JPH0611715B2 - Transdermal absorption enhancer and external preparation containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a percutaneous absorption enhancer and an external preparation containing the same. More specifically, it relates to a percutaneous absorption enhancer containing a specific carboxylic acid amide as an active ingredient, and an external preparation containing the same.

[Conventional technology]

Conventional drug administration methods include oral administration, rectal administration, and
Intradermal administration and the like are usually performed, and oral administration is widely used. However, in the case of oral administration, side effects such as gastrointestinal disorders, anorexia, vomiting, and abdominal pain may be caused, and a large amount of administration is often required to exert its effects, which is a drawback. was there.
In recent years, for the purpose of eliminating such drawbacks, an external preparation for external administration by transdermal administration has been developed with the expectation that this side effect can be reduced and the pharmacological effect can be expressed more safely. However, in many cases, the transdermal absorbability of the medicinal component in such an external preparation is still insufficient, and it cannot be said that the objective can be sufficiently achieved. That is,
Originally, the stratum corneum, which forms the outermost layer of the skin, fulfills the physiological function of a barrier against permeation of substances into the body. In many cases, it is difficult to obtain sufficient transdermal absorption. Therefore, it is necessary to control the permeability of the drug through the stratum corneum and enhance the transdermal absorbability of the drug.

For this purpose, a so-called percutaneous absorption enhancer is generally incorporated into the base. Examples of such absorption promoters include amide compounds such as dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and N, N-diethyl-m-toluamide; azacycloalkanes such as 1-dodecylazacycloheptan-2-one. 2-one derivatives; or esters of alcohols and carboxylic acids such as isopropyl myristate, isopropyl palmitate, diethyl sebacate, diisopropyl adipate or crotonyl-N-ethyl-o-toluidine are known.

[Problems to be solved by the invention]

However, it cannot be said that these absorption enhancers have sufficient absorption enhancing effects, and there are many cases in which practical pharmacological effects cannot be obtained. Further, the absorption enhancers themselves exhibit skin irritation, and as a strong solvent. Due to its nature, it is a problem in practical use, such as general application and usage being restricted due to corrosion of synthetic resin and elution of irritating substances and sensitizing substances from drug containers, clothing, jewelry, etc. Is the current situation.

[Means for solving problems]

The present inventors have conducted extensive studies in view of such circumstances, and as a result, a specific carboxylic acid amide has an action of significantly increasing the transdermal absorbability of a medicinal component, It was found that the pharmacological effect of the medicinal component can be exhibited satisfactorily and safely when administered, and the present invention has been completed.

That is, the present invention has the following general formula (I) (In the formula, R ₁ , R ₂ and R ₃ represent a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms,
_At least one of ₁ , R ₂ and R ₃ represents a linear or branched alkyl group having 9 or more carbon atoms, and when R ₁ is a linear alkyl group, R ₂ and R ₃ are not hydrogen atoms at the same time. The present invention provides a percutaneous absorption enhancer containing a carboxylic acid amide represented by the formula (4) as an active ingredient, and an external preparation containing the same.

