JPH04117323A - Percutaneously absorbing plaster - Google Patents

Abstract

PURPOSE:To obtain a percutaneously absorbing plaster having excellent uniformity of contents of drug, releasability of drug and tackiness to skin, etc., containing a specific polymer as a solubility improver of drug in a patching layer containing drug in a state of an adhering base agent and an acid-added salt. CONSTITUTION:0.1-5.0wt.%, preferably 0.5-4.0wt.% polymer containing basic nitrogen and not having tackiness to skin at normal temperature, e.g. a (co)polymer of polymerizable amine such as (meth)acrylic acid dialkylaminoalkyl or vinylpyrrolidone is contained in a patching layer containing an adhering agent such as acrylic, rubber or silicone and 0.1-20wt.% drug in a state of an acid-added salt (with a proviso that an acid-added salt of 3-{2-[4-(2- methoxyphenyl)-1-piperazinyl]ethyl}-2,4-(1H,3H)-quinazolinedione is omitted) and resultant mixture is held on a supporter.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to an intravenous drug that is applied to biological membranes such as the skin or mucous membranes and is used to administer a required drug to the body's circulatory system through the biological membrane. This invention relates to a skin-absorbable patch.

(Prior art) In general, when administering a drug orally, the gastric or intestinal
Because drug absorption is affected by conditions such as the H value and the presence or absence of contents, it is difficult to maintain a constant amount of drug absorption, and it is difficult to administer a fixed amount of drug gradually over a long period of time. It's also difficult to do. In order to solve these problems, we hope to be able to gently increase the blood concentration of drugs, maintain the effective blood concentration at a constant value over a long period of time, and improve convenience and functionality. Development of a transdermal patch that can be absorbed is progressing.

Some drugs are in the form of pharmacologically acceptable acid addition salts to make them water-soluble. When formulating a drug in the form of an acid addition salt as a transdermal patch, simply incorporating the drug into the adhesive base, which is the main component of the patch, will affect the solubility of the drug in the adhesive base. The drug crystallizes inside or on the surface of the adhesive base.

This phenomenon is caused by the fact that many of the polymer resins that are the main constituents of adhesive bases have poor hydrophilicity, and it is extremely difficult to incorporate the required amount of water-soluble acid-added drugs into these polymers in a dissolved state. Attributable to something. If the drug is contained in an undissolved state in the adhesive base as described above, the resulting patch will be inferior in uniform drug content, drug release properties, and adhesion to the skin.

Conventionally, as a means to improve the solubility of hydrophilic drugs in adhesive bases, at least some of the acidic functional groups such as carboxyl groups and sulfoxyl groups in the polymer resin of the adhesive base have been replaced with alkali metals or alkali It has been proposed to neutralize earth metal hydroxides with basic substances such as aqueous ammonia and triethanolamine (Japanese Unexamined Patent Application Publication No. 1983-1998).
(Refer to Publication No.-29516).

In addition, as another means, it has been proposed to copolymerize (meth)acrylamide having an amino group, such as N,N-dialkylaminoalkyl (meth)acrylamide, with the monomer for producing the polymeric resin of the adhesive base. (Refer to Japanese Patent Application Laid-Open No. 62-228008).

(Problem to be Solved by the Invention) However, in the former method, the basic substance for neutralizing acidic functional groups is a substance that causes skin irritation, so erythema occurs on the skin where it is applied, and in severe cases, Acne formation and edema formation may occur and may even persist for several days after the transdermal patch is removed. Since transdermal patches are applied to the skin for a long period of time, they must not cause skin irritation.

In addition, in the latter method, the adhesive base is made of a copolymer of a monomer for producing a polymer resin and amino group-containing (meth)acrylamide, so it can be changed as appropriate depending on the characteristics of the drug. This is not easy to do, and there are problems in terms of economy and practicality.

In view of the above-mentioned circumstances, an object of the present invention is to incorporate a drug in the form of an acid addition salt into an adhesive base in a dissolved state, thereby improving uniformity of drug content, drug release properties, and adhesion to the skin. It is possible to absorb a sufficient amount of the drug into the body's circulatory system through the skin to achieve the desired medicinal effect, and to reduce skin irritation caused by the contained substances as much as possible. To provide skin-absorbable patches.

