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United States Patent (10) Patent No.: US 9,358,209 B2 Hensby Et Al

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United States Patent (10) Patent No.: US 9,358,209 B2 Hensby Et Al US009358209B2 (12) United States Patent (10) Patent No.: US 9,358,209 B2 Hensby et al. (45) Date of Patent: Jun. 7, 2016 (54) ECONAZOLE COMPOSITION AND 2006/O140984 A1* 6/2006 Tamarkin ............... A61K 8,046 METHODS OF TREATMENT THEREWITH 424/400 2006, O188449 A1 8, 2006 Hirsh et al. (75) Inventors: Christopher N. Hensby, Saint Germain 2006/O193789 A1 ck 8/2006 Tamarkin ............... A61s en Laye (FR); Mats Silvander, Uppsala 2008. O175793 A1 7, 2008 Silvander (SE) 2012/0101139 A1 * 4/2012 Hensby ................ A61K9/0014 514,399 (73) Assignee: Exeltis USA Dermatology, Inc., 2012/0101140 A1* 4/2012 Hensby ................ A61K9/0014 Chatham, NJ (US) 514,399 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 WO 200804.6796 4/2008 U.S.C. 154(b) by 0 days. WO WO2O0804.6796 A2 * 4, 2008 ............. A61K 31.05 (21) Appl. No.: 13/198,995 OTHER PUBLICATIONS 1-1. “Athlete's Foot'. Wikipedia online), retrieved May 17, 2015 (22) Filed: Aug. 5, 2011 Retrieved from the Internet: <URL: http://en.wikipedia.org/wiki/ O O Athletes foots. (65) Prior Publication Data Lambers et al., Natural skin surface pH is on average below 5, which US 2012/O1 OOO80 A1 Apr. 26, 2012 28(5):359-70.*is beneficial for its resident flora; 2006; Int. J. Cosmet. Sci., “Athelete's Foot'. Wikipedia online), retrieved May 17, 2015 Related U.S. Application Data Retrieved from the Internet: <URL: http://en.wikipedia.org/wiki/ Athlete's) foot>.* (60) Provisional application No. 61/406,826, filed on Oct. Rowe, Raymond C., et al. “Handbook of Pharmaceutical 26, 2010. Excipients'. 3 pgs. Veraldi, Topical Fenticonazole in Dermatology and Gynaecology, (51) Int. Cl Drugs, 68 (15): 2183-2194 pp. 2008. we International Search Report & Written Opinion in PCT/US2011/ A6 IK 9/12 (2006.01) 046785, dated Mar, 9, 2012, 12 pgs. A6 IK9/00 (2006.01) International Search Report and Written Opinion in PCT/US2011/ A6 IK3I/4164 (2006.01) 046793, dated Mar. 28, 2012, 5 pgs. (52) U.S. Cl. “Non-Final Office Action of U.S. Appl. No. 13/198.998”, mailed on Apr. 25, 2013, 25 pgs. CPC ............... 19th (E),fleet Ortho Dermatological, Division of Ortho-McNeil Pharmaceutical, ( -. ); ( .01) Inc.—Revised: Mar. 2007 Spectazole (econazole nitrate) in web. (58) Field of Classification Search archive.org/web/20081223202522/http://www.drugs.com/prof CPC ... A61 K9/0014; A61 K9/122: A61K 31/4164 spectazole.html. USPC .................... 424/404, 44; 514/396, 399,945; Final Office Action in U.S. Appl. No. 13/198.998, dated Jan. 14. 548/300. 1,335.1, 346.1 2014, 34 pages. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — Jane C Oswecki U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Don J. Pelto, Esq.; Sheppard, Mullin, Richter & Hampton LLP 599,330 A * 2/1898 Freij ..................... BOSB 3.0486 239,222.17 (57) ABSTRACT 5,002,938 A 3/1991 Wang et al. 5,514,698 A 5, 1996 Ahmad et al. The invention provides a water-based composition for treat 5,919,470 A 7, 1999 Valdez et al. ing an infection by a dermatophyte fungus comprising econa 5.993,830 A * 1 1/1999 Freij ...................... A61K 8.345 Zole or a pharmaceutically acceptable salt thereof. Also pro 7.645.803 B2 1/2010 Tamarkin ............... A61K424/400 8,046 vided are methods of treatment utilizingg uneth water-baseter-based w I - 514,945 foam composition, as well as its preparation. 2004/0241099 A1* 12/2004 Popp ...................... A61K 9,122 424/45 2 Claims, No Drawings US 9,358,209 B2 1. 2 ECONAZOLE COMPOSITION AND Further provided is a composition for treating an infection METHODS OF TREATMENT THEREWITH by dermatophyte fungus or a candida yeast comprising a water-based formulation (comprising: 0.5 to 5 wt % of an CROSS-REFERENCE TO RELATED emollient comprising silicone oil, 2 to 10 wt % of fatty acid, APPLICATION humectant(s), emulsifying agent(s), polymer(s), and a phar maceutically effective amount of an azole or a physiologi This application claims the benefit of U.S. Provisional cally acceptable salt thereof), wherein the formulation is for Application No. 61/406,826, filed on Oct. 26, 2010, the con mulated as a cream, lotion, milk or foam-former. tent of which is incorporated herein by reference in its Additionally provided is a method of reducing the risk of entirety. 