JPH03258719A - Imidazole-based antifungal cream - Google Patents

Abstract

PURPOSE:To obtain the subject cream low in irritation to the skin, having an excellent feeling in use, capable of showing its curative effect continuously and stable physicochemically by using a specified imidazole derivative as the active component and blending a specified base therewith. CONSTITUTION:With 0.1-5wt.% (B)-1-[2-methylthio-1-[2-(pentyloxy)phenyl] ethenyl-1H-imidazole hydrochloride, 2-50wt.% oily substance (e.g. vaseline), 1-20wt.% nonionic surfactant (e.g. glycerin monostearate), 40-90wt.% water, 0.01-2wt.% basic substance (e.g. triethanolamine) and, in addition thereto, preferably a stabilizer are blended. Preparation is then carried out by the conventional method, thus giving objective cream.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to a novel imidazole-based antifungal cream preparation, and more particularly, it has minimal skin irritation and exhibits maximum and sustained effects. The present invention relates to a cream formulation that is physicochemically stable and physicochemically stable.

[Problems to be solved by conventional techniques and inventions] Conventionally,
Imidazole antifungal agents, which have an antibacterial effect against fungi, have a wide antibacterial spectrum and have the advantage of being less likely to develop clinically resistant bacteria, so they are used in creams, gels,
It is commercially available in the form of liquids, ointments, etc.

Among these, creams are the most widely used because they are generally superior to gels and liquids in terms of skin irritation, and are superior to ointments in terms of feel upon use. However, since creams contain emulsifiers and preservatives, it is necessary to select an appropriate base with regard to skin irritation and physicochemical stability. In addition, it is necessary to enhance antibacterial effects, shorten the treatment period, and reduce the number of times of use.
It is necessary to design a base that optimizes therapeutic efficacy. However, these effects have not yet been sufficiently achieved.

Therefore, there has been a desire for an antifungal external preparation that is less irritating to the skin and can fully exhibit excellent effects.

[Means to solve the problem]

Under these circumstances, the present inventors conducted intensive research and found that (B)-1-42-methylthio-1-[2-(pentyloxy)phenyl]ethenyl]-1H-imidazole hydrochloride was used as an active ingredient. The present invention was completed based on the discovery that a cream formulation formulated with a specific base has little skin irritation, can exert a sustained therapeutic effect, and is physicochemically stable.

That is, the present invention provides the following (a) to (e) (a) (B
)-1-(2-methylthio-1-[:2-(pentyloxy)phenyl]ethenyl)-1H-imidazole hydrochloride 0.1 to 5% by weight (b) Oily substance
2-50% by weight (c) Nonionic surfactant 1-20% by weight (d) Water
40-90% by weight (e) Basic substance
The present invention provides an imidazole-based antifungal cream formulation characterized by containing 0.01 to 2% by weight.

In the present invention, component (a) used as an active ingredient (B)-1-[2-methylthio-1-[2-(pentyloxy)phenyl]ethenyl] -LH-imidazole hydrochloride (hereinafter referred to as "compound A '') is a known substance that has excellent antibacterial activity against bacteria, fungi, etc. (Japanese Patent Application Laid-open No. 146864/1986).

Compound A is blended in the total composition in an amount of 0.1 to 5% by weight (hereinafter simply expressed as %), preferably 0.5 to 1.5%.

(c) The oil-based substance as an ingredient is not particularly limited as long as it is used in ordinary cream preparations, such as hydrocarbons such as light liquid paraffin, squalane, white petrolatum, microcrystalline wax, and ceresin; beeswax. Waxes such as , gay wax, and carnauba wax; fatty acid esters such as diethyl sebacate, diisopropyl adipate, epityl lactate, cetyl palmitate, and myristyl myristate; aliphatic alcohols such as stearyl alcohol, octyldodecanol, hexadecyl alcohol, and cetanol Triglycerides such as natural fatty acid triglycerides and medium chain fatty acid triglycerides; fatty acids such as palmitic acid, stearic acid, and myristic acid, etc. can be used.

