WO2006038317A1

WO2006038317A1 - Antifungal composition for external use

Info

Publication number: WO2006038317A1
Application number: PCT/JP2005/003644
Authority: WO
Inventors: Shigeki Sawamura
Original assignee: Kobayashi Pharmaceutical Co., Ltd.
Priority date: 2004-09-30
Filing date: 2005-03-03
Publication date: 2006-04-13
Also published as: JP3800232B2; JP2006104078A

Abstract

[PROBLEMS] To provide an antifungal composition for external use which has antifungal activity and gives a satisfactory use feeling. [MEANS FOR SOLVING PROBLEMS] The antifungal composition for external use comprises (A) an antifungal, (B) at least one adhesion aid selected from the group consisting of crotamiton, propylene carbonate, fatty acid esters, and polyhydric alcohols, (C) a powdery ingredient comprising starch, a water-repellent powder, and titanium oxide, (D) a lower alcohol, and (E) water.

Description

Specification

Antifungal composition for external use

Technical field

[0001] The present invention relates to an antifungal composition for external use that provides an excellent feeling of use.

Background art

[0002] For the treatment of fungal skin diseases such as ringworm, folding screen and candidiasis, external preparations containing antifungal agents are generally used. In particular, for fungal skin diseases that exhibit wet-type symptoms, a powder component is combined with an antifungal agent to dry the affected area and enhance the therapeutic effect! It is said that there is.

[0003] So far, various antifungal agents for external use containing an antifungal agent and a powder component 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 agent composition containing colloidal silica, zinc oxide, talc or the like as a powder component.

[0004] However, in the conventional antifungal external preparation containing a powder component, the powder component is released from the skin force, the external preparation is poorly slippery on the skin, and the application surface of the external preparation is on the skin There are drawbacks such as being easily separated by a non-uniformity. For this reason, conventional antifungal external preparations containing powder components are not satisfactory in terms of feeling of use.

[0005] Against the background of such conventional technology, development of an antifungal composition for external use that can provide an excellent feeling of use has been eagerly desired.

Patent Document 1: Japanese Patent Laid-Open No. 2000-229845

Patent Document 2: Japanese Patent Laid-Open No. 5-246843

Disclosure of the invention

Problems to be solved by the invention

[0006] Accordingly, an object of the present invention is to solve the above-described problems of the prior art. Specifically, the present invention provides an antifungal composition for external use that can exert an antifungal action and has a good feeling of use. The purpose is to provide.

Means for solving the problem

[0007] The inventors of the present invention diligently studied to solve the above-mentioned problems. As a powder component, they used a combination of denpun, water repellent powder and titanium oxide, and together with the powder component, an antifungal agent and an adhesion aid. The composition for external use prepared by blending with the composition exhibits an antifungal action, can form a uniform coated surface on the skin, has a smooth coating surface, and is superior in terms of usability. I found it. The present inventors further provide a gel-like composition prepared by blending water and a lower alcohol together with a gelling agent into the above-mentioned external composition, and has an excellent water absorption ability. I found that it can promote. The present invention has been completed by further studies based on these findings.

[0008] That is, the present invention includes the following aspects of the invention:

Item 1. (A) Antifungal agent, (B) Group force consisting of crotamiton, propylene carbonate, fatty acid ester and polyhydric alcohol At least one adhesion aid selected from (C) starch, water repellent powder and oxidation An antifungal composition for external use, comprising a powder component containing titanium, (D) a lower alcohol, and (E) water.

Item 2. The antifungal composition for external use according to Item 1, further comprising (F) a gelling agent.

Item 2 '. The antifungal composition for external use according to Item 1, further comprising (F) a gelling agent and having a gel-like form.

Item 2 ′ ′. The antifungal composition for external use according to Item 1, which has a gel-like form.

Item 3. Containing 7.2 to 35.42% by weight of (D) lower alcohol and 10.8 to 81.35% by weight of water based on the total weight of the antifungal topical composition Item 3. An antimycotic topical composition according to Item 2.

Item 4. The antifungal composition for external use according to any one of Items 2 or 3, wherein (E) water is contained at a ratio of 150 to 1130 parts by weight with respect to 100 parts by weight of (D) the lower alcohol.

