JPH07304690A - Keratin solubilizer, percutaneous absorption accelerator and external skin preparation - Google Patents

Abstract

PURPOSE:To provide a keratin solubilizer which contains an N-atom-containing semi-polar surfactant and a specific compound, solubilizes the skin keratin layer to promote the percutaneous absorption of drugs and shows high safety and excellent application feeling. CONSTITUTION:The objective solubilizer comprises (A) an N-atom-containing semi-polar surfactant (suitably dimethyllaurylamine oxide, dihydroxyethyllaurylamine oxide or the like) and (B) a compound selected from cyclic or chain monoterpenoid alcohols (suitably 4-isopropenyl-1- cyclohexenecarbinol, 2,6-dimethyl-2,6-octadien-8-ol or the like) and is adjusted in pH to 7.5-11, preferably 8-10. The weight ratio of A/B is preferably 95/5-10/90. These components A and B are usually dissolved or suspended in an aqueous medium and the concentration is preferably 0.0001-5wt.%.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a keratolytic agent, a percutaneous absorption enhancer containing the keratolytic agent as an active ingredient, and a skin external preparation containing the percutaneous absorption enhancer. For more details,
The present invention originally protects the invasion of foreign matter from outside the body,
A keratolytic agent, which promotes percutaneous absorption, which can dissolve the stratum corneum on the surface of the skin that acts as a barrier to prevent leakage of body fluids from the body, and promote absorption of drugs from the skin. Agent and external preparation for skin.

[0002]

2. Description of the Related Art Conventionally, the medicinal ingredients have been administered by oral administration, subcutaneous, intramuscular, or intravenous injection,
It is administered to the mucous membrane of the rectum or the oral cavity, and oral administration is common among them. However, in the case of oral administration, it is difficult to control the blood concentration because a large amount of the medicinal component is absorbed in a short period of time, and the absorbed medicinal component loses its efficacy due to metabolism in the liver during the first circulation. In addition, there are many drawbacks such that the administration of a stimulative medicinal component is likely to cause side effects such as gastrointestinal injury by its administration. In recent years, in order to improve such side effects and drawbacks, external preparations for percutaneous administration have been developed. However, even in such an external preparation, the transdermal absorbability of the medicinal component is often not obtained, and it is difficult to say that the objective has been sufficiently achieved. That is, the surface of the skin, which is called the stratum corneum of the skin, originally has a physiological function as a barrier that prevents the invasion of foreign substances from the outside of the body and prevents leakage of body fluids from the body. However, there is a problem in that sufficient transdermal absorbability cannot be obtained by simply blending the medicinal component into the base that has been commonly used in.

In order to improve such a problem, various keratolytic compositions and percutaneous absorption enhancers containing the keratolytic composition as a component have been proposed in recent years, and can be incorporated into the base of an external preparation. This is commonly done. As such a percutaneous absorption enhancer, for example, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, methyl decyl sulfoxide, etc. are known, but these are percutaneous absorption promoting effect, safety, in terms of usability. It wasn't enough.

On the other hand, Japanese Patent Laid-Open No. 63-77825 describes that a combination of cineol, a nonionic surfactant, water and a drug enhances the safety and skin permeability of the drug. JP-A-63-208536 discloses a technique in which one or more anionic surfactants and one or more surfactants having a nitrogen atom in the molecule other than the anionic surfactant are used as active ingredients. JP-A-5-148158 discloses that the barrier of transdermal absorption is not only the stratum corneum but also the living epidermal cell layer. Found that N-lauroyl sarcosine and β-carotene and / or allantolactone are effective for a living epidermal cell layer, and it has been proposed to solve the above problems. That. However, even with this, sufficient transdermal absorbability has not been obtained yet.

Japanese Unexamined Patent Publication No. 61-85496 discloses the use of cineol and lauric acid diethanolamide as a cleaning agent for fibers, plastics, metals and the like, and Japanese Unexamined Patent Publication No. 1-144495 discloses the same. Disclosed is a detergent comprising a surfactant and a terpene, which has improved rinsability for clothing, tableware, housing, hair, human body and the like, and JP-A-2-182793 discloses an alkyl glycoside,
Disclosed are highly safe detergents for clothes, kitchen, home, hair and body which are composed of anionic surfactants, terpenes and 3-isothiazolone derivatives, and describe the transdermal absorbability of such compounds. Is not accepted at all.

