JPH07103028B2 - Imidazole antifungal topical solution - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel imidazole antifungal external liquid preparation, and more specifically, it has little skin irritation and exerts its effect to the maximum and continuously. And a physicochemically stable external preparation.

[Problems to be Solved by Prior Art and Invention]

Conventionally, imidazole-based antifungal agents having antibacterial activity against fungi have a wide antibacterial spectrum and have the advantage that clinically resistant bacteria are less likely to occur, so that they can be used as dosage forms such as creams, gels, and liquids. It is commercially available.

Of these, liquids generally have better spreadability than other dosage forms and can be applied to specific sites, but
Since it contains alcohol, there is a problem of skin irritation, and it is necessary to select an appropriate base. It is also required to enhance the antibacterial action, shorten the treatment period, and reduce the number of times of use. For this purpose, it is effective in treatment such as enhancing spreadability, maintaining good release, and enhancing storage effect. It is necessary to design the base material so that However, these effects have not been sufficiently obtained.

Therefore, there has been a demand for an antifungal external preparation which has little skin irritation and can sufficiently exhibit excellent effects.

[Means for Solving the Problems]

Under such circumstances, as a result of intensive studies, the present inventors have found that (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride is an active ingredient. As a result, the inventors have found that an external-use liquid formulation blended with a specific base has little skin irritation, can continuously exert a therapeutic effect, and is physicochemically stable, and completed the present invention.

That is, the present invention provides the following (a) to (d) (a) (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride 0.1- 5 W / V% (b) Liquid oily substance 1-50 W / V% (c) Nonionic surfactant 1-20 W / V% (d) Basic substance 0.01-2 W / V% The present invention provides a characteristic imidazole antifungal external liquid preparation.

In the present invention, (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride (hereinafter referred to as “compound A”) of component (a) used as an active ingredient. Is a known substance having an excellent antibacterial action against bacteria, fungi, etc.
63-146864).

The compound A is added in an amount of 0.1 to 5 W / V% (hereinafter simply referred to as%), preferably 0.5 to 1.5% in the total composition.

The liquid oily substance as the component (b) is not particularly limited as long as it is liquid at room temperature, but saturated fatty acid ester is particularly preferable, and examples thereof include diisopropyl adipate, diethyl sebacate, and isopropyl myristate. These can be used alone or in combination of two or more, and are added in an amount of 1 to 50%, preferably 5 to 40% in the total composition.

As the nonionic surfactant as the component (c), a polyoxyalkylene ester type or ether type surfactant is preferable, and an ester type of polyoxyethylene (POE) and a saturated fatty acid, or POE and a saturated aliphatic alcohol is particularly preferable. And ether type surfactants are preferred. Specific examples thereof include POE monolaurate, POE monostearate, POE lauryl ether, POE cetyl ether, and POE hydrogenated castor oil derivative. These are contained in 1 to 20%, preferably 2 to 10% of the total composition.

Examples of the basic substance as the component (d) include alkylamines, organic amines such as mono-, di- or trialkanolamines; inorganic alkalis such as alkali hydroxides and carbonates; among them, monoethanolamine, Diethanolamine, triethanolamine, sodium hydroxide, potassium hydroxide and the like are preferable. The component (d) is mixed in the composition in an amount of 0.01 to 2%, preferably 0.1 to 0.5%.

In addition, the external preparation of the present invention contains ethanol in an amount of 5% in the total composition.
˜70%, preferably 30 to 60% can be added, and purified water is also preferably added.

The liquid preparation for external use of the present invention can be produced by compounding Compound A and using an ordinary method.

[Action]

INDUSTRIAL APPLICABILITY The antifungal external preparation of the present invention has excellent affinity and spreadability to the skin and controls the release of the active ingredient, so that the storage property on the skin is enhanced and a continuous therapeutic effect can be exerted. . In addition, the addition of a basic substance enhances the activity of the active ingredient and reduces skin irritation.

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The imidazole antifungal external liquid preparation of the present invention has little skin irritation, has a good feeling in use, can continuously exhibit an excellent therapeutic effect, and is physicochemically stable.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.

