JPH02255612A - Medical application agent - Google Patents

Abstract

PURPOSE:To obtain a medical application agent, having high releasability and percutaneous absorbability of a drug and simultaneously suppressing the reduction in content of the drug with a change thereof with time by regulating exposed surfaces of a pressure-sensitive adhesive layer containing a basic drug or salt thereof to a pH within a specific range. CONSTITUTION:A medical application agent obtained by including any one of (A) a basic drug except ifenprodil and meteroprolol and a basic substance (preferably an organic carboxylic acid), (B) a basic drug salt and the basic substance (e.g. alkali metal hydroxide and amines) and (C) the basic drug and a salt thereof in a pressure-sensitive adhesive layer, regulating the pH of exposed surfaces thereof to >=7, preferably 7.0-11.5 and laminating the resultant regulated layer onto a flexible support. A copolymer of an alkyl (meth)acrylate and (meth)acrylic acid and a copolymer of the alkyl (meth)acrylate and an alkyl (meth)acrylate having ether bond in the molecule and copolymerizable monomer other than those described above are cited as the pressure-sensitive adhesive.

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to a medical patch containing a basic drug and/or a salt thereof as a medicinal ingredient.

<Prior Art> As a dosage form for absorbing a drug as a medicinal ingredient through the outer skin of the body, there is a medical patch containing a drug. Some of these patches use pressure-sensitive adhesives such as rubber-based or acrylic-based polymeric materials as the base material for the purpose of adhesion to the skin, but these generally have poor drug solubility. It is extremely difficult to maintain uniform dissolution of drugs, especially in the form of Vc salts, and even if the drug is carefully prepared in a dissolved state, the drug contained crystallizes during storage, impairing the transdermal absorption of the drug. It may interfere.

Conventionally, an organic acid was co-existed in a pressure-sensitive adhesive layer containing a drug.

(b) Nine technologies to improve drug release and transdermal absorption (
For example, JP-A-63-79820, JP-A-62-
126119).

(b) Technology aimed at preventing drug content from decreasing due to changes over time and stably containing the drug over a long period of time (e.g., JP-A-60
-193920 publication.

→→+-Machikai No. 56-100715) is known. Incidentally, the above technique is applicable to the exposed surface of the pressure sensitive adhesive layer.
I haven't paid any attention to pHVc.

<Problem to be solved by the invention> The above problem is that in the case of the above-mentioned technology (a), the drug content may decrease, and in the case of the reverse K(E) technology, the release property and transdermal absorption of the drug may be affected. In other words, the actual situation is that a patch that has both characteristics (a) and (b) has not yet been obtained.

Means for Solving the Problems> As a result of intensive studies to solve the above problems, the present inventor found that the drug contained in the pressure-sensitive adhesive layer is in the form of a salt or in a free form (free form). Determine the type of additive and its necessity by focusing on the pH of the exposed surface of the adhesive layer.
The inventors discovered that a patch having both of the characteristics of (a) (→) can be obtained by setting the value of 7 or more, leading to the completion of this invention.

That is, the present invention is pressure sensitive! II! A medical patch comprising an adhesive layer laminated on a flexible support, wherein the exposed surface of the pressure-sensitive adhesive layer has a pH of 7 or more.

The present invention also relates to a medical patch characterized in that the pressure-sensitive adhesive layer contains one of the following components.

(Top) Basic drugs (excluding ifenprodil and metoprolol) and acidic substances (1) Basic drug salts (excluding ifenprodil salts and metoprolol salts) and basic substances.

(lit) tJ [True drugs (excluding ifenprodil and metoprolol) and basic drug salts (excluding ifenprodil salts and metoprolol salts).

The pressure-sensitive adhesive layer used in the present invention is a layer containing and retaining a basic drug salt, its salt, an acidic substance, and a basic substance, and is a layer for adhering the patch of the present invention to the skin surface. It is something.

Preferred pressure-sensitive adhesives include acrylic pressure-sensitive adhesives in terms of adhesion to the skin and drug stability.

As the acrylic pressure-sensitive adhesive, for example, [Meta]
Acrylic acid butyl ester (meth)acrylic acid pentyl ester (meth)acrylic acid hexyl ester (
Meth)acrylic acid heptyl ester (meth)acrylic acid octyl ester.

