USOO79061.40B2 (12) United States Patent (10) Patent No.: US 7,906,140 B2 Bromley et al. (45) Date of Patent: Mar. 15, 2011 (54) COMPOSITIONS FOR MUCOSAL DELIVERY 5,178,878 A 1/1993 Wehling et al................ 424/466 OFAGENTS 5, 182,107 A 1/1993 Friden ........................ 424,85.91 5,234,957 A 8, 1993 Mantelle et al. O O 5,298,246 A 3, 1994 Yano et al. (75) Inventors: Philip James Bromley, Fullerton, CA 5,323,907 A 6/1994 Kalvelage ..................... 206,531 (US); Lee Nickols Huang, Diamond 5,527,527 A 6/1996 Friden ............ 424,178.1 Bar, CA (US) 5,620,708 A 4/1997 Amkraut et al. .............. 424/491 s 5,672,683 A 9, 1997 Friden et al. ....... 530/350 5,702,727 A 12/1997 Amkraut et al. ... ... 424/491 (73) Assignee: Virun, Inc., City of Industry, CA (US) 5,744,155. A 4, 1998 Friedman et al. ............. 424/434 5,833,988 A 11/1998 Friden ................ 424,178.1 (*) Notice: Subject to any disclaimer, the term of this 5,977,307. A 1 1/1999 Friden et al. ... 530/350 patent is extended or adjusted under 35 2. A 1 &28 Esta s al 25: U.S.C. 154(b) by 1526 days. 6,329,508W . B1 12/2001 FridenayWard ............ et al. ... 530,387.3 6,383,513 B1* 5/2002 Watts et al. ................... 424/450 (21) Appl. No.: 11/155,262 (Continued) (22) Filed: Jun. 16, 2005 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data CA 2229286 A1 8, 1999 US 2005/028.1772A1 Dec. 22, 2005 (Continued) OTHER PUBLICATIONS Related U.S. Application Data (60) Provisional application No. 60/580,877, filed on Jun. HandBook of Pharmaceutical Excipients, 1986 Ed. Lecithin, p. 165.* 17, 2004. (Continued) (51) Int. Cl. Primary Examiner — Robert A Wax A6 IK38/00 (2006.01) Assistant Examiner — Melissa S. Mercier (52) U.S. Cl. ................................. 424/450; 514/2: 514/8 (74) Attorney, Agent, or Firm — K&L Gates LLP; Stephanie (58) Field of Classification Search ........................ None Seidman See application file for complete search history. (57) ABSTRACT (56) References Cited Compositions and methods for mucosal delivery of agents are provided. The compositions are intended for administration U.S. PATENT DOCUMENTS to mucosal Surface. Such as oral and nasal mucosa. The com 4,740,365 A 4, 1988 Yukimatsu et al. ........... 424/435 positions provided contain one or more mucoadhesive pro 4,889,720 A 12, 1989 Konishi ........................ 25 teins and an agent to be delivered. Methods for delivery of 4,900,552 A * 2/1990 Sanvordeker et al. ........ 424/422 agent ing th iti ided herei 1 4,921,706 A 5/1990 Roberts et al. ................ 424/450 gen SuS1ng une compos1u1ons prov1de erein are also pro 5,033,252 A 7/1991 Carter .......... .534/25 vided. 5,052,558 A 10/1991 Carter ........................... 206,439 5,154,924 A 10, 1992 Friden ........................ 424,179.1 50 Claims, 1 Drawing Sheet Oral insulin-Human Glucose Levels OO O Time (hrs) US 7,906.140 B2 Page 2 U.S. PATENT DOCUMENTS Lehr, et al., “Visualization studies of the mucoadhesive interface.” 6,426,362 B1* 7/2002 Miller et al. .................. 514,458 Journal of Controlled Release, 18:249-260 (1992). 6,475,511 B2 11/2002 Gohlke et al. ................ 424/441 Nogrady, Medicinal Chemistry A Biochemical Approach, New York: 6,552,024 B1 4/2003 Chen et al. Oxford University Press, pp. 388-392 (1985). 6,638,521 B2 10/2003 Dobrozsi et al. .............. 424/434 Peppas & Buri, "Surface, Interfacial and Molecular Aspects of Poly 6,749,863 B1 6/2004 Chang et al. ... 424/450 mer Bioadhesion on soft tissues.” Journal of Controlled Release, 6,905,688 B2 6, 2005 Rosen et al. 424,192.1 6,926,898 B2 8, 2005 Rosen et al. 424,192.1 2:257-275 (1985). 6,946,134 B1 9, 2005 Rosen et al. 424,192.1 Ryan et al. “Immunomodulators and delivery systems for vaccination 6,994,857 B2 2/2006 Rosen et al. 424,192.1 by mucosal routes' Trends in Biotechnology, vol. 19, No. 8, pp. 7,179,484 B2 * 2/2007 Singh .......... 424/450 293-304. (2001). 2003/0171267 A1 9, 2003 Rosen et al. ... 514/12 Simoes et al., “Mechanisms of gene transfer mediated by lipoplexes 2003/0219472 A1 11, 2003 Pauletti et al. 424/449 associated with targeting ligands or pH-sensitive peptides' Gene 2003/0221201 A1 11/2003 Prior et al. ........................ 800.7 Ther. (11): 1798-807 (1999). 2003/0226155 Al 12/2003 Sadeghi et al. ................... 800.7 2004/0010134 A1 1/2004 Rosen et al. 536,235 Smart et al., “An in-vitro investigation of mucosa-adhesive materials 2004/OO23334 A1 2/2004 Prior ........... 435/69.7 for use in controlled drug delivery,” J. Pharm. Pharmacol. 36:295. 2004/0037809 A1 2/2004 Quay et al. 424,856 (1984). 2004/OO77540 A1 4/2004 Quay .......... ... 514/12 Smart et al., “In vitro techiniques for measuring mucoadhesion.” J. 2005, 0196440 A1* 9, 2005 Masters et al. 424/464 Pharm. Pharmacol. 