JPH07121862B2 - Imidazole antifungal ointment - Google Patents

Description

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

[Problems to be Solved by Prior Art and Invention]

Conventionally, imidazole antifungal agents having an antibacterial effect against fungi have a wide antibacterial spectrum and have the advantage that clinically few resistant bacteria appear clinically. Therefore, they are used as dosage forms such as creams, gels, and liquids. It is commercially available.

However, in general, a liquid preparation has excellent skin spreading properties because it contains alcohol, but it has a drawback that it has a stimulating sensation during use. Further, since the gel agent contains alcohols and the cream agent contains an emulsifier and a preservative, there is a problem that skin irritation occurs as well.

Therefore, an antifungal external preparation having excellent skin-protecting action and anti-inflammatory action and less irritation and rash has been desired.

[Means for Solving the Problems]

Under such circumstances, as a result of earnest studies by the present inventors, (E) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride was used as an active ingredient. As a result, they have found that an ointment mixed with a specific ointment 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 wt% (b) Nonionic surfactant 2-5 wt% (c) Basic substance 0.01-2 wt% (d) Oily ointment base 80 wt% or more containing imidazole antifungal ointment Is provided.

In the present invention, (A) -of the component (a), which is the medicinal component,
1- [2-methylthio-1- [2- (pentyloxy)
Phenyl] ethenyl] -1H-imidazole hydrochloride (hereinafter referred to as "Compound A") is a known substance having an excellent antibacterial action against bacteria, fungi and the like (JP-A-63-1468).
No. 64). The compound A is added in an amount of 0.1 to 5% by weight (hereinafter simply referred to as%), preferably 0.5 to 15%, in the total composition.

As the nonionic surfactant as the component (b), for example, polyoxyalkylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, propylene glycol fatty acid ester, etc. are used. Examples thereof include polyoxyethylene oleyl ether, polyoxyethylene monolaurate, polyoxyethylene hydrogenated castor oil 5, sorbitan sesquioleate, and propylene glycol monostearate. These are 2-5 in the total composition
%, Preferably 2.5 to 3.5%.

Examples of the basic substance as the component (c) include organic amines such as alkylamines, 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. These are added to the entire composition in an amount of 0.01 to 2%, preferably 0.1 to 0.5%.

Examples of the oily ointment of the component (d) include (i) mineral oils such as yellow petrolatum, white petrolatum, paraffin, liquid paraffin, plastibase, Zelen 50W, and silicone, and (ii) diethyl sebacate, diisopropyl adipate, It is preferable to use a medium-chain fatty acid triglyceride and a liquid oil selected from octyldodecanol in combination. 80% or more, preferably 90 to 95%, of these oily and ointment agents is mixed in the entire composition. Further, among these, the liquid oil (ii) is preferably blended in an amount of 2 to 15%, particularly 5 to 10% in the total composition.

Further, the ointment of the present invention, water in the total composition 1-10%,
It is preferably 2 to 5%. Further, it is preferable to combine butylhydroxyanisole or dibutylhydroxytoluene (BHT) and sodium edetate as a stabilizer in combination.

The ointment of the present invention can be produced by compounding Compound A and using an ordinary method.

[Action]

In the antifungal ointment of the present invention, the active ingredient is appropriately dissolved in the base, and when a liquid oil is added, the release of the active ingredient is controlled, so that the storability in the skin is enhanced and the sustained therapeutic effect is obtained. Can be demonstrated.

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The imidazole antifungal ointment of the present invention has little skin irritation, good spreadability, 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 5 g polyoxyethylene hydrogenated castor oil 5 3 g sodium hydroxide 0.14 g purified water 3.86 g BHT 0.05 g sodium edetate 0.05 g white vaseline 86.9 g white vaseline at 70-80 ° C Melt and dissolve BHT.
Separately, add a mixture of other ingredients at room temperature, and add 60-70
The mixture was stirred at ℃ and cooled to 45 ℃ as it was to obtain an ointment.

Example 2 Compound A 1 g Diisopropyl adipate 5 g Sorbitan sesquioleate 3 g Triethanolamine 0.44 g Purified water 2.56 g BHT 0.05 g Sodium edetate 0.05 g White petrolatum 87.9 g As in Example 1, an ointment was prepared. Obtained.

