JP2005104924A - External pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an external pharmaceutical composition which can effectively and safely be used for treatment of dermatomycosis by enhancing antiseptic effect of an antifungal agent, and to provide a method for enhancing antiseptic effect of the antifungal agent. <P>SOLUTION: This external pharmaceutical composition is prepared by formulating an antifungal agent with at least one kind of substance selected from the group consisting of vitamin As and vitamin Es. The method for improving sterilizing power of the antifungal agent comprises formulating the antifungal agent with at least one substance selected from the group consisting of vitamin As and vitamin Es. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an external pharmaceutical composition containing an antifungal agent as an active ingredient. The present invention further relates to a method for enhancing the bactericidal power of an antifungal agent.

  Conventionally, antibacterial agents, particularly antifungal agents, have been used for the treatment of skin fungal infectious diseases such as skin ringworm and skin candidiasis such as athlete's foot and beetle. For example, Patent Document 1 proposes the use of antifungal agents such as imidazole derivatives or triazole derivatives, and Patent Document 2 proposes the use of antifungal agents such as bifonazole and clotrimazole. However, the antifungal agent alone is not sufficient for its therapeutic effect. On the other hand, increasing the amount of the antifungal agent used to enhance the therapeutic effect may adversely affect the skin, such as skin irritation. There is. In addition, various proposals have been made to use a plurality of drugs in combination to assist the action of the antifungal agent (see, for example, Patent Document 3). As a result, the skin may be adversely affected. is there. In particular, when an external preparation is applied to an affected skin area damaged by fungal infection, higher safety is required than when it is used for healthy skin (for example, see Patent Document 4).

For this reason, conventionally, in order to provide safer external preparations for the treatment of skin fungal infectious diseases, a method for enhancing the bactericidal effect of antifungal agents has been demanded.
Japanese Patent Laid-Open No. 57-120516 JP-A-61-282316 JP 2002-284702 A JP-A-9-309827

  The present invention solves the above-mentioned problems, and its object is to provide an external pharmaceutical composition that can be used effectively and safely in the treatment of skin fungal infectious diseases by enhancing the bactericidal effect of antifungal agents. That is. A further object of the present invention is to provide a method for enhancing the bactericidal effect of antifungal agents.

  The present inventors have been diligently studied to solve the above-mentioned problems. By using one or both of vitamin A and vitamin E as an antifungal agent, the antifungal agent has a bactericidal effect. The present invention has been completed by finding enhancement.

The present invention has been developed based on such findings, and has the following aspects:
Item 1. An external pharmaceutical composition comprising an antifungal agent and at least one selected from the group consisting of vitamins A and E.

The invention described in item 1 includes the following aspects of the invention:
Item 1-1. An external pharmaceutical composition comprising an antifungal agent and vitamin A.
Item 1-1-1. Item 1. The external pharmaceutical composition according to Item 1-1, wherein the proportion of the antifungal agent in the external pharmaceutical composition is 0.01 to 20% by weight.
Item 1-1-2. The proportion of vitamin A in the external pharmaceutical composition is vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The topical pharmaceutical composition according to item 1-1 or item 1-1-1, which is 0.01 to 20% by weight in terms of an acceptable blending ratio of the derivatives (the total when two or more are included).
Item 1-1-3. The external pharmaceutical composition according to any one of Items 1-1 to 1-1-2, which contains vitamin A in a proportion of 1,000 to 1,000,000 vitamin A units when the external pharmaceutical composition is adjusted to 100 g .
Item 1-1-4. The external pharmaceutical composition according to any one of Items 1-1 to 1-1-3, which does not contain pyruvic acid or a salt thereof, a fatty acid amide, and a nitroimidazole derivative.
Item 1-1-5. The external pharmaceutical composition according to any one of Items 1-1 to 1-1-4, further comprising vitamin E.
Item 1-1-6. The external pharmaceutical composition according to Item 1-1-5, wherein the proportion of vitamin E in the external pharmaceutical composition is 0.1 to less than 20% by weight.
Item 1-2. An external pharmaceutical composition comprising an antifungal agent and vitamin E.
Item 1-2-1. Item 1. The external pharmaceutical composition according to Item 1-2, wherein the proportion of vitamin E in the external pharmaceutical composition is 0.1 to less than 20% by weight.
Item 1-2-2. Item 1-2 or Item 1-2-1 is a pharmaceutical composition for external use, wherein the vitamin E is oil-soluble.
Item 1-2-3. The external pharmaceutical composition according to any one of Items 1-2 to 1-2-2, wherein the vitamin E is other than a vitamin E tocopheryl derivative.
Item 1-2-4. The external pharmaceutical composition according to any one of Items 1-2 to 1-2-3, which does not contain squalane, pyruvic acid or a salt thereof, and a nitroimidazole derivative.
Item 1-2-5. The external pharmaceutical composition according to any one of Items 1-2 to 1-2-4, further comprising vitamin A.
Item 1-2-6. The proportion of vitamin A in the external pharmaceutical composition is vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The external pharmaceutical composition according to Item 1-2-5, which is 0.01 to 20% by weight in terms of a blending ratio of acceptable derivatives (the total when two or more are included).
Item 1-2-7. Item 1-2-5 or Item 1-2-6, which contains vitamin A at a ratio of 1000 to 1,000,000 vitamin A units when the externally used pharmaceutical composition is adjusted to 100 g.

