JPS62281816A - Sustained release pharmaceutical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, consisting of an adhesive layer containing specific hollow fibers containing a drug in the hollow parts thereof and specific support and having high safety and excellent effect on sustained release of the drug. CONSTITUTION:A sustained release pharmaceutical for percutaneous administration obtained by containing an adhesive layer prepared by containing a drug, e.g. coronary vasodilator, antiarrythmic agent, drug for angina pectoris, hypotensive agent, etc., in hollow fibers, e.g. polyester, etc., having through-holes in the outer peripheral direction and a support containing a film having 4.9-0.5mu thickness, e.g. polyolefin, polyester, polyamide, etc., as part or whole thereof. If the thickness of the above-mentioned support attains >=4.9mu, the flexibility of the pharmaceutical becomes inferior and condition of contact dermatitis is increased. If the thickness attains <=0.5mu, the film is broken by slight external force and the safety of the pharmaceutical is deteriorated. The above-mentioned pharmaceutical may contain an absorption adjuvant, etc., as necessary.

Description

Detailed Description of the Invention 3. Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a sustained-release pharmaceutical preparation for transdermal administration. More specifically, the present invention includes an adhesive layer containing hollow fibers containing a drug in the hollow portions of the specific hollow fibers;
A transdermal drug that is mainly composed of a support that is wholly or partially a film with a thickness of 4.9 microns to 0.5 microns, and is highly safe and has an excellent effect on sustained release of drugs. The present invention relates to sustained release preparations for administration.

<Conventional technology> In the development of pharmaceuticals, it is necessary to develop new compounds with unique medicinal properties, and at the same time, to further enhance the effects of these new chemical substances and chemical substances already used as pharmaceuticals. Various studies have been made to change the dosage form and optimize the administration form.

For example, in order to prolong the duration of a drug with a short half-life, which is a parameter for the effective duration of the drug in the body, the drug may be administered at a concentration above the minimum effective concentration and below the maximum safe concentration, that is, within the effective blood concentration range. Development of so-called sustained-release preparations in which medicinal ingredients are absorbed into the human body over a long period of time is actively underway.

Examples of sustained-release preparations include transdermal absorption preparations such as ointments, sprays, and applications. Since these preparations are applied to the skin in batches, there are problems in that the dosing is inconsistent and the soft spots stick to clothes, etc., resulting in stains. Furthermore, the drug in the ointment is absorbed into the human skin depending on the initial concentration, the applied thickness, the concentration of drug diffusion in the ointment base material, the absorption rate in the skin, etc., but there are uncertain conditions at the time of use. The problem is that it is difficult to apply to pharmaceuticals where there are many factors and effective concentration and side effects are problematic.

As a remedy for this drawback, there are tapes and patches that contain a certain amount of medicinal ingredients in an adhesive and are molded into a certain size (for example, Japanese Patent Application Laid-Open No. 57-116011, Japanese Patent Application Laid-Open No. 58-134020). (see publication).

By using tapes and patches, we are trying to solve the problems that occur with methods such as ointment and spray application.

<Problems to be Solved by the Invention> With conventional tapes and patches, when it is desired to administer a drug at a minimum effective concentration or higher and a maximum safe concentration or higher for as long as possible, for example, simply administering the drug in the adhesive. If the concentration is increased, the initial concentration absorbed into the human body will be higher and may cause skin damage. Furthermore, if the composition of the adhesive is changed to slow down the diffusion rate of the drug in order to reduce the absorption rate of the drug, there is a problem in that the initial absorption concentration of the drug decreases.

Another method of increasing the sustained release effect is to increase the thickness of the adhesive layer, but this generally increases skin irritation or leaves some of the adhesive on the skin as a residue. Problems are likely to occur.

Another method is to lower the drug concentration in the adhesive and increase the area to be applied to the skin. However, if the area to be applied is too large, it becomes difficult to handle the patch, the area of the skin that is irritated becomes large, which is undesirable, or the areas to which it can be applied are limited.

As a solution to these problems, the administration of medicinal ingredients can be sustained in a sustained manner by using a so-called drug reverb type preparation in which the adhesive layer contains a specific hollow fiber containing a drug in its hollow portion.

However, it has been found that when a drug reservoir tape is applied to human skin for a long period of time, a safety problem arises in the form of skin irritation, and the release pattern of the drug is also likely to change.

