JP2013253078A - Medicinal composition containing luliconazole for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a coloration-inhibiting agent which inhibits the chronological coloration 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: A medicinal composition for external use is prepared, the composition containing (A) luliconazole and/or a pharmaceutically acceptable salt thereof and (B) one or more substances selected from the group consisting of an antihistamine, a local anesthetic, a refrigerant, an anti-inflammatory agent, vitamins, a pH adjuster and a germicide. The composition thus prepared is free from chronological coloration due to luliconazole and/or a pharmaceutically acceptable salt thereof. In addition, the composition has an antifungal action and a histamine release-inhibiting action.

Description

  The present invention relates to a coloring inhibitor and a coloring suppression method for an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a histamine release inhibitor comprising luliconazole and / or a pharmaceutically acceptable salt thereof, and an external pharmaceutical composition for antipruritics comprising the same. The present invention further comprises luliconazole and / or a pharmaceutically acceptable salt thereof, and is selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin, a pH adjuster, and a bactericidal agent. The present invention relates to an external pharmaceutical composition containing one or more kinds.

  Representative examples of dermatomycosis include tinea pedis, candidiasis including tinea pedis, onychomycosis, tinea corporis, tinea pedis, etc., candidiasis, or folding syndrome. Of these, ringworm is said to occupy up to about 20% of the Japanese population when including patients who are not aware of the disease (Non-patent Document 1).

  Luliconazole (generic name (-)-(E)-[(4R)-(2,4-dichlorophenyl) -1,3-dithiolane-2-ylidene] (1H-imidazol-1-yl) acetonitrile) is a dithiolane skeleton. It is known as an optically active imidazole fungus agent having Luliconazole has a broad antibacterial spectrum and exhibits a strong antifungal activity especially 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 accessory component such as a skin wound healing promoter (Patent Document 4), and is useful as a comprehensive dermatitis drug based on its antifungal action.

International Publication WO2009 / 028495 International Publication WO2009 / 031644 International Publication No. WO2009 / 031642 JP 2008-69109 A

Pharmacology Journal (Folia Pharmacol. Jpn.) 127, 408-414 (2006)

  Thus, although luliconazole is a drug excellent in antifungal properties, it is colored over time by light irradiation. For this reason, when preserving the drug containing luliconazole, it is necessary to put it in a light-shielding container to suppress coloring. An object of the present invention is to provide a method and a color inhibitor for suppressing coloration with time due to luliconazole of an external pharmaceutical composition containing luliconazole. Furthermore, it is an object of the present invention to provide luliconazole or a histamine release inhibitor containing a specific component in luliconazole, and a pharmaceutical composition for external use for antitussives containing the same.

  As a result of intensive studies to solve the above problems, the present inventors have found that a composition containing such a combination can suppress coloring derived from luliconazole by combining specific components with luliconazole. Furthermore, the present inventors have found that histamine release-inhibiting action is exerted by luliconazole or a composition containing luliconazole containing a specific component, and have completed the present invention.

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

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. 1 type or 2 types or more;
The local anesthetic agent is one selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate, or Two or more;
The refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid and pharmacologically acceptable salts thereof;
The above vitamin preparations include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
The above bactericides are 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 It is preferable that it is 1 type, or 2 or more types selected from the group which consists of.

  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 preferably 0.0001 to 41% by weight of the whole composition. .

  The proportion of the antihistamine agent in the entire external pharmaceutical composition is 0.05 wt% to 10 wt%, and the proportion of the local anesthetic composition in the entire composition is 0.005 wt% to 10 wt%, The proportion of the refreshing agent in the entire composition is 0.0001% to 15% by weight, and the proportion of the anti-inflammatory agent in the entire 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, the proportion of the pH adjuster in the whole composition is 0.0001% by weight to 30% by weight, The proportion of the disinfectant in the entire composition is preferably 0.0001% by weight to 8% by weight.

The present invention also provides 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 agent, a vitamin agent, a pH adjuster and a bactericide.

