JPH0759519B2 - Transdermal absorption enhancer and external preparation for skin containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a percutaneous absorption enhancer and a skin external preparation containing the percutaneous absorption enhancer component. More specifically, it promotes transdermal absorption containing one or more anionic surfactants and one or more surfactants having a nitrogen atom in the molecule other than the anionic surfactant as active ingredients. And an external preparation for skin containing the percutaneous absorption enhancer component and a medicinal component.

[Prior Art] Conventionally, oral administration, administration by injection, and the like have been widely performed as methods for administering medicinal components. However, oral administration has drawbacks such as insufficient absorption, a temporary high concentration in the body to maintain its effect, and side effects such as gastrointestinal disorders and anorexia. It was In addition, administration by injection required rapid absorption but required specialists such as doctors.

In recent years, in order to improve such side effects and drawbacks, external preparations have been developed by a transdermal administration method. However, even with such an external preparation, it is difficult to say that it is in a satisfactory state in many cases because sufficient transdermal absorbability is not yet obtained.

That is, the surface of the skin is called the stratum corneum of the skin, and since it originally has a physiological function as a barrier to prevent the invasion of foreign substances from outside the body, it is simply added to the base conventionally used for external preparations. Sufficient transdermal absorbability cannot be obtained only by incorporating the medicinal component.

In order to improve this, various transdermal absorption enhancers have been proposed in recent years. For example, dimethylsulfoxide, dimethylformamide, dimethylacetamide, methyldecylsulfoxide and the like are known, but it is hard to say that these are sufficient in terms of the transdermal absorption promoting effect, safety and usability.

[Problems to be Solved by the Invention] In view of the above problems, the present inventors have developed a percutaneous absorption enhancer which is excellent in the effect of promoting percutaneous absorption of medicinal components and which is satisfactory in terms of safety and usability. As a result of earnest research to achieve the present invention, the present invention has been completed.

[Means for Solving Problems] That is, the present invention provides one or more anionic surfactants and one or two surfactants having a nitrogen atom in the molecule other than the anionic surfactant. A percutaneous absorption enhancer of a medicinal component having the above as active ingredients, and a skin external preparation containing the desired medicinal component and the above-mentioned percutaneous absorption enhancer component.

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

Examples of the anionic surfactant include anionic surfactants having one or more carboxylic acid groups, sulfonic acid groups, sulfuric acid ester groups, and phosphoric acid ester groups in the molecule. Those having a carboxylic acid group include fatty acid soaps, ether carboxylic acids and salts thereof, carboxylic acid salts such as condensates of amino acids and fatty acids, and those having sulfonates include alkyl sulfonates and sulfosuccinic acid. , Ester sulfonates, alkylallyl and alkylnaphthalene sulfonates, N-acyl sulfonates, formalin condensed sulfonates, and the like, having a sulfate ester group include sulfated oil, ester sulfates, alkyl sulfates. Salts, ether sulfates, alkyl allyl ether sulfates, amide sulfates, etc., and those having a phosphoric acid ester group include alkyl phosphates, amide phosphates, ether phosphates, alkyl allyl ether phosphates, etc. Can be mentioned. One kind or two or more kinds are arbitrarily selected from these.

On the other hand, as a surfactant having a nitrogen atom in the molecule,
Examples thereof include amphoteric surfactants having a nitrogen atom in the molecule, semipolar surfactants, nonionic surfactants, and cationic surfactants. As the amphoteric surfactant, carboxybetaine, sulfobetaine, aminocarboxylic acid salt, imidazoline derivative and the like, as the semipolar surfactant, amine oxide and the like, as the nonionic surfactant, fatty acid alkanolamides, poly Oxyethylene fatty acid amides, alkanolamine esters, polyoxyethylene alkylamines, etc., as cationic surfactants, fatty acid amine salts, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridinium salts, imidazolium salts, etc. Can be mentioned. One kind or two kinds or more are arbitrarily selected from these.

The ratio of the anionic surfactant and the surfactant having a nitrogen atom in the molecule other than the anionic surfactant is 20: 1 to 1:20, preferably 10: 1 to 1:10 in a molecular ratio. is there.

The following are examples of the medicinally active ingredient whose medicinal effect can be increased by using the above-mentioned percutaneous absorption enhancer.

