JPH09286891A - Sticky gel base and sticky composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sticky gel base and a sticky drug suitable for percutaneous or permucosal treatment by blending a methoxyethylene/maleic acid copolymer, a cross-linked N-vinylacetamide, a polyfunctional epoxy compound, etc. SOLUTION: This gel base consists of a methoxyethylene/maleic acid (anhydride) copolymer (A), a cross-linked N-vinylacetamide (B), a polyfunctional epoxy compound (C), water, and a polyhydric alcohol and is applied to the skin or mucous membrane. It is used to give a sticky drug suitable for the percutaneous or permucosal treatment system and the drug dosage based on the principle of iontophoresis. Preferable amounts of components A, B and C are respectively about 5-35wt.%, about 1-8wt.%, and about 6-180 milli-epoxy- equivalents for 100g of component A. The polyhydric alcohol is blended preferably in an amount of about 10-60wt.%. The component B preferably comprises fine cross-linked polymer particles obtained by cross-linking the main chain of N-vinylacetamide and having an average degree of polymerization of 100 to 500,000. The component C comprises, e.g. sorbitol polyglycidyl ether.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an adhesive gel base suitable for transdermal or transmucosal application, and an adhesive composition containing the same. More particularly, the present invention provides an adhesive gel base and adhesive composition particularly suitable for use in transdermal and transmucosal drug administration using the principle of transdermal therapeutic system (TTS) or the principle of iontophoresis. Regarding things.

[0002]

2. Description of the Related Art In recent years, various dosage forms have been developed in the field of external preparations, and their interest is gradually increasing. The reason is that when a drug that is expected to exert its pharmacological effect locally or systemically from the skin or mucous membrane is administered, the drug can be expected to be durable, and the absorption rate of the drug can be easily controlled and side effects due to excessive administration can be prevented. The advantages of being able to effectively administer the drug with little effect of metabolism due to the first-pass effect by the liver as seen in oral administration, and being able to administer the drug with liver damage relatively safely. This is because

Conventionally, as an adhesive composition used for treatment using TTS, one containing a lipophilic base such as a natural rubber type, a synthetic rubber type, an acrylic type or a silicone type is known. Also, as a hydrophilic adhesive, a poultice using a hydrophilic base such as sodium polyacrylate or carboxyvinyl polymer as a base polymer is known.
Further, an adhesive composition obtained by crosslinking a methoxyethylene maleic anhydride copolymer with a polyfunctional epoxy compound in order to increase the adhesive strength is disclosed in JP-A-56-154421 or JP-A-59-204117. .

On the other hand, it is essential that the base contained in the adhesive composition used for the treatment utilizing iontophoresis is a water-soluble base.
Polyvinyl alcohol bases and the like are known. In addition, the pressure-sensitive adhesive composition based on a water-soluble polymer crosslinked with a metal reduces the cohesive force of the gel at the time of energization and the adhesive force decreases, so in order to improve it, a maleic anhydride copolymer or maleic acid is used. A pressure-sensitive adhesive composition containing a copolymer, a polyfunctional epoxy compound and a polyhydric alcohol is disclosed in JP-A-63-63.
It is disclosed in Japanese Patent Publication No.-92683.

[0005]

However, the conventional lipophilic pressure-sensitive adhesive composition requires an organic solvent,
There has been a problem that a large amount of heat is required at the time of production, and a surfactant is required as seen in an emulsion type acrylic pressure-sensitive adhesive. Further, such a lipophilic pressure-sensitive adhesive composition has relatively large skin irritation and has a problem in the working environment during production. Furthermore, a sufficient adhesive force has not yet been obtained for a poultice using such a lipophilic pressure-sensitive adhesive composition.

Further, the conventional hydrophilic pressure-sensitive adhesive compositions disclosed in JP-A-56-154421 and JP-A-59-204117 have a low viscosity at the time of spreading, so that the thickness can be controlled. There was a problem that it was difficult.

On the other hand, conventional karaya gum bases and polyvinyl alcohol adhesive compositions for iontophoresis have the problems of low adhesive strength and poor stability over time.

Further, in the conventional hydrophilic pressure-sensitive adhesive composition disclosed in JP-A-63-92683, the amount of the base polymer in order to make the plaster possible because the viscosity at the time of plastering is low. There is a problem in that it has to be increased, and there is a problem in that it is necessary to neutralize with an alkali in order to dissolve such a base polymer. Therefore, the conventional hydrophilic pressure-sensitive adhesive composition has a problem that the drug diffusion resistance is increased or the transport number is decreased, and the drug permeability is substantially reduced.

[0009]

The present invention has been made in view of the above-mentioned problems of the prior art, has low skin irritation and excellent drug release, and is easy to manufacture and inexpensive to produce. Provided is a hydrophilic adhesive gel base and a hydrophilic adhesive composition for transdermal or transmucosal application, which is suitable for iontophoresis because it has a small impedance and does not cause salting out or polarization. The purpose is to

Therefore, as a result of intensive studies to achieve the above object, the present inventors have found that the base component is methoxyethylene maleic anhydride copolymer or methoxyethylene maleic acid copolymer, N-vinylacetamide. Adhesive gel base consisting of crosslinked product, polyfunctional epoxy compound, water and polyhydric alcohol, and adhesive gel base and drug and / or
Further, they have found that an adhesive composition containing an electrolyte is effective in achieving the above object, and completed the present invention.