Item 2. Item 2. The external pharmaceutical composition according to Item 1, wherein the antifungal agent is at least one selected from the group consisting of morpholine compounds, benzylamine compounds, imidazole compounds, and allylamine compounds.
Item 3. Item 2. The external pharmaceutical composition according to Item 1, wherein the antifungal agent is at least one selected from the group consisting of amorolfine hydrochloride, butenafine hydrochloride, neticonazole hydrochloride, and terbinafine hydrochloride.
Item 4. Item 4. The therapeutic agent for skin fungal infection selected from the group consisting of ringworm, cutaneous candidiasis, vaginal candidiasis, vaginal trichomoniasis, folding screen, psoriasis and seborrheic dermatitis A pharmaceutical composition for external use.

Item 5. A method for enhancing the bactericidal activity of an antifungal agent, comprising mixing at least one selected from the group consisting of vitamins A and E with an antifungal agent.
The invention described in item 5 includes the following aspects of the invention:
Item 5-1. Vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, their pharmaceutically acceptable salts, or their pharmaceuticals per 100 parts by weight of antifungal agent Item 6. The method for enhancing bactericidal activity according to Item 5, wherein the compound is blended at a ratio of 0.05 to 200,000 parts by weight, as a blending ratio of the derivatives permitted in the above (as a sum of two or more kinds).
Item 5-2. Item 5. The method for improving bactericidal activity according to Item 5-1, wherein vitamin A is added to 1 g of the antifungal agent at a ratio of 50 to 100 million vitamin A units.
Item 5-3. Item 5. The method for enhancing bactericidal activity according to Item 5-1, wherein vitamin E is blended at a ratio of 0.5 to less than 200000 parts by weight with respect to 100 parts by weight of the antifungal agent.
Item 5-4. Item 5. The bactericidal activity according to any one of Items 5 to 5-3, wherein the antifungal agent is at least one selected from the group consisting of a morpholine compound, a benzylamine compound, an imidazole compound, and an allylamine compound. Enhancement method.
Item 5-5. Item 5. The method for enhancing bactericidal activity according to any one of Items 5 to 5-4, wherein the antifungal agent is at least one selected from the group consisting of amorolfine hydrochloride, butenafine hydrochloride, neticonazole hydrochloride, and terbinafine hydrochloride.
Item 5-6. Item 5 to 5-5, which is a method for improving the healing effect of a dermatomycotic infection selected from the group consisting of ringworm, cutaneous candidiasis, vaginal candidiasis, vaginal trichomoniasis, folding screen, psoriasis and seborrheic dermatitis. 6. The method for enhancing bactericidal activity according to any one of 5.

The present invention is described in detail below.
I. External pharmaceutical composition The external pharmaceutical composition of the present invention is characterized by containing either vitamin A or vitamin E or both in addition to the antifungal agent.

  Here, the antifungal agent is a substance that has the property of inhibiting fungal growth or killing the pathogen, such as clotrimazole, econazole, miconazole, sulconazole, terconazole, oxyconazole, bifonazole, isoconazole, itraconazole. , Fenticonazole, Dinoconazole, Thioconazole, Croconazole, Ketoconazole, Ranoconazole, Nystatin, Amphotericin B and other imidazole compounds: Amorolfine and other morpholine compounds; Terbinafine and other benzylamine compounds such as butenafine Pyrimidine compounds such as pirox olamine: other, undecylenic acid, zinc undecylenate, moctal, siccanin, tricomycin, pyrrolidone Mention may be made of trinine, exeramide, tolcyclate, tolnaphthalate, haloprozine, and pharmaceutically acceptable acid addition salts thereof. These can also be used 1 type or in mixture of 2 or more types.