Means for Solving the Problems> In view of the above drawbacks, the present inventors have devised a method for reliably administering the medicinal ingredient in a small patch area, allowing the desired amount of drug to be gradually administered over a long period of time, and that is safe. As a result of intensive studies aimed at obtaining a sustained-release preparation with a high level of release, we found that an adhesive layer containing specific hollow fibers containing a drug in the hollow portion and a thickness of 4.
We have found that these objects can be achieved by a formulation consisting mainly of a support that is wholly or partially a film of 9 microns to 0.5 microns, and have reached this publication.

That is, the present invention provides an adhesive layer including hollow fibers having holes penetrating in the outer circumferential direction and containing a drug in the hollow portion of the hollow fibers, and a pressure-sensitive adhesive layer having a thickness of 4.9 microns to 0.5 microns. This is a sustained-release preparation for transdermal administration that mainly consists of a support that is entirely or partially a film.

It is essential that the hollow fibers used in the present invention have holes penetrating in the outer circumferential direction. Here, the hollow fibers having holes penetrating in the outer circumferential direction are scattered over the entire cross section of the hollow fibers, and m
Hollow fibers having Tfill holes arranged in the off-axis direction and at least some of which communicate with the hollow portion are preferred.

Both the outer shape and the shape of the hollow portion in the cross section of the hollow fiber of the present invention may be arbitrary. For example, the outer shape and the hollow part may both be circular, one of the outer shape and the hollow part may be circular and the other has an irregular shape, or both the outer shape and the hollow part may have similar or dissimilar irregular shapes. Further, there is no need to particularly limit the size of the external shape.

The hollowness ratio of the hollow fibers of the present invention may be arbitrary, but it is particularly preferably 5% or more, and the proportion of the pores that communicate in the outer circumferential direction to the cross-sectional area of 1JIll, or the cross-sectional area of the fiber excluding the hollow portion. It is preferably 0.001 to 70%, particularly 0.01 to 50%, and more preferably 1 to 50%.

The hollow fibers of the present invention have an almost infinitely long shape with respect to the fiber outer diameter, and when used in the form of woven fabrics, knitted fabrics, nonwoven fabrics, etc., they have good handling properties, a good feel on the skin, and moderate sustained release of drugs. This is preferable because it makes the most of its characteristics.

Materials for the hollow fibers used in the present invention include, for example, polyesters such as polyethylene terephthalate; polyolefins such as polyethylene and polypropylene; and nylon 6.
, polyamides such as nylon 66; polyurethane, cellulose acetate, polyacrylonitrile, polyvinyl chloride,
Any material can be selected, such as polyvinyl acetate. Among these, polyester is preferred, and polyethylene terephthalate is particularly preferred because of its good drug retention and drug stability.

The hollow fiber used in the present invention is, for example, JP-A-56-20
It can be produced by the methods described in JP-A No. 612, JP-A-56-20613, JP-A-56-43420, and the like.

In the present invention, a plurality of hollow IIIlts having different materials, shapes, or hollow ratios can be used in combination.

Instead of hollow fibers, some non-hollow mt4 may be mixed and used.

In the present invention, a hollow fiber containing a drug is used in the hollow portion of the hollow am having holes penetrating in the outer circumferential direction as described above. The drug may be present in the hollow portion alone, or may be present together with an adhesive described below, or may be present in the hollow portion together with a commonly used injection agent, dissolution aid, diffusion aid, or accelerator. It may exist together with etc.

The drug can be loaded into the hollow portion of the hollow fiber by any method. For example, a method in which a hollow fiber is once immersed in a solution in which a drug is dissolved, and then taken out and the solvent is removed:
A method in which the drug is dissolved in an adhesive solution and then the hollow fibers are immersed: Alternatively, the drug is mixed with an excipient, a dissolution aid, a diffusion aid, a skin absorption enhancer, etc., and then dissolved in a solution form.
A method is used in which the ointment is made into an ointment, and the hollow fibers are immersed in or brought into contact with the ointment. Heating to help infiltrate the drug or drug mixture into the hollow part of the hollow fiber.

Means such as zero pressure, vacuum pressurization, and ultrasonic imaging can also be used.

Examples of drugs used in the present invention include the following.

