JPH05186371A - Percutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To provide a percutaneous absorption preparation permitting the percutaneous absorption of a medicine in an amount sufficient for expressing an expected medicinal effect and reduced in the irritation of skin as low as possible with an absorption accelerating agent. CONSTITUTION:In a percutaneous absorption preparation comprising a medicinal ingredient and an absorption-accelerating agent contained in a basic agent, the percutaneous absorption preparation is characterized in that the absorption- accelerating agent comprises lactic acid and a compound or more selected from a group consisting of polyoxyethylene alkyl ether phosphoric acid salts of formulas I and II (R, R<1>, R<2> are 4-22C alkyl; M<1>, M<2> are alkali metal; l, m, n are 2-16) and lauric acid diethanolamide salts.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tape agent, a patch agent (a reservoir layer containing a drug and a patch layer) which is applied to the skin and is used to administer a required drug through the biological membrane to the body circulation system. The present invention relates to a percutaneous absorption preparation such as a patch formulation, a cream, a liniment, and an ointment.

[0002]

2. Description of the Related Art Generally, in the case of oral administration of a drug, the drug absorbability is always kept constant because the drug absorbability is influenced by the condition such as pH value in the stomach or intestine and the presence or absence of contents. It is also difficult to administer a certain amount of drug gradually over a long period of time. In oral administration, the amount of absorption is not constant and sometimes a rapid increase in blood concentration may cause side effects, and for drugs with a short half-life, the duration of the effective blood concentration may be short and The medicinal effect may not be retained for a long time. Furthermore, injection administration has problems such as pain during administration and inconvenience of administration method.

For example, in oral administration of isosorbide dinitrate, which is one of the antianginal drugs, orthostatic anemia sometimes occurs due to a rapid increase in blood concentration because the absorption amount is not constant.
Side effects such as headaches may occur. Further, since isosorbide nitrate is a drug having a short effective blood concentration, it may not be possible to suppress or prevent seizure at night by oral administration.

Therefore, in order to solve these problems,
The development of transdermal absorption preparations is being actively promoted for the reason that it is possible to maintain a constant effective blood concentration for a long period of time, and further, it is expected that the convenience and functionality will be improved.

From these viewpoints, for example, the following transdermal preparations have been proposed.

In Japanese Patent Laid-Open No. 57-116011, isosorbide nitrate or pentaerythritol tetranitrate is contained as a drug in a polymer having a pressure-sensitive adhesive property at a glass transition temperature of -70 ° C to -10 ° C. Tape formulations are described.

Japanese Unexamined Patent Publication (Kokai) No. 58-134020 discloses an acrylic ester 85 having an alkyl group with 4 to 10 carbon atoms.
~ 99 wt% and acrylic acid or methacrylic acid 1-15
A base layer comprising a copolymer of 100% by weight and isosorbide dinitrate is described.

[0008] By the way, this kind of percutaneous absorption preparation is intended to administer a drug to the circulatory system of the body through the stratum corneum of the skin, which originally has a barrier function of preventing foreign substances from entering the body. It is not always easy to administer a sufficient amount of drug to exert the drug efficacy of, and usually, a measure such as adding an absorption enhancer to the base to increase drug permeability or increasing the patch area is taken. Has been.

When the percutaneous absorption preparation is a patch, it has a side effect of irritating the skin during application, so that the patch area is preferably as small as possible. That is, during the period of applying the preparation to the skin, since the adhesive layer is in contact with the skin surface, the skin in that part is prevented from having normal actions such as secretion, metabolism and expansion and contraction.
You will always be stimulated by the adhesive layer itself. As a result, erythema develops on the patch of the skin, and, in extreme cases, scab formation and edema formation, which may last for several days even after removal of the patch. Therefore, in order to reduce such side effects, it is desired to reduce the application area of the patch by improving the skin permeability of the drug by adding an absorption enhancer.

The following are proposed as percutaneous absorption preparations intended to improve the release of a drug to the skin by adding a specific absorption enhancer as described above.