(Means for Solving the Problems) As a result of repeated studies to achieve the above object, the present invention provides a two-layer adhesive system consisting of an adhesive base and a drug-containing adhesive layer, and a support holding the same layer. In a drug, when a required amount of a drug in the form of an acid addition salt is included in the adhesive layer and a required amount of a specific substance as a drug solubility enhancer is included in the adhesive layer, the solubility of the drug in the adhesive base is improved. This method was completed based on the knowledge that the transdermal absorption of the drug was significantly improved, and there was no skin irritation at all.

That is, the transdermal patch according to the present invention is a transdermal patch comprising an adhesive base and a drug-containing patch layer held on a support, in which the drug is in the form of a pharmacologically acceptable acid addition salt. (However, 3- (2-[4-(
2-methoxyphenyl)-1-piperazinyl]ethyl)
-2゜4- (1H,3H)-quinazolinedione (excluding pharmacologically acceptable acid addition salts) in the adhesive layer.
A transdermal absorption patch characterized in that the adhesive layer contains 0.1 to 50% by weight of a polymer containing basic nitrogen and having no adhesiveness to the skin at room temperature. It is.

Each component of the transdermal patch according to the present invention and the method for producing the patch will be explained in detail below.

i) The adhesive base of the transdermal patch according to the present invention is not particularly limited as long as it is a general adhesive base composition that has pressure-sensitive adhesive properties that can adhere to the skin or mucous membrane for a long time at room temperature. Preferred adhesive bases include acrylic adhesive bases, rubber adhesive bases, silicone adhesive bases, and the like.

1-a) As the acrylic adhesive base, particularly those having 4 carbon atoms
Homopolymers or copolymers of (meth)acrylic acid alkyl esters obtained from ~18 aliphatic alcohols and (meth)acrylic acid, and/or the above (meth)acrylic acid alkyl esters and other functional monomers. Copolymers are preferably used.

The above (meth)acrylic esters include butyl acrylate, isobutyl acrylate, hexyl acrylate,
Octyl acrylate, 2-ethylhexyl acrylate,
Decyl acrylate, isodecyl acrylate, lauryl acrylate, stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, Examples include stearyl methacrylate.

Examples of the above-mentioned functional monomers include monomers having a heptad-carboxyl group having a hydroxyl group, monomers having an amide group, and monomers having an amino group. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate. Examples of the monomer having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid, maleic acid monoalkyl esters such as butyl maleate, maleic acid, fumaric acid, crotonic acid, and the like. Maleic anhydride also provides the same (co)polymerization component as maleic acid. Examples of monomers having an amide group include acrylamide, dimethylacrylamide,
Alkyl(meth)acrylamides such as diethyl acrylamide: alkoxyalkyl(meth)acrylamides such as butoxymethylacrylamide, ethoxymethylacrylamide, etc.
Examples include acrylamide, diacetone acrylamide, and the like. As a monomer having an amino group, (meth)
Examples include dimethylaminoethyl acrylate, diethylaminoethyl (meth)acrylate, and vinylpyrrolidone.

Furthermore, copolymerizable monomers other than those mentioned above may be copolymerized, and examples of the copolymerizable monomers include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, and butadiene. The adhesive base preferably contains 50% by weight or more of (meth)acrylic acid alkyl ester as a (co)polymerization component.

As a monomer component for the acrylic adhesive base, a small amount of a polyfunctional monomer is further added as necessary, and copolymerized with other monomer components.

The addition of this polyfunctional monomer causes very slight crosslinking between the resulting polymers, thereby increasing the internal cohesive strength of the adhesive base. Therefore, the so-called adhesive residue phenomenon when the patch is removed can be almost eliminated, regardless of the properties of the skin to which it is applied or the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on drug release properties or low skin irritation. Examples of such polyfunctional monomers include di(meth)acrylate, tri(meth)acrylate, and tetra(meth)acrylate.
It is not limited to this. More specifically, di(meth)acrylate obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth)acrylic acid; and polyalkylene glycols such as polyethylene glycol and polypropylene glycol. Di(meth)acrylates obtained by combining with (meth)acrylic acid; tri(meth)acrylates such as trimethylolpropane tri(meth)acrylate and glycerin tri(meth)acrylate; and pentaerythritol tetra(meth)acrylate, etc. There are tetra(meth)acrylates. These polyfunctional monomers may be used in combination of two or more types.