That is, the pressure-sensitive adhesive gel base of the present invention is a pressure-sensitive adhesive gel base for a pressure-sensitive adhesive composition applied to the skin or mucous membrane, and is a methoxyethylene maleic anhydride copolymer or a methoxyethylene maleic acid copolymer. , N-vinylacetamide crosslinked product, polyfunctional epoxy compound, water and polyhydric alcohol.

The pressure-sensitive adhesive composition of the present invention is a pressure-sensitive adhesive composition applied to the skin or mucous membrane, which comprises a methoxyethylene maleic anhydride copolymer, a methoxyethylene maleic acid copolymer, or a crosslinked N-vinylacetamide. , A polyfunctional epoxy compound, an adhesive gel base composed of water and a polyhydric alcohol.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred embodiments of the adhesive gel base and the adhesive composition of the present invention will be described in more detail below.

The adhesive gel base of the present invention, as described above,
Methoxyethylene maleic anhydride copolymer or methoxyethylene maleic acid copolymer, N-vinylacetamide cross-linked product, polyfunctional epoxy compound, water and polyhydric alcohol, and the pressure-sensitive adhesive composition of the present invention is the above-mentioned present invention. The adhesive gel base is included.

The pressure-sensitive adhesive gel base and pressure-sensitive adhesive composition of the present invention are hydrophilic pressure-sensitive adhesive gel bases and pressure-sensitive adhesive compositions which can be produced at room temperature and without solvent, respectively, and are methoxyethylene maleic anhydride copolymer or methoxyethylene malein. By using an acid copolymer as the base polymer, the decrease in transport number, that is, the decrease in drug permeation can be suppressed as much as possible. Also, by using a polyfunctional epoxy compound as a cross-linking agent, it is possible to suppress the decrease in adhesive strength during use, and by reacting the carboxyl group of the base polymer with the epoxy group to raise the pH, the skin It reduces irritation and reduces the competition of the drug with hydrogen ions when used for iontophoresis, increasing the skin or mucosal permeability of the drug. Furthermore, the addition of polyhydric alcohol makes it possible to increase the cohesive strength, water retention capacity and drug solubility of the adhesive composition.

In the pressure-sensitive adhesive gel base and pressure-sensitive adhesive composition of the present invention, by using an N-vinylacetamide cross-linked product described later as the gelling agent, the pressure-sensitive adhesive gel base and pressure-sensitive adhesive composition have a thixotropic viscosity. It becomes a non-Newtonian liquid (gel) that it has, dripping is prevented during spreading, and spreading is facilitated. Further, since the N-vinylacetamide crosslinked product according to the present invention does not have a dissociative functional group, it does not compete with a drug or the like, salting out of the drug or the like is prevented, and when used for iontophoresis. Is prevented from being polarized. Furthermore, since the N-vinylacetamide crosslinked product according to the present invention has a large compatibility with polyhydric alcohols and electrolytes, volatilization of water during application is suppressed, and the electrolyte as a charge transfer medium is retained in abundance. As a result, a stable energized state and / or drug permeability is maintained.

The pressure-sensitive adhesive composition of the present invention contains the above-mentioned pressure-sensitive adhesive gel base of the present invention. When the composition is used as a preparation for transdermal / transmucosal administration, it further contains a drug and iontophoresis. When used as a pharmaceutical preparation, it may further contain a drug and / or an electrolyte.

The methoxyethylene maleic anhydride copolymer used in the present invention is hydrolyzed in water to form a methoxyethylene maleic acid copolymer. The amount of the methoxyethylene maleic anhydride copolymer is about 5 as the methoxyethylene maleic anhydride copolymer.
It is preferably 35% by weight (based on the composition obtained). If the blending amount is less than about 5% by weight, the cohesive force is not sufficient, and a paste residue tends to occur at the time of peeling. On the other hand, if it exceeds about 35% by weight, the polymer does not dissolve at room temperature and tends to be impractical. is there.

The N-vinylacetamide crosslinked product used in the present invention has the following general formula: [In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom or a methyl group] and the main chain having N-vinylacetamide as a main repeating unit is crosslinked with a crosslinking agent. It is a polymer and has an average particle size of 10μ when dried.
It is preferably in the form of fine particles of m or less. The average degree of polymerization of the main chain of the crosslinked N-vinylacetamide according to the present invention is preferably 100 to 500,000, and the crosslink density is preferably 1/10000 to 1/10. Further, as the cross-linking agent, a compound having at least two polymerizable unsaturated groups in one molecule is used,
For example, N, N′-lower alkylenebisacrylamide,
Alkylene glycol di (meth) acrylate, polyalkylene glycol di (meth) acrylate, polyol tri (meth) acrylate, divinyl compound, polyallyl compound, N, N'-lower alkylenebis (N-vinylcarboxylic acid amide), N, N '-Polyalkylene glycol bis (N-vinylcarboxylic acid amide), N, N'
-Xylylene bis (N-vinyl carboxylic acid amide). Further, the content of such a crosslinking agent is 0.01-10.
Mol% (based on the monomer component) is preferred.

