Polymer composition and antithrombotic coating agent

Abstract

To provide a polymer composition that achieves both substrate adhesion properties and antithrombogenicity.SOLUTION: Provided is a polymer composition containing a polymer having a monomer unit represented by formula (1). X1, X2, or X3 each independently represent: (I) H; (II) F, Cl, Br, or I; (III) a substituted or unsubstituted alkyl group having 1-12 carbon atoms, a substituted or unsubstituted alkenyl group having 2-10 carbon atoms, a substituted or unsubstituted alkynyl group having 2-10 carbon atoms; or (IV) a methoxy group, an ethoxy group, or a 2-hydroxyethoxy group.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a polymer composition that is characterized by being unlikely to cause a foreign body reaction in a living body when it comes into contact with a living body or a biological substance such as biological tissue including blood, cells, or proteins, and an antithrombotic coating agent that uses the polymer composition. [Background technology]

[0002] In general, medical materials are required to have antithrombotic properties (i.e., the property of suppressing platelet adhesion to the material surface). When a biological substance such as blood comes into contact with the surface of various artificially synthesized materials, the surface of the material is recognized as a foreign body, and, for example, nonspecific adsorption of proteins to the material surface occurs, resulting in denaturation, etc., which results in activation of the coagulation system, complement system, and platelet system, etc. For this reason, for example, in the surface of medical devices that are used in contact with living organisms or biological substances, it is desirable to impart biocompatibility to the surface of the device in order to prevent the device from being recognized as a foreign body and causing a foreign body reaction to the biological substance during use. Various materials showing biocompatibility have been proposed so far, and their practical use in medical settings, etc. is being promoted.

[0003] In order to impart antithrombotic properties to medical materials, hydrophilic groups are imparted to the polymers that constitute the medical materials. The hydrophilic groups of the polymer form a hydrophilic surface when in contact with blood, suppressing platelet adhesion and protein adsorption. For example, 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer is a polymer obtained by polymerizing a unit structure in which a structure (phospholipid polar group) that mimics a substance that constitutes a living body is bound to a polymerizable group such as a vinyl group as a monomer, and by applying a composition containing the MPC polymer to the surface of a medical device, biocompatibility is imparted, platelet adhesion is suppressed, and excellent antithrombotic properties are exhibited. In addition, polyethylene glycol (PEG) is a polymer with a repeating unit of -(C2H4-O)-, which is a chain ether structure, and is known to have very good biocompatibility despite having a structure that is not similar to the substances that constitute the living body (Non-Patent Document 1, Patent Document 1).

[0004] On the other hand, medical materials are also required to have adhesion to substrates. To impart adhesion to substrates to medical materials, hydrophobic groups are added to the polymers that compose the medical materials. The hydrophobic groups of the polymers suppress the elution of the polymer into blood and also increase the adhesion and uniformity with the substrate during coating.

[0005] In other words, polymers used for purposes such as imparting biocompatibility to the surfaces of medical devices are required to have two contradictory properties: hydrophilicity to prevent platelet adhesion, and hydrophobicity to prevent elution and dissolution.

[0006] As for the above-mentioned MPC polymer, since the MPC homopolymer is water-soluble and difficult to use as a medical material, a technique is used in which the MPC homopolymer is copolymerized with a hydrophobic structural unit (such as butyl methacrylate) to achieve both biocompatibility and water insolubility (Patent Document 2).In addition, since the above-mentioned PEG is also water-soluble, efforts are being made to improve water resistance by copolymerizing it with other structural units (Patent Document 3) or forming a crosslinked structure (Patent Document 4).

[0007] The above examples involve the use of techniques such as adding hydrophobic building blocks that do not exhibit biocompatibility or modifying part of the structure of the original biocompatible polymer in order to impart hydrophobicity to the biocompatible polymer in order to make it non-soluble in water, which raises concerns from the standpoint of biocompatibility.

[0008] Poly(2-methoxyethyl acrylate) (PMEA) is a coating material with excellent antithrombotic properties. At the interface between PMEA and blood components, water with a special structure exists as a barrier layer, and precise analysis of electronic states using X-rays has revealed that prior to the formation of the barrier layer, a nano-sized microphase-separated structure is formed at the interface by the interaction between PMEA and water, and a small amount of water molecules adsorbed at specific sites of the phase-separated structure serve as a scaffold for the subsequent growth of the barrier layer (Non-Patent Document 2).

[0009] However, PMEA does not have sufficient adhesion to substrates and there is room for improvement. Therefore, an inorganic / organic hybrid material called SQ / PMEA hybrid, which is a combination with an inorganic compound SQ (silsesquioxane), has been proposed (Patent Document 5). Non-Patent Document 3 also describes the synthesis of an SQ / PMEA hybrid by thiol-initiated radical polymerization of 2-methoxyethyl acrylate (MEA) from a thiol group-containing random-type silsesquioxane (SQ-SH) using 2,2'-azobis-isobutyronitrile as an initiator. The SQ / PMEA hybrid is a material that has excellent adhesion to substrates compared to PMEA homopolymer. However, inorganic / organic hybrid materials are disadvantageous in terms of production cost and production procedure compared to materials made of homopolymers, and the SQ / PMEA hybrid has the problem of reducing antithrombotic properties depending on the amount of SQ to be hybridized.

