Medical instrument and manufacturing method therefor

Abstract

The present invention provides a means capable of further improving antithrombogenicity in a medical instrument.　A medical instrument according to the present invention comprises a substrate and an antithrombotic layer having a polymer fixed to the substrate, wherein the polymer has: a first monomer-derived constitutional unit a which is bonded to the substrate and has an ethylenically unsaturated group and a reactive group that reacts with a hydroxyl group or a carboxyl group; a constitutional unit B which has a polymer chain containing a first antithrombotic monomer-derived constitutional unit b having a carboxyl group and an ethylenically unsaturated group, and in which the constitutional unit a and the end of the polymer chain are bonded; and a copolymer-derived constitutional unit C which is bonded to the constitutional unit b and has a second monomer-derived constitutional unit c1 having an amino group and a second antithrombotic monomer-derived constitutional unit c2.

Description

Medical device and its manufacturing method

[0001] The present invention relates to a medical device and a method for manufacturing the same.

[0002] In recent years, medical materials utilizing various polymeric or metallic materials have been explored, and their potential applications include artificial kidney membranes, plasma separation membranes, catheters, stents, artificial lung membranes, artificial blood vessels, anti-adhesion membranes, artificial skin, stent grafts, covered stents, guidewires, and cardiac pacemakers. In these applications, synthetic polymeric or metallic materials, which are foreign to the body, are used in contact with biological tissues and bodily fluids such as blood. Therefore, medical materials must be biocompatible. The biocompatibility required of medical materials varies depending on their purpose and method of use. However, medical materials that come into contact with blood are required to have properties such as inhibition of the blood coagulation system, inhibition of platelet adhesion and activation, and inhibition of complement activation (antithrombotic properties).

[0003] Typically, medical devices are imparted with antithrombogenicity by coating the substrate constituting the medical device with an antithrombogenic material or by immobilizing an antithrombogenic material on the surface of the substrate. For example, Non-Patent Document 1 discloses a method for modifying medical expanded polyethylene tetrafluoroethylene (ePTFE) by surface graft polymerization. More specifically, this document describes a method in which the ePTFE surface is subjected to argon plasma treatment to generate peroxide groups, followed by reaction with glycidyl methacrylate (GMA) to form methacryloyl groups, and then graft polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) to immobilize MPC polymer chains on the ePTFE surface via GMA-derived structural units. According to this document, graft polymerization using GMA provides a new method for modifying the chemically inert ePTFE surface and enabling it to function as a new medical device.

[0004] Yihua Liu et al., “A surface graft polymerization process on chemically stable medical ePTFE for suppressing platelet adhesion and activation”, Biomaterials Science, The Royal Society of Chemistry, 07 June 2018, Issue 6, Page 1908 to 1915.

[0005] However, according to the investigations of the present inventors, it has become clear that even with the method described in Non-Patent Document 1, there are cases in which a medical device having sufficient antithrombotic properties cannot be obtained.

[0006] Therefore, an object of the present invention is to provide a means for further improving the antithrombotic properties of medical devices.

[0007] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that the above-mentioned problems can be solved by constructing a polymer chain on the surface of a substrate by graft polymerizing an antithrombogenic monomer via a predetermined structural unit, and by bonding a copolymer derived from the antithrombogenic monomer to the polymer chain, thereby completing the present invention.

[0008] That is, the above object can be achieved by the present invention having the following configuration, and the present invention includes the following aspects and configurations.

[0009] One aspect of the present invention is a medical device comprising: 1. a substrate; and an antithrombogenic layer having a polymer fixed to the substrate, wherein the polymer comprises: a structural unit a, bonded to the substrate, derived from a first monomer having an ethylenically unsaturated group and a reactive group reactive with a hydroxyl group or a carboxyl group; a structural unit B having a polymer chain including a structural unit b derived from a first antithrombogenic monomer having a carboxyl group and an ethylenically unsaturated group, and in which the structural unit a is bonded to an end of the polymer chain; and a structural unit C, bonded to the structural unit b, derived from a copolymer having a structural unit c1 derived from a second monomer having an amino group and a structural unit c2 derived from the second antithrombogenic monomer.

[0010] 2. In the medical device described in 1 above, the second antithrombotic monomer is preferably one or more monomers selected from monomers represented by the following formula (I):

[0011]

[0012] In the above formula (I), R １ represents a hydrogen atom or a methyl group, and X represents a group represented by the formula: -O-(R ２ O) ｍ -R ３ a group represented by the formula: —O—(CH ２ CHOH ｎ -CH ２ OH or a tetrahydrofurfuryloxy group, in which R ２ each independently represents a linear or branched alkylene group having 1 to 4 carbon atoms; R ３ represents a linear or branched alkyl group having 1 to 4 carbon atoms; m represents an integer of 1 to 5; and n represents an integer of 1 to 5.

[0013] 3. In the medical device described in 1. or 2. above, the second antithrombotic monomer is preferably one or more selected from methoxymethyl acrylate, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), ethoxymethyl acrylate, ethoxyethyl acrylate (EEA), 2-(2-ethoxyethoxy)ethyl acrylate (EEEA), ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate (THFA), methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, and glycerol (meth)acrylate.

[0014] 4. In the medical device according to any one of 1. to 3. above, the first monomer is preferably one or more selected from glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether.

[0015] 5. In the medical device according to any one of 1. to 4. above, the first antithrombotic monomer is preferably one or more types selected from monomers represented by the following formula (II):

[0016]

[0017] In the above formula (II), R ４ represents a hydrogen atom or a methyl group, R ５ represents a linear or branched alkylene group having 1 to 6 carbon atoms; R ６ and R ７ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; R８ represents a linear or branched alkylene group having 1 to 4 carbon atoms, and Z is —COO － represents Y １ represents an oxygen atom or —NH—.

[0018] 6. In the medical device according to any one of 1. to 5. above, the first antithrombotic monomer is preferably one or more selected from N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, and N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine.

[0019] 7. In the medical device according to any one of 1. to 6. above, the second monomer is preferably one or more monomers selected from the group consisting of monomers represented by the following formula (III) and salts thereof:

[0020]

[0021] In the above formula (III), R ９ represents a hydrogen atom or a methyl group; Y ２ represents an oxygen atom or —NH—; and p represents an integer of 1 to 4.

[0022] 8. In the medical device according to any one of 1. to 7. above, the second monomer is preferably one or more selected from aminomethyl acrylamide, aminomethyl methacrylamide, aminoethyl acrylamide, aminoethyl methacrylamide, aminopropyl acrylamide, aminopropyl methacrylamide (APMA), aminobutyl acrylamide, aminobutyl methacrylamide, aminomethyl acrylate, aminomethyl methacrylate, aminoethyl acrylate, aminoethyl methacrylate, aminopropyl acrylate, aminopropyl methacrylate, aminobutyl acrylate, aminobutyl methacrylate, and salts thereof.

[0023] 9. In the medical device according to any one of 1. to 8. above, in the structural unit C, the molar ratio of the structural unit c1 to the structural unit c2 (c1:c2) is preferably 1:1 to 1:20.

[0024] 10. In the medical device according to any one of 1. to 9. above, the substrate preferably comprises a plastic substrate.

[0025] 11. In the medical device described in 10. above, the plastic substrate is preferably a porous body.

[0026] 12. In the medical device according to any one of 1. to 11. above, the medical device is preferably an artificial blood vessel, a stent graft, a covered stent, or a catheter.

[0027] Another aspect of the present invention is: 13. A method for producing a medical device according to any one of 1. to 12. above, comprising: irradiating at least a portion of the surface of the substrate with plasma; contacting the substrate after the plasma irradiation with the first monomer; contacting the substrate after the contact with the first monomer with the second monomer; and contacting the substrate after the contact with the second monomer with the copolymer.

[0028] FIG. 1 is a diagram illustrating the fixation of the antithrombogenic layer in the present invention. FIG. 2 is a partial cross-sectional view schematically illustrating the structure of a representative embodiment of a medical device according to the present invention. In FIG. 2, 10 represents the substrate, 11 represents the antithrombogenic layer, and 100 represents the medical device. FIG. 3 is a partial cross-sectional view schematically illustrating an example of a different structure as an application example of the embodiment of FIG. 2. In FIG. 3, 10 represents the substrate, 10a represents the substrate core, 10b represents the substrate surface layer, 11 represents the antithrombogenic layer, and 100 represents the medical device. FIG. 4 is a photograph showing a blood circulation circuit for a stent graft. FIG. 5 is a photograph of the appearance of the PET stent graft substrate of Comparative Example 1 (PET SG (unplasma-treated)) after a blood circulation test. FIG. 6 is a photograph of the appearance of the PET stent graft (PET SG-GMA-pCBA-p(MEA-APMA)) in which the MEA-APMA copolymer was fixed via GMA and CBA polymer chains of Example 1 after a blood circulation test. FIG. 7 is an SEM image of the ePTFE artificial blood vessel (ePTFEg (unplasma-treated)) in Comparative Example 2 after a blood circulation test, observed with a scanning electron microscope. FIG. 8 is an SEM image of the ePTFE artificial blood vessel (ePTFEg-GMA-pCBA) in which CBA was polymerized via GMA of Comparative Example 3 after a blood circulation test, observed with a scanning electron microscope. FIG. 9 is an SEM image of the ePTFE artificial blood vessel (ePTFEg-GMA-pCBA-p(MEA-APMA)) in which the MEA-APMA copolymer was fixed via GMA and CBA polymer chains of Example 2 after a blood circulation test, observed with a scanning electron microscope. FIG. 10 is a photograph of the appearance of the silicone tube of Comparative Example 4 (silicone tube (untreated with plasma)) after a blood circulation test. FIG. 11 is a photograph of the appearance of the silicone tube of Example 3 to which the MEA-APMA copolymer was fixed via GMA and CBA polymer chains (silicone tube-GMA-pCBA-p(MEA-APMA)) after a blood circulation test. FIG. 12 is a photograph of the appearance of the polyurethane tube of Example 4 to which the MEA-APMA copolymer was fixed via GMA and CBA polymer chains (PU tube-GMA-pCBA-p(MEA-APMA)) after a blood circulation test.

[0029] According to one aspect of the present invention, there is provided a medical device comprising a substrate and an antithrombogenic layer having a polymer immobilized on the substrate, wherein the polymer is bonded to the substrate and has a polymer chain including a structural unit a derived from a first monomer having an ethylenically unsaturated group and a reactive group reactive with a hydroxyl group or a carboxyl group, a structural unit b derived from a first antithrombogenic monomer having a carboxyl group and an ethylenically unsaturated group, and a structural unit B in which the polymer chain is bonded to the end of the structural unit a, and a structural unit C bonded to the structural unit b and derived from a copolymer having a structural unit c1 derived from a second monomer having an amino group and a structural unit c2 derived from the second antithrombogenic monomer.

[0030] The present inventors have surprisingly found that a medical device having such a configuration has excellent antithrombotic properties (i.e., it can effectively inhibit the adhesion of proteins, cells, etc. that can form thrombi).The mechanism by which the configuration of the present invention exhibits the above-mentioned effects is presumed to be as follows.

[0031] FIG. 1 is a diagram illustrating the fixation of the antithrombogenic layer in the present invention. As shown in FIG. 1 , the medical device according to the present invention is prepared by reacting a substrate on the surface of which hydroxyl groups (—OH) or carboxyl groups (—COOH, not shown) have been formed by plasma irradiation with a first monomer (e.g., glycidyl methacrylate (GMA)) having a reactive group (e.g., a glycidyl group) that reacts with the hydroxyl group or carboxyl group and an ethylenically unsaturated group, thereby fixing a structural unit a derived from the first monomer to the substrate surface. This results in the construction of an ethylenically unsaturated group on the substrate surface. Subsequently, a first antithrombogenic monomer (e.g., N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA)) having a carboxyl group and an ethylenically unsaturated group is graft polymerized onto the ethylenically unsaturated group in the structural unit a, thereby forming a structural unit B having a polymer chain containing a structural unit b derived from the first antithrombogenic monomer. The polymer chain is extended by graft polymerization from the ethylenically unsaturated group of the structural unit a, and therefore the structural unit a and the end of the polymer chain are bonded to each other.２ A copolymer (p(MEA-APMA)) having a structural unit c1 derived from a second monomer (e.g., aminopropylmethacrylamide (APMA)) having a CBA group and a structural unit c2 derived from a second antithrombogenic monomer (e.g., methoxyethyl acrylate (MEA)) is reacted with the polymer chain (dehydration condensation reaction). This causes the carboxyl group derived from CBA and the amino group derived from APMA to form an amide bond (-C(=O)-NH-), thereby immobilizing the structural unit C derived from the copolymer. As a result, an antithrombogenic layer having a polymer containing structural units a, B, and C is immobilized on the substrate surface via a covalent bond. This configuration allows a larger amount of polymer derived from the antithrombogenic monomer to be immobilized on the substrate surface compared to Non-Patent Document 1, thereby further improving the antithrombogenicity of medical devices. The technology described in Non-Patent Document 1 immobilizes the polymer derived from the antithrombogenic monomer on the substrate surface solely by graft polymerization. According to the studies of the present inventors, it was found that there is a limit to the elongation of polymer chains by graft polymerization, and therefore the technique described in Non-Patent Document 1 may not be able to impart sufficient antithrombogenicity. The antithrombogenic layer according to the present invention contains not only the structural unit B having a polymer chain containing the structural unit b derived from the first antithrombogenic monomer, but also the structural unit C derived from a copolymer containing the structural unit c2 derived from the second antithrombogenic monomer, and therefore it is possible to further improve the antithrombogenicity of medical devices. Therefore, the present invention provides a means for further improving the antithrombogenicity of medical devices.

[0032] The above mechanism is merely speculation and does not limit the technical scope of the present invention.

