JP2933944B2 - Medical patch - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a medical patch containing a basic drug and / or a salt thereof as a medicinal ingredient.

<Prior Art> There is a medical patch containing a drug as a dosage form for absorbing a drug as a medicinal ingredient from the outer skin of the body.
Among these patches, there are those in which a pressure-sensitive adhesive such as a rubber-based or acrylic polymer-based material is used as a base material for the purpose of skin adhesion, but these generally have a drug solubility property. Poor, especially it is extremely difficult to uniformly dissolve and retain the salt form of the drug, and even if it is prepared in a dissolved state, crystallization of the contained drug may occur during storage and inhibit the transdermal absorption of the drug. is there.

Conventionally, a technique in which an organic acid coexists in a pressure-sensitive adhesive layer containing a drug to improve (a) drug release and transdermal absorption (for example, JP-A-63-79820, (B) A technique for preventing a decrease in the content of a drug due to daily changes and stably containing the drug for a long period of time (for example, JP-A-60-126119).
193920, JP-A-56-100715) are known. In addition, the above-mentioned technology uses the pH of the exposed surface of the pressure-sensitive adhesive layer.
About, not focused.

<Problem to be Solved by the Invention> The above-mentioned problem is that the content of the drug may be reduced in the case of the above (a) technology, and conversely, in the case of the (b) technology, the drug release and percutaneous absorption may be reduced. Sometimes it is inferior, that is (a)
A patch having the characteristics of (b) has not yet been obtained.

<Means for Solving the Problems> As a result of intensive studies to solve the above problems, the present inventors have found that the drug contained in the pressure-sensitive adhesive layer is in a salt form or a free form (free form). The type of additive and its necessity, and the pH of the exposed surface of the adhesive layer
Was set to 7 or more, it was found that a patch having the characteristics of (a) and (b) could be obtained, and the present invention was completed.

That is, the present invention provides a pressure-sensitive adhesive layer comprising an acrylic pressure-sensitive adhesive obtained by using one or more of alkyl (meth) acrylates having an alkyl group having 4 to 13 carbon atoms. A medical patch laminated on a flexible support, wherein the exposed surface of the pressure-sensitive adhesive layer is
The present invention relates to a medical patch characterized by having a pH of 7 or more, and the pressure-sensitive adhesive layer containing one of the following components.

(I) Basic drugs (excluding ifenprodil and metoprolol) and acidic substances.

(Ii) Basic drug salts (excluding ifenprodil salt and metoprolol salt) and basic substances.

(Iii) Basic drug (however, ifenprodil and metoprolol are excluded) and basic drug salt (however, ifenprodil and metoprolol are excluded) The pressure-sensitive adhesive layer used in the present invention comprises a basic drug and a basic drug. It is a layer for containing and retaining a salt and an acidic substance or a basic substance, and for making the patch of the present invention adhere to the skin surface.

Acrylic pressure-sensitive adhesives are preferred as pressure-sensitive adhesives from the viewpoints of adhesion to the skin and drug stability.

Examples of the acrylic pressure-sensitive adhesive include butyl (meth) acrylate, pentyl (meth) acrylate, hexyl (meth) acrylate, heptyl (meth) acrylate, and octyl (meth) acrylate. , Having 4 to 13 carbon atoms such as nonyl (meth) acrylate, decyl (meth) acrylate, undecyl (meth) acrylate, dodecyl (meth) acrylate and tridecyl (meth) acrylate Polymers using one or more of alkyl (meth) acrylates having an alkyl group, or copolymers of one or more of the esters with one or more copolymerizable monomers, etc. No.

