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US008187615B2

(12) United States Patent (10) Patent No.: US 8,187,615 B2 Friedman (45) Date of Patent: May 29, 2012

(54) NON-AQUEOUS COMPOSITIONS FOR ORAL 6,054,136 A 4/2000 Farah et al. DELIVERY OF INSOLUBLE BOACTIVE 6,140,375 A 10/2000 Nagahama et al. AGENTS 2003/O149061 A1* 8/2003 Nishihara et al...... 514,266.3 FOREIGN PATENT DOCUMENTS (76) Inventor: Doron Friedman, Karme-Yosef (IL) GB 2222770 A 3, 1990 JP 2002-121929 5, 1990 (*) Notice: Subject to any disclaimer, the term of this WO 96,13273 * 5/1996 patent is extended or adjusted under 35 WO 200056346 A1 9, 2000 U.S.C. 154(b) by 1443 days. OTHER PUBLICATIONS (21) Appl. No.: 10/585,298 Pouton, “Formulation of Self-Emulsifying Drug Delivery Systems' Advanced Drug Delivery Reviews, 25:47-58 (1997). (22) PCT Filed: Dec. 19, 2004 Lawrence and Rees, “Microemulsion-based media as novel drug delivery systems' Advanced Drug Delivery Reviews, 45:89-121 (86). PCT No.: PCT/L2004/OO1144. (2000). He et al., “Microemulsions as drug delivery systems to improve the S371 (c)(1), and the bioavailability of poorly water-soluble drugs' (2), (4) Date: Jul. 6, 2006 Expert Opin. Drug Deliv. 7:445-460 (2010). Prajpati et al. “Effect of differences in Chain Lengths of (87) PCT Pub. No.: WO2005/065652 Medium-Chain on /Surfactant/Water Phase Diagrams PCT Pub. Date: Jul. 21, 2005 and Drug Solubility” J. Excipients and Food Chem, 2:73-88 (2011). (65) Prior Publication Data * cited by examiner US 2007/O190O80 A1 Aug. 16, 2007 Primary Examiner — Robert A Wax Assistant Examiner — Jessica Worsham (30) Foreign Application Priority Data (74) Attorney, Agent, or Firm — Browdy and Neimark, Jan. 6, 2004 (ID) ...... 159729 PLLC (51) Int. Cl. (57) ABSTRACT A6 IK9/00 (2006.01) The present invention provides a composition of low water A6 IK38/00 (2006.01) solubility drug, dissolved or dispersed in a non crystalline or A6 IK 4.8/00 (2006.01) low crystalline form in an emulsion type composition of A6 IK3I/70 (2006.01) internal oily-solvent and external non-hydrous and water (52) U.S. Cl...... 424/400: 514/1.1 : 514/44 R: 514/23 soluble solvent, whereas 1) emulsifying stabilizer comprises (58) Field of Classification Search ...... None low fraction of the composition, and 2) emulsions of mean See application file for complete search history. droplets size below one micron is obtained upon dilution with physiological fluids, and 3) facilitated dispersion of biologi (56) References Cited cally active agents in body fluids is obtained, and more par ticularly to facilitating biological availability or improving U.S. PATENT DOCUMENTS clinical performance. 5,342,625 A * 8, 1994 Hauer et al...... 424/455 5,965,160 A 10, 1999 Benita et al. 5,993,858 A 11/1999 Crison et al. 20 Claims, No Drawings US 8,187,615 B2 1. 2 NON-AQUEOUS COMPOSITIONS FOR ORAL ultimately the must be digested and the therapeu DELIVERY OF INSOLUBLE BOACTIVE tic agent must be released in order to be absorbed through the AGENTS intestinal mucosa. Certain Surfactants commonly used in the preparation of The present invention provides a composition of low water 5 pharmaceutical emulsions, such as polyethoxylated castor solubility drug, dissolved or dispersed in a non crystalline or oils, may themselves act as inhibitors of lipolysis. Although low crystalline form in an emulsion type composition of recent work Suggests that certain Surfactant combinations, internal oily-solvent and external non-hydrous and water when used in combination with digestible oils in emulsion soluble solvent, whereas 1) emulsifying stabilizer comprises preparations, can Substantially decrease the lipolysis-inhibit low fraction of the composition, and 2) emulsions of mean 10 ing effect of some common pharmaceutical Surfactants (U.S. droplets size below one micron is obtained upon dilution with Pat. No. 5,645,856), such formulations are still subject to the physiological fluids, and 3) facilitated dispersion of biologi other disadvantages of pharmaceutical emulsions and triglyc cally active agents in body fluids is obtained, and more par eride-based formulations. ticularly to facilitating biological availability or improving Example of self emulsifying system is described in U.S. clinical performance. 15 Pat. No. 6,054,136 (Faraha et al). The invention relates to a composition which can be administered, in particular, orally, BACKGROUND OF INVENTION for pharmaceutical or cosmetic use, capable of forming a micro-emulsion in situ with the biological fluid of the body; The formulation of lipophilic, amphipathic, or sparingly the invention relates more especially to a composition pro water-soluble drugs for oral administration has proven to be viding of a self-micro-emulsifying carrier system for active difficult, since in order to be absorbed, drugs need to be agents, designated in the art by the English term “SMEDDS solubilized in the gastro intestinal fluids which are hydrous (self-micro-emulsifying drug delivery system); these systems and therefore are intrinsically not favorable medium for such have the property of emulsifying in water at the temperature insoluble bioactive molecules. of the human body. Oral drug delivery vehicles must be capable of maintaining 25 This composition as well as otherself emulsifying compo sufficient drug concentration in a bio-available form that will sitions are intended, on the one hand to transport one or more enable expected absorption and biological activity. Such drug soluble or sparingly soluble active agents, and on the other delivery vehicles must also be capable of maintaining the hand to form a micro-emulsion with the biological fluid of the drug in its dissolved state and maintain stability of drug and human body, being understood that one or more active agents dosage form over an extended storage period while avoiding 30 or principles in Solution in a micro-emulsion has better bio the use of physiologically harmful solvents or excipients. availability. However, the self emulsifying systems possess Dissolved state, which enables transport of drug from the major drawback, of typical high surfactant content in the gastro intestinal fluids into the blood circulation, is a state range of 20 to 50%. where single drug molecules are exists individually in the High Surfactant concentration may inhibit lipolysis and is fluid medium. 35 disadvantageous to the intestinal mucous and has potential of One approach to overcome drugs molecules self attraction causing local irritation side effects. and maintain hydrophobic drugs in dissolved or solubilized Thus, there is a need for pharmaceutical compositions that state at the gastro intestinal absorptive mucous is by high overcome the limitations of conventional micelle formula Surfactants content delivery systems. Such as, micelles, self tions, but without Suffering from the disadvantages of trig emulsifying micro-emulsions and related colloidal systems. 40 lyceride-containing formulations or disadvantage of high Sur Micelles are agglomerates of colloidal dimensions formed factant ratio. by amphiphilic compounds or Surfactants. In aqueous solu A need therefore exists in the art of drug delivery to develop tion, micelles can incorporate hydrophobic therapeutic a vehicle that can be used with lipophilic and amphipathic agents in the hydrocarbon core of the micelle. Loading capac insoluble materials, drugs or nutrients and that can be stored ity of micelle formulations is limited by the solubility of the 45 at various temperatures for extended periods of time and be therapeutic agent in the micelle Surfactant and dosage form is dilutable or spontaneously mixing with an aqueous fluid Such intrinsically of high Surfactant ratio. as blood or a buffer solution or gastro-intestinal fluids and Another conventional approach is dissolving hydrophobic deliver the drug to the absorption organ or membrane in a drugs in oily medium Such as triglyceride-based solvents. functional form. This oily solution of lipophilic drug in oily phase may be 50 In particularly, there is a need for such vehicle that will not further processed in two ways. One way is emulsifying in comprise high and significant portion of Surfactants that are aqueous medium by the aid of Surfactants, to produce an irritating to the gastro intestinal mucous. oil-in-water emulsion, which are inherently unstable dosage It is the objective of the present invention to furnish a form, and second way is adding high amount of Surfactant to carrier system for bioactive agents having limited water solu produce thermodynamically stable micro-emulsions prefer 55 bility, whereas an admixture to body fluid is possible or better able self-emulsifying upon dilution in the gastrointestinal dissolution and enhanced absorption is obtained while avoid fluids. The properties of these oil-based formulations are ing the side effects associated with high emulsifiers concen determined by such factors as the size of the triglyceride/ tration. therapeutic agent colloidal particles and the presence or Unexpectedly, it has now been discovered that one: it is absence of Surfactant additives. Size control is a significant 60 possible to formulate significant amount of hydrophobic factor affecting absorption, Smaller particles resulting in bet waterinsoluble drugs in the low surfactant, oil in non-hydrous ter absorption. Solvent, stable emulsion system composition, in a dissolved A further disadvantage of triglyceride-containing compo amorphous state. Two: good mixing of nano size droplets in sitions is the dependence of therapeutic agent absorption on the gastro intestinal fluids is obtained despite low surfactant the rate and extent of lipolysis. Although colloidal emulsion 65 concentration, and three: facilitate drug dissolution formu particles can transport hydrophobic therapeutic agents lated with this system and four: maintaining stable amor through the aqueous environment of the gastrointestinal tract, phous or low crystalline state of drugs in the composition. US 8,187,615 B2 3 4 PRIOR ART non-hydrous emulsion with mean droplet size below one micron, comprising at least one low solubility bioactive com U.S. Pat. No. 6,056,971 (Goldman et al) “Method for pound that is dissolved, solubilized or dispersed in a non enhancing dissolution properties of relatively insoluble crystalline or low crystalline form in the composition, at least dietary Supplements and product incorporating same uses high surfactant concentration 20-90 and 2-50 polyhydric one oily solvent comprising an internal phase, at least one alcohol; the present invention teaches lower Surfactant con emulsifying stabilizer, in a significant low concentration, and centration and at least 50% non-hydrous hydrophilic solvent. a continuous non-hydrous and hydrophilic external phase U.S. Pat. No. 5,965,160 “Self-emulsifiable formulation wherein said composition is easily mixed with body fluids to producing an oil-in-water emulsion' (Benita at al) compris form homogeneous dispersion with mean particle size of less ing an oily component and a surfactant which itself is not an 10 than one micron and improved solubilizing and dissolution of emulsion but rather self-emulsify, become or transformed drug is obtained. into oil-in-water emulsion upon contact with water or body Thus, in one embodiment, this invention comprises an fluids. In contrast, the present invention composition is an admixture of a pharmacologically active agent having low or emulsion itself, as is, before mixing with water and therefore poor water solubility formulated in a non-hydrous emulsion, a different physical form. 15 U.S. Pat. No. 5,993,858 “Method and formulation for and in none or low crystalline molecular form for the admin increasing the bioavailability of poorly water-soluble drugs' istration of therapeutically effective amounts of said active (Amidon etal) a self-microemulsifying excipient formulation agent. for increasing the bioavailability of a drug” “the range of In another embodiment, the invention provides a method concentration of the Surfactant/co-Surfactant broadly ranges for enhancing the dissolution and oral availability of a phar from 15 to 90% (v/v) and more preferably ranges from macologically active agent having low or poor water Solubil approximately from 45% to 55% (v/v). The present inven ity, wherein the method comprises oral administering of the tion teaches much lower, about one tenth, Surfactant concen patient undergoing treatment a mixture of the pharmacologi tration. cally active agent in the solubilizing and dissolution facilitat U.S. Pat. No. 6,096.338 (Lacy etal) is a “Delivery systems for hydrophobic drugs” that comprises 30-45% by weight of 25 ing composition as described herein. said hydrophilic surfactant component, and 20-40% by It has been unexpectedly found that despite low emulsify weight of said lipophilic Surfactant component. "a hydro ing stabilizer concentration used in the current invention philic surfactant component which substantially inhibits the composition, fast and stable dissolution of Sub micron drop in vivo livolysis of said digestible oil'. “The carrier comprises lets is obtained upon dilution with biological fluids and also it a digestible oil and a pharmaceutically acceptable surfactant 30 has been found that less energy, time and pressure is required component for dispersing the oil in vivo upon administration to obtain Small and uniform particle size for emulsion sys of the carrier'. In contrast, the present invention carrier is a tems of oil in non-hydrous composition. real emulsion and comprises about one tenth Surfactant con It has been unexpectedly found that despite low emulsify centration, while maintaining good mixing with physiologi ing stabilizer concentration used in the current invention cal fluids. 35 composition, adequate solubilization and molecular disper U.S. Pat. No. 6,140,375 (Nagahama etal) is a “Microemul sion of low solubility drugs is obtained and re-crystallization sions' states that “The components of the pharmaceutical rate is highly Suppressed. compositions of the present invention in amounts such that upon dilution with an aqueous Solution, the composition DETAILED DESCRIPTION OF THE INVENTION forms a clear, aqueous dispersion.” “The particle sizes in the 40 aqueous dispersions of the present invention are much The present invention provides in one aspecta composition Smaller than the larger particles characteristic of vesicular, comprising an oil in non-hydrous hydrophilic solvent emul emulsion or microemulsion phases. In contrast, the present sion with mean droplet size below one micron, comprising: invention forms turbid emulsions upon dilution with water or (1) a poor or low-solubility drug dissolved or dispersed in the body fluids differently from the above which is characterized 45 composition, whereas all or majority of drug is non crystal by high Surfactant concentration that form clear Solution upon line, and (2) At least one oily solvent comprising the internal dilution with water. phase of the emulsion, and (3) at least one emulsifying stabi Following patents comprising high Surfactant content; lizer, whereas the emulsifying stabilizer content in the final U.S. Pat. No. 6,309.665 (Barthelemy et al) “Composition composition is low, typically below 10%, and (4) a continu with Sustained release of active principle, capable of forming 50 ous non-hydrous and hydrophilic phase, wherein enhanced a microemulsion' and U.S. Pat. No. 6.312,704 (Farah et al) solubilizing effect of bioactive compound in biological fluids “Orally administrable composition capable of providing is obtained. enhanced bioavailability when ingested The systems are “a In another aspect, the invention comprises an emulsion of system which is self-microemulsifying on contact with a oil in non-hydrous composition, wherein the emulsifier sta hydrophilic phase provided, after ingestion, by physiological 55 bilizer is present in a small but sufficient amount so that the fluid. composition is stable at room temperature and also facilitates U.S. Pat. No. 6,383,471 (Lipocine corp.) also teaches high the dissolution of the drug or nutrient at the target organ fluids ratio surfactants compositions, typically from 30% to 80% environment relative to an appropriate control composition. Surfactant content in “Compositions and methods for In yet another aspect, the invention provides a method for improved delivery of ionizable hydrophobic therapeutic 60 co-administering a low or poor solubility drug dissolved or agents'. Such compositions are not emulsions and no refer dispersed in the composition, whereas majority of drug is not ence to particle size is made. crystalline and do not re-crystallize or only slightly crystal lize upon storage. SUMMARY OF THE INVENTION The Drug 65 Compositions of the present invention are preferred for According to the present invention there is provided a low-solubility drugs having a solubility of less than 10 pharmaceutical or nutritional composition in the form of an mg/mL, more preferred for low-solubility drugs having a US 8,187,615 B2 5 6 solubility of less than 1 mg/mL, and even more preferred for polyphenols, curcumin, epigenin. Anti-inflammatory plant low-solubility drugs having a solubility of less than 0.1 extracts Such as aloe Vera, echinacea and chamomile hamma mg/mL. melis extracts, anti-psoriatic Such as chinese Zizipus jujuba. The meaning of “low-solubility drug is that the drug may Astringents such as hammamelis antibacterial Such as arte be either “substantially water-insoluble,” which means that misia, chamomile, golden Seal. Immune modulators such as the drug has a minimum aqueous solubility at physiologically echinacea, anti-aging or anti-cancer or anti-photo damage, relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL, “sparingly anti-inflammatory such as feverfew parthenolides, rejuvena water-soluble that is, has an aqueous solubility up to about tion