Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/08—Antiseborrheics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics

Definitions

• the present invention relates to a skin agent for external use, and more specifically, to an antifungal agent for external use.
• medicaments such as bifonazole, butenafine, and terbinafine have been developed and prescribed as skin medicines for external use.
• 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 an optically active substance (see JP 3278738 B).
• luliconazole which is an optically active substance
• 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).
• an antifungal agent is used for a therapy for tinea (tinea pedis, tinea corporis, or tinea cruris), candidiasis (intertrigo or erosio interdigitalis blastomycetica), chromophytosis, or seborrheic dermatitis, for example.
• 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, 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.
• a formulation that is free of any adverse effect such as an irritation and may be easily administered.
• 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 formulation in a form of a single-phase solution without impairing the solubility of the compound.
• 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 of promoting medicament permeability, but is not in any way known for its contribution to the stability.
• An object of the present invention is to provide a stable formulation having characteristics including containing a compound represented by the general formula (1).
• the inventors of the present invention have intensively studied to search a stable formulation having characteristics including containing a compound represented by the general formula (1).
• 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.
• the present invention is as follows.
• An antifungal agent for external use including: 1) a compound represented by the general formula (1); 2) 50 to 95 mass % of an alcohol; and 3) 0.1 to 35 mass % of water and/or an anionic surfactant.
• 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.
• the present invention may provide a formulation in which the compound represented by the general formula (1) stably exists. Such formulation may be usefully used for seborrheic dermatitis.
• An antifungal agent for external use of the present invention includes a compound represented by the general formula (1), 50 to 95 mass % of an alcohol such as ethanol, and 0.1 to 35 mass % of water. It should be noted that part or all of water may be replaced by an anionic surfactant.
• halogen When X in the compound represented by the general formula (1) represents a halogen, preferred examples of the halogen include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom. Of those, a chlorine atom is particularly preferred.
• the amount of the compound represented by the general formula (1) is preferably 0.01 to 20 mass % and particularly preferably 0.1 to 10 mass % with respect to the total amount of an antifungal agent for external use.
• An alcohol typified by ethanol dissolves the compound, and hence is incorporated in an amount of preferably 50 to 95 mass % and further, more preferably 70 to 90 mass % with respect to the total weight of an antifungal agent for external use. This is because the compound may not be sufficiently dissolved and may be time-dependently precipitated when an alcohol amount is small. Therefore, the above-mentioned amount is particularly preferred in order to exhibit a form of a single-phase solution.
• alcohols which may be mixed with water at an arbitrary ratio are preferred as alcohols other than ethanol, and specific suitable examples include polyvalent alcohols such as 2-propanol, 2-ethyl-1,3-hexanediol, propylene glycol, 1,3-butanediol, glycerin, and polypropylene glycol.
• those alcohols other than ethanol they are preferably used together with ethanol, and a form in which ethanol is used together so that ethanol is incorporated in a amount of 50 mass % or more of an alcohol amount is particularly preferred.
• those alcohols other than ethanol are preferably used in such a form that a part, in particular, a part not more than a half amount of ethanol is replaced by one kind or two or more kinds selected from the alcohols.
• single-phase solution refers to liquid substances dissolved with each other in which no white turbidity is observed and neither liquid crystal nor fine crystal is observed under a polarized light.
• the addition of water may suppress a time-dependent change of the compound in a formulation, for example, a change of the compound into a compound having a changed steric structure such as an S-E isomer represented by the general formula (2) and a Z isomer represented by the general formula (3), in particular, a change of the compound into the S-E isomer.
• the percentage of water is preferably 0.1 to 35 mass % and more preferably 1 to 30 mass % with respect to the total weight of the antifungal agent for external use.
• the percentage of water is, for example, preferably 5 to 35 mass % and more preferably 10 to 30 mass % with respect to the total weight of the antifungal agent for external use.
• anionic surfactants such as sodium dodecyl sulfate and sodium polyoxyethylene (4) lauryl ether phosphate in addition to water, and such ingredients may also be used in place of water.
• anionic surfactants such as sodium dodecyl sulfate and sodium polyoxyethylene (4) lauryl ether phosphate
• an emulsifying system may be adopted in the skin agent for external use of the present invention.
• the skin agent for external use of the present invention be in a form of a single-phase solution.
• the amount ratio of water to the alcohol is preferably 1:99 to 4:6, more preferably 5:95 to 3:7, and particularly preferably 1:7 to 3:5 at amass ratio.
• the preferred amount ratio of the anionic surfactant to the alcohol is preferably 1:99 to 4:6.
