JPH0427212B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to sustained-release pharmaceutical preparations for transdermal administration. More specifically, the present invention mainly consists of an adhesive layer containing hollow fibers containing a drug in the hollow portions of specific hollow fibers, and a support that is entirely or partially a film with a thickness of 4.9 microns to 0.5 microns. The present invention relates to a sustained release formulation for transdermal administration, which is highly safe and has an excellent effect on sustained drug release. <Conventional technology> In the development of pharmaceuticals, it is necessary to develop new compounds with excellent medicinal efficacy, 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, for the purpose of prolonging the duration of a drug with a short half-life, which is also a parameter of the effective duration of the drug in the body, it is possible to lower the drug to 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 being actively conducted. Examples of sustained-release preparations include transdermal preparations such as ointments, sprays, and applications. Since these preparations are applied to the skin in eye-doses, there are problems in that the dosage is not constant and that ointments and the like adhere to clothes and stain them. Furthermore, drugs in ointments are absorbed into human skin depending on factors such as the initial concentration, the applied thickness, the concentration of drug diffusion in the ointment base, and the absorption rate in the skin, 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).
(Refer to Japanese Patent Application Laid-Open No. 1983-134020). 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> Conventional tapes and patches do not contain pharmaceuticals at a minimum effective concentration or higher and a maximum safe concentration or higher.
If you want to administer it for as long as possible, e.g.
If the drug concentration in the adhesive is simply increased, the initial concentration absorbed into the human body will be higher and skin damage may occur. 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 in this case, it generally increases skin irritation or exposes the skin to one part of the adhesive layer.
Problems such as parts remaining as residue are likely to occur. Another method is to lower the drug concentration in the adhesive,
Efforts have also been made to increase the area of application to the skin. However, if the area to be applied is increased, the patch becomes difficult to handle, the area of skin that is irritated increases, which is undesirable, or the areas to which it can be applied are limited. As a solution to these problems, if a so-called drug reservoir type preparation is used, in which the adhesive layer contains a specific hollow fiber containing a drug in its hollow portion, the administration of the medicinal ingredient can be sustained. 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 these drawbacks, the present inventors have devised a method that ensures that the medicinal ingredient is contained in a small patch area, that allows 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 with the aim of obtaining a sustained-release preparation with a high The present invention has been achieved based on the discovery that a formulation consisting mainly of a support that can achieve these objectives. That is, the present invention comprises an adhesive layer containing hollow fibers made of polyester having holes penetrating in the outer circumferential direction and containing a drug in the hollow portion of the hollow fibers, and a film having a thickness of 4.9 microns to 0.5 microns. This is a sustained-release preparation for transdermal administration, which mainly consists of a support containing all or part of the following. 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 preferably hollow fibers having fine holes scattered over the entire cross section of the hollow fibers, arranged in the fiber axis direction, and at least a part of which is in communication with the hollow part. . 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 ratio of holes penetrating in the outer circumferential direction to the cross-sectional area of the fibers is
