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EP-4740974-A1 - MEDICAL INSTRUMENT AND MANUFACTURING METHOD THEREFOR

EP4740974A1EP 4740974 A1EP4740974 A1EP 4740974A1EP-4740974-A1

Abstract

Provided is a means configured to further improve antithrombogenicity in a medical device. A medical device of the present invention is a medical device including: a base material; an antithrombogenic layer including a polymer fixed to the base material, in which the polymer includes: a structural unit a derived from a first monomer bonded to the base material and including a reactive group that reacts with a hydroxyl group or a carboxyl group and an ethylenically unsaturated group; a structural unit B including a polymer chain including a structural unit b derived from a first antithrombogenic monomer including a carboxyl group and an ethylenically unsaturated group, and including a terminal of the polymer chain bonded to the structural unit a; and a structural unit C derived from a copolymer including a structural unit c1 derived from a second monomer including an amino group and bonded to the structural unit b and a structural unit c2 derived from a second antithrombogenic monomer.

Inventors

  • LIU, Yihua
  • KITAHARA, YOKO
  • HIRAKI, Akihiro

Assignees

  • Terumo Kabushiki Kaisha

Dates

Publication Date
20260513
Application Date
20240712

Claims (13)

  1. A medical device comprising: a base material; an antithrombogenic layer including a polymer fixed to the base material, wherein the polymer includes: a structural unit a derived from a first monomer bonded to the base material and including a reactive group that reacts with a hydroxyl group or a carboxyl group and an ethylenically unsaturated group; a structural unit B including a polymer chain including a structural unit b derived from a first antithrombogenic monomer including a carboxyl group and an ethylenically unsaturated group, and including a terminal of the polymer chain bonded to the structural unit a; and a structural unit C derived from a copolymer including a structural unit c1 derived from a second monomer including an amino group and bonded to the structural unit b and a structural unit c2 derived from a second antithrombogenic monomer.
  2. The medical device according to claim 1, wherein the second antithrombogenic monomer is one or two or more selected from a monomer represented by the following Formula (I); wherein, R 1 represents a hydrogen atom or a methyl group, X represents a group represented by formula: -O-(R 2 O) m -R 3 , a group represented by formula: -O-(CH 2 CHOH) n -CH 2 OH, or a tetrahydrofurfuryloxy group, in which each R 2 independently represents a linear or branched alkylene group having carbon atoms in a range of 1 to 4, R 3 represents a linear or branched alkyl group having carbon atoms in a range of 1 to 4, m represents an integer in a range of 1 to 5, and n represents an integer in a range of 1 to 5.
  3. The medical device according to claim 2, wherein the second antithrombogenic monomer is one or two 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.
  4. The medical device according to claim 1, wherein the first monomer is one or two or more selected from glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexyl methyl acrylate, 3,4-epoxycyclohexyl methyl methacrylate, β-methyl glycidyl acrylate, β-methyl glycidyl methacrylate, and allyl glycidyl ether.
  5. The medical device according to claim 1, wherein the first antithrombogenic monomer is one or two or more selected from a monomer represented by the following Formula (II); wherein, R 4 represents a hydrogen atom or a methyl group, R 5 represents a linear or branched alkylene group having carbon atoms in a range of 1 to 6, R 6 and R 7 each independently represent a linear or branched alkyl group having carbon atoms in a range of 1 to 4, R 8 represents a linear or branched alkylene group having carbon atoms in a range of 1 to 4, Z represents -COO - , and Y 1 represents an oxygen atom or -NH-.
  6. The medical device according to claim 5, wherein the first antithrombogenic monomer is one or two 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 two or more selected from a monomer represented by following Formula (III) and a salt thereof; wherein, R 9 represents a hydrogen atom or a methyl group, Y 2 represents an oxygen atom or -NH-, and p represents an integer in a range of 1 to 4.
  8. The medical device according to claim 7, wherein the second monomer is one or two 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.
  9. The medical device according to claim 1, wherein a molar ratio (c1 : c2) of the structural unit c1 to the structural unit c2 in the structural unit C is in a range of 1 : 1 to 1 : 20.
  10. The medical device according to claim 1, wherein the base material includes a plastic base material.
  11. The medical device according to claim 10, wherein the plastic base material is a porous body.
  12. The medical device according to claim 1, wherein the medical device is an artificial blood vessel, a stent graft, a covered stent, or a catheter.
  13. A method for manufacturing the medical device according to claim 1, the manufacturing method comprising: irradiating at least a part of a surface of the base material with plasma; bringing the first monomer into contact with the base material after the plasma irradiation; bringing the first antithrombogenic monomer into contact with the base material after the first monomer is brought into contact; and bringing the copolymer into contact with the base material after the first antithrombogenic monomer is brought into contact.

