JP4692280B2 - Antifungal composition - Google Patents

Description

  The present invention relates to an antifungal composition. More specifically, the present invention relates to an antifungal composition in which the antifungal activity of the allylamine antifungal agent is enhanced.

  Terbinafine is one of the antifungal drugs currently widely used in Japan and is classified as an allylamine antifungal drug, and has a new structure different from conventional imidazole, thiocarbamate, benzylamine, and morpholine. . Its mechanism of action resides in the inhibition of fungal cell membrane ergosterol biosynthesis. Terbinafine selectively inhibits squalene epoxidase in fungal cells, resulting in accumulation of squalene and a decrease in ergosterol content. As a result, strong antifungal activity is shown (see Non-Patent Document 1). Terbinafine has a broad antibacterial spectrum against pathogenic fungi such as Candida, Candida, Cryptococcus, Aspergillus, and Penicillium. In particular, it exhibits a very low MIC value against dermatophytes (see Non-Patent Document 2).

  The following compositions are known as compositions utilizing the excellent antifungal power of terbinafine. One is a composition in which terbinafine is mixed with an antihistamine, a terpene compound and urea. The said composition can improve the skin permeability and skin retention of terbinafine (refer patent document 1). Moreover, the composition which mix | blended additives, such as a methyl salicylate, with terbinafine and promoted the penetration | invasion to an epidermal stratum corneum is known (refer patent document 2).

  However, these compositions do not improve the antifungal power of terbinafine itself.

  In addition, athlete's foot and insects are generally difficult to heal completely, so it is necessary to continue applying the drug for a long time. However, in many patients, symptoms of athlete's foot and insects are cured when fungal activity is eased in the winter, and drug application is interrupted by self-judgment. As a result, the therapeutic effect of the drug cannot be exhibited sufficiently.

  Therefore, if an antifungal agent that exhibits an excellent effect when applied for a short period of time can be provided, it can be expected to exert a great effect on the treatment of athlete's foot and insects.

Hideyo Yamaguchi, “Pathogenic fungi and mycosis”, Nanzandou Co., Ltd., 84-85, 1999 Fungus Magazine Vol.32 No.4 1991 323-332 JP 2002-284702 A Japanese Patent Laid-Open No. 08-20527

  An object of this invention is to provide the antifungal agent composition which has the outstanding effect which enables the treatment of athlete's foot and the insect by the application | coating for a short time.

  The present inventors have made various studies on antifungal agents that are effective against the genus Trichoderma, which is a causative agent of athlete's foot and rotifer. As a result, it has been found that an excellent antifungal effect is exhibited by blending an allylamine antifungal agent and a quaternary ammonium salt fungicide, and the present invention has been completed.

  That is, according to the present invention, there is provided a pharmaceutical composition comprising an allylamine antifungal agent and a quaternary ammonium salt fungicide.

  Preferably, it is a pharmaceutical composition in which the allylamine antifungal agent is one or more selected from terbinafine and salts thereof.

  Preferably, it is a pharmaceutical composition in which the quaternary ammonium salt type fungicide is one or more compounds selected from the group consisting of benzalkonium chloride, benzethonium chloride, and decalinium chloride.

  Preferably, the pharmaceutical composition of the present invention is a pharmaceutical composition that can be used as an antifungal composition. More preferably, the pharmaceutical composition of the present invention is a pharmaceutical composition that can be used as a therapeutic composition for athlete's foot or insect.

  According to another aspect of the present invention, the method comprises the step of administering an effective amount of a composition comprising an allylamine antifungal agent and a quaternary ammonium salt fungicide to a site infected with a fungus of a mammal including a human, Methods of treating mycosis as well as methods of treating athlete's foot or insects are provided.

  According to still another aspect of the present invention, an allylamine antifungal agent and a quaternary ammonium salt type fungicide are prepared for producing a composition for treating mycosis, a composition for treating athlete's foot, or a composition for treating insects. Use of the composition is provided.