Examples of copolymerizable monomers include (a) (meth) acrylic acid, itaconic acid, crotonic acid,
Carboxyl group-containing monomers such as maleic acid, maleic anhydride and fumaric acid; hydroxyl group-containing monomers such as (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxyethyl ester and (meth) acrylic acid hydroxypropyl ester (B) methoxyethyl (meth) acrylate,
(Meth) acrylic acid ethoxyethyl ester, (meth)
Butoxyethyl acrylate, tetrahydrofurfuryl (meth) acrylate, methoxyethylene glycol (meth) acrylate, methoxydiethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, (meth) acrylic acid (C) an alkyl (meth) acrylate having an ether bond in the molecule, such as methoxy polypropylene glycol ester; (Where R represents a hydrogen or a methyl group, X represents a group having at least one nitrogen atom or a nitrogen and oxygen atom), a monomer such as the following, (meth) acrylic acid aminoethyl ester, Alkyl monomers containing alkylaminoalkyl groups such as dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, tert-butyl (meth) acrylate, urethane and urea of (meth) acrylic acid A functional monomer such as an acrylic monomer such as an isocyanate ester; (Where X represents a group having at least one nitrogen atom or a nitrogen and oxygen atom.) The following monomers, vinylcaprolactam, vinylimidazole, vinylmethylimidazole,
Nitrogen atom-containing saturated heterocyclic group-containing vinyl such as vinylphenylimidazole, vinylprolidone, vinylmethylpyrrolidone, vinylpiperidone, vinylpyridine, acryloylmorpholine, vinylmorpholin, vinylthiazole, vinylpyrazine, vinylpiperazine, vinylpyridine and vinylpyrrole Monomer or unsaturated heterocyclic group-containing vinyl monomer, (meth) acrylamide, dimethyl (meth) acrylamide, N-butylacrylamide,
Amide group-containing acrylic monomers such as tetramethylbutylacrylamide, N-methylol (meth) acrylamide, vinyl monomers such as N- (meth) acryloylamino acid, (e) (meth) acrylonitrile, vinyl acetate, propion Vinyl acid, vinyl oxazole, styrene, α-methyl styrene, bis (N, N'-dimethylaminoethyl)
Vinyl monomers such as maleate, styrene sulfonic acid, allyl sulfonic acid, sulfopropyl acrylate,
Sulfoxyl group-containing monomers such as (meth) acryloyloxynaphthalenesulfonic acid, acrylamidomethylpropanesulfonic acid, and acryloyloxybenzenesulfonic acid.

In the present invention, the alkyl (meth) acrylate and the copolymerizable monomer also include various isomers in which the alkyl portion is linear and branched, and various isomers and derivatives in which the position of the substituent is different. Is what you do.

Among these, the acrylic pressure-sensitive adhesive is (meth)
Alkyl acrylate and (meth) in the above (a)
A copolymer with acrylic acid is desirable because it has high polymerizability and improves cohesion and adhesion.

Also, the mixing ratio of the monomer copolymerizable with the alkyl (meth) acrylate in the acrylic pressure-sensitive adhesive should be 50 to 99/1 to 50 by weight. Desirable. In addition, it has an ether bond in the molecule of (b) from the viewpoint of reducing skin irritation (meta)
When an alkyl acrylate is used, an alkyl (meth) acrylate, an alkyl (meth) acrylate having an ether bond in a molecule,
The mixing ratio with the copolymerizable monomer other than the above is by weight.
It is desirable to be 40-80 / 59-10 / 1-40.

When the copolymerizable monomer is vinyl acetate, it is desirable in that the cohesive strength is improved.

In addition, good skin adhesion, and drug solubility,
In the case where a water-soluble monomer having a potentially basic property as described in the above (c) and / or (d) is used from the viewpoint of good release properties, an alkyl (meth) acrylate ester, The compounding ratio with the monomer (c) and / or (d) is desirably in the range of 50 to 96/50 to 4 by weight. Furthermore,
Particularly preferably, alkyl (meth) acrylate is
60 to 90% by weight of the monomer 10 as in (c) and / or (d)
It is advisable to mix up to 30% by weight.

When a monomer such as (c) and / or (d) is used, the polar monomer of (a) can be copolymerized in the copolymer at 20% by weight or less. In this case, cohesiveness and skin adhesion can be improved, and hydrophilicity can be increased.

Further, when the vinylpyrrolidone is used as the monomer as in (c) and / or (d), it is desirable in that the cohesion and hydrophilicity are improved, and as the polar monomer as in (a), Use of (meth) acrylic acid hydroxyethyl ester is desirable in that hydrophilicity is improved.

