JPS6061518A - Gelatinous external composition - Google Patents

Abstract

PURPOSE:A gelatinous external composition, containing ''Clotrimazole '' in a base consisting of a lower alcohol, glycol, stabilizer, gelling agent, neutralizing agent and water, having a high affinity for the skin, and containing a pharmaceutically stable antifungal agent. CONSTITUTION:A gelatinous external composition, obtained by incorporating 0.1-3wt% ''Clotrimazole'', i.e. 1-[(2-2-chlorophenyl)diphenylmethyl] imidazole in a base consisting of 30-50wt% lower alcohol, e.g. ethanol, 5-30wt% glycol, e.g. propylene glycol, 2-10wt% stabilizer, e.g. diisopropyl adipate, 0.1-3wt% gelling agent, e.g. carboxyvinyl polymer, a neutralizing agent and water, and 7-9pH. The above-mentioned composition is capable of extending well on the skin and evaporating the solvent with refreshing feeling. The ''Clotrimazole'' remains in a concentrated state on the skin, and the penetration into the horny layer is rapidly carried out.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a lotrimazole-soluble gel composition for external use that has high affinity for the skin and is pharmaceutically stable.

Traditionally, treatments for skin mycosis include various antibacterial agents, ointments,
External treatments applied to the affected area in the form of creams, liquids, and aerosols are often used, but it is often difficult to completely treat the skin. The main reason for this is that antibacterial agents are difficult to penetrate in a normal composition containing an antibacterial agent because they propagate inside the corner 'eI#i. Therefore, the results of external therapy are greatly influenced by the thickness of the stratum corneum at the lesion site and the strength of the antibacterial agent's penetration into the stratum corneum, as well as the antibacterial activity of the drug. Needless to say, it is important to formulate a drug that is a uniformly dissolved preparation, has excellent drug stability, strong penetrating power, and has an affinity for skin debris.

By the way, in recent years, clotrimazole, i.e., 1,-(
(2-Chlorophenyl)diphenylmethylcoimidazole is active against fungi and is used to treat albinism, candidiasis, and Kawakaze.

However, because ricotrimazole is poorly soluble in water and organic solvents (for the first time ever) and the solvents in which it can be dissolved are limited, its formulation is limited, and currently only creams, sprays (liquid preparations), and vaginal tablets are available. is commercially available.

Gel preparations are also known in Japanese Patent Publication No. 57-48090, but have not been commercially available. Therefore, the present inventors have developed a method that is easier to use than commercially available creams, liquids, and known gel preparations, has a good feel, has a high affinity for the skin, has good formulation stability, and has therapeutic efficacy. The inventors discussed the development of a clotrimazole preparation that would enhance the above-mentioned conditions, and found a dissolving gel composition containing clotrimazole as an active ingredient in a new formulation that fully satisfies the above conditions, thereby completing the present invention.

The gel preparation of the present invention contains clotrimazole as an active ingredient,
Lower alcohols, glycols, stabilizers, gelling agents,
The present invention relates to a gel composition comprising water and a neutralizing agent and having a pH value of 7 to 9.

In other words, the gel preparation of the present invention has clotrimazole of 0.1 to
3% by weight, more preferably 0.5 to 2% by weight, and the lower alcohol is ethanol or n-propertool.

Alcohol cheek 3 arbitrarily selected from isoproper tools etc.
0 to 50% by weight, more preferably 35 to 45% by weight, and glycols include propylene glycol, polyethylene glycol, butylene glycol (e.g., α-butylene glycol, β-butylene glycol, β, γ-butylene glycol, ψ-butylene glycol) ), etc., and can be used alone or in combination, and the blending amount is 5 to 30% by weight, more preferably 5 to 20i1
[%, the stabilizer consists of diisopropyl adibate,
2 to 10% by weight, more preferably 5 to 8% by weight, gelling agents include carboxyvinyl polymer, hydroxypropyl cellulose, high [S-roxyethylene cellulose or methylcellulose, and the blending amount is 0.1 to 3% by weight. %, more preferably 0.1 to 2%, and these can be used alone or in combination. Examples of the neutralizing agent include organic amines such as methanolamine, ethanolamine, jetanolamine, diisopropanolamine, triethanolamine, and triisopropanolamine. Moreover, the neutralizing agent has a pH value of the gel composition in the range of 7 to 9, more preferably 7.5 to 8.
．． An amount that can be adjusted within a range of 5 is required. The remaining water is commonly used water, more preferably purified water.

As described above, clotrimazole is poorly soluble and has low solubility, and in order to completely dissolve clotrimazole and obtain a clear gel, it is necessary to use a large amount of soluble solvent.

On the other hand, in order to obtain a gel of appropriate hardness that has affinity and stability for gel formulations, it is not preferable to use a large amount of solvent.

The present invention overcomes these contradictory requirements by using the above-mentioned bases in the above-mentioned mixing ratios.

The clotrimazole gel preparation of the present invention contains an appropriate amount of a volatile solvent such as a lower alcohol, and also contains diisopropyl adibate, which is also a stabilizer and has skin affinity, penetration promoting action, or dissolving action. Because of this, it spreads well on the skin, the solvent evaporates with a cooling sensation, and clotrimazole forms a colorless and transparent film on the skin that is stable and dissolved in a concentrated state, and does not peel off easily. , and the usability is also very good. In addition, in the main rule, since clotrimazole is completely dissolved, the drug quickly penetrates into the stratum corneum, and a film covers the affected area, so clotrimazole, the main ingredient, does not come into contact with the affected skin for a long time. The gel of the present invention maintains clotrimazole stably and extremely suppresses the production of decomposition products, so it does not cause skin irritation or itching due to decomposition products, or other side effects. It is a gel formulation with unique characteristics that has an extremely low incidence of

Next, the method for producing the Kel formulation of the present invention will be explained.

