WO2007114380A1

WO2007114380A1 - Agent for external application to the skin

Info

Publication number: WO2007114380A1
Application number: PCT/JP2007/057245
Authority: WO
Inventors: Manabu Nozaki; Shigeki Sawamura
Original assignee: Kobayashi Pharmaceutical Co., Ltd.
Priority date: 2006-03-31
Filing date: 2007-03-30
Publication date: 2007-10-11
Also published as: JP2007269693A; JP5132071B2

Abstract

The object is to provide an agent for external application, which can rapidly suppress itching on the skin, particularly on the hypersensitive skin. Disclosed is an agent for external application to the skin, which is characterized in that a lower alcohol (e.g., ethanol) is not used or, if any, is used in a small amount in combination with capsaicin and crotamiton. The agent comprises capsaicin, crotamiton, and a lower alcohol in an amount of not less than 0% by weight and less than 5% by weight. Since the agent contains capsaicin and crotamiton but does not contain a lower alcohol or, if any, contains a lower alcohol in only an extremely small amount, the agent can develop an itching-suppressing effect immediately after the application of the agent to the skin.

Description

Specification

Skin preparation

Technical field

[0001] The present invention relates to an external preparation for skin having an effect of improving sensation.

Background art

[0002] Itching is an unpleasant symptom that cannot be tolerated. The causes are various, such as sensitive skin, atopic dermatitis, and inflammation caused by insect bites. Sensitive skin is further classified into types with disrupted epidermal barriers (eg dry skin), inflammation types, and hypersensitivity types. Other than hypersensitivity type, there are some organic disorders on the skin surface, so be careful about the nature and dosage form of the drug to be administered. On the other hand, the hypersensitivity type is a symptom in which the skin property is healthy but the itch sensory nerve is hypersensitive.

[0003] In order to improve these various itching symptoms, various external preparations such as an external preparation containing an anti-inflammatory component, an external preparation containing a moisturizing ingredient, and an active agent-free hypoallergenic external preparation have been developed. In addition, there are many preparation technologies especially for dry skin (see Patent Document 2). However, it takes a long time until itching is not perceived, and it lacks immediate effect or persistence. Was necessary. In particular, in the case of hypersensitivity-type sensation, the skin surface is healthy, and there has been a significant increase in demand for a preparation with excellent immediate effect and low drug permeability.

[0004] Here, it is known to improve sensation by desensitizing sensory nerves with kabusaicin. The improvement of sensation by kabusaicin is achieved by acting on the sensory nerve and desensitizing the sensory nerve (at this time, the thermal sensation is transmitted to the brain and the sensation is not transmitted). A technique for reducing the feeling of drunkenness using kabusaicin has been reported (see Patent Document 3). However, the technology described in this document was also not satisfactory in terms of immediate effect on the feeling of sensation.

Patent Document 1: Japanese Patent Laid-Open No. 2005-263660

Patent Document 2: Japanese Patent Laid-Open No. 2001-213772

Patent Document 3: Japanese Patent Laid-Open No. 2001-226400 Disclosure of the invention

Problems to be solved by the invention

[0005] An object of the present invention is to provide an external preparation which is excellent in immediate effect and sustainability of kabusaicin and can improve the feeling of itch very quickly.

Means for solving the problem

[0006] As a result of intensive studies in view of the above-mentioned problems of the prior art, the present inventor used kabusaicins together with crotamiton known as an antipruritic agent, and at this time, the lower alcohol was not present or existed. Even when the amount was very small, the effect of kabusaicin on sensory nerves was made effective and continuous, and it was found that the feeling of sensation was improved very quickly and the effect was sustained, and the present invention was completed.

That is, the present invention relates to the following external preparation for skin.

Item 1. A topical skin preparation containing cabsaicins and crotamiton and containing 0 to 5% by weight of lower alcohol.

Item 2. The topical skin preparation according to Item 1, which has a lower alcohol content of 3 to 3% by weight.

Item 3. The skin external preparation according to Item 1 or 2, wherein the content of lower alcohol is greater than or equal to ^ and less than 1% by weight.

Item 4. The topical skin preparation according to any one of Items 1 to 3, containing 0.005 to 0.1% by weight of capsaicin and 3 to 20% by weight of crotamiton.

Item 5. The topical skin preparation according to any one of Items 1 to 4, further comprising water.

Item 6. The skin external preparation according to any one of Items 1 to 5, further comprising at least one selected from the group consisting of a phospholipid and a liquid oil at room temperature.

Item 7. The topical skin preparation according to any one of Items 1 to 6, which is an ointment.

Item 8. The external preparation for skin according to any one of Items 1 to 7, which is used for improving sensation.

