JP2001058961A - Percutaneous absorbefacient and percutaneous absorption-type preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a percutaneous absorbefacient capable of quickly transmitting a desired pharmaceutically active substance through the whole body, and having excellent percutaneous absorbefacient activity, safety and usability by compounding N-mono- or N-di-substituted p-menthane-3-carboxamide. SOLUTION: This percutaneous absorbefacient comprises an N-mono- or N-di-substituted p-menthane-3-carboxamide such as N-methyl-p-menthane-3- carboxamide expressed by the formula [R1 is H or a (substituted) lower alkyl; R2 is a (substituted) lower alkyl]. It is preferable to prepare the percutaneous absorption-type preparation by compounding a pharmaceutically active component such as prednisolone or dexamethasone, and the percutaneous absorbefacient preferably in an amount of 0.1-20 wt.%, more preferably 0.5-10 wt.%. Further, the preparation form is preferably an ointment, cream, poultice or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transdermal absorption enhancer for transdermally administering a medicinal ingredient and a transdermal absorption preparation containing the transdermal absorption enhancer. More specifically, transdermal absorption enhancers and transdermal absorption agents which are excellent in both transdermal absorption and safety, deliver a desired pharmacologically active substance promptly to a local site or through the circulatory system, and are effective for treatment of various diseases. It relates to a type preparation.

[0002]

2. Description of the Related Art In recent years, a transdermal therapeutic system (TTS) capable of delivering a desired drug to the whole body through the skin and exhibiting a therapeutic effect over a long period of time has been developed as a method of administering a drug, and is used for treating angina pectoris. Nitroglycerin, isosorbide dinitrate, clonidine for the treatment of hypertension, estradiol for the treatment of menopause and the like have already been put into practical use. However, the percutaneous administration method of a drug has a drawback that the absorption of a medicinal ingredient is remarkably low as compared with the administration method by oral administration or injection, particularly when the medicinal ingredient is water-soluble. Therefore, development of a transdermal absorption enhancer that acts on the stratum corneum, which is a barrier for drug absorption from the skin, lowers the barrier property of the skin, and improves the transdermal absorption, has been actively performed.

As such a transdermal absorption enhancer, for example, US Pat. No. 3,551,554 discloses an aprotic solvent such as dimethyl sulfoxide and N, N-dimethylformamide. JP-A-51-3
No. 2724, Japanese Patent Application Laid-Open No. 52-83914,
Anionic and / or amphoteric surfactants are disclosed. JP-A-52-1035 discloses 1-dodecylazacycloheptan-2-one (AZONE). Further, as a terpene compound, JP-A No. 2-19
JP-A 3932 discloses terpene ketones such as l-carvone, menthone and piperiton, and JP-A-2-207024 discloses d-limonene. In addition, glycols, fatty acids such as oleic acid, and fatty acid esters such as isopropyl myristate and isopropyl palmitate have been reported. However, these absorption enhancers have a percutaneous absorption promotion effect, safety such as skin irritation,
From the viewpoint of usability such as an intense smell, it cannot be said that it is sufficient, and development of a safe, excellent usability and highly effective transdermal absorption enhancer has been desired.

[0004] On the other hand, N-substituted-p-menthan-3-carboxamide is a derivative of p-menthane and is known as a substance having a cooling effect or a refreshing agent. For example, JP-A-47-16648 describes a substance having a cooling sensation, and JP-A-8-283147 describes a cooling agent.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned problems in transdermal preparations, and has excellent transdermal absorption promoting effects, high safety and high usability. An object of the present invention is to provide a skin absorption enhancer and a percutaneous absorption preparation containing the same.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to develop a transdermal absorption enhancer having the above-mentioned excellent characteristics, and as a result, have found that N-mono- or di-substituted-p-menthane-3 has been developed.
-It has been found that carboxamides significantly enhance the transdermal absorption of drugs. The percutaneous absorption enhancer of the present invention, N-substituted-p-menthan-3-carboxamide, is a known substance, but there is no example in which a remarkable percutaneous absorption promoting action of this substance has been found. Attempts to percutaneously absorb medicinal ingredients as a transdermal absorption enhancer,
This is what the present inventors have achieved for the first time, and is completely new knowledge.