In JP-A-58-79918, indomethacin is added to an acrylic pressure-sensitive adhesive and at least one or more selected from the group of polyoxyethylene alkyl ethers and polyoxyethylene alkylphenyl ethers as an absorption promoter is added. The anti-inflammatory analgesic patch described above is described.

JP-A-64-56622 describes a transdermal absorption enhancer composition containing an ethylene oxide addition type nonionic surfactant having an ethylene oxide addition mole number of 20 or less.

[0013]

The absorption enhancer functions to improve either or both of the drug release from the adhesive layer and the transdermal drug absorbability. However, the addition of an absorption enhancer to the tacky base should not result in reduced tackiness or increased skin irritation. Therefore, it is necessary to select the optimum absorption promoter in consideration of the target drug, the adhesive base to be mixed, and the like.

All of the absorption enhancers used in the above-mentioned percutaneous absorption preparations of the prior art had a low drug permeation promoting action on the skin.

Since the absorption enhancer acts on the skin during the period when the percutaneous absorption preparation is applied to the skin, it should not cause skin irritation.

However, all of the absorption enhancers used in the above-mentioned prior art transdermal absorption preparations have a certain level of percutaneous absorption promotion effect, but have the drawback of strong skin irritation.

In view of the above situation, an object of the present invention is to make it possible to percutaneously absorb a sufficient amount of a drug to exert a desired drug effect, and to stimulate skin by an absorption promoter. Another object of the present invention is to provide a percutaneously absorbable preparation.

[0018]

[Means for Solving the Problems]

The base of the percutaneous absorption preparation used in the present invention is an adhesive base in the case of tapes and poultices, and a non-stick in the case of ointments, creams, patches and liniments. It is an adhesive base.

As the above-mentioned pressure-sensitive adhesive base, any one can be used as long as it is composed of a general pressure-sensitive adhesive composition capable of dissolving a drug and having a pressure-sensitive adhesive property capable of sticking to the skin or mucous membrane at room temperature for a long time. It is not particularly limited. Examples of preferable adhesive bases include bases made of acrylic adhesives, bases made of rubber adhesives, bases made of silicone adhesives, and the like.

The acrylic pressure-sensitive adhesive used in the acrylic pressure-sensitive adhesive base has 1 to 18 carbon atoms, particularly preferably 4 carbon atoms.
A homopolymer of an alkyl (meth) acrylate obtained from an aliphatic alcohol of 18 to (meth) acrylic acid,
Examples thereof include copolymers and copolymers of alkyl (meth) acrylate and other functional monomers.

As the alkyl (meth) acrylate,
For example, butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2
-Ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate,
Examples thereof include lauryl acrylate, stearyl acrylate, methyl acrylate, ethyl acrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate and stearyl methacrylate.

Examples of the functional monomer include a monomer having a functional group such as a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group and a monomer having a pyrrolidone ring. As the monomer having a hydroxyl group,
For example, 2-hydroxyethyl (meth) acrylate,
Examples are hydroxyalkyl (meth) acrylates such as hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, monoalkylmalates such as ethylmalate and butylmalate, maleic acid, fumaric acid and crotonic acid. Maleic anhydride is used as well as maleic acid. Examples of the monomer having an amide group include alkyl (meth) acrylamides such as acrylamide, dimethylacrylamide and diethylacrylamide, N-alkoxymethyl (meth) acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide, and diacetoneacrylamide. .. An example of the monomer having an amino group is dimethylaminoethyl acrylate. An example of the monomer having a pyrrolidone ring is vinylpyrrolidone.

Further, the above-mentioned copolymer may be further copolymerized with a copolymerizable monomer having no functional group. Examples of the copolymerizable monomer include vinyl acetate, styrene and α.
-Methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, etc. can also be used. It is preferable that the adhesive contains 50% by weight or more of an alkyl (meth) acrylate as a (co) polymerization component.

