JP2020007370A - Medicinal composition for external use containing luliconazole - Google Patents

Abstract

To provide: a coloration-inhibiting agent which inhibits coloration with time of a medicinal composition for external use which contains luliconazole and/or a pharmaceutically acceptable salt thereof; a method for inhibiting coloration; a histamine release inhibitor which contains luliconazole and/or a pharmaceutically acceptable salt thereof; and an antipruritic medicinal composition for external use which contains the same.SOLUTION: There is provided a medicinal composition for external use which comprises (A) luliconazole and/or a pharmaceutically acceptable salt thereof and (B) one or two or more selected from the group consisting of an antihistamine, a local anesthetic, a cool-feeling agent, an anti-inflammatory agent, a vitamin agent, a pH adjusting agent and a germicidal agent. The resulting composition is suppressed in coloration with time caused by luliconazole and/or a pharmaceutically acceptable salt thereof. Further, the composition has an antifungal action and a histamine release-inhibiting action.SELECTED DRAWING: None

Description

  TECHNICAL FIELD The present invention relates to a coloring inhibitor and a method for suppressing coloring of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof. Further, the present invention relates to a histamine release inhibitor comprising luliconazole and / or a pharmaceutically acceptable salt thereof, and an external pharmaceutical composition for antipruritus comprising the same. The present invention further comprises luliconazole and / or a pharmaceutically acceptable salt thereof, and is selected from the group consisting of antihistamines, local anesthetics, cooling agents, anti-inflammatory agents, vitamins, pH adjusters, and bactericides. The present invention relates to a pharmaceutical composition for external use containing one or more kinds.

  Representative examples of dermatomycosis include tinea pedis, including tinea pedis, tinea unguium, tinea corporis, tinea cruris, candidiasis, and tinea versicolor. Among them, ringworm is said to account for up to about 20% of the Japanese population, including patients who are not aware of the disease (Non-Patent Document 1).

  Luliconazole (generic name (-)-(E)-[(4R)-(2,4-dichlorophenyl) -1,3-dithiolan-2-ylidene] (1H-imidazol-1-yl) acetonitrile) has a dithiolane skeleton Is known as an optically active imidazole fungicide having Luliconazole has a broad antibacterial spectrum and exhibits a strong antifungal activity particularly against dermatomycosis, and is therefore used as an agent for fungal dermatitis (Patent Documents 1 to 3).

  Luliconazole has also been proposed to be used as an auxiliary component such as a skin wound healing promoter (Patent Document 4), and is also useful as a comprehensive dermatitis drug based on its antifungal action.

International Publication WO2009 / 028495 International Publication WO2009 / 031644 International Publication WO2009 / 031642 JP 2008-69109 A

Journal of Pharmaceuticals of Japan (Folia Pharmacol. Jpn.) 127, 408-414 (2006)

  As described above, luliconazole is a drug having excellent antifungal properties, but is colored over time by irradiation with light. For this reason, when storing a drug containing luliconazole, it is necessary to put the drug in a light-shielding container to suppress coloring. An object of the present invention is to provide a method for suppressing temporal coloring caused by luliconazole in an external pharmaceutical composition containing luliconazole, and a color inhibitor. Another object of the present invention is to provide luliconazole or a histamine release inhibitor containing a specific component in luliconazole, and an external antipruritic pharmaceutical composition containing the same.

  The present inventors have conducted intensive studies to solve the above-described problems, and as a result, have found that by combining luliconazole with a specific component, a composition containing such a combination can suppress coloring caused by luliconazole. Furthermore, the present inventors have found that luliconazole or a composition containing luliconazole containing a specific component exhibits an effect of inhibiting histamine release, and have completed the present invention.

  The present invention relates to a group consisting of (A) luliconazole and / or a pharmaceutically acceptable salt thereof, (B) an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster, and a bactericide. An external pharmaceutical composition containing one or more selected from the group consisting of:

The antihistamine is selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, epinastine, loratadine, fexofenadine, and pharmaceutically acceptable salts thereof. One or more kinds;
The local anesthetic is one selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate. Two or more types;
The cooling agent may be peppermint oil, peppermint oil, fennel oil, cauliflower oil, eucalyptus oil, turpentine oil, l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, thymol, spiranthol, and methyl salicylate. One or more members selected from the group consisting of:
The anti-inflammatory agent is allantoin, glycyrrhizic acid, glycyrrhetinic acid, prednisolone acetate valerate, dexamethasone acetate, hydrocortisone acetate, ufenamate, bufexamac, ibuprofenpiconol, indomethacin, diclofenac, piroxicam, ε-aminocaproic acid, berberine, lysozyme, azulene, One or more members selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid and pharmaceutically acceptable salts thereof;
The above vitamin preparations include ubiquinone derivatives and pharmacologically acceptable salts thereof, such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, and riboflavin. Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, stearic acid ascorbate, palmitic ascorbate, dipalmitic acid L -Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, filoquinone, farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride , Thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate Acid ester monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydroxoco Lamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinamide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl Pantothenic acids such as ethyl ether; biotin, biotisin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate magnesium, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin , Γ-oryzanol, orotic acid, rutin, eriocitrin and one or more selected from the group consisting of pharmacologically acceptable salts thereof,
The pH adjuster is at least one selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, and tromethamol,
The disinfectant is isopropylmethylphenol, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, chlorobutanol, salicylic acid, gluconic acid , Terbinafine hydrochloride, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, and biguanide compounds Preferably, one or more selected from the group consisting of:

  The content of the component (A) is preferably 0.01 to 20% by weight of the whole composition, and the content of the component (B) is preferably 0.0001 to 41% by weight of the whole composition. .

