CN101309706A - Drug release control composition and drug-releasing medical device - Google Patents

Abstract

The drug-releasing medical device of the present invention is a drug release control composition which contains 100 parts by weight of an organic polymer material which is soluble in an organic solvent and is not water-soluble, 5 to 60 parts by weight of a fat-soluble low-molecular release auxiliary agent, and 1 to 70 parts by weight of a drug. When the composition is applied to a stent, a catheter, an organ replacement medical device, an artificial organ, or the like in the form of a coating or the like, a drug releasing function can be imparted to the medical device. The stent for treating coronary artery stenosis of the preferred embodiment sustainedly releases argatroban or sarpogrelate hydrochloride or both agents from the surface thereof. In order to exhibit the releasability in a desired period of time, the drug to be slowly released is carried in a polymer material coated on the metal surface constituting the stent or in a porous stent base material. The polymer material is amorphous and biodegradable, and preferably contains tartrate, malate, or a mono-or diester of glycerin as a release aid.

Description

Drug release controlled composition and drug releasing medical device

technical field

The present invention relates to a controlled drug release composition and the like, and more particularly to a controlled drug release composition imparting a drug release function to a medical device and the like, and a drug releasing medical device holding it, particularly a stent.

Background technique

In recent years, in order to effectively exert the drug effect, not only new drugs but also known drugs have been vigorously developed for their formulations and drug delivery techniques. For example, there is a preparation technology in which a special film is used to coat the medicament so that the effective components are released after a certain period of time. In addition, based on the concept of drug delivery system (DDS), formulation technology using nanospheres and microcapsules including liposomes has been extensively studied. In addition, the functions pursued by these DDS include release controllability, target orientation, ease of ingestion and administration, enhancement of effect and reduction of side effects, and the like.

So far, polymer matrix materials such as polylactic acid and lactic acid/glycolic acid copolymer have been intensively studied as drug sustained release materials used in DDS (Patent Documents 1 and 2, Non-Patent Document 1). However, simply mixing a drug with these biodegradable polymers generally fails to obtain the desired release rate of the drug at the delivery site. Because in such a polymer matrix, the speed of drug diffusion movement is very slow and is not easily dissociated therefrom (Non-Patent Document 1). In order to solve the above-mentioned problems, techniques for ensuring or increasing the drug release amount by making the polymer matrix porous or granulated to increase the contact area have been developed and are in the process of practical use. For the above-mentioned polymer matrix, it is extremely important to control the pore diameter when making a porous body, and a high degree of condition setting is required, which inevitably leads to an increase in manufacturing cost.

On the other hand, with the advancement of medical engineering, technologies have been developed mainly for the purpose of diagnosis and treatment, and achieve the desired purpose by combining, embedding or indwelling some medical appliances, devices or devices inside and outside the living body. However, most people basically hold a negative attitude towards the direct use of the above-mentioned polymer matrix technology on medical devices such as catheters, stents, and artificial blood vessels. This is because it is difficult to form a porous body on the surface of these medical devices by a coating method, and in this field, a smooth plane is instead required in consideration of rejection in a living body.

The stent, which is one of the medical devices applicable to the living body, is used to treat coronary artery occlusive disease. That is, the indwelling stent in the blood vessel can supplement the cut part while preventing the contraction of the blood vessel, effectively reducing the recurrence probability of patients with coronary artery occlusive disease.

So far, various materials, shapes, and operation methods of stents for treating coronary artery occlusive disease including coronary artery occlusive disease have been disclosed. However, the previous materials still cannot completely avoid the risk of restenosis and reocclusion, which leads to the narrowing of the scope of application of angioplasty using stents. Therefore, a stent with less risk of restenosis and reocclusion is highly desired in the medical field.

In addition, drug-releasing stents that combine anticancer agents, immunosuppressants, antibiotics, anticoagulants, etc., with various polymer materials are also being developed (Patent Document 2). However, in such a drug-releasing stent, it is actually not easy to set the timing, release speed, release amount, and release time of the drug according to requirements. For example, sudden release may occur in the early stage after indwelling, and sustained and sustained release may not be achieved, or there may be a problem with the method of loading the drug, which may cause the stent to fall off from the indwelling stent.

Argatroban, which is an antithrombin drug, and Sarpogrelate Hydrochloride, which is an antiplatelet drug, are known as the anticoagulant. Catheters disclosed in Patent Documents 3 and 4 are medical devices having antithrombotic properties by sustained release of argatroban. The current situation is that, until now, there have been no cases where antithrombin drugs such as argatroban or sargrelate hydrochloride were used in stents and their effects were specifically verified, and the release of the drugs necessary for the stent to exhibit anticoagulant properties has not been confirmed. Speed is completely unknown.

Patent Document 1: Japanese Patent Application Laid-Open No. 9-151136

Patent Document 2: Japanese Patent Application Laid-Open No. 9-255590

Patent Document 3: Japanese Patent Application Laid-Open No. 6-292711

Patent Document 4: Japanese Patent Application Laid-Open No. 6-292718

Non-Patent Document 1: [Polymer Processing] Vol. 45, No. 5, Page 222, No. 6, Page 270, 1996

Non-Patent Document 2: "Drug-Eluting Stent", Academy of Medicine, 2003

Contents of the invention

In view of the above circumstances and problems, the present inventors have completed the present invention through intensive studies. That is, they discovered that the release of a drug can be accelerated by adding a certain fat-soluble low-molecular-weight compound, and completed the present invention. The present invention provides a composition capable of accelerating the drug release and continuously releasing the drug stably for a long period of time, and a drug-releasing medical device using the composition.

Furthermore, the present inventors have conducted intensive studies on whether the above-mentioned loading form of the drug also greatly affects the release rate and continuous release time. As a result, it was found that as a polymer material carrying the drug, the compatibility with the drug and the polymer plays an important role in the sustained release of the drug for a certain period of time, and the fact that it is preferably carried on an amorphous polymer, and further completed this paper invention.

It has also been found that by making the stent base material porous and holding the polymer material loaded with the drug in the pores, the drug can be sustained-released for a certain period of time.

The object of the present invention is to provide a drug sustained-release stent that can continuously release the drug for a certain period of time by coating a polymer material containing an anticoagulant on the stent or loading it on a porous stent substrate.

The drug release controlled composition of the present invention is characterized in that it contains 100 parts by weight of an organic solvent-soluble and water-insoluble organic polymer material, 5-60 parts by weight of a fat-soluble low-molecular-weight release aid, 1- 70 parts by weight of the medicament.

The organic polymer material preferably has biodegradability or biocompatibility, or both. The biodegradable material is preferably aliphatic polyester or aliphatic polycarbonate. Specifically, there are polylactic acid, lactic acid/glycolic acid copolymer, polycaprolactone, polyhydroxybutyric acid, and the like.

The release aids are carboxylic acid esters or mono- or di-esters of glycerol. Preferred are esters of organic acids selected from citric acid, tartaric acid, malic acid, or ethyl monoacetate or diacetate of glycerol.

The aforementioned agents are pharmaceuticals, preferably anticoagulants, anticancer agents or immunosuppressants.

The above-mentioned composition may further contain a cell-adhesive substance or an endothelialization-promoting substance on the surface of a medical device.

The drug-releasing medical device of the present invention is characterized by holding the above composition.

Preferably, a layer of the above composition is formed on the surface.

The aforementioned medical device is preferably a medical device that is in contact with a living body, or is combined with or placed in a living body, and specifically includes a stent, a catheter, a wire clip, a medical device for organ replacement, a capsule detector or an artificial organ.

The stent of the present invention is a stent for treating coronary artery stenosis, and is characterized in that argatroban (antithrombin drug) or sargrelate hydrochloride (antiplatelet drug) or the above two agents are slowly released from its surface.

The release rate of the above-mentioned drugs is preferably 1×10 ⁻³ μg/mm ² ·h to 1 μg/mm ² ·h for both argatroban and sargrelate hydrochloride 21 days after the stent is placed.