Item 5. Starch per 100 parts by weight of starch, water repellent powder and titanium oxide

19. 2— 79.7 parts by weight, water repellent powder is 14.7— 59. 3 parts by weight, titanium oxide is 0.4—5

1. The antifungal composition for external use according to any one of Items 1 to 4, which is contained in a proportion of 9 parts by weight. Item 6. The antifungal composition for external use according to any one of Items 1 to 5, wherein the starch is at least one selected from the group consisting of potato starch, corn starch and wheat starch.

Item 7. The antifungal property according to any one of Items 1 to 6, wherein the water-repellent powder is at least one selected from the group power consisting of talc, magnesium stearate, aluminum stearate, and zinc stearate. Composition for external use.

Item 8. The antifungal composition for external application according to any one of Claims 1 to 7, wherein the adhesion aid is at least one selected from the group consisting of crotamiton, propylene carbonate and fatty acid ester.

Item 9. The antifungal composition for external application according to any one of Items 2 to 7, wherein the adhesion aid contains a polyhydric alcohol.

Item 10. The antifungal agent is at least one selected from the group force consisting of oxyconazole, bifonazole, sulconazole, neticonazole, terbinafine, butenafine, amorolfine, ranoconazole and salts thereof. Antifungal composition for external use.

Item 11. The antifungal composition for external use according to any one of Items 2 to 10, wherein the gelling agent is a carboxybule polymer.

Item 12. The antifungal composition for external use according to any one of claims 1 to 11, further comprising an antipruritic agent.

Item 13. 0.3-3% by weight of oxyconazole nitrate; 1-15% by weight of dipropylene glycol; 10-54% by weight of a mixture of corn starch, talc and titanium oxide; 0.05-6% of lidocaine ⁰ I ethanol 7. 2-35 42 weight ^_0/0;. water 10. 8 81.35 by weight%; and carboxymethyl Bulle polymer at a rate of 0.5 1 4 wt%, claim 1乃[12] The antifungal composition for external use according to any one of [12].

The present invention is described in detail below. The antifungal composition for external use of the present invention comprises (i) an antifungal agent, (ii) at least one adhesion aid selected from the group consisting of crotamiton, propylene carbonate, fatty acid ester and polyhydric alcohol, (C) Powder component containing starch, water repellent powder and titanium oxide, (D) Lower alcohol and (Ε) Water It is.

[0010] 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, for example, benzylamine antifungal agents such as butenafine and its salts; Imidazole antifungals such as terenopine and salts thereof; arylamine antifungal agents such as terbinafine and salts thereof; morpholine antifungal agents such as amorolfine and salts thereof; Examples include acid antifungal agents; and antifungi such as antibiotics such as nystatin, tricomycin, variotin, siccanin, and pyrrole-torin. Among these, benzylamine antifungal agent, imidazole antifungal agent, arrylamine antifungal agent, and morpholine are preferable from the viewpoint of exhibiting superior antifungal activity due to high permeability to keratin and storage. It is an 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. be able to. These antifungal agents may be used alone or in any combination of two or more.

[0011] 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. Depending on the total weight of the composition, for example, 0.3 to 3% by weight, preferably 0.4 to 2.5% by weight, more preferably 0.5 to 2% by weight. .

[0012] The (B) adhesion aid contained in the antifungal external composition of the present invention is a component that improves the adhesion of the powder component to the skin, and specifically includes crotamiton, propylene carbonate, fat Acid esters (e.g., isopropyl myristate, octadyl myristate, butyl stearate, ethyl oleate, oleyl oleate, diisopropyl adipate, fatty acid ester of glyceric acid, polyoxyl stearate 40, polyoxyl stearate 45, polyoxyl stearate 55 , Jetyl sebacate, sorbitan fatty acid ester, palmi Isopropyl tinate, glyceryl monooleate, polyoxyethylene sorbitan monooleate, sorbitan monooleate, sorbitan sesquioleate, etc., polyhydric alcohol (eg, propylene glycol, dipropylene glycol, glycerin, concentrated glycerin, 1,3-butylene glycol) Etc.). In particular, crotamiton is a suitable adhesion aid because it has excellent adhesion of the powder component to the affected skin, 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. Further, when the composition is made into a gel, it is desirable to use a polyhydric alcohol as an adhesion aid.

[0013] 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 used, etc., and cannot be defined uniformly. The amount of the adhesion aid is 1 to 15% by weight, preferably 1.5 to 12.5% by weight, more preferably 2 to 10% by weight, based on the total weight of the fungal composition for external use. Within the above range, excellent effects can be obtained in terms of both the adhesion characteristics to the affected skin area and the feeling of use.