  A ratio of the antihistamine in the whole external pharmaceutical composition is 0.05% by weight to 10% by weight, a ratio of the local anesthetic in the whole composition is 0.005% by weight to 10% by weight, The proportion of the cooling agent in the whole composition is 0.0001% to 15% by weight, and the proportion of the anti-inflammatory agent in the whole composition is 0.001% to 5% by weight; The proportion of the vitamin preparation in the whole composition is 0.0001% by weight to 8% by weight, and the proportion of the pH adjuster in the whole composition is 0.0001% to 30% by weight. It is preferable that the ratio of the fungicide to the whole composition is 0.0001% by weight to 8% by weight.

The present invention also relates to a color inhibitor for an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof,
The present invention relates to a coloring inhibitor containing one or more selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster, and a bactericide.

For the coloring inhibitor, the antihistamine is an ethanolamine compound, a propylamine compound, a phenothiazine compound, a piperazine compound, a piperidine compound, epinastine, loratadine, fexofenadine, and pharmaceutically acceptable salts thereof. One or more members selected from the group consisting of:
The local anesthetic is one selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate. Two or more types;
The cooling agent may be peppermint oil, peppermint oil, fennel oil, cauliflower oil, eucalyptus oil, turpentine oil, l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, thymol, spiranthol, and methyl salicylate. One or more members selected from the group consisting of:
The anti-inflammatory agent is allantoin, glycyrrhizic acid, glycyrrhetinic acid, prednisolone acetate valerate, dexamethasone acetate, hydrocortisone acetate, ufenamate, bufexamac, ibuprofen piconol, indomethacin, diclofenac, piroxicam, ε-aminocaproic acid, berberine, lysozyme, azulene, One or more members selected from the group consisting of bromelain, serrapeptase, semi-alkali proteinase, tranexamic acid, and pharmaceutically acceptable salts thereof;
The above vitamin preparations include ubiquinone derivatives and pharmacologically acceptable salts thereof, such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, and riboflavin. Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, stearic acid ascorbate, palmitic ascorbate, dipalmitic acid L -Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, filoquinone, farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride , Thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate Acid ester monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydroxoco Lamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinamide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl Pantothenic acids such as ethyl ether; biotin, biotisin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate magnesium, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin , Γ-oryzanol, orotic acid, rutin, eriocitrin and one or more selected from the group consisting of pharmacologically acceptable salts thereof,
The pH adjuster is at least one selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, and tromethamol,
The disinfectant is isopropylmethylphenol, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, chlorobutanol, salicylic acid, gluconic acid , Terbinafine hydrochloride, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, and biguanide compounds Preferably, one or more selected from the group consisting of:

  The present invention also relates to a method for suppressing coloration of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof, which comprises an antihistamine, a pH adjuster, a local anesthetic, a refreshing agent, an anti-inflammatory agent, The present invention relates to a method for suppressing coloration, wherein one or more selected from the group consisting of vitamin preparations and fungicides are contained in the external pharmaceutical composition.

The antihistamine is selected from the group consisting of ethanolamine compounds, propylamine compounds, phenothiazine compounds, piperazine compounds, piperidine compounds, epinastine, loratadine, fexofenadine, and pharmaceutically acceptable salts thereof. One or more kinds;
The local anesthetic is one selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate. Two or more types;
The cooling agent may be peppermint oil, peppermint oil, fennel oil, cauliflower oil, eucalyptus oil, turpentine oil, l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, thymol, spiranthol, and methyl salicylate. One or more members selected from the group consisting of:
The anti-inflammatory agent is allantoin, glycyrrhizic acid, glycyrrhetinic acid, prednisolone acetate valerate, dexamethasone acetate, hydrocortisone acetate, ufenamate, bufexamac, ibuprofen piconol, indomethacin, diclofenac, piroxicam, ε-aminocaproic acid, berberine, lysozyme, azulene, One or more members selected from the group consisting of bromelain, serrapeptase, semi-alkali proteinase, tranexamic acid, and pharmaceutically acceptable salts thereof;
The above vitamin preparations include ubiquinone derivatives and pharmacologically acceptable salts thereof, such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, and riboflavin. Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, stearic acid ascorbate, palmitic ascorbate, dipalmitic acid L -Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, filoquinone, farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride , Thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate Acid ester monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydroxoco Lamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinamide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl Pantothenic acids such as ethyl ether; biotin, biotisin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate magnesium, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin , Γ-oryzanol, orotic acid, rutin, eriocitrin and one or more selected from the group consisting of pharmacologically acceptable salts thereof,
The pH adjuster is at least one selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, and tromethamol,
The disinfectant is isopropylmethylphenol, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, chlorobutanol, salicylic acid, gluconic acid , Terbinafine hydrochloride, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, and biguanide compounds Preferably, one or more selected from the group consisting of:

  In the above-mentioned method for suppressing coloring, the antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster and a bactericide may include one or more external pharmaceutical compositions selected from the group consisting of: It is preferable that the proportion occupies 0.0001 to 41% by weight.

  The ratio of the antihistamine in the whole external pharmaceutical composition is 0.05% by weight to 10% by weight, and the ratio of the local anesthetic in the whole external pharmaceutical composition is 0.005% by weight to 10% by weight. The ratio of the cooling agent to the total external pharmaceutical composition is 0.0001% by weight to 15% by weight; and the ratio of the anti-inflammatory agent to the total external pharmaceutical composition is 0.001% by weight. % To 5% by weight, and the ratio of the vitamin preparation to the whole external pharmaceutical composition is 0.0001% to 8% by weight, and the ratio of the pH adjuster to the whole composition is 0.1 to 5% by weight. 0001% by weight to 30% by weight, and the ratio of the bactericide to the entire external pharmaceutical composition is preferably 0.0001% by weight to 8% by weight.

  The present invention also relates to (A) a histamine release inhibitor containing luliconazole and / or a pharmaceutically acceptable salt thereof.