Another feature is that the above-mentioned drug for sustained release is carried on the polymer material coated on the metal surface constituting the above-mentioned stent, or on the porous stent substrate.

The polymer material coated on the surface of the stent is preferably amorphous.

The polymer material coated on the surface of the stent is preferably an amorphous biodegradable polymer material.

A preferable polymer material mentioned above is biodegradable polylactic acid or lactic acid-glycolic acid copolymer.

The above-mentioned polymer material preferably further contains an auxiliary agent that promotes the release of the loaded drug.

The auxiliary agents for the above drug release are preferably tartrates or malates, or mono- or di-glycerin esters.

The metal surface constituting the above-mentioned stent may be a porous body, and the above-mentioned drug for sustained release is carried on the porous body. The pore diameter thereof is preferably 0.01 nm to 300 nm.

The controlled drug release composition of the present invention can accelerate the release of the contained drug in the body because it contains a fat-soluble low-molecular release aid. When the medical device holding the composition is delivered or indwelled to a predetermined body part or body surface part, the drug will be released, and the timing, release speed, release amount and release time can be adjusted. The medicines and medical devices used are not particularly limited. Therefore, the drug release controlled composition of the present invention can impart a drug release function to various medical devices.

In the drug-releasing stent of the present invention, since the amorphous polymer material loaded with argatroban and sargrelate hydrochloride has good compatibility with these synthetic anticoagulant drugs, drug burst is less likely to occur from the stent indwelling in the blood vessel. Sexual release, which in turn enables sustained release of the agent at a desired release rate.

By adding a release aid for accelerating the release of the anticoagulant agent, the release rate of the agent can be increased, and a sufficient amount to express the drug effect of the anticoagulant agent can be released from the initial stage of the indwelling stent. Therefore, the drug-releasing stent of the present invention can effectively prevent restenosis and reocclusion of arteries through the action of both the structure of the stent and the anticoagulant.

In addition, by controlling the pore size of the porous scaffold, the drug can be continuously released at a desired release rate.

In the present invention, "medical appliance" refers to "medical appliance", that is, an appliance used in the medical field in a broad sense.

"Sustained-release" refers to the property of slowly releasing the active ingredients in the preparation technology, in order to prevent the initial burst of the drug through the design of the preparation and make the drug effect last for a long time. "Biodegradability" refers to the characteristics of being metabolized at a relatively fast rate in the living body, and then decomposing and disappearing. "In vivo adaptability" refers to a tendency to have affinity for living organisms, not easily rejected by living organisms and cause rejection reactions, and inactive towards living organisms.

The term "carrying" in this specification refers to dispersing drug molecules or forming nanometer to submicron agglomerates in a polymer matrix or a porous body. In this specification, an anticoagulant agent may be described as an anticoagulant or an anticoagulant.

Drug release controlled composition

The drug release controlled composition of the present invention is characterized in that it contains,

100 parts by weight of an organic solvent-soluble and non-water-soluble organic polymer material, 5-60 parts by weight of a fat-soluble low-molecular release aid, and 1-70 parts by weight of a drug.

Here, "drug release control" refers to the adjustment of the timing, speed, release amount, duration, etc. of releasing a drug to a predetermined part of the body, and is not limited to sustained release.

Next, each component contained in this composition is demonstrated.

·Organic polymer materials

It is placed at a predetermined site in the living body, and an organic polymer material that is soluble in an organic solvent and insoluble in water is used as a carrier for loading and delivering a drug to the target site.

Considering that the above-mentioned materials are used in vivo and in vitro as described later, such an organic polymer material preferably has biodegradability, biocompatibility, or both from the viewpoint of in vivo safety.

Polymer materials suitable for the above requirements are especially preferably biodegradable polymers without physiological activity. Biodegradable polymers are hydroxycarbonate homopolymers, hydroxycarbonate oligomers or mixtures thereof. For example, specific examples of hydroxycarbonic acid and hydroxycarbonic acid oligomers include polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polylactide, poly(lactide-glycolate), poly(ethylene glycol-propylene lactide), poly(glycolic acid-caprolactone), polyhydroxybutyrate, polyhydroxyisobutyrate, polyvalerolactone, poly-gamma-hydroxyvaleric acid, poly(hydroxybutyrate-hydroxyvalerate ), polyisobutyl cyanoacrylate, polyalkyl cyanoacrylate, polyethylene succinate, etc. It may also be polyacetylglucosamine, chitosan, gelatin, cellulose acetate-terephthalate and the like.

Among them, aliphatic polyester (such as polyhydroxyalkanoate), aliphatic polycarbonate (such as polyalkylene carbonate), or polycaprolactone are particularly preferable copolymers as materials of the present invention. Specifically, there are lactic acid/glycolic acid copolymers, polylactic acid, polyglycolic acid, polymalic acid and their copolymers, lactic acid-caprolactone copolymers, and polyhydroxybutyric acid. These polymers may be single polymers, copolymers, mixtures thereof, or salts thereof. The biocompatible polymer or biodegradable polymer used in the present invention is relatively easy to obtain and can be easily synthesized by a general synthesis method.

The above-mentioned polylactic acid, aliphatic polyester, and aliphatic carbonate can be dissolved in aromatic organic solvents (benzene, toluene, xylene, etc.), or halogen organic solvents (methylene chloride, chloroform, carbon tetrachloride, 1 , 1,2-trichloroethane, etc.), are water-insoluble polymers. When the agent is dissolved in these solvents, it can be used directly. In fact, many agents are fat-soluble and soluble in organic solvents. On the other hand, when using agents that constitute salts, such as sargrelate hydrochloride, nafamostat, argatroban, etc., they are insoluble in the above-mentioned organic solvents. Therefore, an organic solvent such as a fluoroalcohol such as hexafluoroisopropanol or trifluoroethanol can be used instead of the solvent.

· Release aids

In drug delivery systems, by adding tributyl citrate, glycerin, or long-chain fatty acid esters to the polymer material of the substrate, the sustained release rate of a certain drug can be increased (addition of tributyl citrate, glycerin: Journal of Biomedical Mate rials Research, vol.13, 497-507(1979), Addition of long-chain fatty acid esters: Journal of Controlled Release vol.58, 133-141, (1999)).

If a drug is simply mixed with polymers such as polylactic acid and lactic acid/glycolic acid copolymers as organic polymer materials, the desired release rate of the drug cannot be obtained at the delivery site. The mechanism of the invention is that by adding some fat-soluble low-molecular compound, the release of the medicament from the solvent volatilized and solidified composition can be accelerated. In the composition of the present invention, the auxiliary agent for accelerating drug release is added together with the organic polymer material as a monomer and the drug, and then exerts its effect. That is, the controlled drug release composition of the present invention not only functions to sustain the release of the drug, but also adjusts the timing, speed, release amount, and duration of drug release at a predetermined site in the body.

The low-molecular fat-soluble release aid used in the drug release controlled composition is preferably selected from the viewpoint of drug release effect and safety. In terms of safety, it is preferable that the auxiliary agent itself has low toxicity to the living body, and is almost completely metabolized in the living body, or does not accumulate at all and is not metabolized, but is directly excreted outside the body. Compounds suitable for these requirements include aliphatic carboxylic acid esters or ester compounds having a hydroxyl group in the molecule. For example, there are aliphatic carboxylic acid esters having a hydroxyl group in the molecule, or esters based on polyhydric alcohols such as glycerin. Specifically, preferred are carboxylic acid esters with 2 to 6 carbon atoms such as acetic acid and propionic acid, etc., more preferably esters of organic acids selected from citric acid, tartaric acid, and malic acid, or diesters and monoesters of polyalcohols such as glycerin. .

The long chain alkyl of these esters preferably has 1-12 carbon atoms, more preferably 1-6 carbon atoms. Among them, methyl group, ethyl group, propyl group, butyl group and the like are preferable from the viewpoint of easy availability and compatibility with the drug and the aforementioned organic polymer material.

