-Alu formats, triple layer blister foil (OPA) with contain one or more non-polar ingredients, at least one Sur Soft tempered aluminium in central position, other layers factant, and one or more non-aqueous solvents. Typically, PVC and polyamide, and new generation multilayer blister encapsulation of a pre-gel concentrate to form a soft gel combined materials. composition does not change or alter the identity or concen (0737 d. Formulating the Soft Gel Compositions tration of the ingredients in the pre-gel concentrate, e.g., the 0738. The provided non-aqueous pre-gel concentrates identity and concentration of ingredients in a particular pre contain a high amount of non-aqueous solvent and have dis gel concentrate remain the same in the corresponding softgel played advantageous properties after encapsulation, such as composition after encapsulation. encapsulation in a shell or coating, e.g., a gelating shell or 0744. Each of the provided softgel compositions contains coating, to form a softgel composition. For example, the soft a non-polar ingredient including, but not limited to, the exem gel compositions provided herein that contain a high amount plary non-polar ingredients described herein above. Typi of non-aqueous solvent have advantageous properties. Such cally, the non-polar ingredient is or contains one or more as, for example, the Soft gel compositions contain a high non-polar compounds. The Soft gel compositions provided amount of non-polar ingredient that does not precipitate out herein can contain one non-polar ingredient or more than one of the composition. Additionally, the soft gel compositions non-polar ingredient, such as two, three, four, five, six, seven, provided herein that contain a high amount of non-polar eight, or more non-polar ingredients. The Soft gel composi ingredient display enhanced bioavailability of the non-polar tions provided herein can contain high amounts (i.e., concen ingredients after consumption, for example, human con trations) of non-polar ingredients. Such as up to at or about 90 Sumption, of the softgel composition, as compared to tablets wt % non-polar ingredient. or powders. 0745. The soft gel compositions provided herein contain 0739 The non-aqueous pre-gel concentrates provided pre-gel concentrates that contain one or more non-polar herein are formulated Such that encapsulation of a concen ingredients, where the total amount of non-polar ingredients trate, for example, in a coating or shell, e.g., a gelatin coating is typically present in an amount as a percentage (%) by or shell, yields a soft gel composition that contains a homog weight of the Soft gel compositions (wt %), e.g., from at or enous concentrate, i.e., a concentrate in which the non-polar about 40 wt % to at or about 90 wt %, such as between or ingredients are dissolved in the non-aqueous solvent and do between about 40% and 45%, 40% and 50%, 40% and 55%, not precipitate out. The high solubility of the non-polar ingre 40% and 60%, 40% and 65%, 40% and 70%, 40% and 75%, dients in the non-aqueous solvent leads to advantageous prop 40% and 80%, 40% and 85%, 40% and 90%, 45% and 50%, erties, for example, enhanced bioavailability of the non-polar 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%, ingredients when the Soft gel is consumed, for example, by a 45% and 75%, 45% and 80%, 45% and 85%, 45% and 90%, human. 50% and 55%, 50% and 60%, 50% and 65%, 50% and 70%, US 2016/008 1976 A1 Mar. 24, 2016 72

50% and 75%, 50% and 80%, 50% and 85%, 50% and 90%, 10% and 17%, 10% and 20%, 12% and 15%, 12% and 17%, 55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 12% and 20%, 15% and 17%, 15% and 20%, and 17% and 55% and 80%, 55% and 85%, 55% and 90%, 60% and 65%, 20% non-aqueous solvent(s) by weight of the soft gel com 60% and 70%, 60% and 75%, 60% and 80%, 60% and 85%, positions. Exemplary concentrations of the total amount of 60% and 90%. 65% and 70%, 65% and 75%, 65% and 80%, non-aqueous solvent(s) in the softgel compositions are at or 65% and 85%, 65% and 90%, 70% and 75%, 70% and 80%, about 5%, 7%, 10%, 12%, 15%, 17%, and 20% (wt %) of the 70% and 85%, 70% and 90%, 75% and 80%, 75% and 85%, softgel composition. 75% and 90%, 80% and 85%, 80% and 90%, and 85% and 90% non-polar ingredient by weight of the softgel composi 0750 f. Exemplary Dosages and Administration of the tions. Exemplary concentrations of the total amount of non Soft Gel Compositions polar ingredients in the Soft gel compositions are at or about 0751. The softgel compositions provided herein that con 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, and tain non-aqueous pre-gel concentrates containing non-polar 90% (wt %) of the soft gel compositions. ingredients, can beformulated, for example, for single dosage 0746. Each of the provided soft gel compositions contain (direct) administration, multiple dosage administration, or for pre-gel concentrates that contain at least one Surfactant that is dilution or other modification. The concentration of the non a polyethylene glycol derivative of vitamin E, for example, polar ingredients in the soft gel compositions is typically TPGS, TPGS analogs, TPGS homologs and TPGS deriva effective for delivery of an amount, upon administration, that tives described herein. The surfactant typically has an HLB is effective for the intended treatmentor benefit. Those of skill value of between 12 or about 12 and 20 or about 20, for in the art can readily formulate a composition for administra example, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about 12, tion in accord with the methods herein. For example, to for about 13, about 14, about 15, about 16, about 17, about 18, mulate a soft gel composition, the weight fraction of a non about 19 or about 20, typically between at or about 12 and at polar ingredient is dissolved, Suspended, dispersed, or or about 14. For example, TPGS, such as the TPGS described otherwise mixed, for example as detailed in the Examples, herein, has an HLB value of about 13. below, and then the composition encapsulated by a shell or 0747 The polyethylene glycol derivative of vitamin E, coating, such as a soft shell or coating, e.g., gelatin, and the e.g., TPGS, is typically present in an amount as a percentage resulting softgel capsule is utilized as a vehicle for delivering (%) by weight of the softgel compositions (wt %), e.g., from an effective concentration of non-polar ingredient. For at or about 5% to at or about 40%, such as 5% to 10%, 5% to example, an effective concentration of non-polar ingredient 15%, 5% to 20%, 5% to 25%, 5% to 30%, 5% to 35%, 5% to can be delivered via the soft gel to a human, for example, by 40%, 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, consumption of the soft gel composition. 10% to 35%, 10% to 40%, 15% to 20%, 15% to 25%, 15% to 0752. The precise amount or dose of the non-polar ingre 30%, 15% to 35%, 15% to 40%, 20% to 25%, 20% to 30%, dient administered via the Soft gel composition depends upon 20% to 35%, 20% to 40%, 25% to 30%, 25% to 35%, 25% to one or more considerations, including, for example, the con 40%, 30% to 35%, 30% to 40%, 30% to 30%, 30% to 35%, dition to be treated, the benefit to be conferred, the weight and 30% to 40%, and 35% to 40%, by weight of the soft gel general state of the Subject, and/or the particular characteris compositions. Exemplary concentrations of the polyethylene tics of the Subject. If necessary, a particular dosage and dura glycol derivative of vitamin E, e.g., TPGS, in the soft gel tion and treatment protocol can be empirically determined or compositions are at or about 5%, 7%, 10%, 12%, 15%, 17%, extrapolated. For example, exemplary doses of non-polar 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, and 40% (wt ingredients, such as the non-polar ingredients provided %) of the Soft gel compositions. herein, if necessary, can be used as a starting point to deter 0748. The soft gel compositions contain pre-gel concen mine appropriate dosages for a particular Subject and condi trates that contain one or more non-aqueous solvents. Typi tion or benefit. cally, the non-aqueous solvents include those that are insoluble or only partially soluble in water. Exemplary non 0753. The soft gel compositions containing pre-gel con aqueous solvents include alcohols, such as aromatic alcohols, centrates that contain non-polar ingredients can be formu e.g., benzyl alcohol, alcohol derivatives, such as esters, e.g., lated so that the dose of non-polar ingredient contained within benzylbenzoate, and hydrocarbons, such as cyclic hydrocar a single soft gel capsule is from, for example, 100 g or about bons, e.g., d-limonene. In one example, the Soft gel compo 100 g to 2000 g or about 2000 g, or 200 g or about 200 g to sition contains benzyl alcohol as a non-aqueous solvent. In 2000 g or about 2000 g, such as at or at least about 100 g, 150 another example, the softgel composition contains a mixture g, 200g, 250 g., 300 g, 350 g, 400 g, 450 g, 500 g. 600 g, 700 of benzyl alcohol and d-limonene as the non-aqueous sol g,800 g,900 g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 vents. The softgel compositions provided herein can contain g, 1600 g, 1700 g, 1800 g, 1900 g, or 2000 g, for direct one non-aqueous solvent or more than one non-aqueous sol administration. vent, such as two, three, four, five, or more non-aqueous 0754 Typically, the concentration of non-polar ingredient Solvents. is not more than 90% or about 90% of the weight of the soft 0749. The soft gel compositions provided herein contain gel composition, for example, between 40% or about 40% pre-gel concentrates that contain one or more non-aqueous and 90% or about 90% of the weight of the soft gel compo Solvents, where the total amount of non-aqueous solvent is sition. For example, when the non-polar ingredient is admin typically present in an amount as a percentage (%) by weight istered as a component of the pre-gel concentrate encapsu of the Softgel compositions (wt %), e.g., from at or about 5 wt lated by a shell or coating, e.g., a gelatin shell or coating, as % to at or about 20 wt %, such as between or between about described herein, the non-polar ingredient is administered at 5% and 7%, 5% and 10%, 5% and 12%, 5% and 15%, 5% and a concentration of between 40% or about 40% and 90% or 17%, 5% and 20%, 7% and 10%, 7% and 12%, 7% and 15%, about 90%, although more dilute or higher concentrations can 7% and 17%, 7% and 20%, 10% and 12%, 10% and 15%, be used. Generally, the level of non-polar ingredient can be US 2016/008 1976 A1 Mar. 24, 2016

increased or decreased according to the judgment of a person acid ester in place of maltodextrin or other such binder in a of skill in the art. The amount of the remaining ingredients can pre-spray emulsion permits production of free-flowing dry be adjusted as needed. powders with a higher concentration of non-polar ingredients 0755. In the methods described herein, soft gel composi than previously available. tions containing non-aqueous pre-gel concentrates contain ing non-polar ingredients, such as the soft gel compositions 0760. The pre-spray emulsions also can include additional described herein, can be administered to a Subject for treating ingredients, such as stabilizers, include carbonates and bicar a variety of conditions or conferring a particular beneficial bonates, as described above, and antioxidants. The Sugar fatty effect. In particular, the softgel compositions provided herein acid esters. Such as SFAES, and the carbonate. Such as are intended for use in methods in which other pharmaceuti KHCO, improve the stability of the powders and also the cals, nutraceuticals and/or dietary Supplements, such as resulting beverages and foods into which the powders are known treatments, can be used to convey a benefit to the dissolved. The Sugar fatty acid esters, such as SFAES, act as Subject. The non-polar ingredients contained within the soft emulsifiers in the pre-spray emulsion and powders, and also gel compositions provided herein are typically included in an act as a Solid for drying the pre-spray emulsions to produce amount sufficient to confer a beneficial effect in the absence the powders. Compared to prior art powders prepared from of undesirable side effects on the subject. The amount of emulsions containing a PEG derivative of vitamin E and/or non-polar ingredient to be administered can be determined by other such surfactants that are not solids, such as TPGS alone, one of skill in the art. The precise dosage, which can be only contribute to stability of the pre-spray emulsion, but do determined empirically, can depend on the particular compo not contribute to formation of a powder. By including the sition, the type of condition to be treated and the seriousness sugar fatty acid esters, such as SFAEs, the properties of the of the condition, the type of benefit to be conferred, in addi powders are improved, and higher levels of non-polar ingre tion to other characteristics known to those of skill in the art. dients can be included. (0756 4. Powders and Pre-Spray Emulsions 0757. The high dimer-containing water-soluble vitamin E 0761 Exemplary pre-spray emulsions and powders are derivatives, such as the PEG derivatives of vitamin E, particu described in the examples and below. All contain up to about larly the high dimer-containing TPGS mixtures, are included or at 60% non-polar ingredient: 1-10% TPGS; and a binder in emulsion compositions that are for drying, such as by and Sugarfatty acid esters, such as SFAE and maltodextrin (or spray-drying, to form powders. The pre-spray emulsions other Such binder). Additional optional ingredients include include all of the ingredients in the powders and additionally stabilizers, emulsifiers and antioxidants. For example, one a polar compound. Such as water, which is removed by spray powder described herein includes: 45-55% oil/non polar drying, evaporation or other drying process. The ingredients compound(s): 1-2% TPGS: 15-20% SFAE (emulsifier and include the non-polar ingredient(s), the high dimer-contain binder): 3-10% carbonate, such as KHCO, which serves as ing PEG derivative of vitamin E, in particular, a TPGS mix an antioxidant, binder and keeps the powder dry and/or acts as ture, a Sugar fatty acid, a binder, Such as a maltodextrin, and a leavener); 15-20% green tea extract, which contains 50% other optional ingredients, such as stabilizers, such as a car EGCG powder (antioxidant); 1-2% saponin (quillaja bark; bonate orbicarbonate, antioxidants, such as ascorbic acid or a co-enzyme Q-containing product, and/oran ingestible acid. emulsifier); and 0.1-0.2% Saladizer(R) (thickener and emulsi The emulsions are prepared and then dried to produce the fier). Another exemplary powder contains 55-60% oil/non powders. polar compound(s): 1-2% TPGS (emulsifier); 5-10% SFAE 0758 Typically, drying an emulsion with a high oil load (emulsifier and binder): 3-10% carbonate, such as KHCO results in a product that is not free-flowing and is more like a (antioxidant, binder and keeps the powder dry or acts as a sludge than a powder. Provided are water-soluble powder leavener); 15-25% whey protein/gelatin powder (binder): products that contain high concentrations (more than 20%, 1-2% saponin (quillaja bark; emulsifier) and 0.1-0.2% Sal and particularly, more than 25%,27%, 30%, 35%, 40%, 45%, adizer R (thickener and emulsifier). These amounts and com 47%, or 50%, by weight of the composition) of non-polar positions are exemplary only. Further examples are described ingredients. In order to produce powders for spray drying, it is below. It is understood that for purposes herein, the water necessary to include a threshold amount of solids for forming soluble vitamin E derivative, such as a PEG derivative of the powder. To achieve this, the TPGS is reduced in amount, Vitamin E. Such as TPGS, is a high dimer-containing form and Sugar fatty acid esters, such as SFAES, are added in its described and defined above. Such description is incorpo place and in addition to or in place of a binder, Such as a rated into this section by reference. dextrin. In the absence of the added SFAE, when dried, the 0762. Provided are pre-spray emulsions, which contain emulsions, and particularly the emulsions with higher the non-polar ingredient(s) as described herein above, the amounts of non-polar ingredient, do not form a dry free high dimer-containing water-soluble vitamin E derivative flowing powder, but form a sludge-like oil with too high a mixture, such as a PEG derivative of vitamin E, such as moisture content. The dry powders are added in any desired TPGS, as described and defined above, and the non-polar amount to a beverage, particularly an aqueous beverage, and/ ingredient, as well as the Sugar fatty acid esters, such as an or to a food, to Supplement the beverage or as a way to deliver SFAE or mixture thereof, and a binder, such as maltodextrin, the non-polar ingredient(s) therein. whey and others described herein and/or known to those of 0759. The powders contain sugar fatty acids in place of or skill in the art, and any other ingredients to be included in the in addition to the binders, such as a dextrin, generally used to powder. As described below, these are combined to form a produce powders from emulsions. The resulting powders are pre-spray emulsion which is then dried to form a powder. To free-flowing (not sticky or sludge-like) and water-soluble. form the powder, the pre-spray emulsion can be dried, and Also provided are pre-spray emulsions from which the pow then dissolved in an aqueous medium, Such as water, and ders are produced. Addition of a Sucrose (or other Sugar) fatty dried again. US 2016/008 1976 A1 Mar. 24, 2016 74

0763 a. Pre-Spray Emulsions Containing Non-Polar ratios of the ingredients that yield compositions having one or Ingredients more desired properties. The ingredients include a concen 0764 Provided herein are pre-spray emulsions that con trate that contains non-polar ingredients and a polyalkylene tain the pre-emulsion concentrates containing non-polar glycol Vitamin E derivative, e.g., a high dimer-containing ingredients dispersed in aqueous liquid and have desirable TPGS, a surfactant, such as a Sugar fatty acid ester, e.g., properties, including improved clarity, stability, Smell and Sucrose fatty acid ester, and a polar solvent, e.g., water. In taste. The provided emulsions (and methods for making the Some examples, the pre-spray emulsions further include one emulsions) can be used to formulate any non-polar ingredient or more of a stabilizer, a binder, e.g., maltodextrin, a co in aqueous compositions, including the non-polar ingredients Surfactant, an emulsion stabilizer, and a pH adjuster. In the (e.g., non-polaringredients that are or contain non-polar com provided emulsions, a Surfactant, Such as a Sugar fatty acid pounds) described herein and other known non-polar ingre ester, e.g., Sucrose fatty acid ester, is present in place of or in dients. combination with a binder, e.g., maltodextrin. For example, 0765. In general, emulsions (e.g., oil-in-water emulsions) the pre-spray emulsions provided herein can contain a Sur are colloidal dispersions of two immiscible liquids (e.g., oil factant, such as such as a Sugar fatty acid ester, e.g., Sucrose and water or other aqueous liquid), containing a continuous fatty acid ester, and not containabinder, e.g., maltodextrin. In and a dispersed phase. Emulsions can be used to disperse other examples, the pre-spray emulsions provided herein con non-polar ingredients in aqueous liquids. In an oil-in-water tain a mixture of Surfactant, such as a Sugar fatty acid ester, emulsion, the dispersed phase is an oil phase and the continu e.g., Sucrose fatty acid ester, and binder, e.g., maltodextrin. ous phase is an aqueous (water) phase. There is a need for 0771. The pre-spray emulsions provided herein contain emulsions (e.g., oil-in-water emulsions) containing non-po have high concentrations of non-polar ingredients, for lar ingredients in aqueous liquids and methods and composi example, at least 5%, 7%, 10%, 12%, 15%, 20%, 25%, 30% tions for generating products, such as the water-soluble pow or more non-polar ingredients, such that when the emulsion is ders, that are free-flowing, i.e., not sticky. In particular, dried the resulting powder includes up to as much as 60% emulsions are needed that are more suitable and desirable for non-polar ingredient. The emulsions are formulated Such that human consumption of the non-polar ingredients, for drying the emulsion, e.g., spray drying, yields a powder com example, beverages. For example, emulsions having position that contains high concentrations of non-polar ingre improved clarity (e.g., Small particle size, low turbidity), dient, yet is free-flowing, i.e., not sticky, and water-soluble. stability (e.g., lack of separation), taste and Smell, that can The emulsion dry to form a free-flowing, i.e., not sticky or form powders that are free-flowing, i.e., not sticky, and water sludgy, powder even where a high concentration of non-polar soluble are provided herein. ingredient is present. 0766 Typically, the provided emulsions containing the 0772 ii. Exemplary Ingredients and Typical Concentra concentrates containing non-polar ingredients are nanoemul tion Ranges sions, which are emulsions having dispersed droplets (par (0773 (a) Pre-Emulsion Concentrates ticles) with diameters less than 1000 nm or less than about 0774. Each pre-spray emulsion provided herein contains a 1000 nm, typically, less than 500 nm or less than about 500 pre-emulsion concentrate. Such as the pre-emulsion concen nm, typically less than 300 nm or about 300 nm, typically less trates provided herein, that contain non-polar ingredients that than 250 or less than about 250 nm, typically less than 200 nm are or contain non-polar compounds and a polyalkylene gly or less than about 200 nm, for example, less than or less than col derivative of vitamin E, for example, a polyethylene gly about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, col derivative of vitamin, e.g., TPGS. In some examples, the 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35,36, 37,38, 39, 40, pre-emulsion concentrate contains a preservative, for 41, 42, 43,44, 45,46, 47, 48, 49, 50, 60, 70, 80,90, 100, 110, example, benzyl alcohol. 120, 130, 140, 150, 160, 170, 180, 190, or 200 nm. Typically, 0775. The pre-emulsion concentrates used in formulating the provided nanoemulsion compositions are oil-in-water the pre-spray emulsions contain between or between about 30 nano emulsions, containing the non-polar ingredients dis wt % and 99 wt % non-polar ingredient, typically at least 40 persed in aqueous liquid. wt %, or at least 50 wt %, or more, such as at least 55%, 60%, 0767 The provided emulsion compositions are stabilized 65%, 70%, 75%, 80%, 85%, 90%. 95%, or 99% non-polar by one or more surfactants and/or co-surfactants and/or emul ingredient, by weight, of the pre-emulsion concentrate. When sion stabilizers. Surfactants form an interfacial film in the formulating the pre-spray emulsions provided herein that emulsion, between the oil and water phase, providing stabil contain the pre-emulsion concentrates containing between or ity. Typically, the nanoemulsions of the provided composi between about 30 wt % and 99 wt % non-polar ingredients, tions contain micelles, in which one or more surfactant Sur the emulsions will contain, for example, between or between rounds the non-polaringredient. The micelles are dispersed in about 1 wt % and 40 wt % concentrate, such as between or the water phase. between about 1% and 5%, 1% and 10%, 1% and 15%, 1% 0768. The provided pre-spray emulsions contain the pre and 20%, 1% and 25%, 1% and 30%, 1% and 35%, 1% and emulsion concentrates containing non-polar ingredients, 40%, 5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, which can be spray-dried to provide non-polar ingredients in 5% and 30%, 5% and 35%, 5% and 40%, 10% and 15%, 10% a powder, such as free-flowing, water-soluble powder. The and 20%, 10% and 25%, 10% and 30%, 10% and 35%, 10% pre-spray emulsions can be made using any concentrate con and 40%, 15% and 20%, 15% and 25%, 15% and 30%, 15% taining non-polar ingredients, a Sugar fatty acid ester, and a and 35%, 15% and 40%, 20% and 25%, 20% and 30%, 20% polyalkylene glycol derivative of Vitamin, such as the pre and 35%, 20% and 40%, 25% and 30%, 25% and 35%, 25% emulsion concentrates provided herein. and 40%, 30% and 35%, 30% and 40%, and 35% and 40% 0769 i. Formulating the Pre-Spray Emulsions concentrate containing non-polar ingredients, by weight, of 0770. In the provided methods, the pre-spray emulsions the emulsion. Exemplary concentrations of the total amount are formulated by selecting ingredients and concentration of concentrate containing non-polar ingredients in the emul US 2016/008 1976 A1 Mar. 24, 2016