(meth)acrylic acid nonyl ester (meth)acrylic acid decyl ester [meth]acrylic acid undecyl ester (meth)acrylic acid dodecyl ester (meth)acrylic acid dodecyl ester
Among the (meth)acrylic acid alkyl esters having an alkyl group having 4 to 13 carbon atoms, such as acrylic acid tridecyl ester, one is a combination of two or more, or a combination of two or more of the esters. Examples include copolymers with two or more polymerizable monomers.

Examples of copolymerizable monomers include (a) carboxyl group-containing monomers such as (meth)acrylic acid, itaconic acid, crotonic acid, maleic acid, maleic anhydride, and fumaric acid; Ester A hydroxyl group-containing monomer such as (meth)acrylic acid hydroxyglobyl ester.

(b) (meth)acrylic acid methoxy ether ester (
Meth) acrylic acid ethoxyethyl ester (meth)acrylic acid butoxyethyl ester (meth)acrylic acid tetrahydrofurfuryl ester (meth)acrylic acid methoxyethylene glycol ester, (meth)acrylic acid methoxydiethylene glycol ester (meth)acrylic acid methoxypolyethylene glycol ester Ester (meth)acrylic acid alkyl ester having an ether bond in the molecule, such as (meth)acrylic acid methoxypolyglobylene glycol ester.

(C) General formula (wherein, R is hydrogen or a methyl group, and X is at least one nitrogen atom or a group having nitrogen and oxygen atoms.) The following monomers, (meth)acrylic Acid amine ethyl ester (meth)acrylic acid dimethylamine ethyl ester [meth]acrylic acid diethylaminoethyl ester Acrylic monomer containing an alkylaminoalkyl group such as (meth)acrylic acid tert-butyl ester, urethane of (meth)acrylic acid , urea, functional monomers such as acrylic monomers such as isocyanate esters.

(- General formula % formula % (However, X represents a group having at least one nitrogen atom or nitrogen and oxygen atoms.) The following monomers, vinylcaglolactam, vinylimidazole, vinyl Methylimitasol Vinylphenylimitasol Vinylpyrrolidone, Vinylmethylpyrrolidone, Vinylpiperidone Vinylpyridine #, l, Acryloylmorpholine,
Vinyl morpholine, vinylthiazole Vinyl monomers containing nitrogen atom-containing saturated heterocyclic groups such as vinylpyrazine, vinylpiperazine, vinylpyridine, vinylpyrrole or vinyl monomers containing unsaturated heterocyclic groups, (meth)acrylamide, dimethyl amide group-containing acrylic monomers such as (meth)acrylamide N-butylacrylamide, tetramethylbutylacrylamide 2N-methylol (meth)acrylamide;

Vinyl monomers such as N-(meth)acryloyl amino acids.

(e) Vinyl monomers such as (meth)acrylonitrile, vinyl acetate, vinyl propionate vinyloxazole, styrene, α-methylstyrene, bis(N,N'-dimethylaminoethyl)malenit, styrene sulfonic acid, allyl sulfone acid, sulfopropyl acrylate,
Examples include sulfoxyl group-containing monomers such as (meth)acryloyloxynaphthalenesulfonic acid, acrylamide methylpropanesulfonic acid, and acryloyloxybenzenesulfonic acid.

In the present invention, the (meth)acrylic acid alkyl ester and the copolymerizable monomer include various isomers in which the alkyl moiety is linear or branched, and nine various isomers and derivatives in which the positions of the substituents are different. It is something to do.

Among these, the above-mentioned acrylic pressure-sensitive adhesive.

In the case of a coelectric combination of a (meth)acrylic acid alkyl ester and the (meth)acrylic acid in (a) above.

It is desirable because it has high polymerizability and improves cohesive force and Ii adhesion.

In addition, the blending ratio of monomers copolymerizable with (meth)acrylic acid alkyl ester in the acrylic pressure-sensitive adhesive is 50 to 99/1 to 50 in terms of coulometric ratio and has an ether bond (meth). When using an acrylic acid alkyl ester, a (meth)acrylic acid alkyl ester and a (meth)acrylic acid alkyl ester having an ether bond in 0 molecules.

The blending ratio with copolymerizable monomers other than those mentioned above is preferably 40 to 80,159 to 10/1 to 40 by weight.

Furthermore, it is preferable that the copolymerizable monomer is vinyl acetate because the cohesive force is improved.

In addition, the above (e) and/or (d) have good skin adhesion and good drug solubility and release properties.
When using water-soluble monomers that are potentially basic, such as, the blending ratio of (meth)acrylic acid alkyl ester and monomers such as (C) and/or (a). is preferably in the range of 50 to 96,150 to 4 in terms of weight ratio.Moreover, it is particularly preferable that the alkyl (meth)acrylic acid ester is in the range of 60 to 90ii, and the monomers such as (C) and/or (d) are in the range of 10 to 4. It is preferable to mix 301% by weight.