It is preferably 0.001 to 70%, particularly preferably 0.01 to 50%, and more preferably 1 to 50% of the fiber cross-sectional area excluding hollow portions. The hollow fibers of the present invention have an almost infinitely long shape with respect to the outer diameter of the fibers, and when used in the form of woven fabrics, knitted fabrics, non-woven fabrics, etc., they have good handling properties, a good feel on the skin, and a suitable sustained release of drugs. This is preferable because it makes the most of its characteristics. The material for the hollow fibers used in the present invention is, for example, polyester such as polyethylene terephthalate. Among these, polyethylene terephthalate is preferred because of its good drug retention and drug stability. The hollow fiber used in the present invention is, for example,
−20612 Publication, JP-A-56-20613, JP-A-Sho
It can be produced by the method described in JP 56-43420 and the like. In the present invention, a plurality of hollow fibers having different materials, shapes, or hollow ratios may be used in combination. Instead of hollow fibers, some non-hollow fibers may be mixed and used. In the present invention, the above-described hollow fibers containing a drug in the hollow portions of the hollow fibers having holes penetrating in the outer circumferential direction are used. The drug may exist alone in the hollow portion, or may exist together with an adhesive described below, or may contain commonly used excipients, dissolution aids, diffusion aids, and accelerators. 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 hollow fibers are 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; or a method in which the drug is excipiented. A method is used in which the hollow fibers are mixed with agents, solubilizers, diffusion aids, skin absorption enhancers, etc., and then made into a solution, ointment, etc., and the hollow fibers are immersed in or brought into contact with the solution or ointment. heating to help the drug or drug mixture penetrate into the hollow part of the hollow fiber;
Means such as pressurization, vacuum pressurization, and ultrasonic vibration 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-propanetriol dinitrate and their ester derivatives, isosorbide nitrate, isosorbide-5-mononitrate, pentaerythritol tetranitrate, papaverine hydrochloride, hepronicard, molsidomine, nicomol, sinfibrado,
verapamil, diltiazem cinnarizine hydrochloride,
Coronary vasodilators such as dipyridamole, nifedipine, nicardipine, trapidil, trimetazidine hydrochloride, carbochromene, prenylamine lactate, dilazep hydrochloride, trapidil; (2) pindolol, disopyramide, bupranolol hydrochloride, trichlormethiazide, furosemide,
Antiarrhythmic or antianginal agents such as prazomine hydrochloride, metoprolol tartrate, cartiolol hydrochloride, oxprenol hydrochloride, and propranolol hydrochloride; (3) Antihypertensive agents such as prazosin hydrochloride, ecalazine hydrochloride, and hydrazine hydrochloride; (4) Methyldigoxin , sodium benzoate, caffein, caffein, dopamine hydrochloride, tobutamine hydrochloride, octobamine hydrochloride, dibrophyllin, ubidecarenone, pucladesine sodium, oxprenol hydrochloride, digitalis, dicoxin, ubidecarenone; (5) procaterol hydrochloride, piripralol hydrochloride,
Chlorophedanol hydrochloride, salbutamol sulfate, propranolol hydrochloride, trimethoquinol hydrochloride, hydruterol mesylate, mebutin, pindolol, isoprotenol, isoaminyl citrate, carbocysteine, cefrazine,
Bronchial asthma agents such as Rizaben, Theophylline; (6) Clonidine, Nifedipine, Nicardipine,
Antihypertensive agents or calcium antagonists such as verapamil; (7) Aspirin, salicylic acid, methyl salicylate, ethyl salicylate, choline salicylate, sodium salicylate, salicyrosalicylic acid, salicylamide, glycol salicylate, l-menthol , aminopyrine, antipyrine, clophezone, ketophenylbutazone, camphor, pepper oil, thymol, isopropylantipyrine, phenylbutazone, phebrazone, nicotinic acid benzyl ester, capsicum extract, capsaicin, acetaminophene, oxyphenylbutazone, pentazodine, eptazodine, diflunisal , fenazole, mepyrizole, piroxicam, benzydamine, phenacetin, tiaramide, bufexamac, flufenamic acid, aluminum flufenate, indomethacin, tramadol hydrochloride, ibuprofen, alclofenac, acemethacin, sulpirin, sodium guaiazulene sulfonate, guaiazulene, ketoprofen, fluruby profen, diclofenac sodium,
Fuenoprofen, pirprofen, naproxen, clidanac, sulindac, ibuprofen, penoxabrofen, indobuene, mefenamic acid, tolmetin, metiazic acid, protidic acid, perisoxal citrate, pranoprofen, zontar, phenylbutazone, fenbufen, fentiazac, diflunizal, tiaprofunic acid (8) Lidocaine, Local anesthetics such as benzocaine, ethyl aminobenzoate, procaine hydrochloride, dibucaine, procaine; (9) mefluside, penfluticide, pumetanide,
