JP2006232853A - Antifungal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a product having high therapeutic effects by heightening antifungal activities of a medicine. <P>SOLUTION: The antifungal composition contains at least one selected from the group consisting of allylamine-based antifungal agent, a benzylamine-based antifungal agent and a morpholine-based antifungal agent, and at least one selected from the group consisting of chlorhexidine hydrochloride, isopropylmethylphenol and a quaternary ammonium salt. The preferable antifungal agent is at least one selected from the group consisting of terbinafine, butenafine, amorolfine and salts thereof, and the preferable quaternary ammonium salt is at least one selected from the group consisting of decalinium chloride, benzalkonium chloride and benzethonium chloride. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an antifungal composition comprising as an active ingredient at least one selected from allylamine, benzylamine and morpholine antifungal agents and at least one selected from chlorhexidine hydrochloride, isopropylmethylphenol and quaternary ammonium salts. In particular, the present invention relates to a composition having an excellent therapeutic effect against superficial mycosis (such as tinea pedis, tinea corporis, and tinea rotata) caused by parasitic tinea on the skin.

  In superficial mycosis, fungi mainly invade the skin stratum corneum and proliferate. As a condition for the antifungal agent to exert an excellent medicinal effect against superficial mycosis, the drug itself is a strong anti-mycosis. It is necessary to have fungal activity and to have a high affinity for the site of infection. In recent years, allylamine-based, benzylamine-based, and morpholine-based antifungal agents having excellent antifungal activity and keratin affinity have been put into practical use in order to satisfy these conditions. As these antifungal agents, amorolfine, terbinafine, butenafine, and salts thereof are known, and these all exhibit excellent effects when used alone, but they reduce side effects, reduce patient QOL (quality Development of an antifungal composition exhibiting more powerful activity has been desired for the purpose of improving the life-of-life and reducing the cost of the active ingredient.

  Conventionally, as an antifungal composition containing an allylamine, benzylamine or morpholine antifungal agent as an active ingredient, the base is selected from butenafine hydrochloride, bifonazole, neticonazole hydrochloride, ketoconazole, ranoconazole, terbinafine hydrochloride, amorolfine hydrochloride and lilanaphthalate A stratum corneum antifungal composition comprising at least one selected from methyl salicylate, glycol salicylate, crotamiton, mint oil, and 1-menthol in an antifungal agent having high keratin affinity, and butenafine An antifungal composition in which an antifungal agent such as amorolfine or terbinafine is mixed with an antihistamine, a terpene compound and urea (see Patent Document 2) is known.

  However, the antifungal compositions of Patent Documents 1 and 2 are intended to improve the skin permeability of the antifungal agent, and are not intended to enhance the bactericidal properties of the drug itself.

  Further, an antifungal composition comprising pyrrolnitrin and at least one selected from lanoconazole, butenafine or a salt thereof, and an allylamine antifungal agent has been proposed (see Patent Document 3). It has a strong antifungal effect compared to each single item, and fungal infections such as dermatophytosis such as ringworm, vorticulitis, yellow psoriasis, and deep tinea, mucocutaneous candidiasis, and deep candidiasis It is said that it is useful for the treatment of cerebral dysplasia and is also useful in terms of reducing side effects and improving patient compliance.

However, this antifungal composition has the disadvantage that the bactericidal activity is synergistically improved when the above-mentioned specific antifungal agents are combined, and has low versatility and low cost reduction effect.
Japanese Patent No. 3081766, especially the column of the claims Japanese Patent Application Laid-Open No. 2002-284702, particularly the column of claims International Publication No. WO 00/62776 pamphlet, in particular, the column of claims and the column of industrial applicability

  In view of the above points, an object of the present invention is to increase the antifungal efficacy of a drug and provide a product having a high therapeutic effect.

  The present inventor has proposed chlorhexidine hydrochloride, isopropylmethylphenol as at least one of allylamine, benzylamine, and morpholine antifungal agents that are excellent in keratin retention, keratin affinity, and bactericidal activity. And when it mix | blended with at least 1 of quaternary ammonium salt, it discovered that the antifungal activity of the said drug could be improved significantly and completed this invention based on the knowledge.