  According to the present invention, since the antifungal action of the allylamine antifungal agent can be further enhanced, it is possible to provide an antifungal agent composition that is extremely effective against dermatophytes.

  Therefore, if the antifungal agent composition of the present invention is used, a therapeutic agent for athlete's foot or beetle that can be treated by short-term application can be obtained.

  The allylamine antifungal compound to be blended in the present invention may be any compound having an allylamine skeleton in its chemical structure, but terbinafine is preferred. As a salt of this, as long as it forms a salt with a substituted amino acid group bonded to the naphthalene ring, it can be applied without particular limitation. For example, mineral salts such as hydrochloride, nitrate, sulfate, citric acid, etc. Organic salts such as salts, oxalates, and succinates are preferred, and hydrochlorides are particularly preferred.

  The quaternary ammonium type bactericidal agent may be any cationic surfactant that belongs to a quaternary ammonium salt, and benzalkonium chloride, benzethonium chloride, and decalinium chloride are particularly preferable.

  The allylamine antifungal compound to be blended in the present invention may be an effective amount capable of obtaining an antifungal effect. For example, when terbinafine hydrochloride is blended, it is 0.2 to 2% by mass, preferably 0.5 to 1.5% by mass in the entire composition (in the case of aerosol, in the stock solution).

  The compounding amount of the quaternary ammonium type fungicide varies depending on the component and the antifungal agent to be blended. For example, when terbinafine hydrochloride is blended in the above range as the antifungal agent, 0.01 to 1% by mass, preferably 0.02 to 0.5% by mass, the amount of benzethonium chloride is 0.05 to 2% by mass, preferably 0.1 to 1% by mass, and the amount of decalinium chloride is It is 0.05-2 mass%, Preferably it is 0.1-1 mass%.

  The composition of the present invention is mixed with additives usually used as external preparations as necessary, and is prepared by a conventional method, such as a solution, lotion, emulsion, tincture, ointment, cream, aqueous gel, oily gel. Preparations for external use such as pharmaceuticals, aerosols and powders.

  Ingredients that can be blended in the present invention include water-soluble ingredients such as propylene glycol, 1,3-butylene glycol, glycerin, ethanol, and macrogol, and oily ingredients such as diisopropyl adipate, stearyl alcohol, cetanol, squalane, and medium chain triglycerides. , Polymers such as carboxyvinyl polymer, methylcellulose, ethylcellulose, pH adjusters such as citric acid, sodium hydroxide, diisopropanolamine, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), α-tocopherol, erythorbic acid, Antioxidants such as sodium pyrosulfite, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate, glycerin monostearate, sorbi Emissions monolaurate, polyoxyethylene polyoxypropylene block copolymers, polysorbates, sodium lauryl sulfate, sucrose fatty acid esters, surfactants such as lecithin, stabilizers such EDTA-2Na and the like. In addition, it does not limit at all about the additive described until now.

Hereinafter, the present invention will be described in detail by way of examples and test examples.
Example 1
(cream)
Terbinafine hydrochloride 1.0 g
Decalinium chloride 0.1g
Lidocaine 2.0g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Polysorbate 60 4.0g
Sorbitan monostearate 2.0g
1,3-butylene glycol 15.0 g
Medium chain fatty acid triglyceride 15.0g
Glycerin monostearate 25.0g
EDTA-2Na 0.1g
100g of purified water

  Water phase components (1,3-butylene glycol, decalinium chloride, EDTA-2Na, dipotassium glycyrrhizinate, purified water) and oil phase components (terbinafine hydrochloride, lidocaine, 1-menthol, sorbitan monostearate, polysorbate 60, medium chain Fatty acid triglyceride and glycerin monostearate) were heated and then mixed to prepare a cream by a usual method.