The antihistamine is an ethanolamine compound, propylamine compound, phenothiazine compound, piperazine compound, piperidine compound, epinastine, loratadine, fexofenadine, and pharmaceutically acceptable salts thereof. One or more selected from the group consisting of:
The local anesthetic agent is one selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate, or Two or more;
The refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof;
The above vitamin preparations include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
The above bactericides are 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 It is preferable that it is 1 type, or 2 or more types selected from the group which consists of.

  The present invention also relates to a method for inhibiting coloration of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof, comprising an antihistamine, a pH adjuster, a local anesthetic, a cooling agent, an anti-inflammatory agent, The present invention relates to a coloring suppression method, wherein one or more selected from the group consisting of vitamins and bactericides 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. 1 type or 2 types or more;
The local anesthetic agent is one selected from the group consisting of procaine, tetracaine, lidocaine, dibucaine, bupivacaine, mepivacaine, ropivacaine, levobupivacaine, and pharmaceutically acceptable salts thereof, and ethyl aminobenzoate, or Two or more;
The refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof;
The above vitamin preparations include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
The above bactericides are 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 It is preferable that it is 1 type, or 2 or more types selected from the group which consists of.

  In the coloring suppression method, the one or more external pharmaceutical compositions selected from the group consisting of the antihistamine, the local anesthetic, the cooling agent, the anti-inflammatory agent, the vitamin agent, the pH adjuster and the bactericidal agent are used. The occupying ratio is preferably 0.0001 to 41% by weight.

  The proportion of the antihistamine agent in the entire external pharmaceutical composition is 0.05 wt% to 10 wt%, and the proportion of the local anesthetic agent in the entire external pharmaceutical composition is 0.005 wt% to 10 wt%. Yes, the proportion of the refreshing agent in the entire external pharmaceutical composition is 0.0001% by weight to 15% by weight, and the proportion of the anti-inflammatory agent in the entire 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. It is preferable that the ratio of the bactericidal agent to the whole external pharmaceutical composition is 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.

  In the histamine release inhibitor, one or more selected from the group consisting of (B) an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin, a pH adjuster, and a bactericide It is preferable 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, or a pharmaceutically acceptable product 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 refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof;
The above vitamin preparations include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
The above bactericides are 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 It is preferable that it is 1 type, or 2 or more types selected from the group which consists of.

  The present invention also relates to an external pharmaceutical composition for antipruritics containing the histamine release inhibitor.

  In the external pharmaceutical composition for antipruritics, the content of the component (A) is 0.01 to 20% by weight of the entire external pharmaceutical composition for antipruritics, and the content of the component (B) is the antipruritic agent. It is preferable that it is 0.0001 to 41 weight% of the whole external pharmaceutical composition.

  The proportion of the antihistamine agent in the entire external pharmaceutical composition for antipruritics is 0.05% by weight to 10% by weight, and the proportion of the local anesthetic agent in the entire external pharmaceutical composition for antipruritics is 0.005% by weight to 10% by weight, and the proportion of the refreshing agent in the total external pharmaceutical composition for antipruritics is 0.0001% by weight to 15% by weight. The proportion of the pH adjuster is 0.001% to 5% by weight, and the proportion of the vitamin preparation in the entire external antipruritic pharmaceutical composition is 0.0001% to 8% by weight. The proportion of the whole composition is 0.0001% to 30% by weight, and the proportion of the bactericidal agent to the whole external antipruritic pharmaceutical composition is preferably 0.0001% to 8% by weight. .

  The color suppressant or external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof of the present invention suppresses coloration over time caused by luliconazole, and provides physiological activities such as luliconazole's original antifungal action Hold well without losing. Furthermore, 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-suppressing agent of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof according to the present invention comprises (A) luliconazole and / or a pharmaceutically acceptable salt thereof, and (B) an antihistamine. 1 type, or 2 or more types selected from the group which consists of a local anesthetic, a refreshing agent, an anti-inflammatory agent, a vitamin agent, a pH adjuster, and a disinfectant.

  The method for inhibiting coloration of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof according to the present invention includes (A) an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof. On the other hand, (B) is a method of containing one or more selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin agent, 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 alone. Such a histamine release inhibitor is optionally one or two selected from the group consisting of (B) an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin agent, a pH adjuster, and a bactericide. You may contain a seed or more.