(1) Nitroglycerin, 1,2,3-propanetriol mononitrate, 1,2,3-brobantriol dinitrate and ester derivatives thereof.

Isosorbide nitrate, isosorbite-5-mononitrate, pentaerythritol tetranitrate, papaverine hydrochloride, hebronicard 1 molsidomine.

Nicomol, cinfibrate, verapamil.

Diltiazem cinnarizine hydrochloride, diviridamol, nifedipine, nicardipine, trapidil.

Coronary vasodilators such as trimetazidine hydrochloride, carbochromene, prenylamine lactate, dilazeb hydrochloride, trapidil; (2) pindolol, shisoviramide, bupranolol hydrochloride, trichlormethiazide, furosemide.

Antiarrhythmic or anginal agents such as brazomin hydrochloride, metoprolol tartrate, cartiolol hydrochloride, ofsprenol hydrochloride, propranolol hydrochloride; (3) Antihypertensive agents such as prazosin hydrochloride, ecalazine hydrochloride, hydrazine hydrochloride; (4) Methyldigoxin, Sodium benzoate, caffeine, caffeine, dopamine hydrochloride, tobutamine hydrochloride, octobamine hydrochloride, dibrophylline.

Ubidecarenone, bucladesine sodium, oxprenol hydrochloride, digitalis, dicoxin.

Cardiotropes such as ubidecarenone: (5) Procaterol hydrochloride, bilibralol hydrochloride.

Chlorofedanol hydrochloride, salbutamol sulfate.

Propranolol hydrochloride, trimethoquinol hydrochloride.

Bronchial asthma agents such as hydrotylol mesylate, mebutin, pindolol, isoprotenol, isoaminyl citrate, carbocystine, cefrazine, rizaben, theophylline, etc.: (6) Clonidine, nifedipine, nicardipine.

antihypertensive agents or calcium antagonists such as verapamil; (Sword: Aspirin, salicylic acid, methyl salicylate.

Ethyl salicylate, choline salicylate, sodium salicylate, salicyrosalicylic acid, salicylamide, glycol salicylate, tan-menthol, aminovirine, antipyrine, clofezone, ketophenylbutacin, camphor, peppermint oil, thymol, isopropylantipyrine.

Phenylbutacin, Huebrazone, Nicotinic acid benzyl ester icin, Acetaminophen, Oxyphenbutacin,
Pentazodine, eptazocine, diflunisal, fenazole, mevirizole, and roxicam, benzydamine, phenacetin, tiaramide, bufexamac, flufenamic acid, aluminum flufenamate, indomethacin.

Dramadol hydrochloride, ibuprofen, alclofenac, acemethacin, sulvirin, sodium guaiazulene sulfonate, guaiazulene, ketoprofen,
Flurbiprofen.

Diclofenac sodium, fenoprofen, pirprofen, naproxen, clidanac, sulindac, ibuprofen, benoquiliprofen, indobuene, mefenamic acid, tolmetin, methiazine acid, brotidic acid, berisoxal citrate, pranoprofen,
Syntal, phenylbutacin, fenbufen.

Fentiazac, diflunizal, tiaprofenic acid, fenbufen, tinoridine hydrochloride.

Zomevirac. Pimeprofuen, pendazak.

Fenoprofen calcium, prednisolone.

Anti-inflammatory analgesics or agents for skin diseases such as myloprofen, alclofenac, amfenac, subrofen, and derivatives thereof: (8) Topical agents such as lidocaine, benzicaine, ethyl aminobenzoate, procyone hydrochloride, dibucaine, procylene, etc. Anesthetics; (9) mefluside, penflutiside, bumetanide.

Hydrothiazide, vent flunathiazide,
Antihypertensive diuretics such as reserpine; (g)) Methaqualone, glutethimide, flurazepam.

Promvaleryl urea. Hypnosedatives such as flurazepam hydrochloride, nitrazebam, haloxazolam, triazolam, phenobarbital, chloral hydrate, nimetazepam, estazolam; (11+ levodopa, flufenzine, flutazolam.

