JPH0725675B2 - Liquid mycosis agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to a therapeutic agent for liquid mycosis, and more specifically,
The present invention relates to a liquid fungal disease therapeutic agent which is liquid and has excellent penetrability into the skin and has a high therapeutic effect.

(Prior art and its problems) Clotrimazole is known as a therapeutic agent for dermatomycosis such as ringworm, candidiasis, and tinea versicolor. Although it is used in the form of liquid medicine or ointment as a fungal disease treatment agent, in general, liquid medicine has poor spreadability on the coated surface because it has fluidity, and it easily flows out from the coated surface and the material easily volatilizes. Therefore, there is a drawback that crystals of clotrimazole are broken out and do not sufficiently penetrate into the stratum corneum of the skin. On the other hand, in the case of an ointment, it is sticky and causes discomfort to the user, and since the contact of clotrimazole on the skin is small, the penetration efficiency into the stratum corneum is poor, and it is easily removed by friction with clothes. There is a drawback that. In addition, fungi such as Trichophyton and microspores propagate inside the stratum corneum of the skin, and unless the penetration of the antifungal agent is promoted, a sufficient therapeutic effect cannot be obtained. It is desirable to use an absorption enhancer together in order to promote absorption into the skin.

However, when a conventionally known absorption enhancer is used in combination, the stability of clotrimazole is affected in some cases, and a good antifungal effect cannot be obtained. And, in particular,
In the case of a liquid preparation, it is necessary to uniformly dissolve both clotrimazole and the absorption enhancer, but it is difficult to obtain a stable uniform solution because the solubility of both is different.

(Problems and Solutions of the Invention) In view of the above circumstances, the present inventor, when clotrimazole is used as a therapeutic agent, selects an absorption enhancer suitable for the therapeutic agent, and moreover, makes both the therapeutic agent and the absorption enhancer uniform. As a result of various studies to obtain a therapeutic agent for liquid mycosis that is soluble in, and has excellent spreadability and permeability on the skin, urea was selected as an absorption promoter,
Moreover, they have found that the object of the present invention can be achieved by preparing a liquid product using a mixed solvent containing three components of ethanol, glycols or glycerin and water, and have completed the present invention.

That is, the gist of the present invention is to include clotrimazole 0.1 to 5
% By weight, 3-15% by weight urea, 20-70% by weight ethanol,
A liquid mycosis treatment agent is characterized by containing 1 to 30% by weight of glycols or glycerin, 0.5 to 10% by weight of a nonionic surfactant, and the balance being water.

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

In the present invention, clotrimazole is contained as a therapeutic drug component, and its compounding amount is usually 0.1 to 5% by weight.
Is. If the blending amount is too small, a sufficient antifungal action cannot be expected, and conversely, if the blending amount is too large, the effect does not change and it is not economical.

In the present invention, urea is blended with clotrimazole as a skin absorption promoter, and the blending amount of urea is usually 3 to 15% by weight, preferably 5 to 10% by weight. If this amount is too small, the keratin softening effect on the skin is insufficient, while if too large, it is not desirable from the viewpoint of safety. In addition, generally, as this kind of absorption enhancer, in addition to urea, for example, salicylic acid, lactic acid, dimethylsulfoxide, dimethylacetamide, dimethylformamide, diethyl sebacate, etc. are known. In the case of a liquid product containing sol as a therapeutic ingredient, urea is most suitable in terms of stability and absorption effect of the therapeutic agent.

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 is usually 20 to 70% by weight, preferably 30 to 50% by weight. %, And the blending amount of glycols or glycerin is usually 1 to 30% by weight, preferably 5 to 15% by weight, and the balance is water. Specific examples of glycols include propylene glycol, 1,3-butylene glycol, polyethylene glycol 200,300,400,450,500,600,
1000,1500,1540,2000,4000,6000,9000,20000,30000,600
For example, 00.

Thus, in the present invention, the use of a specific mixed solvent causes
It is possible to uniformly dissolve both clotrimazole and urea, and to obtain a stable liquid product which does not cause layer separation or breakage during storage. As a result, it becomes a therapeutic agent having a large effect of penetrating into the skin. For example, if ethanol or water is not used, a precipitate will form and a homogeneous solution cannot be obtained. If the amount of ethanol used exceeds 70% by weight, skin irritation will increase, and
If it is less than 10% by weight, a precipitate may be formed, which may cause cloudiness.
Not suitable. Further, if the amount of glycols used exceeds 30% by weight, it may become sticky during use, and if it is less than 1% by weight, crystals of clotrimazole may precipitate.
Not suitable.

In the present invention, further, since a nonionic surfactant is used in combination, penetration into the stratum corneum of the skin is further promoted, the therapeutic effect of dermatomycosis is enhanced, and clotrimazole is rapidly and uniformly dissolved. A stable liquid therapeutic agent for mycosis can be obtained. The compounding amount in this case is usually 0.5 to 10% by weight, preferably 2 to 6% by weight. The following may be mentioned as specific examples of the nonionic surfactant.