[0033] Herein, a medical device having the above configuration is also simply referred to as the "medical device according to the present invention" or "medical device." Also, herein, "structural unit a derived from a first monomer having an ethylenically unsaturated group and a reactive group reactive with a hydroxyl group or a carboxyl group" is also simply referred to as the "structural unit a according to the present invention" or "structural unit a." Herein, "structural unit b derived from a first antithrombotic monomer having a carboxyl group and an ethylenically unsaturated group" is also simply referred to as the "structural unit b according to the present invention" or "structural unit b." Herein, "a polymer chain comprising structural unit b derived from a first antithrombotic monomer having a carboxyl group and an ethylenically unsaturated group" is also simply referred to as the "polymer chain according to the present invention" or "polymer chain." Herein, "structural unit B having a polymer chain comprising structural unit b derived from a first antithrombotic monomer having a carboxyl group and an ethylenically unsaturated group, and in which the structural unit a is bonded to the end of the polymer chain" is also simply referred to as the "structural unit B according to the present invention" or "structural unit B." Herein, the "structural unit c1 derived from the second monomer having an amino group" is also referred to simply as the "structural unit c1 according to the present invention" or "structural unit c1." Herein, the "structural unit c2 derived from the second antithrombotic monomer" is also referred to simply as the "structural unit c2 according to the present invention" or "structural unit c2." Herein, the "copolymer having the structural unit c1 derived from the second monomer which is bonded to the structural unit b and has an amino group, and the structural unit c2 derived from the second antithrombotic monomer" is also referred to simply as the "copolymer according to the present invention" or "copolymer." Herein, the "structural unit C derived from the copolymer having the structural unit c1 derived from the second monomer which is bonded to the structural unit b and has an amino group, and the structural unit c2 derived from the second antithrombotic monomer" is also referred to simply as the "structural unit C according to the present invention" or "structural unit C." Herein, a polymer (polymer) comprising the structural unit a, the structural unit B, and the structural unit C is also referred to simply as the "polymer according to the present invention" or "polymer."

[0034] In this specification, when a certain structural unit is defined as being "derived from" a certain monomer, it means that the structural unit is a structural unit that is generated by a condensation reaction of reactive groups possessed by the corresponding monomer and / or is generated by cleavage of one bond of an ethylenically unsaturated group (polymerizable unsaturated double bond).

[0035] As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups. Similarly, the term "(meth)acrylate" encompasses both acrylate and methacrylate. Thus, for example, the term "alkoxyalkyl(meth)acrylate" encompasses both alkoxyalkylacrylate and alkoxyalkylmethacrylate.

[0036] In this specification, the term "X to Y" indicating a range includes X and Y and means "X or more and Y or less." Furthermore, "A and / or B" includes each of A and B and all combinations of one or more thereof, and specifically means at least one of A and B, and also means A, B, and a combination of A and B. Furthermore, unless otherwise specified, measurements of operations and physical properties are performed under conditions of room temperature (20 to 25°C) and a relative humidity of 40 to 50% RH.

[0037] Hereinafter, embodiments of the present invention will be described. Note that the present invention is not limited to the following embodiments, and various modifications can be made within the scope of the claims. Furthermore, the embodiments described in this specification can be arbitrarily combined to form other embodiments. The dimensional proportions in the drawings are exaggerated for the convenience of explanation and may differ from the actual proportions. Furthermore, when embodiments of the present invention are described with reference to the drawings, the same elements are given the same reference numerals in the description of the drawings, and duplicate explanations will be omitted.

[0038] Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to be used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will prevail.

[0039] [Medical Device] Hereinafter, the configuration of a medical device according to one embodiment of the present invention will be described with reference to the accompanying drawings.

[0040] Fig. 2 is a partial cross-sectional view schematically showing the structure of a representative embodiment of a medical device according to the present invention, and Fig. 3 is a partial cross-sectional view schematically showing an example of a different structure as an application example of this embodiment.

[0041] 2 and 3, a medical device 100 according to one embodiment of the present invention includes a substrate 10 and an antithrombogenic layer 11 formed on at least a portion of the substrate 10. Here, the medical device 100 of this embodiment is formed by directly laminating the substrate 10 and the antithrombogenic layer 11 in this order. That is, the substrate 10 and the antithrombogenic layer 11 are laminated adjacent to each other in this order.

[0042] In this embodiment, the polymer constituting the antithrombogenic layer is chemically bonded to the surface of the substrate by a covalent bond (more specifically, the reactive group in the first monomer is covalently bonded to the hydroxyl group (—OH) or carboxyl group (—COOH) generated by the plasma treatment), thereby enabling the antithrombogenicity to be maintained for a long period of time.

[0043] Furthermore, in this specification, the phrase "an antithrombogenic layer is formed on at least a portion of the substrate" is used because, in artificial blood vessels, stent grafts, covered stents, catheters, and the like, which are examples of uses of medical devices, it is not necessary to impart antithrombogenicity to the entire surface (entire surface) of these medical devices, and it is sufficient that the antithrombogenic layer is formed only on the surface portion (which may be a portion or the entire surface) that is required to have antithrombogenicity. For this reason, it is preferable that the antithrombogenic layer is formed on at least the portion of the substrate 10 that comes into contact with blood. For example, when the medical device is an artificial blood vessel, a stent graft, a covered stent, or a catheter, it is preferable that the antithrombogenic layer is formed on the entire surface of the substrate.

[0044] Substrate (Substrate Layer) The substrate 10 constituting the medical device according to one embodiment of the present invention is not particularly limited, but preferably includes at least one of a plastic substrate (polymer substrate) and a metal substrate. As a plastic substrate, an optimal substrate can be appropriately selected depending on the characteristics (e.g., mechanical strength, etc.) required for medical devices such as artificial blood vessels, stent grafts, covered stents, and catheters. For example, a substrate having the characteristics required for a substrate, such as mechanical strength, flexibility, and smoothness, is preferred. Furthermore, as a metal substrate, an optimal substrate can be appropriately selected depending on the characteristics (e.g., mechanical strength, etc.) required for medical devices such as stent grafts, covered stents, stents, guidewires, and cardiac pacemakers. For example, a substrate having the characteristics required for a substrate, such as mechanical strength, elasticity, and toughness, is preferred.

[0045] Preferably, at least the surface of the substrate 10 is made of a plastic or metal substrate. As an example, as shown in FIG. 2, the entire substrate may be made of a plastic or metal substrate. Alternatively, as shown in FIG. 3, a substrate surface layer 10b made of a plastic or metal substrate may be formed on the surface of a substrate core portion 10a made of a material such as a ceramic material. Alternatively, the substrate core portion 10a and the substrate surface layer 10b may be combined (by appropriate reaction treatment) to form the substrate 10. Therefore, the substrate core portion 10a may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components made of different materials are joined together for each portion of the medical device. Furthermore, a separate middle layer (not shown) may be formed between the substrate core portion 10a and the substrate surface layer 10b. Furthermore, with regard to the substrate surface layer 10b, as long as its surface is constructed (formed) of a plastic substrate or a metal substrate, it may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components formed of different materials for each part of the medical device are joined together.

[0046] The plastic material (polymer material) constituting (forming) the substrate 10 and the substrate surface layer 10b is not particularly limited, and may be a polymer material commonly used in medical devices such as artificial blood vessels, stent grafts, covered stents, catheters, etc. Specific examples include polyamide resins such as nylon 6, nylon 11, nylon 12, and nylon 66 (all registered trademarks), polyethylenes such as linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), high-density polyethylene (HDPE), and modified polyethylene, polyolefin resins such as polypropylene, polyester resins such as polyethylene terephthalate (PET), polytrimethylene terephthalate (PTT), polybutylene terephthalate (PBT), and polyethylene naphthalate (PEN), styrene resins such as polystyrene, cyclic polyolefin resins, modified polyolefin resins, epoxy resins, urethane resins, diallyl phthalate resins (allyl resins), polycarbonate resins, polytetrafluoroethylene (PTFE), ePTFE (expanded polyethylene tetrafluoroethylene), and the like. Examples of suitable polymeric materials include fluororesins such as polytetrafluoroethylene (PTE), polyurethane resins, amino resins (urea resins, melamine resins, benzoguanamine resins), acrylic resins, polyacetal resins, vinyl acetate resins, phenolic resins, vinyl chloride resins, silicone resins, polyether resins such as polyether ether ketone (PEEK), and polyimide resins. These may be used alone or in combination. The polymeric material can be appropriately selected depending on the intended use of the medical device. Examples of suitable polymeric materials (plastics) for forming the substrates of artificial blood vessels, stent grafts, covered stents, catheters, and the like preferably include one or more polymeric materials selected from the group consisting of polyester resins, fluororesins, polyurethane resins, and silicone resins. More preferably, the polymeric material (plastic) includes one or more polymeric materials selected from the group consisting of polyester resins, fluororesins, polyurethane resins, and silicone resins. Furthermore, from the viewpoint of mechanical strength, it is more preferable for the polymeric material (plastic) to include polyester resin.

[0047] The metal material constituting (forming) the substrate 10 and the substrate surface layer 10b is not particularly limited, and may be a metal material commonly used in medical devices such as stent grafts, covered stents, stents, guidewires, and cardiac pacemakers. Specific examples include gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel (e.g., SUS304, SUS314, SUS316, SUS316L, SUS420J2, SUS630, and SUS631), nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, and zinc-tungsten alloys. These may be used alone or in combination of two or more. The above-mentioned metal material can be appropriately selected depending on the intended use of the medical device. The metal material constituting (forming) the substrate of a stent graft, covered stent, stent, guidewire, cardiac pacemaker, or the like, which are examples of uses, is preferably one or more selected from the group consisting of stainless steel and nickel-titanium alloys, and from the viewpoint of versatility, it is even more preferably one or more selected from the group consisting of nickel-titanium alloys. That is, in a medical device according to one embodiment of the present invention, the metal is one or more selected from the group consisting of gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, stainless steel, nickel-titanium alloy, nickel-cobalt alloy, cobalt-chromium alloy, and zinc-tungsten alloy. In a more preferred embodiment, the metal is one or more selected from the group consisting of stainless steel and nickel-titanium alloys. In an even more preferred embodiment, the metal is one or more selected from the group consisting of nickel-titanium alloys.

[0048] The material that can be used for the substrate core portion 10a is not particularly limited, and a material that can fully exhibit the optimal function of the substrate core portion 10a depending on the application of the medical device may be appropriately selected. When the substrate 10 and the substrate surface layer 10b are made of a plastic material, examples of the material for the substrate core portion 10a include the various metal materials mentioned above, inorganic materials such as various ceramic materials, and even metal-ceramic composites, but are not limited thereto. When the substrate 10 and the substrate surface layer 10b are made of a metal material, examples of the material for the substrate core portion 10a include the various plastic materials mentioned above, inorganic materials such as various ceramic materials, but are not limited thereto.

[0049] Alternatively, the substrate core portion 10a may be made of a plastic material or a metal material other than the plastic material or metal material that forms (constitutes) the substrate surface layer 10b. Examples of such plastic materials or metal materials are not particularly limited, and include the same materials as those described above. These may be used alone or in combination of two or more types.

[0050] Preferably, the substrate 10 includes or is made of a plastic substrate, or the substrate surface layer 10b includes or is made of a plastic substrate. More preferably, the substrate 10 is made of a plastic material, or the substrate surface layer 10b is made of a plastic material. That is, according to one aspect of the present invention, the substrate includes a plastic substrate. According to a more preferred aspect of the present invention, the substrate is made of a plastic substrate.

[0051] The shape of the substrate 10 is not particularly limited, and may be selected appropriately depending on the intended use, such as a sheet, film, tube, bifurcated or other shape with multiple branches (e.g., Y-shaped), linear (wire), or fibrous (thread) shape. Furthermore, the substrate 10 is preferably composed of a porous body. In this specification, the term "porous body" refers to a structure having voids that allow the progression or penetration of body fluids and / or cells. The average pore diameter of the pores is preferably 1 to 100 μm, more preferably 1 to 20 μm. Here, the average pore diameter is measured by the following method. First, the substrate surface is observed using a scanning electron microscope (SEM), and the pore area of ​​each pore observed within several to several tens of fields of view is measured. Then, the diameter (circle-equivalent diameter) of a perfect circle having the same area as the pore area of ​​each pore is calculated, and the arithmetic mean value of these values ​​is taken as the average pore diameter. A porous body having pores with the above-described pore size has good cell adhesion to vascular endothelial cells, so that the surface of the metal substrate exposed to the blood is more likely to be covered with endothelial cells, thereby further reducing the risk of thrombus formation. That is, in the medical device according to one embodiment of the present invention, the substrate is a porous body. According to a more preferred embodiment of the present invention, the substrate includes a plastic substrate, and the plastic substrate is a porous body. Note that the porous body made of a plastic substrate is not particularly limited, and examples thereof include cloth (woven fabric, nonwoven fabric) made of fiber (yarn) and ePTFE (expanded polytetrafluoroethylene).

[0052] <<Antithrombogenic Layer>> The antithrombogenic layer according to the present invention has a polymer fixed to the substrate. The polymer is bonded to the substrate and has a polymer chain including a structural unit a derived from a first monomer having a reactive group reactive with a hydroxyl group or a carboxyl group and an ethylenically unsaturated group; a structural unit B having a polymer chain including a structural unit b derived from a first antithrombogenic monomer having a carboxyl group and an ethylenically unsaturated group, and having the structural unit a bonded to the end of the polymer chain; and a structural unit C bonded to the structural unit b and derived from a copolymer having a structural unit c1 derived from a second monomer having an amino group and a structural unit c2 derived from the second antithrombogenic monomer. The antithrombogenic layer may have a single-layer structure or a laminate structure of two or more layers. Preferably, the antithrombogenic layer has a single-layer structure. In this specification, "antithrombogenic" refers to the property of reducing blood coagulation on a surface that comes into contact with blood.