Phenobarbital, Phenoparbital sodium,
Methylphenobarbital, thioridazine, diazepam, benzpromalone, reserpine, sulbialbrasim, clocabramine hydrochloride, clotiapibam, chlorpromazine, heroberidol, nitrazepam. Central nervous system drugs such as sodium carbonate; Q2) Psychoactive agents such as 3-(2-aminobutyl)indole acetate: (131 Epinephrine, cortisone acetate, hydrocortisone acetate, hydrourtisone, prednisolone, hydrocortisone sodium succinate, triamcinolone acetonide) , triamcinolone diacetate, dexamethacin phosphate.

Methylprednisolone, dichloridine acetate.

Methylprednisolone acetate, fluoxynolone acetonide, dexamethacin acetate, texamexazone, dexamethacin sodium sulfate, dexamethacin sodium phosphate, varamethacin acetate.

Fluoromesolone, esterone, estradiol, ethinyl estradiol, betamethacin sodium phosphate, betamethacin, betamethacin valerate, formonyl tar, flumethacin bivalate, beclomethasone propionate, fludroxycortide, hydrocortisone butyrate,
Betamethacin dipropionate, gemebrost fluoxinonide, clobetasol propionate.

Corticosteroids such as diflunirtronide valerate, haldinonide, prednisolone valerate, hydrocortisone propionate butyrate: 04 Sulfa drugs such as carfadimethoxine, sulfisoxazole, sulfisomidine, ethambutol hydrochloride, isoniacit, calcium baraminosalicylate Antituberculous drugs such as solid homochlorcifrizine hydrochloride, diphenhydrozine hydrochloride, chlorpheniramine, diphenylimidazole, chlorpheniramine maleate.

Glycyrrhetinic acid, tranilast, ketotinenoic acid antihistamines or antiallergic agents; (16) Myasthenia gravis agents such as pyridostigmine bromide: Gη nicardipine hydrochloride, cinepaside maleate.

Cerebral infarction sequelae such as pentoxifylline and isoenprodil tartrate; Loquat) Penicillin, tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamide, oxytetracycline, tarambicillin hydrochloride, fradiomycin sulfate, erythromycin, tetracycline hydrochloride, Bacanbicillin hydrochloride, fradiomycin, leucomycin, secloxacin.

Cephalosporins, ampicillin, cephalexin, cefaclor, neomycin sulfate, bacitracin, cephalothin sodium, naceicin sulfate, fosfomycin calcium, streptomycin, gentamicin sulfate, @acid fradiomycin, chlamidine S, micamycin.

Antibiotics such as colistin; Overseas: Iodine, povidone-iodine, boric acid, borax.

Oxidol, potassium permanganate, ethanol, isopropanol, formalin, cresol, cimazole hydrochloride, situcanin, phenyl iodo undiginoate,
Hexachlorophene.

Taleosote, resorcinol, acrinol, methylrosarinine chloride, benzethrium chloride, mercuric chloride, methylosal, maculochrome.

O-rhexidine gluconate, alkylpolyaminoethylglycine hydrochloride, benzalkonium chloride, nitrofurazone, nyscutin, acetoflufamine, clotrimazole, sulfamethizole, tolnaftate, pentamycin, amphotericin B, virolnidoline, undecylenic acid, miconazole, trichomycin , variotin, halopromidine, cimazole hydrochloride, and other antibacterial or antifungal agents; ■ Moctar, crisalobin, and other keratin softeners: (21
) Primidone, sodium palproate, nitrazepam,
Antiepileptic drugs such as mebrobamate and clonazepam; ■ Pleomycin, aclacinomycin, adriamycin, carmofu, pivobroman, norf7ran, carbocone, thioinosine, tamoxifen citrate, pebleomycin, tegafur, 5-fluorouracil and its derivatives, mitomycin, etc. Anti-cancer agents; progesterone, hydroxyprogesterone caproate, hydroxyprogesterone acetate.

Testosterone, testosterone enanthate.

Triedysteone, rylormadinone acetate, methylestosterone, dimethisterone, norethisterone, mestranol, estriol benzoate, estradiol dipropionate, estradiol dipropionate, estradiol tripropionate, estradiol valerate, gestolone caproate, fluoxymethisterone , sibrotiin acetate, tanazol, mebithiostane,
Sex hormones such as evithiostanol, dinobrost, methamine, ziprost, bromocriptine mesylate, and ethinyl estradiol acid: Q4 Pyridoxine hydrochloride, cobamacid, nicotinamide, pantethine, calcium pantothenate.