Examples of the N-vinylacetamide crosslinked product according to the present invention include PNVA (G manufactured by Showa Denko KK
X-205), the same PNVA (NA-010), the same PNV
A (NA-300) can be mentioned, among which PNV
A (GX-205) is particularly preferred. N according to the present invention
-The amount of the crosslinked vinylacetamide compounded is about 1 to 8% by weight.
(Based on the composition obtained) is preferred. If the blending amount is less than about 1% by weight, the viscosity tends to be insufficient, while if it exceeds about 8% by weight, the cohesive force tends to decrease.

Examples of the polyfunctional epoxy compound used in the present invention include sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether. , Propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, and the like. The compounding amount of the polyfunctional epoxy compound according to the present invention is 100% by weight of methoxyethylene maleic anhydride copolymer 100.
It is preferably about 6 to 180 milliepoxy equivalents to g. The epoxy equivalent is defined as the gram equivalent divided by the number of epoxy groups. If the compounding amount is less than about 6 mm epoxy equivalent, it tends to have no moldability, while if it exceeds about 180 mm epoxy equivalent, tackiness tends to be lost.

Examples of the polyhydric alcohol used in the present invention include ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-butylene glycol, glycerin and the like, among which polyethylene glycol is used. , Dipropylene glycol, 1,3-butylene glycol and glycerin are preferred. These may be used alone or in combination of two or more. The content of the polyhydric alcohol according to the present invention is preferably about 10 to 60% by weight (based on the composition obtained). If the amount is less than about 10% by weight, a sufficient cohesive force tends not to be obtained, while if it exceeds about 60% by weight, the tackiness tends to disappear.

The drug contained in the adhesive composition of the present invention is not particularly limited, but when used for TTS, for example, salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, benzyl nicotinate, Skin stimulants and analgesics such as ibuprofen, piroxicam, ketoprofen, indomethacin, suprofen, loxoprofen, diclofenac, flurbiprofen; amcinonide, prednisolone valerate acetate, dexamethasone valerate, betamethasone valerate, acetic acid dexamethasone acetate, acetic acid. Hydrocortisone, dexamethasone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide,
Corticosteroids such as fludoxycortide, prednisolone, clobetasol propionate, betamethasone, clobetasone butyrate, hydrocortisone acetate; local anesthetics such as ethyl aminobenzoate, lidocaine, tetracaine, procaine; propranolol, pindolol,
Β-blockers such as carteolol and timolol; coronary vasodilators such as nitroglycerin, isosorbide dinitrate, nifedipine and diltiazem; agents for treating bronchial asthma such as procaterol, isoproterenol and theophylline; diphenhydramine, chlorpheniramine maleate, carbinoxamine , Anti-histamines such as mequitazine and clemastine fumarate; anti-allergic agents such as tranilast, ketotifen fumarate, azelastine, oxatomide and amlexanox; antihypertensive agents such as clonidine;
Other antibacterial agents; hormone agents; crude drug extracts and the like.

When it is used for iontophoresis, it can be dissolved in the adhesive composition (adhesive gel base) of the present invention and dissociated into cations or anions.
Drugs in all therapeutic fields can be used, and in particular, drugs having a molecular weight of 100 to 1,000,000 are widely used.

Examples of such drug groups include antimicrobial agents, antineoplastic agents, hormone agents, antiallergic agents, liver disease agents, diabetes therapeutic agents, metabolic agents, blood agents, anti-inflammatory agents, central nervous system. Acting drugs, peripheral nerve acting drugs, circulatory organ acting drugs, respiratory tract acting drugs, digestive organ acting drugs, narcotics, and urinary frequency treatment agents. The compounding amount of the drug according to the present invention is not particularly limited and may be appropriately selected according to the drug to be used.
It is preferably 0% by weight or less (based on the composition obtained), and particularly preferably 0.000001 to 50% by weight.

Examples of various drugs capable of dissociating into cations are bacampicillin, sultamicillin, cefpodoxime proxetil, cefteram pivoxil, cefmenoxime, cefotiam, doxycycline, minocycline, tetracycline, erythromycin, rokitamycin, amikacin, arbecasin, asbestos. Mycin,
Dibekacin, gentamicin, isepamycin, kanamycin, micronomycin, sisomycin, streptomycin, tobramycin, ethambutol, isoniazid, fluconazole, flucytosine, miconazole,
Acyclovir, chloramphenicol, clindamycin, fosfomycin, vancomycin, aclarubicin, bleomycin, cytarabine, dacarbazine, nimustine, peplomycin, procarbazine, vinblastine, vincristine, vindesine, calcitonin,
Parathyroid hormone (PTH), granulocyte colony-stimulating factor (G-CSF), mechasermin, alimemazine, chlorpheniramine, clemastine, mequitazine,
Azelastine, ketotifen, oxatomide, methylmethionine sulfonium chloride, colchicine, camostat, gabexate, nafamostat, mizoribine, piroxicam, procagotacin, emorfazone, tiaramid, buprenorphine, ergotamine, phenacetin, rilmazafon, triazolam, zopacram, nitrapram, nitropramin, zopicram, nipamostone Bromocriptine, chlorpromazine, sultopride, chlordiazepoxide, cloxazolam, diazepam, etizolam, oxazolam, amitriptyline, imipramine, nortriptyline, setiptiline, ticlopidine,
Atropine, butylscopolamine bromide, eperisone, pancuronium bromide, tizanidine, pyridostigmine bromide, dobutamine, dopamine, benidipine, diltiazem, nicardipine, verapamil, acebutolol, atenolol, carteolol, metoprolol, nipradilol, pindolol, pyridolol, propranolol, propranolol, propranolol, propranolol Tradipyr, ajmaline, apridinine, cibenzoline, disopyramide, flecainide,
Isoprenaline, lidocaine, mexiletine, procaine, procainamide, tetracaine, dibucaine, propaphenone, quinidine, hydrochlorothiazide, trichlormethiazide, tripamide, azosemide, amosulalol, budralazine, bunazosin, cadralazine, clonidine, delapril, enapril, enapril, enapril, eneapril, enapril, eneapril, eneapril, enapri
Hydralazine, labetalol, prazosin, reserpine, terazosin, uradipyr, nicomol, epinephrine, etilefrine, midodrine, papaverine, clenbuterol, fenoterol, mabuterol, procaterol, salbutamol, terbutaline, tulobuterol, tipepidine, ambroxol, bromsol
Cimetidine, famotidine, ranitidine, roxatidine acetate, benexate, omepral, pirenzepine, sulpiride, cisapride, domperidone, metoclopramide, trimebutine, codeine, morphine, fentanyl, pethidine, oxybutynin, ritodrine, terodiline and salts thereof. It is not limited to these.

