WO2005004856A1

WO2005004856A1 - Antifungal composition

Info

Publication number: WO2005004856A1
Application number: PCT/JP2004/009808
Authority: WO
Inventors: Hideki Kohita; Osamu Kondo
Original assignee: Taisho Pharmaceutical Co.,Ltd.
Priority date: 2003-07-11
Filing date: 2004-07-09
Publication date: 2005-01-20
Also published as: JP2005029502A; JPWO2005004856A1; JP4692280B2

Abstract

An antifungal composition capable of exerting excellent antifungal effect upon short-term application thereof. The composition is characterized by comprising an allylamine antifungal drug mixed with a quaternary ammonium salt base bactericidal drug.

Description

Specification

Antifungal composition

Technical field

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

Background art

[0002] Terbinafine is one of the currently widely used antifungal drugs in Japan and is classified as an allylaminine antifungal drug, which is different from conventional imidazoles, thiocarbamates, benzylamines, and morpholines Has a new structure. Its mechanism of action lies in the inhibition of the biosynthesis of fungal cell membrane ergosterol. Terbinafine selectively inhibits squalene epoxidase in fungal cells, resulting in squalene accumulation and reduced ergosterol content. As a result, a strong antifungal activity is exhibited (see Non-Patent Document 1).

. Terbinafine has a broad antibacterial spectrum against pathogenic fungi such as Trichophyton, Candida, Tareptococcus, Aspergillus and Penicillium. Particularly, it shows a very low MIC value against dermatophytes (see Non-Patent Document 2).

[0003] The following compositions are known as compositions utilizing such excellent antifungal activity of terbinafine. One is a composition comprising terbinafine, an antihistamine, a terpene compound, and urea. The composition can enhance the skin permeability and skin retention of terbinafine (see Patent Document 1). Further, a composition is known in which an additive such as methyl salicylate is added to terbinafine to promote penetration into the stratum corneum of the epidermis (see Patent Document 2).

[0004] However, these compositions do not improve the antifungal activity of terbinafine itself.

[0005] In addition, since athlete's foot and worms are generally difficult to completely heal, it is necessary to continue applying the drug for a long period of time. However, many patients discontinue drug application at their own discretion, as the activity of fungi subsides in winter, when the symptoms of athlete's foot and caterpillars subside. As a result, the therapeutic effect of the drug cannot be sufficiently exerted. [0006] Therefore, if an antifungal agent exhibiting an excellent effect in a short-term application can be provided, it can be expected to exert a great effect on the treatment of athlete's foot and scabies.

[0007] Non-patent document 1: Hideyo Yamaro, "Pathogenic fungi and mycosis", Nanzando Co., Ltd., 84-85, 1999 Non-patent document 2: Fungus Journal Vol. 32 No. 4 1991 323-332

Patent Document 1: JP-A-2002-284702

Patent Document 2: JP 08-20527 A

Disclosure of the invention

Problems to be solved by the invention

[0008] An object of the present invention is to provide an antifungal agent composition having excellent efficacy, which enables treatment of athlete's foot and sickness with a short application.

Means for solving the problem

[0009] The present inventors have conducted various studies on antifungal drugs that are effective against Trichophyton, a causal fungus of athlete's foot and scabies. As a result, they have found that the combination of an arylamine antifungal and a quaternary ammonium salt-type bactericide exerts an excellent antifungal effect, thereby completing the present invention.

[0010] That is, according to the present invention, there is provided a pharmaceutical composition comprising an arylamine antifungal and a quaternary ammonium salt-type bactericide.

[0011] Preferably, the pharmaceutical composition is one or two or more allybinamine antifungals selected from terbinafine and salts thereof.

[0012] Preferably, a pharmaceutical composition in which the quaternary ammonium salt-type bactericide is one or more compounds selected from the group consisting of benzalkonium chloride, benzethonium chloride, and decalinium chloride.

[0013] 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 scabies.

According to another aspect of the present invention, a step of administering an effective amount of a composition comprising an arylamine antifungal and a quaternary ammonium salt-type bactericide to a site infected with a fungus of a mammal including humans. A method for treating mycosis and a method for treating athlete's foot or scabies, including Law is provided.