  That is, the antifungal composition according to the present invention comprises at least one selected from the group consisting of an allylamine antifungal agent, a benzylamine antifungal agent and a morpholine antifungal agent (hereinafter referred to as “antifungal component”), And at least one selected from the group consisting of chlorhexidine hydrochloride, isopropylmethylphenol and a quaternary ammonium salt (hereinafter referred to as “combined component”).

  A representative example of an allylamine antifungal agent used in the present invention is terbinafine or a salt thereof, a representative example of a benzylamine antifungal agent is butenafine or a salt thereof, and a representative example of a morpholine antifungal agent is amorolfine or a salt thereof. Salt. The salt is preferably a pharmacologically acceptable inorganic salt such as hydrochloride.

  The content ratio of the antifungal component in the antifungal composition according to the present invention is 0.00001 to 5% by weight, preferably 0.0001 to 2.5% by weight, based on the total amount of the composition. If the content ratio of the antifungal component is too small, a sufficient antifungal effect is not exhibited, and if it is too much, there is a concern about the safety of the composition.

  In the present invention, the quaternary ammonium salt means a cationic surfactant belonging to the quaternary ammonium salt, and preferred examples thereof are decalinium chloride, benzalkonium chloride and benzethonium chloride.

  The content of each combination component in the antifungal composition according to the present invention is 0.00001 to 3000 parts by weight, preferably 0.004096 to 2042.484 parts by weight in the case of chlorhexidine hydrochloride with respect to 1 part by weight of the antifungal agent. More preferably 0.03268 to 255.9378 parts by weight, and in the case of a quaternary ammonium salt, for example, benzalkonium chloride, 0.00001 to 3000 parts by weight, preferably 0.000164 to 16333.087 parts by weight, More preferably, it is 0.00137-204.7502 weight part, and in the case of isopropylmethylphenol, it is 0.00001-100,000 weight part, Preferably it is 0.011466-98039.22 weight part, More preferably, 0.091503-13285. 01 parts by weight. When there are too few combined components, the suitable effect by combined use will reduce, and when too large, it will become disadvantageous in cost. However, the said content rate of a combined use component is an illustration, Comprising: This invention is not limited.

  The antifungal composition according to the present invention includes a preservative, organic / inorganic powder, preservative, lubricant, chelating agent, fragrance, solvent, solubilizer, pH adjuster, in addition to the above-mentioned active ingredient and combination ingredient. Antioxidants, moisturizers, shape-retaining agents, etc. (hereinafter referred to as “additive components”), anti-inflammatory agents, antipruritic agents, cooling agents, bactericides, astringents, blood circulation promoters, skin protectants, tissue repair agents Etc. (hereinafter referred to as “other active ingredients”) may be blended as necessary.

  Examples of anti-inflammatory agents include glycyrrhetinic acid, dipotassium glycyrrhizinate, allantoin, chlorpheniramine maleate, diphenhydramine hydrochloride, 1-menthol, dl-menthol, and dl-camphor.

  Examples of antipruritic agents include lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, procaine hydrochloride, ethyl aminobenzoate, oxypolyentoxide decane, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, and crotamiton.

  Organic and inorganic powders include talc, zinc oxide, titanium oxide, magnesium stearate, zinc stearate, magnesium oxide, magnesium carbonate, calamine, magnesium magnesium aluminosilicate, anhydrous silicic acid, magnesium silicate, kaolin, aerosil, mica Corn starch is exemplified.

  The antifungal composition according to the invention is used in the usual dosage forms used for the treatment of skin diseases. Examples of dosage forms include liquids, ointments (greasy ointments, emulsion ointments, water-soluble ointments), liniments, lotions, powders, emulsions / suspensions, tinctures, vaginal suppositories, aerosols, etc. Preferably, it is an external preparation.

  The antifungal composition according to the present invention can be formulated into the above dosage form by a conventional method using an appropriate base.

  Examples of bases include isopropyl myristate, octyl myristate, butyl stearate, ethyl oleate, oleyl oleate, diisopropyl adipate, glycerin fatty acid ester, polyoxyl stearate 40, 45, 55, diethyl sebacate, sorbitan fatty acid Esters, fatty acid esters such as isopropyl palmitate, glyceryl monooleate, sorbitan monooleate, surfactants such as propylene glycol, 1,3-butylene glycol, macrogol, carboxyvinyl polymer, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, Polymers such as carboxymethyl cellulose, methanol, ethanol, isopropanol, propanol, butanol, benzyl alcohol, glycerin , Liquefiable hydrocarbons such as alcohol solvents such as ethylene glycol, purified water, propellants such as propane, butane straw, pentane, isopentane, neopentane, and mixtures thereof, and phenols, etc. It is appropriately selected according to the shape.

