Antithrombotic material

Abstract

The present application provides a surface treatment agent having excellent antithrombogenicity and biocompatibility, and high hydrophilicity compared with conventional medical materials. The present application is an antithrombogenic material comprising a (meth)acrylate copolymer containing a hydrophobic (meth)acrylate and a hydrophilic (meth)acrylate, the hydrophobic (meth)acrylate being a silicone (meth)acrylate and / or a (meth)acrylic acid alkyl ester, the (meth)acrylate copolymer having a residual monomer amount of 4,000 ppm or less, an inherent viscosity (ηsp / c) of 0.18 dl / g or more and 3.00 dl / g or less, the (meth)acrylate copolymer being water-insoluble, and being a viscous liquid at room temperature.

Description

Technical Field

[0001] This invention relates to an antithrombotic material that imparts blood compatibility to medical devices. More specifically, it relates to an antithrombotic material comprising a (meth)acrylate copolymer comprising a hydrophobic (meth)acrylate and a hydrophilic (meth)acrylate, and comprising at least a silicone (meth)acrylate as the hydrophobic (meth)acrylate, being water-insoluble, and being a viscous liquid at room temperature. Background Technology

[0002] In recent years, research on medical devices utilizing various polymer materials has been advancing, with promising applications in blood filters, artificial kidneys, plasma separators, catheters, artificial lungs, artificial blood vessels, anti-adhesion membranes, and artificial skin. In this context, to allow synthetic materials, which are foreign to the body, to come into contact with and be used within the body's tissues and blood, biocompatibility is required for the medical devices.

[0003] When medical devices are used as materials that come into contact with blood, three factors become important for biocompatibility: (a) inhibition of the blood coagulation system, (b) inhibition of platelet adhesion / activation, and (c) inhibition of complement system activation. In cases where the contact time with blood is short, such as in extracorporeal circulation medical devices (e.g., artificial kidneys, plasma separators), anticoagulants such as heparin and sodium citrate are typically used simultaneously. Therefore, the inhibition of platelet and complement system activation, as mentioned above, is particularly important in cases such as (b) and (c).

[0004] The applicant has studied materials suitable for the above-mentioned uses and has filed an application for an antithrombotic material comprising a (meth)acrylate copolymer formed of alkyl (meth)acrylate, silicone (meth)acrylate, and methoxy polyethylene glycol (meth)acrylate, having a number average molecular weight of 2,000 to 200,000, being water-insoluble, and being a viscous liquid at room temperature, soluble in any of alcohols having 1 to 6 carbon atoms, and having a viscosity of 0.5 to 10,000 Pa·s at 37°C (Patent Document 1).

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: Japanese Patent No. 4793700 Summary of the Invention

[0008] The problem that the invention aims to solve

[0009] The objective of this invention is to provide an antithrombotic material that, compared to conventional medical materials, can be used as a material with a longer contact time with blood, thereby further improving its durability in the face of blood contact.

[0010] Methods for solving problems

[0011] The inventors discovered that by applying the following copolymer to a medical device, a longer-lasting antithrombotic effect can be imparted to the medical device compared to previous methods, thus completing the present invention. The copolymer is obtained by copolymerizing alkyl (meth)acrylate, methoxy polyethylene glycol (meth)acrylate, and silicone (meth)acrylate, wherein the residual monomer content and specific viscosity are adjusted to a specific range. That is, the present invention has the following structure.

[0012] (1) An antithrombotic material comprising a (meth)acrylate copolymer obtained by copolymerizing alkyl (meth)acrylate units represented by general formula 1, silicone (meth)acrylate units represented by general formula 2, and methoxy polyethylene glycol (meth)acrylate units represented by general formula 3 in a molar ratio of 80 to 20 / 10 to 0.01 / 10 to 79.99, having a weight-average molecular weight of 50,000 or more and 1,500,000. The copolymer is 0.00 or less, and is water-insoluble (here, water-insoluble means that when the (meth)acrylate copolymer is left to stand in 99% by mass of physiological saline at 37°C for 30 days relative to 1% by mass of the copolymer, the mass reduction rate of the copolymer is less than 1% by mass), and is a viscous liquid at room temperature, soluble in any alcohol having 1 to 6 carbon atoms, with a residual monomer content of less than 4,000 ppm, and a specific viscosity (ηsp / c) of more than 0.18 dl / g and less than 3.00 dl / g.

[0013] [Chemical Formula 4]

[0014]

[0015] (where R is in the formula) 1 R represents an alkyl group with 8 to 12 carbon atoms. 2 (This indicates a hydrogen atom or a methyl group.)

[0016] [Chemical Formula 5]

[0017]

[0018] (where R is in the formula) 3 R represents a hydrogen atom or a methyl group. 4 R represents an alkylene group having 1 to 6 carbon atoms. 5 (This indicates an alkyl group having 1 to 6 carbon atoms, where n represents an integer from 1 to 30.)

[0019] [Chemical Formula 6]

[0020]

[0021] (where R is in the formula) 6 (This represents a hydrogen atom or a methyl group, where n is an integer from 2 to 4.)

[0022] (2) A medical device comprising the antithrombotic material described in (1).

[0023] Invention Effects

[0024] The antithrombotic material of the present invention is a material with excellent biocompatibility and high durability in contact with blood. Furthermore, as a material, it is a water-insoluble viscous substance; therefore, even when the antithrombotic material carried in a medical device comes into contact with blood, it does not easily dissolve into the blood, allowing the medical device to maintain its antithrombotic properties for a long time. In addition, as a hydrophobic (meth)acrylate, it includes a silicone (meth)acrylate; therefore, due to its water-repellent properties, it is expected to inhibit the hydrolysis of (meth)acrylate copolymers. Detailed Implementation

[0025] In this invention, the (meth)acrylate copolymer comprising hydrophobic and hydrophilic (meth)acrylates preferably exhibits durability against blood contact and is a viscous liquid at room temperature. Here, "durability against blood contact" means that when the (meth)acrylate copolymer is immersed in an alcohol impregnation solution at room temperature for 16 hours, a certain amount of the (meth)acrylate copolymer remains, indicating antithrombotic properties. If a specified amount of (meth)acrylate copolymer remains after immersion in an alcohol impregnation solution at room temperature for 16 hours, it can be determined that it maintains sufficient antithrombotic properties even after 30 days of contact with blood at 37°C. Furthermore, although it is liquid at room temperature, it is viscous, thus having the advantage of inhibiting dissolution into the blood when coated on medical devices or similar applications.

[0026] In this invention, the hydrophilic (meth)acrylate preferably comprises a methoxy polyethylene glycol (meth)acrylate represented by the following general formula 3. In the following general formula 3, compounds with 2 to 10 oxyethylidene units are preferably used. More preferably, 2 to 5. Specifically, examples include methoxydiethylene glycol (meth)acrylate, methoxytriethylene glycol (meth)acrylate, methoxytetraethylene glycol (meth)acrylate, methoxypentaethylene glycol (meth)acrylate, methoxyhexaethylene glycol (meth)acrylate, methoxyheptaethylene glycol (meth)acrylate, methoxyoctaethylene glycol (meth)acrylate, methoxynonethylene glycol (meth)acrylate, and methoxydeethylene glycol (meth)acrylate. If the repeating unit becomes larger, the hydrophilicity increases excessively, and the copolymer dissolves more into the bloodstream; therefore, there is a possibility that it may easily detach from the medical material. Therefore, methoxytetraethylene glycol (meth)acrylate with 4 repeating oxyethylene units and methoxytriethylene glycol (meth)acrylate with 3 repeating oxyethylene units are further preferred. Methoxytriethylene glycol (meth)acrylate with 3 repeating oxyethylene units is particularly preferred.

[0027] [Chemical Formula 7]

[0028]

[0029] (where R is in the formula) 6 (This represents a hydrogen atom or a methyl group, where n is an integer from 2 to 4.)

[0030] In this invention, the hydrophobic (meth)acrylate preferably comprises a silicone (meth)acrylate represented by the following general formula 2. The silicone (meth)acrylate preferably uses a silicone (meth)acrylate with 1 to 50 repeating dimethylsiloxane units. If the repeating units are too large, the viscosity of the resulting copolymer becomes excessively high, sometimes making processing difficult. Conversely, if the repeating units are too small, the viscosity decreases excessively, potentially causing it to easily disappear from the coating surface of medical devices, etc. Therefore, 1 to 20 repeating dimethylsiloxane units are more preferably used.

[0031] [Chemical Formula 8]

[0032]

[0033] (where R is in the formula) 3 R represents a hydrogen atom or a methyl group. 4 R represents an alkylene group having 1 to 6 carbon atoms. 5 (This indicates an alkyl group having 1 to 6 carbon atoms, where n represents an integer from 1 to 30.)

[0034] In this invention, for hydrophobic (meth)acrylates, other hydrophobic (meth)acrylates may be included in addition to silicone (meth)acrylates. There are no particular limitations on other hydrophobic (meth)acrylates; as an example, it is preferable to add a hydrophobic (meth)acrylate represented by the following general formula 1. In the following general formula 1, R is preferably used. 1 Compounds having 8 to 20 carbon atoms, more preferably 8 to 12. Specific examples of such hydrophobic (meth)acrylates include n-hexyl (meth)acrylate, cyclohexyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, lauryl (meth)acrylate, myristyl (meth)acrylate, palmityl (meth)acrylate, stearyl (meth)acrylate, etc. From the viewpoint of cost and performance, 2-ethylhexyl (meth)acrylate and lauryl (meth)acrylate are particularly preferred.

[0035] [Chemical Formula 9]

[0036]

[0037] (where R is in the formula) 1 R represents an alkyl group with 8 to 12 carbon atoms. 2 (This indicates a hydrogen atom or a methyl group.)

[0038] If we specifically list representative substances of the water-insoluble (meth)acrylate copolymers belonging to the present invention, they include silicone (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)hexyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)hexyl acrylate-(meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)hexyl acrylate-(meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, Silicone (meth)acrylate-cyclohexyl methacrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-cyclohexyl methacrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-cyclohexyl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl methacrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl methacrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate Acrylic ester-(meth)acrylate n-octyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate n-octyl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate n-octyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate 2-ethylhexyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate 2-ethylhexyl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate 2-ethylhexyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, Silicone (meth)acrylate-(meth)acrylate lauryl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate n-nonyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate n-nonyl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate n-nonyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer,Silicone (meth)acrylate-(meth)decyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)decyl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)decyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate stearyl ester-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate stearyl ester-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate stearyl ester-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl ester-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl ester-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl ester The following are substances, not limited to: ester-methoxytriethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-(meth)acrylate lauryl ester-methoxytetraethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxydiethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxytriethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxytetraethylene glycol (meth)acrylate copolymers, and silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxytetraethylene glycol (meth)acrylate copolymers, but are (meth)acrylate copolymers formed by (meth)acrylate alkyl ester units represented by general formula 1, silicone (meth)acrylate units represented by general formula 2 below, and methoxy polyethylene glycol (meth)acrylate units represented by general formula 3 below in a molar ratio of 80 to 20 / 10 to 0.01 / 10 to 79.99. If there is too little hydrophobic (meth)acrylate, the copolymer will easily dissolve in blood, etc.; if there is too much, there is a possibility that the blood compatibility of the hydrophilic (meth)acrylate may not be fully utilized. Therefore, a more preferred molar ratio is 80–50 / 5–0.01 / 15–49.99, a further preferred molar ratio is 77–55 / 5–0.01 / 18–44.99, and an even more preferred molar ratio is 73–57 / 5–0.01 / 22–42.99.

[0039] The molecular weight of a copolymer can be expressed by number-average molecular weight (NMR) and weight-average molecular weight (MAM), but MAM has a greater impact on stability and adhesion. Therefore, in this invention, MAM is selected as the indicator. If the MAM is too low, it may easily dissolve into the bloodstream, and there is a possibility of loss of coating strength and stability. In addition, the higher the MAM, the higher the viscosity will be when preparing the coating solution, thus having a secondary effect of improved adhesion to the coating substrate. Therefore, the MAM of the (meth)acrylate copolymer is more preferably 60,000 or higher. Furthermore, when the MAM of the (meth)acrylate copolymer is 1,500,000 or lower, the operability of coating the (meth)acrylate copolymer onto medical devices, etc., is improved, and therefore preferred. More preferably, it is 1,000,000 or lower, and even more preferably 500,000 or lower. Here, MAM is the value obtained by dividing the sum of the molecular weights of all molecules by the sum of their molecular weights, and it is one of the characteristic indicators of polymers.

[0040] Having a weight-average molecular weight of 50,000 or more and 1,500,000 or less for the (meth)acrylate copolymer is also a very important technical condition for achieving specific technical issues related to the purification of the copolymer, the treatment of the processing solution, its suitability for medical devices, and the stability of the coating.

[0041] Methods for determining weight-average molecular weight include terminal group quantification, osmotic pressure method, vapor pressure osmotic pressure determination, vapor pressure depression method, freezing point depression method, boiling point elevation method, gel permeation chromatography (GPC), etc. In this invention, considering ease of operation, the conventional method such as gel permeation chromatography (GPC) is adopted.