[0010] It is known that some polymers having a 2-pyrrolidone structure with a five-membered lactam structure in the side chain portion exhibit good antithrombotic properties. Polyvinylpyrrolidone, which is commonly used as a polymer having a 2-pyrrolidone structure, exhibits a certain antithrombotic property and is water-soluble like the above-mentioned MPC polymer and PEG. For example, Patent Document 6 describes a technique for crosslinking the polyvinylpyrrolidone by irradiation.

[0011] Patent Document 7 describes N-2-(meth)acryloyloxyethyl-2-pyrrolidone in which the above-mentioned 2-pyrrolidone structure is provided in a side chain portion of a main chain having a (meth)acrylic structure, and describes that in order to use the structure as a medical hydrogel, it is necessary to make it water-resistant by copolymerizing it with a hydrophobic structural unit, for example.

[0012] The common feature of the above-mentioned various polymers is that the phenomenon in which a polymer exhibits biocompatibility and the phenomenon in which a polymer exhibits water solubility are essentially similar, which is thought to suggest the existence of a kind of trade-off relationship between biocompatibility and water-solubility. The above-mentioned polymer compositions have excellent antithrombogenicity but have problems such as insufficient adhesion to substrates.

[0013] As described above, it is extremely difficult to realize a polymer composition that has both substrate adhesion and antithrombogenicity. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] JP 2016-63801 A [Patent Document 2] Japanese Patent Application Publication No. 3-39309 [Patent Document 3] JP 2005-23108 A [Patent Document 4] JP 2005-255875 A [Patent Document 5] Patent Publication No. 2021-80323 [Patent Document 6] Japanese Patent Application Publication No. 2-86838 [Patent Document 7] Japanese Patent Application Publication No. 4-28705 [Non-patent literature]

[0015] [Non-Patent Document 1] Tanaka, M. et al., Journal of Biomaterials Science Polymer Edition, 2010, 21, p. 1849-1863 [Non-Patent Document 2] Murakami, D. et al., Langmuir, 2022, p.1090-1098 [Non-Patent Document 3] Nishimura, S. et. al., ACS Applied Polymer Materials, 2020, 2, p. 4790-4801 Summary of the Invention [Problem to be solved by the invention]

[0016] The present invention has been made in view of the above problems, and has an object to provide a polymer composition which has both substrate adhesion and antithrombogenicity. [Means for solving the problem]

[0017] The polymer composition according to the present invention is characterized by comprising a polymer having a monomer unit represented by chemical formula (1).

[0018] [ka]

[0019] In chemical formula (1), m is a natural number from 2 to 12, and n means the number of repeating monomer units. R1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 represents an oxygen atom, a sulfur atom, SO, SO2, or NR3 (wherein R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).

[0020] X1, X2, and X3 are each independently selected from the group represented by (I), (II), (III), or (IV) below (provided that X1, X2, and X3 are not all hydrogen atoms). (I) a hydrogen atom; (II) a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; (III) a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms; In the case where the alkyl group, alkenyl group, and alkynyl group are substituted, they are substituted with one or more groups independently selected from the group consisting of the following (a) to (c): (a) a halogen atom, a hydroxyl group, a carboxy group, a mercapto group, an oxo group, a haloalkyl group having 1 to 6 carbon atoms, and a haloalkoxy group having 1 to 6 carbon atoms; (b) an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 2 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms; (c) an amino group, a carbamoyl group, a sulfamoyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkoxy group, a 4- to 8-membered saturated heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryloxy group, and a 5- to 10-membered heteroaryloxy group; (IV) Methoxy group, ethoxy group, 2-hydroxyethoxy group, 2-methoxyethoxy group, carboxymethoxy group, 5-tetrazolylmethoxy group, cyanomethoxy group, 4-piperidylmethoxy group, 2-(N,N-dimethylamino)ethoxy group, 3-oxetanylmethoxy group, 2-morpholinoethoxy group, 2-(N-methylpiperazino)ethoxy group, 2-pyrrolidinoethoxy group, 2-piperidinoethoxy group , 3-pyrrolidinopropoxy group, 3-tetrahydrofuryloxy group, 4-tetrahydropyranyloxy group, 4-(N-methylpiperidyl)methoxy group, 2-hydroxy-2-methylpropoxy group, carbamoylmethoxy group, piperidino group, morpholino group, piperazino group, 4-cyanopiperidino group, 4-methoxycarbonylpiperazino group, 3,5-dimethylmorpholino group, 3,5-dimethylpiperazino group, 4-methoxypiperidino group, 4-carboxypiperidino group, N-methylsulfonylpiperazino group, 4-methylsulfonylpiperidino group, N-2-hydroxy-2-methylpropylpiperazino group, N-hydroxyacetylpiperazino group, N-acetylpiperazino group, N-methylpiperazino group, N-(3-oxetanyl)piperazino group, 4-hydroxycyclohexyl group, 1-methylpyrazol-4-yl group, 4-(N,N-dimethylamino)phenyl group, 4-ethoxycarbonyloxazol-2-yl group, 4-(N-methylpiperazino)phenyl group, ethoxycarbonyl group, N-(2-morpholinoethyl)carbamoyl group, 2-oxazolyl group, 4-morpholinocarbonyloxazol-2-yl group, 4-pyrrolidinomethyloxazol-2-yl group, or 4-carboxyoxazol-2-yl group; Effect of the Invention