agents, carotenoids, beta-carotene, lycopene, astaxan 1 to 2 mg/mL, or even low to moderate aqueous-Solubility, thons, lutein, tocopheryl and retinol. having an aqueous-solubility from about 1 mg/mL to as high 10 Coronary drugs: including vasodilators such as nitroglyc as about 20 to 40 mg/mL. erin, dinitrate, Calcium-antagonists such as Vera The term “drug or “pharmacologically active agent” or pamile, nifedipine and diltiazem, Cardiac-glycosides such as “bioactive agent as used herein is intended to mean a com digoxine. Analgesics: eg. morphine, buprenorphine, etc.; pound or composition of matter which, when administered to Local anaesthetics: eg. lidocaine, etc.; an organism (human or animal) induces a desired pharmaco 15 Example of cholesterol and lowering drug: logical and/or physiologic effect by local and/or systemic fenofibrate, lovastatin, simvastatin, pravastatin, fluvastatin, action. In general, the terms include the therapeutic or pro atorvastatin, or cerivastatin. phylactic agents in all major therapeutic or prophylactic areas Anxiolytics, sedatives & hypnotics: diazepam, of medicine. A bioactive agent may be a phyto-chemical, nitrazepam, flurazepam, estazolam, flunitrazepam, triaz drug, nutrition agent, Vitamin, peptide, oligonucleotide or olam, alprazolam, midazolam, temazepam, lormetazepam, liposaccharide or combinations thereof. brotizolam, clobazam, clonazepam, lorazepam, oxazepam, Preferred classes of drugs include, but are not limited to, buspirone, etc.; Migraine relieving agents: Sumatriptan, antihypertensives, antianxiety agents, anticlotting agents, ergotamines and derivatives etc.; Drugs against motion sick anticonvulsants, blood glucose-lowering agents, deconges ness: eg. cinnarizine, anti-histamines, etc.; Anti-emetics: eg. tants, antihistamines, antitussives, antineoplastics, beta 25 ondansetron, tropisetron, granisetrone, metoclopramide, etc. blockers, anti-inflammatories, antipsychotic agents, cogni Others: such as disulfuram, vitamin K, etc. tive enhancers, anti-atherosclerotic agents, cholesterol-re Examples of chemotherapeutics agents include but are not ducing agents, antiobesity agents, autoimmune disorder limited to cisplatin (CDDP), procarbazine, mechlorethamine, agents, anti-impotence agents, antibacterial and antifungal cyclophosphamide, camptothecin, ifosfamide, melphalan, agents, hypnotic agents, anti-Parkinsonism agents, anti 30 chlorambucil, bisulfan, nitroSurea, dactinomycin, daunorubi Alzheimer's disease agents, antibiotics, anti-depressants, cin, doxorubicin, bleomycin, plicomycin, mitomycin, etopo antiviral agents, glycogen phosphorylase inhibitors, and cho side (VP16), tamoxifen, taxol, transplatinum, 5-fluorouracil, lesterol transfer protein inhibitors. Vincristin, vinblastin and methotrexate or any analog or The present invention is useful with any drug capable of derivative variant thereof. being formulated as an amorphous drug. The term "drug is 35 Example of antibiotics drugs: Tetracyclines such as tetra conventional, denoting a compound having beneficial pro cycline, doxycycline, oxytetracycline, chloramphenicol etc.; phylactic and/or therapeutic properties when administered to Macrollides Such as erythromycin and derivatives, etc.; Anti an animal, especially humans. The drug does not need to be a virals: Such as acyclovir, idoxuridine, tromantadine etc.; Anti low-solubility drug in order to benefit from this invention, mycotics: Miconazole, ketoconazole, fluconazole, itracona although low-solubility drugs represent a preferred class for 40 Zole, econazole, terconazole, griseofulvin, and polyenes Such use with the invention. Even a drug that nonetheless exhibits as amphotericin B or nystatine etc.; Anti-amoebics: Metron appreciable solubility in the desired environment of use can idazole, metronidazole benzoate and tinidazole etc.; Anti-in benefit from the increased solubility/bioavailability made flammatory drugs: steroids or NSAID's such as indometha possible by this invention if the formulation and administra cin, ibuprofen, piroxicam, diclofenac etc.; Anti-allergics: tion in the presented carrier can reduce the size of the dose 45 Disodium cromoglycate etc., Immunosuppressive agents: needed for therapeutic efficacy or increase the rate of drug cyclosporins etc.; absorption in cases where a rapid onset of the drug's effec Antimicrobial agents that may be used include but are not tiveness is desired. limited to naficillin, oxacillin, Vancomycin, clindamycin, The active agent may be any agent that is traditionally used erythromycin, trimethoprim-Sulphamethoxazole, rifampin, as a medicament and lends itself to being administered 50 ciprofloxacin, broad spectrum penicillin, amoxicillin, gen through the oral cavity. Such active agents may be vitamins, tamicin, ceftriaZOXone, cefotaxime, chloramphenicol, clavu chemotherapeutics; antimycotics; oral contraceptives, nico nate, Sulbactam, probenecid, doxycycline, spectinomycin, tine or nicotine replacementagents, minerals, analgesics, ant cefixime, penicillin G, minocycline, ..beta.-lactamase inhibi acids, muscle relaxants, antihistamines, decongestants, anes tors; meZiocillin, piperacillin, aztreonam, norfloxacin, trime thetics, antitussives, diuretics, anti-inflammatories, 55 thoprim, ceftazidime, ceftriaxone and dapsone. antibiotics, antivirals, psychotherapeutic agents, anti-dia Antifungal agents that may be delivered include but are not betic agents and cardiovascular agents, nutraceuticals and limited to ketoconazole, fluconazole, nystatin, itraconazole, nutritional Supplements. clomitrazole, and amphotericin B. Antiviral agents that may Vitamins and co-enzymes that may be delivered using this be used include but are not limited to acyclovir, trifluridine, invention include but are not limited to water or soluble 60 idoxorudine, foscarnet, ganciclovir, Zidovudine, dideoxycy Vitamins such as thiamin, riboflavin, nicotinic acid, pyridox tosine, dideoxyinosine, stavudine, famciclovir, didanosine, ine, pantothenic acid, biotin, flavin, choline, inositol and Zalcitabine, rifimantadine, and cytokines. paraminobenzoic acid, carnitine, Vitamin C, Vitamin D and its Antihistamines are represented by but are not limited to analogs, vitamin A and the carotenoids, retinoic acid, vitamin cimetidine, ranitidine, diphenydramine, prylamine, promet E and vitamin K and Coenzyme Q10. 65 hazine, chlorpheniramine, chlorcyclizine, terfenadine, carbi Example of botanical bioactive agents, are: polyphenols, noxamine maleate, clemastine fumarate, diphenhydramine isoflavones, resveratrol, Soy isoflavones, grape seed extract hydrochloride, dimenhydrinate, prilamine maleate, tripelen US 8,187,615 B2 7 8 namine hydrochloride, tripelennamine citrate, chlorphe Semi-Solidor Viscous Liquid Drug-Containing Composition niramine maleate, brompheniramine maleate, hydroxy Zine The drug is present in the composition in a molecular pamoate, hydroxyZine hydrochloride, cyclizine lactate, dispersion comprising a low-solubility drug and a semi-solid cyclizine hydrochloride, meclizine hydrochloride, acrivas matrix. At least a major portion of the drug in the dispersion is amorphous. The term “a major portion of the drug means tine, cetirizine hydrochloride, astemizole, levocabastine that at least 60% of the drug is in amorphous form, rather than hydrochloride, and loratadine. a crystalline form. Preferably, the drug in the dispersion is Decongestants and antitussives include agents such as dex Substantially amorphous. As used herein, “substantially tromethorphan, levopropoxyphene napsylate, noscapine, car amorphous' means that the amount of the drug in amorphous betapentane, caramiphen, chlophedianol, pseudoephedrine form is at least 80%. More preferably, the drug in the disper hydrochloride, diphenhydramine, glaucine, pholcodine, and 10 sion is “almost completely amorphous' meaning that the benzonatate. amount of drug in the amorphous form is at least 90% as Anesthetics include etomidate, ketamine, propofol, and measured by X-ray diffraction or differential scanning calo benodiazapines (e.g., chlordiazepoxide, diazepam, cloreze rimetry (DSC), or any other standard quantitative measure pate, halazepam, flurazepam, quazepam, estazolam, triaz ment. 15 The amorphous bioactive agent exists in the semi-solid or olam, alproZolm, midazolam, temazepam, oxazepam, Viscous liquid drug/matrix as a solution or Solid solution or lorazepam), benzocaine, dyclonine, bupivacaine, etidocaine, co-precipitate, where the drug is homogeneously distributed lidocaine, mepivacaine, promoxine, prilocalne, procaine, through the dispersion or a portion of the drug may exist in proparcaine, ropivacaine, tetracaine. Other useful agents may relatively drug-rich domains. Preferably, the dispersion is include amobartital, aprobarbital, butabarbital, butalbital Substantially homogeneous so that the amorphous drug is mephobarbital, methohexital, pentobarbital, phenobarbital, dispersed as homogeneously as possible throughout the dis secobarbital, thiopental, paral, chloral hydrate, ethchlor persion. As used herein, “substantially homogeneous' means Vynol, clutethimide, methprylon, ethinamate, and mep that the amount of the drug presents in drug-rich amorphous robamate. domains within the dispersion is less than 20%. Preferably, Analgesics, include opioids such as morphine, mepidine, 25 the dispersion is "completely homogeneous.” meaning that dentanyl, Sufentranil, alfentanil, aspirin, acetaminophen, ibu the amount of drug in drug-rich domains is less than 10%. profen, indomethacine, naproxen, atrin, isocome, midrin, An amorphous compound has a higher energy level than a aXotal, firinal, phrenilin, ergot and ergot derivatives crystalline compound; therefore, a solid will be more soluble (wigraine, cafergot, ergostat, ergomar, dihydroergotamine), in the amorphous state than in the crystalline State. Improved imitrex. 30 solubility will lead to rapid and more complete dissolution, and in the case of a poorly soluble drug Substance, improved Diuretics include but are not limited to acetazolamide, bioavailability. dichlorphenamide, methazolamide, furosemide, bumetanide, The Oily Solvent Comprising the Internal Phase ethacrynic acid torSeimde, azosemide, muZolimine, piret Oily solvent is any pharmaceutical or food approved Sub anide, tripamide, bendroflumethiazide, benzthiazide, chlo 35 stance which is oily in its nature that is not mixing or dissolv rothiazide, hydrochlorothiazide, hydroflumethiazide, methy ing with water or hydrous mediums. Such oily solvent may be clothiazide, polythiazide, trichlormethiazide, indapamide, natural or synthetic or semi-synthetic, in the form of liquid, metolaZone, quinethaZone, amiloride, triamterene, Spriono semi-solid or Solid at room temperature. lactone, canrenone, and potassium canrenoate. Example of oily solvents are mineral oil, vegetable oil, Anti-inflammatories include but are not limited to salicylic 40 silicon oil, lanolin, refined animal oil, hydrocarbon acid derivatives (e.g. aspirin) paraminophenol derivative (e.g. derived from vegetable animal or marine origin. acetaminophen) indole and indene acetic acids (indometha Example of vegetable oils are: isopropyl miristate, jojoba cin, Sulindac and etodallac) heteroaryl acetic acids (tolmetin oil, almond oil, avocado oil, , capric-caprylic tryg diclofenac and ketorolac) aryl derivatives (ibu lyceride of fractionated coconut oil, nutmeg oil, castor oil, profen, naproxen, ketoprofen, fenopren, oxaprozine), anthra 45 olive oil and , soybean oil, Sunflower oil, canola oil nilic acids (mefenamic acid, meclofenamic acid) enolic acids etc. The oil may be saponifiable or unsaponifiable and liquid (piroXicam, tenoxicam, phenylbutaZone and oxyphenthatra or solid at room temperature. Zone). Special oils are essential oils or polyunsaturated fatty acid Psychotherapeutic agents include thorazine, Serentil, mel or oils or etherified oils and modified semi-synthetic oils. laril, millazine, tindal, permitil, prolixin, trilafon, Stelazine, 50 Example of semi-synthetic oil is a product of inter-esterifica Suprazine, taractan, navan, cloZaril, haldol, halperon, loxi tion of hydrogenated palm oil (Cs-Cs trig tane, moban, orap, risperdal, alprazolam, chlordiaepoxide, lycerides) with at 30° C.-50° C. clonezepam, clorezepate, diazepam, halazepam, lorazepam, A further preferred class of hydrophobic solvents may be oxazepam, prazepam, buspirone, elvavil, anafranil, adapin, selected from the groupf comprising isostearic acid deriva Sinequan, tofranil, Surmontil, asendin, norpramin, pertofrane, 55 tives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, ludiomil, pamelor, Vivactil, prozac, luvox, paxil, Zoloft, maleated Soybean oil, octyl palmitate, isopropyl isostearate, effexor, wellbutrin, serZone, desyrel, nardil, parnate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated eldepryl. lanolin alcohol, cetyl acetate, glyceryl oleate, tocopheryl Cardiovascular agents include but are not limited to nitro linoleate, wheat germ , arachidyl propionate, myri glycerin, isosorbide dinitrate, Sodium nitroprisside, captopril, 60 styl lactate, isopropyl palmitate, decyl oleate, propylene gly enalapril, enalaprilat, quinapril, lisinopril, ramipril, losartan, col ricinoleate, isopropyllanolate, pentaerythrityl tetrastear aminone, lirinone, Vesnerinone, hydralazine, nicorandil, pro ate, neopentylglycol dicaprylate/dicaprate, hydrogenated Zasin, doxazosin, bunaZosin, tamulosin, yohimbine, pro coco-glycerides, isononyl isononanoate, isotridecyl panolol, metoprolol, nadolol, atenolol, timolol, esmolol, pin isononanoate, myristal myristate, isocetyl Stearate and isoa dolol, acebutolol, labetalol, phentolamine, carvedilol, 65 dipate. bucindolol, Verapamil, nifedipine, amlodipine and dob A further class are fatty acids include, but are not limited to, utamine. , , , oleic acid, palmoic US 8,187,615 B2 10 acid, , , octanoic acid, decanoic acid, out use of polyoxyethylene derivative surfactants and without linolenic acid, , , , use of blends surfactants (complex emulgators) required to , and lignic acid, or fatty alcohols, obtain “Self Emulsifying Delivery Systems’. and also mono and . The Continuous Non-Hydrous and Hydrophilic Phase The Emulsifying Stabilizer 5 The continuous non-hydrous and hydrophilic phase is The emulsifying stabilizer is any Surface active agent of made of organic solvents that are completely and immedi pharmaceutical cosmetic or food grade that has an ately miscible with water and physiological fluids amphiphilic nature and that is able to stabilize the emulsion. Preferred pharmaceutically acceptable water-miscible The surfactant can by hydrophilic, hydrophobic, or a mixture non-aqueous solvents suitable for use in the non-aqueous of hydrophilic and hydrophobic surfactants. 10 compositions of this invention include, but are not limited to, Examples are Polyethoxylated Fatty Acids, PEG-Fatty glycols such as propylene glycol and glycerin, polyethylene Acid Diesters, EG-Fatty Acid Mono- and Di-ester Mixtures, glycols of various molecular weights and the like and their Polyethylene Glycol Glycerol Fatty Acid Esters, Alcohol-Oil mixtures. Transesterification Products, Polyglycerized Fatty Acids, Less preferable are organic solvents that are only moder Propylene Glycol Fatty Acid Esters, Mixtures of Propylene 15 ately or partially miscible with water. Glycol Esters-Glycerol Esters, Mono- and Diglycerides, Ste Example of other preferred solvents and possible co-sol rol and Sterol Derivatives, Polyethylene Glycol Sorbitan vents are: polyols or amides or esters, butanediols and iso Fatty Acid Esters, Polyethylene Glycol Alkyl Ethers, Sugar mers thereof, pentaerythritol, sorbitol, mannitol, dimethyl Esters, Polyethylene Glycol Alkyl Phenols, Polyoxyethyl isosorbide, polypropylene glycol, ethers of polyethylene gly ene-Polyoxypropylene Block Copolymers, Sorbitan Fatty cols having an average molecular weight of about 200 to Acid Esters, Ionic Surfactants. about 6000, such as tetrahydrofurfuryl alcohol PEG or meth Preferred stabilizing emulsifiers are non-ionic and PEG oxy PEG, Amides, such as 2-pyrrolidone, 2-piperidone, e-ca free Surface active agents, such as: non ionic condensate of a prolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, carbohydrate and fatty acid, Such as; Sucrose esters of fatty N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide; acids and Glucosides offatty acids and Sorbitan esters offatty 25 Esters, such as ethyl propionate, tributylcitrate, acetyl trieth acids, various esters of mono- and diglycerides of fatty acids ylcitrate, acetyl tributyl citrate, triethylcitrate, ethylbutyrate, and Sucroglycerides, Ascorbic acid esters, Glycerin esters, , propylene glycol diacetate, .epsilon.-caprolactone cetearyl glucosides, Polyacids carbohydrate esters of fatty and isomers thereof, delta.-Valerolactone and isomers acids, Citric acid esters offatty acids, and the colloidal gums thereof, beta.-butyrolactone and isomers thereof; and other and the like. 30 solubilizers known in the art, such as dimethyl acetamide, Further examples of preferred emulsifying stabilizers are dimethyl isosorbide, N-methylpyrrolidones, transcutol. Mix polyglyceryl fatty acids esters such as Polyglyceryl-10-fatty tures and any combination of above solvents are most pref acid, for example: Polyglyceryl-10-tetralinoleate or Polyg erable. lyceryl-10-oleate or Polyglyceryl-10-stearate or Polyglyc Excipients and Additives eryl-10-laurate. 