[0042] In this invention, the specific viscosity (ηsp / c) of the (meth)acrylate copolymer is preferably 0.18 dl / g or more and 3.00 dl / g or less. By using a copolymer (antithrombotic material) within this viscosity range, when coated onto medical devices such as artificial heart-lung circuits and catheters, the copolymer exhibits excellent adhesion to the medical device, maintaining antithrombotic properties over long-term use. A more preferred specific viscosity range is 0.18 dl / g or more and 1.50 dl / g or less, and even more preferably 0.18 dl / g or more and 0.50 dl / g or less.

[0043] Furthermore, in this invention, the hydrophobic (meth)acrylate does not necessarily contain silicone (meth)acrylate. However, silicone, as its basic skeleton is known, exhibits excellent heat and cold resistance, and a low glass transition temperature (Tg), thus possessing the advantage of stable properties across a wide temperature range. Additionally, due to its high bond energy, it possesses advantages such as acid and alkali resistance and high chemical stability. Moreover, its excellent copolymerization with (meth)acrylate monomers makes it a preferred raw material for the (meth)acrylate copolymer of this invention. In recent years, silicone (meth)acrylate has also been recognized as a material with high safety for the body, for example, in materials used in contact lenses. Therefore, it is considered that an excessive amount of silicone (meth)acrylate in the antithrombotic material will not be a problem, and it can be a silicone (meth)acrylate-methoxy polyethylene glycol (meth)acrylate copolymer. However, the price of raw materials for silicone (meth)acrylates is sometimes high, and using silicone (meth)acrylates alone as hydrophobic (meth)acrylates can sometimes be cost-inefficient. Considering performance, quality, and cost, it is sufficient to include 50% by mass or less as the upper limit for the amount of silicone (meth)acrylate added. More preferably, it is 40% by mass or less, and even more preferably, 35% by mass or less. Furthermore, silicone (meth)acrylates can be mixed with the other alkyl (meth)acrylates mentioned above. On the other hand, if the silicone (meth)acrylate content is too low, hydrolysis is promoted during storage, and the long-term stability as an antithrombotic material sometimes decreases. Therefore, the silicone (meth)acrylate content in the hydrophobic (meth)acrylate is more preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1.0% by mass or more.

[0044] The (meth)acrylate copolymer can sometimes be a copolymer obtained by alternating monomers of general formula 2 and general formula 3. In terms of total amount, it can sometimes be a copolymer containing segments or blocks formed by hydrophobic monomers and segments or blocks formed by hydrophilic monomers. It can be roughly inferred that the segments or blocks formed by hydrophobic monomers can sometimes adopt complex structures such as so-called microphase separation structures or mosaic patterns, which function to fix the segments or blocks formed by hydrophilic monomers. In any case, the molecular weight of the copolymer and the type and characteristics of the hydrophilic monomers will have a certain influence, but increasing the amount of hydrophobic monomers can suppress the dissolution of the segments or blocks formed by hydrophilic monomers in the copolymer. In addition, it is believed that slightly increasing the hydrophobic segment also enhances the affinity with hydrophobic medical devices, and can also play a beneficial role in the fixation of the medical device as a coating. Although the behavior related to the presence or absence of segments and their affinity cannot be accurately verified with current technology, the copolymer is a polymer material with good affinity to the body.

[0045] Methoxylated polyethylene glycol (meth)acrylate homopolymers exhibit excellent blood compatibility due to their high hydrophilicity. However, being water-soluble, they suffer from slow dissolution upon prolonged contact with blood or similar substances. The inventors conducted in-depth research on materials that not only possess excellent blood compatibility but also withstand long-term use. They discovered that copolymers obtained by imparting moderate hydrophobicity to prevent dissolution into blood and similar substances, and flexibility to prevent the physical film from peeling off, can solve this problem.

[0046] As described above, the copolymer contained in the treatment solution is essentially formed by two monomeric components that perform different functions of the two-sided interface. That is, it is formed by a part of hydrophilic monomers, segments, or blocks that have functions such as antithrombotic and antidissolution properties for blood, and hydrophobic monomers, segments, or blocks that have functions such as affinity and fixation for medical devices. However, on the other hand, it has also been observed that the monomers, segments, or blocks constituting the copolymer are complementary to each other in the molecular structure, forming molecular bonds or structures that are stable for dissolution, dispersion, etc.

[0047] In this invention, the (meth)acrylate copolymer is preferably soluble in any of the alcohols having 1 to 6 carbon atoms. Solubility in alcohols having 1 to 3 carbon atoms facilitates drying after coating, and is therefore more preferred. Here, "soluble" means that when 1 g of the (meth)acrylate copolymer is immersed in 10 ml of the aforementioned alcohol at 25°C, at least 90% by weight of the (meth)acrylate copolymer dissolves at room temperature within 16 hours.

[0048] In this invention, the antithrombotic material containing (meth)acrylate copolymer may contain antibacterial substances and other substances. There are no particular restrictions on antibacterial substances; examples include ampicillin, nafcillin, amoxicillin, oxacillin, azlocillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, feneccillin, flucloxacillin, piperacillin, mecillin, sulfamethoxazole, methicillin, ticarcillin, mezlocillin, cefaclor, cefotaxime, cefadroxil, cefalexin, cefadroxil, cefamandole, cefadroxil, ceftriaxone, cefuroxime, cefotaxime, cefazolin, ceftriaxone, cefoxitin, cefuroxime, cefazolin, latamoxef, cefalexin, amikacin, neomycin, dibekacin, kanamycin, gentamicin, netilmicin, kanamycin, tobramycin, amphotericin B, neomycin, bacitracin. Antibiotics including nystatin, clindamycin, polymyxin, colistin, spiramycin, erythromycin, streptomycin, spectinomycin, lincomycin, vancomycin, chlortetracycline, oxytetracycline, demeclocycline, rolicycline, doxycycline, tetracycline, minocycline, etc.; antifungal drugs including amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatin, griseofulvin, etc.; parabens including isobutylparaben, isopropylparaben, ethylparaben, butylparaben, propylparaben, etc.; biguanide compounds including chlorhexidine; benzyl chloride; benzalkonium chloride; lauryl sulfate; alkyl polyaminoethyl glycine; fatty acids; domiphen bromide. Compounds with surface activity such as bromide, phenol derivatives such as thymol, phenol, hexachlorophenol, and resorcinol, boric acid compounds such as boric acid and borax, iodine compounds such as iodine, iodoform, and povidone-iodine, metals such as gold, silver, copper, and mercury, metal compounds such as thimerosal and silver sulfadiazine, antibacterial pigment compounds such as rivanol and methylrosaniline, and sulfonamides such as sulfamidone acetate, sulfadiazine, sulfadiazine, and sulfamethoxazole. These antibacterial substances can also be salt compounds such as sodium salts, potassium salts, magnesium salts, calcium salts, hydrochlorides, sulfates, and gluconates. In addition, two or more antibacterial substances can be used in combination.