Antihypertensive diuretics such as hydrothiazide, pentroflunathiazide, reserpine; (10) methaqualone, glutethimide, flurazepam,
Hypnosedatives such as promvaleryl urea, flurazepam hydrochloride, nitrazepam, haloxazolam, triazolam, phenobarbital, chloral hydrate, nimetazepam, and estazolam; (11) Lepodopa, flufengine, flutazolam,
Central nervous system agents such as phenobarbital, phenobarbital sodium, methylphenobarbital, thioridazine, diazepam, benzpromalone, reserpine, sulpialprazome, clocapramine hydrochloride, clotiazepam, chlorpromazine, haloperidol, nitrazepam, sodium carbonate; ( 12) Psychoactive agents such as 3-(2-aminobutyl)indole acetate; (13) Epinephrine, cortisone acetate, hydrocortisone acetate, hydrourtisone, prednisolone, hydrocortisone sodium succinate,
Triamcinolone acetonide, triamcinolone diacetate, dexamethazoniphosphate, methylprednisolone, diclolidine acetate, methylprednisolone acetate, fluoroxynolone acetonide, dexamethasone acetate, texamethasone, dexamethasone sodium sulfate, dexamethasone sodium phosphate, paramethasone acetate, fluoro Mesolone, esterone, estradiol, ethinyl estradiol, betamethasone sodium phosphate, betamethasone, betamethasone valerate, formoyultal, flumethasone pivalate, beclomethasone propionate, fludroxycortide, hydrocortisone butyrate, betamethasone dipropionate, gemeprostflu Corticosteroids such as oxynonide, clobetasol propionate, diflunirtron valerate, halcinonide, prednisolone valerate, and hydrocortisone propionate butyrate; (14) Sulfur drugs such as carfadimethoxine, sulfisoxazole, and sulfisomidine ，
Antituberculous drugs such as ethambutol hydrochloride, isoniazid, calcium para-aminosalcylate; (15) Homochlorcyclidine hydrochloride, diphenhydromine hydrochloride, chlorpheniramine, diphenylimidazole, chlorpheniramine maleate, glycyrrhetinic acid, tranilast (16) Myasthenia gravis drugs such as pyridostigmine bromide; (17) Cerebral infarction sequelae drugs such as nicardipine hydrochloride, cinepacid maleate, pentoxifylline, and ifenprodil tartrate; (18) ) Penicillin, tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamide, oxytetracycline, talampicillin hydrochloride, fradiomycin sulfate, erythromycin, tetracycline hydrochloride, bacampicillin hydrochloride, fradiomycin, leucomycin, secloxacin, cephalosporin, ampicillin, cephalexin , cefaclor, neomycin sulfate, bacitracin, cefalotin sodium,
Antibiotics such as kanamycin sulfate, fosfomycin calcium, streptomycin, gentamicin sulfate, fradiomycin sulfate, chlamidine S, mikamycin, colistin; (19) Iodine, povidone-iodine, boric acid, borax, oxidole, potassium permanganate, ethanol, isopropanol, Formalin, cresol, dimazole hydrochloride, situkanin, phenyl iodo undecinoate, hexachlorophene, creosote, resorcinol, acrylate, methylosarinine chloride, benzethrium chloride, mercuric chloride, methylosal, makiurochrome, chlorhexidine gluconate, alkyl polyaminoethyl hydrochloride Glycine, benzalkonium chloride, nitrofurazone, nystatin, acetoflufamine, clotrimazole, sulfamethizole, tolnaftate, pentamycin, amphotericin B, pyrrolnitrine, undecylenic acid, miconazole, turcomycin, barithion, halopromidine, hydrochloric acid Antibacterial or antifungal agents such as dimazole; (20) Keratin softeners such as Moctal and Crisalopin; (21) Anti-inflammatory agents such as primidone, sodium palproate, nitrazepam, meprobamate, and clonazepam; (22) Bleomycin and aclacinomycin. , adriamycin, carmofu, pipoproman,
Anti-neoplastic agents such as melphalan, carbocone, thioinosine, tamoxifen citrate, pepleomycin, tegafur, 5-fluorouracil and its derivatives, mitomycin; (23) Progesterone, hydroxyprogesterone caproate, hydroxyprogesterone acetate, testosterone, testosterone enanthate , triethisterone, chlormadinone acetate,
Methylesterone, dimethisterone, norethisterone, mestranol, estriol benzoate, estradiol dipropionate, estradiol dipropionate, estradiol tripropionate, estradiol valerate, gestonolone caproate, fluoroxymethisterone, cyprotein acetate, tanazol, mepithiostane , epithiostanol, dinoprosttromethamine, dinoprost, bromocriptine mesylate, ethinyl estradiol acid sex hormones; (24) pyridoxine hydrochloride, cobamacid, nicotinamide, pantethine, calcium pantothenate, flavin adenine dinucleotide, folic acid,
Pyridoxal phosphate, ascorbic acid, vitamin A, vitamin D, vitamin E, ergocalciferol, alphaacalcidol, cholecalciferol, 1α,24-dibitroxycholecalciferol, otatothymine, riboflavin, riboflavin butyrate, etc. (25) Beclomethasone propionate, hexoprenaline sulfate, salbutamol sulfate, opium powder,
