USOO6835392B2 (12) United States Patent (10) Patent No.: US 6,835,392 B2 Hsu et al. (45) Date of Patent: Dec. 28, 2004 (54) DUAL ENHANCER COMPOSITION FOR 5,071,657. A 12/1991 Oloff et al. TOPCAL AND TRANSIDERMAL DRUG 5,152.997 A 10/1992 Ebert et al. DELIVERY 5,318,960 A 6/1994 Toppo 5,432,192 A 7/1995 Sawanishi et al. (75) Inventors: Tsung-Min Hsu, San Diego, CA (US); (List continued on next page.) Eric C. Jacobson, San Diego, CA (US); Rose C. LoBello, San Diego, CA FOREIGN PATENT DOCUMENTS (US); Eric C. Luo, Plano, TX (US) EP O276561 8/1988 (73) Assignee: Dermatrends, Inc., San Diego, CA EP O316065 5/1989 (US) (List continued on next page.) (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S. patent application Ser. No. 09/465,098, Luo et al., filed (21) Appl. No.: 10/389,143 (List continued on next page.) (22) Filed: Mar 13, 2003 Primary Examiner Thurman K. Page 9 ASSistant Examiner-Isis Ghali (65) Prior Publication Data (74) Attorney, Agent, or Firm-Reed & Eberle LLP, US 2003/0161870 A1 Aug. 28, 2003 Dianne E. Reed; Shelley P. Eberle Related U.S. ApplicationO O Data (57) ABSTRACT A permeation enhancer composition is provided for increas (60) Division of application No. 09/972,008, filed on Oct. 4, ing the permeability of skin or mucosal tissue to topically or nowR.E.7. Pat. No. 6,586,000, which is aSSS"'5, continuation-in-part of ceuticallytransdermally active administered agents. The compositionpharmacologically is comprised or cosme: of a application No. 09/569,889, filed on May 11, 2000, now hydroxide-releasing agent and a lipophilic co-enhancer Such abandoned, which is a continuation-in-part of application as a fatty alcohol, a fatty ether, or a fatty acid ester, including No. 09/465,098, filed on Dec. 16, 1999, now abandoned. fatty acid esters of polyols Such as propylene glycol and (51) Int. Cl. .......................... A61F 13/00; A61L 15/00 glycerol. Also provided are pharmaceutical formulations (52) U.S. Cl. ....................... 424/449, 424/443; 424/445, containing a therapeutically effective amount of an active 424/447: 424/44s. 514/946. 514/944 agent in addition to the aforementioned enhancer (58) Field of Search s s 424A49, 443 composition, methods for administering active agents topi 424,445,447,448. 514/946, 9 47.944 cally or transdermally with enhanced permeation, and drug s Y-s s 1 s delivery Systems for application to an individual’s skin or (56) References Cited mucosal tissue, wherein the Systems are formulated So as to contain an active agent to be administered and an effective U.S. PATENT DOCUMENTS permeation enhancing amount of an enhancer composition of the invention. 4,704,282 A 11/1987 Campbell et al. 4,789,547 A 12/1988 Song et al. 4,837,027 A 6/1989 Lee et al. 48 Claims, 1 Drawing Sheet Human Skin Permeation of testosterone from a Matrix Patch 0,4 Tast-19 0.346 mgicrT2 0.35 O), 3 est-180 0.254 mg.cm2 , 25 0, 2 0.15 0, es-P181 0.05 0.051 mglom2 est-8 0.44 mg.cm2. --- O s O 15 20 25 3. time hours) US 6,835,392 B2 Page 2 U.S. PATENT DOCUMENTS 6,004,577 A 12/1999 Murdock 6,019,988 A 2/2000 Parab et al. 5,446,070 A 8/1995 Mantelle 6,019.997 A 2/2000 Scholz et al. 5,460.820 A 10/1995 Ebert et al. 6,123,961 A 9/2000 Aberg 5,462,744. A 10/1995 Gupte et al. 6,132,760 A 10/2000 Hedenstrom et al. 5,462,746 A 10/1995 Wolter et al. 6,139,866 A 10/2000 Chono et al. 5,474,783 A 12/1995 Miranda et al. 6,174,546 B1 1/2001 Therriault et al. 5,498,417 A 3/1996 Lhila et al. 6,204.268 B1 3/2001 Scarborough et al. 5,500.222 A 3/1996 Lee et al. 6.214.374 B1 4/2001 Schmirler et al. 5,527,832 A 6/1996 Chi et al. 6,316,011 B1 11/2001 Ron et al. 5.532.278 A 7/1996 Aberg et al. 5,534,496 A 7/1996 Lee et al. FOREIGN PATENT DOCUMENTS 5,562.917. A 10/1996 Durif et al. 5,573,778 A 11/1996 Therriault et al. EP O709088 5/1996 5,599,554 A 2/1997 Majeti EP O842662 5/1998 5,614,211 A 3/1997 Gale et al. FR 2692145 12/1993 5,674,895 A 10/1997 Guittard et al. JP 218O835 7/1990 5,807,568 A 9/1998 Cody et al. JP 6092843 4/1994 5,817,332 A 10/1998 Urtti et al. KR 9507098 6/1995 5.830,497 A 11/1998 Yamanaka et al. WO WO 94/21271 9/1994 5,834,513 A 11/1998 Ptchelintsev et al. WO WO 99/49844 10/1999 5,847,003 A 12/1998 Ptchelintsev et al. 5,879,690 A 3/1999 Perricone OTHER PUBLICATIONS 5,939,094. A 8/1999 Durif et al. 5.962,018 A 10/1999 Curtis et al. U.S. patent