JP3783104B2 - Antifungal composition for external use - Google Patents

Description

  The present invention relates to an antifungal composition for external use that provides an excellent feeling of use.

  For the treatment of fungal skin diseases such as ringworm, folding screen and candidiasis, an external preparation containing an antifungal agent is generally used. In particular, for fungal skin diseases exhibiting wet-type symptoms, it is said that an external preparation containing a powder component together with an antifungal agent is effective to dry the affected area and enhance the therapeutic effect. .

  So far, various antifungal agents and antifungal agents containing powder components have been proposed. For example, Patent Document 1 discloses an antifungal agent-containing powder aerosol formulation containing talc, corn starch, or the like as a powder component. Patent Document 2 discloses an antifungal composition containing colloidal silica, zinc oxide, talc and the like as a powder component.

  However, in the conventional antifungal external preparation containing a powder component, the powder component is detached from the skin, the external preparation is sticky on the skin, the slip is poor, and the application surface of the external preparation is divided on the skin. There were drawbacks such as non-uniformity. Therefore, none of the conventional antifungal external preparations containing a powder component is satisfactory in terms of the feeling of use.

Against the background of such conventional technology, development of an antifungal composition for external use that provides an excellent feeling of use has been eagerly desired.
JP 2000-229845 A Japanese Patent Laid-Open No. 5-268443

  Accordingly, an object of the present invention is to solve the above-described problems of the prior art. Specifically, an object of the present invention is to provide an antifungal composition for external use which can exhibit an antifungal action and has a good feeling in use.

  The inventors of the present invention diligently studied to solve the above problems, and used starch, water-repellent powder and titanium oxide as a powder component in combination with an antifungal agent and an adhesion aid together with the powder component. It has been found that the prepared composition for external use exhibits an antifungal action, can form a uniform coated surface on the skin, is smooth on the coated surface, and is excellent in terms of usability. The present invention has been completed by further studies based on this finding.

That is, this invention includes the invention of the aspect hung up below:
Item 1. (A) an antifungal agent, (B) an adhesion aid and (C) a powder component, and (C) a starch component, a water-repellent powder and titanium oxide as the powder component Composition.
Item 2. 19.2 to 79.7 parts by weight of starch, 14.7 to 59.3 parts by weight of water-repellent powder, and 0.4 to 51 of titanium oxide per 100 parts by weight of the total weight of starch, water-repellent powder and titanium oxide Item 8. The antifungal composition for external use according to Item 1, which is contained in a proportion of 9 parts by weight.
Item 3. Item 3. The antifungal topical composition according to Item 1 or 2, wherein the starch is at least one selected from the group consisting of potato starch, corn starch and wheat starch.
Item 4. Item 4. The antifungal composition for external application according to any one of Items 1 to 3, wherein the water-repellent powder is at least one selected from the group consisting of talc, magnesium stearate, aluminum stearate, and zinc stearate.
Item 5. Item 5. The antifungal external composition according to any one of Items 1 to 4, wherein the adhesion aid is at least one selected from the group consisting of crotamiton, propylene carbonate, and fatty acid ester.
Item 6. Item 6. The antifungal agent according to any one of Items 1 to 5, wherein the antifungal agent is at least one selected from the group consisting of oxyconazole, bifonazole, sulconazole, neticonazole, terbinafine, butenafine, amorolfine, lanoconazole, and salts thereof. Fungal topical composition.
Item 7. Item 7. The antifungal external composition according to any one of Items 1 to 6, further comprising an antipruritic agent.
Item 8. Item 8. The antifungal external composition according to any one of Items 1 to 7, further comprising at least one selected from the group consisting of lower alcohols, water, and mixtures thereof.
Item 9. Item 7 contains 0.3 to 3% by weight of an antifungal agent, 1 to 15% by weight of an adhesion aid, 10 to 65% by weight of a powder component, and 0.05 to 10% by weight of an antipruritic agent. The antifungal composition for external use described in 1.
Item 10. 0.3 to 3% by weight of antifungal agent, 1 to 15% by weight of adhesion aid, 10 to 65% by weight of powder component, 0.05 to 10% by weight of antipruritic agent, and lower alcohol, water and these Item 9. The antifungal topical composition according to Item 8, containing at least one selected from the group consisting of a mixture in a proportion of 7 to 88.65% by weight.
Item 11. 0.3 to 3% by weight of oxyconazole nitrate; 1 to 15% by weight of crotamiton; 10 to 65% by weight of corn starch, talc and titanium oxide in total; 0.05 to 10% by weight of lidocaine; Item 11. The antifungal topical composition according to Item 10, comprising at least one selected from the group consisting of water and a mixture thereof in a proportion of 7 to 88.65% by weight.
Item 12. Item 12. An antifungal topical aerosol preparation, comprising the antifungal topical composition according to any one of Items 1 to 11 and a propellant.