  The histamine release inhibitor further comprises (B) one or more selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster, and a bactericide. It is preferred to contain.

In the histamine release inhibitor, the antihistamine is an ethanolamine compound, a propylamine compound, a phenothiazine compound, a piperazine compound, a piperidine compound, epinastine, loratadine, fexofenadine, and pharmaceutically acceptable thereof. One or more selected from the group consisting of salts;
The local anesthetic is selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate;
The cooling agent is mint oil, peppermint oil, fennel oil, cinnamon oil, eucalyptus oil, turpentine oil, l-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, thymol, spiranthol, and methyl salicylate. One or more members selected from the group consisting of:
The anti-inflammatory agent is allantoin, glycyrrhizic acid, glycyrrhetinic acid, prednisolone acetate valerate, dexamethasone acetate, hydrocortisone acetate, ufenamate, bufexamac, ibuprofen piconol, indomethacin, diclofenac, piroxicam, ε-aminocaproic acid, berberine, lysozyme, azulene, One or more members selected from the group consisting of bromelain, serrapeptase, semi-alkali proteinase, tranexamic acid, and pharmaceutically acceptable salts thereof;
The above vitamin preparations include ubiquinone derivatives and pharmacologically acceptable salts thereof, such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, and riboflavin. Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, stearic acid ascorbate, palmitic ascorbate, dipalmitic acid L -Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, filoquinone, farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride , Thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate Acid ester monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydroxoco Lamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinamide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl Pantothenic acids such as ethyl ether; biotin, biotisin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate magnesium, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin , Γ-oryzanol, orotic acid, rutin, eriocitrin and one or more selected from the group consisting of pharmacologically acceptable salts thereof,
The pH adjuster is at least one selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, and tromethamol,
The disinfectant is isopropylmethylphenol, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, chlorobutanol, salicylic acid, gluconic acid , Terbinafine hydrochloride, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, and biguanide compounds Preferably, one or more selected from the group consisting of:

  The present invention also relates to a pharmaceutical composition for external use for antipruritus comprising the above histamine release inhibitor.

  In the above external pharmaceutical composition for antipruritus, the content of the component (A) is 0.01 to 20% by weight of the whole external pharmaceutical composition for antipruritus, and the content of the above component (B) is The amount is preferably 0.0001 to 41% by weight of the whole topical pharmaceutical composition.

  The ratio of the antihistamine agent to the whole external pharmaceutical composition for antipruritic is 0.05% by weight to 10% by weight, and the ratio of the local anesthetic to the whole external pharmaceutical composition for antipruritic is 0.005% by weight or more. 10% by weight, wherein the ratio of the cooling agent to the total external use pharmaceutical composition for antipruritic is 0.0001% by weight to 15% by weight, and the use of the anti-inflammatory agent in the total external use pharmaceutical composition for antipruritic use. The occupying ratio is 0.001% by weight to 5% by weight, and the ratio of the above-mentioned vitamin preparation to the whole of the external pharmaceutical composition for antipruritic is 0.0001% by weight to 8% by weight. Preferably, the proportion of the whole composition is 0.0001% by weight to 30% by weight, and the proportion of the fungicide in the whole external pharmaceutical composition for antipruritic is 0.0001% by weight to 8% by weight. .

  The coloring inhibitor or topical pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof of the present invention suppresses coloring with time caused by luliconazole, and has physiological activity such as luliconazole's original antifungal action. Satisfactorily without loss. Further, the external pharmaceutical composition containing luliconazole of the present invention has a histamine release inhibitory action and an antipruritic action.

It is a figure which shows the result of having verified the coloring suppression of the external pharmaceutical composition of this invention.

  The color inhibitor of the external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof of the present invention comprises (A) luliconazole and / or a pharmaceutically acceptable salt thereof and (B) an antihistamine agent. , A local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster, and a bactericide.

  The method for suppressing coloration of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof according to the present invention comprises: (A) adding an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof; On the other hand, (B) a method containing one or more selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster, and a bactericide.

  The present invention further provides a histamine release inhibitor containing luliconazole and / or a pharmaceutically acceptable salt thereof. It has been discovered by the present inventors that luliconazole and / or a pharmaceutically acceptable salt thereof exerts a histamine release inhibitory action by itself. Such a histamine release inhibitor may optionally include (B) one or two selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory, a vitamin, a pH adjuster, and a bactericide. More than one species may be included.

  In the present invention, (A) luliconazole and / or a pharmaceutically acceptable salt thereof, and (B) an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin, a pH adjuster, and a bactericidal agent The present invention provides an external pharmaceutical composition containing one or more selected from the group consisting of agents.

  In the present specification, luliconazole as the component (A) has a generic name of (-)-(E)-[(4R)-(2,4-dichlorophenyl) -1,3-dithiolan-2-ylidene] (1H- Imidazol-1-yl) acetonitrile. Luliconazole may be synthesized and used by a known method, or a commercially available drug may be obtained and used.

  In the method for inhibiting coloration, the agent for inhibiting coloration, the externally applied pharmaceutical composition, the agent for inhibiting histamine release, or the externally applied pharmaceutical composition for antipruritus of the present invention, the externally applied pharmaceutical agent of luliconazole as the component (A) and / or a pharmaceutically acceptable salt thereof. The proportion of the composition or the total amount of the histamine release inhibitor is preferably 0.01% by weight or more and 20% by weight or less, more preferably 0.1% by weight or more and 10% by weight or less, further preferably 0.5% by weight or less. It is not less than 3% by weight and not more than 3% by weight.

  In the method for suppressing coloring, the coloring inhibitor, the external pharmaceutical composition, the histamine release inhibitor, or the external pharmaceutical composition for pruritus of the present invention, the ratio of the total of the component (B) to the total external pharmaceutical composition or histamine release inhibitor is as follows: Preferably, it is in the range of 0.0001% to 41% by weight.