  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 An external pharmaceutical composition containing one or more selected from the group consisting of agents is provided.

  In this specification, the component (A) luliconazole is a generic name (-)-(E)-[(4R)-(2,4-dichlorophenyl) -1,3-dithiolane-2-ylidene] (1H- It refers to the compound of 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 coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the external preparation of the component (A) luliconazole and / or a pharmaceutically acceptable salt thereof The proportion of the composition or 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, and still more preferably 0.5%. % By weight or more and 3% by weight or less.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the proportion of the total of component (B) in the external pharmaceutical composition or histamine release inhibitor is The range is preferably 0.0001 wt% or more and 41 wt% or less.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the antihistamine used is not limited, but includes diphenhydramine, diphenhydramine hydrochloride, dimenhydrinate, etc. 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 and the like. In addition to the hydrochloride, pharmaceutically acceptable salts of the respective compounds can also be used. One or two or more of these drugs can be used in appropriate combination. Of these, diphenhydramine, diphenhydramine hydrochloride, and chlorpheniramine maleate are preferable.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the content of the antihistamine in the external pharmaceutical composition or histamine release inhibitor is 0.05. % By weight or more is preferable, 0.1% by weight or more is more preferable, and 0.5% by weight or more is even more preferable. Further, 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. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. 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. If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

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

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the content of the local anesthetic agent in the external pharmaceutical composition or histamine release inhibitor is 0. 0.005% by weight or more is preferable, 0.01% by weight or more is more preferable, and 0.05% by weight or more is even more preferable. 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. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. The proportion of the local anesthetic agent is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 8 parts by weight with respect to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof. Even more preferably, it is 0.05 to 6 parts by weight. If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

  The cooling agent used in the coloring suppression method, coloring inhibitor, topical pharmaceutical composition, histamine release inhibitor, or antipruritic topical pharmaceutical composition of the present invention is not limited, but mint oil, peppermint oil, fennel oil Examples thereof include essential oils such as cinnamon oil, eucalyptus oil, and turpentine oil, and essential oil components such as l-menthol, dl-menthol, d-camphor, dl-camphor, and d-borneol. In addition, thymol, spiranthol, methyl salicylate, and the like are also included. The structure is preferably a compound belonging to terpenoids. Among them, peppermint oil, eucalyptus oil, turpentine oil, l-menthol, dl-menthol, d-camphor, dl-camphor and d-borneol are preferable.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the content of the refreshing agent in the external pharmaceutical composition or 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 even more preferable. Further, the content of the refreshing agent is preferably 15% by weight or less, more preferably 10% by weight or less, and still more preferably 8% by weight or less. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. The proportion of the refreshing agent is preferably 0.0001 to 15 parts by weight, more preferably 0.001 to 10 parts by weight with respect to 1 part by weight of luliconazole and / or a pharmaceutically acceptable salt thereof. Even more preferably, it is 0.001 to 8 parts by weight. If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

  The anti-inflammatory agent used in the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention is a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent. Any of these can be used. Specifically, allantoin, glycyrrhizic acid, glycyrrhetinic acid or a pharmaceutically acceptable salt thereof, dexamethasone acetate dexamethasone, dexamethasone, prednisolone valerate, prednisolone acetate, prednisolone acetate, hydrocortisone acetate, hydrocortisone, ufenamate, bufexamac, ibuprofen piconol Examples include, but are not limited to, salicylate glycol. That is, further, for example, indomethacin, diclofenac, piroxicam, ε-aminocaproic acid, berberine, lysozyme, azulene, bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof are exemplified. Among them, glycyrrhizic acid, glycyrrhetinic acid or a pharmaceutically acceptable salt thereof, lysozyme, azulene, diclofenac, allantoin, tranexamic acid, and indomethacin are preferable.

