JPH0463852B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a clotrimazole-soluble gel composition that has high affinity for the skin and is pharmaceutically stable. Traditionally, topical treatments have been used to treat skin mycoses, in which various antibacterial agents are applied to the affected area in the form of ointments, creams, liquids, or aerosols, but complete treatment is often difficult. The main reason for this is that skin fungi generally grow inside the stratum corneum, which covers the outermost layer of the skin, and are therefore difficult to penetrate with normal compositions containing antibacterial agents. Therefore, the results of topical therapy are greatly influenced by the thickness of the stratum corneum at the lesion site and the penetration power of the antibacterial agent into the stratum corneum, as well as the antibacterial activity of the drug. It is a homogeneous preparation dissolved in
It goes without saying that a drug formulation that has an affinity for the skin is important. By the way, in recent years, clotrimazole, i.e.
1-[(2-chlorophenyl)diphenylmethyl]
Imidazole is active against fungi and is used to treat ringworm, candidiasis, and tinea versicolor. However, clotrimazole is extremely poorly soluble in water and organic solvents, and the number of solvents in which it can be dissolved is limited, which limits its formulation.
Only sprays (liquids) and vaginal tablets are commercially available. A gel preparation is also known in Japanese Patent Publication No. 57-48090, but it has 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. With the aim of developing a clotrimazole preparation that increases the effectiveness of the present invention, the present inventors have discovered a dissolving gel composition containing clotrimazole as an active ingredient in a new formulation that fully satisfies the above conditions, and have completed the present invention. The gel preparation of the present invention consists of the active ingredients clotrimazole, lower alcohols, glycols, stabilizers, gelling agents, water and neutralizing agents, and
The present invention relates to a gel composition whose pH value is adjusted to 7 to 9. In other words, the gel preparation of the present invention contains clotrimazole.
0.1 to 3% by weight, more preferably 0.5 to 2% by weight,
Lower alcohols include 30 to 50% by weight, preferably 35 to 45% by weight, of alcohols arbitrarily selected from ethanol, n-propanol, isopropanol, etc., 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.
~30% by weight, more preferably 5-20% by weight, the stabilizer consisting of diisopropyl adipate, 2-30% by weight;
10% by weight, more preferably 5 to 8% by weight, gelling agents include carboxyvinyl polymer, hydroxypropyl cellulose, hydroxyethylene cellulose, methylcellulose, etc., and the blending amount is 0.1 to 3% by weight, more preferably 0.1 to 2% by weight. % by weight, and these can be used alone or in combination. Examples of the neutralizing agent include organic amines such as methanolamine, ethanolamine, diethanolamine, 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.
An amount that can be adjusted within the range of ~8.5 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. Such clotrimazole gel formulation of the present invention is
Contains a moderate amount of volatile solvents such as lower alcohols,
In addition, it contains diisopropyl adipate, which is also a stabilizer and has skin affinity, penetration promoting effect, or dissolving effect, so it spreads easily on the skin, and the solvent evaporates with a refreshing feeling.
Clotrimazole forms a stable and concentrated colorless transparent film on the skin, does not peel off easily, and has an extremely good feeling of use. In addition, in this example, clotrimazole is completely dissolved, so the drug quickly penetrates into the stratum corneum.
Furthermore, since the skin covers the affected area, the main ingredient, clotrimazole, comes into contact with the affected area for a long time, and its efficacy lasts for a long time. In addition, 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 caused by decomposition products.
Alternatively, it is a gel preparation with excellent characteristics that causes extremely low incidence of other side effects. Next, a method for producing the gel preparation of the present invention will be explained. First, clotrimazole is dissolved at room temperature or under heat. Add glycols and water to diisopropyladipate, add gelling agent to diisopropyl adipate at room temperature, and stir. Add the gelling agent dispersion and stir. Add the aqueous solution of neutralizer and stir. Note that the above-mentioned operating method is not particularly limited, and production can also be carried out by a normal method at room temperature or under heating. Further, each of the upper solvents and bases are arbitrarily selected from the above description, and the blending amount is appropriately formulated within the above-mentioned weight percentage. Next, in order to confirm the relationship between the PH of the gel formulation of the present invention and the stability of clotrimazole, we produced trial gel formulations with different PH values, stored them at 60°C for 1 hour, and measured their changes over time. The results are shown in Table 1. The experimental results shown in Table 1 revealed that the PH value was unstable in acidic conditions. In addition, the gel preparation of the present invention and reference examples (Tokuko Sho
The gel formulation of Example 1 described in No. 57-48090 was stored at 60°C for two weeks, and its change over time was measured. Table 2 shows the results. 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 has excellent stability against changes over time. It is very useful as an antifungal preparation. The present invention will be explained in more detail below by giving Examples and Experimental Examples. Example 1 1 g of clotrimazole and 40 g of ethyl alcohol
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 diisopropyl adipate and dispersed, and this dispersion was added to the clotrimazole solution and stirred for 50 minutes.
Add 1.2g of diisopropanolamine to this and purified water.
10 g of the solution was added and stirred for 5 minutes to obtain a transparent clotrimazole-containing gel preparation. PH8.2 Example 2 1g of clotrimazole and 43g of ethyl alcohol
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 solution and stirred for 50 minutes. Add 1.3g of triethanolamine to this and purified water.
10 g of the solution was added and stirred for 5 minutes to obtain a transparent clotrimazole-containing gel preparation. PH8.8 Example 3 1g of clotrimazole and 35g of ethyl alcohol
β-Butylene glycol 15 is dissolved in this solution.
g and 30.5 g of purified water were added and stirred for 5 minutes. On the other hand, 0.8 g of carboxyvinyl polymer was added to 7 g of diisopropyl adipate and dispersed, and this dispersion was added to the 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 clotrimazole-containing gel preparation.
PH7.0 Reference example: 1g of clotrimazole to 4g of crotamiton
Heat to 70-80℃ to dissolve, gradually add 40g of ethyl alcohol to make a homogeneous solution, add 20g of 4% carboxyvinyl polymer aqueous solution and stir well, then add triethanolamine while stirring.
10.8 g of a 10% aqueous solution was gradually added, and then purified water was added to make a total amount of 100 g. After sufficient stirring, the mixture was cooled to obtain a transparent gel preparation. PH6.85 Experimental Example 1 In the same manner as in Example 1, the amount of diisopropanolamine was appropriately increased or decreased to obtain a formulation with a pH of 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] Experimental Example 2 The gels of Examples 1 to 3 and Reference Examples were stored at 60°C, and the contents were measured after 2 weeks, and the results shown in Table 2 were obtained.

【table】

Claims (1)

[Claims] 1. 30-50% by weight of lower alcohol, 5-30% by weight of glycols, 2-10% by weight of stabilizer, gelling agent.
A gel-like external composition characterized by containing 0.1 to 3% by weight of clotrimazole in a base consisting of 0.1 to 3% by weight, a neutralizing agent, and the remainder water, and having a pH value adjusted to 7 to 9. . 2. The gel composition for external use according to claim 1, wherein the lower alcohol is selected from the group consisting of ethanol and propanol. 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 comprises diisopropyl adipate. 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 gel composition for external use according to claim 1, wherein the neutralizing agent is selected from the group consisting of organic amines such as methanolamine, ethanolamine, diethanolamine, diisopropanolamine, triethanolamine, or triisopropanolamine.