If desired, a polyfunctional monomer may be added to the acrylic pressure-sensitive adhesive to copolymerize it with other monomer components. The addition of this polyfunctional monomer causes cross-linking between the resulting polymers, which increases the internal cohesive strength of the adhesive. Therefore, the so-called adhesive residue phenomenon at the time of peeling the patch is almost eliminated regardless of the property of the applied skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on the drug release property and the low skin irritation property. Examples of such a polyfunctional monomer include, but are not limited to, di (meth) acrylate, tri (meth) acrylate, and tetra (meth) acrylate. More specifically, hexamethylene glycol di (meth) acrylate, octamethylene glycol di (meth) acrylate and the like obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth) acrylic acid. Di (meth) acrylate, di (meth) acrylate obtained by combining polyalkylene glycols such as polyethylene glycol and polypropylene glycol with (meth) acrylic acid, trimethylolpropane tri (meth) acrylate and glycerin tri (meth) acrylate. ) Tri (meth) acrylates such as acrylate, and tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate. Two or more kinds of these polyfunctional monomers may be added. The amount of the polyfunctional monomer added is 0.5% by weight or less based on the total amount of the monomers used for producing the pressure-sensitive adhesive.

If necessary, a tackifier such as a rosin resin, a polyterpene resin, a coumarone-indene resin, a petroleum resin, or a terpene-phenol resin may be added to the acrylic pressure-sensitive adhesive.

To prepare the acrylic pressure-sensitive adhesive,
Solution polymerization of the required monomer is carried out in the presence of a polymerization initiator. However, the polymerized form is not limited to this. The polymerization reaction conditions are appropriately selected mainly depending on the type of monomer.

Examples of the rubber-based pressure-sensitive adhesive used as the rubber-based pressure-sensitive adhesive base include natural rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-olefin-styrene block copolymer. 100 parts by weight of a rubber elastic material such as coalesce, polyisoprene, polybutene, polyisobutylene, ethylene-vinyl acetate copolymer and the like, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene-phenol resin, etc. 20 to 20 tackifiers
0 parts by weight and, if necessary, an appropriate amount of liquid polybutene, mineral oil, lanolin, liquid polyisoprene, a softening agent such as liquid polyacrylate, a filler such as titanium oxide, an antiaging agent such as butylhydroxytoluene, etc. The thing is illustrated.

Examples of the silicone-based pressure-sensitive adhesive used in the silicone-based pressure-sensitive adhesive base include those containing polydimethylsiloxane as a main component.

As an adhesive base having a good affinity with water, natural polymers such as alkali metal alginate, gelatin, corn starch and tragacanth gum, cellulosic polymers such as methyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose, dextrin and carboxymethyl starch. Examples thereof include starch-based polymers such as polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone.

Compounding agents such as a plasticizer, a filler and an anti-aging agent may be added to the above-mentioned pressure-sensitive adhesive as required.

Examples of the non-sticky base include beeswax, oil and fat,
Examples thereof include lanolin, white petrolatum, paraffin, plastis base, higher fatty acid, higher alcohol, emulsifier, macrogol, and carboxyvinyl polymer.

Drugs (physiologically active substances) used in the present invention
It may be any substance that can permeate the biological membrane transdermally, and typical drugs include isosorbide nitrate, piroxicam, indomethacin, diltiazem and the like.

However, the drug (physiologically active substance) used in the percutaneous absorption preparation of the present invention is not limited to the above. Examples of drugs include antipyretic and anti-inflammatory analgesics, antiepileptics, antipsychotics, antidepressants / anxiolytics, antidepressants,
Hypnotics, sedatives, antispasmodics, muscle relaxants, autonomic nerve agents,
Cerebral circulation / metabolic agent, cardiotonic agent, antianginal agent, hypertensive / arrhythmic agent, vasodilator, antihypertensive agent, pressor agent, diuretic agent,
Respiratory stimulants, antitussive expectorants, bronchodilators, asthma / nasal allergies, respiratory agents, colds, antiemetics, antacids, antiulcers, laxatives, diarrhea, intestinal preparations, liver preparations, Pancreatic disease therapeutic agent, choleretic agent, female hormone agent, androgen agent, hypothalamic and pituitary hormone agent, ovulation inducer, diabetes insipidus treatment agent, thyroid hormone agent, anabolic hormone agent, antithyroid agent, Calcium metabolizers, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, anti-inflammatory enzymes, antihistamines, anti-rheumatic agents, gout remedies, hypoglycemic agents, vitamins, hematopoietic agents, hemostatics, hyperlipidemia remedies, Examples include antibiotics, antitumor agents, immunosuppressants, antidotes, emetics, antiparasitics, antiprotozoal agents, hemorrhoids therapeutic agents, genitourinary agents, local anesthetics, anticoagulants, and the like.