  In the method for suppressing coloring, the coloring inhibitor, the external pharmaceutical composition, the histamine release inhibitor, or the antipruritic external pharmaceutical composition of the present invention, the anti-inflammatory agent in the external pharmaceutical composition or histamine release inhibitor is present. The amount is preferably 0.001% by weight or more, and more preferably 0.01% by weight or more. The content of the anti-inflammatory agent is preferably 5% by weight or less, and more preferably 3% by weight or less. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. The proportion of the anti-inflammatory agent relative 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. Even more preferably, it is 0.01 to 2 parts by weight. If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

  Examples of vitamin agents used in the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention include vitamins B, vitamins C, vitamins D, vitamin E. Any other vitamins can be used, but in particular, a substance having antioxidant properties is preferably used. Vitamins include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof E: Vitamin B2 such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5′-phosphate, riboflavin tetranicotinate; dl-α-tocopherol nicotinate Nicotinic acids such as nicotinic acid benzyl, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate; ascorbigen-A, ascorbic acid stearate, Vitamin Cs such as Scorbyl palmitate, L-ascorbyl dipalmitate; Vitamin Ds such as methyl hesperidin, ergocalciferol, cholecalciferol; Vitamin Ks such as phylloquinone, 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; folic acid such as folic acid, pteroylglutamic acid; nicotinic acid Nicotinic acids such as nicotinic acid amide; pantothenic acids such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthecin, D-panthetin, coenzyme A, pantothenyl ethyl ether; Biotins: ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, sodium ascorbate phosphate, magnesia ascorbate phosphate Vitamin C which is an ascorbic acid derivative such as um; carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, eriocitrin, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone And vitamin-like agents such as pharmacologically acceptable salts thereof. Of these, tocopherol acetate or D-pantenol is particularly preferred.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the content of the vitamin agent in the external pharmaceutical composition or histamine release inhibitor is 0. It is preferably 0001% by weight or more, and more preferably 0.001% by weight or more. Further, the content of the vitamin preparation is preferably 8% by weight or less, more preferably 5% by weight or less, and even more preferably 3% by weight or less. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. The proportion of the vitamin preparation relative to 1 part by weight of luliconazole and / or pharmaceutically acceptable salt thereof is preferably 0.0001-8 parts by weight, more preferably 0.005-5 parts by weight, Even more preferably, it is 0.001 to 3 parts by weight. If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

  Examples of the pH suppressing agent, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or pH adjuster used in the antipruritic external pharmaceutical composition of the present invention include, for example, urea, diisopropanolamine, triethanolamine, trometamol. However, the present invention is not limited to this. Of these, urea, diisopropanolamine, and triethanolamine are preferable.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the content of the pH adjuster in the external pharmaceutical composition or histamine release inhibitor is the composition 0.0001% by weight or more is preferable and 0.001% by weight or more is more preferable with respect to the total amount of the product. 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. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. The ratio of the pH adjuster to 1 part by weight of luliconazole and / or pharmaceutically acceptable salt thereof is preferably 0.0001 to 35 parts by weight, more preferably 0.001 to 30 parts by weight. . If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

  Examples of the antibacterial agent used in the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention include 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, isopropylmethylphenol, salicylic acid, gluconic acid, terbinafine hydrochloride, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorobutanol, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate Preference is given to propyl acid and butyl paraoxybenzoate.

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, the content of the bactericide in the external pharmaceutical composition or histamine release inhibitor is the composition Is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, and still more preferably 0.01% by weight. In addition, the content of the bactericide is preferably 8% by weight or less, more preferably 5% by weight or less, and still more preferably 3% by weight or less based on the total amount of the composition. If it is said range, the effect of this invention mentioned above is fully acquired with the normal usage-amount of a quasi-drug and a pharmaceutical. The proportion of the bactericide with respect to 1 part by weight of luliconazole and / or pharmaceutically acceptable salt thereof is preferably 0.0001-8 parts by weight, more preferably 0.001-5 parts by weight, Still more preferably, it is 0.01-3 weight part. If it is the said range, the effect of coloring suppression and / or histamine release suppression can be exhibited, and a formulation with a good feeling of use is obtained when preparing an aerosol agent, a cream agent, a gel agent, an ointment, and a liquid agent.

