JPH0755911B2 - 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 same. More specifically, one or more selected from the group consisting of amphoteric surfactants and semipolar surfactants, and one or more nonionic surfactants having a nitrogen atom in the molecule as active ingredients. The present invention relates to a percutaneous absorption enhancer, and a skin external preparation 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 the 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 coated stratum corneum, which originally has a physiological function as a barrier to prevent the invasion of foreign substances from outside the body, so 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 selected from the group consisting of an amphoteric surfactant and a semipolar surfactant, and a nonionic surfactant having a nitrogen atom in the molecule. A percutaneous absorption enhancer of a medicinal component, which comprises one or more of the above as an active ingredient, 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.

The amphoteric surfactant is N, N-dimethyl-N-lauryl-N-carboxymethylammonium betaine, N,
Carboxybetaines such as N-dimethyl-N-oleyl-N-carboxymethylammonium betaine, 2-lauryl-N-carboxyethyl-N-hydroxyethylimidazolinium betaine, 2-lauryl-N-carboxymethyl-N-hydroxyethyl Imidazoline derivatives such as imidazolinium betaine, N-cocoalkyl-β-
Aminopropionic acid sodium salt, N-coconut alkyl-β-
Examples thereof include aminocarboxylic acid salts such as iminodipropionic acid-di-soda salt, sulfobetaine, aminobetaine and the like.

The semipolar surfactant is amine oxide such as lauryldimethylamine oxide and bis- (2-hydroxyethyl) laurylamine oxide.

In the present invention, one or more selected from the group consisting of the amphoteric surfactant and the semipolar surfactant are optionally used.

On the other hand, examples of the nonionic surfactant having a nitrogen atom in the molecule include fatty acid alkanolamide, polyoxyethylene fatty acid amide, alkanolamine ester, and polyoxyethylene alkylamine. One kind or two kinds or more are arbitrarily selected from these.

The ratio of the amphoteric surfactant and the semipolar surfactant to the nonionic surfactant having a nitrogen atom in the molecule is 20: 1 to 1:20 in a molecular ratio, preferably 10: 1 to 1:10. is there.

Examples of the drug that can increase the drug efficacy by using the above-mentioned percutaneous absorption enhancer include the following.

That is, steroidal anti-inflammatory agents such as prednisolone, dexamethasone, non-steroidal anti-inflammatory agents such as indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, dihenhydramine, antihistamines such as promethazine, sulfamonomethoxy, sulf Sulfa drug such as famethizole, penicillin, cephalosporin, erythromycin, tetracycline, chloramphenicol, antibiotics such as streptomycin, antifungal agent such as naphthiomate, clotrimazole, 5-fluorouracil, cyclophosphamide, busulfan, Anti-neoplastic agents such as actinomycin, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide,
Analgesics such as aminopyrine, prostaglandin preparations,
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 percutaneous absorption enhancer component 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 component may be used as it is by appropriately mixing it with a medicinal component, but in consideration of the feeling of use and ease of application, etc., it is generally contained in a suitable external preparation for skin, for example, Cream, ointment, gel, lotion,
It is used by blending it with a base such as an emulsion or an 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, amphoteric surfactant and /
Alternatively, the total amount of the semipolar surfactant and the nonionic surfactant having a nitrogen atom in the molecule is 0.001 to 1 in the external preparation.
0% by weight, more preferably 0.01 to 5% by weight. The medicinal properties are
0.001 to 10% by weight, more preferably 0.01 to 5% by weight. Further, the ratio of the amphoteric surfactant and the semipolar surfactant and the nonionic surfactant having a nitrogen atom in the molecule 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 applies 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, ingredients that are generally compounded such as pharmaceuticals, quasi-drugs, and cosmetics can be blended. 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.

[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.

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) Diethanolamide laurate 0.6 (7) N, N-dimethyl -N-lauryl-N-carboxymethylammonium betaine 0.3 (8) Glycerin monofatty acid ester 1.5 (9) Preservative proper amount (10) Clay mineral (bentonite) 6.0 (11) Purified water Residue [Production method] (5) ), (4), (8), (9) are added, and 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 of (11) in which (10) had been added and dispersed 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 Residual [Production Method] Same as the example.

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

That is, the cream prepared in Examples and Comparative Examples and the creams containing no dexamethasone in the above two kinds of creams were randomly allocated to the upper backs of 10 healthy males, and a patch test plaster (manufactured by Torii Pharmaceutical Co., Ltd.) was used. It was applied 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" (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 apparent from the table, the creams of Examples have excellent 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) hydrogenated castor oil 1.5 (5) Lauryl dimethylamine oxide 0.6 (6) POE (15 mol) oleylamine 0.8 (7) N, N-dimethyl-N-lauryl-N-sulfomethylammonium betaine 1.0 (8) Rausulic acid diethanolamide 0.35 (9) Diisopropanolamine 0.35 (10) Purified water Residue [ Manufacturing Method] (5), (6), (7) and (8) are dissolved in (10), and then (3) is well dispersed. This is (2) to (1),
Add (4) to the dissolved product and mix well. Further, (9) 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 (10) Purified water Residue [Production method] According to the example .

Comparative Example 2 Ointment containing 1% of commercially available indomethacin (gel external preparation).

Test Example The drug efficacy of the above-mentioned gel base was examined by a carrageenin edema inhibition rate test and compared.

That is, five 6-week-old male Wistar rats were used as one group, and the volume of the right hind limb of each group of rats was first measured using the 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 footpad edema volume. The edema suppression rate was calculated by the following formula.

However, V _c and V _t 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) Palm fatty acid diethanol amide ethyl alcohol 0.8 (3) Dodecyldimethylamine oxide 0.5 (4) Purified water Residue [Production method] (2) and (3) were dissolved in (4). Then, (1) was thoroughly stirred and dissolved to prepare a sample.

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

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

Test Example A sample of 100 μ was applied to the back skin of a hairless mouse in a group of 3 animals using a torii patch test Bansokou (diameter 1.6 cm). A sponge was placed on top of the band and covered with a thin film of rubber so that the band was in close contact.
Immediately after application, the mixture was placed in a plastic closed container, air was blown, and carbon dioxide gas exhaled and exhaled was absorbed in a 50% methanol solution of monoethanolamine.

At the end of 24 and 48 hours after the application, the bandage of the applied part was removed, and the activity in the bandage was measured. Then, the coated part was stripped eight times with cellophane tape, and the activity in the 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. The remaining whole body is 0.5N sodium hydroxide solution
After adding 30 g and homogenizing with a blender, a certain amount of this was sampled and the activity was measured. The feces and urine excreted by the required time were collected and the activity was measured.

Here, the sum of the amount of exhaled breath, the amount of excreted feces and urine, and the amount stored in the body was taken as the transdermal absorption amount.

The above test results are shown in Table-3.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Isao Murotani 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Examiner, Shiseido Research Institute Co., Ltd. Shoei Hoshino (56) References JP 62-61929 (JP, A) )

Claims (2)

[Claims] 1. An active ingredient comprising one or more selected from the group consisting of an amphoteric surfactant and a semipolar surfactant, and one or more nonionic surfactants having a nitrogen atom in the molecule. A percutaneous absorption enhancer for medicinal components. 2. A medicinal component, one or more selected from the group consisting of amphoteric surfactants and semipolar surfactants, and one or more nonionic surfactants having a nitrogen atom in the molecule. An external preparation for skin, which comprises: