JPH04173734A - Antifungal external agent - Google Patents

Abstract

PURPOSE:To provide an antifungal external agent having excellent medicinal effect-expressing property and stability by employing an amine as a dissolution auxiliary agent. CONSTITUTION:An antifungal agent of the formula (at least one of R<1>-R<3> is halogen and the others are H), such as miconazole, econazole or isoconazole, is dissolved in and compounded with a part or all of an external agent substrate by the use of an amine. The amine includes diphenhydramine, chlorpheniramine maleate, lidocaine and mono-triethanolamine and is used in an amount of 0.01-60wt.% based on all of the composition.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the following general formula (I) (wherein, at least one of R', R' and R3 represents a halogen atom, and the remainder represents a hydrogen atom). This invention relates to a stable and highly therapeutic antifungal external preparation containing an antifungal drug represented by

[Conventional technology]

Fungal infections on the skin include candidiasis and candidiasis. Antifungal drugs are used for these treatments, but since fungi are extremely resistant to drugs, the drugs must have strong antibacterial activity. For this reason, drugs with strong antibacterial activity have been developed, and excellent antifungal drugs have been developed to date. Antifungal drugs represented by general formula (I) (miconazole, econazole, isoconazole, etc.)
is one of them, and is widely used because it has strong antibacterial activity and a wide antibacterial spectrum.

[Problem to be solved by the invention]

However, all antifungal drugs represented by general formula (I) (hereinafter referred to as "antifungal drugs (■)") have very low solubility in common solvents used for external preparations. ,
It has been difficult to prepare external preparations in which these are dissolved. For this reason, liquid liniments have often been used by suspending them in a solvent, but this cannot be said to provide a sufficient therapeutic effect, and there are also problems with stability. Ointments also have low solubility in both water-soluble and non-water-soluble bases, so they are often used dispersed in bases, which poses the same problems as liquid liniments. There are also concerns about separation from the base.

In order to solve these problems, methods of dissolving the anti-odor bactericidal drug (I) have been studied. Japanese Patent Publication No. 1-31485 discloses a method of using peppermint oil, methyl salicylate, crotamiton, etc. as a solubilizing agent in order to dissolve the antifungal drug (I). However, in this method, even if these solubilizing agents are used, it is not possible to dissolve immediately, and it takes time for dissolution to occur.
Furthermore, since it is necessary to heat the drug to 70 to 80°C, there is a risk that the drug will be decomposed.

Therefore, the antifungal drug (I) is dissolved in a base.
There has been a desire for an antifungal external preparation that is stable and has sufficient therapeutic effects.

[Means to solve the problem]

The present inventors conducted intensive research in view of the above-mentioned circumstances and found that the antifungal drug (I) can be easily dissolved in a general base commonly used for external preparations by using amines as a solubilizing agent. The present invention was completed based on the discovery that a stable external preparation can be obtained.

That is, the present invention provides an antifungal external preparation, which is characterized in that the antifungal agent (I) is dissolved and blended into all or part of an external base using an amine.

Various kinds of antifungal drugs (I) can be considered depending on R1 to R3 in the formula, and in the present invention, one type or a combination of two or more of these can be used. There is no particular restriction on the amount to be blended, but it is preferably 0.1 to 10% by weight (hereinafter simply expressed as "%"), particularly preferably 1 to 2%, based on the entire composition.

Examples of amines used in the present invention include:
Diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, lidocaine, lidocaine hydrochloride, propylene hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, oxybupropylene hydrochloride, ethanolamine, jetanolamine, triethanolamine, diisopropanolamine, Examples include triisopropanolamine, n-amylamine, and the like. These may be used alone or in combination of two or more, and the blending amount is not particularly limited as long as it can dissolve the antifungal drug (I) in the base, but 0. 0.01% or more, especially 0.01-60%
is preferred. If it is less than 0.01%, it may not function effectively as a solubilizing agent, which is not preferable.