  The present invention is described in detail below.

  The antifungal composition for external use of the present invention comprises (A) an antifungal agent, (B) an adhesion aid and (C) a powder component, and (C) the powder component contains starch, a water-repellent powder and titanium oxide. It is characterized by this.

  The antifungal agent (A) used in the antifungal topical composition of the present invention is not particularly limited as long as it exhibits an antibacterial action against fungi. Specific examples of the antibacterial agent include benzylamine antifungal agents such as butenafine and salts thereof; bifonazole, neticonazole, ketoconazole, ranoconazole, clotrimazole, miconazole, oxyconazole, thioconazole, croconazole, omoconazole, sulconazole Imidazoline antifungal agents such as terbinafine and salts thereof; morpholine antifungal agents such as amorolfine and salts thereof; thiocarbamic acid antifungal agents such as rilanaphthalate, tolnaftate and tolcyclate And antifungals such as antibiotics such as nystatin, tricomycin, variotin, siccanin, pyrrolnitrin and the like. Among these, benzylamine antifungal agent, imidazole antifungal agent, allylamine antifungal agent, and a benzylamine antifungal agent from the viewpoint of high permeability to keratin and storage and exhibiting superior antifungal action, It is a morpholine antifungal agent. More preferred are oxyconazole, bifonazole, sulconazole, neticonazole, terbinafine, butenafine, amorolfine and lanoconazole and their salts. According to these antibacterial agents, a desired antifungal effect can be obtained once a day. Obtainable. These antifungal agents may be used alone or in any combination of two or more.

  In the antifungal composition for external use of the present invention, the proportion of the antifungal agent depends on the type of antifungal agent used, the form of the composition, the age and sex of the patient, the expected antifungal effect, etc. Although different, for example, 0.3 to 3% by weight, preferably 0.4 to 2.5% by weight, and more preferably 0.5 to 2% by weight with respect to the total weight of the composition.

  The (B) adhesion auxiliary agent contained in the antifungal external composition of the present invention improves the adhesion of the powder component to the skin. As the adhesion aid, those known in the art can be used. Specific examples of the adhesion aid include crotamiton, propylene carbonate, fatty acid esters (for example, isopropyl myristate, octyl myristate, butyl stearate, ethyl oleate, oleyl oleate, diisopropyl adipate, glycerate fatty acid ester, stearin Polyoxyl 40, polyoxyl 45 stearate, polyoxyl 55 stearate, diethyl sebacate, sorbitan fatty acid ester, isopropyl palmitate, glyceryl monooleate, polyoxyethylene sorbitan monooleate, sorbitan monooleate, sorbitan sesquioleate, etc.) And polyhydric alcohols (eg, propylene glycol, dipropylene glycol, glycerin, concentrated glycerin, etc.). Of these, crotamiton, propylene carbonate and fatty acid ester are preferred. In particular, crotamiton is a suitable adhesion aid because it has excellent adhesion of the powder component to the affected skin area, maintains dispersibility of the powder component, and is also excellent in miscibility with the base component. is there. These adhesion aids may be used alone or in any combination of two or more.