[0053] The first monomer is not particularly limited as long as it has a reactive group that reacts with a hydroxyl group or a carboxyl group and an ethylenically unsaturated group.

[0054] Examples of the reactive group that reacts with the hydroxyl group or carboxyl group in the first monomer include an epoxy group (—C ２ H ３ O), glycidyl group (—CH ２ (C ２ H ３ O)), amino group (-NH ２ ) and the like. Among these, epoxy groups and glycidyl groups are preferred as reactive groups because of their high reactivity, with glycidyl groups being more preferred. More specifically, when a plastic substrate is subjected to plasma treatment, hydroxyl groups (-OH) and carboxyl groups (-COOH) are formed on the substrate surface. Furthermore, when a metal substrate is subjected to plasma treatment, hydroxyl groups (-OH) are formed on the substrate surface. The above reactive groups react (condensation reaction) with hydroxyl groups (-OH) and carboxyl groups (-COOH) to form covalent bonds (e.g., ether bonds (-O-), amide bonds (-C(=O)-NH-), etc.). This allows the antithrombogenic layer to be firmly immobilized on the substrate.

[0055] The ethylenically unsaturated group in the first monomer is a group capable of undergoing a polymerization reaction with the first antithrombotic monomer described below. Examples of the ethylenically unsaturated group include an acryloyl group (CH ２ ═CH—C(═O)—), methacryloyl group (CH ２ =C(CH ３ )-C(=O)-), vinyl group (CH ２ ═CH—), allyl group (CH ２ =CH-CH ２ Among these, the first monomer preferably has at least one of an acryloyl group and a methacryloyl group.

[0056] In one embodiment, specific examples of the first monomer include (meth)acrylic acid esters having a glycidyl group (epoxy group), such as glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate; and vinyl ethers having a glycidyl group (epoxy group), such as allyl glycidyl ether, but are not limited thereto. These may be used alone or in combination of two or more. Of these, from the viewpoint of further improving reactivity with hydroxyl groups or carboxyl groups, it is preferable that the first monomer include one or more selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate. Furthermore, it is more preferable that the first monomer contains one or two selected from the group consisting of glycidyl acrylate and glycidyl methacrylate. Furthermore, it is even more preferable that the first monomer contains glycidyl acrylate or glycidyl methacrylate, particularly preferably glycidyl methacrylate, and most preferably glycidyl methacrylate. That is, in the most preferable embodiment of the present invention, the structural unit a is derived from glycidyl methacrylate (GMA).

[0057] In another embodiment, specific examples of the first monomer include, but are not limited to, aminomethyl acrylamide, aminomethyl methacrylamide, aminoethyl acrylamide, aminoethyl methacrylamide, aminopropyl acrylamide, aminopropyl methacrylamide (APMA), aminobutyl acrylamide, and aminobutyl methacrylamide. These may be used alone or in combination of two or more. Among these, from the viewpoint of further improving reactivity with hydroxyl groups or carboxyl groups, it is preferable that the first monomer includes aminopropyl methacrylamide (APMA).

[0058] The first antithrombotic monomer is not particularly limited as long as it has a carboxyl group and an ethylenically unsaturated group and its homopolymer has antithrombotic properties.

[0059] Specific examples of the first antithrombotic monomer include the monomer represented by the following formula (II): Homopolymers derived from these monomers can exhibit excellent antithrombotic properties.

[0060]

[0061] In the above formula (II), R ４ represents a hydrogen atom or a methyl group. From the viewpoint of obtaining excellent antithrombotic properties, R ４ is preferably a methyl group.

[0062] R ５ represents a linear or branched alkylene group having 1 to 6 carbon atoms. Specific examples of the linear or branched alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Among these, from the viewpoint of obtaining excellent antithrombotic properties, R ５ is preferably a linear or branched alkylene group having 1 to 4 carbon atoms, more preferably a methylene group, an ethylene group, or a trimethylene group, and particularly preferably an ethylene group or a trimethylene group.

[0063] R ６ and R７ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples of the linear or branched alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Among these, from the viewpoint of obtaining excellent antithrombotic properties, R ６ and R ７ are each independently preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group), and particularly preferably a methyl group.

[0064] R ８ represents a linear or branched alkylene group having 1 to 4 carbon atoms. Specific examples of the linear or branched alkylene group having 1 to 4 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group. Among these, from the viewpoint of obtaining excellent antithrombotic properties, R ８ is preferably a methylene group, an ethylene group, or a trimethylene group, and more preferably a methylene group.

[0065] Z is -COO － Represents.

[0066] Y １ represents an oxygen atom or —NH—. From the viewpoint of obtaining excellent antithrombotic properties, Y １ is preferably an oxygen atom.

[0067] Examples of carboxybetaine-type zwitterionic monomers represented by formula (II) include N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, and N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine. These may be used alone or in combination of two or more. In the latter case, the structural units derived from each monomer may be present in a block or random configuration. Of these, from the viewpoint of obtaining excellent antithrombotic properties, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine is preferred, and N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) is more preferred. That is, in the most preferred embodiment of the present invention, the structural unit b is derived from N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA).

[0068] The second monomer is not particularly limited as long as it has an amino group. The amino group can form an amide bond with the carboxyl group derived from the first antithrombotic monomer. The second monomer may be a homopolymer having antithrombotic properties.

[0069] Specific examples of the second monomer include a monomer represented by the following formula (III) and a salt thereof:

[0070]

[0071] In the above formula (III), R ９represents a hydrogen atom or a methyl group. From the viewpoint of obtaining excellent antithrombotic properties, R ２ is preferably a methyl group.

[0072] Y ２ represents an oxygen atom or —NH—. From the viewpoint of obtaining excellent antithrombotic properties, Y ２ is preferably —NH—.

[0073] p represents an integer of 1 to 4. From the viewpoint of obtaining excellent antithrombotic properties, p is preferably an integer of 2 to 4, more preferably 2 or 3, and even more preferably 3.

[0074] Specific examples of the second monomer represented by the above formula (III) include, but are not limited to, aminomethyl acrylamide, aminomethyl methacrylamide, aminoethyl acrylamide, aminoethyl methacrylamide, aminopropyl acrylamide, aminopropyl methacrylamide (APMA), aminobutyl acrylamide, aminobutyl methacrylamide, aminomethyl acrylate, aminomethyl methacrylate, aminoethyl acrylate, aminoethyl methacrylate, aminopropyl acrylate, aminopropyl methacrylate, aminobutyl acrylate and aminobutyl methacrylate.These may be used alone or in combination of two or more.In the latter case, the structural units derived from each monomer may be present in block form or random form. Among these, from the viewpoint of further improving the reactivity with carboxyl groups and further imparting antithrombotic properties, the second monomer is preferably one or more selected from aminomethyl acrylamide, aminomethyl methacrylamide, aminoethyl acrylamide, aminoethyl methacrylamide, aminopropyl acrylamide, aminopropyl methacrylamide (APMA), aminobutyl acrylamide, aminobutyl methacrylamide, aminomethyl acrylate, aminomethyl methacrylate, aminoethyl acrylate, aminoethyl methacrylate, aminopropyl acrylate, aminopropyl methacrylate, aminobutyl acrylate, aminobutyl methacrylate, and salts thereof. Furthermore, the second monomer is more preferably one or more selected from aminomethyl acrylamide, aminomethyl methacrylamide, aminoethyl acrylamide, aminoethyl methacrylamide, aminopropyl acrylamide, aminopropyl methacrylamide (APMA), aminobutyl acrylamide, aminobutyl methacrylamide, and salts thereof. Furthermore, the second monomer is more preferably one or more selected from aminoethyl acrylamide, aminoethyl methacrylamide, aminopropyl acrylamide, aminopropyl methacrylamide (APMA), and salts thereof.Furthermore, it is particularly preferable that the second monomer is one or more selected from aminopropyl acrylamide, aminopropyl methacrylamide (APMA), and salts thereof. Furthermore, it is most preferable that the second monomer is selected from aminopropyl methacrylamide (APMA) and salts thereof. That is, in the most preferred embodiment of the present invention, the structural unit c1 is derived from aminopropyl methacrylamide (APMA).

[0075] The second antithrombotic monomer is not particularly limited as long as its homopolymer has antithrombotic properties.

[0076] Specific examples of the second antithrombotic monomer include monomers represented by the following formula (I). Homopolymers derived from these monomers have excellent antithrombotic properties as well as cell adhesive properties to vascular endothelial cells. For this reason, by using one or more monomers selected from the monomers represented by the above formula (I) as the second antithrombotic monomer, an antithrombotic layer having both antithrombotic properties and vascular endothelial cell adhesive properties can be formed on the surface of a substrate. This makes it easier for the surface of the substrate exposed to blood to be covered with endothelial cells in medical devices such as artificial blood vessels, stent grafts, covered stents, and catheters, and further reduces the risk of thrombus formation.

[0077]

[0078] In the above formula (I), R １ represents a hydrogen atom or a methyl group. From the viewpoint of obtaining excellent antithrombotic properties, R １ is a hydrogen atom.

[0079] X is a group of the formula: -O-(R ２ O) ｍ -R ３ a group represented by the formula: —O—(CH ２ CHOH ｎ -CH ２ From the viewpoint of obtaining excellent antithrombotic properties, X is a group represented by the formula: —O—(R ２ O) ｍ -R ３It is preferable that the group is a group represented by the following formula:

[0080] X is a group of the formula: -O-(R ２ O) ｍ -R ３ In the case where R ２ are each independently a linear or branched alkylene group having 1 to 4 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R ２ are each independently more preferably a methylene group, an ethylene group, or a trimethylene group, particularly preferably an ethylene group or a trimethylene group, and most preferably an ethylene group. ２ When there are a plurality of -O- (m is 2 or more), each -R ２ The O- may be the same or different. ３ is a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl groups. Of these, from the viewpoint of obtaining excellent antithrombotic properties, R ３ is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group), and particularly preferably a methyl group. ２ O-) groups and is an integer of 1 to 5. From the viewpoint of obtaining excellent antithrombotic properties, m is preferably an integer of 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0081] X is a group of the formula: -O-(CH ２ CHOH ｎ -CH ２ When n is a group represented by (-CH ２ represents the number of CHOH— groups and is an integer of 1 to 5. From the viewpoint of improving antithrombotic properties, n is preferably an integer of 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0082] Specific examples of the monomer represented by formula (I) include, but are not limited to, methoxymethyl acrylate, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), ethoxymethyl acrylate, ethoxyethyl acrylate (EEA), 2-(2-ethoxyethoxy)ethyl acrylate (EEEA), ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate (THFA), methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, glycerol (meth)acrylate, etc. These may be used alone or in combination of two or more. In the latter case, the structural units derived from each monomer may be present in a block form or in a random form. Of these, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), and tetrahydrofurfuryl acrylate (THFA) are preferred, with 2-methoxyethyl acrylate (MEA) and 3-methoxypropyl acrylate (MC3A) being more preferred. 2-Methoxyethyl acrylate (MEA) is even more preferred. That is, in the most preferred embodiment of the present invention, structural unit c2 is derived from 2-methoxyethyl acrylate (MEA).

[0083] The copolymer according to the present invention essentially contains a structural unit c1 derived from the second monomer and a structural unit c2 derived from the second antithrombotic monomer, but may contain other structural units in addition to these structural units. When the copolymer contains other structural units, examples of the monomers constituting the other structural units include acrylic acid, methacrylic acid, acryloylmorpholine, N,N-dimethylaminoethyl acrylate, N-vinylpyrrolidone, 2-methacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, vinyl methyl ether, 2-hydroxyethyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, 1,4-cyclohexanedimethanol mono(meth)acrylate, and 1-chloro-2-hydroxypropyl (meth)acrylate, 1,6-hexanediol mono(meth)acrylate, pentaerythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropane di(meth)acrylate, trimethylolethane di(meth)acrylate, 2-hydroxy-3-phenyloxypropyl(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, 2-hydroxy-3-phenyloxy(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, cyclohexanedimethanol mono(meth)acrylate, adipic acid, glutaric acid, triethylene glycol, tripropylene glycol, etc. The monomers constituting the other structural units may be used alone or in combination of two or more.

[0084] When the copolymer according to the present invention contains other structural units, the content of the other structural units is preferably more than 0 mol% and less than 5 mol% relative to all structural units constituting the copolymer. That is, when the total of all structural units constituting the copolymer is taken as 100 mol%, the total content of structural units c1 and c2 is preferably 95 mol% or more (upper limit: less than 100 mol%). More preferably, the copolymer is substantially composed of structural units c1 and c2 (content of other structural units = more than 0 mol% and less than 5 mol%). In this form, better antithrombotic properties can be exhibited. Preferably, the copolymer according to the present invention does not contain the other structural units (content of other structural units = 0 mol%).

[0085] The composition of each structural unit can be measured by a known method. １ The composition (molar ratio) of the structural units can be determined by measuring the integral ratio of the intensities of each signal in the H-NMR spectrum.

[0086] In the polymer according to the present invention, the ratio of the number of structural units b to the number of structural units a is not particularly limited, but in order to exhibit sufficient antithrombotic properties, this ratio is preferably 30 or more, more preferably 30 to 200, and even more preferably 30 to 150. That is, in the medical device according to one embodiment of the present invention, the ratio of the number of structural units b to the number of structural units a in the polymer is 30 or more. By controlling the number of moles of the first antithrombotic monomer that is reacted with (contacted with) the base material after the reaction of the first monomer, and the reaction time of the first antithrombotic monomer with the base material, it is possible to obtain a polymer in which a predetermined number of structural units b are linked to one structural unit a.

