(19) 11 Patent Number: 6075056

USOO6075056A United States Patent (19) 11 Patent Number: 6,075,056 Quigley, Jr. et al. (45) Date of Patent: Jun. 13, 2000 54). ANTIFUNGAL/STEROID TOPICAL 5,051,260 9/1991 Chess et al. ............................ 424/449 COMPOSITIONS 5,106,866 4/1992 Maeda et al. ........................... 514/443 5,110,809 5/1992 Wang et al. ............................ 514/171 75 Inventors: John W. Quigley, Jr.; Sui Yuen. Eddie 5.21-a--- 2: Shall Clal. - .- .- . 2.. Hou, both of Foster City, Calif.; 5,310,545 5/1994 Eisen ......................................... 424/49 Bhaskar Chaudhuri, Cupertino, Calif. 5,407,663 4/1995 Eisen ....... ... 424/49 5.506,354 4/1996 McCall et al. .............................. 540/5 73 Assignee: Penederm, Inc., Foster City, Calif. 2- Y-Y-2 f Cal C a f FOREIGN PATENT DOCUMENTS 21 Appl. No.: 08/943,574 440298 A1 7/1991 European Pat. Off. ......... A61K 7/04 (51) Int. Cl. ............................................... A01N 33/02 Fukushiro et al., Butenafine HCI, A New Antifungal Agent, 52 U.S. Cl. .............................................................. 514/649 Recent Prog. Antifungal Chemother., Proc. Int. Conf., 1st, 58 Field of Search ............................................... 514/649 147-57, 1990. 56) References Cited Primary Examiner Jose G. Dees Assistant Examiner Alton Pryor U.S. PATENT DOCUMENTS Attorney, Agent, or Firm-Cooley Godward LLP 4,282,251 8/1981 Berney .................................... 424/316 57 ABSTRACT 4,298,604 11/1981 Hammell. ... 424/240 4,755,534 7/1988 Stuetz ...................................... 514/655 Stable topical formulations comprising an antifungal agent 4,912,124 3/1990 Das et al. ................................ 514/399 and an antiinflammatory Steroid are disclosed, useful for 4,971,800 11/1990 Chess et al. .. ... 424/449 treating fungal diseases and their related inflammation 5,002,938 3/1991 Wang et al. .. ... 514/171 g Tung 5,021,458 6/1991 Maeda et al. ... 514/655 5,045,317 9/1991 Chess et al. ............................ 424/401 26 Claims, No Drawings 6,075,056 1 2 ANTIFUNGAL/STEROID TOPICAL invention relates to Stable topical formulations comprising a COMPOSITIONS non-imidazole bearing antifungal agent (i.e. lacking an imidazole functional group within the molecule), including TECHNICAL FIELD benzylamine-containing antifungal agents, for example The invention relates to topical formulations useful for butenafine, or allylamine-containing antifungal agents Such treating fungal diseases and their related inflammation. In as terbinafine, naftifine, and the like. The topical formulation particular, the invention relates to Stable topical formulations also comprises an antiinflammatory Steroid, for example comprising an antifungal agent and an antiinflammatory betamethasone, betamethasone dipropionate, fluocinonide, Steroid. flu o cino lone ace to nide, hydro cort is one, methylprednisolone, clobetasol, beclomethasone, and the BACKGROUND like. The combination has unexpected advantages in that for Many methods are known for the topical treatment of those formulations that contain an ester-bearing Steroid fungal infections, including the use of antibiotics (e.g. group, the ester is hydrolysed at a much lower rate that nyStatin and amphotericin B), imidazole antifungal agents expected by the components of the topical formulation, thus Such as miconazole, clotrima Zole, econazole and 15 providing increased shelf life for the formulation. Sulconazole, and non-imidazole fungal agents Such as the Additionally, the combination of the antifungal agent and the allylamine derivatives terbinafine and naftifine, and the Steroid demonstrates a Synergistic effect, in that antifungal benzylamine butenafine. activity is unexpectedly Superior to that shown by the Recently, the combination of imidazole antifungal agents antifungal in the absence of the Steroid. As a consequence, with a corticosteroid has been disclosed for the topical the time is greatly reduced for alleviation of the Symptoms treatment of fungal diseases. The purpose of the Steroid is to and for complete eradication of the disease as compared to alleviate the Symptoms of erythma and the related itching the use of the antifungal agent in the absence of a Steroid, or that are normally associated with fungal infections. to known Steroid/antifungal combinations. Another advan Additionally, Steroids may also induce fungal Spores to be tage of the formulation is that it delivers the antifungal agent 25 and the Steroid to the skin, but minimizes the penetration of more Sensitive to treatment by an antifungal agent. the skin with respect to the Steroid, thus avoiding the However, the disadvantage of Such a combination is that potential side effects attendant upon prolonged Steroid use. it is undesirable to use