WO2005032532A1

WO2005032532A1 - Antimycotic composition

Info

Publication number: WO2005032532A1
Application number: PCT/JP2004/011998
Authority: WO
Inventors: Shigeki Sawamura
Original assignee: Kobayashi Pharmaceutical Co., Ltd.
Priority date: 2003-09-30
Filing date: 2004-08-20
Publication date: 2005-04-14
Also published as: TW200511985A; JP2005104916A

Abstract

[PROBLEMS] To provide a product having a high therapeutic effect suitable for the symptoms of weeping superficial mycosis. [MEANS FOR SOLVING PROBLEMS] An antimycotic composition prepared by blending an allylamine type antimycotic agent with a fatty acid ester, a powdery component, an alcoholic solvent and an anti-itch component. As the allylamine type antimycotic agent, it is preferable to use at lease one member selected from the group consisting of terbinafine, naftitine and salts thereof. The allylamine type antimycotic agent is contained in amount of from 0.05 to 5% by weight in the composition.

Description

Specification

Antifungal composition

Technical field

[0001] The present invention relates to an antifungal composition comprising an arylamine antifungal agent, a fatty acid ester, a powder component, an alcoholic solvent, and an antipruritic component. The present invention relates to a composition having an excellent therapeutic effect on sexual mycosis (eg, tinea pedis, tinea corporis, tinea cruris, etc.).

^ Scenic technology

[0002] In superficial mycosis, fungi mainly penetrate into the stratum corneum of the skin and proliferate. Therefore, a condition for an antifungal agent to exhibit excellent medicinal effects against superficial mycosis is that the drug itself must be used. It is necessary that the body has strong antifungal activity and high affinity for the site of infection. In addition, superficial mycosis can be broadly divided into symptoms in which the affected area is relatively dry and symptoms in which the affected area is wet, and a formulation suitable for the condition of the affected area is needed. In recent years, an arylamine antifungal agent having excellent antifungal activity and keratophilicity satisfying such conditions has been put to practical use. As the antifungal agent, terbinafine and its salts, terbinafine hydrochloride and naphthytin, are known to have excellent effects when used alone. Therefore, there is a demand for the development of antifungal agents that can achieve a high therapeutic effect that is more tailored to the symptoms and that can improve the patient's QOL (life comfort).

[0003] Conventionally, as for an arylamine-based antifungal composition, a dry spray-type antifungal composition containing an acyclic silicone polymer, an inorganic or organic filler, and a propellant in the arylamine-based antifungal agent has been known ( Patent Document 1). However, this document states that by adding an acyclic silicone polymer to an antifungal-containing dry spray used for wet athlete's foot, an even amount of active ingredient can be obtained even when intermittent spraying is performed. However, there is no description about the effect on wet superficial antimycoses or the feeling of use. This is limited to the spray type.

[0004] Further, antifungal agents, lower alcohols, isopropanolamines and amylamines An aerosol formulation containing an antifungal agent containing at least one propellant has been proposed (see Patent Document 2). However, this is because the antifungal agent is limited to the azole type, and the dosage form is only an aerosol, and the antifungal effect, which is poor in versatility, is low.

Patent Document 1: Patent No. 3150374

Patent Document 2: Japanese Patent Application Laid-Open No. 2000-229845

Disclosure of the invention

Problems to be solved by the invention

[0005] In view of the above, the present invention provides an antifungal composition capable of obtaining a high therapeutic effect tailored to the symptoms of wet superficial mycosis and achieving improved QOL of patients. Is the subject.

Means for solving the problem

[0006] The inventor of the present invention has found that when a specific component is added to an arylamine antifungal agent excellent in keratin storage properties, keratin affinity and bactericidal activity, a high therapeutic effect is obtained for an affected part wetted by an exudate or moisture. The present invention has been found to give an excellent feeling of use, and the present invention has been completed based on the findings.

[0007] That is, the present invention provides a fatty acid ester, a powder component, an alcohol-based solvent and an antipruritic component (the fatty acid ester, the powder component, the alcohol-based solvent and the antipruritic component are referred to as compounding components) with an arylamine antifungal agent. An antifungal composition comprising:

[0008] In the present invention, a preferred arylamine antifungal agent is at least one selected from the group consisting of terbinafine, naphthytin and salts thereof. The compounding amount of the arylamine antifungal agent is 0.01% to 10% by weight, preferably 0.05% to 5% by weight in the composition. If the amount is too small, a sufficient antifungal effect is not exhibited, and if the amount is too large, the safety of the composition is concerned.