[0014] The antifungal composition for external use of the present invention contains (C) starch, a water-repellent powder and titanium oxide as a powder component.

[0015] The origin of the starch is not particularly limited as long as it is pharmaceutically acceptable. Specific examples of starch used in the present invention include corn starch, potato starch and wheat starch. These starches may be used alone or in any combination of two or more. More preferably used in the present invention is corn starch.

[0016] In the present invention, the water repellent powder is that the powder component with water repellent properties, specifically, the container bottom area 6.25 cm ^2, a water powder and lmL of lg添Ka卩When left as it is, it is a powder component that has the property of separating into two phases, 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 powerful water repellent powder include talc and stearic acid mug Examples thereof include nesium, aluminum stearate, and zinc stearate. 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.

[0017] The titanium oxide used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. A suitable example of the titanium oxide is titanium dioxide.

[0018] The blending ratio of the starch, the water-repellent powder and the titanium oxide is, for example, 19.2 to 79.7 parts by weight of starch and 14 parts of water-repellent powder per 100 parts by weight of the total weight of these three components. 7—59.3 parts by weight, and titanium oxide 0.4 to 51.9 parts by weight; preferably 23.5 to 72.2 parts by weight of starch, 18.8 to 54.6 parts by weight of water repellent powder. Parts, and 0.8 to 47.1 parts by weight of titanium oxide; 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 part of titanium oxide. 3— 42.9 Examples of the ratio of 9 parts by weight. Within the above range, a uniform coated surface can be formed on the skin, and an excellent usability can be obtained.

[0019] The proportion of the (C) powder component contained in the antifungal external composition of the present invention is appropriately set according to the composition of the powder component used, the form of the composition, and the like. An example of Blend ratio of (C) a powder component, based on the total weight of the antifungal composition for external use, in the powder component is the total weight amount, usually 10 54 weight ^_0/0, preferably 12. 5 52 weight ^_0/0, more preferably include ratio to form 15. 2 5 0 wt%. 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.

[0020] The antifungal external composition of the present invention includes (D) a lower alcohol and a base (solvent) as a base (solvent) from the viewpoint of improving the miscibility and solubility of the above-described ingredients and the penetration into the affected area. (E) Water is blended. Examples of the lower alcohol include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and particularly preferably ethanol. The ethanol can also be used as a modified alcohol by adding methanol or benzene. These lower alcohols may be used alone or in any combination of two or more.

[0021] The blending ratio of the (D) lower alcohol is appropriately set according to the type of the antifungal agent to be used, the form of the composition, the type of the lower alcohol to be used, and the like. Relative to the total weight of the composition, 7. 2 35.42 wt ^_0/0, preferably 9. 6 34.04 weight ^_0/0, more preferably 12 32.78 wt ^_0/0.

[0022] The mixing ratio of the above (E) water is appropriately set according to the type of the antifungal agent used, the form of the composition, the type of the lower alcohol used, and the like. for the total weight [this, 10. 8-81. 35 weight ^_0/0, preferably ί or 14. 4-75. 5 wt ^_0/0, further [this preferred municipal district is 18-69.95% by weight.

[0023] In the antifungal topical composition of the present invention, the total amount of (D) the lower alcohol and (i) water is

For example, 18-88.55% by weight, preferably 24-85.1% by weight, based on the total weight of the composition

%, More preferably within the range of 30-81.3% by weight.

[0024] The antifungal composition for external use of the present invention is blended in combination with other bases (solvents) and carriers used in the composition for external use, if necessary, to form a liquid, ointment, gel, It is prepared into a composition for external use in various forms such as sol form, powder form and solid form. Among them, the gel-like antifungal composition is one of the preferred embodiments of the antifungal composition for external use of the present invention because it has excellent water absorption and can promote drying of the affected area.

[0025] A gel-like antifungal composition for external use is prepared by blending an appropriate amount of a pharmaceutically acceptable gelling agent. Examples of the gelling agent used in the present invention include, for example, a carboxyvininoles polymer, ethinoresenorelose, hydroxypropinoresenorelose, hydroxypropyl, methylcellulose, polybulurpyrrolidone, carrageenan, polybulbutyrate, hydroxy Examples thereof include propylcellulose phthalate, methyl methacrylate copolymer, and methacrylic acid jetylaminoethyl methyl methacrylate copolymer. Of these, preferred are carboxybule polymer, polybutylpyrrolidone, hydroxypropyl cellulose, and particularly preferred is carboxybule polymer.