35 The oily solvent in non-hydrous emulsion composition Further examples of preferred emulsifying stabilizers are may further comprise excipients or inactive ingredients or amphiphylic polymers such cellulose derivatives (methylcel additives, such as stabilizers, colorants, polymers, antioxi lulose, hydroxylpropyl cellulose, hydroxylpropyl methyl cel dants, flavoring and fragrance, neutralizing agents and fillers. lulose, ethyl cellulose), and acrylate derivatives such as The term “polymeric' is used conventionally, meaning a Pemulene(R) types from BFGoodrich USA. Also colloidal 40 compound that is made of monomers connected together to silica or natural gums such as, Xanthan gum and microcrys form a larger molecule. A polymeric component generally talline cellulose and microcrystalline cellulose blends with consists of at least about 20 monomers. Thus, the molecular Sodium carboxymethylcellulose are practical emulsifiers sta weight of a polymeric component will generally be about bilizing agents. 2000 daltons or more. Polymeric matrix components gener Preferred Sucrose esters are Sucrose Stearate and Sucrose 45 ally will result in dispersions with improved concentration palmitate (Sisterna SP50 and SP50C or Sisterna SP70) that enhancement relative to non-polymeric matrix components. are blends with free mono esters. Preferred HLB of surfac Exemplary polymeric components for use as the additives tants emulsifying stabilizers is 6 to 18 and more preferably 10 include polyethylene glycols, polyoxyethylene glycols, poly to 15. ethylene-propylene glycol copolymers, polyethylene oxides, Low Surfactant Ratio 50 polyvinyl pyrrolidinone (also referred to as polyvinyl pyrroli It has been found that low concentration of emulsifier done or povidone or PVP), polyvinyl alcohol, polyethylene stabilizer is practically applied to obtain required shelf life vinyl alcohol copolymers, polyvinyl alcohol polyvinyl stability and obtain and maintain below one micron mean acetate copolymers, Xanthan gum, carrageenan, pullulan, particle size. Typical low surfactant ration is below 20%, Zein, hydroxypropyl cellulose, hydroxypropyl methyl cellu preferably below 10% and more preferably below 5% and 55 lose, carboxy methyl cellulose, -functional more preferably from 1% to 5%. ized polymethacrylates, amine-functionalized poly In contrast to significant load of surfactants in “Self Emul methacrylates, chitosan, chitin, polydextrose, dextrin and sifying Delivery Systems, in the range of 20% to 50%, it has starch. Also included within this definition are high molecular been unexpectedly discovered that low surfactant ration com weight proteins such as gelatin and albumin. positions maintain Sub-micron or nano-size mean oil globules 60 The polymers may be bioadhesive polymers coating, posi size when diluted with physiological fluids such as gas tively charged polymers, or matrix forming for slow release trointestinal content or simulated content. The nano-size polymers. The present composition may be further entrapped mean globule diameter is maintained for the period relevant in such bioarodible matrix for slow release or bioadhesive or for physiological drug absorption and for the relevant pH and charged polymers physiological conditions of gastro intestine system. 65 Dosage Forms Also, it has been discovered, that it is possible to obtain The resulting composition of current invention, compris nano-size droplets following dilution with body fluids with ing the low solubility bioactive agent, may be dosed directly US 8,187,615 B2 11 12 for oral administration, diluted into an appropriate vehicle for cooled to ambient temperature. Preferred examples are glyc oral administration, filled into capsules, or delivered by some erin, polyethylene glycols such as Macrogol-1500 or mix other means obvious to those skilled in the art. The compo tures of liquid and solid Macrogols to obtain desired sition may be liquid or semi-solid at room temperature and profile, for example: liquid Macrogol-600 with solid Mac liquid or semi-solid at elevated temperature Such as body 5 rogol-4000. Selective mixtures of Macrogols will also affect temperature. drug release kinetics and it is a tool by the hand of skill in the Preferred consistency of the composition is viscous liquid art to influence dissolution rate and pharmacokinetics. or semi-solid at room temperature, with viscosity of at least Low viscosity non-aqueous solvents will preferably be 1,000 cps and preferably above 5,000 cps. Preferred consis mixed with Solidifying agents such as gelling agents to obtain tency is plastic or pseudo-plastic more preferably with no or 10 low yield value. desired viscosity and semi-solid state of final product. Preferred dosage forms are soft gelatin capsule or hard In a preferred embodiment, the process of producing the Vegetable capsules. More preferable are vegetable caps made non aqueous emulsion composition is by co-melting the of vegetable origin polymers instead of animal origin gelatin hydrophobic drug with oily solvent and emulsifying stabi caps. Dosage forms may be coated or enteric-coated and 15 lizer and co-solubilizer where needed, until clear solution is shaped into many sizes and shapes. obtained. The clear Solution is examined under light micro The delivery system of the present invention results in Scope for absence of crystals or Solid distinct areas. The facilitated solubilization and can be used to improve the oral hydrophilic non-aqueous external phase composition is bioavailability and solubility of said bioactive agent, or for heated to 90° C.-100° C. and slowly added under vigorous safe systemic administration of difficult to formulate drugs. mixing to the hot oil phase and removed from heat Source and Preferred injectable dosage form is produced sterile in vial for cooled. The homogenization is performed while mixture is dilution before use and is passed through 5 or 2 micron filter liquid and before and until Solidifying while cooling to room in line of infusion device. temperature. The semi-solid composition is also suitable for topical Emulsification equipment for producing oil in nonhydrous application of dermatological or cosmetic bioactive agents 25 emulsions does not differ from the equipment used for pre that tend to crystallize upon storage and hence, loose activity. paring emulsions, lotions or dispersion system in the phar Stabilizing low solubility topical drugs in a solubilized state maceutical or cosmetic industry and is typically, mixers, in the semi-solid matrix enables preserving drug activity upon homogenizers, colloidal mills, pressure homogenizers, rotary storage or increase drug absorption over its crystalline state. blenders, etc. Special equipment such as micro-fluidizer or Preparation of Compositions 30 high pressure homogenizer may be used. The current invention, non-aqueous nano delivery system In preferred embodiments of the present invention the fol production process involves two basic consecutive steps; the lowing quantities are preferable: first is the preparing the oily solvent phase comprising the a) Said oily solvent is present in an amount ranging from bioactive agent by solubilizing or dissolving a liquid or Solid about 1-40 wit/wt %, more preferable from 2-20 wit/wt %; and drug in the oily solvent phase until homogeneity is obtained, 35 b) said emulsifying stabilizer is present in an amount rang and the second step is the emulsification and homogenizing ing from about 0.1-20 wit/wt %, or from about 0.1-5 wt/wt %; process of the oil phase with the hydrophilic and non-aqueous and phase. c) said low or poor water insoluble bioactive component is Bioactive agents with high melting point are co-melted in present in an amount ranging from about 0.1-20 wit/wt %. the oily solvent alone or with solubilizing agents, the emul 40 A preferred embodiment of the present invention is the Sifying stabilizer or co-solvents on warm water or on hot oil following process for producing homogeneous amorphous bath when above 100° C. is required. First step in the produc dispersion of hydrophobic drug in non-aqueous nano size tion of nano non-aqueous emulsion of the present invention is droplets semi-solid emulsion; selection of appropriate oily solvent to dissolve the hydro A—Heating and co-melting the drug and selected oils and phobic drug. Selection of various co-solvents and emulsify 45 emulsifying stabilizers until clear solution devoid of ing stabilizer is also a part of the oily solvent phase production solid material is obtained. and hydrophobic drug incorporation in a molecular uniform B—Heating non-aqueous hydrophilic phase to 80° dissolved state. C-100° C. Alternatively, the bioactive agent is dissolved with the oily C Adding the hot non-aqueous phase (B) to hot oily Solvent in a Suitable organic solvent and organic solvent is 50 phase (A) in increments under stirring and mixing. evaporated and mixture is emulsified in the non-aqueous sol D—Homogenizing the emulsion (C) until the hot liquids vent with the aid of the emulsifying stabilizer. Heating and cools into semi-solid state. temperatures are a consequence of used oily solvent and The composition is suitable for filling in Soft gelatin cap emulsifying stabilizer composition. It is necessary to co melt Sules and selected vegetable capsules and filling process is the ingredients and heat different phase. However, it is also 55 preferably performed while composition is soft, not cooled to possible to heat only one phase, internal or external, as well as room temperature. applying modern cold emulsification methods. Many hydro In a most preferred embodiment said emulsifying stabilizer phobic drugs with high melting point, such as above 200°C., is biodegradable (i.e., degradable in the human body and the are lending themselves to co-melt with well selected oily environment) and is substantially free of polyoxyethylene solvent mixture at much lower temperature relative to their 60 and does not inhibit lipolysis and is preferably of botanical melting point. origin. The bioactive agent is dissolved in the oily solvent mixture In an even further preferred embodiment of the present is added and vigorously mixed into the non-hydrous and invention said non-aqueous solvent constitutes a continuous hydrophilic solvents and selected emulsifying stabilizer. phase of said emulsion and a minor portion of water is The non-aqueous and hydrophilic phase is composed of 65 included in said phase. Such ingredients that are viscous liquid at the time of emul In a preferred aspect of the invention, the combination of an sification and preferably of much increased viscosity when oil-in-non-hydrous solvent forms an emulsion that facilitates US 8,187,615 B2 13 14 the dispersion and dissolution of a water insoluble bioactive Viscosity forming agents, such as, carbomers, carbopol, cel component or drug, in a biocompatible, safe and convenient lulose derivatives or natural gums, such as Xanthan gum or dosage form. colloidal fumed silica. Also, non Newtonian characteristics As will be realized, the present invention provides an emul are easily achieved by the same additives. sion which is produced alcohol and/or water free, has a pro 5 Oil-in-anhydrous solvent emulsions are suitable for use in longed shelf life and improved heat stability for withstanding humans and animals, oral, rectal, vaginal, topical, and trans elevated temperatures during a long period of time. Further dermal applications. I.V., I.M. S.C. or other form of injection more, the oil-in-anhydrous solvent emulsion resists Sub-Zero is possible following preparative dilution step, before the temperatures; it is stable upon freezing and does not break at administration, with physiological fluid Such as Saline or minus 20°C. Thaw of oil-in-non-hydrous emulsions is simple 10 and does not affect original properties. Sucrose sterile solution, to obtain physiologically acceptable Oil-in-anhydrous solvent emulsions are easily prepared. It sterile and isotonic product. is possible, to produce coarse oil-in-anhydrous solvent emul The invention is thus, in one embodiment, a method for sions of 5 to 10 microns droplet size with simple stirring and facilitating the magnitude or rate of absorption of a pharma without resort to the use of high shear mixers. It is also easy 15 cologically active agent through the gastro intestinal mucous, to control droplet size by the utilization of appropriate mixing wherein the method involves co-administration of the equipment and energy input. Fine oil-in-anhydrous solvent selected agent in a solubilization enhancer composition com emulsions, having a mean droplet size of below one micron, prising oil in anhydrous solvent emulsion. are achieved with a conventional homogenizer or “Silverson' Mixing with Physiological Fluids type mixer at moderate to high speed and a short duration of Dilution of said composition in simulated gastric or intes mixing. High shear homogenizer mixing is Sufficient to tinal fluids result in fast and complete dispersion and oil-in obtain emulsions containing 0.5 to 1 microns mean droplets water type emulsion is obtained with mean droplet size below size, consequent high pressure homogenization produces 0.5 one micron, and hazy translucent appearance. Dissolution to 0.1 mean particle size. Mean droplet size depends also on testas described in USP may reveal much faster and complete specific formula and selection of emulsification equipment is 25 dissolution; however there is no real solubility of the low done by skill in the art. solubility drug in the medium, but solubilization. No crystals Oil-in-anhydrous solvent emulsions may be prepared in are observed under light microscope for a period sufficient for various hot or cold methods. In hot method, the oily and drug absorption. anhydrous solvent phases are heated separately to 80°C. until Dilution of said composition with isotonic aqueous sterile all ingredients melt and are well dissolved. The phases are 30 combined while mixing. Mixing may be performed with any Solution for injection, available in clinics and hospital, also mixer, blender, homogenizer, etc. which is used for producing results in sub micron type oil in water product that is safe for emulsions. Oil-in-non-hydrous emulsions may also be pre parental I.V. administration. It is possible to dilute said com pared by heating all the ingredients, including oil, non-hy position in a simple setup and obtain non hemolytic formula drous solvent and emulsifying stabilizers in a single batch, 35 due to is-tonicity and very low Surfactants concentration in heating to achieve melting of solids and with continued mix said composition and much lower following dilution. ing to promote emulsification until cooled to room tempera Terminology ture. Mean droplet size below one micron or “sub-micron’ or The bioactive agent is co-melted in the oily phase. The oily "nano-size' as is used herein relates to practical mean droplet phase is formulated to specifically dissolve the hydrophobic 40 size in the range of few to 1,000 nanometers. bioactive agent. Method for facilitating the dissolution or The term HLB is an arbitrary scale from 0 to 40 depicting solubilization of the bioactive agent in the oily phase are for the Hydrophilic/Lipophilic Balance of a surfactant. Products example, use of organic solvent such as which is later with low HLB are more oil soluble. High HLB represents evaporated, co-emulsifiers preferably of low HLB, oily co good water solubility. Note that HLB is a numerically calcu Solvents such as fatty esters, isopropyl miristate or isoadipate, 45 lated number based on the surfactants molecular structure. It described above in the oily solvent agents list, phospholipids is not a measured parameter. and/or heating to high temperature for short period. The bio The term anhydrous and non-hydrous and Nonacqueous are active agent or drug may be formulated during and as part of interchangeable and describe a non water or non aqueous the emulsion production or introduced into ready emulsion medium. composition with or without further heating. 50 The term “bioactive agent' is any compound of synthetic If solvent is used, suitable solvents include, for example, or natural origin, drug or nutrient, Small or large molecule that lower alkyl alcohols such as methanol, ethanol, or any other pharmaceutically-acceptable organic solvent in which the exerts beneficial biological activity on mammalian body. low solubility bioactive agent and the oily solvent have appre While the invention will now be described in connection ciable solubility. 55 with certain preferred embodiments in the following Care should be taken to avoid re-crystallization of bioac examples so that aspects thereof may be more fully under tive agents tending for re-crystallization, by adding crystalli stood and appreciated, it is not intended to limit the invention Zation inhibiting agents such as Viscosity modifiers, salts, to these particular embodiments. On the contrary, it is complexion agents such as polymers or co-solvents such as intended to cover all alternatives, modifications and equiva dimethyl isosorbide and others listed above. Inhibition of 60 lents as may be included within the scope of the invention as re-crystallization where needed is tailored for each drug by defined by the appended claims. Thus, the following skill in the art. examples which include preferred embodiments will serve to Typical oil-in-anhydrous solvent emulsions are character illustrate the practice of this invention, it being understood ized by having viscosity of 10,000 to 100,000 centipoise and that the particulars shown are by way of example and for newtonian flow at ambient temperature. Viscosity may be 65 purposes of illustrative discussion of preferred embodiments reduced by the addition of water. The oil-in-anhydrous sol of the present invention only and are presented in the cause of vent emulsion viscosity may be controlled by addition of providing what is believed to be the most useful and readily US 8,187,615 B2 15 16 understood description of formulation procedures as well as Upon dilution with simulated gastric fluids (SGF) or simu of the principles and conceptual aspects of the invention. lated intestinal fluids (SIF) there is obtained oil-in-water emulsion with mean particle size below one micron. EXAMPLES Example 3 Example 1 Lycopene or AStaxanthin Composition Lovastatin or Atrovastatin Composition 10