Flavin adenine dinucleotide, folic acid, pyridoxal phosphate, ascorbic acid, vitamin A, vitamin D,
Vitamin E, ergocalciferol ferol, 1α,24-zibi1-roxycholecalciferol. Otatothymine, riboflavin.

Vitamin preparations such as riboflavin butyrate; (25)
Beclomethasone propionate, liRMlt hexobrenaline, salbutamol sulfate, opium powder.

Antitussive expectorants such as ethylmorphine hydrochloride, morphine hydrochloride, opium alkaloid hydrochloride, fentanyl citrate, vetidine hydrochloride, phenotyrol hydrobromide, codine phosphate, dihydrocodine phosphate, procaterol hydrochloride, tranilast, pillpine; (26 ) Lysozyme chloride and its anti-inflammatory enzyme agents;
(27) Agents for liver diseases such as aspartate, orotic acid, glucuronolactone, thiocl-l amide, protoporphyrin sodium; (28) Antidotes such as glutathione: (29) Insulin, glibencracit, glymidine sodium. Diabetes treatment agents such as (30) Constipation treatment agents such as pyrosulfute sodium, danthrone, sennoside △・B calcium salt, Cascara Sagrada flow extract; (31) D-penicillamine, bestatin, levamisole, carfenil, platonin, etc. (32) Calindacillin sodium, bipmecillin sodium hydrochloride, cefuroxazine, calfecillin sodium, cefaclor, minoxazine, cefadroxil, hexamine mandelate, sulfamethizole, nitrofurantoin.

Ergomethyline maleate, methylergometrine maleate, sparteine sulfate, ziprost, ziptromethacin, dinobrostone.

Trichomycin, Nyscutin, Pimaricin.

Cystitis agents, chronic cystitis agents or urethral preparations such as estriol, clotrimazole, chlorampf7nicol, amphotericin B, miconazole nitrate, tribenoside, flavoxate hydrochloride: (33) Timolol maleate, 1-hydroxy-pyrido (3- 22) Ophthalmic agents such as 5-phenoxysazone-3-carboxylic acid: (34) Aceglutamide aluminum, cetraxate hydrochloride, renzevin hydrochloride, cimetidine.

[-Anti-ulcer agents such as glutamine and gefarnate; (35
) Agents for arteriosclerosis such as clinofibrate, elastase, simfibrate, benziclane fumarate, and diceritrol; (36) Anti-inflammatory agents such as sodium sulfisomidine, sodium sulfamethoxazole, silver sulfadiazine, gendamycin sulfate, and afenide acetate; Agents for sexually transmitted diseases; (37) Agents for parasitic skin diseases such as clotrimazole, situcanin, exalacit, pimaricin.

These drugs may be used alone or in combination of two or more.

Drugs include coronary vasodilators, antiarrhythmic agents, and angina drugs3.
Cardiac inotropes, antihypertensive agents, and the like are preferred, and coronary vasodilators such as isosorbide nitrate and nitroglycerin are particularly preferred because they have greater sustained release effects than Ike's method. The amount of the drug to be used is appropriately determined depending on the strength of the pharmacological action of the drug used, its absorbability into the skin, and the like.

In the formulation of the present invention, the adhesive layer contains hollow fibers as described above.

As the adhesive layer used in the present invention, a normal pressure-sensitive adhesive is used, such as a rubber-based viscous composition mainly composed of silicone rubber, polyisoprene comb, styrene-butadiene copolymer rubber, acrylic rubber, natural rubber, etc. Materials: Vinyl viscous compositions such as polyvinyl alcohol, ethylene-vinyl acetate copolymerization: Viscous compositions containing silicone adhesives, polyurethane elastomers, polyester elastomers, polybutadiene elastomers, etc. Niacrylic resins, etc. You can choose from. Among these, acrylic resins are preferred, especially from the viewpoints of less skin irritation, moderate tackiness, adhesion, high internal cohesion, and excellent solvent resistance. (meth)acrylic acid alkyl ester of at least 90 to 98 mol%, (2) acrylic acid or/and methacrylic acid 2 to 6
Particularly preferred is an acrylic resin copolymerized with mol%. An example of the (meth)acrylic acid ester of an alkyl group having 4 or more carbon atoms is butyl (meth)acrylate.

Amyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate.

Examples include nonyl (meth)acrylate, decyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and the like. These adhesives may be used alone or in combination of two or more.

In the present invention, in addition to containing a drug in the hollow portion of the hollow fiber, the adhesive may also contain a drug. In the case of a preparation that also contains a drug in the adhesive, when the preparation is administered, the drug first diffuses into the adhesive and is absorbed into the skin. In this case, the drug concentration in the adhesive decreases, but the decreased concentration is filled into the hollow part of the hollow mg and replenished with a high concentration of drug. Such a mechanism results in a formulation in which the drug administration layer can be controlled within a certain range over a longer period of time.

The thickness of the adhesive layer is usually 5 to 1,000 microns, preferably 10 to 500 microns.

An adhesive layer containing hollow fibers can be manufactured as follows.

That is, for example, placing a hollow fiber on a support described below,
A method of applying a pressure-sensitive adhesive to the surface of a hollow fiber: A method of placing a hollow fiber on a support, applying an adhesive monomer, and then reacting it by heating, UV irradiation, or ionizing radiation; A layer of adhesive is made in advance, and then a hollow fiber filled with drug is placed in the hollow part.
A method can be adopted in which the hollow fibers are pressed against the adhesive layer to bury the hollow fibers to the required extent.

The formulation of the present invention is provided with a support that supports the adhesive layer as described above and is made entirely or partially of a film having a thickness of 4.9 microns to 0.5 microns.

If the thickness is 4.9 microns or more, the flexibility of the preparation will be poor, and if it is applied for a long time, skin irritation will increase. In addition, the drug release properties from the formulation also tend to fluctuate.

If the thickness is less than 0.5 micron, the film will be torn by slight external force from clothing, fingernails, friction, etc., and the stability of the formulation will deteriorate. Furthermore, the drug escapes from the film surface during storage or application of the preparation, resulting in poor stability over time.

Materials for the film used in the present invention include, for example, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, polyamides such as nylon 6 and nylon 66, polyvinyl alcohol, nylidene chloride, polyurethane, ethylene-
Vinyl acetate copolymer, metal foil, rubber, etc. can be used.

Among these materials, polyester, especially polyethylene terephthalate, has drug retention properties, appropriate flexibility, and strength, and is highly effective for drug productivity, drug release, stability, and drug retention.
It is preferable because it is excellent in preventing skin irritation.

The formulation of the present invention, which is mainly composed of an adhesive layer and a support layer, contains an absorption aid and a solubilization aid as necessary.

It may contain a diffusion aid, a filler, etc.

Examples of absorption aids or diffusion aids used in the present invention include interfaces such as sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium alkyldiphenyl ether disulfonate, dioctyl sulfosuccinate, and polyoxyalkylphenyl ether sulfate ammonium salt. Activator: ethanol, glycerin,
Alcohols such as diethylene glycol, propylene gellicol, polyethylene glycol, and higher fatty acid alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, diethyltoluamide, dimethylformamide, dioctyl cabacate, and lanolin.

Allantoin, squalene, carbobol, diisopropyl adipate, pyroglutamic acid lauryl ester,
Ethyl laurate, methyl nicotinate, sorbitol and dodecylpyrrolidone derivatives.

Olive oil, castor oil, liquid paraffin, petrolatum, gelatin, amino acids, benzyl nicotinate.

Rementhol, camphor, dodecyl azacyclohebut-2-one, etc. can be used.

Fillers include water, titanium oxide, calcium carbonate, carbon black, red iron oxide, and various dyes and pigments.

Liquid paraffin, petrolatum, lactose, fragrance, deodorizer.

polyethylene, polypropylene, polyester.

Examples include powders and molded products of synthetic resins such as polystyrene.

As described in detail above, the preparation of the present invention has hollow fibers containing a drug in its adhesive layer, and is an extremely excellent preparation in terms of sustained drug release effect.

<Example> The present invention will be explained in more detail by giving examples below. Parts in the examples indicate parts by weight, and the characteristics appearing in the examples were measured by the following method.