Preferred release aids are, for example, diesters of tartaric acid such as dimethyl tartrate, diethyl tartrate, dipropyl tartrate, monomethyl tartrate, monoethyl tartrate, monopropyl tartrate or half esters of tartaric acid; Dimethyl malate, diethyl malate, dipropyl malate, monomethyl malate, monoethyl malate, monopropyl malate and other monoesters of tartaric acid or diesters of malic acid; citric acid Citric acid diesters or citric acid such as dimethyl citrate, diethyl citrate, dipropyl citrate, monomethyl citrate, monoethyl citrate, monopropyl citrate, monobutyl citrate, etc. monoesters; or partial acetates of glycerol (such as glycerol monoacetate, glycerol diacetate, etc.).

The amount of the release aid added is 5 to 60 parts by weight, more preferably 10 to 40 parts by weight, based on 100 parts by weight of the above-mentioned organic polymer material. Within the above range, the drug release rate and the like can be controlled while maintaining the physical properties of the composition and the mechanical strength of the polymer. For example, when coated on a medical device, problems such as detachment of the coating layer do not occur, and the drug can be released at an appropriate speed.

·Pharmacy

The drug component to be controlled for release contained in the controlled drug release composition of the present invention is generally a drug including pharmaceuticals and quasi-drugs. However, depending on the use and purpose, the pharmaceuticals may be cosmetics, agricultural chemicals, etc. in addition to pharmaceuticals.

The target drug is not particularly limited, as long as it is soluble in the organic solvent in which the above-mentioned organic polymer material is dissolved. Therefore, appropriate arbitrary physiologically active drugs can be selected according to the desired therapeutic effects and drug effects, and can be the object of the present invention. Furthermore, it is not limited to one kind of medicine, and it can be used in the form that a plurality of medicines coexist. For example, in combination therapy of two, three or four drugs used in the treatment of gastric ulcer, tuberculosis, cold, etc., a plurality of drugs are used at the same time, and synergistic and synergistic effects are ensured by combination.

Specific examples of drugs include anticoagulants (such as synthetic anticoagulants, antiplatelet drugs, antithrombin drugs), hemostatic agents, angiogenesis inhibitors, vascular strengthening agents, proliferative drugs for preventing restenosis of blood vessels, Antithrombotic drugs or anti-abrasion agents, etc.

There are also anticancer agents, immunosuppressants, antipyretic analgesics, anti-inflammatory agents, antitussive and expectorant agents, antiulcer agents, sedatives, muscle relaxants, antidepressants, antiepileptic drugs, antituberculosis agents, antiarrhythmic agents Abnormal drugs, vasodilators, cardiotonic agents, antiallergic agents, antihypertensive diuretics, diabetes therapeutic agents, hormone agents, physiologically active peptide agents, anesthetic antagonists, bone resorption inhibitors, antirheumatic drugs, contraceptives, liver agents, Stomach and digestive agent, intestinal regulator, vitamin agent, vaccine agent, constipation treatment agent, sore treatment agent, various enzyme preparations, antiprotozoal agent, interferon inducer, insect repellant, external bactericidal disinfectant, parasitic agent Dermatological drugs, contrast media, etc.

More specific applicable drugs are described below, but the present invention is not limited to these examples. The drug may be in the form of a salt or a derivative other than itself.

Anticoagulants include sodium heparin and sodium citrate. As a low-molecular synthetic anticoagulant, argatroban, an antithrombin drug, and sargrel hydrochloride, an antiplatelet drug, exhibit blood suitability. Angiogenesis inhibitors include fumagillin, fumagillin derivatives, and angiogenesis-inhibiting steroids, and hemostatic agents include thrombin, thromboplastin, acetylmenadione, sodium bisulfite menadione, Tranexamic acid, ε-aminocaproic acid, adrenochrome monoaminoguanidine methane sulfonate, sodium carbosulfonate, etc.

Antitumor agents include methotrexate (Methotrexate), actinomycin D, mitomycin C (mitomycinC MMC), bleomycin hydrochloride, daunorubicin hydrochloride, vinblastine sulfate, vinblastine sulfate , Doxorubicin (Adriamycin), Neocarzinostatin (Neocarzinostatin), Fluorouracil, Cytarabine, Coriolus polysaccharide K (Krestin), Blood Streptococcus preparation (picibanil), Lentinan, Betadine (Bestatin), L- Imidazole, carbamide, glycyrrhizin, Cisplastin, Paclitaxel, etc.

Immunosuppressants include rapamycin, cyclosporine, tacrolimus, methotrexate, azathioprine, cyclophosphamide, adrenal corticosteroids (Dexamethasone, etc.), mizoribine (Mizoribine) )wait.

Antibiotics include tetracycline hydrochloride, oxytetracycline hydrochloride, doxycycline hydrochloride, hydropyridine, streptomycin, novobiocin, neomycin, erythromycin, colistin, lindamycin, salinomycin, nigeria Nigericin, kanamycin, kitasamycin, tylosin, furaltadone hydrochloride, vancomycin, spectinomycin, ristocetin, Soymacin, amikacin , neomycin (fradiomycin), sisomycin, gentamicin, kanendomycin (kanendomycin), dibekacin hydrochloride (Dibekacin), rivamycin, tobramycin, ampicillin, a Moxicillin, Ticarcillin, Piperacillin, Cefaloridine, Cephalosporin, Cefsulodin, Cefotiam, Cefmenoxime, Cefmetazole, Cefazolin, cefotaxime, cefoperazone, ceftizoxime, Moxolactam, sulfazecin, aztreonam, Thienamycin, metronidazole, clarithromycin, etc.

Antipyretic, analgesic and anti-inflammatory agents include sodium salicylate, sulpyrine, diclofenac sodium, flufenamic acid sodium, indomethacin sodium, morphine hydrochloride, pethidine hydrochloride, oxymorphine, levorphanol tartrate, etc.

Antitussive and expectorant agents include ephedrine hydrochloride, methylephedrine hydrochloride, narcodine hydrochloride, codeine phosphate, dihydrocodeine phosphate, clophenedanol hydrochloride, aroclamide hydrochloride, picoperine hydrochloride, chlorochloride hydrochloride Peridine, isoproterenol, protopol hydrochloride, albuterol sulfate, terbutaline sulfate, etc.

Anti-ulcer agents include histidine hydrochloride, metoclopramide, etc., sedatives include prochlorperazine, chlorpromazine hydrochloride, flupromazine, atropine sulfate, brominated methylaspartic acid, etc., tendon relaxants There are bipisteronide bromide, myostatin chloride, primidinol mesylate, etc. Antidepressants include imipramine, clomipramine, noxitriptyline, phenethylhydrazine sulfate, etc. Epilepsy drugs include chlordiazepoxide hydrochloride, acetazolamide sodium, phenytoin sodium, and ethosuximide.

Diabetes treatment agents include phenformin hydrochloride, glipizidine sodium, glipizide, etc., anti-tuberculosis agents include sodium p-aminosalicylate, ethambutol hydrochloride, isoniazid, and antiarrhythmic agents include propranol hydrochloride Diltiazem hydrochloride, alprenolol hydrochloride, bufemolol hydrochloride, oxprenolol hydrochloride, etc., vasodilators include diltiazem hydrochloride, oxifadrine hydrochloride, tolazoline hydrochloride, keguandiamine , Permexan Sulfate, etc. Cardiotonic agents include aminophylline, Theophyllol, etiforine hydrochloride, Trans-pi-oxocamphor, etc. Antiallergic agents include chlorpheniramine maleate, methoxyphenamine hydrochloride, diphenhydramine hydrochloride, tripyramine hydrochloride, medizine hydrochloride, clemizole hydrochloride, methoxyphenamine hydrochloride, dipheniramine hydrochloride Lin et al. Antihypertensive diuretics include pentapyrrolidine, hexamethylammonium bromide, mecamylamine hydrochloride, hydrazine hydrochloride, clonidine hydrochloride, etc.