[0009] Among the components used in the present invention, fatty acid esters are blended for the purpose of improving the adhesiveness of the powder component at the time of drug application and the penetration of the active ingredient into the stratum corneum. A high quality drug surface is formed on the affected area to achieve the above object, and further has a drug sustained release action. Preferred fatty acid esters are isopropyl myristate, octyl myristate, butyl stearate, ethyl oleate, oleyl oleate, diisopropyl adipate, glycerin fatty acid ester, polyoxyl stearate 40, 45 and 55, and jeti sebacate. It is at least one selected from the group consisting of glue, sorbitan fatty acid ester, isopropyl palmitate, glyceryl monooleate and sorbitan monooleate. The amount of fatty acid ester composition 2 40 weight ^_0/0, preferably from 5 31.96 wt%. If the amount is too small, the powder component adheres poorly to the affected area, and sufficient drug permeability and sustained release cannot be obtained. If the amount is too large, a sticky feeling is given to the affected part, and a good feeling of use cannot be obtained.

[0010] The powder component may be organic or inorganic, and is preferably talc, zinc oxide, titanium oxide, magnesium stearate, zinc stearate, magnesium oxide, magnesium carbonate, chloramine, magnesium aluminate metasilicate, and silicate anhydride. And at least one selected from the group consisting of magnesium silicate, kaolin, aerosil, myritsu, and corn starch. The mixing ratio of the powder component is 1570% by weight, preferably 2050% by weight. If the amount is too small, the feeling of use is poor. If the amount is too large, the excessive amount of powder prevents the drug from adhering to and penetrating the affected area.

[0011] The antipruritic component is compounded for the purpose of suppressing the pruritus of Megumi, preventing the affected area from being exacerbated by pimples, and preventing drug dropout. The amount of the antipruritic component is 0.01 to 20% by weight, preferably 0.05 to 10% by weight in the composition. If the amount is too small, a sufficient antifungal effect will not be exhibited, and if it is too large, the safety of the composition is concerned. Preferred antipruritic components are lidocaine, dibu strength in, pro strength in, dibu strength in hydrochloride, lidocaine hydrochloride, pro force in hydrochloride, aminoethyl benzoate, oxypolyentoxide dodecane, diphenirubiralin hydrochloride, diphenhydramine hydrochloride, chlorphene. At least one selected from the group consisting of biramine, diphenhydramine salicylate, and crotamiton.

[0012] The alcohol-based solvent dissolves the antifungal agent, and is blended for the purpose of enhancing the permeability to the keratin and the therapeutic effect. The amount of the alcohol solvent is 1580% by weight, preferably 29.94 74.9% by weight in the composition. If the amount is too small, the antifungal agent will not dissolve in the solvent, and sufficient drug effect will not be obtained. If the amount is too large, the solvent will prevent the powder component from adhering to the affected area and prevent the formation of a uniform drug surface. Preferred alcohol solvents are methanolaceous, ethanolaceous, propanolone, butanolone, pendinoleanolonecore, glycerin, ethylene glycol and their structural isomers (for example, isopropanol, t-butanol). At least one selected from the group consisting of

[0013] Preferred antifungal compositions according to the invention, antifungal agents 0. 01- 10 wt%, more preferably rather is 0.5 05 5 wt ^_0/0, 2 40 wt month effect fatty acid Esutenore ^_0/0, more preferably 5 31.96 by weight%, the powder component 15 70 wt%, more preferably 20- 50 wt%, the alcohol solvent 15 80 wt%, more preferably 29.94 74.9 wt%, and the antipruritic ingredient 0.0 1 one 20 weight ^_0/0, but more preferably including 0.05 to 10 wt ^_0/0.

[0014] According to the present invention, it is also possible to provide an aerosol comprising the antifungal composition 5 having the above constitution in an amount of 5 to 30% by weight and a propellant in an amount of from 95 to 70% by weight. Preferred propellants comprise at least one liquefiable aliphatic hydrocarbon such as propane, butanes, pentane, isopentane, neopentane, and the like.