[0006]

Therefore, the present invention solves the above problems and is excellent in the effect of promoting transdermal absorption of medicinal components, and is satisfactory in terms of safety and usability. It is an object of the present invention to provide a keratolytic agent and a percutaneous absorption enhancer which do not require a mechanism, and a skin external preparation containing the percutaneous absorption enhancer.

[0007]

That is, the present invention is selected from the group consisting of (1) at least one semipolar surfactant having a nitrogen atom in the molecule and (2) a cyclic or chain monoterpenoid alcohol. There is provided a keratolytic agent and a transdermal absorption enhancer having a pH in the range of 7.5 to 11 and an external skin preparation containing the medicinal component and the above-mentioned transdermal absorption enhancer component, which contains at least one of the above compounds as an active ingredient. To be done.

The structure of the present invention will be described in detail below. Preferred examples of the semipolar surfactant having a nitrogen atom in the molecule used in the present invention include dimethyllaurylamine oxide, dimethylmyristylcetylamine oxide, dimethylstearylamine oxide, dihydroxylethyllaurylamine oxide, dihydroxylethyl hardened beef tallow. Examples thereof include alkyl amine oxide, dimethyl lauryl polyoxyethylene amine oxide, and dimethyl palm oil fatty acid amine oxide. In addition, these semipolar surfactants can be used alone or as an arbitrary mixture of two or more kinds.

Preferred examples of cyclic and chain monoterpenoid alcohols include 4-isopropenyl-1-cyclohexenecarbinol, 1-methyl-4-isopropenyl-6-cyclohexen-2-ol and 1-methyl-.
4-isopropenyl-2-cyclohexanol, 1-methyl-4-isopropylidene-3-cyclohexanol, 1-methyl-4-isopropenyl-3-cyclohexanol, 1-methyl-4-isopropyl-1-cyclohexene- 3-ol, 1-methyl-4-isopropyl-1-cyclohexene-8-ol, 1-methyl-4-
Isopropenyl-1-cyclohexanol, 1-methyl-4-isopropylidene-1-cyclohexanol, 1
-Methyl-4-isopropyl-1-cyclohexene-4
-Ol, 1-methyl-4-isopropyl-3-cyclohexen-1-ol, 1-methyl-4-isopropylcyclohexane-8-ol, 1-methyl-4-isopropyl-3-cyclohexanol, 1-methyl-4 -Isopropyl-2-cyclohexanol, 1-methyl-4
-Isopropyl-1,8-cyclohexanediol, 1
-Methyl-4-isopropyl-1,4-cyclohexanediol, 2,6-dimethyl-1,6-octadiene-
8-ol and its geometric isomer, 2,6-dimethyl-
2,6-Octadien-8-ol and geometric isomers thereof, 3,7-dimethyl-1,6-octadiene-3-ol, 3,7-dimethyl-1,7-octadiene-3-
All, 2,6-dimethyl-1-octen-8-ol, 2,6-dimethyl-2-octen-8-ol,
2,6-dimethyl-5-oxymethyl-2,6-heptadiene, 2-isopropenyl-5-methyl-4-hexen-1-ol and the like can be mentioned. These monoterpenoid alcohols can be used alone or as an arbitrary mixture of two or more kinds.

The weight ratio of the semipolar surfactant having a nitrogen atom in the molecule to at least one compound selected from the group consisting of cyclic and chain monoterpenoid alcohols is 99.9: 0.1. 0.1: 99.9, preferably 95: 5 to 10:90.

The keratolytic agent of the present invention, a percutaneous absorption enhancer containing the keratolytic agent as an active ingredient, and a skin external preparation containing the percutaneous absorption enhancer having the above-mentioned nitrogen atom in a semipolar surfactant The pH of the solution in which the agent and at least one compound selected from the group consisting of cyclic and chain monoterpenoid alcohols are dissolved is 7.5 to 11, preferably 8 to
It is 10. If the pH is lower than 7.5, there is no keratolytic effect and 1
When it exceeds 1, the skin is adversely affected.

In the present invention, a semipolar surfactant having a nitrogen atom in the molecule and at least one compound selected from the group consisting of cyclic and chain monoterpenoid alcohols are dissolved (or suspended) in an aqueous medium. However, the concentration is preferably 0.00001 to 50% by weight, and more preferably 0.0001 to 5% by weight. If this concentration is less than 0.00001% by weight, the keratolyticity and percutaneous absorbability are low, and if it exceeds 50% by weight, the effect reaches the ceiling.