[0021] According to the present invention, a polymer composition that combines substrate adhesion and antithrombogenicity can be obtained. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 is a photograph showing the substrate adhesion to a polycarbonate substrate for each polymer. [Diagram 2]FIG. 1 is a photograph showing the substrate adhesion to a glass substrate for each polymer. [Diagram 3] FIG. 1 shows platelet adhesion numbers to polycarbonate substrates for each polymer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Hereinafter, an embodiment of the present invention will be described in detail with reference to the attached drawings. However, the embodiment is intended to facilitate understanding of the principles of the present invention, and the scope of the present invention is not limited to the embodiment described below. Other embodiments in which a person skilled in the art appropriately replaces the configuration of the embodiment described below are also included in the scope of the present invention.

[0024] (1) Polymer composition The polymer composition according to the present invention is characterized by comprising a polymer having a monomer unit represented by chemical formula (1).

[0025] [ka]

[0026] Polymers having a pyrrolidone ring in the side chain have excellent antithrombotic properties but poor adhesion to substrates. The present inventors have newly discovered that by providing a pyrrolidone ring with a substituent that enables interaction with a substrate, adhesion and uniformity to a substrate during coating can be improved without impairing antithrombotic properties, and have completed the present invention based on this finding.

[0027] In the above chemical formula (1), the portion corresponding to the m value is a carbon chain that connects the main chain portion of the polymer with the nitrogen atom contained in 2-pyrrolidone, and the carbon chain portion exhibits hydrophobicity. On the other hand, the 2-pyrrolidone portion has strong hydrophilicity. When m is 1, the hydrophobicity is not sufficient, and it is difficult to sufficiently suppress the elution of the polymer into blood. However, when m is any natural number of 2 to 12, the hydrophobicity is sufficient, and it is possible to suppress the elution of the polymer into blood. Preferably, m is any natural number of 2 to 6, more preferably, m is 2, 3, or 4, and most preferably, m is 2. However, if m is a natural number of 13 or more, the hydrophobicity becomes strong, and there is a risk of impairing the antithrombotic properties.

[0028] In chemical formula (1), n ​​means the number of repeating monomer units. Specifically, the polymer composition according to the present invention has a weight average molecular weight of, for example, 30,000 or more. If the weight average molecular weight is less than 30,000, the cohesive force is insufficient, and a strong coating may not be formed. From the viewpoint of operability, the weight average molecular weight of the polymer composition according to the present invention is preferably, for example, 40,000 or more, and more preferably 50,000 or more. In the present invention, the "weight average molecular weight" is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance.

[0029] X1, X2, and X3 are each independently selected from the group represented by the following (I), (II), (III), or (IV), provided that X1, X2, and X3 are not all hydrogen atoms. (I) a hydrogen atom; (II) a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; (III) a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms; In the case where the alkyl group, alkenyl group, and alkynyl group are substituted, they are substituted with one or more groups independently selected from the group consisting of the following (a) to (c): (a) a halogen atom, a hydroxyl group, a carboxy group, a mercapto group, an oxo group, a haloalkyl group having 1 to 6 carbon atoms, and a haloalkoxy group having 1 to 6 carbon atoms; (b) an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 2 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms; (c) an amino group, a carbamoyl group, a sulfamoyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkoxy group, a 4- to 8-membered saturated heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryloxy group, and a 5- to 10-membered heteroaryloxy group; (IV) Methoxy group, ethoxy group, 2-hydroxyethoxy group, 2-methoxyethoxy group, carboxymethoxy group, 5-tetrazolylmethoxy group, cyanomethoxy group, 4-piperidylmethoxy group, 2-(N,N-dimethylamino)ethoxy group, 3-oxetanylmethoxy group, 2-morpholinoethoxy group, 2-(N-methylpiperazino)ethoxy group, 2-pyrrolidinoethoxy group, 2-piperidinoethoxy group , 3-pyrrolidinopropoxy group, 3-tetrahydrofuryloxy group, 4-tetrahydropyranyloxy group, 4-(N-methylpiperidyl)methoxy group, 2-hydroxy-2-methylpropoxy group, carbamoylmethoxy group, piperidino group, morpholino group, piperazino group, 4-cyanopiperidino group, 4-methoxycarbonylpiperazino group, 3,5-dimethylmorpholino group, 3,5-dimethylpiperazino group, 4-methoxypiperidino group, 4-carboxypiperidino group, N-methylsulfonylpiperazino group, 4-methylsulfonylpiperidino group, N-2-hydroxy-2-methylpropylpiperazino group, N-hydroxyacetylpiperazino group, N-acetylpiperazino group, N-methylpiperazino group, N-(3-oxetanyl)piperazino group, 4-hydroxycyclohexyl group, 1-methylpyrazol-4-yl group, 4-(N,N-dimethylamino)phenyl group, 4-ethoxycarbonyloxazol-2-yl group, 4-(N-methylpiperazino)phenyl group, ethoxycarbonyl group, N-(2-morpholinoethyl)carbamoyl group, 2-oxazolyl group, 4-morpholinocarbonyloxazol-2-yl group, 4-pyrrolidinomethyloxazol-2-yl group, or 4-carboxyoxazol-2-yl group;