Description

Technical Field The present invention relates to a medical device and a method for manufacturing the same. Background Art In recent years, medical materials utilizing various polymer materials or metal materials have been studied, and are expected to be used for membranes for artificial kidneys, membranes for plasma skimming, catheters, stents, membranes for artificial lungs, artificial blood vessels, anti-adhesion membranes, artificial skins, stent grafts, covered stents, guide wires, cardiac pacemakers, and the like. In these materials, a synthetic polymer material or metal material, which is a foreign substance for a living body, is used in contact with a biological tissue or a body fluid such as blood. Therefore, the medical materials are required to have biocompatibility. The biocompatibility required for a medical material varies depending on its purpose and use method, but a medical material used as a material in contact with blood is required to have characteristics (antithrombogenicity) of suppressing the blood coagulation system, suppressing the adhesion/activation of platelets, and suppressing the activation of the complement system. Usually, the antithrombogenicity is imparted to the medical device by a method of coating a base material constituting the medical device with an antithrombogenic material or a method of fixing an antithrombogenic material on a surface of a base material. For example, Non Patent Literature 1 discloses a method for modifying medical stretched polyethylene tetrafluoroethylene (ePTFE) by surface graft polymerization. More specifically, this literature describes that a peroxide group is generated by subjecting an ePTFE surface to an argon plasma treatment, a methacryloyl group is constructed by reacting glycidyl methacrylate (GMA), and an MPC polymer chain is fixed to the ePTFE surface via a structural unit derived from GMA by graft polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC). According to this literature, graft polymerization using GMA is considered to provide a new method for modifying a chemically inert ePTFE surface to function as a new medical device. Citation List Non Patent Literature Non Patent Literature 1: 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. Summary of Invention However, according to the study of the present inventors, it has been found that there is a case where a medical device having sufficient antithrombogenicity cannot be obtained even by the method described in Non Patent Literature 1. Therefore, an object of the present invention is to provide a means configured to further improve antithrombogenicity in a medical device. The present inventors have intensively studied to solve the above problems. As a result, the present inventors have found that the above problems can be solved by graft polymerization of an antithrombogenic monomer on a surface of a base material via a predetermined structural unit to construct a polymer chain; and bonding a copolymer derived from an antithrombogenic monomer and the polymer chain, thereby completing the present invention. 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 forms. An aspect of the present invention is 1. A medical device including: a base material;an antithrombogenic layer including a polymer fixed to the base material,in which the polymer includes: a structural unit a derived from a first monomer bonded to the base material and including a reactive group that reacts with a hydroxyl group or a carboxyl group and an ethylenically unsaturated group;a structural unit B including a polymer chain including a structural unit b derived from a first antithrombogenic monomer including a carboxyl group and an ethylenically unsaturated group, and including a terminal of the polymer chain bonded to the structural unit a; anda structural unit C derived from a copolymer including a structural unit c1 derived from a second monomer including an amino group and a structural unit c2 derived from a second antithrombogenic monomer, the structural unit C bonded to the structural unit b.2. In the medical device described in the above 1., the second antithrombogenic monomer is preferably one or two or more selected from a monomer represented by the following Formula (I); wherein, R1 represents a hydrogen atom or a methyl group,X represents a group represented by formula: -O-(R2O)m-R3, a group represented by formula: -O-(CH2CHOH)n-CH2OH, or a tetrahydrofurfuryloxy group, in which each R2 independently represents a linear or branched alkylene group having carbon atoms in a range of 1 to 4, R3 represents a linear or branched alkyl group having carbon atoms in a range of 1 to 4, m represents an integ