The following can be exemplified as the medicinal component which can enhance the medicinal effect by the percutaneous absorption enhancer according to the present invention. That is, muscle relaxants such as bridinol mesylate, acetaminophen, aminophylline, amobarbital sodium, antipyrine, ambicillin, isoniazid, epinephrine, amitributyrin hydrochloride, etilefrine hydrochloride, ephedrine hydrochloride, oxytetracycline hydrochloride, frutosine fluorouracil, phenemitine potassium, Prednisolone, steroidal anti-inflammatory agents such as dexamethasone, indomethacin, acetylcholine chloride, flufenamic acid, non-steroidal anti-inflammatory agents such as mefenamic acid, chlorpheniramine, diphenhydramine,
Antihistamines such as promethazine, sulfa drugs such as sulfamonomethoxine and sulfamethizole, antibiotics such as penicillin, cephalosporins, erythromycin, tetracycline, chloramphenicol and streptomycin, antifungal agents such as naphthiomate and clotrimazole. , 5-fluorouracil, cyclophosphamide,
Busulfan, antineoplastic agents such as actinomycin, morphine, codeine, nalorphine, analgesics such as ventazosin, aspirin, acetanilide, aminopyrine, prostaglandins, barbital, thiovental and other hypnotics and sedatives, chlorbromycin, Antipsychotics such as reserbine and chlordiazeboxoxide, antiparkinsonian agents such as chlorzoxone and levodova, cardiotonic agents such as dichitoxin and digoxin, antiarrhythmic agents such as procainamide hydrochloride and propranol hydrochloride, and anti-arrhythmic agents such as dibilidamol and amyl nitrite. Antiangiogenic agents such as angina pectoris, diazoxide, minoxidil, reserbine, guanethidine nitrate,
UV inhibitors such as paraaminobenzoate ester, hydroquinone, vitamin C esters, melanin production inhibitors such as parahydroxycinnamate, psoriasis puwa therapeutic agents such as 8-methoxypsoralen, vitamins such as vitamin A, vitamin E and vitamin C Examples thereof include hormonal agents such as insulin, estradiol and methyltestosterone, diagnostic agents, patch test allergens, insect repellents, insecticides, moisturizers, keratin softeners and hair dyes.

These medicinal components are rapidly absorbed into the skin by being mixed with the percutaneous absorption enhancer of the present invention and applied to the skin. If it is a medicinal component intended for local action, it penetrates deeply into the skin and exhibits excellent effects.
If it is a medicinal component intended for systemic action, the medicinal component is transferred into the blood, so that the same excellent effect is exhibited. Not only humans but also warm-blooded animals such as domestic animals, dogs and cats can be used.

The blending amount of the medicinal ingredient may be an amount sufficient to exert the medicinal effect, and it varies depending on the kind of medicinal ingredient, the weight of the patient, the symptom, etc., but preferably 1 part by weight of the medicinal ingredient. A skin absorption accelerator is added in an amount of 0.001 to 50 parts by weight, more preferably 0.01 to 5 parts by weight.

The above-mentioned percutaneous absorption enhancer may be used as it is by mixing the medicinal components as appropriate, but in consideration of the feeling of use and the ease of application, the constituents are generally suitable for external skin application. It is preferably used by mixing in a base such as a preparation, for example, cream preparation, ointment preparation, gel preparation, lotion preparation, emulsion, adhesive tape.

The blending amount of each constituent in the external preparation for skin is also different depending on the kind of the medicinal component, but the preferable blending range is generally as follows. That is, the total amount of the semipolar surfactant having a nitrogen atom in the molecule and at least one compound selected from the group consisting of cyclic and chain monoterpenoid alcohols in the external preparation is 0.0
0001 to 50% by weight, preferably 0.0001 to 5% by weight, medicinal component 0.001 to 10% by weight, preferably
It is 0.005 to 5% by weight.