Antitussive expectorants such as ethylmorphine hydrochloride, morphine hydrochloride, opium hydrochloride alkaloids, fentanyl citrate, pethidine hydrochloride, fenoterol hydrobromide, codeine phosphate, dihydrocodeine phosphate, procaterol hydrochloride, tranilast, bisorbin; (26) Chloride Lysozyme and other anti-inflammatory enzymes; (27) Liver disease agents such as aspartate, orotic acid, glucuronolactone, thioctic acid amide, protoporphyrin sodium; (28) Antidotes such as glutathione; (29) Antidiabetic agents such as insulin, glibencraside, and glymidine sodium; (30) Anti-constipation agents such as sodium pyrosulfate, danthrone, sennoside A/B calcium salts, and cascara sagrada flow extract; (31) D-penicillamine, bestatin, Immunological drugs such as levamisole, carfenil, platonin; (32) Calindacillin sodium, bipmecillin sodium hydrochloride, cefuroxazine, calfecillin sodium, cefacrol, minoxacin, cefadroxil, hexamine mandelate, sulfametisol, nitrofurantoin, Ergomethyline maleate, methylergometrine maleate, sparteine sulfate, dinoprost, dinopromethacin, dinoprostone, trichomycin, nystatin, pimarizine, estriol, clotrimazole, chloramphuanicol, amphotericin B, miconazole nitrate, tribenoside , cystitis agents such as flavoxate hydrochloride, chronic cystitis agents or urethritis agents; (33) Timolol maleate, 1-hydroxy-
Pyrido(3-22)5-phenoxysazone-3-
Ophthalmic agents such as carboxylic acids; (34) Aluminum aceglutamide, Cetraxate hydrochloride, Pirenzepine hydrochloride, Cimetidine, L
- Anti-ulcer agents such as glutamine and gefalnate; (35) Arteriosclerotic agents such as clinofibrate, elastase, synfibrate, bencyclane fumarate, and niceritrol; (36) Sulfisomidine sodium, sulfamethoxazole Agents for purulent diseases such as sodium, silver sulfadiazine, gendamicin sulfate, and afenide acetate; (37) Agents for parasitic skin diseases such as clotrimazole, situcanin, exalaside, and pimaridine. These drugs may be used alone or in combination of two or more. Suitable drugs include coronary vasodilators, antiarrhythmic agents, antianginal agents, cardiac inotropic agents, antihypertensive agents, etc. Coronary vasodilators such as isosorbide nitrate and nitroglycerin are particularly preferred compared to other methods. It has a large sustained release effect and is suitable. 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. Vinyl viscous compositions such as polyvinyl alcohol and ethylene-vinyl acetate copolymer; Viscous compositions whose main components are silicone adhesives, polyurethane elastomers, polyester elastomers, polybutadiene elastomers, etc.; Acrylic resins, etc. You can choose from. Among these, acrylic resins are preferred, especially since they are less irritating to the skin.
From the viewpoint of appropriate tackiness, adhesion, high internal cohesion, and excellent solvent resistance, (1) at least 90 to 98 mol% of (meth)acrylic acid alkyl ester of an alkyl group having 4 or more carbon atoms; (2) Acrylic resins copolymerized with 2 to 6 mol% of acrylic acid and/or methacrylic acid are particularly preferred. Examples of (meth)acrylic acid esters of alkyl groups having 4 or more carbon atoms include butyl (meth)acrylate, amyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, Decyl (meth)acrylate, 2-ethylhexyl (meth)
Examples include acrylate. 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. As a result, the drug concentration in the adhesive decreases, but the decreased concentration is filled into the hollow portions of the hollow fibers and replenished by a high concentration of drug. Such a mechanism results in a formulation in which the drug dosage can be controlled within a certain range over a longer period of time. The thickness of the adhesive layer is usually 5 to 1000 microns, preferably 10 to 500 microns. An adhesive layer containing hollow fibers can be manufactured as follows. That is, for example, a method in which a hollow fiber is placed on a support described below and a pressure-sensitive adhesive is applied to the surface of the hollow fiber; after the hollow fiber is placed on a support and an adhesive monomer is applied, heating or UV irradiation, A method of reacting with ionizing radiation; Alternatively, a layer of adhesive is formed on the support in advance, and then hollow fibers filled with the drug in the hollow portion are pressed against this layer of adhesive to form the hollow fibers as required. A method of burying the body to a certain extent can be adopted. 