JP2005239679A - Creamy preparation for external use for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a creamy preparation containing butenafine hydrochloride and having improved therapeutic effect by improving the retainability in the horny layer or skin and the addition of a secondary ingredient and improved storage stability of both of the butenafine hydrochloride and the secondary ingredient. <P>SOLUTION: This creamy preparation for external use for skin contains two or more drugs selected from dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and l-menthol in combination with butenafine hydrochloride and has a pH of 4.5-5.5. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a skin external cream.

  Butenafine hydrochloride is a benzylamine antifungal agent and is used for the treatment of athlete's foot as a topical antifungal agent such as a cream. And the improvement of the composition of an external preparation is tried for the purpose of improving the medicinal effect of butenafine hydrochloride.

  For example, as a preparation for improving skin permeability of butenafine hydrochloride, there is an antifungal liquid external composition containing butenafine hydrochloride as an active ingredient and having a blended water content of 3% or less (see Patent Document 1).

In addition, as a preparation aimed at improving the keratin permeability of butenafine hydrochloride, it contains butenafine hydrochloride as an active ingredient and contains keratinous reservoir containing one or more of methyl salicylate, glycol salicylate, crotamiton, mint oil or menthol. Type antifungal composition for external use (see Patent Document 2).
JP 2001-181182 A JP-A-8-20527

  However, as a result of intensive studies by the present inventors, it has been found that the above preparation has a problem that the stability of butenafine hydrochloride and / or an adjuvant is poor.

  Accordingly, an object of the present invention is to provide a preparation containing butenafine hydrochloride that has improved keratin retention and improved therapeutic effect by the combination of an active drug, and has improved the storage stability of both butenafine hydrochloride and the active drug There is to do.

  To achieve the above object, the present invention comprises dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid, and 1-menthol or more selected from the group consisting of 1 and menthol, and butenafine hydrochloride. And a skin cream for external use characterized by having a pH of 4.5 to 5.5.

  Butenafine hydrochloride may cause side effects such as redness. In the external cream for skin of the present invention, the drug containing butenafine hydrochloride contains two or more drugs selected from the group consisting of dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and l-menthol. Therefore, the occurrence frequency of side effects such as redness can be reduced. In addition, since the pH of the preparation is 4.5 to 5.5, the storage stability of both butenafine hydrochloride and an auxiliary drug (dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and l-menthol) can be improved. it can.

  The external skin cream of the present invention preferably further contains 0.05 to 1.0% by mass of dibutylhydroxytoluene based on the total amount of the preparation. By blending dibutylhydroxytoluene, the storage stability of both butenafine hydrochloride and an adjuvant can be further enhanced.

  The pH of the external skin cream is preferably adjusted with an organic amine. That is, in the external skin cream of the present invention, the pH of the preparation is preferably adjusted to 4.5 to 5.5 with an organic amine such as diethanolamine.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a preparation containing butenafine hydrochloride that has improved keratin retention and improved therapeutic effect by blending of an active drug, and has improved storage stability of both butenafine hydrochloride and the active drug It becomes.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

  The external cream for skin of the present invention contains butenafine hydrochloride as an active ingredient. From the viewpoint of efficacy as an antifungal agent, the amount of butenafine hydrochloride is usually 0.1 to 10% by mass, preferably 1 to 5% by mass based on the whole preparation (hereinafter, unless otherwise specified). “Mass%” means mass% based on the whole preparation).

  The external skin cream of the present invention contains two or more drugs selected from the group consisting of dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and 1-menthol as an adjuvant for butenafine hydrochloride. By blending this adjuvant, it is possible to reduce the incidence of side effects of butenafine hydrochloride and alleviate the symptoms. Hereinafter, each drug will be described.

  Dibucaine hydrochloride is a local anesthetic, and a preparation containing this can alleviate itching caused by athlete's foot. The blending amount of dibucaine hydrochloride is usually 0.01 to 5.0% by mass, preferably 0.05 to 2.0% by mass, from the viewpoint of efficacy as a local anesthetic. The external skin cream of the present invention contains a local anesthetic such as dibucaine or a pharmacologically acceptable salt thereof, lidocaine or a pharmacologically acceptable salt thereof instead of dibucaine hydrochloride. Also good.

  Chlorpheniramine maleate is an antihistamine, and a preparation containing it can relieve itching caused by athlete's foot, reduce the frequency of redness, and relieve symptoms of redness. The blending amount of chlorpheniramine maleate is usually 0.05 to 5.0% by mass, preferably 0.05 to 2.0% by mass, from the viewpoint of efficacy as an antihistamine. The external skin cream of the present invention is an antihistamine agent such as chlorpheniramine or a pharmacologically acceptable salt thereof, diphenhydramine or a pharmacologically acceptable salt thereof instead of chlorpheniramine maleate. May be contained.