[0026] The blending ratio of the gelling agent is appropriately set according to the type of gelling agent, the blending ratio of water and lower alcohol, and the like. As an example, (D) the lower alcohol and (Ε) The gelling agent is 0.1 to 4% by weight, preferably 0.25 to 3.5% by weight, more preferably, based on the total weight of the antifungal composition for external use. For example, a ratio of 0.5 to 3% by weight is exemplified.

[0027] In addition, in the case of a gel-like antifungal composition for external use, (D) the lower alcohol and (i) water And (D) 100 parts by weight of lower alcohol, and (E) 150 to 1130 parts by weight of water, preferably 150 to 786 parts by weight, more preferably 150 to 583 parts by weight It is desirable that By having such a ratio, the effect of obtaining long-term stability of the properties of the preparation under the normal environment can be obtained.

[0028] Further, when the composition of the present invention is prepared into an ointment, sol, etc., in addition to the above (D) alcohol and (E) water, the carrier is further blended in an ointment or sol formulation. Or you may mix | blend an appropriate quantity with a base. Examples of such carriers or bases include oil-based bases such as petrolatum, squalane, noraphine, liquid paraffin, white wax, plastic base, polyethylene glycol, macrogol, etc .; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl, methylcellulose , Polymers such as polybulur pyrrolidone, carrageenan, polybutyl pentylate, hydroxypropyl cellulose phthalate, methyl methacrylate copolymer, dimethylaminoethyl methacrylate methyl methacrylate copolymer, carboxybule polymer, and polyethylene glycol; Higher alcohols such as cetanol and stearyl alcohol; 1. Polyhydric alcohols such as 3-butylene glycol, propylene glycol, dipropylene glycol and glycerins And the like.

[0029] The antifungal composition for external use of the present invention can further suppress the feeling of itchiness in the affected area by further containing an antipruritic agent in addition to the above components, and can have a more excellent feeling of use. Examples of the antipruritic agent used in the present invention include lidocaine, lidocaine hydrochloride, dibu force in, dibucaine hydrochloride, pro force in, pro force in hydrochloride, ethyl benzoate, oxypolypentoxide decane, disulfate hydrochloride. Examples include nilpralin, diphenhydramine hydrochloride, chlorophenyl 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, dibu force in, dibu force in chloride, pro force in or pro force in hydrochloride, and more preferably lidocaine, dib force in or pro force in.

[0030] When an antipruritic agent is compounded, 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. The amount of the antipruritic agent is usually 0.05 to 6% by weight, preferably 0.25 to 5.5% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the external composition for external use. Rate [0031] In the antifungal composition for external use of the present invention, a cell activator, an anti-inflammatory agent, an antibacterial agent, as necessary, in addition to the above-mentioned blending components, as long as the effects of the present invention are not impaired , Moisturizers, fragrances, colorants, other powder ingredients, tissue repair agents, astringents, vitamins, refreshing agents, essential oil components, warmth, thermal components, extracts, surfactants, solvents, solubilizers, pH adjusters, buffers, bases, foaming agents, antifoaming agents, emulsifiers, suspending agents, softeners, viscosifiers, dispersants, excipients, lubricants, antioxidants, preservatives, storage Adequate amounts of optional ingredients such as plasticizers and plasticizers may be added.

[0032] Further, the antifungal external composition prepared in a liquid, powder or sol form is further prepared and used as an antifungal external aerosol formulation in combination with a propellant for aerosol formulation. The propellant for the aerosol formulation is not particularly limited, and examples thereof include aliphatic hydrocarbons such as propane, normal butane, isobutane, pentane, isopentane, neopentane, and dimethyl ether. Aerosol preparations can be prepared by mixing the antifungal topical composition and the propellant, for example, in the proportions shown below; antifungal topical composition: propellant in weight ratio, usually 5-30: 70 —95, preferably 7—28: 72—93, more preferably 9: 1 26: 74—91.

[0033] 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 kind and amount of the compounding ingredients and the form thereof. Since the antifungal composition for external use of the present invention is applied to the skin to form a coated surface with uniform and good adhesion, it is used as an antifungal composition for external application once a day. You can also.