Specific examples of the carboxylic acid amide represented by the general formula (I) include 2-ethyloctanamide, 2-ethyldecane amide, 2-ethyldodecane amide, 2-ethyltetradecane amide, 2-ethylhexadecane amide, and 2-ethyl. Octadecanamide, 2-butylhexanamide, 2
-Butyl octanamide, 2-butyl decanamide, 2
-N-unsubstituted branched chain carboxylic acid amides such as butyl dodecane amide, 2-butyl tetradecane amide, 2-butyl hexadecane amide, and methyl branched isooctadecane amide; N-methyl decanamide, N-methyl dodecane amide, N-methyl Tetradecane amide, N-methyl hexadecane amide, N-methyl octadecane amide,
N-methyleicosanamide, N-ethyldecanoamide, N-ethyldodecaneamide, N-ethyltetradecaneamide, N-ethylhexadecaneamide, N-ethyloctadecaneamide, N-ethyleicosanamide, N
-Butyldecane amide, N-butyl dodecane amide, N
-Butyl tetradecanoamide, N-butyl hexadecanoamide, N-butyl octadecanoamide, N-butyl eicosanamide, N-decylformamide, N-decylacetamide, N-decylpropionamide, N-decylbutanamide, N-dodecylformamide , N-dodecylacetamide, N-dodecylpropionamide, N
-Dodecyl butanamide, N-tetradecyl formamide, N-tetradecyl acetamide, N-tetradecyl propionamide, N-tetradecyl butanamide, N
N-hexadecylformamide, N-hexadecylacetamide, N-hexadecylpropionamide, N-hexadecylbutanamide, N-octadecylformamide, N-octadecylacetamide, N-octadecylpropionamide, N-octadecylbutanamide, etc. Mono-substituted carboxylic acid amides; N, N-dimethyldecaneamide, N, N-dimethyldodecaneamide, N,
N-dimethyl tetradecanoamide, N, N-dimethyl hexadecanoamide, N, N-dimethyl octadecanoamide, N, N-dimethyl eicosanamide, N-ethyl-
N-methyldecane amide, N-ethyl-N-methyldodecane amide, N-ethyl-N-methyltetradecane amide, N-ethyl-N-methylhexadecane amide, N-
Ethyl-N-methyloctadecanamide, N-ethyl-
N-methyleicosanamide, N, N-diethyldecaneamide, N, N-diethyldodecaneamide, N, N-diethyltetradecaneamide, N, N-diethylhexadecaneamide, N, N-diethyloctadecanamide,
N, N-diethyl eicosanamide, N-decyl-N-
Methylformamide, N-decyl-N-methylacetamide, N-decyl-N-methylpropionamide, N-
Decyl-N-methylbutanamide, N-dodecyl-N-
Methylformamide, N-dodecyl-N-methylacetamide, N-methyl-N-tetradecylformamide,
N-methyl-N-tetradecylacetamide, N-hexadecyl-N-methylformamide, N-hexadecyl-N-methylacetamide, N-methyl-N-octadecylformamide, N-methyl-N-octadecylacetamide, N-decyl -N-ethylformamide, N-
Decyl-N-ethylacetamide, N-dodecyl-N-
Ethylformamide, N-dodecyl-N-ethylacetamide, N-ethyl-N-tetradecylformamide,
N-ethyl-N-tetradecylacetamide, N-ethyl-N-hexadecylformamide, N-ethyl-N-
Examples include N, N-disubstituted carboxylic acid amides such as hexadecylacetamide, N-ethyl-N-octadecylformamide, N-ethyl-N-octadecylacetamide.

The carboxylic acid amides (I) can be easily produced by a conventional method in which a carboxylic acid halide or a carboxylic acid ester is reacted with ammonia, a primary amine or a secondary amine.

The percutaneous absorption enhancer of the present invention is prepared by dissolving, dispersing or suspending a carboxylic acid amide as it is or in a suitable solvent such as water, ethanol, propylene glycol or triacetin. Further, the transdermal absorption enhancer of the present invention, if necessary, a compound having a conventionally known transdermal absorption action, such as dimethyl sulfoxide, dimethylacetamide, dimethylformamide,
N, N-diethyl-m-toluamide, azacycloalkane such as 1-dodecylazacycloheptan-2-one-
A 2-one derivative, isopropyl myristate, isopropyl palmitate, diethyl sebacate, an ester of a carboxylic acid with an alcohol such as diisopropyl adipate, crotonyl-N-ethyl-o-toluidine, or the like can also be added.

Thus obtained percutaneous absorption enhancer of the present invention, in the base of the external preparation usually used in the amount of its active ingredient, when added as an auxiliary agent for promoting percutaneous absorption, the total amount of the external preparation is 0.01
It is suitable to blend in an amount of up to 5% by weight. When it is used as a base for promoting transdermal absorption, it can be added in an amount of 10% by weight or more based on the total amount.