In addition, when using monomers such as (C) and/or (d).

Cohesion and skin adhesion can be improved, and R water resistance can be increased.

In addition, it is preferable to use vinylpyrrolidone as a monomer such as (C) and/or (d) in terms of improving cohesive force and hydrophilicity, and use the vinylpyrrolidone as a polar monomer such as (a) to improve cohesion and hydrophilicity. It is preferable to use meth)acrylic acid hydroxyethyl ester because it has the same hydrophilic properties as above.

Other pressure sensitive adhesives include silicone rubber,
Rubber substances such as polyisoprene rubber, polyisobutylene rubber, polybutadiene, styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber, natural rubber, polyvinyl alkyl ether, polyvinyl acetate, polyvinyl acetate parts Saponified products, polyvinyl alcohol, polyvinylpyrrolidone, and cellulose conductors such as methyl cellulose, carboxymethyl cellulose, and dipropyl cellulose in hydrochloride, polysaccharides such as pullulan and dextrin agar, polyurethane elastomers, and polyester elastomers. Can be used.

Also, when using the pressure sensitive adhesive.

If there is a risk of adhesive residue remaining on the skin surface after application due to lack of cohesive force and contamination of the skin surface, appropriate chemical cross-linking treatment (cross-linking Copolymerization ratio of monomers, addition of external crosslinking agent, etc.] It is preferable to subject the composition to physical crosslinking treatment (irradiation with ionizing radiation such as electron beam, ultraviolet crosslinking, etc.).

The dense support supporting the pressure-sensitive adhesive layer includes:
A material that is flexible enough to follow the movements of the skin surface to which it is applied is selected; for example, glass film, non-woven fabric, woven fabric (1 paper), metal foil (1) and foamed film, or a combination of these. can be mentioned.

The basic drug (excluding ifenprodil and metopol) or its salt used in the present invention may be any pharmacologically acceptable drug. Particularly preferred are those having one or more amines (Ss may be different) in their molecular structure. In addition, those having an amide instead of an amine may also be used. Here, the base of the basic drug means a so-called Lewis base defined by Lewis's theory.

In addition, the salt of the basic drug may be an inorganic acid salt f an organic acid salt of any composition, and carboxylic acid salts such as citrate, succinate, fumarate, maleate, tartrate, etc.
Examples include hydrochloride, sulfate, phosphate and the like. For example, (7) hypnotic and sedative drugs such as flurazepam hydrochloride (antipyretic analgesic anti-inflammatory drug nanolysine hydrochloride; benzydamine hydrochloride, perisoxal citrate, phetamine hydrochloride, dramadol hydrochloride, dintothiazine mesylate, propnorphine hydrochloride, fM petrolate putorf 1-nornat).

(stimulant/stimulant) t [methamphetamine, etc.

(Name drugs meclizine hydrochloride, dl-isoprenaline hydrochloride, diphenidol hydrochloride petahistine mesylate.

(6) Phenothiazine drugs for psychiatric and neurological purposes: chlorpromazine hydrochloride, chlorpromazine hibenzate, [la] riflupromazine, pomepromazine maleate, repomepromazine hydrochloride, perazine maleate, Fenrezo. perazine acid, prochlorperazine maleate, trifloperazine maleate, thioproperazine dimethane sulfonate, thioridalline hydrochloride, pur7enazine phendizoate, belphenazine maleate, salt 1 nial 7 enacin, fur 7 maleate Enagin, fluphenazine hydrochloride, spiclomazine hydrochloride, etc.

Phenothiazine-like skeletal system: alpenthixol hydrochloride, etc.

Butyrophenones: fluorobipamide hydrochloride, movellon hydrochloride, etc.

Diphenylmethane type: Hydroxyzine hydrochloride, etc.

Carbipramine series: Carbibramine hydrochloride, carpipramine maleate, clocabramine hydrochloride, etc.

Tricyclic resistance! X; salt, acid migramin. Desipramine hydrochloride, trimigramine maleate, clomipramine hydrochloride, amitributyline hydrochloride, nortributyline hydrochloride, doslevine hydrochloride, fritracene hydrochloride, Hanawa #roanibramine, etc.

Tetracyclic anti-urisers such as mianserin dihydrochloride and magrotiline hydrochloride.