Representative examples of each drug are shown below.

Examples of the antipyretic and anti-inflammatory drug include indomethacin, salicylic acid, glycol salicylate, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutazone,
Examples include mefenamic acid, bendazac, piroxicam, flurbiprofen, pentazocine, buprenorphine hydrochloride, butorphanol tartrate and the like.

Examples of the steroidal anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fludroxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate and propionate. Examples include clobetasol and fluocinonide.

Examples of vasodilators include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, nitroglycerin and the like.

Examples of the antihypertensive / arrhythmic agent include propanolol, atenolol, pindolol, quinidine sulfate, azimarin, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and disopyramide.

Examples of antihypertensive agents include clonidine hydrochloride, captopril, prazosin hydrochloride, penbutolol sulfate, guanabenz acetate, guanfacine hydrochloride, bunazosin hydrochloride, ellanapril maleate, arotinolol hydrochloride, and bunitrolol hydrochloride.

Examples of the antitussive expectorant include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pirbuterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimetoquinol hydrochloride and formoterol fumarate. It is illustrated.

Examples of the antitumor agent include 5-fluorouracil, 1- (2-tetrahydrofuryl) -5-fluorouracil, mitomycin C and the like.

Examples of local anesthetics include benzocaine, procaine, lidocaine and tetracaine.

Examples of the hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone and prostaglandins, and peptide hormones such as insulin.

Examples of the therapeutic agent for asthma / nasal allergy include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate and the like.

Examples of the antihistamine include cycloheptazine hydrochloride, diphenhydramine hydrochloride, phenbenzamine, mequitazine and the like.

Examples of the anticoagulant include heparin and the like.

Examples of antispasmodic agents include scopolamine,
Examples include clofluperol and the like.

Examples of the agents for improving cerebral circulation and metabolism include vinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxine mesylate, ifenprodil tartrate, isoxuprine hydrochloride and the like.

Examples of the antidepressant / anxiolytic agents include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like.

Examples of vitamin D preparations include alfacalcidol, ergocalciferol and the like.

Examples of the hypoglycemic agent include glibenclamide, gliclazide and the like.

Examples of anti-ulcer agents include clevobride malate, famotidine, glycopyrronium bromide and the like.

Examples of sleep agents include phenobarbital and amobarbital.

Examples of antibiotics include tetracycline and chloramphenicol.

The amount of these drugs added varies depending on the type of the drug, the purpose of use of the transdermal preparation, and the like, but is preferably 0.1 to 50% by weight. The saturated solubility of a drug in a base depends on the composition of the base. High release of the drug is obtained by compatibilizing the drug in the base at a concentration as close as possible to its saturated solubility and preventing crystal precipitation. However, even if drug crystals are precipitated in the base, there is no particular problem. It is also possible to encapsulate the drug or the absorption enhancer and to provide a storage layer for the drug or the absorption enhancer.

The transdermal preparations used in the present invention include tapes, poultices, patches, creams, liniments and ointments.

In the above tape preparation, the adhesive base containing a drug, an absorption enhancer, and an additive to be added if necessary,
It is provided on one side of the support, and a preferable adhesive base has good adhesion to the skin.