That is, the present invention relates to N-mono- or di-substituted-p
A percutaneous absorption enhancer comprising menthan-3-carboxamide. More specifically, the present invention provides a compound represented by the general formula (I):

Embedded image (In the formula, R ¹ represents hydrogen or a lower alkyl group which may have a substituent, and R ² represents a lower alkyl group which may have a substituent.) p-menthan
It relates to a transdermal absorption enhancer comprising 3-carboxamide.

[0008] The present invention also relates to a pharmaceutical composition comprising the aforementioned N-
The present invention relates to a transdermal absorption preparation containing a transdermal absorption enhancer comprising a mono- or di-substituted-p-menthan-3-carboxamide. More specifically, the N-mono- or di-substituted-p-menthan-3-carboxamides are N-substituted-p-menthan-3-carboxamides represented by the general formula (I), and are transdermally absorbable. Formulation.

The N-substituent of the N-mono- or di-substituted-p-menthan-3-carboxamide of the present invention is not particularly limited as long as it does not inhibit the percutaneous absorption action, and may be variously substituted or unsubstituted. And substituted hydrocarbon groups. Examples of the hydrocarbon group include an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, and an aralkyl group.
Preferred N-substituents include a substituted or unsubstituted lower alkyl group represented by the general formula (I). The lower alkyl group for the substituent R ¹ or R ² in the general formula (I) of the present invention includes a linear or branched alkyl having 1 to 10, preferably 1 to 6, more preferably 1 to 4 carbon atoms. Groups are preferred. As the lower alkyl group, for example, a methyl group,
Examples include an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a sec-butyl group. These hydrocarbon groups and lower alkyl groups may have a substituent, and preferred substituents include a hydroxyl group and a lower alkoxy group composed of the above-mentioned lower alkyl group. Examples of the lower alkyl group having a substituent include a 2-hydroxyethyl group, a 3-hydroxy-n-propyl group, and a 2-alkyl group.
Hydroxy-n-propyl group, 2-methoxyethyl group,
And a 2-ethoxyethyl group.

Preferred N-mono- or di-substituted-p-menthan-3-carboxamides for use in the present invention include, for example, N-methyl-p-menthan-3-carboxamide, N-ethyl-p-menthan-3. -Carboxamide, N- (2-hydroxyethyl) -p-menthane-
Examples include, but are not limited to, 3-carboxamide, N, N-dimethyl-p-menthan-3-carboxamide, and the like. These N-mono- or di-substituted-p-menthan-3-carboxamides can be used in combination of two or more kinds. In addition, p-menthane is usually a trans form, but is not limited thereto.

The active ingredient used in the percutaneous absorption preparation of the present invention may be any of those which have a percutaneous absorption promoting effect when used in combination with N-mono- or di-substituted-p-menthan-3-carboxamide. There is no particular limitation as long as it can be appropriately selected from conventionally known drugs. Examples of such medicinal ingredients include prednisolone, dexamethasone, hydrocortisone, fluocinolone acetonide, betamethasone valerate, betamethasone dipropionate, clobetasone butyrate, prednisolone succinate and other steroidal anti-inflammatory agents, indomethacin, diclofenac, ibuprofen, Non-steroidal anti-inflammatory drugs such as ketoprofen, flufenamic acid, ketorolac, flurbiprofen, felbinac, suprofen, pranoprofen, thiaprofen, loxoprofen and ester derivatives thereof, tranilast, azelastine,
Antiallergic agents such as ketotifen, ibudilast, oxatomide, emedastine, etc .; antihistamines such as diphenhydramine, chlorpheniramine, promethazine, triperenamine; , Hormonal agents such as methyltestosterone, progesterone and estradiol, antihypertensive agents such as clonidine, reserpine, guanethidine sulfate, cardiotonic agents such as digitoxin and digoxin; Agent, coronary vasodilator such as nitroglycerin, isosorbide dinitrate, papaverine hydrochloride, nifedipine, lidocaine Benzocaine, procaine hydrochloride, a local anesthetic tetracaine such as morphine, aspirin, codeine, acetanilide, analgesics such as aminopyrine, eperisone, tizanidine, tolperisone, Inaperizon,
Skeletal muscle relaxants such as pridinol mesylate, acetophenylamine, nitrofurazone, pentamycin, naphthiomate, miconazole, omoconazole, clotrimazole, butenafine hydrochloride, bifonazole and other antifungal agents, 5-fluorouracil, busulfan, actinomycin, pleomycin , Antineoplastic agents such as mitomycin, dysuria agents such as telolidine hydrochloride and oxybutynin hydrochloride, antiepileptic agents such as nitrazepam and meprobamate, anti-Parkinson's agents such as chlorzoxazone, levodopa, and smoking cessation aids such as nicotine. Examples include vitamins and prostaglandins, but are not limited thereto.

