JPH10182427A - Composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a composition for external use, giving a high antiphlogistic- sedative effect and reduced in skin irritation. SOLUTION: This composition for external use comprises (A) at least one kind of antiphlogistic-sedative medicine selected from among anthranilic acid, phenylacetic acid, indole, propionic acid, pyrazolone, benzothiasin and sulfonamide antiphlogistic-sedative medicines, and (B) at least one kind of local narcotic selected from among oxypolyethoxydodecane, creosote, scopolia extract and belladonna extract.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a composition for external use which has a high anti-inflammatory and analgesic effect and has reduced skin irritation.

[0002]

2. Description of the Related Art Recently, inflammation such as indomethacin and the like, which is more effective than salicylic acid-based drugs which have been conventionally used as a remedy for pain caused by bruises, sprains, muscle fatigue, and pain associated with stiff shoulders. External preparations containing analgesics are used. These anti-inflammatory analgesics are useful in reducing the side effects of systemic action by local administration.

[0003] These external preparations include fatty acid esters, alcohols, terpenes and the like (JP-A-2-142727, JP-A-2-1967) in order to enhance the anti-inflammatory and analgesic effect.
No. 18), a method of increasing the percutaneous absorption of an anti-inflammatory drug to a certain level or more by a percutaneous absorption enhancer.

[0004]

However, when an anti-inflammatory analgesic is used as an external preparation, certain anti-inflammatory analgesics, particularly indomethacin, which is an indole-type anti-inflammatory analgesic, cause unique skin irritation by itself. I found something to do.

[0005] In order to reduce general skin irritation, glycyrrhetinic acid and its salts are usually added, but they are not sufficient to reduce the unique skin irritation caused by anti-inflammatory analgesics. Was.

An object of the present invention is to provide a topical anti-inflammatory analgesic agent which reduces the unique skin irritation caused by an anti-inflammatory analgesic and has a sufficient anti-inflammatory analgesic effect.

[0007]

Means for Solving the Problems As a result of investigation, the present inventors have found that when a topical anesthetic is added to an externally-applied composition containing an anti-inflammatory analgesic, skin irritation is reduced without reducing the anti-inflammatory analgesic effect. The present invention has been completed.

That is, the present invention relates to (A) anthranilic acid type, phenylacetic acid type, indole type, propionic acid type,
At least one anti-inflammatory analgesic selected from pyrazolones, benzothiazines and sulfonamides, and (B) at least one local anesthetic selected from oxypolyethoxide dodecane, creosote, funnel extract and belladonna extract, The composition for external use consists of

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The anti-inflammatory analgesics of the present invention include anthranilic acids (such as fenamic acid), phenylacetic acids (such as diclofenac and fenbufen), indole compounds (such as indomethacin) and propionic acid compounds (ketoprofen and flurburic). Profession), pyrazolones (such as phenylbutazone), benzothiazines (such as piroxicam), and sulfonamides (such as NimeSlide). In particular, the effects of the present invention are exhibited in reducing skin irritation that occurs when indomethacin is used.

In the present invention, local anesthetics include oxypolyethoxide decane, creosote, funnel extract and belladonna extract. The extract can be produced by a conventional method, and a dry extract can also be used.

The compounding amount of the antiphlogistic analgesic in the present invention is preferably 0.1 to 5% by weight in the composition (in the case of an aerosol, in a stock solution). If the amount of the antiphlogistic analgesic is less than 0.1% by weight, the antiphlogistic analgesic effect cannot be expected, and if it exceeds 5% by weight, the unique skin irritation of the antiphlogistic analgesic may remain. .

The amount of the local anesthetic used in the composition of the present invention is 0.15 to 3% by weight for oxypolyethoxydodecane, 0.025 to 0.5% by weight for creosote, and The equivalent amount is preferably 0.5 to 10% by weight, and the belladonna extract is preferably 0.05 to 1% by weight. If the compounding amount is small, the reduction of skin irritation peculiar to anti-inflammatory analgesics is not enough,
This is because if the compounding is excessive, the formulation design becomes difficult such that the formulation balance is lost and phase separation occurs.