[0030] In the chemical formula (1), the presence of at least one of the substituents X1, X2, or X3 can provide adhesion to a substrate, but it is preferable for the substituent X1 to be present at least at the α-position for the purpose of providing adhesion to a substrate, and it is most preferable for the substituent X1 to be present only at the α-position, as shown in the following chemical formula (2).

[0031] [ka]

[0032] X1 is preferably a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms. When the alkyl group, alkenyl group, or alkynyl group is substituted, it is substituted with one or more groups independently selected from the group consisting of the following (a) to (c): (a) a halogen atom, a hydroxyl group, a carboxy group, a mercapto group, an oxo group, a haloalkyl group having 1 to 6 carbon atoms, and a haloalkoxy group having 1 to 6 carbon atoms; (b) an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 2 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms; (c) an amino group, a carbamoyl group, a sulfamoyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkoxy group, a 4- to 8-membered saturated heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryloxy group, and a 5- to 10-membered heteroaryloxy group;

[0033] X1 is more preferably an unsubstituted alkyl group having 1 to 12 carbon atoms, further preferably an ethyl group, an n-propyl group, or an n-butyl group, and most preferably an ethyl group.

[0034] R1 represents either a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and preferably represents a hydrogen atom or a methyl group. As shown in the following chemical formula (3), R1 is most preferably a hydrogen atom.

[0035] R2 is an oxygen atom, a sulfur atom, SO, SO2, or NR3 (wherein R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), and preferably R2 is an oxygen atom or -NH-. As shown in the following chemical formula (3), R2 is most preferably an oxygen atom.

[0036] [ka]

[0037] The most preferred polymer composition according to the present invention is shown in the following chemical formula (4).

[0038] [ka]

[0039] The polymer composition of the present invention has an original structure in which a pyrrolidone ring in a monomer unit is provided with a substituent that enables interaction with a substrate. Therefore, it is possible to synthesize a homopolymer derived from one type of monomer unit, and therefore the composition is advantageous in terms of production cost and production procedure compared to organic-inorganic composite materials and copolymers.

[0040] However, the polymer composition of the present invention can also be synthesized as a copolymer. That is, in order to finely adjust the adhesion to various substrates, it is possible to impart various properties to the polymer composition of the present invention by adding other structural units in addition to the monomer units constituting the polymer composition of the present invention, within a range that does not impair the effects of the polymer composition of the present invention.

[0041] Specifically, examples of monomer units that can be added to synthesize a copolymer other than the monomer units constituting the polymer composition of the present invention include aminoalkyl acrylates such as aminomethyl acrylate, aminoethyl acrylate, and aminoisopropyl acrylate, diaminoalkyl acrylates such as diaminomethyl acrylate, diaminoethyl acrylate, and diaminobutyl acrylate, aminoalkyl methacrylates such as aminomethyl methacrylate and aminoethyl methacrylate, diaminoalkyl methacrylates such as diaminomethyl methacrylate and diaminoethyl methacrylate, methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, hexyl acrylate, and 2-ethylhexyl acrylate. Examples of the alkyl methacrylate include alkyl methacrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, hexyl methacrylate, and other alkyl methacrylates, alkoxy (meth)acrylates such as methoxy (meth)acrylate, alkoxy alkyl (meth)acrylates such as methoxyethyl (meth)acrylate, glycidyl methacrylate, acrylamide, alkyl acrylamides such as t-butyl acrylamide, n-butyl acrylamide, i-butyl acrylamide, hexyl acrylamide, heptyl acrylamide, and other alkyl acrylamides, N,N-dialkyl acrylamides such as N,N-dimethyl acrylamide and N,N-diethyl acrylamide, methacrylamide, N,N-dimethyl methacrylamide, N,N-diethyl methacrylamide, and other alkyl methacrylamides, and propylene.

[0042] The polymer composition according to the present invention may contain additives such as a radical scavenger, a peroxide decomposer, an antioxidant, an ultraviolet absorber, a heat stabilizer, a plasticizer, a flame retardant, and an antistatic agent, if necessary.

[0043] (2) Method for producing polymer composition The method for producing the polymer composition of the present invention is not particularly limited. For example, it is preferable to dissolve the monomer unit represented by the above formula (1), (2), (3) or (4) in a polymerization solvent, mix the obtained solution with a separately prepared polymerization initiator solution to prepare a polymerization reaction liquid, and then carry out the polymerization reaction.