The content of N-mono- or di-substituted-p-menthan-3-carboxamide in the transdermal preparation of the present invention is preferably in the range of 0.1 to 20% by weight based on the total amount of the preparation. Preferably, it is used in the range of 0.5 to 10% by weight. If this amount is less than 0.1% by weight, the effect of promoting percutaneous absorption is not sufficiently exhibited, and if it exceeds 20% by weight, no improvement in the effect is recognized for the amount, and a stable preparation cannot be obtained. Sometimes. As the dosage form of the transdermal absorption preparation of the present invention, dosage forms conventionally used as external preparations, for example, ointments, creams, gels, gel creams, lotions, sprays, cataplasms, tapes, reservoir-type patches, etc.
It can be used as an external preparation of any dosage form.

The transdermal preparation of the present invention contains N-mono- or di-substituted-p-menthane as a transdermal absorption enhancer in the preparation.
By mixing an appropriate amount of 3-carboxamide, it can be produced by a usual method. When the solubility of the N-mono- or di-substituted-p-menthan-3-carboxamide and the base is not good, a solvent can be appropriately used to improve the solubility. Next, the transdermal preparation of the present invention will be described in more detail with respect to a poultice or a tape. For example, as a poultice, as a base, a hydrophilic base obtained by mixing a water-soluble polymer, a polyhydric alcohol and water in consideration of stability with time, release, transdermal absorption, and skin safety. It is preferred that

As the water-soluble polymer used in the hydrophilic base, gelatin, casein, pullulan, dextran, sodium alginate, soluble starch, carboxystarch, dextrin, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, Polyvinyl alcohol, polyethylene oxide, polyacrylic acid, polyacrylamide, sodium polyacrylate, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl ether, methoxyethylene maleic anhydride copolymer, isobutylene maleic anhydride copolymer, N-vinylacetamide, One or two of N-vinylacetamide and acrylic acid and / or acrylate copolymer, etc. More than one is selected, as appropriate. In this case, the content of the water-soluble polymer is 1 to 30% by weight, preferably 1 to 20% by weight, more preferably 1 to 30% by weight of the whole preparation.
15% by weight. If the amount is less than 1% by weight, the viscosity becomes low and the shape-retaining property cannot be maintained.

As the polyhydric alcohol, one or more of polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1.3-butylene glycol, 1.4-butylene glycol, isobutylene glycol, glycerin, diglycerin, sorbitol and the like can be used. If necessary, two or more kinds are appropriately selected, and the compounding amount is 5 to 90% by weight, preferably 10 to 90% by weight.
７０70% by weight, more preferably 20-60% by weight. If it is less than 5% by weight, the moisturizing effect is insufficient, and if it is more than 90% by weight, the solubility of the water-soluble polymer is affected. The amount of water is from 10 to 90% by weight, preferably from 20 to 80% by weight, and is necessary for dissolving the water-soluble polymer and for increasing the viscosity, cohesiveness and shape retention.

Further, in addition to the above essential components, if necessary, a polyvalent metal compound as a crosslinking agent, specifically, aluminum hydroxide, aluminum chloride, calcium hydroxide, calcium chloride, aluminum sulfate, aluminum ammonium sulfate, aluminum sulfate Potassium, magnesium metasilicate aluminate, dihydroxyaluminum aminoacetate and the like, and other crosslinking agents having at least two or more epoxy groups in the molecule, specifically ethylene glycol diglycidyl ether, polyethylene Glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, glycerol polyglycidyl ether , Polyglycerol polyglycidyl ether, sorbitol polyglycidyl ether, sorbitan polyglycidyl ether, trimethylolpropane polyglycidyl ether, pentaerythritol polyglycidyl ether, resorcinol diglycidyl ether, neopentyl glycol diglycidyl ether,
1,6-hexanediol diglycidyl ether and the like can be mentioned, and one or two or more of these crosslinking agents can be suitably compounded appropriately.