[0049] The aforementioned antibacterial substances are mainly divided into water-soluble and water-poorly soluble substances. Examples of water-soluble antibacterial substances include benzalkonium chloride, povidone-iodine, potassium penicillin G, and streptomycin sulfate. Examples of water-poorly soluble antibacterial substances include silver sulfadiazine and chlorhexidine.

[0050] In this invention, when an antithrombotic substance (copolymer) and a water-poorly soluble antibacterial substance are coated onto medical devices, the dissolution of the antibacterial substance is minimal and continuous, maintaining long-term antibacterial activity. The reason for this is unclear, but it may be because the copolymer is water-insoluble, or because the water insolubility of the copolymer and the water-poor solubility of the antibacterial substance work complementaryly. On the other hand, when a copolymer and a water-soluble antibacterial substance are coated, although the copolymer is water-insoluble, the antibacterial substance is water-soluble. Therefore, the dissolution amount is greater than when using a water-poorly soluble antibacterial substance, exhibiting strong instantaneous antibacterial activity, but unable to maintain long-term antibacterial activity. For example, intravascular catheters, infusion tubes, and artificial lungs are medical devices used continuously for one to several days, and such applications require the maintenance of long-term antibacterial activity. Furthermore, by incorporating both water-soluble and water-poorly soluble antibacterial substances into the copolymer, a multi-stage antibacterial effect can be achieved: initially, the strong bactericidal activity is exerted based on the water-soluble antibacterial substance, followed by a long-term antibacterial effect through the water-poorly soluble antibacterial substance. When this multi-stage antibacterial effect is applied to indwelling vascular catheters, the water-soluble antibacterial substance dissolves early, exhibiting strong antibacterial activity. This kills resident skin bacteria introduced into the blood vessel during catheter insertion, reducing the risk of infection at insertion. Moreover, during catheter indwelling, the long-term antibacterial effect of the water-poorly soluble antibacterial substance prevents bacterial colonization on the catheter and the proliferation of bacteria invading from the insertion site, further reducing the risk of infection during indwelling.

[0051] In this invention, the amount of antibacterial substance relative to the mass of the antithrombotic composition is preferably 0.01% by mass or more and 70% by mass or less, more preferably 0.05% by mass or more and 50% by mass or less, even more preferably 0.1% by mass or more and 30% by mass or less, and even more preferably 0.1% by mass or more and 10% by mass or less. If the content of the antibacterial substance is too low, its antibacterial activity may not be fully realized. Furthermore, if the content of the antibacterial substance is too high, it may sometimes result in poor appearance of the medical device after surface treatment such as coating, or increased dissolution of the antibacterial substance in the body, leading to local inflammation due to the dissolved antibacterial substance. Therefore, while the antibacterial substance may be present on the entire surface of the medical device, it is preferable to have it only present near the insertion point where it is inserted into the skin for suppressing local inflammation.

[0052] The antithrombotic material of the present invention can be any of random copolymers, block copolymers, and graft copolymers. Furthermore, there are no particular limitations on the copolymerization reaction itself used to manufacture the antithrombotic material of the present invention; known methods such as free radical polymerization, ionic polymerization, photopolymerization, and polymerization utilizing macromonomers can be used.

[0053] As an example of manufacturing the (meth)acrylate copolymer of the present invention, a manufacturing method based on free radical polymerization is shown below.

[0054] For example, monomers, polymerization solvents, and initiators are added to a stirred reaction apparatus equipped with a reflux tower. After nitrogen purging, heating initiates polymerization, and the polymerization is advanced by maintaining the temperature for a certain time. A chain transfer agent can also be used during the polymerization to control the molecular weight. The solvent is removed from the solution after polymerization to obtain a crude (meth)acrylate copolymer. Next, the obtained crude (meth)acrylate copolymer is purified by stirring in a poor solvent. This purification process is repeated one to several times to improve the purity of the (meth)acrylate copolymer. The copolymer obtained in this manner is then dried.

[0055] As polymerization solvents used in copolymerization, alcohols such as methanol, ethanol, and isopropanol, organic solvents such as ethyl acetate, toluene, benzene, and methyl ethyl ketone, or water can be used. However, in this invention, considering the solubility and ease of obtaining the monomer and the resulting copolymer, ethyl acetate, methanol, and ethanol are preferred. Alternatively, a mixture of several of the aforementioned solvents can be used. The preferred mass ratio of these polymerization solvents to monomers is 20–90 / 60–10, more preferably 30–90 / 70–10, and even more preferably 35–85 / 65–15. If the mass ratio is within the aforementioned range, the polymerization rate can be maximized.

[0056] As polymerization initiators, peroxide-based and azo-based free radical initiators commonly used in free radical polymerization can generally be used. Examples of peroxide-based free radical initiators include inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide, and organic peroxides such as benzoyl peroxide, tert-butyl hydroperoxide, and cumene peroxide. Examples of azo-based free radical initiators include 2,2'-azobisisobutyronitrile, 2,2'-azobis(2-aminodipropane) dihydrochloride, dimethyl 2,2'-azobisbutyrate, and dimethyl 2,2'-azobis(2-methylpropionic acid). Redox initiators that combine a reducing agent with a peroxide-based initiator can also be used. It is preferable to add 0.01% by mass or more and 1% by mass or less of these polymerization initiators relative to the monomer in the polymerization solution. More preferably, the addition amount is 0.05% by mass or more and 0.5% by mass or less, and even more preferably, 0.05% by mass or more and 0.3% by mass or less. By adding the polymerization initiator and the like within the aforementioned range, copolymers with suitable weight-average molecular weights can be obtained with good monomer reaction rates.

[0057] The polymerization temperature varies depending on the type of solvent and initiator, and it is preferable to use a temperature near the 10-hour half-life of the initiator. Specifically, when using the aforementioned initiator, the temperature is preferably 20°C or higher and 90°C or lower. More preferably, it is 30°C or higher and 90°C or lower, and even more preferably, it is 40°C or higher and 90°C or lower. As a chain transfer agent used to control the molecular weight during polymerization, high-boiling-point thiols such as dodecyl mercaptan, thiomalic acid, and mercaptoglycolic acid, as well as isopropanol, phosphorous acid, and hypophosphite can be used.