INGREDIENT % Wiw 15 INGREDIENT % Wiw Lycopene 14.0 Caprylic Capric triglyceride 8.0 Lovastatin 2.0 Triacetin 8.0 Caprylic Capric triglyceride 8.0 Sucrose ester 8.0 Sucrose ester 4.0 Glycerin To 100 Glyceryl monostearate 2.0 Glycerin To 100

25 Example 4 Caprylic/Capric triglyceride (MCT oil) sucrose ester and glyceryl monostearate are heated to 80° C. and co-melted. Lovastatin is added and mixture is heated until co-melted. Coenzyme Q10 Composition Glycerin heated to 80°C. is added and composition is homog enized and cooled to room temperature and filled in hard 30 vegetable caps and evaluated for stability at 40°C. and 5° C. Lovastatin is well solubilized in this composition and no INGREDIENT % Wiw original crystals are observed in the composition following one month storage at 5°C. Coenzyme Q10 1S.O 35 Caprylic Capric triglyceride 8.0 Mean particle size upon dilution and gentle Swirling in Lecithin 8.0 Hydrogenated palm oil hard 4.0 simulated gastric fluids (SGF) or simulated intestinal fluids Sucrose ester 2.O (SIF) is below one micron and remains sub-micron for couple Macrogol 4000 3O.O of hours post dilution. Macrogol 400 To 100 40 Example 2 Coenzyme Q10 is co-melted with Caprylic/Capric triglyc eride, Sucrose ester and Lecithin at 70° C. and Propylene Lycopene or AStaxanthin Composition glycol pre-dispersed with PVP is added and mixture is 45 homogenized until Submicron droplets size is obtained. Example 5

