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Tepzz 9 8 6B T (19) TZZ __ _T (11) EP 2 191 826 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4178 (2006.01) A61K 9/08 (2006.01) 08.03.2017 Bulletin 2017/10 A61K 47/10 (2017.01) A61P 17/00 (2006.01) A61P 17/08 (2006.01) A61P 31/10 (2006.01) (2006.01) (21) Application number: 08829061.4 A61K 9/00 (22) Date of filing: 05.09.2008 (86) International application number: PCT/JP2008/066056 (87) International publication number: WO 2009/031642 (12.03.2009 Gazette 2009/11) (54) PHARMACEUTICAL COMPOSITION PHARMAZEUTISCHE ZUSAMMENSETZUNG COMPOSITION PHARMACEUTIQUE (84) Designated Contracting States: (74) Representative: Thurston, Joanna et al AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Withers & Rogers LLP HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT 4 More London Riverside RO SE SI SK TR London SE1 2AU (GB) (30) Priority: 05.09.2007 JP 2007229619 (56) References cited: WO-A1-03/105841 WO-A1-2007/102242 (43) Date of publication of application: WO-A2-97/02821 JP-A- 2002 193 755 02.06.2010 Bulletin 2010/22 JP-A- 2005 154 306 (73) Proprietors: • BORRAS-BLASCO JOAQUIN ET AL: "A • Pola Pharma Inc. mathematical approach to predicting the Shinagawa-ku percutaneous absorption enhancing effect of Tokyo 141-0031 (JP) sodium lauryl sulphate." INTERNATIONAL • Nihon Nohyaku CO., LTD. JOURNAL OF PHARMACEUTICS (KIDLINGTON), Chuo-ku vol. 269, no.1, 9 January 2004 (2004-01-09), pages Tokyo 104-8386 (JP) 121-129, XP2594939 ISSN: 0378-5173 • KATSUHISA UCHIDA ET AL: "In vitro activity of (72) Inventors: novel imidazole antifungal agent NND-502 • MASUDA, Takaaki against Malassezia species", INTERNATIONAL Yokohama-shi JOURNAL OF ANTIMICROBIAL AGENTS, Kanagawa 244-0812 (JP) ELSEVIER SCIENCE, AMSTERDAM, NL, vol. 21, • KOBAYASHI, Naoko no. 3, 1 March 2003 (2003-03-01), pages 234-238, Yokohama-shi XP008131229, ISSN: 0924-8579, DOI: Kanagawa 244-0812 (JP) 10.1016/S0924-8579(02)00362-X • SASAGAWA, Hideaki Yokohama-shi Kanagawa 244-0812 (JP) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 191 826 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 191 826 B1 Description Technical Field 5 [0001] The present invention relates to a skin agent for external use, and more specifically, to an antifungal agent for external use. Background Art 10 [0002] For diseases such as athlete’s foot and candidiasis to be caused by fungi, medicaments such as bifonazole, butenafine, and terbinafine have been developed and prescribed as skin medicines for external use. [0003] Of those, there may be exemplified, as a particularly promising medicament, a compound represented by a general formula (1) having an effect of shortening a therapeutic period for diseases derived from fungi, which has been reported in recent years as a novel imidazole compound having an antifungal activity, especially, luliconazole, which is 15 an optically active substance (see JP 3278738 B) . Further, such compound is also useful for onychomycosis, and a formulation for onychomycosis has also already been known (for example, see WO 03/105841). That is, the compound represented by the general formula (1) may be said as a useful active ingredient that may be widely used for mycoses (having an antifungal action). 20 25 30 35 40 [0004] It is generally known that an antifungal agent is used for a therapy for tinea (tineapedis, tineacorporis, ortine- acruris), candidiasis (intertrigo or erosio interdigitalis blastomycetica), chromophytosis, or seborrheic dermatitis, for example. However, a formulation used for seborrheic dermatitis is applied to a scalp site around the hair, and thus is used in a larger amount compared with that used for mycoses of the body and mycoses of the hands and feet. Therefore, 45 it is restricted to use a solvent such as methyl ethyl ketone from the viewpoints of possibility of causing an irritation, flammability, and the like. Accordingly, there has been a demand for a formulation that is free of any adverse effect such as an irritation and may be easily administered. In addition, in order to ensure an effect of an antifungal action, it is preferred that a formulation sufficiently dissolves a drug and be in a form of a single-phase solution. Because the compound represented by the general formula (1) has restricted water solubility, one problem is how to prepare a 50 formulation in a form of a single-phase solution without impairing the solubility of the compound. [0005] Meanwhile, various studies are being conducted in order to improve the stab ility of a bulk drug of an antif ungal agent. In particular, in a compound having an asymmetric carbon in the molecule, the maintenance of a steric structure becomes a critical issue in addition to the solubility. This is because the steric