[0044] The polymerization solvent is not particularly limited, but examples thereof include dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphosphoramide, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, t-butanol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, chloroform, tetrahydrofuran, acetone, dioxane, and benzene. The concentration of the monomer unit contained in the polymerization solvent is not particularly limited, but by setting the concentration relatively high, the weight average molecular weight of the resulting polymer composition can be increased. For this reason, the monomer unit concentration in the polymerization solvent is preferably 25% by mass or more, more preferably 30% by mass or more, and particularly preferably 50% by mass or more. In addition, the upper limit of the monomer unit concentration is not particularly limited, but is, for example, a saturated concentration or less, for example, 90% by mass or less, and preferably 70% by mass or less.

[0045] The polymerization initiator used in producing the polymer composition according to the present invention is not particularly limited, and any known initiator can be used. Preferably, a radical polymerization initiator is used because of its excellent polymerization stability. Specifically, persulfates such as potassium persulfate (KPS), sodium persulfate, and ammonium persulfate; peroxides such as hydrogen peroxide, t-butyl peroxide, and methyl ethyl ketone peroxide; 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-methylpropion ... Examples of the azo compounds include azo compounds such as 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine)] dihydrochloride, 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine)] hydrate, 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, di(secondary butyl) peroxydicarbonate, and azobiscyanovaleric acid. The amount of the polymerization initiator is preferably 0.005 to 2 parts by mass, more preferably 0.01 to 2 parts by mass, based on 100 parts by mass of the monomer unit.

[0046] The polymerization conditions are not particularly limited as long as the monomer units can be polymerized under these conditions. Specifically, the polymerization temperature is preferably 30 to 70° C., and more preferably 40 to 60° C. The polymerization time is preferably 1 to 24 hours, and more preferably 3 to 12 hours.

[0047] The atmosphere in which the polymerization reaction is carried out is not particularly limited, and the polymerization reaction can be carried out in the air or in an inert gas atmosphere such as nitrogen gas or argon gas, etc. During the polymerization reaction, the reaction liquid may be stirred.

[0048] The polymer after polymerization can be purified by a general purification method such as reprecipitation, dialysis, ultrafiltration, extraction, etc. Among the above, purification by the reprecipitation method is preferred because it gives a polymer suitable for preparation of a colloidal solution. In this case, diethyl ether is preferably used as a poor solvent for reprecipitation.

[0049] (3) Antithrombotic coating agent The antithrombotic coating agent according to the present invention has a solvent together with the polymer composition according to the present invention. The solvent is not particularly limited, but includes at least one of water and alcohol, and preferably the solvent is alcohol. The alcohol is not particularly limited, but is at least one selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, and 2-methyl-2-propanol, and is preferably methanol. When a solvent containing a mixture of water and alcohol is used, the volume ratio of water to alcohol (water:alcohol) is not particularly limited, but is preferably 5:95 to 45:55, more preferably 10:90 to 45:55, and particularly preferably 10:90 to 30:70.

[0050] The concentration of the polymer composition according to the present invention in the antithrombotic coating agent is not particularly limited, but is preferably 0.1 to 20 wt %, and more preferably 0.2 to 10 wt %.

[0051] Examples of medical devices in which the antithrombotic coating agent is used include, but are not limited to, implantable artificial organs and treatment devices, extracorporeal circulation artificial organs, catheters, guide wires, etc. Specific examples include implantable medical devices such as artificial blood vessels, artificial tracheas, stent artificial skin, and artificial pericardium, which are inserted or replaced in blood vessels or lumens; artificial organ systems such as artificial heart systems, artificial lung systems, artificial heart-lung systems, artificial kidney systems, artificial liver systems, and immune regulation systems; catheters inserted or placed in blood vessels, such as indwelling needles, IVH catheters, drug solution administration catheters, thermodilution catheters, angiography catheters, vasodilator catheters, and dilators or introducers; or guide wires, stylets, etc. for these catheters; and catheters inserted or placed in biological tissues other than blood vessels, such as gastric catheters, nutrition catheters, tube feeding (ED) tubes, urethral catheters, urinary catheters, balloon catheters, and various suction catheters and drainage catheters, including intratracheal suction catheters.

[0052] The material of the medical device on which the antithrombotic coating agent is used is not particularly limited, and examples thereof include various polymer materials such as polycarbonate, polyethylene, polypropylene, polyamide, polyimide, polyurethane, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polycyclohexane terephthalate, polyester, polyvinyl chloride, polyvinylidene chloride (PVDC), polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer (ETFE), glass, metal, ceramic, carbon, and composite materials thereof.

[0053] In the medical device, a coating layer consisting of a coating film of the antithrombotic coating agent according to the present invention is formed on the surface of the substrate. The coating layer is formed on the surface of the substrate by applying the antithrombotic coating agent according to the present invention to cover the surface of the substrate. The method of applying the antithrombotic coating agent according to the present invention to the surface of the substrate can be a known method, and is not particularly limited, and examples thereof include filling, dip coating (immersion method), spraying, spin coating, dropping, doctor blade, brush coating, roll coating, air knife coating, curtain coating, wire bar coating, and gravure coating. The thickness of the coating layer may be appropriately adjusted depending on the application of the medical device, and is not particularly limited, and is formed to be thinner than 1000 μm, for example.