  Glycyrrhetinic acid is an anti-inflammatory drug, and a preparation containing it can reduce the frequency of redness and alleviate symptoms. The blending amount of glycyrrhetinic acid is usually 0.05 to 10.0% by mass, preferably 0.05 to 2.0% by mass, from the viewpoint of efficacy as an anti-inflammatory drug. The external skin cream of the present invention contains an anti-inflammatory drug such as a pharmacologically acceptable salt of glycyrrhetic acid, allantoin or a pharmacologically acceptable salt thereof, instead of glycyrrhetinic acid. Also good.

  l-Menthol has various pharmacological actions, one of which is the growth inhibitory action of Staphylococcus aureus and Candida. Therefore, a preparation containing l-menthol can suppress the growth of skin resident bacteria (Staphylococcus aureus and Candida) that cause deterioration of athlete's foot, and can treat athlete's foot more effectively. It becomes. l-Menthol also has an analgesic action and an antipruritic action, and a formulation containing this can also reduce redness and itching caused by athlete's foot. The compounding quantity of 1-menthol is 0.5-5 mass% normally from a viewpoint of a pharmacological action, Preferably it is 1-3 mass%.

  Thus, since the external skin cream of the present invention contains the above-mentioned adjuvant, the therapeutic effect of butenafine hydrochloride is enhanced.

  The external cream for skin of the present invention is used for patients with skin diseases such as athlete's foot. Patients with skin diseases often have damaged skin surfaces. Therefore, in order to relieve irritation to the skin, it is preferable that the pH of the external cream for skin applied to patients with skin diseases is usually 6-7. That is, a cream having a pH outside the range is more irritating to the skin, increasing the burden on the patient and lowering the compliance. However, the cream preparation for external use containing butenafine hydrochloride and the above-mentioned adjuvant is unstable at pH 6-7, and when the external cream is stored for a long period of time, butenafine hydrochloride and the above-mentioned adjuvant are degraded. They found out.

  And, the present inventors have found that by adjusting the pH of the cream for external use to 4.5 to 5.5, the stability of butenafine hydrochloride and the above-mentioned adjuvant increases, and it is difficult to decompose even when stored for a long time. I found it. Moreover, contrary to the expectation that creams with a pH in this range will have strong irritation to the skin, creams containing butenafine hydrochloride and the above-mentioned adjuvants show little irritation to the skin.

  Therefore, it is necessary to adjust the pH of the cream for external use of the present invention to 4.5 to 5.5. Adjustment of pH is possible by mix | blending a pH adjuster. The blending amount of the pH adjusting agent varies depending on the formulation of the preparation, but those skilled in the art can determine the blending amount of the pH adjusting agent so that the pH of the preparation is 4.5 to 5.5.

  The pH adjuster is preferably an organic amine, and particularly preferably diethanolamine. This is because organic amines such as diethanolamine not only act as a pH adjuster but also serve to assist the stability of emulsification.

  The external skin cream of the present invention preferably further contains 0.05 to 1.0% by mass of dibutylhydroxytoluene in addition to the above components. By adding dibutylhydroxytoluene, which is a stabilizer, to the preparation, it is possible to further improve the stability of butenafine hydrochloride and the adjuvant. Note that the stability of butenafine hydrochloride and / or an adjuvant is not improved by simply adding dibutylhydroxytoluene to the preparation without adjusting the pH of the preparation to 4.5 to 5.5. Dibutylhydroxytoluene can improve the stability of butenafine hydrochloride and an active drug for the first time by adjusting the pH of the preparation to 4.5 to 5.5.

  The external skin cream of the present invention contains an oily base, a surfactant, and water in addition to the above components.

  Examples of the oily base include liquid paraffin, petrolatum, paraffin wax, squalane and the like.

  The surfactant may be any of an anionic surfactant, a nonionic surfactant, a cationic surfactant, or an amphoteric surfactant. Examples of the anionic surfactant include polyoxyethylene alkyl phosphate ester and sodium alkyl sulfate. Nonionic surfactants include, for example, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate, sorbitan fatty acid esters such as polyoxyethylene stearic acid sorbitan, and polyoxyethylene nonyl ether, Examples thereof include polyoxyethylene ethers such as monooxyethylene cetyl ether and monooxyethylene lauryl ether. Examples of the cationic surfactant include benzethonium chloride and benzalkonium chloride.

  The external skin cream of the present invention may contain a higher alcohol, a fatty acid ester, a silicone oil, a polyhydric alcohol or a derivative thereof, a gelling agent and the like in addition to the above components.

  The higher alcohol is an alcohol having 10 to 22 carbon atoms, and is preferably cetyl alcohol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, or behenyl alcohol.

  The fatty acid ester is an ester of a higher fatty acid, and examples thereof include esters of higher fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, caprylic acid, capric acid and alcohols having 1 to 18 carbon atoms.

  Examples of the polyhydric alcohol or derivative thereof include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol and polypropylene glycol, and esters or ethers thereof.

  Examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like.

