JPH10120593A - Antifungal external preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antifungal agent for external use capable of enhancing antifungal effect and promoting treatment of superficial mycosis, especially athlete's foot. SOLUTION: This antifungal agent for external use comprises an antifungal medicine (e.g. clotrimazole or tolnaftate) and tachykinins releasing substance. The tachykinins releasing substance is capsaicin, Japanese pepper extract or vanillylamide nonylate. The dosage form includes an ointment or a plaster and the base includes macrogol oitment and the tacky agent includes an acrylic tacky agent or a rubber-based tacky agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antifungal external preparation, and more particularly to an external preparation for treating superficial mycosis.

[0002]

2. Description of the Related Art For the treatment of superficial mycosis caused by fungi parasitizing the keratin and nails of the body surface, a drug mainly having an antifungal action is used for the purpose of eliminating pathogenic fungi by using a liquid or a liquid. It is performed topically as an external preparation such as an ointment. The transdermally administered drugs include fatty acids, salicylic acids, sulfur-containing organic compounds, tars, antibiotics, imidazoles, and others. Among them, imidazole drugs are widely used because of their relatively excellent antifungal effect.

[0003] These drugs are not only administered in the form of an external preparation, but also administered by a drug absorption promoting technique for allowing a large amount of the drug to reach the stratum corneum inhabiting fungi (Japanese Patent Laid-Open No. 5-30).
Japanese Patent Application Laid-Open No. 7-242), a technique of improving the composition or forming a patch to maintain the adhesion time to the skin.
567, JP-A-7-309755), and various formulation techniques for maximizing the antifungal action of drugs have been proposed.

[0004] However, its therapeutic effect is not always satisfactory, and superficial mycosis known as athlete's foot, etc., is still a worrisome disease, especially in humid Japan.

[0005]

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems, and an object of the present invention is to provide an antifungal external preparation which enhances an antifungal effect and promotes healing.

[0006]

The topical antifungal agent according to claim 1 is characterized by containing an antifungal agent and a tachykinin-releasing substance.

[0007] The antifungal external preparation according to claim 2 is the antifungal external preparation according to claim 1, wherein the tachykinins-releasing substance is capsaicin, pepper extract or nonylate vanillylamide.

The above-mentioned antifungals are not particularly limited as long as they have an antifungal action and can be used externally. Examples thereof include fatty acids (such as undecylenic acid), salicylic acids (such as salicylic acid), and sulfur-containing organic compounds. , Tar, antifungal antibiotics (siccanin, tricomycin, nystatin, pyrrolnitrin, variotin, etc.), imidazoles (croconazole, tinconazole, clotrimazole, ketoconazole, isoconazole, econazole, oxyconazole, sulconazole, miconazole , Thioconazole, bifonazole, lanconazole, etc.), thiocarbamic acids (tolnaphthate, lorcyclate, etc.), allylamines (naphthefin, etc.), polyenes (amphotericin B, etc.), benzamides (exalemide, etc.) ), And the like. These drugs can also be used as salts. These can be used alone or in combination of two or more.

[0009] The content of the antifungal agent in the antifungal external preparation of the present invention varies depending on the type of the antifungal agent.
0% by weight is preferable, and when the external preparation is a dosage form that does not use a support such as an ointment, the external preparation is more preferably 0.5 to 5% by weight, and the external preparation is, for example, a patch. In the case of a dosage form using a support as described above, the content is more preferably 1 to 8% by weight. In addition, in the case of a dosage form using a support, the above-mentioned content is a portion excluding the support (so-called a layer composed of a substance in which a drug is dissolved or mixed and dispersed in an adhesive; hereinafter, referred to as a plaster layer). Content.

The tachykinin-releasing substance is not particularly limited as long as it induces the release of tachykinins such as substance P in a living body. Examples of the substance include capsaicin; capsicum extract; nonylate vanillylamide; capsaicin, capsicum extract and nonyl. Derivatives such as acid vanillylamide; pulverized pepper; and the like. Of these, capsaicin, capsicum extract or vanillyl amide nonylate are preferred.