10 infection from a skin or mucosa piercing procedure compris ing: applying to the skin or mucosa to be pierced an effective BACKGROUND OF THE INVENTION amount of a water based formulation (comprising: 0.5 to 5 wt % of an emollient comprising silicone oil, 2 to 10 wt % of The present invention relates to a water-based composition fatty acid, humectant(s), emulsifying agent(s), polymer(s), of silicone oil, fatty acid(s), and humectant(s), which can be 15 and a pharmaceutically effective amount of an azole or a used to treat fungal diseases, such as tinea pedis, tinea cruris, physiologically acceptable salt thereof), wherein the formu tinea corporis, cutaneous candidiasis, tinea versicolor, and lation is formulated as a spray, cream, lotion, milk or foam the like former; and piercing the skin or mucosa. A foamable composition similar to the vehicle composi tions described herein is described in U.S. Pat. No. 5,993,830. DETAILED DESCRIPTION OF THE INVENTION The composition has been used with Subjects having toxic hand eczema. What was not described, and what has now The azole antifungals include, for example the imidazole, been unexpectedly discovered, is that Such compositions can triazoles and thiazole antifungals. The imidazole antifungals accelerate healing of wounds and control inflammation. This include, for example, Miconazole, Ketoconazole, Clotrima vehicle effectiveness is described herein, and in an applica 25 Zole, Econazole, Bifonazole, Butoconazole. Fenticonazole, tion filed concurrently herewith entitled “Composition and Isoconazole, Oxiconazole, Sertaconazole, Sulconazole and Method for Treating Wounds’ U.S. Provisional Application Tioconazole. The triazoles anfungals include, for example, No. 61/406,864, filed on Oct. 26, 2010. Fluconazole, Itraconazole, Isavuconazole, Ravuconazole, Econazole nitrate (EN) is representative of azole antifun Posaconazole, Voriconazole and Terconazole. The thiazole gals. Econazole nitrate is a topical antifungal agent that is 30 anfungals include, for example, Abafungin. Many if not most currently indicated for a variety of fungal diseases, including of these antifungals may be conveniently used as acid addi tinea pedis, tinea cruris, tinea corporis, and cutaneous can tion salts or other salt forms. A number of these antifungals didiasis, as well as for the treatment of tinea versicolor. share the following structural commonalities: a chiral carbon Econazole nitrate has shown activity against a variety of to which is directly linked an aromatic ring that has one or dermatophytes and yeasts, including most strains of Epider 35 more electron withdrawing groups (such as 2 Such groups, mophyton floccosum, Microsporum audouinii, M. canis, M. which can for example be fluoro or chloro); and one or more gypseum, Trichophyton mentagrophytes, T. rubrum, T. ton azole groups linked to the chiral carbon by a methylene surans, Candida albicans, and Malassezia furfur. Econazole bridge. The azole groups can be linked to the methylene a ring nitrate is a leading antifungal used topically in the United nitrogen of the azole ring. States, with over 20 years of clinical use and history with an 40 Azole antifungal drugs are believed to inhibit the P-450 excellent safety profile. class enzyme 14C-demethylase; the enzyme that converts Because the vehicle used in the invention is effective in lanosterol to ergosterol. Depletion of ergosterol in fungal promoting wound healing, it is believed that the composition membranes is believed to disrupt the fungal membrane. It further containing econazole will be particularly effective in should be recognized that while typically a single azole com treating fungal/yeast infections, and promoting the healing of 45 pound will be used, mixtures can also be used. References in infection-induced or associated injury. “an azole' encompass mixtures unless the contrary is specifi cally recited. SUMMARY OF THE INVENTION In certain embodiments, the formulation of the invention provides a non-irritating composition. Irritation, in certain Provided, in one embodiment, is a method of treating an 50 embodiments, is measured by ISO 10993-10: 2002 Standard, infection by dermatophyte fungus or a candida yeast com “Biological Evaluation of Medical Devices, Part 10-Tests for prising: periodically applying to the infection over a course of Irritation and Sensitization. pp. 6-10, 21, which testing days a water-based formulation (comprising: 0.5 to 5 wt % of method is incorporated herein by reference. In particular, for an emollient comprising silicone oil, 2 to 10 wt % of fatty each test site on shaved dorsal skin of an albino rabbit, gauze acid, humectant(s), emulsifying agent(s), polymer(s), and a 55 incorporating 0.5 mL of test material or negative control pharmaceutically effective amount of anazole antifungal or a material is applied. One test and one control site are used on physiologically acceptable salt thereof), wherein the formu each side of the paravertebral skin. The infused gauzes are lation is formulated as a cream, lotion, milk or foam-former. covered with tape-backed gauze. The trunk of the rabbit is Also provided is a method of treating tinea pedis, tinea wrapped in elastic bandage secured by hypoallergenic tape. cruris, tinea corporis, tinea versicolor or cutaneous candidi 60 After a minimum of 24 hours, the coverings are unwrapped. asis comprising: periodically applying to the infection over a Observations are made at 60 min-2, 24 h--2, 48 h--2 and 72 course of days a water-based formulation (comprising: 0.5 to h+2 post unwrapping.
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