sions are at or about 5%, 7%, 10%, 12%, 15%, 17%, and 20% 20%, 10% and 12%, 10% and 15%, 10% and 17%, 10% and (wt %) of the emulsion. By extension, the amount of non 20%, 12% and 15%, 12% and 17%, 12% and 20%, 15% and polar ingredient present in the pre-spray emulsions is typi 17%, 15% and 20%, and 17% and 20%, sugar fatty acid ester, cally between or between about 5 wt % and 30 wt % of the e.g., Sucrose fatty acid ester, by weight of the Soft gel com emulsion, for example, between or between about 5% and positions. Exemplary concentrations of the total amount of 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and 30%, 10% and 15%, 10% and 20%, 10% and 25%, 10% and 30%, Sugar fatty acid ester, e.g., Sucrose fatty acid ester in the 15% and 20%, 15% and 25%, 15% and 30%, 20% and 25%, pre-spray emulsions are at or about 1%, 3%. 5%, 7%, 10%, 20% and 30%, and 25% and 30% non-polar ingredient, by 12%, 15%, 17%, and 20% (wt %) of the pre-spray emulsions. weight of the pre-spray emulsion. 0781 (1) Sucrose Fatty Acid Ester Surfactants (0776 (b) Surfactants 0782. Sucrose fatty acid ester surfactants contain one or 0777. The provided pre-spray emulsions contain surfac more Sucrose fatty acid esters, which are non-ionic Surfac tants. In particular, the high dimer-containing water-soluble tants that contain Sucrose in the hydrophilic portions and fatty vitamin E derivative, such as a PEG derivative of vitamin E, acids in the hydrophobic portions. The sucrose fatty acid particularly the high dimer-containing TPGS as described esters can be made by well-known methods (see, for example, above. Additionally, the compositions include Sugarfatty acid U.S. Pat. Nos. 3,480,616, 3,644,333, 3,714,144, 4,710,567, esters, such as one or more SFAEs. In the provided methods 4,898,935, 4,996,309, 4,995,911, 5,011,922 and 5,017,697 for producing the emulsions, the Surfactant is added to the and International Patent Application Publication No. WO water phase, the oil phase, or to the water and the oil phase. The emulsions further can contain one or more co-surfactants 2007/082149), typically in an esterification reaction as or emulsifiers. Typically, the Surfactants are natural Surfac described below. tants, for example, a Surfactant that is G.R.A.S. (generally 0783 Because sucrose contains eight hydroxy ( -OH) recognized as safe) by the FDA and/or Kosher certified. In an groups, the esterification reaction can join the Sucrose mol exemplary embodiment, the Surfactant is a Sugar-derived Sur ecule to one fatty acid molecule, or can join it to a plurality of factant, for example, a Sugar fatty acid ester, e.g., Sucrose fatty fatty acid molecules, producing different degrees of esterifi acid ester. cation, e.g., mono-, di-, tri- and poly- (up to octa-) fatty acid 0778 Exemplary of surfactants, in addition to the high esters, but primarily mono-, di-, and/or tri-esters. The degree dimer-containing water-soluble vitamin E derivative compo sitions, such as a TPGS, and the sugar fatty acid esters, such of esterification can depend on conditions of esterification. as used in the provided methods and compositions, are other The esterification reaction can be carried out with a single surfactants having an HLB value of between 12 or about 12 type of fatty acid, or a plurality of fatty acids, Such as fatty and 20 or about 20, for example, 12, 13, 14, 15, 16, 17, 18, 19. acids with varying carbon chain lengths, branched and linear 20, about 12, about 13, about 14, about 15, about 16, about 17, fatty acids, and/or saturated or unsaturated fatty acids. The about 18, about 19 or about 20. The surfactants typically are, esterification reaction with a single fatty acid can produce a and typically have an HLB value between at or about 12 and single ester, and typically forms more than one ester, such as at or about 20. mono- di-, tri- and/or poly-esters, formed from one reaction. 0779 Particular examples of suitable sugar fatty acid esters for use in the provided compositions include the Sugar The relative amounts of mono- di- tri- and/or poly-esters can derived Surfactants, including fatty acid esters of Sugars and depend on reaction conditions. Sugar derivatives. For example, Sugar fatty acid esters include 0784 The fatty acid in the sucrose fatty acid ester can be fatty acid esters of sucrose, glucose, maltose and other Sugars, any fatty acid, and can contain between 4 and 28 carbon esterified to fatty acids of varying lengths (e.g., varying num atoms, typically between 8 and 28 carbon atoms, and typi bers of carbons). The fatty acids typically have carbon chains cally between 8 and 25 carbon atoms, such as between 8 and between 8 and 28 carbons in length, and typically between 8 18 carbonatoms, such as 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and and 20, or between 8 and 18 or between 12 and 18, such as, but 18 carbon atoms. The fatty acid can be synthetic or naturally not limited to, stearic acid (18 carbons), oleic acid (18 car bons), palmitic acid (16 carbons), myristic acid (14 carbons) occurring, and include linear and branched fatty acids. The and lauric acid (12 carbons). Typically, the Sugar ester Sur fatty acids include, but are not limited to, myristic acid, palm factants are Sucrose ester Surfactants, typically Sucrose fatty itic acid, Stearic acid, oleic acid, caproic acid, capric acid, acid ester Surfactants. myristic acid, decanoic acid and pelargonic acid. 0780. The pre-spray emulsions provided herein contain a 0785 Thus, the sucrose fatty acid ester surfactants include Surfactant, Such as a Sugar fatty acid ester, e.g., Sucrose fatty Sucrose monoesters, diesters, triesters and polyesters, and acid ester, where the total amount of Surfactant, e.g., Sucrose mixtures thereof, and typically contain Sucrose monoesters. fatty acid ester, is typically present in an amount as a percent The Sucrose fatty acid ester Surfactants include single fatty age (%) by weight of the emulsion (wt %), e.g., from at or acid esters and also include homogeneous mixtures of about 1 wt % to at or about 20 wt %, such as between or Sucrose esters, containing members with different lengths of between about 1% and 3%, 1% and 5%, 1% and 7%, 1% and fatty acid carbon chain and/or members with different 10%, 1% and 12%, 1% and 15%, 1% and 17%, 1% and 20%, degrees of esterification. For example, the Sucrose fatty acid 3% and 5%, 3% and 7%, 3% and 10%, 3% and 12%, 3% and ester Surfactants include mixtures of monoesters, diesters, 15%, 3% and 17%, 3% and 20%, 5% and 7%, 5% and 10%, triesters, and/or polyesters. The Sugarester Surfactants further 5% and 12%, 5% and 15%, 5% and 17%, 5% and 20%, 7% include Sucrose fatty acid ester analogs and homologs and and 10%, 7% and 12%, 7% and 15%, 7% and 17%, 7% and mixtures thereof. US 2016/008 1976 A1 Mar. 24, 2016 76

0786 Sucrose fatty acid esters are compounds having the following formula shown below: O

O ul R 0795 and the other seven ofX,X,X,X,X,X,X7 and X are each, independently, OH. An exemplary monoester has the following structure:

O

R - O OH HO 0787 where each of X, X, X, X, X, X, X7 and X O independently is: O 0788 a hydroxyl (—OH) group, or OH HO HO OH O 0796 where R is an alkyl group having 3-27 carbons, and typically 7-27 carbons. 1. 0797. The sucrose fatty acid esters include blends of Sucrose fatty acid esters, which typically include monoesters, and can also include diesters, triesters and polyesters, which where: have structures according to Scheme V, above, where two 0789 each R is an alkyl group having 3-27 carbon (diesters), three (triesters) or more (polyesters) of X, X, X, atoms; and X, X, X, X7 and X, (and typically X and X) indepen dently, are 0790 when more than one of X, X, X, X, X, X, X7 and X is O

O l R.

R, 0798. In general, sucrose fatty acid esters, including mix tures of Sucrose fatty acid esters, can have varying HLB 0791) each R can be a different alkyl group (e.g., having values, such as HLB values ranging from at or about 1 to at or about 20. The HLB value of the sucrose fatty acid ester different number of carbonatoms and/or different saturation), generally depends on the degree of esterification (e.g., the or can be the same alkyl group. average degree of esterification in a mixture of different 0792 Typically, in the provided sucrose fatty acid ester esters). Typically, the lower the degree of esterification (e.g., surfactants, each R has between 7 and 27 carbon atoms, and average degree), the higher the HLB value of the sucrose fatty typically between 7 and 19 atoms, such as 7, 8, 9, 10, 11, 12, acid ester or mixture thereof. Exemplary Sucrose esters 13, 14, 15, 16, 17, 18, or 19 carbonatoms or between 7 and 17 include sucrose distearate (HLB-3), sucrose distearate/ carbon atoms. monostearate (HLB 12), sucrose dipalmitate (HLB=7.4): Sucrose monostearate (HLB-15). Sucrose monopalmitate 0793. An alkyl group can be a straight chain or branched (HLB-10); Sucrose monolaurate (HLB 15). Typically, the alkyl group, can be substituted or unsubstituted, and can be a Sucrose fatty acid ester Surfactants in the provided composi saturated “saturated alkyl group” meaning that it does not tions have an HLB value of between at or about 14 and at or contain any alkene or alkyne groups; or an “unsaturated alkyl about 20, such as at or about 14, 15, 16, 17, 18, 19, or 20, and group” meaning that it contains at least one alkene or alkyne typically between at or about 14 and at or about 18, such as, group. An alkyl group that includes at least one carbon-car but not limited to, HLB values of at or about 15, 16 and 17, bon double bond (C—C) also is referred to by the term “alk Such as, for example, Sucrose ester Surfactants including enyl and alkenyl groups optionally can be substituted. An Sucrose monopalmitate. Sucrose monolaurate and Sucrose alkyl group that includes at least one carbon-carbon triple mono Stearate. bond (C=C) also is referred to by the term “alkynyl.” and 0799. The sugar ester surfactants include sucrose ester alkynyl groups optionally can be substituted. blends, for example. Sucrose ester mixtures containing a specified amount (e.g., percent, by weight) of Sucrose 0794 Typically, the sucrose fatty acid ester surfactants monoesters. Exemplary Surfactants include Sucrose ester contain Sucrose fatty acid monoesters, having the structure set mixtures having at least at or about 50%, by weight (w/w), forth below, where one of X, X, X, X, X, X, X7 and X monoester, such as at or about or at leastator about 50, 51, 52, (typically X") is 53, 54, 55,56, 57,58, 59, 60, 61, 62,63, 64, 65,66, 67,68, 69, US 2016/008 1976 A1 Mar. 24, 2016 77

70,71, 72,73,74, 75,76, 77,78, 79,80, 81,82, 83, 84, 85,86, Ester(R), produced by Dai-Ichi Kogyo Seiyaku Co., Ltd of 87, 88, 89,90,91, 92,93, 94, 95, 96, 97,98, 99 or 100%, by Japan (which, in Some examples, can be produced according weight (w/w), Sucrose monoesters, and typically at least at or to the methods described in U.S. Pat. Nos. 4,898,935, 4,996, about 60%, by weight or at least at or about 70%, by weight 309, 4,995,911, 5,011,922 and 5,017,697, and distributed (w/w), monoesters. The Surfactants include mixtures of through Montello Inc., Tulsa, Okla., such as the F-160 and Sucrose esters containing at least at or about 50% sucrose F-140 grade esters sold under the trade name DK Ester R, and monoesters, mixtures of Sucrose esters containing at least at Sucrose esters sold under the trade name SURFHOPER SE or about 60% sucrose monoesters, mixtures of sucrose esters PHARMA, by Mitsubishi-Kagaku Foods Corporation, dis containing at least at or about 70% Sucrose monoesters, mix tributed by Mitsubishi Chemical Performance Polymers, Inc. tures of sucrose esters containing at least at or about 80% These sucrose fatty acid esters are mixtures of esters with Sucrose monoesters, and mixtures of Sucrose esters contain different degrees of esterification. The sucrose fatty acid ing at least at or about 90% Sucrose monoesters, for example, esters further include Ryoto sugar esters, which are food mixtures containing at or about 72%. Sucrose monoesters, at grade esters sold by Mitsubishi-Kagaku Foods Corporation, or about 61% sucrose monoesters, orator about 90% sucrose distributed by Mitsubishi Chemical Performance Polymers, monoesterS. Inc. Exemplary Sucrose fatty acid esters sold under the trade name DK Ester R, and those sold under the trade name SUR 0800 The sucrose fatty acid ester surfactants include FHOPER SE PHARMA and Ryoto sugaresters, are listed in Sucrose fatty acid monoesters, such as Sucrose monocapry the table below. The table lists the average degree of esterifi late. Sucrose monodecanoate. Sucrose monolaurate. Sucrose cation or the fatty acid composition within the mixture, and monomyristate. Sucrose monopalmitate. Sucrose monostear the HLB of the sucrose fatty acid ester surfactant. Any of the ate, Sucrose monopelargonate. Sucrose monoundecanoate, surfactants in the table below can be used. Typically, the Sucrose monotridecanoate, Sucrose monopentadecanoate and Surfactant (e.g., a Surfactant listed in the table below), has an Sucrose monoheptadecanoate. The Sucrose fatty acid esters HLB value between at or about 12 and at or about 20, typi further include mixtures containing varying percentages of cally between at or about 15 and at or about 18, e.g., but not monoesters, diesters, triesters and polyesters, such as, but not limited to, those surfactants in the table having an HLB of 15 limited to, a mixture having at or about 72% monoesters, 23% or 16, such as the Sucrose fatty acid ester Surfactant sold under diesters, 5% triesters and 0% polyesters; a mixture having at the name DKESTER(R) F-160, produced by Dai-Ichi Kogyo or about 61% monoesters, 30% diesters, 7% triesters, and 2% Seiyaku Co., Ltd of Japan, and distributed through Montello polyesters; and a mixtures having at or about 52% Inc., Tulsa, Okla. Other exemplary sucrose fatty acid ester monoesters, 36% diesters, 10% triesters and 2% polyesters. surfactants are described in Youan et al., AAPS PharmaSci 0801. The sucrose fatty acid ester surfactants include 2003:5(2) Article 22: 1-9 and in Okamoto et al., Biol. Pharm. sucrose fatty acid esters sold under the trade name DK Bull. 28(9): 1689-1694 (2005).

Exemplary Sucrose Fatty Acid Ester (SFAE) Surfactants Average Distribution (by weight) Sucrose Fatty Degree of Fatty acid of Ester Acid Ester Esterification composition H.L.B. Mono:Di:Tri:Poly

DK Ester (R) F-160 .23 16 72% monoester; 23% diester; 5% triester DK Ester (R) F-140 35 13 61% monoester; 30% diester; 7% triester; 2% polyester DK Ester (R) F-110 48 11 52% monoester: 36% diester; 10% triester; 2% polyester DK Ester (R) F-90 53 9.5 45% monoester; 39% diester: 12% triester; 4% polyester DK Ester (R) F-70 60 8 39% monoester; 45% diester; 12% triester; 4% polyester DK Ester (R) F-50 69 6 34% monoester; 46% diester; 17% triester; 3% polyester DK Ester (R) F-2OW 3.11 2 11% monoester; 21% diester; 14% triester: 54% polyester DK Ester (R) F-10 4.85 1 O% monoester; 5% diester: 11% triester; 84% polyester SURFHOPE (RSE C12 (100%) 5 3% monoester; PHARMA 68% di-?tri-poly-esters -1205 SURFHOPE (RSE C12 (100%) 16 81% monoester; PHARMA 19% di-?tri-poly-esters -1216 US 2016/008 1976 A1 Mar. 24, 2016 78

-continued

Exemplary Sucrose Fatty Acid Ester (SFAE) Surfactants Average Distribution (by weight) Sucrose Fatty Degree of Fatty acid of Ester Acid Ester Esterification composition H.L.B. Mono:Di:Tri:Poly SURFHOPE OR SE C16 (80%); C18 16 79% monoester; PHARMA (20%) 21% di-?tri-?poly-esters -1616 SURFHOPE OR SE C16 (70%); C18 5 30% monoester; PHARMA (30%) 70% di-?tri-?poly-esters -1805 SURFHOPE OR SE C16 (70%); C18 7 PHARMA (30%) -1807 SURFHOPE OR SE C16 (70%); C18 16 75% monoester; PHARMA (30%) 25% di-?tri-?poly-esters -1816 SURFHOPE OR SE Sucrose stearate 3 Approximately 20% PHARMA (approximately monoester; approximately D-1803 70% stearate) 80% di-?tri-?poly-esters SURFHOPE OR SE Sucrose stearate 3 20% monoester; PHARMA (70% stearate) 80% di-?tri-?poly-esters D-18O3F SURFHOPE OR SE Sucrose stearate 5 30% monoester; PHARMA (70% stearate) 70% di-?tri-?poly-esters D-18O SURFHOPE OR SE Sucrose stearate 7 40% monoester; PHARMA (70% stearate) 60% di-?tri-?poly-esters D-1807 SURFHOPE OR SE Sucrose stearate 9 50% monoester; PHARMA (70% stearate) 50% di-?tri-?poly-esters D-1809 SURFHOPE (R) SE Sucrose stearate 1 55% monoester; PHARMA (70% stearate) 45% di-?tri-?poly-esters D-18 SURFHOPE OR SE Sucrose stearate 1 55% monoester; PHARMA (70% stearate) 45% di-?tri-?poly-esters D-1811F SURFHOPE OR SE Sucrose stearate 5 70% monoester; PHARMA (70% stearate) 30% di-?tri-?poly-esters D-1815 SURFHOPE OR SE Sucrose stearate 6 75% monoester; PHARMA (70% stearate) 25% di-?tri-?poly-esters D-1816 SURFHOPE OR SE Sucrose palmitate 5 70% monoester; PHARMA (80% palmitate) 30% di-?tri-?poly-esters D-1615 SURFHOPE OR SE Sucrose palmitate 6 80% monoester; PHARMA (80% palmitate) 20% di-?tri-?poly-esters D-1616 SURFHOPE OR SE Sucrose laurate 6 80% monoester; PHARMA (95% laurate) 20% di-?tri-?poly-esters D-1216 Ryoto S-970 Sucrose stearate 9 50% monoester Ryoto S-1170 Sucrose stearate 1 55% monoester Ryoto S-1570 Sucrose stearate 5 70% monoester Ryoto S-1670 Sucrose stearate 6 75% monoester Ryoto P-1570 Sucrose palmitate 5 70% monoester Ryoto P-1670 Sucrose palmitate 6 80% monoester Ryoto LWA-1570 Sucrose laurate 5 70% monoester Ryoto L-1695 Sucrose laurate 6 80% monoester Ryoto OWA-1570 Sucrose oleate 5 70% monoester

0802 As noted above, methods for producing Sucrose catalyst (e.g., potassium carbonate) and an organic solvent esters are well known (see, for example, U.S. Pat. Nos. 3,480, (e.g., dimethyl formamide (DMF) or dimethyl sulfoxide 616, 3,644,333, 3,714,144, 4,710,567, 4,898,935, 4,996,309, (DMSO)), followed by purification, or in an aqueous medium 4,995,911, 5,011,922 and 5,017,697 and International Patent process, where Sucrose is mixed in a molten mixture with Application, Publication No. WO 2007/082149). The sucrose fatty acid salt using water without an organic solvent and then fatty acid surfactants can be produced by any well-known reacted with a higher fatty acid methyl ester in the presence of method, and typically in an esterification reaction, for a catalyst, followed by purification, and Such as by any of the example, by reacting Sucrose with a methyl ester of the methods described in International Patent Application Publi desired fatty acid, Such as a solvent process, where Sucrose is cation No. WO 2007/082149, whereby a sucrose molecule reacted with a methyl ester of a fatty acid in the presence of a (which is a disaccharide containing one six-carbon aldo US 2016/008 1976 A1 Mar. 24, 2016 79

