WO1994015591A1

WO1994015591A1 - Onychomycosis remedy composition

Info

Publication number: WO1994015591A1
Application number: PCT/JP1994/000028
Authority: WO
Inventors: Akira Nakagawa; Satoru Miyata; Kenzo Sakai
Original assignee: Hisamitsu Seiyaku Kabushiki Kaisha
Priority date: 1993-01-12
Filing date: 1994-01-12
Publication date: 1994-07-21
Also published as: JPH06211651A

Abstract

An onychomycosis remedy composition comprising a fungicide and a base containing a hydrophobic film forming agent, a fatty acid ester and a solvent. It is a liquid for external use excellent in adhesion to and penetration into nail cuticle and high in retention.

Description

- Specification

Nail white balm therapeutic composition

【Technical field ]

The present invention relates to a composition for treating tinea versicolor, which contains an antifungal agent as an active ingredient. More specifically, the present invention contains an antifungal agent as an active ingredient .. This is mixed with a drug having an effect of promoting absorption of the drug into the nails. A liquid composition for external use for the treatment of tinea unguium having adhesiveness, permeability and storability to the horny layer of nails, which is characterized by the above.

[Background Technology]

Nail leukoplakia is a nail disease caused by filamentous fungi and is a stubborn disease accompanied by opacity, thickening, destruction, and deformity of the nail plate. Until now, as a therapeutic agent for this tinea unguium, an external preparation containing an antifungal agent or an oral preparation containing Griseofulvin has been known, but in the conventional external preparation, the nail preparation is Due to the hard keratin of the skin, the drug could not penetrate inside the nail, and the effect could hardly be achieved.Therefore, as a fundamental treatment method, an oral administration agent containing griseofulvin was usually used. It is mainly used. However, the oral administration of griseofulvin is not effective until it is taken for a long period of time, and on the other hand, side effects on internal organs are a problem, and treatment with external preparations is also a problem. As an agent, Japanese Patent Application Laid-Open No. 62-1552505 discloses a liquid medicine containing 1-hydroxy-2-pyridone. In addition, Japanese Patent Application Laid-Open No. 2-267047 discloses an antifungal agent using a acrylate ester and a polymer / metacrylate ester as a film-forming agent. Although a drug solution containing a drug is disclosed, all of which have adhesiveness of the drug to the nail, but are 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 pedis that cannot be obtained as therapeutic agents are extremely irreversible diseases because they are hard to penetrate because they grow deep in the keratin. It is difficult to treat even on the hands and feet, but especially in the case of tinea unguium; since the keratin of the nail is hard, the drug penetration is poor, and it is impossible to cure tinea unguium with topical agents until now It has been thought that the treatment of tinea unguium is such that it is important to allow the drug to penetrate into the stratum corneum and store it for a long period of time. For the purpose of treating nail leukoplakia, no preparation has been found that has excellent penetrability and retention in the horny layer of the nail and exerts its therapeutic effect satisfactorily.

[Object of the Invention]

Based on the current situation described above, as a therapeutic agent for tinea unguium, it is strongly desired to develop a formulation that has strong adhesiveness to the nail and that allows the drug to sufficiently penetrate into the horny layer of the nail and retain for a long period of time. There is. 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 corneum of the nail.

[Disclosure of Invention] '' The present inventors have conducted intensive studies on a drug formulation that enhances the adhesiveness of drug components to the nails .. and has excellent drug permeability and retention on the horny layer of the nails. We have found that a formulation containing an antifungal agent in a base material containing a forming agent, a solvent and fatty acid ester 'achieves the above object, and completed the present invention.

That is, the present invention provides a composition for the treatment of Aspergillus niger, which comprises a base containing a fatty acid ester, an aqueous lacquer film-forming agent and a solvent, and an antifungal agent combined with the base below. The present invention will be described in detail.