That is, steroidal anti-inflammatory agents such as prednisolone and dexamethasone, non-steroidal anti-inflammatory agents such as indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, diphenhydramine, antihistamines such as promethazine, sulfamonomethoxine, sulfamethizole Such as sulfa drugs. Antibiotics such as penicillin, cephalosporin, erythromycin, tetracycline, chloramphenicol, streptomycin, antifungal agents such as naphthomate and clotrimazole, and anti-malignant tumors such as 5-fluorouracil, cyclophosphamide, busulfan and actinomycin Agent, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide,
Analgesics such as aminopyrine, prostaglandins,
Hypnotics and sedatives such as barbital and thiopental,
Antipsychotic agents such as chlorpromazine, reserpine, chlordiazeboxoxide, antiparkinsonian agents such as chlorzoxazone, levodopa, cardiotonic agents such as dichitoxin, digoxin, antiarrhythmic agents such as procainamide hydrochloride, propranolol hydrochloride, dipyridamole, amyl nitrite, etc. Anti-anginal agents, anti-hypertensive agents such as diazoxide, minoxidil, reserpine, guanethidine nitrate, UV inhibitors such as para-aminobenzoate esters, melanin production inhibitors such as hydroquinone, vitamin C esters, para-hydroxycinnamate, 8- Peanut PU such as methoxypsoralen
VA therapeutic agent, vitamins such as vitamin A, vitamin E and vitamin C, hormones such as insulin, estradiol and methyltestosterone, diagnostic agents, patch test allergens, insect repellents, insecticides or moisturizers, keratin softeners, It is a medicinal ingredient such as a hair dye.

These medicinal components are rapidly absorbed into the skin by being mixed with the transdermal absorption enhancer of the present invention and applied to the skin. A medicinal ingredient intended for local action will penetrate deeply into the skin and exhibit excellent effects, and a medicinal ingredient intended for systemic action will be similarly excellent because the medicinal ingredient is transferred to the blood. Exert the effect.

The object of use is of course human, but it is also effective for other animals.

The amount of the medicinal component to be added may be an amount sufficient to achieve the desired medicinal effect, and it depends on the type of medicinal component, the body weight of the patient, symptoms, etc. Percutaneous absorption enhancer 0.001 to 50, based on weight
Is the weight.

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

The blending amount of each constituent in that case also varies depending on the kind of the medicinal component and the like, but the following ranges are generally preferable ranges. That is, the total amount of the anionic surfactant and the surfactant having a nitrogen atom in the molecule other than the anionic surfactant in the external preparation is 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, Ingredient 0.00
1 to 10% by weight, more preferably 0.01 to 5% by weight. Also,
The ratio of the anionic surfactant and the surfactant having a nitrogen atom in the molecule other than the anionic surfactant is the above-mentioned ratio, that is, a molecular ratio of 20: 1 to 1:20, preferably 10: 1. Or a ratio of 1:10 is applied as is.

In the external preparation for promoting transdermal absorption of the medicinal component according to the present invention,
In addition to the above-mentioned essential constituents, it is possible to add components that are generally added to drugs, quasi drugs, cosmetics and the like. These components include polyhydric alcohols, oils, waxes, acids, alkalis, cationic surfactants, nonionic surfactants, anionic surfactants, amphoteric surfactants, powders, pigments, dyes, antiseptics and antioxidants. Agent, UV absorber, chelating agent, water-soluble polymer, montmorillonite,
Examples include alcohols, solvents, fragrances and the like.

EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 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) Sodium dodecyl sulfate 0.08 (7) Dodecyldimethylamine oxide 0.16 ( 8) Glycerin monofatty acid ester 1.5 (9) Preservative proper amount (10) Clay mineral (bentonite) 6.0 (11) Purified water Residue [Production method] (5) (1), (4), (8), (9) Add 70
Warm to ℃ and dissolve and mix. This is designated as composition (A). (6) and (7) are added to a part of (11) and dissolved, and (2) and (3) are further added and mixed. This is designated as composition (B). While maintaining the temperature at 70 ° C. and stirring the composition (B), the composition (A) is gradually added, preliminarily emulsified, and then emulsified by a homomixer.

This was added to a mixture in which (10) had been added and dispersed in the rest of (11) in advance with stirring, and cooled to obtain a cream.

Comparative Example 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 Suitable amount (8) ) Clay mineral (bentonite) 6.0 (9) Purified water Residue [Production method] Same as in Example 1.

Test Example The creams prepared in Example 1 and Comparative Example 1 were compared for their vasoconstriction effects.

That is, the cream prepared in Example 1 and Comparative Example 1 and the creams containing no dexamethasone in the above two kinds of creams were randomly allocated to the upper backs of 10 men of standing construction, and a patch test plaster (made by Torii Pharmaceutical Co., Ltd. ) Was used and sealed and affixed. 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" (score 2), "clear pallor" (score 1), and "weak pallor" (score 0. 0) due to the pallor phenomenon associated with the vasoconstrictor action of steroids.
5), "No change" (score 0), and an average score was obtained for each base.

The results are shown in Table-1.

As is clear from Table 1, the cream of Example 1 is excellent in the vasoconstriction action.