  In the coloring suppression method of the present invention, a coloring inhibitor, a topical pharmaceutical composition, a histamine release inhibitor, or an antipruritic topical pharmaceutical composition, the antihistamine used is not limited, but includes diphenhydramine, diphenhydramine hydrochloride, dimenhydrinate and the like. Ethanolamine compounds, propylamine compounds such as chlorpheniramine maleate, phenothiazine compounds such as promethazine hydrochloride, piperazine compounds such as hydroxyzine, piperidine compounds such as cyproheptadine hydrochloride, epinastine hydrochloride, loratadine, And fexofenadine hydrochloride. In addition to the hydrochloride, a pharmaceutically acceptable salt of each compound can be used. One or more of these drugs can be used in appropriate combination. Among them, diphenhydramine, diphenhydramine hydrochloride, and chlorpheniramine maleate are preferred.

  In the coloring suppression method of the present invention, a coloring inhibitor, an externally applied pharmaceutical composition, a histamine release inhibitor, or an antipruritic externally applied pharmaceutical composition, the content of the antihistamine in the externally applied pharmaceutical composition or the histamine release inhibitor is 0.05. % By weight or more, preferably 0.1% by weight or more, and more preferably 0.5% by weight or more. The content of the antihistamine is preferably 10% by weight or less, more preferably 5% by weight or less, and still more preferably 2% by weight or less. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. The ratio of the antihistamine to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof is preferably 0.01 to 10 parts by weight, more preferably 0.1 to 5 parts by weight, More preferably, it is 0.5 to 2 parts by weight. Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  The local anesthetic used in the method for suppressing coloring of the present invention, a coloring inhibitor, an external pharmaceutical composition, a histamine release inhibitor, or an external pharmaceutical composition for pruritus is not limited, but includes procaine, tetracaine, lidocaine, and dibucaine. , Bupivacaine, mepivacaine, ropivacaine, levobupivacaine, ethyl aminobenzoate and pharmaceutically acceptable salts thereof can be preferably used. One or more of these drugs can be used in appropriate combination. Among them, procaine, lidocaine, dibucaine, or a pharmaceutically acceptable salt thereof, and ethyl aminobenzoate are preferred.

  In the coloring suppression method, coloring inhibitor, topical pharmaceutical composition, histamine release inhibitor, or antipruritic topical pharmaceutical composition of the present invention, the content of the local anesthetic in the topical pharmaceutical composition or the histamine release inhibitor is 0%. 0.005% by weight or more is preferred, 0.01% by weight or more is more preferred, and 0.05% by weight or more is even more preferred. Further, the content of the local anesthetic is preferably 10% by weight or less, more preferably 8% by weight or less, and still more preferably 6% by weight or less. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. The ratio of the local anesthetic to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 8 parts by weight. And still more preferably 0.05 to 6 parts by weight. Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  The coloring inhibitor of the present invention, a coloring inhibitor, a topical pharmaceutical composition, a histamine release inhibitor, or a refreshing agent used in an external pharmaceutical composition for pruritus are not limited, but include mint oil, peppermint oil, and fennel oil. And essential oils such as l-menthol, dl-menthol, d-camphor, dl-camphor and d-borneol. Other examples include thymol, spilanthol, methyl salicylate, and the like. The compound is preferably a compound belonging to terpenoids as a structure. Among them, mint oil, eucalyptus oil, turpentine oil, 1-menthol, dl-menthol, d-camphor, dl-camphor, and d-borneol are preferable.

  In the coloring suppression method, the coloring inhibitor, the topical pharmaceutical composition, the histamine release inhibitor, or the antipruritic topical pharmaceutical composition of the present invention, the content of the refreshing agent in the topical pharmaceutical composition or the histamine release inhibitor is 0. 0.0001% by weight or more is preferable, 0.001% by weight or more is more preferable, and 0.01% by weight or more is still more preferable. The content of the cooling agent is preferably 15% by weight or less, more preferably 10% by weight or less, and still more preferably 8% by weight or less. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. The ratio of the cooling agent to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof is preferably 0.0001 to 15 parts by weight, more preferably 0.001 to 10 parts by weight. And still more preferably 0.001 to 8 parts by weight. Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  The anti-inflammatory agent used in the method for inhibiting coloration of the present invention, a color inhibitor, an external pharmaceutical composition, a histamine release inhibitor, or an external pharmaceutical composition for pruritus includes a steroidal anti-inflammatory agent or a nonsteroidal anti-inflammatory agent Can be used. Specifically, allantoin, glycyrrhizic acid, glycyrrhetinic acid or a pharmaceutically acceptable salt thereof, dexamethasone acetate valerate, dexamethasone, prednisolone valerate acetate, prednisolone acetate, prednisolone, hydrocortisone acetate, hydrocortisone, ufenamate, bufexamac, ibuprofenpiconol , Glycol salicylate, but is not limited thereto. That is, further examples include, for example, indomethacin, diclofenac, piroxicam, ε-aminocaproic acid, berberine, lysozyme, azulene, bromelain, serrapeptase, semi-alkali proteinase, tranexamic acid, and pharmacologically acceptable salts thereof. Among them, glycyrrhizic acid, glycyrrhetinic acid or a pharmaceutically acceptable salt thereof, lysozyme, azulene, diclofenac, allantoin, tranexamic acid, and indomethacin are preferred.