In the external preparation for promoting percutaneous absorption containing a medicinal component according to the present invention, in addition to the above-mentioned essential components, optional components generally contained in pharmaceuticals, quasi drugs, cosmetics and the like are blended. can do. Such optional components include polyhydric alcohols, oils, waxes, acids, alkalis, cationic surfactants, nonionic surfactants, anionic surfactants, amphoteric surfactants, powders, pigments, dyes, antiseptics and antioxidants. Agents, ultraviolet absorbers, chelating agents, water-soluble polymers, montmorillonite, alcohols, solvents, fragrances and the like.

[0019]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.

Example 1-1 and Comparative Example 1-1 Lauryl dimethyl polyoxyethylene amine oxide as a semipolar surfactant having a nitrogen atom in the molecule shown in Table 1-1, and 1 as a cyclic and chain monoterpenoid alcohol. -Methyl-4-isopropyl-1-cyclohexen-8-ol in an aqueous solution in combination with each concentration of 0.05% by weight, pH 6.9, 7.4, 7.5, 7.6, 8.
It was adjusted to 4, 11.0 and 12.0, and its keratolytic property was tested by the following method.

Performance Evaluation Test 1 (Keratolytic Solubility) The keratin solubility was evaluated using the stratum corneum collected from guinea pigs. The stratum corneum was collected by the following method.
Remove the hair from the back of the guinea pig with hair clippers and depilatory,
After the erythema subsided, the animals were sacrificed, and the entire skin layer was peeled off with scissors. After removing the subcutaneous fat on the back side of the skin with scissors,
After immersing in warm water of 60 ° C. for 1 minute and cooling with ice, the epidermis was peeled off neatly with tweezers and a spatula. The epidermis was treated with 0.1% trypsin in phosphate buffer (pH 7.6) at 37 ° C for 1 hour to digest live cells, washed with water and dried to obtain a stratum corneum. The keratolytic test was performed by the following method. Cut the stratum corneum into 1 × 1 cm squares, immerse in 10 ml of the test solution, and 32 ℃
The state of the stratum corneum was observed over time in a constant temperature bath.

The evaluation results are represented by the following symbols. -: No change in shape of stratum corneum +1: Slight collapse of stratum corneum +2: Significant collapse of stratum corneum +3: Almost collapse of stratum corneum c: No existence of stratum corneum

The test effects are shown in Table 1-1. As is clear from the results shown in Table 1-1, remarkable keratolytic properties were observed in the pH range of 7.5 to 11.

Table 1-1 (Example 1-1 and Comparative Example 1-1) ─────────────────────────────── ─── pH daily are 1 3 8 15 ───────────────────────────────── Comparative example 6.9 - - − − 〃 7.4 +1 +2 +3 +3 ───────────────────────────────── Example 7.5 +2 +3 +3 c 〃 7.6 +2 +3 cc 〃 8.4 cc cc 〃 11.0 +2 +3 cc ──────────────────────── ───────── Comparative example 12.0 +1 +2 +2 +2 ──────────────────────────────── ─

Example 1-2 and Comparative Example 1-2 Lauryl dimethyl polyoxyethylene amine oxide as a semipolar surfactant having a nitrogen atom in the molecule shown in Table 1-2, and 1 as a cyclic and chain monoterpenoid alcohol. -Methyl-4-isopropylcyclohexane-8
-For an aqueous solution combined with all, each concentration is 0.05% by weight, pH is 6.9, 7.4, 7.5, 7.6, 8.4,
Adjusted to 11.0 and 12.0 and tested its keratolyticity by the method described above.

The results are shown in Table 1-2. As is clear from the results of Table 1-2, it is recognized that the keratolyticity is good in the pH range of 7.5 to 11.

Table 1-2 (Example 1-2 and Comparative Example 1-2) ─────────────────────────────── ─── pH daily are 1 3 8 15 ───────────────────────────────── Comparative example 6.9 - - − − 〃 7.4 +1 +1 +2 +3 ────────────────────────────────── Example 7.5 +2 +2 +3 +3 〃 7.6 +2 +2 +3 +3 〃 8.4 +2 +3 cc 〃 11.0 +2 +2 +3 c ──────────────────────── ───────── Comparative Example 12.0 − +1 +1 +2 ──────────────────────────────── ─

Examples 1-3 and Comparative Examples 1-3 Lauryl dimethyl polyoxyethylene amine oxide as a semipolar surfactant having a nitrogen atom in the molecule shown in Table 1-3 and 2 as a cyclic and chain monoterpenoid alcohol. , 6-dimethyl-1,6-octadien-8-ol was used in combination with an aqueous solution in which each concentration was 0.0
5% by weight, pH was adjusted to 6.9, 7.4, 7.5, 7.6, 8.4, 11.0 and 12.0 and its keratolyticity was tested by the above method.