  The blending ratio of the adhesion aid varies depending on the kind of adhesion aid used, the form of the composition, the kind and amount of the powder component to be used, and cannot be uniformly defined. The proportion of the adhesion aid is usually 1 to 15% by weight, preferably 1.5 to 12.5% by weight, more preferably 3 to 10% by weight, based on the total weight of the composition. If it is in the said range, the effect excellent in the point of both the adhesion characteristic to a skin affected part and a usability | use_condition will be acquired.

  Moreover, the antifungal composition for external use of this invention contains starch, water-repellent powder, and titanium oxide as a powder component (C).

  The starch is not particularly limited as long as it is pharmaceutically acceptable. Specific examples of the starch used in the present invention include corn starch, potato starch, wheat starch and the like. These starches may be used alone or in any combination of two or more. The starch used in the present invention is preferably corn starch and potato starch, and more preferably corn starch.

In the present invention, the water-repellent powder is a powder component having water-repellent properties. Specifically, 1 g of powder and 1 mL of water are added to a container having a bottom area of 6.25 cm ² and left to stand. In this case, it is a powder component having the property of being separated into two layers of a liquid phase and a powder phase. In addition, as the water-repellent powder used in the present invention, those known in the art can be used as long as they are pharmaceutically acceptable. Examples of such water-repellent powder include talc, magnesium stearate, aluminum stearate, zinc stearate and the like. These water repellent powders may be used alone or in any combination of two or more. As the water-repellent powder used in the present invention, talc is preferable.

  Titanium oxide used in the present invention is not particularly limited as long as it has water repellency as long as it is pharmaceutically acceptable. A preferable example of the titanium oxide is titanium dioxide.

  As the compounding ratio of the starch, the water repellent powder and the titanium oxide, for example, 19.2 to 79.7 parts by weight of starch and 14.7 to 59. 3 parts by weight, and 0.4 to 51.9 parts by weight of titanium oxide; preferably 23.5 to 72.2 parts by weight of starch, 18.8 to 54.6 parts by weight of water-repellent powder, and titanium oxide 0.8 to 47.1 parts by weight; more preferably 28.6 to 65.8 parts by weight of starch, 22.2 to 49 parts by weight of water-repellent powder, and 1.3 to 42.9 parts by weight of titanium oxide The ratio which becomes is illustrated. If it is in the said range, a uniform application | coating surface can be formed on skin and the outstanding usability can be acquired.

  About the ratio of the (C) powder component contained in the antifungal external composition of this invention, it sets suitably according to the composition of the powder component to be used, the form of a composition, etc. (C) As an example of the blending ratio of the powder component, the powder component is generally 10 to 65% by weight, preferably 12.5 to 57.5% by weight based on the total weight of the antifungal external composition %, More preferably a proportion of 15.2 to 50% by weight. When the powder component (C) is contained within the above range, excellent effects can be obtained in terms of formation of a uniform coated surface on the skin and adhesion of the coated surface.

  In addition to the said component, the antifungal composition for external use of this invention can suppress the pruritus feeling of an affected part by further containing an antipruritic agent, and can be equipped with the more excellent usability | use_condition. Examples of the antipruritic agent used in the present invention include lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, procaine, procaine hydrochloride, ethyl aminobenzoate, oxypolyentoxide decane, diphenylpraline hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate And diphenhydramine salicylate. These antipruritic agents may be used alone or in any combination of two or more. The antipruritic agent is preferably lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, procaine and procaine hydrochloride, more preferably lidocaine, dibucaine and procaine.

  When compounding an antipruritic agent, the proportion of the antipruritic agent varies depending on the type of antipruritic agent used, the form of the composition, the expected effect, etc., and cannot be uniformly defined. For example, an antifungal external composition The proportion of the antipruritic agent is usually 0.05 to 10% by weight, preferably 0.25 to 7.5% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the above.