Ether-type nonionic surfactant Polyoxyethylene alkyl ether (polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, etc.), polyoxyethylene alkylphenyl ether (polyoxyethylene Nonyl phenyl ether etc. Ether ester type nonionic surfactant Polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene monolaurate) Sorbitan, polyoxyethylene sorbitan trioleate, etc.), polyoxyethylene sorbitan glyceryl fatty acid Tell (polyoxyethylene glycerin monostearate etc.), polyoxyethylene propylene glycol fatty acid ester, polyoxyethylene sorbitol fatty acid ester (tetraoleic acid polyoxyethylene sorbit, hexastearate polyoxyethylene sorbit, monolauric acid polyoxyethylene sorbit, Polyoxyethylene sorbit beeswax, etc.), natural oils and fats and polyoxyethylene derivatives of waxes (polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene lanolin, etc.) Ester-type nonionic surfactant Polyoxyethylene fatty acid Ester (polyethylene glycol monooleate, 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 Coconut oil fatty acid diethanolamide, lauric acid diethanolamide, etc. Block polymer type nonionic surfactants Further, if necessary, for example, anti-inflammatory agents such as glycyrrhetinic acid, glycyrrhizinic acid and their derivatives, chlorpheniramine maleate, diphenhydramine and salts thereof, dimenhydrinate, promethazine hydrochloride, etc. Antihistamines, alkanolamines such as triethanolamine, alkylamines such as methylamine, pH adjusters such as ammonia and alkali hydroxide, bactericides, etc.
It can also be blended. In addition, a more excellent effect can be obtained by mixing a crude drug such as tincture of wood peel.

(Effect of the invention) According to the present invention, since it contains urea and a nonionic surfactant as an absorption enhancer together with clotrimazole, the absorption into the stratum corneum of the skin is extremely good, and the skin fungus Highly effective in treating diseases. Moreover, due to the presence of urea, a storage stability of clotrimazole in the liquid preparation is extremely good, which is a previously unknown effect. Moreover, since urea is inexpensive, economic cost does not increase. In addition, the therapeutic agent for liquid mycosis of the present invention is a transparent homogeneous solution, and is a stable solution even during storage without precipitation of a precipitate. Furthermore, when applying this therapeutic agent,
It has no outflow of liquid, and has excellent spreadability and permeability to the skin.

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

Example 1 and Comparative Examples 1-2 Clotrimazole 1 g Absorption enhancer shown in Table 1 5 〃 Ethanol 40 〃 Propylene glycol 5 〃 Polyoxyethylene laurate 2 〃 Glycyrrhetinic acid 0.2 〃 Diphenhydramine hydrochloride 0.5 〃 Woodcutter skin tincture 10 〃 Triethanolamine 1〃 Make up to 100ml with purified water.

When each liquid therapeutic agent adjusted to the above composition was applied to the stratum corneum of the skin, the liquid did not flow out, the permeability was good, and the surface of the skin was not sticky. The liquid therapeutic agent was a transparent solution in which the components were uniformly dissolved.

Then, a storage stability test at 40 ° C. of each liquid therapeutic agent was performed, and the residual rate of clotrimazole was measured,
The results shown in Table 1 were obtained. That is, it can be seen that clotrimazole is significantly decomposed by adding salicylic acid or lactic acid other than urea and cannot be put to practical use as a therapeutic agent.

Comparative Example 3 When a similar liquid therapeutic agent was prepared by adding water instead of adding ethanol in the method of Example 1, a liquid product containing a precipitate in which the components were not uniformly dissolved was obtained.

Example 2 Clotrimazole 2 g Urea 10 〃 Ethanol 50 〃 Glycerin 10 〃 Polyoxyethylene nonylphenyl ether 3 〃 Diphenhydramine 0.5 〃 Purified water to make 100 ml.

When the liquid therapeutic agent prepared in the above composition was applied to the stratum corneum of the skin, the liquid did not flow out, the permeability was good, and the skin surface was not sticky. Also,
This liquid therapeutic agent was a transparent solution in which the components were uniformly dissolved.

Example 3 Clotrimazole 2 g Urea 7 〃 Ethanol 45 〃 Polyethylene glycol 400 10 〃 Polyoxyethylene hydrogenated castor oil 2 〃 Kakikin tincture 10 〃 Purified water to make 100 ml.

When the liquid therapeutic agent prepared in the above composition was applied to the stratum corneum of the skin, the liquid did not flow out, the permeability was good, and the skin surface was not sticky. Also,
This liquid therapeutic agent was a transparent solution in which the components were uniformly dissolved.

Table 2 shows each composition amount (g) of Example 4 and Comparative Examples 4 to 8, and Table 3 shows the difference in solubility and feeling of use.

That is, when ethanol deviates from the range of 20 to 70% by weight (Comparative Examples 4 to 6), and when propylene glycol is 1
When it deviates from the range of 30% by weight (Comparative Examples 7 and 8), at least one of solubility and usability deteriorates, and it cannot be put to practical use as a therapeutic agent.

Claims (1)

[Claims] 1. Clotrimazole 0.1-5% by weight, urea 3
~ 15% by weight, ethanol 20-70% by weight, glycols or glycerin 1-30% by weight, nonionic surfactant
A therapeutic agent for liquid mycosis, characterized by comprising 0.5 to 10% by weight and the balance water.