  Examples of acid addition salts include inorganic acid salts such as hydrochlorides, nitrates, and acetates of the above compounds, and organic acid salts such as lactic acid, tartaric acid, and maleic acid. Specific acid addition salts include, for example, hydrochloric acid addition salts such as croconazole hydrochloride, neticonazole hydrochloride, amorolfine hydrochloride, terbinafine hydrochloride, and butenafine hydrochloride; isoconazole nitrate, iconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, and Nitric acid addition salts such as miconazole nitrate can be exemplified.

  A compound belonging to any one of an imidazole compound, a morpholine compound, an allylamine compound, and a benzylamine compound is preferable. More specifically, examples include neticonazole hydrochloride (imidazole compound), amorolfine hydrochloride (morpholine compound), terbinafine hydrochloride (allylamine compound), and butenafine hydrochloride (benzylamine compound).

  The content of these antifungal agents in the pharmaceutical composition of the present invention is not particularly limited as long as it has an effect of inhibiting fungal growth or killing the pathogenic bacteria, but is usually 0.01 to 20% by weight, preferably 0. The range is 1 to 10% by weight, more preferably 0.1 to 5% by weight.

  The external pharmaceutical composition of the present invention is roughly divided into an external pharmaceutical composition containing vitamin A in addition to the antifungal agent, and an external pharmaceutical composition containing vitamin E in addition to the antifungal agent. It can be classified into two. Hereinafter, these external pharmaceutical compositions will be described.

(I-1) Pharmaceutical composition for external use containing antifungal agent and vitamin A In the present invention, vitamin A refers to vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, and It means these pharmaceutically acceptable salts, as well as their pharmaceutically acceptable derivatives. The vitamin A may be a single product (for example, a pure product) or may be in the form of a composition (for example, a mixture or a crude product) containing the above components. Here, the derivative may be any derivative that belongs to vitamin A and is pharmaceutically acceptable. Specifically, the pharmaceutically acceptable C1 to C30 ester of retinol, preferably C2 to retinol. C20 ester is included. Examples of vitamin A listed in the Japanese Pharmacopoeia include liver oil, strong liver oil, vitamin A oil, retinol acetate, and retinol palmitate.

  The content of these vitamins A in the external pharmaceutical composition of the present invention is not particularly limited as long as it has an effect of enhancing the bactericidal effect of the antifungal agent. Usually, when the final pharmaceutical composition for external use is adjusted to 100 g, vitamin A is 1,000 to 1,000,000 vitamin A units, preferably 10,000 to 500,000 vitamin A units, more preferably 50,000 to 500,000 vitamins. It is preferably contained in a proportion of A units. As long as it is not limited, vitamin A, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, and the like are contained in 100% by weight of the external pharmaceutical composition. The blending ratio of pharmaceutically acceptable salts or pharmaceutically acceptable derivatives thereof (as a sum of two or more kinds) includes 0.01 to 20% by weight. Preferably it is 0.02 to 10 weight%, More preferably, it is the range of 0.05 to 2 weight%.

  The external pharmaceutical composition of the present invention can also contain other desired medicinal ingredients as long as the effects of the present invention are not impaired. Examples of these medicinal components include bactericidal / disinfectants such as chlorhexine hydrochloride, benzalkonium chloride, phenol and liquid phenol; antihistamines such as diphenhydramine, diphenhydramine hydrochloride and chlorpheniramine maleate; antipruritic agents such as crotamiton; Keratin softeners such as salicylic acid; local anesthetics such as lidocaine, lidocaine hydrochloride and dibucaine hydrochloride; anti-inflammatory agents such as glycyrrhetinic acid and β-glycyrrhetinic acid; local stimulants such as l-menthol; zinc oxide and the like Astringent protectants; humectants such as glycerin, lanolin, propylene glycol, 1,3-butylene glycol, and sodium hyaluronate; other corticosteroids, sulfa drugs, antiallergic drugs, antibiotics, antiviral drugs, tissues Recovery accelerator, immunosuppressive agents, fresheners, can be exemplified vitamin D3 compounds, and hemostatic agent.

  As will be described later, the pharmaceutical composition for external use of the present invention can also be blended with various pharmaceutically acceptable carriers and additives for formulation and stabilization. However, it is desirable not to include compounds belonging to pyruvic acid or salts thereof, fatty acid amides, and nitroimidazole derivatives.

  The external pharmaceutical composition of the present invention contains the above vitamin A as a vitamin and does not need to contain other vitamins (for example, vitamin E). However, the blending is not limited. For example, when vitamin E is used in combination, vitamin E can be blended in the range of less than 0.1 to 20% by weight. Preferably it is 0.1 to 15 weight%, More preferably, it is the range of 0.1 to 10 weight%. In addition, as vitamin E, what is mentioned later can be mentioned.