Sugar glucose linked to a five-carbon keto-Sugar fructose, (0805 (c) Stabilizers having the formula: C12H22O11) is joined to one or more 0806. The pre-spray emulsions provided herein can con fatty acids. tain a stabilizer or a stabilizing system. Stabilizers include 0803 For example, the sucrose fatty acid ester can be any compound used to stabilize the non-polar ingredients in produced by esterification using dimethyl formamide (DMF) the emulsions. The stabilizer or stabilizing system can aid in as a solvent, by producing a methyl ester of the fatty acid and retaining one or more desirable properties of the composi then reacting the methyl ester with sucrose in DMF in the tions, for example the appearance, taste or odor. The compo presence of a catalyst (e.g., potassium carbonate), for sitions provided herein, including the pre-spray emulsions example, for 4-6 hours at 83-95°C., for example, using 30 to and spray-dried powders, containing non-polar ingredients 127 parts sucrose to 30 parts methyl ester of the fatty acid and a stabilizer or stabilizing system can retain one or more (e.g., methyl Stearate), 2 parts potassium carbonate and 300 desirable properties of the composition for a period of time parts solvent; by a similar method, but using dimethylsulfox after formulation, Such as at or about 1, 2, 3, 4, 5, 6, or 7 days, ide (DMSO) as the solvent, for example, as described in U.S. at or about 1,2,3,4, 5, 6, 8, 12, 18, 24, or 36 weeks, at or about Pat. No. 3,480,616; or, as described in U.S. Pat. No. 3,644, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 36 months, orator about 1, 2, 333, by mixing sucrose with methyl fatty acid and sodium 3, or 4 years. The stabilizers include, but are not limited to, fatty acid and previously prepared Sucrose ester, using potas carbonates and bicarbonates, acids, antioxidants, and any sium carbonate as a catalyst and water as a solvent; or, as combination thereof. Typically the stabilizer or stabilizing described in U.S. Pat. No. 3,714,144, where sodium, potas system are food-approved, i.e., edible or ingestible, stabiliz sium or lithium soap of the fatty acid is reacted in a molten ers, for example, stabilizers that are safe and/or approved for Sugar Solution for two to twenty minutes under vacuum at human consumption. 170-190° C., and purified, for example, as described in U.S. 0807. Typically, when present, the total amount of stabi Pat. No. 4,710,567, by adding aqueous salt solution followed lizers included in the provided emulsions is less than 20% or by three-phase separation. In one example, the Sucrose fatty about 20%, typically less than 10% or about 10%, for acid esters are prepared and purified as described in U.S. Pat. example, less than 20%, 15%, 10%, 5%, 4.5%, 4%, 3.5%, Nos. 4,898,935, 4,996,309, 4,995,911, 5,011,922 and 5,017, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the 697, by producing the esters by chemical catalysis, such as emulsion. with the solvent process, e.g., using a DMSO solvent and 0808 (1) Bicarbonates and Carbonates potassium carbonate catalyst, or aqueous Solution method, 0809 Exemplary of a stabilizer used in the provided pre followed by extraction and purification of the Sucrose fatty spray emulsions is a bicarbonate or carbonate, for example, acid esters, e.g., by adjusting pH, precipitation, separation any edible or food-approved bicarbonate or carbonate. and neutralization and filtration. Examples of suitable bicarbonates and carbonates include 0804. In another example, the sucrose fatty acid esters can Sodium bicarbonate, potassium bicarbonate, Sodium carbon be produced, as described in International Patent Application ate, potassium carbonate, calcium carbonate, magnesium car Publication No. WO 2007/082149, by mixing and reacting bonate, Zinc carbonate, and any combination thereof. In some Sucrose and vinyl esters of the fatty acids which can produce examples, the carbonate or bicarbonate is a carbonated bev Sucrose fatty acid ester mixtures with a monoester content of erage, such as a soda, flavored Soda, carbonated water or at or about 90%, and/or an acid value of less than 1. Briefly, carbonated juice. Alternatively, the beverage can be carbon this process can be carried out by dissolving Sucrose in a ated by the addition of carbon dioxide. Selection of suitable solvent (e.g., DMSO), at a reaction temperature of between at bicarbonates and carbonates for use in the provided beverage or about 30° C. and at or about 60°C., such as between about compositions is within the skill of the skilled artisan. 40° C. and 60°C. (e.g., at 60°C.), and a catalyst added and the 0810 (2) Ingestible Acids mixture stirred, such as for 30 minutes, followed by removal 0811. The stabilizer used in the pre-spray emulsions can ofundissolved catalyst by decanting or filtration, followed by contain one or more acids, for example, any compound added addition of vinyl fatty acid, and reaction, Such as for at or to the emulsion that can lower the pH of the emulsion. The about 15 minutes, with monitoring to measure amount of acid can be, for example, an edible, ingestible or food-ap vinyl fatty acid ester, for example, until the amount of vinyl proved acid. Exemplary of suitable acids for use in the pro fatty acid ester reaches no more than at or about 10%, by vided pre-spray emulsions are citric acid, phosphoric acid, weight (w/w), of the starting amount. The amount of Sucrose adipic acid, ascorbic acid, lactic acid, malic acid, fumaric and vinyl ester can vary. In one example, the ratio of Sucrose acid, gluconic acid, Succinic acid, tartaric acid, maleic acid, to vinyl ester is between at or about 2:1 and at or about 8:1. In and any combination thereof. In one example, the acid is citric one example, the Sucrose is added at a concentration of at or acid. about 400 nm and the vinyl ester added at a concentration of 08.12 (3) Antioxidants at or about 100 nM. The catalyst can be catalyzed by a base, 0813 The stabilizer used in the pre-spray emulsion can Such as metal oxides, metal hydroxides and metal carbonates, contain an ingestible antioxidant, for example, a molecule Such as potassium hydroxide, Sodium hydroxide, potassium that is capable of inhibiting the oxidation of other molecules. carbonate, sodium carbonate and lithium carbonate, which Antioxidants include molecules that scavenge free radicals. can be added at a concentration of between at or about 1.5 Suitable antioxidants include those that are used as ingredi grams/L and at or about 6 g/L of reaction Volume. In one ents in dietary Supplements. The antioxidant can be a natural example, the vinyl ester is vinyl Stearate and the catalyst is antioxidant or a synthetic antioxidant. potassium carbonate. The resulting mixture can then purified, 0814 Examples of antioxidants include, but are not lim Such as by vacuum distillation and addition of sodium chlo ited to hormones, carotenoids, carotenoid terpenoids, non ride to effect emulsification and purification methods carotenoid terpenoids, flavonoids, flavonoid polyphenolics described in International Patent Application Publication No. (e.g., bioflavonoids), flavonols, flavones, phenols, polyphe WO 2007/082149. nols, esters of phenols, esters of polyphenols, nonflavanoid US 2016/008 1976 A1 Mar. 24, 2016 phenolics, isothiocyanates, vitamins and vitamin cofactors, effects on the reactivities of organometallic compounds' Such as VitaminA, Vitamin C, Vitamin E. Vitamin E phosphate (1976) Coord. Chem. Rev. 18:225-255), and the Hildebrand and ubiquinone (ubidecarenone, coenzyme Q, coenzyme solubility parameters (see, e.g., Giddings et al., "High pres Q10), ascorbic acid, citric acid, rosemary oil, minerals, such Sure gas chromatography of nonvolatile species. Compressed as mineral selenium and manganese, melatonin, C-carotene, gas is used to cause migration of intractable solutes” (1968) B-carotene, lycopene, lutein, Zeanthin, crypoxanthin, res Science 162:67-73). Veratrol, eugenol, quercetin, catechin, gossypol, hesperetin, 0818 Polar solvents include polar protic solvents and curcumin, ferulic acid, thymol, hydroxytyrosol, tumeric, polar aprotic solvents. A polar protic solvent (e.g., water, thyme, olive oil, lipoic acid, glutathione, gulamine, oxalic methanol, ethanol) contains a hydrogen atom attached to an acid, tocopherol-derived compounds, di-alpha-tocopheryl electronegative atom, such that the hydrogen has a proton phosphate, tocotrienols, butylated hydroxyanisole, butylated like character and/or the bond between the hydrogen and hydroxytoluene, ethylenediaminetetraacetic acid, tert-butyl electronegative atom is polarized. Polar aprotic solvents, on hydroquinone, acetic acid, pectin, tocotrienol, tocopherol, the other hand (e.g., acetone, acetonitrile), generally do not coenzyme Q10 (coC10), Zeaxanthin, astaxanthin, canthaxan contain positively polarized hydrogen atoms. tin, Saponins, limonoids, kaempfedrol, myricetin, isorhamne 0819. The polar solvents in the provided compositions tin, proanthocyanidins, quercetin, rutin, luteolin, apigenin, typically are polar protic solvents, including, but not limited tangeritin, hesperetin, naringenin, erodictyol, flavan-3-ols to, water, alcohols, such as dihydric alcohols which contain (e.g., anthocyanidins), green tea extract, gallocatechins, epi two hydroxyl groups (for example, glycols, e.g., propylene catechin and its gallate forms, epigallocatechin and its gallate glycol, ethylene glycol, tetraethylene glycol, triethylene gly forms, theaflavin and its gallate forms, thearubigins, isot col, trimethylene glycol), trihydric alcohols which contain lavone phytoestrogens, genistein, daidzein, glycitein, anytho three hydroxyl groups (e.g., glycerin, butane-1,2,3-triol, pen cyanins, cyaniding, delphinidin, malvidin, pelargonidin and tane-1,3,5-triol, 2-amino-2-hydroxymethyl-propane-1,3- peonidin. In one example, the antioxidant is vitamin C. In diol), monohydric alcohols (e.g., methanol, ethanol, pro another example, the antioxidant is a coenzyme Q-containing panol, isopropanol, n-butanol and t-butanol) and other compounds, such as ubiquinone (ubidecarenone, coenzyme alcohols; and acids, such as acetic acid and formic acid. Other Q, coenzyme Q10). polar solvents include, but are not limited to, acetone, aceto 0815 (d) Polar Solvents nitrile, butyl acetate, dimethylformamide, dimethyl sulfox 0816. The pre-spray emulsions provided herein include ide, dioxane, ethyl acetate, tetrahydrofuran and hexameth one or more polar solvents. Polar solvents are well known in ylphosphoric triamide. Typically, the polar solventis water, or the art. The polarity of a solvent generally indicates which is an alcohol that typically contains two or more hydroxyl compounds are soluble in the solvent, and with which other groups, such as a trihydric or dihydric alcohol. Such as, but not Solvents/liquids the solvent is miscible. Generally speaking, limited to, glycerol and propylene glycol. The polar solvents polar compounds are more readily solubilized in water and further include low molecular weight polyethylene glycols other polar solvents than are non-polar ingredients. Polar (PEGs), such as PEGs having a molecular weight not more solvents are more likely to be miscible with water and other than at or about 600 kDa, such as between or about between polar solvents and liquids. 200 kDa and 600 kDa, typically not more thanator about 400 0817. The polarity of a solvent can be assessed by mea kDa, for example, not more than 200 kDa. Suring a number of different parameters according to well 0820. In one example, the polar solvent has a dielectric known methods (see, e.g., Przybitek, “High Purity Solvent constant greater than at or about 15, and typically between at Guide. Burdick and Jackson Laboratories, Inc., 1980), such or about 20 and at or about 80, such as at or about 80.1. In as by determining a property of the solvent, Such as the another example, the polar solvent has a polarity index dielectric constant, the dipole moment or the polarity index. between at or about 3 and at or about 9. In another example, For example, polar solvents generally have high dielectric the dipole moment of the polar solvent is between 1.5 and 3. constants, typically dielectric constants greater than at or and typically between at or about 1.8 and 2.8, such as 1.85 (for about 15 (see, e.g., Lowery et al., “Mechanism and Theory in dielectric constants of solvents, see, for example, Landolt Organic Chemistry.” Harper Collins Publishers, 3rd ed., Bornstein, New Series IV/17, “Static Dielectric Constants of 1987, p. 177), such as at or about 15, 16, 17, 18, 19, 20, 21, 22, Pure Liquids and Binary Liquid Mixtures.” Springer, 2008: 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 40, 45, 50,55, and “CRC Handbook of Chemistry and Physics.” Lide, ed., 60, 65, 70, 75, 80 85,90 or greater than 90. For example, the 82nd edition, CRC Press, 2001; for dipole moment of sol dielectric constant of water is at or about 80.10 at 20° C. Polar vents, see, for example, “CRC Handbook of Chemistry and Solvents generally have high polarity indices, typically Physics.” Lide, ed., 82nd edition, CRC Press, 2001; and for greater than at or about 3 (see, e.g., Snyder, "Classification of polarity indices of solvents, see, for example, Snyder, "Clas the solvent properties of common liquids” (1974) J. Chro sification of the solvent properties of common liquids. J. matog. A 92:223-230), such as at or about 3, 4, 5, 6, 7, 8 or 9 Chromatography A. 92:223-230, 1974). or greater than 9. Polar solvents generally have large dipole 0821. When present, such as in the pre-spray emulsions, moments, typically greater thanator about 1.4 Debye, Such as the amount of the polar solvent typically is present in a high at or about 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2.2.3, 2.4, 2.5, concentration, for example, the total amount of polar solvent 2.6, 3.0, 3.5, 4 or greater than 4 Debye (see, e.g., “CRC as a percentage (%) by weight of the liquid concentrate (wt %) Handbook of Chemistry and Physics. Lide, ed., 82nd edi can be, e.g., between or between about 25% and 70%, such as tion, CRC Press, 2001, p. 15(14)-15(18)). Other methods of between or between about 35% and 65%, such as 35% to assessing solvent polarity are known in the art, including, but 40%, 35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, not limited to, the Kosower Zscale (Kosower, “An introduc 35% to 65%, 40% to 45%, 40% to 50%, 40% to 55%, 40% to tion to physical organic chemistry.” Wiley, 1969, p. 293), the 60%, 40% to 65%, 45% to 50%, 45% to 55%, 45% to 60%, donor number and donor acceptor scale (Gutmann, "Solvent 45% to 65%, 50% to 55%, 50% to 60%, 50% to 65%, 55% to US 2016/008 1976 A1 Mar. 24, 2016

60%, 55% to 65%, and 60% to 65% polar solvent, by weight, example, by preventing or slowing oxidation of the non-polar of the pre-spray emulsion. Exemplary concentrations of the ingredients. Exemplary of a co-surfactant that can be used in polar solvent in the pre-spray emulsions are at or about 45%, the provided concentrates is a phospholipid, for example, 48%, 50%, 52%, 55%, 56%, 57%, 58%, 60%, 62%, 65%, phosphatidylcholine. Other exemplary co-surfactants include 68%, and 70% (w/w) of the pre-spray emulsion. non-ionic Surfactants, such as Sugar-derived surfactants, 0822. In the provided methods for making the pre-spray including fatty acid esters of Sugars and Sugar derivatives, and emulsions, the polar solvent is added to the water phase. In PEG-derived surfactants, such as PEG derivatives of sterols, one example, the polar solvent is water, e.g., purified water, PEG derivatives of fat-soluble vitamins and PEG-Sorbitan Such as water that is purified prior to adding it to the concen fatty acid esters. Other exemplary co-Surfactants are fish col trate formula, for example, by charcoal filter, ion exchange, lagen, for example, the fish collagen sold by Norland Prod reverse osmosis, UV Sterilization and/or filtering using a fil ucts Inc. (Cranbury Township, N.J.) and Saponin, such as ter, for example, a 50-100 micron filter. Typically, when a saponin from quillaja bark, including the Saponin from quil filter is used, it is an end point of use filter, which filters the laja bark sold by Desert King International (San Diego, water before it reaches the tank in the provided process. Calif.) and Sigma Aldrich (St. Louis, Mo.). Alternatively, previously filtered water can be added to the 0829. When present, the amount of the co-surfactant typi COncentrates. cally is present in a concentration less than or less than about 0823 (e) Binders 10%, typically less than or less than about 5%, for example, 0824. As discussed above, the provided pre-spray emul the total amount of co-surfactant as a percentage (%), by sions contain a binder for forming a powder when dried. The weight, of the emulsion (wt %) can be, e.g., less than or less binder is any ingestible material that capable of adhering than about 10%, such as less than or about 5%, 4.5%, 4%, other materials together during drying. Such as spray-drying 3.5%, 3.15%, 3%, 2.5%, 2%, 1.75%, 1.5%, 1.25%, 1%, and/or lyophilization. Exemplary binders include, but are not 0.75%, 0.5%, 0.25%, 0.15% or less, by weight, of the emul limited to, polysaccharides, polyols, starches, and gums. For Sion. example, the binder can be, maltodextrin, lactose, Sucrose, 0830 (1) Phospholipids maltodextrin, starch, polyethylene glycol, gums, hypromel 0831 Exemplary of the co-surfactants that can be used in lose, methylcellulose, macrocrystalline cellulose, polyethyl the provided emulsions are phospholipids. Phospholipids are ene glycol, Sorbitol, other Sugars, and pectin. An exemplary amphipathic lipid-like molecules, typically containing a binder is maltodextrin, a moderately Sweet polysaccharide hydrophobic portion at one end of the molecule and a hydro produced from starch as a creamy white hygroscopic powder. philic portion at the other end of the molecule. A number of Maltodextrin is easily digestible, being absorbed as rapidly as phospholipids can be used as co-surfactants in the provided glucose. Maltodextrin can be derived from any starch. In the compositions, for example, lecithin, including phosphatidyl U.S., this starch is usually corn or potato, whereas elsewhere choline (PC), phosphatidylethanolamine (PE), dis (e.g., Europe), it is commonly wheat. tearoylphosphatidylcholine (DSPC), phosphatidylserine 0825. When present, the amount of binder, such as malto (PS), phosphatidylglycerol (PG), phosphatidic acid (PA), dextrin, typically is present in an amount of between or phosphatidylinositol (PI), sphingomyelin (SPM) or a combi between about 5% and 30% binder, such as between or nation thereof. Typically, the phospholipid is phosphatidyl between about 5% and 7%, 5% and 10%, 5% and 12%, 5% choline (PC), which sometimes is referred to by the general and 15%, 5% and 17%, 5% and 20%, 7% and 10%, 7% and name “lecithin.” Exemplary of the phospholipids that can be 12%, 7% and 15%, 7% and 17%, 7% and 20%, 7% and 28%, used as co-surfactants in the provided compositions are the 10% and 12%, 10% and 15%, 10% and 17%, 10% and 20%, phospholipids sold by Lipoid, LLC (Newark, N.J.), for 15% and 17%, 15% and 20%, and 17% and 20%, 15%-28%, example, Purified Egg Lecithins, Purified Soybean Lecithins, 15%-25%, by weight of the emulsion. Hydrogenated Egg and Soybean Lecithins, Egg Phospholip 0826. As described herein, the sugar fatty acid esters, such ids. Soybean Phospholipids, Hydrogenated Egg and Soybean as the SFAE(s), are included, not only for the surfactant Phospholipids, Synthetic Phospholipids, PEG-ylated Phos properties, but also in addition to the binder or in place of pholipids and phospholipid blends. Exemplary of the phos Some or all of the binder. Typically, when a binder, e.g., phatidylcholine that can be used as a co-surfactant in the maltodextrin, is present, the total amount of binder, e.g., provided compositions is the phosphatidylcholine composi maltodextrin, and Surfactant, for example, Sugar fatty acid tion sold by Lipoid, LLC, under the name Lipoid S100, which ester, e.g., Sucrose fatty acid ester, is between about 5% and is derived from soy extract and contains greater than or 40% binder and sugar fatty acid ester, such as between or greater than about 95% phosphatidylcholine. between about 5% and 10%, 5% and 15%, 5% and 20%, 5% 0832 (2) PEG-Derived Surfactants and 25%, 5% and 30%, 5% and 35%, 5% and 40%, 10% and 0833 Exemplary PEG-derived surfactants include, but are 15%, 10% and 20%, 10% and 25%, 10% and 30%, 10% and not limited to, PEG derivatives of sterols, e.g., a cholesterolor 35%, 10% and 40%, 15% and 20%, 15% and 25%, 15% and a sitosterol (including, for example, any of the PEG deriva 30%, 15% and 35%, 15% and 40%, 20% and 25%, 20% and tives disclosed in U.S. Pat. No. 6,632.443); PEG derivatives 30%, 20% and 35%, 20% and 40%, 25% and 30%, 25% and offat-soluble vitamins, for example, some forms of vitamin A 35%, 25% and 40%, 30% and 35%, 30% and 40%, and 35% (e.g., retinol) or vitamin D (e.g., vitamin D1-D5); and PEG and 40% total binder and Surfactant, e.g., Sucrose fatty acid Sorbitan fatty acid esters, such as polysorbates, including ester, by weight of the emulsion. polyoxyethylene (20) sorbitan monooleate (also called 0827 (f) Co-Surfactants (Emulsifiers) polysorbate 80) and analogs (e.g., homologs) of polysorbate 0828 The pre-spray emulsions can further contain one or 80, such as, for example, polysorbate 20 (polyoxyethylene more co-surfactants (emulsifiers). For example, a co-surfac (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene tant can be included to improve emulsification of the non (20) sorbitan monopalmitate) and polysorbate 60 (polyoxy polar ingredients and/or the stability of the emulsion, for ethylene (20) Sorbitan monostearate); and Stearic acid deriva US 2016/008 1976 A1 Mar. 24, 2016