  In the present invention, examples of the “pharmaceutically acceptable salt” of luliconazole or other compounds include salts with alkali metal salts, alkaline earth metal salts, organic bases, and the like, such as sodium, potassium, calcium, Examples thereof include salts with magnesium, ammonium, diethanolamine, ethylenediamine and the like. These salts can be 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. Furthermore, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, Examples include 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, Malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salts with organic acids such as salicylic acid; or aspartic acid, glutamic acid And salts with acidic amino acids such as

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

  In the coloring suppression method, coloring inhibitor, external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition of the present invention, luliconazole and / or its pharmaceutically acceptable salt and / or antihistamine, local anesthetic agent In addition to one or more selected from the group consisting of a cooling agent, an anti-inflammatory agent, a vitamin agent, a pH adjuster, and a bactericidal agent, mainly luliconazole and / or a pharmaceutically acceptable salt thereof Arbitrary components can be included as long as the medicinal effect is not lost.

  The coloring inhibitor, the external pharmaceutical composition, the histamine release inhibitor, and the antipruritic external 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 an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin, a pH adjuster, and a bactericide. Coloring inhibitor containing one or more kinds, coloring suppression method, histamine release inhibitor, antipruritic external pharmaceutical composition, external pharmaceutical composition is used in the form of a skin external preparation as a pharmaceutical or quasi-drug Can be done. In these external preparation forms, in addition to the components (A) and (B), known bases that are added to external preparations for skin (quasi-drugs, pharmaceuticals) within a range that does not impair the effects of the present invention. Or a support | carrier can be mixed and used. In addition, such skin external preparations include, for example, transdermal absorption accelerators, surfactants, oils, alcohols, moisturizers, thickeners, preservatives, antioxidants, chelating agents, stabilizers, Dispersant, fragrance, colorant, pigment, pearl luster imparting agent, blood circulation promoting component, moisturizing component, UV absorbing component, UV scattering component, cleaning component, astringent component, amino acids, keratin softening component, cell activation component, dissolution aid An agent, water, etc. can be blended. An additive can be used individually by 1 type or in combination of 2 or more types.

  The drug that is the external pharmaceutical composition of the present invention is, for example, a liquid, suspension, emulsion, cream, ointment, gel, liniment, aerosol, powder as known forms of pharmaceuticals or quasi drugs. Examples thereof include a sheet agent obtained by impregnating a chemical liquid into a sheet such as an agent, a poultice, and a nonwoven fabric. Among them, it is preferably used in the form of a solution, suspension, emulsion, cream, ointment, gel. By setting it as this form, the external pharmaceutical composition of this invention can fully exhibit an antifungal action, a histamine release inhibitory action, etc.

<Base or carrier>
Bases or carriers include liquid paraffin, squalane, gelled hydrocarbons (such as plastibase), ozokerite, α-olefin oligomers, hydrocarbons such as light liquid paraffin; methyl polysiloxane, cross-linked methyl polysiloxane, 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 copolymer 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 silicones and silicone resins; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; isopropyl myristate , Esters such as octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate; polysaccharides such as dextrin and maltodextrin; lower levels such as ethanol and isopropanol Alcohol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether , 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 Examples include 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.

  A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

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

  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 sorbitan penta-2-ethylhexylate, 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 hardened Hardened castor oil derivatives such as castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan (polysorbate 20) monolaurate, monostearate Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan (polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), polyoxyethylene (20) sorbitan isostearate; Glyceryl alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; polyoxyethylene / methylpolysiloxane copolymer; Silicone surfactants such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG-9 polydimethylsiloxyethyl dimethicone; laurate, Amphoteric surfactants such as luminate, cocoyl glutamate, palm oil methylalanine salt, acylmethyltaurine salt, anionic surfactant such as polyoxyethylene lauryl sulfate, lauryl diaminoethylglycine salt, 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 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 paraoxybenzoate, isopropyl paraoxybenzoate, benzyl paraoxybenzoate, and phenoxyethanol.

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

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

Examples of solubilizers include methyl ethyl ketone and N-methyl-2-pyrrolidone.
An additive can be used individually by 1 type or in combination of 2 or more types.