MAO inhibitors: Nafrazine hydrochloride, etc.

Penzodiazebis: chlordiazepoxide hydrochloride, etc.

Others: methylphenidate hydrochloride, bipradrol hydrochloride, etc.

) Skeletal muscle relaxants such as pricinol mesylate, eperisone hydrochloride, tolperisone hydrochloride, etc.

(Intimidating antispasmodic cholinergic blockers: atropine sulfate, scopolina hydrobromide ξ
), dicyclomine hydrochloride, diethylaminoethyl hydrochloride diphenylhydroxypropionate, pipetanate hydrochloride,
Piperidrate hydrochloride.

Oxyphencyclyban hydrochloride, hydrochloric acid; t-thixene, etc.

Others: bapaverine hydrochloride, etc.

(b) Antiparkinsonian drugs such as piperidine hydrochloride, piperidine lactate, trihexyphenidyl hydrochloride, amantadine hydrochloride, pyroheptene hydrochloride, profenamine hibenzate, profenatone hydrochloride, mazaticol hydrochloride, etc.

(Of course antihysteine drug Ethanolamine type: diphenhydramine hydrochloride.

Diphentomine teritylate, carbinoxamine maleate, etc.

Monoamine ξ: dl-chlorpheniramine maleate,
d-Chlorpheniramine maleate.

Phenothiazines: such as alimemazine tartrate.

Others: inchibenzyl hydrochloride, triprolidine hydrochloride, clemizole hydrochloride, cyprohebutadine hydrochloride, homochlorcifrizine hydrochloride, diphenylbilarin hydrochloride, ibroheptine hydrochloride, zinctin maleate, lemastine fumarate.

(→Carotonic drugs dl-inproterenol hydrochloride, l-isoproterenol hydrochloride, dopamine hydrochloride, dopramine hydrochloride.

Metaraminol bitartrate, etylefrine hydrochloride.

Norphenephrine hydrochloride, etc.

(b) Medications for arrhythmia Procainamide type: Procainamide hydrochloride, etc.

Xylidine type: lidocaine hydrochloride, etc.

Quinidine series: Quinidine sulfate, etc.

β-blocking drugs: glopranolol hydrochloride, alprenolol hydrochloride, gutzetrol hydrochloride, bupranolol hydrochloride, oxprenolol hydrochloride, indenolol hydrochloride, carteolol hydrochloride, befunolol hydrochloride, acebutolol hydrochloride, 7'/%Cl-HCl, Contains timolol maleate and alpunolol hydrochloride.

Others: shisopyramide diphosphate, taxiletine hydrochloride. Verapamil hydrochloride, abrindin hydrochloride, etc.

(a Hydralazine series of antihypertensive drugs = Xl! acid ecalazine, hydralazine hydrochloride, etc.

LaQuolphia: #L acidic acid dimethylaminoethyl serpic acid, etc.

Alkaloids such as dihydroergotoxine dimesylate.

Others: Guanhuacine hydrochloride, clonidine hydrochloride.

bunazosin hydrochloride, punitrol hydrochloride, prazosin hydrochloride, propranolol hydrochloride, beflorulur hydrochloride, guanabenz acetate, dinaragril maleate, guanethidine sulfate,
Betanisin sulfate.

Benztrol sulfate, etc.

(vasoconstrictors such as phenylephrine hydrochloride, methaminol hydrochloride, dihydroergolamine mesylate).

(-44 Coronary vasodilators ethanenone hydrochloride.
) Hamill, carbochromene hydrochloride, prenylamine lactate, etc.

(7) Peripheral vasodilators Isodisprine hydrochloride. Citrate dimethate.

Nicotinic alcohol tartrate, bamethane sulfate.

Tolazoline hydrochloride etc.

(A Other circulatory organ drugs nicardipine hydrochloride, birithioxine hydrochloride, flunarizine hydrochloride, fuclofenokitate hydrochloride. Moxysilito hydrochloride,
7Provincan ξmalate, benzicrane fumarate, cinepazide maleate, thiaglide hydrochloride, etc.

(b) Respiratory stimulants aVerine series: lobeline hydrochloride, etc.

Dimorphora ξ series: tartaric acid, valorphan, etc.

Others: Zinfurin hydrochloride, Doxapram hydrochloride.

such as naloxone hydrochloride.

(η Antitussive expectorant centrally acting antitussive agent codeine diphosphate, dihydrocodeine phosphate, dexto i methorphan hydrobromide, carbetapentane citrate, penproperine phosphate, tebepidine hibenzate, isoaminyl citrate, zinmol phan phosphate , oxelazine citrate, eprazinone hydrochloride, clobutinol hydrochloride, clofedanol hydrochloride, hominoben hydrochloride, etc.