In addition, fillers such as kaolin, zinc oxide, titanium dioxide, talc, bentonite and synthetic aluminum silicate, preservatives such as thymol, methylparaben and ethylparaben, ascorbic acid, stearic acid ester, dibutylhydroxytoluene, Antioxidants such as butylhydroxyanisole, gallic ester, vitamin E, vitamin E acetate, disodium edetate,
UV absorbers such as 2-hydroxy-4-methoxybenzophenone, ethyl p-aminobenzoate, 2- (2-hydroxy-5-methylphenyl) benzotriazole, glycol salicylate, methyl salicylate, phenyl salicylate, sorbitan fatty acid esters, and glycerin One or more kinds of components composed of emulsifiers such as fatty acid esters, decaglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and polyoxyethylene alkyl ethers may be appropriately blended.

As a support for the cataplasm, it is important to select a material which does not affect the release of the active ingredient.
That is, a support having no interaction with the medicinal component and no adsorption is essential. For example, a film or sheet of polyethylene, polypropylene, polyvinyl chloride, polyester, nylon, polyurethane, or the like, or a porous body, foam, cloth, or nonwoven fabric thereof, or a laminate of the film or sheet with a porous body, foam, cloth, or nonwoven fabric It is selected from products. In addition, as the release coating, polyethylene, polypropylene, polyester, or those obtained by releasing these with silicone, release paper, or the like can be used.

Next, the method for producing the poultice will be described in more detail. The poultice containing the absorption promoter of the present invention can be easily produced according to a known production method. For example, a water-soluble polymer is mixed with a polyhydric alcohol or water, dispersed and dissolved to form a uniform kneaded product, and if necessary, a stabilizer, an antioxidant, an ultraviolet absorber, an emulsifier, a preservative,
Add antibacterial agent etc. Next, the medicinal component and N-mono- or di-substituted-p-menthan-3-carboxamide are added, and the mixture is uniformly dispersed and spread directly on the support, or spread on paper or film which has been subjected to a release treatment. Postpone,
Thereafter, it can also be manufactured by pressure transfer to a support to be used. The order in which the respective bases, medicinal ingredients or other components are blended in the above production method is merely an example, and is not limited to this blending order.

The adhesive agent may be appropriately selected from known adhesive agents as an adhesive base in consideration of skin safety, release of active ingredients, adhesion to skin, and the like. Preferred examples of the pressure-sensitive adhesive include an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, and a silicone-based pressure-sensitive adhesive. As the acrylic pressure-sensitive adhesive, in particular, a homopolymer or a copolymer of an alkyl (meth) acrylate having 4 to 18 carbon atoms in the alkyl group,
Alternatively, a copolymer of the above alkyl (meth) acrylate and another functional monomer is preferably used.

Examples of the rubber adhesive include natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene,
Styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer and the like are exemplified.

As the silicone-based adhesive, those containing polyorganosiloxane and polydimethylsiloxane as main components are used. Examples of the tackifier include rosin-based rosin and hydrogenated, disproportionated, polymerized, and esterified rosin derivatives: terpene resins such as α-pinene and β-pinene: terpene-phenol resins: aliphatic, Aromatic, alicyclic and copolymeric petroleum resins and alkyl-
Phenyl resin: Xylene resin and the like are exemplified.

The softening agent plasticizes and softens the base polymer and maintains proper adhesion to the skin. Examples of the softener include higher fatty acid esters such as polybutene, polyisobutylene, liquid paraffin, and isopropyl myristate, and vegetable oils such as silicone oil, almond oil, olive oil, camellia oil, persic oil, and peanut oil.

In the case of a tape preparation, a support that does not affect the release of the medicinal component is desirably used as the support, and stretchable and non-stretchable ones are used. For example, films or sheets of polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane or the like as a synthetic resin film or a laminate thereof, a porous film, foam, paper, cloth and It is selected from a nonwoven fabric or the like. This tape agent can be easily manufactured according to a conventionally known manufacturing method. For example, in the case of a synthetic rubber tape, using a mixer such as a kneader or a mixer, the adhesive base is heated at 120 to 160 ° C. And a softener and a tackifier are mixed by heating, and then the medicinal ingredient and N
-Substituted-p-menthan-3-carboxamide is added and mixed and spread directly on a polypropylene or polyester film or, once spread on a paper or film which has been subjected to a release treatment, a desired support is prepared. Covering and pressure transfer may be performed.

