JPS60228412A - Antimycotic agent for external application - Google Patents

Abstract

PURPOSE:To obtain the titled preparation giving a flexible coating film when applied to the skin and dried, and having excellent stability with time and high infiltration property and adhesivity to the skin, by dissolving an antimycotic compound, a film-forming resin and a plasticizier in a solvent under specific condition. CONSTITUTION:3-40pts.wt. of preferably an antimycotic compound, especially clotrimazole, 100pts.wt. of a film-forming resin (e.g. ethylcellulose, polyvinyl butyral, etc.) and 33-200pts.wt. of a plasticizier to impart flexibility to the coating film (e.g. isopropyl myristate, diethyl sebacate, etc.) are dissolved in 400-1,800pts.wt. of a solvent (e.g. ethanol). The pH of the preparation shaken together with 10 times volume of water is adjusted to >=7. The adjustment of the pH improves the stability of the principal drug with time, releasability of the drug from the coating film, and the infiltration property to the skin. It has higher therapeutic effect than conventional antimycotic drug for external application having acidic pH.

Description

[Detailed Description of the Invention] BACKGROUND OF THE INVENTION [Technical Field] This invention relates to an antifungal topical preparation containing an antifungal compound such as clotrimazole as an active ingredient, and particularly relates to an antifungal preparation containing an antifungal compound such as clotrimazole as an active ingredient. The present invention relates to an antifungal external preparation that has excellent permeability of antifungal compounds into the skin and does not easily come off when in contact with clothing or the like.

[Prior Art and its Problems] Clotrimazole has a strong antifungal effect and has an excellent therapeutic effect on bald spots, nuchal leukoplasia, etc. Clotrimazole is insoluble in water, so conventionally it has been mainly dissolved in polyethylene glycol, propylene glycol, or nonionic surfactants, etc. 1, and emulsified by adding water and petrolatum, etc., or cream preparations made with ethanol, water, crotamiton, etc. , gel preparations and elastic liquid plaster formulations made of carboxyvinyl polymers (e.g., JP-A-57-122
016), it has been applied in the form of a tincture using ethanol as a solvent or a liquid preparation using propylene glycol or polyethylene glycol as a solvent. However, all formulations have drawbacks such as decomposition of the active ingredient during long-term storage, resulting in decreased antifungal activity and precipitation of the active ingredient. In addition, non-volatile liquids, creams, gels, etc. cannot exhibit sufficient effects because the preparations are rubbed off by friction with clothing after application. On the other hand, an elastic liquid plaster formulation as shown in JP-A-57-122016 forms a film that adheres to the skin, but the drug is entrapped in the film and cannot sufficiently contact the skin surface.

Also, the utilization rate for the amount of drug administered is low. Tinctures that use ethanol as a solvent have the disadvantage that after application, the ethanol evaporates and crystals of the active ingredient precipitate, resulting in insufficient absorption into the skin.

In view of the above-mentioned problems, the purpose of the present invention is to provide a drug that does not lose its medicinal efficacy even when stored for a long period of time, has excellent permeability of the drug into the skin, and is easily peeled off by contact with clothing, etc. The purpose of the present invention is to provide an antifungal topical preparation that does not contain any antifungal agents.

The present invention is an antifungal external preparation in the form of a solution dissolved in a solvent, which comprises: 100 parts by weight of a film-forming resin; 33 parts by weight of a plasticizer that imparts flexibility to the film formed by the film-forming resin; 200 parts by weight and an antifungal compound, the pH of the solution when shaken after adding 10 times the amount of water to the total amount of the preparation is 7 or more, and when applied to the skin and dried, the skin Provided is an antifungal topical preparation that forms a flexible film that tightly adheres to the skin.

Ethyl cellulose or polyvinyl butyral is preferred as the film-forming resin.

In addition, as the plasticizer, isopropyl myristate, diethyl sepacate, diethyl phthalate, diisopropyl adipate, or glycerinoleate is preferable.

Clotrimazole is preferred as the antifungal compound, and its content is preferably 3 to 40 parts by weight.

The solvent is preferably ethanol, and its content is preferably 400 to 1800 parts by weight.