[0087] The terminus of the polymer chain containing the structural unit b is not particularly limited and can be appropriately determined depending on the type of monomer used. In one embodiment, the terminus of the polymer chain according to the present invention is a hydrogen atom. Furthermore, when the polymer chain according to the present invention is prepared by radical polymerization, the terminus of the polymer can be capped with a structural unit (functional group) derived from the polymerization initiator. In the latter form (a form capped with a functional group derived from the polymerization initiator), the terminus of the polymer can be a carboxyl group.

[0088] In the polymer according to the present invention, the molar ratio (c1:c2) of the structural unit c1 derived from the second monomer having an amino group to the structural unit c2 derived from the second antithrombotic monomer in the structural unit C is not particularly limited. From the viewpoint of improving the reactivity with the structural unit B and the antithrombotic properties, this molar ratio is preferably 1:1 to 1:20, more preferably 1:3 to 1:18, and even more preferably 1:5 to 1:15. That is, in the medical device according to one embodiment of the present invention, the molar ratio (c1:c2) of the structural unit c1 to the structural unit c2 in the structural unit C is 1:1 to 1:20. This molar ratio can be controlled by the amounts of the second monomer and the second antithrombotic monomer blended when synthesizing a copolymer having the structural units c1 and c2. The composition of each structural unit is substantially the same as the ratio of the amounts (moles) of the monomers charged when producing the copolymer. The molar ratio (c1:c2) is １ H-NMR, １３ It can be measured by using analytical means such as C-NMR.

[0089] The structure of the copolymer according to the present invention is not particularly limited and may be a random copolymer, an alternating copolymer, a periodic copolymer, or a block copolymer. Preferably, the copolymer according to the present invention is a random copolymer or a block copolymer. That is, the copolymer according to the present invention is preferably a random copolymer having a segment having structural unit c1 and a segment having structural unit c2, or a block copolymer having a block consisting of structural unit c1 and a block consisting of structural unit c2. From the viewpoint of improving the bonding between structural unit B and structural unit C (improving antithrombotic properties), the copolymer according to the present invention is more preferably a random copolymer. The weight-average molecular weight of the polymer according to the present invention is several thousand to several million, preferably 10,000 to 5 million. In this specification, the "weight-average molecular weight" refers to a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance and tetrahydrofuran (THF) as a mobile phase. The molecular weight of the polymer according to the present invention can also be calculated from the type and number of structural units. From the standpoint of improving the bond between the structural unit B and the structural unit C (improving antithrombotic properties), in the polymer according to the present invention, the ratio of the structural unit c1 to the structural unit b is preferably 10 or more and 1,000 or less, more preferably 50 or more and 800 or less, even more preferably 100 or more and 500 or less, and particularly preferably 200 or more and 400 or less.

[0090] The thickness (dry film thickness) of the antithrombogenic layer is, for example, about 0.1 to 10 μm, preferably about 0.5 to 5 μm, and more preferably about 1 to 3 μm.

[0091] [Method for producing a medical device] Another aspect of the present invention also provides a method for producing the medical device. That is, one embodiment of the present invention is a method for producing the medical device (also simply referred to in this specification as "the method for producing a medical device according to the present invention"), comprising the steps of irradiating at least a portion of the surface of the substrate with plasma, contacting the substrate after the plasma irradiation with the first monomer, contacting the substrate after the contact with the first monomer with the first antithrombotic monomer, and contacting the substrate after the contact with the first antithrombotic monomer with the copolymer.

[0092] Hereinafter, preferred embodiments of each step performed in the method for producing a medical device according to the present invention will be described, but the method for producing a medical device according to the present invention is not limited to the following embodiments.

[0093] <<Plasma Irradiation Step (Plasma Treatment Step)>> In this step, at least a part of the surface of the substrate is irradiated with plasma (plasma treatment is performed). This oxidizes the surface of the substrate, and as described above, hydroxyl groups (—OH) and carboxyl groups (—COOH) can be generated. Then, by contacting the first monomer with such a substrate surface, reactive groups (for example, epoxy groups (—C ２ H ３ O), glycidyl group (—CH ２ (C ２ H ３ O)), amino group (-NH ２ ) or the like) reacts (condensation reaction) with hydroxyl groups (—OH) or carboxyl groups (—COOH) formed on the surface of the substrate to form ether bonds (—O—), amide bonds (—C(═O)—NH—), etc. As a result, the polymer according to the present invention is firmly fixed on the substrate, making it possible to produce a medical device that can maintain antithrombogenicity for a long period of time.

[0094] Since the desired plasma treatment can be performed even on the thin and narrow inner surfaces of small-diameter artificial blood vessels, stent grafts, etc., the plasma irradiation step is preferably performed by ionized gas plasma treatment.

[0095] Before irradiating the surface of the substrate with ionized gas plasma, it is advisable to clean the surface of the substrate by an appropriate method. That is, it is preferable to remove oils, grease, dirt, etc. adhering to the surface of the substrate before generating hydroxyl groups (-OH) and carboxyl groups (-COOH) on the surface of the substrate by irradiating the surface with ionized gas plasma. The cleaning method is not particularly limited, and can be performed by cleaning with an appropriate solvent (for example, ultrasonic cleaning, immersion in a cleaning solvent, or flushing with a cleaning solvent).

[0096] The pressure conditions for the plasma treatment are not particularly limited, and either reduced pressure or atmospheric pressure is possible. Atmospheric pressure is preferred because it allows plasma gas to be irradiated from any angle, the device can be made smaller because a vacuum device is not required, a space-saving, low-cost system configuration can be achieved, and it is also economically advantageous. Furthermore, by irradiating plasma gas while rotating the plasma irradiation nozzle around the object to be treated, such as an artificial blood vessel or a stent graft, the entire circumference of the object can be uniformly plasma-treated without unevenness.

[0097] The ionized gas that can be used in the plasma treatment is one or more gases selected from the group consisting of helium, neon, argon, krypton, air, oxygen, carbon dioxide, carbon monoxide, water vapor, nitrogen, hydrogen, etc. The plasma treatment conditions (irradiation time, RF output, applied current, gas flow rate, inter-electrode gap, plasma irradiation distance) are not particularly limited and can be appropriately selected depending on the bonding strength between the first monomer and the substrate (ease of immobilization), the type and area of ​​the substrate used, etc.

[0098] For example, the irradiation time in the plasma treatment is preferably more than 10 seconds, more preferably 30 seconds to 10 minutes, and particularly preferably 1 to 5 minutes. Under these conditions, a sufficient amount of the first monomer can be bound (immobilized) to the surface of the substrate.

[0099] As an example, the LF output in the plasma treatment is preferably 100 to 300 W, and more preferably 200 W.

[0100] As an example, the gas flow rate in the plasma treatment is preferably 5 to 20 sccm, and more preferably 15 sccm.

[0101] The temperature of the workpiece (substrate) in the plasma treatment is not particularly limited, and may be room temperature or may be heated or cooled. From an economical point of view, it is preferable to perform the treatment at a temperature (e.g., 5 to 35°C) at which a heating or cooling device is not required.

[0102] Plasma irradiation devices (systems) that can be used for plasma treatment are not particularly limited, and examples include plasma irradiation devices (systems) that have a plasma generating tube that introduces gas molecules and excites them to generate plasma, and an electrode that excites the gas molecules in the plasma generating tube, and that emit plasma from one end of the plasma generating tube. However, the present invention is not limited to such configurations (systems). Examples include devices that employ a high-frequency induction system, a capacitively coupled electrode system, a corona discharge electrode-plasma jet system, a parallel plate system, a remote plasma system, an atmospheric pressure plasma system, a low-pressure plasma system, an ICP high-density plasma system, and the like. Additionally, commercially available ionized gas plasma irradiation devices (systems), particularly atmospheric pressure plasma irradiation devices (systems), that are suitable for irradiation of artificial blood vessels, stent grafts, covered stents, catheters, and the like, can be used. Specifically, plasma irradiation equipment such as DURADYNE (product name or trademark) manufactured by TRI-STAR TECHNOLOGIES, and plasma irradiation equipment such as PLASMABEAM and Pico Full PC manufactured by DIENER ELECTRONIC can be used, but the present invention is not limited to these.

[0103] After the plasma treatment, the substrate is exposed to an oxygen gas-containing atmosphere, whereby the surface of the substrate is oxidized to generate hydroxyl groups (-OH) and carboxyl groups (-COOH).

[0104] <<First Monomer Contact Step>> In this step, the first monomer is brought into contact with the substrate after the plasma irradiation. As a result, the reactive group (e.g., epoxy group (-C ２ H ３O), glycidyl group (—CH ２ (C ２ H ３ O)), amino group (-NH ２ ) and the like) react (condensation reaction) with hydroxyl groups (—OH) or carboxyl groups (—COOH) formed on the surface of the substrate, forming covalent bonds (for example, ether bonds (—O—), amide bonds (—C(═O)—NH—), etc.).

[0105] In this step, a specific method for contacting the first monomer with the substrate after plasma irradiation may be either a method of contacting the first monomer directly with the substrate, or a method of preparing a first monomer solution by dissolving the first monomer in a solvent and then contacting the first monomer solution with the substrate. From the viewpoint of forming a more uniform antithrombogenic layer, it is preferable to employ the latter method of contacting the first monomer solution with the substrate.

[0106] The solvent used in preparing the first monomer solution is not particularly limited and is appropriately selected depending on the type of the first monomer (and other components, if used). From the viewpoint of high solubility, water (reverse osmosis water (RO water), pure water, ion-exchanged water, distilled water, etc.); alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and organic solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), dimethyl sulfoxide, N,N-dimethylformamide (DMF), acetone, dioxane, and benzene are preferably used. These solvents may be used alone or in combination of two or more (in the form of a mixed solvent).

[0107] The concentration of the first monomer in the first monomer solution is not particularly limited. For example, the concentration of the first monomer in the first monomer solution is preferably 0.01 to 20% by mass, more preferably 0.05 to 15% by mass, particularly preferably 0.1 to 10% by mass, and most preferably 1 to 5% by mass. When the concentration of the first monomer is within the above range, the resulting antithrombogenic layer can fully exhibit the effects of the present invention.

[0108] Next, the first monomer solution prepared as described above is brought into contact with the plasma-irradiated substrate. Here, the specific method of "contacting" can be appropriately selected from conventionally known methods such as a method of applying the first monomer solution to the surface of the substrate or a method of immersing the substrate in the first monomer solution. Among these, the immersion method is preferred because it is easy to operate.

[0109] When an antithrombotic layer is formed on a thin and narrow inner surface of an artificial blood vessel, a stent graft, a covered stent, a catheter, etc., the substrate may be immersed in the first monomer solution and degassed by reducing the pressure inside the system. By reducing the pressure and degassing, the solution can be quickly penetrated into the thin and narrow inner surface, and the bonding of the first monomer to the substrate surface can be promoted.

[0110] Alternatively, the contact by the immersion method may be performed while stirring the first monomer solution. This further promotes contact between the first monomer solution and the workpiece, such as an artificial blood vessel or a stent graft. The stirring can be performed using a known device, such as a stirrer, an orbital shaker, a rotary shaker, or a paint shaker. The stirring conditions are not particularly limited. From the viewpoint of more efficient contact between the workpiece, such as an artificial blood vessel, and the first monomer solution, the stirring speed is, for example, 200 to 600 rpm, preferably 300 to 400 rpm. From the same viewpoint, the immersion time (stirring time) is, for example, 0.5 to 24 hours, preferably 1 to 12 hours. The temperature of the first monomer solution during contact by the immersion method may be around room temperature (e.g., 20 to 40°C), but it may also be heated (e.g., 40 to 60°C).

[0111] Furthermore, when an antithrombogenic layer is to be formed only on a portion of a substrate, the first monomer can be bonded to a desired surface portion of the substrate by immersing only a portion of the substrate in the first monomer solution.

[0112] When it is difficult to immerse only a portion of the substrate in the first monomer solution, the surface portion of the substrate that does not require the formation of an antithrombogenic layer can be protected (coated, etc.) with a suitable detachable (removable) member or material in advance, and the substrate can then be immersed in the first monomer solution. The protective member (material) covering the surface portion of the substrate that does not require the formation of an antithrombogenic layer can then be removed, thereby bonding the first monomer to the desired surface portion of the substrate. However, the present invention is not limited to these formation methods, and any conventionally known method can be appropriately used to bond the first monomer. For example, when it is difficult to immerse only a portion of the substrate in the first monomer solution, other coating methods (e.g., a method of applying the first monomer solution to a predetermined surface portion of a medical device using an application device such as a sprayer, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor knife) may be used instead of the immersion method. When the structure of a cylindrical medical device requires that both the outer and inner surfaces of the device have an antithrombogenic layer, the immersion method (dipping method) is preferably used, since the first monomer can be bonded to both the outer and inner surfaces at the same time.

[0113] In this step, if necessary, the substrate may be washed after contact with the first monomer. The method of washing is not particularly limited, and can be performed by washing with an appropriate solvent (e.g., ultrasonic washing, immersion in a washing solvent, pouring the washing solvent, etc.). The washing time is not particularly limited, but is preferably 1 to 60 minutes. If necessary, the above washing treatment may be repeated multiple times (e.g., 2 to 5 times).

[0114] <<First Antithrombogenic Monomer Contacting Step>> In this step, the first antithrombogenic monomer is brought into contact with the substrate after the contact with the first monomer, whereby the ethylenically unsaturated group derived from the first monomer bonded to the substrate and the first antithrombogenic monomer are polymerized to form an antithrombogenic layer on the surface of the substrate.

[0115] In this step, a specific method for contacting the first antithrombotic monomer with the substrate after contacting the first monomer may be either a method in which the first antithrombotic monomer is directly contacted with the substrate after contacting the first monomer, or a method in which the first antithrombotic monomer is dissolved in a solvent to prepare a first antithrombotic monomer solution, and then the first antithrombotic monomer solution is contacted with the substrate after contacting the first monomer. From the viewpoint of forming a more uniform antithrombotic layer, it is preferable to employ the latter method in which the first antithrombotic monomer solution is contacted with the substrate after contacting the first monomer.