INGREDIENT % Wiw Lycopene 2O.O 50 Indomethacin Composition Caprylic Capric triglyceride 2O.O Sucrose ester S.O Glyceryl monostearate S.O Glycerin To 100 INGREDIENT % Wiw 55 Indomethacin S.O The Lycopene and Sucrose ester are heated on hot oil bath Caprylic Capric triglyceride 1O.O until co-melted and no Lycopene crystals are detected. The Glycryl monostearte 1.O MCT oil is heated to 80° C. and added to Lycopene/sucrose Sucrose ester 4.0 Polyvinyl pyrollidone K90 O.2 ester mixture under vigorous mixing. Mixing is continued 60 Glycerin To 100 until mixture is cooled to 80° C. Glycerin is added under vigorous mixing and composition is cooled to room tempera ture under high shear mixing. Major part of Lycopene, about Indomethacin, Caprylic/Capric triglyceride, Glyceryl 80% is solubilized in the oily phase and major part of the monostearte and Sucrose ester are mixed together and heated Lycopene is amorphousand do not re-crystallize to original 65 until co-melted and emulsified in glycerin mixture and pre typical crystals following six months storage at ambient tem dispersed PVP. Mean particle size of 400 nanometers is perature. obtained. US 8,187,615 B2 17 18 Example 6 low dispersion. Mean droplet size was also reduced below 400 nanometers by means of passing hot composition Benzodiazepine Composition through high pressure homogenizer. Example 9 Ketoconazole or Itraconazole Composition INGREDIENT % ww Benzodiazepine 1.O Caprylic/Capric triglyceride (MCT oil) 8.O 10 Sucrose ester 4.0 Polyvinyl pyrollidone K90 0.4 INGREDIENT % Wiw Macrogol 4000 3S.O Macrogol 400 To 100 Ketoconazole S.O Caprylic Capric triglyceride 1O.O 15 Glyceryl monostarate 2.0 Benzodiazepine is co-melted on oil bath with the MCT oil Sucrose ester 2.0 and Arlacel 481. Other ingredient are mixed and heated sepa Glycerin To 100 rately to 80°C. and added slowly to Hydrocortisone and MCT oil phase under vigorous mixing. Mixture is then homog Vegetable hard capsules regular 00 size, were filled with enized with high shear homogenizer to obtain Sub micron Ketoconazole composition of example 8 and have been found droplet size. stable and retained shape and appearance following 30 days storage in plastic bag at 40°C. and 75 relative humidity. Example 7 Example 10 Nifedipine Composition 25 Ketoconazole or Itraconazole Composition