3. Detailed Description of the Invention Conventionally, this type of antifungal topical preparations generally had acidic pH (hydrogen ion intensity index).6 As a result of intensive research, the present inventor surprisingly discovered that If the formulation is adjusted so that the pH of the solution when shaken with 10 times the volume of water is 7 or higher, the drug will remain at a high rate even after long-term storage.
It has been found that it has excellent stability and drug permeability into the skin, allowing high medicinal efficacy to be obtained. This is due to the adhesion to the skin due to the use of film-forming resin and the sealing effect due to suppressing the spread of water on the skin.
This is due to the synergistic effect of promoting the release of the main drug, high permeability, and high drug stability by adding 10 times the volume of water to the formulation and making the pH of the liquid 7 or higher when shaken. Conceivable.

Preferred examples of film-forming resins that can be used in the antifungal external preparation of the present invention include ethylcellulose, polyvinylbutyral, cellulose acetate, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose phthalate methylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone, vinylpyrrolidone, Vinyl acetate copolymer, vinyl pyrrolidone acetate vinyl alkylamino acrylic acid copolymer, vinyl pyrrolidone dimethyl ethyl methacrylate 1'-1 copolymer/metacarboxylic acid 6 7'taka; Lupoxy ester copolymer, acrylic resin alkanol Examples include amine liquid, styrene maleic acid polymer, and polyhydroxyethyl methacrylate. Among these, particularly preferred are ethyl cellulose and polyvinyl butyral. As ethylcellulose, ethylcellulose ethanol/toluene (volume ratio 1:1)5
The viscosity of the % solution measured by a rotational viscometer at 25°C is 6C.
P (centipoise) to 220CP (0,008A
: ILO, 22N/m) and the degree of substitution by ethoxy group is preferably 2.2 to 2.6. Polyvinyl butyral has a viscosity of 10CP to 370C when a 20% solution of polyvinyl butyral in ethanol/toluene (body f1 ratio 1:1) is measured with a rotational viscometer at 20°C.
P (0.01 to 0.37 N/Otori), the number of acetyl groups remaining in five molecules is 8 wolX or less, and the hydroxyl group is preferably 20 to 40 mo1%.

Preferred plasticizers are alkanol esters of aliphatic or aromatic organic acids and fatty acid esters of glycerin. This is because these have the function of promoting the penetration of the main drug into the skin. Specific examples of preferred plasticizers include diethyl sebacate, diethyl phthalate, diisopropyl adipate, isopropyl myristate, and glycerin monooleate. This is because these can be blended into the film-forming resin in large amounts, and as a result, the penetration promoting effect can be better exhibited. The amount of plasticizer is 10 parts of the film-forming resin.
0 parts by weight to 33 to 200 parts by weight. If it is less than 33 parts by weight, the flexibility will be insufficient, and if it exceeds 200 parts by weight, it will fall off from the skin and will not form a film when applied to the skin.

Preferred antifungal compounds include clotrimazole, miconazole nitrate, econazole nitrate, isoconazole nitrate, pyrrolnidoline, tolnaftate, pimafucin, and the like. Among these, clotrimazole, which has a broad antibacterial spectrum, is particularly preferred. The content of the antifungal compound is preferably 3 to 40 parts by weight based on 100 parts by weight of the film-forming resin.If it is less than 3 parts by weight, the antibacterial effect may be reduced, and if it exceeds 40 parts by weight, the content may vary depending on the type of antifungal compound. may cause unwanted side effects.

Examples of solvents used in the antifungal external preparation of this invention include ethanol, propatool, and butanol.

Preferred are isobutanol, acetone, methyl ethyl ketone, methyl isobutyl ketone and ethyl acetate. Among these, ethanol is particularly preferred from the viewpoint of toxicity and odor after coating and drying. The content of the solvent is the film-forming resin,
It is necessary to use a film-forming resin 1 to a level that can sufficiently dissolve the plasticizer and antifungal compound and not easily run off when the formulation is applied to the skin.
00 parts by weight, preferably 400 to 1800 parts by weight. If it is less than 400 parts by weight, it will be difficult to dissolve other ingredients, and if it exceeds 1,800 parts by weight, the viscosity of the formulation will become too low and there is a risk that the formulation will run off the skin when applied to the skin. In this specification, the term "dissolve" refers to sufficiently dispersing the film-forming resin, plasticizer, and antifungal compound in the formulation. lθ~100 at °C
．． 000 centivoise.