(I-2) Pharmaceutical composition for external use containing antifungal agent and vitamin E In the present invention, vitamin E means tocopherol, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof. . Here, the derivative may be any one that belongs to vitamin E and is pharmaceutically acceptable, and specifically, a pharmaceutically acceptable C1 to C30 ester of tocopherol, preferably C2 to C of tocopherol. C20 ester is included. Examples of substances listed in the Japanese Pharmacopoeia include d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, tocopherol succinate, tocopherol calcium succinate, tocopherol acetate , And tocopherol. Examples that are not listed in the Japanese Pharmacopoeia include d-α-tocopherol acetate, dl-α-tocopherol acetate, d-δ-tocopherol, dl-α-tocopherol, DL-α-tocopherol nicotinate, tocopherol nicotinate, linol Examples include acid DL-α-tocopherol, d-α-tocopherol, and natural vitamin E. The vitamin E targeted by the present invention is preferably oil-soluble. It is not always necessary to be a water-soluble derivative of vitamin E having improved solubility in water, such as vitamin E tocopheryl derivatives (for example, D-α-tocopheryl polyethylene glycol-1000-succinate).

  The content of these vitamin Es in the external pharmaceutical composition of the present invention is not particularly limited as long as it has an effect of enhancing the bactericidal effect of the antifungal agent. Usually, it can be appropriately selected from the range of less than 0.1 to 20% by weight. Preferably it is 0.1 to 15 weight%, More preferably, it is the range of 0.1 to 10 weight%.

  The pharmaceutical composition for external use of the present invention contains the above vitamin E as a vitamin and does not need to contain other vitamins. However, the composition is not limited, and for example, vitamin A can be used in combination. In this case, when the final pharmaceutical composition for external use is 100 g, vitamin A contains 1,000 to 1,000,000 vitamin A units, preferably 10,000 to 500,000 vitamin A units, more preferably 50,000 to 500,000 vitamins. It can adjust so that it may be contained in the ratio of A unit. As long as it is not limited, vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, and the like are contained in 100% by weight of the external pharmaceutical composition. As a blending ratio of these pharmaceutically acceptable salts or pharmaceutically acceptable derivatives thereof (as a sum of two or more kinds), a range of 0.01 to 20% by weight can be mentioned. Preferably it is 0.02 to 10 weight%, More preferably, it is the range of 0.05 to 2 weight%.

  Examples of vitamin A include those mentioned above. Examples of preparations containing both vitamins E and A include tocopherol and vitamin A oil (20 mg of tocopherol in 1 g, 5 mg of vitamin A oil [5,000 vitamin A units]) (Juvera Juvela ointment: Sannova Eisai Co., Ltd.) it can.

  In the external pharmaceutical composition of the present invention comprising the antifungal agent, vitamin Es and vitamin As, the particularly preferred combination of the content of each component is 0.01-20% by weight of the antifungal agent, vitamin Es 0.1 to less than 20% by weight, and vitamin A types 0.01 to 20% by weight (1,000 to 100 million vitamin A units / 100 g pharmaceutical composition); preferably 0.1 to 10% by weight of antifungal agent, vitamin E 0.1 to 15% by weight of vitamins and 0.02 to 10% by weight of vitamins A (10,000 to 500,000 vitamin A units / 100 g pharmaceutical composition); more preferably 0.1 to 5% by weight of antifungal agent, Vitamin E 0.1 to 10% by weight and Vitamin A 0.05 to 2% by weight (50,000 to 500,000 vitamin A units / 100 g pharmaceutical composition).

  The external pharmaceutical composition of the present invention can also contain other desired medicinal ingredients as long as the effects of the present invention are not impaired. Examples of these medicinal components include bactericidal / disinfectants such as chlorhexine hydrochloride, benzalkonium chloride, phenol and liquid phenol; antihistamines such as diphenhydramine, diphenhydramine hydrochloride and chlorpheniramine maleate; antipruritic agents such as crotamiton; Keratin softeners such as salicylic acid; local anesthetics such as lidocaine, lidocaine hydrochloride and dibucaine hydrochloride; anti-inflammatory agents such as glycyrrhetinic acid and β-glycyrrhetinic acid; local stimulants such as l-menthol; zinc oxide and the like Astringent protectants; humectants such as glycerin, lanolin, propylene glycol, 1,3-butylene glycol, and sodium hyaluronate; other corticosteroids, sulfa drugs, antiallergic drugs, antibiotics, antiviral drugs, tissues Recovery accelerator, immunosuppressive agents, fresheners, can be exemplified vitamin D3 compounds, and hemostatic agent.