  In the antifungal composition for external use of the present invention, as long as it does not interfere with the effects of the present invention, in addition to the above-described ingredients, a cell activator, anti-inflammatory agent, antibacterial agent, moisturizer , Fragrances, colorants, other powder components, tissue repair agents, astringents, vitamins, refreshing agents, essential oil components, warmth, thermal components, extracts, surfactants, solvents, solubilizers, pH adjusters, Buffering agents, bases, foaming agents, antifoaming agents, emulsifiers, suspending agents, softeners, thickeners, dispersants, excipients, lubricants, antioxidants, preservatives, preservatives, plasticizers, etc. An appropriate amount of these optional components may be blended.

  The antifungal composition for external use of the present invention is blended with the above components in combination with a base (solvent) or carrier used in the composition for external use, and is liquid, ointment, gel, sol, powder, It is prepared into a composition for external use in various forms such as solid.

  The antifungal composition for external use of the present invention includes lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and isobutanol from the viewpoint of enhancing the miscibility of the above-described ingredients and active ingredients and the penetration into the affected area. It is desirable to add a base (solvent) such as water, or a mixture of these lower alcohols and water. Of the above bases (solvents), preferably a lower alcohol, and a mixture of a lower alcohol and water, more preferably from the viewpoint of effectively exerting the drying action of the powder component on the skin and the solubility of the active ingredient. A lower alcohol, particularly preferably ethanol. The ethanol can also be used as a denatured alcohol by adding methanol or benzene. When a mixture of lower alcohol and water is used as the base (solvent), the proportion of the lower alcohol in the mixture is, for example, 4 to 95% by weight, preferably 5 to 60% by weight, Preferably 6-40 weight% is illustrated. The mixing ratio of the base (solvent) can be appropriately set according to the form of the antifungal composition for external use. For example, the base (solvent) is 7 to 7 based on the total weight of the composition. The ratio is 88.65% by weight, preferably 20 to 85.35% by weight, and more preferably 33 to 80.8% by weight.

  If the composition of the present invention is prepared in the form of an ointment, gel, sol or the like, it is blended into an ointment, gel or sol preparation together with or instead of the base (solvent). An appropriate amount of carrier or base can be blended. Examples of such carriers or bases include oil-based bases such as petrolatum, squalane, paraffin, liquid paraffin, white wax, plastic base, polyethylene glycol, macrogol; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl, methylcellulose, polyvinylpyrrolidone , Carrageenan, polyvinyl butyrate, hydroxypropylcellulose phthalate, methyl methacrylate copolymer, diethyl aminoethyl methacrylate methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol and other polymers; higher alcohols such as cetanol and stearyl alcohol; 1 And polyhydric alcohols such as 3-butylene glycol, propylene glycol, dipropylene glycol, and glycerin. It is.

  The antifungal external composition prepared in a liquid, powder or sol form is further prepared and used as an antifungal external aerosol preparation in combination with a propellant for aerosol preparation. Although it does not restrict | limit especially as a propellant for aerosol formulations, For example, aliphatic hydrocarbons, such as propane, normal butane, isobutane, pentane, isopentane, neopentane, and dimethyl ether are mentioned. The aerosol formulation can be prepared by mixing the antifungal topical composition and the propellant, for example, in the proportions shown below; antifungal topical composition: propellant in a weight ratio, usually 5-30: 70. -95, preferably 7-28: 72-93, more preferably 9-26: 74-91.

  In the antifungal composition for external use of the present invention, the application amount and the number of applications per day can be appropriately set according to the type and amount of the compounding component and the form thereof. The antifungal topical composition of the present invention is applied to the skin to form a coated surface with uniform and good adhesion, so that it is used as an antifungal topical composition that can be applied once a day. You can also.

  The antifungal composition for external use of the present invention is effective for fungal skin diseases, particularly superficial fungal skin diseases. In particular, since an excellent drying effect is imparted by the powder component, it exhibits an excellent therapeutic effect against wet superficial fungal skin diseases.

  When applied to an affected skin area of a fungal skin disease, the antifungal composition for external use of the present invention forms a uniform application surface with a powder component, and has a drying effect on the affected skin area and a medicinal effect of an antifungal agent. It can be exhibited efficiently.

  Moreover, since the antifungal external composition of this invention can form the smooth application | coating surface on skin, it is favorable also in the point of use feeling.