Examples of the antifungal agent as the active ingredient of the present invention include terbinafine hydrochloride, neticoconazol hydrochloride / re, omoconazol nitrate, butenafine hydrochloride, isoconazole nitrate, miconazole nitrate, and Examples include econazole nitrate, sulconazole nitrate, oxiconazole nitric acid, thioconazole, tolucyclyl cosoconazole, miconazole nitrate, econazole nitrate, sulconazol nitrate / re, and oxyconazol nitrate / re. You can Among these antifungal agents, omoconazol nitrate / resin and butenafine hydrochloride are particularly preferable because they have high permeability to the stratum corneum and excellent storability in the stratum corneum. is there . The antifungal agent as an active ingredient is blended in an amount of 0.3 to 5% by weight, preferably 0 · 5 to 3% by weight. If the compounding amount is too small, the effect will not be sufficiently obtained, and if the compounding amount is too large, the drug will not dissolve in the solvent, and there is a formulation problem, which is not preferable. Examples of the fatty acid ester as a component include Sebac

2 2 I

These include diisopropyle quinoate, benzyl ethenosuccinate, diisopropylate adipate, and jeti / lepi adipate. Among them, diisopropyl sebacate b, which is effective as a solvent, has the most excellent effect of promoting absorption of the drug into the nail.

Hydrophobic film-forming agents include pyroxylline (nitrocellulose moistened with isopropanol or other suitable solvent), alkyd resin, acrylic acid. · Styrene copolymer, acrylic acid ■ Meta-acrylic acid amide copolymer, butyl acrylate · Meta-acrylic acid copolymer, acrylic acid hydroxide Cypropill-meta-acryl octyl acrylate Noetyl 'acrylate octyl amide copolymer, acryl amide ■ Polyvinyl alcohol copolymer, methacryl dimethyl acrylate Noethyl-methacrylic acid ester copolymer, acrylic acid-methacrylic acid methyl-methacrylic acid-methacrylic acid ammonium-methylammoniumethyl copolymer Examples of the resin include ethylene resin, ethylene-vinyl acetate copolymer, polyester resin, soluble nylon, polyvinyl butyral, cellulose acetate citrate, cellulose acetate phthalate, and toluene sulphonamide resin. However, pyroxylline is most preferred from the viewpoint of safety and usability.

Solvents include ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, and adipic acid. Phosphorus acid pill, seno-oxy acid di-sodium pill, seno'i

5 o 5 o It can be exemplified by decyl citrate, etanol, isoprononol, xylylene, triene, aceton, and urea triacetin.

5 The amount of the film forming agent is 0.5 to 35% by weight, preferably 1 to 20% by weight, using the above substances alone or in combination. If it is 0.5% or less, the adhesiveness of the drug to the nail is poor, and if it is 35% by weight or more, the coating becomes thick and the usability is poor, and the absorbability of the drug to the nail is also reduced. Solvents may be used alone or in combination at 20 to 96% by weight, preferably 70 to 95% by weight. If it is less than 20% by weight, it will be difficult to dissolve the drug, and if it is more than 96% by weight, it will be difficult to mix other ingredients. Fatty acid esters are 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 viewpoint of use such as irritation of the skin and strong odor. Also, plasticizers for film-forming agents such as camphor, phthalic acid esters, quinic acid esters, castor oil, etc. can be blended as necessary.

Specific examples of the present invention will be described below, but the present invention is not limited to these examples.

Example 1

Fatty acid esters, relative to the total weight of the composition, were 17% by weight of diisopropyl sebacate and a hydrophobic film-forming agent. Then, 15% by weight of pyroxylline and 12% by weight of the alkyd resin were dissolved in a solvent consisting of 33% by weight of ethyl acetate, 10% by weight of ethanol and 7% by weight of toluene. 1% by weight of ocomonazole 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.

In the following, according to the preparation method of this example, a composition for treating tinea unguium using the constituent components described in the following example was obtained.

Example 2

Composition Ingredients wt% Omoconazole nitrate 1 Pyroxylline 5 Polyvinyl butyral 15 Disopropyl adipate 3 Ethanol 76

100 cases 3

Composition Ingredients% by weight omoconazole nitrate 1 Soluble nitrogen 20 Ethyl acetate 28 Ethanol 46 Ethyl enosuccinate 5

100 , Composition% by weight

Py sigma lin 15 Alky, Zodo resin. 12 Camphor 5 Disopropi Sebacate / Le 17 Ethyl acetate 35 Ethanol 15

100 cases 5

Composition Ingredients wt% Omoconazole nitrate 3 Acrylic acid resin (Eudragit Ε

: Higuchi Shokai Co., Ltd. 10 Kamper 0 Diisop adipate pill 15 Ethyl acetate 36 Ethanol 33