According to still another aspect of the present invention, an arylamine antifungal agent and a quaternary ammonium salt for producing a composition for treating mycosis, a composition for treating athlete's foot, or a composition for treating scabies. The use of a composition incorporating a salt-type fungicide is provided. The invention's effect

[0016] According to the present invention, the antifungal activity of an arylamine antifungal agent can be further enhanced, and therefore, it has become possible to provide an antifungal agent composition that is extremely effective against dermatophytes. .

[0017] Therefore, if the antifungal agent composition of the present invention is used, a therapeutic agent for athlete's foot and sickness that can be treated with a short-term application can be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] The arylamine antifungal agent to be blended in the present invention may be any one having an arylamine skeleton in its chemical structure, but terbinafine is preferred. Any salt can be used without particular limitation as long as it forms a salt with the substituted amino acid group bonded to the naphthalene ring, and examples thereof include mineral salts such as hydrochloride, nitrate and sulfate, and quinone. Organic acid salts such as acid salts, oxalates, and succinates are preferred, and hydrochlorides are particularly preferred.

[0019] The quaternary ammonium-type bactericide is preferably a cationic surfactant belonging to quaternary ammonium salt, and particularly preferably benzalkonium chloride, benzethonium chloride, decalinium chloride and the like.

[0020] The arylamine antifungal agent to be blended in the present invention may be any effective amount capable of obtaining an antifungal effect. For example, when terbinafine hydrochloride is blended, the content is 0.2 to 2% by mass, preferably 0.5 to 1.5% by mass in the whole composition (in the case of azole, in a stock solution).

[0021] The amount of the quaternary ammonium fungicide differs depending on the component and the antifungal to be mixed. For example, when terbinafine hydrochloride is compounded in the above range as an antifungal, the amount of benzalkonium chloride is adjusted. Is 0.01-1% by mass, preferably 0.02-0.5% by mass, and the blending amount of benzenium chloride is 0.05-2% by mass, preferably 0.1-1% by mass, and decalinium chloride. Is 0.05 to 2% by mass, preferably 0.1 to 1% by mass. [0022] The composition of the present invention may be mixed with an additive usually used as an external preparation, if necessary, and mixed in a usual manner with a liquid, lotion, emulsion, tincture, ointment, cream, aqueous gel. And external preparations such as oily gels, aerosols and powders.

[0023] Components that can be blended in the present invention include water-soluble components such as propylene glycol, 1,3-butylendalcol, glycerin, ethanol, macrogol, diisopropyl adipate, stearyl alcohol, cetanol, squalane, and medium-chain triglyceride. Oily components such as carboxyvinyl polymer, polymers such as methylcellulose and ethylcellulose, pH adjusters such as citric acid, sodium hydroxide and diisopropanolamine, dibutylhydroxytoluene (BHT), butylhydroxydisole (BHA), anti-oxidants such as heart tocopherol, erythorbic acid, sodium pyrosulfite, polyoxyethylene hardened castor oil, sorbitan monostearate, sorbitan monopalmitate, glycerin monostearate, sorbitan Noraureto, polyoxyethylene polyoxypropylene block Kukoporima, polysorbates, sodium lauryl sulfate, sucrose fatty acid esters, surfactants such as Residencial Chin, stabilizers such EDTA_2Na the like. It should be noted that there is no particular limitation on the soybean pastes described so far.

Example

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples.

Example 1

(Cream)

Terbina hydrochloride: 1. Og

Decalinium chloride 0.1 lg

Lidocaine 2. Og

0.5 g of dipotassium glycyrrhizinate

Tomentor 1. Og

Polysonolate 60 4. Og

Sorbitan monostearate 2. Og

1, 3-butylene glycol 15. Og

Medium chain fatty acid triglyceride 15. Og Glycerin monostearate 25. Og

EDTA-2Na 0.lg

100g of purified water

[0025] Aqueous 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, polysonole) Bate 60, medium-chain fatty acid triglyceride, daliserine monostearate) were mixed after heating, respectively, to produce a cream by the usual method.