The percutaneous absorption enhancer of the present invention is a lot of external preparations which are expected to have a pharmacological effect by being absorbed by application to the skin or hair, nails and the like, for example, liquid sprays, lotions, ointments, creams, It can be advantageously used for gels, sols, aerosols, poultices, plasters, tape preparations and the like. Examples of those whose drug efficacy is increased by the use of the percutaneous absorption agent of the present invention include prednisolone, steroidal anti-inflammatory agents such as dexamethasone, non-steroidal anti-inflammatory agents such as indomethacin, flufenamic acid, mefenamic acid, triperenamin, incypennine. Zir, chlorpheniramine, diphenhydramine, antihistamines such as promethazine, sulfamonomethoxine, sulfa drugs such as sulfamethizole, penicillin, cephalosporin,
Erythromycin, tetracycline, chloramphenicol, antibiotics such as streptomycin, naphthiomate, antifungal agents such as clotrimazole, 5-fluorouracil, cyclophosphamide, busulfan, antineoplastic agents such as actinomycin, morphine, codeine, Analgesics such as nalorphine, pentazocine, aspirin, acetoalinide, aminopyrine, prostaglandins, hypnotics and analgesics such as barbital and thiopental, psychotropic agents such as chlorpromazine, reserpine, chlordiazepoxide, antiepileptics, chlorzoxazone, levodopa, etc. Anti-Parkinson's disease drug, dichitoxin, digoxin and other cardiotonic agents, procainamide hydrochloride, propranolol and other antiarrhythmic agents, dipyridamole, nitrite Anti-anginal agents, such as, reserpine,
Antihypertensive agents such as guanethidine sulfate, UV suppressants such as para-aminobenzoate esters, hydroquinone,
Vitamin C esters, melanin production inhibitors such as parahydroxycinnamate, PUVA remedies for psoriasis such as 8-methoxypsoralen, vitamins such as vitamin A, vitamin E, vitamin C, insulin, estradiol, methyltestosterone, etc. Hormones, diagnostic agents, patch test allergens, insect repellents, insecticides, moisturizers, keratin softeners, hair dyes, etc.
It is not limited to these.

[Operation and effect of the invention]

The percutaneous absorption enhancer of the present invention is effective as an auxiliary agent or base for many drugs, pesticides, growth hormones, etc., which are expected to be absorbed by application to animals, insects, plants and the like to have a pharmacological effect.

〔Example〕

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

Example The following indomethacin-containing external preparation was prepared, and its transdermal absorption was tested.

[Formulation]

Invention product 1 N, N synthesized in accordance with Reference Example 1 with 0.21 g of indomethacin
-A liquid external preparation for which the concentration of indomethacin was 3.5% by adding 2.79 g of dimethyldodecanamide and further 3 g of ethanol.

Inventive Product 2 A liquid external preparation having 0.21 g of indomethacin, 2.79 g of N-dodecyl-N-ethylacetamide synthesized according to Reference Example 2, and 3 g of ethanol to give an indomethacin concentration of 3.5%.

Inventive product 3 A gel-type external preparation Inteban ointment (manufactured by Sumitomo Chemical Co., Ltd.) containing 1% by weight of commercially available indomethacin was added to 97 g of N, N-.
An ointment containing 3 g of dimethyldodecane amide.

Comparative product 1 A commercially available gel-type external preparation Inteban ointment (manufactured by Sumitomo Chemical Co., Ltd.) containing 1% by weight of indomethacin.

Comparative product 2 A liquid external preparation to which 100 g of purified water was added to a mixture of 1 g of indomethacin, 14 g of N, N-diethyl-meta-toluamide and 45 g of ethanol.

Comparative product 3 1 g of indomethacin, 14 g of dimethyl sulfoxide,
Liquid external preparation for 100 g by adding purified water to a mixture of 45 g of ethanol.