The mixing ratio of the antiphlogistic analgesic to the local anesthetic is 0.05 to 30 parts by weight of oxypolyethoxydodecane and 0.0 part by weight of creosote per 1 part by weight of the antiphlogistic analgesic.
1 to 5 parts by weight, funnel extract is 0.25 in terms of crude drug equivalent
To 100 parts by weight, and the amount of belladonna extract is preferably 0.025 to 10 parts by weight in terms of a crude drug. This is because skin irritation is reduced by the balance of the components.

The composition for external use of the present invention preferably has a pH in the range of 3.5 to 7.0, more preferably 4.0 to 6.5, from the viewpoint of reducing skin irritation and the stability of the compounded drug.

The composition for external use of the present invention may be in the form usually used for external preparations. Preferred examples include liquids, creams, ointments, gels, patches, aerosols and the like. And can be produced by a conventional method.

The external composition of the present invention may contain water, lower alcohols (methanol, ethanol, denatured ethanol, isopropyl alcohol, etc.) and solubilizers (diisopropyl adipate, isopropyl myristate, 1,3-butylene, etc.) as necessary. Glycol, propylene glycol, polyethylene glycol, glycerin, medium-chain fatty acid triglycerides, fatty acid esters, various vegetable oils, various animal oils, polyhydric alcohol fatty acid esters, alkyl glyceryl ethers, hydrocarbons, lactic acid, sodium hydroxide, etc.), surfactants (Sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fat Ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, poly Oxyethylene beeswax derivatives, polyoxyethylene lanolin derivatives, polyoxyethylene alkylamides, polyoxyethylene alkylamines, lecithin derivatives, polymer emulsifiers, etc., emulsion stabilizers (higher alcohols, etc.), gelling agents (various polymer compounds, etc.) ), Adhesives, and other commonly used base components for obtaining the desired dosage form. Depending on the purpose of use, vasodilators (carpronium chloride, nicotine Benzyl, assembly extract, Panax ginseng extract, Vitamin E acetate, Pepper tincture, etc., corticosteroids (hydrocortisone acetate, hydrocortisone butyrate propionate, etc.), keratolytic agents (urea, salicylic acid, etc.), humectants (sodium hyaluronate, chondroitin) Sulfuric acid, cordyceps extract, saffron extract, etc.), fungicides (chlorhexidine gluconate, isopropylmethylphenol, quaternary ammonium salts, hinokitiol, etc.), antioxidants (dibutylhydroxytoluene, isopropylgallate, etc.), fresheners ( Menthol, peppermint oil, camphor and the like), fragrances, pigments and the like can be blended as long as the effects of the present invention are not impaired.

[0017]

Industrial Applicability According to the present invention, it has become possible to provide a composition for external use containing an anti-inflammatory analgesic, which is highly effective and does not cause the unique skin irritation of the anti-inflammatory analgesic.

[0018]

The present invention will now be described more specifically with reference to examples and test examples.

Example 1 (External solution) (Components) (Blending amount W / v%) Indomethacin 0.75 Roth extract 5.0 Diisopropyl adipate 5.0 Isopropyl myristate 3.0 Glycerin 2.0 Polyoxyethylene alkyl Ether 3.0 Denatured ethanol 45.0 Purified water Total 100 ml The above components were stirred and uniformly dissolved to obtain a solution for external use.

Example 2 (External Cream) (Components) (Blending amount W%) Indomethacin 1.0 Roth extract 5.0 Medium-chain fatty acid triglyceride 20.0 Diisopropyl adipate 5.0 Propylene glycol 12.0 Polyoxyethylene Sorbitan monostearate 6.0 Sorbitan monostearate 3.0 Glycerin monostearate 8.0 Purified water Total 100 g With the above formulation, a cream for external use was obtained by a usual method of manufacturing an emulsifier.

Example 3 (gel) (Components) (Blending amount W%) Indomethacin 0.5 Roth extract 3.0 Polyethylene glycol monostearate 5.0 Diisopropyl adipate 3.0 1,3-butylene glycol 8. 0 Polyvinylpyrrolidone 0.5 Carboxyvinyl polymer 1.5 Diisopropanolamine Appropriate amount Denatured ethanol 30.0 Purified water Total 100 g Using the above formulation, a gel for external use was produced by a usual method for producing a gel.

Example 4 (Patch) (Components) (Blending amount W%) Indomethacin 0.5 Roth extract 5.0 Polyoxyethylene sorbitan monooleate 1.0 Propylene glycol 5.0 Polyacrylic acid 7.0 Polyacrylic acid Sodium 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100 g An external patch was produced by the above-mentioned formulation by a conventional method of patch production.

Example 5 (Aerosol) (Components) (Blending amount W%) Indomethacin 0.4 Roth extract 3.0 Polyoxyethylene sorbitan tristearate 1.2 Diisopropyl adipate 2.0 1,3-butylene glycol 1.2 Ethanol 20.0 Purified water 12.2 Isopentane 10.0 Liquefied petroleum gas 3.0 Dimethyl ether 47.0 An aerosol for external use was manufactured according to the above formulation by a conventional method for manufacturing an aerosol.

Example 6 (Patch) (Components) (Blending amount W%) Ketoprofen 0.5 Roth extract 3.0 Polyoxyethylene sorbitan monooleate 1.0 Propylene glycol 5.0 Polyacrylic acid 7.0 Polyacrylic acid Sodium 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100 g With the above formulation, an external patch was produced by a conventional method of patch production.

Example 7 (Patch) (Components) (Blending amount W%) Flurbiprofen 0.5 Roth extract 3.0 Polyoxyethylene sorbitan monooleate 1.0 Propylene glycol 5.0 Polyacrylic acid 7.0 Sodium polyacrylate 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Suitable amount Purified water Total 100 g For the above components, an external patch was manufactured according to the patch production method.

Example 8 (Patch) (Components) (Blending amount W%) Fenbufen 0.5 Roth extract 3.0 Polyoxyethylene sorbitan monooleate 1.0 Propylene glycol 5.0 Polyacrylic acid 7.0 Polyacrylic acid Sodium 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100 g With the above formulation, an external patch was produced by a conventional method of patch production.

Example 9 (Patch) (Ingredient) (Blending amount W%) Piroxicam 0.5 Roth extract 3.0 Polyoxyethylene sorbitan monooleate 1.0 Propylene glycol 5.0 Polyacrylic acid 7.0 Polyacrylic acid Sodium 6.0 Silicic anhydride 1.0 Tartaric acid 0.5 Aluminum glycinate Suitable amount Aluminum hydroxide Appropriate amount Purified water Total 100 g With the above formulation, an external patch was produced by a conventional method of patch production.

Example 10 (External solution) (Components) (Blending amount W / v%) Indomethacin 0.75 Oxypolyethoxydodecane 5.0 Diisopropyl adipate 5.0 Isopropyl myristate 3.0 Glycerin 2.0 Polyoxy Ethylene alkyl ether 3.0 Denatured ethanol 45.0 Purified water Total 100 ml The above components were stirred and uniformly dissolved to obtain a solution for external use.

Example 11 (External solution) (Components) (Blending amount W / v%) Indomethacin 0.75 Creosote 5.0 Diisopropyl adipate 5.0 Isopropyl myristate 3.0 Glycerin 2.0 Polyoxyethylene alkyl Ether 3.0 Denatured ethanol 45.0 Purified water Total 100 ml The above components were stirred and uniformly dissolved to obtain a solution for external use.

Example 12 (External Solution) (Components) (Blending amount W / v%) Indomethacin 0.75 Belladonna extract 5.0 Diisopropyl adipate 5.0 Isopropyl myristate 3.0 Glycerin 2.0 Polyoxyethylene alkyl Ether 3.0 Denatured ethanol 45.0 Purified water Total 100 ml The above components were stirred and uniformly dissolved to obtain a solution for external use.