100 cases 6

Composition Ingredients% by weight Omoconazole Nitrate 5 pi π-xylene 15 alk ,, / resin 12 camp

One _Adipic acid dizop mouth pill 17

11 2 5 o 5 Ethyl acetate 30 Ethanol 10 Normal rain 6

100 cases 7

Composition Ingredients% by weight Butenafin hydrochloride 1 Pyroxylline 15 Aki, Zodo resin 12 Camphor 5 Disopropyl senohexanoate 17 Ethyl acetate; Re 33 Ethano -Nore 10

Three true

100 cases 8

Composition component wt%

Λ

Butenafine hydrochloride

20-pi σ-kilin 15 acrylic resin (Eudragit Ε

: Higuchi Shokai Co., Ltd.) 12 Camper S Seno'disodium citrate pill 17 Ethyl acetate 33 'Ethanol 1C Tren

100 cases 9

Composition Ingredients% by weight Butenafine hydrochloride 3 pi σ xylline 15 Polyvinylacetate Jetyl

Amino Acetate 12 Acetyl tryptyl quinate 5 Disopropyl sebacate 17 Ethyl acetate 33 Ethanol 10 Ethanol 5

100 Example 10 2573 ο Composition Ingredients% by weight Butenafin Hydrochloride 3 Pycylline 15 Polyvinylacetate Jetyl

Amino Acetate

Acetate citrate / Li-butyl

Cenosuccinate disopropyl pill

Ethyl acetate

Ethanol

― C ― ― .Uren '5

100 11

Composition Ingredients% by weight Omoconazole Nitrate 3 Pi π-xylline 15 cN—Kan'Far 2 Propylene Carbonate 4 Diisopate Sebac Pill 3 Ethyl Acetate 15 Ethanol 40 Petit Acetate / Le 18

100 cases 12

, Composition% wt 5

Omoco nitrate 10 sol 3 pins σ silicone 10 units 20 d! — Strength, 2 Disopropyl sebacate 2 Ethyl acetate 28 Ethanol 15 Butyl acetate 20

100 cases 14

Composition Ingredients% by weight Omoconazole Nitrate 3 sigma Xylline 10 Acetone 20 d I—Kampha 2 Adipic Acid Disoup Pill

Ethyl acetate; Re 28 Ethanol 150 Butyl acetate 20

100 cases 15

Composition Ingredients% by weight

5 Pyroxylline Acetone 20 ci I Monocarbon 2 Jetyl sebacate 2 Ethyl acetate 26 Ethanol / Le 15 Butyl acetate 20

100 cases 16

Composition Ingredients% by weight

Pyroxylline 1 d l — Camphor 2 Propylene carbonate 4 Disopropyl cisenoate 3 Ethyl acetate 29 Ethanol / le 40 Butyl acetate 18

100 cases 17

Composition Ingredients% by weight Econazole Nitrate 3 Pyroxylline 15 cM—Camper 2 Ace 20 20 Dizop sebacate pill 2 — Ethyl acetate 28 Ethanol 15 Butyl acetate 15

100 cases 18

Composition Ingredients wt% Oxiconazole nitrate 3 Pyroxylline 15 d l — Camphor 2 Aceton 20 Disopropil senocinate 2 Ethyl acetate 23 Ethanol 15 Butyl acetate 20

100 cases 19

Composition Ingredients% by weight Sulconazole nitrate 3 pi σ xylline 5 d I — Camphor 2 Propylene carbonate 4 Cenosuccinic acid disodium pill

Ethyl succinate 25 Ethanol 40 Butyl acetate 18 100 cases 20

Composition Ingredients .M.A Nitrate nitrate

Pyroxylline 15 cM—Strength Phase 2 Phase 20 Sebacate Disoup Pill 2 Ethyl Acetate 28 Ethanol 15 Butyl Acetate 20

100 cases 21

Composition Ingredients ¾ i. Tioconazole 3 Pyroxylline 5 d I — Camphor 2 Propylene carbonate 4 Diisopropyl sebacate 3 Ethyl acetate 25 Ethanol 40 Butyl acetate 18