[0054] A coating layer is formed on the surface of the substrate by drying the surface of the substrate coated with the antithrombotic coating agent according to the present invention. The drying step can be performed, for example, by heating in an oven at 20 to 80° C. for 0.5 to 20 hours. The atmosphere in the drying step is not particularly limited, and the drying step can be performed in air or in an inert gas atmosphere such as nitrogen gas or argon gas. EXAMPLES

[0055] 1) Synthesis of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-pyrrolidone

[0056] [ka]

[0057] 10.1g of 1-(2-hydroxyethyl)-2-pyrrolidone and 0.138g of p-toluenesulfonic acid monohydrate were dissolved in 80mL of dichloromethane. 7.78g of 3,4-dihydro-2H-pyran was slowly added dropwise in an ice bath and stirred at room temperature overnight. 5% aqueous potassium carbonate solution was added to the reaction solution while stirring until no bubbles were generated. The target product was extracted from the aqueous layer using 100mL of chloroform. This operation was performed three times. All the organic layers were combined and dehydrated using anhydrous magnesium sulfate. The target product was obtained by distilling off the solvent under reduced pressure.

[0058] 2) Synthesis of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-ethyl-2-pyrrolidone

[0059] [ka]

[0060] 6.10 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-pyrrolidone was dissolved in 90 mL of dehydrated tetrahydrofuran and cooled to -35°C under nitrogen atmosphere. 22 mL of lithium bis(trimethylsilyl)amide (LHMDS) tetrahydrofuran solution (1.3 M) was slowly added dropwise thereto and stirred for 90 minutes. 7.12 g of iodoethane dissolved in 30 mL of dehydrated tetrahydrofuran was added dropwise thereto and stirred overnight. The reaction solution was placed in an ice bath and distilled water was added dropwise to stop the reaction. The separated organic layer was collected, and the aqueous layer was further extracted three times with 100 mL of chloroform. All the organic layers were combined and dehydrated using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The product was purified by silica gel chromatography using acetone / tetrahydrofuran (v / v=2:1) ​​as a developing solvent to obtain the target product.

[0061] 3) Synthesis of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-propyl-2-pyrrolidone

[0062] [ka]

[0063] 8.36 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-pyrrolidone was dissolved in 120 mL of dehydrated tetrahydrofuran and cooled to -35°C under nitrogen atmosphere. 29.5 mL of lithium bis(trimethylsilyl)amide (LHMDS) tetrahydrofuran solution (1.3 M) was slowly added dropwise thereto and stirred for 90 minutes. 13.5 g of iodopropane dissolved in 60 mL of dehydrated tetrahydrofuran was added dropwise thereto and stirred overnight. The reaction solution was placed in an ice bath and distilled water was added dropwise to stop the reaction. The separated organic layer was collected, and the aqueous layer was further extracted three times with 100 mL of chloroform. All the organic layers were combined and dehydrated using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The product was purified by silica gel chromatography using acetone / tetrahydrofuran (v / v=2:1) ​​as a developing solvent to obtain the target product.

[0064] 4) Synthesis of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-butyl-2-pyrrolidone

[0065] [ka]

[0066] 12.5 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-pyrrolidone was dissolved in 180 mL of dehydrated tetrahydrofuran and cooled to -35°C under nitrogen atmosphere. 45.0 mL of lithium bis(trimethylsilyl)amide (LHMDS) tetrahydrofuran solution (1.3 M) was slowly added dropwise thereto and stirred for 90 minutes. 21.6 g of iodobutane dissolved in 60 mL of dehydrated tetrahydrofuran was added dropwise thereto and stirred overnight. The reaction solution was placed in an ice bath and distilled water was added dropwise to stop the reaction. The separated organic layer was collected, and the aqueous layer was further extracted three times with 100 mL of chloroform. All the organic layers were combined and dehydrated using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The product was purified by silica gel chromatography using acetone / tetrahydrofuran (v / v=2:1) ​​as a developing solvent to obtain the target product.

[0067] 5) Synthesis of N-(2-hydroxyethyl)-3-ethyl-2-pyrrolidone

[0068] [ka]

[0069] 2.89 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-ethyl-2-pyrrolidone was dissolved in 70 mL of methanol, and 0.297 g of Amberlyst (registered trademark) 15 was added and stirred at room temperature overnight. Thereafter, the reaction solution was filtered to remove Amberlyst (registered trademark) 15, and the solvent was distilled off under reduced pressure to obtain the target product.

[0070] 6) Synthesis of N-(2-hydroxyethyl)-3-propyl-2-pyrrolidone

[0071] [ka]

[0072] 2.78 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-propyl-2-pyrrolidone was dissolved in 70 mL of methanol, and 0.281 g of Amberlyst (registered trademark) 15 was added and stirred at room temperature overnight. Thereafter, the reaction solution was filtered to remove Amberlyst (registered trademark) 15, and the solvent was distilled off under reduced pressure to obtain the target product.

