JPH02292219A - Liquid treating agent for mycosis - Google Patents

Abstract

PURPOSE:To obtain the subject remedy effective for dermatomycosis such as trichophytosis and candidasis, having excellent absorption in keratin layer of skin, free from layer separation and precipitation during the term of preservation by dissolving clotrimazole and urea in a specific mixed solvent. CONSTITUTION:Clotrimazole and urea are dissolved in a mixed solvent of ethanol, a glycol or glycerin and water to give a liquid treating agent. The blending ratio is 0.1 to 5wt.% clotrimazole and 3 to 15wt.%, preferably 5 to 10wt.% urea. The blending ratio of the mixed solvent blended is usually 20 to 70wt.%, preferably 30 to 50wt.% ethanol, usually 1 to 30wt.%, preferably 5 to 15wt.% glycol or glycerin and the residue of water. Further, the subject treating agent remedy is preferably used with 2 to 6wt.% ionic surfactant.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a therapeutic agent for liquid mycosis.
The present invention relates to a liquid mycosis therapeutic agent that is liquid, has excellent skin permeability, and has a high therapeutic effect.

(Prior art and its problems) Clotrimazole is known as a therapeutic agent for skin fungal diseases such as white spot, candidiasis, and corianderma.As a therapeutic agent for mycotic diseases, it is used in the form of a liquid or ointment. However, in the case of liquid formulations, they are generally fluid, so they have poor spreading properties on the applied surface, tend to flow out from the applied surface, and the solvent evaporates easily, causing clotrimazole crystals to precipitate and cause skin irritation. It has the disadvantage of not sufficiently penetrating into the stratum corneum.On the other hand, ointments are sticky and cause discomfort to the user, and clotrimazole does not penetrate the stratum corneum as efficiently as it comes into contact with the skin. Furthermore, it has the disadvantage that it is easily removed due to friction with clothing, etc.Furthermore, fungi such as Alterinibacterium and Microsporobacterium proliferate within the stratum corneum of the skin, so they do not promote the penetration of antifungal agents. Otherwise, a sufficient therapeutic effect cannot be obtained, so it is generally desirable to use an absorption enhancer in combination in order to promote the absorption of drugs into the stratum corneum.

However, if a conventionally known absorption enhancer is used in combination, the stability of clotrimazole may be affected in some cases, making it impossible to obtain a good antifungal effect. And especially,
In the case of a liquid formulation, it is necessary to uniformly dissolve both clotrimazole and the absorption enhancer, but it has been difficult to obtain a stable homogeneous solution because the solubility of the two is different.

(Problems to be solved by the invention and means for solving the problem) In view of the above-mentioned circumstances, the present inventor selected an absorption enhancer suitable for clotrimazole as a therapeutic agent, and moreover, uniformly distributed both the therapeutic agent and the absorption enhancer. As a result of various studies in order to obtain a liquid mycosis treatment agent that dissolves in water and has excellent spreadability and permeability into the skin, we selected urea as the absorption enhancer, and three components: ethanol, glycols or glycerin, and water. The present inventors have discovered that the object of the present invention can be achieved by preparing a liquid product using a mixed solvent containing the following, and have completed the present invention.

That is, the gist of the present invention resides in a liquid mycosis therapeutic agent characterized by dissolving clotrimazole and urea in a mixed solvent consisting of (a) ethanol, (b) glycols or glycerin, and (C) water.

Hereinafter, the configuration of the present invention will be explained in detail.

The present invention contains clotrimazole as a therapeutic drug component, and its content is usually 0.1 to 5% by weight. If the amount is too small, a sufficient antifungal effect cannot be expected; on the other hand, if the amount is too large, the effect remains the same and it is not economical.

In the present invention, urea is blended together with clotrimazole as an absorption enhancer into the skin, and the amount of urea blended is usually 3 to 15% by weight, preferably 5 to 10% by weight. If the amount used is too small, the keratin softening effect on the skin will be insufficient, while if it is used too much, it is undesirable from the viewpoint of safety. In addition to urea, this type of absorption enhancer generally includes, for example,
Salicylic acid, lactic acid, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, diethyl sebacate, etc. are known, but in the case of the liquid product containing clotrimazole of the present invention as a therapeutic ingredient, the stability and absorption effect of the therapeutic agent From this point of view, urea is the most suitable.

In the present invention, the above-mentioned clotrimazole and urea are dissolved in a specific mixed solvent consisting of ethanol-glycols or glycerin-water, and the amount of ethanol blended is usually 20 to 70% by weight, preferably 30 to 50% by weight. The content of glycols or glycerin is usually 1 to 30% by weight, preferably 5 to 15% by weight, and the remaining amount is water. Specific examples of glycols include propylene glycol, 1,3-butylene glycol, polyethylene glycol 200, 300, 4
00,450,500,600,1000,1500,
1540, 2000.4000, 6000, 9000,
Examples include 20000, 30000.60000.

