USOO841.4914B2

(12) United States Patent (10) Patent No.: US 8,414.914 B2 Bromley et al. (45) Date of Patent: *Apr. 9, 2013

(54) COMPOSITIONS FOR MIUCOSAL DELVERY (56) References Cited OFAGENTS U.S. PATENT DOCUMENTS (75) Inventors: Philip James Bromley, Fullerton, CA 4,740,365 A 4, 1988 Yukimatsu et al...... 424/435 (US); Lee Nickols Huang, Diamond 4,889,720 A 12, 1989 Konishi et al...... 424/447 4,900,552 A 2f1990 Sanvordeker et all ... 424/422 Bar, CA (US) 4,921,706 A 5/1990 Roberts et al...... 424/450 5,033,252 A 7/1991 Carter ...... 534/25 (73) Assignee: Virun, Inc., Walnut, CA (US) 5,052,558 A 10, 1991 Carter ...... 206,439 5,154,924 A 10, 1992 Friden ...... 424,179.1 (*) Notice: Subject to any disclaimer, the term of this 5,178,878 A 1/1993 Wehling et al...... 424/466 5, 182,107 A 1/1993 Friden ...... 424,85.91 patent is extended or adjusted under 35 5,234,957 A 8, 1993 Mantelle et al. U.S.C. 154(b) by 0 days. 5,298,246 A 3, 1994 Yano et al. 5,323,907 A 6/1994 Kalvelage ...... 206,531 This patent is Subject to a terminal dis 5,527,527 A 6/1996 Friden ...... 424,178.1 claimer. (Continued) (21) Appl. No.: 13/507,928 FOREIGN PATENT DOCUMENTS CA 2229286 8, 1999 (22) Filed: Aug. 6, 2012 WO WO 2006/0098.25 1, 2006 (65) Prior Publication Data (Continued) US 2012/03O8644 A1 Dec. 6, 2012 OTHER PUBLICATIONS U.S. Appl. No. 60/527,962, filed Dec. 8, 2003, Masters et al. Related U.S. Application Data (Continued) (63) Continuation of application No. 12/930,978, filed on Primary Examiner — Anand Desai Jan. 20, 2011, now Pat. No. 8,252,323, which is a Assistant Examiner — Melissa Mercier continuation of application No. 1 1/155,262, filed on (74) Attorney, Agent, or Firm — McKenna Long & Aldridge Jun. 16, 2005, now Pat. No. 7,906, 140. LLP; Stephanie Seidman (60) Provisional application No. 60/580,877, filed on Jun. (57) ABSTRACT 17, 2004. Compositions and methods for mucosal delivery of agents are provided. The compositions are intended for administration (51) Int. C. to mucosal Surface, Such as oral, gastrointestinal and nasal A6 IK38/00 (2006.01) mucosa. The compositions provided contain one or more (52) U.S. C. mucoadhesive proteins and an agent to be delivered. Methods USPC ...... 424/450; 514/1 for delivery of agents using the compositions provided herein (58) Field of Classification Search ...... None are also provided. See application file for complete search history. 24 Claims, 1 Drawing Sheet

Oral insulin - Human G lucose Levels 250

200

10 O

50 i i Time (hrs) US 8,414.914 B2 Page 2

U.S. PATENT DOCUMENTS Ectotropin-6TM Website Printout, found at: www.ibe-technology. 5,620,708 A 4, 1997 Amkraut et al...... 424/491 com/ectotropin.htm retrieved on Jan. 20, 2006). 5,672,683 A 9, 1997 Friden et al. ... 530/350 Fehniger et al., “Exploring the context of the lung proteome within 5,702,727 A 12, 1997 Amkraut et al. ... 424/491 the airway mucosa following allergen challenge. J Proteome Res. 5,744, 155 A 4, 1998 Friedman et al...... 424/434 3(2):307-320 (2004). 5,833,988 A 11/1998 Friden ...... 424,178.1 Good, R., "Surface free energy of solids and liquids: Thermodynam 5,977,307 A 11/1999 Friden et al. ... 530/350 5,993,846 A 11/1999 Friedman et al. .. 424/434 ics, molecular forces, and structure.” Journal of Colloid and Interface 6,071.535 A 6/2000 Hayward et al...... 424/450 Science. 59(3):398-419 (1977). 6,329,508 B1 12/2001 Friden ...... 530,387.3 Gu et al., “Binding of acrylic polymers to mucin/epithelial Surfaces: 6,383,513 B1 5, 2002 Watts et al. . ... 424/450 structure-property relationships.” Critical Reviews in Therapeutic 6.426,362 B1 7/2002 Miller et al. 514,458 Drug Carrier Systems 5(1): 21-67 (1988). 6,475,511 B2 11/2002 Gohlke et al. ... 424/441 Handbook of Pharmaceutical Excipients, “Lecithin.” Published by 6,552,024 B1 4/2003 Chen et al...... 514,252.16 American Pharmaceutical Association: Washington DC and the Phar 6,638,521 B2 10/2003 Dobrozsi et al...... 424/434 6,749,863 B1 6/2004 Chang et al...... 424/450 maceutical Society of Great Britain: London, p. 165 (1986). 6,905,688 B2 6, 2005 Rosen et al. 424,192.1 HexaTropin-6TM Website Printout, found at: www.ibe-technology. 6,926,898 B2 8, 2005 Rosen et al. 424,192.1 com/hexatropin.htm retrieved on Jan. 20, 2006). 6,946,134 B1 9, 2005 Rosen et al. 424,192.1 Lehr et al., “Visualization studies of the mucoadhesive interface.” 6,994,857 B2 2/2006 Rosen et al. 424,192.1 Journal of Controlled Release, 18:249-260 (1992). 7,179,484 B2 2/2007 Singh ...... 424/450 Nogrady, M., Medicinal Chemistry a Biochemical Approach, Oxford 7,906,140 B2 * 3/2011 Bromley et al. 424/450 University Press, New York, pp. 388-392 (1985). 8,252.323 B2 * 8/2012 Bromley et al...... 424/450 8,282,977 B2 10/2012 Bromley ...... 426,72 Oratropin-1TM Website Printout, foundat: www.ibe-technology.com/ 2003/017.0311 A1 9, 2003 Russell .... 424/489 oratropin.htm retrieved on Jan. 20, 2006). 2003/0171259 A1 9/2003 Modi et al...... 514/2 Peppas, N. and P. Burl. "Surface, interfacial and molecular aspects of 2003/0171267 A1 9, 2003 Rosen et al. ... 514/12 polymer bioadhesion on soft tissues,” Journal of Controlled Release, 2003/0219472 A1 11, 2003 Pauletti et al. . 424/449 2:257-275 (1985). 2003/0221201 A1 11/2003 Prior et al...... 800.7 Press Release: “OmegaH2O.R. clear shelf stable Omega-3, CoQ10 2003/0226155 Al 12/2003 Sadeghi et al...... 800.7 2004/0010134 A1 1/2004 Rosen et al. 536,235 and other nonpolar compounds U.S. Appl. No. 12/383.244 approved 2004/OO23334 A1 2/2004 Prior ...... 435/69.7 in Europe and Notice of Allowance in U.S.” Published on Jun. 4. 2004/0037809 A1 2/2004 Quay et al...... 424,856 2012 online Retrieved from:

2010.0041622 A1 2/2010 Bromley et al. 514/52 pages. 2011/01171.84 A1 5/2011 Bromley ... 424/450 Ryan et al. “Immunomodulators and delivery systems for vaccination 2011/0236364 A1 9/2011 Bromley ...... 424/94.1 by mucosal routes' Trends in Biotechnology, 293-304 (2001). 2012fOO16026 A1 1/2012 Bromley ...... 514,560 Simoes et al., “Mechanisms of gene transfer mediated by lipoplexes FOREIGN PATENT DOCUMENTS associated with targeting ligands or pH-sensitive peptides.” Gene Ther. (11): 1798-1807 (1999). WO WO 2009,11715.1 9, 2009 Smart et al., “An in-vitro investigation of mucosa-adhesive materials WO WO 2009,117152 9, 2009 WO WO 2010/OO8475 1, 2010 for use in controlled drug delivery,” J. Pharm. Pharmacol. 36:295-299 WO WO 2010/O19255 2, 2010 (1984). WO WO 2011 119228 9, 2011 Smart et al., “In vitro techiniques for measuring mucoadhesion.” J. Pharm. Pharmacol. 34:70P (1982). OTHER PUBLICATIONS Tabor et al., " Surface forces and surface interactions' Journal of Colloid and Interface Science. 58(1):2-13 (1977). U.S. Appl. No. 60/887,754, filed Feb. 1, 2007, Borowy-Borowski et Virun home Webpage found at www.virun.com accessed on Mar. al. 24, 2011), 59 pages. Almeida et al., “Nasal delivery of vaccines,” Journal of Drug Target Virun Improving Life Through Safe & Effective Oral Delivery found ing, 3:456-467 (1996). at: www.sldeshare.net/virun?virun-improving-life-through-safe-ef Alonso et al., “Biodegradable nanostructures as carriers for fective-oral-delivery accessed on May 11, 2009), 15 pages. transmucosal delivery.” Presented at the 226th ACS National Meet Virun Intricate Science; found at www.slideshare.net/virun?virun ing, New York, NY, Sep. 8, 2003. Abstract. 1 page. intricate-science accessed May 25, 2011, 22 pages. Ansel, H., Introduction to Pharmaceutical Dosage Forms, Fourth Vogelson. C., “Advances in drug delivery systems. Modern Drug Edition, Philadelphia: Lea& Febiger, p. 126 (1985). Discovery, 4(4):59-50.52 (2001). Budavari, et al.(Eds.) The Merck Index, 12th Edition, Whitehouse Wadell, C. "Nasal drug delivery—in vitro studies on factors influ Station, N.J.Merck & Co., pp. THER-1 to THER-28, (1996). encing permeability and implications on absorption.” Acta Drug Delivery Technology, Alkaline Acidic Triggering Effect pam Universitatis Upsaliensis. Comprehensive Summaries of Uppsala phlet, Archimedes Laboratories, Inc., City of Industry, CA, 2 pages, Dissertations from the Faculty of Pharmacy 278. Upsala. ISBN Sep. 2005. 91-554-5449-6 pp. 1-55 (2002). Drug Delivery Technology, Pre-Clinical Abstract, Oral Wright, R., "Companies to watch Nutraceuticals World.” located Pharmacokinetics of MAPED (Mucosa Adhesive Protein Engineered at: www.nutraceuticalsworld.com/articles/2009/06/companies-to Drugs) Bound in Human Recombinant Insulin, Archimedes Labora watch, (2009) accessed on Jun. 4, 2009), 7 pages. tories, Inc., City of Industry, CA, 6 pages, Sep. 2005. Zaghloul et al., “Development, characterization and optimization of Drug Delivery Technology, Undenatured Protein pamphlet, 2 pages, ibuprofen self-emulsifying drug delivery system applying face cen Archimedes Laboratories, Inc., City of Industry, CA, 2 pages, Sep. tered experimental design.” International Journal of Pharmacy and 2005. Technilogy: 3(1): 1674-1693 (2011). US 8,414.914 B2 Page 3

International Search Report, issued Oct. 25, 2005, in connection with Examination Report, issued Sep. 13, 2010, in connection with cor corresponding International Application No. PCT/US2005/021424. responding Indian Patent Application No. 00458/DELNP 2007, 4 4 pages. pageS. Written Opinion, issued Oct. 25, 2005, in connection with corre Response to Office Action, Issued Mar. 1, 2010, in connection with sponding International Application No. PCT/US2005/021424, 7 corresponding Chinese Patent Application No. 200580028061.8, 11 pageS. pageS. Internation Preliminary Report on Patentability, issued Dec. 20. Notice of Allowance, issued Oct. 27, 2010, in connection with U.S. 2006, in connection with corresponding International Application Appl. No. 1 1/155,262, 6 pages. No. PCT/US2005/021424, 14 pages. Office Action, issued Dec. 30, 2010, in connection with Chinese Examination Report, issued Dec. 13, 2007, in connection with cor Application No. 200580028061.8, 6 pages. responding European Patent Application No. 057622409, 7 pages. Instructions for Response to the Office Action, issued Dec. 30, 2010, Response to Examination Report, issued Dec. 13, 2007, in connec in connection with Chinese Application No. 200580028061.8, 21 tion with corresponding European Patent Application No. 05762240. pageS. 9, 9 pages. Foreign Associate Communication, received Jun. 14, 2011, reporting Examination Report, issued Jul. 21, 2008, in connection with corre results of a phone interview with Examiner dated Jun. 14, 2011 and sponding European Patent Application No. 05762240.9, 3 pages. Jun. 17, 2011, in connection with corresponding Chinese Application Office Action and translation, Issued Oct. 17, 2008, in connection No. 200580028061.8, 4 pages. with corresponding Chinese Patent Application No. 200580028061. Instructions for Response to Interview with Examiner, sent Jun. 22. 8, 9 pages. 2011, in connection with Chinese Application No. 200580028061.8. Examination Report, issued Dec. 3, 2008, in connection with corre 10 pages. sponding Canadian Patent Application No. 2.578,709, 2 pages. Foreign Associate Further Communication, received Jul. 1, 2011, in Response to Examination Report, issued Dec. 3, 2008, in connection connection with corresponding Chinese Application No. with corresponding Canadian Patent Application No. 2,578,709, 12 200580028061.8, 8 pages. pageS. Further Instructions for Response to Interview with Examiner, sent Response to Examination Report, issued Jul. 21, 2008, in connection Jul. 6, 2011, in connection with corresponding Chinese Application with corresponding European Patent Application No. 05762240.9, 8 No. 200580028061.8, 3 pages. pageS. Response to Examination Report, issued Jul. 6, 2010, in connection Restriction Requirement, issued Jan. 30, 2009, in connection with with Indian Patent Application No. 458/DELNP/2007, 24 pages. U.S. Appl. No. 1 1/155,262, 14 pages. Notice of Grant and translation, issued Sep. 5, 2011, in connection Response and Instructions for Response to Office Action, issued Oct. with Chinese Application No. 200580028061.8, 4 pages. 17, 2008, in connection with corresponding Chinese Patent Applica Restriction Requirement, issued Dec. 6, 2011, in connection with tion No. 200580028061.8, 9 pages. U.S. Appl. No. 12/930,978, 12 pages. Office Action, issued Jun. 2, 2009, in connection with U.S. Appl. No. Response to Restriction Requirement, issued Dec. 6, 2011, in con 1 1/155,262, 21 pages. nection with U.S. Appl. No. 12/930,978, 7 pages. Notice of Allowance, issued Jul. 23, 2009, in connection with corre Office Action, issuedMar. 1, 2012, in connection with U.S. Appl. No. sponding Canadian Patent Application No. 2.578,709, 2 pages. 12/930,978, 6 pages. Response to Office Action, issued Jun. 2, 2009, in connection with Response to Office Action, issued Mar. 1, 2012, in connection with U.S. Appl. No. 1 1/155,262. 21 pages. U.S. Appl. No. 12/930,978, 7 pages. Office Action, IssuedMar. 1, 2010, in connection with corresponding Notice of Allowance, issued Apr. 20, 2012, in connection with U.S. Chinese Patent Application No. 200580028061.8, 11 pages. Appl. No. 12/930,978, 9 pages. Office Action, issued Mar. 18, 2010, in connection with U.S. Appl. Decision to Grant, issued Jul. 12, 2012, in connection with corre No. 1 1/155,262, 11 pages. sponding European Patent Application No. 05762240.9, 1 page. Response to Office Action, issued Mar. 18, 2010, in connection with U.S. Appl. No. 1 1/155,262, 29 pages. * cited by examiner U.S. Patent Apr. 9, 2013 US 8,414.914 B2

*::::::::

*:::::: .

US 8,414,914 B2 1. 2 COMPOSITIONS FOR MIUCOSAL DELVERY Thus, there continues to be a need for the development of OFAGENTS compositions and methods for convenient delivery of Such Substances to animals, including humans, efficiently. Accord RELATED APPLICATIONS ingly, among the objectives herein, it is an objective to pro vide compositions and methods for convenient delivery of This application is a continuation of now allowed U.S. agents to be delivered to a Subject. application Ser. No. 12/930,978, entitled “COMPOSITIONS FORMUCOSAL DELIVERY OF AGENTS, to Bromley et SUMMARY al., filed Jan. 20, 2011 now U.S. Pat. No. 8,252,323, which is 10 Provided herein are compositions and methods for formu a continuation of U.S. application Ser. No. 1 1/155,262, now lation of the compositions for mucosal delivery and admin U.S. Pat. No. 7,906,140, issued Mar. 15, 2011, entitled istration of agents to animals, including humans. Provided are COMPOSITIONS FOR MUCOSAL DELIVERY OF compositions and methods for administering Substances to AGENTS,” to Bromley et al., filed Jun. 16, 2005, which animals, including humans, employing a carrier that facili claims priority under 35 U.S.C. S 119(e) to U.S. Provisional 15 tates entry of the Substance to the mucosa in a non-specific Application Ser. No. 60/580,877, entitled “COMPOSI a. TIONS FOR MUCOSAL DELIVERY OF AGENTS to The compositions provided herein are stable emulsions of Bromley et al., filed Jun. 17, 2004. The subject matter of these oil in water or water in oil, wherein an agent to be delivered is applications is incorporated by reference herein. dissolved in either the oil phase or the water phase. The This application is related to International PCT application emulsions are typically stabilized by Surface active molecules No. PCT/US2005/021424, filed Jun. 16, 2005. The subject in the emulsion. The surfactant molecules form various matter of PCT application No. PCT/US2005/021424 is incor macro-molecular structures in an emulsion, such as micelles, porated by reference herein. inverse micelles, lipid bilayers (liposomes) and cubosomes. The exact macromolecular structure formed depends on the FIELD 25 relative sizes of the hydrophilic and hydrophobic regions of the surface active molecule. The agent to be delivered can be Provided herein are pharmaceutical compositions for distributed between the hydrophobic and hydrophilic phases delivery of agents. Compositions formulated as emulsions for of an oil-in-water or water-in-oil type emulsion, or can be mucosal delivery are provided. present predominantly in one of the phases. In certain 30 embodiments, the active agent in the emulsion is encapsu BACKGROUND lated in a delivery vehicle Such as a micelle, a liposome or a cubosome or a mixture thereof. Numerous pharmaceutical Substances are available for The compositions provided have a mucoadhesive property administration to animals, including humans, for a variety of whereby the composition, when administered either orally or purposes. These Substances include, for example, therapeutic 35 nasally, adheres to and/or anchors to a Subject's mucous agents, such as drugs; dietary Supplements, such as vitamins; membrane for a period of time sufficient to quantitatively prophylactic agents, such as antigens for use in vaccines; and deliver the agent to be delivered to the subject. The compo diagnostic agents, such as labeled imaging agents. Adminis sitions contain a mucoadhesive Substance that imparts the tration of these Substances can be via a number of routes composition a property of adhering oranchoring to a mucosal including intramuscular, Subcutaneous and oral administra 40 membrane thereby effecting absorption of the agent through tion. Intramuscular or Subcutaneous administration of the the mucosal membrane. Typically, the mucoadhesive protein Substance Suffers from disadvantages: relatively specialized is present in an amount Sufficient to confer mucoadhesive skills are required to administer the pharmaceutical; large property to the composition. Such mucosal absorption allows scale administration can be difficult to perform; it is expen entry of the agent being delivered into the systemic circula sive; and a number of side reactions can occur to the Substance 45 tion without first passing through the liver, and thus alleviates administered. Many antibiotics (i.e., tetracycline and penicil the loss of activity upon passage through the liver. lin), and hormones (i.e., progesterone and estrogen) can be The mucoadhesive substances for use herein include, but administered successfully via the oral route. are not limited to natural or synthetic proteins, polypeptides There are, however, biologically active agents, for example or fragments thereof that have the property of adhering or certain dietary Supplements, drugs, hormones and immuno 50 penetrating into a mucus membrane for a period of time gens, whose efficacy is almost totally lost upon oral admin Sufficient to achieve quantitative delivery of an agent to be istration. Included among those agents that cannot be effec delivered. In certain embodiments, the compositions are tively orally administered are polypeptide agents, such as designed for mucosal delivery of a therapeutically-effective Calcitonin, Erythropoetin, Granulocyte Colony Stimulating amount of a biologically active agent to the Subject. The Factor, Stem Cell Factor, Granulocyte Colony Stimulating 55 mucoadhesive protein is generally dissolved in the water Factor, LHRH analogues, Somatostatin, Insulin, Interferons, phase. In certain embodiments the mucoadhesive protein can Plasminogen Activator Inhibitors and species of DNA and be dissolved in the oil phase. The mucoadhesive protein is RNA. Oral delivery of certain protein and polypeptide drugs typically anchored to polar head groups of the delivery is complicated by the presence of proteolytic digestive vehicles in the emulsion. enzymes in the stomach and intestines. Unprotected proteins, 60 In certain embodiments, the compositions provided herein which are administered orally, are largely degraded by Such are formulated to contact the mucosal membrane from about enzymes before they are able to pass through the enteric wall 5-24 hours or even longer, in some embodiments about 5, 10. and enter blood circulation. To some extent this effect can be 12, 14, 16, 18, 20, 22 or up to 24 hours. In some embodiments, overcome by the administration of extremely large doses of the compositions provided herein are formulated to contact the pharmaceutical agent. This approach, however, is not 65 the mucosal membrane from about 1 minute up to about 180, economically feasible for many pharmaceutical agents and 120, 100, 60, 40, 30, 20, 10, 5, 4, 3, or 2 minutes. In certain may result in undesired side effects. embodiments, the compositions provided herein are formu US 8,414,914 B2 3 4 lated to adhere or penetrate into the mucosal membrane from disorders, such as neural disorders, respiratory disorders, about 5-24 hours or even longer, in some embodiments for immune system disorders, muscular disorders, reproductive about 5, 10, 12, 14, 16, 18, 20, 22 or up to 24 hours. In some disorders, gastrointestinal disorders, pulmonary disorders, embodiments, the compositions provided herein are formu digestive disorders, metabolic disorders, cardiovascular dis lated to adhere or penetrate into the mucosal membrane from orders, renal disorders, proliferative disorders, cancerous dis about 1 minute up to about 180, 120, 100, 60, 40, 30, 20, 10, eases and inflammation. The therapeutics delivered using the 5, 4, 3, or 2 minutes. In other embodiments, the compositions methods provided herein include, but are not limited to anti provided herein are formulated to adhere and penetrate into convulsants, analgesics, antiparkinsons, anti-inflammatories, the mucosal membrane from about 5-24 hours or even longer, calcium antagonists, anesthetics, antimicrobials, antimalari in some embodiments, for about 5, 10, 12, 14, 16, 18, 20, 22 10 als, antiparasitics, antihypertensives, antihistamines, anti or up to 24 hours. In some embodiments, the compositions pyretics, alpha-adrenergicagonists, alpha-blockers, biocides, provided herein are formulated to adhere and penetrate into bactericides, bronchial dilators, beta-adrenergic blocking the mucosal membrane from about 1 minute up to about 180, drugs, contraceptives, cardiovascular drugs, calcium channel 120, 100, 60, 40, 30, 20, 10, 5, 4, 3, or 2 minutes. In certain inhibitors, depressants, diagnostics, diuretics, electrolytes, embodiments, the compositions provided herein are formu 15 enzymes, hypnotics, hormones, hypoglycemics, hyperglyce lated to adhere to the mucosal membrane from about 5-24 mics, muscle contractants, muscle relaxants, neoplastics, gly hours or even longer, in some embodiments for about 5, 10, coproteins, nucleoproteins, lipoproteins, ophthalmics, psy 12, 14, 16, 18, 20, 22 or up to 24 hours. In some embodiments, chic energizers, sedatives, Steroids, sympathomimetics, the compositions provided herein are formulated to adhere to parasympathomimetics, tranquilizers, urinary tract drugs, the mucosal membrane from about 1 minute up to about 180, vaccines, vaginal drugs, vitamins, minerals, nonsteroidal 120, 100, 60, 40, 30, 20, 10, 5, 4, 3, or 2 minutes. In certain anti-inflammatory drugs, angiotensin converting enzymes, embodiments, the compositions provided herein are formu polynucleotides, polypeptides, polysaccharides, and nutri lated to penetrate into the mucosal membrane from about tional Supplements including herbal Supplements. In certain 5-24 hours or even longer, in some embodiments for about 5, embodiments, the methods are for delivery of dietary supple 10, 12, 14, 16, 18, 20, 22 or up to 24 hours. In some embodi 25 ments, including but not limited to vitamins, minerals, hor ments, the compositions are formulated to penetrate into the mones and antioxidants. mucosal membrane from about 1 minute up to about 180, 120, Methods of making the compositions are also provided. 100, 60, 40, 30, 20, 10, 5, 4, 3, or 2 minutes. The compositions provided herein are prepared by mixing an Compositions provided herein can have a wide range of oil phase with a water phase at a mixing speed that does not Viscosities, typically in a range that assists retention of the 30 degrade and disintegrate any of the active ingredients of the composition on a mucosal Surface. Generally, the Viscosity composition. The mixing speed can range from about 100 ranges from an oil like viscosity, honey like viscosity, ketchup RPM up to about 60,000 RPM. The temperature, pressure, like Viscosity, chocolate syrup like Viscosity to peanut butter and pH conditions during the mixing step are maintained so like or butter like viscosity. The viscosity of the compositions that all the components in the oil and water phase are dis can be measured by methods known to those of skill in the art, 35 Solved and the active ingredients are not degraded in any way. including measurement by using a viscometer Such as Brook A Suitable temperature during the mixing step can be deter field LVDV-I+ viscometer and T spindles with a heliopath mined empirically for a particular combination of ingredients adapter. The viscosity of the compositions provided can range in the composition. Typically, the temperature is maintained from 10 cps, 100 cps, 1000 cps, 10,000 cps, 100,000 cps, or at about 100-120° F., in some embodiments at about 115° F. 200,000 cps up to more than 500,000 cps at 72° F. 40 The pressure during the mixing is maintained at about 25 PSI The compositions provided herein are formulated to (pounds per square inch). The pH during the mixing step is a remain stable over a relatively long period of time. For function of the particular mucoadhesive protein and the agent example, the compositions provided herein are stored at room to be delivered in the composition. Typically the pH is basic or temperature, and remain stable for more than 1 day, 1 week, neutral. 1 month and in certain embodiments up to more than 1 year. 45 The compositions can be prepared by mixing the water In certain embodiments, the compositions provided herein phase with an oil phase to form a water-in-oil emulsion. The are delivered to the oral mucosa or nasal mucosa. In certain agent to be delivered can be dissolved in the oil phase or in the embodiments, the compositions are delivered to intestinal water phase. Typically, a mucoadhesive protein is present in COSa. the water phase in an amount Sufficient to confer mucoadhe Also provided herein are methods of using the composi 50 sive property to the composition. In certain embodiments, the tions. In certain embodiments, the methods provided herein compositions adhere oranchor to the mucosal Surface for an are used for delivery of one or more agents to be delivered amount of time sufficient to achieve quantitative delivery of including, but not limited to biologically active agent Such as the agent to be delivered. The compositions provided herein minerals, vitamins, synthetic or natural compounds, pharma can also include one or more Surface active agent, and one or ceutical drugs, nutritional Supplements, herbs, hormones, or 55 more additives, such as a polymer, a cosolvent, an antioxi the like, which when introduced into the body cause a desired dant, an antiseptic, a buffering agent, a chelating agent, a biological response, Such as altering body function at the colorant, a flavorant, an odorant, an osmotic modifier, a pre cellular, tissue or organ level and/or altering cosmetic appear servative, a solubilizer, a tonicifier, a trace element, a visco ance. In certain embodiments, the methods are used to deliver modulator, or a mixture thereof. Such additives are known to a biological agent, wherein the agent is a drug or other phar 60 those of skill in the art and are described herein. maceutical ingredient which suffers significant loss of activ Articles of manufacture, containing packaging material for ity in the lumen of the gastrointestinal tractor in the tissues of a composition for mucosal delivery and administration, a the gastrointestinal tract during absorption process or upon composition for mucosal delivery of biologically active passage through the liver after absorption in the intestinal agents and a label that indicates that the composition is for tract. 65 achieving a desired biological response, such as altering body In certain embodiments, the methods provided herein are function or altering cosmetic appearance. In certain embodi useful for delivery of therapeutics used intreatment of various ments, the articles of manufacture, contain a packaging mate US 8,414,914 B2 5 6 rial, a composition for mucosal delivery of biologically active when applied to a mucosal epithelium adheres to or pen agents and a label that indicates that the composition is useful etrates a Subject's mucous membrane for a period of time for treatment, prevention or amelioration of one or more Sufficient to quantitatively deliver a composition provided symptoms of diseases or disorders contemplated herein. herein to the Subject. The composition can anchor in and/or penetrate into a mucosal Surface. Adhesion of mucoadhesives BRIEF DESCRIPTION OF THE DRAWINGS to a mucous membrane occurs generally, although not neces sarily or exclusively, via secondary chemical bonds. Such as FIG. 1 indicates variance in blood glucose levels in a hydrogenbonding and Vander Waal forces (Taboret al., 1977 human after administration of a composition provided herein J. ColloidInterface Sci. 58:2 and Good 1977 J. ColloidInter for 3 consecutive days. 10 face Sci. 59:398). Parameters, such as mechanical binding to mucous membrane perse or the degree of biological effect of DETAILED DESCRIPTION an agent delivered can be used as a measurement parameter to detect and quantitate mucoadhesion. A. Definitions As used herein, mucoadhesive compositions are viscous Unless defined otherwise, all technical and scientific terms 15 aqueous solutions. Their mucoadhesive (or penetrative) prop used herein have the same meaning as is commonly under erties can be assessed by comparisonto a control composition stood by one of skill in the art to which the invention(s) that does not contain the mucoadhesive protein(s) added to belong. All patents, patent applications, published applica the mucoadhesvie composition. At similar viscosities, the tions and publications, Genbank sequences, websites and emulsion prepared with a mucoadhesive protein or protein other published materials referred to throughout the entire binds to a mucosal Surface more strongly (i.e. more is bound disclosure herein, unless noted otherwise, are incorporated by or penetrates or is delivered) compared to a control emulsion reference in their entirety. In the event that there area plurality without the mucoadhesive protein or protein(s). Such of definitions for terms herein, those in this section prevail. increase in delivery or binding or penetration is at least about Where reference is made to a URL or other such identifier or 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% address, it understood that such identifiers can change and 25 greater mucosal binding than a control emulsion. particular information on the internet can come and go, but As used herein, mucoadhesive proteins refer to any natural equivalent information can be found by searching the inter or synthetic proteins, polypeptides or fragments thereof that net. Reference thereto evidences the availability and public possess the mucoadhesive property. Non-limiting examples dissemination of Such information. of mucoadhesive proteins include mucin proteins and trans As used herein, mucosa or mucus membrane refers to 30 ferrins. In certain embodiments, the protein for use in the epithelial tissue that lines the internal cavities of the body, compositions and methods provided herein is lactoferrin. In such as oral cavity, the respiratory tract, the gastrointestinal certain embodiments, the mucoadhesive protein present in a tract, the lungs, and the genitalia. The mucous membrane or composition provided herein is in an amount Sufficient to mucosa protects the body from foreign matter and pathogens confer a mucoadhesive property to the composition. and is permeable to a certain extent. Agents delivered through 35 As used herein, “biologically compatible substance” refers the mucosa enter circulation in hours or for as long as about to a Substance which when administered to a Subject, such as 24 hours after administration (i.e. about 4-24 hours for insu a human, does not produce undesired or toxic effects. lin). Entry of the agent to be delivered is a function of the drug As used herein, “an agent, is any substance that can be and the mucoadhesive protein selected. The compositions delivered via compositions provided hereinto a mucosal Sur provided herein exploit the limited permeability of the 40 face of a Subject. mucosa and generally are formulated for delivery through the As used herein, “a biologically active agent.” “a biological oral and nasal mucosa, although they can be used formulated agent, or “an agent is any Substance which when intro for delivery through any mucosal Surface, including the duced into the body causes a desired biological response, mouth, nasal passages, gastrointestinal tract, lungs and the Such as altering body function at the cellular, tissue or organ mucosal layer of other tissues and organs. 45 level and/or altering cosmetic appearance. Such substance As used herein, mucosal delivery refers to delivery of an can be any synthetic or natural element or compound, protein, agent in which the agent is introduced to the body across a cell, or tissue including a pharmaceutical, drug, therapeutic, mucous membrane which allows for the avoidance of the nutritional Supplement, herb, hormone, or the like, or any gastrointestinal tract and first pass liver metabolism and con combinations thereof. The terms also encompass pharmaceu sequently allows the agent to directly enter into circulation. 50 tically acceptable, pharmacologically active derivatives of This can include passage through the gastrointestinal tract as those active agents specifically mentioned herein, including, by oral ingestion, but refers to delivery through the muscosa but not limited to, salts, esters, amides, prodrugs, active of Such locus. metabolites, isomers, fragments, analogs, and the like. When As used herein, "contact to mucosal surface” refers to the terms “biologically active agent.” “biological agent' and contact of the composition into the mucosal Surface for an 55 "agent” are used, then, or when a particular active agent is amount of time sufficient to achieve quantitative delivery of specifically identified, it is intended to include the active the composition. Contact of the composition can result in agent perse as well as pharmaceutically acceptable, pharma adhesion and/or penetration of the composition into the cologically active salts, esters, amides, prodrugs, active mucosal Surface. The compositions provided herein can con metabolites, isomers, fragments and analogs. tact the mucosal surface from 30 seconds up to about 24 60 As used herein, a Subject is defined as an animal, including hours. In certain embodiments, the composition contacts the a mammal, typically a human. mucosal surface for about 5, 10, 12, 14, 16, 18, 20, 22 or up to As used herein, quantitative delivery refers to delivery of a 24 hours. In some embodiments, the compositions provided Substantial portion of the amount administered, and is typi herein contact the mucosal membrane from about 1 minute up cally, greater than 50%, 60%, 70%, 80%, 85%, 90%, 91%, to about 180, 120, 100, 60, 40, 30, 20, 10, 5, 4, 3, or 2 minutes. 65 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. As used herein, mucoadhesive property refers to a property As used herein, therapeutically effective amount refers to whereby a natural or synthetic Substance, Such as a protein, an amount of the active agent for a desired therapeutic, pro US 8,414,914 B2 7 8 phylactic, or other biological effect or response when a com As used herein, a “delivery vehicle' refers to macro-mo position is administered to a subject in a single dosage form. lecular structures in an emulsion, Such as micelles, inverse The particular amount of active agent in a dosage will vary micelles, lipid bilayers (liposomes) and cubosomes or a mix widely according to conditions such as the nature of the active ture thereof. agent, the nature of the condition being treated, the age and As used herein, “protein is associated with a delivery size of the subject. vehicle' means the mucoadhesive protein is associated with a As used herein, an emulsion is defined as a colloidal dis delivery vehicle via chemical or physical interaction, such as persion of two immiscible liquids, such as oil and water, in the hydrogen bond or van der waal's forces. The mucoadhesive form of droplets. The emulsions are generally stabilized by an protein, Such as lactoferrin can be for example, associated 10 with the polar head groups of the delivery vehicles, such as interfacial film of Surface active agents or Surfactant mol micelles via a chemical interaction, Such as a hydrogen bond. ecules, such as polysorbate-80 and the stability of an emul As used herein, "agent is associated with a delivery sion can be determined by well known routine methods. vehicle' means the delivery vehicle contains the agent to be As used herein, Surfactants (or 'surface-active agents') are delivered. The agent can be for example, encapsulated in a chemical or naturally occurring entities which, when dis 15 micelle or encapsulated in the liposome bilayers. Solved in an aqueous solution, reduce the Surface tension of As used herein, Viscosity refers to a physical property of the Solution or the interfacial tension between the aqueous fluids that determines the internal resistance to shear forces phase and the oil phase, to form a stable oil in water or water and is expressed in centipoise (cp). in oil emulsion. The Surfactant molecules are amphiphilic and The oil phase in the emulsion provided herein can be any contain hydrophilic head groups and hydrophobic tails. The nontoxic oil, biocompatible oil, which includes, but is not Surfactant molecules form various macro-molecular struc limited to mono-, di- and triglycerides, fatty acids and their tures in an emulsion, Such as micelles, inverse micelles, lipid esters, ethers and esters of propylene glycolor other polyols. bilayers (liposomes) and cubosomes. The exact macromo The fatty acids and esters (used as such or where they form lecular structure which is formed depends on the relative sizes part of a glyceride) can be short chain, medium chain or long of the hydrophilic and hydrophobic regions of the surface 25 chain. As used herein, medium chain represents a hydrocar active molecules. bon chain of Cs to C and short chain is a hydrocarbon chain Micelle formation is favored when the cross sectional area of less than Cs and long chain means a hydrocarbon chain of of the hydrophilic region of the surface active molecule is more than C. The water phase in the emulsion can be water, greater than that of the hydrophobic part of the molecule. For aqueous Solutions, alcohols, alcohol Solutions, and the like. example, Sodium palmitate contains a hydrocarbon chain (the 30 As used herein, the stability of a composition provided hydrophobic portion of the molecule) and an ionic base (the herein refers to the length of time at a given temperature that hydrophilic portion of the molecule), and acts as an emulsi greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, fying agent that binds water and oil phases. That is, it allows 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or oil and water to be broken into tiny droplets suspended or 99% of the initial amount of the agent to be delivered, e.g., dispersed in water as spherical micelles, wherein the hydro 35 insulin, is present in the composition. Thus, for example, a philic head groups arrange at the periphery of the sphere and composition that is stable for 30 days at 25°C. would have hydrophobic tails are at the center. greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, When the cross sectional area of the hydrophobic region of 85%, 90% 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or the molecule is greater than that of the hydrophilic part of the 99% of the initial amount of active ingredient present in the molecule, the formation of hexagonal phase structures, some 40 composition at 30 days following storage at 25°C. times referred to as an inverse micelle is favored, e.g., As used herein, pharmaceutically acceptable derivatives of dimyristoyl-phosphatidylethanolamine (DMPE). a compound include salts, esters, enol ethers, enol esters, For surface active molecules in which the cross sectional acids, bases, Solvates, hydrates or prodrugs thereof. Such area of the hydrophilic region of the molecule is slightly less derivatives can be readily prepared by those of skill in this art than, or equal to, that of the hydrophobic part of the molecule, 45 using known methods for Such derivatization. The com Such as many phospholipids (which are amphipathic type of pounds produced can be administered to animals or humans lipids that contain phosphate, that is, molecules containing without substantial toxic effects and either are pharmaceuti one phosphate, a glycerol and one or more fatty acids), the cally active or are prodrugs. Pharmaceutically acceptable formation of bilayers is favored, e.g., dipalmitoylphosphati salts include, but are not limited to, amine salts, such as but dylcholine (DPPC). These bilayers are two dimensional 50 not limited to N,N'-dibenzylethylenediamine, chlorop sheets in which all of the hydrophobic portions, e.g., acyl side rocaine, choline, ammonia, diethanolamine and other chains, are shielded from interaction with water except those hydroxyalkylamines, ethylenediamine, N-methylglucamine, at the ends of the sheet. An energetically unfavorable inter procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2- action of the acyl chains with water results in the folding of pyrrolidin-1-ylmethylbenzimidazole, diethylamine and the bilayers to form three-dimensional vesicles. These 55 other alkylamines, piperazine and tris(hydroxymethyl)ami vesicles are referred to as “liposomes. Liposomes may be nomethane; alkali metal salts, such as but not limited to formed as a single bilayer enclosing a single aqueous space lithium, potassium and sodium; alkali earth metal salts. Such (small unilamellar vesicles; SUVS) or may be composed of as but not limited to barium, calcium and magnesium; tran concentric bilayers with many aqueous spaces alternating sition metal salts, such as but not limited to Zinc, and other with the bilayers (multilamellar vesicles: MLVS). Liposomes 60 metal salts, such as but not limited to Sodium hydrogen phos can be used to encapsulate both hydrophobic and hydrophilic phate and disodium phosphate; and also including, but not active agents. Hydrophobic active agents are typically parti limited to, salts of mineral acids, such as but not limited to tioned within the bilayers whereas hydrophilic active agents hydrochlorides and Sulfates; and salts of organic acids. Such are typically trapped within the aqueous compartments. The as but not limited to acetates, lactates, malates, tartrates, advantages of using liposomes as a carrier/encapsulation sys 65 citrates, ascorbates. Succinates, butyrates, Valerates and tem is that they are stable and can protect the active agents fumarates. Pharmaceutically acceptable esters include, but from degradation, e.g., by oxygen, digestive enzymes, etc. are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, US 8,414,914 B2 9 10 aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of site of need. The faster the drug reaches its target area, the acidic groups, including, but not limited to, carboxylic acids, faster it can begin to elicit its desired effect. Further, the phosphoric acids, phosphinic acids, Sulfonic acids, Sulfinic avoidance of the gastrointestinal tract and first pass metabo acids and boronic acids. lism means that much less of the drug can be administered to Pharmaceutically acceptable solvates and hydrates are achieve the same effect, allowing for lower dosages to be complexes of a compound with one or more solvent or water administered and fewer side effects. molecule, in certain embodiments 1 to about 100, in other Some common modes of mucosal administration include embodiments 1 to about 10, in further embodiments one to oral and nasal administrations. Those of skill in the art are about 2, 3 or 4, solvent or water molecules. familiar with a variety of modes of administration (see, e.g., As used herein, treatment means any manner in which one 10 Almeida et al. Journal of Drug Targeting 3, 456-467 (1996), or more of the symptoms of a condition, disorder or disease which provides a review of mucosal administration of vac are ameliorated or otherwise beneficially altered. Treatment cines in general, and nasal administration of vaccines in par also encompasses any pharmaceutical use of the composi ticular). The compositions upon contacting with the mucosal tions herein, such as use for treating diabetes. Surface, adhere thereto or penetrate through the mucosal Sur As used herein, amelioration of the symptoms of a particu 15 face, for an amount of time sufficient to achieve quantitative lar disorder by administration of a particular pharmaceutical delivery of the composition, including, but not limited to less composition refers to any lessening, whether permanent or than 1 minute up to more than 3 hours. Various parameters temporary, lasting or transient that can be attributed to or known in the art can be used for measurement of mucoadhe associated with administration of the composition. Sion. Such parameters include, but are not limited to, As used herein, a prodrug is a compound that, upon in vivo mechanical binding to mucous membrane perse or the degree administration, is metabolized or otherwise converted to the of biological effect of an agent delivered. The compositions biologically, pharmaceutically or therapeutically active form are formulated to adhere to or penetrate into the mucosal of the compound. To produce a prodrug, the pharmaceutically surface for about 1,2,3,4,5,10,15, 20, 25, 30, 35, 40, 50, 60, active compound is modified such that the active compound 70, 80, 90, 100, 120, 150 minutes or up to more than 180 will be regenerated by metabolic processes. The prodrug can 25 minutes after being delivered to the mucosa. In certain be designed to alter the metabolic stability or the transport embodiments, compositions are formulated to adhere to or characteristics of a drug, to mask side effects or toxicity, to penetrate into the mucosal surface for about 1, 2, 3, 4, 5, 6, 7, improve the flavor of a drug or to alter other characteristics or 8, 9, 10, 12, 14, 16, 18, 20, 22, 24 or more hours. properties of a drug. By virtue of knowledge of pharmacody Mucosal delivery of agents can be effected either in the namic processes and drug metabolism in Vivo, those of skill in 30 absence or in the presence of a carrier. Mucosal administra this art, once a pharmaceutically active compound is known, tion in the presence of a carrier serves various purposes. Such can design prodrugs of the compound (see, e.g., Nogrady as controlled release of biologically active molecules, target (1985) Medicinal Chemistry A Biochemical Approach, ing of biologically active molecules to specific tissues, and Oxford University Press, New York, pages 388-392). facilitating penetration into the mucosal layer. It is to be understood that the compounds for use in the 35 2. Compositions compositions and methods provided herein can contain chiral The compositions provided herein, which provide mucosal centers. Such chiral centers may be of either the (R) or (S) delivery of agents, are formulated as emulsions, including oil configuration, or may be a mixture thereof. Thus, the com in water and water in oil emulsions. In preparing the compo pounds for use in the compositions provided herein may be sitions, an agent to be delivered is dissolved either in the oil enantiomerically pure, or bestereoisomeric or diastereomeric 40 phase or the water phase prior to forming an emulsion. The mixtures. It is to be understood that the chiral centers of the compositions optionally include additional ingredients. Such compounds provided herein may undergo epimerization in as Surface active agents for stabilizing the emulsions. vivo. Thus, one of skill in the art will recognize that admin Compositions provided herein can have a wide range of istration of a compound in its (R) form is equivalent, for viscosities, typically ranging from about 10 cps; 50 cps; 100 compounds that undergo epimerization in vivo, to adminis 45 cps: 300 cps; 500 cps; 750 cps: 1000 cps;3000 cps: 6000 cps: tration of the compound in its (S) form. 8000 cps; 10,000 cps; 20,000 cps; 30,000 cps: 40,000 cps: B. Compositions 50,000 cps: 60,000 cps; 70,000 cps: 80,000 cps; 90,000 cps: 1. Mucosal Delivery 100,000 cps: 150,000 cps: 200,000 cps: 130,000 cps: 250,000 Provided herein are compositions and methods for cps; or 280,000 cps up to more than 500,000 cps at 72°F. The mucosal delivery of agents, particularly agents that are nor 50 Viscosity of the compositions can be measured by methods mally difficult to administer or ineffective when administered known to those of skill in the art, including measurement by orally or nasally. The compositions provided herein contain using a viscometer such as Brookfield LVDV-I+ viscometer one or more mucoadhesive proteins that impart a mucoadhe and T spindles with a heliopath adapter. sive property to the composition. Contacting a mucosal Sur In the compositions provided herein, oil phase, aqueous face in a Subject with a composition results in delivery of 55 phase and emulsifier can be used in a wide range of ratios to composition, including active and inactive components into make the emulsions. The oil-in-water emulsions contain at circulation. The compositions provided herein are for deliv least 25% of water by weight, in one embodiment between ery of agents, such as biologically active agents, through 30% and 80% and in another embodiment between 40% and mucosa, such as oral, nasal or intestinal mucosa. 95%. The oil phase in the oil in water emulsions is at least 1%, Mucosal delivery systems offer benefits over other meth 60 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, ods of delivery. For example, absorption through the mucous 30% or more by weight of the emulsion. The emulsifier or membrane leads the delivered active agent directly into the surfactant in the emulsions is at least 0.5%, 1%, 2%, 3%, 4%, circulatory system. This allows such agents, in certain 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% by weight of embodiments, to bypass the gastrointestinal tract as well as the emulsion. first pass liver metabolism. Secondly, the biologically active 65 The water-in-oil emulsions contain at least 25% of oil by agents such as drugs directly enter the circulatory system, weight, in one embodiment between 30% and 80% and in which allows the therapeutic to be rapidly transported to the another embodiment between 40% and 95% of oil by weight. US 8,414,914 B2 11 12 The water phase in the water in oil emulsions is at least 1%, The mucoadhesive proteins can associate with the delivery 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, vehicle via chemical orphysical interaction. For example, the 30% or more by weight of the emulsion. The emulsifier or mucoadhesive protein can be hydrogen bonded with polar surfactant in the emulsions is at least 0.5%, 1%, 2%, 3%, 4%, headgroups of the micelles or the liposomes or other vehicles 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% by weight of 5 that are present in the emulsion in the compositions provided the emulsion. herein. Such compositions when administered either orally or The compositions provided herein also can include one or nasally, to a subject in need thereof, adhere to or penetrate more other additives, such as a polymer, a cosolvent, an through the mucosal membrane via chemical or physical antioxidant, an antiseptic, a buffering agent, a chelating bond. Such as secondary chemical bonds, including hydrogen agent, a colorant, a flavorant, an odorant, an osmotic modifier, 10 bonding and Vander Waal forces, thereby providing sustained a preservative, a solubilizer, a tonicifier, a trace element, a or prolonged coating of the composition on the epithelium of viscomodulator and a mixture thereof. Such additional addi the oral cavity or nasal cavity depending on the mode of tives can be present in the oil phase, the aqueous phase, or administration. The Sustained coating of the composition both. allows for increased contact time between the composition 15 and the epithelial layer, which in turn results in enhanced a. Mucoadhesive Proteins absorption of the active agent in to the mucosal layer. The compositions contain one or more mucoadhesive pro The amount of mucoadhesive protein in the compositions teins. The mucoadhesive proteins for use in the compositions provided herein, is an amount that results in quantitative and methods provided herein include any protein that imparts delivery of an agent formulated therewith. The amount to be a mucoadhesive property to the composition whereby the added can vary depending upon the agent delivered and other composition when administered to a Subject's mucosal Sur components of a composition, but it can be determined face. Such as oral or nasal mucosa, adheres or penetrates into empirically by formulating compositions and testing them for the mucosal epithelium of the subject for a period of time delivery using any Suitable assay known to those of skill in the Sufficient to achieve quantitative delivery of an agent to be art or as described herein. delivered. In certain embodiments, the compositions adhere 25 Typically, the mucoadhesive protein is presentata concen to or penetrate through the mucosal membrane for a period of tration of about 0.05% by weight up to about 80%, generally time sufficient to locally deliver a therapeutically-effective 0.1, 0.2,0.3, 0.4,0.5, 1,2,3,4,5,6,7,8,9, 10, 15, 20, 25, 30, amount of an active agent in the composition. Adhesion of or 40% by weight up to about 50% by weight, of the total mucoadhesive protein to the mucous membrane occurs pri weight of the composition. In other embodiments, the marily via secondary chemical bonds. Such as hydrogen 30 mucoadhesive protein is present at a concentration of about bonding and Van der Waal forces. 0.1% by weight up to about 30% by weight of the total weight Any mucoadhesive protein that is biologically compatible of the composition. In other embodiments, the mucoadhesive can be employed. Mucoadhesive proteins for use herein protein is present at a concentration of about 0.1% by weight include, but are not limited to natural or synthetic proteins, up to about 20% by weight of the total weight of the compo polypeptides or fragments thereof that possess the mucoad 35 sition. In other embodiments, the mucoadhesive protein is hesive property. Mucoadhesive proteins can be screened for present at a concentration of about 0.05% by weight up to their ability to be used as mucoadhesives for mucosal delivery about 15% by weight of the total weight of the composition. of compositions provided herein according to the methodol In other embodiments, the mucoadhesive protein is present at ogy described in Smart et al., 1982 J. Pharm. Pharmacol. a concentration of about 0.05% by weight up to about 12% by 34:70P and Smartet al., 1984.J. Pharm. Pharmacol. 36:295. 40 weight of the total weight of the composition. In other The methodology involves estimating values of adhesive embodiments, the mucoadhesive protein is present at a con strength between the mucoadhesive protein and the mucous centration of about 0.05% by weight up to about 10% by membrane. weight of the total weight of the composition. In other In certain embodiments, the mucoadhesive proteins are embodiments, the mucoadhesive protein is present at a con selected from a family of mucin proteins and transferrins. In 45 centration of about 0.05% by weight up to about 8% by certain embodiments, the mucoadhesive protein is from the weight of the total weight of the composition. In other transferrin family and is selected from bovine lactoferrin, embodiments, the mucoadhesive protein is present at a con human lactoferrin, lactoferrin binding proteins, recombinant centration of about 0.05% by weight up to about 5% by human lactoferrin, lactoferricin, lactoferricin b, transferrin weight of the total weight of the composition. In other binding proteins, bovine transferrin, ovotransferrin, neutro 50 embodiments, the mucoadhesive protein is present at a con phil granules, apo-lactoferrin and lanthanide-lactoferrin. In centration of about 8% by weight up to about 10% by weight certain embodiments, the mucoadhesive proteins are selected of the total weight of the composition. In other embodiments, from among lactoferrin, lactoferrin binding proteins, recom the mucoadhesive protein is present at a concentration of binant lactoferrin, lactoferricin, lactoferricin b, transferrin about 9% by weight up to about 10% by weight of the total binding proteins, transferrin, ovotransferrin, neutrophil gran 55 weight of the composition. In other embodiments, the ules, apo-lactoferrin, immunoglobulin, albumin and lan mucoadhesive protein is present at a concentration of about thanide-lactoferrin. In certain embodiments, the mucoadhe 15% by weight of the total weight of the composition. In other sive protein is selected from albumin, immunoglobulin and embodiments, the mucoadhesive protein is present at a con lactoferrin. centration of about 12% by weight of the total weight of the In certain embodiments, the mucoadhesive protein for use 60 composition. In other embodiments, the mucoadhesive pro in the compositions and methods provided herein is lactofer tein is present at a concentration of about 10% by weight of rin. In certain embodiments, the compositions contain one, the total weight of the composition. In other embodiments, two or three mucoadhesive proteins. In certain embodiments, the mucoadhesive protein is present at a concentration of the compositions contain one mucoadhesive protein. In cer about 9.5% by weight of the total weight of the composition. tain embodiments, the mucoadhesive protein in the compo 65 In other embodiments, the mucoadhesive protein is present at sitions provided herein is present in an amount Sufficient to a concentration of about 9% by weight of the total weight of confer a mucoadhesive property to the composition. the composition. In other embodiments, the mucoadhesive US 8,414,914 B2 13 14 protein is presentata concentration of about 8% by weight of 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, the total weight of the composition. In other embodiments, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more by weight. the mucoadhesive protein is present at a concentration of Thus, in certain embodiments, the oil is present at about 3, 4, about 6% by weight of the total weight of the composition. In or 5% by weight up to about 90% by weight of the total weight other embodiments, the mucoadhesive protein is present at a of the composition. In other embodiments, the oil is present at concentration of about 4% by weight of the total weight of the a concentration of about 3, 4, or 5% by weight up to about composition. In other embodiments, the mucoadhesive pro 85% by weight of the total weight of the composition. In other tein is present at a concentration of about 2% by weight of the embodiments, the oil is presentata concentration of about 5% total weight of the composition. In other embodiments, the by weight up to about 70% by weight of the total weight of the mucoadhesive protein is present at a concentration of about 10 composition. In other embodiments, the oil is present at a 1% by weight of the total weight of the composition. In other concentration of about 5% by weight up to about 50% by embodiments, the mucoadhesive protein is present at a con weight of the total weight of the composition. In other centration of about 0.8% by weight of the total weight of the embodiments, the oil is presentata concentration of about 5% composition. In other embodiments, the mucoadhesive pro by weight up to about 45% by weight of the total weight of the tein is present at a concentration of about 0.6% by weight of 15 composition. In other embodiments, the oil is present at a the total weight of the composition. In other embodiments, concentration of about 5% by weight up to about 40% by the mucoadhesive protein is present at a concentration of weight of the total weight of the composition. In other about 0.4% by weight of the total weight of the composition. embodiments, the oil is presentata concentration of about 5% In other embodiments, the mucoadhesive protein is present at by weight up to about 35% by weight of the total weight of the a concentration of about 0.1% by weight of the total weight of composition. In other embodiments, the oil is present at a the composition. In other embodiments, the mucoadhesive concentration of about 5% by weight up to about 30% by protein is presentata concentration of about 0.05% by weight weight of the total weight of the composition. In other of the total weight of the composition. embodiments, the oil is presentata concentration of about 5% b. Oils by weight up to about 20% by weight of the total weight of the The oils for use in the compositions include any oil 25 composition. In other embodiments, the oil is present at a obtained from a natural or synthetic source that is suitable for concentration of about 45% by weight of the total weight of consumption by a subject. Oils suitable for administration to the composition. In other embodiments, the oil is present at a Subjects, including humans, are known. Any Such oil can be concentration of about 40% by weight of the total weight of used. The oil can be of vegetable or animal origin. The oil the composition. In other embodiments, the oil is present at a phase also can be synthetic or semisynthetic oils that are 30 concentration of about 35% by weight of the total weight of nontoxic to a Subject. Exemplary of oils for use herein the composition. In other embodiments, the oil is present at a include, but are not limited to mono-, di- and triglycerides, concentration of about 30% by weight of the total weight of fatty acids, such as oleic, linoleic, palmitic, Stearic, conju the composition. In other embodiments, the oil is present at a gated forms thereof and their esters, ethers and esters of concentration of about 20% by weight of the total weight of propylene glycol or other polyols. In certain embodiments, 35 the composition. In other embodiments, the oil is present at a the oils are short, medium or long chain triglycerides. In concentration of about 10% by weight of the total weight of certain embodiments, the oils are medium chain triglycerides the composition. In other embodiments, the oil is present at a (MCTs). In certain embodiments, the MCT is tricaprylic trig concentration of about 7% by weight of the total weight of the lyceride ester (also known as Neobee(R) M5). Exemplary composition. In other embodiments, the oil is present at a Sources for oils contemplated herein include, but are not 40 concentration of about 5% by weight of the total weight of the limited to All Spice, Almond, Anise, Apple, Apricot, AVo composition. cado, Basil, Bayberry, Benzoin, Bergamot, Borage Seed, c. Surface Active Agents Cajeput, Calendula, Canola, Carnation, Carrot seed, Cassia The compositions provided herein can contain one or more bark, Castor, Cayenne, Cedarwood, Chamomile, Cinnamon, Surface active agents that are added in an amount Sufficient to Citronella, Conjugated Linolenic Acid, Clary sage, Clove 45 form a stable emulsion. The appropriate amount of Surface bud, Coconut, Cod Liver, Corn, Cranberry, Cypress, Evening active agent is a function of the agent for delivery and other Primrose, Eucalyptus, Evergreen, Fir, Fish 18:12, Flax Seed, components present in the emulsion, since some agents can Frangipani, Frankincense, Freesia, Gardenia, Ginger, Grape have self-emulsifying properties and other agents and com Seed, Grapefruit, Heather, Honeysuckle, Hyacinth, Jasmine, ponents affect Surface tension. Jojoba, Juniper berry, Lavender, Lecithin, Lemon, Lemon 50 The Surface active agents for use herein are substances balm, Lemon, Verbena, Lemongrass, Lilac, Lily of the valley, which, when dissolved in an aqueous solution, reduce the Lime, Magnolia, MCT, Menthol, Mulberry, Musk, Myrrh surface tension of the solution or the interfacial tension Oat, Olive, Orange, Oregano, Palm, Patchouli, Peach, Pen between the aqueous phase and the oil phase, to form a stable nyroyal, Peppermint, Petitgrain, Pine, Pumpkin Seed, Rice oil in water or water in oil emulsion. The surfactant molecules Bran, Rose, Rosemary, Rosewood, Safflower, Sage, Salmon, 55 are amphiphilic and contain hydrophilic head groups and Sandalwood, Sesame, Shark Liver, Soy Bean, Spearmint, hydrophobic tails. The surfactant molecules form various Squalene, Strawberry, Sunflower, Tangerine, Tea tree, Thuja macro-molecular structures in an emulsion, such as micelles, (Cedar leaf), Thyme, Tuna, Vanilla, Vitamin E. Wheat Germ. inverse micelles, lipid bilayers (liposomes) and cubosomes. Wintergreen and Ylangylang. In certain embodiments, the oil The exact macromolecular structure which is formed depends phase contains oat oil and tri caprylic triglyceride ester (also 60 on the relative sizes of the hydrophilic and hydrophobic known as NeobeeRM5). regions of the Surface active molecule. In certain embodi The oil is present in an amount sufficient to dissolve the oil ments, the Surface active agent is selected from Sodium lauryl soluble ingredients in the composition. The amount generally Sulfate; Sorbitan laurate, Sorbitan palmitate, Sorbitan Stearate is a function of the locus of administration, the agent to be (available under the tradename SpanR 20, 40, 60 etc.); administered and other Such parameters and can be empiri 65 polysorbates Such as polyoxyethylene (20) Sorbitan monolau cally determined. For example, in Some embodiments, the oil rate, polyoxyethylene (20) Sorbitan monopalmitate, polyoxy is present at a concentration of about 1%, 2%. 3%, 4%. 5%, ethylene (20) sorbitan monostearate (available under the US 8,414,914 B2 15 16 tradename TWEENS(R) 20, 40, 60 etc.); benzalkonium chlo (Ammonium Salt), Palmitoyl Coenzyme A (Ammonium ride, mixed chain phospholipids, cationic lipids, oligolipids, Salt), Stearoyl Coenzyme A (Ammonium Salt), Oleoyl Coen phospholipids, carnitines, sphingosines, sphingomyelins, Zyme A (Ammonium Salt), Arachidoyl Coenzyme A (Am ceramides, glycolipids, lipoproteins, apoproteins, monium Salt), Arachidonoyl Coenzyme A (Ammonium amphiphilic proteins, amphiphilic peptides, amphiphilic Syn Salt), Behenoyl Coenzyme A (Ammonium Salt), Tricosanoyl thetic polymers, and combinations thereof. Other exemplary Coenzyme A (Ammonium Salt), Lignoceroyl Coenzyme A Surface active agents for use herein include, but are not lim (Ammonium Salt), Nervonoyl Coenzyme A (Ammonium ited to: Salt), Hexacosanoyl Coenzyme A (Ammonium Salt), i) Natural lipids, i.e. Cholesterol, Sphingosine and Deriva Docosahexaenoyl Coenzyme A (Ammonium Salt), tives, Gangliosides, Sphingosine derivatives (Soy Bean), 10 V) Oxidized lipids, i.e. 1-Palmitoyl-2-AZelaoyl-sn-Glyc Phytosphingosine and derivatives (Yeast), Choline (Phos ero-3-Phosphocholine, 1-O-Hexadecyl-2-AZelaoyl-sn-Glyc phatidylcholine), Ethanolamine (Phosphatidylethanola ero-3-Phosphocholine, 1-Palmitoyl-2-Glutaroyl-sn-Glyc mine), Glycerol (Phosphatidyl-DL-glycerol), Inositol (Phos ero-3-Phosphocholine (PGPC), 1-Palmitoyl-2-(9'-oxo phatidylinositol), Serine (Phosphatidylserine (Sodium Salt)), Nonanoyl)-sn-Glycero-3-Phosphocholine, 1-Palmitoyl-2- Cardiolipin, Phosphatidic Acid, Egg Derived, Lyso (Mono 15 (5'-oxo-Valeroyl)-sn-Glycero-3-Phosphocholine, Acyl) Derivatives (Lysophosphatides), Hydrogenated Phos vi) Ether lipids, i.e.: Diether Lipids (Dialkyl Phosphatidyl pholipids, Lipid Tissue Extracts, choline, Diphytanyl Ether Lipids), Alkyl Phosphocholine ii) Synthetic lipids, i.e. Asymmetric Fatty Acid, Symmetric (Dodedylphosphocholine), O-Alkyl diacylphosphatidylcho Fatty Acid Saturated Series, Symmetric Fatty Acid Un linium (1,2-Diacyl-sn-Glycero-3-Ethylphosphocholine), saturated Series, Acyl Coenzyme A (Acetoyl Coenzyme A, Synthetic PAF & Derivatives (1-Alkyl-2-Acyl-Glycero-3- Butanoyl Coenzyme A, Crotanoyl Coenzyme A, Hexanoyl Phosphocholine & Derivatives), Coenzyme A, Octanoyl Coenzyme A, Decanoyl Coenzyme vii) Fluorescent lipids, i.e.: Glycerol Based (Phosphatidyl A, Lauroyl Coenzyme A, Myristoyl Coenzyme A, Palmitoyl choline (NBD), Phosphatidic Acid (NBD), Phosphatidyle Coenzyme A, Stearoyl Coenzyme A, Oleoyl Coenzyme A. thanolamine (NBD), Phosphatidylglycerol (NBD), Phos Arachidoyl Coenzyme A, Arachidonoyl Coenzyme A, 25 phatidylserine (NBD)), Sphingosine Based (Ceramide Behenoyl Coenzyme A, Tricosanoyl Coenzyme A. Lignocer (NBD), Sphingomyelin (NBD), Phytosphingosine (NBD), oyl Coenzyme A, Nervonoyl Coenzyme A, Hexacosanoyl Galactosyl Cerebroside (NBD)), Headgroup Labeled Lipids Coenzyme A, (Glycerol Based) (Phosphatidylethanolamine (NBD), Phos iii) Sphingolipids, i.e. D-erythro (C-18) Derivatives (Sph phatidylethanolamine (Lissamine Rhodamine B), Dioleoyl ingosine, Such as: D-erythro Sphingosine (synthetic), Sphin 30 Phosphatidylethanolamine (Dansyl, Pyrene, Fluorescein), gosine-1-Phosphate, N.N Dimethylsphingosine, N.N.N-Tri Phosphatidylserine (NBD), Phosphatidylserine (Dansyl)), methylsphingosine, Sphingosylphosphorylcholine, 25-NBD-Cholesterol, Sphingomyelin and Glycosylated Sphingosine), Ceramide viii) Other lipids including, but not limited to Lecithin, Derivatives (Ceramides, D-erythro Ceramide-1-Phosphate, Ultralec-P (ADM), Soy powder, Glycosulated Ceramides), Sphinganine (Dihydrosphin 35 ix) Surfactants including, but not limited to polyethylene gosine) (Sphinganine-1-Phosphate, Sphinganine (C20), glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan D-erythro Sphinganine, N-Acyl-Sphinganine C2, N-Acyl palmitate, Sorbitan Stearate (available under the tradename Sphinganine C8, N-acyl-Sphinganine C16, N-Acyl-Sphinga SpanR 20-40-60 etc.); polysorbates such as polyoxyethylene nine C18, N-Acyl-Sphinganine C24, N-Acyl-Sphinganine (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan C24:1), Glycosylated (C18) Sphingosine and Phospholipid 40 monopalmitate, polyoxyethylene (20) Sorbitan monostearate Derivatives (Glycosylated-Sphingosine) (Sphingosine, BD (available under the tradename TWEENSR 20-40-60 etc.); Glucosyl, Sphingosine, BD-Galactosyl, Sphingosine, benzalkonium chloride. BD-Lactosyl), Glycosylated-Ceramide (D-Glucosyl-31-1' In certain embodiments, the phospholipids for use are Ceramide (C8), D-Galactosyl-B1-1" Ceramide (C8), D-Lac phosphatidylcholines, phosphatidylethanolamines, phos tosyl-B1-1" Ceramide (C8), D-Glucosyl-B1-1" Ceramide 45 phatidylserines, phosphatidylglycerols, phosphatidylinosi (C12), D-Galactosyl-B1-1" Ceramide (C12), D-Lactosyl-(1- tols, phosphatidic acids, mixed chain phospholipids, lyso 1' Ceramide (C12)), Glycosylated-Phosphatidylethanola phospholipids, hydrogenated phospholipids, partially mine (1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N- hydrogenated phospholipids, and mixtures thereof. Lactose), D-erythro (C17) Derivatives (D-erythro In certain embodiments, the Surface active agent is selected Sphingosine, D-erythro Sphingosine-1-phosphate), 50 from polysorbate-80, lecithin and phosphatidylcholine. The D-erythro (C20) Derivatives (D-erythro Sphingosine), Surface active agents are present in an amount Sufficient to L-threo (C18) Derivatives (L-threo Sphingosine, Safingol form a stable emulsion. (L-threo Dihydrosphingosine)), Sphingosine Derivatives The amount of Surface active agent can be empirically (Egg, Brain & Milk) (D-erythro-Sphingosine, Sphingomy determined and is a function of the agent selected and the elin, Ceramides, Cerebrosides, Brain Sulfatides), Ganglio 55 desired form of the resulting composition. The amount sides (Gangliosides Structures, Gangliosides—Ovine Brain, include can be from less than 0.1% by weight up to 35% or Gangliosides Porcine Brain), Sphingosine Derivatives more. In certain embodiments, the Surface active agent is (Soy Bean) (Glucosylceramide), Phytosphingosine Deriva presentata concentration of about 1%, 2%. 3%, 4%. 5%, 6%, tives (Yeast) (Phytosphingosine, D-ribo-Phytosphingosine 7%, 8%, 9%, 10%, 15%, 20% or 25% by weight up to about 1-Phosphate, N-Acyl Phytosphingosine C2, N-Acyl 60 30% by weight of the total weight of the composition. In Phytosphingosine C8, N-Acyl Phytosphingosine C18, certain embodiments, the Surface active agent is present at a iv) Acyl coenzyme A, i.e. Acetoyl Coenzyme A (Ammo concentration of about 1% by weight up to about 20% by nium Salt), Butanoyl Coenzyme A (Ammonium Salt), Cro weight of the total weight of the composition. In certain tanoyl Coenzyme A (Ammonium Salt), Hexanoyl Coenzyme embodiments, the Surface active agent is present at a concen A (Ammonium Salt), Octanoyl Coenzyme A (Ammonium 65 tration of about 1% by weight up to about 15% by weight of Salt), Decanoyl Coenzyme A (Ammonium Salt), Lauroyl the total weight of the composition. In other embodiments, Coenzyme A (Ammonium Salt), Myristoyl Coenzyme A the Surface active agent is presentata concentration of about US 8,414,914 B2 17 18 1% by weight up to about 10% by weight of the total weight tem, Smooth muscles, blood circulatory system, synaptic of the composition. In other embodiments, the Surface active sites, neuro-effector junctional sites, endocrine system, hor agent is present at a concentration of about 1% by weight up mone systems, immunological system, reproductive system, to about 8% by weight of the total weight of the composition. skeletal system, autocoid systems, alimentary and excretory In other embodiments, the Surface active agent is present at a systems, histamine systems, and the like. The active agents concentration of about 1% by weight up to about 6% by that can be delivered using the compositions provided herein weight of the total weight of the composition. In other include, but are not limited to, anticonvulsants, analgesics, embodiments, the Surface active agent is present at a concen antiparkinsons, anti-inflammatories, calcium antagonists, tration of about 1% by weight up to about 4% by weight of the anesthetics, antimicrobials, antimalarials, antiparasitics, anti total weight of the composition. In other embodiments, the 10 hypertensives, antihistamines, antipyretics, alpha-adrenergic Surface active agent is presentata concentration of about 20% by weight of the total weight of the composition. In other agonists, alpha-blockers, biocides, bactericides, bronchial embodiments, the Surface active agent is present at a concen dilators, beta-adrenergic blocking drugs, contraceptives, car tration of about 15% by weight of the total weight of the diovascular drugs, calcium channel inhibitors, depressants, composition. In other embodiments, the Surface active agent 15 diagnostics, diuretics, electrolytes, enzymes, hypnotics, hor is present at a concentration of about 13% by weight of the mones, hypoglycemics, hyperglycemics, muscle contracta total weight of the composition. In other embodiments, the nts, muscle relaxants, neoplastics, glycoproteins, nucleopro Surface active agent is presentata concentration of about 11% teins, lipoproteins, ophthalmics, psychic energizers, by weight of the total weight of the composition. In other sedatives, steroids, sympathomimetics, parasympathomimet embodiments, the Surface active agent is present at a concen ics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, tration of about 8% by weight of the total weight of the Vitamins, minerals, nonsteroidal anti-inflammatory drugs, composition. In other embodiments, the Surface active agent angiotensin converting enzymes, polynucleotides, polypep is presentata concentration of about 6% by weight of the total tides, polysaccharides, and nutritional Supplements including weight of the composition. In other embodiments, the Surface herbal Supplements. active agent is present at a concentration of about 4% by 25 The level of agent to be delivered is from about 0.01% up weight of the total weight of the composition. In other to about 50%, from about 0.1% up to about 40%, from about embodiments, the Surface active agent is present at a concen 0.1% up to about 30%, from about 0.1% up to about 20%, tration of about 2% by weight of the total weight of the from about 0.1% up to about 10%, from about 0.1% up to composition. In other embodiments, the Surface active agent about 9%, from about 0.1% up to about 8%, from about 0.1% is presentata concentration of about 1% by weight of the total 30 up to about 7%, from about 0.1% up to about 6%, from about weight of the composition. 