[0073] 7) Synthesis of N-(2-hydroxyethyl)-3-butyl-2-pyrrolidone

[0074] [ka]

[0075] 4.83 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-3-butyl-2-pyrrolidone was dissolved in 150 mL of methanol, and 0.495 g of Amberlyst (registered trademark) 15 was added and stirred at room temperature overnight. Thereafter, the reaction solution was filtered to remove Amberlyst (registered trademark) 15, and the solvent was distilled off under reduced pressure to obtain the target product.

[0076] 8) Synthesis of N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone

[0077] [ka]

[0078] 1.68g of N-(2-hydroxyethyl)-3-ethyl-2-pyrrolidone and 1.22g of triethylamine were dissolved in 30mL of dehydrated dichloromethane and stirred under ice cooling. 0.981g of acryloyl chloride dissolved in 20mL of dehydrated dichloromethane was added dropwise under ice cooling and stirred at room temperature overnight. The reaction solution was then washed three times with 100mL of 1M hydrochloric acid, three times with 100mL of 5% potassium carbonate aqueous solution, and three times with 100mL of saturated saline. The organic layer was collected and dehydrated with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The product was purified using an alumina column using dichloromethane as a developing solvent to obtain the target product.

[0079] 9) Synthesis of N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone

[0080] [ka]

[0081] 1.69g of N-(2-hydroxyethyl)-3-propyl-2-pyrrolidone and 0.893g of triethylamine were dissolved in 30mL of dehydrated dichloromethane and stirred under ice cooling. 0.865g of acryloyl chloride dissolved in 20mL of dehydrated dichloromethane was added dropwise under ice cooling and stirred at room temperature overnight. The reaction solution was then washed three times with 100mL of 1M hydrochloric acid, three times with 100mL of 5% potassium carbonate aqueous solution, and three times with 100mL of saturated saline. The organic layer was collected and dehydrated with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The product was purified using an alumina column using dichloromethane as a developing solvent to obtain the target product.

[0082] 10) Synthesis of N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone

[0083] [ka]

[0084] 2.43g of N-(2-hydroxyethyl)-3-butyl-2-pyrrolidone and 1.56g of triethylamine were dissolved in 50mL of dehydrated dichloromethane and stirred under ice cooling. 1.20g of acryloyl chloride dissolved in 35mL of dehydrated dichloromethane was added dropwise under ice cooling and stirred at room temperature overnight. The reaction solution was then washed three times with 100mL of 1M hydrochloric acid, three times with 100mL of 5% potassium carbonate aqueous solution, and three times with 100mL of saturated saline. The organic layer was collected and dehydrated with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. The product was purified using an alumina column using dichloromethane as a developing solvent to obtain the target product.

[0085] 11) Synthesis of Poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone)

[0086] [ka]

[0087] 0.23g of N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone and 1.8mg of 2,2'-azobisisobutyronitrile (AIBN) were dissolved in 0.86mL of dehydrated dimethylformamide. Dissolved oxygen in the system was removed by freeze degassing, and the reaction was carried out at 60°C for 16 hours. The reaction solution was poured into a large excess of diethyl ether to precipitate the produced polymer. The product was purified by reprecipitation using methanol as a good solvent and diethyl ether as a poor solvent to obtain the target product. (Weight average molecular weight: 50,300) 12) Synthesis of Poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone)

[0088] [ka]

[0089] 0.237g of N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone and 1.7mg of 2,2'-azobisisobutyronitrile (AIBN) were dissolved in 0.81mL of dehydrated dimethylformamide. Dissolved oxygen in the system was removed by freeze degassing, and the reaction was carried out at 60°C for 16 hours. The reaction solution was poured into a large excess of diethyl ether to precipitate the polymer that was produced. The product was purified by reprecipitation using methanol as a good solvent and diethyl ether as a poor solvent, and the target product was obtained. (Weight average molecular weight: 48,100) 13) Synthesis of Poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone)

[0090] [ka]

[0091] 0.715g of N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone and 4.36mg of 2,2'-azobisisobutyronitrile (AIBN) were dissolved in 1.94mL of dehydrated dimethylformamide. Dissolved oxygen in the system was removed by freeze degassing, and the reaction was carried out at 60°C for 12 hours. The reaction solution was poured into a large excess of water to precipitate the produced polymer. The product was purified by precipitation using methanol as a good solvent and water as a poor solvent, and the target product was obtained. (Weight average molecular weight: 48,300)

[0092] 13) Substrate adhesion test Coating onto polycarbonate (φ14 mm) was carried out as follows: The polymer was dissolved in methanol to a concentration of 0.20 wt % to prepare a coating liquid.

[0093] As a comparative polymer, the following PMEA (where n represents the number of repeating monomer units) was prepared.

[0094] [ka]

[0095] As a reference example, the following polymer PNAHxP (where n represents the number of repeating monomer units) was prepared.

[0096] [ka]

[0097] As the polymers according to the present invention, poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone), poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone), and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone) were prepared.