  A typical formulation is prepared as follows.

  Liquids are alcohol, solvents such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, bases such as purified water, antifungal components, concomitant components, necessary The additive component added according to the above and other active ingredients are uniformly mixed.

  The ointment is a uniform mixture of bases such as petrolatum, white wax, paraffin, vegetable oil, plastic base, polyethylene glycol, macrogol, antifungal ingredients, concomitant ingredients, additives added as needed, and other active ingredients. Mixed.

  Gel agent is based on carboxyvinyl polymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, purified water, lower alcohol, polyhydric alcohol, polyethylene glycol, etc., antifungal component, combination component, if necessary It is a gel-like product obtained by uniformly mixing an additive component added in addition to other active ingredients.

  Aerosol is an alcoholic solvent such as methanol, ethanol, isopropanol, propanol, butanol, benzyl alcohol, glycerin, ethylene glycol, bases such as purified water, antifungal ingredients, concomitant ingredients, additive ingredients added as needed, And other active ingredients are uniformly mixed, and the resulting mixture can be liquefied in a container equipped with a valve, actuator, etc., such as a propellant such as propane, butane soot, pentane, isopentane, neopentane, or a mixture thereof. Filled with.

  The dosage of the antifungal component in the antifungal composition according to the present invention is selected according to the dosage form, the content ratio of the active ingredient and the concomitant ingredient, the type of fungus, the degree of symptoms, etc. The range is 10 mg / day, preferably 0.05 to 5 mg / day. The administration frequency may be once a day.

  ADVANTAGE OF THE INVENTION According to this invention, the antifungal efficacy of a drug can be improved and the product with a high therapeutic effect can be provided.

Next, the composition of the present invention will be specifically described with reference to examples.
Formulation Example 1 (Oil-based ointment)
Butenafine hydrochloride 1g
Isopropylmethylphenol 3g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
JP Macrogol Ointment Suitable amount 100g

Formulation Example 2 (hydrophilic ointment)
Amorolfine hydrochloride 0.5575 g
Chlorhexidine hydrochloride 0.01g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Carboxyvinyl polymer 1.5g
Ethanol 40g
Purified water appropriate amount 100g

Formulation Example 3 (Aerosol)
Terbinafine hydrochloride 1g
Benzalkonium chloride 0.05g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 4 (Aerosol)
Terbinafine hydrochloride 1g
Benzalkonium chloride 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 5 (Aerosol)
Terbinafine hydrochloride 1g
Isopropylmethylphenol 3g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 6 (Aerosol)
Terbinafine hydrochloride 1g
Isopropylmethylphenol 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 7 (Aerosol)
Terbinafine hydrochloride 1g
Isopropylmethylphenol 3g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 8 (Aerosol)
Terbinafine hydrochloride 1g
Chlorhexidine hydrochloride 1g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 9 (Aerosol)
Terbinafine hydrochloride 1g
Chlorhexidine hydrochloride 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 10 (Aerosol)
Terbinafine hydrochloride 1g
Chlorhexidine hydrochloride 0.01g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol. .

Formulation Example 11 (Aerosol)
Butenafine hydrochloride 1g
Chlorhexidine hydrochloride 1g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

Formulation Example 12 (aerosol)
An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Butenafine hydrochloride 1g
Chlorhexidine hydrochloride 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 13 (Aerosol)
Butenafine hydrochloride 1g
Isopropylmethylphenol 3g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 14 (Aerosol)
Butenafine hydrochloride 1g
Isopropylmethylphenol 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 15 (Aerosol)
Butenafine hydrochloride 1g
Benzalkonium chloride 0.05g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 16 (aerosol)
Butenafine hydrochloride 1g
Benzalkonium chloride 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 17 (aerosol)
Amorolfine hydrochloride 0.5575 g
Chlorhexidine hydrochloride 1g
Lidocaine 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 18 (aerosol)
Amorolfine hydrochloride 0.5575 g
Chlorhexidine hydrochloride 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 19 (Aerosol)
Amorolfine hydrochloride 0.5575 g
Isopropylmethylphenol 3g
Lidocaine 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 20 (aerosol)
Amorolfine hydrochloride 0.5575 g
Isopropylmethylphenol 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 21 (Aerosol)
Amorolfine hydrochloride 0.5575 g
Benzalkonium chloride 0.01g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 22 (Aerosol)
Amorolfine hydrochloride 0.5575 g
Benzalkonium chloride 0.05g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

  An undiluted solution and propellant (LPG) are appropriately filled into a combination container to produce an aerosol.