In addition, when using the pressure-sensitive adhesive, if there is a possibility that after applying the skin due to lack of cohesive force, there is a possibility of causing a glue residue phenomenon on the applied skin surface and causing contamination of the skin surface, the skin adhesiveness. Appropriate chemical cross-linking treatment (such as copolymerization of a cross-linkable monomer and addition of an external cross-linking agent) and physical cross-linking treatment (irradiation with ionizing radiation such as an electron beam or ultraviolet cross-linking) so as not to impair. It is preferably applied to the composition.

As the support for supporting the pressure-sensitive adhesive layer, a material having flexibility to follow the movement of the skin surface to be applied is selected.For example, a plastic film, a nonwoven fabric, a woven fabric, paper , A metal foil, a foamed film, or a combination thereof.

The basic drug (excluding ifenprodil and metoprolol) or a salt thereof used in the present invention may be any pharmacologically acceptable one. Particularly, those having one or more amines (types may be different) in its molecular structure are preferable. In addition, what has an amide instead of an amine may be used. Here, the base of the basic drug means a so-called Lewis base defined by Lewis theory.

The salt of the basic drug may be an inorganic acid salt or an organic acid salt having any composition, such as a carboxylate such as a citrate, a succinate, a fumarate, a maleate, or a tartrate; , Sulfates, phosphates and the like. For example, (a) hypnotic / sedative agent flurazepam hydrochloride, etc. (a) antipyretic analgesic anti-inflammatory drug tinolidine hydrochloride, benzidamine hydrochloride, perisoxal citrate, refetamine hydrochloride, tramadol hydrochloride, dimethothiazine mesylate, bubrenorphine hydrochloride, butorphanol tartrate, etc. Stimulants, such as methamphetamine hydrochloride, (d) narcotics, meclizine hydrochloride, dl-isoprenaline hydrochloride, diphenidol hydrochloride, betahistine mesylate, etc. (o) Psychiatry drugs Phenothiazines: chlorpromazine hydrochloride, chlorpromazine hibenzate, triflupromazine hydrochloride, malein Levomepromazine acid, Levomepromachine hydrochloride, Perazine maleate, Perazine fendizate, Prochlorperazine maleate, Trifloperazine maleate, Thiopane dimethanesulfonate Perazine, hydrochloric Chioridarin, Fenjizo acid Purufenajin, maleic acid perphenazine, hydrochloric Purufenajin, maleic acid fluphenazine,
Fluphenazine hydrochloride, spicromadine hydrochloride, etc. Phenothiazine-like skeletal system: flupentixol hydrochloride, etc. Butyrophenone system: floropipamide hydrochloride, moperon hydrochloride, etc. Diphenylmethane system: hydroxyzine hydrochloride, etc. Carpipramine system: carpipramine hydrochloride, carpipramine maleate, clocapramine hydrochloride Tricyclic antidepressants: imipramine hydrochloride, desipramine hydrochloride, trimipramine maleate, clomipramine hydrochloride,
Amitriptyline hydrochloride, nortriptyline hydrochloride, doslipin hydrochloride, melitracene hydrochloride, lofepramine hydrochloride, etc. Tetracyclic antidepressants: mianserin hydrochloride, maprotiline hydrochloride, etc. MAO inhibitors: saflazine hydrochloride, etc. Benzodiazepines: chlordiazepoxide hydrochloride, etc. Others: methylpheni hydrochloride Dating, pipradrol hydrochloride, etc. (f) Skeletal muscle relaxants pridinol mesylate, eperisone hydrochloride, triperizone hydrochloride, etc. (x) antispasmodic cholinergic blockers: atropine sulfate, scopolamine hydrobromide, dicyclomine hydrochloride, diphenylhydroxypropionic acid hydrochloride Diethylaminoethyl, pipetanate hydrochloride,
Piperidolate hydrochloride, oxyphencycline hydrochloride,
Methixene hydrochloride, etc. Others: Papaverine hydrochloride, etc. (h) Antiparkinsonian drugs piperidene hydrochloride, piperidene lactate, trihexyphenidyl hydrochloride, amantadine hydrochloride, pyroheptin hydrochloride, profenamine hibenzate, profenamine hydrochloride, mazaticol hydrochloride, etc. Antihistamines Ethanolamines: diphenhydramine hydrochloride, diphenhydramine salicylate, carbinoxamine maleate, etc. Monoamines: dl-chlorpheniramine maleate, d