Steroids for topical treatment for In particular, the invention relates to a topical antifungal extended periods of time. Steroids can penetrate the skin and composition comprising: cause undesirable side effects, including skin atrophy, Sup pression of the hypothalamic-pituitary-adrenal axis, Cush a) a therapeutically effective amount of an antifungal com ing's Syndrome, gluco Suria, hyperglycemia, etc. pound of Formula I: Additionally, the addition of a Steroid may actually decrease the effectiveness of Some antifungal compounds, because of Formula I the potential of Steroids to function as a deactivating agent. R1 R3 Additionally, Some antifungal compounds are quite toxic in 35 their own right. Air ---N XY Currently, the commercially available products that con tain a mixture of an antifungal and a steroid are Lotrisone R2 cream (clotrimazole 1%/betamethasone dipropionate 40 0.064%), Daktacort cream (miconazole nitrate wherein: 2%/hydrocortisone 1%) and Canesten HC cream R", R, and Rare independently hydrogen or lower alkyl; (clotrimazole 1%/hydrocortisone 1%). However, as a con X is -CH=CH- or -(CH), ; Sequence of the prolonged time necessary to effect Success in which n is 0, 1 or 2; ful treatment, these products exhibit the undesirable side 45 Y is -C=C-R', aryl, or heteroaryl; effects noted above. in which R" is lower alkyl; and It would therefore be advantageous to have a formulation Ar is aryl or heteroaryl; that retains the advantages of combining an agent useful for or a pharmaceutically acceptable Salt thereof; treating fungal diseases with a Steroid capable of reducing b) a therapeutically effective amount of an antiinflammatory the associated inflammation, with the ability to rapidly 50 Steroid; and eradicate fungal infections and eliminate the Symptoms c) pharmaceutically acceptable excipients Sufficient to form thereof, and as a consequence minimize the risk of unde a topical composition. sirable side effects. Such a formulation would ideally deliver The pharmaceutically acceptable excipients are chosen from the antifungal agent and the Steroid to the skin, and maintain a mixture of Solvents, emollients, humectants, and emulsi the combination on the skin for the period of time necessary 55 fiers. Solvents may be propylene glycol, butylene glycol, to effect treatment, but minimize the penetration of the skin heXylene glycol, polyethylene glycols, polypropylene with respect to the active ingredients, thus avoiding the glycols, polyurethane compounds, including hydroxy potential Steroid Side effects noted above. Surprisingly, we terminated polyurethanes, in particular polyolprepolymer-2, have discovered Such a formulation. polyolprepolymer-14, or polyolprepolymer-15. Emollients Relevant Literature 60 may be white petrolatum, mineral oil, propylene glycol Combinations of antifungals and Steroids are disclosed in dicaprylate, lower fatty acid esters and lower alkyl ethers of U.S. Pat. Nos. 4,912,124, 5,002,938, 5,021,458, 5,110,809, propylene glycol, cetyl alcohol, cetostearyl alcohol, Stearyl 5,174,475, 5,219,877, 5,407,663, and 5,310,545, alcohol, cetyl esters wax, Spermaceti wax, and white wax. SUMMARY OF THE INVENTION Humectants may be glycerin and Sorbitol, and emulsifiers 65 may be glyceryl monoStearate, glyceryl monoleate, poly The present invention relates to topical formulations oxyethylene cetyl ether, polyoxyethylene cetostearyl ether, useful in the treatment of fungal diseases. In particular, the polyoxyethylene Stearyl ether, and polyethylene glycol 6,075,056 3 4 Stearate. The pH is adjusted where necessary to a pH of Nos. 5,021,458 and 5,106,866, or include an allylamine about 3.5-7.0, using an acid e.g. hydrochloric acid phos moiety, for example naftifine and terbinafine, are disclosed phoric acid, or a base e.g. diethanolamine, triethanolamine, in U.S. Pat. Nos. 4,282,251 and 4,755,534, each of which is Sodium hydroxide, or known buffering agents, e.g. phos incorporated by reference. Antifungals of particular interest phates Such as monobasic Sodium phosphate, and dibasic 5 include, but are not limited to, terbinafine, naftifine, and Sodium phosphate, and citrates well known in the art. A butenafine. preservative is generally present, for example benzyl Terbinafine is a compound of Formula I wherein Ar is alcohol, Sodium benzoate, parabens, and the like. 1-naphthyl, R' is hydrogen, R is methyl, R is hydrogen, X Another aspect of the invention is a method of treating is -CH=CH-, and Y is -C=C-R", in which R" is fungal diseases by application to the skin of a mammal the t-butyl, and has the Structure: claimed topical compositions. Another aspect of the invention is an article of manufac ture comprising the claimed topical compositions in com bination with labeling instructions for

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