The results are shown in Table 1-3. As is clear from the results of Table 1-3, it is recognized that the keratolyticity is good in the pH range of 7.5 to 11.

Table 1-3 (Examples 1-3 and Comparative Examples 1-3) ─────────────────────────────── ─── pH daily are 1 3 8 15 ───────────────────────────────── Comparative example 6.9 - - − − 〃 7.4 +1 +1 +2 +2 ────────────────────────────────── Example 7.5 +2 +2 +2 +3 〃 7.6 +2 +2 +3 +3 〃 8.4 +3 +3 +3 +3 〃 11.0 +1 +2 +3 +3 ───────────────────────── ───────── Comparative Example 12.0 +1 +1 +1 +1 +2 ───────────────────────────────── ─

Comparative Example 1-4 An aqueous solution combining lauryldimethylamine oxide as a semipolar surfactant having a nitrogen atom in the molecule and sodium lauryl sulfate or sodium lauryl polyoxyethylene sulfate as an anionic surfactant,
Each concentration was adjusted to 0.05% by weight and its keratolytic ability was tested. The pH was adjusted to 8.4.

The results are shown in Table 1-4. Both combinations were shown to be keratolytic, but not as good as Example 1-1.

Table 1-4 (Comparative Example 1-4) ───────────────────────────────── semi-polar anionic 1 3 8 15 surfactant surfactant having intramolecular daily are ────────────────────────────── ─ ─ lauryl dimethyl lauryl sulfate +1 +2 +3 c amine oxide sodium 〃 lauryl poly +1 +1 +2 +3 sodium oxyethylene sulfate ────────────────────────── ───────

Specific examples of the keratolytic agent according to the present invention will be described below based on more specific prescription examples. In addition, the compounding amount in the following examples is shown by weight%. Example 1-4 Lauryl dimethyl polyoxyethylene amine oxide 0.15 1-methyl-4-isopropyl-1-cyclohexene-8-ol 0.08 polyoxyethylene (40 mol) Effect castor oil 2.0 glycerin 15.0 Preservative Suitable amount Perfume Suitable amount Water Balance pH is adjusted with sodium bicarbonate and sodium carbonate 8.
Adjusted to 4.

Example 1-5 Lauryl dimethylamine oxide 0.15 1-Methyl-4-isopropyl-1-cyclohexene-8-ol 0.07 Propylene glycol 5.0 Glycerin 7.0 Hyaluronic acid 0.02 Ethyl alcohol 3 0.0 Preservative Suitable amount Chelating agent Suitable amount Perfume Suitable amount Water Balance pH is calculated using sodium hydrogen carbonate and sodium carbonate 8.
Adjusted to 4.

Example 1-6 Lauryl dimethylamine oxide 0.12 2,6-dimethyl-1,6-octadiene-8-ol 0.06 glycerin 5.0 polyoxyethylene glycol (molecular weight 400) 4.0 polyacryl Sodium acid 1.6 Ethyl alcohol 5.0 Preservatives Suitable amount Chelating agent Suitable amount Perfume Suitable amount Water Balance pH is sodium bicarbonate and sodium carbonate 8.
Adjusted to 4.

Next, an example of the transdermal absorption agent according to the present invention will be described. Example 2-1 (Transdermal Absorbent) 0.175 g of lauryl dimethyl polyoxyethylene amine oxide and 0.175 g of 1-methyl-4-isopropyl-1-cyclohexen-8-ol were added to purified water 125
A percutaneous absorbent having a pH adjusted to 8.4 was obtained.
0.7 g of a purified aqueous solution containing 2.1 g of acetylcholine chloride was added to this percutaneous absorption agent and uniformly mixed to obtain a test solution.

Comparative Example 2-1 (Transdermal Absorbent) 0.175 g of lauryldimethylpolyoxyethyleneamine oxide was dissolved in 125 g of purified water to obtain a transdermal absorbent having a pH adjusted to 8.4. 0.7 g of a purified aqueous solution containing 2.1 g of acetylcholine chloride was added to this percutaneous absorption agent and uniformly mixed to obtain a test solution.