Example 1 Compound A 1 g Diethyl sebacate 15 g POE (10) monolaurate 5 g Triethanolamine 0.465 g Ethanol 56 g Total amount 100 ml with purified water After dissolving compound A in ethanol, diethyl sebacate and POE (10) monolaurate Mix rates. to this,
Triethanolamine dissolved in an appropriate amount of purified water was added, and the total amount was 100 ml with purified water to obtain a liquid preparation for external use.

Example 2 Compound A 1 g Diethyl sebacate 30 g Diisopropyl adipate 10 g POE (5.5) Cetyl ether 5 g Triethanolamine 0.465 g Ethanol 35 g Purified water 100 ml in total As in Example 1, an external preparation was prepared.

Example 3 Compound A 1 g Diethyl sebacate 30 g POE (60) hydrogenated castor oil 5 g Sodium hydroxide 0.115 g Ethanol 42 g Total amount 100 ml with purified water In the same manner as in Example 1, an external preparation was prepared.

Example 4 Compound A 1 g Isopropyl myristate 10 g POE (10) monolaurate 10 g Triethanolamine 0.465 g Ethanol 56 g Total amount 100 ml with purified water A liquid preparation for external use was produced in the same manner as in Example 1.

Comparative Example Compound A 1 g Diethyl sebacate 30 g POE (10) monooleate 5 g Ethanol 42 g Total amount 100 ml with purified water In the same manner as in Example 1, a liquid preparation for external use was produced.

Test Example 1 (Efficacy Test) For the external preparations produced in Examples 1 to 4 and Comparative Example,
A Trichophyton infection treatment test was performed. The results are shown in Fig. 1.

(Test method) Trichophyton menta was extracted from four places on the back of the guinea pig.
A bacterial solution of the grophytes TIMM 1189 strain was inoculated, and from the 5th day after the bacterial inoculation, the test solution was applied once a day for 14 consecutive days, and the lesion score was determined according to the following criteria. The lower the lesion score, the higher the efficacy.

+1: A small number of small erythema or erythematous papules scattered on the islands, or a condition in which the lesions have improved and new hair has grown.

+2: A condition in which erythema spreads over the entire infected area and peels the epidermis.

+3: Inflammatory symptoms such as strong redness and swelling are partially observed, and abundant scaling occurs.

+4: A state in which thick crust formation is observed.

As is clear from FIG. 1, the external preparation of the present invention was found to be highly effective.

Test Example 2 (Safety Test) Regarding the external liquid preparations produced in Examples 1 to 4 and Comparative Example,
A skin irritation test was performed. The results are shown in Table 1.

(Test method) A test solution was applied to a commercially available patch test plaster (manufactured by Torii Pharmaceutical Co., Ltd.), and 48 test subjects (28 healthy subjects) were applied to the lower and middle backs.
It was applied for a time. 1 hour and 24 hours after the removal, the degree of erythema (the degree of irritation to the skin) at the application site of the preparation was evaluated.

Minor erythema was ±, and clear erythema was +, which is shown as a percentage of the whole.

As is clear from Table 1, the liquid preparation for external use of the present invention had very little skin irritation.

Test Example 3 (Stability Test) Regarding the liquid preparations for external use produced in Examples 1 to 4 and Comparative Example,
Stability tests were performed. The results are shown in Table 2.

(Test method) The sample was stored in a thermostatic chamber at 40 ° C for 6 months, and tested for appearance change and component content (residual rate).

As is clear from Table 2, the external preparation of the present invention was excellent in stability both in physical properties and components.

[Brief description of drawings]

FIG. 1 is a drawing showing the results of the efficacy test in Test Example 1 as the relationship between the number of days after inoculation and the average lesion score.

Claims (3)

[Claims] 1. The following (a) to (d) (a) (E) -1 [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride 0.1-5 W. / V% (b) Liquid oily substance 1 to 50 W / V% (c) Nonionic surfactant 1 to 20 W / V% (d) Basic substance 0.01 to 2 W / V% An imidazole antifungal external liquid preparation. 2. The imidazole antifungal external liquid preparation according to claim 1, wherein the liquid oily substance is a saturated fatty acid ester. 3. The imidazole according to claim 1, wherein the nonionic surfactant is an ester type nonionic surfactant of polyoxyethylene and a saturated fatty acid or an ether type polyoxyethylene and a saturated aliphatic alcohol. Antifungal external preparation.