JPS63146817A - Antifungal agent for external use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an antifungal agent for external use, and more particularly to an antifungal agent for external use that contains griseofulpine as an active ingredient and has good percutaneous absorption.

[Conventional technology]

Griseofulpine, represented by the following formula (f), has a strong skin antifungal effect and is used orally for the treatment of severe mycosis. Griseofulpine is generally sold in tablet form and is widely used to inhibit the growth of various pathogenic fungi that infect the skin, hair, nails, etc. of humans and animals, and has the greatest clinical efficacy among antifungal agents. It is said that.

[Problem that the invention seeks to solve]

However, although griseofulpine has excellent clinical effects when administered orally, side effects such as headache, dizziness, gastrointestinal disorder, kidney disorder, and liver disorder have been highlighted, which has become a problem with oral preparations. On the other hand, although griseofulpine has a high antifungal effect, it is extremely difficult to dissolve in water and ordinary media, and when dissolved in solvents such as ethanol and methyl ethyl ketone, griseofulpine precipitates as crystals at the application site, causing skin irritation. However, it has not been used as an external preparation due to its lack of penetration into hair, nails, etc.

Therefore, external antifungal agents such as tolnaftate, clotrimazole, virolnidoline, and cinnazole have been developed as substitutes for griseofulpine.

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.

[Means for solving problems]

The present inventors conducted tax considerations to obtain the most effective formulation with no side effects for griseofulpine, which has an excellent antifungal effect, and found that an external preparation obtained by dissolving griseofulpine in a specific compound is superior. The present invention was completed based on the discovery that the topical preparation has an antifungal effect and that the antifungal effect can be further enhanced by using an absorption aid in combination with this external preparation.

Therefore, the present invention provides one or two selected from the group consisting of griseofulpinto, benzyl nicotinate, ethyl nicotinate, menthol, camphor, methyl salicylate, glycol salicylate, crotamiton, diphenhydramine, and hypenzol alcohol color. This invention consists of a first invention that provides an antifungal agent for external use containing at least one kind of griseofulpine solubilizing agent, and a second invention that provides an antifungal agent for external use that further contains an absorption aid in this external antifungal agent. be.

The present invention One or more griseofulpine solubilizers selected from the group consisting of benzyl thehanicotinate, ethyl nicotinate, menthol, camphor, methyl salicylate, glycol salicylate, crotamiton, diphenhydramine, and hibenzol alcohol (hereinafter referred to as However, even when griseofulpine is added to a topical base using these compounds, as is the case with ordinary topical preparations, crystal precipitation is observed.
The desired external preparation cannot be obtained. In order to obtain the preparation of the present invention, it is necessary to dissolve griseofulpine in advance in a griseofulpine dissolving agent such as benzyl nicotinate in an amount sufficient to dissolve it, and then to prepare the preparation using a known external radical, r. . In the present invention, the griseofulpine solubilizing agent not only dissolves griseofulpine, but is also expected to have an auxiliary medicinal effect as an external preparation, and will further enhance the effect of the main antifungal component.

In addition, menthol and camphor, which are the two main components of the griseofulpin dissolving agent, are said to have six forms, but any or eight forms can be used.

Furthermore, menthol is widely recognized as a main component of extracted oils from plants, and natural extracted oils containing these menthols can also be included in the scope of the present invention. That is, peppermint oil and eucalyptus oil can also be used as griseofulpine solubilizers.

To prepare the external antifungal agent of the present invention, griseofulpine is preferably blended in an amount of 0.01 to λ0% by weight (hereinafter simply expressed as %). Furthermore, when the griseofulpine solubilizing agent is used only as a solvent, only the amount that dissolves griseofulpine is sufficient. The required minimum amount is generally 5 to 30 parts by weight of griseofulpine! is the department.

This invention also includes cases where one or more of these are used to utilize the adjuvant effects of each as an external preparation. In such cases, the griseofulpine can be dissolved and then the desired amount of other compounds added.