Examples of various drugs capable of dissociating into anions include amoxicillin, ampicillin, aspoxycillin, benzylpenicillin, methicillin, piperacillin,
Sulbenicillin, Ticarcillin, Cefachlor, Cefadroxil, Cephalexin, Cefatrizine, Cefixime, Cefradine, Cefloxazin, Cefamandole, Cefazolin, Cefmetazole, Cefminox, Cefoperazone, Cefotaxime, Ceftaxime, Ceftitam, Ceftitam, Cefotaxine, Ceftazol, Ceftixox, Ceftazin, Ceftroxam, Ceftazin, Ceftazin, Ceftazin, Ceftazin, Ceftazin, Ceftixox, Ceftaxin
Aztreonam, Carmonam, Flomoxef, Imepenem, Latamoxef, Ciprofloxacin, Enoxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Vidarazone, Fluorouracil, Methotrexate, Phosphate dexamethasone, Levothyroxine, Nicloxtra, Nigroxacin, Angrexanox, Anoxelnoxacin Benzbromarone, carbazochrome, tranexamic acid, alclofenac, aspirin, diclofenac, ibuprofen, indomethacin, ketoprofen, mefenamic acid, sulindac, thiaprofenic acid, tolmethine, sulpirin, lobenzarit, penicillamine, amobarbital, pentobarbital, pentobarbital, pentobarbital, pentobarbital. Phenytoin, Ruproic acid, droxidopa, levodopa, baclofen, dantrolene, denopamine, furosemide, acetazolamide, bumetanide, canrenoic acid, ethacrynic acid, alacepril, captopril, lisinopril, methyldopa, clofibrate, pravastatin, probucol, alprostadil, aminophylline, cysteine theophylline. And salts thereof, but are not limited thereto.

The pressure-sensitive adhesive composition of the present invention may contain an electrolyte as described above, and examples of such an electrolyte include sodium chloride, calcium chloride, cation exchange resin, anion exchange resin and the like. The blending amount of the electrolyte according to the present invention is not particularly limited and is appropriately selected according to the electrolyte to be used, but is preferably about 0.01 to 10% by weight (based on the obtained composition).

Further, the pressure-sensitive adhesive composition of the present invention may further contain a stabilizer, a preservative, an absorption promoter, a pH adjusting agent and the like, if necessary.

Next, an example of a method for producing the adhesive gel base and the adhesive composition of the present invention will be described.

First, methoxyethylene maleic anhydride copolymer or methoxyethylene maleic acid copolymer is added to purified water in an amount preferably about 5 times (weight basis) and left to stand at room temperature for one day to dissolve. Separately, the N-vinylacetamide crosslinked product is gradually added to the polyhydric alcohol with stirring to uniformly disperse the product. Then, the prepared aqueous solution of methoxyethylene maleic acid copolymer is added to the obtained dispersion, and the remaining purified water and, if necessary, the drug and / or the electrolyte are added and uniformly dispersed and dissolved. Finally, a polyfunctional epoxy compound is added to the above dispersion liquid, and the mixture is stirred until it becomes uniform to obtain an adhesive composition (adhesive gel base) of the present invention (hereinafter, this method is referred to as "method 1").
That).

As another method, a methoxyethylene maleic anhydride copolymer or a methoxyethylene maleic acid copolymer is added to purified water while heating and dissolved, and then a polyhydric alcohol is added, and It is also possible to add the N-vinylacetamide crosslinked product with stirring to obtain the adhesive gel base of the present invention. In this case, the adhesive composition of the present invention can be obtained by adding a drug and / or an electrolyte at an arbitrary timing (hereinafter, this method is referred to as “method 2”).

The adhesive composition of the present invention is spread on a suitable support, covered with a liner and cut into a desired shape to obtain a product (sticking member), or once subjected to a release treatment. It is also possible to obtain a product by spreading the pressure-sensitive adhesive composition of the present invention on a film and then transferring and pressure-bonding it to an appropriate support. Further, an electrode is formed by printing a conductive paste in advance on the plaster surface of the support or by adhering a metal foil, and the adhesive composition of the present invention is spread on the electrode to form an ion. A product for tophoresis can be obtained.