0.1% up to about 5%, from about 0.1% up to about 4%, from The stable emulsions provided herein can contain one or about 0.1% up to about 3%, from about 0.1% up to about 2%, more delivery vehicles selected from among micelles, lipo or from about 0.1% up to about 1% by weight of the compo Somes and cubosomes and mixtures thereof, that encapsulate sition. The agent to be delivered can be water soluble, slightly the active agent. The delivery vehicles encapsulating the 35 water soluble, or oil soluble. In certain embodiments, the active agent are then absorbed in the epithelium where the agent to be delivered is selected from anticonvulsants, anal active agent is delivered. gesics, antiparkinsons, anti-inflammatories, calcium antago d. Agents for Delivery nists, anesthetics, antimicrobials, antimalarials, antiparasit The compositions provided herein can contain one or more ics, antihypertensives, antihistamines, antipyretics, alpha agents for delivery to a Subject. Generally the agents are those 40 adrenergic agonists, alpha-blockers, biocides, bactericides, that confer a biological effect. Any agent that can be formu bronchial dilators, beta-adrenergic blocking drugs, contra lated as described herein can be administered in the compo ceptives, cardiovascular drugs, calcium channel inhibitors, sitions provided herein. Where the agent is a therapeutic, the depressants, diagnostics, diuretics, electrolytes, enzymes, compositions contain atherapeutically effective amount of an hypnotics, hormones, hypoglycemics, hyperglycemics, agent to be delivered. The particular amount of active agent in 45 muscle contractants, muscle relaxants, neoplastics, glycopro a dosage will vary widely according to the nature of the active teins, nucleoproteins, lipoproteins, non denatured whey pro agent, the nature of the condition being treated, the age and tein, ophthalmics, psychic energizers, sedatives, steroids, size of the Subject, and other parameters. sympathomimetics, parasympathomimetics, tranquilizers, Generally, the amount of active agent in the composition urinary tract drugs, vaccines, vaginal drugs, vitamins, miner will vary from less than about 0.01% by weight to about 20% 50 als, nonsteroidal anti-inflammatory drugs, angiotensin con by weight of the composition or more and typically are for Verting enzymes, polynucleotides, polypeptides, polysaccha mulated for single dosage administration. A single dosage can rides, and nutritional Supplements including herbal vary from about 0.01 ug to 10 mg of an agent per kilogram of Supplements. body weight of the host, with dosages from about 0.1 lug to 1 In certain embodiments, the active agent is selected as mg/kg being commonly employed. These concentrations, 55 follows: however, are general guidelines only and particular amounts C-Adrenergic agonists such as Adrafinil, Adrenolone, and dosages may be selected based on the active agent being Amidephrine, Apraclonidine, Budralazine, Clonidine, administered, the condition being treated, and the treatment Cyclopentamine, Detomidine, Dimetofrine, Dipivefrin, regimen being employed. The concentration can be an Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, Guanfa amount of a drug oran active agent that is sufficient to provide 60 cine, Hydroxyamphetamine, Ibopamine, Indanazoline, the desired local or systemic effect and performance at a Isometheptene, Mephentermine, Metaraminol, Methoxam reasonable benefit/risk ratio to a subject attending any medi ine Hydrochloride, Methylhexaneamine, Metizolene, Mido cal treatment. drine, Naphazoline, Norepinephrine, Norfenefrine, Octo Agents for delivery are selected frominorganic and organic drine, Octopamine, Oxymetazoline, Phenylephrine drugs including, but not limited to drugs that act on the 65 Hydrochloride, Phenylpropanolamine Hydrochloride, Phe peripheral nerves, adrenergic receptors, cholinergic recep nylpropylmethylamine, Pholedrine, Propylhexedrine, Pseu tors, nervous system, skeletal muscles, cardiovascular sys doephedrine, Rilmenidine, Synephrine, Tetrahydrozoline, US 8,414,914 B2 19 20 Tiamenidine, TramaZoline, Tuaminoheptane, Tymazoline, tin, Bufexamac, Bumadizon, Butacetin, Calcium Acetylsali Tyramine and Xylometazoline; cylate, Carbamazepine, Carbetidine, Carbiphene, Carsalam, B-Adrenergic agonists such as Albuterol, Bambuterol, Chloralantipyrine, Chlorthenoxazin(e), Choline Salicylate, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Deno Cinchophen, Ciramadol, Clometacin, Cropropamide, pamine, Dioxethedrine, Dopexamine, Ephedrine, Epineph Crotethamide, Dexoxadrol, Difenamizole. Diflunisal, Dihy rine, Etafedrine, Ethylnorepinephrine, Fenoterol. Formot droxyaluminum Acetylsalicylate, Dipyrocetyl. Dipyrone, erol, Hexoprenaline, Ibopamine, Isoetharine, Isoproterenal, Emorfazone, Enfenamic Acid, Epirizole, Etersalate, Ethen Mabuterol, Metaproterenol, Methoxyphenamine, Oxy Zamide, Ethoxazene, Etodolac, Felbinac, Fenoprofen, Floc fedrine, Pirbuterol, Prenalterol, Procaterol, Protokylol, tafenine, Flufenamic Acid, Fluoresone, Flupirtine, Flupro Reproterol, Rimiterol, Ritodrine, Soterenol, Terbuterol and 10 quaZone, Flurbiprofen, Fosfosal, Gentisic Acid, Glafenine, Xamoterol; Ibufenac, Imidazole Salicylate, Indomethacin, Indoprofen, C-Adrenergic blockers such as Amosulalol, Arotinolol. IsofeZolac, Isoladol, Isonixin, Ketoprofen, Ketorolac, p-Lac Dapiprazole, Doxazosin, Ergoloid Mesylates, Fenspiride, tophenetide, Lefetamine, Loxoprofen, Lysine Acetylsalicy Indoramin, Labetalol, Nicergoline, PraZosin, Terazosin, late, Magnesium Acetylsalicylate, Methotrimeprazine, Meto Tolazoline, Trimazosin and Yohimbine; 15 foline, Miroprofen, Morazone, Morpholine Salicylate, B-Adrenergic blockers such as Acebutolol, Alprenolol. Naproxen, Nefopam, Nifenazone, 5' Nitro-2' propoxyaceta Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, nilide, Parsalmide, Perisoxal, Phenacetin, Phenazopyridine Bevantolol, Bisoprolol, Bopindolol, Bucumolol. Befetolol, Hydrochloride, Phenocol, Phenopyrazone, Phenyl Acetyl Bufuralol, Bunitrolol, Bupranolol. Butidrine Hydrochloride, salicylate, Phenyl Salicylate, Phenyramidol, PipebuZone, Butofilolol, Carazolol, Carteolol, Carvedilol, Celiprolol, Piperylone, Prodilidine, Propacetamol, Propyphenazone, Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, Inde Proxazole, Quinine Salicylate, RamifenaZone, Rimazolium nolol, Labetalol, Levobunolol, Mepindolol, Metipranalol, Metilsulfate, Salacetamide, Salicin, Salicylamide, Salicyla Metoprolol, Moprolol, Nadoxolol, Nifenalol, Nipradillol, mide O-Acetic Acid, Salicylsulfuric Acid, Salsalte, Salver Oxprenolol, Penbutolol, Pindolol, Practolol, Pronethalol, ine, Simetride, Sodium Salicylate, Sulfamipyrine, Suprofen, Propranolol, Sotalol, Sulfinalol, Talinolol, Tertatolol, 25 Talniflumate, Tenoxicam, Terofenamate, Tetradrine, Tinori Timolol, Toliprolol and Xibenolol; dine, Tolfenamic Acid, Tolpronine, Tramadol, Viminol, Xen Alcohol deterrents such as Calcium Cyanamide Citrated, bucin and Zomepirac: Disulfuram, Nadide and Nitrefazole; Androgens such as Androsterone, Boldenone, Dehydroe Aldose reductase inhibitors such as Epalrestat, Ponalrestat, piandrosterone, Fluoxymesterone, Mestanolone, Mester Sorbinil and Tolrestat; 30 olone, Methandrostenolone, 17-Methyltestosterone, 17C.- Anabolics such as Androisoxazole, Androstenediol, Methyltestosterone 3-Cyclopentyl Enol Ether, Bolandiol, Bolasterone, Clostebol, Ethylestrenol; Formyl Norethandrolone, Normethandrone, Oxandrolone, Oxymes dienolone, 4-Hydroxy-19-nortestosterone, Methandriol, terone, Oxymetholone, Prasterone, Stanlolone, Stanozolol, Methenolone, Methyltrienolone, Nandrolone, Nandrolone Testosterone, Testosterone 17-Chloral Hemiacetal, Testoster Decanoate, Nandrolone p-Hexyloxyphenylpropionate, Nan 35 one 17 B-Cypionate, Testosterone Enanthate, Testosterone drolone Phenpropionate, Norbolethone, Oxymesterone, Nicotinate, Testosterone Pheynylacetate, Testosterone Propi Pizotyline, Quinbolone, Stenbolone and Trenbolone: onate and Tiomesterone; Analgesics (dental) Such as Chlorobutanol, Clove and Anesthetics Such as Acetamidoeugenol, Alfadolone Eugenol; Acetate, Alfaxalone, Amucaine. Amolanone, Amylocalne Analgesics (narcotic) Such as Alfentanil, Allylprodine, 40 Hydrochloride, Benoximate, Benzocaine, Betoxycaine, Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, Biphenamine, Bupivacaine. Butacaine, Butaben, Butanilic Buprenorphine. Butorphanol, Clonitazene, Codeine, aine, Burethamine. Buthalital Sodium, Butoxycaine, Cartic Codeine Methyl Bromide, Codeine Phosphate, Codeine Sul aine, 2-Chloroprocaine Hydrochloride, Cocaethylene, fate, Desomorphine, Dextromoramide, DeZocine, Diampro Cocaine, Cyclomethycaine, Dibucaine Hydrochloride, mide, Dihydrocodeine, Dihydrocodeinone Enol Acetate, 45 Dimethisoquin, Dimethocaine, Diperadon Hydrochloride, Dihydromorphine, Dimenoxadol, Dimepheptanol, Dimeth Dyclonine, Ecgonidine, Ecgonine, Ethyl Aminobenzoate, ylthiambutene, Dioxaphetyl Butyrate, Dipipanone, Eptazo Ethyl Chloride, Etidocaine, Etoxadrol, B-Eucaine, Euprocin, cine, Ethoheptazine, Ethylmethlythiambutene, Ethylmor Fenalcomine, Fomocaine, Hexobarbital, Hexylcaine Hydro phine, Etonitazene, Fentanyl, Hydrocodone, Hydrocodone chloride, Hydroxydione Sodium, Hydroxyprocaine, Hydrox Bitartrate, Hydromorphone, Hydroxypethidine, Isometha 50 ytetracaine, 1sobutyl p-Aminobenzoate, Kentamine, Leuci done, Ketobemidone, Levorphanol, Lofentanil, Meperidine, nocaine Mesylate, LeVoxadrol, Lidocaine, Mepivacaine, Meptazinol, Metazocine, Methadone Hydrochloride, Meto Meprylcaine Hydrochloride, Metabutoxycaine Hydrochlo pon, Morphine, Morphine Derivatives, Myrophine, Nalbu ride, Methohexital Sodium, Methyl Chloride, Midazolam, phine, Narceline, Nicomorphine, Norlevorphanol, Normetha Myrtecaine, Naepaine, Octacaine, Orthocaine, Oxethazaine, done, Normorphine, Norpipanone, Opium, Oxycodone, 55 Parethoxycaine, Phenacaine Hydrochloride, Phencyclidine, Oxymorphone, Papavereturn, Pentazocine, Phenadoxone, Phenol, Piperocaine, Piridocaine, Polidocanol, Pramoxine, Phenazocine, Pheoperidine, Piminodine, Piritramide, Pro Prilocalne, Procaine, Propanidid, Propanocaine, Propara heptazine, Promedol, Properidine, Propiram, Propoxyphene, caine, Propipocaine, Propofol, Propoxycaine Hydrochloride, Sufentanil and Tilidine; Pseudococaine, Pyrrocaine, Quinine Urea Hydrochloride, Analgesics (non-narcotic) Such as Acetaminophen, 60 Risocaine, Salicyl Alcohol, Tetracaine Hydrochloride. Thial Acetaminosalol, Acetanilide, Acetylsalicylsalicylic Acid, barbital. Thimylal. Thiobutabarbital. Thiopental Sodium, Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis(acetyl Tolycaine, Trimecaine and Zolamine; salicylate), Aminochlorthenoxazin, 2-Amino-4-picoline, Anorexics Such as Aminorex, Amphecloral, Amphet Aminopropylon, Aminopyrine, Ammonium Salicylate, Anti amine, BenZaphetamine, Chlorphentermine, Clobenzorex, pyrine, Antipyrine Salicylate, Antrafenine, ApaZone, Aspirin, 65 Cloforex, Clortermine, Cyclexedrine. Destroamphetamine Benorylate, Benoxaprofen, BenZpiperylon, BenZydamine, Sulfate, Diethylpropion, Diphemethoxidine, N-Ethylam p-Bromoacetanilide, 5-Bromosalicylic Acid Acetate, Buce phetamine, Fenbutrazate, Fenfluramine, Fenproporex. Furfu US 8,414,914 B2 21 22 rylmethylamphetamine, Levophacetoperate, Mazindol, Arotinolol, Atenolol, Bevantolol, Bretylium Tosylate, Bucu Mefenorex, Metamfeproamone, Methamphetamine, Norps molol, Bufetolol, Bunaftine, Bunitrolol, Bupranolol, Butid eudoephedrine, Phendimetrazine, Phendimetrazine Tartrate, rine Hydrochloride, Butobendine, Capobenic Acid, Cara Phenmetrazine, Phenpentermine, Phenylpropanolamine Zolol, Carteolol, Cifenline, Cloranolol, Disopyramide, Hydrochloride and Picilorex: Encamide, Esmolol, Flecamide, Gallopamil, Hydroquini Anthelmintics (Cestodes) Such as Arecoline, Aspidin, dine, Indecamide, Indenolol, Ipratropium Bromide, Aspidinol, Dichlorophen(e). Embelin, Kosin, Napthalene, Lidocaine, Lorajmine, Lorcamide, Meobentine, Metipra Niclosamide, Pellertierine, Pellertierine Tannate and Quina nolol, Mexiletine, Moricizine, Nadoxolol, Nifemalol, Oxpre cr1ne; nolol, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline, Anthelmintics (Nematodes) such as Alantolactone. Amos 10 canate, Ascaridole, Bephenium, Bitoscanate, Carbon Tetra Procainamide Hydrochloride, Pronethalol, Propafenone, chloride, Carvacrol, Cyclobendazole, Diethylcarbamazine, Propranolol, Pyrinoline, Quinidine Sulfate, Quinidine, Diphenane, Dithiazanine Iodide, Dymanthine, Gentian Vio Sotalol, Talinolol, Timolol, Tocamide, Verapamil, Vicquidil let, 4-Hexylresorcinol, Kainic Acid, Mebendazole, and Xibenolol; 2-Napthol, Oxantel, Papain, piperazine, piperazine Adipate, 15 Antiarteriosclerotics such as Pyridinol Carbamate; piperazine Citrate, piperazine Edetate Calcium, piperazine Antiarthritic/Antirheumatics such as Allocupreide Tartrate, Pyrantel, Pyrvinium Pamoate, C.-Santonin, Stilba Sodium, Auranofin, Aurothioglucose, Aurothioglycanide, Zium Iodide, Tetrachloroethylene, Tetramisole, thiabenda Azathioprine, Calcium 3-Aurothio-2-propanol-1-sulfonate, Zole, Thymol, Thymyl N-Isoamylcarbamate, Triclofenol pip Celecoxib, Chloroquine, Clobuzarit, Cuproxoline, Diacerein, erazine and Urea Stibamine; Glucosamine, Gold Sodium Thiomalate, Gold Sodium Thio Anthelmintics (Onchocerca) Such as Ivermectin and sulfate, Hydroxychloroquine, KebuZone, Lobenzarit, Melit Suramin Sodium; tin, Methotrexate, Myloral and Penicillamine; Anthelmintics (Schistosoma) Such as Amoscanate, Antibacterial (antibiotic) drugs including: Aminoglyco Amphotalide, Antimony Potassium Tartrate, Antimony sides such as Amikacin, Apramycin, Arbekacin, Bambermy Sodium Gluconate, Antimony Sodium Tartrate, Antimony 25 cins, Butirosin, Dibekacin, Dihydrostreptomycin, Sodium Thioglycollate, Antimony Thioglycollamide, Becan Fortimicin(s), Gentamicin, Isepamicin, Kanamycin, Micro thone, Hycanthone, Lucanthone Hydrochloride, Niridazole, nomicin, Neomycin, Neomycin Undecylenate, Netilmicin, Oxamniquine, Praziquantel, Stibocaptate, Stibophen and Paromomycin, Ribostamycin, Sisomicin, Spectinomycin, Urea Stibamine; Streptomycin, Streptonicozid and Tobramycin; Anthelmintics (Trematodes) such as Anthiolimine and Tet 30 rachloroethylene; Amphenicols such as AZidamfenicol, Chloramphenicol, Antiacne drugs such as Adapelene, Algestone Chloramphenicol Palmitate, Chloramphenicol Pantothenate, Acetophenide, AZelaic Acid, Benzoyl Peroxide, Cyoctol, Florfenicol and Thiamphenicol; Cyproterone, Motretinide, Resorcinol, Retinoic Acid, Tetro Ansamycins such as Rifamide, Rifampin, Rifamycin and quinone and Tretinonine; 35 Rifaximin: Antiallergics such as Amlexanox, Astemizole, AZelastine, B-Lactams, including: Carbapenems such as Imipenem: Cromolyn, Fenpiprane. Histamine, Ibudilast, Nedocromil, Cephalosporins such as Cefactor, Cefadroxil, Cefaman Oxatomide, Pentigetide, Poison Ivy Extract, Poison Oak dole, Cefatrizine, Cefazedone, Cefazolin, Cefixime, Extract, Poison Sumac Extract, Repirinast, Tranilast, Trax Cefinenoxime, Cefodizime, Cefonicid, CefoperaZone, Cefo anoX and Urushiol: 40 ranide, Cefotaxime, Cefotiam, Ce?pimizole, Ce?piramide, Antiamebics Such as Arsthinol, Bialamicol, Carbarsone, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, Ceftazi Cephaeline, Chlorbetamide, Chloroquine, Chlorphenoxam dime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftri ide, Chlortetracycline, Dehydroemetine, Dibromopropami axone, Cefuroxime, CefuZonam, Cephacetrile Sodium, dine, Diloxanide, DephetarSone, Emetine, Fumagillin, Glau Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin, carubin, Glycobiarsol, 8-Hydroxy-7-iodo-5- 45 Cephalothin, Cephapirin Sodium, Cephradine and Piveefal quinolinesulfonic Acid, Iodochlorhydroxyquin, Iodoquinol, exin; Paromomycin, Phanquinone, Phearsone Sulfoxylate, Poly Cephamycins such as CefbuperaZone, Cefnmetazole, benzarsol, Propamidine, Quinfamide, Secnidazole, Sulfar Cefninox, Cefotan and Cefoxitin; side, Teclozan, Tetracycline. Thiocarbamizine. Thiocarbar Monobactams such as Aztreonam, Carumonam and Tige Sone and Timidazole; 50 monam, Antiandrogens Such as Bifluranol, Cyoctol, Cyproterone, Oxacephems such as Flomoxef and Moxalactam; Delmadinone Acetate, Flutimide, Nilutamide and Oxen Penicillins such as Amdinocillin, Amdinocillin Pivoxil, dolone; Amoxicillin, Ampicillin, Apalcillin, Aspoxicillin, AZidocil Antianginals such as Acebutolol. Alprenolol. Amiodarone, lin, AZlocillin, Bacampicillin, Benzylpenicillinic Acid, Ben Amlodipine, 55 Zylpenicillin Sodium, Carbenicillin, Carfecillin Sodium, Car Arotinolol, Atenolol, Bepridil, Bevantolol, Bucumolol, indacillin, Clometocillin, Cloxacillin, Cyclacillin, Bufetolol, Bufuralol, Bunitrolol, Bupranolol, Carazolol, Car Dicloxacillin, Diphenicillin Sodium, Epicillin, Fenbenicillin, teolol, Carvedilol, Celiprolol, Cinepazet Maleate, Diltiazem, Floxacillin, Hetacillin, Lenampicillin, Metampicillin, Methi Epanolol, Felodipine, Gallopamil, Imolamine, Indenolol. cillin Sodium, Mezlocillin, Nafcillin Sodium, Oxacillin, Isosorbide Dinitrate, Isradipine, Limaprost, Mepindolol, 60 Penamecillin, Penethamate Hydriodide, Penicillin G Beneth Metoprolol, Molsidomine, Nadolol, Nicardipine, Nifedipine, amine, Penicillin G Benzathine, Penicillin G Benzhydry Nifenalol, Nilvadipine, Nipradillol, Nisoldipine, Nitroglyc lamine, Penicillin G Calcium, Penicillin G Hydrabamine, erin, Oxprenolol, Oxyfedrine, OZagrel, Penbutolol, Pen Penicillin G Potassium, Penicillin G Procaine, Penicillin N, taerythritol Tetranitrate, Pindolol, Pronethalol, Propranolol. Penicillin O, Penicillin V, Penicillin V BenZathine, Penicillin Sotalol, Terodiline, Timolol, Toliprolol and Verapamil: 65 V Hydrabamine, Penimepicycline, Phenethicillin Potassium, Antiarrhythmics such as Acebutolol, Acecaine, Adenosine, Piperacillin, Pivampicillin, Propicillin, Quinacillin, Sulbeni Ajmaline, Alprenolol, Amiodarone, Amoproxan, Aprindine, cillin, Talampicillin, Temocillin and Ticarcillin; US 8,414,914 B2 23 24 Lincosamides Such as Clindamycin and Lincomycin; tyZine, Benapryzine, Benzetimide, Benzilonium Bromide, Macrollides such as Azithromycin, Carbomycin, Clarithro Benztropine Mesylate, Bevonium Methyl Sulfate, Biperiden, mycin, Erythromycin, Erythromycin Acistrate, Erythromy Butropium Bromide, N-Butylscopolammonium Bromide, cin Estolate, Erythromycin Glucoheptonate, Erythromycin Buzepide, Camylofine, Caramiphen Hydrochloride, Chlor Lactobionate, Erythromycin Propionate, Erythromycin benzoxamine, Chlorphenoxamine, Cimetropium Bromide, Stearate, Josamycin, Leucomycins, Midecamycins, Mioka Clidinium Bromide, Cyclodrine, Cyclonium Iodide, mycin, Oleandomycin, Primycin, Rokitamycin, Rosarami Cycrimine Hydrochloride, Deptropine, Dexetimide Dibuto cin, Roxithromycin, Spiramycin and Troleandomycin; line Sulfate, Dicyclomine Hydrochloride, Diethazine, Dife Polypeptides such as Amphomycin, Bacitracin, Capreo merine, Dihexyverine, Diphemanil Methylsulfate, N-(1,2- mycin, Colistin, Enduracidin, Enviomycin, Fusafungine, 10 Gramicidin(s), Gramicidin S, Mikamycin, Polymyxin, Poly Diphenylethyl) nicotinamide, Dipiproverine, Diponium myxin B-Methanesulfonic Acid, Pristinamycin, Ristocetin, Bromide, Emepronium Bromide, Endobenzyline Bromide, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine, Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Eto Tyrothricin, Vancomycin, Viomycin, Viomycin Pantothenate, midoline, Eucatropine, Fenpiverinium Bromide, Fentonium Virginiamycin and Zinc Bacitracin; 15 Bromide, Flutropium Bromide, Glycopyrrolate, Heteronium Tetracyclines such as Apicycline, Chlortetracycline, Clo Bromide, Hexocyclium Methyl Sulfate, Homatropine, Hyos mocycline, Demeclocycline, Doxycycline, Guamecycline, cyamine, Ipratropium Bromide, Isopropamide, Levomepate, Lymecycline, Meclocycline, Methacycline, Minocycline, Mecloxamine, Mepenzolate Bromide, Metcaraphen, Meth Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracy antheline Bromide, Methixene, Methscopolamine Bromide, cline, Sancycline, Senociclin and Tetracycline; and Octamylamine, Oxybutynin Chloride, Oxyphencyclimine, other antibiotics such as Cycloserine, Mupirocin and Oxyphenonium Bromide, Pentapiperide, Penthienate Bro Tuberin; mide, Phencarbamide, Phenglutarimide, Pipenzolate Bro Antibacterial drugs (synthetic), including: 2,4-Diami mide, Piperidolate, Piperilate, Poldine Methysulfate, Pridi nopyrimidines such as Brodimoprim, Tetroxoprim and Tri nol, Prifinium Bromide, Procyclidine, Propantheline methoprim; 25 Bromide, Propenzolate, Propyromazine, Scopolamine, Sco Nitrofurans such as Furaltadone, Furazolium Chloride, polamine N-Oxide, Stilonium Iodide, Stramonium, Sultropo Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Nifurpra nium, Thihexinol, Thiphenamil, Tiemonium Iodide, Time Zine, Nifurtoinol and Nitrofurantoin: pidium Bromide, Tiquizium Bromide, Tridihexethyl Iodide, Quinolones and Analogs such as Amifloxacin, Cinoxacin, Trihexyphenidyl Hydrochloride, Tropacine, Tropenzile, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flume 30 Tropicamide, Trospium Chloride, Valethamate Bromide and quine, Lomefloxacin, Miloxacin, Nalidixic Acid, Norfloxa Xeny tropium Bromide: cin, Ofloxacin, Oxolinic Acid, Pefloxacin, Pipemidic Acid, Anticonvulsants such as Acetylpheneturide, Albutoin, Piromidic Acid, Rosoxacin, Temafloxacin and Tosufloxacin; Aloxidone, Aminoglutethimide, 4-Amino-3-hydroxybutyric Sulfonamides Such as Acetyl Sulfamethoxypyrazine, Acid, Atrolactamide, Beclamide, Buramate, Calcium Bro Acetyl Sulfisoxazole, AZosulfamide, Benzylsulfamide, 35 mide, Carbamazepine, Cinromide, Clomethiazole, Clon Chloramine-B, Chloramine-T, Dichloramine T. Formosul azepam, Decimenide, Diethadione, Dimethadione, Doxeni fathiazole, N. Formylsulfisomidine, N°-f-D-Glucosylsulfa toin, Eterobarb, Ethadione, Ethosuximide, Ethotoin, nilamide, Mafenide, 4'-(Methylsulfamoyl)sulfanilanilide, Fluoresone, Garbapentin, 5-Hydroxytryptophan, Lamot p-Nitrosulfathiazole, Noprylsulfamide, Phthalylsulfaceta rigine, Lamictal, Magnesium Bromide, Magnesium Sulfate, mide, Phthalylsulfathiazole, Salazosulfadimidine, Succinyl 40 Mephenyloin, Mephobarbital, Metharbital, Methetoin, sulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy MethSuximide, 5-Methyl-5-(3-phenanthryl)hydantoin, ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, 3-Methyl-5-phenylhydantoin, Narcobarbital, Nimetazepam, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethi Nitrazepam, Paramethadione, Phenacemide, Phenetharbital, dole, Sulfaguanidine, Sulfaguanole, Sulfalene, Sulfaloxic Pheneturide, Phenobarbital, Phenobarbital Sodium, Phen Acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfame 45 suximide, Phenylmethylbarbituric Acid, Phenyloin, Pheth thizole, Sulfamethomidine, Sulfamethoxazole, Sul enylate Sodium, Potassium Bromide, Pregabalin, Primidone, famethoxypyridazine, Sulfametrole, Sulfamidochrysoidine, Progabide, Sodium Bromide, Sodium Valproate, Solanum, Sulfamoxole, Sulfanilamide, Sulfanilamidomethanesulfonic Strontium Bromide, Suclofenide, Sulthiame, Tetrantoin, Acid Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, Tiagabine, Trimethadione, Valproic Acid, Valpromide, N-Sulfanilylsulfanilamide, Sulfanily lurea, Sulfanilyl-3,4- 50 Vigabatrin and Zonisamide: xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sul Antidepressants, including: Bicyclics Such as Binedaline, faproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, CaroXaZone, Citalopram, Dimethazan, Indalpine, Fencam Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, ine, Fluvoxamine Maleate, Indeloxazine Hydrochloride, Sulfisomidine and Sulfisoxazole; Nefopam, Nomifensine, Oxitriptan, Oxypertine, Paroxetine, Sulfones such as Acedapsone, Acediasulfone, Acetosul 55 Sertraline. Thiazesim, Trazodone, Venlafaxine and Zometap fone Sodium, Dapsone, Diathymosulfone, Glucosulfone 1ne, Sodium, Solasulfone. Succisulfone, Sulfanilic Acid, p-Sulfa Hydrazides/Hydrazines such as Benmoxine, Iproclozide, nilylbenzylamine, pp'-Sulfonyldianiline-N,N'digalactoside, Iproniazid, Isocarboxazid, Nialamide, Octamoxin and Sulfoxone Sodium and Thiazolsulfone; and Phenelzine; others such as Clofoctol, Hexedine, Methenamine, Meth 60 Pyrrolidones such as Cotinine, Rolicyprine and Rolipram; enamine Anhydromethylene-citrate, Methenamine Hippu Tetracyclics such as Maprotiline, Metralindole, Mianserin rate, Methenamine Mandelate, Methenamine Sulfosalicylate, and Oxaprotiline; Nitroxoline and Xibornol; Tricyclics Such as Adinazolam, Amitriptyline, Amitriptyli Anticholinergics such as Adiphenine Hydrochloride, noxide, Amoxapine, Butriptyline, Clomipramine, Demexip Alverine, Ambutonomium Bromide, Aminopentamide, 65 tiline, Desipramine, Dibenzepin, Dimetracrine, Dothiepin, Amixetrine, Amprotropine Phosphate, Anisotropine Methyl Doxepin, Fluacizine, Imipramine, Imipramine N-Oxide, bromide, Apoatropine, Atropine, Atropine N-Oxide, Benac Iprindole, Lofepramine, Melitracen, Metapramine, Nortrip US 8,414,914 B2 25 26 tyline, Noxiptilin, Opipramol, Pizotyline, Propizepine, Prot niramine, Dimethindene, Metron S. Pheniramine, Pyrrob riptyline, Quinupramine, Tianeptine and Trimipramine; and utamine. Thenaldine, Tolpropamine and Triprolidine; others such as Adrafinil, Benactyzine, Bupropion, Butace Aminoalkyl ethers such as Bietanautine, Bromodiphenhy tin, Deanol, Deanol Aceglumate, Deanol Acetamidoben dramine, Carbinoxamine, Clemastine, Diphenylpyraline, Zoate, Dioxadrol, Etoperidone, Febarbamate, Femoxetine, Doxylamine, Embramine, Medrylamine, Mephenphy Fenpentadiol, Fluoxetine, Fluvoxamine, Hematoporphyrin, dramine, p-Methyldiphenhydramine, Orphenadrine, Phenyl Hypercinin, Levophacetoperane, Medifoxamine, Minaprine, toloxamine, Piprinhydrinate and Setasine; Moclobemide, Oxaflozane, Piberaline, Prolintane, Pyrisuc Ethylenediamine derivatives such as Alloclamide, p-Bro cideanol, Rubidium Chloride, Sulpiride, Sultopride, Tenilox mtripelennamine, Chloropyramine, Chlorothen, Histapyrro azine, Thozalinone, Tofenacin, Toloxatone, Tranylcyprom 10 dine, Methafurylene, Methaphenilene, Methapyrilene, Phen ine, L-Tryptophan, Viloxazine and Zimeldine; Antidiabetics, including: Biguanides such as Buformin, benzamine, Pyrilamine, Talastine. Thenyldiamine, Metformin and Phenformin; Thonzylamine Hydrochloride, Tripelennamine and Zola Hormones such as Glucagon, Insulin, Insulin Injection, mine; Insulin Zinc Suspension, Isophane Insulin Suspension, Prota 15 Piperazines such as Cetirizine, Chlorcyclizine, Cinnariz mine Zinc Insulin Suspension and Zinc Insulin Crystals; ine, Clocinizine and Hydroxy Zine; Sulfonylurea derivatives such as Acetohexamide, 1-Butyl Tricyclics, including: Phenothiazines Such as Ahistan, 3-metanilylurea, Carbutamide, Chlorpropamide, Glibornu Etymemazine, Fenethazine, N-Hydroxyethylpromethazine ride, Gliclazide, Glipizide, Gliquidone, Glisoxepid, Gly Chloride, Isopromethazine, Mequitazine, Promethazine, buride, Glybuthiazol(e), Glybuzole, Glyhexamide, Pyrathiazine and Thiazinamium Methyl Sulfate; and Glymidine, Glypinamide, Phenbutamide, Tolazamide, Tolb others such as AZatadine, Clobenzepam, Cyproheptadine, utamide and Tolcyclamide; and Deptropine, Isothipendyl, Loratadine and Prothipendyl; and others such as Acarbose, Calcium Mesoxalate and Migli other antihistamines such as Antazoline, Astemizole, tol; Azelastine, Cetoxime, Clemizole, Clobenztropine, Antidiarrheal drugs such as Acetyltannic Acid, Albumin 25 Diphenazoline, Diphenhydramine, Fluticasone Propionate, Tannate, Alkofanone, Aluminum Salicylates—Basic, Cat Mebhydroline, Phenindamine, Terfenadine and Tritoqualine: echin, Dilfenoxin, Diphenoxylate, Lidamidine, Loperamide, Antihyperlipoproteinemics, including: Aryloxyalkanoic Mebiquine, Trillium and Uzarin; acid derivatives such as Beclorbrate, Bezafibrate, Binifibrate, Antidiuretics such as Desmopressin, Fely pressin, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric Acid, Etofi Lypressin, Ornipressin, Oxycinchophen, Pituitary—Poste 30 rior, Terlipressin and Vasopressin; brate, Fenofibrate, Gemfibrozil, Nicofibrate, Pirifibrate, Ron Antiestrogens such as Delmadinone Acetate, Ethamoxyt ifibrate, Simfibrate and Theofibrate; riphetol, Tamoxifen and Toremifene: Bile acid sequesterants such as Cholestyramine Resin, Antifungal drugs (antibiotics), including: Polyenes such as Colestipol and Polidexide: Amphotericin-B, Candicidin, Dermostatin, Filipin, Fun 35 HMG CoA reductase inhibitors such as Fluvastatin, Lov gichromin, Hachimycin, Hamycin, Lucensomycin, Mepartri astatin, Pravastatin Sodium and Simvastatin: cin, Natamycin, Nystatin, Pecilocin and Perimycin; and oth Nicotinic acid derivatives Aluminum Nicotinate, Acipi erS Such as AZaserine, Griseofulvin, Oligomycins, Neomycin moX, Niceritrol, Nicoclonate, Nicomol and Oxiniacic Acid; Undecylenate, Pyrrolnitrin, Siccanin, Tubercidin and Viridin; Thyroid hormones and analogs such as EtiroXate, Thyro Antifungal drugs (synthetic), including: Allylamines such 40 propic Acid and Thyroxine; and as Naftifine and Terbinafine; others such as Acifran, AZacosterol, Benfluorex, B-Benza Imidazoles such as Bifonazole, Butoconazole, Chlordan lbutyramide, Carnitine, Chondroitin Sulfate, Clomestone, toin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Detaxtran, Dextran Sulfate Sodium,5,8,11,14, 17-Eicosapen Enilconazole, Fenticonazole, Isoconazole, Ketoconazole, taenoic Acid, Eritadenine. Furazabol, Meglutol, Melinamide, Miconazole, Omoconazole, Oxiconazole, Nitrate, Sulcona 45 Mytatrienediol, Ornithine, Y-Oryzanol, Pantethine, Pen Zole and Tioconazole; taerythritol Tetraacetate, C.-Phenylbutyramide, Pirozadil, Triazoles such as Fluconazole, Itraconazole and Tercona Probucol, C-Sitosterol, Sultosilic Acid, piperazine Salt, Tia Zole; and denol, Triparanol and Xenbucin: others such as Acrisorcin, Amorolfine, Biphenamine, Bro Antihypertensive drugs, including: Arylethanolamine mosalicylchloranilide, Buclosamide, Calcium Propionate, 50 derivatives such as Amosulalol, Bufuralol, Dilevalol, Labe Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, talol, Pronethalol, Sotalol and Sulfinalol; Diamthazole, Dihydrochloride. Exalamide, Flucytosine, Aryloxypropanolamine derivatives such as Acebutolol. Halethazole, Hexetidine, Loflucarban, Nifuratel, Potassium Alprenolol. Arotinolol, Atenolol, Betaxolol, Bevantolol, Iodide, Propionic Acid, Pyrithione, Salicylanilide, Sodium Bisoprolol, Bopindolol, Bunitrolol, Bupranolol, Butofilolol, Propionate, Sulbentine, Tenonitrozole, Tolciclate, Tolindate, 55 Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and Zinc Carazolol, Cartezolol, Carvedilol, Celiprolol, Cetamolol, Propionate; Epanolol, Indenolol, Mepindolol, Metipranolol, Metoprolol, Antiglaucoma drugs such as Acetazolamide. Befunolol. Moprolol, Nadolol, Nipradilol, Oxprenolol, Penbutolol, Pin Betaxolol, Bupranolol, Carteolol, Dapiprazoke. Dichlorphe dolol, Propranolol, Talinolol, Tetraolol, Timolol and Tolip namide, Dipivefrin, Epinephrine, Levobunolol, Methazola 60 rolol; mide, Metipranolol, Pilocarpine, Pindolol and Timolol; Benzothiadiazine derivatives such as Althiazide, Bendrof Antigonadotropins such as Danazol, Gestrinone and Par lumethiazide, Benzthiazide, Benzylhydrochlorothiazide, oxypropione; Buthiazide, Chlorothiazide, Chlorthalidone, Cyclopenthiaz Antigout drugs such as Allopurinol, Carprofen, Colchi ide, Cyclothiazide, Diazoxide, Epithiazide, Ethiazide, Fen cine, Probenecid and Sulfinpyrazone; 65 quizone, Hydrochlorothiazide, Hydroflumethiazide, Methy Antihistamines, including: Alkylamine derivatives Such as clothiazide, Meticrane, Metolazone, Paraflutizide, Acrivastine, Bamipine, Brompheniramine, Chlorphe Polythiazide, Tetrachlormethiazide and Trichlormethiazide: US 8,414,914 B2 27 28 N-Carboxyalkyl (peptide/lactam) derivatives such as Ala Arylpropionic acid derivatives such as Alminoprofen, cepril, Captopril, Cilazapril, Delapril, Enalapril, Enalaprilat, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Fosinopril, Lisinopril, Moveltipril, Perindopril, Quinapril Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, and Ramipril; Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Dihydropyridine derivatives such as Amlodipine, Fello Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, dipine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Protizinic Acid, Suprofen and Tiaprofenic Acid; Nisoldipine and Nitrendipine; Pyrazoles such as Difenamizole and Epirizole; Guanidine derivatives such as Bethanidine, Debrisoquin, Pyrazolones Such as Apazone, BenZpiperylon, Feprazone, GuanabenZ, Guanacline, Guanadrel, GuanaZodine, Mofebutazone, Morazone, Oxyphenbutazone, Phenylbuta Guanethidine, Guanfacine, Guanochlor, Guanoxabenz, and 10 Zone, PipebuZone, Propyphenazone, Ramifenazone, Suxibu GuanoXan; Zone and ThiazolinobutaZone; Hydrazines and phthalazines Such as Budralazine, Salicylic acid derivatives Such as Acetaminosalol, Aspirin, Cadralazine, Dihydralazine, Endralazine, Hydracarbazine, Benorylate, Bromosaligenin, Calcium Acetylsalicylate, Hydralazine, Pheniprazine, Pildralazine and Todralazine; Diflunisal, Etersalate, Fendosal, Gentisic Acid, Glycol Sali Imidazole derivatives such as Clonidine, Lofexidine, 15 cylate, Imidazole Salicylate, Lysine Acetylsalicylate, Phentolamine, Phentolamine Mesylate, Tiamenidine and Mesalamine, Morpholine Salicylate, 1-Naphthyl Salicylate, Tolonidine; Olsalazine, Parsalmide, PhenylAcetylsalicylate, Phenyl Sali Quaternary ammonium compounds AZamethoniurn Bro cylate, Salacetamide, Salicylamine O-Acetic Acid, Salicyl mide, Chlorisondamine Chloride, Hexamethoniurn, Penta sulfuric Acid, Salsalate and Sulfasalazine; cynium Bis(methylsulfate), Pentamethonium Bromide, Pen Thiazinecarboxamides such as Droxicam, Isoxicam, tolinium Tartrate, Phenactropinium Chloride and Piroxicam and Tenoxicam, and Trimethidinium Methosulfate; others such as e-Acetamidocaproic Acid, S-Adenosylme Quinazoline derivatives such as AlfuZosin, BunaZosin, thionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine, Doxazosin, Prasosin, Terazosin and TrimaZosin; Bendazac, Benzydamine, Bucolome. Difenpiramide, Dita Reserpine derivatives such as Bietaserpine, Deserpidine, 25 Zol, EmorfaZone, GuaiaZulene, Nabumetone, Nimesulide, Rescinnamine, Reserpine and Syrosingopine; Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime, Pro Sulfonamide derivatives such as Ambuside, Clopamide, quaZone, Proxazole and Tenidap: Furosemide, Indapamide, QuinethaZone, Tripamide and Antimalarial drugs such as Acedapsone, Amodiaquin, Xipamide; and Arteether, Artemether, Artemisinin, Artesunate, Bebeerine, others such as Ajmaline, Y-Aminobutyric Acid, Bufeniode, 30 Berberine, Chirata, Chlorguanide, Chloroquine, Chlor Candesartan, Chlorthalidone, Cicletanine, Ciclosidomine, proguanil, Cinchona, Cinchonidine, Cinchonine, Cyclogua Cryptenamine Tannates, Eprosartan, Fenoldopam, Flose nil, Gentiopicrin, Halofantrine, Hydroxychloroquine, Meflo quinan, Indoramin, Irbesartan, Ketanserin, Losartan, Meb quine Hydrochloride, 3-Methylarsacetin, Pamaquine, utamate, Mecamylamine, Methyldopa, Methyl 4-Pyridyl Plasmocid, Primaquine, Pyrimethamine, Quinacrine, Qui Ketone Thiosemicarbazone, Metolazone, Minoxidil, 35 nine, Quinine Bisulfate, Quinine Carbonate, Quinine Dihy Muzolimine, Pargyline, Pempidine, Pinacidil, Piperoxan, drobromide, Quinine Dihydrochloride, Quinine Ethylcar Primaperone, Protoveratrines, Raubasine, Rescimetol, Ril bonate, Quinine Formate, Quinine Gluconate, Quinine menidine, Saralasin, Sodium Nitroprusside, Ticrynafen, Tri Hydriodide, Quinine Hydrochloride, Quinine Salicylate, methaphan Camsylate, Tyrosinase, Urapidil and Valsartan; Quinine Sulfate, Quinine Tannate, Quinine Urea Hydrochlo Antihyperthyroids such as 2-Amino-4-methylthiazole, 40 ride, Quinocide, Quinoline and Sodium Arsenate Diabasic; 2-Aminothiazole, Carbimazole, 3,5-Dibromo-L-tyrosine, Antimigraine drugs such as Alpiropride, Dihydroergota 3,5-Diiodotyrosine, Hinderin, Iodine, lothiouracil, Methima mine, Eletriptan, Ergocornine, Ergocorninine, Ergocryptine, Zole, Methylthiouracil, Propylthiouracil, Sodium Perchlor Ergot, Ergotamine, FlumedroXone acetate, Fonazine, ate, Thibenzazoline. Thiobarbital and 2-Thiouracil; Lisuride, Methysergid(e), Naratriptan, Oxetorone, Pizoty Antihypotensive drugs such as Amezinium Methyl Sulfate, 45 line, Rizatriptan and Sumatriptan; Angiotensin Amide, Dimetofrine, Dopamine, Etifelmine, Antinauseant drugs such as Acetylleucine Monoethanola Etilefrine, Gepefrine, Metaraminol, Midodrine, Norepineph mine, Alizapride, BenZquinamide, Bietanautine, Bro rine, Pholedrine and Synephrine; mopride, Buclizine, Chlorpromazine, Clebopride, Cyclizine, Antihypothyroid drugs such as Levothyroxine Sodium, Dimenhydrinate, Diphenidol, Domperidone, Granisetron, Liothyronine, Thyroid, Thyroidin, Thyroxine, Tiratricol and 50 Meclizine, Methalltal, Metoclopramide, Metopimazine, TSH: Nabilone, Ondansetron, Oxypendyl, Pipamazine, Piprinhy Anti-Inflammatory (non-steroidal) drugs, including: Ami drinate, Prochlorperazine, Scopolamine, Tetrahydrocannab noarylcarboxylic acid derivatives Such as Enfenamic Acid, inols. Thiethylperazine. Thioproperzaine and Trimethoben Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Zamide: Acid, Mefanamic Acid, Niflumic Acid, Talniflumate, Terofe 55 Antineoplastic drugs, including: Alkylating agents, such as namate and Tolfenamic Acid; Alkylsulfonates such as Busulfan, Improsulfan and Piposul Arylacetic acid derivatives such as Acemetacin, fan; Alclofenac, Amfenac, Bufexamac, Cinmetacin, Clopirac, AZiridines such as BenZodepa, Carboquone, Meturedepa Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Fen and Uredepa; clorac, Fenclozic Acid, Fentiazac, Glucametacin, Ibufenac, 60 Ethylenimines and methylmelamines Such as Altretamine, Indomethacin, IsofeZolac, 1soXepac, Lonazolac, Metiazinic Triethylenemelamine, Triethylenephosphoramide, Triethyl Acid, Oxametacine, Proglumetacin, Sulindac, Tiaramide, enethiophosphoramide and Trimethylolomelamine; Tolimetin and Zomepirac, Nitrogen mustards such as Chlorambucil, Chlornaphazine, Arylbutyric acid derivatives such as Bumadizone. Buti Cyclophosphamide, Estramustine, Ifosfamide, Mechlore bufen, Fenbufen and Xenbucin; 65 thamine, Mechlorethamine Oxide Hydrochloride, Mel Arylcarboxylic acids such as Clidanac, Ketorolac and phalan, Novembichin, Phenesterine, Prednimustine, Trofos Tinoridine; famide and Uracil Mustard; US 8,414,914 B2 29 30 Nitrosoureas such as Carmustine, Chlorozotocin, Fote Hydrochloride, Pentamidine, Propamidine, Puromycin, mustine, Lomustine, Nimustine and Ranimustine; and Quinapyramine, Stilbamidine, Suramin Sodium, Trypan Red others such as Camptothecin, Dacarbazine, Mannomus and Tryparasmide; tine, Mitobronitol, Mitolactol and Pipobroman; Antipuritics such as Camphor, Cyproheptadine, Dichlor Antibiotics such as Aclacinomycins, Actinomycin F, isone, Glycine, Halometasone, 3-Hydroxycamphor, Men Anthramycin, AZaserine, Bleomycins, Cactinomycin, Caru thol, Mesulphen, Methdilazine, Phenol, Polidocanol, bicin, Carzinophilin, Chromomycins, Dactinomycin, Dauno Risocaine, Spirit of Camphor. Thenaldine, Tolpropamine and rubicin, 6-Diazo-5-oxo-L-norleucine, Doxorubicin, Epirubi Trimeprazine; cin, Mitomycins, Mycophenolic Acid, Nogalamycin, Antipsoriatic drugs such as Acitretin, Ammonium Salicy Olivomycins, Peplomycin, Plicamycin, Porfiromycin, Puro 10 late, Anthralin, 6-AZauridine, Bergapten(e), Chrysarobin, mycin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Etretinate and Pyrogallol; Zinostatin and Zorubicin; Antipsychotic drugs, including: Butyrophenones such as Antimetabolites, including: Folic acid analogs such as Benperidol, Bromperidol, Droperidol, Fluanisone, Haloperi Denopterin, Methotrexate, Pteropterin and Trimeterxate; dol, Melperone, Moperone, Pipamperone, Spiperone, Timi Purine analogs such as Fludarabine, 6-Mercaptopurine, 15 perone and Trifluperidol; Thiamiprine and Thioguanine; and Phenothiazines Such as Acetophenazine, Butaperazine, Pyrimidine analogs such as Ancitabine, AZacitidine, Carphenazine, Chlorproethazine, Chlorpromazine, Clospira 6-AZauridine, Carmofur, Cytarabine, Doxifluridine, Enocit Zine, Cyamemazine, Dixyrazine, Fluphenazine, Imiclo abine, Floxuridine Fluorouracil and Tegafur, pazine, Mepazine, Mesoridazine, Methoxypromazine, Enzymes such as L-Asparaginase; and Metofenazate, Oxaflumazine, Perazine, Pericyazine, others such as Aceglatone, Amsacrine, Bestrabucil, Bisant Perimethazine, Perphenazine, Piperacetazine, Pipotiazine, rene, Bryostatin 1, Carboplatin, Cisplatin, Defosfamide, Prochlorperazine, Promazine, Sulforidazine. Thiopropazate, Demecolcine, Diaziquone, Eflornithine, Elliptiniurn Acetate, Thioridazine, Trifluoperazine and Triflupromazine: Etoglucid, Etoposide, Gallium Nitrate, Hydroxyurea, Inter Thioxanthenes such as Chlorprothixene, Clopenthixol, feron-C, Interferon-B, Interferon-Y, Interleukin-2, Lentinan, 25 Flupentixol and Thiothixene; Letrozole, Lonidamine, MitoguaZone, Mitoxantrone, Mopi other tricyclics such as BenZquinamide, Carpipramine, damol, Nitracrine, Pentostatin, Phenamet, Pirarubicin, Podo Clocapramine, Clomacran, Clothiapine, Clozapine, phyllinic Acid, 2-Ethylhydrazide, Polynitrocubanes, Procar Opipramol, Prothipendyl, Tetrabenazine, and Zotepine; and bazine, PSK7, Razoxane, Sizofuran, Spirogermanium, Taxol. others such as Alizapride, Amisulpride, Buramate, Fluspir Teniposide, TenuaZonic Acid, Triaziquone, 2.2.2"-Trichlo 30 ilene, Molindone, Penfluridol, Pimozide, Spirilene and rotriethylamine, Urethan, Vinblastine, Vincristine, Vindesine Sulpiride; and Vinorelbine; Antipyretics such as Acetaminophen, Acetaminosalol, Antineoplastic (hormonal) drugs, including: Androgens Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Alu Such as Calusterone, Dromostanolone Propionate, Epi minum Bis(acetylsalicylate), Aminochlorthenoxazin, Ami tiostanol, Mepitiostane and Testolactone; 35 nopyrine, Aspirin, Benorylate, BenZydamine, Berberine, Antiadrenals such as Aminoglutethimide, Mitotane and p-Bromoacetanilide, Bufexamac, Bumadizon, Calcium Ace Trilostane; tylsalicylate, Chlorthenoxazin(e), Choline Salicylate, Clid Antiandrogens such as Flutamide and Nilutamide; and anac, Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Antiestrogens Such as Tamoxifen and Toremifene; Dipyrone, Epirizole, Etersalate, Imidazole Salicylate, Antineoplastic adjuncts including folic acid replenishers 40 Indomethacin, IsofeZolac, p-Lactophenetide, Lysine Acetyl such as Frolinic Acid; salicylate, Magnesium Acetylsalicylate, Meclofenamic Acid, Antiparkinsonian drugs such as Amantadine, Benserazide, Morazone, Morpholine Salicylate, Naproxen, NifenaZone, Bietanautine, Biperiden, Bromocriptine, Budipine, Caber 51-Nitro-2'-propoxyacetanilide, Phenacetin, Phenicarbazide, goline, Carbidopa, Deprenyl (a/k/a L-deprenyl, L-deprenil. Phenocoll, Phenopyrazone, PhenylAcetylsalicylate, Phenyl L-deprenaline and selegiline), Dexetimide, Diethazine, 45 Salicylate, PipebuZone, Propacetamol, Propyphenazone, Diphenhydramine, Droxidopa, Ethopropazine, Ethylbenzhy RamifenaZone, Salacetamide, Salicylamide O-Acetic Acid, dramine, Levodopa, Naxagolide, Pergolide, Piroheptine, Sodium Salicylate, Sulfamipyrine, Tetrandrine and Tinori Pramipexole, Pridinol, Prodipine, Quinpirole, Remacemide, dine; Ropinirole, Terguride, Tigloidine and Trihexyphenidyl Antirickettsial drugs such as p-Aminobenzoic Acid, Hydrochloride; 50 Chloramphenicol, Chloramphenicol Palmitate, Chloram Antipheochromocytoma drugs such as Metyrosine, Phe phenicol Pantothenate and Tetracycline; noxybenzamine and Phentolamine; Antiseborrheic drugs such as Chloroxine, 3-O-Lauroylpy Antipneumocystis drugs such as Eflornithine, Pentamidine ridoxol Diacetate, Piroctone, Pyrithione, Resorcinol, Sele and Sulfamethoxazole; nium Sulfides and Tioxolone; Antiprostatic hypertrophy drugs such as Gestonorone 55 Antiseptics, including: Guanidines such as Alexidine, Caproate, Mepartricin, Oxendolone and Proscar; Ambazone, Chlorhexidine and Picloxydine: Antiprotozoal drugs (Leishmania) Such as Antimony Halogens and halogen compounds Such as Bismuth Iodide Sodium Gluconate, Ethylstibamine, Hydroxy stilbamidine, Oxide, Bismuth Iodosubgallate, Bismuth Tribromophenate, N-Methylglucamine, Pentamidine, Stilbamidine and Urea Bornyl Chloride, Calcium Iodate, Chlorinated Lime, Cloflu Stibamine; 60 carban, Fluorosalan, Iodic Acid, Iodine, Iodine Monochlo Antiprotozoal drugs (Trichomonas) Such as AcetarSone, ride, Iodine Trichloride, Iodoform, Methenamine Tetraiod Aminitrozole, Anisomycin, AZanidazole, Forminitrazole, ine, Oxychlorosene, Povidone-Iodine, Sodium Hypochlorite, Furazolidone, Hachimycin, Lauroguadine, Mepartricin, Met Sodium Iodate, Symclosene, Thymol Iodide, Triclocarban, ronidazole, Nifuratel, Nifuroxime, Nimorazole, Secnidazole, Triclosan and Troclosene Potassium; Silver Picrate, Tenonitrozole and Tinidazole; 65 Mercurial compounds Such as Hydrargaphen, Meralein Antiprotozoal drugs (Trypanosoma) Such as BenZnida Sodium, Merbromin, Mercuric Chloride, Mercuric Chloride, Zole, Eflornithine, Melarsoprol, Nifurtimox, Oxophenarsine, Ammoniated, Mercuric Sodium p-Phenol-sulfonate, Mercu US 8,414,914 B2 31 32 ric Succinimide, Mercuric Sulfide, Red, Mercurophen, Mer Antiulcerative drugs such as Aceglutamide Aluminum curous Acetate, Mercurous Chloride, Mercurous Iodide, Complex, e-Acetamido-caproic Acid Zinc Salt, Acetoxolone, Nitromersol, Potassium Tetraiodo-mercurate(II), Potassium Arbaprostil, Benexate Hydrochloride, Bismuth Subcitrate Triiodomercurate (II) Solution. Thimerfonate Sodium and Sol (Dried), Carbenoxolone, Cetraxate, Cimetidine, Enpros Thimerosal; 5 til, Esaprazole, Famotidine, Ftaxilide, Gefarnate, GuaiaZu Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5- lene, Irsogladine, Misoprostol, Nizatidine, Omeprazole, nitrofuran, Nidroxy Zone, Nifuroxime, Nifurzide and Nitro Ornoprostil, Y-Oryzanol, Pifamine, Pirenzepine, Plaunotol, furaZone; Ranitidine, Rioprostil, Rosaprostol, Rotraxate, Roxatidine Phenols such as Acetomeroctol, Bithionol, Cadmium Sali Acetate, Sofalcone, Spizofurone. Sucralfate, Teprenone, Tri cylate, Carvacrol, Chloroxylenol, Clorophene, Cresote, 10 moprostil, Trithiozine, Troxipide and Zolimidine: Cresol(s), p-Cresol, Fenticlor, Hexachlorophene, 1-Naphthyl Antiurolithic drugs such as Acetohydroxamic Acid, Salicylate, 2-Naphthyl Salicylate, 2.4.6-Tribromo-m-cresol, Allopurinol, Potassium Citrate and Succinimide: and 3',4',5'-Trichlorosalicylanilide; Antivenin drugs such as Lyovac antivenin, Quinolines such as Aminoquinuride, BenZOXiquine, BroX Antiviral drugs, including: Purines and pyrimidinones yduinoline, ChloroXine, Chlorquinaldol, Cloxyquin, Ethyl 15 Such as Acyclovir, Cytarabine, Dideoxyadenosine, Dideoxy hydrocupreine, Euprocin, Halquinol, Hydrastine, 8-Hydrox cytidine, Dideoxyinosine, Edoxudine, Floxuridine, Ganci yduinoline, 8-Hydroxyquinoline Sulfate and clovir, Idoxuridine, Inosine Pranobex, MADU, Penciclovir, Iodochlorhydroxyquin; and Trifluridine, Vidarabine and Zidovudine; and others such as Aluminum Acetate Solution, Aluminum others such as Acetylleucine Monoethanolamine, Amanta Subacetate Solution, Aluminum Sulfate, 3-Amino-4-hy dine, Amidinomycin, Cosalane, Cuminaldehyde Thiosemi droxybutyric Acid, Boric Acid, Chlorhexidine, Chloroazo carbazone, Foscarnet Sodium, Imiquimod, Interferon-C. din, m-CresylAcetate, Cupric Sulfate, Dibromopropamidine, Interferon-B, Interferon-Y, Kethoxal, Lysozyme, Methisa Ichthammol. Negatol, Noxytiolin, Ornidazole, B-Propiolac Zone, Moroxydine, Podophyllotoxin, Ribavirin, Rimanta tone, C-Terpineol; 25 dine, Stallimycin, Statolon, Tromantadine and Xenazoic Antispasmodic drugs such as Alibendol, Ambucetamide, Acid; Aminopromazine, Apoatropine, Bevonium Methyl Sulfate, Anxiolytic drugs, including: Arylpiperazines such as Bus Bietamiverine. Butaverine, Butropium Bromide, N-Bu pirone, Gepirone, Ipsapirone and Tandospirone; tylscopolammonium Bromide, Caroverine, Cimetropium Benzodiazepine derivatives such as Alprazolam, Bro Bromide, Cinnamedrine, Clebopride, Coniine Hydrobro 30 mazepam, Camazepam, Chlordiazepoxide, Clobazam, Clo mide, Conine Hydrochloride, Cyclonium Iodide, Difemer razepate, Clotiazepam, Cloxazolam, Diazepam, Ethyl ine, Diisopromine, Dioxaphetyl Butyrate, Diponium Bro Loflazepate, Etizolam, Fludiazepam, Flutazolam, Fluto mide, Drofenine, Emepronium Bromide, Ethaverine, prazepam, Halazepam, Ketazolam, Lorazepam, Loxapine, Feclemine, Fenalamide, Fenoverine, Fenpiprane, Fenpiver Medazepam, Metaclazepam, Mexazolam, Nordazepam, inium Bromide, Fentonium Bromide, Flavoxate, Flopropi 35 one, Gluconic Acid, Guaiactamine, Hydramitrazine, Hyme Oxazepam, Oxazolam, Pinazepam, Prazepam and Tofiso cromone, Leiopyrrole, Mebeverine, Moxaverine, Nafiverine, pam, Octamylamine, Octaverine, Pentapiperide, Phenamacide Carbamates Such as Cyclarbamate, Emylcamate, Hydrox Hydrochloride, Phloroglucinol, Pinaverium Bromide, Piperi yphenamate, Meprobamate, Phenprobamate and Tybamate; late, Pipoxolan Hydrochloride, Pramiverin, Prifinium Bro 40 and mide, Properidine, Propivane, Propyromazine, Prozapine, others such as Alpidem, BenZoctamine, Captodiamine, Racefemine, Rociverine, Spasmolytol, Stilonium Iodide, Chlormezanone, Etifoxine, Flesinoxan, Fluoresone, Sultroponium, Tiemonium Iodide, Tiquizium Bromide, Tiro Glutamic Acid, Hydroxyzine, Lesopitron, Mecloralurea, pramide, Trepibutone, Tricromyl, Trifolium, Trimebutine, Mephenoxalone, Mirtazapine, Oxanamide, Phenaglycodol. N,N-Dimethyl-3,3-diphenyl-propylamine, Tropenzile, Tro 45 Suriclone and Zatosetron; spium Chloride and Xeny tropium Bromide: Benzodiazepine antagonists such as Flumazenil; Antithrombotic drugs such as Anagrelide, Argatroban, Cil Bronchodilators, including: Ephedrine derivatives such as ostazol, Chrysoptin, Daltroban, Defibrotide, Enoxaparin, Albuterol, Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Fraxiparine, Indobufen, Lamoparan, OZagrel, Picotamide, Clorprenaline, Dioxethedrin, Ephedrine, Epinephrine, Plafibride, Reviparin, Tedelparin, Ticlopidine, Triflusal and 50 Eprozinol, Etafedrine, Ethylnorepinephrine, Fenoterol, Warfarin; Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Antitussive drugs such as Alloclamide, Amicibone, Ben Metaproterenol, N-Methylephedrine, Pirbuterol, Procaterol, properine, BenZonatate, Bibenzonium Bromide, Bromoform, Protokylol, Reproterol, Rimiterol, Salmeterol, Soterenol, Butamirate. Butethamate, Caramiphen Ethanedisulfonate, Terbutaline and Tulobuterol; Carbetapentane, Chlophedianol, Clobutinol, Cloperastine, 55 Quaternary ammonium compounds Such as Bevonium Codeine, Codeine Methyl Bromide, Codeine N-Oxide, Methyl Sulfate, Clutropium Bromide, Ipratropium Bromide Codeine Phosphate, Codeine Sulfate, Cyclexanone, Dex and Oxitropium Bromide: tromethorphan, Dibunate Sodium, Dihydrocodeine, Dihy Xanthine derivatives such as Acefylline, Acefylline pipera drocodeinone Enol Acetate, Dimemorfan, Dimethoxanate, zine, Ambuphylline, Aminophylline, Bamifylline, choline C.C.-Diphenyl-2-piperidinepropanol, Dropropizine, Drote 60 Theophyllinate, Doxofylline, Dyphylline, Enprofylline, banol, Eprazinone, Ethyl Dibunate, Ethylmorphine, Fomi Etamiphyllin, Eto?ylline, Guaithylline, Proxyphylline. Theo noben, Guaiapate, Hydrocodone, Isoaminile, Levopro bromine, 1-Theobromineacetic Acid and Theophylline; and poxyphene, Morclofone, Narceline, Normethadone, others such as Fenspiride, Medibazine, Montelukast, Noscapine, Oxeladin, Oxolamine, Pholcodine, Picoperine, Methoxyphenamine, Tretoquinol and Zafirlukast; Pipazethate, Piperidione, Prenoxdiazine Hydrochloride, 65 Calcium channel blockers, including: Arylalkylamines Racemethorphan, Taziprinone Hydrochloride, Tipepidine such as Bepridil, Ditiazem, Fendiline, Gallopamil, Preny and Zipeprol; lamine, Terodiline and Verapamil: US 8,414,914 B2 33 34 Dihydropyridine derivatives such as Felodipine, Israd lamine, Propylhexedrine, Pseudoephedrine, Tetrahydrozo ipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, line, Tymazoline and Xylometazoline; Nisoldipine and Nitrendipine; Dental agents, including: Bisphosphonates (anti-periodon Piperazine derivatives such as Cinnarizine, Flunarizine and tal disease and bone resorption) Such as Alendronate, Clodr Lidoflazine; and onate, Etidronate, Pamidronate and Tiludronate; Carries Pro others such as Bencyclane, Etafenone and Perhexyline; phylactics such as Arginine and Sodium Fluoride; Calcium regulators such as Calcifediol, Calcitonin, Cal Desensitizing Agents such as Potassium Nitrate and Citrate citriol, Clodronic Acid, Dihydrotachysterol, Elcatonin, Oxalate: Etidronic Acid, Ipriflavone, Pamidronic Acid, Parathyroid Depigmentors such as Hydroquinine, Hydroquinone and Hormone and Teriparatide Acetate; 10 Monobenzone; Cardiotonics such as Acefylline, Acetyldigititoxins, Diuretics, including: Organomercurials such as Chlorm 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, erodrin, Meralluride, Mercamphamide, Mercaptomerin Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, Sodium, Mercumallylic Acid, Mercumatilin Sodium, Mercu Cymarin, Denopamine, Deslanoside, Ditalin, Digitalis, Digi rous Chloride and Mersalyl: toxin, Digoxin, Dobutamine, Dopamine, Dopexamine, 15 Pteridines such as Furterene and Triamterene; Enoximone, Erythrophleine, Fenalcomine, Gitalin, Gitoxin, Purines such as Acefylline, 7-Morpholinomethyltheophyl Glycocyamine, Heptaminol, Hydrastinine, Ibopamine, Lano line, Pamabrom, Protheobromine and Theobromine; todises, Metamivam, Milrinone, Neriifolin, Oleandrin, Oua Steroids such as Canrenone, Oleandrin and Spironolac bain, Oxyfedrine, Prenalterol, Proscillaridin, Resibufogenin, tone; Scillaren, Scillarenin, Strophanthin, Sulmazole. Theobro Sulfonamide derivatives such as Acetazolamide, Ambu mine and Xamoterol; side, AZosemide, Bumetanide, Butazolamide, Chlorami Chelating agents such as Deferoxamine, Ditiocarb nophenamide, Clofenamide, Clopamide, Clorexolone, Sodium, Edetate Calcium Disodium, Edetate Disodium, Ede Diphenylmethane-4.4'-disulfonamide, Disulfamide, Ethox tate Sodium, Edetate Trisodium, Penicillamine, Pentetate Zolamide. Furosemide, Indapamide, Mefruside, Methazola Calcium Trisodium, Pentetic Acid, Succimer and Trientine; 25 mide, Piretanide, QuinethaZone, Torasemide, Tripamide and Cholecystokinin antagonists such as Proglumide; Xipamide; Cholelitholytic agents such as Chenodiol, Methyl tert-Bu Uracils such as Aminometradine and Amisometradine; tyl Ether, Monooctanoin and Ursodiol; others such as Amanozine, Amiloride, Arbutin, Chloraza Choleretics such as Alibendol, Anethole Trithione, AZin nil, Ethacrynic Acid, Etozolin, Hydracarbazine, Isosorbide, tamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Cyclobuty 30 Mannitol, Metochalcone, Muzolimine, Perhexyline, Tic rol, Cyclovalone, Cynarin(e), Dehydrocholic Acid, Deoxy rynafen and Urea; cholic Acid, Dimecrotic Acid, O.-Ethylbenzyl Alcohol, Dopamine receptor agonists such as Bromocriptine, Exiproben, Febuprol, Fencibutirol, Fenipentol, Florantyrone, Dopexamine, Fenoldopam, lbopamine, Lisuride, Naxagolide Hymecromone, Menbutone, 3-(o-Methoxyphenyl)-2-pheny and Pergolide; lacrylic Acid, Metochalcone, Moquizone, Osalmid, Ox Bile 35 Ectoparasiticides such as Amitraz, Benzyl Benzoate, Car Extract, 4.4'-Oxydi-2-butanol, Piprozolin, Prozapine, 4-Sali baryl, Crotamiton, DDT. Dixanthogen, Isobornyl Thiocy cyloylmorpholine, Sincalide, Taurocholic Acid, Timonacic, anoacetate—Technical, Lime Sulfurated Solution, Lindane, Tocamphyl, Trepibutone and Vanitiolide; Malathion, Mercuric Oleate, Mesulphen and Sulphur Phar Cholinergic agents such as Aceclidine, Acetylcholine Bro maceutical; mide, Acetylcholide Chloride, Aclatonium Napadisilate, 40 Enzymes, including: Digestive enzymes Such as C.-Amy Benzpyrinium Bromide, Bethanechol chloride, Carbachol, lase (Swine Pancreas), Lipase, Pancrelipase, Pepsin and Ren Carpronium chloride, Demecarium Bromide, Dexpanthenol, n1n, Diisopropyl Paraoxon, Echothiophate Iodide, Edrophonium Mucolytic enzymes Such as Lysozyme; chloride, Eseridine, Furtrethonium, Isofluorophate, Metha Penicillin inactivating enzymes Such as Penicillinase; and choline chloride, Muscarine, Neostigmine, Oxapropanium 45 Proteolytic enzymes such as Collagenase, Chymopapain, Iodide, Physostigmine and Pyridostigmine Bromide: Chymotrypsins, Papain and Trypsin; Cholinesterase inhibitors such as Ambenonium Chloride, Enzyme inducers (hepatic) Such as Flumecinol; Distigmine Bromide and Galanthamine; Estrogens, including: Nonsteroidal estrogens such as Ben Cholinesterase reactivators such as Obidoxime Chloride Zestrol, Broparestrol, Chlorotrianisene, Dienestrol, Diethyl and Pralidoxime Chloride; 50 stilbestrol, Diethylstilbestrol Diproprionate, Dimestrol, Fos Central nervous system stimulants and agents such as festrol, Hexestrol, Methallenestril and Methestrol; and Amineptine. Amphetimine, Amphetaminil, Bemegride, Ben Steroidal estrogens such as Colpormon, Conjugated Estro Zphetamine, Brucine, Caffeine, Chlorphentermine, Clofenci genic Hormones, Equilenin, Equilin, Estradiol, Estradiol clan, Clortermine, Coca, Demanyl Phosphate, Dexoxadrol, Benzoate, Estradiol 17 B-Cypionate, Estriol, Estrone, Ethinyl Dextroamphetamine Sulfate, Diethylpropion, N-Ethylam 55 Estradiol, Mestranol, Moxestrol, Mytatrienediol, Quinestra phetamine, Ethamivan, Etifelmin, Etryptamine, Fencamfam diol and Quinestrol; ine, Fenethylline, Fenozolone, Fluorothyl, Galanthamine, Gastric secretion inhibitors such as Enterogastrone and Hexacyclonate Sodium, Homocamfin, Mazindol, Mefexam Octreotide; ide, Methamphetamine, Methylphenidate, Nikethamide, Glucocorticoids such as 21-Acetoxypregnenolone, Pemoline, Pentylenetetrazole, Phendimetrazine, Phenmetra 60 Alclometasone, Algestone, Amicinonide, Beclomethasone, zine, Phentermine, Picrotoxin, Pipradrol, Prolintane and Betamethasone, Budesonide, Chloroprednisone, Clobetasol, Pyrovalerone; Blovetasone, Clocortolone, Cloprednol, Corticosterone, Cor Decongestants such as Amidephrine, Cafaminol, Cyclo tisone, CortivaZol, Deflazacort, Desonide, DeSoximetaSone, pentamine, Ephedrine, Epinephrine, Fenoxazoline, Indiana Dexamethasone. Diflorasone. Diflucortolone. Difluprednate, Zoline, Metizoline, Naphazoline, Nordefrin Hydrochloride, 65 Enoxolone, Fluazacort, Flucloronide, Flumethasone, Octodrine, oxymetazoline, Phenylephrine Hydrochloride, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocor Phenylpropanolamine Hydrochloride, Phenylpropylmethy tin Butyl, Fluocortolone, Fluorometholone, Fluperolone US 8,414,914 B2 35 36 Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandre Triethiodide, Hexacarbacholine Bromide, Hexafluorenium nolide. Formocortal, Halcinonide, Halometasone, Halopre Bromide, Idrocilamide, Laudexium Methyl Sulfate, Lepto done Acetate, Hydrocortamate, Hydrocortisone, Hydrocorti dactyline, Memantine, Mephenesin, Mephenoxalone, sone Acetate, Hydrocortisone Phosphate, Hydrocortisone Metaxalone, Methocarbamol, Metocurine Iodide, 21-Sodium Succinate, Hydrocortisone Tebutate, Nimetazepam, Orphenadrine, Pancuronium Bromide, Phen Mazipredone, Medrysone, Meprednisone, Methylpredniso probamate, Phenyramidol, Pipecurium Bromide, Promox lone, Mometasone Furoate, Paramethasone, Prednicarbate, olane, Quinine Sulfate, Styramate. Succinylcholine Bromide, Prednisolone, Prednisolone 21-Diethylaminoacetate, Pred Succinylcholine Chloride. Succinylcholine Iodine, Suxetho nisone Sodium Phosphate, Prednisolone Sodium Succinate, nium Bromide, Tetrazepam, Thiocolchicoside, Tizanidine, Prednisolone Sodium 21-m-Sulfobenzoate, Prednisolone 10 Tolperisone, Tubocurarine Chloride, Vecuronium Bromide 21-Stearoylglycolate, Prednisolone Tebutate, Prednisolone and Zoxolamine; 21-Trimethylacetate, Prednisone, Prednival, Prednylidene, Narcotic antagonists such as Amiphenazole, Cyclazocine, Prednylidene 21-Diethylaminoacetate, Tixocortol, Triamci Levallorphan, Nadide, Nalmefene, Nalorphine, Nalorphine nolone, Triamcinolone Acetonide, Triamcinolone Bene Dinicotinate, Naloxone and Naltrexone; tonide and Triamcinolone Hexacetonide; 15 Neuroprotective agents such as Dizocilpine; Gonad-Stimulating principles such as Buserelin, Clomi Nootropic agents such as Aceglutamide, Acetylcarnitine, phene, Cyclofenil, Epimestrol, FSH, HCG and LH-RH: Aniracetam, Bifematlane. Exifone, Fipexide, ldebenone, Gonadotropic hormones such as LH and PMSG: Indeloxazine Hydrochloride, Nizofenone, Oxiracetam, Growth hormone inhibitors such as Octreotide and Soma Piracetam, Propentofylline, Pyritinol and Tacrine; to statin: Ophthalmic agents such as 15-ketoprostaglandins; Growth hormone releasing factors such as Sermorelin; Ovarian hormone Such as Relaxin; Growth stimulants such as Somatotropin; Oxytocic drugs such as Carboprost, Cargutocin, Deami Hemolytic agents such as Phenylhydrazine and Phenylhy nooxytocin, Ergonovine, Gemeprost, Methylergonovine, drazine Hydrochloride: Oxytocin, Pituitary (Posterior), Prostaglandin E, Prostaglan Heparin antagonists such as Hexadimethrine Bromide and 25 din F, and Sparteine; Protamines; Pepsin inhibitors such as Sodium Amylosulfate; Hepatoprotectants such as S-Adenosylmethionine, Peristaltic stimulants such as Cisapride; Betaine, Catechin, Citiolone, Malotilate, Orazamide, Phos Progestogens such as Allylestrenol, Anagestone, Chlorma phorylcholine, Protoporphyrin IX, Silymarin-Group. Thio dinone Acetate, Delmadinone Acetate, Demegestone, ctic Acid and Tiopronin; 30 Desogestrel, Dimethisterone, Dydrogesterone, Ethisterone, Immunomodulators such as Amiprilose, Bucillamine, Ethynodiol, Fluorogestone Acetate, Gestodene, Gestonorone Ditiocarb Sodium, Inosine Pranobex, Interferon-y, Interleu Caproate, Haloprogesterone, 17-Hydroxy-16-methylene— kin-2, Lentinan, Muroctasin, Platonin, Procodazole, Tetrami progesterone, 17C.-Hydroxyprogesterone, 17C.-Hydrox sole, Thymomodulin, Thymopentin and Ubenimex: yprogesterone Caproate, Lynestrenol, Medrogestone, Immunosuppressants such as Azathioprine, Cyclosporins 35 Medroxyprogesterone, Megestrol Acetate, Melengestrol, and Mizoribine; Norethindrone, Norethynodrel, Norgesterone, Norgestimate, Ion exchange resins such as Carbacrylic Resins, Norgestrel, Norgestrienone, Norvinisterone, Pentagestrone, Cholestyramine Resin, Colestipol, Polidexide, Resodec and Progesterone, Promegestone, Quingestrone and Trengestone; Sodium Polystyrene Sulfonate; Prolactin inhibitors such as Metergoline; Lactation stimulating hormone such as Prolactin; 40 Prostaglandins and prostaglandin analogs such as Arbap LH-RHagonists such as Buserelin, Goserelin, Leuprolide, rostil, Carboprost, Enprostil, Gemeprost, Limaprost, Miso Nafarelin, and Triptorelin; prostol, Ornoprostil, Prostacyclin, Prostaglandin E. Prostag Lipotropic agents such as N-Acetylmethionine, Choline landin E, Prostaglandin F. Rioprostil, Rosaprostol, Chloride, Choline Dehydrocholate, Choline Dihydrogen Cit Sulprostone and Trimoprostil; rate, Inositol, Lecithin and Methionine; 45 Protease inhibitors such as Aprotinin, Camostat, Gabexate Lupus erythematosus Suppressants such as Bismuth and Nafamostat; Sodium Triglycollamate, Bismuth Subsalicylate, Chloro Respiratory stimulants such as Almitrine, Bemegride, Car quine and Hydroxychloroquine; bon Dioxide, Cropropamide, Crotethamide, Dimefline, Mineralocorticoids such as Aldosterone, Deoxycorticos Dimorpholamine, Doxapram, Ethamivan, Fominoben, terone, Deoxycorticosterone Acetate and Fludrocortisone; 50 Lobeline, Mepixanox, Metamivam, Nikethamide, Picro Miotic drugs such as Carbachol, Physostigmine, Pilo toxin, Pimeclone, Pyridofylline, Sodium Succinate and carpine and Pilocarpus; Tacrine; Monoamine oxidase inhibitors such as Deprenyl, IprocloZ Sclerosing agents such as Ethanolamine, Ethylamine, ide, Iproniazid, Isocarboxazid, Moclobemide, Octamoxin, 2-Hexyl-decanoic Acid, Polidocanol, Quinine Bisulfate, Qui Pargyline, Phenelzine, Phenoxypropazine, Pivalylbenzhy 55 nine Urea Hydrochloride, Sodium Ricinoleate, Sodium Tet drazine, Prodipine, Toloxatone and Tranylcypromine; radecyl Sulfate and Tribenoside; Mucolytic agents such as Acetylcysteine, Bromhexine, Sedatives and hypnotics, including: Acyclic ureides such Carbocysteine, Domiodol, Letosteine, Lysozyme, Mecys as Acecarbromal, Apronalide, Bromisovalum, Capuride, Car teine Hydrochloride, Mesna, Sobrerol, Stepronin, Tiopronin bromal and Ectylurea; and Tyloxapol; 60 Alcohols such as Chlorhexadol, Ethchlorvynol, Muscle relaxants (skeletal) Such as Afloqualone, Alcuro Meparfynol, 4-Methyl-5-thiazoleethanol, tert-Pentyl Alco nium, Atracurium Besylate, Baclofen, BenZoctamine, Ben hol and 2.2.2-Trichloroethanol: Zoquinonium Chloride, C-Calebassine, Carisoprodol, Chlo Amides such as Butoctamide, Diethylbromoacetamide, rmeZanone, Chlorphenesin Carbamate, Chlorproethazine, Ibrotamide, Isovaleryl Diethylamide, Niaprazine, Triceta ChlorZoxaZone, Curare, Cyclarbamate, Cyclobenzaprine, 65 mide, Trimetozine, Zolpidem and Zopiclone; Dantrolene, Decamethonium Bromide, Diazepam, Barbituric acid derivatives such as Allobarbital, Amobar Eperisone, Fazadinium Bromide, Flumetramide, Gallamine bital, Aprobarbital, Barbital, Brallobarbital, Butabarbital US 8,414,914 B2 37 38 Sodium, Butalbital, Butallylonal, Butethal, Carbubarb, Nicametate, Nicergoline, Nicofuranose, Nicotinyl Alcohol, Cyclobarbital, Cyclopentobarbital, Enallylpropymal, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, Prostaglan 5-Ethyl-5-(1-piperidyl) barbituric Acid, 5-Furfuryl-5-isopro din E, Suloctidil and Xanthinol Niacinate; pylbarbituric Acid, Heptabarbital, Hexethal Sodium, Hex Vasoprotectants such as Benzarone, Bioflavonoids, Chro obarbital, Mephobarbital, Methitural, Narcobarbital, Neal mocarb, Clobenoside, Diosmin, Dobesilate Calcium, Escin, barbital, Pentobarbital Sodium, Phenallymal, Phenobarbital, Folescutol, Leucocyanidin, Metescufylline, Quercetin, Rutin Phenobarbital Sodium, Phenylmethylbarbituric Acid, and Troxerutin; Probarbital, Propallylonal, Proxibarbal, Reposal, Secobar Vitamins, vitamin Sources, and vitamin extracts Such as bital Sodium, Talbutal, Tetrabarbital, Vinbarbital Sodium and Vitamins A, B, C, D, E, and K and derivatives thereof, Cal Vinylbital; 10 ciferols, Glycyrrhiza and Mecobalamin; Benzodiazepine derivatives such as Brotizolam, Dox Vulnerary agents such as Acetylcysteine, Allantoin, Asiati efazepam, Estazolam, Flumitrazepam, Flurazepam, Halox coside, Cadexomer Iodine, Chitin, Dextranomer and aZolam, Loprazolam, Lorimetazepam, Nitrazepam, Oxaceprol; Quazepam, Temazepam and Triazolam; Anticoagulants such as heparin; and Bromides such as Ammonium Bromide, Calcium Bro 15 Miscellaneous such as Erythropoietin (Hematinic), mide, Calcium Bromolactobionate, Lithium Bromide, Mag Filgrastim, Finasteride (Benign Prostate Hypertrophy) and nesium Bromide, Potassium Bromide and Sodium Bromide; Interferon B1-C. (Multiple Sclerosis). Carbamates such as Amyl Carbamate Tertiary, Ethi In certain embodiments, the agent to be delivered is one or namate, Hexapropymate, Meparfynol Carbamate, Novonal more proteins, hormones, Vitamins or minerals. In certain and Tricholorourethan; embodiments, the agent to be delivered is selected from insu Chloral derivatives such as Carbocloral, Chloral Betaine, lin, IGF-1, testosterone, vinpocetine, hexarelin, GHRP-6 or Chloral Formamide, Chloral Hydrate, Chloralantipyrine, calcium. In certain embodiments, the compositions contain Dichloralphenazone, Pentaerythritol Chloral and Triclofos; two or more agents. Piperidinediones such as Glutethimide, Methyprylon, Pip The above list of active agents is based upon those catego eridione, Pyrithyldione, Taglutimide and Thalidomide; 25 ries and species of drugs set forth on pages THER-1 to THER Quinazolone derivatives such as Etaqualone, Mecloqua 28 of The Merck Index, 12th Edition, Merck & Co. Rahway, lone and Methaqualone; and N.J. (1996). This reference is incorporated by reference in its others such as Acetal, Acetophenone, Aldol, Ammonium entirety. Valerate, Amphenidone, d-Bornyl C-Bromoisovalerate, IV. Polymers d-Bornyl Isovalerate, Bromoform, Calcium 2-Ethylbu 30 The compositions optionally contain one or more polymers tanoate, Carfimate, C.