Formulation Example 23 (Liquid)
Terbinafine hydrochloride 1g
Chlorhexidine hydrochloride 1g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

Formulation Example 24 (Liquid)
Terbinafine hydrochloride 1g
Benzalkonium chloride 0.05g
Lidocaine 2.5g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

Formulation Example 25 (Liquid)
Butenafine hydrochloride 1g
Chlorhexidine hydrochloride 1g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

Formulation Example 26 (Liquid)
Amorolfine hydrochloride 0.5575 g
Chlorhexidine hydrochloride 1g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
Zinc oxide 10g
Talc 20g
Isopropyl myristate 20g
Ethanol appropriate amount 100g

Formulation Example 27 (liniment)
Butenafine hydrochloride 1g
Isopropylmethylphenol 3g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
JP Phenolic / Zinc Hana Liniment Suitable amount 100g

  A liniment is prepared by mixing the above ingredients.

Formulation Example 28 (powder)
Amorolfine hydrochloride 0.5g
Chlorhexidine hydrochloride 1g
Diphenhydramine hydrochloride 2g
Glycyrrhetinic acid 1g
60g of dry potassium aluminum sulfate
Talc appropriate amount 100g

  The above ingredients are mixed to make a powder.

performance test
(1) Preparation of test drug solution
As a stock solution
1) 4 wt% ethanol solution of terbinafine hydrochloride 2) 4 wt% ethanol solution of butenafine hydrochloride 3) 4 wt% ethanol solution of trimethylcetylammonium pentachlorophenate 4) 0.1 wt% ethanol solution of benzalkonium chloride
5) A 2 wt% ethanol solution of chlorhexidine hydrochloride 6) A 6 wt% ethanol solution of isopropylmethylphenol was prepared.

  0.1 ml of each of the original solutions 1) to 6) and 1.9 ml of dimethyl sulfoxide were added to 8 ml of distilled water. Thus, test drug solutions 1) to 6) were prepared by diluting each original solution 100 times.

  Next, 0.2 ml of each mixture of the original solution 1) and the original solution 4), the original solution 1) and the original solution 5), and the original solution 1) and the original solution 6) (each mixture is 0.1 ml of the former + 0.1 ml of the latter) ) And 1.8 ml of dimethyl sulfoxide were added to 8 ml of distilled water to prepare the following test drug solutions 7) to 9).

  0.2 ml of each mixture of original solution 2) and original solution 4), original solution 2) and original solution 5), original solution 2) and original solution 6) (each mixture is 0.1 ml of the former + 0.1 ml of the latter) and dimethyl The following test drug solutions 10) to 12) were prepared by adding 1.8 ml of sulfoxide to 8 ml of distilled water.

7) Test drug solution containing terbinafine hydrochloride and benzalkonium chloride (final drug concentration is 0.04% by weight of the former + 0.001% by weight of the latter)
8) Test drug solution containing terbinafine hydrochloride and chlorhexidine hydrochloride (final drug concentration is 0.04% by weight of the former + 0.02% by weight of the latter)
9) Test drug solution containing terbinafine hydrochloride and isopropylmethylphenol (final drug concentration is 0.04% by weight of the former + 0.06% by weight of the latter)
10) Test drug solution containing butenafine hydrochloride and benzalkonium chloride (final drug concentration is 0.04% by weight of the former + 0.001% by weight of the latter)
11) Test drug solution containing butenafine hydrochloride and chlorhexidine hydrochloride (final drug concentration is 0.04% by weight of the former + 0.02% by weight of the latter)
12) Test drug solution containing butenafine hydrochloride and isopropylmethylphenol (final drug concentration is 0.04% by weight of the former + 0.06% by weight of the latter)
As a comparison, 0.2 ml of each mixture of the original solution 3) and the original solution 6) (each mixture is 0.1 ml of the former + 0.1 ml of the latter) and 1.8 ml of dimethyl sulfoxide are added to 8 ml of distilled water, and the following test is performed. A drug solution 13) was prepared.