  In the coloring control method, the coloring inhibitor, the topical pharmaceutical composition, the histamine release inhibitor, or the antipruritic topical pharmaceutical composition of the present invention, the content of the anti-inflammatory agent in the topical pharmaceutical composition or the histamine release inhibitor is 0. 0.001% by weight or more is preferable, and 0.01% by weight or more is more preferable. Further, the content of the anti-inflammatory agent is preferably 5% by weight or less, more preferably 3% by weight or less. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. The ratio of the anti-inflammatory agent to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof is preferably 0.001 to 5 parts by weight, more preferably 0.01 to 3 parts by weight. And still more preferably 0.01 to 2 parts by weight. Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  The vitamins used in the method for suppressing coloring, the coloring inhibitor, the topical pharmaceutical composition, the histamine release inhibitor, or the topical pharmaceutical composition for pruritus of the present invention include vitamin B, vitamin C, vitamin D, and vitamin E. And other vitamins can be used, but a substance having an antioxidant property is particularly preferably used. Examples of vitamins include ubiquinone derivatives and pharmaceutically acceptable salts thereof such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, and the like. E; vitamin B2 such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate; dl-α-tocopherol nicotinate Nicotinic acids such as benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate; ascorbigen-A, stearic acid ascorbate, Vitamin Cs such as scorbic acid palmitate and L-ascorbyl dipalmitate; Vitamin Ds such as methyl hesperidin, ergocalciferol and cholecalciferol; Vitamin Ks such as filoquinone and farnoquinone; γ-oryzanol, dibenzoylthiamine , Dibenzoyl thiamine hydrochloride; thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate Vitamin B1 such as thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate; Vitamin B6 such as syn, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride; vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin; folate such as folic acid and pteroylglutamic acid; nicotinic acid , Nicotinic acids such as nicotinic acid amide; pantothenic acids such as pantothenic acid, calcium pantothenate, pantoenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl ethyl ether; biotin, bioticin and the like Biotins: ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, sodium ascorbate phosphate, magnesium ascorbate phosphate Vitamin C which is an ascorbic acid derivative such as uranium; carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, eriocitrin, vitamin H, pantothenic acid, pantethine, pyrroloquinoline quinone And pharmacologically acceptable salts thereof such as vitamin-like agents. Of these, tocopherol acetate or D-panthenol is particularly preferred.

  In the method for suppressing coloring, the coloring inhibitor, the topical pharmaceutical composition, the histamine release inhibitor or the antipruritic topical pharmaceutical composition of the present invention, the content of the vitamin agent in the topical pharmaceutical composition or the histamine release inhibitor is 0.1%. It is preferably at least 0001% by weight, more preferably at least 0.001% by weight. Further, the content of the vitamin preparation is preferably 8% by weight or less, more preferably 5% by weight or less, and still more preferably 3% by weight or less. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. Per 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof, the proportion of the vitamin is preferably 0.0001 to 8 parts by weight, more preferably 0.005 to 5 parts by weight, Still more preferably, it is 0.001 to 3 parts by weight. Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  Examples of the pH control agent used in the color control method of the present invention, a color control agent, an external pharmaceutical composition, a histamine release inhibitor, or an external pharmaceutical composition for pruritus include, for example, urea, diisopropanolamine, triethanolamine, and tromethamol. However, the present invention is not limited to this. Among them, urea, diisopropanolamine and triethanolamine are preferred.

  In the coloring suppression method of the present invention, a coloring inhibitor, an externally applied pharmaceutical composition, a histamine release inhibitor, or an antipruritic externally applied pharmaceutical composition, the content of the pH adjuster in the externally applied pharmaceutical composition or the histamine release inhibitor is the composition It is preferably at least 0.0001% by weight, more preferably at least 0.001% by weight, based on the total amount of the product. Further, the content of the pH adjuster is preferably 35% by weight or less, more preferably 30% by weight or less, based on the total amount of the composition. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. The ratio of the pH adjuster to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof is preferably 0.0001 to 35 parts by weight, more preferably 0.001 to 30 parts by weight. . Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  Examples of the disinfectant used in the method for suppressing coloring of the present invention, a coloring inhibitor, a topical pharmaceutical composition, a histamine release inhibitor, or an antipruritic topical pharmaceutical composition include, for example, isopropylmethylphenol, decalinium chloride, benzalkonium chloride, Benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, chlorobutanol, salicylic acid, gluconic acid, terbinafine hydrochloride, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds ( Li hexamethylene biguanide, etc.) is exemplified, the invention is not limited to this. Among them, isopropyl methyl phenol, salicylic acid, gluconic acid, terbinafine hydrochloride, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorobutanol, methyl parahydroxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate Propyl acid and butyl paraoxybenzoate are preferred.

  In the coloring suppression method, the coloring inhibitor, the topical pharmaceutical composition, the histamine release inhibitor, or the antipruritic topical pharmaceutical composition of the present invention, the bactericide content in the topical pharmaceutical composition or the histamine release inhibitor is the composition 0.0001% by weight or more, more preferably 0.001% by weight or more, even more preferably 0.01% by weight, based on the total amount of The content of the fungicide is preferably 8% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less based on the total amount of the composition. Within the above range, the effects of the present invention described above can be sufficiently obtained with the usual use amount of quasi-drugs and pharmaceuticals. The ratio of the fungicide to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof is preferably 0.0001 to 8 parts by weight, more preferably 0.001 to 5 parts by weight, Even more preferably, it is 0.01 to 3 parts by weight. Within the above range, the effect of suppressing coloration and / or histamine release can be exerted, and a preparation having a good feeling in use can be obtained when preparing aerosols, creams, gels, ointments, and liquids.

  In the present invention, the `` pharmaceutically acceptable salt '' of luliconazole or another compound includes, for example, alkali metal salts, alkaline earth metal salts, salts with organic bases and the like, sodium, potassium, calcium, Magnesium, ammonium or salts with diethanolamine, ethylenediamine and the like. These salts are obtained, for example, by converting a sulfate group or a carboxyl group present in luliconazole or the like into a salt by a known method. Further, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, Salts of amines such as N-methylglucamine and L-glucamine; and salts with basic amino acids such as lysine, δ-hydroxylysine and arginine. Also, for example, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, Salts with organic acids such as malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid; or aspartic acid, glutamic acid And salts with acidic amino acids.