-Chloralose, Clomethiazole, Cypripe that modify the viscosity of the composition. The polymer dium, Doxylamine, Etodroxizine, Etomidate, Fenadiazole, used can coat the liposome/micelle/proteins to keep the solu Homofenazine, Hydrobromic Acid, Mecloxamine, Menthyl tion from degrading until it reaches the site of absorption, Valerate, Opium, Paraldehyde, Perlapine, Propiomazine, Ril Such as the mucosal lining. In certain embodiments, the poly mazafone, Sodium Oxybate, Sulfonethylmethane and Sul 35 mers for use herein are selected from homopolymers such as fonmethane; polyolefins including polyethylene, polypropylene, poly Thrombolytic agents such as APSAC, Plasmin, Pro-Uroki butene, and polymers of higher alpha-olefins; styrenic poly nase, Streptokinase, Tissue Plasminogen Activator and mers including polystyrene, polymers made from Styrene Urokinase; monomers with pendant alkyl groups such as poly(alpha Thyrotropic hormones such as TRH and TSH: 40 methylstyrene) and poly(para-methyl styrene), and haloge Uricosurics such as BenZbromarone, Ethebenecid, Orotic nated versions of the above styrenic polymers; polydienes Acid, Oxycinchophen, Probenecid, Sulfinpyrazone, Tic including polybutadiene, polyisoprene, and other polymers rynafen and Zoxazolamine; made from alkylated diene monomers; polyamides; polyim Vasodilators (cerebral) such as Bencyclane, Cinnarizine, ides; polycarbonates; polyisobutylene; acrylics such as poly Citicoline, Cyclandelate, Ciclonicate, Diisopropylamine 45 (methyl methacrylate), poly(butyl methacrylate), poly Dichloroacetate, Eburnamonine, Fenoxedil, Flunarizine, (acrylic acid); silicones such as poly(dimethyl siloxane) and Ibudilast, Ifenprodil, Nafronyl, Nicametate, Nicergoline, the like; polysulfones; vinyl polymers such as poly(vinyl Nimodipine, Papaverine, Pentifylline, Tinofedrine, Vincam chloride), poly(vinyl flouride), poly(vinyl alcohol), poly(vi ine, Vinpocetine and Viduidil; nyl phenol), poly(vinylidene chloride), poly(vinylidene flou Vasodilators (coronary) Such as Amotriphene, BendaZol, 50 ride), poly(tetrafluoroethylene), poly(acrylonitrile), and the Benfurodil Hemisuccinate, BenZiodarone, Chloacizine, like; polyesters including poly(ethylene glycol) esters, poly Chromonar, Clobenfurol, Clonitrate, Dilazep, Dipyridamole, (ethylene terephthalate), poly(butylene terephthalate), and Droprenilamine, Efloxate, Erythritol, Erythrity1 Tetranitrate, the like; polyethers including poly(ethylene oxide), poly(pro Etafenone, Fendiline, Floredil, Ganglefene, Hexestrol Bis(B- pyleneoxide), poly(oxymethylene), and the like; poly(phe diethylaminoethyl ether), Hexobendine, Itramin Tosylate, 55 nylene oxide); poly(phenylene Sulfide); poly(acrylates); poly Khellin, Lidoflazine, Mannitol Hexanitrate, Medibazine, (benzimidazoles) and the like; and other polymers made from Nicorandil, Nitroglycerin, Pentaerythritol Tetranitrate, Pen polymerizable monomers; statistical copolymers of the trinitrol, Perhexyline, Pimethylline, Prenylamine, Propatyl monomers or repeat units described above including for Nitrate, Pyridofylline, Trapidil, Tricromyl, Trimetazidine, example copolymers of ethylene with other monomers such TroInitrate Phosphate and Visnadine: 60 as alpha-olefins including propylene, butene-1, hexene, Vasodilators (peripheral) Such as Aluminum Nicotinate, octene, and the like; dienes; vinyl acetate; Vinyl alcohol; vinyl Bamethan, Bencyclane, Betahistine, Bradykinin, Brovin chloride; vinylidene chloride; copolymers of isobutylene camine, Bufeniode, Buflomedil, Butalamine, Cetiedil, with other monomers including isoprene, butadiene, para Ciclonicate, Cinepazide, Cinnarizine, Cyclandelate, Diiso methylstyrene, styrene, and the like; copolymers of Styrene propylamine Dichloroacetate, Eledoisin, Fenoxedil, Fluna 65 with other monomers including butadiene, isoprene, maleic rizine, Hepronicate, Ifenprodil, Inositol Niacinate, ISOXSu anhydride, acrylonitrile, oxazoline, and the like; copolymers prine, Kallidin, Kallikrein, Moxisylyte, Nafronyl, of butadiene with other monomers including acrylonitrile; US 8,414,914 B2 39 40 copolymers of propylene with other monomers including tion of about 1% by weight of the total weight of the compo ethylene, butene, hexane, dienes, and the like; block copoly sition. In other embodiments, PEG 400 distearate is present at mers made from units of any of the above homopolymers or a concentration of about 0.1% by weight of the total weight of copolymers including styrene-diene block polymers such as the composition. styrene-isoprene-styrene triblock copolymer, styrene-butadi e. Cosolvent ene-styrene triblock copolymers, styrene-ethylene/propy The compositions provided herein can also contain one or lene-styrene triblock copolymers (all ratios of ethylene to more cosolvents. Such cosolvents are non-toxic, pharmaceu propylene), and the like; graft copolymers made from units of tically acceptable Substances, typically liquids, which do not any of the above homopolymers or copolymers including substantially negatively affect the solubility of the active poly(ethylene-graft-propylene), poly(styrene-graft-butadi 10 agents at the concentrations used. The cosolvent can aid in ene) and the like; and derivatized versions of any of the above dissolving the active agent or for the mucoadhesive materials, homopolymers or copolymers including for example those or both. The cosolvent in certain embodiments, is a polyhy made by Sulfonation, amination, and carboxylation and the dric alcohol or combination of polyhydric alcohols. In certain like. Such as Sulfonated polystyrene, Sulfonated ethylene embodiments, the cosolvent is ethylene glycol, dipropylene propylene-diene monomer, and the like. The term “polymer 15 glycol, propylene glycol, polyethylene glycol, glycerin, buty as used herein also includes combinations or mixtures of lene glycol, hexylene glycol, polyoxyethylene, polypropy more than one polymer wherein Such combination or mixture lene glycol, Sorbitol, ethylene glycol, or a mixture thereof. exists in single or multiphase blends. The amount of cosolvent in the compositions provided Generally the identity and composition (i.e. the ratio or hereindepends on the solubility of the active agent and/or the amount of each type of copolymer unit desired) of the copoly mucoadhesive Substance in the oil or water phase. Typically, mer can be varied depending on the characteristics desired in the cosolvent is present in an amount Sufficient to achieve the end product. It is within the skill of one ordinarily skilled complete dissolution of the active agent. In certain embodi in the art to make such selections. ments, the cosolvent is propylene glycol and is present at a In certain embodiments, the polymer for use herein is concentration of about 1% by weight up to about 30% by polyethylene glycol ester. In certain embodiments, the poly 25 weight of the total weight of the total composition. In other ethylene glycol ester is selected from PEG 200 monolaurate, embodiments, propylene glycol is present at a concentration PEG 200 dilaurate, PEG 300 monolaurate, PEG 300 dilau of about 1% by weight up to about 20% by weight of the total rate, PEG 400 monolaurate, PEG 600 dilaurate, PEG 600 weight of the total composition. In other embodiments, pro monolaurate, PEG 200 dilaurate, PEG 1000 monolaurate, pylene glycol is present at a concentration of about 1% by PEG 1000 dilaurate, PEG 1540 monolaurate, PEG 1540 30 weight up to about 15% by weight of the total weight of the dilaurate, PEG 4000 monolaurate, PEG 4000 dilaurate, PEG total composition. In other embodiments, propylene glycol is 6000 monolaurate, PEG 6000 dilaurate, PEG 200 monostear presentata concentration of about 1% by weight up to about ate, PEG 200 distearate, PEG 300 monostearate, PEG 300 10% by weight of the total weight of the total composition. In distearate, PEG 400 monostearate, PEG 600 distearate, PEG other embodiments, propylene glycol is present at a concen 600 monostearate, PEG 200 distearate, PEG 1000 monostear 35 tration of about 15% by weight of the total weight of the total ate, PEG 1000 distearate, PEG 1540 monostearate, PEG 1540 composition. In other embodiments, propylene glycol is distearate, PEG 4000 monostearate, PEG 4000 distearate, presentata concentration of about 13% by weight of the total PEG 6000 monostearate, PEG 6000 distearate, PEG 200 weight of the total composition. In other embodiments, pro monooleate, PEG 200 dioleate, PEG 300 monooleate, PEG pylene glycol is present at a concentration of about 11% by 300 dioleate, PEG 400 monooleate, PEG 600 dioleate, PEG 40 weight of the total weight of the total composition. In other 600 monooleate, PEG 200 dioleate, PEG 1000 monooleate, embodiments, propylene glycol is present at a concentration PEG 1000 dioleate, PEG 1540 monooleate, PEG 1540 of about 9.5% by weight of the total weight of the total dioleate, PEG 4000 monooleate, PEG 4000 dioleate, PEG composition. In other embodiments, propylene glycol is 6000 monooleate and PEG 6000 dioleate. presentata concentration of about 7.5% by weight of the total In certain embodiments, the polymer used herein is PEG 45 weight of the total composition. In other embodiments, pro 400 distearate. In certain embodiments, PEG 400 distearate is pylene glycol is present at a concentration of about 5% by present at a concentration of about 0.1% by weight up to weight of the total weight of the total composition. In other about 10% by weight of the total weight of the composition. embodiments, propylene glycol is present at a concentration In other embodiments, PEG 400 distearate is present at a of about 3% by weight of the total weight of the total com concentration of about 0.1% by weight up to about 8% by 50 position. In other embodiments, propylene glycol is presentat weight of the total weight of the composition. In other a concentration of about 1% by weight of the total weight of embodiments, PEG 400 distearate is present at a concentra the total composition. tion of about 0.1% by weight up to about 6% by weight of the f. Other Additives total weight of the composition. In other embodiments, PEG The compositions provided herein can further contain one 400 distearate is present at a concentration of about 0.1% by 55 or more other additives such as taste modifying agents, a weight up to about 4% by weight of the total weight of the buffering agent, a chelating agent, a colorant, an osmotic composition. In other embodiments, PEG 400 distearate is modifier, a preservative, a sterilizer, a solubilizer, a tonicifier, present at a concentration of about 0.1% by weight up to a trace element, and a viscomodulator. about 2% by weight of the total weight of the composition. In Taste modifying agents for use herein include, but are not other embodiments, PEG 400 distearate is present at a con 60 limited to flavoring agents, Sweetening agents and taste mask centration of about 2% by weight of the total weight of the ing agents and are exemplified by: the essential oils or water composition. In other embodiments, PEG 400 distearate is soluble extracts of menthol, wintergreen, peppermint, Sweet presentata concentration of about 1.8% by weight of the total mint, spearmint, natural and artificial Vanilla, cherry, choco weight of the composition. In other embodiments, PEG 400 late, fudge, butterscotch, cinnamon, clove, lemon, orange, distearate is present at a concentration of about 1.5% by 65 raspberry, rose, spice, violet, herbal, fruit, strawberry, grape, weight of the total weight of the composition. In other pineapple, peach, kiwi, papaya, mango, coconut, apple, cof embodiments, PEG 400 distearate is present at a concentra fee, plum, watermelon, nuts, durean, green tea, grapefruit, US 8,414,914 B2 41 42 banana, butter, cream custard, camomile, Sugar, dextrose, 1. Equipment Used in Exemplary Procedures Provided lactose, mannitol. Sucrose, Xylitol, maltitol, acesulfame Herein Include: potassium, talin, glycyrrhizin, Sucralose, aspartame, saccha i) Tanks rin, Sodium saccharin, Sodium cyclamate and honey. In cer Two tanks, one for the oil phase and the other for a water 5 phase. The size of the tank can vary depending on the amount tain embodiments, the taste modifying agent is selected from of oil and water required to prepare the emulsion. natural and artificial Vanilla, cream custard, banana, fudge, ii) Mixers butterscotch, coconut and chocolate. Mixers are used to blend, mix, emulsify and keep the Buffering agents include, but are not limited to acidulants material circulating in order to maintain temperature, Viscos and alkalizing agents exemplified by citric acid, fumaric acid, ity, and other parameters to ensure the product meets the lactic acid, tartaric acid, malic acid, as well as sodium citrate, 10 desired consistency. Mixers used in the procedures hereinare: Sodium bicarbonate and carbonate, sodium or potassium shears, inline mixers/mixing, Ribbon, Plow/Paddle Blenders, phosphate and magnesium oxide. Forberg Mixers, Conveyors, Bag Dumps & Compactors, Coloring agents for use in the compositions include, but are V-Blenders, Blade Mixers, Double Cone Mixers, Continuous not limited to FD & C coloring agents, natural coloring Mixers, Speedflow Mixers, Batch Mixers, Double Ribbon 15 Blenders, Paddle and Ribbon Mixers with Choppers, Plow agents, and natural juice concentrates, pigments such as tita Blenders/Turbulent Mixers, Fluidizing Forberg-Type Mixers, nium oxide, silicon dioxide and Zinc oxide. Air Mixers, Active Mixers, Passive Mixers, Top Entry Mix Stabilizers as used in the compositions provided herein, ers, Side Entry Mixers, Static Mixers, Fixed Entry Mixers, include, but are not limited to anti-oxidants, chelating agents, Portable Mixers—both direct and gear drive, Sanitary Mix and enzyme inhibitors as exemplified by ascorbic acid, Vita ers, Drum Mixers, Bulk Container (IBC) Mixers, Lab Stir min E, butylated hydroxyanisole (BHA), butylated hydroxy rers, Variable Speed Mixers, dough mixer, vertical mixer, toluene (BHT), propyl gallate, dilauryl thiodipropionate, spiral mixer, twin arm mixer, fork mixer, double spiral mixer, thiodiproprionic acid, gum guaiac, citric acid, edetic acid and all agitators, and any other mixer applicable, agitator mixer, its salts and glutathione. Banbury Mixer, Rubber Mixer, Blondheim Mixer, Chum 25 Mixer, Conical Mixer, Continuous Mixer, Disperser Mixer, The compositions can contain preservatives which include, Pan Mixer, Emulsifier Mixer, Hobart Mixer, Liquifier Mixer, but are not limited sodium benzoate, potassium Sorbate, para Littleford Mixer, Meat Mixer, Plow Mixer, Mixmuller Mixer, bens and derivatives, such as methyl paraben, propyl paraben, Nauta Mixer, Oakes Mixer, Planetary Mixer, Pony Mixer, Sorbic acid and its salts, propionic acids and its salts, Sulfur PUGMixer, Ribbon Mixer, Ross Mixer, Rotary Mixer, Sigma dioxide and Sulfites, acetic acid and acetates, and nitrites and Mixer, Single Arm Mixer, Tote Bin Mixer, Tumble Mixer, nitrates. 30 Tumble Mixer, Vacuum Mixer, Turbolizer Mixer, Twin Shell g. Exemplary Compositions Mixer, V-Type Mixer, Zig-Zag Mixer or side arm mixer. Provided herein are compositions containing one or more iii) Heating Apparatus agents formulated for mucosal delivery. The compositions Heating apparatus are used to heat the oil, water and emul sion phases and for cleaning/sanitizing equipment before and provided are oil in water or water in oil emulsions. In certain 35 after use. Exemplary heating apparatus that can be used in the embodiments, the oil phase in the compositions contains oat procedures provided herein are: Electrical jacketed tanks/ oil. The oil phase further contains one or more ingredients kettles, water jacketed tanks/kettles, submersible heaters, selected from the agent to be delivered, medium chain trig semi-submersible heaters, immersible heaters, over-the-side lycerides, propylene glycol, preservatives and Surfactants. heaters, straight hairpin heater tubes, steel sheath heaters, The water phase of the compositions contains water and one 40 circular shaped heater tubes, incoloy sheath heaters, Strip or more ingredients selected from preservatives, Surfactants, heaters, finned strip heaters, enclosure heaters, cartridgeheat agent to be delivered and mucoadhesive proteins. In an exem ers, bolt heaters, component tubular heaters, finned tubular plary embodiment, the mucoadhesive protein is albumin, heaters, explosion resistant heaters, preweld heaters, bushing immunoglobulin or lactoferrin; preservatives are selected heaters, flanged heaters, bottom outlet heaters, circulation heaters, low temperature duct heaters and process heaters and from one among potassium Sorbate, sodium benzoate, methyl 45 other applicable heater apparatus. paraben, propyl paraben and benzyl alcohol; the Surfactants Temperatures for heating solution and for cleaning/sanitiz are phosphatidylcholine and polysorbate-80. ing range from 65° F. to about 220 F. During the dissolving The compositions can contain oat oil from about 3% by and mixing steps, the temperature of the oil, water and emul weight up to about 25% by weight, generally about 3%, 4%, sion phase is maintained at a level where the components of 7%, 7.5%, 8%, 15% or 25% by weight of the composition. 50 the composition retain their activity, for example the tempera The amount of MCT in the composition can be from about ture is maintained Such that the mucoadhesive protein does 10% by weight up to about 35% by weight, generally, 11%, not denature during the process and the agent to be delivered 13%, 17%. 30% or 31% by weight of the composition. An does not degrade. A suitable temperature during the mixing exemplary composition can contain propylene glycol from step can be determined empirically for a particular combina 55 tion of ingredients in the composition. Typically, the tempera about 8% by weight up to about 12% by weight, typically, 1%, ture is maintained at about 100-120° F., in some embodi 8%, 9%, 10% or 11% by weight of the composition. The ments, at about 115° F. In certain embodiments, the mucoadhesive proteins are present, for example, from about temperature of the oil, water and emulsion phase during the 1% by weight up to about 11% by weight, typically 9%. 9.5% process is maintained at about 120°F. In other embodiments, or 10% by weight of the composition. 60 the temperature of the oil, water and emulsion phase is main C. Methods of Manufacturing the Compositions tained at about 100°F. In other embodiments, the temperature The compositions provided herein are stable emulsions of is maintained at about 60-70 F. In other embodiments, the oil in water or water in oil and are prepared by dissolving the temperature is maintained at about 50 F. components of the composition in the oil and/or water phases The pressure for water jackets is maintained at a level and mixing the two phases under constant temperature and 65 selected so that the components of the composition do not pressure. They can be prepared by any suitable method for degrade. In certain embodiments, the pressure is maintained making emulsions. at a range from 1 PSI to 120 PSI (pounds per square inch). In US 8,414,914 B2 43 44 certain embodiments, the pressure is 50 PSI. In other embodi the mixture is mixed to dissolve the preservatives. A prede ments, the pressure is 30 PSI. In other embodiments, the termined amount of lipids, phospholipids and polymers to pressure is 25 PSI. In other embodiments, the pressure is 10 achieve a stable emulsion is added and dissolved. The tem PSI. perature of the water phase is maintained at all times at a level 2. Exemplary Procedures for Preparing the Compositions 5 that prevents denaturation of the mucoadhesive proteins. The Exemplary procedures for preparing the compositions are mucoadhesive protein, required in an amount Sufficient to described below: achieve quantitative delivery of the agent to be delivered, is a. Procedure A added to the water phase and mixed to dissolve. Where the Included among the compositions provided herein are oil agent to be delivered is water soluble, it is added and mixed to in water emulsions where the agent to be delivered is soluble 10 dissolve. The mixing is carried out at a speed where complete in the water phase or in the oil phase. Such compositions can dissolution of the ingredients is achieved without denaturing be prepared by any suitable method known in the art, includ or otherwise leading to degradation of the any active ingre ing the following procedure. The compositions are prepared dients. Generally, mixing is carried out at about 10 rpm, 50 at a temperature and pressure at which all the oil and water rpm, 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm or up to soluble components are soluble in the oil and water phases, 15 about 1000 rpm in water phase. In certain embodiments, the respectively and the mucoadhesive protein and the agent to be reactor vessel. Such as reactor tank, is closed to prevent evapo delivered are not degraded in any way. For example, the ration of any of the ingredients or maintained at other condi temperature for heating the Solution can be maintained at tions that minimize evaporation, such as contained in a beaker about 100°-150° F., in certain embodiments, 115° F., for all in small volume. When the combination of ingredients is such phases; and the pressure is at maintained about 20-30 pounds- 20 that evaporation is not a problem, the reaction vessel does not per-square inch (PSI). In certain embodiments, when using necessarily have to be sealed. this range and a waterjacket, the pressure can be about 25 PSI. iii) Formation of Emulsion i) Oil Phase The oil phase is added to the water phase. This can be The oils used in the oil phase are weighed, added in a achieved, for example, by pumping, manually adding or any Suitable vessel. Such as a reactor tank and mixed to form a 25 other means of transferring from the oil tank to the water tank. Solution. The solution is heated and maintained at a tempera As the oil phase is being added to the water phase, the mixture ture where all the oil soluble components can be dissolved in is mixed at a speed sufficient to create the emulsion without the oil phase while retaining their activity. A suitable tem denaturing or otherwise leading to degradation of the any perature during the mixing step can be determined empiri active ingredients. The mixing can be effected at about 100 cally for a particular combination of ingredients in the com- 30 rpm, 300 rpm, 500 rpm, 700 rpm, 1000 rpm, 10,000 rpm, position. Typically, the temperature is maintained at about 20,000 rpm, 30,000 rpm, 40,000 rpm, 50,000 rpm, 60,000 100-120° F., in some embodiments at about 115°F. A cosol rpm or up to about 100,000 rpm. The mixing step can involve vent, Such as propylene glycol, is weighed and mixed with the shearing or just light mixing to create the emulsion. In certain oil solution at a speed where complete dissolution of the embodiments, mixing is achieved by shearing. In certain ingredients is achieved without denaturing or otherwise lead- 35 embodiments, the pH of the emulsion is a function of the ing to degradation of the any active ingredients. Generally, mucoadhesive protein used. The emulsion is maintained at mixing is carried out at about 10 rpm, 50 rpm, 100 rpm, 150 neutral or basic pH throughout these steps. rpm, 200 rpm, 250 rpm, 300 rpm or up to about 1000 rpm in b. Procedure B oil phase. The oil preservatives, for example, methyl paraben Included among the compositions provided herein are and propyl paraben are weighed and added to the oil phase 40 water-in-oil emulsions, where the agent for delivery is soluble and the mixture is mixed to dissolve the preservatives. A in the oil phase. They can be prepared by any suitable method, sterile solution of benzyl hydroxide or benzyl benzoate is including the following procedure and any modifications added and dissolved in the solution followed by addition of thereof. In all phases the temperature and pressure of the emulsifiers, lipids, phospholipids and polymers. If the agent solution are maintained at a level sufficient to dissolve all the to be delivered is soluble in the oil phase, it is added and 45 ingredients while retaining the activity of mucoadhesive pro mixed to dissolve. The temperature and pressure are main tein and the agent to be delivered. The temperature generally tained throughout the procedure to retain the activity of the is maintained at about 90°F. to 110°F, typically at about 100° agent to be delivered. In certain embodiments, the reactor F. or 115°F. A suitable temperature during the mixing step vessel is closed to prevent evaporation of any of the ingredi can be determined empirically for a particular combination of ents or maintained at other conditions that minimize evapo- 50 ingredients in the composition. Typically, the temperature is ration, Such as contained in a beaker in Small Volume. When maintained at about 100-120° F., in some embodiments, at the combination of ingredients is such that evaporation is not about 115°F. Pressure is adjusted to achieve the dissolution of a problem, the reaction vessel does not necessarily have to be the components while maintaining the activity of the mucoad sealed. hesive protein and the agent to be delivered. For the tempera ii) Water Phase 55 ture range used in the procedures provided herein, the pres The required amount of water used in the water phase is Sure (in pounds-per-square inch PSI) is in the range of about weighed and added in a Suitable vessel. Such as a reactor tank. 20 to about 30 PSI, typically the pressure in the water jacket The water phase is heated and maintained at a predetermined for heating the mixture is maintained at about 25 PSI. Gen temperature such that the mucoadhesive protein and the erally the water phase is added to the oil phase to produce a active agent, when soluble in the water phase, retain their 60 composition for mucosal delivery. activities. For example, in the compositions that contain i) Oil Phase lactoferrin, the temperature is maintained at or below 100 The oils used in the oil phase are weighed and mixed. The degrees F. or about 115° F., but not lower than 65-68 degrees Solution is heated up to and maintained at a temperature F. in order prevent lactoferrin from denaturing. The tempera where all the oil soluble components can be dissolved in the ture and pressure are monitored and maintained throughout 65 oil phase while retaining their activity, typical temperature is the procedure. The preservatives, for example, Na Benzoate 100° F. and the temperature is maintained throughout the and K Sorbate are weighed and added to the water phase and procedure. In some embodiments, suitable temperature dur US 8,414,914 B2 45 46 ing the mixing step can be determined empirically for a par prepared by any suitable method known in the art, including ticular combination of ingredients in the composition. Typi the following procedure. The compositions are prepared at a cally, the temperature is maintained at about 115° F. A temperature and pressure at which all the oil and water cosolvent, such as propylene glycol is weighed and dissolved soluble components are soluble in the oil and water phases, at a predetermined RPM whereby complete dissolution of 5 respectively and the mucoadhesive protein and the agent to be ingredients is achieved without denaturing or otherwise lead delivered are not degraded in any way. For example, the ing to degradation of the any active ingredients. Required temperature for heating the Solution can be maintained at amount of oil preservatives, such as methyl paraben and pro about 100°-150° F. for all phases; and the pressure is at pyl paraben are added to oil phase, followed by sterile solu maintained about 20-30 pounds-per-square inch (PSI). For tion of benzyl hydroxide or benzyl benzoate. Emulsifiers are 10 example, when using temperature in this range and a water added and mixed to the oil phase, followed by addition of required amounts of lipids, phospholipids and polymers. Any jacket, the pressure can be about 25 PSI. oil soluble active agent is then weighed and added to the oil i) Oil Phase phase. In certain embodiments, the reactor vessel is closed to Required amounts of all the oils used in this oil phase are prevent evaporation of any of the ingredients or maintained at 15 weighed and mixed. The solution is heated and maintained at other conditions that minimize evaporation, Such as con a temperature where all the oil soluble components can be tained in a beaker in small volume. When the combination of dissolved in the oil phase while retaining their activity. In ingredients is such that evaporation is not a problem, the certain embodiments, the temperature is maintained at about reaction vessel does not necessarily have to be sealed. 100° F-150°F, typically at 100° F., or about 115° F. for all ii) Water Phase phases. A cosolvent, such as propylene glycol is weighed and The required amount of water used in the water phase is dissolved at a predetermined RPM whereby complete disso weighed and added in a reactor tank. Water is heated and lution of ingredients is achieved without denaturing or other maintained at a temperature suitable for dissolution of the wise leading to degradation of the any active ingredients. mucoadhesive protein and to prevent any degradation of the Required amount of oil preservatives. Such as methyl paraben agent to be delivered. A cosolvent, such as propylene glycol is 25 and propyl parabenare added to oil phase, followed by sterile weighed and dissolved. Preservatives, for example, Na Ben solution of benzyl hydroxide or benzyl benzoate. Emulsifiers Zoate and KSorbate are weighed and added to the water phase are added and mixed in the oil phase, followed by addition of and the mixture is mixed to dissolve the preservatives. required amounts of lipids, phospholipids and polymers to Required amount of lipids, phospholipids and polymers to achieve a stable emulsion. If the agent to be delivered is achieve stable emulsion are added and dissolved. For the 30 soluble in the oil phase, it is added and mixed to dissolve. The compositions containing mucoadhesive proteins, such as temperature and pressure are maintained throughout the pro lactoferrin, temperature is maintained at or below 100 cedure to retain the activity of the agent to be delivered. In degrees F., in certain embodiments, 115° F., but not lower certain embodiments, the reactor vessel. Such as reactor tank, than room temperature in order prevent the protein from is closed to prevent evaporation of any of the ingredients or denaturing. Temperature and pressure are maintained 35 maintained at other conditions that minimize evaporation, throughout the procedure. The mucoadhesive protein, such as contained in a beaker in small volume. When the required in an amount Sufficient to achieve quantitative deliv combination of ingredients is such that evaporation is not a ery of the agent to be delivered, is added to the water phase problem, the reaction vessel does not necessarily have to be and mixed to dissolve. An agent to be delivered, if soluble in sealed. the water phase, is added and mixed to dissolve. In certain 40 ii) Water Phase embodiments, the reactor vessel. Such as reactor tank, is The required amount of water used in the water phase is closed to prevent evaporation of any of the ingredients or weighed and added in a reactor tank. The water phase is maintained at other conditions that minimize evaporation, heated and maintained at a predetermined temperature Such such as contained in a beaker in small volume. When the that the mucoadhesive protein and the active agent, when combination of ingredients is such that evaporation is not a 45 soluble in water phase, retain their activities. For example, in problem, the reaction vessel does not necessarily have to be the compositions that contain lactoferrin, the temperature is sealed. maintained at or below 100 degrees F., or about 115°F. but not iii) Formation of Emulsion lower than 65-68 degrees F. in order prevent lactoferrin from The water phase is added to the oil phase. This can be denaturing. The temperature and pressure are monitored and achieved, for example, by pumping, manually adding or any 50 maintained throughout the procedure. A cosolvent, such as other means of transferring from the oil tank to the water tank. propylene glycol is weighed and dissolved at a predetermined As the oil phase is being added to the water phase, the mixture RPM whereby complete dissolution of the ingredients is is mixed at a speed sufficient to create the emulsion without achieved without denaturing or otherwise leading to degra denaturing or otherwise leading to degradation of the any dation of the any active ingredients. Preservatives, for active ingredients. The mixing can be effected at about 100 55 example, Na Benzoate and KSorbate are weighed and added rpm, 300 rpm, 500 rpm, 700 rpm, 1000 rpm, 10,000 rpm, to the water phase and the mixture is mixed to dissolve the 20,000 rpm, 30,000 rpm, 40,000 rpm, 50,000 rpm, 60,000 preservatives. Required amount of lipids, phospholipids and rpm or up to about 100,000 rpm. In certain embodiments, polymers to achieve stable emulsion are added and dissolved. mixing is achieved by shearing. The emulsion is maintained Temperature and pressure are maintained throughout the pro at a temperature lower than the denaturing temperature of 60 cedure. The mucoadhesive protein, required in an amount proteins, typically at about 100° F or about 115° F. The sufficient to achieve quantitative delivery of the agent to be emulsion is maintained at neutral or basic pH during these delivered, is added to the water phase and mixed to dissolve. steps. Where the agent to be delivered is water soluble, it is added c. Procedure C and mixed to dissolve. In certain embodiments, the reactor This procedure can be used for either oil in water or water 65 vessel, reactor tank is closed to prevent evaporation of any of in oil emulsion where the agent to be delivered is soluble in the ingredients or maintained at other conditions that mini the water phase or in the oil phase. Such compositions can be mize evaporation, such as contained in a beaker in Small US 8,414,914 B2 47 48 volume. When the combination of ingredients is such that Typically, in the compositions provided herein, one or evaporation is not a problem, the reaction vessel does not more agents to be delivered or pharmaceutically acceptable necessarily have to be sealed. derivatives thereofis (are) present in the concentration that is iii) Formation of Emulsion effective for delivery of an amount, upon administration, that The water phase is added to the oil phase or oil phase can be alters a biological function, Such as a body function at the added to water phase. This can be achieved, for example, by cellular, tissue or organ level and/or alters cosmetic appear pumping, manually adding or any other means of transferring ance of a subject. Such alteration of a biological function or from the oil tank to the water tank. As the two phases are being cosmetic appearance includes, but is not limited to treatment added, the mixture is mixed at a speed sufficient to create the of diseases or disorders including, but are not limited to, emulsion without denaturing or otherwise leading to degra 10 neural disorders, respiratory disorders, immune system dis dation of the any active ingredients. The mixing can be orders, muscular disorders, reproductive disorders, gas effected at about 100 rpm, 300 rpm, 500 rpm, 700 rpm, 1000 trointestinal disorders, pulmonary disorders, digestive disor rpm, 10,000 rpm, 20,000 rpm, 30,000 rpm, 40,000 rpm, ders, metabolic disorders, cardiovascular disorders, renal 50,000 rpm, 60,000 rpm or up to about 100,000 rpm. The 15 disorders, proliferative disorders, cancerous diseases and mixing step can involve shearing or just light mixing to create inflammation. the emulsion. In certain embodiments, mixing is achieved by The compositions typically contain an agent to be deliv shearing. The emulsion is maintained at a temperature lower ered in an amount Sufficient to exert a therapeutically useful than the denaturing temperature of proteins, typically at about effect in the absence of undesirable side effects on the subject. 100°F. or about 115°F. The emulsion is maintained at neutral It is understood that the number and degree of side effects or basic pH (pH 8-9) throughout these steps. depends upon the condition for which the compositions are It is noted that various parameters described in the general administered. For example, certain toxic and undesirable side procedures described above for the preparation of the water in effects are tolerated when treating life-threatening illnesses, oil and oil in water emulsions represent exemplary embodi Such as tumors, that would not be tolerated when treating ments and are not intended to limit the scope of the Subject 25 disorders of lesser consequence. matter provided herein. The concentration of the agent to be delivered in the com D. Formulations position will depend on absorption, inactivation and excre The compositions provided herein contain one or more tion rates thereof, the dosage schedule, and amount adminis agents for administration to a subject via the mucosa. The tered as well as other factors knownto those of skill in the art. agents can be anything to be administered and in any amount. 30 Typically the compositions contain therapeutically effective Typically a therapeutically effective dosage should produce a amounts of one or more biologically active agents that alter a serum concentration of active ingredient from about 0.1 biological function, such as a body function at the cellular, ng/ml to about 50-100 ug/ml. The compositions typically tissue or organ level and/or alters cosmetic appearance of a should provide a dosage of from about 0.01 mg to about Subject. In certain embodiments, the compositions provided 35 100-2000 mg of the agent to be delivered, depending upon the herein are intended for delivery of biologically active agents agent selected and adjusted for body Surface area and/or through oral or nasal mucosa, thereby allowing for the avoid weight. Typically, a daily dosage of about between 0.05 ance of the gastrointestinal tract and first pass liver metabo mg/kg and 0.5 mg/kg, in certain embodiments 10 mg/kg lism and consequently allowing the biologically active agent should be sufficient. The dosage is a function of the agent to directly enter into circulation. 40 delivered. In certain embodiments, single dosages per admin The compositions provided herein are useful in altering a istration contain 1-2 milliliters of 1, 10, 100, 200, 250, 500, biological function, such as a body function at the cellular, 650, 1000, 1500, or 2000-2500mgs oftotal material delivered tissue or organ level and/or altering cosmetic appearance of a and is a function of the agent delivered. In certain embodi Subject. In certain embodiments, the compositions provided ments, 1,2,3,4, 5 or more servings of the composition can be herein are useful in the prevention, treatment, or amelioration 45 administered per day depending upon the agent delivered and of one or more of the symptoms of diseases or disorders that disease treated. It is understood that the amount to administer can be treated by any agent that can be delivered to a mucosal is a function of the agent to be delivered, the alteration of a Surface via the compositions provided herein. The diseases or biological function or cosmetic appearance desired, and pos disorders treatable by the compositions provided include, but sibly the side effects that will be tolerated. Dosages can be are not limited to neural disorders, respiratory disorders, 50 empirically determined using recognized models for each immune system disorders, muscular disorders, reproductive effect desired. disorders, gastrointestinal disorders, pulmonary disorders, Typically, the compositions are provided for administra digestive disorders, metabolic disorders, cardiovascular dis tion to humans and animals in unit or multiple dosage forms orders, renal disorders, proliferative disorders, cancerous dis as oil-water emulsions containing Suitable quantities of one eases and inflammation. 55 or more agents to be delivered orpharmaceutically acceptable The compositions provided herein contain one or more derivative thereof. The unit-dose forms as used herein refers agent to be delivered or pharmaceutically acceptable deriva to physically discrete units suitable for human and animal tives thereof. The compositions can be formulated into stable Subjects and packaged individually as is known in the art. emulsions for mucosal delivery. In certain embodiments, the Each unit-dose contains a predetermined quantity of the agent compositions have been found to be stable for up to 6 months. 60 to be delivered sufficient to produce the desired effect, in The compositions are formulated as emulsions for admin association with the required additives in the composition. istration to the oral or nasal mucosal membranes. Typically Unit-dose forms can be administered in fractions or multiples the compositions described above are formulated using tech thereof. Examples of unit dosage include capsules filled with niques and procedures well known in the art (see, e.g., Ansel liquid compositions. A multiple-dose form is a plurality of (1985) Introduction to Pharmaceutical Dosage Forms, 65 identical unit-dosage forms packaged in a single container to Fourth Edition, p. 126)), including the procedures described be administered in segregated unit-dose form. Examples of above. multiple-dose forms include vials and bottles. US 8,414,914 B2 49 50 E. Methods of Use of the Compositions from anticonvulsants, analgesics, antiparkinsons, anti-in Provided herein are methods of mucosal delivery of agents flammatories, calcium antagonists, anesthetics, antimicrobi to Subjects. The methods for mucosal delivery of an agent als, antimalarials, antiparasitics, antihypertensives, antihista provided herein include providing a composition for mucosal mines, antipyretics, alpha-adrenergic agonists, alpha delivery and contacting the composition with a mucosal Sur blockers, biocides, bactericides, bronchial dilators, beta face of a subject, whereby the agent is delivered into the adrenergic blocking drugs, contraceptives, cardiovascular circulatory system of the Subject. Contacting a mucosal Sur drugs, calcium channel inhibitors, depressants, diagnostics, face, such as the oral, nasal or other mucosal Surface, of a diuretics, electrolytes, enzymes, hypnotics, hormones, subject with a composition provided herein permits delivery hypoglycemics, hyperglycemics, muscle contractants, of the composition and hence of any selected agent that can be 10 muscle relaxants, neoplastics, glycoproteins, nucleoproteins, formulated as an emulsion. Contacting can be effected by any lipoproteins, ophthalmics, psychic energizers, sedatives, Ste suitable method. For example, methods provided herein roids, sympathomimetics, parasympathomimetics, tranquil include the steps of providing a pharmaceutical composition izers, urinary tract drugs, vaccines, vaginal drugs, vitamins, as described herein, including an agent for delivery and minerals, nonsteroidal anti-inflammatory drugs, angiotensin administering the composition to the mucosa of the Subject, 15 converting enzymes, polynucleotides, polypeptides, polysac generally either by oral, intranasal inhalation or other method charides, and nutritional Supplements including herbal whereby the composition contacts mucosa in the Subject. Supplements. In the methods provided herein, the compositions can con Hence, provided herein are methods for treatment of dis tact, adhere and/or penetrate into the mucosal lining from eases or disorders that can be treated by mucosal administra about 1 minute up to about 24 hours or more, typically, about tion of active agents, such diseases and disorders include, but 1, 2, 3, 5, 10, 15, 20, 30, 60, or 120 minutes. In some embodi are not limited to neural disorders, respiratory disorders, ments, in the methods provided herein, the compositions can immune system disorders, muscular disorders, reproductive contact, adhere and/or penetrate into the mucosal lining for disorders, gastrointestinal disorders, pulmonary disorders, about 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or up to 24 hours. digestive disorders, metabolic disorders, cardiovascular dis The compositions provided herein can be administered by 25 orders, renal disorders, proliferative disorders, cancerous dis methods known to those of skill in the art, including, but not eases and inflammation. limited to delivering the composition in oral cavity or nasal The immune system disorders that can be treated by the cavity. The composition can be sprayed into the oral cavity or compositions provided herein include, but are not limited to nasal cavity, administered as soft capsule filled with the liquid systemic lupus erythematosus, rheumatoid arthritis, ankylos composition or contacted to the mucosal Surface in the oral 30 ing spondylitis, multiple Sclerosis, insulin resistant diabetes and nasal cavity by any other means known in the art. When mellitus, autoimmune thyroiditis, Hashimoto's thyroiditis, delivering with a soft capsule, the capsule can then be chewed autoimmune hemolytic anemia, hemolytic anemia, thromb by the subject to release the composition into the oral cavity. ocytopenia, autoimmune thrombocytopenia purpura, autoim The intranasal composition is applied to the nasal mucosa via mune neonatal thrombocytopenia, idiopathic thrombocy topical application (spray and/or drops) of a safe and effective 35 topenia purpura, autoimmunocytopenia, Goodpasture's amount of the composition. The frequency of administration syndrome, myasthenia gravis, Grave's disease (hyperthy of the composition may vary, depending upon personal or roidism), type II collagen-induced arthritis, antiphospholipid medical needs, but generally ranges from about once per day syndrome, dermatitis, allergic encephalomyelitis, myocardi to about four times daily. tis, relapsing polychondritis, rheumatic heart disease, neuri The compositions are designed for delivery to a mucosal 40 tis, uveitis ophthalmia, polyendocrinopathies, Reiter's Dis membrane whereby the agent to be delivered gets absorbed ease, Stiff-Man Syndrome, autoimmune pulmonary into the mucosa and directly enters into circulation. The inflammation, autism, Guillain-Barre Syndrome, insulin amount of agent that is absorbed through the mucosal lining dependent diabetes mellitus, autoimmune inflammatory eye can be assessed by methods known in the art and described disorders, Scleroderma with anti-collagen antibodies (often herein. For example, the amount of agent absorbed can be 45 characterized, e.g., by nucleolar and other nuclear antibod assessed by measuring the amount of agent administered to ies), mixed connective tissue disease (often characterized, the Subject and comparing it to the amount thereof found in a e.g., by antibodies to extractable nuclearantigens (e.g., ribo blood sample. The blood sample can be obtained at different nucleoprotein)), polymyositis (often characterized, e.g., by time intervals. The interval of time can be empirically deter nonhistone ANA), pernicious anemia (often characterized, mined based on Such factors as the agent to be delivered and 50 e.g., by antiparietal cell, microsomes, and intrinsic factor the mode of administration. The amount of agent to be deliv antibodies), idiopathic Addison's disease (often character ered per dosage depends on the amount of agent absorbed ized, e.g., by humoral and cell-mediated adrenal cytotoxicity, through the mucosal lining and other factors such as age and infertility (often characterized, e.g., by antispermatozoal anti physical condition of the Subject. bodies), glomerulonephritis (often characterized, e.g., by In certain embodiments, the methods are used for delivery 55 glomerular basement membrane antibodies or immune com of minerals, vitamins, pharmaceutical drugs, nutritional plexes), bullous pemphigoid (often characterized, e.g., by Supplements, hormones, or the like, which when introduced IgG and complement in basement membrane), Sjogren's Syn into the body cause a desired biological response, such as drome (often characterized, e.g., by multiple tissue antibod altering body function at the cellular, tissue or organ level or ies, and/or a specific nonhistone ANA (SS-B)), diabetes mel altering cosmetic appearance. In certain embodiments, the 60 litus (often characterized, e.g., by cell-mediated and humoral agent delivered is a drug or other pharmaceutical ingredient, islet cell antibodies), and adrenergic drug resistance (includ particularly one that has a significant loss of activity in the ing adrenergic drug resistance with asthma or cystic fibrosis) lumen of the gastrointestinal tract or in the tissues of the (often characterized, e.g., by beta-adrenergic receptor anti gastrointestinal tract during the absorption process or upon bodies), chronic active hepatitis (often characterized, e.g., by passage through the liver after absorption in the intestinal 65 Smooth muscle antibodies), primary biliary cirrhosis (often tract. In certain embodiments, the methods provided herein characterized, e.g., by mitochondria antibodies), other endo are useful for delivery of one or more active agents selected crine gland failure (often characterized, e.g., by specific tis US 8,414,914 B2 51 52 Sue antibodies in some cases), vitiligo (often characterized, In certain embodiments, the methods provided herein are e.g., by melanocyte antibodies), vasculitis (often character useful for treatment of heart diseases, such as arrhythmias, ized, e.g., by Ig and complement in vessel walls and/or low carcinoid heart disease, high cardiac output, low cardiac out serum complement), post-M-1 (often characterized, e.g., by put, cardiac tamponade, endocarditis (including bacterial), myocardial antibodies), cardiotomy syndrome (often charac heart aneurysm, cardiac arrest, congestive heart failure, con terized, e.g., by myocardial antibodies), urticaria (often char gestive cardiomyopathy, paroxysmal dyspnea, cardiac acterized, e.g., by IgG and IgM antibodies to IgE), atopic edema, heart hypertrophy, congestive cardiomyopathy, left dermatitis (often characterized, e.g., by IgG and IgM antibod Ventricular hypertrophy, right ventricular hypertrophy, post ies to IgE), asthma (often characterized, e.g., by IgG and IgM infarction heart rupture, Ventricular septal rupture, heart Valve antibodies to IgE), and many other inflammatory, granuloma 10 tous, degenerative, and atrophic disorders. diseases, myocardial diseases, myocardial ischemia, pericar In certain embodiments, the compositions are used in the dial effusion, pericarditis (including constrictive and tuber methods to treat allergy related conditions, including, but not culous), pneumopericardium, postpericardiotomy syndrome, limited to allergic reactions include, but are not limited to, pulmonary heart disease, rheumatic heart disease, Ventricular asthma, rhinitis, and eczema. 15 dysfunction, hyperemia, cardiovascular pregnancy complica In certain embodiments, the compositions are used in the tions, Scimitar Syndrome; cardiovascular syphilis, and car methods to treat inflammatory conditions including, but are diovascular tuberculosis. not limited to, for example inflammation associated with The methods provided in certain embodiment, are used for infection (e.g., septic shock, sepsis, or systemic inflammatory treatment of diseases and disorders of the respiratory system response syndrome), ischemia-reperfusion injury, endotoxin including, but are not limited to, nasal vestibulitis, nonallergic lethality, complement-mediated hyperacute rejection, rhinitis (e.g., acute rhinitis, chronic rhinitis, atrophic rhinitis, nephritis, cytokine or chemokine induced lung injury, inflam vasomotor rhinitis), nasal polyps, and sinusitis, juvenile matory bowel disease, Crohn's disease, overproduction of angiofibromas, cancer of the nose and juvenile papillomas, cytokines (e.g., TNF or IL-1.), respiratory disorders (e.g., Vocal cord polyps, nodules (singer's nodules), contact ulcers, asthma and allergy); gastrointestinal disorders (e.g., inflam 25 Vocal cord paralysis, laryngoceles, pharyngitis (e.g., viral and matory bowel disease); cancers (e.g., gastric, ovarian, lung, bacterial), tonsillitis, tonsillar cellulitis, parapharyngeal, bladder, liver, and breast); CNS disorders (e.g., multiple scle abscess, laryngitis, laryngoceles, allergic disorders (eosino rosis; ischemic brain injury and/or stroke, traumatic brain philic pneumonia, hypersensitivity pneumonitis (e.g., extrin injury, neurodegenerative disorders (e.g., Parkinson's disease sic allergic alveolitis, allergic interstitial pneumonitis, and Alzheimer's disease); AIDS-related dementia; and prion 30 organic dust pneumoconiosis, allergic bronchopulmonary disease); cardiovascular disorders (e.g., atherosclerosis, aspergillosis, asthma, Wegener's granulomatosis (granulo myocarditis, cardiovascular disease, and cardiopulmonary matous vasculitis), Goodpasture's syndrome)), pneumonia bypass complications); as well as many additional diseases, (e.g., bacterial pneumonia (e.g., Streptococcus pneumoniae conditions, and disorders that are characterized by inflamma (pneumoncoccal pneumonia), Staphylococcus aureus (sta tion (e.g., hepatitis, rheumatoid arthritis, gout, trauma, pan 35 creatitis, sarcoidosis, dermatitis; renal ischemia-reperfusion phylococcal pneumonia), Gram-negative bacterial pneumo injury, Grave's disease, systemic lupus erythematosus, dia nia (caused by, e.g., Klebsiella and Pseudomonas spp.), betes mellitus; and allogenic transplant rejection). Mycoplasma pneumoniae pneumonia, Hemophilus influen In certain embodiments, the methods provided herein are Zae pneumonia, Legionella pneumophila (Legionnaires dis useful for treatment of cancers or neoplasms that include, but 40 ease), and Chlamydia psittaci (Psittacosis)), and viral pneu are not limited to, myelogenous leukemia, Hodgkin’s dis monia (e.g., influenza, chickenpox (varicella), obstructive ease, non-Hodgkin’s lymphoma, lymphocyte leukemia, plas airway diseases (e.g., asthma, chronic obstructive pulmonary macytomas, multiple myeloma, Burkitt's lymphoma, EBV disease (COPD), emphysema, chronic or acute bronchitis), transformed diseases, hyperproliferative disorders occupational lung diseases (e.g., silicosis, black lung (coal Lymphoblastic Leukemia, Myeloid Leukemia, Adrenocorti 45 workers’ pneumoconiosis), asbestosis, berylliosis, occupa cal Carcinoma, Hepatocellular Cancer, Liver Cancer, Soft tional asthmas, byssinosis, and benign pneumoconioses), Tissue Sarcoma, Anal Cancer, Astrocytoma, Bile Duct Can Infiltrative Lung Disease (e.g., pulmonary fibrosis (e.g., cer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain fibrosing alveolitis, usual interstitial pneumonia), idiopathic Tumors, Breast Cancer, Cancer of the Renal Pelvis and Ure pulmonary fibrosis, descquamative interstitial pneumonia, ter, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical 50 lymphoid interstitial pneumonia, histiocytosis X (e.g., Let Cancer, Colon Cancer, Endocrine Pancreas Islet Cell Carci terer-Siwe disease, Hand-Schuller-Christian disease, eosino noma, Endometrial Cancer, Ependymoma, Epithelial Cancer, philic granuloma), idiopathic pulmonary hemosiderosis, Sar Esophageal Cancer, Ewing's Sarcoma and Related Tumors, coidosis and pulmonary alveolar proteinosis), Acute Exocrine Pancreatic Cancer, Extracranial Germ. Cell Tumor, respiratory distress syndrome (also called, e.g., adult respira Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Can 55 tory distress syndrome), edema, pulmonary embolism, bron cer, Eye Cancer, Breast Cancer, Gaucher's Disease, Gallblad chitis (e.g., viral, bacterial), bronchiectasis, atelectasis, lung der Cancer, Gastric Cancer, Gastrointestinal Carcinoid abscess (caused by, e.g., Staphylococcus aureus or Legionella Tumor, Germ Cell Tumors, Gestational Trophoblastic Tumor, pneumophila), and cystic fibrosis. Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular In certain embodiments, the methods are for treatment of Cancer, Hypopharyngeal Cancer, Intestinal Cancers, 60 autoimmune disorders, such as systemic lupus erythemato Intraocular Melanoma, Islet Cell Carcinoma, Islet Cell Pan Sus, rheumatoid arthritis, ankylosing spondylitis, multiple creatic Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Sclerosis, autoimmune thyroiditis, Hashimoto's thyroiditis, Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung autoimmune hemolytic anemia, hemolytic anemia, thromb Cancer, Lymphoproliferative Disorders, Macroglobulinemia, ocytopenia, autoimmune thrombocytopenia purpura, autoim Melanoma, Nasal Cavity and Paranasal Sinus Cancer, 65 mune neonatal thrombocytopenia, idiopathic thrombocy Nasopharyngeal Cancer, and any other hyperproliferative topenia purpura, purpura (e.g., Henoch-Schönlein purpura), disease. autoimmunocytopenia, Goodpasture’s syndrome, myasthe US 8,414,914 B2 53 54 nia gravis, Grave's disease (hyperthyroidism), and diabetes -continued mellitus. In certain embodiments, the methods are for treat ment of diabetes. ngredient (Oil) mg serving %f serving mg batch In certain embodiments, the methods are for mucosal Methyl Paraben (in oil) 3 O.O375 375 delivery of insulin to a subject in need thereof. In certain 5 Propyl Paraben (in oil) 3 O.O375 375 Lecithin (in oil) 59 O.7375 7375 embodiments, the methods are for delivery of dietary supple Polysorbate 80 (In water Phase) 3OO 3.75 37500 ments, including but not limited to vitamins, minerals, hor Calcium Citrate, 17% Ca 82O 10.25 1 O2SOO mones and antioxidants. In certain embodiments, the meth (168 mg of elemental Ca) ods provided herein are for delivery of vitamins. In other Benzyl OH 35 O4375 4375 10 Lactoferrin 94% (in water) 50 O.625 62SO embodiments, the methods provided herein are for delivery of Luo Han Gao 80% 24 O.3 3OOO minerals. In other embodiments, the methods provided herein Sucralose 59 O.7375 7375 are for delivery of calcium. In other embodiments, the meth Butterscotch (BU-166) 21 O.2625 2625 ods provided herein are for delivery of COQ10. In other Coconut (CC-116) 24 O.3 3OOO embodiments, the methods provided herein are for delivery of Nat & Art. Vanilla (L-6729) 22 0.275 2750 15 Fudge (CT-151) 2O O.25 2SOO testOSterOne. Chocolate (CT-147) 37 O4625 4625 F. Articles of Manufacture The compositions provided herein can be packaged as Totals 8OOOOOO 1OOOOOO 11 OOOOO articles of manufacture containing packaging material, a composition provided herein, and a label that indicates that Water phase was prepared by weighing appropriate quan the composition is for mucosal delivery. In instances where the active agent is useful for altering a body function or tities of water, preservatives, polysorbate 80, lactoferrin, cal altering cosmetic appearance of the Subject, the compositions cium, and Saladizer R gum blend, mixing the ingredients to can be packaged as articles of manufacture containing pack dissolve all the components at 120° F. aging material, a composition provided herein Suitable for Oil phase was prepared by weighing the appropriate mucosal administration, and a label that indicates that the 25 amounts of oat oil, MCT, propylene glycol, methyl & propyl composition is used for altering a body function or altering parabens, benzyl OH, PEG, and lecithin, heating the mixture cosmetic appearance of the Subject. In certain embodiments, to 120°F. and mixing until all the ingredients dissolve. the compositions can be packaged as articles of manufacture containing packaging material, a composition provided Emulsion was prepared by heating the water and oil phases herein suitable for mucosal administration, and a label that 30 to 160°F., and adding water phase to oil phase slowly while indicates that the composition is used for delivery of dietary mixing. The emulsion was cooled to 95° F., followed by Supplements. In certain embodiments, the compositions can addition of flavors/sweeteners and additional water if needed be packaged as articles of manufacture containing packaging to make up the batch of 1.1 Kg. material, a composition provided herein Suitable for mucosal administration, and a label that indicates that the composition 35 EXAMPLE 2 is used for delivering a therapeutic agent to a subject in need thereof. Preparation of Libido Formulation: The articles of manufacture provided herein contain pack Appropriate quantities of the raw materials were weighed aging materials. Packaging materials for use in packaging for the 0.55 Kg batch as shown below: pharmaceutical products are well known to those of skill in 40 the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, ngredient (Oil) mg serving %f serving mg/batch inhalers, pumps, bags, vials, containers, bottles, and any MCT (Neobee M-5) (Oil 3O8 30.8 154OOO packaging material Suitable for a selected formulation and 45 Phase) intended mode of administration and treatment. Oat Oil (Oil Phase) 150.2 15.02 75100 Water 231 23.1 115500 The following examples are exemplary only and are not Propylene Glycol (In Oil 8O 8 4OOOO intended to limit the scope of the subject matter claimed Phase) herein. K-Sorbate (Preserves)(Water 2 O.2 1OOO 50 phase) Na-Benzoate (Preserves) 2 O.2 1OOO EXAMPLE1 (Water phase) Polymer (PEG 400 DS) (Oil 2O 2 1OOOO Preparation of Calcium Formulation: Phase) Appropriate quantities of the raw materials were weighed Methyl Paraben (Oil Preserves) 1 O.1 500 55 Propyl Paraben (Oil Preserves) 1 O.1 500 for the 1.1 Kg batch as shown below: Lecithin (Ultralec-P, 15 1.5 7500 Phospholipids) (Oil Phase) Polysorbate-80 (Lipids) (In 35 3.5 17500 water Phase, after filter after Ingredient (Oil) mg serving %f serving mg/batch Salidizer) Benzyl OH (Sterilizer, protein 5 O.S 2SOO MCT (Neobee M-5)(in oil) 1368.7 17.10875 171087.5 60 preserver) (Oil Phase) Oat Oil (in oil) 2046 25.575 255750 Testosterone (in Oil, in 75 7.5 37500 Water 2O88.3 26.1037S 261037.5 iposome) Propylene Glycol (In Oil Phase) 830 10.375 103.750 Vinpocetine (in Oil, in 6 O.6 3OOO K-Sorbate (in oil) 6 0.075 750 iposome) Na-Benzoate (in oil) 6 0.075 750 (Lactoferrin 94% minimum) 52 5.2 26OOO Saladizer (R) (In Water phase) 8 O.1 1OOO 65 (Water phase) Polymer (PEG 400 DS) (in oil) 170 2.125 212SO Sucralose (At the end) 12 1.2 6OOO US 8,414,914 B2 56 -continued EXAMPLE 4 Ingredient (Oil) mg serving %f serving mg/batch Preparation of Insulin Formulation: Nat. Banana (BA-133) (At the 3.4 O.34 1700 Appropriate quantities of the raw materials were weighed end) for the 0.053 Kg batch as shown below: Nat & Art. Vanilla (VA-158) 1.4 O.14 700 (At the end) Totals 1OOO.OOO 1OOOOOO 55OOOO Ingredient (Oil) mg serving %f serving mg/batch 10 MCT (Neobee M-5) 65 13.OOOO1 6SOO Water phase was prepared by weighing appropriate quan (Oil Phase) tities of water, preservatives, polysorbate 80, and lactoferrin Oat Oil (Oil Phase) 39.9375 7.987506 3993.75 mixing the ingredients to dissolve all the components at 130 Water (Water phase) 162.559 32.51.1824 16255.9 140°F. Propylene Glycol 53.25 10.6SOOO8 5325 (In Oil Phase) Oil phase was prepared by weighing the appropriate 15 K-Sorbate (Preserves) 0.665625 O.1331,251 66.5625 amounts of oat oil, MCT, propylene glycol, methyl & propyl (Water phase) parabens, benzyl OH, lecithin, testosterone and vinpocetine Na-Benzoate (Preserves) 0.665625 O.1331,251 66.5625 (Water phase) and heating the mixture to 130-140°F. and mixing until all the Methyl Paraben 0.665625 O.1331,251 66.5625 ingredients dissolve. (Oil Preservative) Emulsion Phase was prepared by mixing the water and oil Propyl Paraben 0.665625 O.1331,251 66.5625 (Oil Preservative) followed by cooling the emulsion. LIPOID 100 S100 (94% 48 9.6OOOO72 4800 Phosphatidycholine (PC)) EXAMPLE 3 Powder Polysorbate-80 (Lipids) 66.5625 13.312S1 6656.25 25 (In water Phase) Preparation of COQ10 Formulation: Benzyl OH (Sterilizer, 3.3281.25 0.66562SS 332.812S preservative) (Oil Phase) Appropriate quantities of the raw materials were weighed Human Recombinant Insulin S.1 1.02OOOO8 510 for the 1.1 Kg batch as shown below: (Sigma Aldrich) (Lactoferrin 94% minimum) 47.5 9.SOOOO71 47SO 30 (Water phase) Triethanolamine (TEA) Water 4 O.80OOOO6 400 ngredient (Oil) mg/serving %/serving mg/batch Phase (add before Insulin) Triethanolamine (TEA) 2.1 O.42OOOO3 210 MCT (Neobee M-5) (Oil Phase) 311 31.1 31.100 Oil Phase Oat Oil (Oil Phase) 151 15.1 15100 Water 231 23.1 23100 Totals SOO.OOO 1OO.OOOO 53177.16O12 Propylene Glycol (In Oil Phase) 83 8.3 8300 35 K-Sorbate (Preserves) 2 O.2 2OO (Water phase) Water phase was prepared by weighing appropriate quan Na-Benzoate (Preserves) 2 O.2 2OO tities of water, K-Sorbate, Na benzoate, Polysorbate-80 and (Water phase) Polymer (PEG 400 DS) (Oil Phase) 2O 2 2OOO triethanolamine was added and dissolved by mixing with a Methyl Paraben (Oil Preserves) 1 O.1 1OO 40 high speed mixer. The solution was maintained at pH 8.00 Propyl Paraben (Oil Preserves) 1 O.1 1OO 8.35 and temperature 115°F. Oil phase was prepared in a 600 Lecithin (Ultralec-P, 15 1.5 1SOO Phospholipids) (Oil Phase) mL Pyrex beaker. Appropriate quantities of oat oil, MCT, Polysorbate-80 (Lipids) 36 3.6 3600 propylene glycol, methyl paraben, propyl paraben, Benzyl (In water Phase) OH, Lipoid S 100 and triethanolamine were added and the Benzyl OH (Sterilizer, 5 O.S 500 45 mixture was heated up to 115° F. to dissolve the ingredients. preservative) (Oil Phase) COQ10 30 3 3OOO Emulsion Phase was prepared by mixing the oil and water (Lactoferrin 94% minimum) 1OO 10 1OOOO phase at 115°F., followed by cooling the emulsion and adding (Water phase) additional water to match the volume/weight to the total batch Sucralose (At the end) 3 O.3 3OO size. The emulsion was sheared at 2000 rpm at 115°F. until it Nat. Banana (BA-133) (At the end) 5 O.S 500 50 Nat & Art. Vanilla (L-10181) 3 O.3 3OO began to thicken. (At the end) EXAMPLE 5 Totals 1OOOOOO 100.OOOO 11 OOOO Preparation of Anti-Depression Formulation: Water phase was prepared by weighing appropriate quan 55 Appropriate quantities of the raw materials were weighed tities of water, preservatives, polysorbate 80, and lactoferrin for the 1.1 Kg batch as shown below: mixing the ingredients to dissolve all the components at 98-100°F. Oil phase was prepared by weighing the appropriate 60 Ingredient (Oil) mg serving %f serving mg batch amounts of oat oil, MCT, propylene glycol, methyl & propyl MCT (Oil Phase) 930 11.625 34875 parabens, benzyl OH, lecithin, and COQ10 and heating the Oat Oil (Oil Phase) 330 4.125 12375 mixture to 110° F. and mixing until all the ingredients dis Water 3967.2 49.59 148770 solve. Propylene Glycol (In Oil 742.8 9.285 27855 Phase) Emulsion Phase was prepared by adding the oil and water 65 K-Sorbate 6 0.075 225 phase followed by cooling the emulsion and addition of fla Na-Benzoate 6 0.075 225 Voring agents. US 8,414,914 B2 57 58 -continued ngredient (Oil) mg serving %f serving mg batch Ingredient (Oil) mg serving %fserving mg batch Salidizer (In Oil Phase) 15 0.1875 562.5 Water 15409 S136333333 S64996.67 Carmine Red (at the 34 O.425 1275 5 Non-denatured 11OOO 36.666666.67 403333.33 beginning) whey protein Polymer DS (PEG 40ODS) 170 2.125 6375 Na Benzoate 78 O.26 2860 Methyl Paraben (Oil Phase) 3 O.O375 112.5 K-Sorbate 78 O.26 2860 Propyl Paraben (Oil Phase) 3 O.O375 112.5 Antifoam 322 1.073333333 11806.667 Lecithin (Oil Phase) 40 O.S 1SOO Oat Oil 96S 3.216666,667 3S383.333 Span 60 (Oil Phase) 40 O.S 1SOO 10 Propylene Glycol 285 O.9S 10450 PS-80 (In Oil) 190 2.375 71.25 Methyl Paraben 30 O.1 1100 Phycamine 8SO 10.625 3.1875 Propyl Paraben 30 O.1 1100 Graviola (10:1) 2OO 2.5 7500 PEG-400 628 2.093333333 23026.667 L-5-HTP 150 1875 5625 Lecithin 400 1.333333333 14666.667 Vinpocetine (Oil Phase) 8 O.1 3OO Span 60 69 O.23 25.30 Non-denatured whey protein 50 O.625 1875 15 Benzyl OH 142 O.473333333 5206.6667 powder PS-80 164 O.S46666,667 6O13.3333 BOH (Oil Phase) 35 O4375 1312.5 Sucralose Powder 97 O.323333333 3556.6667 Sucralose 76 O.95 28SO Nat. Fudge (CT-151) 158 O.S266666.67 5793.3333 Nat Spearmint (MI-110) 154 1.925 5775 Nat. Chocolate (CT-147) 145 O.4.83333333 5316.6667

