JPS6169719A - Antifungal agent for external use - Google Patents

Abstract

PURPOSE:An antifungal agent for external use having no crystal precipitation at the applied part of griseofulvin, having percutaneous absorption and prolonged effect free from side effects, obtained by blending griseofulvin with two solvents having different boiling points. CONSTITUTION:Griseofulvin shown by the formula is blended with a solvent having <80 deg.C boiling point and a solvent having >=120 deg.C boiling point, to give an antifungal agent for external use. Especially methyl ethyl ketone is preferable as the solvent <80 deg.C boiling point, and ethylene glycol mono-n-butyl ether, or diethylene glycol monomethyl ether is preferable as the solvent having >=120 deg.C boiling point. Further addition of an absorption auxiliary, preferably, an ester of (poly)glycerol and an alcohol, or an ester compound of the (poly) glycerol and a fatty acid can raise more antifungal effects. Concentration of griseofulvin on the applied part can be kept, and the antifungal agent has im proved percutaneous absorption.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an antifungal agent for external use, and more particularly to an antifungal agent containing griseofulvin as an active ingredient.

[Conventional technology]

Griseofulvin, represented by , has a strong skin antifungal effect and is used orally for the treatment of severe fungal diseases.

Griseofulvin is sold in tablet form and is widely used to inhibit the growth of various pathogenic fungi that infect the skin, hair, and nails of humans and animals, and is said to have the greatest clinical efficacy among antifungal agents. It is said.

However, griseofulvin is administered orally.

Although it has excellent clinical effects, problems such as headache, dizziness, gastrointestinal disorder, kidney disorder, and liver disorder have been highlighted, and topical antifungal agents such as tolnaftate, clotrimazole, and pyrrolnidoline are being used as alternatives to griseofulvin. has come to be developed.

[Problem that the invention seeks to solve]

However, although these developed drugs are currently used for mild athlete's foot diseases, the current situation is that sufficient therapeutic effects cannot be expected, as symptoms recur if administration is interrupted during treatment.

On the other hand, although griseofulvin has a high antifungal effect, it is extremely difficult to dissolve in water and ordinary media, and it is also difficult to dissolve in ethanol,
When dissolved in a solvent such as methyl ethyl ketone, griseofulvin precipitates as crystals at the application site, and it has not yet been used as an external antifungal agent because it does not penetrate the skin, hair, nails, etc.

[Failure to solve the problem]

As a result of intensive study on the most effective form of use of griseofulvin, which has such an extremely excellent antifungal effect, the present inventor found that there are no side effects when used externally, and that it can be used as a solvent with a boiling point of less than 80°C and with a boiling point of 120°C. If used in combination with the above, a topical preparation with excellent skin absorption can be obtained;
Furthermore, they have discovered that the antifungal effect can be further enhanced by using an absorption aid, and have completed the present invention.

That is, the present invention provides solvents with a boiling point of less than 80°C and a boiling point of 12°C.
The present invention provides an antifungal agent for external use containing griseofulvin as an active ingredient in a solvent at 0°C or higher.

The solvent used in the present invention with a boiling point of 80°C or less is preferably one with a boiling point of 50°C or higher and lower than 80°C, such as methanol, tetrahydro7ran, ethanol, acetone, methyl ethyl ketone, ethyl acetate, diisopropyl ether, etc. Methyl ethyl ketone, ethanol and acetone are preferred, and methyl ethyl ketone is particularly preferred.

Further, as the solvent with a boiling point of 120°C or higher used in the present invention, those with a boiling point of 150 to 200°C are more suitable, such as propylene glycol, butylene glycol, ethylene glycol, polyethylene glycol, ethylene glycol diacetate, ethylene glycol dimethyl ether. , ethylene glycol monoacetate, ethylene glycol motsubutyl ether, ethylene glycol monoethyl ether, ethylene glycol monoethyl ether acetate, ethylene glycol monomethyl ether, ethylene glycol monomethyl ether acetate, diethylene glycol, diethylene glycol diethyl ether, diethylene glycol dimethyl ether,
Glycols such as diethylene glycol laurate, diethylene glycol mobutyl ether, and diethylene glycol monomethyl ether are mentioned, and among these, ethylene glycol mono-n-butyl ether and diethylene glycol mobutyl ether are particularly preferred.

The amount of the solvent with a boiling point of less than 80°C may be the amount necessary to completely dissolve the active ingredient griseofulvin, but
Generally, it is preferable that the total composition of the external antifungal agent be 10 to 90 times more effective. In addition, solvents with a boiling point of 120°C or higher should be used 0.1 to 9 times as much as solvents with a boiling point of less than 80°C, and 10 to 90% by weight of the total composition.
It is preferable to use If the amount of solvent with a boiling point of 120°C or higher is higher than this, the local volatility of the drug will deteriorate,
This is not preferable because it cannot increase the effective degree of griseofulvin, and conversely, if it is too low, the local griseofulvin concentration becomes too high due to the volatilization of the low boiling point solvent, and crystals are precipitated, which is not preferable.

In addition, griseofulvin is included in the external antifungal agent of the present invention.
．． It is preferable to blend 01 to zO weight*chi.

The absorption aid used in the present invention is not particularly limited as long as it is a substance that generally promotes transdermal absorption of pharmacologically active substances; for example, an alcohol ester having 1 to 8 carbon atoms of a monocarboxylic acid having 4 to 24 carbon atoms; C1-C3 alcohol ester of C4-C10 dicarboxylic acid, azacycloalka/-2-one derivatives such as 1-dodecyl azacycloalka/-2-one, ether of glycerol or polyglycerol and alcohol Ester compounds of glycerol or polyglycerol with alcohols or fatty acids are particularly preferred.