  As will be described later, the pharmaceutical composition for external use of the present invention can also be blended with various pharmaceutically acceptable carriers and additives for formulation and stabilization. However, it is desirable not to contain compounds belonging to squalane, pyruvic acid or salts thereof, and nitroimidazole derivatives.

  In any of the above-mentioned external pharmaceutical compositions (I-1) and (I-2), the dosage form is not particularly limited. For example, the above components (antifungal agent, vitamin A) are contained in the base material. And / or vitamin E) dissolved or mixed and dispersed into a powder, cream, paste, jelly, gel, emulsion, liquid, etc. (eg, powder, ointment, Suppositories (including vaginal tablets), liniments, creams, lotions, sprays, etc.) Base materials and adhesives in which the above components are dissolved or mixed and dispersed on a support (For example, haps, plasters, tapes, etc.) can be mentioned.

  As the above base, under the above-mentioned conditions, each component used in the present invention can be uniformly melted, blended and dispersed in the base and is pharmaceutically acceptable. Well-known ones can be used as bases for powders, ointments, suppositories (including vaginal tablets), liniments, creams, lotions, sprays and the like. For example, sodium alginate, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone, etc. Polymers; beeswax, olive oil, cacao oil, sesame oil, soybean oil, jojoba oil, avocado oil, coconut oil, peanut oil, beef tallow, lard, lanolin, etc., oils such as polyoxyethylene hydrogenated castor oil; white petrolatum; liquid paraffin, Mineral oils such as silicone oil, volatile silicone oil, petrolatum; hydrocarbon gel ointment (for example, plastibase (trade name; manufactured by Taisho Pharmaceutical Co., Ltd.)); lauric acid, Higher fatty acids such as stinic acid, stearic acid, oleic acid; esters such as cetyl lactate, isopropyl myristate, octyldodecyl myristate; higher alcohols such as cetyl alcohol, octyldodecanol, lauryl alcohol, stearyl alcohol; polyethylene glycol; mono Nonionic surfactants such as glyceryl stearate, glyceryl monooleate, propylene glycol monostearate, polyoxyethylene cetyl alcohol ether; anionic interfaces such as sodium cetyl sulfate, sodium stearate, sodium N-acyl glutamate Activators; lower alcohols such as ethanol and isopropanol; triethanolamine; water and the like.

  The said support body is suitably selected according to the dosage form (For example, a poultice agent, a plaster agent, a tape agent etc.). For example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-1 Examples thereof include carbon oxide copolymers, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate resin films, aluminum sheets, woven fabrics, nonwoven fabrics, and the like, and laminated sheets thereof.

  The pressure-sensitive adhesive may be any pharmaceutically acceptable one, and a conventionally known one can be used. For example, acrylic adhesives, rubber adhesives, silicon adhesives, urethane adhesives and the like can be mentioned.

  Further, if necessary, antioxidants such as ascorbic acid, tocopherol, citric acid, dibutylhydroxytoluene; preservatives such as dehydroacetic acid, salicylic acid, methyl paraoxybenzoate, propyl paraoxybenzoate, and thymol; polyethylene glycol, xanthan gum, Thickeners such as sodium carboxymethylcellulose and carboxypropylcellulose; acids such as citric acid, lactic acid, hydrochloric acid, and boric acid, or sodium dihydrogen phosphate, sodium citrate, sodium hydroxide, potassium hydroxide, and triethanol Buffers (pH adjusters) such as alkalis such as amines; inorganic fillers such as kaolin, bentonite, zinc oxide, and titanium oxide can also be blended.

  The external pharmaceutical composition of the present invention can be prepared according to a production method conventionally used for general-purpose external preparations according to the form. The pharmaceutical composition for external use of the present invention can be used by being applied, sprayed or inserted into the affected skin area.

  The amount to be used varies depending on the degree and size of the symptom of the affected area, the type of disease, etc., but usually 0.01 to 10 g per day is used once or a plurality of times.

  External diseases targeted by the external pharmaceutical composition of the present invention are infections caused by fungi (dermatomycosis, subcutaneous mycosis, and mucosal mycosis), and secondary diseases caused thereby, specifically, Ringworm caused by ringworms (scabycomycosis); Cutaneous candidiasis and vaginal candidiasis caused by Candida: vaginal trichomoniasis caused by infection with Trichomonads; folding screen caused by Bacterial fungi; other psoriasis and seborrheic dermatitis Etc. can be illustrated. Ringworm (ringworm mycosis) is a skin disease caused by ringworm fungus, vesicular ringworm, small bullous spotted ringworm, superficial head ringworm (shirakumo), scabies, foot ringworm, hand ringworm Insect ringworm, tinea corporalis, tinea rotunda, and tinea biloba.