An important feature of the antifungal external preparation of the present invention is that the pH of the liquid when 10 times the amount of water is added to the preparation and shaken is 7 or higher. By adjusting the formulation in this way, the stability of the crude drug over time, the release of the crude drug from the coating, and the permeability of the main drug into the skin are enhanced. Although the reasons for this are not entirely clear, one reason for the increased skin permeability is that the hydrogen bonds in the keratin proteins that make up the stratum corneum of the skin are weakened by basic preparations.
This is thought to be because the main drug can easily reach the fungi living in the stratum corneum.

However, if the pH of the formulation becomes too high, it may cause skin irritation, so in practice, the above-mentioned
It is preferable to adjust H to 7 to 10. The pH can be adjusted using, for example, alkylamines such as methylamine, diethylamine, tripropylamine, alkanolamines such as methanolamine, diisopropanolamine, triethanolamine, etc. This can be done by adding to the formulation organic bases such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and inorganic bases such as ammonia.

In addition, in the antifungal external preparation of the present invention, a penetration aid or a stabilizer may be added in order to further improve the permeability of the antifungal compound into the skin and the stability during long-term storage.

Nonionic surfactants are used as penetration aids.

Polyhydric alcohols, crotamiton, urea, salicylic acid, etc. can be used. Particularly effective and preferred ones include propylene glycol, polyethylene glycol 400, rubitan sesquioleate, polyoxyethylene (5) nonylphenyl ether, urea, salicylic acid, propylene carbonate, 1,3-butanediol, hexyldodecanol, phenyl Examples include ethyl alcohol, benzyl alcohol, and glycerin.

Preferred stabilizers are organic amines such as dialkylamines, trialkylamines, alkanolamines.

Among these, from the viewpoint of toxicity, diisobutylamine, triethanolamine, ethylamine, dipropylamine, trimethylamine, propatoolamine, jetanolamine, and tripropaturamine, which are ruamizos, are particularly preferred.

IV. Specific Effects of the Invention As mentioned above, the antifungal external preparation of the present invention contains 100 parts by weight of a film-forming resin, 33 to 200 parts by weight of a plasticizer,
Contains antifungal compounds and solvents, 10% for the total amount of the formulation
When double the amount of water is added to the preparation and shaken, the pH of the liquid is 7 or more, and it is configured to form a flexible film that adheres to the skin when applied to the skin and dries. The drug does not decompose or precipitate even after long-term storage, has a high persistence rate and is excellent in stability, and the active drug is released from the coating and penetrates into the skin well.

Further, by adjusting the pH to 7 to IO, it is possible to obtain an antifungal external preparation that is good from the viewpoint of skin irritation.

E When ethyl cellulose or polyvinyl butyral is used as the fertilizer film-forming resin, an antifungal external preparation that provides a film with particularly good adhesion to the skin can be obtained.

Furthermore, when isopropyl myristate, diethyl sebacate, diethyl phthalate, diisopropyl adipate, or glycerin monooleate is employed as a plasticizer, an antifungal external preparation with particularly excellent permeability of herbal medicines into the skin can be obtained.

When clotrimazole is used as the antifungal compound and its content is 3 to 40 parts by weight per 100 parts by weight of the film-forming resin, an antifungal external preparation with a broad antibacterial spectrum and excellent medicinal efficacy can be obtained.

When ethanol is used as a solvent and its content is 400 to 1800 parts by weight per 100 parts by weight of the film-forming resin, an antifungal topical product with almost no toxicity, almost no odor from the film, and excellent adhesion to the skin. A formulation is obtained.

Next, Examples and Comparative Examples of the present invention will be shown to explain the present invention in further detail. Prior to explaining each test example, the composition and preparation method of each example and comparative example will be described.