Example 2

(Genole cream)

Terbina hydrochloride: 1. Og

Benzalkonium chloride 0.05 g

2. Og

0.5 g of dipotassium glycyrrhizinate

Tomentor 1. Og

Polysonolate 80 3. Og

1,3 butylene glycol 5.Og

Medium chain fatty acid triglyceride 10. Og

Stearyl alcohol 4. Og

Cetanol 4. Og

Canoleboxivini / Repolymer 1. Og

Diisopropanolamine

EDTA-2Na 0.lg

100 g of purified water

[0027] The carboxybutyl polymer was dissolved in purified water, and the carboxybutyl polymer was swollen and then heated. The oil phase components (terbinafine hydrochloride, lidocaine, polysorbate 80, medium-chain fatty acid triglyceride, stearyl alcohol, cetanol, 1_ menthol) are heated and mixed, added to the previously prepared swelling solution of carboxybutyl polymer, and dissolved in purified water. did The aqueous phase components (benzalkonium chloride, dipotassium glycyrrhizinate, EDTA_2Na) and 1,3-butylene glycol were added and emulsified. After adding a neutralizing agent (diisopropanolanolamine) dissolved in purified water, the mixture was cooled to produce a gel cream.

Example 3

(Genole cream)

Terbina hydrochloride: 1. Og

Benzalkonium chloride 0.05 g

Lidocaine 2. Og

0.5 g of dipotassium glycyrrhizinate

Tomentor 1. Og

Polysonolate 80 2. Og

Medium chain fatty acid triglyceride 5. Og

Stearyl alcohol 2. Og

Cetanol 2. Og

3. Og

Canoleboxivini / Repolymer 1. Og

EDTA-2Na 0.lg

Purified water total lOOg

[0029] The carboxyvinyl polymer was dissolved in purified water, and the carboxyvinyl polymer was swollen and then heated. The oil phase components (terbinafine hydrochloride, lidocaine, polysorbate 80, medium-chain fatty acid triglyceride, stearyl alcohol, cetanol, 1-menthol, squalane) are heated and mixed, added to the previously prepared carboxybutyl polymer swelling liquid, and purified water is added thereto. The aqueous phase components (Benzalkonidium benzil, dipotassium glycyrrhizinate, EDTA-2 Na) dissolved in the mixture were added, and the mixture was emulsified and then cooled to produce a gel cream.

Example 4

(Genole cream)

Terbinafine hydrochloride 1. Og

Benzalkonium chloride 0.05 g 2. Og

0.5 g of dipotassium glycyrrhizinate

Tomentor 1. Og

Polysonolate 80 2. Og

Otatildodecyl myristate 3.Og

Medium chain fatty acid triglyceride 8. Og

Stearyl alcohol 2. Og

Setano Nore 2. Og

Canoleboxybininole polymer 1.0 g

Dimethylpolysiloxane 0.3 g

EDTA-2Na 0.lg

Purified water total lOOg

[0031] The carboxyvinyl polymer was dissolved in purified water, and the carboxyvinyl polymer was swollen and then heated. Oil phase components (terbinafine hydrochloride, lidocaine, polysorbate 80, medium-chain fatty acid triglyceride, stearyl alcohol, cetanol, 1-menthol, dimethylpolysiloxane, otatyl dodecyl myristate) are heated and mixed, and the carboxybutyl polymer prepared earlier is swelled. Aqueous phase components (benzalcodium chloride, dipotassium glycyrrhizinate, EDTA_2Na) dissolved in purified water were added to the solution, and the mixture was emulsified and cooled to produce a gel tarme.

Example 5

(Genole cream)

Terbinafine hydrochloride 1. Og

Benzalkonium chloride 0.05 g

Lidocaine 2.0 g

0.5 g of dipotassium glycyrrhizinate

1_ Men's One Note 1.0 g

Polyethylene glycol monostearate 2.0 g

8.0 g of medium-chain fatty acid triglyceride Call 3. Og

Cetanol 3. Og

Canoleboxivini / Repolymer 1. Og

Dimethylpolysiloxane 0.3 g

EDTA-2Na 0.lg

Purified water total lOOg

[0033] The carboxybutyl polymer was dissolved in purified water to swell the carboxybutyl polymer, and then heated. The 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 the carboxybutyl polymer previously prepared is swollen. In addition to the liquid, an aqueous phase component (Shiiro Benzanoreconidum, dipotassium dalicyrrhizinate, EDTA_2Na) dissolved in purified water was emulsified with Kadone and cooled to produce a gel cream.

Example 6

(Lotion)

Terbinafine hydrochloride 1. Og

2. Og

Decalinium chloride 0.1 lg

0.5 g of dipotassium glycyrrhizinate

Tomentor 1. Og

Polyethylene glycol 400 20.Og

Ethanore 50. Og

Purified water total lOOmL

In the above formulation, _c produced a lotion in a conventional manner

Example 7

(Lotion)

Terbinafine hydrochloride 1.0 g

Lidocaine 2.0 g Benzalkonidium chloride 0.05 g Dipotassium glycyrrhizinate 0.5 g Tolmenthol 1. Og 1,3 butylene glycol 20. Og Ethananol 50. Og Purified water All lOOmL The above formulation was used to prepare a mouthwash in the usual manner.