The content of the tachykinin-releasing substance in the antifungal external preparation of the present invention may be such that when the external preparation is in a dosage form that does not use a support such as an ointment, the content decreases. In general, 0.0005 to 5% by weight is preferable since sufficient effects are hardly obtained, and inflammation and the like are easily caused by the released tachykinins when the effect is high.
0.001 to 0.25% by weight is more preferable. The external preparation is, for example, in the case of a dosage form using a support such as a patch, when the content is low, it is difficult to obtain a sufficient effect, and when the content is high, inflammation and the like are easily caused by the released tachykinins. Therefore, in general, 0.0005 to 2
0% by weight is preferable, and 0.001 to 0.5% by weight is more preferable. In the case of a dosage form using a support, the above content is the content in the plaster layer.

The dosage form of the antifungal external preparation of the present invention is not particularly limited. For example, the above-mentioned drug (antifungal drug, tachykinin releasing substance) is dissolved or mixed and dispersed in a base, Gels, creams, pastes, etc. (solutions, gels, creams, ointments, etc.), or the above drugs dissolved or mixed and dispersed in a base are spread on a support (Eg, a cataplasm), and a patch obtained by spreading a plaster layer on a support (a patch such as a plaster or a tape).

The above-mentioned base may be any pharmaceutically acceptable base, and may be a conventionally known base such as a liquid, gel, cream, ointment and the like. , Gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene
Polymers such as maleic anhydride copolymer, polyvinyl ether and polyvinyl pyrrolidone; beeswax, olive oil,
Fats and oils such as cocoa oil, sesame oil, soybean oil, camellia oil, peanut oil, beef oil, pork oil, lanolin; white petrolatum;
Paraffin; Hydrocarbon gel ointment (for example, Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.); Higher fatty acids such as stearic acid; Higher alcohols such as cetyl alcohol, octyl dodecanol, stearyl alcohol; polyethylene glycol; glycerin monostearate; Ethylene cetyl ether; self-emulsifying propylene glycol monostearate, triethanolamine;
Water.

The above-mentioned base may further contain, if necessary, a percutaneous absorption enhancer for a drug; an additive for retaining the drug on the skin; an antioxidant; a preservative; an antipruritic or an anti-inflammatory agent. Is also good.

The support is appropriately selected according to its dosage form (eg, cataplasm, plaster, tape, etc.), and is preferably a flexible material that is impermeable or hardly permeable to drugs. Cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide Resin films such as copolymers, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, and polybutylene terephthalate, aluminum sheets, woven fabrics, nonwoven fabrics, etc.
And a laminated sheet thereof. The resin film may be foamed. The support may be provided with a hole for ventilation.

The pressure-sensitive adhesive used in the plaster layer may be any pharmaceutically acceptable adhesive that has an adhesive force that adheres to the skin, and may be a conventionally known one. Agents, rubber-based adhesives, silicone-based adhesives and the like. When the pressure-sensitive adhesive is spread on the support, any type of pressure-sensitive adhesive such as a solvent-based, emulsion-based, or hot-melt-based adhesive can be used.

Examples of the acrylic pressure-sensitive adhesive include alkyl (meth) acrylate polymers and copolymers. Examples of the alkyl (meth) acrylate monomer include butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and ( Isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, and stearyl (meth) acrylate. Further, an alkyl (meth) acrylate monomer copolymerized with another functional monomer may be used. Examples of the functional monomer include a monomer having a hydroxyl group, a carboxyl group, an amide group, an amino group, and a pyrrolidone ring.

Examples of the rubber pressure-sensitive adhesive include styrene-isoprene-styrene block copolymer, natural rubber and synthetic rubber. As the silicon-based pressure-sensitive adhesive, a pressure-sensitive adhesive mainly containing polymethylsiloxane or the like is used.

In addition to such an adhesive, a hydrophilic adhesive such as polyvinyl ether may be used.

Such adhesives have adhesive strength, stability,
Depending on the purpose of promoting moisture permeability, promoting the transfer of drugs to the skin, etc., terpene resins, alicyclic synthetic resins, rosin resins, polybutenes, liquid paraffin, long chain fatty acids, higher alcohols, kaolin , Bentonite, titanium oxide, zinc white, an antioxidant, a preservative, an antipruritic or an anti-inflammatory agent, and the like.