The absorption aid used in the second aspect of the present invention is not particularly limited as long as it is a substance that generally promotes transdermal absorption of pharmacologically active substances, such as dimethyl sulfoxide (DMSO).
, Zometellactamide (DMA) s Dimethylformamide (DMF), Zorogylene gelicol, Diethyl-m-toluamide (DEFT), Eishin (1
-dodecyl azacyclohebutan-2-one), alcohol ester having 1 to 8 carbon atoms of monocarboxylic acid having 4 to 24 carbon atoms, dicarboxylic acid having 4 to 10 carbon atoms having 1 to 1 carbon atoms
3 alcohol ester, azacycloalkan-2-one derivatives such as 1-dodecyl azacycloalkan-2-one, glycerol or ? Suitable examples include ethers of liglycerol and alcohols or ester compounds of fatty acids, especially glycerol or ester compounds. Ester compounds of liglycerol and alcohol or ester compounds of fatty acids are preferred.

Glycerol or? As the ether of liglycerol and alcohol, for example, the following formula (maximum) and (1), [in the formula * R1+ J w R3 and R, (n R1
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
Except when I +J +R3 and n11110R1 are all hydrogen atoms. n represents an integer of 0 to 60. ] Examples include the following.

? As an ester compound of liglycerol and fatty acid,
For example, zoglycerin 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 The absorption aid is 0.5 to 50% in the external antifungal agent of the second invention.
% is preferable.

Preferred dosage forms of the external antifungal agent of the present invention include gel,
Examples include gel cream, cream, liquid preparation, etc. As bases for external preparations for making these dosage forms, those known per se are used.1For example, as a dull base, carboxyvinyl? Examples include cold aqueous solutions of rimers and aqueous solutions of water-soluble basic substances (eg, sodium hydroxide). By using this base to formulate a solution of griseofulpine dissolved in ethyl nicotinate or the like, a glu preparation can be easily obtained.

In addition, examples of the gel cream base include those obtained by adding an emulsifier (preferably a nonionic surfactant) and an oily substance (e.g. fluid 9 rough-in) to the above gel base; , hydrophilic ointment (listed in the Japanese Pharmacopoeia). Furthermore, examples of the liquid agent include a mixture of ethanol and water.

In preparing the external antifungal agent of the present invention, in addition to the above-mentioned examples, external bases, preservatives, and other additives known in the art may be appropriately selected and used. Conditions for preparing this external preparation can be selected as appropriate.

[Effect]

The griseofulpine dissolving agent of the present invention is thought to have the effect of improving the absorbability of griseofulpine at the application site by dissolving griseofulpine.

〔Effect of the invention〕

Since the external antifungal agent of the present invention solubilizes griseofulpine in the formulation, there is no crystal precipitation of griseofulpine at the application site. Therefore, it has extremely high percutaneous absorption and excellent therapeutic effects. Furthermore, since it is used as an external preparation, side effects can be significantly reduced compared to when it is used as an internal medicine.

〔Example〕

The present invention will be explained in more detail with reference to Examples below.

Example 1 Liquid: (Composition) ■ Griseofulpine 0.5%
■ Benzyl nicotinate 10.0■
Ethanol 30.0■
Methyl ethyl ketone 59.5 total 10
0.0 (Production method) Heat (1) to 50-60°C, add (2), mix and stir to dissolve. ■ and ■ were added to this to obtain a liquid preparation.

Example 2 Gel: (Composition) ■Griseofulpine 0.5%■
Ethyl nicotinate 10.0■
4% capo? -L liquid 38.6■
20% sodium hydroxide solution 26 ■ Purified water 48.3 Total 100.0 (Production method) Heat (1) to 50-60°C, add (2), mix and stir to dissolve. Separately, stir ■ well, add ■, then add ■ and stir. To this was added (2), which had been dissolved in (2), and thoroughly stirred to obtain a gel.

Example 3 Cream: (Composition) ■Griseofulpine 0.5%■
Methyl salicylate 10.0■ Stearic acid 5.0■ Setanol 5.0■ White petrolatum 3.0■ Fluidity, 92
Finn 6.0■ Sorbitan monostearate 1.0■ Purified water
66.2 (Production method) Heat ■ to 60-70℃ and dissolve ■, ■, ■, ■, ■
, ■, and ■ were added and stirred. 0 was heated to 60-70°C and gradually added, mixed and stirred thoroughly to obtain a cream. Example 4 Glucream: (Composition) ■ Griseofulpine 0.5 %■
Crotamiton 10,0■
Isopropyl myristate 2.0■
Fluid Q Rough-in 5.0 ■ Lauro Macrogol i.