Example 8

(Lotion)

Terbinafine hydrochloride 1. Og Lidocaine 2. Og Benzetonium chloride 0.lg Dipotassium glycyrrhizinate 0.5 g Tolmenthol 1.0 g Propylene glycolone 20. Og Ethanolone 50. Og Purified water All lOOmL In the above formulation, use the usual method A chilling agent was produced.

Example 9

(Aerosol)

Stock solution:

Terbinafine hydrochloride 1.0 g Benzalkonium chloride 0.05 g Dipotassium glycyrrhizinate 0.5 g 1,3-butylene glycol 10. Og Ethananol 50. Og Purified water Total lOOmL Propellant: DME 50mL

A stock solution was prepared by dissolving other stock solution components in a base of ethanol and purified water. After filling the container, a valve was attached and the propellant was filled to produce an aerosol.

[0038] Test example 1

The FIC index (Fractional

Inhibitory Concentration index) was measured, and the synergistic effect of the phase caro 'was measured.

The following components were used as samples.

Specimen 1: Benzalkonium chloride

Sample 2: Benzetonium chloride

[0040] Test strain

Trichophyton mentagrophytes (Nor isolate)

Trichophyton rubrum (fe floor isolate)

(Test method)

The susceptibility test was performed by the microfluidic dilution method proposed by the Japanese Society for Medical Mycology (Standardization Committee). 0.165M MOPS-RPMI1640 was used as a sensitivity measurement medium.

[0042] agents inoculated solution was adjusted to about 10 ⁵ conidia / mL in medium containing, they were cultured for up to 4 days at 27 ° C,. Antibacterial activity was determined visually when the growth control clearly turned red. The MIC value (minimum inhibitory concentration, / ig / mL) was defined as the minimum concentration of the blue well similar to the negative control. The FIC index (Fractional Inhibitory and oncentration index) was calculated using the checkerboard method.

Equation 1

[0043]

k .. ― Terbinafine hydrochloride MIC when used together MIC when used together

F Hn τ, TAS = ~ ― +

MIC with terbinafine acid alone MIC with other agent alone

In the judgment, the combination effect was judged as an antagonistic effect when the value was 2 or more, an additive effect when the value was 2 or less and 1 or more, and a synergistic effect when the value was 1 or less.

[0045] The results of the obtained FIC index are shown in Table 1 (Effect of combined use of terbinafine hydrochloride and Shii-dani benzalkonium) and Table 2 (Combined effect of use of terbinafine hydrochloride and Shii-dani benzetonium). . [Table 1]

Strain: Tnchophyton mentsgrop ytes

[Table 2]

Strain: I chopayton rubrum As described in Tables 1 and 2, the FIC index value of terbinafine hydrochloride and benzalkonium chloride was 0.63, and the FIC index value of terbinafine hydrochloride and benzethonium chloride was 0.78. It was found that these combinations have a synergistic effect on typical fungal species of athlete's foot.

Industrial applicability

[0048] The present invention is an antifungal composition exhibiting an excellent antifungal effect, obtained by blending a quaternary ammonium salt fungicide with an arylamine antifungal. By utilizing the antifungal agent composition of the present invention, it is possible to treat athlete's foot and sickness with a shorter application time than before.

Claims

The scope of the claims

[1] A pharmaceutical composition comprising an arylamine antifungal and a quaternary ammonium salt fungicide.

[2] The pharmaceutical composition according to claim 1, wherein the arylamine antifungal is one or more selected from terbinafine and salts thereof.

[3] The quaternary ammonium salt-type bactericide according to claim 1 or 2, wherein the quaternary ammonium salt-type bactericide is one or more compounds selected from the group consisting of Shioizani Benzanorekonium, Shioizani Benzetonium, and decalinium chloride. A pharmaceutical composition according to claim 1.

[4] The pharmaceutical composition according to any one of claims 1 to 3, which is an antifungal composition.

[5] The pharmaceutical composition according to any one of claims 1 to 3, which is a composition for treating athlete's foot or scabies.