Totals 8OOOOOO 1OOOOOO 33OOOO 2O Totals (+3.0% of Active) 3OOOO 1OO.OOOO 11 OOOOO

Water phase was prepared in a 600 mL Pyrex beaker. Water phase was prepared in a 1500 mL Pyrex beaker. Appropriate amount of water, preservatives, color, L-5 HTP. Appropriate amounts of water, K-Sorbate, Na benzoate, Car mine red, and Polysorbate-80 were added and dissolved by phycomine, graviola (10:1) were added and dissolved by mixing with a slow speed mixer. Non-denatured whey protein mixing with a slow speed mixer. Non-denatured whey protein 25 and anti-foam was mixed at pH 6.80 and a temperature of was added and mixed while maintaining the temperature at 115° F. Oil phase was prepared in a 600 mL Pyrex beaker. 120° F. Oil phase was prepared in a 600 mL Pyrex beaker. Appropriate quantities of oat oil, propylene glycol, PEG-400, Appropriate quantities of oils, propylene glycol, PS-80, methyl paraben, propyl paraben, lecithin, and span 60 were methyl and propyl parabens, PEG, lecithin were added and added and the mixture was heated up to 115°F. to dissolve the mixed to dissolve the ingredients followed by addition of 30 ingredients. Emulsion Phase was prepared by adding the oil vinpocetine and Salidizer R at 120° F. Emulsion Phase was and water phase at 115°F., followed by cooling the emulsion prepared by adding the oil and water phase at 120° F., fol and adding flavoring agents. lowed by cooling the emulsion to 95° F. and adding flavoring In Examples 7-12, the amount of each ingredient needed to agents. achieve the indicated amount/serving was calculated based 35 on the specific gravity of the final composition. EXAMPLE 6 EXAMPLE 7 Preparation of Non-Denatured Whey Protein Formulation: Preparation of CoQ10 Formulation: Appropriate quantities of the raw materials were weighed Appropriate quantities of the raw materials were weighed for the 1.1 Kg batch as shown below: for the 1.3 Kg batch as shown below:

Amount Ingredient (Oil) mg serv. needed (mg) 9of serving mg/batch MCT (Neobee M-5) (Oil Phase) 55 57.695 11.OOOO 144237.5 Oat Oil (Oil Phase) 39.9375 41.894.4375 7.9875 104736.1 Water (Water phase) 155.909 163S48541 31.1818, 4.08871.4 Propylene Glycol (In Oil Phase) 45 47.2OS 9.OOOO 118O12.5 K-Sorbate (Preserves) (Water phase) 0.665625 O.69824O63 O.1331 1745.6O2 Na-Benzoate (Preserves) (Water phase) 0.665625 O.69824O63 O.1331 1745.6O2 Methyl Paraben (Oil Preservative) 0.665625 O.69824O63 O.1331 1745.6O2 Propyl Paraben (Oil Preservative) 0.665625 O.69824O63 O.1331 1745.6O2 LIPOID 100 S100 (94% 48 50.352 9.6OOO 12588O Phosphatidycholine (PC)) Powder Polysorbate-80 (Lipids) (In water Phase) 66.5625 69.824.0625 13.3125 174560.2 Benzyl OH (Sterilizer, preservative) (Oil 3.3281.25 3.4912O313 O.6656 8728.008 Phase) COQ10 (Oil Phase) 30 31.47 6.OOOO 78675 (Lactoferrin 94% minimum) (Water 47.5 49.8275 9.SOOO 124568.8 phase) Triethanolamine (TEA) Water Phase (add 4 4.196 O.8000 10490 before Insulin) Triethanolamine (TEA) Oil Phase 2.1 2.2029 O42OO 5507.25

