JP2001181182A - Antifungal liquid composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve skin permeability of an active ingredient in an antifungal preparation for external use comprising butenafine hydrochloride as the active ingredient. SOLUTION: This antifungal liquid composition for external use comprises the butenafine hydrochloride as the active ingredient and is obtained by regulating the amount of water formulated to <=3 wt./vol.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external antifungal composition containing butenafine hydrochloride as an active ingredient and having improved skin penetration of the active ingredient.

[0002]

2. Description of the Related Art Butenafine hydrochloride is a benzylamine antifungal agent, and has been used as an active ingredient of an antifungal external preparation. From the viewpoint of the affinity, the solubility of butenafine hydrochloride, and the like, the dosage form of a cream or a liquid for external use containing water of about 30 to 70 w / v% (hereinafter, unless otherwise specified, "%" means w / v%). have.

[0003]

In order to enhance the efficacy of an antifungal preparation for external use, it is necessary to improve the skin permeability of the active ingredient, and the present invention relates to an antifungal preparation comprising butenafine hydrochloride as the active ingredient. It is intended to improve skin penetration of the active ingredient in an external preparation.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above-mentioned object, and as a result, by using a liquid preparation with a minimum water content, the amount of butenafine hydrochloride permeating the skin has been increased. The present inventors have found that it is possible to improve skin permeability and to use an aerosol of butenafine hydrochloride, which has not been conventionally produced. Thus, the present invention has been completed. That is, the present invention
An object of the present invention is to provide an antifungal liquid external composition containing butenafine hydrochloride as an active ingredient and containing 3% or less of water. The composition may be in the form of a liquid for external use, or may be a stock solution of an aerosol. The present invention provides a composition for external use of an antifungal liquid of the present invention in the form of a stock solution of an aerosol, and a propellant. Also provided is an antifungal aerosol formulation comprising:

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Butenafine hydrochloride, which is an active ingredient of the composition for external use of the liquid according to the present invention, is usually contained in an amount of 0.1% based on the total amount of the composition from the viewpoint of efficacy and solubility as an antifungal agent.
2-5%, preferably 0.5-2%.

In the present invention, it is necessary that the water content in the liquid composition is 3% or less, preferably substantially no water is mixed, and further, it is necessary to reduce the water content of the components as much as possible. The amount of butenafine hydrochloride, an active ingredient, permeates the skin and improves skin permeability. Also, butenafine hydrochloride, for example, when coexisting with water in an aerosol container such as an aluminum aerosol can, even if the inner surface of the container is coated with resin, there is a problem that corrosion is caused by the presence of pinholes, However, it is possible to obtain an aerosol by reducing the water content as much as possible.

[0007] Thus, the liquid composition of the present invention is an alcoholic solution of butenafine hydrochloride in which the mixing of water is suppressed as described above, and is, for example, a solution of a lower alcohol such as methanol, ethanol or denatured alcohol.

[0008] The other components are not particularly limited. However, in order to improve the skin affinity of the composition and the solubility of butenafine hydrochloride, a surfactant such as HLB is required.
It is preferable that 5% or less of a hydrophilic surfactant having 0 or more, especially polyoxyethylene hydrogenated castor oil having an addition polymerization mole number of 20 to 100 of ethylene oxide is used. As humectants, propylene glycol, dipropylene glycol, 1,3-butylene glycol, molecular weight 2
It is also preferable to mix 10% or less of a glycol such as polyethylene glycol of 00 to 600 and a polyol such as glycerin. Further, various chelating agents,
Pharmaceutically acceptable additives such as antioxidants, preservatives, preservatives, and fragrances may be added as appropriate.

The composition of the present invention is preferably adjusted to pH 3 to 8 in order to reduce skin irritation. For example, an organic acid salt such as diethanolamine can be used as a pH adjuster.

The composition of the present invention can be made into a liquid form for external use or a stock solution of an aerosol by mixing and dissolving each component according to a method known per se. In addition, the composition of the obtained aerosol stock solution and the injection used for ordinary aerosols such as dimethyl ether (DME), liquefied propane gas (LPG), fluorocarbons, N ₂ , CO ₂ gas, and alternative fluorocarbon gas. The aerosol of the present invention can be produced by mixing the mixture with an agent and filling the mixture into an ordinary aerosol or spray container. The mixing ratio of the composition and the propellant is not particularly limited, but usually,
The composition / propellant volume ratio (filling ratio) is selected from the range of 1: 1 to 2: 8. Alternatively, talc or other powder may be mixed into a powder aerosol by a method known per se.

The topical liquid preparation and aerosol preparation of the present invention can be used as an antifungal topical preparation in the same manner as a conventional butenafine hydrochloride preparation.

[0012]

EXAMPLES The present invention will be described in more detail with reference to Test Examples and Examples, but the present invention is not limited thereto. Test Example 1 Skin Penetration Test According to the prescription shown in Table 1, each component was mixed and dissolved to prepare a sample for skin penetration test. In the table, HCO-6
0 means polyoxyethylene hydrogenated castor oil having an added mole number of ethylene oxide of 60.