[0058] In this invention, the (meth)acrylate copolymer is obtained by copolymerizing hydrophilic and hydrophobic monomers, thus possessing both hydrophilic and hydrophobic properties. Therefore, the copolymerized solution contains a mixture of unreacted hydrophilic monomers (methoxy polyethylene glycol (meth)acrylate) and hydrophobic monomers (silicone (meth)acrylate, or, depending on the case, alkyl (meth)acrylate), as well as the (meth)acrylate copolymer. To separate the water-insoluble (meth)acrylate copolymer from the mixture, for example, the copolymer solution can be added dropwise to a solvent dissolving the hydrophilic monomer for purification, followed by purification using a solvent dissolving the hydrophobic monomer. Furthermore, by using a poorly reprecipitating solvent prepared by mixing alcohol and water in a specific ratio, the (meth)acrylate copolymer can be efficiently recovered. Alternatively, a purification method can be adopted: adding a poor solvent, consisting of a mixture of alcohol and water in a specific ratio, to the water-insoluble (meth)acrylate copolymer in the solution after the polymerization reaction has been completed, stirring at a certain temperature to separate the (meth)acrylate copolymer, then recovering the precipitate by decantation, and repeating the purification process by adding washing liquid.

[0059] In this invention, as a poor solvent for purifying the copolymer, it is preferable to use a poor solvent that does not dissolve the copolymer but dissolves both the hydrophilic monomer and the hydrophobic monomer.

[0060] In this invention, the alcohol used for the reprecipitation treatment is preferably an alcohol with 1 or more but less than 10 carbon atoms, more preferably an alcohol with 1 or more but less than 7 carbon atoms, and even more preferably an alcohol with 1 or more but less than 4 carbon atoms. Specific examples of such alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxy-1-propanol, tert-butanol, etc. From the perspective of achieving low-temperature and short-time drying, methanol, ethanol, 1-propanol, and 2-propanol are more preferred.

[0061] In this invention, the amount of residual monomer (the amount of monomer that did not react during polymerization) is related to safety and is therefore important. It is obvious that reducing the amount of residual monomer in the antithrombotic material will meet the standards outlined in the guidelines regarding leaching from medical devices. However, by keeping the amount of residual monomer at a very low level, such as below 4,000 ppm, unexpected effects such as improved adhesion and retention of the antithrombotic material on the surface of medical devices are achieved. Furthermore, the amount of polymer obtained is expressed as a percentage of the monomer input, in terms of recovery rate.

[0062] By performing one purification process, or 2 to 8 as needed, as described above, water-insoluble (meth)acrylate copolymers with an unreacted monomer content of 4,000 ppm or less can be recovered with a high recovery rate of 30% by mass or more. It is believed that when the copolymer contains a high amount of unreacted monomers, oligomers, and polymerization residues, these substances can dissolve into the bloodstream and become pathogenic factors contributing to shock symptoms in patients. While most of these pathogenic factors can be removed during purification, for patient safety, a content of 3,000 ppm or less is more preferable, 2,000 ppm or less is more preferable, and 1,000 ppm or less is particularly preferred.

[0063] The volume ratio of the crude (meth)acrylate copolymer to the unsuitable solvent in this invention is preferably 1:1 to 1:20, more preferably 1:3 to 1:10. If the volume ratio is within the aforementioned range, the purification efficiency and recovery rate can be maximized.

[0064] The preferred purification temperature for the crude (meth)acrylate copolymer of the present invention is 30–60°C, more preferably 40–60°C. If the purification temperature is within the aforementioned range, the viscosity of the crude (meth)acrylate copolymer decreases due to heating, making separation from undesirable solvents easier and maximizing the recovery rate of the (meth)acrylate copolymer.

[0065] In this invention, if the recovery rate of the purified (meth)acrylate copolymer is higher than 90% by mass, unreacted monomers may be present in the recovered product; if it is lower than 20% by mass, production efficiency decreases. Therefore, the recovery rate is preferably 20-90% by mass. While limiting the recovery rate to 20-90% by mass will result in the loss or discarding of some copolymer, it minimizes the introduction of unreacted monomers, making it an unavoidable choice from this perspective. This is because, given the specific case of copolymers with both hydrophilic and hydrophobic properties suitable for medical devices, this level of consideration is necessary.

[0066] To use the purified copolymer to impart antithrombotic properties to medical devices, the solvent needs to be removed by drying. As a drying method, for example, drying can be carried out at 60°C under reduced pressure below 1 Torr; if insufficient drying is achieved, further reduced pressure drying can be performed.

[0067] The antithrombotic material of the present invention described above is water-insoluble and can preferably be used as a surface treatment agent for medical devices, etc. Specifically, it can be obtained by coating a solution obtained by dissolving the obtained antithrombotic material in an organic solvent onto the surface of a substrate such as a medical device, and then removing the solvent. Methods for loading the antithrombotic material of the present invention onto the surface of a substrate include known methods such as coating, graft polymerization based on radiation, electron beams, or ultraviolet light, and methods utilizing chemical reactions with functional groups of the substrate. Among these, coating is preferred from a practical standpoint due to its ease of manufacturing process. There are no particular limitations on the coating method; methods such as application, spraying, and immersion can be used. For example, the coating method based on application can be implemented with simple operations, such as immersing the substrate in a coating solution prepared by dissolving the antithrombotic material of the present invention in a suitable organic solvent such as alcohol, chloroform, acetone, tetrahydrofuran, or dimethylformamide, then removing excess solution, followed by air drying, etc. Alternatively, heating the coated substrate to dry it is also preferred. This further improves the adhesion between the substrate and the antithrombotic material of the present invention, enabling more secure fixation.

[0068] As for the organic solvent, choose one that will cause minimal damage to the medical device used as the substrate. Specifically, methanol, ethanol, isopropanol, n-propanol, acetone, n-hexane, cyclohexane, tetrahydrofuran, etc., can be used. ， 4-Dioxane, cyclohexanone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., wherein methanol, ethanol, and isopropanol with low boiling points and easy drying after coating are preferred.

[0069] The (meth)acrylate copolymers of the present invention, obtained by copolymerizing alkyl (meth)acrylates and / or silicone (meth)acrylates with methoxy polyethylene glycol (meth)acrylates, are suitable for use as blood-compatible materials because their hydrophilicity and hydrophobicity are moderately balanced. In particular, (meth)acrylate copolymers containing silicone (meth)acrylates in a specific range are suitable for use as processing materials for medical devices and artificial organs because they can inhibit the adsorption and adhesion of proteins in blood. Furthermore, the (meth)acrylate copolymers of the present invention can be used alone or in mixtures of two or more.

[0070] It is believed that when medical devices treated with this antithrombotic material come into contact with blood, the highly hydrophilic methoxy polyethylene glycol (meth)acrylate protrudes to the surface and exerts its antithrombotic properties. In addition, the hydrophobic (meth)acrylate remains near the substrate, thereby preventing direct contact between blood and the medical device.