tives, including, for example, polyethylene glycol 400 dis example, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 1.5%, tearate (PEG 400DS), such as the PEG 400 DS sold by Stepan 2%, 2.5%, 3%, 3.5%, 4%, 4.5%. 5%, 6%, 7%, 8%, 9% or 10% Lipid Nutrition (Maywood, N.J.). wfw of the emulsion. 0834 (g) Emulsion Stabilizers (Co-Emulsifiers) The pre 0839 (h) pH Adjusters spray emulsions can further contain one or more emulsion 0840 One or more pH adjusters can be added to the emul stabilizers (co-emulsifiers), which can be used to stabilize the sions at an appropriate concentration to achieve a desired pH. emulsions containing the pre-emulsion concentrates. For One or more of a plurality of pH adjusting agents can be used. example, the emulsion stabilizer can increase the Viscosity of The pH adjusting agent typically is safe for human consump the concentrate. One or more emulsion stabilizers can be tion, for example, GRAS certified. The pH adjuster can be added, for example, during formulation after evaluation of an citric acid. An exemplary pH adjuster includes the citric acid initial emulsion, particularly if the oil and water phases of the sold by Mitsubishi Chemical (Dublin, Ohio). Another exem initial emulsion appear to be separating. Addition of the emul plary pHadjuster is phosphoric acid, such as Food Grade 80% sion stabilizer can prevent separation of the oil and water Phosphoric Acid, sold by Univar. phases. 0841 b. Powder Compositions Containing Non-Polar 0835 Exemplary of an emulsion stabilizer that can be Ingredients included in the provided emulsions is a composition contain 0842. The pre-spray emulsions containing the pre-emul ing a blend of gums, for example, gums used as emulsifying sion concentrates provided hereinare dried, such as by evapo agents, for example, a blend containing one or more of Xan ration of the water, spray drying or lyophilization or other than gum, guar gum and sodium alginate. Exemplary of Such drying method to produce the powders The water-soluble an emulsion stabilizer includes the emulsion stabilizer sold powders are prepared bremoving all of the polar solvent, Such under the brand name SALADIZER(R), available from TIC as water, from the pre-spray emulsion, to form a free-flowing Gums, Inc. (Belcamp, Md.). Other gums can be included in powder that does not contain any, or only minimal amounts, the emulsion stabilizer, for example, gum acacia, ester gums of polar solvent. The resulting powders contain high concen and Sugar beet pectin. Exemplary emulsion stabilizers trations of non-polar ingredients and display advantageous include modified food starches. These include the modified properties. They are free-flowing, i.e., not sticky, powder gum acacia sold under the name Tic Pretested(R) Ticamulsion rather than a sludge-like, oily Substance. They contain high A-2010 Powder, available from TIC Gums, Inc. (Belcamp, concentration of non-polar ingredients. The powders pro Md.). Other exemplary emulsion stabilizers containing an vided herein typically contain the same ingredients as the ester gum are, for example, the emulsion stabilizer sold under corresponding pre-spray emulsion, with the exception of the the name Tic Pretested(R) Ester Gum 8BG, available from TIC polar solvent, e.g., water, that is removed during the drying Gums, Inc. (Belcamp, Md.) or Ester Gum 8BG, available process. Removal of the polar solvent, e.g., water, from the from Hercules/Pinova (Brunswick, Ga.). Others sold by pre-spray emulsion results in an increased concentration (i.e., Ingredion, Inc. (Westchester, Ill.) under the trademarks CAP wt %) of each ingredient in the powder compared to the SULR, FIRMTEXR, THERMFLOR), THERMTEXR, and corresponding emulsion. For example, the pre-spray emul TEXTRAR) and others, can be included in the compositions sions provided herein contain between or between about 5 wt provided herein. Other blends of similar gums can also be % and 30 wt % non-polar ingredient(s) and produce powders used as emulsion stabilizers. that contain between or between about 10 wt % and 60 wt %, 0836. Also exemplary of an emulsion stabilizer that also Such as greater than 30% non-polar ingredient(s) after spray can serve as a binder is whey protein. Whey protein is a drying. The provided powders (and methods for making the protein contained in the milk serum (whey) obtained by powders) can be used to formulate any non-polar ingredient removing casein and other components from milk, and com in a water-soluble powder, including the non-polar ingredi prises lactoalbumin, lactoglobulin, and lactoferrin as main ents (e.g., non-polar ingredients that are or contain non-polar components. Whey protein is knownto have Such functions as compounds) described herein and other known non-polar a stamina improver, a fatigue reliever, and an immunity ingredients. enhancer. In addition, it is used as a protein Supplement mate 0843 Methods of producing powders from liquid compo rial in athletic nutrient foods and diet foods. Whey proteins sitions are well known to the skilled artisan. Exemplary pro are often used in food emulsion systems because of their cesses for producing powders include, but are not limited to ability to stabilize oil-in-water (O/W) emulsions. An exem spray drying, freeze drying and absorption plating. The meth plary whey protein is the whey protein isolate sold by Mar ods for forming the powders include spray drying. Spray quez Brothers International (Hanford, Calif.). drying processes and spray drying equipment are described 0837. Another exemplary emulsion stabilizer is green tea generally in Perry's Chemical Engineers Handbook, pp. extract, which is high in epigallocatechingallate (EGCG) and 20-57 (Sixth Edition 1984). More details on spray drying epicatechingallate (ECG). Green tea extract is known to have processes and equipment are reviewed by Marshall (1954) high antioxidant activity and the ability to provide stability to "Atomization and Spray-Drying.” Chem. Eng. Prog. Monogr. emulsions. An exemplary green tea extract that can be used in 50: Series 2 and Masters, “Spray Drying Handbook” (Fourth the pre-spray a green tea extract that contains 40% EGCG, Edition 1985). Methods for spray drying are well known (see, Such as one sold by Guilin Layn Natural Ingredients, Corp. e.g. U.S. Pat. Nos. 5,430,021 and 6,534,085 and U.S. Publi (Guilin, China). cation No. US 2007/0184117). In general, spray drying is 0838. When present, the emulsion stabilizer is typically used to dry aheated liquid by passing it through hot gas. One present at a concentration of less than 10%. Such as less than or more spray nozzles is used to atomize the liquid in a or less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, cooling tower or chamber. As the material is atomized or 1%, by weight, of the emulsion. For example, the emulsion (sprayed), the Surface tension causes a uniform spherical stabilizer can be added to the water phase at a concentration of particle to form, which is passed through the cooling chamber between 0.01% or about 0.01% and 10% or about 10%, for and hardens into a solid intact sphere. The spray dried par US 2016/008 1976 A1 Mar. 24, 2016

ticles can be between at or about 0.5 microns and at or about fatty acid ester, in place of or in combination with a binder, 100 microns, and typically are less than at or about 10 e.g., maltodextrin, and additional ingredients, including, but microns, typically less than at or about 5 microns, and typi not limited to, stabilizers, e.g., bicarbonates or carbonates, cally less than at or about, or at or about, 1 micron. acids, and/or antioxidants, co-surfactants (emulsifiers), e.g., 0844. The powder compositions provided herein can be phospholipids and/or PEG-derived surfactants, emulsion sta made from any emulsion containing non-polar ingredients, a bilizers (co-emulsifiers), pH adjusters, e.g., citric acid, and Sugar fatty acid ester, and a polyalkylene glycol derivative of any of the ingredients provided herein in Section B.2.b., with Vitamin E. Such as the pre-spray emulsions provided herein. the exception of polar solvents, e.g., water. As noted, for purposes herein the PEG derivative of vitamin E 0851 Each of the provided powder compositions contains is a high dimer-containing composition as described herein. a non-polar ingredient, including, but not limited to, the 0845 i. Formulating the Powder Compositions exemplary non-polar ingredients described herein above. 0846. The powder compositions provided herein are Typically, the non-polar ingredient is or contains one or more water-soluble and have high concentrations of non-polar non-polar compounds. The powder compositions provided ingredients, for example, at least 10%, 20%, 30%, 40%, 50%, herein can contain one non-polar ingredient or more than one 55% and more, such as 60%, and are stable and free-flowing, non-polar ingredient, such as two, three, four, five, six, seven, i.e., not sticky, sludgy or oily. The powders also contain a eight, or more non-polar ingredients. The powder composi Sugar fatty acid ester(s), e.g., a Sucrose fatty acid ester, that tions provided herein can contain high amounts (i.e., concen also acts as a binder and/or in combination with a binder, that trations) of non-polar ingredients. Such as up to at or about 60 does not contribute to the oil load of the powder, resulting in wt % non-polar ingredient. a powder with the high concentrations of non-polar ingredi 0852. The powders provided herein contain high amounts ents. The Sugar fatty acid esters, such as Sucrose fatty acid of non-polar ingredients, e.g., non-polar ingredients that are esters, are present in the water-soluble powders in place of or or contain non-polar compounds, for example, between or in combination with a binder, and result in powders that are between about 10 wt % and 60 wt % non-polar ingredient, water-soluble, free-flowing, i.e., not sticky, and contain high such as between or between about 10% and 15%, 10% and concentrations of non-polar ingredients. 20%, 10% and 25%, 10% and 30%, 10% and 35%, 10% and 0847 The pre-emulsion concentrates and pre-spray emul 40%, 10% and 45%, 10% and 50%, 10% and 55%, 10% and sions provided herein are formulated Such that drying the 60%, 15% and 20%, 15% and 25%, 15% and 30%, 15% and resulting emulsion, e.g., spray drying, yields a powder com 35%, 15% and 40%, 15% and 45%, 15% and 50%, 15% and position that contains high concentrations of non-polar ingre 55%, 15% and 60%, 20% and 25%, 20% and 30%, 20% and dient, yet is free-flowing, i.e., not sticky, and water-soluble. A 35%, 20% and 40%, 20% and 45%, 20% and 50%, 20% and number of parameters of the concentrates and emulsions, 55%, 20% and 60%, 25% and 30%, 25% and 35%, 25% and including ingredients, their relative concentrations, and 40%, 25% and 45%, 25% and 50%, 25% and 55%, 25% and methods for making the concentrates and emulsions, affect 60%, 30% and 35%, 30% and 40%, 30% and 45%, 30% and the ability of emulsion to form a free-flowing, i.e., not sticky, 50%, 30% and 55%, 30% and 60%, 35% and 40%, 35% and powder when a high concentration of non-polar ingredient is 45%, 35% and 50%, 35% and 55%, 35% and 60%, 40% and present. By extension, these parameters of the concentrates 45%, 40% and 50%, 40% and 55%, 40% and 60%, 45% and and emulsions also affect the advantageous properties of the 50%, 45% and 55%, 45% and 60%, 50% and 55%, 50% and powders, for example, the solubility of the powder, for 60%, and 55% and 60%, by weight of the powder. The powder example, in an aqueous solution. compositions that contain high amounts of non-polar ingre 0848 Thus, the pre-spray emulsions are formulated such dient and a Sugar fatty acid ester Surfactant in place of or in that after drying, e.g., spray drying, the resulting powder combination with a binder, e.g., maltodextrin, exhibit desir compositions display one or more advantageous properties, able properties, for example, the powder is a free-flowing, i.e., for example, the powder is free-flowing, i.e., not sticky, and/ not sticky, powder that is water-soluble. or the powder is water-soluble. In one example, the advanta 0853 Each of the provided powder compositions contain geous property is the ability of the provided emulsions to a pre-emulsion concentrate that contains at least one Surfac yield powder compositions that have no or only a minimal tant that is a polyethylene glycol derivative of vitamin E, for amount of polar solvent, e.g., water and are free-flowing, i.e., example, TPGS, TPGS analogs, TPGS homologs and TPGS not sticky, after drying, for example, spray drying. In another derivatives described herein. The surfactant typically has an example, the advantageous property relates to the ability of HLB value of between 12 or about 12 and 20 or about 20, for the pre-spray emulsions to be dried, e.g., spray dried, to form example, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about 12, a powder that contains a high concentration of non-polar about 13, about 14, about 15, about 16, about 17, about 18, ingredients and is water-soluble. about 19 or about 20, typically between at or about 12 and at 0849 ii. Ingredients and Concentration Ranges or about 14. For example, TPGS, such as the TPGS described 0850. Each of the provided powder compositions contains herein, has an HLB value of about 13. a pre-spray emulsion that has been dried, for example, spray 0854. The polyethylene glycol derivative of vitamin E, dried, to remove all or almost all of the polar solvent, e.g., e.g., TPGS, is typically present in an amount as a percentage water. The pre-spray emulsions, and thus, the powder com (%) by weight of the powder compositions (wt %), e.g., from positions provided herein, contain the pre-emulsion concen at or about 0.1% to at or about 20%, such as 0.1% to 0.5%, trates provided herein that contain non-polar ingredients and 0.1% to 1%, 0.1% to 2%, 0.1% to 5%, 0.1% to 7%, 0.1% to a polyalkylene glycol Surfactant, e.g., TPGS. In some 10%, 0.1% to 12%, 0.1% to 15%, 0.1% to 20%, 0.5% to 1%, examples, the pre-emulsion concentrate contains a preserva 0.5% to 2%, 0.5% to 5%, 0.5% to 7%, 0.5% to 10%, 0.5% to tive, e.g., benzyl alcohol. The pre-spray emulsions, and thus, 12%, 0.5% to 15%, 0.5% to 20%, 1% to 2%, 1% to 5%, 1% to the powder compositions provided herein additionally con 7%, 1% to 10%, 1% to 12%, 1% to 15%, 1% to 20%, 2% to tain a Surfactant, such as a Sugar fatty acid ester, e.g., Sucrose 5%, 2% to 7%, 2% to 10%, 2% to 12%, 2% to 15%, 2% to US 2016/008 1976 A1 Mar. 24, 2016

20%, 5% to 7%, 5% to 10%, 5% to 12%, 5% to 15%, 5% to 55%, 35% and 60%, 40% and 45%, 40% and 50%, 40% and 20%, 7% to 10%, 7% to 12%, 7% to 15%, 7% to 20%, 10% to 55%, 40% and 60%, 45% and 50%, 45% and 55%, 45% and 12%, 10% to 15%, 10% to 20%, 12% to 15%, 12% to 20%, 60%, 50% and 55%, 50% and 60%, and 55% and 60% total and 15% to 20%, by weight, of the powder compositions. amount of binder, e.g., maltodextrin, and Sugar fatty acid Exemplary concentrations of the polyethylene glycol deriva ester, e.g., Sucrose fatty acid ester, by weight of the powder tive of vitamin E, e.g., TPGS, in the powder compositions are compositions. Exemplary concentrations of the total amount at or about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, of binder, e.g., maltodextrin, and Sugar fatty acid ester, e.g., 7%, 10%, 12%, 15%, 17% and 20% (wt %) of the powder Sucrose fatty acid ester in the powder compositions are at or compositions. about 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 0855. The powder compositions contain a sugar fatty acid 40%, 45%, 50%, 55%, and 60% (wt %) of the powder com ester Surfactant in place of or in combination with a binder, positions. e.g., maltodextrin. Typically, the Sugar fatty acid ester is a 0858 Typically, when the powder compositions provided Sucrose fatty acid ester. The Surfactant, e.g., Sucrose fatty acid herein contain a mixture of Surfactant, such as a Sugar fatty ester, does not contribute to the oil load of the composition, acid ester, e.g., Sucrose fatty acid ester, and binder, e.g., mal thus allowing the addition of high concentrations of non-polar todextrin, Such as a mixture of Surfactant, e.g., Sucrose fatty ingredients and formation of a free-flowing, i.e., not sticky, acid ester, and binder, e.g., that is present in an amount powder. In one example, the powder contains a Sugar fatty between or about between 5 wt % and 60 wt %, the mixture acid ester, e.g., Sucrose fatty acid ester, in place of a binder, contains at least or about at least 5% Sugar fatty acid ester, e.g., maltodextrin. In another example, the powder contains a e.g., Sucrose fatty acid ester, e.g., at least or about at least 5%, Sugar fatty acid ester, e.g., Sucrose fatty acid ester, in combi 7%, 10%, 15%, 20%, or more, sugar fatty acid ester, e.g., nation with a binder, e.g., maltodextrin. sucrose fatty acid ester, by weight of the powder. 0856. The powder compositions provided herein contain a Surfactant, Such as a Sugar fatty acid ester, e.g., Sucrose fatty E. EXEMPLARY METHODS FOR PREPARING acid ester, where the total amount of Surfactant, e.g., Sucrose PRODUCTS CONTAINING HIGH fatty acid ester, is typically present in an amount as a percent DIMER-CONTAINING WATER-SOLUBLE age (%) by weight of the powder compositions (wt %), e.g., VITAMINEDERIVATIVE MIXTURES from at or about 5 wt % to at or about 30 wt %, such as 0859 Methods for preparing products containing the high between or between about 5% and 7%, 5% and 10%, 5% and dimer-containing water-soluble vitamin E derivative mix 12%, 5% and 15%, 5% and 17%, 5% and 20%, 5% and 25%, tures, e.g., TPGS compositions, for example, products for 5% and 30%, 7% and 10%, 7% and 12%, 7% and 15%, 7% human consumption, such as food and beverage products, in and 17%, 7% and 20%, 7% and 25%, 7% and 30%, 10% and particular aqueous food and beverage products, are provided 12%, 10% and 15%, 10% and 17%, 10% and 20%, 10% and herein. For example, methods for preparing the concentrates 25%, 10% and 30%, 12% and 15%, 12% and 17%, 12% and provided herein are described. Equipment for use in the meth 20%, 12% and 25%, 12% and 30%, 15% and 17%, 15% and ods and general steps of the methods are described below. The 20%, 15% and 25%, 15% and 30%, 17% and 20%, 17% and methods include bench-top manufacturing processes, which 25%, 17% and 30%, 20% and 25%, 20% and 30%, and 25% are used to make Small quantities of the products. The meth and 30% sugarfatty acid ester, e.g., Sucrose fatty acid ester, by ods also include scaled-up manufacturing processes, which weight of the soft gel compositions. Exemplary concentra are used to make larger batches of the products. Any of the tions of the total amount of Sugar fatty acid ester, e.g., Sucrose bench-top processes can be scaled up to perform the methods fatty acid ester in the powder compositions are at or about 5%, using the scaled-up processes. Any of the provided products 7%, 10%, 12%, 15%, 17%, 20%, 25% and 30% (wt %) of the can be made using either scaled-up or bench-top processes. powder compositions. The concentrates and liquid dilution compositions provided 0857. The powder compositions provided herein can con herein can be made following the methods provided in U.S. tain a binder. Exemplary binders include, e.g., maltodextrin. Pat. No. 8,282,977 and U.S. Pub. Nos. 2009-0297491 and Typically, when a binder, e.g., maltodextrin, is present in the 2012-OO16O26. powder composition, the total amount of binder, e.g., malto 0860) 1. Equipment Employed in the Methods dextrin, and Surfactant, such as a Sugar fatty acid ester, e.g., 0861 Equipment used in various steps of the provided Sucrose fatty acid ester, is typically present in a total amount methods for making the products can include, for example, as a percentage (%) by weight of the powder compositions vessels, such as tanks, for mixing the water and oil phases and (wt %), e.g., from at or about 5 wt % to at or about 60 wt %, the product; scales; mixers, for example standard mixers and such as between or between about 5% and 10%, 5% and 15%, homogenizers; heating and cooling apparatuses, such as 5% and 20%, 5% and 25%, 5% and 30%, 5% and 35%, 5% water-jacketed tanks, hot plates, water baths and chillers and 40%, 5% and 45%, 5% and 50%, 5% and 55%, 5% and (coolers), including recirculating coolers; transfer appara 60%, 10% and 15%, 10% and 20%, 10% and 25%, 10% and tuses, for example, transfer devices, such as, pumps, hoses 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% and and sanitary fittings; ball valves; purifiers, for example, fil 50%, 10% and 55%, 10% and 60%, 15% and 20%, 15% and ters. Such as carbon filters, ion exchange equipment, reverse 25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and osmosis equipment, end-point filters and end product filters; 45%, 15% and 50%, 15% and 55%, 15% and 60%, 20% and evaluation devices, for example, pH and temperature meters; 25%, 20% and 30%, 20% and 35%, 20% and 40%, 20% and and other equipment. The choice of equipment depends on a 45%, 20% and 50%, 20% and 55%, 20% and 60%, 25% and plurality of factors, including batch size and the manufactur 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% and ing process. 50%, 25% and 55%, 25% and 60%, 30% and 35%, 30% and 0862 a. Scales 40%, 30% and 45%, 30% and 50%, 30% and 55%, 30% and 0863. One or more scales can be used to measure the 60%, 35% and 40%, 35% and 45%, 35% and 50%, 35% and amount of the ingredients before adding them to the appro US 2016/008 1976 A1 Mar. 24, 2016 priate vessel. Alternatively, the ingredients can be weighed in oil phase and the water phase prior to combining the two the vessel, for example, in a tank on top of a scale. phases. In some examples, an additional vessel, for example, 0864 Any of a plurality of well-known, commercially a holding and/or packaging tank, can be used for holding sold scales can be used to weigh the ingredients. The choice of and/or packaging the products and/or for addition/mixing of scale(s) can depend on a number of factors, including the additional ingredients to the products. mass of the product being made (e.g., the batch size) and the 0874. A number of vessels are available for mixing ingre ingredient being weighed. In one example, multiple scales are dients. Typically, the vessels are cleaned, for example, rinsed, used to weigh the various ingredients of the products. In Soaped and/or sanitized, according to known procedures prior general, relatively larger capacity (i.e., weight) scale(s) are to use and between uses, such as with the cleaning procedures used in making larger batches of the products while relatively described below. Smaller capacity Scale(s) are used in making Smaller batches. 0875. In the bench-top process, the vessel can be a con 0865 Exemplary of the scales used to weigh the ingredi tainer, for example, a bench-top container, Such as a flask, ents using the provided methods are a Toledo Scale (Model beaker (e.g., a Pyrex R beaker), vial, measuring container, GD13X/USA); a Sartorius Basic Analytical Scale (Model bottle and/or other bench-top container. BA110S), which is a basic series analytical scale with a 110 g 0876. In the scaled-up manufacturing process, the vessels capacity and a resolution of 0.1 mg; and an OHAUS Scale can be tanks, for example, water phase tanks, oil phase tanks (Model CS2000), which is a compact portable digital scale and holding/packaging tanks Typically, the tanks are having a 2000 g capacity and a resolution of 1 g. equipped with one or more mixers, for example, a standard 0866 b. Purifiers mixer and/or homogenizer, which are used to mix the ingre 0867 Purifiers, such as filters, are used in the provided dients that are added to the tank. In one example, the tank is methods to remove impurities from the ingredients prior to further equipped with a heating and/or cooling device. For their addition to and/or from the product or to and/or from a example, the tank can be a water-jacketed tank. The tempera phase of the product. For example, the water added to the ture of the water-jacketed tank is controlled through the water water phase typically is purified water. In one example, one or jacket, for example, to heat the contents, such as during mix more purifiers, for example, carbon filters, ion exchange puri 1ng. fiers, reverse osmosis purifiers, and/or end point filters can be 0877 Exemplary of the tanks that can be used with the used to filter water, for example, city water, prior to its addi provided methods are water-jacketed tanks, for example, the tion to the water phase. For example, the water can be filtered Overly 550 gallon water-jacketed tank (Model 10576501G), to remove impurities, such as sediment, from the water. which has a 550 gallon capacity and typically is used as a 0868 Purifiers that can be used with the provided methods water phase tank, the Schweitzer's 450 gallon tank (Model include filters, for example, 100 micron filters and carbon #5214-C), which has a 450 gallon capacity and typically is filters, which are filters that use activated carbon to remove used as an oil phase tank and the Royal 190 gallon water impurities by chemical adsorption. Carbon filtering typically jacketed tank (Model 9977-5), which has a 190 gallon capac is used for water purification and is particularly effective at ity and can be used as a water or oil phase tank when mixing filtering out chlorine, sediment, Volatile organic compounds smaller volumes. Other tanks are well known and can be used and other impurities. Typically, the particles removed by car with the provided methods for mixing the products, for bon filters are between about 0.5 microns and about 50 example, the phases of the product. microns. Other filters are well known and can be used with the 0878 d. Mixers provided methods. 0879 Mixers are used in the methods to blend, mix and/or 0869. The purifiers also include reverse osmosis purifiers, emulsify the products and ingredients, mixtures and phases of which use mechanical pressure to purify liquids, for example, the products. In some examples, the mixers can be used to water. In one example, the pressure forces the water through keep the ingredients and/or mixture circulating to maintain a semi-permeable membrane to remove impurities. temperature, viscosity and/or other parameters of the mix 0870. The purifiers also include exchange purifiers, for ture. Suitable mixers include, but are not limited to, standard example, an ion exchange purifier. The ion exchange purifier mixers, for example, those that can be used to mix ingredients can use a resin bed, Such as a Zeolite resin bed, to replace salts, and maintain a homogeneous mixture, Such as while heating Such as cations, e.g., magnesium and calcium, with other a mixture of ingredients. Exemplary of the standard mixers cations, such as Sodium and potassium cations. Such purifiers are LIGHTNINR) mixers (LIGHTNIN, Rochester, N.Y.), for can be purchased, for example, from Aqua-Pure Filters example, Model Numbers XJC117 and ND-2. In one (Clarkston, Mich.). example, the LIGHTNINR mixers are fixed-mount, gear 0871. In one example, the purifier is an end product filter drive high-flow mixers, for use with closed tanks Another (e.g., a 100 micron filter; Product No. BPEM 100-5GP; FSI, example of a standard mixer is a mixer sold by IKAR), for Michigan City, Ind.). This filter is used to filter any impurities example, overhead IKAR mixers. Exemplary IKAR mixers out of the final product (e.g., the final pre-emulsion compo include Model Nos. RW-14 Basic and RE-16S, which are sition). Other filters also are known and can be used with the laboratory stirrers that can be used to mix ingredients. In provided methods. Some examples, the mixer can be attached to the vessel, e.g., 0872 c. Vessels the tank, Such as by mounting or clamping onto the tank, such 0873. One or more, typically two or more, vessels, can be as at the top of the tank. In other examples, the mixer can be used in the methods to contain the ingredients of the provided placed in the vessel for mixing. products, for example, during mixing and/or heating or cool 0880. The mixer can be a homogenizer which can be used, ing. The vessels can be tanks, for example, water-jacketed for example, to emulsify mixtures, i.e., forman emulsion. The tanks; pots; and/or beakers, for example, Pyrex(R) beakers. homogenizer can be used to mix phases of the compositions, Separate vessels (e.g., an oil phase tank and a water phase e.g., oil and water phases, after combining the phases, in order tank) can be used for mixing and heating the ingredients of the to form an emulsion. The homogenizer provides high-shear US 2016/008 1976 A1 Mar. 24, 2016