Hormone agents include prednisolone sodium phosphate, prednisone succinic acid, dexamethasone sodium sulfate, betamethasone sodium phosphate, diethylstilbestrol acetate, hexestrol phosphate, and methimazole.

Narcotic antagonists include alomorphine hydrochloride, naloxone hydrochloride, levalprofen tartrate, etc., and bone resorption inhibitors include (sulfur-containing alkyl) aminomethanesulfonic acid, etc.

The physiologically active peptides are not particularly limited as long as they are oligopeptides or polymeric peptides, as long as they have physiological activity. Preferably the molecular weight is about 200 to 80,000. Specific examples are luteinizing hormone-releasing hormone or its derivatives, insulin, somatostatin or its derivatives, growth hormone, prolactin, cortico-stimulating hormone, thyroid-stimulating hormone, melanocyte-stimulating hormone, parathyroid hormone, vasopressor vasopressin, oxytocin, calcitonin, glucagon, human gastrin, secretin acetate, cholecystokinin, trypsin, angiotensin, enkephalin, protein synthesis Stimulating peptide, human chorionic gonadotropin, human placental hormone, luteinizing hormone, follicle-stimulating hormone, various types of interferon, interleukin, endorphin, kyotorphin, serum tuftsin (Tuftsin) ), thymopoietin, thymosin, thymostimulin (thymostimulin), thymus factor, tumor necrosis factor, colony-stimulating factor, nerve growth factor, neuropeptide substance P, vasodilator, motilin, dynorphin, bombesin , melanin, bradykinin, asparaginase, urokinase, lysozyme chloride, polymyxin B, colistin, gramicidin, bacitracin, erythropoietin, platelet-derived growth factor , growth hormone release factor, epithelial growth factor, etc.

Contrast agents include iodine-based X-ray contrast agents (iodixanol, iopamidol, Aesophan, etc.), MRI contrast agents (gadolinium compounds), ultrasound contrast agents (Echovist, Levovis), near-infrared fluorescent contrast agents (ind Docyanine green compounds), etc.

In addition to medical drugs, it can also be various cosmetics (creams, lotions, body creams, mascara, hair conditioners, whitening agents, etc.), pesticides (antibacterial agents, herbicides, insecticides, etc., specifically as in Japanese patents Japanese Patent Laid-Open Publication No. 7-330629), plant growth hormones, plant hormones, insect hormones, etc.

The release rate of the drug is set according to the lowest concentration of the drug in the blood or tissue, so each drug should be analyzed separately. Similarly, the release time should also be set in consideration of the patient's personal information, condition, and treatment. Purpose, processing content, etc. Therefore, the addition amount of the medicament cannot be uniformly determined. Considering the efficacy and cost, it is usually 1 to 150 parts by weight, preferably 5 to 70 parts by weight, and more It is selected and added within the range of 10 to 60 parts by weight. When it is within the above range, the solubility and side effects of the drug can be controlled to the minimum, and at the same time, the maximum drug effect can be exhibited.

·Other additives

The drug release controlled composition of the present invention is a composition containing the above-mentioned organic polymer material, a drug, and a release aid, and is suitable for use in the following medical devices. If necessary, the composition may contain a cell-adhesive substance or an endothelialization-promoting substance on the surface of a medical device.

Examples of cell-adhesive substances include collagen, fibronectin, vitronectin, and laminin.

The endothelialization-promoting substance is a substance that promotes the migration, fixation, and proliferation of endothelial cells on the surface of the stent at an early stage after indwelling when it is applied to the following medical devices, especially the stent described later in the vascular system. Such endothelialization-promoting substances include cell-adhesive oligopeptides and the like.

The endothelial cells that cover the innermost layer of the vascular intima not only have the function of covering the inner wall of the blood vessel, but also perform various functions such as antithrombotic, repair, normal maintenance of blood vessels and blood flow, angiogenesis, production and secretion of various factors and regulatory substances, etc. . Vascular endothelial cells are not only involved in the healing process of damage to the inner wall of blood vessels, but also involved in the so-called angiogenesis. Regardless of the situation, the process of moving, migrating, migrating, and Fixation, followed by migration, fixation and proliferation of smooth muscle cells and endothelial cells.

If you pay attention to the behavior of these endothelial cells, you can find that in order to avoid the main cause of restenosis and reocclusion, that is, the rejection of the living body to the stent, it is necessary to allow the cells in the blood vessel to migrate, fix, and proliferate at an early stage after treatment. on the support surface. If such endothelialization occurs, the stent will quickly form a state that simulates the inner wall of the blood vessel, and the stent will not be easily rejected by the living body, and the immune and foreign body exclusion functions will not be activated. That is, migration of monocytes and macrophages that cause inflammatory reactions to the stent placement site is less likely to occur. In order to promote the endothelialization of the surface of the stent, the composition may contain an endothelialization promoting substance.

In addition, binders, solubilizers, emulsifiers, stabilizers, etc. that are generally used in formulation technology may be contained as needed. The selection and content of adjuvants and additives used in formulations can be appropriately determined according to the above-mentioned organic polymer materials and pharmaceuticals, and medical devices to which the present composition is applied.

Drug releasing medical device

With the advancement of medical engineering, there have been technologies that are mainly for the purpose of diagnosis and treatment, and achieve the desired purpose by combining, embedding or indwelling certain medical appliances, devices or devices inside and outside the living body. The drug-releasing medical device of the present invention relates to such technology, and is a medical device that holds the above-mentioned composition in contact with a living body, binds it, or indwells it in a living body. There are no particular limitations on the drug-releasing medical device holding the above-mentioned composition. The devices to which the above-mentioned composition is applied are usually medical devices used in the medical field, but are actually determined according to the needs of the medical field.

The medical devices described herein include so-called "medical devices". Specific examples include various catheters and drip sets for internal and external connections, stents, wire clips, staplers, hemostats, sutures, fracture fixation devices, pacemakers, and medical devices for organ replacement. Appliances (artificial blood vessels, artificial trachea, artificial valves, artificial crystals, artificial bones, artificial joints, etc.), artificial organs (artificial skin, artificial breasts, artificial lungs, artificial hearts, etc.), etc., used for wound dressing materials near the body surface , contact lenses, inlays, artificial tooth roots, crowns, implant beds, synthetic resins for restoration, CTR materials for dentistry, etc. It also includes biosensors (such as capsule endoscopes for capsule detectors), embedded radiation sources, and the like.

The drug-releasing medical device of the present invention holds the drug release controlled composition of the present invention, whereby the drug is released at a predetermined site in the body. That is, when the drug-releasing medical device is combined or left in a predetermined body interior or body surface site, the retained drug is released, and the timing, release speed, release amount, and release time are adjusted. The form of retention varies depending on the type, use, etc. of the medical device. For example, coating by coating and spraying, and inclusion, entanglement, bonding, adhesion, and fixation into holes, and loading of the composition of the present invention may be possible. There are no particular limitations on various applicable forms such as winding of a film or tape for drug delivery. The easiest method is to form a layer of the composition on the surface of a medical device, and since the surface becomes a mechanical surface, it can be applied in a wide range of fields.

The method of holding the drug release controlled composition of the present invention on the intended medical device includes removing the solvent after soaking the medical device in the composition solution, spraying the solution on the surface of the medical device and then removing the solvent, or applying the solution to the medical device. After the solvent and the like are removed after application to the medical device, the composition for controlling drug release is bonded and fixed to the surface of the medical device in a layered form. When such a coating is applied to a medical device, the thickness of the coating layer is in the range of 1 to several thousand nm, preferably tens to hundreds of nm. The thinner the cladding, the less the peeling. When the composition of the present invention is embedded in a medical device as a single body instead of coating, there is no problem with its thickness, and any form such as a plate shape, a spherical shape, or a rod shape can be selected.

