JPH07206711A - Composition for treatment of trichophytosis unguium - Google Patents

Abstract

PURPOSE:To obtain a composition for the treatment of trichophytosis unguium, exhibiting excellent adhesivity and penetrability of the drug component to the horny layer of nail and having high storability. CONSTITUTION:This composition for the treatment of trichophytosis unguium is produced by preparing a base agent containing (A) a hydrophobic film-forming agent, preferably pyroxylin (nitrocellulose wet with isopropanol or other proper solvent), (B) a fatty acid ester such as diisopropyl sebacate, diethyl sebacate and diisopropyl adipate and (C) a solvent such as ethyl acetate, acetone, ethanol, isopropanol and xylene and compounding the base agent with (D) an antimycotic agent, preferably omoconazole nitrate or butenafine hydrochloride having high penetrability to horny layer and excellent storability in horny layer. The amount of each component in the composition is 0.3-5wt.% (preferably 0.5-3wt.%) for the component D, 0.5-35wt.% for A, 0.2-20wt.% for B and 20-90wt.% for C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition for treating tinea unguium containing an antifungal agent as an active ingredient. More specifically, the present invention relates to the horny layer of nails, which comprises an antifungal agent as an active ingredient and is mixed with a drug having an effect of promoting absorption of the drug into the nails. It is intended to provide a liquid composition for external use for treating tinea unguium having adhesiveness, permeability and retention.

[0002]

BACKGROUND ART Tinea unguium is a nail disease caused by dermatophytes and is a stubborn disease accompanied by symptoms such as cloudiness, thickening, destruction, and deformation of the nail plate. Until now, as a therapeutic agent for this tinea unguium, an external preparation containing an antifungal agent or an oral administration preparation containing griseofulvin has been known, but in the conventional external preparation, the drug is used because the keratin of the nail is hard. However, the oral administration agent containing griseofulvin is usually mainly used as a fundamental therapeutic method because it cannot penetrate into the nail and its effect can hardly be achieved. However, oral administration of griseofulvin
On the other hand, side effects on the internal organs are a problem because the effect cannot be achieved unless it is taken for a long period of time. Further, as a therapeutic agent using an external preparation, JP-A-62-1552
Japanese Patent Publication No. 05 discloses a nail varnish containing 1-hydroxy-2-pyridone. Further, JP-A-2-264708 discloses a nail varnish containing an antifungal agent containing a copolymer of acrylic acid ester and methacrylic acid ester as a film-forming agent. Although the adhesion of the drug to the drug is recognized, it cannot be said that the therapeutic agent is satisfactory in terms of the permeability of the drug into the inside of the horny layer of the nail. Ringworms such as tinea pedis (athlete's foot) and tinea peduncle are diseases that are difficult to penetrate and are extremely difficult to cure because they parasitize deep parts of the corneum. It is difficult to treat even on the hands and feet, but especially in the case of tinea unguium, it is impossible to cure tinea unguium with topical agents until now because the keratin of the nail is hard and drug penetration is poor. Was even thought to be. As described above, regarding the treatment of tinea unguium, it is an important key to treat it by allowing the drug to penetrate into the keratin and storing it for a long period of time. It has not been found that the drug product has excellent penetrability and storability and exhibits its therapeutic effect satisfactorily.

[0003]

OBJECT OF THE INVENTION From the above-mentioned present situation, as a therapeutic agent for tinea unguium, it is strongly desired to develop a formulation which has strong adhesiveness to the nail, and in which the drug sufficiently penetrates into the horny layer of the nail and is stored for a long period of time. ing. An object of the present invention is to provide a pharmaceutical composition for treating tinea unguium, which is excellent in the adhesiveness, penetrability and retention of drug components to the horny layer of the nail.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies on a formulation which enhances the adhesion of drug components to the nails and has excellent drug permeability and retention on the stratum corneum of the nails. The inventors have found that a formulation in which an antifungal agent is added to a base containing a forming agent, a solvent and fatty acid esters achieves the above-mentioned object, and completed the present invention. That is, the present invention provides a composition for treating tinea unguium in which an antifungal agent is added to a base containing a fatty acid ester, a hydrophobic film forming agent and a solvent.