dispersion of solids and emulsification of immiscible liquids 0885 Heating apparatuses that can be used in the provided at high shear rates. Suitable homogenizers include, but are not methods are those that are capable of heating the mixture to limited to, high-shear homogenizers, for example, reversible betweenator about 45° C. and at or about 85°C., for example, homogenizers sold by Arde Barinco, Inc. (Norwood, N.J.). to at or about 45° C., 46°C., 47°C., 48°C., 49°C., 50° C., 51° Exemplary Arde Barinco, Inc. reversible homogenizers are C., 520C., 530 C, 540 C., 550 C., 56° C. 570 C. 580 C., 590 Model CJ-50 (a 3600 rpm mixer having a 6-inch rotor diam C., 60° C., 61° C., 62° C., 63° C., 64° C., 65° C., 66° C., 67° eter, tip speed of 5575 ft/minute, emersion depth of 33 inches, C., 680 C, 690 C., 70° C. 710 C., 720 C., 73° C. 740 C., 750 and six separate openings at the bottom and top, which con C., 76° C., 770 C., 780 C. 790 C., 80° C. 810 C., 820 C. 830 centrate the liquid into six chambers, reducing the Surface C., 84°C. or 85°C. Typically, the heating apparatus is used to volume and creating a shear effect); and Model CJ-4E (a heat the mixtures to a temperature of at or about 60° C. 10,000 rpm mixer with fan-cooled motor, optimized for 1 to 0886. The heating apparatus can be a water jacket, for 5 gallon batch sizes, having a 1.875 inch rotor diameter, tip example, a water jacket on a water-jacketed tank, which can speed of 4920 rpm, and immersion depth of 16 inches). The be controlled, for example, by a control panel. Such as to homogenizers further include other homogenizers, for adjust the temperature of the contents of the tank. Other example, other reversible homogenizers sold by Arde Bar Suitable heating apparatuses are immersible and/or submers inco, Inc. ible heaters, for example, 12 KW or 13 KW sanitary heaters, 0881. In one example, the homogenizer is attached to the including food-grade heaters, that can be immersed into the top of the vessel, for example, the tank, for example, by tanks, typically while mixing and typically when higher tem clamps or by channel locks and an electrical hoist. In another peratures are required. Such as when temperatures greater example, the homogenizer is placed in the vessel. The Arde than 60° C. or about 60° C., or greater than 80° C. or about 80° Barinco reversible homogenizers contain axial flow impel C. are required. The heating apparatuses also include stoves, lers, which create two distinct mixing actions, depending on for example, propane Stoves, and hot plates, for example, direction. Downward “vortex flow” pulls solids from the top Thermolyne(R) hot plates (e.g., Model Nos. 846925 and and bottom of the mixture, while upward “umbrella flow” SP46615). controls mixing at the highest shear and recirculation rates 0887. The coolingapparatus can be any apparatus that can without splashing or incorporating air. The reversible homog cool the ingredients and combinations thereof. Such as rapidly enizers typically are equipped with an adjustable baffle plate, cooling and/or cooling while mixing the ingredients. Typi which can be adjusted to control the type of mixing, for cally, the cooling apparatus is capable of cooling the mixtures example at different times during mixing, e.g., during emul to a temperature betweenator about 25°C. and at or about 45° sification. C., for example, to at or about 25°C., 26°C., 27°C., 28°C., 0882. A number of other mixers are well known and can be 29° C., 30° C., 310 C., 32° C., 33°C., 34° C., 35° C., 36°C., used with the provided methods. Exemplary of suitable mix 37° C., 38°C., 39° C., 40° C., 41° C., 42° C., 43° C., 44° C. ers that can be used with the provided methods are homog or 45°C. In some examples, the cooling apparatus can cool enizers, inline mixers, ribbon mixers, plow mixers, paddle the mixture to a temperature between at or about 30° C. and at mixers, Forberg R mixers, conveyors, bag dumps and com or about 35° C. Typically, the cooling is rapid cooling. For pactors, V-blenders, blade mixers, double cone mixers, con example, the products can be cooled to a temperature between tinuous mixers, speedflow mixers, batch mixers, double rib at or about 30° C. and at or about 35° C. in at or about 15 bon blenders, paddle and ribbon mixers with choppers, plow minutes to at or about 2 hours, for example, in at or about 30 blenders, turbulent mixers, fluidizing Forberg-type mixers, minutes to at or about 60 minutes, such as inator about 30, 31, air mixers, active mixers, passive mixers, top-entry mixers, 32,33,34, 35,36, 37,38,39, 40, 41, 42, 43,44, 45,46, 47, 48, side-entry mixers, static mixers, fixed-entry mixers, portable 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59 or 60 minutes. In an mixers (e.g., direct and gear drive), sanitary mixers, drum exemplary method, the products can be cooled to a tempera mixers, bulk container (IBC) mixers, lab stirrers, variable ture between at or about 30° C. to at or about 35° C. in at or speed mixers, dough mixer, Vertical mixer, spiral mixer, twin about 30 minutes to at or about 60 minutes. arm mixer, fork mixer, double spiral mixer, all agitators, 0888 Suitable cooling apparatuses for used in the meth agitator mixers, Banbury(R) mixers, rubber mixers, Blond ods include chillers, for example, recirculating coolers. The heim mixers, churn mixers, conical mixers, continuous mix cooling apparatuses can be attached to the vessel. Such as ers, disperser mixers, panmixers, emulsifier mixers, Hobart R. remotely or by a tank mounted in the cooler, to repeatedly mixers, liquifier mixers, Littleford mixers, meat mixers, plow circulate fluid from the tank, through the chiller and back to mixers, Mix-Muller(R) Mixers, vertical screw mixers (e.g., the vessel, to rapidly cool and maintain the temperature of the Nauta mixers), Oakes mixers, planetary mixers, pony mixers, mixture during mixing. Exemplary of cooling apparatuses pug mixers, Ross mixers, rotary mixers, Sigma mixers, single that can be attached to the tank and used with the provided arm mixers, tote bin mixers, tumble mixers, vacuum mixers, methods are open-loop chillers and closed-loop chillers, for Turbolizer mixers, twin shell mixers, V-type mixers, ZigZag example, those sold by Turmoil (West Swanzey, N.H.), such mixers, side-arm mixers, hand-held mixers, stir rods, stir as Model No. OC-1000 RO. Suitable cooling apparatuses also bars, magnetic mixers, overhead mixers (e.g., mechanical include water baths and ice baths, for example, water baths and/or electric overhead mixers), and any mixer known to and/or ice baths in which the vessel is placed, for example, those of skill in the art. during homogenizing. Other cooling apparatuses are well 0883 e. Heating/Cooling Apparatuses known by those of skill in the art and can be used with the 0884) Equipment that can be used in the methods includes provided methods. heating and cooling apparatuses. The heating and cooling 0889 f. Transfer Devices apparatuses can be used to control the temperature of the 0890 Transfer devices can be used with the provided ingredients and combinations thereof. Such as while generat methods to transfer liquid from one vessel to another vessel. ing the products. Transfer devices can be used in the methods to combine the US 2016/008 1976 A1 Mar. 24, 2016

phases and form the emulsion. For example, transfer device example, the product is first made with the bench-top process can be used to transfer the water phase from the water phase and then the method is scaled up to make larger quantities of vessel to the oil phase vessel or to transfer the oil phase from the product. the oil phase vessel to the water phase vessel. Transfer devices 0896. The bench-top process can be performed on a bench, include, for example, transfer pumps and associated accesso counter, table or any other suitable surface. Typically, the ries (e.g., fittings), including ball valves, sanitary fittings (for bench-top process is used to make emulsions having rela example, sanitary fittings sold by Granger, Inc. (Lake Forrest, tively smaller volumes than those made with the scaled-up Ill.)) and transfer hoses (for example, hoses sold by Sani-Tech process. For example, Volumes less than 1 L or about 1 L, or West (Oxnard, Calif.)), such as food grade hoses attached to less than 1 gallon or about 1 gallon, for example, less than or a transfer pump, for example, the food grade Sani-Tech(R) about 500 mL, for example, less than or about 1000 mL. 900 STHT-R-HD Braid-Reinforced Heavy Duty Silicone Hose. mL,800 mL,700 mL, 600 mL,500 mL, 450 mL,400 mL,350 Suitable transfer pumps include the Teel Pump (Model mL,300 mL, 250 mL, 200 mL, 150 mL, 100 mL, or 50 mL or 2P377B; Granger, Inc., Lake Forrest Ill.), a self-priming less, can be made using the bench-top process. pump having a power rating of 2 HP, 60 Hz voltage, 208-230/ 0897 For the bench-top process, the equipment can be 460 AC, speed of 3450 rpm; and other pumps, such as self Sufficiently compact to be used on a bench-top or other simi priming pumps from Granger, Inc. The transfer device can lar Surface, and can be sufficiently compact to be moved, for also include equipment for manually transferring the liquid to example, lifted, by the artisan using the methods. For another vessel, for example, by pouring, pipetting and/or example, the vessels, such as water phase vessels, oil phase other well-known methods of manually transferring liquids. vessels, holding vessels, and packaging vessels, can be 0891 g. Evaluation Equipment bench-top vessels. Exemplary bench-top vessels include, for 0892 Evaluation equipment includes equipment that can example, flasks, beakers, vials, measuring containers, bottles be used to evaluate properties of the products and/or phases of and/or other bench-top containers. In some examples, the the products, such as the temperature, pH, clarity, color, activ vessel in the bench-top process is a PyrexR) beaker. ity, smell and/or taste of the products. Suitable evaluation 0898 Typically, the mixers for use in the bench-top pro equipment includes pH and temperature meters, such as the cesses of the provided methods are mixers that can be used in pH and temperature meter sold by Hanna Instruments (Model the bench-top vessels. Mixers that can be used in the bench No. HI8314; Ann Arbor, Mich.), which can be used to mea top vessels include, for example, standard mixers, such as sure the temperature and the pH of the product. Temperature hand-held mixers, stir rods, stir bars, magnetic mixers and meters can also include temperature probes, for example, overhead mixers, including, for example, mechanical and/or digital and/or water-proof temperature probes, such as tem electric overhead mixers, and any other mixer that is suitable perature probes sold by Cooper-Atkins (Middlefield, Conn.), for use in the bench-top vessel. Exemplary standard mixers for example, the Cooper-Atkins digital waterproof tempera include those sold by IKAR, for example, overhead IKAR ture probe (Model # DPP400W). The products can be evalu mixers, such as Model Nos. RW-14 Basic and RE-16S, which ated and analyzed to Verify the amounts of the non-polar are laboratory stirrers and can be used to mix ingredients, ingredients and to verify that the products meet industry Such as to generate the oil and water phases. Suitable bench standards, such as to Verify that the products do not contain top mixers also include homogenizers, for example, revers levels of microbials and heavy metals that are above accept ible homogenizers. An exemplary reversible homogenizer is able levels. Typically, these tests are performed by sending a the Arde Barinco reversible homogenizer, Model no. CJ-4E, sample of the product to a commercial testing facility, as which can be used to emulsify the phases. described in section 2(g), below. 0899) Typically, the heating and cooling apparatuses are 0893 2. General Methods for Producing the Composi those that can be used with the bench-top vessels, such as hot tions plates, ice baths and/or water baths, into (or onto) which the 0894. In general, the methods useful for making the con vessels can be placed, for example, for rapid cooling. The centrates provided herein are performed by generating an oil evaluation device used in the bench-top process, for example, phase and generating a water phase (for the liquid nanoemul the temperature and/or pH meters, typically are capable of sion concentrates) and combining (e.g., using a transfer being placed in the bench-top vessels. device) and mixing the phases to form emulsions. The oil and 0900 For the bench-top process, combining the oil and water phases typically are generated in separate vessels. The water phases typically is carried out manually, e.g., by pour vessels can be, for example, tanks Generation of the water ing, pipetting and/or another manual transfer device. phase and generation of the oil phase can be performed simul 0901. The scaled-up manufacturing process of the meth taneously or sequentially, in any order. Typically, both phases ods typically is used to make products of relatively larger are heated to a desired temperature prior to combining the Volumes, such as Volumes greater than 1 L or about 1 L, or phases. For example, the phases can be heated to 60° C. prior greater than 1 gallon (gal) or about 1 gallon. For example, to combining the phases. The provided methods can include Volumes greater than or about 0.5 L, for example, greater than additional steps. In some examples, the additional steps or about 0.5 L, 1 L, or 2L, or greater than or about 1 gal, 2 gal, include evaluating properties of the products, adding addi 3 gal, 4 gal, 5 gal, 6 gal, 7 gal, 8 gal, 9 gal, 10 gal, 11 gal, 12 tional ingredients (e.g., taste-modifying agents), packaging gal, 13 gal, 14 gal, 15 gal, 16 gal, 17gal, 18 gal, 19 gal. 20 gal, and/or filtering. 21 gal, 22 gal, 23 gal, 24 gal, 25 gal, 26 gal, 27 gal, 28 gal, 29 0895. The provided methods can be performed using a gal, 30 gal, 40 gal, 50 gal, 60 gal, 70 gal, 80 gal, 90 gal, 100 bench-top manufacturing process (for Small batch sizes) or gal, 150 gal, 200 gal, 250 gal, 300 gal, 350 gal, 400 gal, 450 performed using a scaled-up manufacturing process (for gal, 500 gal, 550 gal, 600 gal, 650 gal, 700 gal, 800 gal, 900 larger batch sizes). Each of the provided products can be gal, or 1000 gal or more, can be made using the scaled-up made with either the bench-top or scaled up process. In one manufacturing process. US 2016/008 1976 A1 Mar. 24, 2016

0902. In general, equipment used for the scaled-up pro the water phase ingredients include an emulsion stabilizer, the cess is compatible with larger Volume batches (batch sizes). emulsion stabilizer is the last ingredient added to the water For example, the vessels for use in the scaled-up processes phase vessel. can be tanks, for example, water-jacketed tanks, which are 0907 b. Water Phase Production equipped with water jackets that can be used as heating appa 0908. To produce the water phase, appropriate amounts of ratuses to heat the oil and water phase ingredients during the water phase ingredients are added to the water phase generation of the oil and water phases. The water jackets vessel. Water phase vessels can include tanks, for example, typically are controlled via control panels. The transfer water-jacketed tanks such as, but not limited to, the Overly device can include devices attached to and connecting the 550 gallon water-jacketed tank, or any other tank described tanks, such as transfer pumps and associated fittings, for herein. The amounts of the water phase ingredients are mea example, ball valves and hoses that are attached to the tanks Sured, e.g., weighed, either prior to adding to the water phase Mixers for use in the scaled-up process can be standard mix vessel or are measured in the water phase vessel. In one ers, for example, mounted mixers, such as LIGHTNINR) example, the water phase ingredients are measured by weigh mixers, e.g., Model Nos. XJC117 (a fixed-mount, gear drive ing the ingredients on a scale (e.g., one or more of the scales high-flow mixer) and ND2. described herein; the choice of scale depends on the desired 0903 Prior to beginning the methods, the water jacket amount of the ingredient), before addition to the water phase lines on any water-jacketed oil phase and water phase tank vessel. Typically, the appropriate amount of the water phase can be bled. The water jacket switches can then be turned on ingredient is calculated based on the desired concentration to maintain a pressure in the water jackets of between at or (e.g., weight/weight (w/w), molarity (M), Volume/weight about 20 psi and at or about 40 psi (pounds per square inch). (V/w) or volume/volume (v/v)), of the ingredient in the final If the pressure in the waterjacket falls below 20 psi during the product. method, the line can be bled and checked for bubbles while 0909 Water phase ingredients can include water, typically purging the line. purified water. In one example, unpurified water, for example, 0904 a. Water Phase Ingredients city water, is purified to remove impurities using one or more 0905. The water phase includes one or more polar sol purifiers (e.g., purifiers described herein) prior to adding it to vents, such as water, diols, such as propylene glycol and Sugar the water phase vessel. In another example, unpurified water, alcohols, such as glycerin, and, in some examples includes for example, city water, is purified by passing the water other water phase ingredients. Typically, water phase ingre through the following purifiers, typically sequentially, in the dients are hydrophilic and/or amphipathic ingredients of the following order: a carbon filter, an ion exchange purifier, a liquid nanoemulsion concentrate. For example, oils and other reverse osmosis purifier and an end-point filter, for example, lipophilic ingredients typically are not added to the water a 100 micron end-point filter. phase. Certain ingredients, for example, ingredients having 0910. In general, the water phase ingredients are added, hydrophobic and hydrophilic moieties, for example, Surfac mixed and/or heated in the water phase vessel. The water tants and co-surfactants, can be added to either the oil or the phase vessel can be a water phase tank, for example, a water water phase, or to the oil and the water phase. Exemplary jacketed tank, Such as one of the tanks described herein (e.g., water phase ingredients include, but are not limited to, polar an Overly 550 gallon water-jacketed tank). In one example, Solvents, e.g., water, typically filtered water, propylene gly ingredients are heated to temperatures between at or about col, glycerin and other diols; emulsion stabilizers; pH adjust 45° C. and at or about 85°C., for example, to at or about 45° ers, for example, phosphoric acid and/or citric acid; flavors; C., 46° C. 470 C., 48° C., 499 C., 50° C. 510 C., 52° C., 53° Surfactants; co-surfactants, for example, phosphatidylcholine C., 540 C., 550 C., 56° C. 57°C., 58° C., 59° C., 60° C. 610 and Sucrose fatty acid esters; and preservatives. C., 62° C., 63° C., 64° C., 65° C., 66° C., 67° C., 68°C, 69° C., 70° C. 710 C., 720 C., 73° C. 740 C., 75° C., 76° C., 770 0906 Water phase ingredients can be added to the water C., 78° C. 79° C., 80°C., 81° C., 82°C., 83° C., 840 C. or 850 phase simultaneously and/or sequentially, in a specific order. C. In one example, the water phase ingredients are heated to In one example, one or more water phase ingredients is added a temperature of at or about 60°C., for example, by adjusting first and heated, prior to addition of further ingredient(s). In the temperature on a water-jacketed tank or using another one example, when the water phase ingredients include a heating apparatus. polar solvent and an emulsion stabilizer, these ingredients are added sequentially, in the following order: 1) polar solvent, 0911. The mixing can be carried out with a standard mixer, and 2) emulsion stabilizer. In one example, when the water a homogenizer, or any other Suitable mixer, Such as, but not phase ingredients include water and an emulsion stabilizer, limited to, the mixers described herein. Exemplary mixers these ingredients are added sequentially, in the following include standard mixers, such as LightninR mixers (e.g., order: 1) water, and 2) emulsion stabilizer. In another Model No. XJC117, a fixed-mount gear drive high-flow example, when the water phase ingredients include a Surfac mixer) and homogenizers, such as Arde Barinco reversible tant, a polar solvent (e.g., water) and an emulsion stabilizer, homogenizers (e.g., Model No. CJ-4E). The mixer can be these ingredients are added to the water phase vessel sequen attached to the top of the water phase vessel, for example, tially, in the following order: 1) surfactant; 2) polar solvent attached to the tank, Such as mounted on the top of the tank. (e.g., water); and 3) emulsion stabilizer. Alternatively, the 0912. The water phase ingredients can be added to the water phase ingredients can be added in any other order. water phase simultaneously or sequentially in any order. Typically, when the water phase includes a surfactant, par Typically, the water, e.g., purified water, is added before ticularly when the surfactant is a surfactant that is solid at adding the other water phase ingredients. In one example, one room temperature, for example, tocopherol polyethylene gly or more of the ingredients are mixed and/or heated in the col Succinate surfactant, the Surfactant is the first water phase water phase tank before adding the other water phase ingre ingredient added to the water phase vessel. Typically, when dients. US 2016/008 1976 A1 Mar. 24, 2016