As the drug-releasing medical device of the present invention, the applicable form varies depending on each medical device, so not all of them are listed here. Representative examples include the application of stents in the field of surgery or inlays. (inlay) application in dental treatment. Preferably, it is a stent, a catheter, a wire clip, a capsule detector, a medical device for organ replacement, or an artificial organ.

Detailed ways

A stent is preferably exemplified as a medical device to which the drug release controlled composition of the present invention is applied. Therefore, as an example of the specific application of the present invention, a method of imparting drug sustained release to a stent and such a stent will be described below.

Angioplasty is often used as a treatment method for coronary artery occlusive disease, which is one of the main causes of myocardial infarction. This method mainly uses balloon dilation to secure blood vessel flow, and angioplasty using laser ablation, and has many good therapeutic results. On the other hand, the rate of restenosis and reocclusion of blood vessels after treatment is as high as 40 to 50%, which is also the problem of this technique.

For physical problems such as restenosis and reocclusion, drug administration, reinsertion and expansion of balloon catheters, or laser treatment have been tried, but none of them can be regarded as fundamental solutions, and they also bring great pain and pressure to patients . For this purpose, a stent placed inside the blood vessel is used. The stent can supplement the cut part while preventing the constriction of blood vessels, effectively reducing the recurrence probability of patients with arterial occlusive disease.

A stent for a blood vessel is a tubular small device medical device made of a metal material or a polymer material. A representative example of a typical treatment method for treating an occluded blood vessel is as follows: a stent for a blood vessel is placed in a vascular occlusion site via a balloon catheter inserted into the lumen of the blood vessel. Next, expand the diameter of the stent irreversibly by inflating a balloon, or indwell in the arterial vessel and heat it by magnetic induction to expand the stent itself, thereby ensuring the patency of the blood vessel. This method is used to maintain good blood flow in the long term.

So far, various materials, shapes, and surgical methods of stents for treating coronary artery occlusive disease including coronary artery occlusive disease have been developed. However, the existing materials still cannot completely avoid the risk of restenosis and reocclusion, which has become the bottleneck of angioplasty using stents. Therefore, a stent with less risk of restenosis and reocclusion is strongly required in the medical field. When a preferred embodiment of the drug-releasing medical device described above is applied to a stent, anticoagulants, anticancer agents, immunosuppressants, and the like can be used as drugs. The method of imparting drug release function to the stent, especially the sustained release of the drug, is optional, (1) the method of applying (coating, embedding, etc.) a composition containing the drug on the surface of the stent, (2) loading the release or sustained release A method in which the drug to be released and, if necessary, a carrier carrying a release aid is coated on the surface of the stent. In the aspect (1), it is preferable to use the above-mentioned controlled drug release composition containing an organic polymer material and a drug. In the method (2), the polymer material covering the surface of the stent is loaded with a drug for sustained release or the like.

Specific synthetic anticoagulants are preferably sargrelate hydrochloride and argatroban. A composition containing this agent is coated on the surface of the stent as a coating. The drug is continuously released from the surface of the drug-releasing stent to the blood or the blood vessel wall at a desired release rate. Since the composition of the present invention has a high drug release rate, it is released in a sufficient amount to express the drug effect of the anticoagulant from the initial stage of the indwelling stent.

As long as the stent has the above-mentioned features, it can adopt any structure, shape, material, size or state, and various applications and applications of the present invention are relatively easy for those skilled in the art. Therefore, the above-mentioned stent is suitable for all occasions where the aim is to prevent restenosis and reocclusion of blood vessels (blood vessels, lymphatic vessels, bile ducts, urinary tracts, trachea, etc.).

The stent of the present invention is characterized in that argatroban (antithrombin drug) or sargrelate hydrochloride (antiplatelet drug) or both of the above-mentioned agents are slowly released from the surface. Preferably, the above-mentioned sustained-release agent is carried on a polymer material coated on the metal surface constituting the stent, or on a porous stent substrate. The stent of the present invention is preferably used in the treatment of coronary artery stenosis.

bracket

The material and structure of the stent of the present invention may be a stent of any design except that the surface treatment described below is carried out. This shows that the present invention can prevent the above-mentioned restenosis and reocclusion in advance while maintaining the characteristics and functions of various stents.

The stent may not change in shape before and after being inserted into the blood vessel, or may be balloon-expandable, self-expandable, or a combination thereof. Any material can be used as the material used for the stent of the present invention as long as it has physical properties that can realize its design. Specifically, there are metal materials that have been used such as stainless steel, cobalt/chrome alloy, tantalum, titanium, tungsten, platinum, cobalt and their alloys.

When a material other than metal is used, as will be described later, it is suitable for the purpose of the present invention, that is, the material can carry an anticoagulation agent. Materials suitable for the stated requirements include PET (polyethylene terephthalate), PBT (polybutylene terephthalate), polycarbonate, polyethylene, polypropylene, polyacetal, polystyrene, etc. . The biodegradable polymer is preferably polyhydroxyesters such as polylactic acid, polyglycolic acid, polymalic acid and their polymers, and polycaprolactone.

The metal material is preferably used for the stent of the present invention, and its shape can be cylindrical, corrugated, structure with bends, mesh, steel wire-like solid molding, as long as it does not damage the strength and blood vessel wall after being placed in the blood vessel Questions can take a variety of shapes.

Anticoagulants

At least one of argatroban (antithrombin drug) and sargrelate hydrochloride (antiplatelet drug) is released from the surface of the stent of the present invention. For this purpose, synthetic anticoagulant agents of argatroban or sargrelate hydrochloride or both are carried in, and coated on, a polymer material constituting the metal surface of the stent.

Argatroban, which is an antithrombin drug used in the present invention, is one of drugs that inhibit blood coagulation, and is an arginine derivative-based synthetic antithrombin drug having a chemical structure represented by the following formula. The three-branched structure of argatroban highly inhibits the main effects of thrombin by sterically binding to the active site of thrombin, namely, the generation of fibrin, the stabilization of fibrin caused by the activation of factor XIII, and the aggregation of platelets , thereby acting as an antithrombin drug. As mentioned above, since it acts directly on thrombin, it is more reliable than heparin in terms of individual differences, and its action is also expressed quickly. And there is no natural inhibitor, and the molecular weight is small, so it also has an effect on thrombin bound to fibrin, and can reliably prevent the formation of thrombus. Moreover, it also has an inhibitory effect on white thrombus formed under high shear stress which cannot be prevented by heparin.

【Formula 1】

Sargrelate hydrochloride, another blood coagulation inhibitor used in the present invention, has the effect of inhibiting platelet activation, and its mechanism of action is speculated as follows:

The 5-hydroxytryptamine (Serotonin) (5-HT) released by the activated platelets that bind and condense on the vascular endothelial barrier has _various pharmacological effects. Enhance the aggregation of platelets at the site of the disorder, and shrink the blood vessels at the site of the disorder, while proliferating the smooth muscle of the blood vessels, resulting in peripheral circulation disorders. Anplag exhibits the effect of inhibiting platelet aggregation, especially the effect of inhibiting platelet aggregation enhanced by 5-hydroxytryptamine, and the effect of inhibiting vasoconstriction through selective block with 5-HT ₂ . Therefore, sargrelate hydrochloride is effective for various types of thrombosis including those of chronic arterial occlusive disease.

[Formula 2]

These two agents are extremely effective especially in the inhibition of initial thrombus, and are widely used clinically as anticoagulant therapy in the form of oral or intravenous administration. On the other hand, prevention of coronary artery occlusion due to thrombus formation at the indwelling site within a short period of several months after the indwelling stent is a major issue. Therefore, when the stent of the present invention is placed in a blood vessel, it is possible to prevent occlusion due to thrombus formation by slowly releasing these anticoagulant agents from the stent. As a result, restenosis and reocclusion of blood vessels can be effectively suppressed at the site where the stent is placed.