INGREDIENT % Wiw 30 Nifedipine 6.O INGREDIENT % Wiw Caprylic Capric triglyceride 12.0 Ketoconazole 5.0 Stearic acid 2.0 Caprylic Capric triglyceride 1O.O Pemulene TR2 O.2 Stearic acid 2.0 Triethanolamine O.OS Glyceryl monostarate 2.0 Sorbitan monostearate 2.0 35 Polyglyceryl-10 stearate 2.0 Sorbitan tristearate 2.0 Sorbitan oleate 1.O Macrogol 4000 12.0 Ethyl cellulose 1.O Macrogol 400 To 100 Macrogol 4000 3O.O Propylene glycol To 100 Nifedipine mixture with Caprylic/Capric triglyceride, Stearic acid and sorbitans is heated in microwave oven until 40 co-melted and clear Solution is obtained. All other ingredients Example 11 are mixed and heated on hot plate to 70° C. and added slowly and under vigorous mixing into Nifedipine oil phase. 100 Ketoconazole or Itraconazole Composition grams of emulsion is removed from heat source and homog enizing while cooling with an ultra-turax type high shear 45 homogenizer for one minute. The composition is left to cool slowly at ambient temperature. INGREDIENT % Wiw Example 8 50 Ketoconazole 4.0 Triacetin 6.0 Piroxicam Composition Hydrogenated palm oil 6.0 Sucrose ester 2.O Glycerin To 100