[0116] The solvent (polymerization solvent) used in preparing the first antithrombotic monomer solution is not particularly limited as long as it can dissolve the first antithrombotic monomer and a suitable polymerization initiator. Examples include, but are not limited to, one or more solvents selected from water (e.g., reverse osmosis water (RO water), pure water, ion-exchanged water, distilled water, etc.); alcohols such as ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, t-butanol, ethylene glycol, diethylene glycol, propylene glycol, and dipropylene glycol; and organic solvents such as chloroform, tetrahydrofuran, acetone, dioxane, and benzene. The concentration of the first antithrombotic monomer contained in the first antithrombotic monomer solution is not particularly limited, but setting the concentration relatively high can increase the weight-average molecular weight of the resulting polymer. For example, the concentration (total concentration) of the antithrombotic monomer in the first antithrombotic monomer solution is preferably 10% by mass or more, and more preferably 15% by mass or more. The upper limit of the monomer concentration (total concentration) is not particularly limited, but is, for example, equal to or lower than the saturated concentration, for example, equal to or lower than 70% by mass, and preferably equal to or lower than 50% by mass.

[0117] In this step, the first antithrombotic monomer is brought into contact with the substrate after contacting with the first monomer, whereby the ethylenically unsaturated group derived from the first monomer bonded to the substrate and the first antithrombotic monomer undergo polymerization (graft polymerization). The specific method of polymerization is not particularly limited, and conventionally known polymerization methods, such as radical polymerization and polymerization using a macroinitiator, can be applied. Examples of polymerization methods include (i) a method in which the first antithrombotic monomer and a suitable polymerization initiator are dissolved in a polymerization solvent, and the resulting polymerization reaction solution is heated to carry out the polymerization reaction; and (ii) a method in which the first antithrombotic monomer is dissolved in a polymerization solvent, and the resulting solution is mixed with a separately prepared polymerization initiator solution to prepare a polymerization reaction solution, and then the polymerization reaction is carried out. From the viewpoint of ease of operation, method (i) is preferred.

[0118] The polymerization reaction solution may be degassed before the polymerization reaction, for example, by bubbling with an inert gas such as nitrogen gas or argon gas for about 5 minutes to 1 hour.

[0119] The polymerization initiator used here is not particularly limited, and known initiators can be used. Preferably, a radical polymerization initiator is used because of its excellent polymerization stability. Specific examples include persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; and peroxides such as hydrogen peroxide, t-butyl peroxide, methyl ethyl ketone peroxide, 3-hydroxy-1,1-dimethylbutyl peroxyneodecanoate, α-cumyl peroxyneodecanoate, 1,1,3,3-tetrabutyl peroxyneodecanoate, t-butyl peroxyneodecanoate, t-butyl peroxyneoheptanoate, t-butyl peroxypivalate, t-amyl peroxyneodecanoate, t-amyl peroxypivalate, di(2-ethylhexyl)peroxydicarbonate, and di(s-butyl)peroxydicarbonate. azo compounds such as azobisisobutyronitrile (AIBN), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride, 2,2'-azobis[2-(2-imidazolin-2-yl)propane]disulfate dihydrate, 2,2'-azobis(2-methylpropionamidine)dihydrochloride, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]tetrahydrate, and 4,4'-azobis(4-cyanovaleric acid). The polymerization initiators may be used alone or in combination of two or more.

[0120] Furthermore, for example, the radical polymerization initiator may be used in combination with a reducing agent such as sodium sulfite, sodium bisulfite, or ascorbic acid to form a redox initiator. The amount (addition amount) of the polymerization initiator is preferably 0.01 to 5 mass %, more preferably 0.05 to 3 mass %, relative to 100 mass % of the total first antithrombotic monomer. Alternatively, the amount (addition amount) of the polymerization initiator is preferably 0.01 to 5 mol, more preferably 0.05 to 3 mol, relative to 100 mol of the total first antithrombotic monomer. Such an amount (addition amount) of the polymerization initiator allows the polymerization reaction to proceed efficiently.

[0121] When the method (ii) is used, the solvent in which the polymerization initiator is dissolved in advance (the solvent for the polymerization initiator solution) is not particularly limited as long as it can dissolve the polymerization initiator, and examples thereof include the same solvents as the polymerization solvent. The solvent for the polymerization initiator solution may be the same as or different from the polymerization solvent, but is preferably the same solvent as the polymerization solvent in consideration of ease of control of polymerization, etc.

[0122] By heating the polymerization reaction solution prepared as described above, the ethylenically unsaturated group derived from the first monomer bonded to the base material and the first antithrombotic monomer can be polymerized. Here, as the polymerization method, for example, in addition to the above-mentioned radical polymerization, known polymerization methods such as anionic polymerization and cationic polymerization can be used, but in consideration of ease of operation, radical polymerization is preferably used.

[0123] The polymerization conditions are not particularly limited as long as they allow the ethylenically unsaturated group derived from the first monomer bonded to the base material to polymerize with the first antithrombotic monomer. For example, the polymerization temperature is preferably 30 to 150°C, more preferably 40 to 100°C. The polymerization time is preferably 30 minutes to 30 hours, more preferably 1 to 10 hours. Under such conditions, the polymerization reaction can proceed efficiently.

[0124] During the polymerization, a chain transfer agent, a polymerization rate adjuster, a surfactant, and other additives may be used as needed.

[0125] The environment in which the polymerization reaction is carried out is not particularly limited, and the reaction can be carried out in air or in an inert gas atmosphere such as nitrogen gas or argon gas, but is preferably carried out in a nitrogen gas atmosphere. The reaction solution may be stirred during the polymerization reaction.

[0126] In this step, if necessary, the substrate may be washed after contact with the first antithrombotic monomer. The method of washing is not particularly limited, and can be performed by washing with an appropriate solvent (e.g., ultrasonic washing, immersion in a washing solvent, pouring the washing solvent, etc.). The washing time is not particularly limited, but is preferably 1 to 60 minutes. If necessary, the above washing treatment may be repeated multiple times (e.g., 2 to 5 times).

[0127] <<Copolymer Contacting Step>> In this step, the copolymer is brought into contact with the substrate after contacting the first antithrombotic monomer. As a result, a carboxyl group derived from the antithrombotic monomer bound to the substrate reacts with an amino group derived from the copolymer (dehydration condensation reaction) to form an amide bond (—C(═O)—NH—), thereby fixing the structural unit C derived from the copolymer.

[0128] First, the synthesis method of the copolymer used in this step will be described. The copolymer can be synthesized by known polymerization methods (radical polymerization, polymerization using a macroinitiator, polycondensation). For example, when each constituent unit is arranged randomly (the copolymer is a random copolymer), (i) a method in which the second monomer, the second antithrombotic monomer, an appropriate polymerization initiator, and monomers constituting other constituent units added as needed are dissolved in a polymerization solvent, and the resulting polymerization reaction solution is heated to carry out the polymerization reaction; (ii) a method in which the second monomer, the second antithrombotic monomer, and monomers constituting other constituent units added as needed are dissolved in a polymerization solvent, and the resulting solution is mixed with a separately prepared polymerization initiator solution to prepare a polymerization reaction solution, and the polymerization reaction is carried out. From the viewpoint of ease of operation, method (i) is preferred.

[0129] Here, the polymerization solvent is not particularly limited as long as it can dissolve the second monomer, the second antithrombogenic monomer, and a suitable polymerization initiator, as well as the monomers constituting other structural units added as needed. Examples of the polymerization solvent include, but are not limited to, one or more selected from water (reverse osmosis water (RO water), pure water, ion-exchanged water, distilled water, etc.); alcohols such as ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, t-butanol, ethylene glycol, diethylene glycol, propylene glycol, and dipropylene glycol; and organic solvents such as chloroform, tetrahydrofuran, acetone, dioxane, and benzene. The concentrations of the second monomer and second antithrombogenic monomer contained in the polymerization reaction solution, as well as the monomers constituting other structural units added as needed, are not particularly limited. However, by setting the concentrations relatively high, the weight-average molecular weight of the resulting copolymer can be increased. For example, the concentration (total concentration) of the second monomer, the second antithrombotic monomer, and the monomers constituting other constituent units added as needed in the polymerization reaction solution is preferably 10% by mass or more, more preferably 15% by mass or more. The upper limit of the monomer concentration (total concentration) is not particularly limited, but is, for example, the saturated concentration or less, for example, 70% by mass or less, preferably 50% by mass or less.

[0130] In the polymerization reaction solution, the mixing ratio of the second monomer and the second antithrombogenic monomer is preferably adjusted to the above-mentioned preferred composition (molar ratio).

[0131] The polymerization reaction solution may be degassed before the polymerization reaction, for example, by bubbling with an inert gas such as nitrogen gas or argon gas for about 5 minutes to 1 hour.

[0132] The polymerization initiator used here is not particularly limited, and known initiators can be used. Preferably, a radical polymerization initiator is used because of its excellent polymerization stability. Specific examples include persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; and peroxides such as hydrogen peroxide, t-butyl peroxide, methyl ethyl ketone peroxide, 3-hydroxy-1,1-dimethylbutyl peroxyneodecanoate, α-cumyl peroxyneodecanoate, 1,1,3,3-tetrabutyl peroxyneodecanoate, t-butyl peroxyneodecanoate, t-butyl peroxyneoheptanoate, t-butyl peroxypivalate, t-amyl peroxyneodecanoate, t-amyl peroxypivalate, di(2-ethylhexyl)peroxydicarbonate, and di(s-butyl)peroxydicarbonate. azo compounds such as azobisisobutyronitrile (AIBN), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride, 2,2'-azobis[2-(2-imidazolin-2-yl)propane]disulfate dihydrate, 2,2'-azobis(2-methylpropionamidine)dihydrochloride, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]tetrahydrate, and 4,4'-azobis(4-cyanovaleric acid). Among these, the polymerization initiator is preferably an azo compound, more preferably an azo compound having a hydroxyl group or a carboxyl group at its terminal, further preferably 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]tetrahydrate, or 4,4'-azobis(4-cyanovaleric acid), and particularly preferably 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]tetrahydrate or 4,4'-azobis(4-cyanovaleric acid).The polymerization initiators may be used alone or in combination of two or more.

[0133] Furthermore, for example, the radical polymerization initiator may be used in combination with a reducing agent such as sodium sulfite, sodium bisulfite, or ascorbic acid to form a redox initiator. The amount (addition amount) of the polymerization initiator is preferably 0.01 to 5 mass %, more preferably 0.05 to 3 mass %, relative to 100 mass % of the total of the second monomer, the second antithrombotic monomer, and the monomers constituting the other structural units. Alternatively, the amount (addition amount) of the polymerization initiator is preferably 0.1 to 5 mol, more preferably 0.5 to 3 mol, relative to 100 mol of the total of the second monomer, the second antithrombotic monomer, and the monomers constituting the other structural units. Such an amount (addition amount) of the polymerization initiator allows for more efficient production of the copolymer.

[0134] When the method (ii) is used, the solvent in which the polymerization initiator is dissolved in advance (the solvent for the polymerization initiator solution) is not particularly limited as long as it can dissolve the polymerization initiator, and examples thereof include the same solvents as the polymerization solvent. The solvent for the polymerization initiator solution may be the same as or different from the polymerization solvent, but is preferably the same solvent as the polymerization solvent in consideration of ease of control of polymerization, etc.

[0135] By heating the polymerization reaction solution prepared as described above, the second monomer, the second antithrombotic monomer, and the monomers constituting other structural units can be copolymerized. Here, as the polymerization method, for example, in addition to the above-mentioned radical polymerization, known polymerization methods such as anionic polymerization and cationic polymerization can be used, but in consideration of ease of operation, radical polymerization is preferably used.

[0136] The polymerization conditions are not particularly limited as long as they allow the second monomer, the second antithrombotic monomer, and the monomers constituting the other structural units to be polymerized. For example, the polymerization temperature is preferably 30 to 150°C, more preferably 40 to 100°C. The polymerization time is preferably 30 minutes to 30 hours, more preferably 1 to 10 hours. Under such conditions, the copolymer can be produced more efficiently.

[0137] During the polymerization, a chain transfer agent, a polymerization rate adjuster, a surfactant, and other additives may be used as needed.

[0138] The environment in which the polymerization reaction is carried out is not particularly limited, and the reaction can be carried out in the air or in an inert gas atmosphere such as nitrogen gas or argon gas, etc. The reaction solution may be stirred during the polymerization reaction.

[0139] After polymerization, the copolymer is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction, and particularly preferably by reprecipitation.

[0140] The purified copolymer can be dried by any method, such as freeze-drying, drying under reduced pressure (vacuum drying), spray drying, or heat drying. However, freeze-drying or drying under reduced pressure (vacuum drying) is preferred from the viewpoint of having little effect on the physical properties of the copolymer.

[0141] Furthermore, for example, when the structural units are arranged in blocks (the copolymer is a block copolymer), a living radical polymerization method or a polymerization method using a macroinitiator is preferably used. The living radical polymerization method is not particularly limited, but for example, methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, etc., as well as atom transfer radical polymerization (ATRP) methods, etc., can be applied in the same manner or with appropriate modifications. Furthermore, in a polymerization method using a macroinitiator, for example, a copolymer can be prepared by preparing a macroinitiator having a second monomer and a radically polymerizable group such as a peroxide group, and then polymerizing the macroinitiator with the second antithrombotic monomer in a polymerization solvent.

[0142] Next, the step of contacting the copolymer with the substrate after contacting the first antithrombotic monomer will be described. In this step, a solution containing the copolymer, a solvent, and, if necessary, other components (also referred to simply as a "coating liquid" in this specification) is prepared, and the coating liquid is applied to the substrate, causing a dehydration condensation reaction between the carboxyl groups derived from the first antithrombotic monomer and the amino groups in the copolymer to form amide groups.