As medical devices for imparting antithrombotic properties for sustained release of argatroban, there are catheters disclosed in JP-A-6-292711 and JP-A-6-292718 as described above. The former describes the technology of melting and kneading argatroban into a thermoplastic polymer material to form a catheter (catheter tube), and the latter describes soaking the catheter in an organic solvent in which argatroban is dissolved and soaking the tube with argatroban. The method of adding tunes. In these technologies, the base material of the catheter basically needs to use a material with good mechanical strength and formability, and the preferred materials that can be used include crystalline thermoplastic elastomer materials such as segmented nylon, segmented polyurethane, and segmented polyester. .

·Pharmaceutical loading in the stent

The drug-releasing stent of the present invention carries the above-mentioned anticoagulant drug, and when it is indwelled in a predetermined blood vessel, the carried drug is released within a certain period of time. The method of loading the above-mentioned copolymer containing the drug on the stent can be applied in various forms and is not particularly limited, but it is preferable to adopt a loading form in which the release timing, release rate, release amount, and time can be adjusted. For example, there is a method of providing micropores on the metal surface constituting the stent by laser drilling or plasma etching, and enclosing a drug; a method of forming a stent using a porous metal or a porous inorganic material, and enclosing the drug in the porous part; The method of forming a polymer layer containing the drug on the metal surface constituting the stent; the method of directly using the polymer material containing the drug to make the stent itself; the method of winding the film or ribbon for drug delivery loaded with the drug. Among them, the most convenient method is to form a polymer layer containing the drug on the metal surface constituting the stent. This method has a wide range of applications because it can utilize existing scaffold technology and the surface of the scaffold can be directly transformed into a functional surface.

When the metal surface constituting the stent is a porous body, the drug for sustained release is dispersed in a polymer and loaded on the pores of the porous body. By controlling the pore size of the porous stent substrate and holding the drug-loaded polymer material in the pores, the drug can be continuously released at a desired release rate. The pore diameter in the above-mentioned porous stent base material is preferably 0.01 nm to 300 nm, more preferably 0.1 nm to 100 nm.

Mounting polymer materials for stent coating

The present inventors found that, as a polymer material carrying the drug, the compatibility between the drug and the polymer plays an important role in the sustained release of the drug over a certain period of time, especially the fact that it is more desirable to carry the drug on an amorphous polymer. Furthermore, a material having a glass transition point of 37° C. or lower in body temperature is preferable. When a material with a glass transition point of 37° C. or lower is placed in the blood vessel, the polymer is above the glass transition point, and the molecular mobility of the main chain increases, thereby promoting the release of the drug. When a crystalline polymer is used, the polymer crystal phase and the drug phase are clearly phase-separated, causing surface segregation of the drug phase. This results in a complete release of the medicament at one time, a so-called burst release, after which the release will be greatly reduced.

On the other hand, the anticoagulant agent used in the present invention has a basic group or an ionic group as shown in its chemical formula, so it not only has hydrophilicity, but also has relatively high lipophilicity, and has a relatively low solubility in water, and High solubility in alcohol. Therefore, it has low compatibility with high-molecular materials such as highly hydrophobic polyolefins. Like crystalline polymer materials, it is expected that these materials will also undergo sudden release due to phase separation and a sharp decrease in dissolution rate thereafter. For example, in (meth)acrylic ester polymer materials, the ester residue is preferably methyl ester, ethyl ester, propyl ester, butyl ester with 4 or less carbon atoms, or a hydroxyl group, methyl ester, etc. that can express hydrophilicity. Oxygen, alkyl esters of oxirane ether groups (-(CH ₂ CH ₂ O)-).

Therefore, as the polymer material for coating of the present invention, preferred amorphous polymer materials include polybutyl methacrylate, polyethyl methacrylate, polypropyl methacrylate, polyhydroxyethyl methacrylate, etc. Polyalkyl methacrylate, poly(hydroxyalkyl) methacrylate and their copolymers; polyalkyl acrylate such as polybutyl acrylate, polyethyl acrylate, polypropyl acrylate, polymethoxyethyl acrylate, etc. And their copolymers; aliphatic polycarbonates such as polybutylene carbonate and polyvinyl carbonate and their copolymers; vinyl acetate, vinylpyrrolidone, partially saponified polyvinyl alcohol, polyvinyl ether and other polyvinyl compounds and Copolymers thereof; biodegradable polymers with lactic acid and glycolic acid as a component, DL-lactic acid-glycolic acid copolymer, etc., but not limited thereto.

The above-mentioned amorphous polymers are different from crystalline polymers in that they have excellent solubility in organic solvents, and many organic solvents can be used when coating the stent, thereby increasing the technical convenience.

release aid

As mentioned above, adding a release aid (ie, "release aid") to the polymer material forming the DDS matrix can increase the sustained release rate of the drug, and the stent is no exception. Therefore, in the stent of the present invention, when the above drug is used and the desired release rate cannot be obtained in combination with the polymer material, the desired release rate can be obtained by using a release aid. Especially when the polymer material has a higher glass transition point than body temperature, it is more effective. When polylactic acid, lactic acid-glycolic acid copolymer and other biodegradable polymer materials are used, the glass transition point will be lowered by adding a release aid, so efficient. These additives are basically all fat-soluble, but are preferably low-molecular substances showing some degree of water solubility. The reason for this comes from compatibility with both polymers and pharmaceuticals. Long-chain aliphatic esters lacking in hydrophilicity and the like are not preferable due to lack of compatibility with the agent. On the other hand, low-molecular-weight compounds such as glycerin, which have low water solubility and lipophilicity, are not preferred because of low compatibility with polymer materials and the drug. Preferred release aids of the present invention are esters of organic acids selected from citric acid, tartaric acid, malic acid, or di- and mono-esters of glycerol (such as ethyl monoacetate or ethyl diacetate, etc.). Specific examples thereof include the esters shown above.

These additives may be used alone or in combination of two or more. The amount to be added can be appropriately set according to the release rate of the drug, but it is preferably in the range of about 5 to 60 wt%, more preferably 10 to 60 wt%, based on the weight of the polymer material. Within this range, the coating layer has sufficient mechanical strength while obtaining a good additive effect, and the coating layer is not easy to fall off from the stent.

Chemical coating layer

A method of forming a drug-containing polymer layer, that is, the above-mentioned polymer layer containing a drug, on the surface of a stent is to dissolve other additives including a drug, a polymer material, and a release aid if necessary, in a solvent in which they can be dissolved together. The obtained solution is applied to the surface of the stent; the soaking method is used to soak the stent in the solution and then taken out to dry; the spray coating method is used to spray the solution onto the surface of the stent to form a coating on the stent, etc. Among them, the dipping method is a reliable method for coating, and by this method, both the inner surface and the outer surface of the stent can be easily coated. In particular, by properly coating the inner surface of the stent in contact with blood, sufficient performance can be obtained for imparting antithrombotic properties and reducing reocclusion of arterial vessels.

The thickness of the formed coating layer is preferably between 0.05 μm and 30 μm. Within this range, a sufficient amount of drug can be loaded, and the release of the drug within the target time can be ensured. Moreover, it has good tracking performance for the deformation of the stent accompanying the heartbeat, and the coating layer is less prone to cracking and falling off.

Drug load

The drug load of the stent in the present invention is determined by the drug release rate and the required release duration. The sudden short-term large-scale release causes the agent to be exhausted over a long period of time, so this situation must be avoided. From the viewpoint of preventing initial thrombus formation, the release duration is preferably sustained release over several weeks to several months. Therefore, the release rate of the medicament is that at the time point after 3 weeks (21 days) after the stent is indwelled, the dissolution time of any one of the medicaments in argatroban or sargrelate hydrochloride is preferably 1×10 ^{− 3} μg/mm ² ·h to 1 μg/mm ² ·h, more preferably 1×10 ^-3 μg/mm ² ·h to 0.5 μg/mm ² ·h. When it is within this range, the anticoagulant activity can be sustained for a long period of time, which is preferable.