Example 3 Compound A 1 g Medium chain fatty acid triglyceride 10 g Sorbitan sesquioleate 3 g Diethanolamine 0.32 g Purified water 2.68 g BHT 0.05 g Sodium edetate 0.05 g White petrolatum 82.9 g An ointment was prepared in the same manner as in Example 1. It was

Example 4 Compound A 1 g Octyldodecanol 10 g Sorbitan sesquioleate 3 g Potassium hydroxide 0.16 g Purified water 2.84 g BHT 0.05 g Sodium edetate 0.05 g White petrolatum 82.9 g As in Example 1, an ointment was prepared. Obtained.

Comparative Example 1 Compound A 1 g Diethyl sebacate 5 g Lauromacrogol 3 g Sodium hydroxide 0.12 g Purified water 3.17 g BHT 0.02 g Sodium edetate 0.02 g Japanese macrogol ointment 87.67 g Japanese macrogol ointment 70-80 After melting at 0 ° C, lauromacrogol was added thereto, BHT, sodium edetate and diethyl sebacate were added and stirred, compound A was added and stirred, and the mixture was cooled to 40 ° C as it was to obtain an ointment.

Comparative Example 2 Compound A 1 g Diethyl sebacate 5 g Cetyl lactate 2 g Lauromacrogol 3 g Sodium hydroxide 0.14 g Purified water 3.46 g BHT 0.05 g Sodium edetate 0.05 g JP Macrogol ointment 85.3 g Same as Comparative Example 1 Then, an ointment was obtained.

Comparative Example 3 Compound A 1 g Diethyl sebacate 5 g Propylene glycol 3 g Lauromacrogol 3 g Diethanolamine 0.32 g Purified water 2.68 g JP Macrogol ointment 85 g An ointment was obtained in the same manner as in Comparative Example 1.

Comparative Example 4 Compound A 1 g Diethyl sebacate 5 g Sorbitan sequioleate 3 g Purified water 3 g BHT 0.05 g Sodium edetate 0.05 g White petrolatum 87.9 g As in Example 1, an ointment was obtained.

Test Example 1 (Efficacy Test) An infection test was conducted on the ointments prepared in Examples 1 to 4 and Comparative Examples 1 to 4. The results are shown in Fig. 1.

(Test method) Trichophyton men's hair was removed from the back and 4 areas of the guinea pig.
Inoculated with tagrophytes TIMM 1189 strain, and after inoculation, 5
From the day, the test ointment 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 found as an island-like powder, or a condition in which the lesion is relieved and new hair grows.

+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 ointment of the present invention was found to be highly effective.

Test Example 2 (Safety Test) A skin irritation test was conducted on the ointments prepared in Examples 1 to 4 and Comparative Examples 1 to 4. The results are shown in Table 1.

(Test method) A test patch ointment was applied to a commercially available patch test plaster (manufactured by Torii Pharmaceutical Co., Ltd.), and the test subjects (30 healthy people) were provided with 48 on the upper back.
I pasted it on time. After 1 hour and 24 hours after the removal, the erythema degree (the degree of irritation to the skin) of the preparation-applied part 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 ointment of the present invention had very little skin irritation.

Test Example 3 (Stability Test) A stability test was performed on the ointments prepared in Examples 1 to 4 and Comparative Examples 1 to 4. The results are shown in Table 2.

(Test method) It was stored in a constant temperature bath (40 ° C) for 6 months and tested for discoloration, bleeding, and component content (residual rate).

As is clear from Table 2, the ointment of the present invention has a discoloration,
It was confirmed that bleeding did not occur, the component content did not change, and it was stable.

[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 (1)

[Claims] 1. The following (a) to (d) (a) (Ε) -1- [2-methylthio-1- [2- (pentyloxy) phenyl] ethenyl] -1H-imidazole hydrochloride 0.1 to 5: % By weight (b) Nonionic surfactant 2-5% by weight (c) 0.01-2% by weight of basic substance (d) Oil-based ointment base 80% by weight or more of an imidazole antifungal ointment.