-Chlorpheniramine maleate, etc. Phenothiazines: alimemazine tartrate, etc. Others: isotipendyl hydrochloride, triprolidine hydrochloride, clemizole hydrochloride, cyproheptadine hydrochloride, homochlorcyclidine hydrochloride, diphenylpyraline hydrochloride, iproheptin hydrochloride, dimethindene maleate, clemastine fumarate (Co) cardiotonic drugs dl-isoproterenol hydrochloride, l-isoproterenol hydrochloride, dopamine hydrochloride, dobutamine hydrochloride, metalaminol hydrogen tartrate, ethylephrine hydrochloride, norphenephrine hydrochloride, etc. (sa) drugs for arrhythmia procainamide hydrochloride: bromine hydrochloride Cainamide, etc. Xylidine type: lidocaine hydrochloride, etc. Quinidine type: quinidine sulfate, etc. β-blockers: propranolol hydrochloride, alprenolol hydrochloride, bufetrol hydrochloride, buffinol hydrochloride Planolol, oxprenolol hydrochloride, indenolol hydrochloride, carteolol hydrochloride, befnolol hydrochloride, acebutolol hydrochloride, bucmorol hydrochloride, timolol maleate, arotinolol hydrochloride, etc. Others: disopyramide phosphate, mexiletine hydrochloride, verapamil hydrochloride, aprinzin hydrochloride, etc. B) Antihypertensive drugs Hydralazine: ecarazine hydrochloride, hydralazine hydrochloride, etc. Lauorphia: dimethylaminoethyl reserpine hydrochloride, etc. Alkaloid: dihydroergotoxin mesylate, etc. Others: guanfacine hydrochloride, clonidine hydrochloride, bunazosin hydrochloride, bunitrolol hydrochloride, prozosin hydrochloride , Propranolol hydrochloride, labetalol hydrochloride, guanabenz acetate, enalapril maleate, guanethidine sulfate, betanidine sulfate, pen sulfate Trolls, etc. (S) Vasoconstrictors Phenifurin hydrochloride, methoxamine hydrochloride, dihydroergotamine mesylate, etc. (SE) Coronary vasodilators Etaphenone hydrochloride, Oxyfedrine hydrochloride, Dilazeb hydrochloride, Diltiazem hydrochloride, Trimetazidine hydrochloride, Verapamil hydrochloride, Carbochromene hydrochloride , Preniramine lactate, etc. (so) Peripheral vasodilators isoxsuprine hydrochloride, nicametharate citrate, nicotinic tartrate alcohol, bamethane sulfate, trizoline hydrochloride, etc. (ta) Other cardiovascular drugs nicardipine hydrochloride, pyrithioxine hydrochloride, flunarizine hydrochloride, hydrochloride Meclofenoxate, moxycilit hydrochloride, brovincamine fumarate, bensicran fumarate,
Cinepazide maleate, tiapride hydrochloride, etc. (h) Respiratory stimulants Roverine type: lobeline hydrochloride, etc. Dimorpholamine type: levallorphan tartrate, etc. Others: dimephrine hydrochloride, doxapram hydrochloride, naloxone hydrochloride, etc. (T) Antitussive expectorant Central antitussive : Codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, carbetapentane citrate, benproperin phosphate, tipepidine hibenzate, isoaminyl citrate, dimemorphuan phosphate, oxerazine citrate, ebrazino hydrochloride, clobutinol hydrochloride, Other antitussives: Noscapine hydrochloride, etc. expectorants: L-ethylcystine hydrochloride, L-methylcystine hydrochloride, bromhexine hydrochloride, ambroxol hydrochloride, etc. Stimulant: dl-epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine hydrochloride, isoproterenol sulfate, dl-isoproterenol hydrochloride, orciprenaline sulfate, terbutaline sulfate, salbutanol sulfate, trimethoquinol hydrochloride, Chlorprenaline hydrochloride, methoxyphenamine hydrochloride, hexoprenaline sulfate, bitolterol mesylate, procaterol hydrochloride, tulobuterol hydrochloride, pirbuterol hydrochloride, fenoterol hydrobromide, formoterol fumarate,
Clenbuterol hydrochloride, mabuterol hydrochloride, etc. Antiallergic drugs: Ketotifen fumarate, azelastine hydrochloride, etc. (H) Hormone clomiphene citrate, etc. (G) Topical drug for purulent diseases, mafenide acetate, etc. Anti-inflammatory drugs Isotipezil hydrochloride, etc. (d) Drugs for parasitic skin diseases, etc. Miconazole nitrate, econazole nitrate, iconon nitrate, cononazole nitrate, oxyconazole nitrate, croconazole hydrochloride, etc. (nu) Vitamin Vitamin B ₁ series: disetiamine hydrochloride, hydrochloric acid Vitamin B ₆ : pyridoxine hydrochloride, etc. (vi) Hemostatics Adrenochrome guanylhydrazone mesylate, etc. (no) Anticoagulant ticlopinzine hydrochloride, etc. (c) Antidote, addictive addictive mesylate (E) sugar, such as deferoxamine Urinary drugs Metformin hydrochloride, buformin hydrochloride, etc. (f) Antineoplastic drugs Alkylating drugs: nitrodiene mustard-N-oxide hydrochloride, isoprosulfan tosylate, nimustine hydrochloride, etc. Antimetabolites: Ancitabine hydrochloride, plants Alkaloids: vinblastine sulfate, vincristine sulfate, vindesine sulfate, etc. Anticancer anti-products: daunorubicin hydrochloride, doxorubicin hydrochloride, etc. Others: Tamoxifen citrate, procarbazine hydrochloride, etc. (f) Narcotics Opium alkaloids: ethyl morphine hydrochloride, morphine hydrochloride , Codeine phosphate, dihydrocodeine phosphate, etc. Core alkaloids: cocaine hydrochloride, etc. Synthetic drugs: pethidine hydrochloride, fentanyl citrate, etc.