[0071] One method for confirming the durability of this antithrombotic material against dissolution in blood is alcohol impregnation at room temperature. A mixture of methanol and ethanol is preferred. Since a solvent consisting of an 80 / 20 mass ratio of methanol and ethanol has a stronger dissolution capacity than blood, the persistence of the antithrombotic effect can be evaluated by impregnating the antithrombotic material in the aforementioned mixed solvent for 16 hours.

[0072] In this invention, the (meth)acrylate copolymer has the property of being insoluble in methanol but soluble in ethanol. If methanol and ethanol are mixed in a specified ratio to form an alcohol impregnation solution for confirming the durability (persistence of antithrombotic properties) after 30 days of contact with blood at 37°C, even a short period such as 16 hours can confirm the durability after 30 days of contact with blood at 37°C. The mass ratio of methanol to ethanol in the alcohol impregnation solution is preferably 90–60:10–40, more preferably 90–70:10–30. It should be noted that in the test using evaluation sheets described later, if the adhesion of blood clots is low, i.e., the number of evaluation sheets with blood clots confirmed after solvent impregnation is less than 1 out of 10, and the (meth)acrylate copolymer residue is 0.1 μg / cm³, then the test is successful. 2 The above indicates that it has sufficient durability.

[0073] In this invention, one method for evaluating the blood compatibility of (meth)acrylates is the blood coagulation test. Specifically, this method utilizes the reaction in which fibrin in plasma gels due to calcium ions, forming a fibrin gel. After contact with the sample, plasma containing calcium ions is immersed in water to confirm the presence or absence of blood clots, thereby confirming the blood compatibility of the polymer. The less blood clots, the higher the blood compatibility. In the evaluation using evaluation sheets described later, if fewer than 4 out of 10 evaluation sheets show blood clot adhesion, the blood compatibility can be considered good.

[0074] In this invention, a method for calculating the coating amount of a sample can be quantified based on NMR. Specifically, the method involves extracting the substrate coated with the sample into ethanol, drying the extract to dryness, and then performing NMR analysis. The coating amount is calculated from the area of ​​the peak. Durability can be evaluated by comparing the coating amounts before and after alcohol impregnation. For example, if the residual amount of (meth)acrylate copolymer in the evaluation sheet after impregnation in 99.5% ethanol is 3.0 μg / cm³, then... 2 Based on the above, it can be determined that it can fully demonstrate antithrombotic properties in the initial stage of blood contact.

[0075] Medical devices whose surfaces are coated with the antithrombotic material of the present invention exhibit excellent antithrombotic properties. Examples of such medical devices include, for instance, blood filters, blood storage containers, blood circuits, indwelling needles, catheters, guidewires, stents, artificial lung devices, dialysis devices, anti-adhesion materials, wound dressing materials, tissue adhesives, and tissue regeneration repair materials. In particular, medical devices having an extracorporeal circulation circuit, wherein a blood contact portion is preferred.

[0076] This includes all materials commonly used as substrates for medical devices. Examples include polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, poly-4-methyl-1-pentene, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubber such as polydimethylsiloxane with crosslinking portions, polymethyl methacrylate, polyvinylidene fluoride, polytetrafluoroethylene, polysulfone, polyethersulfone, polyacetal, polystyrene, ABS resin and mixtures of these resins, metals such as stainless steel, titanium, and aluminum. The antithrombotic material of the present invention not only balances material composition, molecular weight, viscosity, etc., but also optimizes coating conditions, thus enabling uniform and firm coating regardless of the material, shape, or surface properties to be coated.

[0077] In this invention, the method for loading the antithrombotic material onto a medical device is not particularly limited. For example, the medical device can be immersed in a treatment solution prepared by dissolving or dispersing the antithrombotic material in an organic solvent, and then the solvent can be removed by heating or the like. The concentration of the (meth)acrylate copolymer in the treatment solution is preferably 0.001% by mass or more and 10% by mass or less. If the concentration of the (meth)acrylate copolymer is too low, its performance may not be adequate, for example, when applied to a medical device; therefore, 0.01% by mass or more is more preferable. In addition, if the concentration is too high, the solution viscosity will increase excessively, which may lead to a decrease in operability; therefore, 5% by mass or less is preferred.

[0078] Example

[0079] The present invention will now be described in detail through examples, but the present invention is not limited thereto.

[0080] (Evaluation of alcohol solubility)

[0081] Add 1 g of the sample to a 50 mL vial, then add 99 g of ethanol and mix thoroughly. After 30 minutes, visually confirm the dissolution. A case where substances insoluble in ethanol cannot be visually observed is marked as ○ (good), and a case where substances insoluble in ethanol can be visually observed is marked as × (bad).

[0082] (Evaluation of water insolubility)

[0083] Add 100g of water to a solution that has been determined to be ○ (good) in terms of alcohol solubility, and mix. If the turbidity does not disappear even after 30 minutes of continued mixing, classify it as ○ (good); if the turbidity disappears after 30 minutes of continued mixing, classify it as × (bad).

[0084] (Determination of weight-average molecular weight)

[0085] Weigh 15 mg of sample into a vial, add 3.0 mL of mobile phase for GPC assay, and let stand overnight. Filter the solution using a 0.45 μm hydrophilic PTFE membrane filter cartridge (Millex-LH, Millipore, Japan). For GPC assay, a 515 HPLC pump and a 717plus autosampler (Waters, Japan) were used, with a 2×PLge1 5μm MIXED-D column (7.5×300 mm, Agilent Technologies). The assay was performed at a column temperature of 40 °C. For the mobile phase, tetrahydrofuran for HPLC containing butylated hydroxytoluene as a stabilizer (FUJIFILM Wako Pure Chemical Corporation) was used. Detection was performed using RI, with an injection of 20 μL. Molecular weight correction was performed using monodisperse polystyrene (Easi Cal PS-1, Agilent Technologies).

[0086] (Determination of specific viscosity)

[0087] Weigh 1g of sample into a glass bottle and add 15mL of acetone (FUJIFILM Wako Pure Chemical Corporation). Mix by hand shaking once every 20 minutes. After 1-2 hours, confirm dissolution by visual inspection and transfer to a 25mL volumetric flask. After co-washing, add acetone to adjust to 25mL. Then, filter using a 5μm diameter filter (Merck), and use the resulting solution as the test solution. Using an Ubbelohde viscometer with a viscometer constant C = 0.003426 (cSt / s), measure the drop time of the sample solution and acetone at 30°C, and calculate the specific viscosity using the following formula 1.

[0088] (A / B-1) / C=(A / B-1) / (S / 25×100)=(A / B-1) / (S×4)

[0089] A: The number of seconds (seconds) it takes for the sample solution to fall;

[0090] B: The number of seconds it takes for acetone to fall;

[0091] S: Weight of the test sample (g);

[0092] C: Sample solution concentration (g / dL).