application Ser. No. 09/569,889, Luo et al., filed 5,985,317 A 11/1999 Venkateshwaran et al. May 11, 2000. A A. Toppo Aungst et al. (1990), “Contributions of Drug Solubilization, 5.990,1132- Y - 2 A 11/1999f1999 YamazakiHsu et al. et al. Partitioning, Barrier Disruption, and Solvent Permeation to 5.990,179 A 11/1999 Gyory et al. the Enhancement of Skin Permeation of Various Compounds 5,993,851 A 11/1999 Foldvari with Fatty Acids and Amines, Pharmaceutical Research 5,994,372 A 11/1999 Yaksh 7(7):712-718. U.S. Patent Dec. 28, 2004 US 6,835,392 B2 N cN 2 Y. ed o o (zuoyfu) euouasosal go unouw aaen uno US 6,835,392 B2 1 2 DUAL ENHANCER COMPOSITION FOR skin permeability include: Sulfoxides Such as dimethylsul TOPCAL AND TRANSIDERMAL DRUG foxide (DMSO) and decylmethylsulfoxide (CMSO); DELIVERY ethers such as diethylene glycol monoethyl ether (available commercially as TranscutolCE) and diethylene glycol CROSS-REFERENCE TO RELATED monomethyl ether, Surfactants Such as Sodium laurate, APPLICATIONS Sodium lauryl Sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween This is a divisional of U.S. patent application Ser. No. (20, 40, 60,80) and lecithin (U.S. Pat. No. 4,783,450); the 09/972,008, filed Oct. 4, 2001, and now issued as U.S. Pat. 1-Substituted azacycloheptan-2-ones, particularly 1-n- No. 6,582,724; which is a continuation-in-part of U.S. patent dodecyl-cyclazacycloheptan-2-one (available under the application Ser. No. 09/738,410, filed Dec. 14, 2000, and trademark AZone(R) from Nelson Research & Development now issued as U.S. Pat. No. 6,586,000; which was a continuation-in-part of U.S. patent application Ser. No. Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989.816, 4,316,893, 09/569,889, filed May 11, 2000, now abandoned; which was 4,405,616 and 4,557,934); alcohols such as ethanol, a continuation-in-part of U.S. patent application Ser. No. propanol, octanol, benzyl alcohol, and the like; fatty acids 15 Such as lauric acid, oleic acid and Valeric acid; fatty acid 09/465,098, filed Dec. 16, 1999, now abandoned; the dis esterS Such as isopropyl myristate, isopropyl palmitate, closures of which are incorporated by reference. methylpropionate, and ethyl oleate; polyols and esters thereof Such as propylene glycol, ethylene glycol, glycerol, TECHNICAL FIELD butanediol, polyethylene glycol, and polyethylene glycol This invention relates generally to the topical and trans monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); dermal administration of pharmacologically active agents, amides and other nitrogenous compounds Such as urea, and more particularly relates to permeation enhancer com dimethylacetamide (DMA), dimethylformamide (DMF), positions for enhancing the permeability of skin or mucosal 2-pyrrollidone, 1-methyl-2-pyrrollidone, ethanolamine, tissue to topically applied pharmacologically active agents. diethanolamine and triethanolamine; terpenes, alkanones, 25 and organic acids, particularly Salicylic acid and Salicylates, BACKGROUND ART citric acid and Succinic acid. Percutaneous Penetration Skin is a structurally complex, relatively thick membrane. Enhancers, eds. Smith et al. (CRC Press, 1995) provides an In order to deliver a drug into and through the skin, i.e., excellent overview of the field and further background “transdermally, drug molecules must first penetrate the information on a number of chemical and physical enhanc Stratum corneum and any material on its Surface. They must CS. then penetrate the viable epidermis, the papillary dermis, Although many chemical permeation enhancers are and the capillary walls into the blood stream or lymph known, there is an ongoing need for enhancers that are channels. To be So absorbed, molecules must overcome a highly effective in increasing the rate at which a drug different resistance to penetration in each type of tissue. permeates the skin, do not result in Skin damage, irritation, Transport across the Skin membrane is thus a complex 35 Sensitization, or the like, and can be used to effect transder phenomenon. However, it is the cells of the Stratum corneum mal delivery of even high molecular weight drugs. Such as that present the primary barrier to absorption of topical peptides, proteins, and nucleic acids. Furthermore, it would compositions or transdermally administered drugs.