Mosquito 1" Clotrimazole 1g Methyl ethyl ketone 35ml Propylene glycol 181 Total amount of ethyl alcohol 100g PH 5,8 ■ Add clotrimazole Ig to propylene glycol 181, heat and dissolve, add methyl ethyl ketone 351 and ethyl alcohol to make the total amount 100g and mixed and adjusted.

Clotrimazole 1 g Polyethylene glycol 400 99 Total amount 100 g PH 5,4 1 Female Clotrimazole Ig was added to 99 g of polyethylene glycol 400, dissolved by heating, and then mixed.

Clotrimazole Ig Crotamine 2g Carboxyvinyl polymer 1g Propylene glycol 10g Isopropyl adipate 1.1g Ethyl alcohol 40g Diisopropanolamine 1.1g 1 43.8 Total amount 100g pH 5,8 1 Clotrimazole Ig In addition to 2 g of crotamiton and propylene glycol Log, after heating and dissolving, 40 g of ethyl alcohol, 43.8 g of purified water, 1.1 g of diisopropyl adipate, and 1.0 g of carboxyvinyl polymer.
After adding and heating and dissolving, siirolobanolamine 1
．． 1 g was added and mixed to prepare.

Clotrimazole 1g Propylene glycol 6g Diethyl phthalate 19g Stearic acid 5g Glyceryl monostearate 5g Polyoxyethylene sorbitan monostearate 3.8g Sorbitan monostearate 1.2 g Methylparaben 0.06g Propylparaben 0.03g Sodium edetate 0.03g 58.88 Total amount 100g pH 5.1 1g Clotrimazole Ig was added to 6g of propylene glycol and dissolved by heating, followed by 19g of diethyl phthalate, 5g of stearic acid, and 5g of glyceryl monostearate. , polyoxyethylene rubitan monostearate 3.8g
, add 1.2 g of sorbitan monostearate, warm, dissolve and mix, and separately add methylparaben O, OEG, propylparaben 0.03g, and sodium edetate 0.0
3 g was dissolved in 58.88 g of purified water, mixed and emulsified, and stirred until cooled.

Clotrimazole 1g Diethyl sebacate 5g Polyvinylpyrrolidone 5g Isopropyl alcohol 89 Total amount 100g PH5,5 1 store 89g of isopropyl alcohol and clotrimazole tg
was added and dissolved, 5 g of diethyl sebacate and 5 g of polyvinylpyrrolidone were added, and the mixture was dissolved and mixed by heating.

Ratio E Example 6 Clotrimazole 1g Diethyl sebacate 10g Ethylcellulose 10g Ethyl alcohol 79 Total amount 100g pH 5,7 1 store Add Clotrimazole Ig to 79g of ethyl alcohol and dissolve, then add diethyl sebacate log and ethyl cellulose log, It was prepared by heating, dissolving and mixing.

Clotrimazole 1g Diethyl sebacate 10g Ethylcellulose 10g Diisopropanolamine 0.05g Thyl alcohol 178.95 Total amount 100g po7.

1st Woman: Add clotrimazole Ig to 79.85 g of toluethyl alcohol, dissolve by heating, then add cellulose < diethyl sinate log, 10 g of ethyl cellulose, and 0.05 g of diisopropanolamine, dissolve by heating, and mix. It was prepared by

"Shikibashi" Clotrimazole 1g Isopropyl myristate 15g Ethyl cellulose 10g Polyethylene glycol 400 3g Diisopropazole amine 0.005g Ethyl alcohol 71 Total amount 100g p) 17.5 Add 1g of clotrimazole to 71g of ethyl alcohol and warm After dissolving, add 15 g of isopropyl myristate, 10 g of ethyl cellulose, 400 g of polyethylene glycol.
3g of diisopropamelamine and 0.005g of diisopropamelamine were added, heated, and mixed.

Tip JL! LH Clotrimazole 1g Diisopropyl adipate 10g Polyvinyl butyral 10g Triethanolamine 0.05 g Propylene glycol 8g Impropatul 70.95 Total amount 100g H8-1 1 g of clotrimazole Ig Impropatul 70.95
After dissolving in g, diisopropyl adipate 10g, polyvinyl butyral 10g, propylene glycol 8g
, 0.05 g of triethanolamine was added and dissolved under heating.