Among these, saturated aliphatic compounds are particularly preferred as aliphatic compounds. Further, specifically, stearyl alcohol, white petrolatum, medium chain fatty acid triglyceride, diethyl sebacate, octyldodecanol, and squalane are particularly preferred. These can be used alone or in combination of two or more, and are blended in the total composition in an amount of 2 to 50%, preferably 10 to 30%.

As the nonionic surfactant of component (c), for example, a polyoxyalkylene surfactant such as polyoxyalkylene sorbitan fatty acid ester, polyoxyalkylene alkyl ether, polyalkylene glycol fatty acid ester, polyoxyalkylene hydrogenated castor oil; Examples include fatty acid ester surfactants such as sorbitan fatty acid ester and glycerin fatty acid ester, specifically sorbitan monostearate, polyoxyethylene sorbitan monostearate, glyceryl monostearate,
Examples include polyoxyethylene heptyl ether, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil 60.

These should be present in the total composition in an amount of 1 to 20%, preferably 2 to 10%.
% is added.

Component (d) water is blended in the total composition in an amount of 40 to 90%, preferably 60 to 80%.

Examples of the basic substance as component (e) include organic amines such as alkylamines and mono-, di- or trialkanolamines; inorganic alkalis such as alkali hydroxides and alkali carbonates; among these, monoethanolamine, Jetanolamine, triethanolamine, sodium hydroxide, potassium hydroxide and the like are preferred. Component (e) is 0.01 to 2%, preferably 0.1 to 0% in the total composition.
．． Contains 5%.

Furthermore, the cream preparation of the present invention preferably contains stabilizers used in ordinary external preparations, such as butylated hydroxyanisole, dibutylated hydroxytoluene,
Antioxidants such as propyl gallate; preservatives such as paraoxybenzoate and dehydroacetic acid; chelating agents such as sodium edetate; and the like can be used in a conventional manner.

The cream formulation of the present invention can be manufactured by adding Compound A and following a conventional method.

[Effect]

In the cream formulation of the present invention, since the active ingredient is appropriately dissolved in the base, it is possible to control the release of the active ingredient, improve its retention in the skin, and exert a sustained therapeutic effect. Furthermore, when a liquid oily substance is blended, it becomes excellent in spreadability and percutaneous absorption as well as in physicochemical stability.

Furthermore, by incorporating a basic substance, the activity of the active ingredient is increased and skin irritation is reduced.

〔Effect of the invention〕

The imidazole-based antifungal cream preparation of the present invention has little skin irritation, feels good when used, can continuously exert excellent therapeutic effects, and is physicochemically stable.

〔Example〕

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

Example 1 Compound A 1.0g Stearyl alcohol 4.0g White petrolatum
5.0g Medium-chain fatty acid triglyceride 12.0g Glyceryl monostearate 3.0g Methyl roseoxybenzoate
0.2g Butyl paraoxybenzoate 0.1g
Sodium edetate 0.02g Triethanolamine 0.465g Purified water Amount to make the total amount 100g Oil phase component 6
Dissolve at 0 to 70°C, add Compound A dissolved in a portion of purified water with stirring, add the aqueous phase in which the basic substance and other components are dissolved, and emulsify at 70 to 75°C. , and cooled to room temperature to obtain a cream formulation.

Example 2 Compound A Setanol white vaseline diethyl sebacate glyceryl monostearate Polyoxyethylene heptyl ether (25B, 0.) 1.0g 5.0g 6.0g 12.0g 4.0g 2.0g Methyl paraoxybenzoate Butyl paraoxybenzoate Sodium edetate triethanolamine purified water Same as Example 1. Example 3 Compound A stearyl alcohol white vaseline Octyldodecanol sorbitan monostearate 0.2g 0.1g 0.02g 0.465g Amount to make the total amount 100g A cream formulation was produced.

1.0g 4.0g 5.0g 15.0g 2.0g Methyl paraoxybenzoate Butyl paraoxybenzoate Sodium edetate Sodium hydroxide purified water Example 1 Example 4 Compound A Setanol white vaseline white beeswax Squalane glyceryl monostearate 0.2g 0.1g 0.02g 0.115g Amount where the total amount is ioog A cream formulation was produced in the same manner as above.