The polyfunctional monomer is used in an amount of 0.005 to 0.5% by weight based on the total monomers used for producing the adhesive base.

If the amount of the polyfunctional monomer used is less than 0.005% by weight, the effect of improving internal cohesive force due to crosslinking will be small, and if it exceeds 0.5% by weight, the adhesive base obtained by polymerization will gel. It is easy to use, and a favorable t1 effect appears on the diffusion and release of the drug.

1-b) The rubber adhesive base contains 100 parts by weight of a rubber elastic body, 20 to 200 parts by weight of a tackifying resin, and an appropriate amount of a modifier such as a softener, as well as an anti-aging agent and other stabilizers. A transdermal absorption enhancer may be added if necessary. As the rubber elastic body, natural rubber (cis-1
, 4-isoprene), synthetic rubber (trans-1,4-isoprene), styrene-isoprene-styrene block copolymer, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer Polymers, styrene-isoprene-butylene block copolymers, ethylene-vinyl acetate copolymers, silicone rubber, etc. are preferably used for strength.

Examples of tackifying resins include rosin-based rosin and hydrogenated, disproportionated, polymerized, and esterified rosin derivatives, terpene resins such as α-pinene and β-pinene, terpene-phenolic resins, and aliphatic resins. , aromatic, alicyclic, and copolymerized petroleum resins, as well as alkyl-phenol resins, xylene resins, and the like. As the softening agent, polybutene, process oil, liquid isobutylene, liquid polyacrylate, castor oil, cottonseed oil, palm oil, coconut oil, beeswax, carnauba wax, lanolin, etc. are used.

1-C) As the silicone adhesive base, those containing poly-1-dimethylsiloxane as a main component can be used.

1-d) The adhesive base may contain, for example, rosin resin,
Tackifiers such as polyterpene resins, coumaron-indene resins, petroleum-based resins, and terpene-phenolic resins; liquid polybutene, mineral oil, lanolin, liquid polyisoprene,
Compounding agents such as a plasticizer such as liquid polyacrylate; a filler; and an anti-aging agent are added as necessary.

11) The drug used in the transdermal patch of the present invention is in the form of a pharmacologically acceptable acid addition salt and is capable of permeating biological membranes transdermally or transmucosally. It is acceptable as long as it is not particularly limited (however, 3- +
2-[4-(2-methoxyphenyl)-1-piperazinylconityl l-2,4-(excluding pharmacologically acceptable acid addition salts of II(,3H)-quinazolinedione). Acid addition salts include hydrochloride, nitrate, sulfate, hydrobromide, phosphate, citrate, tartrate, maleate, fumarate, lactate, mesylate, acetate, etc. Illustrated. Examples of drugs include antipyretic and antiinflammatory analgesics, skeletal muscle relaxants,
Steroid anti-inflammatory agents, vasodilators, antihypertensive/arrhythmia agents, antihypertensive agents, cardiac inotropic agents, antitussive expectorants, antitumor agents, local anesthetics, hormonal agents, asthma/nasal allergy treatment agents, antihistamines, anticoagulants , antispasmodic, cerebral circulation/metabolism improving agent,
Examples include psychiatric agents, autonomic nerve agents, antidepressants and antianxiety agents, vitamin D preparations, hypoglycemic agents, antiulcer agents, sleeping pills, and antibiotics.

Examples of antipyretic and antiinflammatory analgesics include tiaramide hydrochloride, tinoridine hydrochloride, benzydamine hydrochloride, and ergolamine tartrate.

Examples of psychiatric drugs include amitributin hydrochloride, imibramine hydrochloride, and clocabramine hydrochloride.

Examples of skeletal muscle relaxants include tolperisone hydrochloride.

Examples of autonomic nerve agents include isoproterenol hydrochloride, epinephrine hydrochloride, dicyclomine hydrochloride, and the like.