In the case of an acrylic tape, an adhesive base, a drug and an absorption promoter, and if necessary, a compounding agent are dissolved or dispersed in a suitable solvent, and the resulting solution or dispersion is directly applied to the surface of a support.・ Dry, thickness 30 ~ 200μm
Is formed. Alternatively, the solution or dispersion may be applied on a protective release paper, and the adhesive layer obtained after drying may be adhered to a support. The solvent used in this production method is not particularly limited as long as it is an organic solvent that is compatible with all of the components such as the adhesive base and the drug, and examples thereof include aromatic hydrocarbons such as toluene, benzene, and xylene. ,
Esters such as ethyl acetate and halogenated hydrocarbons such as carbon tetrachloride, chloroform and methylene chloride.

Next, ointments which are other transdermal absorbents,
The formulation of the gel, cream, gel cream, lotion, reservoir patch, liniment, and aerosol will be briefly described. Ointments include, in addition to the active ingredient and N-mono- or di-substituted-p-menthan-3-carboxyamide, higher fatty acids such as myristic acid or esters thereof, waxes such as spermaceti, and surfactants such as polyoxyethylene. And at least a hydrocarbon such as hydrophilic petrolatum. The formulation of this ointment is, for example, 5 to 15% by weight of higher fatty acid or its ester, 1 to 10% by weight of surfactant, 0.5 to 10% by weight of active ingredient, N-mono- or di-substituted-p-menthane- 0.1 to 20% by weight of 3-carboxamide is mixed at room temperature or under heating, 4 to 10% by weight of waxes, 50 to 90% by weight of hydrocarbons
And heat or melt by heating, keeping at 50-100 ° C,
After all components become a transparent solution, they are mixed uniformly with a homomixer. Thereafter, the temperature is lowered to room temperature with stirring to obtain an ointment.

The gel agent includes, in addition to the active ingredient and N-mono- or di-substituted-p-menthan-3-carboxamide, a lower alcohol such as ethanol, water, a gelling agent such as a carboxyvinyl polymer, and triethanolamine. And at least a neutralizing agent. The formulation of this gel is expanded, for example, by adding 0.5 to 5% by weight of a gelling agent to 55% by weight or less of water. On the other hand, the medicinal ingredient 0.5-10
% By weight and 0.1 to 20% by weight of N-mono- or di-substituted-p-menthan-3-carboxamide are dissolved in a mixture of 40% by weight or less of glycols and 60% by weight or lower alcohol. These two are mixed, and a neutralizing agent is further added to adjust the pH.
It is adjusted so as to be 4 to 7, and a gelling agent is obtained.

The cream contains, in addition to the active ingredient and N-mono- or di-substituted-p-menthan-3-carboxamide,
It comprises at least an emulsifier such as a higher fatty acid ester such as myristate, water, a hydrocarbon such as liquid paraffin, and a polyoxyethylene alkyl ether.
The formulation of this cream is as follows:
A mono- or di-substituted-p-menthan-3-carboxamide, a higher fatty acid ester, water, hydrocarbons, and an appropriate amount of an emulsifier are added, mixed, and stirred.

The gel cream has an intermediate property between the gel and the cream. In addition to the components of the cream, a gelling agent such as a carboxyvinyl polymer and a diisopronolamine are used. PH neutralizer
It is obtained by adjusting to 4 to 8, preferably 5 to 6.5. The formulation of the gel cream is, for example, 0.5 to 10% by weight of the active ingredient and N-mono- or di-substituted-p-
0.1-20% by weight of menthan-3-carboxamide and 25% by weight or less of higher fatty acid ester and lower alcohol 4
Dissolve in a mixture of 0% by weight or less, and further add 5% by weight or less of an emulsifier. On the other hand, 0.5 to 5% by weight of a gelling agent is added to water to swell. Next, they are mixed and uniformly emulsified with a homomixer, and after emulsification, a neutralizing agent is added to adjust the pH to 4-8.
Adjust to

The lotion contains at least a lower alcohol such as ethanol, water and / or a glycol in addition to the active ingredient and N-mono- or di-substituted-p-menthan-3-carboxamide. The compounding formulation of this lotion is prepared by adding an appropriate amount of the above-mentioned active ingredient, N-mono- or di-substituted-p-menthan-3-carboxyamide, lower alcohol, water and / or glycols,
Obtained by stirring.