The present invention will be described in detail below. The antifungal agent as the active ingredient of the present invention, terbinafine hydrochloride, neticonazole hydrochloride, omoconazole nitrate, butenafine hydrochloride, isoconazole nitrate, miconazole nitrate,
Examples thereof include econazole nitrate, sulconazole nitrate, oxyconazole nitrate, thioconazole, tosiclate cosoconazole, miconazole nitrate, econazole nitrate, sulconazole nitrate, and oxyconazole nitrate. Among these antifungal agents, omoconazole nitrate and butenafine hydrochloride are preferable because they have particularly high permeability to the stratum corneum and excellent storability in the stratum corneum. The compounding amount of the antifungal agent as an active ingredient is 0.3 to 5% by weight, preferably 0.5 to 3% by weight. If the compounding amount is small, the effect cannot be sufficiently obtained, and if the compounding amount is too large, the drug is not dissolved in the solvent, which causes a problem in formulation and is not preferable.

[0006] Examples of the fatty acid ester as a blending component include diisopropyl sebacate, diethyl sebacate,
Examples thereof include diisopropyl adipate and diethyl adipate. Among them, diisopropyl sebacate, which is also effective as a solvent, is most effective in promoting absorption of the drug into the nail.

As the hydrophobic film forming agent, pyroxyline (nitrocellulose moistened with isopropanol or other suitable solvent), alkyd resin, acrylic acid / styrene copolymer, acrylic acid / methacrylic acid amide copolymer Coalescence, butyl acrylate / methacrylic acid copolymer, hydroxypropyl acrylate / butylaminoethyl methacrylate / octylamide acrylic acid copolymer, acrylamide / polyvinyl alcohol copolymer, dimethylaminoethyl methacrylate / methacrylic acid ester Acrylic resins such as copolymers, ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate acrylate copolymers, ethylene-vinyl acetate copolymers, polyester resins, soluble nylon, polyvinyl butyral, Cellulose acetate butyrate,
Cellulose acetate phthalate, toluene sulfonamide resin and the like can be mentioned, but pyroxyline is most preferable from the viewpoint of safety and usability.

As the solvent, ethyl acetate, butyl acetate,
Acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl adipate, diisopropyl sebacate, diethyl sebacate, ethanol, isopropanol, xylene, toluene, acetone, triacetin, etc. can be illustrated.

The coating amount of the film-forming agent is 0.5% by weight based on the above substances alone or in combination.
35% by weight, preferably 1 to 20% by weight is blended.
If it is 0.5% or less, the drug has poor nail adhesion, and if it is 35% by weight or more, the coating becomes thick and the usability deteriorates, and the drug absorbability to the nail also decreases. The solvent, alone or in combination, is 20 to 96% by weight, preferably 70 to
95% by weight is blended. When it is 20% by weight or less, it becomes difficult to dissolve the drug, and when it is 96% by weight or more, it becomes difficult to mix other components. The fatty acid ester is blended in a proportion of 0.2 to 20% by weight, preferably 1 to 10% by weight. If it is less than 0.2%, the absorption promoting effect cannot be obtained. Further, if it is 20% by weight or more, it is not preferable from the point of use such as skin irritation or strong odor. If necessary, a plasticizer for a film-forming agent such as camphor, phthalic acid ester, citric acid ester, castor oil, etc. may be added.

[0010]

[Examples] Specific examples of the present invention will be described below. However, the present invention is not limited to these examples. Example 1 17% by weight of diisopropyl sebacate as a fatty acid ester, 15% by weight of pyroxylin as a hydrophobic film forming agent and 1% of alkyd resin based on the total weight of the composition.
2 wt% was dissolved in a solvent consisting of 33 wt% ethyl acetate, 10 wt% ethanol and 7 wt% toluene. 1% by weight of okomonazole nitrate as an antifungal agent was stirred and uniformly dissolved in this solution to obtain a composition for treating tinea unguium containing an antifungal agent. Hereinafter, according to the preparation method of this example, a composition for treating tinea unguium using the composition components described in the following example was obtained.