■ 4% car? ? -L liquid 30.0
■ 20% sodium hydroxide solution 2.0■
・Purified water 49.5 (manufacturing method) Heat ■ to 50-60℃, add ■ and dissolve, add ■,
Add ① and ② and stir to obtain a solution.

On the other hand, (2) and (2) were added to (2) and heated to 50 to 60°C with stirring, and the above solution was added and thoroughly stirred to obtain a glucream.

Example 5 Liquid: (Composition) ■ Griseofulpine 0.5
%■ Menthol 3
．． 0 ■ Camphor
3. .

■ Benzyl alcohol 5.
0 ■ Ethanol 3
0,0■ Methyl ethyl ketone
4 & 5 (Manufacturing method) (Warm, ■, ■ to 50-60°C, add ■, stir, and dissolve. Next, add ■, ■, and ■ to obtain a liquid preparation.

Example 6 Liquid: (Composition) (O griseofulpine 0.5
%■ Glycol salicylate 3.
0 ■ Diphenhydramine
1.0 ■ Benzyl alcohol
5.0 ■ Ethanol
30.0■ Methyl ethyl ketone
50.5 (Production method) Heat ①, ②, and ② to 50 to 60°C, add ② and dissolve. Next, add ■, ■, and ■ to obtain a liquid preparation.

Example 7 A small amount of the topical antifungal agent prepared in Examples 1 to 6 was placed on a slide glass, a cover glass was placed on it, and the resultant was examined under a polarizing microscope.
The presence or absence of crystals in the preparation was observed. The following were used as controls. The results are shown in Table 1.

Control product 1 ■ Griseofulpine 0.5% ■
Ethanol 30.0■
Methyl ethyl ketone 69.5 control product 2 ~ ■ Griseofulpine 0.5% ■
4% cargo? -L liquid 38.6■
20% sodium hydroxide solution Z6 ■ Purified water 58.3 Control product 3 ■ Griseofulpine 0.5% ■
Stearic acid 5.0■
Setanol 5.0■ White Vaseline 3.0■ Liquid No. Q Rough-in 16. O■ Monostearic acid? Lyoxyethylene sorbitan 3.3■
Sorbitan monostearate 1.0 ■ M water 66.2 Control product 4 ■ Griseofulpine 0.5% (
Isozolovir myristate 7.0
■ Fluid) 9 rough-in 1α0■
Lauro Macrogol 1.0■
4% carb? -L liquid 30.0■
20% sodium hydroxide solution 20 ■ Purified water 49.5 Control product 5 ■ Griseofulvi 7 0.5% ■
Ethanol 30.0
■ Methyl ethyl ketone 59.
5 Control product 6 ■ Griseofulpine 0
．． 5%■ Ethanol
30.0■ Methyl ethyl ketone
59.5 or less Umbrella White Table 1 As is clear from the results, no crystals were observed in the formulation of the product of the present invention compared to the control product.

Example 8 A group of 5 Japanese white female domestic rabbits weighing 3-weight were taken, and their abdomens were dehaired to a size of 10 x 14 cIL.
The external preparations of Control Products 1 and 5 were each applied in an amount equivalent to 30% of griseofulpine, blood was collected from the ear vein over time, and the blood concentration of griseofulpine was measured. This result is the second
Shown in the table.

Table 2 As is clear from the results, the product of the present invention exhibited extremely high percutaneous absorption compared to the control product.

In addition, as a transdermal absorption aid, %1-0-n-dodecyl-3
-〇-Methyl-2+ Q + 21 , 37-zohydroxysolobylglycerol-containing formulation showed an even higher blood concentration.

that's all 1-book---11

Claims (1)

[Scope of Claims] 1. Griseofulpine and one or more selected from the group consisting of benzyl nicotinate, ethyl nicotinate, menthol, camphor, methyl salicylate, glycol salicylate, crotamiton, diphenhydramine, and benzyl alcohol. A topical antifungal agent containing a griseofulpine solubilizing agent. 2. Griseofulpine and one or more griseofulpine solubilizers selected from the group consisting of benzyl nicotinate, ethyl nicotinate, menthol, camphor, methyl salicylate, glycol salicylate, crotamiton, diphenhydramine, and benzyl alcohol; An antifungal agent for external use containing an absorption aid.