[0143] Other components contained in the coating solution include a dehydration condensation agent. In particular, the coating solution is used to condense the carboxyl group (-COOH) of the first antithrombogenic monomer bonded to the substrate and the amino group (-NH ２ From the viewpoint of promoting the condensation reaction with the carboxyl group (—COOH), it is preferable that the coating liquid further contains a dehydration condensation agent. The dehydration condensation agent is not particularly limited as long as it is water-soluble and capable of reacting with a carboxyl group (—COOH) in an aqueous solution. Specific examples include triazine condensation agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), a water-soluble salt of 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC).

[0144] When the coating liquid further contains a dehydrating condensation agent, the amount of the dehydrating condensation agent in the coating liquid is not particularly limited, but it is preferable that the agent is present in excess relative to the copolymer. For example, the dehydrating condensation agent in the coating liquid is present in an amount of more than 1 mole and not more than 8 moles, preferably 1.5 to 7 moles, more preferably 3 to 5 moles, relative to 1 mole of the copolymer. If the amount of the dehydrating condensation agent is within the above range, the amino groups (—NH ２ The dehydration condensation agent may be used alone or in combination of two or more kinds.

[0145] The solvent used to prepare the coating liquid is not particularly limited and is appropriately selected depending on the type of copolymer (and other components, if used). From the viewpoint of high solubility, water (reverse osmosis water (RO water), pure water, ion-exchanged water, distilled water, etc.); alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and organic solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), dimethyl sulfoxide, N,N-dimethylformamide (DMF), acetone, dioxane, and benzene are preferably used. These solvents may be used alone or in combination of two or more (in the form of a mixed solvent).

[0146] The concentration of the copolymer in the coating solution is not particularly limited. For example, the concentration of the copolymer in the coating solution is preferably 0.01 to 20% by mass, more preferably 0.05 to 15% by mass, and particularly preferably 0.1 to 10% by mass. If the concentration of the copolymer is within the above range, the resulting antithrombogenic layer can fully exhibit the effects of the present invention. In addition, the viscosity of the solution falls within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, even if the concentration is outside the above range, it can be used sufficiently as long as it does not affect the effects of the present invention.

[0147] The method for applying (coating) the coating liquid to the surface of the substrate after contact with the first antithrombotic monomer is not particularly limited, and conventionally known methods can be applied, such as application / printing, immersion (dipping, dip coating), spraying, spin coating, mixed solution-impregnated sponge coating, bar coating (e.g., wire bar), die coating, reverse coating, comma coating, gravure coating, doctor knife, etc. Of these, the immersion (dipping, dip coating) and bar coating methods are preferred, and the immersion method is more preferred.

[0148] When an antithrombogenic layer is formed on a thin and narrow inner surface of an artificial blood vessel, a stent graft, a covered stent, etc., the substrate may be immersed in the coating solution and degassed by reducing the pressure in the system. By reducing the pressure and degassing, the solution can be quickly penetrated into the thin and narrow inner surface, and the formation of the antithrombogenic layer can be promoted.

[0149] Alternatively, the application (coating) may be carried out while stirring the coating liquid. This can further promote contact between the coating liquid and the workpiece, such as an artificial blood vessel. The stirring can be carried out using known devices such as an orbital shaker, rotary shaker, or paint shaker. The stirring conditions are not particularly limited. From the viewpoint of more efficient contact between the workpiece, such as an artificial blood vessel, and the coating liquid, the stirring speed is, for example, 100 to 800 rpm, preferably 200 to 700 rpm. From the same viewpoint, the stirring time is, for example, 1 to 20 hours. The stirring temperature may be around room temperature (e.g., 20 to 40°C), but heating may be used as long as it is lower than the boiling point of the solvent used.

[0150] The amount of coating liquid to be applied is preferably selected so that the thickness (dry film thickness) of the resulting antithrombogenic layer falls within the above range.

[0151] In this step, the antithrombogenic layer may be washed, if necessary. The washing method is not particularly limited, but may include immersing the antithrombogenic layer in a washing solvent, pouring the washing solvent over the antithrombogenic layer, or a combination of these. The washing solvent used here is not particularly limited as long as it does not dissolve the antithrombogenic layer. Water (e.g., ion-exchanged water, distilled water, RO water, filtered water, sterilized water, purified water, etc.) or warm water is preferably used. The temperature of the washing water is not particularly limited, but is preferably 20°C to 80°C. The washing time (the time during which the washing solvent is brought into contact with the antithrombogenic layer) is not particularly limited, but is preferably 1 to 60 minutes. After the washing step, a drying step may be further carried out. The drying method and drying conditions (temperature, time, etc.) are not particularly limited, and conventionally known methods can be used.

[0152] By the above method, a medical device with excellent antithrombotic properties can be produced.

[0153] [Uses of Medical Devices] The medical device according to the present invention has excellent antithrombotic properties. Examples of medical devices according to the present invention include implantable artificial organs and treatment instruments, extracorporeal circulation artificial organs, catheters, guide wires, etc. Among these, the medical device is preferably an intravascular device, and specific examples include artificial blood vessels, stents, stent grafts, covered stents, artificial valves, valve clips, and auxiliary circulation pump catheters. The medical device according to one embodiment of the present invention is an artificial blood vessel, a stent graft, a covered stent, or a catheter. Other examples of medical devices include the following: Specific examples include implantable medical devices such as artificial trachea, artificial skin, and artificial pericardium; artificial organ systems such as artificial heart systems, artificial lung systems, artificial heart-lung systems, artificial kidney systems, artificial liver systems, and immunoregulatory systems; catheters inserted or placed in blood vessels such as indwelling needles, IVH catheters, drug solution administration catheters, thermodilution catheters, angiography catheters, vasodilator catheters, dilators, and introducers; guide wires and stylets for these catheters; and catheters inserted or placed in biological tissues other than blood vessels, such as gastric catheters, nutrition catheters, enteral feeding (ED) tubes, urethral catheters, urinary catheters, balloon catheters, and various suction catheters and drainage catheters, including endotracheal suction catheters.

[0154] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, the terms "parts" and "%" may be used, but unless otherwise specified, they represent "parts by mass" or "% by mass." Furthermore, unless otherwise specified, each operation was performed at room temperature (25°C).

[0155] <Synthesis of methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) random copolymer (p(MEA-APMA(14 / 1)))> (1) Preparation A water bath was filled with tap water, and the water surface was covered with a polypropylene (PP) ball. Next, the water bath was placed on a magnetic stirrer, and the temperature was set to 80°C.

[0156] (2) Polymerization of p(MEA-APMA) To a 250 mL three-neck flask, 2.00 g (11 mmol) of N-(3-aminopropylmethacrylamide) hydrochloride (APMA) (Combi-Blocks), 20.24 g (156 mmol) of 2-methoxyethyl acrylate (MEA), 0.44 g (1.6 mmol) of 4,4'-azobis(4-cyanovaleric acid) (ACVA) (Fujifilm Wako Pure Chemical Industries, Ltd.) as a polymerization initiator, 30 mL of 1,4-dioxane, and 20 mL of RO water were added. A stirrer was placed in the three-neck flask, and the mixture was stirred at room temperature (25°C) until all reagents were dissolved. Nitrogen bubbling was performed through the end neck of the three-neck flask for 30 minutes. A condenser was attached to the center neck of the three-neck flask, and cooling water was allowed to flow through it. A thermocouple was inserted through the remaining neck of the three-neck flask to record the solution temperature during the reaction. The three-necked flask was immersed in a water bath set at 80°C and reacted for 3 hours. After the reaction had continued for the predetermined time, the three-necked flask was removed from the water bath and cooled to room temperature (25°C). This yielded a reaction solution containing p(MEA-APMA).

[0157] (3) Purification of p(MEA-APMA) 250 mL each of hexane and isopropyl alcohol (IPA) was added to a 1-L beaker. The reaction solution obtained in 1-2 above was poured into this 1-L beaker, stirred for 15 minutes, and the supernatant was gently removed. The precipitated polymer was dissolved in a 4:1 (v / v) tetrahydrofuran (THF)-ethanol mixed solution (THF = 40 mL, ethanol = 10 mL) (Polymer Solution 1). A 70:30 (v / v) hexane-IPA solution (hexane = 350 mL, IPA = 150 mL) was further added to this polymer solution 1, and the mixture was stirred for 15 minutes to precipitate the polymer. The supernatant was gently removed. The precipitated polymer was again dissolved in a 4:1 (v / v) tetrahydrofuran (THF)-ethanol mixed solution (THF = 40 mL, ethanol = 10 mL) (Polymer Solution 2). Furthermore, 500 mL of hexane was added to this polymer solution 2, and the mixture was stirred for 20 minutes to precipitate the polymer, after which the supernatant was gently removed. The precipitated polymer was dissolved in a small amount (30 mL) of ethanol and transferred to a plastic cup. The plastic cup was placed in a draft chamber, and the solvent was thoroughly evaporated in the draft chamber. The mixture was then vacuumed at room temperature (25°C) for 20 hours to dry the polymer. This yielded an MEA-APMA random copolymer (MEA:APMA = 14:1 (molar ratio)) [p(MEA-APMA)].

[0158] <Formation of an antithrombogenic layer on a PET stent graft> (1) Preparation of a PET stent graft base material A polyethylene terephthalate (PET) stent graft (thin-diameter portion length 135 mm, diameter 8 mm) was cut into a length of 2 cm. The cut PET stent graft was immersed in ethanol for 1 minute. This procedure was repeated three times for cleaning, and a PET stent graft base material (PET SG (untreated with plasma), Comparative Example 1) was obtained.

[0159] (2) Plasma treatment of PET stent graft substrate The cleaned PET stent graft was dried overnight at room temperature in a fume hood and then placed in a plasma irradiation device (Pico Full PC, manufactured by DIENER ELECTRONIC, low-pressure type) and subjected to plasma irradiation (argon ionized gas plasma irradiation) for 3 minutes under the following conditions: pressure: 0.3 mbar, power: 50%, introduced gas: 100% Ar gas, LF output: 200 W, gas flow rate: 15 sccm. After plasma irradiation, the PET stent graft was removed into the atmosphere and allowed to stand for 30 minutes. This resulted in a PET stent graft substrate with a plasma-treated surface (PET SG (after plasma treatment)).

[0160] (3) Bonding of Glycidyl Methacrylate (GMA) 0.435 mL (3.3 mmol) of glycidyl methacrylate (GMA) (Fujifilm Wako Pure Chemical Industries, Ltd.) and 33 mL of ethanol were placed in a recovery flask, and the reagent was dissolved. Nitrogen gas was introduced into the reagent solution in the recovery flask using a glass tube for 5 minutes, and the gas in the system was replaced with nitrogen gas. The plasma-treated PET stent graft substrate was placed in this reagent solution, and nitrogen gas was introduced for another 5 minutes. The flask was then covered with a rubber stopper. The recovery flask was placed in a 37°C water bath and allowed to react for 4 hours. The PET stent graft was then removed, and the unreacted GMA was washed with ethanol for 1 hour and dried at room temperature. This resulted in a GMA-bonded PET stent graft (PET SG-GMA).

[0161] (4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) 5.91 g (27.45 mmol) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA), 5.7 mg (0.018 mmol) of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70, Fujifilm Wako Pure Chemical Industries, Ltd.), and 30 mL of ethanol were placed in a beaker and stirred at room temperature until all reagents were dissolved. The reagent solution in the beaker was transferred to an eggplant flask, and nitrogen gas was introduced using a glass tube for 5 minutes to replace the gas in the system with nitrogen gas. A GMA-bonded PET stent graft (PET SG-GMA) was placed in this reagent solution, and nitrogen gas was introduced for another 5 minutes. The mouth of the eggplant flask was then covered with a rubber stopper. The recovery flask was placed in a 37°C water bath and allowed to react for 4 hours. The PET stent graft was then removed and washed by immersion in ethanol to remove any unreacted CBA, followed by drying at room temperature. This resulted in a PET stent graft in which CBA had been polymerized via GMA (PET SG-GMA-pCBA).

[0162] (5) Bonding of methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) copolymer (p(MEA-APMA)) 1.248 g (4.5 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (dehydration condensation agent) was dissolved in 1.5 mL of RO water to prepare a DMT-MM solution. 200 mg (1.5 mmol) of the methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) copolymer (p(MEA-APMA)) synthesized above was dissolved in 20 mL of RO water to prepare a p(MEA-APMA) solution. This p(MEA-APMA) solution was transferred to a 50 mL Falcon (registered trademark, the same applies hereinafter) tube, and a PET stent graft in which CBA was polymerized via GMA (PET SG-GMA-pCBA) was added. Thereafter, the DMT-MM solution was added dropwise, and the mixture in the Falcon tube was immediately stirred using an orbital shaker. The stirring was carried out at a speed of 400 rpm for 3 hours. After stirring, the Falcon tube was removed from the orbital shaker and allowed to stand overnight at room temperature to confirm the primary amino group (-NH ２ ) was reacted with the carboxyl group (—COOH) of CBA. The PET stent graft was removed from the Falcon tube and immersed in 50 mL of RO water for 5 minutes. This procedure was repeated three times to wash the PET stent graft, which was then removed from the RO water and allowed to stand at room temperature to dry. This resulted in a PET stent graft in which the MEA-APMA copolymer was fixed via the GMA and CBA polymer chains (PET SG-GMA-pCBA-p(MEA-APMA), Example 1).

[0163] <Blood Circulation Test 1> A blood circulation test was carried out by the following method for each of the PET SG (untreated with plasma, Comparative Example 1), PET SG-GMA-pCBA-p (MEA-APMA), and Example 1 prepared above, to evaluate antithrombotic properties.