[0093] (Measurement of mass reduction)

[0094] Place the weighing bottle in an electric furnace set to 105°C and dry for 30 minutes. Then, cool it in the desiccator for 20 minutes and measure the mass of the weighing bottle. Weigh 0.5 g of the sample into a weighing bottle. Similarly, place the weighing bottle in an electric furnace set to 105°C and dry for 2 hours. Then, cool it in the desiccator for 20 minutes and measure the mass of the weighing bottle. Calculate the mass reduction (%) from the obtained mass of each weighing bottle. If the mass reduction (%) is less than 5%, the sample is considered to be sufficiently dried.

[0095] (Determination of residual monomer content)

[0096] Dissolve 0.2 g of the sample in 2 mL of acetone (FUJIFILM Wako Pure Chemical Corporation), then dilute appropriately, and quantify the residual monomer by GC determination. The assay apparatus used was a GC-2010Plus (Shimadzu Corporation), and the column was an Rtx-5 (GL Sciences Corporation). The injection port temperature was set to 150 °C, the detector temperature to 280 °C, and the column oven temperature to 40 °C. If the residual monomer concentration is below 4,000 ppm, it is considered sufficiently purified.

[0097] (Determination of copolymer composition ratio)

[0098] 20 mg of the sample was dissolved in 1 mL of deuterated chloroform and analyzed using a 400 MHz superconducting Fourier transform nuclear magnetic resonance (400-MR, Agilent Technologies). 1 H-NMR determination.

[0099] (Evaluation of sheet material production)

[0100] Ethanol was added to the sample to make a total of 100g, and the sample was dissolved to prepare ethanol solutions of various concentrations, thus obtaining treatment solutions. Samples with concentrations shown in Table 2 were prepared. Half of a polycarbonate sheet (4cm×2cm×0.1cm) was immersed in the treatment solution for 10 seconds, then the polycarbonate sheet was removed and dried on both sides with air at a flow rate of 10mL / min for 30 seconds each. Then, it was dried at room temperature for 16 hours to prepare the evaluation sheet.

[0101] (Blood clotting test)

[0102] Add 800 μL of rabbit blood (model: 003-00053-01, Japan Bio Serum) to a 15 mL centrifuge tube. Add 66.6 μL of 80 mM calcium chloride solution and stir thoroughly. Use the resulting solution as the test blood solution. Place the evaluation sheet on a plastic petri dish. Place the petri dish in a water bath set to 37°C. Add 200 μL of the test blood solution to both the untreated and treated portions of the evaluation sheet. Then, incubate at 37°C for 25 minutes. Immerse the incubated evaluation sheet in 100 mL of physiological saline (Otsuka Pharmaceutical Co., Ltd.) and gently agitate. Check the number of blood clots adhering to the surface of the evaluation sheet after removing it from the physiological saline. If fewer than 4 out of 10 evaluation sheets show blood clots, the blood compatibility is considered good.

[0103] (Coating Quantity Test)

[0104] The evaluation sheet was immersed in 5 mL of ethanol (99.5% by mass) for 30 minutes to obtain an extract. Nitrogen gas was purged onto the extract at 40°C, and the mixture was dried until the ethanol odor disappeared. This process was repeated three times. 0.13 mg of dimethyl isophthalate was added to the total volume of the dried solid, and then dissolved in 0.6 mL of deuterated chloroform. The solution was then subjected to treatment at 30°C. 1 H-NMR determination. The coating amount is calculated from the obtained peak area. The coating amount is calculated using the following formula.

[0105] Coating amount = C × 218.023 × B × 1000000 ÷ 19400 ÷ A

[0106] A: Sample weight;

[0107] B: Weight of dimethyl isophthalate;

[0108] C: The integral value of the peak from methoxytriethylene glycol acrylate when the integral value of the peak from 1,3-dimethyl-2-imidazolidineone is set to 100.

[0109] (Alcohol immersion treatment test)

[0110] The evaluation sheets were immersed in 150 mL of an alcohol impregnation solution (methanol:ethanol = 80% by mass: 20% by mass) for 16 hours. After impregnation and thorough drying, the blood coagulation test and coating quantification were performed on the evaluation sheets as described above.

[0111] (Example 1)

[0112] Polymerization was carried out in 1628.3 g of ethanol (Kishida Chemical Co., Ltd.) at 85°C for 3 hours, with 471.8 g of methoxytriethylene glycol acrylate (MTEGA) (Shinnakamura Chemical Co., Ltd.), 78.0 g of silicone methacrylate (PDMSMA) (Gelest Co., Ltd., product name: MCR-M11), and 694.5 g of 2-ethylhexyl acrylate (EHA) (Toa Synthetic Co., Ltd.). The polymer was then added to 1.2325 g of azobisisobutyronitrile (AIBN) (FUJIFILM Wako Pure Chemical Corporation). After polymerization, the product was dried at atmospheric pressure at 85°C for 2 hours. Then, it was dried under reduced pressure at 60°C for 1 hour to obtain a concentrate. The concentrate was divided into two equal parts, concentrate A and concentrate B. Next, 3162.7 g of methanol (Kishida Chemical Co., Ltd.) and 305.3 g of water were added to 612.1 g of concentrate A, and the mixture was stirred for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to the precipitate, and the mixture was stirred for 30 minutes. After standing for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to obtain precipitate A. The amounts of methanol added were 3161.7 g, 3161.4 g, and 3163.9 g, respectively. Similarly, 3162.3 g of methanol and 303.1 g of water were added to 614.4 g of concentrate B, and the mixture was stirred for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to the precipitate, and the mixture was stirred for 30 minutes. After standing for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to obtain precipitate B. The amounts of methanol added were 3165.5 g, 3167.5 g, and 3165.4 g, respectively. Precipitates A and B were combined and dried under reduced pressure at 40°C for 1.5 hours to obtain copolymer 1.