Examples of antispasmodics include amantadine hydrochloride, isocysprine hydrochloride, trihexyphenidyl hydrochloride, tolperisone hydrochloride, and the like.

Examples of antihistamines include diphenhydramine hydrochloride, butadine hydrochloride, promethazine hydrochloride, homochlorcifrizine hydrochloride, and chlorpheniramine maleate.

Examples of cardiotonic agents include etilefrine hydrochloride and dopamine hydrochloride.

Examples of antiarrhythmic agents include acebutolol hydrochloride, alprenolol hydrochloride, oxprenolol hydrochloride, propranolol hydrochloride, and the like.

Examples of antihypertensive agents include ecalazine hydrochloride, clonidine hydrochloride, nicardipine hydrochloride, hydralazine hydrochloride, metoprolol tartrate, and betanisin sulfate.

Examples of antitussive and expectorant agents include ebrazinone hydrochloride, chlorbrenaline hydrochloride, and methylephedrine hydrochloride.

The content of this drug in the adhesive layer is in the range of 0.1 to 20% by weight. If this content is less than 0.1% by weight, it is necessary to significantly increase the size of the patch and expand the area to which it is applied in order to absorb a sufficient amount of the drug to exert the desired medicinal effect. Such large patches are not easy to use, have a poor feeling during application, and are difficult to apply for long periods of time. In addition, this content is 20% by weight
If it exceeds this, the drug becomes supersaturated in the adhesive base, and drug crystals precipitate on the surface of the adhesive base, reducing the adhesion.
After all, it is difficult to stick it on for a long time. A particularly preferable content of the drug is in the range of 0.5 to 15% by weight in the adhesive layer.

(tit) Polymers containing basic nitrogen have no stickiness to the skin at room temperature. A typical example of the polymer is a polymer containing an amino group, but it is also possible to use a polymer containing an amide group, a polymer containing an imino group, a polymer containing an imide group, etc. The amino group may be primary, secondary or tertiary. Also 2
The substituted alkyl group of the primary or tertiary amino group may form a ring. Examples of such polymers include (meth)
Homopolymers of polymerizable amines such as dialkylaminoalkyl (meth)acrylates such as dimethylaminoethyl acrylate and diethylaminoethyl (meth)acrylate, vinylpyrrolidone, or copolymers between these, and the above-mentioned polymerizable amines. Copolymers of at least one of these and other copolymerizable monomers, polyvinyl acetal dialkylamino acetate such as polyvinyl acetal diethylamino acetate, and the like can be mentioned. The molecular weight of the polymer is usually adjusted to 1,000 to 500,000.

Examples of the copolymerizable monomers include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, and isodecyl acrylate. , lauryl acrylate, stearyl acrylate, acrylic acid 2
-Hydroxyethyl, hydroxypropyl acrylate,
Methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-methacrylate
Examples include ethylhexyl, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl methacrylate, 2-hydroxyethyl methacrylate, and hydroxypropyl methacrylate.

Particularly suitable polymers containing basic nitrogen are:
Copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate (manufactured by Röhm, trade name "Eudragit E100", molecular weight:
33000.

Polyvinyl acetal diethylamino acetate (manufactured by Sankyo Co., Ltd., trade name rAEAJ, molecular weight = 48000, nitrogen content weight ratio: 2)
．． 0% by weight).

The content of the polymer containing basic nitrogen varies depending on the type of adhesive base, but is 0.1 to 50% by weight in the adhesive layer.
is within the range of If this content is less than 0.1% by weight, the acid addition salt form of the drug cannot be incorporated into the adhesive base in a dissolved state, and crystals of the drug will precipitate, resulting in the desired medicinal efficacy not being achieved. It is difficult for the drug to be absorbed into the body's circulatory system through the skin in sufficient quantities to cause If this content exceeds 50% by weight, the skin adhesion of the adhesive base will be relatively reduced, making it impossible to obtain good adhesion. A particularly preferred content of the basic nitrogen-containing polymer is in the range of 0.5 to 40% by weight in the adhesive layer.

iv) The support is a flexible but non-drug-permeable sheet that provides self-supporting properties to the transdermal patch and also serves to prevent volatilization and migration of the drug in the patch layer. It is composed of films, laminates of these, metal vapor-deposited materials, woven or non-woven fabrics, paper, foil, etc. Examples of support materials include cellulose acetate, ethyl cellulose, polyethylene terephthalate,
Examples include vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, aluminum, and the like. Among these materials, a material that has conformability to the skin surface is preferably used. In particular, a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is preferred. The thickness of the support is 500 μm or less, preferably 5 to 150 μm.