In addition, the content of the basic drug and / or a salt thereof used in the present invention may be an amount that exerts its pharmacological effect,
The pressure sensitive adhesive per unit area per 20~5000μg / cm ^2, preferably it is desirable that the 100~4000μg / cm ^2. Above 20
If the content is lower than the range of 50005000 μg / cm ² , sufficient pharmacological effect may not be exhibited.If the content is high, the pharmacological effect may not be improved by increasing the amount, and problems such as skin irritation may occur. There is fear.

Conventional pressure-sensitive adhesives generally have poor drug solubility,
In particular, it is extremely difficult to uniformly dissolve and hold a salt form drug, and even if it is kept, it is often hardly released. Although the free form of these drugs is certainly easily retained and released in many cases, as compared with the drug in the form of a salt, the release properties can be satisfied in many cases. However, the content of the drug may decrease due to daily changes during storage.

In the present invention, in order to eliminate these drawbacks, the pressure-sensitive adhesive layer contains a basic drug, a salt thereof, an acidic substance, or a basic substance in a combination of the above (i), (ii) and (iii), and the exposed surface thereof PH is maintained at 7 or more.

If the pH is maintained at 7 or more, an acidic substance or a basic substance may be added to the adhesive layer as needed. Here, the pH of the exposed surface is measured using a flat electrode, and is defined as a value when water is dropped on the exposed surface of the pressure-sensitive adhesive layer and the pH of the dropped water reaches equilibrium. You. Since the pressure-sensitive adhesive layer does not contain water, the acidic substance and the basic substance are different from a so-called pH adjuster. If the pH is not 7 or more, the drug does not sufficiently transfer to the skin surface, so that satisfactory transdermal absorption cannot be obtained.

In the case of the above (i), an acidic substance is contained. Also (i
In the case of i) and (iii), a salt of a basic drug is contained, and a drug in a salt form originally contains an acidic substance due to its molecular structure. Therefore, in any of (i), (ii) and (iii), an acidic substance is necessarily contained in addition to the basic drug. The presence of the acidic substance is effective in preventing a decrease in the content of the medicinal component due to daily change.

As such an acidic substance, any substance may be used as long as it is in a pharmaceutically acceptable range from the viewpoint of safety, but an organic acid is preferably used, and a carboxylic acid is particularly preferable. For example, there are citric acid, succinic acid, tartaric acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, lactic acid and the like.