Clotrimazole 1g Diethyl sebacate 10g Ethylcellulose 10g Urea 5g Diisopropazole amine 0.02g Methyl ethyl ketone 35g Ethyl alcohol 38.98 Total amount 100g pH 7,8 1 Add clotrimazole to 37.98 g of ethyl alcohol, 35g of methyl ethyl ketone After adding and dissolving 1 g of sol, 10 g of diethyl sebacate, log of ethyl cellulose, 5 g of urea, and 0.02 g of diisopropanolamine were added and dissolved by heating, followed by mixing to prepare.

Length JILj! L5 = Clotrimazole 1g Diethyl phthalate 15g Polyvinyl butyral 8g Triethanolamine 0.02g Crotamiton 2g Acetone 20g Ethyl alcohol 60:88 Total amount 100g pH 9,1 One owl of clotrimazole Ig was mixed with 20g of acetone, 80.88g of ethyl alcohol In addition, dissolve diethyl phthalate 1
5 g of polyvinyl butyral, 0.02 g of triethanolamine, and 2 g of crotamiton were added, dissolved and mixed by heating to prepare.

Clotrimazole Ig Glycerin monooleate 5g Ethyl cellulose 10g Diisopropaturamine 0.008g Diethyl sebacate 5g Polyoxyethylene (5) nonylphenyl ether 5g Isopropyl alcohol 73 Total amount 100g PH7,7 List L Polyoxy Ethylene (5) nonylphenyl ether 5g
, clotrimazole I in 73 g of isopropyl alcohol
After adding and dissolving 5g of glycerin monooleate,
Ethyl cellulose Log.

A mixture was prepared by adding 0.008 g of diisopropanolamine and 5 g of diethyl sebacate, dissolving and mixing with heating.

Support] U starvation 1 Clotrimazole 1g Diethyl sebacate 10g Ethyl cellulose 10g Diisopropazole amine 0.25g Ethyl alcohol 78.75 Total amount 100g p) 110.0 1 store Ethyl alcohol 78.75 g to Clotrimazole 1
Add and dissolve 10 g of ethyl cellulose, 10 g of diethyl sebacate, 0.25 g of diisopropanolamine.
g was added and heated to dissolve and mix.

In order to examine the stability of the clotrimazole preparations of Examples 1 to 6 and Comparative Examples 1 to 5 under long-term storage, the residual rates of the crude drugs were measured and compared under room temperature storage.

The residual rate was determined by extracting the formulation with methanol.

The extract was quantitatively determined using the internal standard method of high performance liquid chromatography under the following operating conditions.

Operating conditions Detector Ultraviolet absorption photometer (wavelength 230 nm) Separation tube ODS system column temperature 40°C Mobile phase Methyl alcohol: 0.05M ammonium dihydrogen phosphate = 85:15 (volume ratio) Flow rate 1.0ml/layer in.

The results are shown in FIG. 1. From the same figure, Examples 1 to 1 of this invention
It can be seen that in Sample No. 6, the residual rate did not decrease at all even after 7 months had passed, and it was more stable than Comparative Examples 1 to 5 having conventional base compositions.

Therefore, Comparative Example 6 and Example 1.7 were examined for stability under long-term storage in the same manner as Test Example 1, and the pH of the formulation and the stability of clotrimazole were examined. Note that in these three examples, all other components and their contents were the same except that the pH was adjusted with diisopropanolamine.

The results are shown in FIG. 2. From the same figure, Example 1 of the present invention (
pH 7,0), Example 7 (pH 10,0) is much more stable than Comparative Example 6 (pH 5,7), p)
It can be seen that I greatly influences the stability of crude drugs.