Example 2
(Gel cream)
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Lidocaine 2.0g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Polysorbate 80 3.0g
1,3 Butylene glycol 5.0g
Medium chain triglyceride 10.0g
Stearyl alcohol 4.0g
Cetanol 4.0g
Carboxyvinyl polymer 1.0g
Diisopropanolamine appropriate amount EDTA-2Na 0.1g
100g of purified water

  The carboxyvinyl polymer was dissolved in purified water to swell the carboxyvinyl polymer, and then heated. Oil phase components (terbinafine hydrochloride, lidocaine, polysorbate 80, medium chain fatty acid triglyceride, stearyl alcohol, cetanol, 1-menthol) are heated and mixed, and added to the carboxyvinyl polymer swelling solution prepared earlier, and dissolved in purified water The aqueous phase components (benzalkonium chloride, dipotassium glycyrrhizinate, EDTA-2Na) and 1,3 butylene glycol were added and emulsified. A neutralizing agent (diisopropanolamine) dissolved in purified water was added and cooled to produce a gel cream.

Example 3
(Gel cream)
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Lidocaine 2.0g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Polysorbate 80 2.0g
Medium chain triglyceride 5.0g
Stearyl alcohol 2.0g
Cetanol 2.0g
Squalane 3.0g
Carboxyvinyl polymer 1.0g
EDTA-2Na 0.1g
100g of purified water

  The carboxyvinyl polymer was dissolved in purified water to swell the carboxyvinyl polymer, and then heated. Oil phase components (terbinafine hydrochloride, lidocaine, polysorbate 80, medium chain fatty acid triglyceride, stearyl alcohol, cetanol, 1-menthol, squalane) are heated and mixed, and added to the carboxyvinyl polymer swelling liquid prepared above, and purified water is added thereto. A water phase component (benzalkonium chloride, dipotassium glycyrrhizinate, EDTA-2Na) dissolved in was added and cooled after emulsification to produce a gel cream.

Example 4
(Gel cream)
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Lidocaine 2.0g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Polysorbate 80 2.0g
Octyldodecyl myristate 3.0g
Medium chain triglyceride 8.0g
Stearyl alcohol 2.0g
Cetanol 2.0g
Carboxyvinyl polymer 1.0g
Dimethylpolysiloxane 0.3g
EDTA-2Na 0.1g
100g of purified water

  The carboxyvinyl polymer was dissolved in purified water to swell the carboxyvinyl polymer, and then heated. Oil phase components (terbinafine hydrochloride, lidocaine, polysorbate 80, medium-chain fatty acid triglyceride, stearyl alcohol, cetanol, 1-menthol, dimethylpolysiloxane, octyldodecyl myristate) were heated and mixed, and the carboxyvinyl polymer swelling liquid prepared earlier In addition to this, an aqueous phase component (benzalkonium chloride, dipotassium glycyrrhizinate, EDTA-2Na) dissolved in purified water was added thereto and cooled after emulsification to produce a gel cream.

Example 5
(Gel cream)
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Lidocaine 2.0g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Polyethylene glycol monostearate 2.0g
Medium chain triglyceride 8.0g
Stearyl alcohol 3.0g
Cetanol 3.0g
Carboxyvinyl polymer 1.0g
Dimethylpolysiloxane 0.3g
EDTA-2Na 0.1g
100g of purified water

  The carboxyvinyl polymer was dissolved in purified water to swell the carboxyvinyl polymer, and then heated. Oil phase components (terbinafine hydrochloride, lidocaine, polyethylene glycol monostearate, medium-chain fatty acid triglyceride, stearyl alcohol, cetanol, 1-menthol, dimethylpolysiloxane) are heated and mixed and added to the carboxyvinyl polymer swelling liquid prepared above. To this, an aqueous phase component (benzalkonium chloride, dipotassium glycyrrhizinate, EDTA-2Na) dissolved in purified water was added and cooled after emulsification to produce a gel cream.