[0034]

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

(Example 1) Methoxyethylene maleic anhydride copolymer (manufactured by ISP, trade name: GANTREZ AN-169) 10 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA) GX-205) 3 parts by weight Glycerin 20 parts by weight Purified water 63.5 parts by weight Ethylene glycol diglycidyl ether 0.5 parts by weight Clonidine 3 parts by weight.

The components in this formulation were blended according to the above-mentioned method 1 to obtain the pressure-sensitive adhesive composition of the present invention, and the composition was sandmat-treated polyethylene terephthalate (P
ET) film (manufactured by Fujimori Industry Co., Ltd.) with a thickness of 200
It was spread so as to have a thickness of μm, and it was attached to a release surface of a release-treated PET liner (manufactured by Teijin Ltd.) and cut into an appropriate shape to obtain an adhesive member provided with the adhesive composition of the present invention. .

(Example 2) Methoxyethylene maleic anhydride copolymer (manufactured by ISP, trade name: GANTREZ AN-139) 25 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA) GX-205) 2 parts by weight Propylene glycol 30 parts by weight Purified water 39.3 parts by weight Ethylene glycol diglycidyl ether 0.7 parts by weight Isosorbide dinitrate 3 parts by weight.

The components in this formulation were blended according to the above-mentioned method 1 to obtain the adhesive composition of the present invention, and the composition was subjected to a sand mat-treated PET film (Fujimori Industry Co., Ltd.).
Manufactured) to a thickness of 200 μm, laminated with a release surface of a release-treated PET liner (manufactured by Teijin Ltd.), cut into an appropriate shape to give the adhesive composition of the present invention. The attached member provided was obtained.

(Example 3) Methoxyethylene maleic acid copolymer (manufactured by ISP, trade name: GANTREZ S-97) 12 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA GX) -205) 3 parts by weight 1,3-butylene glycol 45 parts by weight Purified water 36.5 parts by weight Diglycerol polyglycidyl ether 1 part by weight Tulobuterol 2.5 parts by weight.

The components in this formulation were blended according to the above-mentioned method 1 to obtain the adhesive composition of the present invention, and the composition was subjected to a sand mat-treated PET film (Fujimori Industry Co., Ltd.).
Manufactured) to a thickness of 200 μm, laminated with a release surface of a release-treated PET liner (manufactured by Teijin Ltd.), cut into an appropriate shape to give the adhesive composition of the present invention. The attached member provided was obtained.

(Example 4) Methoxyethylene maleic anhydride copolymer (manufactured by ISP, trade name: GANTREZ AN-169) 9 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA) GX-205) 4 parts by weight Glycerin 30 parts by weight Purified water 53 parts by weight Polyglycerol polyglycidyl ether 1 part by weight Lidocaine hydrochloride 3 parts by weight Epinephrine 0.006 parts by weight.

The components in this formulation were prepared according to the above-mentioned method 1 to obtain the pressure-sensitive adhesive composition of the present invention, and the composition was formed on a 40 μm silver film attached to a blender (manufactured by 3M Co.) in a thickness of 40 μm. Spread to 200 μm,
A release-treated PET liner (manufactured by Teijin Ltd.) was attached to the release surface and cut into an appropriate shape to obtain an iontophoresis patch having the adhesive composition of the present invention.

(Example 5) Methoxyethylene maleic anhydride copolymer (manufactured by ISP, trade name: GANTREZ AN-139) 20 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA) GX-205) 3 parts by weight Glycerin 30 parts by weight Purified water 43 parts by weight Polyglycerol polyglycidyl ether 1 part by weight Lidocaine hydrochloride 3 parts by weight Epinephrine 0.006 parts by weight.

The components in this formulation were prepared according to the above-mentioned method 1 to obtain the pressure-sensitive adhesive composition of the present invention, and the composition was applied to a 40 μm silver film attached to a blender (manufactured by 3M Co.) in a thickness of 40 μm. Spread to 200 μm,
A release-treated PET liner (manufactured by Teijin Ltd.) was attached to the release surface and cut into an appropriate shape to obtain an iontophoresis patch having the adhesive composition of the present invention.

(Example 6) Methoxyethylene maleic acid copolymer (manufactured by ISP, trade name: GANTREZ S-97) 13 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA GX) -205) 2.5 parts by weight Polyethylene glycol (Macrogol 400) 30 parts by weight Purified water 49.5 parts by weight Glycerol polyglycidyl ether 2 parts by weight Lidocaine hydrochloride 3 parts by weight Epinephrine 0.006 parts by weight.

The components in this formulation were prepared according to the above-mentioned method 1 to obtain the pressure-sensitive adhesive composition of the present invention, and the composition was applied to a 40 μm silver film attached to a blender (manufactured by 3M Company) in a thickness of 40 μm. Spread to 200 μm,
A release-treated PET liner (manufactured by Teijin Ltd.) was attached to the release surface and cut into an appropriate shape to obtain an iontophoresis patch having the adhesive composition of the present invention.

(Example 7) Methoxyethylene maleic anhydride copolymer (manufactured by ISP, trade name: GANTREZ AN-139) 25 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA) GX-205) 2 parts by weight Dipropylene glycol 15 parts by weight Purified water 55.3 parts by weight Polyglycerol polyglycidyl ether 1.8 parts by weight Sodium chloride 0.9 parts by weight.

