JPH0226603B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to an antifungal external gel. PRIOR ART Today, tolnaftate and undecylenic acid are frequently used as dermal antifungal agents. Tolnaftate, i.e. N-methyl-N-
(3-Tolyl)thiocarbamic acid-2-naphthyl ester exhibits excellent antifungal activity, particularly against Trichophyton. In addition, undecylenic acid is a physiologically occurring fatty acid contained in human sweat, and has a mild effect on the human body, but it has a 10 ^-4 μ
g/ml, and exhibits an inhibitory effect on candidiasis at a concentration of about 10 ^-3 μg/ml, and both are used as therapeutic agents for athlete's foot, jock itch, and jock itch. In general, gels are transparent, jelly-like external preparations that have the characteristics of high permeability of the active ingredient into the skin and low stickiness when applied.
However, since the main drug must be dissolved,
Selection of the solvent becomes difficult. Tolnaftate is sparingly soluble in various polar solvents, and the solvents in which it can be dissolved are limited, and formulations containing it are mainly macrogol ointments, emulsion ointments, liquid preparations, and some gel preparations for external use. On the other hand, although undecylenic acid has no problem in solubility in solvents, when it is added to a gel base, the gel is destroyed and the viscosity is reduced. Therefore, no antifungal topical gel containing undecylenic acid is currently available on the market. Methyl ethyl ketone is known as a solvent for dissolving tolnaftate, and polyethylene glycols used in macrogol ointments are known. For example, JP-A-55-45662 discloses a tolnaftate-dissolving gel for external use. That is, in this publication, tolnaftate is dissolved in methyl ethyl ketone and polyethylene glycol, a gelling agent is added, and water and alcohol are further added to an extent that tolnaftate does not precipitate. However, since it contains polyethylene glycol, it causes stickiness on the applied surface and makes it uncomfortable to use.
Furthermore, polyethylene glycol is not an excellent solvent for permeating tolnaftate into the skin, and does not take full advantage of its characteristics as a gel base. Composition of the Invention The present inventors focused on the skin permeability of tolnaftate and undecylenic acid, conducted intensive research on external gels, obtained a lot of knowledge, and completed the antifungal external gel according to the present invention. be. The antifungal topical gel according to the present invention is a topical gel containing tolnaftate and/or undecylenic acid, propylene glycol and/or 1,3-butylene glycol, and is characterized by not containing lower monohydric alcohol. It preferably contains 1 to 4% by weight of tolnaftate and/or 3 to 10% by weight of undecylenic acid based on the agent. Glycols to be incorporated into the external gel according to the present invention include propylene glycol, 1,3-butylene glycol, or a mixture thereof, and the amount thereof is 3 to 60% by weight, preferably 10 to 45% by weight based on the agent. Weight%. The external gel according to the present invention can also contain ketones, water, carboxyvinyl polymer, and a neutralizing agent. The ketones are preferably methyl ethyl ketone, acetone, or a mixture thereof, and the amount thereof is 10 to 60% by weight, preferably 15 to 55% by weight based on the agent. In the present invention, the water content is 1 to 35% by weight, preferably 5 to 30% by weight. In addition, the carboxyvinyl polymer blended into the antifungal topical gel according to the present invention is an acidic polymer compound, mainly an acrylic acid polymer, and the commercially available product is Carbopol (BFGoodrich Chemical Co., Ltd.).
(manufactured by Wako Pure Chemical Industries, Ltd.) or Hibis Wako (manufactured by Wako Pure Chemical Industries, Ltd.). The amount of carboxyvinyl polymer blended is 0.3 to 5% by weight based on the agent.
Preferably it is 0.5 to 2.5% by weight. Usually, the carboxyvinyl polymer is neutralized with a basic substance to obtain a suitable gel, if necessary. These basic substances include amines such as monoethylamine, diethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, tributylamine, trioctylamine, etc.; ammonia; alkali; metal salts,
Examples include sodium hydroxide, potassium hydroxide, sodium borate, potassium carbonate, etc. Among these, amines are particularly preferably used. A neutralizing agent is used so that the pH of the external gel becomes 4 to 10. EXAMPLES The present invention will be specifically explained in detail with reference to Examples below. Example 1 An antifungal external gel containing tolnaftate as shown in Table 1 was applied to the back skin of a hairless mouse, and the amount of tolnaftate permeated was measured. The results were as shown in Table 1.

【table】

[Table] As shown in the results in Table 1, the antifungal topical gel of the present invention containing propylene glycol and 1,3-butylene glycol had superior permeability compared to the conventional gel containing polyethylene glycol. . Furthermore, when coated with propylene glycol or 1,3-butylene glycol, the coated surface did not become sticky, unlike the conventional example containing polyethylene glycol 400, and the feeling of use was particularly good. Example 2 The amount of undecylenic acid permeated through the antifungal topical gel shown in Table 2 using undecylenic acid was measured in the same manner as in Example 1. The results were as shown in Table 2.