In this way, in the present invention, by using a specific mixed solvent,
It is possible to uniformly dissolve both clotrimazole and urea, and to obtain a stable liquid product that does not undergo layer separation or precipitation during storage.

As a result, it becomes a therapeutic agent that has a large penetration effect into the skin. For example, if ethanol or water is not used, a precipitate will form and a homogeneous solution cannot be obtained. In addition, if the amount of ethanol used is too large, it may form a precipitate and become cloudy, and if the amount of glycols used is too large, it may become sticky during use, so take these into consideration when adjusting the amount used. It is necessary to select

In the present invention, it is desirable to use a nonionic surfactant in combination, since even more excellent effects can be obtained. In this case, the blending amount is usually 0. It is 5 to 10% by weight, preferably 2 to 6% by weight.

Specific examples of nonionic surfactants include the following.

■Ether type nonionic surfactants Polyoxyethylene alkyl ether (polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, etc.), polyoxyethylene alkyl phenyl ether (polyoxyethylene alkyl phenyl ether) (oxyethylene nonyl phenyl) ■Koichi terester type nonionic surfactant Polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polymonopalmitate) (oxyethylene sorbitan, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, etc.), polyoxyethylene sorbitan glyceryl fatty acid ester (polyoxyethylene glycerin monostearate, etc.), polyoxyethylene propylene glycol fatty acid ester, polyoxyethylene Sorbitol fatty acid esters (polyoxyethylene sorbitate tetraoleate, polyoxyethylene sorbitol hexasteate, polyoxyethylene sorbitol monolaurate, beeswax, polyoxyethylene sorbitol, etc.)
, polyoxyethylene derivatives of natural oils and fats and waxes (polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene lanolin, etc.) ■ Ester-type nonionic surfactants Polyoxyethylene fatty acid esters (monooleic acid poly (ethylene glycol, polyethylene glycol monostearate, polyethylene glycol monolaurate, etc.), polyhydric alcohol esters (sorbitan monooleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, etc.) ■Nitrogen-containing nonionic surfactant such as coconut oil fatty acid diethanolamide, lauric acid diethanolamide, etc. ■Protect polymer type nonionic surfactant In addition, if necessary, for example, glycyrrhetinic acid, glycyrrhizic acid, and derivatives thereof, etc. anti-inflammatory agents, antihistamines such as chlorpheniramine maleate, diphenhydramine and its salts, dimenhydrinate, promethazine hydrochloride, alkanolamines such as triethanolamine, alkylamines such as methylamine, ammonia, alkali hydroxide A pH adjuster such as, a bactericidal agent, etc. may be added as appropriate. In addition, even better effects can be obtained by incorporating herbal medicines such as Mizuokepi tincture.

(Effects of the Invention) According to the present invention, since urea is contained as an absorption enhancer together with clotrimazole, absorption into the stratum corneum of the skin is very good. Moreover, the presence of this absorption enhancer does not inhibit the stability of clotrimazole, which is preferable. Moreover, the liquid mycosis therapeutic agent of the present invention is a transparent homogeneous solution, and is a stable solution without precipitation of precipitates even during storage. Furthermore, when this therapeutic agent is applied, there is no leakage of liquid, and it has excellent spreadability and permeability into the skin.

(Example) Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the description of the following embodiments unless it exceeds the gist thereof.

Example 1 and Comparative Examples 1-2 Clotrimazole 1q Absorption enhancer shown in Table 1 5 tt Ethanol
4Qrt propylene glycol
5 II polyoxyethylene laurate
2 // Glycyrrhetin M O. 2〃Diphenhydramine hydrochloride 0.5〃Birch bark tincture 10l! Dilute to 100 ml with 1 liter of triethanolamine/purified water.

When each of the liquid therapeutic agents prepared with the above composition was applied to the stratum corneum of the skin, there was no leakage, good permeability, and no stickiness on the skin surface. Moreover, this liquid therapeutic agent was a transparent solution in which the components were uniformly dissolved.

Then, a storage stability test was conducted on each liquid therapeutic agent at 40° C., and the residual rate of clotrimazole was measured, and the results shown in Table 1 were obtained.

In other words, it can be seen that when salicylic acid or lactic acid other than urea is added, clotrimazole is significantly degraded and cannot be used practically as a therapeutic agent.

Clotrimazole 2g urea
7″ ethanol
45l/polyethylene glycol 4
00 10//Borioxyethylene hydrogenated castor oil
2 II Wood ridge bark tincture 1
Make up to 100ml with 0# purified water.

When the liquid therapeutic agent prepared with the above composition was applied to the stratum corneum of the skin, there was no leakage, good permeability, and no stickiness on the skin surface. Also,
This liquid therapeutic agent was a transparent solution in which the ingredients were uniformly dissolved.

Claims (1)

[Claims] (1) A liquid mycosis therapeutic agent, characterized in that clotrimazole and urea are dissolved in a mixed solvent consisting of (a) ethanol, (b) glycols or glycerin, and (c) water.