The components in this formulation were prepared according to the above-mentioned method 1 to obtain the adhesive composition of the present invention, and the silver chloride / silver film (0.9% sodium chloride) attached to a blender (3M). 0.5% silver film in aqueous solution
mA / cm ² , 60 minutes of direct current application) to spread the composition to a thickness of 500 μm, and release treatment P
Attached to the release surface of ET liner (manufactured by Teijin Ltd.),
It was cut into an appropriate shape to obtain an iontophoresis patch having the adhesive composition of the present invention.

Comparative Example 1 Methoxyethylene maleic anhydride copolymer (trade name: GANTREZ AN-169, manufactured by ISP) 10 parts by weight glycerin 20 parts by weight Purified water 66.5 parts by weight Ethylene glycol diglycidyl ether 0.1. 5 parts by weight Clonidine 3 parts by weight.

The components in this formulation were blended according to the method 1 described above to obtain a comparative adhesive composition, and the composition was subjected to a sand mat-treated PET film (Fujimori Industry Co., Ltd.).
Apply a plaster on top to a thickness of 200 μm, and perform a release treatment P
Attached to the release surface of ET liner (manufactured by Teijin Ltd.),
The adhesive member provided with the comparative pressure-sensitive adhesive composition was obtained by cutting into an appropriate shape.

Comparative Example 2 Methoxyethylene maleic anhydride copolymer (trade name: GANTREZ AN-169, manufactured by ISP) 30 parts by weight Glycerin 20 parts by weight Purified water 45.5 parts by weight Ethylene glycol diglycidyl ether 1. 5 parts by weight Clonidine 3 parts by weight.

The components in this formulation were blended according to the method 1 described above to obtain a comparative adhesive composition, and the composition was subjected to a sand mat-treated PET film (Fujimori Industry Co., Ltd.).
Apply a plaster on top to a thickness of 200 μm, and perform a release treatment P
Attached to the release surface of ET liner (manufactured by Teijin Ltd.),
The adhesive member provided with the comparative pressure-sensitive adhesive composition was obtained by cutting into an appropriate shape.

(Comparative Example 3) Methoxyethylene maleic anhydride copolymer (manufactured by ISP, trade name: GANTREZ AN-169) 10 parts by weight N-vinylacetamide crosslinked product (manufactured by Showa Denko KK, trade name: PNVA) GX-205) 3 parts by weight Purified water 83.5 parts by weight Ethylene glycol diglycidyl ether 0.5 parts by weight Clonidine 3 parts by weight.

The components in this formulation were blended according to the method 1 described above to obtain a comparative adhesive composition, and the composition was subjected to a sand mat-treated PET film (Fujimori Industry Co., Ltd.).
Apply a plaster on top to a thickness of 200 μm, and perform a release treatment P
Attached to the release surface of ET liner (manufactured by Teijin Ltd.),
The adhesive member provided with the comparative pressure-sensitive adhesive composition was obtained by cutting into an appropriate shape.

(Comparative Example 4) Styrene-isoprene-styrene block copolymer (manufactured by Nippon Synthetic Rubber Co., Ltd., trade name: SIS 5002) 20 parts by weight hydrogenated rosin glycerin ester (manufactured by Arakawa Industry Co., Ltd., trade name) : Ester H) 38 parts by weight Liquid paraffin 39 parts by weight Clonidine 3 parts by weight.

The components other than clonidine in this formulation were heated and stirred at 180 ° C. to dissolve them, and then clonidine was added to obtain a comparative pressure-sensitive adhesive composition. The composition was sandmat-treated PET film (Fujimori Industry Co., Ltd.). 2) thickness on top
It was spread so as to have a thickness of 00 μm, and was bonded to a release surface of a release-treated PET liner (manufactured by Teijin Ltd.) and cut into an appropriate shape to obtain an adhesive member provided with a comparative adhesive composition.

Comparative Example 5 Isobutylene maleic anhydride copolymer (Kuraray Co., Ltd., trade name: Isoban-10) 13 parts by weight Sodium hydroxide 2.6 parts by weight N-vinylacetamide crosslinked product (Showa Denko ( Co., Ltd., trade name: PNVA GX-205) 2.5 parts by weight polyethylene glycol (Macrogol 400) 30 parts by weight purified water 46.9 parts by weight glycerol polyglycidyl ether 2 parts by weight lidocaine hydrochloride 3 parts by weight epinephrine 0.006 Parts by weight.

The isobutylene maleic anhydride copolymer and sodium hydroxide in this formulation were dissolved in purified water at the boiling temperature. When the temperature of the resulting solution dropped to room temperature, polyethylene glycol was added, and N-vinylacetamide was gradually added while stirring. When the obtained composition became uniform, glycerol polyglycidyl ether and lidocaine hydrochloride were added to obtain a comparative adhesive composition. The composition has a thickness of 200 μm on a 40 μm silver film attached to a blender (3M).
The adhesive member for iontophoresis, which is coated with a comparative pressure-sensitive adhesive composition after being spread to have a thickness of m, bonded to a release surface of a release-treated PET liner (manufactured by Teijin Ltd.), cut into an appropriate shape Got

(Comparative Example 6) Isobutylene maleic anhydride copolymer (Kuraray Co., Ltd., trade name: Isoban-10) 25 parts by weight Sodium hydroxide 5 parts by weight N-vinylacetamide crosslinked product (Showa Denko KK) Product name: PNVA GX-205) 2 parts by weight Dipropylene glycol 15 parts by weight Purified water 50.3 parts by weight Polyglycerol polyglycidyl ether 1.8 parts by weight Sodium chloride 0.9 parts by weight.