〔Test method〕

Indomethacin percutaneous absorption test: 7 Japanese female rabbits weighing about 3 kg were grouped into one group, and the external preparation of the present invention and the comparative product were applied to the normal dehaired abdominal skin (10 cm × 14 cm) of the rabbits in each group. 20 each of indomethacin
An amount equivalent to mg was applied, and blood was collected from the ear vein 4 hours, 10 hours, and 20 hours later, and the blood concentration of indomethacin was measured.

〔result〕

Formulation Maximum blood concentration (Cmax; ng / ml) Invention product 1 1890 Invention product 2 1810 Invention product 3 970 Comparative product 1 95 Comparative product 2 190 Comparative product 3 150 As is apparent from the above results, the invention is All of the products 1 to 3 exhibited extremely high transdermal absorbability of indomethacin as compared with the comparative product.

Reference Example 1 N, N-dimethyl dodecanamide _{(R 1 = C 11 H 23} , R 2 =
Preparation of R ₃ = CH ₃ ) Attach a Dimroth condenser gas inlet tube to a 300 ml two-necked flask. A solution of dodecanoyl chloride (47.3 g) in chloroform (100 ml) was added thereto, and the mixture was stirred under ice cooling. From gas inlet tube N
40 g of dimethylamine dried through aOH-CaCl ₂ tube
(4 equivalents) is passed over 3 hours. Chloroform (100 ml) was added to the reaction product, the chloroform layer was washed with water, 1N HCl and saturated saline and dried over sodium sulfate, and then chloroform was distilled off to obtain 46.0 g of a cloudy oily substance. This was applied to a short column of 150 g of silica gel and eluted with ethyl acetate / n-hexane = 1/1, and the solvent was distilled off to obtain 44.3 g of the colorless oily target product.
Yield 90.1% Elemental analysis Actual value (%) C 73.93 H 12.98 N 6.41 Calculated value (%) C 73.95 H 12.85 N 6.16 Reference example 2 N-dodecyl-N-ethylacetamide (R ₁ = CH ₃ , R ₂ = C ₁₂ H ₂₅ , Synthesis of R ₃ = C ₂ H ₅ ) 5.0 g of lithium aluminum hydride was suspended in 100 ml of anhydrous THF, and the suspension was stirred under a nitrogen stream and under ice cooling. A solution of 18.7 g of N-dodecylacetamide in 50 ml of anhydrous THF was added dropwise thereto over 1.5 hours, and the mixture was heated under reflux for 2 hours after the completion of the addition. After cooling, 150 ml of ether was added, excess lithium aluminum hydride was killed with water, the organic layer was dried over sodium sulfate, and the solvent was distilled off.
16.9 g of crude product of -dodecyl-N-ethylamine was obtained. This was dissolved in 100 ml of ether, a solution of 8.1 g of acetic anhydride in 50 ml of ether was added dropwise under ice cooling, neutralized with sodium bicarbonate, the organic layer was dried over sodium sulfate and the solvent was distilled off to obtain 20.2 g of a crude product. Using a silica gel short column, this was eluted with n-hexane / ethyl acetate = 3/1 to remove the origin,
The solvent was distilled off, the residue was dissolved in methanol and treated with activated carbon to obtain 15.6 g of a colorless oily target product. Yield 74.3%

Claims (2)

[Claims] 1. A general formula (I) (In the formula, R ₁ , R ₂ and R ₃ represent a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms,
_At least one of ₁ , R ₂ and R ₃ represents a linear or branched alkyl group having 9 or more carbon atoms, and when R ₁ is a linear alkyl group, R ₂ and R ₃ are not hydrogen atoms at the same time. ) A percutaneous absorption enhancer containing a carboxylic acid amide represented by the formula (4) as an active ingredient. 2. The general formula (I) (In the formula, R ₁ , R ₂ and R ₃ represent a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms,
_At least one of ₁ , R ₂ and R ₃ represents a linear or branched alkyl group having 9 or more carbon atoms, and when R ₁ is a linear alkyl group, R ₂ and R ₃ are not hydrogen atoms at the same time. ) An external preparation containing a carboxylic acid amide represented by the formula (4) as a percutaneous absorption enhancer.