  The “pharmaceutically acceptable salt” as used in the present invention may include a solvate or hydrate of a salt.

  In the method for suppressing coloring, the coloring inhibitor, the external pharmaceutical composition, the histamine release inhibitor or the external pharmaceutical composition for pruritus of the present invention, luliconazole and / or its pharmaceutically acceptable salt and / or antihistamine, local anesthetic , Besides one or more selected from the group consisting of fresheners, anti-inflammatory agents, vitamins, pH adjusters, and fungicides, mainly luliconazole and / or its pharmaceutically acceptable salts Arbitrary components can be contained as long as the medicinal effect is not lost.

  The coloring inhibitor, topical pharmaceutical composition, histamine release inhibitor and antipruritic topical pharmaceutical composition of the present invention are provided in any form that can be widely used as pharmaceuticals and quasi-drugs. Preferably, it is provided as a preparation that can be used as an antifungal skin external preparation.

(Skin external preparation form)
Luliconazole of the present invention and / or a pharmaceutically acceptable salt thereof, and / or selected from the group consisting of antihistamines, local anesthetics, cooling agents, anti-inflammatory agents, vitamins, pH adjusters, and bactericides. One or more kinds of color inhibitors, color inhibition methods, histamine release inhibitors, topical pharmaceutical compositions for pruritus, topical pharmaceutical compositions are used in the form of skin external preparations as pharmaceuticals or quasi-drugs Can be done. In these external preparations, in addition to the component (A) and the component (B), a known base added to the skin external preparation (quasi-drug, pharmaceutical) as long as the effects of the present invention are not impaired. Alternatively, a carrier can be mixed and used. In addition, such skin external preparations include, for example, transdermal absorption enhancers, surfactants, oils, alcohols, humectants, thickeners, preservatives, antioxidants, chelating agents, stabilizers, Dispersants, fragrances, coloring agents, pigments, pearlescent agents, blood circulation promoting components, moisturizing components, ultraviolet absorbing components, ultraviolet scattering components, washing components, astringent components, amino acids, keratin softening components, cell activating components, solubilizing aids Agent, water and the like. The additives can be used alone or in combination of two or more.

  The drug which is a pharmaceutical composition for external use of the present invention may be in the form of a drug or a quasi-drug in a known form, for example, a liquid, suspension, emulsion, cream, ointment, gel, liniment, aerosol, powder. Agents, cataplasms, sheet materials in which a sheet of non-woven fabric is impregnated with a chemical solution, and the like. Among them, preferably, they are used in the form of solutions, suspensions, emulsions, creams, ointments, and gels. By adopting such a form, the external pharmaceutical composition of the present invention can sufficiently exhibit an antifungal action, a histamine release inhibitory action, and the like.

<Base or carrier>
Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, gelled hydrocarbons (such as plastic base), ozokerite, α-olefin oligomer, light liquid paraffin; methylpolysiloxane, cross-linked methylpolysiloxane, and highly polymerized methyl. Polysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkyl polyether-modified silicone, silicone / alkyl chain Modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone Silicone oils such as phenyl-modified silicone and silicone resin; cellulose derivatives such as ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; polyvinylpyrrolidone; carrageenan; polyvinylbutyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; Esters such as octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate and pentaerythritol tetra-2-ethylhexanoate; polysaccharides such as dextrin and maltodextrin; lower grades such as ethanol and isopropanol Alcohol: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether Ter, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl Glycol ethers such as ethers; polyhydric alcohols such as polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin and isoprene glycol; and aqueous bases such as water.

  The base or carrier can be used alone or in combination of two or more.

  Examples of the transdermal absorption enhancer include fatty acids having 6 to 20 carbon atoms, aliphatic alcohols, fatty acid esters, fatty acid ethers, and the like.

  Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, erythorbic acid, L-cysteine hydrochloride, and the like.

  Examples of the surfactant include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol penta-2-ethylhexylate sorbitan, and diglycerol sorbitan tetra-2-ethylhexylate. Sorbitan fatty acid esters; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated Hydrogenated castor oil derivatives such as castor oil 60 (HCO-60) and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), monostea Polyoxyethylene (20) sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan isostearate; poly Oxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; polyoxyethylene methylpolysiloxane copolymer; Silicone-based surfactants such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG-9 polydimethylsiloxyethyl dimethicone; Amphoteric surfactants such as anionic surfactants such as lumitate, cocoyl glutamate, coconut oil methylalanine salt, acylmethyltaurine salt, polyoxyethylene lauryl sulfate, lauryldiaminoethylglycine salt, and coconut oil fatty acid betaine salt Agents and the like.

  Examples of the thickener include guar gum, locust bean gum, carrageenan, xanthan gum, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl methacrylate, and alkyl methacrylate. Copolymer, polyethylene glycol, bentonite, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer, (acryloyldimethyltaurine ammonium / vinylpyrrolidone) copolymer, hydrophobized hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, carmellose sodium, Polyacry Such as sodium and the like.

  Examples of the preservative include benzoic acid, dehydroacetic acid, isobutyl parahydroxybenzoate, isopropyl paraoxybenzoate, benzyl paraoxybenzoate, and phenoxyethanol.

  Examples of the chelating agent include EDTA disodium salt and EDTA calcium disodium salt.

  Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole, and the like.

Examples of the solubilizer include methyl ethyl ketone and N-methyl-2-pyrrolidone.
The additives can be used alone or in combination of two or more.

<Other active ingredients>
The coloring inhibitor of the present invention, the coloring suppressing method, the histamine release inhibitor, the external pharmaceutical composition for pruritus, and the external pharmaceutical composition can optionally contain other active ingredients as long as the effects of the present invention are not impaired. . Specific examples of the active ingredient include a moisturizing component, a peptide or a derivative thereof, an amino acid or a derivative thereof, a cell activating component, and a blood circulation promoting component.

  Examples of moisturizing components include polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol and diglycerin; sugars such as trehalose, xylitol and oligosaccharides; sodium hyaluronate, heparin-like substances, and chondroitin sulfate High molecular compounds such as sodium, collagen, elastin, keratin, chitin, chitosan; amino acids such as glycine, aspartic acid and arginine; natural moisturizing factors such as sodium lactate and sodium pyrrolidonecarboxylate; ceramide, cholesterol, and phospholipids And lipids such as plant extracts such as chamomile extract, hamamelis extract, cha extract and perilla extract.

  Examples of the peptide or its derivative include keratin-decomposed peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-decomposed peptide, collagen-degraded peptide, hydrolyzed collagen, hydroxypropylammonium chloride-hydrolyzed collagen, and elastin-degraded peptide , Conchiolin degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein degradable peptide And acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

  Examples of amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine. , Leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnosine, creatine and the like.

  Cell activating components Cell activating components include amino acids such as γ-aminobutyric acid and ε-aminoproic acid; retinols such as retinol palmitate; α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponins, Photosensitizer No. 301 and the like.

  As the blood circulation promoting component, a plant-derived component is preferably exemplified. For example, Panax ginseng, Ashitaba, Arnica, Ginkgo, Emisoso, Dutch oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, hawthorn, hawthorn, skull, cassava, thyme, clove, thyme, ninja , Spruce, carrot, garlic, butcher bloom, grapes, buttons, marronnier, melissa, yuzu, yokuninin, rosemary, rosehip, chimney, touki, spruce, peach, apricot, walnut, corn-derived components; glucosyl hesperidin, etc. No.

  The term “coloring” as used in the present invention refers to coloring that can be detected by a device such as an absorptiometer, regardless of the form of an external pharmaceutical composition containing luliconazole, for example. Although coloring that can be visually recognized may be used, coloring that is difficult to detect by visual inspection is also referred to as coloring. For example, a drug in the form of a cream containing luliconazole is white, and a liquid substance containing luliconazole is preferably colorless and transparent, but changes color to yellow over time by light irradiation. In this specification, the degree of coloring can be detected by the absorbance at 450 nm of the liquid containing luliconazole, but the coloring is not limited to this and can be detected. Coloring suppression refers to preventing, delaying, and reducing such coloring. In the present specification, the suppression of coloration refers to detecting a color resulting from a change with time of luliconazole at 450 nm absorbance with a liquid containing the same concentration of luliconazole as a control, and improving the coloration at a detectable level. Say.

  The histamine release inhibitory effect of the present invention can be detected by an in vitro test using cells in which the amount of released histamine is suppressed as compared to a control in which the composition of the present invention is not used.

  In the present invention, the external pharmaceutical composition containing luliconazole, the histamine release inhibitor, or the external pharmaceutical composition for antipruritus further has an irritation suppressing effect. Here, the stimulus-suppressing effect can be detected by an increase or decrease in cell viability in an in vitro test using cells, as compared to a control in which the composition of the present invention is not used.

  The drug containing luliconazole may be used in the form of a kit. Specifically, there may be mentioned an embodiment in which different components constituting the pharmaceutical composition are packaged in advance in separate containers or packs, and are mixed immediately before use. Containers include, for example, sealed ampules, test tubes, vials, flasks, bottles, syringes, or the like.

  Next, the present invention will be specifically described by way of examples, but the present invention is not limited to the following examples.

(Example 1)
(A) To a liquid containing 1% luliconazole (1% Lulicon solution, manufactured by Pola Pharma Co., Ltd.), add each component (B) alone so that the final concentration is as shown in Table 1, and add 10 minutes. The composition was prepared by stirring. The prepared aqueous composition was subjected to a coloring evaluation test.

(Comparative Example 1)
As a composition containing luliconazole, 1% lulicone solution was directly subjected to an evaluation test, and the measured value was used for calculation of a coloring inhibition rate.

(Coloring suppression evaluation test)
3 ml of each of the aqueous compositions of Examples and Comparative Examples was placed in a glass screw-neck bottle (5 ml), and D65 was used with a light stability device (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Science Co., Ltd.). Using a lamp as a light source, light of 5,000 LUX was irradiated for 192 hours at 25 ° C., and exposed to light having an integrated irradiation amount of 960,000 LUX · hr. Thereafter, 200 μL of each sample was dispensed into a 96-well plate, and the absorbance at 450 nm was measured using a microplate reader. Based on the measured values, the color inhibition rate was determined according to the following equation. Color inhibition ratio (%) = (1−measured value of composition of example / measured value of luliconazole) × 100

  As a result, as apparent from FIG. 1 and Table 1, the topical pharmaceutical composition of the present invention has an action of suppressing coloration caused by the temporal change of luliconazole. FIG. 1 corresponds to Table 1, and the bar graph of FIG. 1 shows that the components are 0.1%, 0.5%, 1.0%, 2.0%, 3.0%, and 5% from the left. 0.0% is shown.

(Example 2)
(A) A solution containing luliconazole (1% by weight) and anhydrous ethanol as a solvent (Luricon solution 1%, manufactured by Polar Pharma Co., Ltd.) and various components (B) were combined. The final concentration of the component (A) was 0.0005, 0.005% by weight. The final concentrations of the component (B) were adjusted to the concentrations shown in Tables 2 to 7, respectively. The components (A) and (B) were prepared using a PIPES buffer (+). The prepared composition was subjected to a histamine release inhibition evaluation test and an irritation inhibition evaluation test.
(Reference Example and Comparative Example 2)
As a control composition, luliconazole 0.0005, 0.005% by weight or each component (B) was adjusted to the values shown in the table, and subjected to a histamine release inhibition evaluation test and a stimulus inhibition evaluation test.