Example 6
(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Decalinium chloride 0.1g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Polyethylene glycol 400 20.0g
Ethanol 50.0g
100 mL of purified water
With the above formulation, a lotion preparation was produced by a conventional method.

Example 7
(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
1,3 butylene glycol 20.0g
Ethanol 50.0g
100 mL of purified water
With the above formulation, a lotion preparation was produced by a conventional method.

Example 8
(lotion)
Terbinafine hydrochloride 1.0 g
Lidocaine 2.0g
Benzethonium chloride 0.1g
Dipotassium glycyrrhizinate 0.5g
1-menthol 1.0 g
Propylene glycol 20.0g
Ethanol 50.0g
100 mL of purified water
With the above formulation, a lotion preparation was produced by a conventional method.

Example 9
(Aerosol)
Stock solution:
Terbinafine hydrochloride 1.0 g
Benzalkonium chloride 0.05g
Dipotassium glycyrrhizinate 0.5g
1,3-butylene glycol 10.0 g
Ethanol 50.0g
100 mL of purified water
Propellant:
DME 50mL
Other stock solution components were dissolved in a base of ethanol and purified water to produce a stock solution. After filling the container, a valve was attached and a propellant was filled to produce an aerosol.

Test example 1
The FIC index (Fractional Inhibition Concentration index) was measured by the combination of terbinafine hydrochloride and each specimen, and the additive / synergistic effect was measured.

The following components were used as specimens.
Sample 1: Benzalkonium chloride Sample 2: Benzethonium chloride

Test strain Trichophyton mentagrophytes (clinical isolate)
Trichophyton rubrum (clinical isolate)

(Test method)
The susceptibility test was performed by the micro liquid dilution method proposed by the Japanese Society for Medical Mycology (Standardization Committee). As a medium for measuring sensitivity, 0.165M MOPS-RPMI1640 was used.

The medium containing the drug was inoculated with a bacterial solution prepared to about 10 ⁵ conidia / mL and cultured at 27 ° C. for a maximum of 4 days. The antibacterial activity was judged visually when the growth control was clearly red. The minimum concentration of wells exhibiting the same blue color as the negative control was defined as the MIC value (minimum growth inhibitory concentration, μg / mL). The FIC index (Fractional Inhibition Concentration index) was calculated by the checkerboard method.
Formula 1

  Judgment of the combined effect was made with an antagonistic action greater than 2, an additive action greater than 2 to 1, an additive action, and a synergistic effect less than 1.

  The obtained FIC index results are shown in Table 1 (combination effect when terbinafine hydrochloride and benzalkonium chloride are used in combination) and Table 2 (combination effect when terbinafine hydrochloride and benzethonium chloride are used together).

表１および２に記載のように、塩酸テルビナフィンと塩化ベンザルコニウムのＦＩＣインデックス値は０．６３、塩酸テルビナフィンと塩化ベンゼトニウムのＦＩＣインデックス値は０．７８であった。これらの併用が水虫の代表的な菌種に対して相乗効果を有することがわかった。

As shown in Tables 1 and 2, the FIC index values of terbinafine hydrochloride and benzalkonium chloride were 0.63, and the FIC index values of terbinafine hydrochloride and benzethonium chloride were 0.78. These combinations were found to have a synergistic effect on representative species of athlete's foot.

  The present invention is an antifungal composition exhibiting an excellent antifungal effect, which is obtained by blending an allylamine antifungal with a quaternary ammonium salt type fungicide. By using the antifungal agent composition of the present invention, it is possible to treat athlete's foot and a beetle by application in a shorter time than before.

Claims (3)

(1) One or more selected from terbinafine and salts thereof, and (2) one or two compounds selected from the group consisting of benzalkonium chloride and benzethonium chloride Composition. It is an antifungal agent composition, the pharmaceutical composition according to claim 1. The pharmaceutical composition according to claim 1 , which is a composition for treating athlete's foot or a beetle.