JP2951725B2 - Topical composition for tinea unguium - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an external composition for tinea unguium, which contains an antifungal agent as an active ingredient. More specifically, the present invention relates to an external composition for treating tinea unguium, which has good absorbability of a drug to nails and has no color change upon application.

2. Description of the Related Art Ringworm, such as tinea pedis (athlete's foot) and tinea unguium, is a disease that is difficult to penetrate and is very difficult to cure even if an external preparation is used to treat it because it is deep in the keratin. Especially in the case of tinea unguium, which is a disease of the nail caused by dermatophytes and associated with symptoms such as cloudiness, thickening, destruction, and deformation of the nail plate, it is difficult to attach drugs to the nail. In addition, since the keratin of the nail is hard, the permeability of the drug is even worse, and it has been conventionally difficult to obtain the desired effect on the treatment of onychomycosis with an external preparation. For this reason, oral treatments containing griseofulvin and the like are usually used as the conventional treatment methods. However, an oral preparation of griseofulvin has no effect unless taken for a long period of time, so that side effects on internal organs have been a problem.

On the other hand, some attempts have been reported to use a film-forming agent as an external preparation. For example, a nail varnish containing 1-hydroxy-2-pyridone (Japanese Patent Laid-Open No. 62-155205) and a nail varnish containing a copolymer of acrylate and methacrylate (Japanese Patent Laid-Open No. 2-155205)
No. 264708), all of which have a certain degree of adhesion of the drug to the nail, but the drug does not easily penetrate into the keratin of the nail, so that the above-mentioned problems cannot be solved. It is hard to say that the preparation has a therapeutic effect. Further, those using cellulose derivatives (JP-A-6-9342, JP-A-3-60814 and WO94 / 15591) have been reported, but they are not suitable for safety reasons or they are easily washed off with water. When nitrocellulose (Japanese Pharmacopoeia: Piroxylin) is used (Japanese Patent Application Laid-Open No. 3-60814 and WO94 / 15591), nitrocellulose reacts with nail protein and is continuously used. Thus, there is a problem that the nail or the skin around the nail is colored yellow or black by interacting with clothes fibers.

In addition, none of the other film-forming agents is satisfactory as an external preparation for tinea unguium in view of the strength, dryness, and usability of the film.

Thus, regarding the treatment of tinea unguium with external preparations,
It is important to make the drug penetrate into the stratum corneum and retain it for a long period of time, and a formulation with excellent usability without coloring etc. has been desired. No formulation was satisfactory.

Accordingly, the object of the present invention is to provide an external preparation for tinea unguium, which is safe, has high adhesiveness to the nail, and sufficiently penetrates the keratin of the nail, and has excellent transdermal absorbability. It is a formulation that is stored in nails for a long period of time, and even when used continuously for a long period of time, the nails, the surrounding skin or the fiber components of clothes do not react with drugs or film-forming agents and are not colored. To obtain an excellent preparation.

DISCLOSURE OF THE INVENTION The present inventors have been conducting intensive studies on an external preparation for tinea unguium, and surprisingly, a formulation containing an antifungal agent in a base containing hydroxypropylcellulose as a film-forming agent is described above. The inventors have found that the problems can be solved at once, and have completed the present invention. That is, by using hydroxypropylcellulose as a film-forming agent, the adhesiveness to nails is strong, the permeability and retention of the drug to the keratin of nails are good, and the nails or around the nails when applied for a long period of time. A preparation having no skin coloration was obtained. Hydroxypropylcellulose is a non-aqueous preparation because it dissolves in both water and an organic solvent, but can be washed away with water after the preparation is applied to nails. Further, by blending a fatty acid ester as an absorption promoter, the absorbability of the drug to nails could be significantly increased.

As active ingredients of the present invention, omoconazole nitrate, butenafine hydrochloride, isoconazole nitrate, miconazole nitrate, econazole nitrate, sulconazole nitrate, oxyconazole nitrate, thioconazole, exalamide, tolcyclate, terbinafine hydrochloride, amorolfine hydrochloride,
Examples include neticonazole hydrochloride, ketoconazole, and lanconazole. Of these antifungal agents, omoconazole nitrate and butenafine hydrochloride are preferred because they have particularly high permeability into the stratum corneum and have excellent storage properties in the stratum corneum.

The amount of the antifungal agent, which is an active ingredient, is 0.3 to 10% by weight, particularly 0.5 to 10% in consideration of the intended effect and solubility in a solvent.
5% by weight is preferred.