0913. In an exemplary method provided herein, the water sion stabilizer. Alternatively, the oil phase ingredients can be phase is generated by combining water, e.g., purified water, added in a different order, for example, any order. Two or and a preservative in the water phase vessel. The water phase more oil phase ingredients can be added simultaneously. is then mixed using a mixer Such as a homogenizer, for 0917. Typically, when the oil phase includes a surfactant, example an Arde Barinco reversible homogenizer (e.g., particularly when the Surfactant is a surfactant that is solid at Model No. CJ-4E), typically using the “reverse' setting. The room temperature, for example, tocopherol polyethylene gly homogenizer can be attached to the top of the water phase col Succinate Surfactant, the Surfactant is the first oil phase vessel. The water phase mixture is then heated to the desired ingredient added to the oil phase vessel. Typically, when the temperature, for example, to a temperature of at or about 60° oil phase ingredients include an emulsion stabilizer, the emul C. After the mixture of water phase ingredients reaches the sion stabilizer is the last ingredient added to the oil phase desired temperature, e.g., at or about 60° C., an emulsion vessel. Typically, the non-polar ingredient either is the last stabilizer, such as the SALADIZER(R) brand emulsion stabi ingredient added to the oil phase vessel, or is added immedi lizer (blend of Xanthan gum, guar gum and sodium alginate) ately prior to addition of the emulsion stabilizer, which is the is added to the water phase. The water phase mixture is then last ingredient added to the oil phase vessel. mixed, for example, using a homogenizer, until the ingredi (0918 d. Oil Phase Production ents are mostly dispersed. Additional water phase ingredients 0919. To produce the oil phase, appropriate amounts of the are then added to the water phase tank at a temperature of at oil phase ingredients are added to the oil phase vessel. Oil or about 60°C. The mixture is then mixed until the ingredi phase vessels can include tanks, for example, water-jacketed ents are dispersed, using a mixer, such as a standard water tanks, such as, but not limited to, the Royal 190 Gallon water phase mixer, for example, a Lightnin R) mixer (e.g., Model jacketed tank, or any other tank described herein. The No. XJC117). Typically the heat is maintained at a tempera amounts of the oil phase ingredients are measured, e.g., ture of at or about 60°C. Typically, the ingredients are mixed weighed, either prior to adding to the oil phase vessel or are until combined and maintained at the desired temperature weighed/measured in the oil phase vessel. In one example, the e.g., at or about 60° C., until combining with the oil phase. oil phase ingredients are measured by weighing the ingredi 0914 c. Oil Phase Ingredients ents on a scale (e.g., one or more of the scales described 0915. The oil phase includes the high dimer-containing herein; the choice of scale depends on the desired amount of water-soluble vitamin Ederivative surfactant, e.g., TPGS, the the ingredient), before addition to the oil phase vessel. Typi non-polar ingredient(s), for example, non-polar ingredients cally, the appropriate amount of the oil phase ingredient is that are or contain non-polar compounds and, in some calculated based on the desired concentration (e.g., weight/ examples, other oil phase ingredients. Typically, oil phase weight (w/w), molarity (M), volume/weight (V/w) or volume/ ingredients include one or more lipophilic and/or amphip volume (v/v)), of the ingredient in the final product. athic ingredients of the liquid nanoemulsion concentrate. Oil 0920. In general, the oil phase ingredients are added, phase ingredients typically do not include aqueous ingredi mixed and/or heated in the oil phase vessel. Mixing the oil ents or hydrophilic ingredients. Certain ingredients, for phase ingredients can be carried out with a standard mixer or example, ingredients having hydrophobic and hydrophilic other mixer, such as, but not limited to, the mixers described moieties, for example, Surfactants and co-Surfactants, can be herein, for example, a Lightnin R) mixer (e.g., Model No. added to either the oil or the water phase, or to the oil and the XJC117, a fixed-mount gear drive high-flow mixer). Heating water phase. Exemplary of ingredients used in the oil phase of the oil phase ingredients is carried out using a heating appa the provided concentrates are non-polar ingredients, for ratus, such as those described herein, typically a water jacket example, non-polar ingredients that are or contain non-polar on a water-jacketed tank. In one example, the ingredients are compounds, including any of the non-polar compounds or heated to temperatures between at or about 45° C. and at or ingredients provided herein; emulsion stabilizers, pH adjust about 85°C., for example, to at or about 45° C., 46°C., 47°C., ers, for example, phosphoric acid and/or citric acid; Surfac 48° C. 490 C., 50° C., 51° C., 52° C., 53° C., 540 C., 550 C., tants; co-surfactants, for example, phosphatidylcholine and/ 56° C. 57°C., 58° C., 59° C., 60° C. 610 C., 62° C., 630 C., or Sucrose fatty acid esters; preservatives, and oils, for 649 C., 650 C., 66° C., 670 C, 680 C, 69° C., 70° C. 710 C., example, non-polar solvents and other oil phase ingredients. 720 C., 73° C. 740 C., 750 C., 76° C., 770 C., 780 C. 790 C. 0916 Oil phase ingredients can be added to the oil phase 80°C., 81°C., 82°C., 83°C.,84°C. or 85°C. In one example, simultaneously and/or sequentially, for example, in any order the oil phase ingredients are heated to a temperature of at or or in a specific order. In one example, one or more oil phase about 60°C., for example, by adjusting the temperature on a ingredients is added first and heated, prior to addition of water-jacketed tank. further ingredient(s). In one example, when the oil phase 0921. The oil phase ingredients can be added to the oil ingredients include a Surfactant, a preservative, a solvent, a phase vessel simultaneously or sequentially in any order. In co-Surfactant, and a non-polar ingredient, these ingredients one example, one or more of the ingredients are added, mixed are added sequentially, in the following order: 1) Surfactant; and/or heated, prior to the addition of the other ingredients to 2) preservative; 3) solvent; 4) co-Surfactant; 5) non-polar the vessel. ingredient; and 6) emulsion stabilizer. In another example, 0922. In an exemplary method provided herein, the oil when the oil phase ingredients include a Surfactant, a preser phase is generated by combining an oil. Such as a fatty acid Vative and a non-polar ingredient, the ingredients are added (e.g., coconut oil) and a stimulant (e.g., theobromine) in the sequentially, in the following order: 1) Surfactant; 2) preser oil phase vessel. The oil phase is then heated to the desired Vative; and 3) non-polar ingredient. In another example, when temperature, for example, to a temperature of at or about 60° the oil phase ingredients include a surfactant, a preservative, C., by adjusting the temperature on a water-jacketed tank, a non-polar ingredient and an emulsion stabilizer, the ingre until dissolved. After the mixture of oil phase ingredients dients are added sequentially, in the following order: 1) Sur reaches the desired temperature, e.g., at or about 60° C., a factant; 2) preservative; 3) non-polar ingredient; and 4) emul surfactant, for example, TPGS, such as the TPGS composi US 2016/008 1976 A1 Mar. 24, 2016 90 tions described herein is added to the oil phase. In some bined oil and water phases is circulated through the cooler, examples, the oil phase ingredients are mixed (e.g., using a typically while mixing, and then back to the vessel, to rapidly mixer as provided herein) during generation of the oil phase. cool and maintain the temperature of the mixture during Typically, the oil phase ingredients are mixed until combined mixing. Typically, the phases are mixed and cooled until the and maintained at the desired temperature, e.g., at or about at phases are emulsified and the temperature of the emulsifica 60° C., prior to combining with the water phase. tion reaches betweenator about 25°C. andator about 43°C., 0923 e. Combining Phases typically between at or about 30° C. and at or about 35° C. For 0924. After the oil phase and the water phase are gener example, the emulsification can be cooled to a temperature of ated, the phases can be combined, for example, by using at or about 25°C., 26° C., 27°C., 28°C., 29° C., 30° C., 31 transfer device, and mixed, e.g., homogenized, to form an C., 32° C., 33° C., 34° C., 35° C., 36° C., 37° C., 38°C., 390 emulsion. In one example, the oil phase is transferred from C., 40° C., 41° C., 42° C. or 43° C. Typically, when the the oil phase vessel to the water phase vessel. In another cooling is rapid cooling, the temperature can be reached in example, the water phase is transferred from the water phase less than or about 2 hours, typically less than or about 1 hour. vessel to the oil phase vessel. In another example, the oil and For example, the emulsification can be cooled to the desired water phases are transferred to another vessel. Such as an temperature, e.g., between at or about 25°C. and at or about emulsifying vessel. 43° C., in at or about 30 minutes to at or about 60 minutes, 0925 Transfer device can include any device for transfer such as in at or about 30, 31, 32,33, 34,35, 36, 37,38, 39, 40, ring the contents of one vessel to another vessel, as described 41, 42,43,44, 45,46, 47,48, 49, 50, 51, 52,53,54, 55,56, 57, above. For example, suitable transfer device include transfer 58, 59 or 60 minutes. pumps and associated equipment, such as, but not limited to, 0929 Cooling can be performed before or after additional combinations of sanitary fittings, hoses and/or ball valves; steps, such as adding additional ingredients and/or evaluation manual transfer device, for example, pouring and/or pipetting of the product. In one example, the cooling is carried out after device; and any other suitable transfer device known to those the addition of additional ingredients, for example, taste of skill in the art. Typically, the phases are kept clean, e.g., modifying agents, and/or pH adjusting agents. sterile, during transfer. Sterility of the phases can be main 0930 g. Filtration, Additions, Evaluation and Packaging tained, for example, by transfer device having sanitary fittings 0931. After combining the oil and water phases to form a and/or by combining the phases in a sterile environment. In mixture, i.e., emulsion, one or more additional steps can be one example, the transfer device include a transfer pump, for carried out to modify, evaluate, analyze and/or package the example, a Teel pump (Model No. 2P377B; Granger, Inc.), product. Typically, taste-modifying agents are added to the sanitary fittings, transfer hoses, for example, food grade emulsion, such as flavoring agents (e.g., flavoring agents that hoses, such as those sold by Sani-Tech West, and ball valves, confer fruit flavors, such as peach, or other flavors, such as which are attached to the tanks and connect the tanks pina colada) and Sweetening agents (e.g., Sucralose). Other 0926 Simultaneous with and/or subsequent to the combi ingredients can be added, such as masking agents (e.g., NAT nation of the phases, a mixer, for example, a homogenizer masking agent) and pH adjusting agents (e.g., acids, Such as, (e.g., a reversible homogenizer), can be used to emulsify the but not limited to citric acid). The pH adjusting agent can be water and oil phases. In one example, a homogenizer, e.g., a used to adjust the pH of the emulsion, for example, to a pH of homogenizer mounted on one of the tanks, is turned on, the between at or about 2 and at or about 5, e.g., to at or about 2 ball valves are opened, and the transfer pump is turned on to and at or about 3.5. Thus, the provided products typically effect transfer of the contents of one tank to another, for have a pH of between at or about 2 and at or about 5, e.g., at example, to transfer the contents of the oil phase tank to the or about 2 and at or about 3.5, such as a pH of at or about 2, water phase tank. As the phases are combined, they can be 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, mixed by the homogenizer to form an emulsion. The position 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, of the homogenizer in the tank can be adjusted, for example, 4.9 or 5. by adjusting abaffle plate, e.g., moving the baffle plate further 0932. Before and/or after adding additional ingredients, into/out of the mixture, in order to achieve and maintain the the product can be evaluated. Such as by measuring the pH emulsion. Typically, the phases are homogenized (i.e., emul and/or the temperature. Measurements can be taken using an sified) by operating the mixer, e.g., homogenizer, at a speed instrument Such as those described herein. In one example, Sufficient to form an emulsion. In one example, the homog additional ingredients (e.g., pH adjusters) are added based on enizer is operated at a speed of between at or about 1000 and information obtained by evaluating the product. The product at or about 1500 rpm. Mixing typically is continued until the can be analyzed and evaluated to verify and/or determine phases are combined, typically in an emulsion. other properties of the product, for example, to verify that the 0927 f. Cooling product contains the appropriate amounts of the non-polar 0928 The emulsion can be cooled during and/or after ingredients and other ingredients. For example, the products mixing to promote stability and emulsification, for example, can be evaluated to verify that microbial and heavy metal by preventing or minimizing oxidization. The cooling can be (e.g., arsenic, cadmium, mercury, lead and others) levels are rapid cooling and can be performed using one or more cooling within the acceptable range according to food and beverage apparatuses, for example, any of the cooling apparatuses standards. In one example, the acceptable microbial levels are described herein or any cooling apparatus known to those of not more than 1,000 cfu/g microbes (e.g., yeast, bacteria, skill in the art. Suitable cooling apparatuses for use with the mold and other microbes) and negative for E. coli and Sal methods include recirculating coolers and water and ice monella. In another example, the acceptable heavy metal baths. An exemplary cooling apparatus is a recirculating levels are not more than 10 ppm heavy metals and not more cooler, such as those sold by Turmoil (Model No. OC-1000 than 0.2 ppm lead and 2 ppm arsenic. When a standard exists RO; West Swanzey, N.H.). When the cooling apparatus is a for a particular amount and/or property, the amount/property recirculating cooler, fluid from the vessel containing the com is verified by tests in accordance with U.S. Pharmacopeia US 2016/008 1976 A1 Mar. 24, 2016