  Furthermore, since the antifungal composition for external use of the present invention can form a coated surface having good adhesion, it can be prepared as a once-daily preparation and can reduce the burden on the patient. There is.

  EXAMPLES Hereinafter, although a test example and an Example are given and this invention is demonstrated, this invention is not limited to these Examples. In addition, unless otherwise indicated, the unit of the numerical value shown in the following table | surface is a weight (g).

Test Example 1 Surface Characteristics Confirmation Test Compositions (Examples 1-14 and Comparative Examples 1-17) having the formulations shown in Table 1-4 were prepared, the following tests were performed, and the feeling of use and the uniformity of the coated surface were evaluated. .
(1) Evaluation method of feeling of use In order to evaluate the feeling of use, a dynamic friction coefficient (MIU) was measured according to the following method.
1. The MIU of artificial leather (5 cm × 13 cm) was measured with a KES-SE surface property tester (manufactured by Kato Tech).
2. Spread 1 g of each composition (Example 1-14 and Comparative Example 1-17) on the same artificial leather evenly with a finger in the range of 3 cm × 6 cm, and apply MIU on the coated surface to a KES-SE surface property tester. (Measured by Kato Tech Co., Ltd.) This usability evaluation test was performed at n = 3.
3. According to the following evaluation criteria, the feeling of use was evaluated from the measured average value of MIU.
<Evaluation criteria for usability>
○ The average value of MIU after application is smaller than the average value of MIU before application × Average value of MIU after application is larger than the average value of MIU before application #: MIU correlates with slip characteristics A decrease in the MIU value means an improvement in the slip, and an increase in the MIU value means an improvement in the slip.

(2) Evaluation method of uniformity of coated surface 1 g of each composition (Example 1-14 and Comparative Example 1-17) was applied uniformly to a synthetic leather (5 cm × 13 cm) with a finger within a range of 3 cm × 6 cm. The properties of the coated surface were evaluated based on the following evaluation criteria.
<Evaluation criteria for uniformity of coated surface>
○ A uniform coated surface that does not form a patchy or sliced coating surface △ A patchy coating surface is not formed, but a small amount of a sliced coating surface is formed × A patchy or sliced coating surface The results obtained are also shown in Table 1-4. From this result, it became clear that when the starch component, water-repellent powder and titanium oxide are used in combination with crotamiton as a powder component, an excellent feeling of use and uniformity are imparted to the coated surface. On the other hand, it was confirmed that when any one of starch, water-repellent powder and titanium oxide was applied, an excellent coated surface could not be formed in both usability and uniformity.

Test example 2
Antifungal compositions for external use (Examples 15-18 and Comparative Examples 18-19) having the compositions shown in Table 5 were prepared. Using this antifungal composition for external use, the following tests were conducted to evaluate the antipruritic effect and sensory evaluation. In addition, the feeling of use was evaluated by measuring the MIU value in the same manner as in the above test example.