  13) Test drug solution containing trimethylacetylammonium pentachlorophenate and isopropylmethylphenol (final drug concentration is 0.04% by weight of the former + 0.06% by weight of the latter)

(2) Bacteria used: Tricophyton mentagrophytes

(3) Medium used: Sabraud Liquid Broth Modified Antibiotic Medium 13 (manufactured by BECTON DICKINSON) (the amount of purified water to be dissolved is halved)
(4) Preparation of bacterial solution: After culturing the bacterium on Sabouraud agar medium “Nissui” (Nissui Pharmaceutical Co., Ltd.) at 25 ° C. for 5 to 10 days, the sterilized physiological saline of Japanese Pharmacopoeia (manufactured by Otsuka Pharmaceutical Co., Ltd.) It is released with a solution for suspension of bacteria containing 0.05% by weight of Tween 80 (manufactured by Katayama Chemical Co., Ltd.), filtered through a sterilized filter (100 μm, cell strainer: manufactured by FALCON), and a suspension of bacteria (bacteria) Several 10 ⁴ to 10 ⁵ pieces / μl).

(5) Test method: 100 μl of the modified subload medium was dispensed into each well of a microplate having 96 wells arranged in a plurality of rows. 100 μl of the test drug solution 1) was dispensed into each well of the first row of the microplate and well suspended. The suspension in the first row well was transferred to the second row well and well suspended. This operation was sequentially repeated in the direction of the third row, the fourth row, and so on, and the next adjacent row to prepare a dilution series.

  Each well was inoculated with 5 μl of a suspension of bacteria, and the bacteria were cultured at a temperature of 37 ° C. for 48 hours, and further cultured at 25 ° C. for 1 week, and then the presence or absence of residual viable bacteria was visually determined.

  The same operation as described above was performed for the test drug solutions 2) to 11).

  Thus, MIC (minimum growth inhibitory concentration: μg / ml) was measured by the liquid dilution method.

(6) Determination of antifungal properties Based on the obtained MIC value, FIC (fractional inhibitory concentration) index was calculated by the following formula.

FIC index = a / a0 + b / bO
a0 = MIC when using antifungal component alone
a = MIC of antifungal component when combined use of antifungal component and combination component
bO = MIC when used in combination
b = MIC of combination component when combined use of antifungal component and combination component

  The obtained MIC is shown in Tables 1 to 4, and the FIC index is shown in Table 5.

About amorolfine hydrochloride, as a result of having tested by the same operation as terbinafine hydrochloride and butenafine hydrochloride, the test result similar to these was shown.

Antifungal criteria are as follows:
When the FIC index value (Fi)> 2, the combination component is antagonistic to the antifungal component, and when 2 ≧ Fi> 1, the combination component exhibits additive action against the antifungal component, and when 1 ≧ Fi, the combination component is combined. The ingredient exhibits a synergistic effect on the antifungal ingredient.

  From comparison between Table 1 and Table 2 and comparison between Table 3 and Table 4, terbinafine hydrochloride or butenafine hydrochloride is used as an antifungal component, and benzalkonium chloride, chlorhexidine hydrochloride or isopropylmethylphenol is blended as a concomitant component. It can be seen that the antifungal composition exhibits a high antifungal effect without interfering with each other, which is stronger than the single use of the antifungal component and the combination component.

  Moreover, it is recognized from Table 5 that the antifungal composition obtained by blending the above antifungal component with the above combination component exhibits a high synergistic effect.

  In contrast, in an antifungal composition comprising trimethylacetylammonium pentachlorophenate as an antifungal component and isopropylmethylphenol as a concomitant component, the concomitant component is antagonistic to the antifungal component. I understand that there is.

Claims (3)

  At least one selected from the group consisting of an allylamine antifungal agent, a benzylamine antifungal agent and a morpholine antifungal agent, and at least one selected from the group consisting of chlorhexidine hydrochloride, isopropylmethylphenol and a quaternary ammonium salt. An antifungal composition comprising.   The antifungal composition according to claim 1, wherein the antifungal agent is at least one selected from the group consisting of terbinafine, butenafine, amorolfine and salts thereof. The antifungal composition according to claim 1 or 2, wherein the quaternary ammonium salt is at least one selected from the group consisting of decalinium chloride, benzalkonium chloride and benzethonium chloride.