[0034] The antifungal composition for external use of the present invention is effective for fungal skin diseases, particularly superficial fungal skin diseases. In particular, since the powder component provides an excellent drying effect, it exhibits an excellent therapeutic effect on wet superficial fungal skin diseases.

The invention's effect

[0035] When applied to the skin affected area of the fungal skin disease, the antifungal external composition of the present invention forms a uniform coated surface by the powder component, and the dry action of the skin affected area or the antifungal agent The drug effect can be exhibited efficiently.

[0036] Further, the antifungal topical composition of the present invention can form a smooth coated surface on the skin. Therefore, it is also good in terms of usability.

[0037] Furthermore, since the antifungal topical composition of the present invention can form a coated surface with good adhesion, it can be prepared into a once-per-day application formulation and can reduce the burden on the patient. There are also advantages in this respect.

[0038] In particular, the gel-like antifungal composition for external use has an excellent water-absorbing action, absorbs moisture and moisture from the affected area, keeps the affected area comfortable, and adverse effects on the drug by them ( For example, it can be expected to be effective in preventing dilution, spillage, etc.) and is suitable for long-term use. Moreover, since the gel-like antifungal composition for external use can be formulated without substantially using an oily component, a good feeling of use with no stickiness can be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described with reference to test examples and examples, but the present invention is not limited to these examples. The unit of numerical values shown in the following table is weight (g) unless otherwise specified.

[0040] Test Example 1 Special Confirmation Test

A composition having the formulation shown in Table 1 (Example 1 and Comparative Examples 1 to 4) was prepared, and the following tests were conducted!

(1) Surface characteristics, (2) functionality, and (3) water absorption were evaluated.

[0041] [Table 1]

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Oxiconazole nitrate 1 1 1 1 1 Lidocaine 2 2 2 2 2 Carboxyvinyl polymer 1 1 1 1 1 Corn starch 10-22. 5--Talc 6.5 --22.5-Titanium oxide 6---22.5 Dipropylene glycol 3 3 3 3 3 Water 50. 5 73 50. 5 50. 5 50.5 Ethanol 20 20 20 20 20 Mouth `` Direct 100 100 100 100 100 Surface MIU ○ XXXX

Characteristics Uniformity ○ ― X X ○

Adhesion ◎ Δ Δ Δ Δ Uniformity Δ X Functionality ◎ ○ Δ

Smooth feeling X Δ Δ X Evaluation ◎

Actual feeling ◎ X Δ Δ ◎ Overall feeling of use ◎ Δ Δ Δ X Water absorption power ○ ○ ○ ○ ○ (1) Evaluation of surface characteristics

) (Slip) ¾ flat

In order to evaluate the feeling of use, the dynamic friction coefficient (MIU) was measured according to the following method.

1. The MIU of artificial leather (5 cm x 13 cm) was measured with a KES-SE surface property tester (manufactured by Kato Tech).

2. On the same artificial leather, spread each lg composition (Example 1 and Comparative Example 1 4) uniformly in the range of 3cm X 6cm with fingers, and apply MIU of the coated surface to the KES-SE surface property tester ( Measured by Kato Tech). This usability evaluation test was conducted at n = 3.

3. The feeling of use was evaluated from the measured average value of MIU according to the following evaluation criteria.

〇 Average value of MIU after application Smaller than average value of MIU before application

X Average value of MIU after application Greater than average value of MIU before application

#: MIU is a value that correlates with slip characteristics, and a decrease in MIU value is an improvement in slip, MIU An increase in value means a slippage.

, Coating rif:! ^ One review

Each composition of lg (Example 1 and Comparative Example 14) is applied to artificial leather (5cm x 13cm) uniformly in the range of 3cm x 6cm with fingers, and the properties of the coated surface are based on the following evaluation criteria. evaluated.

〇 No patchy or sliced coating surface is formed! /, Uniform coating surface

△ A patchy coated surface is not formed, but a small amount of sliced coated surface is formed

X A patchy or sliced application surface is formed

The results obtained are also shown in Table 1. From the results of Comparative Examples 2 to 4, it was confirmed that the use of only starch, water repellent powder, and titanium oxytitanium, respectively, failed to form a coated surface excellent in both feeling of use and uniformity. As a powder component, when starch, water-repellent powder and titanium oxide are used in combination, it is clear that the coated surface has excellent usability and uniformity.

(2) Dragon

An appropriate amount of the antifungal composition for external application was applied between the toes of subjects (two people with wet athlete's foot athletes and three healthy people in total). 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 of use with the following five grades. Went.