Hydroxypropylcellulose as a film-forming agent includes HPC-L, HPC-M, HPC-H of Nippon Soda Co., Ltd., HPC-EF, HPC-LE, HPC-MF, manufactured by Shin-Etsu Chemical Co., Ltd. And the like.

The amount of hydroxypropylcellulose is preferably 0.5% by weight to 10% by weight, particularly preferably 1% to 5% by weight in consideration of adhesion to nails, stickiness, dryness of a film, and the like.

The base component includes, in addition to the film-forming agent, an organic solvent, a solubilizing agent for a drug, and / or an absorption promoter.

As the organic solvent, a lower alcohol is preferable, and ethanol, isopropanol and the like can be mentioned. Ethanol is particularly preferable in consideration of the solubility of hydroxypropylcellulose and the like. The lower alcohol is preferably used in an amount of 20 to 90% by weight, particularly preferably 40 to 80% by weight in consideration of sufficient solubility in the drug and the film forming agent and quick drying.

Examples of the dissolution aid include ethyl acetate, acetone, butyl acetate, propylene carbonate, triacetin, crotamiton, menthol, camphor, and the like. These may be used alone or in combination of two or more. The compounding amount is preferably 5 to 60% by weight, particularly preferably 10 to 45% by weight in consideration of the solubility, safety or odor of the drug.

Examples of the absorption enhancer include fatty acid esters such as diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, and diethyl adipate. Among them, diisopropyl sebacate, which is also effective as a solvent, has the most absorption enhancement effect. Are better. The compounding amount is preferably 0.2 to 20% by weight, particularly preferably 1 to 10% by weight in consideration of the absorption promoting effect, skin irritation, odor, drying property of the film, and the like.

In order to produce the external composition for tinea unguium of the present invention, an antifungal agent is dissolved in a solvent, a solubilizing agent and an absorption enhancer by stirring, and hydroxypropyl cellulose is added thereto, and the mixture is dissolved by stirring.