(USP) and/or AOAC (Association of Analytical Communi acid and/or HPO. After discharging the water from the ties) standards. Samples can be analyzed in accordance with vessel, the tanks can be sanitized, such as with isopropyl these standards by sending a sample of the product to a alcohol (IPA), and let dry. commercial testing facility. Such as Eurofins U.S. (Des 0938 i. Clarity Moines, Iowa) or Advanced Botanical Consulting & Testing, 0939 Compositions containing the high dimer-containing Inc. (Tustin, Calif.), or any other facility that performs tests in PEG derivative of vitamin E mixture, such as TPGS, are more accordance with these standards. clear (less turbid) than compositions containing the high 0933 For example, the amount of some non-polar ingre monomer PEG derivative of vitamin E, such as TPGS, such as dients, such as caffeine anhydrous, chromium picolinate and that available from Eastman Chemical Company, as vitamin B12, typically is verified according to USP standards. described herein. The clarity of each of the compositions The density and pH of the composition and the level of containing the concentrates that contained the high dimer microbes, e.g., yeast, mold, E. coli and Salmonella, also typi (about 51%) TPGS mixture (composition), prepared accord cally are verified according to USP standards. The amount of ing to Example 1 below, was determined and compared to the fatty acids, e.g., coconut oil, can be verified according to clarity of the concentrates that contained the commercially AOAC standards, for example, by gas chromatography (GC), available standard TPGS composition (low dimer-contain gas liquid chromatography (GLC) or other fatty acid profiling ing) from Eastman. methods. The levels of heavy metals, such as lead and arsenic, 0940. The clarity of each concentrate was evaluated by a are tested using inductively coupled plasma mass spectrom turbidity analysis using a nephelometer. The concentrates etry (ICP-MS), or by sending a sample of the composition for were prepared for the analysis using the following steps. testing to a testing facility, such as Eurofins U.S. (Des Eight ounces of water was heated in a Pyrex(R) beaker by Moines, Iowa) or Advanced Botanical Consulting & Testing, placing the beaker on a Thermolyne hot plate (Model Inc. (Tustin, Calif.), or any other facility capable of perform #846925) until the water reached 49.8°C. The concentrate ing Such tests. Additionally, Fourier transform infrared spec was then added to the heated water and stirred with a stir rod troscopy (FTIR) typically is used to obtain a fingerprint of the until dispersed. The resulting aqueous composition was product, to Verify that no other compounds except the desired cooled to room temperature (about 25°C.). The cooled aque ingredients are present in the product. ous composition was added to an amber-glass screw-top vial (Alcon) for evaluation. The vials that contained the aqueous 0934. The emulsifications can be purified, for example, compositions were sent to ACZLaboratories, Inc. (Steamboat filtered, prior to use, using any of purification device Springs, Colo.) for turbidity analysis using a nephelometer. described herein or any other suitable purification device. Results of the analysis are listed in the form of Nephelometric Water can be added in the case of evaporation, to bring the product up to the appropriate volume. HPLC, GC, GLC, Turbidity Units (NTU) and are indicated in Tables A-C below. FTIR and ICP-MS can be performed according to well known methods (see, for example, Analytical Chemistry: An TABLE A Introduction, 6th Ed., Douglas A. Skoog et al. (1994) Chap Turbidity (NTU) of aqueous compositions containing 10% fish oil ters 22 (FTIR) and 27 (GC/GLC, HPLC) and U.S. Pat. No. 6,265,717 (ICP-MS)). Composition Turbidity (NTU) 0935. After evaluation, purification, and/or addition of all TPGS (Example 1) + 10% fish oil 12.1 the ingredients, the product can be packaged, for example, TPGS (Eastman) + 10% fish oil 76.8 into large containers for storage or into Smaller containers for administration, Such as bottles or ampoules (as described below). The products can be transferred to the packaging TABLE B containers using transfer device. Such as transfer device described herein, including transfer pumps and fittings as Turbidity (NTU) of aqueous compositions containing 15% fish oil described above or by manual transfer. For example, the Composition Turbidity (NTU) product can be packaged for storage in containers, such as totes, e.g., 275 gallon totes (such as the 275 gallon bottle with TPGS (Example 1) + 15% fish oil 38.5 a reconditioned CageTote tank IBC, Item No. REN275: TPGS (Eastman) + 15% fish oil 233 Qualsery Enterprises, Inc. (www.qualservcontainer.com)), by transferring the mixture using a food grade hose (Sani Tech(R) STHT-R-HD braid-reinforced heavy duty silicone Table C hose: Sani-Tech West). After transfer, the tote can be closed and sealed, e.g., tied, such as with a cable tie. Turbidity (NTU) of aqueous compositions containing 20% fish oil 0936 h. Cleaning the Equipment Composition Turbidity (NTU) 0937. The equipment used in the provided methods can be TPGS (Example 1) + 15% fish oil 718 cleaned prior to, and typically after, use. For example, the TPGS (Eastman) + 15% fish oil 1OOO methods include cleaning all the equipment in a sink and/or rinsing the vessels, e.g., tanks, and hose lines. The tanks can 0941. As the data demonstrate, aqueous compositions that be cleaned by filling with hot water, washing with soap and contained the liquid nanoemulsion concentrates that were water, rinsing with water. The pH of the water can be checked prepared with the high dimer-containing TPGS composition, before discharging the water from the vessel. The water can prepared as described in Example 1 (i.e., TPGS compositions be adjusted to the desired pH, for example to a pH between 6 that contained the higher amounts of TPGS dimer and lower and 9, by adding a pH adjusting agent, such as Soda ash, citric amounts of TPGS monomer), exhibited significantly lower US 2016/008 1976 A1 Mar. 24, 2016 92 turbidity than those compositions that contained the liquid homogenizers. An exemplary reversible homogenizer is the nanoemulsion concentrates prepared using commercially Arde Barinco reversible homogenizer, Model no. CJ-4E. available TPGS (i.e., TPGS compositions that contained 0948 Typically, the heating and cooling apparatuses are higher amounts of TPGS monomer and lower amounts of those that can be used with the bench-top vessels, such as hot TPGS dimer). Additional data are provided in U.S. applica plates, ice baths and/or water baths, into (or onto) which the tion Ser. No. 14/207,310, now published as US-2014 vessels can be placed, for example, for rapid cooling. The O271593-A1. evaluation device used in the bench-top process, for example, 0942. 3. General Methods for Preparing Aqueous Pre-Gel the temperature and/or pH meters, typically are capable of Concentrates (Compositions that are Introduced into or For being placed in the bench-top vessels. mulated in Soft Gel Shells or Capsules) 0949. The scaled-up manufacturing process of the meth 0943. In general, the methods useful for making the pre ods typically is used to make pre-gel concentrates of rela gel concentrates provided herein are performed by combining tively larger Volumes, such as Volumes greater than 1 L or the ingredients, i.e., non-polar ingredients, non-aqueous sol about 1 L, or greater than 1 gallon (gal) or about 1 gallon. For vents, and a surfactant, and mixing to form a homogenous example, Volumes greater than or about 0.5 L, for example, pre-gel concentrate. The pre-gel concentrate typically is gen greater than or about 0.5 L, 1 L, or 2L, or greater than or about erated in a vessel. The vessel can be, for example, a tank. 1 gal, 2 gal, 3 gal, 4 gal, 5gal, 6 gal, 7 gal, 8 gal, 9 gal, 10 gal, Typically, the mixture is heated to a desired temperature to 11 gal, 12 gal, 13 gal, 14 gal, 15 gal, 16 gal, 17 gal, 18 gal, 19 form a homogenous mixture. For example, the mixture can be gal, 20 gal, 21 gal, 22gal, 23 gal, 24gal, 25gal, 26 gal, 27 gal, heated to 60°C. The provided methods can include additional 28 gal, 29 gal, 30 gal, 40 gal, 50 gal, 60 gal, 70 gal, 80 gal, 90 steps. In some examples, the additional steps include evalu gal, 100 gal, 150 gal, 200 gal, 250 gal, 300 gal, 350 gal, 400 ating properties of the pre-gel concentrates, adding additional gal, 450 gal, 500 gal, 550 gal, 600 gal, 650 gal, 700 gal, 800 gal, 900 gal, or 1000 gal or more, can be made using the ingredients, packaging and/or filtering. scaled-up manufacturing process. 0944. The provided methods can be performed using a 0950 In general, equipment used for the scaled-up pro bench-top manufacturing process (for Small batch sizes) or cess is compatible with larger Volume batches (batch sizes). performed using a scaled-up manufacturing process (for For example, the vessels for use in the scaled-up processes larger batch sizes). Each of the provided pre-gel concentrates can be tanks, for example, water-jacketed tanks, which are can be made with either the bench-top or scaled up process. In equipped with water jackets that can be used as heating appa one example, the pre-gel concentrate is first made with the ratuses to ingredients during generation of the pre-gel con bench-top process and then the method is scaled up to make centrate. The waterjackets typically are controlled via control larger quantities of the product. panels. The transfer device can include devices attached to 0945. The bench-top process can be performed on a bench, and connecting the tanks, such as transfer pumps and associ counter, table or any other suitable surface. Typically, the ated fittings, for example, ball valves and hoses that are bench-top process is used to make pre-gel concentrates hav attached to the tanks Mixers for use in the scaled-up process ing relatively smaller volumes than those made with the can be standard mixers, for example, mounted mixers, such as scaled-up process. For example, Volumes less than 1 L or LIGHTNINR) mixers, e.g., Model Nos. XJC117 (a fixed about 1 L, or less than 1 gallon or about 1 gallon, for example, mount, gear drive high-flow mixer) and ND2. less than or about 500 mL, for example, less than or about 0951 Prior to beginning the methods, the water jacket 1000 mL, 900 mL, 800 mL, 700 mL, 600 mL, 500 mL, 450 lines on any water-jacketed oil phase and water phase tank mL,400 mL,350 mL, 300 mL, 250 mL,200 mL, 150 mL, 100 can be bled. The water jacket switches can then be turned on mL, or 50 mL or less, can be made using the bench-top to maintain a pressure in the water jackets of between at or process. about 20 psi and at or about 40 psi (pounds per square inch). 0946 For the bench-top process, the equipment can be If the pressure in the waterjacket falls below 20 psi during the Sufficiently compact to be used on a bench-top or other simi method, the line can be bled and checked for bubbles while lar Surface, and can be sufficiently compact to be moved, for purging the line. example, lifted, by the artisan using the methods. For 0952 a. Ingredients example, the vessels can be bench-top vessels. Exemplary 0953. The pre-gel concentrates include a surfactant, for bench-top vessels include, for example, flasks, beakers, vials, example, a polyalkylene glycol derivative of vitamin E, e.g., measuring containers, bottles and/or other bench-top contain TPGS, the non-polar ingredients, for example, non-polar ers. In some examples, the vessel in the bench-top process is ingredients that are or contain non-polar compounds, and a Pyrex(R) beaker. non-aqueous solvents. Typically, the ingredients do not 0947 Typically, the mixers for use in the bench-top pro include aqueous ingredients, e.g., water. Exemplary of ingre cesses of the provided methods are mixers that can be used in dients used in the provided pre-gel concentrates are non-polar the bench-top vessels. Mixers that can be used in the bench ingredients, for example, non-polar ingredients that are or top vessels include, for example, standard mixers, such as contain non-polar compounds, including any of the non-polar hand-held mixers, stir rods, stir bars, magnetic mixers and compounds and ingredients provided herein; Surfactants, overhead mixers, including, for example, mechanical and/or including any of the polyalkylene glycol derivatives of Vita electric overhead mixers, and any other mixer that is suitable min E provided herein; and non-aqueous solvents, for for use in the bench-top vessel. Exemplary standard mixers example, solvents that have no water solubility or are only include those sold by IKAR, for example, overhead IKAR partially solubility in water. mixers, such as Model Nos. RW-14 Basic and RE-16S, which 0954 b. Production of the Non-Aqueous Pre-Gel Concen are laboratory stirrers and can be used to mix ingredients, trates Such as to for a homogenous concentrate. Suitable bench-top 0955 Typically, the ingredients are weighed and/or mea mixers also include homogenizers, for example, reversible Sured, for example, using one or more scales (e.g., one or US 2016/008 1976 A1 Mar. 24, 2016

more of the scales described herein), before they are added to 0961 c. Transfer and/or Packaging the mixing vessel (e.g., any vessel described herein). In one 0962. After mixing, the pre-gel concentrate is transferred, example, the amount of each ingredient to be added is deter using one or more transfer means, to another vessel, for mined according to the provided methods for formulating the example, a holding or packaging vessel and/or a storage con pre-gel concentrates. Typically, the desired concentration, by tainer. Any transfer means can be used. For example, any weight (w/w), of the final pre-gel concentrate is used to cal means for transferring the contents of one vessel to another culate the amount of each ingredient that is added to the vessel as described above, for example, transfer pumps and vessel. Alternatively, the desired volume per weight, volume associated equipment, for example, sanitary fittings, hoses per Volume or weight per Volume can be used to calculate the and/or ball valves; and manual transfer means, for example, correct amount of an ingredient to be measured and added to pouring and/or pipetting means or other known transfer the vessel. means. In some examples, the mixture is kept clean, for 0956. The ingredients can be added simultaneously and/or example, Sterile during transfer, for example, by using trans sequentially, for example, in any order or in a specific order. fer means with sanitary fittings and/or combining the phases In one example, one or more ingredients are added first and in a sterile environment. heated, prior to addition of further ingredient(s). Typically, 0963. In one example, the mixture is transferred to a hold when the ingredients include a surfactant, a non-aqueous ing tank. In another example, the pre-gel concentrate, after Solvent and a non-polar ingredient, the ingredients are added being made and filtered, is transferred, e.g., by hot filling sequentially, in the following order: 1) Surfactant; 2) non while the concentrate is a liquid, to a storage container, e.g., a aqueous solvent; 3) non-polar ingredient. Alternatively, the vial, plastic bottle, or bag-in-a-box type packaging. Typically, ingredients can be added in a different order, for example, any the concentrate is allowed to cool naturally in the storage order. Two or more ingredients can be added simultaneously. container. Alternatively, a cooling apparatus, e.g., a refrigera tor, freezer or water bath, can be used to cool the concentrate 0957 Typically, when the oil phase includes a surfactant, in the storage container. The pre-gel concentrate can remain a particularly when the Surfactant is a surfactant that is solid at liquid as it cools or, alternatively, can Solidify or partially room temperature, for example, a tocopherol polyethylene Solidify as it cools in the storage container, e.g., becomes a glycol Succinate Surfactant, the Surfactant is the first ingredi waxy Solid. ent added to the vessel. Typically, the non-polar ingredients 0964 4. Exemplary Methods for Preparing Pre-Spray are the last ingredients added to the vessel. Emulsions and Powders 0958 Typically, in order to dissolve the ingredients, the 0965 Methods for preparing the pre-spray emulsions ingredients are mixed in the mixing vessel using a standard include those described above and exemplified below for mixer (e.g., any of the standard mixers described herein) and preparing emulsions. The powders containing a high amounts heated using a heating apparatus (e.g., any of the heating of non-polar ingredients and a Sugar fatty acid ester-binder apparatuses described herein). Typically, the ingredients are mixture are prepared by any Suitable drying methods. Equip heated Such that the ingredients reach an elevated tempera ment for use in the methods and general steps of the methods ture, for example, between about 45° C. or about 45° C. and are described herein The methods include bench-top manu 85°C. or about 85°C., for example, 45,46, 47, 48,49, 50, 51, facturing processes, which are used to make Small quantities 52,53,54, 55,56, 57,58, 59, 60, 61, 62,63, 64, 65, 66, 67,68, of the concentrates. The methods also include scaled-up 69, 70, 71, 72, 73,74, 75,76, 77,78, 79,80, 81, 82, 83, 84 or manufacturing processes, which are used to make larger 85°C., typically, 60° C. or about 60°C. Typically, the ingre batches of the compositions and powders. Any of the bench dients are heated at an elevated temperature, for example, at top processes can be scaled up to perform the methods using 60° C. or about 60° C., until the ingredients dissolve, e.g., the scaled-up processes. Any of the emulsions and powders until a homogenous mixture is formed. can be made using either scaled-up or bench-top processes. For example exemplary methods include those described in 0959. The ingredients typically are homogenized, con U.S. Pat. No. 8,282,977 and U.S. Pub. Nos. 2009-0297491 tinuously or intermittently, until the ingredients become and 2012-001 6026. homogeneous at the elevated temperature, for example, at 0966 a. General Methods for Producing the Emulsions between about 45° C. or about 45° C. and 85°C. or about 85° and Powders C., for example, 45,46, 47, 48,49, 50, 51, 52, 53, 54, 55,56, 0967. As described above, emulsions are prepared by gen 57,58, 59, 60, 61, 62,63, 64, 65, 66, 67,68, 69,70, 71, 72,73, erating an oil phase (e.g., the pre-emulsion concentrate) and 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84 or 85°C., typically, generating a water phase and combining (e.g., using a transfer 60° C. or about 60°C. In one example, the baffle plate of the device) and mixing the phases to form emulsions, e.g., the mixer is adjusted, for example, by moving the baffle plate pre-spray emulsions. The dry powders are generated from the further down into the mixture or further up out of the mixture, pre-spray emulsions by drying, for example, by spray drying to control the type of mixing, for example, to Switch from the pre-spray emulsions. The oil and water phases typically downward flow to upward flow and vice versa, during mixing are generated in separate vessels. The vessels can be, for of the ingredients. In another example, the homogenizer can example, tanks Generation of the water phase and generation be adjusted to increase or decrease shear or to maintain the of the oil phase can be performed simultaneously or sequen shear at a particular speed. Methods for homogenizing ingre tially, in any order. Typically, both phases are heated to a dients are well known and other methods can be used to desired temperature prior to combining the phases. For homogenize in the provided methods. example, the phases can be heated to between 60° C. and 70° 0960 Typically, after all the ingredients have been added C. prior to combining the phases. The provided methods can and made homogeneous, the pre-gel concentrate is filtered include additional steps. In some examples, the additional using an end-product filter (e.g., a 100 micron end-product steps include evaluating properties of the products, adding filter), to remove any impurities. additional ingredients (e.g., taste-modifying agents), packag US 2016/008 1976 A1 Mar. 24, 2016 94 ing and/or filtering. The methods and equipment for prepar converted into a spray of droplets. The pattern of the resultant ing the emulsions are as described above. droplets may be largely dependent on the properties of the 0968 b. Drying the Emulsions to Produce Powders liquid to be spray dried, including its bulk density, in con 0969. After combining the oil phase and water phase to junction with the speed and configuration of the atomizer form the emulsion, the emulsion can be dried into a powder. wheel. In desirable conditions, rotation of the atomizer wheel The emulsion is dried, for example, spray dried, into a powder occurs with minimal vibration, at high peripheral speeds and after the emulsion has been cooled to a desired temperature, with smooth internal surfaces, for maximum efficacy. The e.g., between or between about 25°C. and 43°C., such as at optimum speed and wheel configuration for a specific liquid or about 30°C. The methods for forming the powders include can be determined empirically by one of skill in the art. In spray drying. Spray drying processes and spray drying equip Some examples, the spray of droplets contacts the hot air, for ment are described generally in Perry's Chemical Engineers example air at a temperature of about 180°C., present in the Handbook, pp. 20-57 (Sixth Edition 1984). More details on drying chamber, triggering the formation of dry particles and spray drying processes and equipment are reviewed by Mar cooling of the hot air due to the evaporation of water or shall (1954) Atomization and Spray-Drying.” Chem. Eng. chemical solvent from the concentrated liquid sample. The Prog. Monogr. 50: Series 2 and Masters, "Spray Drying resultant powder and cooler, humid air are separately, and Handbook” (Fourth Edition 1985). Methods for spray drying continuously, discharged from the chamber. In some are well known (see, e.g., U.S. Pat. Nos. 5,430,021 and 6,534, examples, the dry powder is cooled and bagged after separa 085 and U.S. Publication No. 2007/0184117). In general, tion from the cooler, humid air. After powder recovery, some spray drying is used to dry a heated liquid by passing it powders are rewet by re-dissolving the powder in water or a through hot gas. One or more spray nozzles is used to atomize Solvent and the composition is Subject to a second round of the liquid in a cooling tower or chamber. As the material is spray drying and collection. In some examples the powders atomized (sprayed), the Surface tension causes a uniform are then sifted, for example through a 60-80 Lum mesh screen. spherical particle to form, which is passed through the cool 0973. As will be appreciated by one of skill in the art, the ing chamber and hardens into a solid intact sphere. The spray inlet temperature and the outlet temperature of the spray drier dried particles can be between at or about 0.5 microns and at are not critical but will be of such a level to provide the desired or about 100 microns, and typically are less thanator about 10 particle size, of less than at or about 1 micron, and to result in microns, typically less than at or about 5 microns, and typi a powder that has a desired property. The inlet and outlet cally less than at or about, or at or about, 1 micron. temperatures can be adjusted depending on the melting char 0970 Exemplary of a spray dryer is a cyclone spray dryer. acteristics and composition of the emulsion. The inlet tem During spray drying with a cyclone spray dryer, the homog perature typically is betweenator about 60° C. and at or about enized mixture is pumped into an atomizing device where it is 170° C. with outlettemperatures betweenator about 40°C. to broken into small droplets. Upon contact with a stream of hot at or about 120°C. Typical inlet temperatures are from at or air, the moisture is removed very rapidly from the droplets about 90° C. to at or about 120° C. and typical outlet tem while still suspended in the drying air. The dry powder is peratures are from at or about 60° C. to at or about 90° C. The separated from the moist air in cyclones by centrifugal action. flow rate which is used in the spray drying equipment will The centrifugal action is caused by the great increase in air generally be at or about 3 mL per minute to at or about 15 mL speed when the mixture of particles and air enters the cyclone per minute. The atomizer air flow rate will vary between system. The dense powder particles are forced toward the values of at or about 25 L per minute to at or about 50 L per cyclone walls while the lighter, moist air is directed away minute. Commercially available spray dryers are well known through the exhaust pipes. The powder settles to the bottom of to those of skill in the art, and Suitable settings for any par the cyclone where it is removed through a discharging device. ticular dispersion can be readily determined by one of skill in Sometimes the air-conveying ducts for the dry powder are the art without undue experimentation. Operating conditions connected with cooling systems which admit cold air for Such as inlet temperature and outlet temperature, feed rate, transport of the product through conveying pipes. Cyclone atomization pressure, flow rate of the drying air, and noZZle dryers have been designed for large production schedules configuration can be adjusted in accordance with the manu capable of drying ton-lots of powder per hour. facturer's guidelines. 0971 The methods provided herein produce powders 0974. In some examples, a processing aid, such as addi using a standard spray dryer. The liquid to be dried, for tional solvent, for example, water, is added to the emulsion. example a solution, Suspension or emulsion, may be fed into The processing aid, e.g., water, allows the emulsion to pass an atomizer to generate the powder. The atomizer may be, for through the pump of the dryer more easily, for example, by example, a rotary (wheel) atomizer or nozzle atomizer. In making the emulsion less thick. The processing aid, for some examples, a fluid bed dryer may also be used. The example, water, is evaporated during the spray drying process atomizer is typically an open-mode design with single-point and is not present in the final dry powder. powder discharge, an open-mode design with dual-point 0975. The resulting powder can be processed further, such powder discharge, or a closed-cycle design with single-point as by adding polar solvent and repeating the drying process. powder discharge, oran alternative form of atomizer. In some This can improve to properties of the powders. examples, the atomizer is contained within a dryer consisting 0976 c. Storing the Powders of a feed pump to funnel in the liquid, for example the emul 0977. The resulting powders are very stable and can be Sion, an atomizer, an air heater, an air dispenser, a drying stored in any convenient manner, including in packets, such as chamber, systems for powder recovery, and process control packets containing an amount for a single dose or use or systems. multiple doses. The amount in each pack depends upon the 0972. In order to prepare the dry powder using a spray intended application. drier, the liquid, e.g., emulsion, is fed into a rotary wheel or 0978. In some examples, the dry powder is stored into a high pressure nozzle atomizer at a uniform rate, and thereby capsule form or is pressed into a tablet. For use as tablets, the US 2016/008 1976 A1 Mar. 24, 2016 compositions can contain other excipients generally included ingredients and other ingredients. For example, the products in tables. These excipients include tablet disintegrants, such can be evaluated to verify that microbial and heavy metal as corn starch, glidants, such as silicon dioxide, and lubricants (e.g., arsenic, cadmium, mercury, lead and others) levels are Such as magnesium Stearate. Ordinarily these compositions within the acceptable range according to food and beverage contain minor amounts by weight of glidants and lubricants, standards. In one example, the acceptable microbial levels are e.g., each two percent (2%) or less by weight. Tablet disinte not more than 1,000 cfu/g microbes (e.g., yeast, bacteria, grants are optionally present and, if present, are included in mold and other microbes) and negative for E. coli and Sal Sufficient amounts to assure that the tablet disintegrates upon monella. In another example, the acceptable heavy metal ingestion. For example, disintegrants, such as corn starch, can levels are not more than 10 ppm heavy metals and not more be employed at concentrations of from about Zero to about 30 than 0.2 ppm lead and 2 ppm arsenic. When a standard exists percent by weight of the composition. for a particular amount and/or property, the amount/property 0979 The free-flowing, i.e., not sticky, powders also can is verified by tests in accordance with U.S. Pharmacopeia be used to administer the non-polar ingredients by inhalation (USP) and/or AOAC (Association of Analytical Communi using a dry powder inhaler (DPI). Such dry powder inhalers ties) standards. Samples can be analyzed in accordance with typically administer the ingredient as a free-flowing powder these standards by sending a sample of the product to a that is dispersed in the air-stream during inspiration. In order commercial testing facility. Such as Eurofins U.S. (Des to achieve a free-flowing powder, the ingredients are typically Moines, Iowa) or Advanced Botanical Consulting & Testing, formulated with a suitable excipient such as lactose or starch. Inc. (Tustin, Calif.), or any other facility that performs tests in For example, such a dry powder formulation can be made, for accordance with these standards. example, by combining the lactose with the non-polar ingre 0983. For example, the amount of some non-polar ingre dient and then dry blending the components. Alternatively, if dients, such as caffeine anhydrous, chromium picolinate and desired, the non-polar ingredient can be formulated without vitamin B12, typically is verified according to USP standards. an excipient. The pharmaceutical composition is then typi The density and pH of the composition and the level of cally loaded into a dry powder dispenser, or into inhalation microbes, e.g., yeast, mold, E. coli and Salmonella, also typi cartridges or capsules for use with a dry powder delivery cally are verified according to USP standards. The amount of device. Examples of dry powder inhaler delivery devices fatty acids can be verified according to AOAC standards, for include Diskhaler (GlaxoSmithKline, Research Triangle example, by gas chromatography (GC), gas liquid chroma Park, N.C.) (see, e.g., U.S. Pat. No. 5,035,237); Diskus tography (GLC) or other fatty acid profiling methods. The (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 6,378,519: Tur levels of heavy metals, such as lead and arsenic, are tested buhaler (AstraZeneca, Wilmington, Del.) (see, e.g., U.S. Pat. using inductively coupled plasma mass spectrometry (ICP No. 4,524,769); Rotahaler (GlaxoSmithKline) (see, e.g., U.S. MS), or by sending a sample of the composition for testing to Pat. No. 4,353.365) and Handihaler (Boehringer Ingelheim). a testing facility, such as Eurofins U.S. (Des Moines, Iowa) or Further examples of suitable DPI devices are described in Advanced Botanical Consulting & Testing, Inc. (Tustin, U.S. Pat. Nos. 5,415,162, 5,239,993, and 5,715,810 and ref Calif.), or any other facility capable of performing Such tests. erences cited therein. Additionally, Fourier transform infrared spectroscopy 0980 d. Filtration, Additions, Evaluation and Packaging (FTIR) typically is used to obtain a fingerprint of the product, 0981. After combining the oil and water phases to form a to Verify that no other compounds except the desired ingre mixture, i.e., emulsion, or after spray drying the emulsion to dients are present in the product. forma dry powder, one or more additional steps can be carried 0984. After evaluation, purification, and/or addition of all out to modify, evaluate, analyze and/or package the product. the ingredients, the product, e.g., emulsion or dry powder, can Typically, taste-modifying agents are added to the emulsion, be packaged, for example, into large containers for storage or Such as flavoring agents (e.g., flavoring agents that confer into Smaller containers for administration, such as bottles or fruit flavors, such as peach, or other flavors, such as pina ampoules (as described below). The products can be trans colada) and Sweetening agents (e.g., Sucralose). Other ingre ferred to the packaging containers using transfer device. Such dients can be added. Such as masking agents (e.g., NAT mask as transfer device described herein, including transfer pumps ing agent) and pH adjusting agents (e.g., acids. Such as, but and fittings as described above or by manual transfer. For not limited to citric acid). The pH adjusting agent can be used example, the product can be packaged for storage in contain to adjust the pH of the emulsion, for example, to a pH of ers, such as totes, e.g., 275 gallon totes (such as the 275 gallon between at or about 2 and at or about 5, e.g., to at or about 2 bottle with a reconditioned CageTote tank IBC, Item No. and at or about 3.5. Thus, the provided products typically REN275; Qualsery Enterprises, Inc. (www.qualservcon have a pH of between at or about 2 and at or about 5, e.g., at tainer.com)), by transferring the mixture using a food grade or about 2 and at or about 3.5, such as a pH of at or about 2, hose (Sani-Tech(R) STHT-R-HD braid-reinforced heavy duty 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, silicone hose: Sani-Tech West). After transfer, the tote can be 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, closed and sealed, e.g., tied, such as with a cable tie. 4.9 or 5. 0985. The following examples are included for illustrative 0982. Before and/or after adding additional ingredients, purposes only and are not intended to limit the scope of the the product can be evaluated, such as by measuring the pH invention. and/or the temperature. Measurements can be taken using an F. EXAMPLES instrument Such as those described herein. In one example, additional ingredients (e.g., pH adjusters) are added based on Example 1 information obtained by evaluating the product. The product can be analyzed and evaluated to verify and/or determine A. Method of Producing TPGS Compositions other properties of the product, for example, to verify that the 0986 d-C.-Tocopheryl polyethylene glycol 1000 succinate product contains the appropriate amounts of the non-polar (TPGS 1000) was synthesized from vitamin E succinate US 2016/008 1976 A1 Mar. 24, 2016 96 according to the following general procedure. See also, U.S. added to the remaining methanol layer. The solution was patent application Ser. No. 14/207.310 and International again stirred and allowed to separate into layers. The cyclo Patent Application No. PCT/US 14/25006. hexane layer was removed, and the remaining methanol layer 0987 Polyethylene glycol (PEG) 1000 (168.7 kg) was was further diluted with an additional 270 L of methanol. added to a reaction flask containing 1430 L of toluene, fol Activated carbon (18 kg) was added and the solution was lowed by the addition of 71.5 kg of vitamin E (C-tocopheryl heated to 55-60° C. and maintained at this temperature for 1 acid) Succinate and 2.86 kg of p-toluene Sulfonic acid. The hour. The Solution was then cooled to room temperature, reaction mixture was heated to 110-112° C. and refluxed for filtered through 30 kg of Celite R. Hyflo(R) filter aid, and up to 6.5 hours, removing the water formed during the esteri washed with 100 L of methanol. The methanol solution was fication reaction by azeotropic distillation. The reaction was passed through a micron filter, then concentrated via vacuum terminated when the desired amounts of TPGS monomer and distillation below 60° C. to obtain -98-102 kg of a TPGS TPGS dimer were formed, as indicated by high performance composition. All traces of solvent were then removed by liquid chromatography (HPLC) and thin layer chromatogra purging with nitrogen at 55° C. for two hours to obtain -98 phy (TLC), resulting in the TPGS compositions set forth in 102 kg of a purified TPGS composition that contained TPGS Table 1a below. Each TPGS composition in Table 1a was monomer and TPGS dimer. formed by terminating the reaction at a different time point, 0989. One typical batch of TPGS prepared to contain a up to 6.5 hours, and contained various amounts of TPGS high dimer concentration, and used in the Examples below, monomer and TPGS dimer. The remainder of the TPGS com had the following components: position was made up of unreacted Starting materials, such as vitamin E and PEG The reaction was terminated by cooling TPGS monomer: 48% the reaction mixture to room temperature, followed by wash TPGS dimer: 51% ing with 25 L of a 10% solution of NaHCO. The solution stirred for 10 minutes, and after stirring was allowed to sepa Vitamin E: 0.42% rate into layers. The organic (toluene) layer was removed, 6 kg of activated carbon (charcoal) was added, and the Solution 0990 Vitamin E succinate: 0.46%. was heated to 55-60° C. and maintained at this temperature 0991. Other typical batches contained: for 1 hour. The solution was then cooled to room temperature, filtered through 10 kg of Celite(R) Hyflo R filter aid (Sigma TPGS monomer: 46.09%-43.15% w/w Aldrich, St. Louis, Mo.) and then washed with 100 L of TPGS dimer: 39.07%-50.28% W/w toluene. The filtered toluene solution was concentrated by Other: up to about 3%-3.2% w/w vacuum distillation below 60°C. to remove the toluene. Water 0992 For example, the batches used in Example 11, (140 L) was added to remove traces of toluene and was then removed via vacuum distillation below 60° C. to obtain -180 below, contained: kg of a crude C-tocopheryl polyethylene glycol 1000 succi TPGS monomer: 46.55%-48.72% w/w nate composition that contained a mixture of TPGS monomer TPGS dimer: 46.88%-47.33% W/w and TPGS dimer, along with unreacted PEG 1000 and C-to copherol. Other: up to about 3.95%-6.55% w/w B. Evaluation of the Clarity of the TPGS-Containing TABLE 1A Compositions by a Turbidity Analysis Amounts of TPGS monomer and TPGS diner formed during reaction 0993. The clarity of the TPGS compositions prepared above was evaluated by a turbidity analysis. TPGS composi Total (% TPGS Monomer Dimer OOle -- tions 1-11 were formulated as 1 g concentrates and each were composition (%) (%) % dimer) dissolved in 8 oz. of water. The resulting aqueous liquid dilution compositions then were evaluated for clarity by mea 1 43.90 53.90 97.8O 2 428O 48.8O 91.60 Suring turbidity using a nephelometer. Results of the evalua 3 40.95 53.15 94.10 tion are set forth in Table 2 below. 4 43.52 49.8O 93.32 5 SS-88 29.27 85.15 0994). Each of the eleven TPGS compositions listed in 6 52.92 33.70 86.62 Table 1 above was diluted in water (purified according to the 7 42.76 51.10 93.86 provided methods) using the following steps. 8 40.39 S4.90 95.29 9 57.70 40.40 98.10 0995 Eight ounces of water was heated in a Pyrex(R) bea 10 39.35 35.56 74.91 ker by placing the beaker on a Thermolyne hot plate (Model 11 6O.OO 38.10 98.10 #846925) until the water reached 49.8° C. The TPGS com position concentrate was then added to the heated water and 0988 A series of extractions were performed on the crude stirred with a stir rod until dispersed. The resulting aqueous TPGS composition. The crude TPGS composition (~180 kg) TPGS composition was cooled to room temperature (about was dissolved in 360 L of methanol and then 540 L of cyclo 25°C.). The cooled aqueous TPGS composition was added to hexane was added. The solution was stirred and then allowed an amber-glass screw-top vial (Alcon) for evaluation. to separate into layers. The cyclohexane layer was removed 0996. The vials containing the aqueous TPGS composi and an additional 540 L of cyclohexane was added to the tions were sent to ACZ Laboratories, Inc. (Steamboat remaining methanol layer. The solution was stirred and then Springs, Colo.) for turbidity analysis using a nephelometer. allowed to separate into layers. The cyclohexane layer was Results are listed in the form of Nephelometric Turbidity again removed and an additional 540 L of cyclohexane was Units (NTU) and are indicated in Table 1b below. US 2016/008 1976 A1 Mar. 24, 2016 97