[0164] (1) Preparation of Circulation Circuit A polyvinyl chloride (PVC) tube (Saitama Kasei Kogyo Co., Ltd., SCB04T070, size: 6.0 (inner diameter) x 9.0 (outer diameter) mm, 9.5 x 14.2 mm) and a variant connector (Saneki Chemical Industry Co., Ltd., CB00X320N) were coated with an antithrombotic agent by passing a 0.5% by mass solution of polymethoxyethyl acrylate (PMEA) in methanol. A sample for evaluation was inserted into the PVC tube to prepare a circuit (Figure 4). To prevent the stent graft from shifting position during blood circulation, both ends of the stent graft were narrowed with cable ties from the outside of the tube, forming a blood circulation circuit for the stent graft.

[0165] (2) Blood Collection: 1 mL of heparin (10,000 u / 10 mL) and 10 mL of PBS were added to a 1 L blood collection bottle. Pig blood was collected up to the 1000 mL line of the blood collection bottle to obtain 1 L of blood with a heparin concentration of 1 u / mL. After collection, the blood was filtered on-site using a built-in filter unit (Filter unit: AS ONE Corporation, FH-PP47; Mesh: SEFER Corporation, HC-58) and loaded into a Terumo separation bag (Terumo Corporation, BB-T020CJ). The bag was crushed to remove as much air as possible. The tubing connected to the bag was tied and sealed, and the blood was transported to the laboratory.

[0166] (3) Measurement of activated clotting time (ACT) of blood at the start of the experiment. An operating adapter (TC-MP, manufactured by Terumo Corporation) was inserted into the central opening of the bag. An indwelling needle (SR-OT1451C, manufactured by Terumo Corporation) was inserted into the operating adapter. The inner needle was removed, leaving the catheter in place, and a three-way stopcock (TS-TR2K, manufactured by Terumo Corporation) was connected to the catheter hub. A 5 mL Terumo syringe was filled with blood, and the syringe was primed once. After priming, blood was collected into the syringe. An ACT measurement cartridge (JACT-LR, manufactured by Heiwa Bussan Co., Ltd.) was inserted into a Hemochron (Hemochron Signature Elite, manufactured by Heiwa Bussan Co., Ltd.), and 50 μL of the collected blood was dripped. The ACT displayed on the screen was recorded. The above measurements confirmed that the ACT was approximately 200 sec, and the blood was used in the experiment.

[0167] (4) Blood Circulation Test A 5 mL Terumo syringe was filled with 4 mL of blood and then connected to the catheter hub of an indwelling needle. Blood was filled into the blood circulation circuit through the catheter, and both ends of the circuit were connected (blood filling rate: 35%). The blood-filled circuit was placed in a rotating device installed in an incubator at 40°C. The rotating device was turned on, and the blood was circulated at 20 rpm for 2 hours.

[0168] (5) Fixation and Observation of Sample After blood circulation, the power of the rotating device was turned off, and the circulated blood was collected in a pipette tube with the tip cut off. The evaluation sample was removed from the circuit and lightly washed with physiological saline. The washed sample was fixed by immersing it in a glutaraldehyde solution diluted to 1% by mass (Kanto Chemical Industry Co., Ltd., 17502-72) at 4°C for 12 hours or more. The sample was then removed from the glutaraldehyde solution and washed with RO water. After drying at room temperature, the appearance was observed. Photographs of the appearance of each sample of Comparative Example 1 and Example 1 are shown in Figures 5 and 6, respectively.

[0169] (6) Results As shown in FIGS. 5 and 6, it was confirmed that the PET SG-GMA-pCBA-p (MEA-APMA) of Example 1 significantly suppressed thrombus formation compared to the PET SG (untreated with plasma) of Comparative Example 1.

[0170] <Formation of an antithrombogenic layer on an ePTFE artificial blood vessel> (1) Preparation of an ePTFE artificial blood vessel base material An expanded polyethylene tetrafluoroethylene (ePTFE) artificial blood vessel (manufactured by Gore Japan, LLC, product name: Gore-Tex (registered trademark) EPTFE Graft II, SGS-054L) was cut into a length of 5 cm. The cut ePTFE artificial blood vessel was washed by leaving it to stand in ethanol to obtain an ePTFE artificial blood vessel base material (ePTFEg (untreated with plasma), Comparative Example 2).

[0171] (2) Plasma treatment of ePTFE artificial blood vessel substrate The washed ePTFE artificial blood vessel was placed in a plasma irradiation device (Pico Full PC, manufactured by DIENER ELECTRONIC, low-pressure type) and subjected to plasma irradiation (argon ionized gas plasma irradiation) for 3 minutes under the following conditions: pressure: 0.3 mbar, power: 50%, introduced gas: 100% Ar gas, LF output: 200 W, gas flow rate: 15 sccm. After plasma irradiation, the ePTFE artificial blood vessel was removed into the atmosphere and allowed to stand for 30 minutes. This resulted in the production of an ePTFE artificial blood vessel substrate (ePTFEg (after plasma treatment)) with a plasma-treated surface.

[0172] (3) Bonding of Glycidyl Methacrylate (GMA) 0.145 mL (1.1 mmol) of glycidyl methacrylate (GMA) (Fujifilm Wako Pure Chemical Industries, Ltd.) and 11 mL of ethanol were placed in a glass bottle, and the reagent was dissolved. The reagent solution in the glass bottle was transferred to a glass tube, and nitrogen gas was introduced into the glass tube for 5 minutes to replace the gas in the system with nitrogen gas. The plasma-treated ePTFE artificial blood vessel substrate was placed in this reagent solution, and nitrogen gas was introduced through the glass tube for 5 minutes, after which the glass tube was covered with a rubber stopper. The glass bottle was placed in a 37°C water bath and allowed to react for 4 hours. The ePTFE artificial blood vessel was then removed, and the unreacted GMA was washed with ethanol for 1 hour and dried at room temperature. This resulted in an ePTFE artificial blood vessel bonded with GMA (ePTFEg-GMA).

[0173] (4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) 1.97 g (9.15 mmol) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA), 1.9 mg (0.006 mmol) of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70, Fujifilm Wako Pure Chemical Industries, Ltd.), and 10 mL of ethanol were placed in a glass bottle and stirred at room temperature until all the reagents were dissolved. The reagent solution in the glass bottle was transferred to a glass tube, and nitrogen gas was introduced into the glass tube for 5 minutes to replace the gas in the system with nitrogen gas. A GMA-bonded ePTFE artificial blood vessel (ePTFEg-GMA) was placed in this reagent solution, and nitrogen gas was introduced through the glass tube for 5 minutes. The glass tube was then covered with a rubber stopper. The glass bottle was placed in a water bath at 37°C and allowed to react for 4 hours. The ePTFE artificial blood vessel was then removed and washed by immersing it in ethanol to remove unreacted CBA. This yielded an ePTFE artificial blood vessel in which CBA had been polymerized via GMA (ePTFEg-GMA-pCBA, Comparative Example 3).

[0174] (5) Bonding of methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) copolymer (p(MEA-APMA)) 1.248 g (4.5 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (dehydration condensation agent) was dissolved in 1.5 mL of RO water to prepare a DMT-MM solution. 200 mg (1.5 mmol) of the methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) copolymer (p(MEA-APMA)) synthesized above was dissolved in 20 mL of RO water to prepare a p(MEA-APMA) solution. This p(MEA-APMA) solution was transferred to a 50 mL Falcon (registered trademark, the same applies hereinafter) tube, and an ePTFE artificial blood vessel in which CBA was polymerized via GMA (ePTFEg-GMA-pCBA) was added. Thereafter, the DMT-MM solution was added dropwise, and the mixture in the Falcon tube was immediately stirred using an orbital shaker. The stirring was carried out at a speed of 400 rpm for 3 hours. After stirring, the Falcon tube was removed from the orbital shaker and allowed to stand overnight at room temperature to confirm the primary amino group (-NH) of the p(MEA-APMA) copolymer. ２ ) was reacted with the carboxyl group (—COOH) of CBA. The ePTFE artificial blood vessel was removed from the Falcon tube and immersed in 50 mL of RO water for 5 minutes. This procedure was repeated three times to wash the ePTFE artificial blood vessel, and then removed from the RO water and allowed to stand at room temperature to dry. This resulted in an ePTFE artificial blood vessel (ePTFEg-GMA-pCBA-p(MEA-APMA), Example 2) in which the MEA-APMA copolymer was immobilized via the GMA and CBA polymer chains.

[0175] <Blood Circulation Test 2> For each of the evaluation samples prepared above, ePTFEg (untreated with plasma, Comparative Example 2), ePTFEg-GMA-pCBA (Comparative Example 3), and ePTFEg-GMA-pCBA-p(MEA-APMA) (Example 2), a blood circulation test was carried out by the following method to evaluate antithrombotic properties.

[0176] (1) Preparation of Circulation Circuit A 0.5% by mass solution of polymethoxyethyl acrylate (PMEA) in methanol was passed through a polyvinyl chloride (PVC) tube (Φ4.7 mm) and a 4.7 mm straight connector to form an antithrombotic coating. Straight connectors were connected to both ends of the PVC tube, and an evaluation sample was connected between the connectors. To prevent kinking, the outside of the sample was reinforced with a Φ9.5 mm PVC tube. This was used as a blood circulation circuit for an artificial blood vessel.

[0177] (2) Obtaining blood This was done in the same manner as in "(2) Obtaining blood" in <Blood circulation test 1> above.

[0178] (3) Measurement of activated clotting time (ACT) for blood at the start of the experiment This was performed using the same method as "(3) Measurement of activated clotting time (ACT) for blood at the start of the experiment" in <Blood circulation test 1> above.

[0179] (4) Blood Circulation Test A 43 cm long circuit was filled with saline and placed in a rotating device installed in an incubator at 40°C. The rotating device was turned on, and saline was circulated at 20 rpm for 10 minutes, after which the saline was removed. Next, 4 mL of blood was filled into the circuit, and the circuit was placed in the rotating device installed in an incubator at 40°C. The rotating device was turned on, and blood was circulated at 20 rpm for 1 hour.

[0180] (5) Fixation and Observation of Samples After blood circulation, the rotating device was turned off and the circulated blood was collected. The evaluation samples were removed from the circuit and washed with physiological saline. After washing, the samples were fixed with a 1 (w / v)% glutaraldehyde PBS solution. After leaving the samples at 4°C overnight, the samples were washed with distilled water. Each sample was dried at room temperature, platinum was vapor-deposited, and then observed and photographed (1000x magnification) with a scanning electron microscope (SEM). SEM photographs of the samples from Comparative Examples 2 and 3 and Example 2 are shown in Figures 7 to 9.

[0181] (6) Results As shown in Figure 9, almost no thrombus formation was observed on the surface of ePTFEg-GMA-pCBA-p (MEA-APMA) of Example 2. On the other hand, thrombus formation was observed on a portion of the surface of ePTFEg-GMA-pCBA of Comparative Example 3 shown in Figure 8. This shows that the present invention can further improve the antithrombogenicity of medical devices compared to conventional techniques.

[0182] <Formation of antithrombogenic layer on silicone tube> (1) Preparation of silicone tube A silicone tube (manufactured by Hagitec Co., Ltd., product name: Labolan (registered trademark) silicone tube, outer diameter 2 mm, inner diameter 1 mm) was cut into a length of 10 cm. The cut silicone tube was washed by leaving it to stand in ethanol, and a silicone tube substrate (untreated with plasma) (Comparative Example 4) was obtained.

[0183] (2) Plasma treatment of silicone tube The cleaned silicone tube was set in a plasma irradiation device (Pico Full PC, manufactured by DIENER ELECTRONIC, low pressure type) and subjected to plasma irradiation (argon ionized gas plasma irradiation) for 3 minutes under the following conditions: pressure: 0.3 mbar, power: 50%, introduced gas: Ar gas 100%, LF output: 200 W, gas flow rate: 15 sccm. After plasma irradiation, the silicone tube was taken out into the atmosphere and left to stand for 30 minutes. This resulted in a silicone tube substrate (silicone tube (after plasma treatment)) with a plasma-treated surface.

[0184] (3) Bonding of Glycidyl Methacrylate (GMA) 0.145 mL (1.1 mmol) of glycidyl methacrylate (GMA) (Fujifilm Wako Pure Chemical Industries, Ltd.) and 11 mL of ethanol were placed in a glass bottle, and the reagent was dissolved. The reagent solution in the glass bottle was transferred to a glass tube, and nitrogen gas was introduced into the glass tube for 5 minutes to replace the gas in the system with nitrogen gas. A plasma-treated silicone tube substrate was placed in this reagent solution, and nitrogen gas was introduced through the glass tube for 5 minutes, after which the glass tube was covered with a rubber stopper. The glass bottle was placed in a 37°C water bath and allowed to react for 4 hours. Thereafter, the silicone tube was removed, and the unreacted GMA was washed with ethanol for 1 hour and dried at room temperature. This resulted in a silicone tube bonded with GMA (silicone tube-GMA).

[0185] (4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) 1.97 g (9.15 mmol) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA), 1.9 mg (0.006 mmol) of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70, Fujifilm Wako Pure Chemical Industries, Ltd.), and 10 mL of ethanol were placed in a glass bottle and stirred at room temperature until all the reagents were dissolved. The reagent solution in the glass bottle was transferred to a glass tube, and nitrogen gas was introduced into the glass tube for 5 minutes to replace the gas in the system with nitrogen gas. A silicone tube with GMA bonded (silicone tube-GMA) was placed in this reagent solution, and nitrogen gas was introduced through the glass tube for 5 minutes. The glass tube was then covered with a rubber stopper. The glass bottle was placed in a 37°C water bath and allowed to react for 4 hours. After that, the silicone tube was removed and washed by immersing it in ethanol to remove unreacted CBA. This yielded a silicone tube in which CBA had been polymerized via GMA (silicone tube-GMA-pCBA).