The upper limit of the release rate of the drug is not particularly limited as long as it does not exceed the toxic amount. However, since the amount of the drug loaded on the stent is limited, considering that the maximum amount is several hundred μg and the minimum sustained release is required for about 40 days, it can be inferred that The actual maximum velocity is about 1 μg/mm ² ·h. For example, the dissolution rate of argatroban from the catheter is about 1.0×10 ^-4 to 1.0×10 ^-1 μg/cm ² ·min, preferably 2.5×10 ^-4 to 7.0×10 ^-3 μg/cm ² · Minutes (Artificial Organs, 14(2), p679-682(1985)). Considering the clinical cognitions related to the effective concentration of argatroban and sargrelate hydrochloride in blood and the above-mentioned cognitions, the release speed of argatroban and sargrelate hydrochloride in the present invention is described in the above-mentioned document "artificial organ "The recorded range is more appropriate. However, the above disclosure is aimed at the release rate of the catheter on the premise of short-term indwelling, but the present invention is for permanent indwelling, so it is necessary to prevent the formation of thrombus within at least 3 weeks after indwelling. After this period of time has elapsed, the risk of thrombus formation is greatly reduced as endothelial cells and the like are regenerated. Therefore, in addition to maintaining the release rate immediately after indwelling, it is extremely important to maintain the release rate after about 3 weeks after indwelling.

Example

The present invention is further specifically described by the following examples, but the present invention is not limited to these examples. Numerical conditions such as materials, usage amounts, concentrations, treatment time, treatment temperature, and treatment methods used in the examples are only preferred examples within the scope of the present invention.

[Examples 1-3, Comparative Examples 1-3]

As shown in Table 1, dissolve 90 mg of polylactic acid and lactic acid/glycolic acid copolymer, 10 mg of triethyl citrate as a release aid, and 10 mg of sarcogrelate hydrochloride as an antiplatelet drug in 1 mL of hexafluoroisopropanol , cast on a glass dish with a diameter of 41 mm, and air-dry to obtain a drug carrier. Soak it in 100 mL of pH 7.4 phosphate buffer, sample the buffer regularly, and measure the absorbance (Abs) at 270 nm as the characteristic absorption band of sarcogrelate hydrochloride, thereby tracking the amount of dissolution of the drug. Table 1 shows the absorbance values from the start of dissolution to 3 weeks after.

As Comparative Examples 1 to 3, the same dissolution test was performed under the same conditions as in the Examples except that no release aid was added.

[Table 1]

Polymer (lactic acid/glycolic acid molar ratio) Release aid (10mg) release amount (Abs) Example 1 100/0 have 0.173 Comparative example 1 100/0 none 0.013 Example 2 85/15 have 0.120 Comparative example 2 85/15 none 0.027 Example 3 50/50 have 0.067 Comparative example 3 50/50 none 0.002

[Examples 4 to 6, Comparative Example 4]

Dissolve 90 mg of lactic acid/glycolic acid (50/50) copolymer, 10 mg of alkyl tartrate diester as a release aid, and 10 mg of sarcogrelate hydrochloride as an antiplatelet drug in 1 mL of hexafluoroisopropanol. Cast on a glass dish with a diameter of 41mm, and air-dry to obtain the drug carrier. Soak it in 100 mL of pH 7.4 phosphate buffer, sample the buffer regularly, and measure the absorbance at 270 nm, which is the characteristic absorption band of sarcogrelate hydrochloride, so as to track the amount of dissolution of the drug. Table 2 shows the absorbance values from the start of the dissolution to 3 weeks later.

[Table 2]

release aid release amount (Abs) Example 4 Dimethyl tartrate 0.033 Example 5 Diethyl tartrate 0.007 Example 6 Diisopropyl tartrate 0.003 Comparative example 4 none 0.002

[Examples 7 to 10, Comparative Examples 5 and 6]

As shown in Table 3, 90 mg of polylactic acid and lactic acid/glycolic acid copolymer, 10 mg of diethyl tartrate or triethyl citrate as a release aid, and 10 mg of argatroban as an antithrombin drug were dissolved in Cast in 1 mL of hexafluoroisopropanol on a glass dish with a diameter of 41 mm, and air-dry to obtain the drug carrier. It was soaked in 100 mL of pH 7.4 phosphate buffer solution, the buffer solution was regularly sampled, and the absorbance value at 330 nm, which is the characteristic absorption band of argatroban, was measured to track the dissolution amount of the drug. Table 3 shows the absorbance values from the start of the dissolution to 3 weeks afterward.

As Comparative Examples 5 and 6, the same dissolution test was performed under the same conditions as in the Examples except that no release aid was added.

[table 3]

Polymer (90mg) (Lactic acid/glycolic acid molar ratio) Release aid (10mg) release amount (Abs) Example 7 100/0 Diethyl tartrate 0.310 Example 8 100/0 Triethyl citrate 0.092 Comparative Example 5 100/0 none 0.056 Example 9 50/50 Diethyl tartrate 0.200 Example 10 50/50 Triethyl citrate 0.052 Comparative example 6 50/50 none 0.034

[Examples 11 to 16, Comparative Examples 7 and 8]

As shown in Table 4, 90 mg of polylactic acid and lactic acid/glycolic acid copolymer, 10 to 30 mg of diethyl tartrate as a release aid, and 10 mg of argatroban as an antithrombin drug were dissolved in 1 mL of hexafluoro In isopropanol, cast on a SUS316L dish with a diameter of 18mm, and air-dry to obtain the drug carrier. It was soaked in 50 mL of pH 7.4 phosphate buffer solution, the buffer solution was regularly sampled, and the absorbance value at 330 nm, which is the characteristic absorption band of argatroban, was measured to track the dissolution amount of the drug. Table 4 shows the absorbance values from the start of dissolution to 7 days later.

As Comparative Examples 7 and 8, the same dissolution test was carried out under the same conditions as in Examples except that no release aid was added.

[Table 4]

Polymer (90mg) (Lactic acid/glycolic acid molar ratio) Diethyl tartrate (mg) Release after 7 days (Abs) Example 11 100/0 10 0.0146 Example 12 100/0 20 0.030 Example 13 100/0 30 0.047 Comparative example 7 100/0 none 0.007 Example 14 50/50 10 0.012 Example 15 50/50 20 0.017 Example 16 50/50 30 0.010 Comparative example 8 50/50 none 0.008

[Example 17-19]

As shown in Table 5, 90 mg of polylactic acid, 30 mg of diethyl tartrate as a release aid, and argatroban as an antithrombin drug in the amount shown in Table 5 were dissolved in 1 mL of hexafluoroiso In propanol, 600 μL of this solution was cast on a SUS316L dish with a diameter of 18 mm, and air-dried to obtain a drug carrier. It was soaked in 50 mL of pH 7.4 phosphate buffer solution, the buffer solution was regularly sampled, and the absorbance value at 330 nm, which is the characteristic absorption band of argatroban, was measured to track the dissolution amount of the drug. Table 5 shows the absorbance values from the start of dissolution to 2 weeks later.

[table 5]

Polymer (90mg) (Lactic acid/glycolic acid molar ratio) Diethyl tartrate (mg) Argatroban (mg) Release after 14 days (Abs) Example 17 100/0 30 20 0.10 Example 18 100/0 30 30 0.19 Example 19 100/0 30 40 0.21

[Example 20, 21]

Dissolve 90 mg of polylactic acid, 30 mg of diethyl tartrate or diethyl malate as a release aid, and 30 mg of argatroban as an antithrombin drug in 1 mL of hexafluoroisopropanol, and dissolve 600 μL of the The solution was cast on a SUS316L dish with a diameter of 18mm, and air-dried to obtain the drug carrier. It was soaked in 50 mL of pH 7.4 phosphate buffer solution, the buffer solution was regularly sampled, and the absorbance value at 330 nm, which is the characteristic absorption band of argatroban, was measured to track the dissolution amount of the drug. Table 6 shows the absorbance values from the start of dissolution to 2 weeks after.