A release paper may be attached on the plaster layer for the purpose of protecting this layer.

The method for producing the antifungal external preparation of the present invention will be described. Solutions, gels, creams, ointments and the like are the same as in the conventional general production methods for each. The production methods differ depending on the polarity, solubility and preparation method of the drug, and are not limited, but examples are shown below. That is, in the case of a liquid preparation, a predetermined amount of an antifungal agent and a tachykinin-releasing substance are dissolved and dispersed in a predetermined amount of a solvent such as ethanol or propylene glycol, and mixed with a predetermined amount of water. If it is a gel,
Dissolve a predetermined amount of antifungal agent and tachykinins releasing substance in a predetermined amount of solvent such as ethanol and propylene glycol,
It is dispersed, dissolved and dispersed in water or the like, uniformly mixed with a gelling agent such as polyacrylic acid, and adjusted to a gelling pH with a pH adjuster such as triethanolamine to produce the product. In the case of a cream, an antifungal agent and a tachykinin-releasing substance are dissolved and dispersed in water in which a surfactant is dissolved, and then emulsified while adding an oily component such as squalane. In the case of an ointment, for example, a predetermined amount of a macrogol ointment (polyethylene glycol 400 and polyethylene glycol 4) may be used.
000) is heated and dissolved, and a predetermined amount of an antifungal agent and a tachykinin releasing substance are added to dissolve and disperse.

The patch is the same as in the conventional method for producing a patch. That is, a plaster solution obtained by uniformly dissolving or dispersing the components of the plaster layer in an appropriate solvent is uniformly spread on a support, and then the solvent is removed to produce the plaster solution. Also,
After the plaster solution is spread on release paper, the solvent is removed and the support is stuck to the plaster exposed surface to produce the plaster. Alternatively, the hot-melt components of the plaster layer are melted by heat, and a plaster solution in which all components are uniformly mixed or dispersed is spread on a support or release paper while being melted, and similarly produced.

The antifungal external preparation of the present invention is usually applied to an affected part several times a day for liquids, gels, creams, ointments and the like. In the case of patches, usually 1
One sheet per day is applied to the affected area.

[0025]

Next, embodiments of the present invention will be described. (Examples 1 to 15 and Comparative Examples 1 to 7) Take a predetermined amount (% by weight) of Macrogol ointment of JP Pharmacopoeia shown in Table 1, dissolve it at 70 ° C, and use clotrimazole and tolnaftate as antifungal agents. A predetermined amount (% by weight) shown in Table 1 was added and dissolved. Thereafter, a predetermined amount (% by weight) of capsaicin shown in Table 1 as a tachykinin-releasing substance under melting at 70 ° C.
The pepper extract and nonylate varnish were added, mixed uniformly, and cooled to obtain an antifungal external preparation (ointment).

[0026]

[Table 1]

Performance Evaluation Using the ointments obtained in Examples 1 to 15 and Comparative Examples 1 to 7 as test samples, the performance was evaluated as follows. The back skin (about 15 cm ² ) of the guinea pig was shaved, the stratum corneum was peeled off with an adhesive tape, and 5 × 10 ⁵ T. mentagrophytes suspended in physiological saline were inoculated. From the fourth day after the inoculation, the test sample was transdermally administered every day. Approximately 45 mg of the test sample was uniformly applied to the affected area (the inoculated part of tinea) and covered with gauze and fixed with a bandage. On the 8th day after the start of the application, the skin of the affected area was excised, and 10 substantially uniform skin pieces were prepared from the excised skin. Place each of these skin pieces on a Sabouraud agar plate (1 in total).
0 plates) and cultured at 28 ° C. for 14 days. The above operation was repeated for each test sample at a number of 3 (that is, the total number of skin pieces tested was 30). After the completion of the culture, the growth of Schistococcus colonies from the skin pieces on each Sabouraud agar plate was observed, and the ratio of the number of skin pieces where no Schizophrenia colonies were observed to the total number of skin pieces (%) Was used as an index of the antifungal effect as a negative conversion rate, and is shown in Table 1.

From Table 1, it can be seen that the ointment containing the antifungal and the tachykinins releasing substances capsaicin, capsicum extract or vanillylamide nonylate has a remarkably negative conversion rate as compared with the ointment containing only the antifungal. high,
It can be seen that the antifungal effect is enhanced.