(2) The transdermal patch according to the present invention usually has a release paper on its application surface. As the release paper, a material obtained by siliconizing a polyethylene terephthalate film is often used, but of course, the release paper is not limited to this. The thickness of the release paper is 100 μm or less, preferably 5 to 5
It is 0 μm.

vi) As a method for manufacturing the transdermal patch according to the present invention, a conventional method for manufacturing an adhesive tape can be applied. A typical example thereof is a solvent coating method, and other methods such as an emulsion coating method, a hot melt method, and a method using electron beam crosslinking are also used. To produce the transdermal patch according to the present invention by a solvent coating method, for example, an adhesive base, a drug, an absorption enhancer, and, if necessary, a compounding agent are dissolved or dispersed in an appropriate solvent. The solution or dispersion is directly applied to the surface of the support and dried to form a sticking layer having a thickness of 30 to 200 μm. Alternatively, this solution or dispersion may be applied onto a protective release paper, and after drying, the resulting adhesive layer may be brought into close contact with the support.

(Function) The transdermal patch according to the present invention is a two-layer patch consisting of an adhesive base, a drug-containing patch layer, and a support holding the same layer. In addition to containing the required amount in the adhesive layer, the adhesive layer contains the required amount of a specific substance as a drug solubility enhancer, so the drug is contained in the adhesive base in a dissolved state. Accordingly, the patch is characterized by uniform drug content, drug release properties,
It has excellent adhesion to the skin, and a sufficient amount of the drug can be absorbed into the body's circulatory system through the skin to exert the desired medicinal effect.

The detailed mechanism of action of basic nitrogen-containing polymers on drug solubility is not clear, or the basic nitrogen-containing groups such as amino groups contained in the polymers are in the form of acid addition salts. It is thought that the solubility of the drug in the adhesive base is increased by dissociating the acid and free-integrating the drug.

Furthermore, no skin irritation caused by the basic nitrogen-containing polymer was observed.

(Example) Next, the present invention will be specifically explained based on examples.

(a) Production Example 1 of transdermal absorption patch ■) Preparation of acrylic adhesive base 65 mol% of 2-ethylhexyl acrylate (302,
0g), vinylpyrrolidone 35 mol% (98.0g)
, and 0.02 mol% (40.0-g) of 1°6-hexamethylene glycol dimethacrylate were placed in a separable flask, and 400 g of ethyl acetate was added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60° C. under a nitrogen atmosphere, and a polymerization initiator solution prepared by dissolving 2 g of lauroyl peroxide in a mixed solvent of 100 g of cyclohexane and 240 g of ethyl acetate was added little by little.
The polymerization reaction was carried out for 12 hours. In this way, an ethyl acetate solution of an acrylic adhesive base having a solid content concentration of 35% by weight was obtained.

II) Preparation of coating solution To the obtained adhesive base solution, clonidine hydrochloride and a copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate (manufactured by Rehm) as a basic nitrogen-containing polymer were added. , Product name: “Eudragit E”
100J, molecular weight: 33000, nitrogen content weight ratio:
5.0% by weight), so that the solid content (sum of weight of adhesive base, drug, and basic nitrogen-containing polymer) concentration is 28.6% by weight, and adhesive base, drug, and basic nitrogen-containing polymer. The content of the contained polymer in solid bone is 76.3% by weight and 6% by weight, respectively.
．． Blended so as to be 8% by weight and 16.9% by weight,
Further, 250 parts by weight of tetrahydrofuran was added to 100 parts by weight of this blend, and the entire liquid was mixed uniformly using a day silver. A coating solution containing the patch formulation was thus prepared.