  The pharmaceutical composition for external use ((I-1), (I-2)) of the present invention uses the antifungal agent alone by using vitamin A or / and vitamin E in combination with the antifungal agent. It is superior in sterilization effect. For this reason, depending on the purpose, it is possible to reduce the amount of the antibacterial activity as it is, and it is a preferred skin external preparation from the viewpoint of efficacy and side effects.

II. Method for Enhancing Bactericidal Activity of Antifungal Agent The method of the present invention can be carried out by using an antifungal agent in combination with at least one selected from the group consisting of vitamins A and E.

  Here, examples of the antifungal agent to be used include those described in (I) above. Preferably, it belongs to morpholine compounds, benzylamine compounds, imidazole compounds, and allylamine compounds. Specific examples include amorolfine hydrochloride, butenafine hydrochloride, neticonazole hydrochloride, and terbinafine hydrochloride.

  Examples of the vitamin A used in combination with the antifungal agent include those described in (I) above. Preferred are liver oil, strong liver oil, vitamin A oil, retinol acetate and retinol palmitate, more preferably liver oil, vitamin A oil and retinol palmitate.

  The proportion of vitamin A used in combination with the antifungal agent is such that the fungicidal power of the antifungal agent, especially the fungicidal power against fungi such as ringworm, Candida, Trichomonas protozoa, or fungus, etc. If there is no particular limitation, it can be appropriately selected and adjusted according to the type of antifungal agent to be used. For example, vitamin A can be used in the range of 50 to 100 million vitamin A units per 1 g of the antifungal agent. It is preferably used in the range of 1,000 to 5,000,000 vitamin A units, more preferably 10,000 to 5,000,000 vitamin A units. In addition, although it does not restrict | limit in particular in this limit, the ratio of vitamin A with respect to 100 weight part of antifungal agents is vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3, 4-didehydroretinol, these pharmacologically As a blending ratio of an acceptable salt or a pharmaceutically acceptable derivative thereof (as a sum of two or more kinds), a range of 0.05 to 200,000 parts by weight can be given. Preferably it is 0.2-10000 weight part, More preferably, it is the range of 1-2000 weight part.

  Moreover, what is described in said (I) can be mentioned as vitamin E used in combination with an antifungal agent. Preferably d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, tocopherol calcium succinate, tocopherol acetate, and tocopherol, more preferably tocopherol acetate, d- α-tocopherol and tocopherol can be exemplified.

  The proportion of vitamin E used in combination with antifungal agents is such that the fungicidal power of antifungal agents, especially the fungicidal power against fungi such as ringworm, Candida, Trichomonas, or genus B. If there is no particular limitation, it can be appropriately selected and adjusted according to the type of antifungal agent to be used. For example, vitamin E can be blended at a ratio of less than 0.5 to 200,000 parts by weight, preferably 1 to 20000 parts by weight, more preferably 2 to 10,000 parts by weight with respect to 100 parts by weight of the antifungal agent.

  As described above, vitamin A or vitamin E is used alone or in combination with an antifungal agent, so that the antifungal agent can exert a bactericidal activity, particularly ringworm, Candida, Trichomonas protozoa, or folding fungus, etc. Can enhance and improve the bactericidal activity against fungi, but it is also possible to combine vitamin A and vitamin E. In this case, the combination of vitamin A and vitamin E includes, for example, a combination of vitamin A oil and tocopherol acetate, a combination of vitamin A oil and d-α-tocopherol acetate, retinol palmitate and tocopherol acetate. Combinations can be mentioned. Moreover, as a compounding ratio of vitamin A in this case, vitamin A is 50 to 10 million vitamin A units, preferably 1000 to 5 million vitamin A units, more preferably 1 to 5 million per 1 g of the antifungal agent. The ratio which becomes a vitamin A unit can be mentioned. Although it does not restrict | limit in particular in this limit, The ratio of vitamin A with respect to 100 weight part of antifungal agents is vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3, 4-didehydroretinol, these pharmacologically acceptable. As a compounding ratio of these salts or pharmaceutically acceptable derivatives thereof (when two or more kinds are included, the total amount thereof) is in the range of 0.05 to 200,000 parts by weight. Preferably it is 0.2-10000 weight part, More preferably, it is the range of 1-2000 weight part. Moreover, as a ratio of vitamin E with respect to 100 weight part of antifungal agents, the range of less than 0.5-200000 weight part, Preferably it is 1-20000 weight part, More preferably, 2-10000 weight part can be mentioned.