Totals SOO.OOO 524.500 1OOOOOO 1311249.0 US 8,414,914 B2 60 -continued Procedure # Phase pH Temp C.

Step (1) PS-80.H2OTEA 8.61 45.4 Step (2) PS-80, IGF-1 8.3 42.1 Step (3) PS-80 Lactof 8.11 43.7 Step (4) Quality Control 8.34 24.5

1. Oil Phase: Oil phase was prepared first as follows: 10 Antifoam was added as needed. All lactoferrin was dissolved until there were no clumps in the Solution. Equipment used: Corning Hot Plate, IKA mixer type RE 16 3. Emulsion Phase: Emulsion phase was prepared as follows: S1 serial No 93-133-35, 600 mL Pyrex Beaker. Equipment used: Arde Barinco Mixer Type 74D serial No Ingredients were added in the following order: Oat Oil, L-1274 MCT, propylene glycol, methyl and propyl parabens, benzyl 15 Oil phase was added to water phase (each at 115°F) at 14% OH and TEA. The mixture was heated to 115° F., and mixed of RPM for 10 minutes while cooling. After 10 minutes, the at 250 rpm to dissolve the ingredients. Phosphatidylcholine mixing speed was lowered to 10% RPM. Mixing was contin (lipoid S100) was added at 115° F. at 250 rpm and mixed to ued with Arde Barinco mixer while maintaining enough shear dissolve. CoQ10 was added to the mixture and dissolved to a for the emulsion and the mixture was cooled during the pro light orange color. CCSS, 2. Water Phase: Water phase was prepared as follows: 4. Finished product: The finished product had a pH above Equipment used: Corning Hot Plate, Arde Barinco Mixer 8.00 and was tested for amount of CoQ10 present. Type 74D serial No L-1274, 1500 ml Pyrex Beaker, Hanna EXAMPLE 8 Instruments pH meter model HI8314. Ingredients were added in the following order: water, 25 Preparation of Oratropin-1 Formulation: K-Sorbate, Na Benzoate, Polysorbate 80, and TEA. The pH Appropriate quantities of the raw materials were weighed was maintained at >8.30. Solution was heated slowly and for the 1.3 Kg batch as shown below:

Amount Ingredient (Oil) mg/serv. needed (mg) %/serving mg/batch

MCT (Neobee M-5) (Oil Phase) 65 68.185 13.OOOO 170462.5 Oat Oil (Oil Phase) 39.9375 41.894.4375 7.9875 104736.1 Water (Water phase) 167.619 175.832331 33.5238 439S80.8 Propylene Glycol (In Oil Phase) 53.25 55.85925 10.6SOO 139648.1 K-Sorbate (Preserves) (Water phase) 0.665625 O.69824O63 O.1331 1745.6O2 Na-Benzoate (Preserves) (Water phase) 0.665625 O.69824O63 O.1331 1745.6O2 Methyl Paraben (Oil Preservative) 0.665625 O.69824O63 O.1331 1745.6O2 Propyl Paraben (Oil Preservative) 0.665625 O.69824O63 O.1331 1745.6O2 LIPOID 100 S 100 (94% Phosphatidycholine 48 50.352 9.6OOO 12588O (PC)) Powder Polysorbate-80 (Lipids) (In water Phase) 66.5625 69.824.0625 13.3125 174560.2 Benzyl OH (Sterilizer, preservative) (Oil 3.3281.25 3.4912O313 O.6656 8728.008 Phase) GF-1 O.04 O.041.96 O.OO8O 104.9 (Lactoferrin 94% minimum) (Water phase) 47.5 49.8275 9.SOOO 124568.8 Triethanolamine (TEA) Water Phase (add 4 4.196 O.8000 10490 before Insulin) Triethanolamine (TEA) Oil Phase 2.1 2.2029 O42OO 5507.25

Totals SOO.OOO 524.500 1OOOOOO 1311249.0

Procedure # Phase pH Temp C.

Step (1) PS-80.H2OTEA 8.61 45.4 Step (2) PS-80, IGF-1 8.3 42.1 Step (3) PS-80 Lactof 8.11 43.7 Step (4) Quality Control 8.34 24.5

60 stirred with a stirring rod until all the PS-80 was dissolved 1. Oil Phase: Oil phase was prepared first as follows: into the solution (straw yellow color). Temperature was main tained at 115°F. and pH at above 8.30, adjusting with TEA as Equipment used: Corning Hot Plate, IKA mixer type RE 16 needed. Lactoferrin was added to the straw-yellow solution S1 serial No 93-133-35, 600 ml Pyrex Beaker. while mixing with the Arde Barinco Mixer at 10% RPM on 65 Ingredients were added in the following order: Oat Oil, Forward. Temperature was maintained at 115° F. and the MCT, propylene glycol, methyl and propyl parabens, benzyl mixer at 10% of RPM until a good dispersion was observed. OH and TEA. The mixture was heated to 115° F., and mixed US 8,414,914 B2 61 62 at 250 RPM to dissolve the ingredients. Phosphatidylcholine 1. Oil phase: Oil phase was prepared first as follows: (lipoid S100) was added at 115° F. at 250 RPM and mixed to Equipment used: Corning Hot Plate, IKA mixer type RE 16 dissolve. S1 serial No 93-133-35, 600 ml Pyrex Beaker 2. Water Phase: Water phase was prepared as follows: Ingredients were added in the following order: Oat Oil, Equipment used: Corning Hot Plate, Arde Barinco Mixer MCT, propylene glycol, methyl and propyl parabens, benzyl Type 74D serial No L-1274, 1500 ml Pyrex Beaker, Hanna OH and TEA. The mixture was heated to 115° F., and mixed Instruments pH meter model HI8314. at 250 RPM to dissolve the ingredients. Phosphatidylcholine Ingredients were added in the following order: water, (lipoid S100) was added at 115° F. at 250 RPM and mixed to K-Sorbate, Na Benzoate, Polysorbate 80, and TEA. The pH dissolve. was maintained at >8.30. Solution was heated slowly and 10 stirred with a stirring rod until all the PS-80 was dissolved 2. Water Phase: Water phase was prepared as follows: into the solution (straw yellow color). Temperature was main Equipment used: Corning Hot Plate, Arde Barinco Mixer tained at 115°F. pH was maintained at above 8.30, adjusting Type 74D serial No L-1274, 1500 ml Pyrex Beaker, Hanna with TEA as needed. IGF-1 was added to the straw-yellow Instruments pH meter model HI8314. solution, while maintaining temperature at 115° F. and pH at 15 Ingredients were added in the following order: water, 8.30. Lactoferrin was added with the Arde Barinco Mixer at K-Sorbate, Na Benzoate, Polysorbate 80 (PS-80), and TEA. 10% RPM on Forward. Temperature was maintained at 115° The pH was maintained at >8.30. Solution was heated slowly F. and the mixer at 10% of RPM until a good dispersion was and stirred with a stirring rod until all the PS-80 was dissolved observed. Antifoam was added as needed. All lactoferrin was into the Solution (straw yellow color). Temperature was main dissolved so that the solution did not contain any lumps. tained at 115°F. and pH at above 8.30, adjusting with TEA as 3. Emulsion Phase: Emulsion phase was prepared as follows: needed. Hexarelin & GHRP-6 agonist were added at 115° F. Equipment used: Arde Barinco Mixer Type 74D serial No pH was maintained at above 8.30. Lactoferrin was added to L-1274 the solution while mixing with the Arde Barinco Mixer at Oil phase was added to water phase (each at 115°F) at 14% 10% RPM on Forward. Temperature was maintained at 115° of RPM for 10 minutes while cooling. After 10 minutes the 25 F. and the mixer at 10% of RPM until a good dispersion was mixing speed was lowered to 10% RPM. Mixing was contin observed. Antifoam was added as needed. All lactoferrin was ued with Arde Barinco mixer while maintaining enough shear dissolved until there were no clumps in the solution. for the emulsion and the mixture was cooled during the pro 3. Emulsion Phase: Emulsion phase was prepared as follows: CCSS, 4. Finished product: The finished product had a pH above 30 Equipment used: Arde Barinco Mixer Type 74D serial No 8.00 and was tested for the amount of IGF-1. L-1274 Oil phase was added to water phase (each at 115°F) at 14% EXAMPLE 9 of RPM for 10 minutes while cooling. After 10 minutes the mixing speed was lowered to 10% RPM. Mixing was contin Preparation of Hexatropin-6 Formulation: 35 ued with Arde Barinco mixer while maintaining enough shear Appropriate quantities of the raw materials were weighed for the emulsion and the mixture was cooled during the pro for the 1.3 Kg batch as shown below: CCSS,

Amount Ingredient (Oil) mg serv. needed (mg) %f serving mg/batch MCT (Neobee M-5) (Oil Phase) 65 68.185 13.OOOO 170462.5 Oat Oil (Oil Phase) 39.9375 41.894.4375 7.9875 104736.1 Water (Water phase) 167.459 175.664491 33.4918 439161.2 Propylene Glycol (In Oil Phase) 53.25 55.85925 10.6SOO 139648.1 K-Sorbate (Preserves) (Water phase) O.665625 O.69824O63 O.1331 1745.602 Na-Benzoate (Preserves) (Water phase) O.665625 O.69824O63 O.1331 1745.602 Methyl Paraben (Oil Preservative) O.665625 O.69824O63 O.1331 1745.602 Propyl Paraben (Oil Preservative) O.665625 O.69824O63 O.1331 1745.602 LIPOID 100 S100 (94% Phosphatidycholine 48 50.352 9.6OOO 12588O (PC)) Powder Polysorbate-80 (Lipids) (In water Phase) 66.5625 69.824.0625 13.312S 1745602 Benzyl OH (Sterilizer, preservative) (Oil 3.3281.25 3.4912O313 0.6656 8728.008 Phase) Hexarelin O.1 O.1049 O.O2OO 262.25 GHRP-6 (Growth Hormone Peptide-6) O.1 O.1049 O.O2OO 262.25 Agonist (Lactoferrin 94% minimum) (Water phase) 47.5 49.8275 9.SOOO 124568.8 Triethanolamine (TEA) Water Phase (add 4 4.196 O.8000 10490 before Insulin) Triethanolamine (TEA) Oil Phase 2.1 2.2029 O4200 5507.25

Totals SOOOOO 524. SOO 1OOOOOO 1311249.O Procedure # Phase pH Temp C.