Further, the basic substance to be coexisted is a substance having a stronger base than the drug, and a basic substance in a pharmaceutically acceptable range is particularly preferable from the viewpoint of safety. Examples thereof include inorganic substances such as sodium hydroxide and potassium hydroxide, amines such as triethanolamine, diethanolamine, triisopropanolamine and diisopropanolamine, and basic amino acids such as arginine. The basic substance is effective in improving the release property of the drug by making the salt of the basic drug free.

The content of these acidic substances and basic substances is 0.1 to 10 mol, preferably 0.5 to 10 mol per 1 mol of the coexisting drug.
5 moles.

When the acidic substance and the basic substance coexist in the pressure-sensitive adhesive layer as described above, the above-mentioned disadvantage is solved. Although the reason for this is not clear, in the pressure-sensitive adhesive layer, the free form of the basic drug and / or the basic drug released from the salt of the basic drug and the coexisting acidic substance and / or basic substance are removed. Some intermolecular force acts between the composition containing the separated acid or basic substance and the functional group of the pressure-sensitive adhesive component.
This intermolecular force is different from the intermolecular force generated in the solution in the mode and degree of action, for example, there are various forces such as a force not generated in the solution and a force weaker than the force in the solution. It is considered that the above disadvantages can be eliminated.

<Effect of the Invention> As described above, the basic drug according to the present invention and / or
Alternatively, a medical patch containing the salt thereof has high release properties and transdermal absorbability of a medicinal component, and at the same time, suppresses a decrease in the content of the medicinal component due to daily change.

<Examples> Examples of the present invention will be described below, and will be described more specifically. However, the present invention is not limited to these examples, and various modifications are possible. In addition, "parts" in the text indicates parts by weight.

Production Example 1 55 parts of 2-ethylhexyl acrylate, 30 parts of methoxyethyl acrylate, 15 parts of vinyl acetate, and 0.3 part of azobisisobutyronitrile were charged into a four-necked flask, and charged under an inert gas atmosphere. The temperature was raised to 63 ° C to start the polymerization reaction. The reaction was continued for 10 hours while controlling the reaction temperature while dropping 125 parts of ethyl acetate, and the mixture was further aged at 75 to 80 ° C for 2 hours to obtain a pressure-sensitive adhesive solution. I got

Production Example 2 95 parts of 2-ethylhexyl acrylate, 5 parts of acrylic acid, and 0.2 part of benzoyl peroxide were charged into a four-necked flask, and heated to 62 to 65 ° C. under an inert gas atmosphere to carry out a polymerization reaction. The reaction was started for 8 hours by controlling the reaction temperature while dropping 125 parts of ethyl acetate.
For 2 hours to obtain a pressure-sensitive adhesive solution.

Production Example 3 80 parts of isononyl acrylate, 15 parts of 1-vinyl-2-pyrrolidone, 5 parts of methacrylic acid 2-hydroxyethyl ester and 66.7 parts of ethyl acetate were charged in a four-necked flask under an inert gas atmosphere. Then, 0.2 parts of azobisisobutyronitrile as a polymerization initiator was added, and polymerization was carried out for 7 hours while controlling the reaction while dripping 190.4 parts of ethyl acetate while stirring the inner bath at 62 to 65 ° C., and further 75 to 75 ° C. 80 ℃
And aged for 3 hours to obtain a pressure-sensitive adhesive solution.

Production Example 4 Three kinds of polyisobutylene, that is, VISTANEXMML-80
(Viscosity average molecular weight 990,000) 35 parts, HIMOL 4H (viscosity average molecular weight 40000) 15 parts and HV-300 (viscosity average molecular weight 12)
60) 50 parts were dissolved in toluene to obtain a pressure-sensitive adhesive solution.

Examples 1 to 20, Comparative Examples 1 to 18 Using the copolymer solutions obtained in Production Examples 1 to 4,
Patches were prepared with the contents of Table 4. Here, after each component was blended in a predetermined amount in the copolymer solution, it was applied on a 75 μm-thick polyester release liner, and then transferred onto the following support which was dried.