(Examples 16 to 23 and Comparative Examples 8 to 11)
A predetermined amount (parts by weight) of an acrylic pressure-sensitive adhesive (ethyl acetate solution containing a copolymer consisting of 85 parts by weight of 2-ethylhexyl acrylate and 15 parts by weight of vinylpyrrolidone at a ratio of 20% by weight) shown in Table 2 and myristin Isopropyl acid, clotrimazol as an antifungal agent and capsaicin and capsicum extract as tachykinins releasing substances,
It was mixed and dissolved to obtain a plaster solution. This plaster solution was applied on a polyethylene film having a thickness of 40 μm so that the thickness after drying became 50 μm, and dried at 60 ° C. for about 20 minutes to obtain an antifungal external preparation (patch). .

(Examples 24 to 27 and Comparative Examples 12 to 1)
5) A predetermined amount (parts by weight) of rubber-based pressure-sensitive adhesive (styrene-isoprene-styrene block copolymer), aliphatic saturated hydrocarbon resin, liquid paraffin (half the amount shown in Table 3) and antioxidation shown in Table 3 Agent (dibutylhydroxytoluene)
After blending and heating and mixing at 130 ° C to make it uniform,
Clotrimazol as an antifungal agent and vanillyl amide nonylate as a substance releasing tachykinins dissolved in liquid paraffin (half the amount shown in Table 3) were added and uniformly mixed to prepare a plaster. With this paste in the molten state,
After spreading on release paper made of silicon-treated polyethylene-coated paper and reaching room temperature, a support (rayon nonwoven fabric) was overlaid to obtain an antifungal external preparation (paste).

[0031]

[Table 2]

[0032]

[Table 3]

Performance Evaluation Using the patches obtained in Examples 16 to 27 and Comparative Examples 8 to 15 as test samples, performance was evaluated as follows. The back skin (about 15 cm ² ) of the guinea pig was shaved, the stratum corneum was peeled off with an adhesive tape, and 5 × 10 ⁵ T. mentagrophytes suspended in physiological saline were inoculated. From the fourth day after the inoculation, the test sample was transdermally administered every day. The test sample was affixed to 20 cm ² so that the inoculated portion could be covered, covered with gauze, and fixed with a plaster. On the 8th day after the start of the application, the skin of the affected area was excised, and 10 substantially uniform skin pieces were prepared from the excised skin. Each of these skin pieces was placed on a Sabouraud agar plate (tested on a total of 10 plates) and cultured at 28 ° C. for 14 days. The above operation was repeated for each test sample at a number of 3 (that is, the total number of skin pieces tested was 30). After the completion of the culture, the growth of Schistococcus colonies from the skin pieces on each Sabouraud agar plate was observed, and the ratio of the number of skin pieces where no Schizophrenia colonies were observed to the total number of skin pieces (%) Was used as an index of the antifungal effect as a negative conversion rate, and is shown in Tables 2 and 3.

From Tables 2 and 3, it can be seen that the patch containing the antifungal drug and the tachykinins releasing substances capsaicin, capsicum extract or vanillyl amide nonylate is remarkably compared with the patch containing only the antifungal drug. It can be seen that the negative rate is high and the antifungal effect is enhanced.

[0035]

The composition of the antifungal external preparation according to claim 1 comprises:
As described above, the present invention provides an antifungal external preparation which enhances the antifungal effect and particularly promotes the healing of superficial mycosis such as athlete's foot, because it contains an antifungal agent and a tachykinins releasing substance.

The composition of the antifungal external preparation according to claim 2 is as described above, and the tachykinins releasing substance is capsaicin, capsicum extract or nonylate vanillylamide. Provided is an antifungal external preparation which enhances an antifungal effect and particularly promotes the cure of superficial mycosis such as athlete's foot.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 35/78 A61K 35/78 R

Claims (2)

[Claims] 1. An external antifungal agent comprising an antifungal agent and a tachykinins releasing substance. 2. The tachykinins releasing substance is capsaicin,
2. The antifungal external preparation according to claim 1, which is a pepper extract or a nonylate vanillylamide.