[0186] (5) Bonding of methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) copolymer (p(MEA-APMA)) 624 mg (2.25 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (dehydration condensation agent) was dissolved in 5 mL of RO water to prepare a DMT-MM solution. 200 mg (1.5 mmol) of the methoxyethyl acrylate (MEA)-aminopropyl methacrylamide (APMA) copolymer (p(MEA-APMA)) synthesized above was dissolved in 20 mL of RO water to prepare a p(MEA-APMA) solution. This p(MEA-APMA) solution was transferred to a 50 mL Falcon (registered trademark, the same applies hereinafter) tube, and a silicone tube in which CBA had been polymerized via GMA (silicone tube-GMA-pCBA) was added. Thereafter, the DMT-MM solution was added dropwise, and the mixture in the Falcon tube was immediately stirred using an orbital shaker. The stirring was carried out at a speed of 100 rpm for 3 hours. After stirring, the Falcon tube was removed from the orbital shaker and allowed to stand overnight at room temperature to confirm the primary amino group (-NH) of the p(MEA-APMA) copolymer. ２ ) was reacted with the carboxyl group (—COOH) of CBA. The silicone tube was removed from the Falcon tube and immersed in 50 mL of RO water for 5 minutes. This procedure was repeated three times to wash the silicone tube, and then the silicone tube was removed from the RO water and allowed to stand at room temperature to dry. This yielded a silicone tube in which the MEA-APMA copolymer was immobilized via the GMA and CBA polymer chains (silicone tube-GMA-pCBA-p(MEA-APMA), Example 3).

[0187] <Blood Circulation Test 3> A blood circulation test was carried out by the following method for each of the evaluation samples prepared above, that is, the silicone tube (untreated with plasma, Comparative Example 4) and the silicone tube-GMA-pCBA-p(MEA-APMA) (Example 3), to evaluate their antithrombogenicity.

[0188] (1) Preparation of Circulation Circuit A polyvinyl chloride (PVC) tube (Saitama Kasei Kogyo Co., Ltd., SCB04T070, size: 6.0 (inner diameter) x 9.0 (outer diameter) mm, 9.5 x 14.2 mm) and a variant connector (Saneki Chemical Industry Co., Ltd., CB00X320N) were passed through a 0.5% by mass solution of polymethoxyethyl acrylate (PMEA) in methanol to form an antithrombotic coating. Both ends of the tube were connected to the connector and looped. A 1 cm incision was made parallel to the circuit at the point opposite the connector, and a micropipette tip with its tip cut was inserted into the incision. Next, the evaluation sample was cut to approximately 10 cm and inserted approximately 6 cm into the circuit using the lumen of the micropipette tip as a guide. The micropipette tip was removed from the circuit, and the circuit inlet with the sample inserted and the opening outside the circuit were sealed with adhesive or the like.

[0189] (2) Obtaining blood This was done in the same manner as in "(2) Obtaining blood" in <Blood circulation test 1> above.

[0190] (3) Measurement of activated clotting time (ACT) for blood at the start of the experiment This was performed using the same method as "(3) Measurement of activated clotting time (ACT) for blood at the start of the experiment" in <Blood circulation test 1> above.

[0191] (4) Blood Circulation Test This was carried out in the same manner as in "(4) Blood Circulation Test" in <Blood Circulation Test 1> above.

[0192] (5) Observation of Samples After blood circulation, the rotating device was turned off and the circulated blood was collected. The evaluation samples were removed from the circuit, washed with saline, and then visually observed. Photographs of the appearance of each sample of Comparative Example 4 and Example 3 are shown in Figures 10 and 11, respectively.

[0193] (6) Results As shown in Figure 11, almost no thrombus formation was observed on the surface of the silicone tube-GMA-pCBA-p (MEA-APMA) of Example 3. On the other hand, thrombus formation was observed on the surface of the silicone tube (untreated with plasma) of Comparative Example 4 shown in Figure 10. This demonstrates that the antithrombogenicity of medical devices can be further improved according to the present invention.

[0194] <Formation of antithrombogenic layer on PU tube> (1) Preparation of PU tube A polyurethane (PU) tube (manufactured by Terumo Clinical Supply Corporation, product name: DewX (registered trademark) Eerna, outer diameter 1.7 mm, inner diameter 0.8 mm) was cut into a length of 10 cm. The cut PU tube was washed by leaving it to stand in ethanol to obtain a PU tube substrate (untreated with plasma).

[0195] (2) Plasma treatment of PU tube The cleaned PU tube was placed in a plasma irradiation device (Pico Full PC, manufactured by DIENER ELECTRONIC, low-pressure type) and subjected to plasma irradiation (argon ionized gas plasma irradiation) for 3 minutes under the following conditions: pressure: 0.3 mbar, power: 50%, introduced gas: 100% Ar gas, LF output: 200 W, gas flow rate: 15 sccm. After plasma irradiation, the PU tube was removed into the atmosphere and allowed to stand for 30 minutes. This resulted in a PU tube substrate (PU tube (after plasma treatment)) with a plasma-treated surface.

[0196] (3) Bonding of Glycidyl Methacrylate (GMA) 0.145 mL (1.1 mmol) of glycidyl methacrylate (GMA) (Fujifilm Wako Pure Chemical Industries, Ltd.) and 11 mL of ethanol were placed in a glass bottle, and the reagent was dissolved. The reagent solution in the glass bottle was transferred to a glass tube, and nitrogen gas was introduced into the glass tube for 5 minutes to replace the gas in the system with nitrogen gas. The plasma-treated PU tube substrate was placed in this reagent solution, and nitrogen gas was introduced through the glass tube for 5 minutes, after which the glass tube was covered with a rubber stopper. The glass bottle was placed in a 37°C water bath and reacted for 4 hours. The PU tube was then removed, and the unreacted GMA was washed with ethanol for 1 hour and dried at room temperature. This resulted in a PU tube bonded with GMA (PU tube-GMA).

[0197] (4) Polymerization of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA) 1.97 g (9.15 mmol) of N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CBA), 1.9 mg (0.006 mmol) of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70, Fujifilm Wako Pure Chemical Industries, Ltd.), and 10 mL of ethanol were placed in a glass bottle and stirred at room temperature until all the reagents were dissolved. The reagent solution in the glass bottle was transferred to a glass tube, and nitrogen gas was introduced into the glass tube for 5 minutes to replace the gas in the system with nitrogen gas. A PU tube with GMA bonded (PU tube-GMA) was placed in this reagent solution, and nitrogen gas was introduced through the glass tube for 5 minutes. The glass tube was then covered with a rubber stopper. The glass bottle was placed in a water bath at 37°C and reacted for 4 hours. After that, the PU tube was taken out and washed by immersing it in ethanol to remove unreacted CBA. This yielded a PU tube in which CBA had been polymerized via GMA (PU tube-GMA-pCBA).

[0198] (5) Bonding of Methoxyethyl acrylate (MEA)-Aminopropyl Methacrylamide (APMA) Copolymer (p(MEA-APMA)) 624 mg (2.25 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (dehydration condensation agent) was dissolved in 1.5 mL of RO water to prepare a DMT-MM solution. 200 mg (1.5 mmol) of the methoxyethyl acrylate (MEA)-Aminopropyl Methacrylamide (APMA) copolymer (p(MEA-APMA)) synthesized above was dissolved in 20 mL of RO water to prepare a p(MEA-APMA) solution. This p(MEA-APMA) solution was transferred to a 50 mL Falcon (registered trademark, the same applies hereinafter) tube, and a PU tube in which CBA had been polymerized via GMA (PU tube-GMA-pCBA) was added. Thereafter, the DMT-MM solution was added dropwise, and the mixture in the Falcon tube was immediately stirred using an orbital shaker. The stirring was carried out at a speed of 400 rpm for 3 hours. After stirring, the Falcon tube was removed from the orbital shaker and allowed to stand overnight at room temperature to confirm the primary amino group (-NH) of the p(MEA-APMA) copolymer. ２ ) was reacted with the carboxyl group (—COOH) of CBA. The PU tube was removed from the Falcon tube and immersed in 50 mL of RO water for 5 minutes. This procedure was repeated three times to wash the PU tube, and then the PU tube was removed from the RO water and allowed to stand at room temperature to dry. This resulted in a PU tube in which the MEA-APMA copolymer was fixed via the GMA and CBA polymer chains (PU tube-GMA-pCBA-p(MEA-APMA), Example 4).

[0199] <Blood Circulation Test 4> The PU tube-GMA-pCBA-p (MEA-APMA) (Example 4) prepared above was subjected to a blood circulation test in the same manner as in <Blood Circulation Test 3> above, to evaluate its antithrombogenicity. A photograph of the appearance of the sample of Example 4 is shown in Figure 12. As shown in Figure 12, almost no thrombus formation was observed on the surface of the PU tube-GMA-pCBA-p (MEA-APMA) of Example 4.

[0200] This application is based on Japanese Patent Application No. 2023-116081, filed on July 14, 2023, the disclosure of which is incorporated by reference in its entirety.

[0201] 10...substrate, 10a...substrate core portion, 10b...substrate surface layer, 11...antithrombogenic layer, 100...medical device.

Claims

1. A medical device comprising: a substrate; and an antithrombogenic layer having a polymer fixed to the substrate, wherein the polymer comprises: a structural unit a derived from a first monomer having an ethylenically unsaturated group and a reactive group reactive with a hydroxyl group or a carboxyl group; a structural unit B having a polymer chain including a structural unit b derived from a first antithrombogenic monomer having a carboxyl group and an ethylenically unsaturated group, and having an end of the polymer chain bonded to the structural unit a; and a structural unit C derived from a copolymer bonded to the structural unit b, and having a structural unit c1 derived from a second monomer having an amino group and a structural unit c2 derived from the second antithrombogenic monomer.

2. The medical device according to claim 1, wherein the second antithrombotic monomer is one or more monomers selected from the monomers represented by the following formula (I): In the above formula (I), R １ represents a hydrogen atom or a methyl group, and X represents a group represented by the formula: -O-(R ２ O) ｍ -R ３ a group represented by the formula: -O-(CH ２ CHOH) ｎ -CH ２ OH or a tetrahydrofurfuryloxy group, in which R ２ each independently represents a linear or branched alkylene group having 1 to 4 carbon atoms; R ３ represents a linear or branched alkyl group having 1 to 4 carbon atoms; m represents an integer of 1 to 5; and n represents an integer of 1 to 5.

3. The medical device according to claim 2, wherein the second antithrombotic monomer is one or more selected from the group consisting of methoxymethyl acrylate, 2-methoxyethyl acrylate (MEA), 3-methoxypropyl acrylate (MC3A), ethoxymethyl acrylate, ethoxyethyl acrylate (EEA), 2-(2-ethoxyethoxy)ethyl acrylate (EEEA), ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, butoxyethyl acrylate, methoxybutyl acrylate, tetrahydrofurfuryl acrylate (THFA), methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, 2-(2-ethoxyethoxy)ethyl methacrylate, propoxymethyl methacrylate, butoxyethyl methacrylate, tetrahydrofurfuryl methacrylate and glycerol (meth)acrylate.

4. The medical device according to claim 1, wherein the first monomer is one or more selected from glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, β-methylglycidyl methacrylate and allyl glycidyl ether.

5. The medical device according to claim 1, wherein the first antithrombotic monomer is one or more monomers selected from the monomers represented by the following formula (II): In the above formula (II), R ４ represents a hydrogen atom or a methyl group; R ５ represents a linear or branched alkylene group having 1 to 6 carbon atoms; R ６ and R ７ each independently represents a linear or branched alkyl group having 1 to 4 carbon atoms; R ８ represents a linear or branched alkylene group having 1 to 4 carbon atoms; Z is -COO － represents Y １ represents an oxygen atom or --NH--.

6. The medical device according to claim 5, wherein the first antithrombotic monomer is one or more selected from N-(meth)acryloyloxymethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxypropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxymethyl-N,N-diethylammonium-α-N-methylcarboxybetaine, N-(meth)acryloyloxyethyl-N,N-diethylammonium-α-N-methylcarboxybetaine and N-(meth)acryloyloxypropyl-N,N-diethylammonium-α-N-methylcarboxybetaine.

7. The medical device according to claim 1, wherein the second monomer is one or more monomers selected from the group consisting of monomers represented by the following formula (III) and salts thereof: In the above formula (III), R ９ represents a hydrogen atom or a methyl group; Y ２ represents an oxygen atom or --NH--; and p represents an integer of 1 to 4.

8. The medical device according to claim 7, wherein the second monomer is one or more selected from aminomethylacrylamide, aminomethylmethacrylamide, aminoethylacrylamide, aminoethylmethacrylamide, aminopropylacrylamide, aminopropylmethacrylamide (APMA), aminobutylacrylamide, aminobutylmethacrylamide, aminomethylacrylate, aminomethylmethacrylate, aminoethylacrylate, aminoethylmethacrylate, aminopropylacrylate, aminopropylmethacrylate, aminobutylacrylate, and aminobutylmethacrylate, and salts thereof.

9. The medical device according to claim 1, wherein in said structural unit C, the molar ratio of said structural unit c1 to said structural unit c2 (c1:c2) is 1:1 to 1:

20.

10. The medical device of claim 1, wherein the substrate comprises a plastic substrate.

11. The medical device according to claim 10, wherein the plastic substrate is a porous body.

12. The medical device according to claim 1, which is an artificial blood vessel, a stent graft, a covered stent or a catheter.

13. The method for producing a medical device according to claim 1, comprising: irradiating at least a portion of the surface of the substrate with plasma; contacting the substrate after the plasma irradiation with the first monomer; contacting the substrate after the contact with the first monomer with the first antithrombotic monomer; and contacting the substrate after the contact with the first antithrombotic monomer with the copolymer.

Images