The above-mentioned poultices are prepared by applying the above-mentioned adhesive base containing a drug, an absorption promoter, water and additives, which are optionally added, in a layered manner on one side of a support, and the preferred adhesive base is Has a good affinity with water. If the adhesive base has poor adhesiveness, it is fixed to the skin surface with a plaster or adhesive tape.

The above-mentioned patch is composed of a non-adhesive reservoir layer and an adhesive layer consisting of the above-mentioned adhesive, which are sequentially laminated on one surface of a support, and the reservoir layer contains a drug, an absorption promoter and The non-adhesive base containing an additive added as necessary is retained. The reservoir layer is attached to the skin via the adhesive layer, and the drug in the reservoir layer is transdermally absorbed through the adhesive layer.
However, the drug and the absorption promoter in the reservoir layer may be included in the adhesive layer.

The above-mentioned creams, ointments and liniments are drug-containing pastes, slurries or liquids prepared by uniformly mixing the non-adhesive base with a drug, an absorption enhancer and optionally added additives. It is a thing.

A fat-soluble dissolving agent, purified water, a water-soluble dissolving agent, a pH adjusting agent and the like may be added to the cream and ointment. Examples of the fat-soluble dissolving agent include liquid paraffin, isopropyl myristate, diethyl sebacate, and the like, and examples of the water-soluble dissolving agent include ethanol, glycerin, propylene glycol, and the like.

As a support for tapes, poultices and patches, it is flexible but imparts self-supporting properties to transdermal preparations, and volatilizes or migrates the drug in the adhesive base layer or reservoir layer. The thing which plays a role of preventing is used. As the material of the support, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-
Examples thereof include vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride and aluminum. These materials are used, for example, as a single layer sheet or film or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics.
As the support, one made of a material having conformability to the skin surface is preferably used, and a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is particularly preferable. The thickness of the support is preferably 5
˜100 μm.

An adhesive base layer is formed on one surface of the support to form a tape preparation, and a reservoir layer and an adhesive layer are sequentially laminated on one surface of the support to form a patch preparation. In the patch agent, a suitable control film may be present between the reservoir layer and the adhesive layer.

In the preparation of the tape preparation, an ordinary method for producing an adhesive tape can be applied to form the adhesive base layer. A typical example thereof is a solvent coating method, and in addition to this, a hot melt coating method, an electron beam curing emulsion coating method and the like are used. To form the adhesive base layer by a solvent coating method, for example, a drug, an absorption promoter, and an additive that is added as necessary are dissolved or dispersed in an appropriate solvent, and the resulting solution or dispersion is supported. Apply directly to one side of the body and dry to form an adhesive base layer with the required thickness. Further, this solution or dispersion may be coated on a protective release paper and the adhesive base layer obtained after drying may be brought into close contact with the support.
The thickness of the adhesive base layer varies depending on the purpose of use, but is preferably 10 to 200 μm.

The tape preparation is usually provided with a release paper on its sticking surface in order to protect the surface of the adhesive base layer until use. The patch has a release paper on the sticking surface of the adhesive layer. As the release paper, a polyethylene terephthalate film treated with silicon is often used, but the release paper is not limited to this. The thickness of the release paper is 10
The thickness is 00 μm or less, preferably 30 to 200 μm.

In order to produce a poultice, an adhesive base, a drug, an absorption promoter, water and additives which are added if necessary are uniformly mixed, and the obtained drug-containing paste is applied to one side of a support. Apply in layers. In addition to the drug-containing paste,
Other additives such as purified water, a moisturizer, an inorganic filler, a viscosity modifier, a cross-linking agent and an antioxidant may be added. Examples of moisturizers include glycerin and propylene glycol, and examples of inorganic fillers include kaolin, bentonite, zinc white, titanium dioxide and the like.

The obtained transdermally absorbable preparations of various dosage forms are usually applied or applied directly to the surface of the skin or mucous membrane for the purpose of transdermally or transmucosally administering the drug to the internal circulatory system. It Further, these percutaneously absorbable preparations may be applied or applied to the skin or mucous membrane for the purpose of treating a diseased part of the skin or mucous membrane.