5 points: Very good

4 points: good

3 points: normal

2 points: not good

1 point: bad

The obtained scores of each test subject were totaled and judged according to the following criteria for sensory evaluation of each antifungal composition for external use.

◎: 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

X: Total score 5 or more and 9 or less

The results obtained are also shown in Table 1. From the results of Example 1, the antifungal composition for external use of the present invention has a very good feeling in use in all of adhesion, uniformity, smooth feeling, actual feeling and comprehensive feeling in addition to the antifungal action. It became clear that it was obtained.

(3) 7k force flat

200 μg of each antifungal composition for external application (Example 1 and Comparative Example 14) was applied to artificial leather (3 cm × 3 cm), and this was floated on physiological saline with the coated surface facing down. After 1 and 3 minutes, the artificial leather was pulled up, drained for 10 seconds, and then weighed. As a control, the same operation as described above was performed using only artificial leather. The water absorption for 1 minute and the water absorption for 3 minutes were calculated based on the following formula.

[Weight before standing]-[Weight after standing for 1 minute] = Water absorption per minute

[Weight before standing]-[Weight after standing for 3 minutes] = Water absorption for 3 minutes

From the water absorption amounts obtained for 1 minute and 3 minutes, the water absorption of each antifungal composition for external use was evaluated according to the following criteria.

◯: There was a significant difference in the t-test between the application group and the control group for water absorption for 3 minutes (rejection rate 10%)

△: There was a significant difference in the t-test between the application group and the control group for the 1-minute water absorption, but the 3-minute water absorption was significant in the t-test between the application group and the control group. There was no difference (rejection rate 10%)

X: There was a significant difference in the t-test between the application group and the control group for both 3 minutes water absorption and 1 minute water absorption (rejection rate 10%)

The results obtained are also shown in Table 1. From the results of Example 1, the antifungal topical composition of the present invention is excellent in water absorption, absorbs moisture and moisture from the affected area, keeps the affected area comfortable, and adverse effects on the drug (for example, Dilution, spills, etc.) and therefore for a long time It was confirmed that it can be suitably used for the application.

[0045] Test Example 2 Stable test

(1) Low temperature cycle test

Each antifungal composition for external use (Example 2-12) was allowed to stand in an environment where the temperature continuously changed in the low temperature cycle shown below, and the properties (separation) were evaluated after 10 days. <Low temperature cycle>

In the low temperature cycle, the operation was performed in the order of (1) → (2) → (3) → (4) as follows.

(1) 0—Change from —20 ° C to 5 ° C over 1 hour

(2) Hold at 5 ° C for 1-12 hours

(3) Transition from 5 ° C to 20 ° C over 12-13 hours

(4) Hold at -20 ° C for 13-24 hours

(2) Temperature cycle test

Each antifungal composition for external use (Example 2-12) was allowed to stand in an environment where the temperature continuously changed during the high-temperature cycle shown below, and the properties (separation) were evaluated after 10 days. <High temperature cycle>

In the high temperature cycle, the operation was performed in the order of (1) → (2) → (3) → (4) as follows.

(1) 0—Transition from −20 ° C to 42 ° C over 1 hour

(2) 1-11 Hold at 42 ° C for 12 hours

(3) Transition from 42 ° C to 20 ° C over 12-13 hours

(4) Hold at -20 ° C for 13-24 hours

(3) 翩遞

Each antifungal composition for external use (Example 2-12) was allowed to stand at 50 ° C., and after 10 days, the properties (separation) were evaluated.

[0046] The results of the stability test are shown in Table 2-3. From these results, it was confirmed that the antifungal composition for external use of the present invention has excellent stability.

〇 No separation was confirmed in all the stability tests of (1) Low temperature cycle test, (2) High temperature cycle test, and (3) High temperature test. Separation was confirmed in all of the above (1) low temperature cycle test, (2) high temperature cycle test and (3) high temperature test or any stability test.