1i1) Preparation of transdermal absorption patch After applying the coating solution obtained in step 11) onto a release paper made by siliconizing a polyethylene terephthalate film with a thickness of 48 μm, the coating solution was applied in a gear oven at 60°C for 30 minutes. It was dried to form a sticking layer with a thickness of 80 μm. Next, a 38 μm thick support made of a laminate of polyethylene terephthalate and ethylene-vinyl acetate copolymer was brought into close contact with the adhesive layer. Thus, a transdermal patch was prepared.

Example 2 In step If) of Example 1, diphenhydramine hydrochloride was used as the drug, and polyvinylpyrrolidone (manufactured by BASF, trade name "Koriton ni 25", molecular weight = 25000, nitrogen content weight ratio: 12.
2% by weight), and added the drug and polyvinylpyrrolidone to the acrylic adhesive base solution obtained in step i) until the solid bone content of the adhesive base, drug, and basic nitrogen-containing polymer was 86%, respectively. .5 wt%, 3.9 wt% and 9
．． Example 1 except that the content was 6% by weight.
A transdermal patch was prepared using the same procedure as above.

Example 3 In step 11) of Example 1, propranolol hydrochloride was used as the drug, and the drug and basic nitrogen-containing polymer "Eudragit E100" were added to the acrylic adhesive base solution obtained in step i) as an adhesive. Example 1 except that the solid bone contents of the base, drug, and basic nitrogen-containing polymer were 85.7% by weight, 4.8% by weight, and 9.5% by weight, respectively. A transdermal patch was prepared using the same procedure as above.

Comparative Example 1 A transdermal patch was prepared in the same manner as in Example 1, except that the basic nitrogen-containing polymer was not used.

Comparative Example 2 A transdermal absorption preparation was prepared in the same manner as in Example 2, except that the basic nitrogen-containing polymer was not used.

Comparative Example 3 A transdermal absorption preparation was prepared in the same manner as in Example 3, except that the basic nitrogen-containing polymer was not used.

(b) Performance evaluation of transdermal patches i) Skin permeability test For each transdermal patch obtained in the above Examples and Comparative Examples, drug permeation through the excised skin of hairless mice was conducted using the method shown in Test 1. A sex test was conducted.

Test 1 First, a diffusion cell (1) shown in the attached drawing was prepared. The diffusion cell (1) has a bottomed cylindrical receptor tank (2).
and a bottomed cylindrical donor tank (3) placed above it.
It consists of There is an opening (4) in the center of the bottom wall of the donor tank (3).
), and an upper flange (5) and a lower flange (6) are provided at the lower end of the donor tank (3) and the upper end of the receptor layer (2), respectively. The donor tank (3) and the receptor tank (2) are stacked airtightly and concentrically by stacking the lower flanges (6) in an opposing manner. A laterally protruding sampling port (7) is attached, and a magnetic stirrer (9) is placed inside the receptor tank (2).

After sacrificing a hairless mouse (6 weeks old, male) by cervical dislocation, the skin was immediately peeled off and subcutaneous fat was removed.
A piece of skin measuring m x 5 cm was obtained.

This piece of skin (8) is attached to the upper flange (5) of the diffusion cell (1).
) and the lower flange (6), and the donor tank (3
> opening (4) was completely closed with a piece of skin (8). Place the transdermal patch on the upper surface of the skin piece (8) in an area of 3.
．． A test piece (lO) obtained by punching out a 14 cm2 circle was attached. The receptor tank (2) was filled with a receptor liquid prepared by the following method.

Next, the diffusion cell (1) was placed in a constant temperature bath kept at a temperature of 37'', and the receptor liquid was stirred using a magnetic stirrer. 24 hours after the start of the test, 1 m/ml of receptor liquid was added from Sun Ringo (A). The amount of drug permeated into this receptor fluid was measured by high performance liquid chromatography.

Table 1 shows the permeation amount measurement values obtained for each cut-and-cut transdermal patch, expressed as a relative ratio when the value of the patch of the comparative example is set to 1.