  According to the method of the present invention, by using vitamin A or / and vitamin E in combination with an antifungal agent, the bactericidal effect of the antifungal agent alone, in particular, ringworm, Candida, Trichomonas protozoa, or folding screen The bactericidal power against fungi can be enhanced. Therefore, the present invention can be effectively used to enhance the bactericidal effect of an antifungal agent or the bactericidal effect of a composition containing an antifungal agent. By enhancing the bactericidal power of antifungal agents, the curative effect of antifungal agents and compositions containing them (externally used pharmaceutical compositions) against skin fungal infections such as ringworm and candidiasis such as athlete's foot and worms is improved. be able to. Further, by enhancing the bactericidal power of the antifungal agent, it is possible to reduce the amount of the antifungal agent added to the external pharmaceutical composition while maintaining an effective bactericidal effect, and as a result, it is economical. Possible side effects can be prevented.

  In the external pharmaceutical composition according to the first invention, the antifungal agent contains at least one of vitamin A and vitamin E, so that fungi, particularly trichomycetes, Candida, Trichomonas protozoa, or folding fungus The fungicidal effect on fungi such as the above is higher than the case of using an antifungal agent alone, and by using at least one of vitamin A or vitamin E in combination with the antifungal agent, It is possible to reduce the amount, and as a result, possible side effects can be prevented. Therefore, the pharmaceutical composition for external use of the present invention is a safer and more effective therapeutic agent for ringworm (for example, a therapeutic agent for athlete's foot and insect), a therapeutic agent for folding screen, a therapeutic agent for candidiasis or a therapeutic agent for trichomonas, and a fungal infection. It can be effectively used as an external preparation such as a therapeutic agent for secondary skin diseases.

  Further, according to the second invention, by using at least one of vitamin A and vitamin E in combination with the antifungal agent, the fungicidal effect of the antifungal agent against the fungus, in particular, ringworm, Candida, Trichomonas protozoa or folding screen Bactericidal efficacy against fungi such as bacteria can be enhanced.

  EXAMPLES Hereinafter, although an Example etc. are given and this invention is demonstrated, this invention is not limited to these Examples.

Examples 1 to 3 and Comparative Example 1
Each component shown in Table 1 was mixed and stirred until all components were dissolved in the base material to prepare a lotion preparation.

Test Example 1 Guinea pig treatment effect on experimental ringworm (bactericidal evaluation)
Using the lotion preparations obtained above (Examples 1 to 3, Comparative Example 1) as test agents, the therapeutic effect on ringworm of the pharmaceutical composition for external use of the present invention was examined based on the reverse culture test method.

First, ringworm was experimentally developed in Hartley male guinea pigs (8 weeks old, 6 animals: body weight 400-600 g), and the therapeutic effect was examined. First, after removing the hair from the back of the guinea pig (side of the body 2 cm away from the spine, 2 cm x 2 cm, 5 locations / animal), strip the area twice with a 2 cm square cloth adhesive tape, The upper stratum corneum was removed. The next day (on the day of bacterial inoculation), the hair removal site was stripped once again with a 2 cm square cloth adhesive tape to remove the upper skin stratum corneum, and the skin surface was disinfected with sake cotton just before the bacterial inoculation. To this portion, 0.1 ml of a spore suspension of inoculum (Tricophyton mentagrophytes TIMM 1189) prepared to 2 × 10 ⁷ conidia / ml was applied.

  For each guinea pig, 0.3 ml of the lotions of Examples 1 to 3 and Comparative Example 1 were applied to 4 of the 5 skin surfaces inoculated with the fungus, and the remaining 1 site was used as an untreated control site (bacterial fluid inoculation only). The lotion was applied once a day for 10 days continuously from 5 days after the bacterial inoculation.

<Reverse culture test>
(1) Euthanize 15 days after inoculation under ether anesthesia.
(2) Cut the skin of each test site.
(3) Place the extracted skin in a 50 mL centrifuge tube containing 20 mL of 0.1% Zetconk solution and stir using a vortex mixer for about 30 seconds to disinfect.
(4) Place the disinfected skin in a 50 mL centrifuge tube containing 20 mL of physiological saline, and stir for about 30 seconds to wash the disinfectant.
(5) Divide the skin into 6 pieces of appropriate size.
(6) Place each piece on the Sabouraud agar plate supplemented with antibiotics with the skin epidermis side down and incubate at 27 ° C for 14 days in a constant temperature culture apparatus. The culture result is judged on the 15th day after the start of the culture.
(7) If at least one colony of T. mentagrophytes has grown around the skin piece, it is determined that the bacteria are positive. The bacterial negative rate (%) for each small piece is determined by the following formula for each test substance group.

