JPH1121229A - Antifungal external preparation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject external preparation, hardly having irritation, excellent in safety and stability and having good use feeling, in which the active ingredient is absorbed from affected part by including an antifungal agent, a water-soluble polymer and a nonionic surfactant. SOLUTION: This external preparation comprises (A) 0.1-30 wt.% antifungal agent (e.g. tolnaftate, clotrimazole or siccanin), (B) 0.1-10 wt.% water-soluble polymer (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose or polyvinyl alcohol) and (C) 0.05-10 wt.% nonionic surfactant (e.g. polysorbate 80, polyoxyethylene hardened castor oil or polyoxyethylenelauryl ether). The external preparation is preferably obtained by dispersing the antifungal agent by using the water-soluble polymer and the nonionic surfactant and formulating the resultant dispersion with a proper base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to
The present invention relates to an antifungal topical preparation having improved stability.

[0002]

2. Description of the Related Art Various drugs having antifungal properties and excellent therapeutic effects on tinea cruris, tinea cruris, tinea pedis varicella, etc. are known. There is a problem. For example, tolnaftate, clotrimazole, siccanin, etc. are soluble in solvents such as acetone, chloroform, methyl ethyl ketone, etc., but are hardly soluble in water and other organic solvents, so they are formulated into liquid and semi-solid preparations. To do so, first, it is dissolved in acetone, methyl ethyl ketone, or the like, and alcohol, propylene glycol, a cream base, and the like are mixed therein. However, in these preparations, the solvent is easily volatilized, causing instability of the preparation, and the antifungal agent, which is the main drug, is precipitated as crystals on the coated surface, and sufficient absorption from the coated surface cannot be obtained. further,
Depending on the administration site, the type and dosage of the organic solvent that can be used are limited due to its irritation, and are considerably restricted.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide an antifungal topical preparation which is less irritating, has excellent safety and stability, has a good feeling in use, and in which the active ingredient is properly absorbed from the affected part. It is to get.

[0004]

Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies, and as a result, have used an antifungal agent in a dispersed state using a water-soluble polymer and a nonionic surfactant. As a result, the present inventors have found that the use of an organic solvent such as acetone or methyl ethyl ketone, which has conventionally been indispensable for dissolution, can be avoided, and have completed the present invention.

That is, the present invention is as follows. (1) An antifungal external preparation containing an antifungal agent, a water-soluble polymer, and a nonionic surfactant. (2) The antifungal external preparation according to the above (1), wherein the antifungal agent is dispersed in a water-soluble polymer in the presence of a nonionic surfactant. (3) 0.1 to 30% by weight of the antifungal agent, 0.1 to 10% by weight of the water-soluble polymer, and 0.05 to 0.05% of the nonionic surfactant.
The antifungal external preparation according to the above (1) or (2), which contains 10% by weight. (4) The antifungal external preparation according to any of (1) to (3), further comprising a carboxyvinyl polymer. (5) The antifungal external preparation according to (4), further comprising an inorganic base or an organic amine. (6) The antifungal external preparation according to the above (4) or (5), which contains 0.1 to 5% by weight of a carboxyvinyl polymer. (7) The antifungal external preparation according to any one of (1) to (6), wherein the dispersed antifungal agent has an average particle size of 10 μm or less. (8) A method for producing an external antifungal preparation, comprising dispersing an antifungal agent in a water-soluble polymer in the presence of a nonionic surfactant and then mixing a base.

[0006] The antifungal agent which is contained as a main component in the antifungal external preparation of the present invention includes, for example, tolnaftate,
Clotrimazole, siccanin, econazole, miconazole nitrate and the like are used. In order to exhibit the usefulness of the present invention, drugs poorly soluble in water, such as tolnaftate, clotrimazole and siccanin, are preferred. The antifungal agent is preferably used in a proportion of generally 0.1 to 30% by weight based on the total amount of the preparation. If added in an amount of 30% by weight or more, sufficient dispersion becomes difficult, and formulation becomes impossible. Particularly preferably, the content is 10% by weight or less. When the antifungal agent is dispersed in a water-soluble polymer, the average particle size is usually 10 μm or less, preferably 3 μm or less, and particularly preferably 1 μm or less.

As the water-soluble polymer used in the present invention, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like are used alone or in combination of two or more. Hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinyl alcohol are particularly preferred. In general, the water-soluble polymer is preferably used at a ratio of 0.1 to 10% by weight based on the total amount of the preparation. If it is used in an amount of 10% by weight or more, the viscosity increases, and it becomes difficult to produce a uniform dispersion. Especially 5% by weight
The following uses are preferred:

As the nonionic surfactant used in the present invention, polyoxyl stearate 40, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether and the like are used alone or in combination of two or more. Are used as a mixture. Polysorbate 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether are particularly preferred. The nonionic surfactant is preferably used in a proportion of generally 0.05 to 10% by weight based on the total amount of the preparation.
When the nonionic surfactant is used in an amount of 10% by weight or more, the main agent is dissolved, and the main agent is aggregated or recrystallized with the passage of time. Particularly, addition of 3% by weight or less is preferable.

In a preferred embodiment of the preparation of the present invention, an antifungal agent is dispersed using a water-soluble polymer and a nonionic surfactant, and an appropriate base is blended.
Examples of the base include the following. Examples of the base for a suspension include carboxyvinyl polymer, dextran, gum arabic, sodium alginate, agar, gelatin, tragacanth and the like.
Examples of bases for ointments include petrolatum, fatty oil, purified lanolin, paraffin, wax, stearic acid, stearyl alcohol, and medium-chain triglycerides. As a suppository (rectal or vaginal) base, for example, cocoa butter, lauric fat, glycerogelatin, macrogol, hard fat, medium-chain fatty acid triglyceride, stearyl alcohol and the like are used.