[0015] The antifungal composition according to the present invention includes, in addition to the arylamine antifungal agent and the above-mentioned components, a preservative, a preservative, a lubricant, a chelating agent, a fragrance, a solvent, a solubilizing agent, and a pH adjuster. , Antioxidants, moisturizers, shape-retaining agents, etc. (hereinafter referred to as `` additives ''), anti-inflammatory agents, cooling agents, bactericides, astringents, blood circulation promoters, skin protectants, tissue repair agents, etc. Hereinafter, referred to as “another active ingredient”).

[0016] Examples of the anti-inflammatory agent include glycyrrhetinic acid, dipotassium glycyrrhizinate, allantoin, 1 menthol, dl menthol, and dl camphor.

[0017] The antifungal composition according to the present invention is used in a usual dosage form used for treating a skin disease. Examples of dosage forms include solutions, ointments (oil-based ointments, emulsion ointments, water-soluble ointments), liniment IJ, lotions, powders, emulsified suspensions, tinctures, vaginal suppositories, aerosols And the like, and an aerosol is preferable.

[0018] The antifungal composition according to the present invention can be formulated into the above-mentioned dosage form by a conventional method using an appropriate base.

The [0019] base, alcohol solvents, or to, in accordance with the dosage form of interest, propylene render recall, 1, ₃ - butylene da recall, surfactants Qi ij such macrogol, carboxy Sibi Nino les polymer Use a base to which polymers such as etinoresenorelose, methinoresenorelose, hydroxypropinoresenorelose, and carboxymethylcellulose, purified water, a propellant, and phenols are added. [0020] A typical formulation is prepared as follows.

[0021] The liquid agent is prepared by uniformly mixing an allyluamine antifungal agent, a compounding component, an additive component added as necessary, and other active components with an alcoholic solvent or a base obtained by adding purified water or the like thereto. Mix.

[0022] The ointment is prepared by adding an allylamine antifungal agent, a compounding ingredient, and a base obtained by adding vaseline, white wax, paraffin, vegetable oil, plastic base, polyethylene glycol, macrogol, and the like to an alcohol solvent. And the other active ingredients are uniformly mixed.

[0023] The gel is obtained by adding an acrylamine-based antifungal agent, It is a gel-like substance obtained by uniformly mixing the compounding components, the additional components added as needed, and other active ingredients.

[0024] The aerosol is prepared by adding an arylamine-based antifungal agent, a compounding component, an additive component added as necessary, and other active components to an alcohol-based solvent or a base obtained by adding purified water or the like thereto. And the resulting mixture is mixed with a propellant such as a hydrocarbon that can be liquefied into a container equipped with a valve, actuator, etc., such as propane, butane granules, pentane, isopentane, neopentane, and the like, and mixtures thereof. Filled.

[0025] The dose of the arylamine antifungal agent in the antifungal composition according to the present invention is selected depending on the dosage form, the content ratio of the active ingredient to the compounding ingredient, the type of fungus and the degree of symptoms, etc. The range is from 0.01 to 10 mg / day, preferably from 0.05 to 5 mg / day. The frequency of administration is once a day.

The invention's effect

According to the present invention, by blending a specific component with an arylamine antifungal agent having excellent keratin storage properties, keratin affinity and bactericidal activity, it is possible to adjust to the symptoms of wet superficial mycosis. Further, an antifungal composition which can obtain a high therapeutic effect and can improve the QOL of a patient can be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION Next, the composition of the present invention will be specifically described with reference to Examples _c. [0028] Formulation Example 1 (Aerosol)

2g

Dipotassium glycyrrhizinate lg

Chlorhexidine hydrochloride 0.2 g

Zinc oxide 10g

0.5 g of magnesium stearate

Talc 55.3 g

Isopropyl myristate 15g

/ ー Nore ― Λ5Κ _

100g

Formulation Example 2 (Aerosol)

2.5g

Acid

Zinc oxide 10g

Talc 10g

Isopropyl myristate 5g

Ethanore 70 / 5g

100g

Formulation Example 3 (Aerosol)