Example 2 Gel (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxyvinyl polymer 1.2 (4) Polyoxyethylene (hereinafter referred to as POE; 40 mol) hydrogenated castor oil 1.5 (5) Sodium dodecyl sulfate 0.5 ( 6) Sodium dodecylphosphate 0.6 (7) Sodium laurylisothionate 0.2 (8) Dodecyldimethylamine oxide 1.14 (9) Lauric acid diethanolamide 0.2 (10) Diisopropanolamine 0.35 (11) Purified water Residue [Production method] (5) ), (6), (7), (8) and (9) are dissolved in (11) and then (3) is well dispersed. This is added to a solution obtained by adding (1) and (4) to (2) and mixed well. Further, (10) was added to this mixture and mixed well with stirring to obtain a gel.

Comparative Example 2 (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxyvinyl polymer 1.2 (4) POE hydrogenated castor oil 1.5 (5) Diisopropanolamine 0.35 (6) Purified water Residue [Production Method] In Example 2 According to

Comparative Example 3 A commercially available ointment containing 1% indomethacin (gel external preparation).

Test Example With respect to the above gel base, its drug efficacy was examined and compared by a carrageenin edema inhibition rate test.

That is, 5 male Wistar rats aged 6 weeks were treated as one group, and first, the volume of the right hind limb of each group of rats was measured using a rat hind footpad edema volume measuring device KM-357 (Natsume Seisakusho). Then, 0.2 g of the sample is applied to the right hind leg of the rat. Two hours later, 0.05 ml of 1% carrageenin sodium salt was subcutaneously injected into 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 application of the sample was taken as the volum edema volume, The edema suppression rate was calculated by the following formula.

However, Vc and Vt represent the average footpad edema volume of the control group (no test sample application) and the test sample application group, respectively.

The above test results are shown in Table 2.

As is clear from the table, it can be seen that the gel bases of Examples have excellent carrageenin edema inhibitory action.

Example-3 (1) Hydroquinone 1.0% (2) Sodium dodecyl sulfate 0.2 (3) Dodecylmethylamine oxide 0.7 (4) Purified water Residue [Production method] (2), (3) were dissolved in (4), (1) was added and well dissolved by stirring to obtain a sample.

Comparative Example-4 (1) Hydroquinone 1.0% (2) Purified water Residual [Production Method] Same as in Example 3.

Comparative Example-5 (1) Hydroquinone 1.0% (2) Urea 5.0 (3) Purified water Residual [Production Method] Same as in Example 3.

Test Example A 100 μm sample was applied to the skin on the back of three hairless mice per group with a plaster for a Torii patch test (diameter: 1.6 cm).
A sponge was placed on the adhesive plaster and further covered with a thin rubber film so that the adhesive plaster was in close contact. Immediately after the application, the mixture was placed in a plastic sealed container, air was blown, and carbon dioxide gas exhaled and exhaled was absorbed in a 50% methanol solution of monoethanolamine.

After application, the adhesive plaster on the application part was removed at 24 and 48 hours, and the activity in the adhesive plaster was measured. Then, the coated part was stripped eight times with cellophane tape, and the activity in the stratum corneum adhered to the cellophane tape was measured. Then, the animal was slaughtered, the skin of the application part was peeled off, and the activity in the skin was measured. To the remaining whole body, 30 g of 0.5 N sodium hydroxide aqueous solution was added to make a homogenate with a blender, and a certain amount of this was collected and the activity was measured. In addition, feces excreted by the required time and urine were collected and the activity was measured.

Here, the sum of the inhaled excretion amount, the fecal / urine excretion amount, and the accumulated amount in the body was defined as the percutaneous absorption amount in the body.

The above test results are shown in Table-3.

[Effect of the Invention] The percutaneous absorption enhancer and the external preparation for skin according to the present invention are excellent percutaneous absorption enhancer of the medicinal component, and are also safe and have a good feeling in use.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Isao Murotani 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Examiner, Shiseido Research Institute, Ltd. Shoei Hoshino (56) Reference JP-A-52-83914 (JP, A) ) JP-A-51-32724 (JP, A) JP-A-62-240613 (JP, A)

Claims (2)

[Claims] 1. An effective use of (a) one or more kinds of anionic surfactants and (b) one or more kinds of surfactants having a nitrogen atom in the molecule other than the anionic surfactants. A percutaneous absorption enhancer of a medicinal component, wherein (a) :( b) has a molecular ratio of 20: 1 to 1:20 as a component. 2. (a) one or more anionic surfactants, and (b) one or more surfactants having a nitrogen atom in the molecule other than the anionic surfactant,
(C) contains a medicinal component, and (a) :( b) is a molecular ratio.
20: 1 to 1:20 and the total content of (a) and (b) is 0.01
The external preparation for skin is characterized in that it is -5% by weight.