Examples 1 to 8, Comparative Examples 1 to 5: Polyester films having a thickness of 9 µm.

Examples 9 to 12, Comparative Examples 6 to 9: A polyethylene film having a thickness of 30 µm.

Examples 13 to 16, Comparative rows 10 to 13: Transferred to the ethylene-vinyl acetate copolymer side of a 9-μm-thick polyester film obtained by laminating a 20 μm-thick ethylene-vinyl acetate copolymer (vinyl acetate content: 28% by weight). .

Examples 17 to 20, Comparative Examples 14 to 18: Polyester films having a thickness of 12 µm.

The characteristics of the patches obtained in each of Examples and Comparative Examples were
Tables 1 to 4 and FIGS.

The measuring method of each characteristic of Tables 1 to 4 and FIGS. 1 to 5 is as follows.

Surface pH (Tables 1 to 4) Examples 1 to 20 and Comparative Example 1 obtained as described above
The patches of Nos. To 18 were cut out to 12 mmφ, 0.1 ml of distilled water was dropped on the surface of the pressure-sensitive adhesive layer exposed by peeling off the liner, and the pH value at which the dropped water reached almost equilibrium was measured. Here, reaching almost equilibrium means that the value does not change for more than 30 seconds. In addition, the surface pH showed the average value of four examples, respectively.

Skin transfer rate (Tables 1 to 4) Patches of Examples 1 to 20 and Comparative Examples 1 to 18 cut out to a size of 30 mmφ were stuck on the back of a shaved rabbit for 8 hours, then peeled off, and the remaining drug was treated with methanol. And quantified, and the apparent transfer rate to the skin surface with respect to the initial content was calculated.

 In addition, the skin transfer rate showed the average value of three cases, respectively.

Rat Plasma Concentration (Fig. 1) Dopamine Hydrochloride The patch obtained in Example 1 was cut out to an appropriate size so that the dosage of dopamine hydrochloride would be 1 mg per 1 kg of rat body weight, and this rat was shaved. It was stuck to the abdomen and peeled 24 hours later. At 2, 4, 8, 24, and 30 hours after application, the drug concentration of the plasma sampled was measured by a conventional method, and the plasma concentration was determined. FIG. 1 shows the average values of the quantitative values of three cases in which the experiment was performed.

The same patch test as in Example 1 was performed using the patch obtained in Comparative Example 1, and the results are also shown in FIG.

Bunitrolol hydrochloride The patch obtained in Example 9 was cut out to an appropriate size such that the dose of bunitrolol hydrochloride was 10 mg per 1 kg of rat body weight, and the same experiment as that for dopamine hydrochloride was performed. It was shown to.

The same patch test as in Example 9 was performed using the patch obtained in Comparative Example 6, and the results are also shown in FIG.

The patch obtained in cinepazide maleate Example 13 was cut out to an appropriate size so that the dose of maleepazide maleate was 5 mg per 1 kg of rat body weight, and the same experiment as that for dopamine hydrochloride was performed. The results are shown similarly.

Also, using the patch obtained in Comparative Example 10, the above Example
The same sticking test as in Example 13 was performed, and the results are also shown in FIG.

The patch obtained in clomiphene citrate Example 17 was cut out to an appropriate size so that the dose of clomiphene citrate was 1 mg per 1 kg of rat body weight, and the same experiment as that for dopamine hydrochloride was performed. The results are shown in the same manner.

Also, using the patch obtained in Comparative Example 14, the above Example
A sticking test similar to that of No. 17 was performed, and the results are also shown in FIG.

Percentage of remaining drug The patches obtained in Examples 1 to 20 and Comparative Examples 1 to 18 were stored at 50 ° C. for 1, 2, 3 months, and then a 30 mmφ sample was cut out. And the residual ratio with respect to the initial content was calculated, and the results are shown in FIGS. Each point in the figure indicates the average value of two examples.

From FIG. 1, it can be seen that each example has a higher plasma concentration and is stable for a long period of time as compared with each comparative example.

In addition, from FIGS. 2 to 5, each example has a higher residual rate of each drug than Comparative Examples 4, 5, 8, 9, 12, 13, 17, and 18 in which the skin transfer rate was good. It can be seen that the stability in the pressure-sensitive adhesive layer has been improved.