Terbinafine hydrochloride

Diphenhydramine hydrochloride 2g

', Diacid

Chlorine hydrochloride Zinc oxide 10g Talc 10g Isopropyl myristate 30g Ethanore 5g

100g

Formulation Example 4 (Aerosol)

Terbinafine hydrochloride

2.5g acid

Chlorine hydrochloride

Zinc oxide 10 g Talc 30 g Isopropyl myristate 18.5 g Ethanore ME _

100g

Formulation Example 5 (Aerosol)

2.5g acid

Zinc oxide 10 g Talc 20 g Isopropyl myristate 20 g Ethanore 45.5 g_

100g

Formulation Example 6 (Aerosol) Diphenhydramine hydrochloride 2g Isopropyl methylphenol 3g

Zinc oxide 10g

Talc 17g

20g isopropyl myristate

Ethanore 6g

100g

[0034] The above-mentioned stock solution and propellant (LPG) are filled in a combination container in a ratio of stock solution: propellant = 1: 9 to produce an aerosol.

[0035] Performance test

1) Usability test

The antifungal composition Sampnore of Example 1 and Comparative Examples 14 to 14 having the compounding ratios shown in Table 1 was evaluated for feeling of use by the following method. In other words, apply the test sample to the same place between the toes of the 7 panelists, apply easily at the time of application, easy to dry, 8 hours after application, the smoothness of the applied area (between the toes), and A score was given for the overall feeling of use based on the overall evaluation based on the following evaluation criteria.

[0036] Evaluation criteria

Good: 5 points

Somewhat good: 4

Neither: 3 points

Somewhat bad: 2 points

Bad: 1 point

The highest score is the score when all the subjects rated “Good: 5 points” in all the evaluation items. 5 points x 7 people x 4 items = 140 points.

[0037] The lowest score is the score when all subjects evaluate as "bad, 1 point" for all evaluation items. It is a core, 1 point X7 people X4 items = 28 points.

The results obtained are shown in Table 2-6. From these tables, it can be seen that the composition of Example 1 exhibits a good feeling in use.

[table 1]

(g)

[Table 2]

Table 2

[Table 3] Table 3

[Table 6] Table 6

2) Scratch test

The antifungal effect of the antifungal composition Sampnole of Example 1 and Comparative Examples 14 to 14 shown in Table 1 in mice was evaluated by the following method.

[0039] 4.8 mg of Compound 48/80 (manufactured by ICN Biomedicals, Inc) as an itching-inducing substance was dissolved in 1 ml of physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.), and the obtained solution was subjected to a test.

[0040] As a test animal, a 6-week-old ddY-type clean mouse (male) was kept for 1 week, acclimated, and used for the test. First, the weight of the mouse was measured, and the back was shaved with a clipper. Then, 200 mg of the test sample was applied to the shaved portion, and the finger was printed 20 times with a finger. Then, 30 minutes after the application of the test sample, ether anesthesia was performed, and the itch-inducing substance was intradermally administered at a rate of 20 μΐ per mouse weighing 40 g (lml micro syringe, 26G X 1 / 2.45 X 13 mm injection needle). From 5 minutes after intradermal administration, the number of mouse scratches (the action of the mouse directly touching the part to which the substance was administered by mouth) was counted for 20 minutes. The test was performed for 6 animals for each test sample, and the average of the obtained values was calculated. The smaller the value, the better.

[0041] Positive subjects receiving only the itch-inducing substance were administered, and negative subjects receiving only physiological saline were also tested.

Table 7 shows the obtained results. Table 7 shows that the composition of Example 1 exerts a good antipruritic effect.

[Table 7] Table 7

3) Effectiveness test

The antifungal effects in guinea pigs of the antifungal compositions Sampnore of Example 1 and Comparative Example 14 having the compounding ratios shown in Table 1 were evaluated by the following method.

[0043] <Animals used>

Slc: Haryley guinea pig 6 weeks old (male)

(Use 6 animals per test sample)

Trichophyton mentagrophytes

First, the bacteria were cultured on Sabouraud agar slant medium (manufactured by Eiken Chemical Co., Ltd.) for 14 days at 27 ° C, and then sterilized physiological saline was added to release the bacteria. A sterilized filter (100 μπι (Trainer: manufactured by FALCON) to prepare a bacterial solution of 2 × 10 ⁷ / ml.