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Reference Example 1

Test Example 1 (Pork Nail Absorption Test) In order to examine the nail absorbability of the composition for treating tinea unguium of the present invention, a swine nail was used to prepare the preparations of Examples 12, 14 and 15 and Reference Example 1 described above. The absorption test was carried out. The test results are shown in FIG. 1 and Table 1. (Test method) Pork claw (Kyushu cooperative slaughterhouse) 1 cm in diameter
It was punched out using a leather punch. The formulation of the present invention was applied thinly on the surface of the nail using a brush. The applied nail was placed on a gauze moistened with physiological saline and allowed to stand at 25 ° C. Two hours after administration, the residual drug at the administration site was wiped off with gauze moistened with ethanol, and then the nail was punched out with a skin punch to a size of 4 mm to obtain a sample. The nail is fixed to the cryostat stage with the coated surface facing upwards and fixed by CMC,
Cliostat (Leitz 1720 digital
l Cryostat, Leica) and 5 μm thick sections were prepared. The 10 sections were collected together in a vial, and the radioactivity was measured with a liquid scintillation counter (Packard, TRI-CARB 1600TR). The amount of omoconazole nitrate absorbed was calculated from the measurement results, converted into the concentration per unit volume, and AUC was further calculated from the concentration.

[Table 1] DES: Diethyl sebacate DIS: Diisopropyl sebacate DID: Diisopropyl adipate As is clear from the results shown in Table 1 and FIG. 1, the composition for treating tinea unguium according to the present invention shown in the above-mentioned examples contains no fatty acid esters. It was confirmed that the drug absorption was superior to that of the combined preparation.

Test Example 2 (Skin Safety Test) In order to examine the safety of the composition for treating tinea unguium of the present invention on human skin, a human patch test was conducted on healthy adult males. (Test method) Using the formulation shown in the above-mentioned example, a commercially available nail polish formulation, and vaseline, each of them was applied to the inside of the upper arm of 10 healthy adult males, and after drying, the sample was subjected to the patch test of Torii Pharmaceutical Co., Ltd. Covered with a bandage. Four
Remove the bandage after 8 hours, 1 hour and 2 after drug removal
After a while, the skin condition was examined. The composition for treating tinea unguium according to the present invention was as irritating as white petrolatum, but hardly irritating to human skin.

[0037]

EFFECTS OF THE INVENTION The composition for treating tinea unguium according to the present invention is excellent in that the drug has high penetrability and storability in the corneum of the nail, and the drug penetrates into the nail and is stored in the nail for a long time. The antifungal effect is obtained. In addition, it is highly safe with almost no irritation on human skin. From the above points, the composition for treating tinea unguium according to the present invention is extremely excellent as a therapeutic agent for tinea unguium, which has hitherto been hardly obtained a therapeutic effect by external application.

[Brief description of drawings]

FIG. 1 shows the results of a pig nail absorption test of Test Example 1.

Claims (3)

[Claims] 1. A composition for treating tinea unguium, which comprises a base containing a hydrophobic film-forming agent, a fatty acid ester and a solvent, and an antifungal agent. 2. The composition for treating tinea unguium according to claim 1, wherein the fatty acid ester is selected from diisopropyl sebacate, diethyl sebacate and diisopropyl adipate. 3. The content of the antifungal agent is 0.3 to 5% by weight, and the content of the hydrophobic film forming agent is 0.5 to 35% by weight.
The compounding amount of the solvent is 20 to 96% by weight and the compounding amount of the fatty acid ester is 0.2 to 20% by weight.
A composition for treating tinea unguium of item 1 to 2.