First, 1) Clotrimazole is melted at room temperature or under heat. Add glycols and water to ■■. ■
Add gelling agent to diisopropyl adipate at room temperature) and stir. Add the gelling agent dispersion from ■■ to ■ and stir. ■
Add the aqueous solution of neutralizing agent to ■ and stir.

In addition, the above-mentioned one-shiba production method is not particularly limited,
It can also be produced by conventional methods at room temperature or under heating. Further, each of the above-mentioned solvents and bases are arbitrarily selected from the above description, and the blending amounts are appropriately formulated within the above-mentioned weight percentages.

Next, in order to confirm the relationship between the pH of the gel formulation of the present invention and the stability of clo-1-rimazole, we produced trial gel formulations with different pH values, stored them at 60°C for one week, and observed their changes over time. The measured results are shown in Table 1. The experimental results shown in Table 1 revealed that the pi value was unstable in acidic conditions.

In addition, the gel preparation of the present invention and reference examples (Japanese Patent Publication No. 57-4
The gel formulation of Example 1 described in 8090) was
Table 2 shows the results of storing at ℃ for 2 weeks and measuring changes over time.
Shown below. The experimental results shown in Table 2 revealed that the gel formulation of the present invention had excellent stability.

As is clear from the above experimental results, the clotrimazole-containing gel formulation of the present invention is a novel gel formulation first discovered by the present inventors, and is extremely stable against changes over time. It is very useful as an antifungal preparation.

The present invention will now be described in more detail with reference to Examples and Experimental Examples.

Example 1 1 g of clotrimazole was dissolved in 40 g of ethyl alcohol, and 15 g of propylene glycol and 23.8 g of purified water were added to this solution and stirred for 5 minutes.

On the other hand, 1 g of carboxyvinyl polymer was added to 8 g of Shiitubu 1-1 bil adipate and dispersed, and this dispersion was added to the SENORI+:r l-IJ-7 sol solution and stirred for 50 minutes. Add 1.2g of diisopropanolamine to this.
A solution dissolved in 10 g of ice cubes was added and stirred for 5 minutes to obtain a transparent gel preparation containing lotrimazole. pl+
112 Example 2 1 g of clotrifsol was dissolved in 43 g of ethyl alcohol, and 10 g of propylene glycol and 27.9 g of purified water were added to this solution and stirred for 5 minutes.

On the other hand, 0.8 g of carboxyvinyl polymer was added to 6 g of diisopropyl adipate and dispersed, and this dispersion was added to the clotrimazole/8 solution and stirred for 50 minutes. A solution of 1.3 g of triethanolamine dissolved in 10 g of purified water was added to the mixture and stirred for 5 minutes to obtain a transparent gel preparation containing lotrimazole.

pl+8.8 Example 3 1 g of clotrimazole was dissolved in 35 g of ethyl alcohol, and 15 g of β-butylene glycol and 30.5 g of purified water were added to this solution and stirred for 5 minutes. On the other hand, 7 g of diisopropyl adipate and 0 carboxyvinyl polymer
, 8 g was added and dispersed, and this dispersion was added to the above clotrimazole solution and stirred for 50 minutes. A solution of 0.7 g of diisopropanolamine dissolved in 10 g of purified water was added to this and stirred for 5 minutes to obtain a transparent gel preparation containing lotrimazole. pl+7.0 Reference example: 1 g of clotrimazole to 4 g of crotamiton (approximately 70~)
(Heat to 0°C to dissolve, then gradually add 40g of ethyl alcohol to make a homogeneous solution. Add carboxyvinyl polymer 4% water'M?112OB and stir well. Gradually add 10.8 g of a 1()% aqueous solution of triethanolamine to the solution with stirring, and add purified water to bring the total amount to 1.
After stirring thoroughly, the mixture was cooled to obtain a transparent gel preparation. pH 6,85 Experimental Example 1 In the same manner as in Example 1, the amount of diisopropanolamine was increased or decreased as appropriate to obtain a preparation with a pl+6.5 to 9.0.

When these were stored at 60°C and the content was measured after one week, the results shown in Table 1 were obtained.

Table 1 ★ The content at the time of preparation was taken as 100%.

Experimental Example 2 The gels of Examples 1 to 3 and Reference Examples were stored at 60°C,
When the content was measured after two weeks, the results shown in Table 2 were obtained.

Table 2 The content at ``t[M'' was taken as 100%.

Claims (1)

[Claims] +11 30 to 50% by weight of lower alcohol, 5 to 30% by weight of glycol, 2 to 10% by weight of stabilizer, 0.1 to 3% by weight of gelling agent, and the balance is water. 0.1 to 3% by weight of clotrimazole is contained in a base consisting of the following, and the pH value is adjusted to 7 to 9. , I. A gel-like external composition characterized by being prepared. (2) The gel-like external composition according to claim 1, wherein the lower alcohol is selected from the group consisting of ethanol and propatool. (3) The gel composition for external use according to claim 1, wherein the glycol is selected from the group consisting of propylene glycol, butylene glycol, or polyethylene glycol. (4) The gel composition for external use according to claim 1, wherein the stabilizer is diisopropyladibate. (5) The gel composition for external use according to claim 1, wherein the gelling agent is selected from the group consisting of carboxyvinyl polymer, hydroxyethylene cellulose, hydroxypropyl cellulose, or methyl cellulose. (6) The neutralizing agent according to claim 1, wherein the neutralizing agent is selected from the group consisting of organic amines such as methanolamine, ethanolamine, jetanolamine, diisopropanolamine, triethanolamine, or triisopropanolamine. Gel composition for external use.