<Other active ingredients>
The coloring inhibitor, coloring suppression method, histamine release inhibitor, antipruritic external pharmaceutical composition, and external pharmaceutical composition of the present invention 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 ingredient, a peptide or a derivative thereof, an amino acid or a derivative thereof, a cell activation ingredient, a blood circulation promoting ingredient, and the like.

  As moisturizing ingredients, 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 analog, chondroitin sulfate Macromolecular compounds such as sodium, collagen, elastin, keratin, chitin, chitosan; amino acids such as glycine, aspartic acid, arginine; natural moisturizing factors such as sodium lactate, sodium pyrrolidonecarboxylate; ceramide, cholesterol, phospholipids Examples of such lipids include plant extract extracts such as chamomile extract, hamamelis extract, tea extract and perilla extract.

  Peptides or derivatives thereof include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, elastin-degrading peptide , Conchiolin degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soy proteolytic peptide, hydrolyzed soy protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein degrading peptide Acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

  As amino acids or their derivatives, 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 activation component Cell activation component includes amino acids such as γ-aminobutyric acid and ε-aminoproic acid; retinol such as retinol palmitate; α-hydroxy acids such as glycolic acid and lactic acid; tannin, flavonoid, saponin, Photosensitive element 301 etc. are mentioned.

  As the blood circulation promoting component, a plant-derived component is preferably exemplified. For example, Panax ginseng, Ashitaba, Arnica, Ginkgo, Enmezo, Dutch oak, Chamomile, Roman chamomile, Carrot, Gentian, Burdock, Rice, Hawthorn, Shiitake, Hawthorn, Prunus, Senkyu, Assembly, Thyme, Clove, Chinpi, Toki, Tonin , Spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpi, spruce, spruce, peach, apricot, walnut, corn; glucosyl hesperidin Can be mentioned.

  “Coloring” as used in the present invention refers to coloring that can be detected by an instrument such as an absorptiometer regardless of the form of the external pharmaceutical composition containing luliconazole. Coloring that can be visually observed may be used, but coloring that is difficult to detect by visual observation is also referred to herein as coloring. For example, a cream-form drug containing luliconazole is white, and a liquid substance containing luliconazole is preferably colorless and transparent, but it changes to yellow over time due to light irradiation. In the present 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. Coloration inhibition refers to preventing, delaying, and reducing such coloration. In the present specification, coloring suppression refers to detecting a color derived from a change with time of luliconazole at 450 nm absorbance using a liquid containing the same concentration of luliconazole as a control, and improving the level at which the degree of coloring can be detected. Say.

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

  In the present invention, the external pharmaceutical composition, histamine release inhibitor, or antipruritic external pharmaceutical composition containing luliconazole further has a stimulus-suppressing action. 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 with a control in the case where the composition of the present invention is not used.

  In addition, you may use the chemical | medical agent containing luliconazole in the form of a kit. Specifically, an embodiment in which different constituents constituting the pharmaceutical composition are packaged in advance in separate containers or packs and mixed immediately before use. Containers include, for example, sealed ampoules, test tubes, vials, flasks, bottles, syringes, or the like.

  EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.

Example 1
(A) Into a liquid containing 1% luliconazole (1% luricon liquid, manufactured by Pola Pharma Co., Ltd.), various components (B) are added alone so that the final concentrations are as shown in Table 1, respectively, for 10 minutes. The composition was prepared by stirring. The prepared aqueous composition was subjected to a color evaluation test.

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

(Coloring inhibition evaluation test)
3 ml of each of the aqueous compositions of Examples and Comparative Examples was placed in a glass screw cap bottle (5 ml), and D65 was used using a light stability device (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Science Co., Ltd.) Using a lamp as a light source, 5,000 LUX light was irradiated for 192 hours at 25 ° C., and exposure was performed with 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 with a microplate reader. Based on the measured value, the coloration inhibition rate was determined according to the following formula. Coloration inhibition rate (%) = (1−measured value of composition of example / measured value of luliconazole) × 100

  As a result, as is clear from FIG. 1 and Table 1, the pharmaceutical composition for external use of the present invention has an inhibitory action on coloring caused by a change with time of luliconazole. FIG. 1 corresponds to Table 1, and the bar graph of FIG. 1 shows, from the left, each component being 0.1%, 0.5%, 1.0%, 2.0%, 3.0%, and 5 The value when 0.0% is shown.