TABLE 1B marked with a “*”66: were added in overage to ensure the stated amount of non-polar ingredient was in the final product. Turbidity (NTU) of aqueous TPGS compositions 0999 Each of the pre-emulsion concentrates set forth in Total (% Tables 2-18, below, were prepared using a bench-top process. TPGS Monomer Dimer OOle -- Turbidity Larger amounts of the pre-emulsion concentrates can be composition (%) (%) % dimer) (NTU) made by Scaling up the bench-top process or using a scaled-up 1 43.90 53.90 97.8O 8 manufacturing process, for example, to make larger batch 2 428O 48.8O 91.60 8.2 sizes of the pre-emulsion concentrates. Accordingly, each of 3 40.95 53.15 94.10 10 the pre-emulsion concentrates in Tables 2-18 also can be 4 43.52 49.8O 93.32 10 made with the provided methods as described and a scaled-up 5 SS-88 29.27 85.15 14 6 52.92 33.70 86.62 14 process. Further details for each pre-emulsion concentrate are 7 42.76 S1.10 93.86 18.5 provided in each individual Table. 8 40.39 S4.90 95.29 39.4 1000 The bench-top process for making the pre-emulsion 9 57.70 40.40 98.10 71 10 39.35 35.56 74.91 8O concentrates was performed using the following general 11 6O.OO 38.10 98.10 8O steps. For each of the pre-emulsion concentrates set forth in Tables 2-18, below, the indicated amount of each ingredient was weighed using a Toledo Scale (Model GD13X/USA), Sartorius Basic Analytical Scale (Model BA110S) or an Example 2 OHAUS Scale (Model CS2000). Selection of scale depended on the weight of each ingredient being weighed. Preparation of Pre-Emulsion Concentrates 1001 The initial ingredients (all ingredients except the Containing TPGS and Non-Polar Ingredients non-polar ingredients) were added in the indicated amounts (g/batch) to a vessel (a Pyrex(R) beaker), and mixed with a 0997 Pre-emulsion concentrates were prepared according standard mixer (IKAR model No. RE-16 S1, an overhead to the method described below with the ingredients detailed in mixer (laboratory stirrer) compatible with the bench-top pro Tables 2-18. The pre-emulsion concentrates contained cess). While mixing, the ingredients were heated by a Ther between 31.5% and 97.43% by weight (of the concentrate) of molyne hot plate (Model if SP46615) to reach a temperature one or more non-polar ingredients and TPGS (C-tocopheryl of between 60° C. and 70° C. polyethylene glycol succinate) or benzyl alcohol, or TPGS 1002. After the initial ingredients dissolved, e.g., formed a and benzyl alcohol. The TPGS was prepared as described in homogeneous mixture, and reached the desired temperature, Example 1, above. e.g., 60°C., the non-polar ingredients were added. The ingre 0998. The pre-emulsion concentrates contained as much dients then were homogenized by placing a reversible as about 97% non-polar ingredients that are or contain non homogenizer (Arde Barinco, Inc.; Model CJ-4E) in the vessel polar compounds. The remainder was TPGS or benzyl alco (beaker) and turning on at 850-1200 RPM. Mixing with the hol, or TPGS and benzyl alcohol. Non-polar ingredients homogenizer was continued while maintaining the tempera included: a fish oil that contains 50% of the non-polar com ture using the hot plate. The baffle plate on the homogenizer pounds DHA/EPA (sold as VivoMega 3322 TG by GC Rieber was adjusted to achieve and maintain an emulsion, for Oils, Kristiansund, Norway); an algal oil that contains 40% of example, by moving the baffle plate further into and/or out of the non-polar compound DHA (sold by GC Rieber Oils, the ingredient mixture. Homogenization continued at Kristiansund, Norway); an algal oil that contains 35% of the between 60° C. and 70° C. until the mixture became homo non-polar compound DHA and contains 350 mg DHA/g oil geneous. For the preparation of Some pre-emulsion concen (life's DHATMS35-0300, sold by DSM Nutritional Products trates, an additional Solvent, such as ethanol, tetrahydrofuran Inc., Kaiseraugst, Switzerland); a conjugated linoleic acid or hexanes, was added to aid in dissolving the non-polar (CLA) that contains 79.6% CLA (Clarinol R. G-80, sold by ingredients. The additional solvent was then evaporated Stepan Lipid Nutrition, Maywood, N.J.); a medium chain before further use of the solid phase composition. triglyceride (MCT) oil that contains 98% MCT (sold by 1003. Unless otherwise indicated, when the ingredients Abitec, Janesville, Wis. and Stepan Lipid Nutrition, May include a surfactant, a preservative and one or more non-polar wood, N.J.); a flaxseed oil that contains 50% C:18-3 alpha ingredients, these ingredients were added sequentially, in the linolenic acid (ALA) (sold by San Mark Ltd., Greensboro, following order: 1) surfactant; 2) preservative; 3) non-polar N.C.); resveratrol (sold by MaxSun Industries Inc., Walnut, ingredient. When the ingredients include a Surfactant, a pre Calif.); Vinpocetine (sold by Cyvex Nutrition, Irvine, Calif.); servative, a solvent and one or more non-polar ingredients, sesamin (sold by KEBNutraceutical USA, Inc., Minneapolis, these ingredients were added sequentially, in the following Minn.); a turmeric/curcumin composition that contains 95% order: 1) surfactant; 2) preservative; 3) solvent; 4) non-polar curcumin (sold by Siddharth International, Mumbai, India); a ingredient. The ingredients were heated with the hot plate phosphatidylserine (PS) composition that contains 40% until the temperature reached between 60° C. and 70° C. A phosphatidylserine and lesser amounts of phosphatidylinosi temperature probe (Model # DPP400W, Cooper-Atkins) was tol and phosphatidylethanolamine (sold by Doosan Corpora used to measure the temperature of the mixing ingredients. tion and distributed by Perrimondo LLC); vitamin Eacetate 1004 The composition then was filtered, through a 100 that contains 1360 IU tocopheryl/g vitamin E oil (sold by micron end-product filter, and packaged (transferred) by fill DSM Nutritional Products Inc., Kaiseraugst, Switzerland); ing into one or more storage containers, for example, plastic alpha-lipoic acid (sold by Pure Assay Ingredients, Walnut, bottles or 5 gallon pails, where it was cooled to room tem Calif.); quercetin (sold by Pure Assay Ingredients, Walnut, perature (about 25°C.). Alternatively, the composition was Calif); pyrroloquinoline quinone (PQQ; Nascent Health Sci packaged into a bag-in-a-box-type storage container. ences, Allentown, N.J.); and mixtures thereof. Ingredients Depending on the particular ingredients, the resulting con US 2016/008 1976 A1 Mar. 24, 2016

centrates either were a solid to semi-solid composition at TABLE 7 room-temperature (having a waxy consistency) or remained as a liquid. Pre-emulsion concentrate containing resveratrol and TPGS TABLE 2 Ingredient wt % of composition Pre-emulsion concentrate containing fish oil (50% DHA/EPA) and TPGS Resveratrol 3S.OO (non-polar ingredient) Ingredient wt % of composition

Fish oil (50% DHA/EPA blend)* 39.50 (non-polar ingredient) Total 1OOOO TPGS 6O.SO

Total 100.00 TABLE 8

Pre-emulsion concentrate containing vinpocetine and TPGS TABLE 3 Ingredient wt % of composition Pre-emulsion concentrate containing algal oil (40% DHA) and TPGS Vinpocetine 3S.OO Ingredient wt % of composition (non-polar ingredient) TPGS 6S.OO Algal oil (40% DHA) 84.00 (non-polar ingredient) TPGS 16.00 Total 1OOOO

Total 1OOOO

TABLE 9 TABLE 4 Pre-emulsion concentrate containing Sesamin and TPGS Pre-emulsion concentrate containing algal oil (35% DHA) and TPGS Ingredient wt % of composition Ingredient wt % of composition Sesamin 35.00 (non-polar ingredient) Algal oil (35% DHA) 97.35 TPGS 6S.OO (non-polar ingredient) TPGS 2.65 Total 1OO

Total 100.00

TABLE 10 TABLE 5 Pre-emulsion concentrate containing turmerici curcumin 95% curcumin) and TPGS Pre-emulsion concentrate containing CLA oil (79.6% CLA) and TPGS Ingredient wt % of composition Ingredient wt % of composition Turmerici curcumin (95% curcumin) 31. SO CLA oil (79.6% CLA) 97.43 (non-polar ingredient) (non-polar ingredient) TPGS 68. SO TPGS 2.57 Total 1OOOO Total 100.00

TABLE 11 TABLE 6 Pre-emulsion concentrate containing turmerici curcumin Pre-emulsion concentrate containing MCT oil (98% MCT) and TPGS 95% curcumin) and TPGS Ingredient wt % of composition Ingredient wt % of composition MCT oil (98% MCT) 97.42 Turmerici curcumin (95% curcumin) 37.10 (non-polar ingredient) (non-polar ingredient) TPGS 2.58 TPGS 62.90

Total 100.00 Total 1OOOO US 2016/008 1976 A1 Mar. 24, 2016 99

TABLE 12 TABLE 16-continued

Pre-emulsion concentrate containing phosphatidylserine Pre-emulsion concentrate containing quercetin, TPGS, and benzyl alcohol (40% phosphatidylserine) and TPGS Ingredient wt % of composition TPGS 64.50 Ingredient wt % of composition Benzyl alcohol O.SO (preservative) Phosphatidylserine (40% PS) 6840 (non-polar ingredient) Total 100.00 TPGS 31.60

Total 100.00 TABLE 17 Pre-emulsion concentrate containing PQQ, TPGS, and benzyl alcohol Ingredient wt % of composition TABLE 13 PQQ 3S.OO Pre-emulsion concentrate containing phosphatidylserine (non-polar ingredient) 40% phosphatidylserine). MCT oil (98% MCT) and TPGS TPGS 64.50 Benzyl alcohol OSO Ingredient wt % of composition (preservative) Phosphatidylserine (40% PS) 68. SO Total 1OOOO (non-polar ingredient) MCT oil (98% MCT) 17.8O (non-polar ingredient) TPGS 13.70 TABLE 1.8 Total 100.00 Pre-emulsion concentrate containing fish oil (50% DHAEPA), flaxseed oil (50% ALA), TPGS, and benzyl alcohol Ingredient wt % of composition TABLE 1.4 Flaxseed oil (50% ALA) 79.02 Pre-emulsion concentrate containing vitamin E acetate, TPGS, and (non-polar ingredient) Fish oil (50% DHAEPA) O.40 benzyl alcohol (non-polar ingredient) Ingredient wt % of composition TPGS 20.08 Benzyl alcohol O.SO Vitamin Eacetate (1360 IU tocopheryl/g oil) 95.43 (preservative) (non-polar ingredient) TPGS 4.07 Total 100.00 Benzyl alcohol O.SO (preservative) Total 100.00 Example 3 Preparation of Pre-Spray Emulsions Containing TABLE 1.5 TPGS and Non-Polar Ingredients Pre-emulsion concentrate containing alpha-lipoic acid, TPGS and 1005 The pre-emulsion concentrates of Tables 2-18 were benzyl alcohol used to prepare pre-spray emulsions. The pre-spray emul sions were prepared by combining a pre-emulsion concen Ingredient wt % of composition trate with the ingredients detailed in Tables 19-39, below, Alpha-lipoic acid 7O.OO according to the general procedure described below. The (non-polar ingredient) resulting pre-spray emulsions contained between 5.25% and TPGS 2O.OO 19.49% by weight non-polar ingredient(s) that is or contains Benzyl alcohol 1O.OO (preservative) non-polar compounds, as shown in Table 40, below. 1006. The ingredients in the pre-spray emulsions Total 100.00 included: a pre-emulsion concentrate prepared as described above in Example 2 (see Tables 2-18); an emulsion stabilizer that is blend of Xanthan gum, guar gum and Sodium alginate, sold under the product name SALADIZER(R), available from TABLE 16 TIC Gums, Inc. (Belcamp, Md.); a binder, maltodextrin (Ar Pre-emulsion concentrate containing quercetin, TPGS, and benzyl alcohol cher Daniels Midland Company, Decatur, Ill.); a sucrose fatty acid ester (SFAE) sold under the trade name DK Ester(R) Ingredient wt % of composition (produced by Dai-Ichi Kogyo Seiyaku Co., Ltd of Japan) in Quercetin 35.00 place of some or all of the maltodextrin; citric acid, a pH (non-polar ingredient) adjuster, stabilizers, including vitamin C (Pure Assay Ingre dients, Walnut, Calif.), potassium bicarbonate (Armand