[Brief description of the drawings]

FIG. 1 shows Examples 1, 9, 13, and 17 and Comparative Examples 1, 6, 10, and 14.
FIG. 2 is a characteristic diagram showing the time-dependent changes in the plasma concentration of each drug in FIG. 2, FIG. 2 is Examples 1 to 8 and Comparative Examples 1 to 5, FIG. 3 is Examples 9 to 12 and Comparative Examples 6 to 9, and FIG. The figure is a characteristic line diagram showing the drug residual ratios of Examples 13 to 16 and Comparative Examples 10 to 13, and FIG. 5 is a line diagram showing the drug residual ratios of Examples 17 to 20 and Comparative Examples 14 to 18, respectively.

Claims (16)

(57) [Claims] 1. A pressure-sensitive adhesive layer comprising an acrylic pressure-sensitive adhesive obtained by using one or two or more of alkyl (meth) acrylates having an alkyl group having 4 to 13 carbon atoms is flexible. A medical patch which is laminated on a support, wherein the pH of the exposed surface of the pressure-sensitive adhesive layer is 7 or more, and any one of the following components is contained in the pressure-sensitive adhesive layer. A medical patch characterized by being contained. (I) Basic drugs (excluding ifenprodil and metoprolol) and acidic substances. (Ii) Basic drug salts (excluding ifenprodil salt and metoprolol salt) and basic substances. (Iii) Basic drugs (however, ifenprodil and metoprolol are excluded) and basic drug salts (however, ifenprodil and metoprolol salts are excluded). 2. The medical patch according to claim 1, wherein the acrylic pressure-sensitive adhesive is a copolymer of alkyl (meth) acrylate and (meth) acrylic acid. 3. An acrylic pressure-sensitive adhesive obtained by blending an alkyl (meth) acrylate with another copolymerizable monomer in an amount of 50 to 99% by weight / 1 to 50% by weight. The medical patch according to claim 1, wherein the patch is used. 4. An acrylic pressure-sensitive adhesive comprising an alkyl (meth) acrylate, an alkyl (meth) acrylate having an ether bond in a molecule, and a copolymerizable monomer other than the above. Claim (1) which is a copolymer.
The medical patch according to the above. 5. The medical patch according to claim 4, wherein the copolymerizable monomer is vinyl acetate. 6. A copolymer comprising an alkyl (meth) acrylate, an alkyl (meth) acrylate having an ether bond in the molecule, and a copolymerizable monomer other than the above, in an amount of from 40 to 80. The medical patch according to claim (4), which is obtained by blending the composition in an amount of from 5% by weight / 59 to 10% by weight / 1 to 40% by weight. 7. An acrylic pressure-sensitive adhesive comprising an alkyl (meth) acrylate, a water-soluble monomer represented by the following general formula, and a copolymerizable polar monomer other than the above. The medical patch according to claim 1, which is a copolymer. (However, R represents a hydrogen or methyl group, and X represents a group having at least one nitrogen atom or a nitrogen atom and an oxygen atom.) 8. The medical patch according to claim 7, wherein the water-soluble monomer is vinylpyrrolidone. 9. The medical patch according to claim 7, wherein the polar monomer is hydroxyethyl (meth) acrylate. 10. A copolymer comprising 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, The medical patch according to claim 7, which is obtained by mixing 0 to 20% by weight of a monomer. 11. The basic drug and / or the basic drug salt,
The medical patch according to claim 1, which has one or more amines in the molecule. 12. A basic drug and / or a basic drug salt,
The medical patch according to claim 1, wherein the pressure-sensitive adhesive layer contains 20 to 5000 µg / cm ² per unit area. 13. The medical patch according to claim 1, wherein the acidic substance is an organic acid. 14. The medical patch according to claim 13, wherein the organic acid is an organic carboxylic acid. 15. An acidic substance is used in an amount of 0.1 to 1 mol of a basic drug.
The medical patch according to claim 1, wherein the patch is contained in an amount of from 10 to 10 mol. 16. The pH of the exposed surface of the pressure-sensitive adhesive layer is 7.0-1.
The medical patch according to claim 1, which is 1.5.