55 INGREDIENT % Wiw Example 12 Piroxicam 1O.O Triacetin 1O.O Tacrolimus or Picrolimus Composition Sucrose ester 2.0 Glyceryl nonostearate 2.0 60 Stearic acid 2.0 Glycerin To 100 INGREDIENT % Wiw

Homogenizing is performed with ultra-turax type high Tacrolimus 4.0 shear homogenizer. Mean droplet size of semi-solid compo 65 Hydrogenated castor oil 6.O sition of example 7 was measured with photon correlation Triacetin 4.0 spectrometry; 600 nanometers mean droplet size and uniform US 8,187,615 B2 20 -continued Mean droplet size is 600 nanometers and Cyclosporin is uniformly dispersed in the composition while majority of Cyclosporin is non-crystalline. INGREDIENT % Wiw

Sucrose ester 2.O Example 16 Propylene glycol 22.0 Chitosan 1.O Cold Process, Principle Base Composition Macrogol 4000 To 100 10

Example 13 INGREDIENT % Wiw 15 A drug 2.0-10.0 Hydrocortisone Composition Caprylic Capric triglyceride 1O.O Pemulene TR2 1.O Polyethylene glycol 400 40.O Glycerin To 100

INGREDIENT % Wiw The preparation of this example composition is made at Hydrocortisone 2.O Caprylic Capric triglyceride 8.0 ambient temperature or optionally mild heating and is pref Triacetin 2.O 25 erably suitable for formulation of heat sensitive bioactive Sucrose ester 4.0 agents, drugs. This composition will also tolerate many co Glycerin 83 solvents such as triacetin or dimethyl isosorbide.

30 Example 17 Example 14 Cyclosporin or Peptide Drug Cold Process Composition Genistein Composition 35

INGREDIENT % Wiw INGREDIENT % Wiw Cyclosporin 2.0 Genistein 1.O 40 Caprylic Capric triglyceride 8.0 Caprylic Capric triglyceride 12.0 Triacetin 4.0 Glyceryl monostearate 2.O Pemulene TR2 1.O Sucrose ester 4.0 Macrogol 400 40.O Glycerin To 100 Glycerin To 100

45 Tri-ethanol-amine or is added to adjust Example 15 the pH of the composition to suite peptide required pH for optimal stability.