Examples Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1: Ingredient% by weight Omoconazole nitrate 3 Hydroxypropylcellulose (Nisso HPC-M) 3 Ethyl acetate 40 Ethanol 54 100 Omoconazole nitrate was dissolved in ethanol and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 2: Ingredient% by weight Butenafine hydrochloride 3 Hydroxypropylcellulose (Nisso HPC-M) 10 Ethyl acetate 40 Ethanol 47 100 Butenafine hydrochloride was dissolved in ethanol and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 3: Component Wt% omoconazole nitrate 3 Hydroxypropylcellulose (Nisso HPC-M) 1.5 Ethyl acetate 20 ethanol 75.5 100 Omoconazole nitrate was dissolved in ethanol and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 4: Ingredient Weight% Omoconazole nitrate 1 Hydroxypropylcellulose (Nisso HPC-H) 1 Diisopropyl sebacate 5 Ethyl acetate 34 ethanol 59 100 Omoconazole nitrate was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 5: Ingredient% by weight Omoconazole nitrate 3 Hydroxypropylcellulose (Nisso HPC-M) 5 Diisopropyl sebacate 5 Ethyl acetate 37 Ethanol 50 100 Omoconazole nitrate was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 6: Ingredient% by weight Omoconazole nitrate 3 Hydroxypropylcellulose (Nisso HPC-M) 10 Diisopropyl sebacate 12 Ethyl acetate 25 Ethanol 50 100 Omoconazole nitrate was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 7: Component% by weight Omoconazole nitrate 5 Hydroxypropylcellulose (Nisso HPC-H) 2 Diisopropyl adipate 5 Ethyl acetate 48 ethanol 40 100 Omoconazole nitrate was dissolved in ethanol, diisopropyl adipate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 8: Component Wt% omoconazole nitrate 1 Hydroxypropylcellulose (Nisshin HPC-H) 2 Diisopropyl sebacate 2 Ethyl acetate 45 ethanol 50 100 Omoconazole nitrate was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 9: Component Weight% omoconazole nitrate 2 Hydroxypropylcellulose (Shin-Etsu Chemical HPC-MF) 2 Diethyl sebacate 5 Ethyl acetate 7 Ethanol 84 100 Omoconazole nitrate was dissolved in ethanol, diethyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 10: Component wt% butenafine hydrochloride 7 Hydroxypropylcellulose (Nisshin HPC-H) 2 Diisopropyl sebacate 3 Ethyl acetate 47 Ethanol 41 100 Butenafine hydrochloride was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 11: Ingredient weight% miconazole nitrate 1 hydroxypropylcellulose (Nisso HPC-H) 2 diisopropyl sebacate 5 ethyl acetate 32 ethanol 60 100 Miconazole nitrate was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 12: Ingredient% by weight Econazole nitrate 3 Hydroxypropylcellulose (Nisso HPC-H) 2 Diisopropyl sebacate 10 Ethyl acetate 25 Ethanol 60 100 Econazole nitrate was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 13: Component Weight% Terbinafine hydrochloride 3 Hydroxypropylcellulose (Nisso HPC-H) 2 Diisopropyl sebacate 5 Ethyl acetate 25 Ethanol 65 100 Terbinafine hydrochloride was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 14: Ingredient% by weight Neticonazole hydrochloride 3 Hydroxypropylcellulose (Nisso HPC-H) 2 Diisopropyl sebacate 5 Ethyl acetate 30 Ethanol 50 100 Neticonazole hydrochloride was dissolved in ethanol, diisopropyl sebacate and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 15: Ingredient% by weight Omoconazole nitrate 3 Hydroxypropylcellulose (Nisso HPC-H) 2 Diisopropyl sebacate 3 Ethyl acetate 40 dl-Camphor 2 Ethanol 60 100 Omoconazole nitrate and dl-Camphor are treated with ethanol,
Dissolved in diisopropyl sebacate and ethyl acetate.
Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Example 16: Ingredients% by weight Omoconazole nitrate 5 Hydroxypropylcellulose (Nitric acid HPC-H) 2 Diisopropyl sebacate 5 1-Menthol 2 Crotamiton 2 Ethyl acetate 34 Ethanol 50 100 Omoconazole nitrate and 1-menthol are ethanol, diisopropyl sebacate , Crotamiton and ethyl acetate. Hydroxypropylcellulose was added to the solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Reference Example 1: Component Weight% omoconazole nitrate 3 pyroxylin 5 dl-camphor 2 acetone 10 ethyl acetate 33 ethanol 47 100 Omoconazole nitrate and dl-camphor were dissolved in ethanol, acetone and ethyl acetate. Pyroxylin was added to this solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Reference Example 2: Component Weight% omoconazole nitrate 3 pyroxyline 10 propylene carbonate 2 dl-camphor 2 ethyl acetate 28 ethanol 55 100 Omoconazole nitrate and dl-camphor were dissolved in ethanol, propylene carbonate and ethyl acetate. Pyroxylin was added to this solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Reference Example 3: Component Weight% omoconazole nitrate 3 pyroxylin 3 diisopropyl sebacate 2 propylene carbonate 3.5 dl-camphor 2 ethanol 47 ethyl acetate 19.5 butyl acetate 20 100 omoconazole nitrate and dl-camphor were treated with ethanol,
Dissolved in diisopropyl sebacate, ethyl acetate and butyl acetate. Pyroxylin was added to this solution, and the mixture was stirred to obtain an external composition for tinea unguium containing an antifungal agent.

Test Example 1: Pig Nail Absorption Test In order to examine the nail absorbency of the external composition for tinea unguium of the present invention, an absorption test was performed on the compositions of Example 3 and Reference Example 3 described above using pig nails. . The test results are shown in Table 1.

(Test method) Pig nails were punched out to a diameter of 1 cm using a leather punch and used. Each of the preparations of Example and Reference Example 3 was
It was thinly applied to the surface of the nail once a day. The applied nail was placed on a gauze moistened with distilled water and allowed to stand at 25 ° C. After continuous administration for 7 days, the remaining drug at the administration site was wiped off with gauze moistened with ethanol, and the nail was punched out to a size of 4 mm in diameter with a skin punch to obtain a specimen. The nail is fixed on the cryostat stage with carboxymethylcellulose with the coated side up and the cryostat (Leitz 1720 digital Cryos
tat, Leica) to make a section having a thickness of 5 μm.

The ten sections were collectively collected in a vial, and a liquid scintillation counter (Packard, TRI-CARB1) was used.
The radioactivity was measured at 600TR).

The amount of omoconazole nitrate absorbed was calculated from the measurement results, converted to the concentration per unit volume, and the AUC (area under the nail concentration) was calculated from the concentration.
−depth of penetration curve) was calculated.

As is clear from the results in Table 1, Example 3 of the present invention
Reference Example 3 in which the absorption enhancer (diisopropyl sebacate) was blended (the absorption enhancer was not blended) was prepared.
Omoconazole nitrate was much better at absorbing nails than the formulation.