The reservoir type patch comprises at least (1) a backing material layer, (2) a drug storage layer, (3) a drug release layer, and (4) a pressure-sensitive adhesive layer. (A) at least a glycol, a lower alcohol, water, a water-soluble polymer, (b) at least an aliphatic alcohol and a polyhydric alcohol (in addition to the component, N-mono- or di-substituted-p-menthan-3-carboxamide) c) A base material containing at least one of paraffins and silicons.

These transdermal preparations of the present invention may contain various pharmacologically acceptable additives such as stabilizers, antioxidants, fragrances, fillers, and other additives within a range not to impair the purpose of the present invention. Can be added.

[0033]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 Lotion Ethanol: Purified Water (1: 1 weight mixture) 91.5% by weight Propylene glycol 5.0% by weight N-ethyl-p-menthan-3-carboxyamide 3.0% by weight Indomethacin 0 The above components were stirred and mixed to prepare an indomethacin-containing lotion.

Example 2 Cream Liquid paraffin 10.0% by weight Medium-chain fatty acid triglyceride 5.0% by weight Polyethylene glycol monostearate 3.0% by weight Glycerin 5.0% by weight Carboxyvinyl polymer 1.0% by weight Diisopropanol Amine 0.4% by weight Methyl parahydroxybenzoate 0.2% by weight Ketoprofen 1.0% by weight N- (2-hydroxyethyl) -p-menthane-3-carboxamide 3.0% by weight Purified water Remaining amount of each of the above components Was stirred and mixed to prepare a ketoprofen-containing cream.

Example 3 Ointment White Vaseline 76.0% by weight Glycerin monostearate 10.0% by weight Tallow 10.0% by weight Silicone oil 1.0% by weight N-ethyl-p-menthan-3-carboxyamide 2 1.0% by weight Flurbiprofen 1.0% by weight The above components were stirred and mixed to prepare a flurbiprofen-containing ointment.

Example 4 Gel Preparation Carboxyvinyl polymer 1.5% by weight Hydroxypropylcellulose 2.0% by weight Ethanol 17.0% by weight Purified water 35.3% by weight Propylene glycol 30.0% by weight Propylene carbonate 10.0% by weight % Triethanolamine 0.2% by weight N, N-dimethyl-p-menthane-3-carboxamide 3.0% by weight Indomethacin 1.0% by weight The above components were stirred and mixed to prepare an indomethacin-containing gel.

Example 5 Poultice Gelatin 5.0% by weight Sorbitol 10.0% by weight Carboxymethylcellulose 3.5% by weight Glycerin 25.0% by weight Kaolin 7.0% by weight Sodium polyacrylate 3.0% by weight N-Ethyl-p-menthan-3-carboxamide 2.0% by weight Diclofenac sodium 0.5% by weight Purified water 44.0% by weight A paste obtained by heating and mixing the above components is put on a base cloth. It was spread to prepare a cataplasm containing diclofenac sodium.

Example 6 Tape Agent Silicone pressure-sensitive adhesive 89.0% by weight (BIO-PSA X7-2920) (in terms of solid content) N- (2-hydroxyethyl) -p-menthan-3-carboxyamide 8 3.0% by weight Clonidine 3.0% by weight A mixture obtained by stirring and mixing the above components was spread on a support,
The solvent was evaporated to prepare a clonidine-containing tape.

Example 7 Tape Agent Acrylic resin-based solvent-based pressure-sensitive adhesive 77.0% by weight (trade name: NISSETSU PE-300) (in terms of solid content) N, N-dimethyl-p-menthan-3-carboxyamide 15.0% by weight isosorbide dinitrate 8.0% by weight A mixture obtained by stirring and mixing the above components was spread on a support,
The solvent was evaporated to prepare a tape preparation containing isosorbide dinitrate.

Example 8 Tape Agent Styrene-isoprene-styrene block copolymer 21.0% by weight (trade name: CALIFLEX TR-1107) Polyisobutylene (trade name Vistanex) 5.0% by weight Rosin ester derivative (trade name) Name KE-311) 14.0% by weight Liquid paraffin 57.0% by weight N-methyl-p-menthane-3-carboxamide 2.0% by weight Ketotifen 1.0% by weight A support obtained by heating and stirring each of the above components is supported. It was spread on the body to prepare a ketotifen-containing tape.