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 microns, the film will tear due to 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. Examples of the film material used in the present invention include polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate, polyamides such as nylon 6 and nylon 66, polyvinyl alcohol, vinylidene chloride, polyurethane, and ethylene-vinyl acetate copolymer. Combination, metal foil, rubber, etc. can be used. Among these materials, polyester, especially polyethylene terephthalate, has drug retention properties, appropriate flexibility, and strength, and is excellent in terms of drug productivity, drug release, stability, and prevention of skin irritation. Preferably. The preparation of the present invention, which is mainly composed of an adhesive layer and a support layer, may contain an absorption aid, a dissolution aid, a diffusion aid, a filler, etc. as necessary. Examples of absorption aids or diffusion aids used in the present invention include sodium lauryl sulfate, sodium dodecylbenzene sulfonate, sodium alkyl diphenyl ether disulfonate, dioctyl sulfosuccinate, and polyoxyalkyl phenyl ether sulfate. Surfactants such as ammonium salts; alcohols such as ethanol, glycerin, diethylene glycol, propylene glycol, polyethylene glycol, and higher fatty acid alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, diethyltoluamide, dimethylformamide , dioctyl cabate, lanolin, allantoin, squalene, carbopol, diisopropyladipate, pyroglutamic acid lauryl ester, ethyl laurate, methyl nicotinate, sorbitol and dodecylpyrrolidone derivatives, olive oil, castor oil, liquid paraffin, petrolatum, gelatin, amino acids, Benzyl nicotinate, l-menthol, camphor, dodecyl azacycloheptan-2-one, etc. can be used. Fillers include water, titanium oxide, calcium carbonate, carbon black, red iron, various dyes and pigments, liquid paraffin, vaseline, lactose, fragrance,
Examples include deodorizing agents, powders and molded products of synthetic resins such as polyethylene, polypropylene, polyester, and 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. (i) Water absorption rate test method (according to JIS-L1018) The fibers are made into cloth, and the cloth is washed with a 0.3% aqueous solution of anionic detergent Zab (manufactured by Kao Soap Co., Ltd.) at 40℃ for 30 minutes in a household electric washing machine. Repeat the washing a specified number of times, then dry the sample. Place the sample horizontally, and pour 1 drop of water (0.04cm) from a height of 1cm above the sample.
cc) Drop the sample and measure the time until the water is completely absorbed by the sample and no reflected light is observed. (ii) Water absorption measurement method The sample obtained by drying the fabric is immersed in water for at least 30 minutes, and then dehydrated for 5 minutes in the dehydrator of a household electric washing machine. It was calculated from the weight of the dry sample and the weight of the sample after dehydration using the following formula. Water absorption rate = (sample weight after dehydration - dry sample weight) / dry sample weight (%) (iii) Blood concentration measurement method of isosorbide nitrate After separating crystals from 3 ml of collected blood, 4 ml
The extract was extracted with n-hexane, concentrated, added with ethyl acetate to make 100 ml, and quantified by GC-ECD. Moreover, the hollow fibers and adhesive solution used in the examples were created by the following method. (1) Hollow fiber sample (1) 297 parts of dimethyl terephthalate, 265 parts of ethylene glycol, 53 parts of sodium 3,5-di(carbomethoxy)benzenesulfonate (11.7 mol% based on dimethyl terephthalate), 4 parts of manganese acetate 0.084 parts of aqueous salt and 1.22 parts of sodium acetate trihydrate are placed in a glass flask equipped with a rectifying tower, and transesterification is carried out according to a conventional method. After the theoretical amount of methanol has been distilled off, the reaction product is added to a rectifying tower. Add a 56% aqueous solution of orthophosphoric acid to the polycondensation flask as a stabilizer.
0.090 parts and antimony trioxide as polycondensation catalyst
Add 0.135 parts, heat at 275℃, under normal pressure for 20 minutes, 30mm
The reaction was carried out for 15 minutes under reduced pressure of Hg, and then for 100 minutes under high vacuum. The final internal pressure was 0.36 mmHg, the intrinsic viscosity of the obtained copolymer was 0.407, and 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 and intrinsic viscosity of this copolymer
0.640 polyethylene terephthalate chips 85
5 in a Nauta mixer (manufactured by Hosokawa Iron Works).