The transdermal absorbability of the transdermal absorbents obtained in Example 2-1 and Comparative Example 2-1 was tested by the following method. The results are shown in Table 2-1.

Performance Evaluation Test 2 (Percutaneous Absorption Rate of Drug) Hair was removed from the abdomen of 8-week-old, male, Wistar rats.
The test solutions obtained in Example 2-1 and Comparative Example 2-1 were placed in a cylindrical tube having a diameter of 1 cm and the bottom of which was sealed at the hair removal site, and the cylindrical tube was fixed to the abdomen with an adhesive so that air could not enter. Two
This solution was recovered after 4 hours. The number of repetitions was 6 times for each cylindrical tube. The residual amount of the drug in these recovery cylindrical tubes was measured by high performance liquid chromatography. The difference between the initial amount of drug in the cylindrical tube and the amount remaining after the test was taken as the amount of drug transferred to the skin of the rat for 24 hours, and the ratio of the amount transferred to the initial drug amount was shown in the table as the transdermal absorption rate.

Table 2-1: Percutaneous absorption rate of drug ────────────────────── Tape agent Percutaneous absorption rate (% by weight) ──── ────────────────── Example 2-1 70.9 Comparative Example 2-1 7.5 ──────────────── ──────

As is clear from the results of Table 2-1, the test solution of Example 2-1 containing the percutaneous absorption enhancer of the present invention was
Compared with the test solution of Comparative Example 2-1 which does not contain these, about 1
The percutaneous absorption rate was 0 times.

Next, an example of the external preparation for skin (cream) according to the present invention will be described. The blending amount is% by weight. Example 3-1 (Cream) (1) Dexamethasone 0.025 (2) Propylene glycol 8.0 (3) Glycerin 5.0 (4) Liquid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Lauryl dimethylamine oxide 0.12 (7) 1-methyl-4-isopropyl-1-cyclohexen-8-ol 0.12 (8) Glycerin monofatty acid ester 1.5 (9) Preservative A suitable amount (10) Clay mineral ( Bentonite) 6.0 (11) Purified water Residual pH is 8. using sodium hydrogen carbonate and sodium carbonate.
Adjusted to 4.

The above-mentioned compounding composition was prepared and a cream was prepared by the following procedure. First, the component (5) is added to the component (1),
(4), (8) and (9) were added and heated to 70 ° C,
Dissolved and mixed. This is designated as Composition C. Next, the component (1
Ingredients (6) and (7) were added to part of 1) and dissolved, and then ingredients (2) and (3) were added and mixed to adjust the pH to 8.4. This is designated as Composition D. Keep the temperature at 70 ° C,
While the composition D was stirred, the composition C was gradually added thereto, preliminarily emulsified, and then emulsified with a homomixer. This was added to a mixture in which the component (10) had been added and dispersed in the rest of the component (11) with stirring and cooled to obtain a cream.

Comparative Example 3-1 (Cream) (1) Dexamethasone 0.025 (2) Propylene Glycol 8.0 (3) Glycerin 5.0 (4) Liquid Paraffin 1.0 (5) Diisopropyl Adipate 3.0 (6) Glycerin monofatty acid ester 1.5 (7) Preservative proper amount (8) Clay mineral (bentonite) 6.0 (9) Purified water Residual pH is calculated using sodium hydrogen carbonate and sodium carbonate 8.
Adjusted to 4. A cream was prepared according to Example 3-1.

With respect to the creams prepared in Example 3-1 and Comparative Example 3-1, the vasoconstrictor action was evaluated by the following method. Performance evaluation test 3 (vasoconstrictor action) The same formulation except that the cream prepared in Example 3-1 and Comparative Example 3-1 was further added to the upper back of 10 healthy males, and the two types of creams and dexamethasone were not included. Each of these creams was randomly assigned, applied using a patch test adhesive plaster (manufactured by Torii Pharmaceutical Co., Ltd.), and sealed.
After 4 hours, the bandage was peeled off, the sample was removed, and the sample was allowed to stand for 4 hours, and then judged. Judgment criteria are "prominent pallor phenomenon" (score 2), "clear pallor phenomenon" (score 1), "weak pallor phenomenon" (score 0.5) due to the pallor phenomenon associated with the vasoconstrictor action of steroids. "No change" (score 0)
The average score was calculated for each base. The results are shown in Table 3-1.
Shown in.