Preferred dosage forms of the external preparation of the present invention are liquid liniments, ointments, gels, etc. The external base used therein is not particularly limited, but - those that can be used for boat fishing and are highly safe are preferred. For example, lower alcohols such as ethanol and propatool; glycols such as propylene glycol, polyethylene glycol, and chrycerin; fats and oils such as diolive oil and soybean oil; fatty acid higher alcohols such as cetanol alcohol; stearic acid. , higher fatty acids such as oleic acid; fatty acid esters such as beeswax, white beeswax, and isopropyl myristate; hydrocarbons such as vaseline, liquid paraffin, plastibase, and lanolin.

These exemplified bases may be used alone, or in combination of two or more, or in combination with one or more of these and water. These bases are antifungal drugs (
I) may be blended in an amount that can dissolve it, but the amount ranges from 0.01 to 99
．． It is preferable to mix 89%, especially 10 to 99.89%.

In addition to the above-mentioned essential ingredients, the external preparation of the present invention includes gelling agents such as hydrobovine dipropylcellulose, ethylcellulose, phorihinylpyrrolidone, carboxyvinyl polymer, and sodium alginate; emulsifiers, absorption enhancers, antioxidants, and colorants. Agents, fragrances, etc. may be added as necessary, as long as they do not impair the effects of the present invention.

The external preparation of the present invention can be produced by conventional methods except for adding the amines, but it is preferable to dissolve the amines in the base and then dissolve the antifungal drug (I). The solution thus obtained may further be made into an emulsion or gel.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 (Liquid coating agent) Miconazole nitrate 1% diphenhydramine 1% ethanol
98% total 1
Diphenhydramine was added to a small amount of 00% ethanol and stirred to form a homogeneous solution. Miconazole nitrate was added to this solution, stirred and dissolved, and ethanol was further added to obtain a preparation.

Example 2 (Liquid coating agent) Miconazole nitrate 2% lidocaine
2% total
Lidocaine was added to a small amount of 100% ethanol and stirred to dissolve. Miconazole nitrate was added to this solution, stirred and dissolved, and ethanol was further added to obtain a preparation.

Example 3 (Liquid coating agent) Miconazole nitrate 3% jetanolamine 10% total
Jetanolamine was added to a small amount of 100% ethanol and stirred to form a homogeneous solution. Miconazole nitrate was added to this solution, stirred and dissolved, and ethanol was further added to obtain a preparation.

Example 4 (gel) Miconazole nitrate 1% diphenhydramine 1% propylene glycol 45% 2-propatol
25% hydroxypropylcellulose
5% total 100%2
-Propertool, propylene glycol and diphenhydramine were mixed to form a homogeneous solution, to which cominazole nitrate was added and dissolved with stirring.

Hydroxypropyl cellulose and purified water were added to this solution and stirred to obtain a preparation.

Example 5 (Ointment) Miconazole nitrate 1% jetanolamine 3% white petrolatum
86% total
100% white petrolatum and stearic acid were dissolved by heating, and jetanolamine was added to form a homogeneous solution. Miconazole nitrate was added to this, stirred and dissolved, and then solidified at room temperature to obtain a preparation.

Example 6 (Cream) Miconazole nitrate 1% lidocaine 2% cetanol 5% polyoxyethylene (30) cetyl ether 2% glycerin monostearate (self-emulsifying type) 10% liquid paraffin
10% white petrolatum
5% triethanolamine
3% propylene glycol
10% total
100% cetanol, polyoxyethylene (
30) Cetyl ethyl, glycerin monostearate,
Liquid paraffin and white petrolatum were dissolved by heating, and after lidocaine and triethanolamine were added thereto, miconazole nitrate was further added and dissolved with stirring to form an oil phase. Separately, a mixture of purified water and propylene glycol was used as an aqueous phase, and while the aqueous phase and oil phase were heated to 70 to 80°C, both phases were mixed and emulsified to obtain a preparation.

In all of the external preparations of the present invention of Examples 1 to 6, the antifungal drug (I) as a medicinal ingredient was dissolved in the preparation, so the expression of antifungal activity was good, and the preparation was also stable. .

〔Effect of the invention〕

According to the present invention, since the antifungal agent is uniformly dissolved in the external use base, it has been possible to provide an antifungal external use agent with excellent efficacy and stability.

that's all

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, at least one of R^1, R^2 and R^3 represents a halogen atom. , the remainder is a hydrogen atom] is dissolved in all or a part of an external base using an amine and blended therein.