Example 9 Tape agent Styrene-isoprene-styrene block copolymer 20.0% by weight (trade name: CALIFLEX TR-1111) Polyisobutylene (trade name Vistanex) 12.0% by weight Liquid paraffin 30.0 % By weight Rosin ester derivative (trade name: FORAL 105) 30.0% by weight N- (2-hydroxyethyl) -p-menthane-3-carboxamide 7.0% by weight Testosterone 1.0% by weight Each of the above components is heated. The stirred mixture was spread on a support to prepare a testosterone-containing tape.

Example 10 Reservoir type patch (1) Backing material layer Aluminum laminated polyester film (2) Drug storage tank layer 4 g of the following gel composition was enclosed. Tulobuterol hydrochloride 3.0% by weight N-ethyl-p-menthan-3-carboxamide 5.0% by weight Stearyl alcohol 10.0% by weight Cetyl alcohol 10.0% by weight Behenyl alcohol 10.0% by weight 22.0% by weight propylene glycol % 1,3-butylene glycol 35.0% by weight Lauryl alcohol 5.0% by weight (3) Drug-releasing layer Cotran (4) Pressure-sensitive adhesive layer Silicon-based pressure-sensitive adhesive (peripheral portion of support) In (4), this reservoir-type patch was constructed, and a release liner was applied to the surface of the pressure-sensitive adhesive to form a laminate.

Comparative Example 1 Lotion agent Ethanol: Purified water (1: 1 weight mixture) 94.5% by weight Propylene glycol 5.0% by weight Indomethacin 0.5% by weight The above components were stirred and mixed to prepare a lotion agent containing indomethacin. did.

Comparative Example 2 Lotion Ethanol: Purified Water (1: 1 weight mixture) 94.45% by weight Propylene glycol 5.0% by weight N-ethyl-p-menthan-3-carboxyamide 0.05% by weight Indomethacin 0 The above components were stirred and mixed to prepare an indomethacin-containing lotion.

Comparative Example 3 Lotion Ethanol: Purified Water (1: 1 weight mixture) 72.5% by weight Propylene glycol 5.0% by weight N-ethyl-p-menthan-3-carboxyamide 22.0% by weight Indomethacin 0 The above components were stirred and mixed to prepare an indomethacin-containing lotion.

Comparative Example 4 Cream Liquid paraffin 10.0% by weight Medium-chain fatty acid triglyceride 5.0% by weight Polyethylene glycol monostearate 3.0% by weight Glycerin 5.0% by weight Carboxyvinyl polymer 1.0% by weight Diisopropanol Amine 0.4% by weight Methyl parahydroxybenzoate 0.2% by weight Ketoprofen 1.0% by weight Purified water balance The above components were stirred and mixed to prepare a ketoprofen-containing cream.

Comparative Example 5 Tape agent Styrene-isoprene-styrene block copolymer 20.0% by weight (trade name: CALIFLEX TR-1111) Polyisobutylene (trade name Vistanex) 12.0% by weight Liquid paraffin 30.0 % By weight Rosin ester derivative (trade name: Foral 105) 30.0% by weight Menthone 7.0% by weight Testosterone 1.0% by weight The above components were heated and stirred and spread on a support to prepare a testosterone-containing tape. did.

Comparative Example 6 Tape Agent Styrene-isoprene-styrene block copolymer 20.0% by weight (trade name: Califrex TR-1112) Polyisobutylene (trade name Vistanex) 12.0% by weight Liquid paraffin 30.0 % By weight Rosin ester derivative (trade name: FORAL 105) 30.0% by weight d-limonene 7.0% by weight Testosterone 1.0% by weight The above components were heated and stirred and spread on a support, and a testosterone-containing tape was prepared. Was prepared.

Test Example 1 Hairless Mouse Skin Permeation Test The exfoliated skin of a hairless mouse was placed in a diffusion cell having an effective diffusion area of 0.785 cm ² , and the stratum corneum side was a donor phase.
The dermis was mounted so that the dermis side was in the receptor phase, and a transdermal absorption experiment was performed using the indomethacin-containing lotion preparations of Example 1 and Comparative Examples 1 to 3. PH for receptor phase
5 ml of a 7.4 phosphate buffer solution was added as a receptor solution. After 4, 8, and 24 hours, the receptor liquid was sampled, and the permeation amount of indomethacin was determined by HPLC. The results are shown in FIG. FIG. 1 shows that Example 1 showed significantly higher indomethacin permeation than Comparative Example 1.
That is, a high absorption promoting effect of N-ethyl-p-menthan-3-carboxamide was observed. In addition, N-ethyl-p-menthan-3-carboxamide was 0.1%
In Comparative Example 2 containing less than 20% and Comparative Example 3 containing more than 20%, the permeation amount was smaller than that in Example 1.