The absorption enhancer used in the present invention is a combination with lactic acid and at least one compound selected from polyoxyethylene alkyl ether phosphate and lauric acid diethanolamide.

The above polyoxyethylene alkyl ether
The phosphate is a compound represented by the general formula (1) or (2).
Is. Where R, R¹And R²Is an alkyl group, charcoal
If the prime number is less than 4, there is no absorption promoting effect and the carbon number is 22.
If it exceeds it, it will give a high irritation to the skin.¹And R²
The alkyl group of is limited to 4 to 22. Also, R, R ¹
And R²May be the same or different and may be linear or
Various alkyl groups may be used.

[0071]

[Chemical 3]

[0072]

[Chemical 4]

In the formula, as the alkali metal of M and M ¹ ,
Examples include sodium and potassium.

The polyoxyethylene alkyl ether phosphate represented by the general formula (1) is preferably sodium polyoxyethylene lauryl ether phosphate or sodium polyoxyethylene oleyl ether phosphate.

The polyoxyethylene alkyl ether phosphate represented by the general formula (2) is preferably potassium dipolyoxyethylene nonylphenyl ether phosphate, sodium dipolyoxyethylene oleyl ether phosphate, or the like.

The above polyoxyethylene alkyl ether phosphate and lauric acid diethanolamide may be used alone or in combination of two or more, preferably 0.05 to 0.05% in the base. 5% by weight,
More preferably, it is 0.2 to 2% by weight.

The addition amount of the above-mentioned lactic acid is preferably 0.1 to 10% by weight, more preferably 0.5 to 5 in the base.
% By weight.

In order to further improve the transdermal absorbability of the drug, lactic acid and another absorption promoter other than the above polyoxyethylene alkyl ether phosphate and lauric acid diethanolamide may be added.

The amount of the drug or absorption enhancer contained in the above-mentioned base corresponds to the amount of the ointment, cream or liniment added to the preparation itself, and the amount of the tape or poultice to the support or peel from the preparation. It corresponds to the amount added to the part excluding the paper, that is, the part of the adhesive base, and the patch agent corresponds to the amount added to the base contained in the reservoir layer and / or the adhesive layer.

[0080]

The percutaneous absorption preparation according to the present invention uses a combination of lactic acid and polyoxyethylene alkyl ether phosphates (1) and (2) and lauric acid diethanolamide as an absorption enhancer to obtain a unit area and a unit. The release amount of the drug per unit time and the migration of the drug into the skin are significantly improved. Thus, the combined use of lactic acid and polyoxyethylene alkyl ether phosphate and lauric acid diethanolamide as the absorption enhancer provides an excellent drug absorption enhancing effect which cannot be obtained when these compounds are used alone. .. It is considered that this is because the absorption enhancer changes the physical properties of the base material and penetrates into the skin to reduce the barrier function of the stratum corneum. As a result, the partition coefficient of the drug between the base and the skin changes, or the diffusion rate of the drug in the skin is increased, the release amount of the drug is improved, and the required amount of the drug easily permeates the skin. It is then absorbed into the body's circulatory system.

Therefore, in the case of a tape preparation, a transdermal absorption preparation having a larger effective dose than the conventional preparation containing the same area as that of the conventional drug-containing transdermal preparation can be obtained. In other words, the same effect as the conventional product can be obtained with the transdermal preparation having an area smaller than that of the conventional product.

Therefore, even in a person who is sensitive to skin irritation, the occurrence of erythema is avoided or the area of erythema is reduced. And because the area of the preparation is small,
The sticking operation is easy and there is no discomfort due to sticking.

[0083]

EXAMPLES Next, examples of the present invention will be described. In the following, "parts" means "parts by weight". The evaluation methods and measurement methods for the skin migration test, skin irritation test, and skin permeability test shown in the results are as follows.