(Example 2)
(A) A liquid containing 1% by weight of luliconazole and using anhydrous ethanol as a solvent (1% of a riccon liquid, manufactured by Polar Pharma Co., Ltd.) and various components (B) were combined. The final concentration of the component (A) was 0.0005 and 0.005% by weight. The final concentrations of the component (B) were adjusted to the concentrations shown in Tables 2 to 7, respectively. PIPES buffer (+) was used for the preparation of component (A) and component (B). The prepared composition was subjected to a histamine release inhibition evaluation test and a stimulation inhibition evaluation test.
(Reference Example and Comparative Example 2)
As the control composition, luliconazole 0.0005, 0.005% by weight or each component (B) was prepared to the values shown in the table and subjected to a histamine release inhibition evaluation test and a stimulation 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. under 5% CO ₂ for 24 hours, and then 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. under 5% CO ₂ for 1.5 hours. After 1.5 hours, after removing the supernatant, 200 μL of Example 2 and Comparative Example 2 containing 10 μM of calcium ionophore reagent were added to each well and 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 formula.
Histamine release rate = (Histamine amount in the composition addition group of each Example / Reference Example / Comparative Example / Histamine amount with PIPES buffer (+) addition) × 100

(Stimulus suppression evaluation test)
A stimulus inhibition 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. under 5% CO ₂ for 24 hours, and then the supernatant was removed. 100 μL of each of the compositions prepared in Example 2 and Comparative Example 2 was added and pretreated for 1.5 hours under conditions of 37 ° C. and 5% CO ₂ , and then the mitochondrial reducing ability was measured by the WST-8 method. Based on the measured value, the cell viability was determined according to the following formula using the mitochondria reducing ability as an index. The higher the cell survival rate, the higher the stimulus suppression effect. Cell survival rate (%) = (measured value of the composition addition group of each example, reference example, comparative example / measured value of addition of PIPES buffer (+)) × 100

  The results of the histamine release inhibition evaluation test are shown in Tables 2 to 8, and the results of the stimulation 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 has been found that the composition of the present invention has a histamine release inhibitory effect and may further exhibit a stimulus suppressive effect.

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

 (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 containing Example 1 was more prone to the cream preparation containing Comparative Example 1. It was confirmed that the formulation was not sticky.

 (Composition preparation example) Solution

(Composition preparation example) Gel agent

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, and the usability was evaluated. As a result, the gel preparation containing Example 1 was more prone to stretching than the gel preparation containing Comparative Example 1. It was confirmed that the formulation was not sticky.

 (Composition preparation example) Ointment

Claims (16)