Other antitussives: Noscapi ν hydrochloride, etc.

Expectorants: monoethylcysteine hydrochloride, methylcysteine hydrochloride, bromhexine hydrochloride, amproxol hydrochloride, etc.

Sympathomimetic agents: dl-epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride.

l-methylephedrine hydrochloride, ingroterenol sulfate, dl-ingloterenol hydrochloride, orciprenaline sulfate, terbutaline sulfate, salbutanol sulfate, trimethoquinol hydrochloride, chlorbrenalin hydrochloride, methoxyphenamine hydrochloride, hexyprenaline sulfate, bitolterol mesylate.

Procaterol hydrochloride, tulopterol hydrochloride, pyrubutyrol hydrochloride, phenotylol hydrobromide, formotyol fumarate, clenbuterol hydrochloride, mapterol hydrochloride, etc.

Antiallergic drugs: ketotefen fumarate, azelastine hydrochloride, etc.

(Kahormone Citric acid lomifuene.

(G) Topical drugs for purulent diseases mafuenide acetate etc.

(e) Analgesic, antipruritic, astringent, anti-inflammatory drug Inothipendyl hydrochloride etc.

(-1 Drugs for parasitic skin diseases such as miconazole nitrate, econazole nitrate, iconazole nitrate, sconazole nitrate, oxiconazole nitrate, croconazole hydrochloride, etc.)

(To) Vitamin Bi series: Dicethiamine hydrochloride, cichotiamine hydrochloride, etc.

Vitamin B6: Pyridoxine hydrochloride, etc.

) hemostatic drugs , adrenochrome guanylhydrazone mesylate, etc.

(Foundation) Anticoagulant Ticlopidine hydrochloride etc.

(Antidote/addictive drug rack) Deferoxamine mesylate, etc.

(→Diabetes drugs ffl acid) formin, buformin hydrochloride, etc.

(Antineoplastic alkylating agent: Nitrogen hydrochloride mustard-N-
#+cyto, improsulfan tosylate.

Nimustine hydrochloride etc.

Metabolism 6 Antidrugs: Ancitabine hydrochloride, etc.

Plant alkaloids: vinblastine sulfate, vincristine sulfate, vindesine sulfate, etc.

Anticancer antibiotics: daunorubicin hydrochloride, doxorubicin hydrochloride, etc.

Others: Tamoxifen citrate, clocarbazine hydrochloride, etc.

(to) drugs Opium alkaloids: Ethylmorphine hydrochloride.

Morphine hydrochloride, codeine phosphate, dihydrocodeine phosphate, etc.

Coca alkaloids: Cocaine hydrochloride, etc.

Synthetic narcotics: pethidine hydrochloride, fentanyl citrate, etc.

The content of the basic drug and/or its salt used in the present invention may be any amount as long as it exhibits its pharmacological effect, but the content may be 20 to 5001 JAfi/unit area in the pressure sensitive adhesive.
d, preferably 100 to 4000 All/e11. If the content is lower than the above range of 20 to 5000 μi/14, it may not exhibit sufficient medicinal efficacy, and if it is higher, it may not be possible to improve the pharmacological effect by increasing the amount, and there may be problems such as skin irritation. There is also a risk that this may occur.

Conventional pressure-sensitive adhesives generally have poor drug solubility, and in particular, it is extremely difficult to uniformly dissolve and retain salt-form drugs, and even if the drug is retained, it is often hardly released. Although the free forms of these drugs are certainly more easily maintained in solution and have satisfactory release characteristics than salt-form drugs, the drug content may decrease during storage due to changes over time.

In the present invention, in order to eliminate these drawbacks, the pressure-sensitive adhesive layer contains a basic drug, its salt, an acidic substance, and a basic substance in the combination of (is) (t4) (i...), and its exposure The pH of the surface of the field 7 is maintained at 7 or higher.

Also, if the pH is kept above 7, it is an acidic substance.

A basic substance may optionally be added to the adhesive layer. Here, the pH of the exposed surface is measured using a flat electrode, and is the value when water is dropped onto the exposed surface of the pressure-sensitive adhesive layer and p) of the dropped water reaches equilibrium. Since the pressure-sensitive adhesive layer does not contain water, the acidic and basic substances are different from the so-called pH15II agents.If the pH is not 7 or higher, the drug will not transfer sufficiently to the skin surface. Satisfactory percutaneous absorption cannot be obtained.