  The external skin cream of the present invention may contain a transdermal absorption enhancer. The transdermal absorption enhancer may be any compound as long as it is a compound in which the transdermal absorption promoting action of butenafine hydrochloride is observed. Examples of such a transdermal absorption enhancer include, for example, fatty acids having 6 to 20 carbon atoms, aliphatic alcohols, fatty acid esters or fatty acid esters, aromatic organic acids, aromatic alcohols, aromatic organic acid esters, aromatic ethers, Examples thereof include lactic acid ester, monoterpene, sesquiterpene, Azone or derivatives thereof, glycerin fatty acid ester, sorbitan fatty acid ester, polysorbate, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, and sucrose fatty acid ester. Among these, fatty acid esters and aliphatic alcohols are preferable, and isopropyl myristate, isopropyl palmitate, sorbitan monooleate, or oleyl alcohol is particularly preferable.

  The external skin cream of the present invention may contain an antioxidant, an antiseptic, a preservative, a moisturizer, a chelating agent, a fragrance, and other additives that are usually blended in the external skin cream.

  The external skin cream of the present invention can be produced by mixing and emulsifying each component according to a conventional method.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not limited to these Examples.

(Example 1 and Comparative Examples 1-2)
Table 1 (excluding pH values, the numerical values in Table 1 represent mass% based on the whole preparation) containing butenafine hydrochloride, dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and menthol. )) According to the prescription. More specifically, the water phase and the oil phase were each heated to 80 ° C., and both were mixed and emulsified with sufficient stirring. Then, the skin cream for external use was obtained by cooling to room temperature, stirring.

  When diethanolamine, which is a pH adjuster, was not added, the pH of the obtained preparation was 3.7 (Comparative Example 1). Moreover, the formulation (Example 1) of pH 5.1 and the formulation (Comparative Example 2) of pH 6.5 were obtained by adding diethanolamine.

  The thus obtained preparation was stored at 50 ° C. for 1 month, and the stability of each drug was examined. The content of each drug in the preparation was measured by a conventional method (HPLC method). A value obtained by dividing the content of the drug after storage for 1 month by the content of the drug immediately after preparation preparation was expressed as a residual rate (%), and the residual rate (%) of each drug is summarized in Table 2.

  As is clear from the results shown in Table 2, in Comparative Examples 1 and 2, the residual ratio of butenafine hydrochloride and / or an active drug is low, whereas in Example 1, the residual ratio of butenafine hydrochloride and an active drug is low. it was high. From the above, it was confirmed that the external preparation for skin of the present invention has improved storage stability of both butenafine hydrochloride and an adjuvant.

(Examples 2-3 and Comparative Examples 3-4)
Table 3 (excluding pH values, the numerical values in Table 3 represent mass% based on the whole preparation) containing butenafine hydrochloride, dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and menthol. )) According to the prescription. More specifically, the water phase and the oil phase were each heated to 80 ° C., and both were mixed and emulsified with sufficient stirring. Then, the skin cream for external use was obtained by cooling to room temperature, stirring.

  When diethanolamine, which is a pH adjuster, was not added, the pH of the resulting preparation was 3.7 (Comparative Examples 3 and 4). Moreover, the formulation (Examples 2 and 3) of pH 5.0 was obtained by adding diethanolamine. Further, dibutylhydroxytoluene (BHT) is added as a stabilizer to the skin external creams of Example 3 and Comparative Example 4.

  The thus obtained preparation was stored at 40 ° C. for 6 months, and the stability of each drug was examined. The content of each drug in the preparation was measured by a conventional method (HPLC method). The value obtained by dividing the content of the drug after storage for 6 months by the content of the drug immediately after preparation preparation was expressed as a residual rate (%), and the residual rate (%) of each drug is summarized in Table 4.

  As is clear from the results shown in Table 4, in Comparative Examples 3 and 4, the residual ratio of butenafine hydrochloride and / or an adjuvant is low, whereas in Examples 2 and 3, the residual of butenafine hydrochloride and an adjuvant is left. The rate was high. In Example 3 to which dibutylhydroxytoluene was added, the residual rate was particularly high, and no decomposition product was detected. From the above, it was confirmed that the external preparation for skin of the present invention has improved storage stability of both butenafine hydrochloride and an adjuvant.

Claims (5)

  It contains at least two drugs selected from the group consisting of dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and 1-menthol, and butenafine hydrochloride, and has a pH of 4.5 to 5.5. An external cream for skin.   Contains 3 or more drugs selected from the group consisting of dibucaine hydrochloride, chlorpheniramine maleate, glycyrrhetinic acid and 1-menthol, and butenafine hydrochloride, and has a pH of 4.5 to 5.5 An external cream for skin.   The external skin cream according to claim 1 or 2, further comprising 0.05 to 1.0% by mass of dibutylhydroxytoluene based on the total amount of the preparation.   The external skin cream according to any one of claims 1 to 3, wherein the pH of the preparation is adjusted to 4.5 to 5.5 with an organic amine. . The external skin cream according to claim 4, wherein the organic amine is diethanolamine.