[0044] <Test method>

Guinea pigs were bred for 1 week, acclimated, and then tested. First, the back of the guinea pig was depilated under anesthesia with bentovalpital sodium (50 mg / ml / kg; Nembutal injection (manufactured by Dainippon Pharmaceutical Co., Ltd.) in the abdomen). Thus, for each guinea pig, 6 test sites of 2 cm × 2 cm were provided at 2 cm intervals so that the test substance did not cross. Next, the hair removal site (test site) was stripped three times with a 2 cm square cloth adhesive tape to remove the upper part of the stratum corneum of the skin. After disinfecting the skin surface with alcohol wool, 0.1 ml of bacterial solution was inoculated per site. After inoculation, the test animals are kept at a humidity of 60-68% and a temperature of 27 ° C. From the 5th day after inoculation, 0.3 g of the test sample is applied once a day continuously for 8 days. Imprinted with fingers 20 times. The degree of lesion at the infected site was observed once a day and scored according to the following criteria. [0045] Evaluation criteria for lesion degree

Levels with no local lesions: 0

A condition in which a small number of small erythema or erythematous papules are seen in the form of an island-like powder, or a condition in which the lesions have regressed and new hair has developed: 1

Erythema spread to infected area with epidermis detachment: 2

Inflammatory reactions such as partial redness and swelling are observed, and abundant scales are formed: 3 Thickened skin is formed, hemorrhagic erosions or ulcers are observed: 4 Test starting power is also on day 13 (drug The efficacy of the antifungal activity of the test sample was evaluated based on the average value of the scores at the six test sites (day 8 from the start of application).

Table 8 shows the obtained results. Table 8 shows that the composition of Example 1 exhibits effective antifungal activity.

[Table 8]

Table 8

D: good antifungal activity, Δ: poor antifungal activity,.: No antifungal activity

Claims

The scope of the claims

[1] An antifungal composition comprising an arylamine antifungal agent, a fatty acid ester, a powder component, an alcohol solvent and an antipruritic component.

[2] The antifungal composition according to claim 1, wherein the arylamine antifungal agent is at least one selected from the group consisting of terbinafine, naphthytin and salts thereof.

[3] Fatty acid esters are isopropyl myristate, octyl myristate, butyl stearate, ethyl oleate, oleyl oleate, diisopropyl adipate, glycerin fatty acid ester, polyoxyl stearate 40, 45, 55, getyl sebacate, 3. The antifungal composition according to claim 1, which is at least one selected from the group consisting of sorbitan fatty acid ester, isopropyl palmitate, glyceryl monooleate, and sorbitan monooleate.

[4] The powder component is talc, zinc oxide, titanium oxide, magnesium stearate, zinc stearate, magnesium oxide, magnesium carbonate, calamine, magnesium metasilicate aluminate, citric anhydride, magnesium silicate, kaolin, aerosil, 14. The antifungal composition according to claim 13, wherein the antifungal composition is at least one selected from the group consisting of My power and corn starch.

[5] The antipruritic component is lidocaine, jib force in, pro force in, dib force in hydrochloride, lidocaine hydrochloride, pro force in hydrochloride, aminoethyl benzoate, oxypolyentoxide dodecane, diphenylpyrline hydrochloride, diphenhydramine hydrochloride, chlorphene 15. The antifungal composition according to claim 14, which is at least one selected from the group consisting of biramine, diphenhydramine salicylate, and crotamiton.

[6] The alcohol solvent solvent according to any one of claims 15 to 15, which is at least one selected from the group consisting of methanol, ethanol, propanol, butanol, benzyl alcohol, glycerin, ethylene glycol and structural isomers thereof. Antifungal composition.

[7] 0.05-5% by weight of antifungal agent, 5-31.96% by weight of fatty acid ester, 20-50% by weight of powder component, 29.94-74.9% by weight of alcoholic solvent, 17. The antifungal composition according to claim 16, comprising 0.05 to 10% by weight of an antipruritic component.

[8] The antifungal composition according to any one of claims 11 to 7, 5 to 30% by weight, and a propellant 95 to 70 Weight percent aerosol