As the ether of glycerol or polyglycerol and alcohol, for example, the following formula (I) and (old, OR, OR, ukc4 [Boshin, R,, R,, R, and R, (n (7) R4
may be the same or different) each have a hydrogen atom and a carbon number of 1
~24 saturated or unsaturated linear or branched aliphatic hydrocarbon groups or aromatic hydrocarbon groups. However, R,
, R, , R, and n R1s are all hydrogen atoms. n indicates the number of eagle from 0 to 6o. ].

As an ester compound of polyglycerol and fatty acid,
For example, diglycerin monooleate, triglycerin monostearate, tetraglycerin monostearate, tetraglycerin tristearate, tetraglycerin pentastearate, tetraglycerin monooleate, tetraglycerin pentaolate, tetraglycerin monolaurate, hexaglycerin monostearate. rate, hexaglycerin sesquistearate, hexaglycerin tristearate, hexaglycerin pentasterate, hexaglycerin monooleate, hexaglycerin pentaolate, hexaglycerin monolaurate, decaglycerin monooleate, decaglycerin decaolate, decaglycerin monolaurate Examples include rate.

The absorption aid is preferably incorporated in the external antifungal agent of the present invention in an amount of 0.5 to 50 weight.

[Effect]

The mixed system of two types of solvents having different boiling points according to the present invention has the effect of preventing crystal precipitation at the application site of griseofulvin, which is a medicinal ingredient in the external antifungal agent of the present invention.

〔Effect of the invention〕

The present invention provides an antifungal agent for external use containing griseofulvin as a main ingredient, which has an extremely high antifungal effect.

The topical antifungal agent of the present invention does not cause griseofulvin crystal precipitation at the application site, and the concentration of griseofulvin on the application site is maintained, so its transdermal absorption is sustained, and no side effects are observed, so it can be used externally. It exhibits an extremely excellent antifungal effect.

〔Example〕

The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (Composition) ■ Griseofulvin o, is m ■ Ethylene glycol mono-butyl ether 15 ■ Ethanol 10 Total 100 Dissolve the above ■ in 70i and then add ■ and ■. Furthermore, I added a ■ of cruelty and stored it away from light.

Example 2 (Composition) ■ Griseofulvin 1 part by weight ■ Ethylene glycol-mono-butyl ether 30 ■ 1-dodecyl azacyclohebutan-2-one 20 ■ Methyl ethyl ketone Balance meter 100 Disperse the above ■ in ■ 30F, then add ■ , further add ■ to 100? It was stored protected from light.

Example 3 (Composition) ■ Griseofulvin 1 part by weight ■ Ethylene glycol-mono-butyl ether 3゜ ■ l-0-n
-Dodecyl-3-〇- Methyl-2-0-2',3'-dihydroglobylglycerol 2゜■Methyl ethyl ketone 4゜Total 100 Comparative Example 1 (Composition) ■Griseofulvin 1 11 parts■Ethanol 20 ■Methyl ethyl ketone Balance meter 100 Comparative Example 2 (Composition) ■ Griseofulvin 1 part by weight ■ Ethanol 20 ■ Acetone 20 ■ Methyl ethyl ketone Balance meter 100 Comparative Example 3 (Composition) ■ Griseofulvin 1 part by weight ■ Ethylene glycol-mono-butyl ether Balance meter 100 Example 4 Transdermal absorption test $! : About 3 to 90 days ago, 7 female domestic rabbits of Japanese color were grouped together, and the topical antifungal agent of the present invention of Examples 1 to 3 or the comparison was applied to the normal depilated abdominal skin (lOX14Crn) of each group of domestic rabbits. Example 1.2
Comparative products (3) and (3) were each applied in an amount equivalent to 35In9 of griseofulvin, and samples were taken from the ear vein 4 hours, 10 hours, and 20 hours later to measure the blood concentration of griseofulvin. The results are shown in Table 1.

As is clear from the above results in Table 1, all of the products of the present invention exhibited extremely high percutaneous absorption. In particular, l-0-n-dodecyl-3-〇-methyl-2-0-2' as a transdermal absorption aid.
, 3'-dino-idroxypropylglycerol, the external anti-symptomatic agent of the present invention showed extremely high percutaneous absorption of griseofulvin.

Example 5 Therapeutic Test: Age 19-35 Foot Mouth #! (Sweating albinism, Hakuju Hakusuma)
The subjects were 30 people suffering from the disease.The products of the present invention according to Examples 1 to 3 were applied once a day in the morning, and the therapeutic effects were evaluated on the 3rd day and 1st day.
Observations were made on day 0 and day 20, and the degree of improvement was determined by the following method.

(Method for determining effectiveness) Effectiveness: Disappearance of rubella or marked improvement.Efficacy: Moderately effective, where rubella is significantly improved;
Improvement of rubella is observed Ineffective: Rubella remains unchanged and no improvement is observed Exacerbation: Rubella is worsened It has become clear that this method is effective. In particular, l-0- as a transdermal absorption aid.
n-dodecyl-3-0-methyl-2-0-2',3'-
The external antifungal agent of the present invention contains dimethyl hydroxypropyl glycerol.

It has shown extremely high therapeutic efficacy.

that's all

Claims (1)

[Scope of Claims] 1. An antifungal agent for external use, characterized in that griseofulvin is blended as an active ingredient in a solvent with a boiling point of less than 80°C and a solvent with a boiling point of 120°C or more. 2. The external antifungal agent according to claim 1, which further contains an absorption aid. 3. The external antifungal agent according to claim 1 or 2, which is used as a treatment for athlete's foot.