A test was conducted to compare the release properties of crude drugs from the antifungal external preparation of the present invention and the conventional antifungal external preparation. Third
As shown in the figure, a branched container 1 was filled with O, IN hydrochloric acid 2, the opening was covered with a silicone rubber membrane 3 having a thickness of 100 gm, and 3 g of an antifungal topical preparation 4 was placed thereon. Hydrochloric acid 2
was stirred with a magnetic stirrer 5 for 8 hours, and the amount of clotrimazole released into the hydrochloric acid 2 through the silicone rubber membrane 3 was measured in the same manner as in Test Example 1, 1 hour after the start of the test.
Measurements were made three times for 8 hours. The antifungal external preparations tested were Examples 1 to 5 and 7 and Comparative Examples 1 to 6.

The results are shown in FIG. 4. As can be seen from the figure, it can be seen that the antifungal topical preparation of the example of this invention released a larger amount of the main drug from the preparation than the antifungal topical preparation of the comparative example. . In particular, Example 1 (pH 7,0), Example 7 (pH
The release properties of to and o) were higher than those of Comparative Example 6 (pH 5, 7), indicating that the pH of the formulation also greatly affects the release properties of crude drugs from the formulation.

Ward JL#! ! Examples 1.3.
The antifungal external preparations of Example 5.7 and Comparative Examples 1, 2, 3, and 8 were tested for activity.

Hair the back of a Hartley guinea pig weighing 350 to 450 g with clippers, make a slight scratch on the skin with emery paper, and incubate the back culture of the second-year-old white fungus (Trichophyton mentagrophytes) from the animal.
A bacterial solution containing 10 spores per ml was prepared and inoculated into the bathtub of a guinea pig.

On the third day after inoculation, Example 1.3, 5゜7, Comparative Example 1.2,
The antifungal external preparations 3.6 were applied to the hot water area, and on the 7th day, the animals were sacrificed and the skin at the application site was peeled off. This skin was cultured on a Sabouraud agar medium at 27° C. for 10 days, and the presence or absence of M. albicans was determined. The number of animals was 50 for each antifungal topical preparation, and the cure rate was determined by the following formula.

I'm not going to meet Saburo Kai. Total number of animals (50) x100 = healing rate The results are shown in the table below.

From this table, it can be seen that the antifungal external preparation of Example 1 of the present invention exhibits a better cure rate than the antifungal external preparation of Comparative Example. In particular, Example 1 (pH 7.0).

Example 7 (poto-o) cure rate t, Comparative Example 6
(pH 5, 7), indicating that the pH of the formulation affects its activity.

[Brief explanation of drawings]

Figures 1 and 2 are graphs showing the stability over time of the herbal medicines in the antifungal topical preparations of Examples and Comparative Examples of the present invention, and Figure 3 is from the antifungal topical preparations of Examples and Comparative Examples of the present invention. FIG. 4 is a diagram for explaining the method for testing the release properties of the main drug, and FIG. 4 is a diagram showing the results. 1. Container, 2. Hydrochloric acid, 3. Silicone rubber membrane, 4. Φ Antifungal topical preparation Figure 2. Storage period (times) Storage period (hours)

Claims (6)

[Claims] (1) An antifungal external preparation in the form of a solution in a solvent, comprising 100 parts by weight of a film-forming resin, and 33 to 2 parts of a flexibilizing agent that imparts flexibility to the film formed by the film-forming resin.
00 parts by weight and an antifungal compound, P of the liquid when 10 times the amount of water relative to the total amount of the preparation is added to the preparation and shaken.
An antifungal external preparation that has H of 7 or more and forms a flexible film that adheres closely to the skin when applied to the skin and dried. (2) The antifungal external preparation according to claim 1, wherein the pH is 7 to 1O. (3) The antifungal external preparation according to claim 1, wherein the film-forming resin is ethyl cellulose or polyvinyl butyral. (4) The antifungal external preparation according to claim 1, wherein the plasticizer is isopropyl myristate, diethyl sebacate, diethyl phthalate, diimpropyl adipate, or glycerin monooleate. (5) The antifungal external preparation according to claim 1, wherein the antifungal compound is clotrimazole, and the content thereof is 3 to 40 parts by weight. (6) The antifungal external preparation according to claim 1, wherein the solvent is ethanol and the content thereof is 400 to 1800 parts by weight.