In the case of (Ii+), acidic substances are included.
7 (In the case of town, it contains a salt of a basic drug, and the salt form of the drug has a molecular structure that is inherently acidic.

In either case, an acidic substance is necessarily included in addition to the basic drug.

The presence of nucleic acid substances is effective in preventing the content of medicinal ingredients from decreasing due to changes over time.

As such an acidic substance, any 6fl acid substance may be used within a pharmaceutically acceptable range from the viewpoint of safety, but organic acids are preferably used, and carboxylic acids are particularly preferable. For example, citric acid, succinic acid, tartaric acid, maleic acid,
Fumaric acid, benzoic acid.

These include tericylic acid and lactic acid.

Further, the basic substance to be co-present is a stronger base than the drug, and is particularly preferably a basic substance within a pharmaceutically acceptable range from the viewpoint of safety. For example, sodium hydroxide,
Inorganic substances such as potassium hydroxide, triethanolamine, jetanolamine, triisocropanolamine,
Examples include amines such as diingropanolamine, and basic amino acid salts such as arginine. The basic substance is effective in freeing the salt of the basic drug and improving the release properties of the drug.

The content of these acidic substances and tXX injection substances is 0.1 to 10 mol per mol of the coexisting drug.

Preferably it is 0.5 to 5 mol.

By adding a negative substance and a basic substance to the pressure-sensitive adhesive layer in this way, the above-mentioned drawbacks can be overcome.

The reason for this is not clear, but with pressure-sensitive adhesive M liquid,
Composition containing a basic substance and pressure-sensitive adhesive Some kind of intermolecular force acts between the agent and the functional group of the agent component. This intermolecular force is different in its mode of action and degree from the intermolecular force that occurs in a liquid.1For example, it does not occur in a solution. , lW There are various forces such as weaker force than the force in liquid liquid, and due to these influences, the above-mentioned disadvantages can be overcome.1 As explained above, the medical patch containing the basic drug and/or its salt according to the present invention The drug has high release properties and transdermal absorption of medicinal ingredients, and at the same time, it is possible to suppress the decrease in the content of the medicinal ingredients due to changes over time.

<Examples> Examples of the present invention will be shown below and will be explained more specifically, but the present invention is not limited to these in any way.

Various modifications are possible. Note that parts in the main text indicate parts by weight.

Manufacturing example 1 55 parts of acrylic acid 2-ethylhexyl ester.

30 parts of acrylic acid methoxyethyl ester, 15 parts of vinyl acetate, and 0.3 parts of azobisisobutyronitrile were placed in a four-loaf flask, and the mixture was heated to 60 to 60 g under an inert gas atmosphere.
The temperature was raised to ℃ to start the polymerization reaction.

125 parts IZ) The reaction was continued for 10 hours while controlling the reaction temperature while adding *1 FL of ethyl acetate, and then aged for 2 hours at 75 to 80°C to obtain a pressure-sensitive adhesive liquid.

Manufacturing example 2 Acrylic @ 2-ethyl bexyl ester 95 parts.

5 parts of acrylic acid and 0.2 parts of benzoyl peroxide were placed in a four-hole flask under an inert gas atmosphere.

The temperature was raised to 62-65°C to start the polymerization reaction, and 125 parts of ethyl acetate was added dropwise while controlling the reaction temperature to continue the reaction for 8 hours, and further aged at 75-80°C for 2 hours to form a pressure-sensitive adhesive. A drug solution was obtained.

Production Example 3 In a four-bottle flask under an inert gas atmosphere, 80 parts of isononyl acrylate, 15 parts of 1-vinyl-2-pyrrolidone, 2-hydrodiethyl methacrylate ss, and 66.7 parts of ethyl acetate were added. During the preparation, 0.2 parts of azobisisobutyronitrile was added as an initiator, and 190.4 parts of ethyl acetate was added dropwise while stirring at an internal temperature of 62 to 65°C while controlling the reaction. After time molding, the temperature was further raised to 75-80°C and aged for 3 hours to obtain a pressure-sensitive adhesive m liquid.Production Example 4 Three types of polyisobutylene, Sokuchi, VI STANEX
MML-80 (viscosity average molecular weight 990000) 35
and HIMOL 4H (viscosity average molecular weight 4L10
00) 15 parts 50 parts of M5 technology HV-300 (viscosity average molecular weight 1260) was dissolved in toluene to obtain a pressure-sensitive adhesive m liquid.