The isobutylene maleic anhydride copolymer and sodium hydroxide in this formulation were dissolved in purified water at boiling temperature. When the temperature of the obtained solution dropped to room temperature, dipropylene glycol was added, and N-vinylacetamide was gradually added while stirring. When the obtained composition became uniform, polyglycerol polyglycidyl ether and sodium chloride were added to obtain a comparative adhesive composition. Thickness of the composition on a silver chloride / silver film (manufactured by applying a direct current to a silver film in a 0.9% sodium chloride aqueous solution at 0.5 mA / cm ² for 60 minutes) attached to a blender (3M). Of PET liner (Teijin Co., Ltd.)
The adhesive member for iontophoresis provided with the comparative pressure-sensitive adhesive composition was obtained by sticking to a release surface of (1) and cutting into an appropriate shape.

Comparative Example 7 Karaya gum 40 parts by weight Glycerin 50 parts by weight Propylene glycol 3 parts by weight Purified water 3 parts by weight Sodium chloride 0.7 parts by weight Calcium chloride 0.6 parts by weight.

A mixture of the components in this formulation was heated to 80 ° C.
A comparative pressure-sensitive adhesive composition was obtained by stirring and mixing while heating to 0.degree. Thickness of the composition on a silver chloride / silver film (manufactured by applying a direct current to a silver film in a 0.9% sodium chloride aqueous solution at 0.5 mA / cm ² for 60 minutes) attached to a blender (3M). To a thickness of 500 μm, bonded to a release surface of a release-treated PET liner (manufactured by Teijin Ltd.), cut into an appropriate shape, and attached with an adhesive composition for comparative iontophoresis The member was obtained.

Test Example 1 The viscosity of the pressure-sensitive adhesive compositions of the present invention of Examples 1 to 7 and the comparative pressure-sensitive adhesive compositions of Comparative Examples 1 to 3 at room temperature immediately before spreading were measured. Also,
Whether or not the plaster protruded from the cut surface after spreading and cutting was confirmed after leaving the obtained patch member at room temperature for 2 weeks. It should be noted that the case where the plaster did not squeeze out was ◯, and the case where the plaster did not squeeze out was x. The results are shown in Table 1.

As is clear from the results shown in Table 1, none of the pressure-sensitive adhesive compositions of the present invention obtained in Examples 1 to 7 allowed the paste to spread easily and reliably without sticking out of the plaster. I was able to. The comparative pressure-sensitive adhesive composition of Comparative Example 1 having the same formulation as in Example 1 except that N-vinylacetamide was removed had a low viscosity, and sticking out of the plaster was observed. Further, although the comparative pressure-sensitive adhesive composition of Comparative Example 2, which was a formulation in which the amount of the base polymer was increased as compared with the formulation of Comparative Example 1, the sticking out of the plaster was observed. Therefore, it was confirmed that the pressure-sensitive adhesive composition of the present invention is highly useful in the production method. Further, salting out of the drug was not confirmed in the adhesive compositions of the present invention obtained in Examples 1 to 7.

[0065]

[Table 1]

Test Example 2 A patch member provided with the pressure-sensitive adhesive composition of the present invention of Examples 1 to 7 and a patch member provided with the comparative pressure-sensitive adhesive composition of Comparative Example 3 were spread for 2 weeks at room temperature. After standing, the liner was peeled off, and the state of the plaster when the support surface was bent 90 degrees was observed. No change in shape was observed in the pressure-sensitive adhesive compositions of the present invention obtained in Examples 1 to 7 when the support surface was returned to its original state, but a polyhydric alcohol was not added in Comparative Example. For the comparative pressure-sensitive adhesive composition of 3, cracks were observed in the plaster. Therefore, it was confirmed that the pressure-sensitive adhesive composition of the present invention was excellent in stability over time and was highly useful in physical properties.

(Test Example 3) A patch member having the adhesive composition of the present invention of Example 1 and a patch member having the comparative adhesive composition of Comparative Example 4 were each cut into a circle having a diameter of 2 cm,
After sticking on the back of the dehaired Japanese white rabbits (A to D) for 48 hours, the sticking member was peeled off and the skin condition was observed. Table 2 shows the results.

As is clear from the results shown in Table 2, no abnormality was observed in any of the test animals to which the adhesive composition of the present invention obtained in Example 1 was applied, but it was an oily base. Erythema was observed in all the test animals to which the comparative adhesive composition of Comparative Example 4 was applied. Therefore, it was confirmed that the adhesive composition of the present invention is highly useful in terms of skin irritation.