(Histamine release inhibition evaluation test)
RBL-2H3 cells were seeded at a density of 2.3 × 10 ⁵ cells / mL in a 96-well plate at 200 μL / well, cultured at 37 ° C. for 24 hours under 5% CO ₂ , and the supernatant was removed. 100 μL of each of the compositions prepared in Example 2 and Comparative Example 2 was added, and pretreatment was performed at 37 ° C. and 5% CO ₂ for 1.5 hours. After 1.5 hours, the supernatant was removed, 200 μL of Example 2 and Comparative Example 2 containing 10 μM of the calcium ionophore reagent were added to each well, and the mixture was reacted at 37 ° C. under 5% CO ₂ for 30 minutes. . The supernatant of each well was collected, and the amount of histamine was measured by ELISA. Based on the measured values, the histamine release rate was determined according to the following equation.
Histamine release rate = (Histamine amount of the composition-added group of each Example / Reference Example / Comparative Example / Histamine amount of PIPES buffer (+) added) × 100

(Stimulation suppression evaluation test)
A stimulus suppression evaluation test was performed by evaluating cytotoxicity. RBL-2H3 cells were seeded at a density of 2.3 × 10 ⁵ cells / mL in a 96-well plate at 200 μL / well, cultured at 37 ° C. for 24 hours under 5% CO ₂ , and the supernatant was removed. After adding 100 μL of each of the compositions prepared in Example 2 and Comparative Example 2 and performing a pretreatment for 1.5 hours at 37 ° C. and 5% CO ₂ , the mitochondrial reducing ability was determined by the WST-8 method. The cell viability was determined based on the measured values and using the mitochondrial reducing ability as an index according to the following formula. The higher the cell survival rate, the higher the stimulus suppression effect. Cell viability (%) = (measured value of composition added group of each Example / Reference Example / Comparative Example / measured value of PIPES buffer (+) addition) × 100

  The results of the histamine release inhibition evaluation test are shown in Tables 2 to 8, and the results of the stimulus inhibition evaluation test are shown in Table 9.

この結果、本発明の組成物は、ヒスタミン遊離抑制効果を有し、さらに刺激抑制効果を示す場合があることがわかった。

As a result, it was found that the composition of the present invention has an effect of suppressing histamine release, and may further exhibit an effect of suppressing stimulation.

(Composition Preparation Example) Aerosol The following ointment is prepared. The unit of the numerical value in the formulation example is “% by weight”. The following luliconazole is not the commercial product used in the examples, but refers to the luliconazole compound itself.

 (Composition preparation example) cream

実施例1および比較例1を利用して、クリーム製剤を調製して皮膚で使用して使用感を評価した結果、実施例1含有クリーム剤は比較例1含有クリーム製剤と比較して、のびがよく、べたつかない製剤であることが確認された。

Using Example 1 and Comparative Example 1, a cream preparation was prepared and used on the skin to evaluate the feeling of use.As a result, the cream preparation containing Example 1 exhibited a longer growth than the cream preparation containing Comparative Example 1. It was well confirmed that the preparation was not sticky.

 (Composition preparation example)

(Composition Preparation Example) Gel

実施例1および比較例1を利用して、ゲル製剤を調製して皮膚に使用して使用感を評価した結果、実施例1含有ゲル製剤は比較例1含有ゲル製剤と比較して、のびがよく、べたつかない製剤であることが確認された。

Using Example 1 and Comparative Example 1, a gel preparation was prepared and used on the skin to evaluate the feeling of use.As a result, the gel preparation containing Example 1 exhibited a longer growth than the gel preparation containing Comparative Example 1. It was well confirmed that the preparation was not sticky.

 (Composition preparation example) ointment

Claims (7)

(A) luliconazole and / or a pharmaceutically acceptable salt thereof, (B) one or more selected from the group consisting of a bactericide, an anti-inflammatory agent, and a cooling agent, and ethanol. ,
The pharmaceutical composition for external use, wherein the content of the component (A) is 0.01 to 20% by weight of the whole composition, and the content of the component (B) is 0.0001 to 41% by weight of the whole composition. .   The external pharmaceutical composition according to claim 1, further comprising a base for external preparation for skin, a carrier for external preparation for skin, or an additive for external preparation for skin.   The external pharmaceutical composition according to claim 1 or 2, which is a gel, a liquid, or an aerosol. (A) Luliconazole and / or a pharmaceutically acceptable salt thereof, and a color inhibitor for an external pharmaceutical composition containing ethanol,
(B) It contains one or more selected from the group consisting of a bactericide, an anti-inflammatory agent, and a cooling agent, and the content of the component (A) is 0.01 to 20 of the whole composition. % By weight, and the content of the component (B) is 0.0001 to 41% by weight of the whole composition.   (A) A method for suppressing coloring of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof and ethanol, comprising (B) a bactericide, an anti-inflammatory agent, and a refreshing agent. One or more selected from the group is contained in the external pharmaceutical composition, the content of the component (A) is 0.01 to 20% by weight of the whole composition, and the content of the component (B) A coloring suppression method, wherein the content is 0.0001 to 41% by weight of the whole composition.   (A) luliconazole and / or a pharmaceutically acceptable salt thereof, (B) one or more selected from the group consisting of a bactericide, an anti-inflammatory agent, and a cooling agent, and ethanol. A histamine release inhibitor, wherein the content of the component (A) is 0.01 to 20% by weight and the content of the component (B) is 0.0001 to 41% by weight. (A) luliconazole and / or a pharmaceutically acceptable salt thereof, (B) one or more selected from the group consisting of a bactericide, an anti-inflammatory agent, and a cooling agent, and ethanol. Wherein the content of the component (A) is 0.01 to 20% by weight of the whole composition, and the content of the component (B) is 0.0001 to 41% by weight of the whole composition. Pharmaceutical composition.

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