[0013]

[Table 1]

Hartley guinea pigs (4)
) Of the abdomen was shaved with an electric clipper, and the skin was removed. This was attached to a self-made Franz cell (diameter 2 cm). The receptor phase was 1/15 M phosphate buffer (pH 5.
3) 26 ml (32 ° C.), apply (open) 2 ml of each specimen, and after 22 hours, rinse the specimen on the skin with running water,
After further washing with ethanol, the sample-applied portion of the skin was punched out with a 2 cm diameter punch. Shred it,
After ultrasonic extraction in methanol, the amount of butenafine hydrochloride transferred into the skin was measured by HPLC under the following conditions, and the measured value was defined as the skin penetration amount. HPLC conditions Detector: UV absorption spectrophotometer (measuring wavelength: 282 nm) Column: A stainless steel tube having an inner diameter of about 4 mm and a length of about 150 mm filled with octadecylsilylated silica gel for liquid chromatography. Water Puresil C18 Ф4.6 × 150 mm Column temperature: constant temperature around 25 ° C. Mobile phase: acetonitrile / water (43: 7) Flow rate: adjusted so that the retention time of butenafine hydrochloride is about 13 minutes (1.2 ml / Min) The results are shown in Table 2 and FIG. The results in Table 2 are the average of three measurements, and FIG. 1 is a graph of the results in Table 2, where the vertical axis is the amount of permeation (μg / cm ² ), and the horizontal axis is the amount of water (%). ).

[0015]

[Table 2]

As is clear from the results shown in Table 2 and FIG. 1, when the water content is 3% or less, the amount of butenafine hydrochloride permeating the skin increases, and the permeability is remarkably improved.

Example 1 A solution for external use was prepared according to the following formulation by a conventional method. In addition,
The number in parentheses after the polyoxyethylene hydrogenated castor oil is the number of moles of ethylene oxide added (the same applies hereinafter). Ingredients Butenafine hydrochloride 1.0 g Polyoxyethylene hydrogenated castor oil (40) 0.6 g Dipropylene glycol 6.8 g Diethanolamine 0.33 g Modified to 100 ml of denatured alcohol Example 2 A liquid preparation for external use was prepared according to the following formulation by the usual method. . Ingredients Butenafine hydrochloride 1.0 g Polyoxyethylene hydrogenated castor oil (60) 0.6 g Dipropylene glycol 6.8 g Denatured alcohol adjusted to 100 ml

Example 3 A solution for external use was prepared according to the following formulation by a conventional method. Ingredients Butenafine hydrochloride 1.0 g Polyoxyethylene hydrogenated castor oil (60) 0.6 g Dipropylene glycol 6.8 g Purified water 1.0 g Modified to 100 ml of denatured alcohol did. Component Butenafine hydrochloride 1.0 g Polyoxyethylene hydrogenated castor oil (60) 0.6 g Dipropylene glycol 6.8 g Purified water 3.0 g Adjusted to 100 ml denatured alcohol

Example 5 An aerosol stock solution was prepared according to the formulation of Example 1.
15 ml of this stock solution and 35 ml of LPG were filled into an aerosol pressure-resistant container coated with an epoxyphenol urea resin or a polyamide imide resin, and an aerosol valve and a button were attached to prepare an aerosol.

[0020]

As described above, according to the present invention, the skin penetration of the active ingredient is markedly reduced by reducing the water content of the antifungal external preparation containing butenafine hydrochloride to 3% or less. It is possible to manufacture an aerosol agent of butenafine hydrochloride by solving the problem of corrosion of the aerosol container.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the amount of butenafine hydrochloride permeating the skin and the water content in the composition.

Continued on the front page F term (reference) 4C076 AA11 AA13 AA24 BB31 CC31 DD08 DD37 DD38 DD50 EE23 FF34 FF68 4C206 AA01 AA02 FA08 MA02 MA03 MA05 MA33 MA37 MA83 NA05 ZA89 ZB35

Claims (9)

[Claims] 1. An antifungal liquid external composition comprising butenafine hydrochloride as an active ingredient and having a water content of 3 w / v% or less. 2. The antifungal liquid external composition according to claim 1, which is an alcoholic solution. 3. The antifungal liquid external composition according to claim 2, which is an ethanolic solution. 4. A method of adding a hydrophilic surfactant having an HLB of 10 or more to 5
The antifungal liquid external composition according to any one of claims 1 to 3, which contains w / v% or less. 5. The antifungal composition for external use according to claim 1, which contains a humectant in an amount of 10% w / v or less. 6. The method according to claim 1, wherein the pH is 3 to 8.
4. The composition for external use of an antifungal liquid according to the above item. 7. The antifungal liquid external composition according to claim 1, which is in the form of a liquid for external use. 8. The antifungal liquid external composition according to claim 1, which is an aerosol stock solution. 9. An antifungal aerosol comprising the antifungal external composition according to claim 8 and a propellant.