[Table 2]

Table 3]

Example

8 9 1 0 1 1 1 2 Oxiconazole nitrate 1 1 1 1 1 Lidocaine 2 2 2 2 2 Carboxyvinyl polymer 0.5 1.5 1.5 1.5 1.5 Corn starch 16 7 10 10 10 Talc 10 4.5 6.5 6.5 6.5 Titanium oxide 9 4 6 6 6 Dipropylene glycol 4.5 2---

1,3_ Butylene glycol--2.5-One Propylene glycol---2.5 One Glycerin----2.5 Water 40 63 50.5 50.5 50.5 Ethanol 17 15 20 20 20 Total 100 100 100 100 100 Stability 〇〇〇〇

[0049] Participant Example 1 14

Prepare antibacterial topical compositions (Reference Examples 1-14 and Comparative Reference Examples 1-17) with the formulations shown in Table 4-7, and follow the methods in Test Example 1 above to determine the surface characteristics (feeling of use and uniformity of the coated surface). ) Was evaluated.

[0050] The results obtained are also shown in Table 4-7. From this result, it became clear that when using starch, water repellent powder and acid titanium as a powder component together with crotamiton, an excellent feeling and uniformity are imparted to the coated surface. On the other hand, if any one of starch, water-repellent powder and titanium oxide is lacking, it is confirmed that an excellent coated surface cannot be formed in terms of both usability and uniformity. It was.

[0051] [Table 4] Reference example

1 2 3 4 5 6 7 Butenaf hydrochloride

1 1 1 1 1 1 1

corn

10 20 20 20 20 20 10 Starch

Talc 10 20 10 10 10 10 5 Titanium oxide 15 8 0. 4 1 8 15 5 Crotamine 10 10 10 10 10 10 10 Ethanol Remainder Remainder Remainder Remainder Remainder Remainder Remaining Total amount 100 100 100 100 100 100 100 Feeling of use (MIU

○ ○ ○ ○ ○ ○ ○ Evaluation of values)

Uniformity ○ ○ ○ ○ ○ ○ ○ 5]

Reference example

8 9 1 0 1 1 1 2 1 3 1 4 Butenaf hydrochloride

1 1 1 1 1 1 1

corn

--20 20 20 10 20

20 ― ― ― ― ― ―

Zo potato

20 ― ― ― Talc 10 10 ― ― 10 10 Stearic acid ― ― 10 ― ― ― ― Magnesium

Stearic acid ― One ― 10 ― ― ― Aluminum

Stearic acid ― ― ― 1 10 ― ― Zinc

Titanium oxide 15 15 15 15 15 15 15 Kuroyu Sun 10 10 10 10 10 5 5 Ethanol Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining Remaining ί = ι ρ `` 100 100 100 100 100 100 100 Usability (MIU

○ ○ ○ ○ ○ ○ ○ Evaluation of values)

Uniformity ○ ○ ○ ○ ○ ○ ○ 6]

Comparison reference 1 row

1 2 3 4 5 6 7 8 9 Butenaf hydrochloride

1 1 1 1 1 1 1 1 1

corn

10 20 30 ― ― ― 10 20 30 Talc ― One ― 10 20 30 10 10 10 Titanium oxide ― ■ ― ― ― One ― Crotamine 10 10 10 1 0 10 10 10 10 10 Ethanol Residue Residue Residual Residual Residual Residual Residual Residual Residual Balance a υΓ 100 100 100 100 100 100 100 100 100 Usability (MIU

○ ○ ○ X X X X ○ ○ Evaluation of values)

Uniformity X X X ○ ○ ○ Δ X X [Table 7] Comparative reference example

Participant 仞 5— ί 8

Antifungal compositions for external use having the composition shown in Table 8 (Reference Example 15-18 and Comparative Reference Example 18-19) were prepared. Using this antifungal topical composition, according to the method of Test Example 1 above, The feeling of use and sensory evaluation were performed, and the antipruritic effect was further evaluated according to the following method.

[0056] Evaluation of the effect of skin patch

1. ddY clean mice (male, 6 weeks old) were bred for 1 week and habituated.

2. The weight of the mouse was measured, and the back was shaved with a clipper.

3. The antifungal composition for external use (Examples 15 to 18 and Comparative Examples 18 to 19) 200 mg was evenly applied to the shaved part and rubbed with fingers.

4. 30 minutes after application of antifungal composition for external use, ether anesthesia was performed, and an itching-inducing substance (4.8 mg of Compound48 / 80 (ICN Biomedicals, Inc.) dissolved in 1 mL of physiological saline) per 40 g body weight Mice were administered intradermally at a rate of 20 μL.

5. From 5 minutes to 25 minutes after intradermal administration, the number of mouse scratches (behavior in which the mouse directly scrambles the part where the intradermally administered substance was administered) was counted.