Evaluation of antipruritic effect ddY clean mice (male, 6 weeks old) were bred for 1 week and acclimated.
2. The weight of the mouse was measured, and the back part was shaved with a clipper.
3. 200 mg of the antifungal composition for external application (Examples 15-18 and Comparative Examples 18-19) was evenly applied to the shaved portion and rubbed with fingers.
4). 30 minutes after application of the antifungal composition for external use, ether anesthesia was performed, and an itching-inducing substance (4.8 mg of Compound 48/80 (ICN Biomedicals, Inc.) dissolved in 1 mL of physiological saline) was added at 20 μL per 40 g of body weight. Mice were administered intradermally at a rate.
5). Between 5 minutes and 25 minutes after intradermal administration, the number of mouse scratches (behavior in which the mouse directly scratches the part where the intradermally administered substance was administered) was counted.
6). As a positive control, the same test was performed on the itch-inducing substance administered without applying the antifungal topical composition, and the number of scratches was counted. In addition, the evaluation test of this antipruritic effect was done by n = 6.
7). According to the following criteria, the antipruritic effect of each antifungal topical composition was evaluated.
○: The average number of scratches is less than ¼ of the average number of scratches of the positive control. Δ: The average number of scratches is not less than ¼ and less than 1/2 of the average number of scratches of the positive control. 1/2 or more of the average number of scratches
An appropriate amount of the antifungal composition for external application was applied between toes to sensory evaluation subjects (a total of 5 people including 2 wet athlete's foot athletes and 3 healthy subjects). After application, after wearing a sock and shoes and having a normal life for one day, each subject evaluates each of adhesion, uniformity, smooth feeling, actual feeling, and overall feeling with the following five grades. went.
5 points: very good 4 points: good 3 points: normal 2 points: bad 1 point: bad Total scores obtained for each subject were totaled according to the following criteria, and each antifungal composition for external use The sensory evaluation of the product was judged.
<Evaluation criteria for sensory evaluation>
A: Total score 20 or more and 25 or less ○: Total score 15 or more and 19 or less Δ: Total score 10 or more and 14 or less ×: Total score 5 or more and 9 or less The results obtained are shown in Table 5. As a result, it was revealed that the antifungal composition for external use of the present invention can provide a very good feeling in use in addition to the antifungal action.

Example 19-25 Antifungal topical aerosol preparation An antifungal composition for external use (Example 19-25) having the formulation shown in Table 6 was prepared. The antifungal composition for external use (Examples 19 to 25) was filled with a propellant (dimethyl ether) in an aerosol container at a weight ratio of the antifungal composition for external use: propellant = 1: 4, A topical aerosol formulation was produced. Similarly, the antifungal composition for external use (Examples 19-25) together with a propellant (liquefied petroleum gas) and the antifungal composition for external use: propellant = 1: 4 in an aerosol container To prepare an antifungal topical aerosol formulation.

Examples 26-28 Ointment An ointment having the formulation shown in Table 7 was prepared according to a conventional method.

Claims (10)

(C) a powder component comprising (A) an antifungal agent, (B) at least one adhesion aid selected from the group consisting of crotamiton, propylene carbonate, fatty acid ester and polyhydric alcohol , and (C) a powder component As an antifungal composition for external use, comprising starch, a water-repellent powder and titanium oxide. 19.2 to 79.7 parts by weight of starch, 14.7 to 59.3 parts by weight of water-repellent powder, and 0.4 to 51 of titanium oxide per 100 parts by weight of the total weight of starch, water-repellent powder and titanium oxide The antifungal composition for external use according to claim 1, which is contained at a ratio of 9 parts by weight. The antifungal composition for external use according to claim 1 or 2, wherein the starch is at least one selected from the group consisting of potato starch, corn starch and wheat starch. The antifungal composition for external use according to any one of claims 1 to 3, wherein the water-repellent powder is at least one selected from the group consisting of talc, magnesium stearate, aluminum stearate and zinc stearate. The antifungal composition for external use according to any one of claims 1 to 4, wherein the adhesion aid is at least one selected from the group consisting of crotamiton, propylene carbonate and fatty acid ester. The antifungal agent is at least one selected from the group consisting of oxyconazole, bifonazole, sulconazole, neticonazole, terbinafine, butenafine, amorolfine, lanoconazole, and salts thereof according to any one of claims 1 to 5. Antifungal topical composition. Furthermore, the antifungal external composition in any one of Claims 1 thru | or 6 containing an antipruritic agent. Furthermore, the antifungal composition for external use in any one of the Claims 1 thru | or 7 containing at least 1 sort (s) selected from the group which consists of a lower alcohol, water, and these mixtures. 0.3 to 3% by weight of oxyconazole nitrate; 1 to 15% by weight of crotamiton; 10 to 65% by weight of a mixture of corn starch, talc and titanium oxide; 0.05 to 10% by weight of lidocaine; The antifungal composition for external use according to claim 8, comprising at least one selected from the group consisting of water and a mixture thereof in a proportion of 7 to 88.65% by weight. An antifungal topical aerosol preparation, comprising the antifungal topical composition according to any one of claims 1 to 9 and a propellant.