• water and the anionic surfactant are incorporated so that the ratio of the water to the anionic surfactant comes to preferably 20:1 to 1:1.
• the antifungal agent for external use of the present invention may contain, apart from the above ingredients, an arbitrary ingredient generally used for a skin agent for external use.
• the arbitrary ingredient include: oils and waxes such as macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, hydrogenated coconut oil, hydrogenated oil, Japan wax, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibota wax, lanolin, reduced lanolin, hard lanolin, and jojoba wax; hydrocarbons such as liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, vaseline, and microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, ste
• Red No. 202 Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, and Red No.
• organic powders such as a polyethylene powder, polymethyl methacrylate, a nylon powder, and an organopolysiloxane elastomer; a p-aminobenzoate-based ultraviolet absorbent; an anthranilate-based ultraviolet absorbent; a salicylate-based ultraviolet absorbent; a cinnamate-based ultraviolet absorbent; a benzophenone-based ultraviolet absorbent; a sugar-based ultraviolet absorbent; ultraviolet absorbents such as 2-(2′-hydroxy-5′-t-octylphenyl)benzotriazole and 4-methoxy-4′-t-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; vitamins such as vitamin A and derivatives thereof, vitamin Bs such as vitamin B 6 hydrochloride, vitamin B 6 tripalmitate, vitamin B 6 dioctanoate, vitamin B 2 and derivatives thereof, vitamin B 12 , and vitamin B 15 and derivatives thereof;
• the antifungal agent When the antifungal agent for external use of the present invention is applied to seborrheic dermatitis, the antifungal agent preferably has an appropriate viscosity for the purpose of preventing a medicament from being dissipated by dripping to sites other than the applied site.
• a cellulose-based thickener such as carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and ethylcellulose
• a gelling agent such as a methyl vinyl ether-maleic anhydride copolymer, an acrylic resin alkanolamine solution, polyvinylpyrrolidone, and a carboxyvinyl polymer which may be modified with an alkyl group.
• the total amount of such gelling agent is preferably 0.01 to 5 mass % and more preferably 0.1 to 2.5 mass % with respect to the total amount of the antifungal agent for external use. This is because an effect of preventing dripping may not be exerted when the amount is too small, and a form of a single-phase solution as one preferred mode may be impaired when the amount is too large.
• a flammable solvent such as methyl ethyl ketone and N-methyl-2-pyrrolidone excluding an alcohol typified by ethanol out of solvents may be incorporated. It is preferred to incorporate the flammable solvent in an amount of 1 mass % or less with respect to the total amount of the antifungal agent for external use, and it is more preferred to incorporate substantially no flammable solvent. This is because, even if such solvent does not exist, a form of a single-phase solution may be achieved in the construction of the antifungal agent for external use of the present invention, and negative factors such as possibility of causing an irritation and flammability possessed by the solvent may be eliminated.
• the term “flammable solvent” as used herein refers to special flammables and first class petroleum designated under the Fire Defense Law.
• the antifungal agent for external use of the present invention may be produced by treating the above-mentioned essential ingredient, preferred ingredient, arbitrary ingredient, and the like in accordance with a conventional method, and for example, is preferably produced by such procedure as shown in the following examples.
• the antifungal agent for external use of the present invention produced as described above is applied to, for example, cosmetics involving quasi drugs, skin pharmaceutical compositions for external use, and skin goods for external use, and is particularly preferably applied to antifungal skin medicines for external use.
• the antifungal agent for external use is preferably applied to skin medicines for seborrheic dermatitis for external use that are applied to a wide range of sites and are administered to sites sensitive to an irritation because the properties of the antifungal agent may be highly utilized.
• the antifungal agent for external use may also be effectively applied to mycoses of the body such as tinea corporis, mycoses of the hands and feet such as tinea pedis, and onychomycosis such as tinea unguium, and hence, the application of the antifungal agent to such mycoses also falls within the technical scope of the present invention.
• Luliconazole was dissolved by adding an appropriate amount of ethanol.
• POE (20) sorbitan monostearate (“NIKKOL TS-10MV”; manufactured by Nihon Surfactant Kogyo K.K.) was gradually added, water was further added, and homogenization was performed (Table 1).
• the resultant was named as Skin agent A for external use.
• Skin agent B for external use as a control was prepared in the same manner as in Skin agent A for external use except that ethanol was added in place of water.
• Form of formulation a form of a single-phase and homogeneously dissolved solution was confirmed through a visual check.
• luliconazole was dissolved in ethanol.
• POE (20) sorbitan monooleate (“NIKKOL TO-10MV”; manufactured by Nihon Surfactant Kogyo K.K.) was gradually added, water was further added, and homogenization was performed to prepare Skin agent C for external use.