(1) Water absorption rate test method (according to JTS-11018) The fibers were made into a cloth, and the cloth was washed with 7-ionic detergent Zab (
The sample was washed with a 0.3% aqueous solution manufactured by Kao Soap Co., Ltd. for 30 minutes at 40℃ using a domestic electric washing machine for a predetermined number of times, and then dried. One drop of water (0.04 cc) is added, and the time is measured until the water is completely absorbed by the sample and no reflected light is measured in vA.

(H) Water Absorption Measuring Method A sample obtained by drying a fabric is immersed in water for 30 minutes or more, and then dehydrated for 5 minutes in a household electric washing machine. It was determined by the following formula from the weight of the sample after hanging the dry sample and dehydrating it.

Water absorption rate - (Sample weight after dehydration - Dry sample weight) / Dry sample volume (%) (A)! Blood concentration measurement method of isosorbide 1181 acid 3
Crystals were separated from the blood collected in step d, extracted with 4d of n-hexane, concentrated, ethyl acetate was added to make 100d, and the mixture was fixed by GC-ECD.

Moreover, Hollow II navy blue and adhesive solution used in the examples were created by the following method.

(1) Hollow system sample (1) 297 parts of dimethyl terephthalate, 2 parts of ethylene glycol
65 parts, 53 parts of sodium 3.5-dicarbomethoxy)benzenesulfonate (11.7 mol% based on dimethyl terephthalate), 0.084 part of manganese acetate tetrahydrate, and 1.22 parts of sodium acetate trihydrate. of the mixture was placed in a precision substrate glass flask, and the transesterification reaction was carried out according to a conventional method. After the theoretical amount of methanol had been distilled off, the reaction product was placed in a precision substrate polycondensation flask, and 5% of orthophosphoric acid was added as a stabilizer.
Added 10.0 parts of 6% aqueous solution and 0.135 parts of antimony trioxide as a polycondensation catalyst, and after reacting at a temperature of 275°C for 20 minutes under normal pressure and 15 minutes under reduced pressure for 30 minutes, under high vacuum. The reaction was allowed to proceed for 100 minutes. Final internal pressure is 0.36m
1- to +, and the obtained copolymer had an intrinsic viscosity of 0.407. The softening point was 200°C. After the reaction was completed, the copolymer was made into chips according to a conventional method.

15 parts of chips of this copolymer and an intrinsic viscosity of 0.64
After mixing with 85 parts of polyethylene terephthalate chips of No. 0 for 5 minutes in a Nauta mixer (manufactured by Ironkosho Co., Ltd.), the mixture was heated at 110°C for 2 hours in a nitrogen stream, and further heated for 150 minutes.
After drying at C for 7 hours, ffl! It was kneaded and made into chips. The intrinsic viscosity of this chip is 0.525. The softening point was 262°C.

The chips were dried in a conventional manner and placed in a spinneret with a width of 0.05 mm.
A circular slit with a diameter of 0.6 m and an arc-shaped opening with two closed places was used, and the yarn was spun according to a conventional method to obtain a hollow fiber with a ratio of outer diameter to inner diameter of 2:1 (hollowness ratio 25%)
made. This raw yarn is 300 denier/24 filaments, and using this raw yarn, a drawing ratio of 442
A multifilament of 71 denier/24 filaments was obtained by drawing at a double speed. This multifilament was knitted into a knitted fabric, scoured and dried by a conventional method, and then treated with a 1% caustic soda aqueous solution at boiling temperature for 2 hours to give an alkali weight loss rate of 17% and a water absorption rate of 3 seconds.

A fabric with a water absorption rate of 82% was obtained.

The obtained hollow fibers were hollow fibers having fine pores that were scattered over the entire cross section of the hollow fibers and arranged in the fiber direction, and at least a portion of them were in communication with the hollow portion.

(2) Hollow fiber sample (2) This is a knitted fabric made from 1U in the preparation of hollow fiber sample (1) without alkali treatment, and the water absorption rate is 2.
30 seconds, the fabric has a water absorption rate of 38%.

This hollow fiber does not have holes penetrating in the outer circumferential direction.

(3) Adhesive solution 2-ethylhexyl acrylate 97.4 parts, methacrylic acid 2.5 parts, polyethylene glycol (polymerization degree 14
) Dimethacrylate 0.1 part, benzoyl peroxide 1.0
and 100 parts of ethyl acetate were charged into a reaction vessel equipped with a reflux condenser and a stirrer, and slowly heated at 60°C under a nitrogen atmosphere for 1j! Polymerization was continued for 9 hours while feeling itchy. The polymerization conversion rate was 99.9%.