After mixing for 2 minutes at 110°C in a nitrogen stream,
After further drying at 150°C for 7 hours, the mixture was melt-kneaded at 290°C using a twin-screw extruder to form chips. The intrinsic viscosity of this chip is 0.525, and the softening point is
It was 262℃. The chips are dried in a conventional manner and placed in a spinneret.
A circular slit of 0.05 mm and a diameter of 0.6 mm with two closed arc-shaped openings was used and spun according to a conventional method to obtain hollow fibers with an outer diameter to inner diameter ratio of 2:1. The hollow rate was 25%). This raw yarn was 300 denier/24 filaments, and was drawn in a conventional manner at a draw ratio of 4.2 times to obtain a multifilament of 71 denier/24 filaments. This multifilament was knitted into a knitted fabric, and after being scoured and dried by a conventional method, it was treated with a 1% caustic soda solution at boiling temperature for 2 hours to produce a fabric with an alkali weight loss rate of 17%, a water absorption rate of 3 seconds, and a water absorption rate of 82%. I got it. The obtained hollow fibers are arranged in the direction of the fibers scattered throughout the cross section of the hollow fibers, and at least one of the
The part was a hollow fiber having micropores communicating to the hollow part. (2) Hollow fiber sample (2) The stockinette fabric obtained in the preparation of hollow fiber sample (1) was not subjected to alkali treatment, and the fabric had a water absorption rate of 230 seconds and a water absorption rate of 38%. This hollow fiber does not have holes penetrating in the outer circumferential direction. (3) Adhesive solution 97.4 parts of 2-ethylhexyl acrylate, 2.5 parts of methacrylic acid, 0.1 part of polyethylene glycol (degree of polymerization 14) dimethacrylate, 1.0 part of benzoyl peroxide, and 100 parts of ethyl acetate in a reflux condenser.
The mixture was placed in a reaction vessel equipped with a stirrer and polymerization was continued for 9 hours at 60°C under a nitrogen atmosphere with gentle stirring. The polymerization conversion rate was 99.9%. 500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid concentration to about 20%. An ethyl acetate solution containing the adhesive was applied onto 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 After impregnating 10 parts of hollow fiber sample (1) with 10 parts of an acetone solution containing 2 parts of isosorbide nitrate, the fiber was air-dried to remove the acetone. This hollow fiber sample containing isosorbide nitrate is sandwiched between two adhesive layers, and a thickness is further applied to one surface of the adhesive layer whose surface is not in contact with the hollow fiber sample.
A 3μ polyethylene terephthalate film was attached and pressurized to obtain a formulation in which the adhesive layer, hollow fiber sample, and film were laminated and molded. This preparation was cut into 2cm x 4cm pieces, and 5mg was added to the preparation.
A preparation containing isosorbide nitrate was made and the weight was approx.
It was applied to the depilated back of a 3.1 kg rabbit, blood was collected at a predetermined time, and the blood concentration was measured. The results are shown in Table-1. Further, the drug content of the preparation after attaching a release paper to the free adhesive surface and heating it at 40° C. for one month was 4.8 mg. 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 an 11 μm thick polyethylene terephthalate film was used instead of the 3 μm thick polyethylene terephthalate film, 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 thick vinylidene chloride film 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 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 3.9 mg. Comparative Example 4 When a polyethylene terephthalate film having a thickness of 3 μm was stretched simultaneously in the vertical and horizontal directions in a constant temperature bath heated to 300° C. and the film was broken, the thickness of the film immediately before breaking was 0.43 μm to 0.46 μm. Using the film thus obtained in place of the 3μ polyethylene terephthalate film of Example 1, a formulation was prepared in the same manner as in Example 1, and the resulting formulation was heated at 40°C for one month in the same manner as in Example 1. After treatment, the drug content of the formulation was 3.8 mg. Examples 2 to 4 and Comparative Examples 4 to 6 A so-called placebo preparation 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. 6 patches were randomly applied to the center of the backs of 3 healthy adults aged 20 to 30 years and weighing 56 to 72 kg, and the condition of the skin rash was determined when the patches were removed two days after application. did. Table 2 shows the results of the judgment based on the total score of the three people, with 0 indicating no reaction, 1 indicating slight redness, 2 indicating obvious redness, and 3 indicating rash on the papilla examination. It was shown to.

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Claims (1)

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