Cyclosporin Composition 50 Example 18

Amphotericin Composition INGREDIENT % Wiw 55 Cyclosporin 4.0 Caprylic Capric triglyceride 8.0 Triacetin 4.0 Oleic acid 2.0 INGREDIENT % Wiw Polyglyceryl-10 oleate 2.0 60 Amphotericin A or B 2.0 Sucrose ester 2.0 Caprylic Capric triglyceride 6.O Glycerin To 100 Dimethyl isosorbide 2.0 Lecithin 2.0 Sucrose ester 2.0 Cyclosporin is co-melted with the Caprylic/Capric triglyc Glyceryl monostearate O.S Glycerin To 100 eride, Triacetin, Oleic acid, Polyglyceryl-10 oleate, and 65 Sucrose ester until homogeneous. Hot glycerin is slowly added while mixing and composition is homogenized. US 8,187,615 B2 21 22 Example 19 Example 23

Ceftriaxone Composition Omega 3 Fatty Acids Composition 5

INGREDIENT % Wiw INGREDIENT % Wiw Ceftriaxone 2O.O 10 Caprylic Capric triglyceride S.O Oleic acid S.O EPA + DMA (70% omega-3 Fish oil) 2O.O Glyceryl monostearate 2.O Tocopherol Succinate 2.0 Sucrose ester 2.O Sucrose ester 4.0 Stearic acid S.O Glycerin To 100 15 Hydroxypropylcellulose 2.0 Ethylene Diamine Tetra 0.4 Glycerin To 100 Example 20 2O Griseofulvin Composition Example 24

25 Glibenclamide Composition

INGREDIENT % Wiw

Griseofulvin 1O.O Liquid paraffin 1O.O INGREDIENT % Wiw Lanolin fatty acid ester S.O 30 Hydroxypropylcellulose 4.0 Glibenclamide 2.0 Dimethyl isosorbide To 100 Coconut oil 12.0 Sucrose ester 2.0 Tocopheryllinoleate 2.0 Glycerin To 100 Example 21 35

COX-2 Inhibitor Composition Example 25

40 Etoposide or Taxol Composition

INGREDIENT % Wiw COX-2 inhibitor 1O.O Paraffin wax 1O.O 45 Lanolin fatty acid ester S.O INGREDIENT % Wiw Hydroxypropylcellulose 4.0 Glycerin 40.O Etoposide 1O.O Triacetin 4.0 Dimethyl isosorbide To 100 Tocopheryllinoleate 4.0 Glyceryl monosteararte 2.0 50 Dimethyl isosorbide 2.0 Pemulene TR2 1.O Sucrose ester 2.0 Example 22 Glycerin To 100

Progesteron or Estradiol Composition 55 Etoposide is co-melted on oil bath with Triacetin, Toco pheryl linoleate, Glyceryl monosteararte, Dimethyl isosor bide, and Sucrose ester until homogeneouse liquid is obtained and majority of Etoposide crystals meltas observed with light INGREDIENT % Wiw 60 microscope. Hot glycerin is slowly added under vigorous Progesterone 1.O mixing. Pemulene is sprinkled into the composition under Paraffin wax 1O.O mixing. Composition is homogenized and cooled to room Lanolin fatty acid ester S.O temperature. Composition is filled in capsules. Mean droplet Hydroxypropylcellulose 4.0 Glycerin 40.O size is controlled between 2,000-200 nanometers by magni Dimethyl isosorbide To 100 65 tude of homogenization and equipment selection. Droplet size is preserved upon dilution and mixing with simulated intestinal fluids. US 8,187,615 B2 23 24 Example 26 7. The pharmaceutical or nutritional composition of claim 1, wherein said emulsifying stabilizer is present in an amount Acyclovir or Nucleoside Analogue Composition ranging from about 0.1 to about 5% wt/wt. 8. The pharmaceutical or nutritional composition of claim 1, wherein the emulsifying stabilizer is selected from the group consisting of: (i) non-ionic condensation products of a carbohydrate and a fatty acid, wherein the carbohydrate is Sucrose, glucoside or Sorbitan; (ii) mono- or di-glycerides of INGREDIENT % Wiw fatty acids; (iii) Sucroglycerides; (iv) polyglycerol esters of Acyclovir 1O.O fatty acids; (v) propane-1,2-diol esters offatty acids; and (vi) MCT oil S.O 10 poly acid carbohydrate esters of fatty acids. Sucrose ester S.O 9. The pharmaceutical or nutritional composition of claim Hydroxypropylcellulose 4.0 1, wherein said low solubility bioactive agent is selected from Glycerin 40.O the group consisting of a drug, a peptide or polypeptide, a Dimethyl isosorbide To 100 nucleotide and a glycolipid and has an aqueous solubility of less than 10 mg/ml. Acycloviris dissolved in Dimethyl isosorbide at 50° C. and 15 10. The pharmaceutical or nutritional composition of claim MCT oil and Sucrose esters are added and co-melted at 70° C. 1, wherein the non-hydrous and hydrophilic phase comprises Hydroxypropylcellulose is added to the glycerin and heated a polyalcohol selected from the group consisting of glycerin, to 90° C. and added slowly to the Acyclovir phase with propylene glycol, polyethylene glycol, dimethyl isosorbide, homogenization. Homogenization continues until cooling to and mixtures thereof. room temperature. 11. The pharmaceutical or nutritional composition of claim It will be evident to those skilled in the art that the invention 1, wherein the composition is liquid at temperatures ranging is not limited to the details of the foregoing illustrative from 50° C. to 100° C. and semi-solidat ambient temperature. examples and that the present invention may be embodied in 12. A process for producing the pharmaceutical or nutri other specific forms without departing from the essential tional composition according to claim 1 in the form of a attributes thereof, and it is therefore desired that the present 25 semi-solid emulsion, the process comprising: embodiments and examples be considered in all respects as A) heating and co-melting the bioactive agent, the oily illustrative and not restrictive, reference being made to the Solvent and the emulsifying stabilizer until a clear Solu appended claims, rather than to the foregoing description, and tion devoid of solid material is obtained; all changes which come within the meaning and range of B) heating the non-hydrous hydrophilic solvent to 80° equivalency of the claims are therefore intended to be 30 C-100° C.; embraced therein. C) adding the hot non-hydrous solvent of (B) to the hot oily phase of (A) in increments under stirring and mixing, thus obtaining an emulsion; and What is claimed is: D) homogenizing the emulsion (C) until the hot liquid 1. A pharmaceutical or nutritional composition, in the form cools, thus obtaining the desired semi-solid emulsion. of a stable non-hydrous emulsion dispersion, comprising: 35 a) an originally crystalline hydrophobic bioactive agent, 13. A method for administering an originally crystalline b) an oily solvent; hydrophobic bioactive agent with facilitated dissolution and c) a non-hydrous hydrophilic solvent; and oral availability of the bioactive agent, comprising orally d) an emulsifying stabilizer present in an amount of 0.1 to administering to a patient in need a pharmaceutical or nutri 10% of the emulsion dispersion, tional composition in accordance with claim 1. wherein said bioactive agent is dissolved or dispersed in 40 14. The pharmaceutical composition of claim 1, wherein said oily solvent such that the majority of the bioactive the bioactive agent is a drug. agent is non-crystalline and does not re-crystallize or 15. The pharmaceutical composition of claim 1, wherein at only slightly crystallizes upon storage, wherein said oily least 60% of the drug is in amorphous form. Solvent comprises the internal phase of the emulsion 16. The pharmaceutical composition of claim 15, wherein 45 at least 80% of the drug is in amorphous form. dispersion, and wherein said non-hydrous hydrophilic 17. The pharmaceutical composition of claim 16, wherein Solvent comprises the continuous phase of said emulsion at least 90% of the drug is in amorphous form. dispersion, 18. The pharmaceutical or nutritional composition of claim whereby Sub-micron mean droplet size is obtained upon 9 having an aqueous solubility of less than 1 mg/mL. dilution of the composition with physiological fluids. 19. The pharmaceutical or nutritional composition of claim 2. The pharmaceutical or nutritional composition of claim 50 18 having an aqueous solubility of less than 0.1 mg/mL. 1, wherein facilitated dissolution of the bioactive agent is 20. The pharmaceutical or nutritional composition of claim obtained. 1, wherein the bioactive agent is selected from the group 3. The pharmaceutical or nutritional composition of claim consisting of vitamins, chemotherapeutics, antimycotics, oral 1, wherein facilitated solubilizing effect of the bioactive agent contraceptives, nicotine or nicotine replacementagents, min in physiological fluids is obtained and oily particles retain 55 their size upon dilution with physiological fluids for the time erals, analgesics, antacids, muscle relaxants, antihistamines, needed for systemic absorption. decongestants, anesthetics, antitussives, diuretics, anti-in 4. The pharmaceutical or nutritional composition of claim flammatories, antibiotics, antivirals, anti-amoebics, anti-al 1, wherein at least a major portion of the bioactive agent is lergics, anti-emetics, psychotherapeutic agents, anti-diabetic uniformly and molecularly dispersed in the composition. agents, cardiovascular agents, antimicrobial agents, antifun 60 gal agents, anxiolytics, sedatives, hypnotics, migraine reliev 5. The pharmaceutical or nutritional composition of claim ing agents, immune modulators, rejuvenation agents, astrin 1, wherein said bioactive agent is present in an amount rang gents, coronary drugs, cholesterol and triglyceride lowering ing from about 0.1 to about 40% wit/wt. 6. The pharmaceutical or nutritional composition of claim drugs, drugs against motion sickness, nutraceuticals and 1, wherein said oily solvent is present in an amount ranging nutritional Supplements. from about 1 to about 40% wit/wt. k k k k k