34:70P (1982). 2005/O197495 A1 9, 2005 Naidu ......... 530/400 Tabor et al., "Surface forces and surface interactions' Journal of 2006, OO84794 A1 4/2006 Rosen et al. ... 530,363 Colloid and Interface Science, vol. 58, Issue 1. pp. 2-13 (1977). 2006/0093594 A1 5/2006 Naidu ........................ 424/9345 Oratropin-1TM Website Printout, foundat: www.ibe-technology.com/ oratropin.htm retrieved on Jan. 20, 2006 6 pages). FOREIGN PATENT DOCUMENTS Ectotropin-6TM Website Printout, found at: www.ibe-technology. WO 2006/00982.5 1, 2006 com/ectotropin.htm retrieved on Jan. 20, 20064 pages. WO WO 2009,11715.1 9, 2009 HexaTropin-6TM Website Printout, found at: www.ibe-technology. WO WO 2009,117152 9, 2009 com/hexatropin.htm retrieved on Jan. 20, 20063 pages). U.S. Appl. No. 60/527,962, filed Dec. 8, 2003, Masters et al. OTHER PUBLICATIONS Virun Improving Life Through Safe & Effective Oral Delivery found Almeida et al. "Nasal Delivery of Vaccines,” Journal of Drug Target at: www.slideshare.net/virun?virun-improving-life-through-safe-ef ing 3, 456-467 (1996). fective-oral-delivery accessed on May 11, 2009). Ansel, Introduction to Pharmaceutical Dosage Forms, Fourth Edi Wright, R., “Companies to watch Nutraceuticals World,” at: www. tion, Philadelphia: Lea& Febiger, p. 126 (1985). nutraceuticalsworld.com/articles/2009/06/companies-to-watch, Budavari, et al.(Eds.) The Merck Index, 12th Edition, Whitehouse (2009) accessed on Jun. 4, 2009). Station, N.J.Merck & Co., pp. THER-1 to THER-28 (1996). U.S. Appl. No. 12/383,244, filed Mar. 20, 2009. Drug Delivery Technology, Alkaline Acidic Triggering Effect pam U.S. Appl. No. 12/383.241, filed Mar. 20, 2009. phlet.2 pages, Archimedes Laboratories, Inc., Sep. 2005. U.S. Appl. No. 12/456,926, filed Jun. 23, 2009. Drug Delivery Technology, Pre-Clinical Abstract, Oral U.S. Appl. No. 12/583,209, filed Aug. 13, 2009. Pharmacokinetics of MAPED (Mucosa Adhesive Protein Engineered An English language translation of a Chinese Examination Report, Drugs) Bound in Human Recombinant Insulin, 6 pages, Archimedes issued Mar. 1, 2010, in connection with corresponding Chinese Laboratories, Inc., Sep. 2005. Patent Application No. 200580028061.8. Drug Delivery Technology, Undenatured Protein pamphlet, 2 pages, Examination Report, issued Jul. 21, 2008, in connection with Euro Archimedes Laboratories, Inc., Sep. 2005. pean Patent Application No. 05762240.9. Good, Surface free energy of Solids and liquids: Thermodynamics, Office Action, issued Nov. 26, 2008, in connection with Chinese molecular forces, and structure Journal of Colloid and Interface Sci Patent Application No. 200580028061.8. ence, vol. 59, Issue 3, pp. 398-419 (1977). Examination Report, issued Dec. 3, 2008, in connection with Cana Gu, et al. “Binding of Acrylic Polymers to Mucin/Epithelial Sur dian Patent Application No. 2.578,709. faces: Structure-Property Relationships.” Critical Reviews in Thera peutic Drug Carrier Systems 5(1): 21-67 (1988). * cited by examiner U.S. Patent Mar. 15, 2011 US 7,906,140 B2 Figure 1 Oral insulin - Human Glucose Levels O a. s E Ye O (9 P CD US 7,906,140 B2 1. 2 COMPOSITIONS FOR MIUCOSAL DELVERY istration of agents to animals, including humans. Provided are OFAGENTS compositions and methods for administering Substances to animals, including humans, employing a carrier that facili RELATED APPLICATIONS tates entry of the Substance to the mucosa in a non-specific 5 a. This application claims priority under 35 U.S.C. S 119(e) to The compositions provided herein are stable emulsions of U.S. provisional application Ser. No. 60/580,877, entitled oil in water or water in oil, wherein an agent to be delivered is COMPOSITIONS FOR MUCOSAL DELIVERY OF dissolved in either the oil phase or the water phase. The AGENTS’ to Bromley et al. filed Jun. 17, 2004. The subject emulsions are typically stabilized by Surface active molecules matter of the provisional application is incorporated by ref 10 in the emulsion. The surfactant molecules form various erence herein. This application is related to International PCT application macro-molecular structures in an emulsion, such as micelles, No PCT/US05/21424 filed on the same day herewith. The inverse micelles, lipid bilayers (liposomes) and cubosomes. subject matter of the PCT application is incorporated by The exact macromolecular structure formed depends on the reference herein. relative sizes of the hydrophilic and hydrophobic regions of 15 the surface active molecule. The agent to be delivered can be FIELD distributed between the hydrophobic and hydrophilic phases of an oil in water or water in oil type emulsion, or can be Provided herein are pharmaceutical compositions for present predominantly in one of the phases.