6. As a positive control, an anti-fungal composition for external use was applied and an itching-inducing substance was applied in the same manner, and the number of scratches was counted. The evaluation test for the antipruritic effect was conducted at η = 6.

7. The antipruritic effect of each antifungal composition for external use was evaluated according to the following criteria.

〇: Average scratch frequency force The average scratch frequency of positive control is less than 1Z4

△: Average scratch frequency force 1Z4 or more of positive control average scratch frequency 1Z2

X: Average scratch frequency force 1Z2 or more of the average scratch frequency of the positive control The results obtained are also shown in Table 8. As a result, it was clarified that the antifungal composition for external use of Reference Examples 15 to 18 has a very good feeling in use in addition to the antifungal action.

[0057] [Table 8] Reference example Comparative reference example

1 5 1 6 1 7 1 8 1 8 1 9 Oxicona nitrate

1 1 1 1 1 1

P Zol

Adult lidocaine 2. 5 2. 5 2. 5 1 2. 5 2. 5 min

20 20 20 10 40 ― Open

Talc 10 10 10 10 ― 10 Titanium oxide 15 15 15 15 One Crotamine 5 5 5 10 10 10 Propylene carbonate ― 10-One ― ― Myristic acid

Ten

Sopropyl

Ethanol Remainder Remainder Remainder Remainder Remainder Remainder Total 100 100 100 100 100 100 Usability (MIU rating)

○ ○ ○ ○ ○ X value)

Antipruritic effect 〇〇〇 XX Δ X

Claims

The scope of the claims

[1] (A) Antifungal agent, (B) Group power consisting of crotamiton, propylene carbonate, fatty acid ester and polyhydric alcohol. At least one adhesion aid selected from (C) starch, water repellent powder and oxidation An antifungal composition for external use, comprising a powder component containing titanium, (D) a lower alcohol, and (E) water.

[2] The antifungal composition for external use according to claim 1, further comprising (F) a gelling agent.

[3] Containing (D) lower alcohol in a proportion of 7.2—35.42% by weight and (E) water in a proportion of 10.8—81.35% by weight, based on the total weight of the antifungal composition for external use The antimycotic composition for external use according to claim 2.

[4] The antifungal composition for external use according to any one of claims 2 and 3, wherein (E) water is contained in a ratio of 150 to 1130 parts by weight per 100 parts by weight of (D) lower alcohol.

[5] Starch, 19 parts per 100 parts by weight of starch, water repellent powder and titanium oxide

2— 79.7 parts by weight, water repellent powder 14.7— 59. 3 parts by weight, titanium oxide 0.4.

The antifungal composition for external use according to any one of claims 1 to 4, which is contained in a proportion of 9 parts by weight.

6. The antifungal composition for external use according to any one of claims 1 to 5, wherein the starch is at least one selected from the group power consisting of potato starch, corn starch and wheat starch.

7. The antifungal according to any one of claims 1 to 6, wherein the water-repellent powder is at least one selected from the group power consisting of talc, magnesium stearate, aluminum stearate and zinc stearate. Topical composition.

8. The antifungal composition for external use according to any one of claims 1 to 7, wherein the adhesion aid is at least one selected from the group power consisting of crotamiton, propylene carbonate and fatty acid ester.

[9] The antifungal composition for external use according to any one of claims 2 to 7, wherein the adhesion aid contains a polyhydric alcohol.

[10] The antifungal agent comprises oxiconazole, bifonazole, sulconazole, neticonazole, terbinafine, butenafine, amorolfine, lanoconazole and salts thereof. 10. The antifungal composition for external use according to any one of claims 1 to 9, wherein the composition is at least one selected for group power.

[11] The antifungal composition for external use according to any one of claims 2 to 10, wherein the gelling agent is a carboxybule polymer.

[12] The antifungal composition for external use according to any one of claims 1 to 11, further comprising an antipruritic agent.

[13] 0. nitrate Okishikonazoru 3-3 wt%; 1 one 15 weight dipropylene glycol ^_0/0; maize starch, talc and a mixture of titanium oxide 10 54 weight ^_0/0; lidocaine 0. 05 6 weight ⁰ I ethanol 7. 2-35 42 weight ^_0/0;. water 10. 8 81.35 weight ^_0/0; in a proportion of 0.5 1 4% by weight and carboxy Bulle polymer, The antifungal composition for external use according to any one of claims 1 to 12.