500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20%.

An ethyl acetate solution containing the adhesive was applied onto a silicone-coated release paper to a dry thickness of 30 μm, and dried at 90° C. for 5 minutes to obtain an adhesive layer.

Example 1 A hollow fiber sample was impregnated with 10 parts of an acetone solution containing 10 parts of isosopide nitrate, and then air-dried to remove the acetone.

This hollow fiber sample containing isosorbide nitrate was sandwiched between two adhesive layers, and a 3μ thick polyethylene terephthalate film was attached to one surface of the adhesive layer whose surface was not in contact with the hollow fiber sample, and pressure was applied. A formulation was obtained in which the adhesive layer, the hollow fiber sample, and the film were laminated and molded.

This preparation was cut into pieces of 2 ax x 4 crpr, and a preparation containing 51119 isosorbide nitrate was made and applied to the depilated back of a rabbit weighing 3.1 kg. Blood was collected at a predetermined time to determine the blood concentration. was measured. The results are shown in Table-1. Furthermore, after attaching a release paper to the surface of the free adhesive layer of the preparation and heating it at 40° C. for one month, the drug content of the preparation was 4.81 ftg.

Comparative Example 1 A preparation was prepared in the same manner as in Example 1, except that hollow fiber sample (2) was used instead of hollow fiber sample (1), and the blood concentration was measured. The results are shown in Table-1.

Comparative Example 2 A preparation was prepared in the same manner as in Example 1, except that a polyethylene terephthalate film with a thickness of 11 μm was used instead of a polyethylene terephthalate film with a thickness of 3 μm, and the blood concentration was measured. The results are shown in Table-1.

Comparative Example 3 A preparation was prepared in the same manner as in Example 1, except that a 15 μm film of vinylidene chloride was used instead of the 3 μm thick polyethylene terephthalate film, and the blood concentration was measured. The results are shown in Table-1.

Furthermore, after attaching a release paper to the surface of the free adhesive layer of the preparation and heating it at 40° C. for one month, the drug content in the preparation was 3.91RjJ.

Comparative Example 4 A polyethylene terephthalate film with a thickness of 3 μm was
When the film was stretched simultaneously in the longitudinal and transverse directions in a constant temperature bath heated to 0° C. to break, the thickness of the film immediately before breaking was 0.43 μ to 0.46 μ. - The thus obtained film was used in place of the 3μ polyethylene terephthalate film of Example 1, and Example 1 was prepared.
A preparation was prepared in the same manner as in Example 1, and the drug content of the preparation after heating at 40° C. for one month in the same manner as in Example 1 was 3.8 rftg.

Examples 2 to 4 and Comparative Examples 4 to 6 A so-called bracebo formulation was prepared in the same manner as in Example 1, except that isosorbide nitrate was not used and the film shown in Table 2 was used instead of the 3μ polyethylene terephthalate film. , age 20-30 years old 2 weight 56
Six strips were randomly applied to the center of the backs of three adults weighing ~72 kg each, and the state of skin irritation was determined when they were removed two days after application.

Judgment is O for no reaction, and 1 for slight redness. Things that are clearly red 2. 3. Examination of mounds etc. where rash appears
Table 2 shows the results of the judgment based on the sum of the judgment points of the three people.

Table-1 Rabbit blood concentration (unit: nMm) Table-2 Human patch test

Claims (1)

[Scope of Claims] 1. An adhesive layer containing hollow fibers having holes penetrating in the outer circumferential direction and containing a drug, and a thickness of 4.9 microns to 0.5 microns. A sustained-release preparation for transdermal administration, which mainly consists of a support that is entirely or partially a film. 2. Claim 1 in which the hollow fiber is polyester
Sustained-release formulation for transdermal administration as described in . 3. Claim 1 in which the film is polyester
The sustained-release preparation for transdermal administration according to item 1 or 2. 4. The sustained release preparation for transdermal administration according to any one of claims 1 to 3, wherein the drug is a coronary vasodilator. 5. The sustained release preparation for transdermal administration according to any one of claims 1 to 4, wherein the adhesive layer is made of an acrylic resin.