Comparative Example 1 (External solution) A comparative solution was obtained in the same manner as in Example 1, except that the funnel extract was omitted from the formulation of Example 1 and the whole amount was prepared with purified water.

Comparative Example 2 (External solution) The funnel extract of Example 1 was prepared using glycyrrhetinic acid 0.1 W / V
%, And a liquid formulation for comparison was obtained in the same manner as in Example 1 except that the formulation was changed to%.

Comparative Example 3 (External solution) A comparative solution was obtained in the same manner as in Example 1 except that indomethacin and the funnel extract were removed from Example 1 and the total amount was adjusted with purified water.

Test Example 1 In a skin irritation test, 6 healthy males aged 25 to 35 years
Went by name. Each one of the liquid preparations of Example 1 and Comparative Examples 1 to 3
0 μl was applied to a patch test adhesive bandage (mini size: manufactured by Torii Pharmaceutical Co., Ltd .; hereinafter, referred to as “patch adhesive”), and was adhered to the back of the subject for 24 hours. At this time, a patch bond to which no drug was applied as a blank was similarly closed and applied for 24 hours. Twenty-four hours later, the patch bond was peeled off, the stimulus was visually judged, and the value immediately after was determined. After 1 hour, 3 hours, 5 hours, and 24 hours, the same determination was made. The visual judgment was 0 for no reaction, 1 for faint erythema, and 2 for clear erythema, and calculated the average value of the scores of the six subjects at each time. The results are shown in Table 1.

[0035]

[Table 1]

From the results shown in Table 1, Example 1 clearly reduced the skin irritation of indomethacin. In addition, even in comparison with Comparative Example 2 in which glycyrrhetinic acid, which is widely used as a skin irritation inhibitor, was added, Example 1 was found to have a high effect of suppressing the unique skin irritation of indomethacin.

Test Example 2 An efficacy questionnaire test was performed on the preparations obtained in Example 1 and Comparative Example 1 for 10 patients complaining of stiff shoulders. Dosage and administration is limited to four times a day.
The patient was instructed to apply an appropriate amount to the affected area several times a day. At the end of administration, the degree of improvement in stiff shoulder symptoms as compared to the start of administration was “marked improvement”, “moderate improvement”, “mild improvement”, “unchanged”,
The evaluation was made on a five-point scale of “deterioration”. The results are shown in Table 2.

[0038]

[Table 2]

Claims (7)

[Claims] (1) at least one anti-inflammatory analgesic selected from (A) anthranilic acid, phenylacetic acid, indole, propionic acid, pyrazolone, benzothiazine and sulfonamide; and (B) oxy An external composition comprising at least one local anesthetic selected from polyethoxydodecane, creosote, funnel extract and belladonna extract. 2. The topical composition according to claim 1, wherein the anti-inflammatory drug is indomethacin. 3. The composition for external use according to claim 1, wherein the antiphlogistic analgesic is 0.1 to 5% by weight of the whole preparation, and the blending amount of the local anesthetic is 0.001 to 10% by weight. 4. The composition according to claim 1, wherein the amount of oxypolyethoxide dodecane is 0.05 to 30 parts by weight based on 1 part by weight of the antiphlogistic analgesic.
3. The composition for external use according to any one of 3. 5. The topical composition according to claim 1, wherein the amount of creosote is 0.01 to 5 parts by weight based on 1 part by weight of the antiphlogistic analgesic. 6. A fungicidal analgesic, 1 part by weight, and 0.25 to 100 parts by weight of a fungal extract in terms of a crude drug.
The composition for external use according to any one of claims 1 to 3. 7. The composition for external use according to any one of claims 1 to 3, wherein the amount of the belladonna extract is 0.025 to 10 parts by weight in terms of a crude drug per 1 part by weight of the anti-inflammatory analgesic.