1) Skin transfer test A test piece of the patch was applied to the dehaired back of Japanese white rabbits (
An area of 10 cm ² ) was attached, and after 24 hours, this was peeled and collected. The collected test pieces were subjected to extraction treatment with methanol, and the residual amount of the drug in the patch was measured by high performance liquid chromatography to determine the difference between the amount of the drug before application and the amount after application of the patch. The amount transferred to the skin was represented by an average value obtained by repeating this operation 4 times and dividing the total sum of the measured values by 4 times of repetition.

2) Skin Irritation Test The erythema state of the skin one hour after the peeling of the patch in the skin migration test was visually observed and evaluated according to the following 5 grades. 0: No erythema 1: Minor erythema barely discernible 2: Clear erythema 3: Moderate erythema 4: Strong erythema of deep crimson The skin irritation of the skin absorption preparation is the sum of the scores at each time divided by 4 times. The average value is shown.

3) Skin Permeability Test First, a Franz type diffusion cell 1 shown in FIG. 1 was prepared. The diffusion cell 1 is a cylindrical bottomed receptor tank 2
And a bottomed cylindrical donor tank 3 arranged on the tank. An opening 4 is provided in the center of the bottom wall of the donor tank 3, and the bottom wall extends in the circumferential direction and has a flange 5
Is provided. A flange 6 is provided on the upper part of the receptor tank 2, and a sampling port 7 protruding laterally is attached to the side wall. The flange 5 and the flange 6 are opposed to each other and overlapped, and the donor tank 3 and the receptor tank 2 are stacked in an airtight and concentric manner. A magnetic stirrer 9 is placed inside the receptor tank 2.

Hairless mice (8-week-old, male) were sacrificed by cervical dislocation, and immediately the back skin was peeled off to remove subcutaneous fat and muscle layer to obtain a skin piece of about 5 cm × 5 cm. The skin piece 8 was sandwiched between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor tank 3 was completely closed by the skin piece 8.

100 mg of the cream was applied to a PET film having a thickness of 15 μm punched into a circle (3.14 cm ² ) and applied to the upper surface of the skin piece 8.

The receptor layer 2 was filled with the receptor solution, placed in a constant temperature bath maintained at a temperature of 37 ° C., and the magnetic stirrer was rotated by a magnetic stirrer and stirred. 24 hours after the start of the test, 1 ml of the receptor liquid was sampled from the sampling port 7, and the amount of the drug in the sampled receptor liquid was measured by high performance liquid chromatography. After collecting the receptor fluid, the receptor fluid was replenished after the collection.
The permeation amount was represented by an average value obtained by dividing the sum of the measured values by 4 times by repeating the above operation 4 times.

The receptor liquid is NaH.₂PO_FourIs 5
× 10^-Fourmol / l, Na₂HPO _FourIs 2 × 10^-Fourmo
l / l, NaCl 1.5 × 10^-1mol / l and Gen
1N Na in an aqueous solution containing 10 ppm of tamycin
Aqueous solution 8 whose pH was adjusted to 7.2 by adding an aqueous OH solution
20 parts by weight of polyethylene glycol 400 in 0 parts by weight
Obtained by dissolving.

Synthesis of Adhesives A and B A predetermined amount of the monomer shown in Table 1 and 400 parts of ethyl acetate were fed to a separable flask equipped with a stirrer and a cooling device, and heated to 60 ° C. while stirring and purging with nitrogen. .. A solution prepared by dissolving 2 parts of lauroyl peroxide in 100 parts of cyclohexane was divided into 10 parts, and 1 was added to a separable flask to initiate polymerization. The remaining 9 was added at 1-hour intervals from the 5th hour after the start of the reaction, and the reaction was continued for 19 hours after the addition was completed. To adjust the viscosity, 50 parts of ethyl acetate was added 5 times every 5 hours after the reaction was started. After the reaction was completed, the reaction mixture was cooled, and ethyl acetate was added so that the solid content concentration became 35% by weight.