The external preparation of the present invention can be prepared into a dosage form such as a suspension, an ointment, a plaster, a suppository (rectal or vaginal) by adding known additives as appropriate. Additives, depending on the dosage form, suspending agents, stabilizers, preservatives,
Excipients, solvents and other known materials are used as appropriate.

In producing the external preparation of the present invention,
Usually, one or more antifungal agents are dispersed in a water-soluble polymer and a nonionic surfactant, and then added to a base, and homogenized by a conventional method. In particular, when a suspension is prepared, an aqueous solution of a carboxyvinyl polymer, a water-soluble basic substance, or the like is used as a formulation auxiliary or base. Examples of the carboxyvinyl polymer include Carbopol 934, 940, and 941 (trade name) manufactured by Goodrich Chemical Company, USA, and Hibiswako (trade name) manufactured by Wako Pure Chemical Industries, Ltd. These are hydrophilic polymers having a free carboxy group, and their aqueous solutions exhibit acidity. In the aqueous solution, a water-soluble base substance, for example, ammonia, an inorganic base such as an alkali hydroxide aqueous solution, an alkylamine, a dialkylamine, a trialkylamine, an alkanolamine, a dialkanolamine, a trialkanolamine or an organic amine such as trimethylolaminomethane By neutralizing with, a viscous gel can be produced. When a carboxyvinyl polymer is included, it is preferably used in a proportion of generally 0.1 to 5% by weight, particularly preferably 0.1 to 2% by weight, based on the total amount of the preparation. If added in excess, the viscosity will increase, making it difficult to discharge from the container. If the addition is insufficient, aggregation and sedimentation of the active ingredient occur, resulting in a non-uniform state. By increasing the viscosity, it is possible to prevent precipitation of the active ingredient contained in the suspension state. Similarly, it can be formulated into ointments, plasters, and suppositories (rectal or vaginal) by conventional methods.

[0012]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Clotrimazole 1 g Polyvinyl alcohol 1 g Polysorbate 80 0.5 g 1% carboxyvinyl polymer aqueous solution 50 g 1% sodium hydroxide 2.9 g Purified water 44.6 g 100 g Clotrimazole was added to polysorbate 80 With mixing and stirring, polyvinyl alcohol and purified water are added and mixed. 1% carboxyvinyl polymer aqueous solution, 1%
Sodium hydroxide and purified water were added to make the total amount 100 g, and the mixture was stirred well to obtain a suspending agent.

Example 2 Clotrimazole 1 g Polyvinylpyrrolidone 3 g Polyoxyethylene lauryl ether 0.5 g 1% aqueous carboxyvinyl polymer 30 g Ethanolamine 3.6 g Purified water 61.9 g 100 g Polyoxyethylene lauryl ether Trimazole is mixed, and while stirring, polyvinylpyrrolidone and purified water are added and mixed. A 1% carboxyvinyl polymer aqueous solution, ethanolamine and purified water were added thereto to make the total amount 100 g, and the mixture was stirred well to obtain a suspending agent.

Example 3 Clotrimazole 1 g Hydroxypropylcellulose 1 g Polyoxyethylene hydrogenated castor oil 10 2 g Vaseline 96 g 100 g After mixing clotrimazole and hydroxypropylcellulose, polyoxyethylene hydrogenated castor oil 10 was added. In addition, vaseline is added to make an ointment.

Example 4 Clotrimazole 1 g Hydroxypropylcellulose 1 g Polyoxyethylene lauryl ether 0.5 g Witepsol 97.5 g 100 g A small amount of Witepsol was added to polyoxyethylene lauryl ether, clotrimazole and hydroxypropyl The cellulose was heated to about 50 to 60 ° C., clotrimazole was sufficiently mixed, the remaining witepsol was added, and the mixture was uniformly mixed. The mixture was poured into a plastic container and allowed to stand to obtain a suppository.

[0017]

According to the present invention, an antifungal agent can be prepared into an external preparation without using an irritating solvent such as an organic solvent, and a safe antifungal external preparation with less irritation can be obtained. In particular, it can be applied to vaginal administration requiring lower irritation and safety, and is effective for various fungal infections.

Claims (8)

[Claims] 1. An antifungal external preparation comprising an antifungal agent, a water-soluble polymer and a nonionic surfactant. 2. The antifungal external preparation according to claim 1, wherein the antifungal agent is dispersed in a water-soluble polymer in the presence of a nonionic surfactant. 3. An antifungal agent comprising 0.1 to 30% by weight, a water-soluble polymer of 0.1 to 10% by weight and a nonionic surfactant of 0.05 to 10% by weight. The antifungal topical preparation according to claim 1 or 2. 4. The antifungal topical preparation according to claim 1, further comprising a carboxyvinyl polymer. 5. The antifungal external preparation according to claim 4, further comprising an inorganic base or an organic amine. 6. A carboxyvinyl polymer of 0.1 to 5
The antifungal external preparation according to claim 4 or 5, which is contained by weight. 7. The dispersed antifungal agent having an average particle size of 10
The antifungal external preparation according to any one of claims 1 to 6, wherein the preparation has a size of not more than μm. 8. A method for producing an antifungal external preparation, comprising dispersing an antifungal agent in a water-soluble polymer in the presence of a nonionic surfactant and then mixing a base.