Criteria- ・ ・ ・ ・ No change ± ・ ・ ・ Weak redness ＋ ・ ・ ・ ・ ・ ・ ・ Clear redness ++ ・ ・ ・ ・ ・ ・ Serious edema

[0070]

[Table 2]

Test Example 4 In order to confirm the drug release property of the adhesive composition of the present invention, the local anesthetic effect of lidocaine was evaluated by the following method as an index of drug permeability. That is, the patch for iontophoresis provided with the adhesive composition of the present invention of Examples 4 to 6 and the patch for iontophoresis provided with the comparative adhesive composition of Comparative Example 5 were used as circles having a diameter of 2 cm. Cut into the shape of an anode,
On the other hand, the adhesive member provided with the pressure-sensitive adhesive composition of the present invention of Example 7 was cut into a circle having a diameter of 2 cm and applied as a cathode to five healthy adult males, and after each energizing time shown in Table 3. The application site was lightly punctured with an injection needle and evaluated according to the following evaluation criteria. The results are shown in Table 3.

As is clear from the effect index after each energization time shown in Table 3, when the pressure-sensitive adhesive compositions of the present invention obtained in Examples 4 to 6 were used, all were remarkable within 15 minutes. The effect index was shown, but when the comparative pressure-sensitive adhesive composition of Comparative Example 5 using the base polymer having a functional group having a high dissociation property was used, the effect index was not sufficient even after 60 minutes of energization.
Therefore, it was confirmed that the adhesive composition of the present invention is highly useful in terms of drug release. In addition, polarization was not confirmed in the pressure-sensitive adhesive compositions of the present invention obtained in Examples 4 to 6.

Judgment Evaluation Criteria Evaluation score ────────────────────────────────── (No change) 0 (±) A little pain 0.2 ± I feel touching but no pain 0.5 + No pain (hard to touch) 1.0 ++ No feeling at all 2.0 ─── ────────────────────────────── Effect index: (sum of evaluation points / number of test cases) × 100 Effective value> 100.

[0074]

[Table 3] Energization condition: pulse current 6mA, frequency 30kHz, ON
/ OFF = 3/7.

(Test Example 5) Iontophoresis patch with the adhesive composition of the present invention of Example 7 and iontophoresis patch with the comparative adhesive compositions of Comparative Examples 6 and 7. Each member is cut into a circle with a diameter of 2.5 cm, the PET film is peeled off, and the diameter is 2.5 cm.
It was stuck to a 40 μm thick silver film that was cut into a circle. Connect the silver film of the adhesive member for iontophoresis to the anode and the silver chloride / silver film to the cathode, and
The voltage value was measured after 1, 2 and 3 hours when a direct current of 1 mA was applied by connecting a kΩ resistor in series. The results are shown in Table 4.

As is clear from the results shown in Table 4, as compared with the case of using the pressure-sensitive adhesive composition of the present invention obtained in Example 7, a comparative example using a base polymer having a functional group having a high dissociation property. The voltage value is large when the comparative pressure-sensitive adhesive composition of No. 6 is used and when the comparative pressure-sensitive adhesive composition of Comparative Example 7 which is a karaya gum-based pressure-sensitive adhesive composition having a low water content is used. Therefore, it was confirmed that the pressure-sensitive adhesive composition of the present invention has a low impedance and is highly useful in terms of electrical characteristics. Also,
No polarization was confirmed in the adhesive composition of the present invention obtained in Example 7.

[0077]

[Table 4]

[0078]

As described above, the pressure-sensitive adhesive gel base and pressure-sensitive adhesive composition of the present invention can be manufactured without the need for a heat source, and since the plaster does not stick out during spreading, it can be easily and continuously produced. It can be applied and can be manufactured at low cost. In addition, the adhesive gel base and adhesive composition of the present invention have low skin irritation, excellent stability over time, and excellent drug release. Furthermore, the pressure-sensitive adhesive gel base and pressure-sensitive adhesive composition of the present invention have small impedance and excellent electrical characteristics, and further, salting out and polarization do not occur, and therefore they can be suitably used for iontophoresis.

As described above, the adhesive gel base and the adhesive composition of the present invention ensure a high level in all of handleability, skin irritation, stability over time, drug release, electrical characteristics and economical efficiency. It is industrially very useful as an adhesive gel base for transdermal / transmucosal application and an adhesive composition.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/10 A61K 47/10 Z 47/32 47/32 F N C08K 5/053 C08K 5/053 5/15 5/15 C08L 39/00 LJY C08L 39/00 LJY C09J 135/00 JDA C09J 135/00 JDA 139/00 JDF 139/00 JDF // A61N 1/30 A61N 1/30

Claims (5)

[Claims] 1. A pressure-sensitive adhesive gel base for a pressure-sensitive adhesive composition applied to skin or mucous membrane, which comprises methoxyethylene maleic anhydride copolymer or methoxyethylene maleic acid copolymer, N-vinylacetamide cross-linked polymer, An adhesive gel base comprising a functional epoxy compound, water and a polyhydric alcohol. 2. An adhesive composition applied to the skin or mucous membrane, which comprises a methoxyethylene maleic anhydride copolymer or a methoxyethylene maleic acid copolymer, an N-vinylacetamide crosslinked product, a polyfunctional epoxy compound, water and An adhesive composition containing an adhesive gel base comprising a polyhydric alcohol. 3. The pressure-sensitive adhesive composition according to claim 2, further comprising a drug. 4. The pressure-sensitive adhesive composition according to claim 2, further comprising an electrolyte. 5. The pressure-sensitive adhesive composition according to any one of claims 2 to 4, which is used for iontophoresis.