• Skin agent D for external use as a control was prepared in the same manner as in Skin agent C for external use except that ethanol was added in place of water.
• Form of formulation a form of a single-phase and homogeneously dissolved solution was confirmed through a visual check.
• luliconazole was dissolved in ethanol.
• polyoxyethylene hydrogenated castor oil 40 (“NIKKOL HCO-40”; manufactured by Nihon Surfactant Kogyo K. K.) was gradually added, water was further added, and homogenization was performed to prepare Skin agent E for external use.
• Skin agent F for external use as a control was prepared in the same manner as in Skin agent E for external use except that ethanol was added in place of water.
• Form of formulation a form of a single-phase and homogeneously dissolved solution was confirmed through a visual check.
• Example 2 In the same manner as in Example 1, luliconazole was dissolved in ethanol. To the resulting solution, polyethylene glycol 200 (“PEG-200”; manufactured by TOHO Chemical Industry Co., LTD.) was gradually added, water was further added, and homogenization was performed to prepare Skin agent G for external use. Further, Skin agent H for external use as a control was prepared in the same manner as in Skin agent G for external use except that ethanol was added in place of water.
• PEG-200 polyethylene glycol 200
• Form of formulation a form of a single-phase and homogeneously dissolved solution was confirmed through a visual check.
• luliconazole was dissolved in ethanol.
• hydroxypropylmethylcellulose 2910 (“METOLOSE 60SH-4000”; manufactured by Shin-Etsu Chemical Co., Ltd.) was gradually added and homogeneously dispersed.
• water was added to prepare skin agents for external use.
• the skin agents for external use having water amounts of 23.6 mass % and 17.9 mass % with respect to the total mass were named as Skin agent I for external use and Skin agent J for external use, respectively.
• Skin agent K for external use as a control was prepared in the same manner as in Skin agent J for external use except that ethanol was added in place of water.
• Form of formulation a form of a single-phase and homogeneously dissolved solution was confirmed through a visual check.
• Example 2 In the same manner as in Example 1, luliconazole was dissolved in ethanol. To the resulting solution, sodium dodecyl sulfate (“NIKKOL SLS”; manufactured by Nikko Chemicals Co., Ltd.) was gradually added and homogeneously dispersed to prepare Skin agent L for external use. Further, Skin agent M for external use as a control was prepared in the same manner as in Skin agent L for external use except that ethanol was added in place of sodium dodecyl sulfate.
• NIKKOL SLS sodium dodecyl sulfate
• a single-phase solution or a gel formulation may be prepared by dissolving luliconazole with an alcohol typified by ethanol in the skin agent for external use, and adding water and the like, and an increase in the S-E isomer and the Z isomer having different steric structures of luliconazole may be suppressed compared with the case where water and the like are not compounded.
• Skin agent for external use N was prepared in the same operation as that in Example 6 in accordance with the following prescription. After preservation at 60° C. for 1 week, the amount of the S-E isomer was measured by the above-mentioned technique, and as a result, a peak of the S-E isomer was detected only at a trace level. The skin agent for external use N is found out to have a similar effect.
• Skin agent for external use 0 was prepared in the same operation as that in Example 7 in accordance with the following prescription. After preservation at 60° C. for 1 week, the amount of the S-E isomer was measured by the above-mentioned technique, and as a result, a peak of the S-E isomer was detected only at a trace level. The skin agent for external use 0 is found to have a similar effect.
• Skin agent for external use P was prepared in the same operation as that in Example 8 in accordance with the following prescription. After preservation at 60° C. for 1 week, the mass of the other analogous substances was measured by the above-mentioned technique, and as a result, peaks corresponding to the substances were not observed. The skin agent for external use P is found to have a similar effect.
• the preparation may be performed by compounding an alcohol such as ethanol and water in certain ranges into the compound represented by the general formula (1), to thereby improve the stability of the compound in a formulation.

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• 2008
  • 2008-09-05 WO PCT/JP2008/066056 patent/WO2009031642A1/fr active Application Filing
  • 2008-09-05 KR KR1020107007255A patent/KR20100075475A/ko active IP Right Grant
  • 2008-09-05 US US12/676,346 patent/US20100204293A1/en not_active Abandoned
  • 2008-09-05 EP EP08829061.4A patent/EP2191826B1/fr active Active
  • 2008-09-05 CN CN2008801059132A patent/CN101808637B/zh active Active
  • 2008-09-05 JP JP2009531290A patent/JP5529539B2/ja active Active
• 2012
  • 2012-09-04 US US13/603,220 patent/US8513296B2/en active Active

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