    Bacteria negative rate by small piece (%) = [Bacteria negative pieces / total pieces] x 100

  Similar results were obtained when amorolfine hydrochloride, butenafine hydrochloride, or neticonazole hydrochloride was used in place of terbinafine hydrochloride.

Formulation Example 1
A spray was prepared by a conventional method according to the following formulation.
Amorolfine hydrochloride 0.2 (g)
Vitamin A oil (1 million vitamin A units / g) 1.0
Lidocaine 0.5
Isopropylmethylphenol 0.06
l-Menthol 0.2
dl-Camphor 0.1
Polyoxyethylene polyoxypropylene cetyl ether 1.0
Polyoxyethylene hydrogenated castor oil 4.0
Talc 3.0
Alcohol 29.94
Liquefied petroleum gas 60.0
Total 100.0 g.

Formulation example 2
A cream was prepared by a conventional method according to the following formulation.
Butenafine hydrochloride 1.0 (g)
Tocopherol acetate 2.0
Lidocaine 2.0
Diphenhydramine 1.0
Isopropylmethylphenol 0.1
l-Menthol 0.2
dl-Camphor 0.1
Polyoxyethylene polyoxypropylene cetyl ether 1.0
Polyoxyethylene hydrogenated castor oil 4.0
Talc 3.0
Alcohol 25.6
Liquefied petroleum gas 60.0
Total 100.0g.

Formulation Example 3
A liquid preparation was prepared by a conventional method according to the following formulation.
Neticonazole hydrochloride 1.0 (g)
Retinol palmitate (1 million vitamin A units / g) 0.5
D-α-Tocopherol acetate 1.0
Benzethonium chloride 0.1
l-Menthol 1.0
dl-Camphor 0.1
Alcohol 96.3
Total 100.0g.

  ADVANTAGE OF THE INVENTION According to this invention, the external pharmaceutical composition which is excellent in bactericidal power and whose skin irritation is relieved can be provided. In particular, the pharmaceutical composition for external use of the present invention can be effectively used for skin diseases caused by infection with ringworm, for example ringworm such as athlete's foot and beetle, and candidiasis. Furthermore, according to the present invention, it is possible to enhance the antibacterial activity of antifungal agents, particularly against ringworm. In addition, according to the present invention, the amount of use can be reduced by enhancing the antibacterial activity of the antifungal agent, which can alleviate and reduce adverse side effects (for example, skin irritation) that can be caused by the antifungal agent. It becomes possible.

Claims (8)

An external pharmaceutical composition comprising an antifungal agent and at least one selected from the group consisting of vitamins A and E. The external pharmaceutical composition according to claim 1, wherein the proportion of the antifungal agent in the external pharmaceutical composition is 0.01 to 20% by weight. The external pharmaceutical composition according to claim 1 or 2, wherein the proportion of vitamin E in the external pharmaceutical composition is less than 0.1 to 20% by weight. The proportion of vitamin A in 100% by weight of the external pharmaceutical composition is vitamin A1, vitamin A2, vitamin A3, vitamin A acid, 3,4-didehydroretinol, pharmaceutically acceptable salts thereof, or these Vitamin A class when the blending ratio of pharmaceutically acceptable derivatives (the total when two or more are included) is 0.01 to 20% by weight and the external pharmaceutical composition is adjusted to 100 g. The pharmaceutical composition for external use according to any one of claims 1 to 3, wherein the composition contains 1000 to 1 million vitamin A units. The external pharmaceutical composition according to any one of claims 1 to 4, wherein the antifungal agent is at least one selected from the group consisting of morpholine compounds, benzylamine compounds, imidazole compounds, and allylamine compounds. . The external pharmaceutical composition according to any one of claims 1 to 5, wherein the antifungal agent is at least one selected from the group consisting of amorolfine hydrochloride, butenafine hydrochloride, neticonazole hydrochloride, and terbinafine hydrochloride. The therapeutic agent for dermatomycosis infection selected from the group consisting of ringworm, cutaneous candidiasis, vaginal candidiasis, vaginal trichomoniasis, folding screen, psoriasis and seborrheic dermatitis. Topical pharmaceutical composition. A method for enhancing the bactericidal activity of an antifungal agent, comprising mixing at least one selected from the group consisting of vitamins A and E with an antifungal agent.