[Preparation method of receptor liquid] NaH2PO, (5X10-' mol), Na2HPO4
(2X10-'mol), NaC/ (1゜5X10-
'mol) and gentamicin 10mg in distilled water 500ml
m/, and the pH of the resulting solution was adjusted to 0.1 N NaO.
After adjusting the volume to 7.2 with H aqueous solution, reduce the volume to 1 with distilled water.
000m/bound.

ii) Drug solubility test For each of the transdermal patches obtained in the above Examples and Comparative Examples, the presence or absence of drug crystal precipitation in the formulation was visually observed, and the solubility of the drug in the adhesive base was investigated. .

The observation results are shown in Table 1.

111) Skin Adhesion Test For each of the transdermal patches obtained in the above Examples and Comparative Examples, a drug adhesion test to the prickly skin of rabbits was conducted using the method shown in Test 2.

Test 2 The back of one rabbit (of the New Zealand White breed) was pricked with clippers and a shaver, and a test piece of a transdermal patch (area: 3.14 cm2) was applied to the pricked part. After 24 hours, the area where the test piece had peeled off was measured, and the ratio to the area of the test piece was determined. This test was repeated three times for each formulation. The average value of the determined values (the value obtained by dividing the sum of the values for each time by the number of repetitions of 3) was taken as the skin adhesion index of each transdermal absorption patch.

Table 1 shows these values for each transdermal patch.

iv) Skin irritation test Each of the transdermal patches obtained in the above Examples and Comparative Examples was subjected to an irritation test on rabbit skin using the method shown in Test 3.

Test 3 A test piece (area: 3.14 cm2) of a transdermal patch was applied to the back skin of a rabbit that had been pricked in the same manner as in Test 2, and the test piece was peeled off after 24 hours. One hour after the patch was removed, the state of erythema on the skin at the patch was visually observed.

This test was repeated three times for each formulation. In this test, no edema or formation of epithelium was observed.

The degree of erythema was evaluated using the following 4-grade criteria from 0 to 3.

0...No erythema 1...Mild erythema 2...Clear erythema 3...The average value of the severe erythema rating (the sum of the scores for each time divided by the number of repetitions 3) was calculated for each course. This was used as the skin irritation index for skin-absorbable patches.

Table 1 shows the observation results for each transdermal patch.

(The following is a blank space) Table 1 As is clear from Table 1, the adhesive layer contains 0.1 to 20% by weight of the drug in the form of an acid addition salt, and 0.1 to 20% by weight of the basic nitrogen-containing polymer.
Transdermal patches containing 1 to 50% by weight (Examples 1.2 and 3) have better skin permeability and drug It was found to be significantly superior in both solubility and skin adhesion, and did not cause any skin irritation.

(Effect of the invention) The transdermal patch according to the present invention is a two-layer patch consisting of an adhesive base, a drug-containing patch layer, and a support holding the same layer. is contained in the adhesive layer in a required amount, and a specific substance as a drug solubility enhancer is also contained in the adhesive layer in a required amount, so that the drug can be contained in a dissolved state in the adhesive base. I can,
As a result, the patch can be made to have excellent drug uniformity, drug release properties, adhesion to the skin, etc., and can thereby deliver a sufficient amount of the drug to exert the desired drug effect. can be absorbed transdermally into the body's circulatory system.

Furthermore, no skin irritation caused by the basic nitrogen-containing polymer was observed.

Thus, according to the transdermal absorption patch of the present invention, by including a required amount of the drug in the form of an acid addition salt in the patch layer and a required amount of the basic nitrogen-containing polymer, the above-mentioned effect can be achieved. A unique and remarkable effect can be achieved.

[Brief explanation of drawings]

The drawing is a perspective view of a diffusion cell used to test the skin permeability of drugs contained in transdermal formulations. that's all

Claims (1)

[Claims] (1) A transdermal patch comprising an adhesive base and a drug-containing patch layer held on a support, where the drug is in the form of a pharmacologically acceptable acid addition salt (provided that 3-{
(excluding pharmacologically acceptable acid addition salts of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-2,4-(1H,3H)-quinazolinedione) in the adhesive layer. The adhesive layer contains 1 to 20% by weight of a polymer that contains basic nitrogen and is not sticky to the skin at room temperature.
A transdermal patch characterized by containing 1 to 50% by weight.