[0092]

[Table 1]

Adjustment of Adhesive C As a rubber elastic body, styrene-isoprene-styrene block copolymer (Califlex TR manufactured by Shell Chemical Co., Ltd.
1107) 100 parts, aliphatic hydrogenated petroleum resin (Arakawa Chemical Co., Alcorn-P90) 140 parts, polybutene (Nisseki Chemical Co., HV-300) 25 parts and cyclohexane 483.38 parts are stirred and cooled. The mixture was supplied to a separable flask equipped with the same and stirred at 25 ° C. for 96 hours to be dissolved to obtain an adhesive having a solid content concentration of 35.41% by weight.

Examples 1 to 17 and Comparative Examples 1 to 11 Predetermined amounts of adhesives shown in Tables 2 to 4, isosorbide dinitrate,
Piroxicam, indomethacin, diltiazem, lactic acid,
Polyoxyethylene ether phosphate and lauric acid diethanolamide were fed to the dissolver and mixed uniformly. The obtained mixed liquid was applied onto a polyethylene-treated polyethylene terephthalate film (thickness: 38 μm),
An adhesive layer having a thickness of 80 μm is formed by drying at 60 ° C. for 30 minutes, and then transferred onto a polyethylene terephthalate-ethylene / vinyl acetate copolymer layer having a thickness of 50 μm to obtain the percutaneous absorption preparation of the present invention. It was

The transdermal absorption preparations obtained in Examples 1 to 14 and Comparative Examples 1 to 8 were subjected to a skin migration test and a skin irritation test, and the results are shown in Tables 2 and 3.

[0096]

[Table 2]

[0097]

[Table 3]

The percutaneous absorption preparations obtained in Examples 15 to 17 and Comparative Examples 9 to 11 were subjected to a skin permeability test and a skin irritation test, and the results are shown in Table 4.

[0099]

[Table 4]

Examples 18 and 19, Comparative Example 12 Emulsion mixture of predetermined amounts of indomethacin, lactic acid and sodium polyoxyethylene lauryl ether phosphate shown in Table 5 with 26 parts of white vaseline, 35 parts of isopropyl myristate and 35 parts of cetanol. These were mixed well with a device (Mizuho Industry Co., Ltd.) to prepare a cream.

A skin permeability test and a skin irritation test were conducted on the obtained cream preparation, and the results are shown in Table 5.

[0102]

[Table 5]

[0103]

The percutaneous absorption preparation of the present invention comprises at least one compound selected from lactic acid and polyoxyethylene alkyl ether phosphates (1) and (2) and lauric acid diethanolamide as an absorption enhancer. By using the combination with, it is possible to absorb a sufficient amount of drug through the skin to develop the desired drug effect, and the application area required for drug administration is small, resulting in skin damage during long-term use. There is little, and there is little or no skin irritation due to absorption enhancers.

Further, in the transdermal preparation of the present invention, since a sufficient amount of the drug as described above is easily transdermally absorbed, a large amount of the drug as in the prior art is used. It is possible to maintain the effective blood concentration for a long time without the need for compounding, and it does not denature the drug, has excellent compatibility with the base, and changes the compatibility between the drug and the base. Since the drug is not given, the drug may be deposited from the surface of the transdermal preparation, so that the bioavailability of the drug can be enhanced.

In addition, since a transdermal preparation having a small area as described above can provide sufficient medicinal effect, it is possible to avoid the occurrence of erythema even in a person who is sensitive to skin irritation, or to reduce the erythema area. Can be reduced. Since the transdermal preparation requires a small area in this way, the sticking operation can be performed easily and the discomfort caused by sticking can be reduced.

[Brief description of drawings]

FIG. 1 is a perspective view showing a Franz type diffusion cell.

Claims (1)

[Claims] 1. A percutaneous absorption preparation comprising a drug and an absorption enhancer in a base, wherein the absorption enhancer is lactic acid and a polyoxyethylene alkyl ether phosphorus represented by the following formulas (1) and (2). A percutaneous absorption preparation comprising one or more compounds selected from the group consisting of acid salts and lauric acid diethanolamide salts. [Chemical 1] [Chemical 2]