structure may be easily changed in a dissolution state. Any of the addition of sugars (see JP 2000-169372 A) and the adjustment of a pH (see JP 06-065076 55 A) has been conducted as one measure for the above, for example. In addition, it is known that an imidazole derivative is easily dissolved by polyethylene glycol, to thereby provide satisfactory stability (see JP 05-070351 A) . Further to this (WO 97/02821 A2) discloses an antifungal agent for treating mycoses and (JP 2005 154306 A) discusses an aerosol composition for external use using alcohol, water and an antifungal agent. Additionally, Borras-Blasco Joaquinet al 2 EP 2 191 826 B1 discuss the permeability of various antifungal agents in their paper "A mathematical approach to predicting the perco- taneous absorption enhancing effect of sodium lauryl sulfate, International Journal of Pharmaceuticals, Vol. 269, No. 1, 2004". Also of note is WO 2007/102442 A1 which discloses an external treatment using luliconazole.However,thereisno definite law for maintenance property of such steric structure. Thus, it may be said that the case where the steric structure 5 may be maintained is rare initself. Further, suchcombination is incidentally found out under the present situation. In a formulation containing the compound represented by the general formula (1), there has been no finding about whether or not the maintenance of the steric structure of the compound becomes a problem, and further, it is not known how to achieve such maintenance of the steric structure. Under such backgrounds, in pharmaceutical administration and reg- ulations, there is a demand for means for ensuring the stability suited for the compound represented by the general 10 formula (1). [0006] In addition, an alcohol typified by ethanol and water are widely used medium ingredients in formulation. It is known that those ingredients may cause hydrolysis or the like to affect the stability of an active ingredient. However, there has been no finding that the ingredients have a preferred contribution to the stability in a specified mixing ratio. Further, an anionic surfactant such as sodium dodecyl sulfate has been known to have a surfactant action and an action 15 of promoting medicament permeability, but is not in any way known for its contribution to the stability. Disclosure of the Invention Problem to be solved by the Invention 20 [0007] The present invention has been made under such circumstances . An object of the present invention is to provide a stable formulation having characteristics including containing a compound represented by the general formula (1). 25 30 35 40 45 Means for solving the Problem [0008] The inventors of the present invention have intensively studied to search a stable formulation having charac- teristics including containing a compound represented by the general formula (1). As a result, the inventors have found 50 that, in a formulation of a compound represented by the general formula (1), one problem is the maintenance property of a steric structure, and the stability relating to such maintenance property of a steric structure is improved by dissolving the compound in an alcohol and adding a specified proportion of water. The mass ratio of an alcohol to water as described above is 0.1 to 35 mass% of the water with respect to a range of 50 to 95 mass% of the alcohol. It should be noted that such formulation system preferably takes a form of a single-phase solution. 55 [0009] Based on such finding, the inventors of the present invention have completed the present invention. That is, the present invention is as follows. (1) An antifungal agent for external use, including: 1) a compound represented by the general formula (1); 2) 50 to 3 EP 2 191 826 B1 95 mass% of an alcohol; and 3) 0.1 1 to 35 mass% of water wherein part or all of the water is replaced by sodium dodecyl sulfate; and 1% mass% or less with respect to a total amount of the antifungal agent for external use of a flammable solvent comprising N-methyl-2-pyrrolidone and/or methyl ethyl ketone and excluding alcohol. 5 10 15 20 (2) The antifungal agent for external use according to the item (1) or (2), in which the antifungal agent is in a form of a single-phase solution. 25 (3) The antifungal agent for external use according Item (1) or item (2), including substantially no flammable solvent excluding an alcohol. (4) The antifungal agent for external use according to any one of the items (1) to (3), wherein a disease to which the antifungal agent is applied is selected from the group consisting of tinea (tinea pedis, tinea corporis, or tinea cruris), candidiasis (intertrigo or erosio interdigitalis blastomycetica), chromophytosis, and seborrheic dermatitis.
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