  (A) Luliconazole and / or a pharmaceutically acceptable salt thereof, (B) selected from the group consisting of an antihistamine, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin, a pH adjuster, and a bactericide. An external pharmaceutical composition containing one or more kinds. 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. 1 type or 2 types or more;
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 refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid and pharmacologically acceptable salts thereof;
The vitamin preparation includes dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
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 The external pharmaceutical composition according to claim 1, which is one or more selected from the group consisting of:   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 either 1 or 2.   The proportion of the antihistamine agent in the whole external pharmaceutical composition is 0.05% by weight to 10% by weight, and the proportion of the local anesthetic agent in the whole composition is 0.005% by weight to 10% by weight, The proportion of the refreshing agent in the whole composition is 0.0001% by weight to 15% by weight, and the proportion of the anti-inflammatory agent in the whole composition is 0.001% by weight to 5% by weight, The proportion of the vitamin preparation in the entire composition is 0.0001 wt% to 8 wt%, and the ratio of the pH adjuster in the entire composition is 0.0001 wt% to 30 wt%, The external pharmaceutical composition according to claim 3, wherein the proportion of the disinfectant in the whole composition is 0.0001 wt% to 8 wt%. A color suppressant for an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof,
A coloring inhibitor containing one or more selected from the group consisting of an antihistamine, a local anesthetic, a refreshing agent, an anti-inflammatory agent, a vitamin, a pH adjuster and a bactericidal agent. 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. 1 type or 2 types or more;
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 refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof;
The vitamin preparation includes dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
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 The coloring inhibitor of Claim 5 which is 1 type, or 2 or more types selected from the group which consists of.   A method for suppressing coloration of an external pharmaceutical composition containing luliconazole and / or a pharmaceutically acceptable salt thereof, comprising an antihistamine, a pH adjuster, a local anesthetic, a cooling agent, an anti-inflammatory agent, a vitamin agent, and bactericidal The coloring suppression method which contains 1 type, or 2 or more types selected from the group which consists of an agent in this 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. 1 type or 2 types or more;
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 refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof;
The vitamin preparation includes dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
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 The coloring suppression method of Claim 7 which is 1 type, or 2 or more types selected from the group which consists of.   The ratio of the antihistamine agent, local anesthetic agent, refreshing agent, anti-inflammatory agent, vitamin agent, pH adjuster, and one or more selected from the group consisting of bactericides to the external pharmaceutical composition is 0. The coloring suppression method of Claim 7 or 8 which is 0001-41 weight%.   The proportion of the antihistamine agent in the entire external pharmaceutical composition is 0.05% by weight to 10% by weight, and the proportion of the local anesthetic agent in the entire external pharmaceutical composition is 0.005% by weight to 10% by weight. Yes, the proportion of the refreshing agent in the entire external pharmaceutical composition is 0.0001 wt% to 15 wt%, and the proportion of the anti-inflammatory agent in the entire external pharmaceutical composition is 0.001 wt% % 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 0.00%. Color suppression of any one of Claims 7-9 which is 0001 weight%-30 weight%, and the ratio which occupies for the said external pharmaceutical composition with respect to the said external pharmaceutical composition is 0.0001 weight%-8 weight%. Method.   (A) A histamine release inhibitor containing luliconazole and / or a pharmaceutically acceptable salt thereof.   Furthermore, (B) 1 type, or 2 or more types selected from the group which consists of an antihistamine, a local anesthetic, a refreshing agent, an anti-inflammatory agent, a vitamin agent, a pH adjuster, and a disinfectant are contained. Histamine release inhibitor. 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. 1 type or 2 types or more;
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 refreshing 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 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 selected from the group consisting of bromelain, serrapeptase, semi-alkaline proteinase, tranexamic acid, and pharmacologically acceptable salts thereof;
The vitamin preparation includes dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, etc., ubiquinone derivatives and pharmacologically acceptable salts thereof, riboflavin Flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, Β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L Ascorbyl, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, 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 phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, 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-panthecin, D-panthetin, coenzyme A, pantothen Pantothenic acids such as ethyl ether; biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, 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 one or more selected from the group consisting of urea, diisopropanolamine, triethanolamine, triisopropanolamine, trometamol,
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 The histamine release inhibitor according to claim 11 or 12, which is one or more selected from the group consisting of:   The pharmaceutical composition for external use for antitussives containing the histamine release inhibitor of any one of Claims 11-13.   The content of the component (A) is 0.01 to 20% by weight of the whole external pharmaceutical composition for antipruritics, and the content of the component (B) is 0. 0% of the whole external pharmaceutical composition for antipruritics. The external pharmaceutical composition for antipruritics according to claim 14, which is 0001 to 41% by weight.   The proportion of the antihistamine agent in the entire external pharmaceutical composition for antipruritics is 0.05 wt% to 10 wt%, and the proportion of the local anesthetic agent in the entire external pharmaceutical composition for antipruritics is 0.005 wt% to 10% by weight, and the ratio of the refreshing agent to the whole external pharmaceutical composition for antipruritics is 0.0001% by weight to 15% by weight. The proportion of the pH adjuster is 0.001 wt% to 5 wt%, and the proportion of the vitamin preparation in the entire external antipruritic pharmaceutical composition is 0.0001 wt% to 8 wt%, The proportion of the whole composition is 0.0001 wt% to 30 wt%, and the proportion of the fungicide to the whole external antipruritic pharmaceutical composition is 0.0001 wt% to 8 wt%. 15 for antipruritic use Pharmaceutical compositions.

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