100 cases 22

Composition component wt% Urucycler Uka

Pyroxine 15 d l—Camphor 2 Acetate 20 Diisopropyl senocinate 2 Ethyl acetate 28 Ethanol 15 Butyl acetate 20

100 cases 23

Composition Ingredients% by weight Exalamide 3 Pyroxylline 5 d I—Campane 2 Propylene carbonate 4 Disodium cisenoate mouth

Ethyl acetate 25 Ethanol 40 Butyl acetate 18

100 cases 24

Composition Ingredients% by weight Nitric acid "10 oz. 3 p σ zizirine

cH—Camper 2 Acetane 20 Disoup sebac Pill 2 Ethyl acetate 28 Ethanol 15 Butyl acetate 20

100 Consideration 1

Composition Ingredients% by weight Omoconizo nitrate 3 p σ xylline 10 d! 1 camp 2 ace 20

X-Tanol 15 Ethyl drupate 30 Butyl acetate 20

100 Test Example 1 (Pig nail absorption test)

In order to examine the nail absorbability of the composition for treating nail baldness according to the present invention, an absorption test was carried out on the preparations of Examples 12, 14 and 15 and Reference Example 1 described above using pig nails. The test results are shown in Figure 1 and Table 1.

( Test method )

Pork claws (Kyushu Kyodo Slaughterhouse) were punched out using a 1 CI diameter skin punch. The preparation of the present invention was applied thinly on the surface of the nail using a brush. The applied nail is saline It was placed on gauze moistened with water and left 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 mni to obtain a sample. The nail was fixed on the cryostat stage with the coated surface facing the CMC, and a 5m-thick section was made using a cryostat (Leitz 1720 d ig i ta l Cryostat, Le i ca). did.

The 10 slices were collected and collected in a vial, and the radioactivity was measured with a liquid scintillation counter (PACKARD, TRI-CARB 1600TR).

Based on the measurement results, the amount of absorbed omoconazole nitrate was calculated and converted to a concentration per unit volume, and AUC was also determined from that concentration.

Table 1. Effect of blending fatty acid esters

7 'DES: Seno' Jetyl silicate

0 I S: diisocinocinate mouth pill

D I D: Diisophthalic acid. / Re

As is clear from the results shown in Table 1 and FIG. 1, the composition for the treatment of nail polish of the present invention, which is shown in the above-mentioned example, is superior in drug absorption as compared with the preparation containing no fatty acid esters. Ruko was recognized.

Test Example 2 (Peeling safety test)

In order to examine the safety of the composition for the treatment of nail baldness according to the present invention against the human skin shield, a hyperpa '/ test was performed on healthy adult males.

(Test method >

Using the formulation shown in the above example, the commercially available Maniyukia drug and Vaseline, each was applied to the inside of the upper arm of 10 healthy adult males, dried, and then the sample was taken from Torii Pharmaceutical Co., Ltd. Patchtes Covered with a threatening bond. The sores were removed 48 hours later, and the condition of skin-hitting was examined 1 and 2 hours after drug removal.

The composition for treating tinea cruris according to the present invention is as irritating as white petrolatum, with almost no irritation to skin thorns and Ί.

[The invention's effect ]

The composition for the treatment of nail whitening according to the present invention has a high permeability and retention of the drug to the horny layer of the nail, and the drug penetrates into the nail and is retained for a long time in the nail, which is excellent. Antifungal The effect is obtained. In addition, it is also highly safe with almost no irritation in Hibaru.

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 not been able to obtain a therapeutic effect when applied externally.

[Brief description of drawings]

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

9

Claims

, The scope of the claims

1. A composition for treating tinea unguium, which is characterized in that a base containing a hydrophobic film-forming agent, a fatty acid ester and a solvent is mixed with an antifungal agent.

2. The composition for treating tinea unguium according to claim 1, wherein the fatty acid ester is selected from diisopropyl sebacate, decyl sebacate and diisopropyl adipate.

3. 0.3 to 5% by weight of the antifungal agent, 0.5 to 35% by weight of the hydrophobic film-forming agent, 20 to 96% by weight of the solvent, and 20 to 96% by weight of the fatty acid ester. The composition for treating tinea unguium according to claim 1 or 2, which is in the range of 2 to 20% by weight.