Examples 1-20. Comparative examples 1 to 18 Using the copolymer m liquids obtained in Production Examples 1 to 4 above.

The barking ratio of the patch according to the contents of Tables 1 to 4. here.

Each component is blended in a predetermined amount into the copolymer liquid, and after t, the thickness is 75 mm.
The mixture was coated on a polyester mold release liner of 100 μm, dried, and transferred onto the following support.

Examples 1-8. Comparison rows 1 to 5: Polyester film with a thickness of 9 μm.

Examples 9-12. Comparative Examples 6 to 9: Polyethylene film with a thickness of 30 μm.

Examples 13-162 Comparative Examples 10-13...thickness 20μ
Conventional ethylene-vinyl acetate copolymer (vinyl acetate content 2
8%) was laminated and transferred to the ethylene-vinyl acetate copolymer side of a 9μ thick polyester film.

Examples 17-20. Comparative Examples 14-18...thickness 12μ
Groove polyester film.

The custom-made patches obtained in each example and comparative example were
This is shown in Table 4 and Figures 1 to 5.

The measurement method for each characteristic shown in Tables 1 to 4 and Figures 1 to 5 below is as follows.

Surface pH (Tables 1 to 4) Examples 1 to 20 and Comparative Example 1 obtained as described above
A patch of ~18 was cut out to a size of 12 mφ, the liner was peeled off to expose it, and distilled water of 0.11 E/ml was dropped onto the surface of the specific pressure sensitive adhesive layer, and the tpH value was measured after each drop of water reached an almost equilibrium VC. Here, "almost reaching equilibrium" means that the value does not change for 30 seconds or more. Note that the surface pH is 4
The average value of each example is shown.

Skin transfer rate (Tables 1 to 4) The patches prepared in Examples 1 to 14 and Comparative Examples 1 to 3.5 to 7.9 were cut out to a size of 30JllIφ and were applied to the back of the eel's stinging hair for 8 hours, and then peeled off. The remaining drug was extracted with methanol, quantified, and the apparent transfer rate to the skin surface relative to the initial content was calculated.

Note that the skin transfer rate is the average value of three cases.

Rat Plasma Concentration (Figure 1) The dopamine hydrochloride patch obtained in Example 1 was cut out to an appropriate size so that the dose of dopamine hydrochloride was 1) Cf9 in the rat body. This was applied to the bristled abdomen of the rat and peeled off after 24 hours. After pasting 2゜4.8, 24.30
Samples were taken at 1 hour, and the drug concentration in the plasma was measured using a conventional method, and the concentration in the plasma was determined. FIG. 1 shows the average value of the quantitative values of the three experimental cases.

In addition, in Comparative Example 1, the patch used in Example 1 was used.
A pasting test similar to that was conducted, and the results are also shown in Figure 1.

Pnitrol hydrochloride The patch obtained in Example 9 was cut out to an appropriate size so that the dose of pnitrol hydrochloride was 10 times per rat's body weight, and the same experiment as that for dopamine hydrochloride described above was carried out. The results are also shown in the same ratio.

In addition, using the nine patches obtained in Comparative Example 6, the above Example 9
A similar pasting test was conducted and the results are also shown in FIG.

Cinepazide maleate The nine patches obtained in Example 13 were cut out to an appropriate size so that the dose of cinepazide maleate was 511,117 ml per rat body weight, and then the above-mentioned dobamide hydrochloride patch was cut out.
We conducted an experiment similar to the one regarding the

The results are also shown in the same way.

Further, using the nine patches obtained in Comparative Example 10, a patch test similar to that of Example 13 was conducted, and the results are also shown in FIG.

Romifuen Citrate The patch obtained in Example 17 was cut out to an appropriate size so that the dose of Romifune Citrate would be 967th51η in rat body IE1, and the same experiment as that for dopamine hydrochloride described above was carried out. conduct.

The result is also a reminder.

Further, using the nz patch obtained in Comparative Example 14, a patch test similar to that of Example 17 was conducted, and the results are also shown in FIG.

Drug residual rate The adhesive patches obtained in Examples 1 to 20 and Comparative Examples 1 to 18 were stored at 50°C for 2.3 months, and after 9 days, the adhesive patches obtained in Examples 1 to 20 and Comparative Examples 1 to 18 were
A sample of 0 deformation φ was cut out, the a* drug was extracted with methanol or ethanol, and the residual rate relative to the initial content was calculated, and the results are shown in Figures 2 to 5. Note that each point in the figure represents the average value of two examples.