Step (1) PS-80.H2OTEA 8.61 45.4 Step (2) PS-80.Hex, GHRP-6 8.3 42.1 Step (3) PS-80 Lactof 8.11 43.7 Step (4) Quality Control 8.34 24.5 US 8.4 14,914 B2 63 64 4. Finished product: The finished product has a pH above 8.00 tained at 115°F. and pH at above 8.30, adjusting with TEA as was tested for contents of GHRP-6 agonist and Hexarelin. needed. Insulin was added to the straw-yellow solution, while maintaining temperature at 115° F. and pH at 8.30. Albumin EXAMPLE 10 was added with the Arde Barinco Mixer at 10% RPM on 5 Forward. Temperature was maintained at 115° F. and the Preparation of Insulin-Albumin Formulation: mixer at 10% of RPM until a good dispersion was observed. Appropriate quantities of the raw materials were weighed Antifoam was added as needed. All lactoferrin was dissolved for the 0.11 Kg batch as shown below: so that the solution did not contain any lumps.

Amount Ingredients Mg/serv. needed (mg) 9of serving mg/batch MCT (Neobee M-5) (Oil Phase) 65 68.185 13.OO46 13637 Oat Oil (Oil Phase) 39.9375 41.894.4375 7.9903 8378.8875 Water (Water phase) 150.597 157.976253 30.13OO 31595.2SO6 Propylene Glycol (In Oil Phase) 53.25 55.85925 10.6538 11171.85 K-Sorbate (Preserves) (Water phase) O.665625 O.69824.0625 O.1332 139.6481.25 Na-Benzoate (Preserves) (Water phase) O.665625 O.69824.0625 O.1332 139.6481.25 Methyl Paraben (Oil Preservative) O.665625 O.69824.0625 O.1332 139.6481.25 Propyl Paraben (Oil Preservative) O.665625 O.69824.0625 O.1332 139.6481.25 LIPOID 100 S100 (94% 48 50.352 9.6034 100704 Phosphatidycholine (PC)) Powder Polysorbate-80 (Lipids) (In water 66.5625 69.824.0625 13.3172 13964.812S Phase) Benzyl OH (Sterilizer, preservative) 3.3281.25 3.4912O312S O.6659 698.24.0625 (Oil Phase) Human Recombinant Insulin (Sigma 10 11 2.O980 2200 Aldrich) (Albumin) (Water phase) 47.5 49.8275 9.SO33 996S.S Triethanolamine (TEA) Water Phase 10.4 10.9096 2.0807 2181.92 (add before Insulin) Triethanolamine (TEA) Oil Phase 2.1 2.2029 O42O1 440.58

Totals 499.338 524.315 1OOOOOO 104863.0337 Procedure Phase pH Temp C. Step (1) PS-8OH2OTEA 8.61 45.4 Step (2) PS-80. Insulin 8.3 42.1 Step (3) PS-80, Albumin 8.27 43.7 Step (4) Finished Product 8.42 13.6

1. Oil phase: Oil phase was prepared first as follows: 3. Emulsion phase: Emulsion phase was prepared as follows: Equipment used: Corning Hot Plate, IKA mixer type RE 16 40 Equipment used: Arde Barinco Mixer Type 74D serial No S1 serial No 93-133-35, 80 ml Pyrex Beaker. L-1274 Ingredients were added in the following order: Oat Oil O MCT, propylene glycol, methyl and propyl parabens, benzyls ERE y added tO S. p ch at 6 F.) at s O OH and TEA. The mixture was heated to 115° F., and mixed of K O d all 1 6. Evi N. n1nutes t at 250 RPM to dissolve the ingredients. Phosphatidylcholine 45 E. E. r owered to hi M. Mixing was SR (lipoid S100) was added at 115° F. at 250 RPM and mixed to t 1 e BarME, W1 ity E. Sea dissolve. COQ10 was added to the mixture and dissolved to a or the emulsion and the mixture was cooled during the pro light orange color. CCSS, 2. Water Phase: Water phase was prepared as follows: 4. Finished product: The finished product had a pH above Equipment used: Corning Hot Plate, Arde Barinco Mixer 50 8.00 and was tested for the amount of insulin. Type 74D serial No L-1274, 250 ml Pyrex Beaker, Hanna Instruments pH meter model HI8314. EXAMPLE 11 Ingredients were added in the following order: water, K-Sorbate, Na Benzoate, Polysorbate 80, and TEA. The pH was maintained at >8.30. Solution was heated slowly and 55 Preparation of Insulin-Lactoferrin Formulation: stirred with a stirring rod until all the PS-80 was dissolved Appropriate quantities of the raw materials were weighed into the solution (straw yellow color). Temperature was main for the 0.53 Kg batch as shown below:

Amount Ingredients mg serv. needed %fserving mg batch MCT (Neobee M-5) (Oil Phase) 65 68.185 12.986S 6818S Oat Oil (Oil Phase) 39.9375 41.894.4375 7.9792 41894.4375 Water (Water phase) 150.597 157.976253 30.0882 157976.253 Propylene Glycol (In Oil Phase) 53.25 55.85925 10.6390 SS859.25 K-Sorbate (Preserves) (Water phase) 0.665625 O.69824.0625 O.1330 698.24.0625 US 8,414,914 B2 65 -continued Na-Benzoate (Preserves) (Water phase) O.665625 O.69824.0625 O.1330 698.24.0625 Methyl Paraben (Oil Preservative) O.665625 O.69824.0625 O.1330 698.24.0625 Propyl Paraben (Oil Preservative) O.665625 O.69824.0625 O.1330 698.24.0625 LIPOID 100 S100 (94% Phosphatidycholine 48 50.352 9.5901 SO352 (PC)) Powder Polysorbate-80 (Lipids) (In water Phase) 66.5625 69.824.0625 13.2987 69824.0625 Benzyl OH (Sterilizer, preservative) (Oil 3.3281.25 3.4912O312S O.6649 3491.2O312S Phase) Human Recombinant Insulin (Sigma 10.6621.17 11.7283292S 2.2338 11728.32925 Aldrich) (Lactoferrin 94% minimum “transferring) 47.5 49.8275 9.4902 49827.5 (Water phase) Triethanolamine (TEA) Water Phase (add 10.4 10.9096 2.0778 109.09.6 before Insulin) Triethanolamine (TEA) Oil Phase 2.1 2.2029 O41.96 22O2.9

Totals SOOOOO S25.043 1OO.OOOO S2SO43.4979 Procedure # Phase pH Temp C.

Step (1) PS-80.H2OTEA 8.61 45.4 Step (2) PS-80. Insulin 8.3 42.1 Step (3) PS-80 Lactof 8.27 43.7 Step (4) Finished Product 8.42 13.6

1. Oil Phase: Oil phase was prepared first as follows: Forward. Temperature was maintained at 115° F. and the Equipment used: Corning Hot Plate, IKA mixer type RE 16 25 mixer at 10% of RPM until a good dispersion was observed. S1 serial No 93-133-35, 250 ml Pyrex Beaker Antifoam was added as needed. All lactoferrin was dissolved Ingredients were added in the following order: Oat Oil, so that the solution did not contain any lumps. MCT, propylene glycol, methyl and propyl parabens, benzyl 3. Emulsion Phase: Emulsion phase was prepared as follows: OH and TEA. The mixture was heated to 115° F., and mixed 30 Equipment used: Arde Barinco Mixer Type 74D serial No at 250 RPM to dissolve the ingredients. Phosphatidylcholine L-1274 (lipoid S100) was added at 115° F. at 250 RPM and mixed to Oil phase was added to the water phase (each at 115°F) at dissolve. 14% of RPM for 10 minutes while cooling. After 10 minutes 2. Water Phase: Water phase was prepared as follows: the mixing speed was lowered to 10% RPM. Mixing was Equipment used: Corning Hot Plate, Arde Barinco Mixer 35 continued with Arde Barinco mixer while maintaining Type 74D serial No L-1274, 600 ml Pyrex Beaker, Hanna enough shear for the emulsion and the mixture was cooled Instruments pH meter model HI8314 during the process. Ingredients were added in the following order: water, K-Sorbate, Na Benzoate, Polysorbate 80, and TEA. The pH 4. Finished product: The finished product had a pH above was maintained at >8.30. Solution was heated slowly and 8.00 and was tested for the amount of insulin. stirred with a stirring rod until all the PS-80 was dissolved 40 into the solution (straw yellow color). Temperature was main EXAMPLE 12 tained at 115°F. and pH at above 8.30, adjusting with TEA as needed. Insulin was added to the straw-yellow solution, while Preparation of Insulin-Lactoferrin Formulation: maintaining temperature at 115° F. and pH at 8.30. Lactofer Appropriate quantities of the raw materials were weighed rin was added with the Arde Barinco Mixer at 10% RPM on for the 0.65 Kg batch as shown below:

Amount Ingredients mg serv. needed %fserving mg batch

MCT (Neobee M-5) (Oil Phase) 65 84.5 13.0428 84SOO Oat Oil (Oil Phase) 39.9375 51.91875 8.O138 51918.75 Water (Water phase) 150.597 195.7761 30.2186 195776.1 Propylene Glycol (In Oil Phase) 53.25 69.225 10.6851 6922S K-Sorbate (Preserves) (Water phase) 0.665625 O.865312S O.1336 865.312S Na-Benzoate (Preserves) (Water phase) 0.665625 O.865312S O.1336 865.312S Methyl Paraben (Oil Preservative) 0.665625 O.865312S O.1336 865.312S Propyl Paraben (Oil Preservative) 0.665625 O.865312S O.1336 865.312S LIPOID 100 S100 (94% Phosphatidycholine 48 624 9.6316 62400 (PC)) Powder Polysorbate-80 (Lipids) (In water Phase) 66.5625 86.5312S 13.3563 86531.25 Benzyl OH (Sterilizer, preservative) (Oil Phase) 3.3281.25 4.326S625 0.6678 4326.5625 Human Recombinant Insulin (Sigma Aldrich) 10.662117 11.72832925 18103 11728.32925 (Lactoferrin 94% minimum “transferring) (Water 47.5 61.75 9.5313 61750 phase) US 8,414,914 B2 68 -continued Triethanolamine (TEA) Water Phase (add before 10.4 13.52 2.0868 13520 Insulin) Triethanolamine (TEA) Oil Phase 2.1 2.73 O.4214 2730 Totals SOOOOO 647.867 1OO.OOOO 64.7867.2417 Procedure # Phase pH Temp C.

Step (1) PS-80.H2OTEA 8.61 45.4 Step (2) PS-80. Insulin 8.3 42.1 Step (3) PS-80 Lactof 8.27 43.7 Step (4) Finished Product 8.42 13.6

1. Oil Phase: Oil phase was prepared first as follows: 15 lactoferrin was dissolved so that the solution did not contain Equipment used: Corning Hot Plate, IKA mixer type RE 16 any lumps. 3. Emulsion Phase: Emulsion phase was prepared as follows: S1 serial No 93-133-35, 600 ml Pyrex Beaker Equipment used: Arde Barinco Mixer Type 74D serial No Ingredients were added in the following order: Oat Oil, L-1274 MCT, propylene glycol, methyl and propyl parabens, benzyl Oil phase was added to water phase (each at 115°F) at 14% OH and TEA. The mixture was heated to 115° F., and mixed of RPM for 10 minutes while cooling. After 10 minutes the at 250 RPM to dissolve the ingredients. Phosphatidylcholine mixing speed was lowered to 10% RPM. Mixing was contin (lipoid S100) was added at 115° F. at 250 RPM and mixed to ued with Arde Barinco mixer while maintaining enough shear dissolve. for the emulsion and the mixture was cooled during the pro CCSS, 2. Water Phase: Water phase was prepared as follows: 25 4. Finished product: The finished product had a pH above Equipment used: Corning Hot Plate, Arde Barinco Mixer 8.00 and was tested for the amount of insulin. Type 74D serial No L-1274, 250 ml Pyrex Beaker, Hanna EXAMPLE 13 Instruments pH meter model HI8314 Ingredients were added in the following order: water, Preparation of Insulin-Immunoglobulin Formulation: K-Sorbate, Na Benzoate, Polysorbate 80, and TEA. The pH 30 Appropriate quantities of the raw materials were weighed was maintained at >8.30. Solution was heated slowly and for the 0.11 Kg batch as shown below:

Amount Ingredients mg serv. needed %fserving mg batch MCT (Neobee M-5) (Oil Phase) 65 68.185 13.0046 13637 Oat Oil (Oil Phase) 39.9375 41.894.4375 7.9903 8378.8875 Water (Water phase) 150.597 157.976253 30.1300 31595.2506 Propylene Glycol (In Oil Phase) 53.25 55.85925 10.6538 11171.85 K-Sorbate (Preservis) (Water phase) 0.665625 O.69824.0625 O.1332 139.6481.25 Na-Benzoate (Preservis) (Water phase) 0.665625 O.69824.0625 O.1332 139.6481.25 Methyl Paraben (Oil Preservative) 0.665625 O.69824.0625 O.1332 139.6481.25 Propyl Paraben (Oil Preservative) 0.665625 O.69824.0625 O.1332 139.6481.25 LIPOID 100 S 100 (94% Phosphatidycholine (PC)) Powder 48 50.352 9.6034 10070.4 Polysorbate-80 (Lipids) (In water Phase) 66.5625 69.824.0625 13.3172 13964.812S Benzyl OH (Sterilizer, preservatizer) (Oil Phase) 3.3281.25 3.4912O312S O.6659 698.24.0625 Human Recombinant Insulin (Sigma Aldrich) 10 11 2.098O 2200 IGG (Immunoglobulin) (Water phase) 47.5 49.8275 9.SO33 996.S.S Triethanolamine (TEA) Water Phase (add before Insulin) 10.4 10.9096 2.0807 218.192 Triethanolamine (TEA) Oil Phase 2.1 2.2029 O42O1 440.58 Totals 499.338 524.315 1OOOOOO 104863.0337

Procedure # Phase pH Temp C. Step (1) PS-8OH2OTEA 8.61 45.4 Step (2) PS-80. Insulin 8.3 42.1 Step (3) PS-80, IGG 8.27 43.7 Step (4) Finished Product 8.42 13.6 stirred with a stirring rod until all the PS-80 was dissolved 1. Oil Phase: Oil phase was prepared first as follows: into the solution (straw yellow color). Temperature was main 60 Equipment used: Corning Hot Plate, IKA mixertype RE 16 tained at 115°F. and pH at above 8.30, adjusting with TEA as S1 serial No 93-133-35, 80 ml Pyrex Beaker. needed. Insulin was added to the straw-yellow solution, while Ingredients were added in the following order: Oat Oil, maintaining temperature at 115° F. and pH at 8.30. Lactofer MCT, propylene glycol, methyl and propyl parabens, benzyl rin was added while mixing the solution with the Arde Bar OH and TEA. The mixture was heated to 115° F., and mixed inco Mixer at 10% RPM on Forward. Temperature was main 65 at 250 RPM to dissolve the ingredients. Phosphatidylcholine tained at 115° F. and the mixer at 10% of RPM until a good (lipoid S100) was added at 115° F. at 250 RPM and mixed to dispersion was observed. Antifoam was added as needed. All dissolve. US 8,414,914 B2 69 70 2. Water Phase: Water phase was prepared as follows: TABLE 1-continued Equipment used: Corning Hot Plate, Arde Barinco Mixer Type 74D serial No L-1274, 250 ml Pyrex Beaker, Hanna DOG #71, Weight of dog = 22 kg, Instruments pH meter model HI8314. IV dosing: DOSE = 0.01 mg/kg Ingredients were added in the following order: water, 5 Time Plasma Insulin Plasma Glucose K-Sorbate, Na Benzoate, Polysorbate 80, and TEA. The pH (min) (ngmL) (mg/dL) was maintained at >8.30. Solution was heated slowly and 2O 7.6 41 stirred with a stirring rod until all the PS-80 was dissolved 25 5.9 42 into the solution (straw yellow color). Temperature was main 40 2.5 39 10 60 1.2 48 tained at 115°F. and pH at above 8.30, adjusting with TEA as 120 O.19 69 needed. Insulin was added to the straw-yellow solution, while 18O O.08 87 maintaining temperature at 115° F. and pH at 8.30. Immuno 240 O.08 86 globulin was added with the Arde Barinco Mixer at 10% RPM on Forward. Temperature was maintained at 115° F. and the mixer at 10% of RPM until a good dispersion was observed. 15 Antifoam was added as needed. All immunoglobulin was TABLE 2 dissolved so that the solution did not contain any lumps. DOG 71, Weight of dog = 22 kg 3. Emulsion Phase: Emulsion phase was prepared as follows: P.O dosing: DOSE = 0.02 mg/kg Equipment used: Arde Barinco Mixer Type 74D serial No L-1274 Plasma Insulin Plasma Oil phase was added to water phase (each at 115°F) at 14% Time (h) ng/mL Glucose of RPM for 10 minutes while cooling. After 10 minutes the 5 O.17 8O mixing speed was lowered to 10% RPM. Mixing was contin 5.5 O.O2 76 ued with Arde Barinco mixer while maintaining enough shear 6 O 79 25 6.5 O.O6 86 for the emulsion and the mixture was cooled during the pro 7 O.2 84 CCSS, 7.5 O.1 85 4. Finished product: The finished product had a pH above 8 O46 85 8.00 and was tested for the amount of insulin. 8.5 O.23 85 9 O.13 84 9.5 O.45 85 30 EXAMPLE 1.4 10 1.1 88 1O.S O42 99 Oral Bioavailability and Pharmacokinetic Studies in Dogs 11 O.68 88 11.5 O.68 1OO Oral bioavailability of insulin composition was determined 12 O.38 82 using an IV study followed by an oral crossover study and the 16 0.55 85 relative areas of under the curve, plasma half life, C and 35 24 O.S 87 T was calculated. Protocol Outline Mongrel dogs (20-30 kg) were used (n=2) for the study. The dogs were fasted overnight for both the studies in order to TABLE 3 achieve baseline glucose and insulin levels. 40 DOG #72, Weight of dog = 28 kg, IV Study: IV injection of 0.01 mg/kg human insulin was IV dosing: DOSE = 0.01 mg/kg administered to the dogs. Blood samples were taken at: 2, Time Plasma Insulin Plasma Glucose 5, 10, 15, 20, 25, 40, 60, 120, 180, and 240 minutes. Blood (min) (ngmL) (mg/dL) was analyzed for glucose and insulin levels for all time points. 45 2 27.3 89 5 21.4 60 Oral Study: 4 days were allowed for washout following the IV 10 11.4 31 study. Insulin composition of Example 12 was orally 15 6.5 28 administered between lips and gums at a dose of 0.02 2O 3.4 35 mg/kg. Blood samples were taken at 5, 5.5, 6.5, 7, 7.5, 8, 25 2.7 24 50 40 0.7 21 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 16, and 24 hours and 60 O.2 33 analyzed for insulin and glucose levels. 120 O.04 68 Following data collection, plasma concentration, plasma 18O O 102 half-life, peak concentration (C) and time to reach C 240 O.04 99 (t) were determined. From the areas under the curve, per cent oral bioavailability was determined. 55 TABLE 4 TABLE 1. DOG #72. Weight of dog. = 28 kg. P.O. dosing: DOSE = 0.02 mg/kg DOG #71, Weight of dog = 22 kg, IV dosing: DOSE = 0.01 mg/kg Plasma Insulin Plasma Glucose 60 Time (h) (ngmL) (mg/dL) Time Plasma Insulin Plasma Glucose (min) (ngmL) (mg/dL) 5 O.17 82 5.5 O.O2 97 2 SO.2 89 6 O 89 5 26.6 82 6.5 O.O6 90 10 15.9 57 65 7 O.2 84 15 10.1 46 7.5 O.1 89 US 8,414,914 B2 71 72 TABLE 4-continued TABLE 6-continued

DOG #72. Weight of dog. = 28 kg. P.O. dosing: DOSE = 0.02 mg/kg INTRAVENOUSPHARMACOKINETIC ANALYSIS FORMIPROCELLE-INSULIN IN DOGS Plasma Insulin Plasma Glucose Miprocelle-Insulin Time (h) (ngmL) (mg/dL) Analytical Range 0.01-3000 (ng/mL) TTIRFA: 3021 8 O46 93 IV. Dose OO1 8.5 O.23 103 9 O.13 93 1 2.5 0.7 1.60 9.5 O.45 101 2 1.2 O.2 0.7 10 O.28 95 10 3 O.OO O.OO O.O 1O.S 1.1 88 4 O.O2 O.04 O.O3 11 O42 95 11.5 O.68 88 Half-life (hr) O.23 12 O.38 91 Tmax (hr) O.O3 16 0.55 103 Cmax (ng mL) 38.5 24 O.SO 92 15 AUC O-T (hr * ng/mL) 7.4

EXAMPLE 1.5 TABLE 5

PHARMACOKINETIC ANALYSIS FOR ORAL INSULIN IN Oral Bioavailability and Pharmacokinetic Studies in Rats DOGS Preliminary studies for oral bioavailability and pharmaco Miprocelle-Insulin kinetics in rats were conducted with various insulin formula Analytical Range 0.01-3000/mL TTIRFA: 3021 tions (albumin-insulin (example 10), IgG-insulin (example PO Dose 0.02 mg/kg 13) and lactoferrin-insulin (example 12) were administered to 25 rats at a volume of 0.2 mL at 230-250 mg between the gum Time Animal #Concentration and lips. The formulations were spotted throughout the gum and lip interface so they were evenly distributed. Blood (hr) 71 72 Mean samples were withdrawn via retro-orbital bleed at the times S.OO O.17 O.OO O.85 shown in Tables 7-8. 5.50 O.O2 O.OS O.04 30 6.OO O.OO O.O2 O.O1 Control animals showed no human insulin at any time. 6.50 O.O6 O.12 O.09 Human insulin appeared in the blood for all treatment 7.OO O.2 O.O O.1 between 4-5 hours. 7.50 O.1 O.12 O.1 8.OO O46 O.25 O.35 8.50 O.23 0.67 O.45 35 9.OO O.13 O.OS O.09 Animal Insulin Glucose 9.SO O45 O.O6 O.25 Composition No. Time (h) ng/ml (mg/DI) 1O.OO O.28 O.34 O.62 1O.SO 1.10 1...SO 1.30 Control 1 3 <200 10 11.00 O42 O.20 O.31 4 <200 23 11...SO O.68 O.40 1.10 5 <200 O6 40 12.00 O.38 O.22 O.30 14 <200 46 16.00 0.55 1.00 O.78 18 <200 64 24.00 OSO O.O2 O.26 2 3 <200 12 4 <200 16 Pharmacokinetic Estimates 5 <200 15 14 <200 Half-life (hr) 18.00 45 18 <200 62 Tmax (hr) 1O.SO <2.00 (mean) 131 (mean) Cmax (ng mL) 1.3 Lactoferrin-insulin 1 3 <200 13 AUC O-T (hr * ng/mL) 8.9 4 <200 21 % Bioavailability 61% 5 5.8O 14 <200 59 50 18 <200 238 2 3 <200 16 TABLE 6 4 <200 11 5 6.40 44 INTRAVENOUSPHARMACOKINETIC 14 <200 66 ANALYSIS FORMIPROCELLE-INSULIN IN DOGS 18 <200 73 Miprocelle-Insulin 55 2.82 (mean) 146 (mean) Analytical Range 0.01-3000 (ng/mL) Albumin + insulin 1 3 <200 24 TTIRFA: 3021 4 18.10 09 IV. Dose OO1 5 14 <200 50 Time Animal #Concentration (ng/mL) 18 <200 2O6 2 3 QNS 13 (hr) 71 72 Mean 60 4 S400 18 5 <200 65 O.O3 SO.2 27 39 14 QNS 15 O.08 26.6 21 24 18 <200 209 O.17 15.9 11.4 13.7 11.73 (mean) 143 (mean) O.25 10.10 6.50 8.30 IgG + insulin 1 3 <200 21 O.33 7.60 340 5.50 65 4 54.70 O42 S.90 2.70 4.30 5 <200 32 US 8,414,914 B2 74 -continued Since modifications will be apparent to those of skill in this art, it is intended that this invention be limited only by the Animal Insulin Glucose Scope of the appended claims. Composition No. Time (h) ng/ml (mg/DI) What is claimed is: 14 <2.OO 166 5 1. A composition, comprising: 18 <2.OO 278 a mucoadhesive protein that is presentata concentration of 2 3 <2.OO 110 4 5:60 about 1% by weight up to about 50% by weight of the 5 <2.OO 108 total weight of the composition; 14 <2.OO 171 an agent for delivery; and 18 <2.OO 208 10 a delivery vehicle associated with the agent, wherein: 7.63 (mean) 157 (mean) the composition is formulated as an emulsion and is formulated for mucosal delivery to the oral or gas trointestinal tract mucosa; the mucoadhesive protein is associated with the delivery EXAMPLE 16 15 vehicle via a chemical or physical bond, whereby the composition adsorbs to the mucosa for effecting sys Studies in Human temic delivery of the agent; Composition of Example 12 was administered (0.5 cc) to a the composition has a viscosity of about 50,000 cps up to human Subject for 3 days according the following protocol 500,000 cps at about 72° F., whereby the composition and the glucose levels were monitored. 2O is retained on a mucosal Surface; and the delivery vehicle is selected from among a micelle, inverse micelle, liposome, cubosome and a mixture thereof. Blood Glucose-Day 1 2. The composition of claim 1, wherein the mucoadhesive 25 protein is an immunoglobulin or an albumin. Time Glucose Units Notes 3. The composition of claim 1, wherein the emulsion is an 7:30 PM 94 7:35PM: Dinner oil in water or a water in oil emulsion. 8:15 PM 186 8:17 PM: Oral Insulin 4. The composition of claim 1, wherein the agent is dis 8:29PM 208 8:45 PM 18O solved in the oil phase or is dissolved in the water phase. 9:15 PM 166 30 5. A composition, comprising: 9:46 PM 135 a mucoadhesive protein present at a concentration of about 1:40 AM 103 9% by weight up to about 10% by weight of the total 7:00AM 113 weight of the composition; 7:35AM 108 an agent for delivery; and Blood Glucose-Day 2 Notes 35 a delivery vehicle associated with the agent; wherein: the composition is formulated for mucosal delivery to Time Glucose Units 9:45 AM: Oral Insulin the oral or gastrointestinal mucosa or nasal or lung 12:55 PM 100 1:00 PM; Lunch muCOSa; 1:40 PM 200 the mucoadhesive protein is associated with the delivery 2:47 PM 146 40 vehicle: 4:25 PM 103 4:53 PM 90 the mucoadhesive protein is associated with the delivery 5:26 PM 103 vehicle via a chemical or physical bond; and 6:20 PM 99 6:20 PM; Dinner the delivery vehicle is selected from among a micelle, 6:50 PM 102 inverse micelle, liposome, cubosome and a mixture 7:21 PM 112 45 thereof. 9:10 PM 110 9:56 PM 138 6. The composition of claim 5, wherein the mucoadhesive 10:30 PM 127 protein is an immunoglobulin or an albumin. 7. The composition of claim 1, wherein the agent alters a Blood Glucose-Day 3 body function or alters cosmetic appearance. 50 8. The composition of claim 1, wherein the agent is a Time Glucose Units Notes therapeutic agent. 1:45 PM 103 1:50 PM; Lunch 9. The composition of claim 5, wherein the agent alters a 2:25 PM 138 2:30 PM; More Food 3:02 PM 153 body function or alters cosmetic appearance. 3:25 PM 134 3:30; More Food 10. The composition of claim 5, wherein the agent is a 3:45 PM 132 55 therapeutic agent. 3:53 PM 136 11. The composition of claim 1, wherein the agent is 4:27 PM 138 4:46 PM 150 selected from among antidiabetics, anticonvulsants, analge 6:17 PM 110 6:18 PM; Dinner sics, antiparkinsons, anti-inflammatories, calcium antago 6:47 PM 115 nists, anesthetics, antimicrobials, antimalarials, antiparasit 7:24 PM 127 60 ics, antihypertensives, antihistamines, antipyretics, alpha 8:04 PM 108 9:45 PM 158 adrenergic agonists, alpha-blockers, biocides, bactericides, 10:35 PM 122 bronchial dilators, beta-adrenergic blocking drugs, contra ceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, The comparison of data collected on day 1, 2 and 3 indi- 65 hypnotics, hormones, hypoglycemics, hyperglycemics, cates (see FIG. 1) that the blood glucose levels were being muscle contractants, muscle relaxants, neoplastics, glycopro regulated in a more Sustained manner on the third day. teins, nucleoproteins, lipoproteins, ophthalmics, psychic US 8,414,914 B2 75 76 energizers, sedatives, steroids, sympathomimetics, parasym ics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, pathomimetics, tranquilizers, urinary tract drugs, vaccines, Vitamins, minerals, nonsteroidal anti-inflammatory drugs, vaginal drugs, vitamins, minerals, nonsteroidal anti-inflam angiotensin converting enzymes, polynucleotides, polypep matory drugs, angiotensin converting enzymes, polynucle tides, polysaccharides, nutritional Supplements and combina otides, polypeptides, polysaccharides and nutritional Supple tions thereof. mentS. 21. A method for mucosal delivery of an agent, comprising: 12. The composition of claim 1, wherein the agent is a contacting the composition of claim 5 with a mucosal hormone or a nutritional Supplement. surface of a subject, whereby the agent is delivered into 13. The composition of claim 5, wherein the agent is a the circulatory system of the subject. hormone or a nutritional Supplement. 10 22. The composition of claim 1, wherein the mucoadhesive 14. The composition of claim 1, wherein the agent is a drug. protein is presentata concentration of about 5% by weight up 15. The composition of claim.5, wherein the agent is a drug. to about 50% by weight of the total weight of the composi 16. The composition of claim 1, wherein the agent is a tion. polypeptide drug. 23. The composition of claim 1, wherein the mucoadhesive 17. The composition of claim 1 that is formulated for oral 15 protein is presentata concentration of about 1% by weight up or nasal administration. to about 11% by weight of the total weight of the composi 18. The composition claim 1 that has a viscosity of about tion. 100,000 cps up to about 500,000 cps. 24. A composition, comprising: 19. A method for mucosal delivery of an agent, comprising: a mucoadhesive protein that is presentata concentration of contacting the composition of claim 1 with a mucosal about 1% by weight up to about 50% by weight of the surface of a subject, whereby the agent is delivered into total weight of the composition; the circulatory system of the subject. an agent for delivery; and 20. The method of claim 19, wherein the agent is selected a delivery vehicle associated with the agent, wherein: from among antidiabetics, anticonvulsants, analgesics, anti the composition is formulated as an emulsion and is parkinsons, anti-inflammatories, calcium antagonists, anes 25 formulated for mucosal delivery to the oral or gas thetics, antimicrobials, antimalarials, antiparasitics, antihy trointestinal tract mucosa; pertensives, antihistamines, antipyretics, alpha-adrenergic the mucoadhesive protein is associated with the delivery agonists, alpha-blockers, biocides, bactericides, bronchial vehicle via a chemical or physical bond, whereby the dilators, beta-adrenergic blocking drugs, contraceptives, car composition adsorbs to the mucosa for effecting sys diovascular drugs, calcium channel inhibitors, depressants, 30 temic delivery of the agent; and diagnostics, diuretics, electrolytes, enzymes, hypnotics, hor the delivery vehicle is selected from among a micelle, mones, hypoglycemics, hyperglycemics, muscle contracta inverse micelle, liposome, cubosome and a mixture nts, muscle relaxants, neoplastics, glycoproteins, nucleopro thereof. teins, lipoproteins, ophthalmics, psychic energizers, sedatives, steroids, sympathomimetics, parasympathomimet