Test Example 2 Measurement of Rat Blood Concentration The abdomen of a Wistar male rat weighing 160 to 190 g was dehaired, and a cylindrical glass cell having an inner diameter of 10 mm and a height of 10 mm was fixed with a biological adhesive. Next, 1.0 g of the ketoprofen-containing cream of Example 2 and Comparative Example 4 was applied,
Blood was collected from the carotid artery over time, and the blood concentration was measured by HPLC. The results are shown in FIG. As is clear from FIG. 2, N- (2-hydroxyethyl) -p-menthane-3
-Example 2 containing carboxamide showed a significantly higher ketoprofen blood concentration than Comparative Example 4. That is, N- (2-hydroxyethyl) -p-menthane-
It supports the usefulness of 3-carboxamide as an absorption promoter.

Test Example 3 Evaluation of Usability (Sensory Test) The tapes of Example 9 and Comparative Examples 6 to 7 were applied to the forearms of 20 healthy male and female subjects, and the odor when applied was volatilized from the support side. A comparative study was conducted. The method of judgment was such that the subject was reported with the following scores. The scores answered by each subject are totaled, and the average value of 20 subjects is shown in Table 3. Has a strong smell ... 4 points Has a smell ... 3 points Has a slight smell ... 2 points No smell ... 1 point

[0053]

[Table 1]

As is clear from the results shown in Table 1, the tape preparation of Example 9 containing N-ethyl-p-menthan-3-carboxamide of the present invention was almost completely different from the terpene compound of Comparative Example. It was odorless and excellent in usability.

[0055]

EFFECTS OF THE INVENTION The percutaneous absorption enhancer and the percutaneous absorption preparation of the present invention, by incorporating N-mono- or di-substituted-p-menthan-3-carboxamide, significantly increase the percutaneous absorption of the drug. It is to let. Further, the percutaneous absorption enhancer and the percutaneous absorption-type preparation of the present invention have less odor and are excellent in safety such as skin irritation. That is, a percutaneous absorption preparation comprising the percutaneous absorption enhancer of the present invention is safe and excellent in usability, and can rapidly deliver a desired drug to a local site or the whole body through a circulatory system. Therefore, it is extremely useful for treating various diseases.

[Brief description of the drawings]

FIG. 1 is a graph comparing indomethacin permeation of the lotion obtained in Example 1 with the lotions of Comparative Examples 1 to 3 by a hairless mouse skin permeation test.

FIG. 2 is a graph comparing the blood concentration of ketoprofen in rats of the cream obtained in Example 2 with the cream of Comparative Example 4.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Eiji Oda 408, Tashirodamachi, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd. F-term (reference) 4C076 AA08 AA09 AA17 AA74 AA81 BB31 CC05 CC11 DD09 DD28 DD34 DD38 DD46 DD50 DD52 DD59 EE09 EE24 EE27 EE32 EE42 EE54 FF34

Claims (5)

[Claims] 1. N-mono- or di-substituted-p-menthane-3
A transdermal absorption enhancer consisting of carboxamide. 2. N-mono- or di-substituted-p-menthane-3
The carboxamide is of the general formula (I) (In the formula, R ¹ represents hydrogen or a lower alkyl group which may have a substituent, and R ² represents a lower alkyl group which may have a substituent.) p-menthan
The transdermal absorption enhancer according to claim 1, which is 3-carboxamide. 3. The transdermal absorption enhancer according to claim 1, wherein the optionally substituted lower alkyl group in R ¹ and R ² in the general formula (I) is a hydroxy lower alkyl group. . A transdermal preparation comprising a pharmaceutically active ingredient and the percutaneous absorption enhancer according to any one of claims 1 to 3. 5. The percutaneous absorption preparation according to claim 4, wherein the percutaneous absorption enhancer accounts for 0.1 to 20% by weight of the total amount of the percutaneous absorption preparation.