Item 9. The external preparation for skin according to any one of Items 1 to 8, which is used for improving the sensation of hypersensitive skin.

[0008] The topical skin preparation of the present invention contains kabusaicins and crotamiton, and is characterized by containing 0 to 5% by weight of a lower alcohol. That is, in the skin external preparation of the present invention, the lower alcohol is not used in combination with capsaicins and crotamiton, or Is a small amount even when used together. In the present invention, by adopting such a configuration, the effect of improving sensation is exhibited from a very early stage after application to the skin.

[0009] In the present invention, capsaicins include capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, etc., which can be used alone or in combination of two or more. Capsaicin is preferable because of its effective action. Moreover, capsaicins can be blended in the skin external preparation of the present invention in the form of not only the capsaicin itself but also a plant, plant extract or the like (for example, capsicum extract, capsicum tincture, etc.) containing capsaicin. In the present invention, the content of kabusaicins is cuff. Usually from 0.005 to 0 as the latest. 1 weight ^_0/0, preferably from 0.01 to 0.025 wt%. When the content is within these ranges, a high desensitizing action is obtained, and pain sensation tends not to occur.

In the present invention, the content of crotamiton is usually 3 to 20% by weight, preferably 5 to 15% by weight. If the content is in these ranges, the effect of enhancing the action of kabusaicin is high, and the skin irritation tends to be low.

[0011] In the present invention, the content of the lower alcohol is 0 or more and less than 5% by weight, preferably 0 to 3% by weight, more preferably 0 or more and less than 1% by weight, and the lower alcohol is not contained. That is the most preferred. In the present invention, the content of lower alcohol is low! /, The effect of improving the feeling of dullness is exerted early. In the present invention, when a lower alcohol is contained, those that can be used in the field of external preparations can be used without particular limitation, and may be contained alone or in combination of two or more. Examples of lower alcohols include absolute ethanol, ethanol, methanol, isopropanol, and modified alcohols thereof (such as a phenol-modified alcohol and an 8-acetylated sucrose-modified alcohol). Preferred lower alcohols are absolute ethanol, ethanol, methanol, isopropanol, and more preferred lower alcohols are absolute ethanol, ethanol, isopropanol.

[0012] In the present invention, examples of water that can be desirably mixed to contain water include purified water, distilled water, sterilized water, physiological saline, deep sea water, and the like, preferably purified water. is there. [0013] In the present invention, from the viewpoint of improving transdermal absorbability, it is desirable to select one or more phospholipids and room temperature liquid oil components. Examples of phospholipids that can be added include phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, plasmalogens, ether lipids, cardiolipin and other glyceport phospholipids, and lecithins containing these in combination (soybean lecithin, egg yolk) Lecithin, purified hydrogenated soybean phospholipid), and sphingophospholipids such as sphingomyelin. Lecithin is preferred.

[0014] Examples of liquid oil at room temperature include hydrocarbons such as liquid paraffin, light liquid paraffin, and squalane, ester oils such as isopropyl myristate, isopropyl palmitate, decyl oleate, and otatildodecyl myristate. Examples include beeswax, olive oil, cacao oil, sesame oil, soybean oil, camellia oil, peanut oil, cow oil, pig oil, chicken oil, lanolin and other fats and oils.

[0015] The present invention can contain other active ingredients as necessary within a range not impairing the effects of the present invention. Other active ingredients include, for example, steroid drugs (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorfelamine maleate, etc.), Local anesthetic (Lido force-in, dibu force-in, pro force-in, tetracaine, bupino force-in, mepino force-in, black mouth pro-in, pronoracaine, mepril force-in or salts thereof, benzoic acid alkyl ester ( For example, ethyl aminobenzoate, ethyl ethyl parabutylaminobenzoate), orthocaine, oxesasein, oxypolyentoxydecane, funnel extract, percaminpase, tecitdecite, etc.), anti-inflammatory agent (daricyrrhetinic acid) Dipotassium glycyrrhizinate, monoammonium glycyrrhetinate, allantoin, salicylic acid, glycol salicylate, etc., bactericides (chlorinated benzalkonium, decalium chloride, benzethonium chloride, isopropylmethylphenol, chlorhexidine hydrochloride) Chlorhexidine darconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (thianthol, etc.), skin protectants (collodion, castor oil, etc.).