Table 3-1 ────────────────────────────────── Cream agent Average score after 4 hours ─ ───────────────────────────────── Example 3-1 1.89 Comparative Example 3-1 1.0 Implementation System without dexamethasone from Example 3-1 0 System without dexamethasone from Comparative 3-1 0 ───────────────────────────── As is clear from the results shown in Table 3-1, the cream of Example 3-1 has an excellent vasoconstrictor action.

Next, the external preparation for skin (gel) according to the present invention
An example will be described. The blending amount is% by weight. Example 4-1 (gel) (1) indomethacin 1.0 (2) ethyl alcohol 50.0 (3) carboxyvinyl polymer 1.2 (4) polyoxyethylene hydrogenated castor oil 1.5 (5) lauryldimethylamine Oxide 0.8 (6) 2,6-Dimethyl-1,6-octadiene-8-ol 0.8 (7) Diisopropanolamine 0.35 (8) Purified water Residual pH is sodium bicarbonate and sodium carbonate. Use 8.
Adjusted to 4.

A gel was prepared by preparing the above-mentioned compounding composition. First, dissolve components (5) and (6) in component (8).
After adjusting the pH to 8.4, the component (3) was well dispersed. This was added to a solution obtained by adding and dissolving the components (1) and (4) to the component (2), mixed well, and further the component (7) was added to this mixture and well mixed with stirring to obtain a gel.

Comparative Example 4-1 (Gel) (1) Indomethacin 1.0 (2) Ethyl alcohol 50.0 (3) Carboxyvinyl polymer 1.2 (4) Polyoxyethylene hydrogenated castor oil 1.5 (5) Diisopropanolamine 0.35 (6) Purified water Residual pH is 8. using sodium hydrogen carbonate and sodium carbonate.
Adjusted to 4. A gel was prepared according to Example 4-1.

Comparative Example 4-2 (Ointment) Ointment containing 1% by weight of commercially available indomethacin (gel external preparation)

With respect to the above gel base, its drug efficacy was examined and compared by the following carrageenin paw edema inhibitory rate test. Performance evaluation test 4 (carrageenin paw edema inhibitory rate) A group of 5 Wistar male rats aged 8 weeks
First, the volume of the right hind paw of the rats in each group was measured using a rat hind paw footpad edema volume measuring device KM-357 (manufactured by Natsume Seisakusho), and then 0.2 g of the sample was applied to the right hind paw of the rat. Two hours later, 0.05 ml of 1% carrageenin sodium salt was subcutaneously injected to the same site, and the volume of the right hind limb was measured 3 hours after the injection of carrageenin sodium salt, and the difference from the volume of the right hind limb before applying the sample was defined as the paw edema volume. The paw edema suppression rate was calculated by the following formula. Paw edema inhibition rate (%) = (Vc−Vt) / Vc × 100 where Vc and Vt represent the average paw edema volume of the control group (no test sample application) and the test sample application group, respectively. The results are shown in Table 4-1.

Table 4-1 ────────────────── Carrageenin paw edema inhibition rate (%) ────────────────── Example 4-1 61.0 Comparative Example 4-1 10.6 Comparative Example 4-2 8.4 ───────────────────

As is clear from the results shown in Table 4-1, the gel base of Example 4-1 is excellent in the carrageenin edema inhibitory action.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masao Takahashi 3664 Honmachida, Machida-shi, Tokyo

Claims (3)

[Claims] 1. A method comprising (1) at least one semipolar surfactant having a nitrogen atom in the molecule and (2) at least one compound selected from the group consisting of cyclic and chain monoterpenoid alcohols. A keratolytic agent consisting of and having a pH in the range of 7.5-11. 2. An active ingredient comprising (1) at least one semipolar surfactant having a nitrogen atom in the molecule and (2) at least one compound selected from the group consisting of cyclic and chain monoterpenoid alcohols. As pH value of 7.5
The percutaneous absorption enhancer of the medicinal component which is the range of -11. 3. A compound selected from the group consisting of (I) a medicinal component, (II) (1) at least one semipolar surfactant having a nitrogen atom in its molecule, and (2) a cyclic or chain monoterpenoid alcohol. An external preparation for skin, which comprises at least one of the above compounds and has a pH of 7.5 to 11.