[Table] As shown in the results in Table 2, the antifungal topical gel containing propylene glycol or 1,3-butylene glycol containing undecylenic acid had particularly excellent permeability compared to the comparative example containing polyethylene glycol. . Moreover, when the coating containing propylene glycol or 1,3-butylene glycol was applied, the coated surface did not become sticky unlike the conventional example, and the feeling of use was particularly good. Example 3 The amount of permeation of tolnaftate and undecylenic acid in the antifungal external gel shown in Table 3 containing tolnaftate and undecylenic acid was measured in the same manner as in Example 1. The results were as shown in Table 3.

[Table] From the results in Table 3, propylene glycol combined with tolnaftate and undecylenic acid,
Antifungal external gels containing 1,3-butylene glycol have stronger antibacterial activity than those containing polyethylene glycol 400. That is, when tolnaftate and undecylenic acid are used together, the tolnaftate permeation amount is 18.8, 17.9, and ng/πcm ² /24hr, respectively, when 40.0g of propylene glycol or 1,3-butylene glycol is blended with 1.0g of tolnaftate. As shown in Table 1, when using tolnaftate alone, add propylene glycol or 1,3-butylene glycol to 2.0 g of tolnaftate.
When combined with 45.0g, the permeation amount of tolnaftate was 16.8 and 17.3ng/πcm ² /24hr, respectively, and although the amounts of tolnaftate and glycols were both small, the permeation was higher when used together than when used alone. This trend was exactly the same for undecylenic acid. Propylene glycol, 1,
When 3-butylene glycol was used, its permeation amount was particularly excellent. Example 4 The amount of permeation of tolnaftate and undecylenic acid was measured in the same manner as in Example 1 through an antifungal external gel of the following formulation according to the present invention in which tolnaftate and undecylenic acid are used in combination. The results were as shown in Table 4. Tolnaftate 1.0% by weight Undecylenic acid 3.0 Diphenhydramine 0.5 Propylene glycol 25.0 Methyl ethyl ketone 50.0 Carbopol 940 2.4 Triisopropanolamine 0.7 Diisopropyl adipate 3.0 Add purified water to total volume 100.0 〃 Example 5 Tolnaftate and undecylene The amount of permeation of tolnaftate and undecylenic acid was measured in the same manner as in Example 1 through the gel preparation for external use according to the present invention in which an acid was used in combination as described below. The results were as shown in Table 4. Tolnaftate 1.0% by weight Undecylenic acid 3.0 Diphenhydramine 0.5 Urea 3.0 Glycyrrhetinic acid 0.3 1,3-Butylene glycol 35.0 Methyl ethyl ketone 35.0 Carbopol 940 1.5 Metrose 60SH-40 00 (Shin-Etsu Chemical) 1.5 〃 Triethanol Amine 0.5 Diethyl sebacate 3.0 Fragrance Total amount 100.0% by weight with addition of a small amount of purified water Example 6 The permeation amount of tolnaftate was measured in the same manner as in Example 1 in the following external gel according to the present invention containing only tolnaftate. The results were as shown in Table 4. Tolnaftate 4.0% by weight Lidocaine 2.0 Glycyrrhetinic acid 0.5 Methyl ethyl ketone 55.0 1,3-butylene glycol 15.0 Carbopol 940 2.0 Triethanolamine 0.8 Total volume with purified water 100.0 Example 7 Unde The present invention containing silenic acid alone The amount of undecylenic acid permeated through the following external gel was measured in the same manner as in Example 1. The results were as shown in Table 4. Undecylenic acid 10.0% by weight Methyl salicylate 2.0 〃 Methyl ethyl ketone 18.0 〃 Propylene glycol 50.0 〃 Carbopol 940 2.5 〃 Metrose 60SH-4000 (Shin-Etsu Chemical) 2.0 〃 Triisopropanolamine 0.5 〃 Add purified water to make 100.0 〃

[Table] The results in Table 4 show that the tolnaftate and undecylenic acid of the antifungal topical gel containing propylene glycol or 1,3-butylene glycol according to the present invention are superior to the commercially available products containing polyethylene glycol, that is, Comparative Examples A and B. It was clear that its permeability was excellent. As shown in the examples, the antifungal topical gel of the present invention may optionally include antipruritic agents such as diphenhydramine, analgesics such as lidocaine, keratolytic agents such as urea, anti-inflammatory agents such as glycyrrhetinic acid, etc. Stabilizers such as sodium edetate and antioxidants, penetration enhancers such as diethyl sebacate and diisopropyl adipate, thickeners such as methylcellulose, fragrances, and the like can be appropriately blended. Effects of the Invention The antifungal topical gel according to the present invention has excellent solubility of tolnaftate and undecylenic acid, no precipitation of the active ingredient even during long-term storage at low temperatures, particularly excellent permeability into the skin, and when applied. It is non-sticky and exhibits a high therapeutic effect.

Claims (1)

[Scope of Claims] 1. An antifungal gel for external use containing tolnaftate and/or undecylenic acid and propylene glycol and/or 1,3-butylene glycol, characterized in that it does not contain lower monohydric alcohol. External gel. 2. The antifungal external gel according to claim 1, which contains 1 to 4% by weight of tolnaftate and/or 3 to 10% by weight of undecylenic acid. 3. In the external gel according to claim 1, the content of propylene glycol and/or 1,3-butylene glycol is 3% relative to the external gel.
Antifungal topical gel that is ~60% by weight.