[0016] In addition, the present invention may contain a base in order to obtain a desired dosage form. For example, alginic acid Sodium, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, carrageenan, mannan, agarose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer , Polymers such as polybutyl ester, polyvinyl pyrrolidone, carboxyvinyl polymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan; hydrocarbons such as white petrolatum, yellow petrolatum, paraffin, ceresin wax, microcrystalline wax;匕 Hydrocarbon (for example, trade name Plastibase, manufactured by Bristol-Myers Squibb); Steer Higher fatty acids such as acids; higher alcohols such as cetanol, otatildodecanol, stearyl alcohol; polyethylene glycol (eg, macrogol 4000); propylene glycol, glycerin, dipropylene glycol, 1,3 butylene glycol, concentrated Polyhydric alcohols such as glycerin; fatty acid esters such as monooleic acid ester and glyceryl stearate; phosphate buffer and the like. The type and amount of the base can be appropriately selected depending on the dosage form.

[0017] In addition, the present invention can contain an additive as long as it does not impair the effects of the present invention. Additives include, for example, solubilizers (polybulurpyrrolidone, etc.), inorganic fillers (talc, kaolin, bentonite, zinc oxide, titanium oxide, etc.), anti-aging agents, pH regulators (triethanolamine, etc.) , Moisturizers (urea, ceramide), preservatives (methyl paraoxybenzoate, propyl parabenzoate, citrate, sodium citrate, boric acid, borax, etc.), thickeners (sodium chondroitin sulfate, etc.), antioxidants (Dibutylhydroxytoluene, etc.), refreshing agent (1 menthol, dl-menthol, d-camphor, dl-camphor, light-loading oil, camphor oil, lactate menthyl, cooling agent, limonene, thymol, wikial oil, eucalyptus oil , Xylitol, etc.) can be used. Preferred additives include pH adjusters, humectants, preservatives, antioxidants and the like.

[0018] The dosage form of the present invention is not particularly limited as long as it can be applied to the skin. Examples include ointments, gels, liniments, lotions, emulsions, powders, suspensions, aerosols. Agents, liquids, and plasters, cataplasms, tapes, and plasters with a base supported on a support. Preferably, ointments, emulsions, suspensions, gels, lotions, It is a liquid, and more preferably an ointment.

[0019] The support is suitably selected according to its dosage form (eg, poultice, tape, etc.). The drug is preferably impermeable or impermeable and flexible. For example, cellulose acetate, Ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate--carbon oxide copolymer, ethylene-butyl acrylate Resin films such as carbon oxide copolymers, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, polybutylene terephthalate; aluminum sheets, woven fabrics, nonwoven fabrics, and laminated sheets of these It is done.

[0020] The amount of the external preparation for skin use of the present invention varies depending on the type of disease, the degree of symptoms, the size of the affected area, etc. Normal once 50 to 500 mg, preferably 100 to 300 mg per affected area The number of times may be one or more suitable times per day.

[0021] The external preparation for skin of the present invention can be produced by a conventional method according to the dosage form. For example, when manufacturing an ointment, water-soluble active ingredients and polymers are dispersed in water to form an aqueous phase, and other active ingredients are dissolved in oil to obtain an oil phase, which is 80 to 90 ° C. The ointment can be produced by combining these at a high temperature and stirring and mixing with a device capable of stirring and mixing under a closed condition such as a vacuum emulsifier, or emulsifying with an in-line high-pressure emulsifier.

[0022] When applied to the skin, the external preparation for skin of the present invention is excellent in the immediate effect and sustainability of kabusaicin, and exhibits an action of improving sensation very quickly and continuously. In particular, improvement of sensation caused by skin irritation, sensation caused by nervousness, for example, mild irritation such as fiber stimulation or cosmetic application ( Effective for improving hypersensitivity skin sensation.

The invention's effect

[0023] When the external preparation for skin of the present invention is applied to the skin, the immediate effect of kabusaicin increases, the feeling of sensation is quickly improved, and the effect can be sustained. Surprisingly, such an effect is largely related to the fact that the lower alcohol is not contained or is made very low even if it is contained. BEST MODE FOR CARRYING OUT THE INVENTION

[0024] Hereinafter, the present invention will be described in detail with reference to examples and the like, but the present invention is not limited thereto. The unit of numerical values in the table is g (gram).

Example

[0025] Example 1

Ointments containing the components shown in Table 1 were produced. In other words, propylene glycol and carboxyvinyl polymer are added to water to form an aqueous phase, the remaining components are mixed to form an oil phase, and then heated to 80 to 90 ° C., mixed, and sealed. An ointment was prepared by stirring and mixing in a vacuum emulsifier capable of stirring and mixing under conditions.

[0026] Examples 2-8

An ointment containing the components shown in Table 1 was produced in the same manner as in Example 1. Diphenhydramine and tocopherol acetate were added to the oil phase.

[0027] Comparative Examples 1 to 14

An ointment was produced in the same manner as in Example 1 using the components shown in Tables 2 and 3. Diphenhydramine, tocopherol acetate and 1 menthol were added to the oil phase, ethanol was added to the formulation after emulsification, and glycerin and d-sorbitol were added to the aqueous phase.

[0028] Test Example 1

Using the ointments of Examples 1 to 8 and Comparative Examples 1 to 14, a sensory test on the thermal sensation of the skin was performed. The skin was dry! Healthy subjects (hypersensitive skin) were the subjects (5 subjects), and the subjects and the comparative preparations were applied to the neck of the subjects. , 5 and 10 minutes later, using the semantic scale used in the SD method, etc., the evaluation was made in 6 steps (minimum 0 points, maximum 5 points) (higher scores for higher thermal feeling). It was. The evaluation items and evaluation methods are as follows. The results are shown in Tables 1-3.

[0029] Evaluation items

Warmth

Evaluation methods

The total score of 6 grades given by 5 subjects is shown in the following categories.

[0030] ©: 13 points or more

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[0034] Test Example 2

Using the ointments of Examples 1 to 3 and Comparative Examples 1 to 4, a sensory test for improving skin irritation was performed. The skin is dry! Healthy subjects (hypersensitive skin) are subjects (3 subjects), and when the subject develops itching, the preparations of Examples and Comparative Examples are applied to the site where itching occurred. We have been asked to evaluate the itching suppression effect immediately after application and 5 minutes after application using a semantic scale used in the SD method, etc. (5 points minimum, 1 point maximum). Evaluation items and evaluation methods are as follows. The results are shown in Table 4.

[0035] Evaluation items

Improvement effect of drunkenness

Evaluation methods

The total score of the five grades given by the three subjects was expressed in the following categories.

○: 11 to 13 points

△: 6 ~ 10 points

X: 3-5 points

[0037] [Table 4]

From the results of Comparative Examples 17 and 12, it was shown that when only one of capsaicin and crotamiton was combined, an immediate effect of warmth could not be obtained. In addition, it was shown that when ethanol was added without adding crotamiton, the force that produced a thermal sensation 10 minutes after application was lacking in immediate effect. Further, Comparative Example 8: L0 From these results, it was shown that even when capsaicin and crotamiton were used in combination, immediate thermal sensation was not obtained when ethanol was contained in an amount of 5% by weight or more. On the other hand, in Examples 1 to 8 in which Kabusaicin and crotamiton were used in combination and the ethanol content was less than 5% by weight, it was shown that an immediate and lasting thermal feeling was obtained.

[0039] Further, from Table 4, in Comparative Examples 1 to 4, a slight antipruritic effect was observed with lidocaine, but the immediate effect of the antipruritic effect was insufficient, so that of kabusaicin and crotamiton! In the case where only one of them was added, it was shown that an immediate effect of improving sensation could not be obtained. In contrast, in Examples 1 to 3, capsaicin and crotamiton are used in combination, so that the effect of improving wrinkle is demonstrated immediately after application, and the effect of improving wrinkle is excellent. Immediate effect was seen.

[0040] By comparing Tables 2 and 4, it was confirmed that the thermal sensation and the improvement effect of sensation in Examples 1-3 and Comparative Examples 1-4 were correlated. Furthermore, from Table 4 which is the result of the improvement test of itchiness using humans with healthy skin properties in Test Example 2, the preparations of the examples are effective in improving itchiness, especially sensation of hypersensitive skin. It was confirmed to speak excellently.

[0041] Formulation example

According to the composition described in Table 5, ointments, emulsions, solutions, aerosols and gels were prepared by conventional methods.

[0042] [Table 5]

Industrial applicability

The external preparation for skin of the present invention is useful in the field of external preparation for skin intended to quickly suppress itchiness, particularly hypersensitivity itchiness.

Claims

The scope of the claims

[1] A skin external preparation containing kabusaicins and crotamiton, and containing 0 to 5% by weight of a lower alcohol.

[2] The topical skin preparation according to claim 1, wherein the content of the lower alcohol is 0 to 3% by weight.

[3] The external preparation for skin according to claim 1 or 2, which has a lower alcohol content of not less than 1% and less than 1% by weight.

[4] The skin external preparation according to any one of claims 1 to 3, comprising 0.005 to 0.1% by weight of capsaicin and 3 to 20% by weight of crotamiton.

[5] The external preparation for skin according to any one of claims 1 to 4, further comprising water.

6. The external preparation for skin according to any one of claims 1 to 5, further comprising at least one selected from the group consisting of phospholipids and oil at room temperature.

[7] The external preparation for skin according to any one of claims 1 to 6, which is an ointment.

[8] The external preparation for skin according to any one of [1] to [7], wherein the preparation is for improving sensation.

[9] The external preparation for skin according to any one of claims 1 to 8, which is used for improving the sensation of hypersensitive skin.