From FIG. 1, it can be seen that each Example has a higher concentration in plasma than each Comparative Example, and the concentration is stable over a long period of time.

Moreover, from FIGS. 2 to 5, each Example has a good skin transfer rate, and Comparative Example 4. J 8.9.12.13.17゜18
It is recognized that the residual ratio of each drug is higher than that of the sample, and the stability in the pressure-sensitive adhesive layer is improved.

[Brief explanation of drawings]

Figure 1 shows Example 1.9.13.17 and Comparative Example 1.3゜5.
．． A custom-made diagram showing the change in plasma concentration of each drug over time, Figure 2 shows Examples 1 to 8 and Comparative Examples 1 to 51M3 Figure 4 shows Examples 9 to 12 and Comparative Examples 6 to 9. The figure shows Example 13~
16 and Comparative Examples 10 to 13° FIG. 5 is a characteristic diagram showing the drug residual rates of Examples 17 to 20 and Comparative Examples 14 to 18, respectively. Figure 1

Claims (17)

[Claims] (1) A medical patch comprising a pressure-sensitive adhesive layer laminated on a flexible support, wherein the pH of the exposed surface of the pressure-sensitive adhesive layer is 7 or more, and the pressure-sensitive adhesive A medical patch characterized in that the layer contains any one of the following components. (i) Basic drugs (excluding ifenprodil and metoprolol) and acidic substances. (ii) Basic drug salts (excluding ifenprodil salts and metoprolol salts) and basic substances. (iii) Basic drugs (excluding ifenprodil and metoprolol) and basic drug salts (excluding ifenprodil salts and metoprolol salts). (2) The medical patch according to claim (1), wherein the pressure-sensitive adhesive layer comprises an acrylic pressure-sensitive adhesive. (3) The medical patch according to claim (2), wherein the acrylic pressure-sensitive adhesive is a copolymer of a (meth)acrylic acid alkyl ester and (meth)acrylic acid. (4) The acrylic pressure-sensitive adhesive is obtained by blending (meth)acrylic acid alkyl ester and other copolymerizable monomers in an amount of 50 to 99% by weight/1 to 50% by weight. A medical patch according to claim (2). (5) The acrylic pressure-sensitive adhesive contains (meth)acrylic acid alkyl ester and an ether bond in the molecule (
The medical patch according to claim 2, which is a copolymer of a meth)acrylic acid alkyl ester and a copolymerizable monomer other than the above. (6) Claim in which the copolymerizable monomer is vinyl acetate (
5) The medical patch described above. (7) The copolymer contains 40 to 80% by weight of a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkyl ester having an ether bond in the molecule, and a copolymerizable monomer other than the above. The medical patch according to claim 5, which is obtained by blending /59 to 10% by weight/1 to 40% by weight. (8) The acrylic pressure-sensitive adhesive is a copolymer of a (meth)acrylic acid alkyl ester, a water-soluble monomer represented by the general formula below, and a copolymerizable polar monomer other than the above. The medical patch according to claim (2). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and/or ▲mathematical formulas,
Chemical formulas, tables, etc. are available▼ (However, R is hydrogen or a methyl group, and X is a group containing at least one nitrogen atom or nitrogen and oxygen atoms.) (9) The medical patch according to claim (8), wherein the water-soluble monomer is vinylpyrrolidone. (10) The medical patch according to claim (8), wherein the polar monomer is (meth)acrylic acid hydroxyethyl ester. (11) The copolymer contains 50 to 96% by weight of an alkyl (meth)acrylate, 4 to 50% by weight of a water-soluble monomer represented by the above general formula, and a copolymerizable polar monomer other than the above. The medical patch according to claim 8, which is obtained by blending 0 to 20% by weight of the body. (12) The medical patch according to claim (1), wherein the basic drug and/or basic drug salt has one or more amines in the molecule. (13) The basic drug and/or basic drug salt is 20 to 5000 μg/cm^2 per unit area of the pressure-sensitive adhesive layer.
The medical patch according to claim (1), which contains: (14) The medical patch according to claim (1), wherein the acidic substance is an organic acid. (15) Claim (14) wherein the organic acid is an organic carboxylic acid.
The medical patch described. (16) Acidic substance is 0.1 to 1 per mole of basic drug
The medical patch according to claim (1), containing 0 mol. (17) The pH of the exposed surface of the pressure sensitive adhesive layer is 7.0 to 1.
1.5. The medical patch according to claim (1).