Test Example 2: Stability test A fixed amount of the preparations of Examples 1 to 16 and Reference Examples 1 to 3 was dropped on human nail powder and stored in a 60 ° C constant temperature bath to observe the change in coloration of the preparation. did. The results are shown in Table 2.

As is evident from the results in Table 2, the preparations of the present invention shown in Examples have no reactivity with human nails and change in coloring due to temperature as compared with the preparations of Reference Example containing pyroxylin (main component: nitrocellulose). Did not.

Test Example 3: Human nail application test In order to examine the color change in the human nail, the preparations of Examples 3 to 6 and the preparations of Reference Examples 1 to 3 were applied to the human toes daily for 2 days.
Application for 6 weeks, and the color change of the finger was observed. The results are shown in Table 3.

As is clear from the results in Table 3, the preparations of the present invention shown in Examples did not show coloring of the nail or the surrounding skin in the application test on human nails, but were shown in Reference Examples 1 to 3. In the preparation using nitrocellulose as the film-forming agent to be formed, a color change was observed.

Test Example 4: Skin Safety Test In order to examine the safety of the external use composition for tinea unguium of the present invention on human skin, a human patch test was performed on healthy adult males. The test results are shown in Table 4.

(Test Method) Using the composition of Example 1 and the composition of Reference Example 3 described above,
Each was applied to the inner side of the upper arm of 27 healthy adult males, dried, and then covered with a patch test patch of Torii Pharmaceutical Co., Ltd. After 48 hours, the bandage was peeled off, and one hour after removing the drug, the condition of the skin was examined.

(Judgment method) Score- : No response 0 ±: Slight erythema (redness) 05 +: Erythema 1 ++: Erythema + edema 2 +++: Erythema + edema + papule or small blister 3 As is clear from the results in Table 4, the composition of Example 4 of the present invention was superior in safety on human skin as compared with the composition of Reference Example 3 containing pyroxylin.

Effect of the Invention The external preparation for tinea unguium, in which hydroxypropylcellulose is blended as a film-forming agent, has good percutaneous absorbability, can be easily washed off with water, and can be continuously applied to the nail. Also, there is no reaction with the drug or nails and no change in coloring is observed, so that it is excellent in usability. Unlike commonly used film-forming agents such as nitrocellulose and alkyd resins, the use of a plasticizer is unnecessary, and it is also preferable in terms of skin safety.

From the above points, the external composition for tinea unguium of the present invention is industrially very useful as a remedy for tinea unguium, which has been conventionally difficult to treat with an external preparation.

Claims (10)

(57) [Claims] 1. An external composition for tinea unguium, comprising an antifungal agent mixed with a base containing hydroxypropylcellulose. 2. The composition according to claim 1, which contains an organic solvent and a solubilizing agent as a base. 3. A composition containing 0.5 to 10% by weight of hydroxypropylcellulose, 20 to 90% by weight of an organic solvent and 5 to 60% by weight of a solubilizer and 0.3 to 10% by weight of an antifungal agent. The composition according to claim 1, characterized in that: 4. The composition according to claim 2, further comprising an absorption enhancer as a base. 5. Hydroxypropyl cellulose 0.5 to 10% by weight, organic solvent 20 to 90% by weight, solubilizer 5 to 60% by weight
2. The composition according to claim 1, wherein 0.3 to 10% by weight of an antifungal agent is mixed with a base containing 0.2 to 20% by weight of an absorption enhancer. 6. The composition according to claim 1, wherein the organic solvent is ethanol and / or isopropanol. 7. The method according to claim 1, wherein the solubilizer is one or more selected from ethyl acetate, acetone, butyl acetate, propylene carbonate, triacetin, crotamiton, menthol, and camphor. A composition according to any one of claims 1 to 3. 8. An absorption enhancer comprising diisopropanol sebacate, diethyl sebacate, diisopropyl adipate,
The composition according to claim 4, wherein the composition is one or more fatty acid esters selected from diethyl adipate. 9. The antifungal agent is omoconazole nitrate, butenafine hydrochloride, isoconazole nitrate, miconazole nitrate, econazole nitrate, sulconazole nitrate, oxyconazole nitrate, thioconazole, exalamide, tolcyclate, terbinafine hydrochloride, amorolfine hydrochloride, neticonazole hydrochloride, lanconazole. The composition according to any one of claims 1 to 5, wherein the composition is at least one member selected from the group consisting of: 10. The composition according to claim 1, wherein the organic solvent is ethanol and the absorption promoter is diisopropyl sebacate.