[Table 6]

release aid release amount (Abs) Example 20 Dimethyl tartrate 0.35 Example 21 Diethyl malate 0.16

[Example 22, 23]

Dissolve 90 mg of polylactic acid, 20 mg of glycerol monoacetate, or 20 mg of glycerin diacetate as a release aid, and 20 mg of argatroban, an antithrombin drug, in 1 mL In hexafluoroisopropanol, 600 μL of the solution was cast on a SUS316L dish with a diameter of 18 mm, and air-dried to obtain a drug carrier. It was soaked in 50 mL of pH 7.4 phosphate buffer solution, the buffer solution was regularly sampled, and the absorbance value at 330 nm, which is the characteristic absorption band of argatroban, was measured to track the dissolution amount of the drug. Table 7 shows the absorbance values from the start of the dissolution to 3 weeks later.

[Table 7]

release aid release amount (Abs) Example 22 monoacetate 0.425 Example 23 Diacetate 0.198

The release rate in the following examples is defined as such. The drug carrier was continuously soaked in phosphate buffer solution (PBS) of pH 7.4 at 37° C. for 21 days, and the change of PBS absorbance value during this period was observed. Calculate the amount of solvent dissolved in the 24 hours from the difference between the absorbance value on the 20th day and the absorbance value on the 21st day, and divide it by 24 hours and the body surface area to obtain the release rate (unit: μg/(h·mm ² )). The surface area of the stent was obtained by observing the thickness and the developed shape of the stent under a microscope, and the area was obtained from these.

[Example 24-33]

Dissolve 15 mg of argatroban or sargrelate hydrochloride and 50 mg of the amorphous polymer shown in Table 8 in 0.6 mL of methanol, develop on a SUS dish with a diameter of 16 mm, and air-dry or vacuum-dry to obtain a drug carrier . Soak the carrier in 50mL of pH7.4 phosphate buffer, sample the buffer regularly, measure the absorbance of argatroban at its characteristic absorption band at 330nm, and measure the absorbance at 270nm of sarcogrelate hydrochloride, and then measure the dissolution amount to obtain the release rate. The results are shown in Table 8.

[Table 8]

PolyMEA: poly(2-methoxyethyl acrylate); PolyHEMA: poly(2-hydroxydiethyl methacrylate); PolyEVE: polyethyl vinyl ether; Poly(MEA/HEMA): enoic acid-2 - Copolymer of methoxyethyl ester/2-hydroxydiethyl methacrylate; PolyDnPAAm: poly(N,N-di-n-propyl acrylate)

[Comparative examples 9 to 14]

The release of argatroban and sarcogrelate hydrochloride was obtained in the same manner as in Example 24, except that crystalline polycaprolactone, polyhydroxybutyric acid, and caprolactam were used instead of the amorphous polymer shown in Example 24. speed. The results are shown in Table 9.

[Table 9]

[Examples 34-40, Comparative Examples 15-17]

To 50 mg of amorphous (DL) polylactic acid and (DL) polylactic acid/glycolic acid copolymer shown in Table 10, 15 mg of a release aid, 15 mg of argatroban or sarcogrelate hydrochloride were added, and dissolved in In 0.5 mL of hexafluoroisopropanol, it was cast on a SUS dish with a diameter of 16 mm, and air-dried or vacuum-dried to obtain a drug carrier. Soak it in 50mL of pH7.4 phosphate buffer solution, sample the buffer solution regularly, measure the absorbance value at 330nm of its characteristic absorption band for argatroban, measure the absorbance value at 270nm for sarcogrelate hydrochloride, and then measure the dissolution amount to obtain the release velocity. As a comparative example, the same dissolution test was performed under the same conditions as in Examples 34 to 40 except for using crystalline poly(L) lactic acid and (L) lactic acid-glycolic acid copolymer (50:50). Table 10 shows the results of these Examples and Comparative Examples.

[Table 10]

[Example 41]

(Stent retention test)

Dissolve 24 mg of argatroban, 24 mg of sargrelate hydrochloride, 24 mg of diethyl tartrate, and 80 mg of (DL) lactic acid/glycolic acid copolymer (50:50) in 10 mL of hexafluoroisopropanol to prepare became a coating liquid. A Co-Cr alloy coronary stent (diameter 1.55φ, length 17.4 mm) was immersed in the coating solution, and 0.6 mg was coated on the surface of the stent by the dip coating method. Three coated stents and three uncoated bare metal stents were indwelled in the coronary arteries of three piglets aged 12 months, and they were killed one month later. evaluate. The drug-coated stents were all in better condition than the non-coated stents (bare metal stents), confirming the stenosis inhibitory effect of argatroban and sargrelate hydrochloride.

Claims (20)

1, a kind of medicament discharges the control combination thing, it is characterized by, and contains: the fat-soluble low molecule that dissolves in organic solvent and non-water-soluble high-molecular organic material, 5～60 weight portions of 100 weight portions discharges the medicament of auxiliary agent and 1～70 weight portion.

2, medicament as claimed in claim 1 discharges the control combination thing, described high-molecular organic material have biological degradability, live body fitness or its both.

3, medicament as claimed in claim 1 discharges control combination thing, monoesters or diester that described release auxiliary agent is carboxylate or glycerol.

4, medicament as claimed in claim 1 discharges the control combination thing, and described medicament is pharmaceuticals.

5, medicament as claimed in claim 4 discharges the control combination thing, and above-mentioned pharmaceuticals are anticoagulant, anticarcinogen or immunosuppressant.

6, medicament as claimed in claim 2 discharges the control combination thing, and the high-molecular organic material of described biological degradability is aliphatic polyester or fatty poly-ester carbonate.

7, medicament as claimed in claim 6 discharges the control combination thing, and the high-molecular organic material of described biological degradability is polylactic acid, lactic acid/ethanol copolymer, polycaprolactone or poly-hydroxyl butyric acid.

8, discharge the control combination thing as claim 1 or 3 described medicaments, described release auxiliary agent is to be selected from the organic acid ester in citric acid, tartaric acid or the malic acid.

9, discharge the control combination thing as medicament as described in any one of the claim 1～8, also contain cell adhesion material or endothelialization and promote material.

10, a kind of medicament release property medical apparatus is characterized by, and keeps any described medicament of claim 1～9 to discharge the control combination thing.

11, medicament release property medical apparatus as claimed in claim 10 is characterized by, and is formed with the layer of described compositions on the surface.

12, as claim 10 or 11 described medicament release property medical apparatus, described medical apparatus is, be contacted with live body in conjunction with or keep somewhere in intravital medical apparatus.

13, as any described medicament release property medical apparatus of claim 10～12, described medical apparatus is that support, conduit, wire clamp, organ replace with medical apparatus, capsule detector or artificial organ.

14, a kind of support is to be used for the treatment of the support of being preced with stricture of artery, it is characterized by, from its surperficial slow release argatroban (antithrombase medicine) or sarpogrelate hydrochloride (antiplatelet drug) or this two kinds of medicaments.

15, support as claimed in claim 14, described rate of release be, after keeping somewhere this support 21 days, and argatroban and sarpogrelate hydrochloride are all 1 * 10 ^-3μ g/mm ²H～1 μ g/mm ²H.

16, support as claimed in claim 14 is characterized by, and is coated in the macromolecular material on the metal surface that constitutes described support, is equipped with the described medicament that slow release is used.

17, support as claimed in claim 16, the macromolecular material that is coated on described rack surface is an amorphism.

18, support as claimed in claim 16, the macromolecular material that is coated on described rack surface is non-crystalline biodegradable polymer.

19, as any described support of claim 16～18, it is characterized in that described macromolecular material also contains the auxiliary agent of the release that promotes the medicament that carries.

20, as any described support of claim 14～19, it is characterized by, the metal surface that constitutes described support is a porous body, and the described medicament that slow release is used is equipped in the porous body.