Polyoxyethylene heptyl ether (20B, 0°) Methyl paraoxybenzoate Sodium paraoxybenzoate butyl edetate Triethanolamine 1.0g 5.0g 6.0g 2.0g 10.0g 3.2g 1.8g 0.2g 0. 1g 0.02g 0.465g Purified water A cream formulation was produced in the same manner as in the Example.

Example 5 Compound A 1.0g cetanol 5. Ogg colored petrolatum 6. Og middle finger fatty acid triglyceride 10゜0g diethyl sebacate
5.0g glyceryl monostearate
4.0g Methyl paraoxybenzoate 0
．． 2g Butyl paraoxybenzoate 0.1g Sodium edetate 0.02g Triethanolamine 0.465g Purified water
A cream formulation was produced in the same manner as in Example 1, with the total amount being 100 g.

Comparative Example Compound A 1.0g Stearyl Alcohol 4.0g White Vaseline
5.0g oleic acid
10.0 g Glyceryl monostearate 3.0 g Methyl paraoxybenzoate
0.2g Butyl paraoxybenzoate 0.
1g propylene glycol 5. Og sodium edetate 0.02g purified water
Amount test example 1 where the total amount is 100 g (
Efficacy Test) An infection test was conducted on the cream formulations produced in Examples 1 to 5 and Comparative Example. The results are shown in Figure 1.

(Test method) Hair was removed from 4 places on the back of a guinea pig, and Trichophyt was removed.
onmentagrophytes TIMM 118
A bacterial solution of 9 strains was inoculated, and from 5 to 5 days after the bacterial inoculation, the test formulation
It was applied once a day for 14 consecutive days, and the lesion score was determined according to the following criteria. A lower lesion score indicates higher efficacy.

+1: A condition in which a few small erythema or erythematous papules are observed scattered in an island pattern, or a condition in which the lesions have improved and new body hair has grown.

+2: A state in which erythema spreads over the entire infected area and is accompanied by epidermal peeling.

+3 2 Inflammatory symptoms such as strong redness and swelling are observed in some areas,
A condition that produces an abundance of scales.

+4: A state in which thickened Shiyu formation is observed.

As is clear from FIG. 1, the cream formulation of the present invention is
It was recognized that the effectiveness was high.

Test Example 2 (Safety Test) A skin irritation test was conducted on the cream formulations produced in Examples 1 to 5 and Comparative Example. The results are shown in Table 1.

(Test method) The test preparation was applied to a commercially available batch test bandage [Torii Pharmaceutical side part], and 48 cm was applied to the middle and lower backs of subjects (28 healthy people).
Applied for hours. One hour and 24 hours after removal, the degree of erythema (degree of skin irritation) at the application site of the preparation was determined. Slight erythema is rated as dirt, obvious erythema is rated as 10, and the percentage is shown as a percentage of the total.

As is clear from Table 1, the cream formulation of the present invention is
Skin irritation was extremely low.

Test Example 3 (Stability Test) A stability test was conducted on the cream formulations produced in Examples 1 to 5 and Comparative Example. The results are shown in Table 2.

(Test method) The sample was stored in a constant temperature bath (45°C) for 6 months and tested for discoloration, separation, and component content (residual rate).

Table 2 Note) Discoloration: - No change + Slight yellowing Separation: - No separation Fully effective As is clear from Table 2, the cream formulation of the present invention:
It was confirmed that the product was stable, with no discoloration or separation, and no change in component content.

[Brief explanation of drawings]

FIG. 1 is a drawing showing the results of the efficacy test in Test Example 1 in terms of the relationship between the number of days after inoculation and the average lesion score. 7 (Start of treatment) Days after vaccination

Claims (1)

[Claims] 1. The following (a) to (e) (a) (B) -1-[2-methylthio-1-[2-(pentyloxy)phenyl]ethenyl] -1H-imidazole hydrochloride 0.1 to 5% by weight (b) Oily substances 2 to 50% by weight (c) Nonionic surfactants 1 to 20% by weight (d) Water 40 to 90% by weight (e) Basic substances 0.01 to 50% by weight 2% by weight of an imidazole antifungal cream preparation.