[0113] (Example 2)

[0114] Polymerization was carried out in 165.18 g of ethanol (Kishida Chemical Co., Ltd.) at 85°C for 3 hours, with 94.25 g of methoxytriethylene glycol acrylate (MTEGA) (Shinnakamura Chemical Co., Ltd.), 15.59 g of silicone methacrylate (PDMSMA) (Gelest Co., Ltd., product name: MCR-M11), and 138.68 g of 2-ethylhexyl acrylate (EHA) (Toa Synthetic Co., Ltd.). The polymer was then added to 94.25 g of methoxytriethylene glycol acrylate (MTEGA) (Shinnakamura Chemical Co., Ltd.), 0.2469 g of azobisisobutyronitrile (AIBN) (FUJIFILM Wako Pure Chemical Corporation). After polymerization, the product was dried at atmospheric pressure at 85°C for 1 hour. Then, it was dried under reduced pressure at 60°C for 1.5 hours to obtain a concentrate. The concentrate was divided into two equal parts, concentrate A and concentrate B. Next, 631.97 g of methanol (Kishida Chemical Co., Ltd.) was added to 122.51 g of concentrate A, and the mixture was stirred at 60°C for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to this precipitate, and the mixture was stirred at 60°C for 30 minutes. After standing for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to obtain precipitate A. The amounts of methanol added were 631.98 g, 632.03 g, and 632.05 g, respectively. Similarly, 631.99 g of methanol was added to 122.50 g of concentrate B, and the mixture was stirred at 60°C for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to this precipitate, and the mixture was stirred at 60°C for 30 minutes. After standing for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to obtain precipitate B. The amounts of methanol added were 631.98 g, 632.00 g, and 632.01 g, respectively. Precipitates A and B were combined and dried at atmospheric pressure at 85°C for 30 minutes, followed by vacuum drying at 40°C for 1 hour to obtain copolymer 2.

[0115] (Comparative Example 1)

[0116] Polymerization was carried out in 165.18 g of ethanol (FUJIFILM Wako Pure Chemical Corporation) at 85°C for 3 hours, with 94.25 g of methoxytriethylene glycol acrylate (MTEGA) (Shinnakamura Chemical Co., Ltd.), 15.59 g of silicone methacrylate (Gelest Corporation, product name: MCR-M11), and 138.68 g of 2-ethylhexyl acrylate (EHA) (Toa Gosei Co., Ltd.). The reaction mixture was then added to 94.25 g of methoxytriethylene glycol acrylate (MTEGA) (Shinnakamura Chemical Co., Ltd.) and 0.247 g of azobisisobutyronitrile (AIBN) (FUJIFILM Wako Pure Chemical Corporation). After polymerization, the mixture was dried at atmospheric pressure at 85°C for 1 hour. Then, it was dried under reduced pressure at 60°C for 1.5 hours to obtain a concentrate. 696.35 g of methanol (FUJIFILM WakePure Chemical Corporation) was added to the concentrate, and the mixture was stirred for 30 minutes. After stirring, the mixture was allowed to stand for 1 hour, and the supernatant was removed by decantation. The precipitate was dried under normal pressure at 85°C for 30 minutes, and then dried under reduced pressure at 40°C for 1 hour to obtain copolymer 3.

[0117] (Comparative Example 2)

[0118] Polymerization was carried out in 580.03 g of ethanol (Kishida Chemical Co., Ltd.) at 85°C for 3 hours, with 94.27 g of methoxytriethylene glycol acrylate (MTEGA) (Shinnakamura Chemical Co., Ltd.), 15.60 g of silicone methacrylate (PDMSMA) (Gelest Co., Ltd., product name: MCR-M11), and 138.66 g of 2-ethylhexyl acrylate (EHA) (Toa Synthetic Co., Ltd.). The polymer was then added to 54.27 g of azobisisobutyronitrile (AIBN) (FUJIFILM Wako Pure Chemical Corporation). After polymerization, the product was dried at atmospheric pressure at 85°C for 1 hour. Then, it was dried under reduced pressure at 60°C for 1.5 hours to obtain a concentrate. The concentrate was divided into two equal parts, concentrate A and concentrate B. Next, 632.00 g of methanol (Kishida Chemical Co., Ltd.) was added to 122.53 g of concentrate A, and the mixture was stirred at room temperature for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to the precipitate, and the mixture was stirred at room temperature for 30 minutes. After standing for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to obtain precipitate A. The amounts of methanol added were 632.09 g, 632.09 g, and 632.32 g, respectively. Precipitate A was dried at atmospheric pressure at 85°C for 30 minutes, and then dried under reduced pressure at 40°C for 1 hour to obtain copolymer 4.

[0119] As shown in Tables 1 and 2, when evaluation sheets were prepared using copolymers from the examples with high specific viscosity and high weight-average molecular weight, good results were obtained in the blood coagulation test after alcohol impregnation. The copolymers from the examples have a higher specific viscosity than conventional (meth)acrylate copolymers; therefore, it is speculated that the coating thickness is more uniform. The mechanism is shown in Table 3.

[0120] That is, if the copolymer of the example is coated, when the ethanol is removed, the water in the air adhering to the surface of the coating is not locally present, so the coating thickness becomes uniform. It is presumably a result that the uncoated areas (uneven coating defects) caused by subsequent alcohol impregnation treatment can be suppressed. Furthermore, it can be seen that sufficient durability against dissolution in blood is maintained.

[0121] [Table 1]

[0122]

[0123] [Table 2]

[0124]

[0125] [Table 3]

[0126]

[0127] In this invention, it was found that good blood compatibility was also observed after 16 hours of alcohol impregnation at room temperature. This result shows that blood compatibility can be maintained for a longer period of time compared to conventional antithrombotic materials.

[0128] Industrial availability

[0129] The copolymer of the present invention exhibits excellent blood compatibility and can be used as a highly hydrophilic material. Furthermore, since it is a water-insoluble, viscous substance, it provides a material that can be coated onto the entire blood circuit without compromising the properties of the medical device material. Therefore, it makes a significant contribution to industrial development.

Claims

1. An antithrombotic material, characterized in that, The copolymer comprises the following (meth)acrylate copolymer, which is obtained by copolymerizing alkyl (meth)acrylate units represented by general formula 1, silicone (meth)acrylate units represented by general formula 2, and methoxy polyethylene glycol (meth)acrylate units represented by general formula 3 in a molar ratio of 80 to 20 / 10 to 0.01 / 10 to 79.99, and has a weight-average molecular weight of 60,000 or more and 1,500,000 or less. The (meth)acrylate copolymer is water-insoluble and a viscous liquid at room temperature, soluble in any of the alcohols having 1 to 6 carbon atoms, with a residual monomer content of less than 4,000 ppm and a specific viscosity ηsp / c of ​​more than 0.18 dl / g and less than 3.00 dl / g. Here, "water insoluble" means that when the (meth)acrylate copolymer is left to stand in 99% by mass of physiological saline at 37°C for 30 days (1% by mass of the copolymer), the mass reduction rate of the copolymer is less than 1% by mass. In Equation 1, R 1 R represents an alkyl group with 8 to 12 carbon atoms. 2 Indicates a hydrogen atom or a methyl group. In Equation 2, R 3 R represents a hydrogen atom or a methyl group. 4 R represents an alkylene group having 1 to 6 carbon atoms. 5 This indicates an alkyl group having 1 to 6 carbon atoms, where n represents an integer from 1 to 30. In Equation 3, R 6 This represents a hydrogen atom or a methyl group, and n represents an integer from 2 to 4.

2. A medical device, characterized in that, It includes the antithrombotic material as described in claim 1.

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