[0098] The coating liquid was applied to the substrate surface at 40.8 μL / cm 2 The solution was dropped so that the thickness of the solution became 1 / 4000 and the solution was spin-coated at 4,500 rpm for 30 seconds for PMEA, PNAHxP, and poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone). The solution was spin-coated at 4,000 rpm for 40 seconds for poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone) and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone).

[0099] The results are shown in Figure 1. Figure 1 is a photograph showing the adhesion of each polymer to a polycarbonate substrate. As shown in Figure 1, in the case of PMEA, the substrate surface is exposed and the adhesion to the substrate is insufficient. However, in the cases of poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone), poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone), and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone) according to the present invention, the substrate surface is not exposed and the adhesion to the substrate is excellent.

[0100] Next, the substrate was changed to a glass substrate (φ14 mm) and coating was performed in the same manner as in the case of the polycarbonate substrate.

[0101] The results are shown in Figure 2. Figure 2 is a photograph showing the adhesion of each polymer to a glass substrate. As shown in Figure 2, in the case of PMEA, the substrate surface is exposed and the adhesion to the substrate is insufficient. However, in the cases of poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone), poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone), and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone) according to the present invention, the substrate surface is not exposed and the adhesion to the substrate is excellent.

[0102] 14) Platelet adhesion test The platelet adhesion test was carried out as follows. First, similarly to the above-mentioned 13) Substrate adhesion test, polymer PMEA was prepared as a comparative example, polymer PNAHxP was prepared as a reference example, and poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone), poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone), and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone) were prepared as polymers according to the present invention. Then, similarly to the above-mentioned 13) Substrate adhesion test, coating was carried out on a polycarbonate substrate.

[0103] Blood samples were purchased from the Japanese Red Cross Society and were experimental blood samples collected in Japan. Immediately after arrival, the blood samples were dispensed into vacuum blood collection tubes and stored in a refrigerator. After dispensing, the blood samples were used in the experiment within 2 days. The blood samples were left to stand at room temperature for 30 minutes before use and returned to room temperature. The blood samples were slowly stirred by inversion 5 times and then centrifuged at 400 rcf for 5 minutes in a centrifuge. The entire supernatant was collected and used as platelet-rich plasma (PRP). After collection, the sediment was further centrifuged at 2500 rcf for 10 minutes. The entire supernatant was collected and used as platelet-poor plasma (PPP). The platelet concentration in PRP was calculated by counting the platelets in PRP diluted 800-fold with phosphate-buffered saline using a hemocytometer, and the concentration was found to be 1.28 × 10 8 PRP was diluted with PPP to obtain cells / mL.

[0104] The platelet suspension was then applied to each substrate sample at 313 μL / cm2 (Platelet seeding density: 4.0 × 10 7 cells / cm 2 ) and incubated at 37°C for 1 hour. The platelet suspension was then removed and the substrate was washed twice with phosphate-buffered saline. To immobilize the platelets adhering to the substrate surface, the substrate was immersed in a 1% aqueous glutaraldehyde solution and incubated at 37°C for 2 hours. After immobilization, the substrate was washed by immersing once in phosphate-buffered saline (10 minutes), once in phosphate-buffered saline:water = 1:1 (8 minutes), and twice in water (10 minutes). After removing the water, the substrate was dried for 1 day in a container containing silica gel. After drying, the substrate surface was observed under a scanning electron microscope and the number of adhered platelets was counted.

[0105] The results are shown in Figure 3. Figure 3 shows the number of platelets adhered to the polycarbonate substrate for each polymer. Inhibition of platelet adhesion means excellent antithrombotic properties. As shown in Figure 3, in the case of PMEA, platelets adhered to the substrate surface and antithrombotic properties were insufficient. However, in the case of poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone), poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone), and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone) according to the present invention, platelets did not adhere to the substrate surface and antithrombotic properties were excellent. [Industrial Applicability]

[0106] It can be used to coat medical devices.

Claims

1. A polymer composition comprising a polymer having a monomer unit represented by chemical formula (1) However, in the chemical formula (1), m is a natural number from 2 to 12, n means the number of repeating monomer units, R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ２ is an oxygen atom, a sulfur atom, SO, SO ２ , or NR ３ (However, R ３ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; X １ , X ２ , or X ３ are each independently selected from the group represented by the following (I), (II), (III) or (IV) (wherein X １ , X ２ , and X ３ are not all hydrogen atoms.) (I) a hydrogen atom; (II) a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; (III) a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms; In the case where the alkyl group, alkenyl group, and alkynyl group are substituted, they are substituted with one or more groups independently selected from the group consisting of the following (a) to (c): (a) a halogen atom, a hydroxyl group, a carboxy group, a mercapto group, an oxo group, a haloalkyl group having 1 to 6 carbon atoms, and a haloalkoxy group having 1 to 6 carbon atoms; (b) an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 2 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms; (c) an amino group, a carbamoyl group, a sulfamoyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkoxy group, a 4- to 8-membered saturated heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryloxy group, and a 5- to 10-membered heteroaryloxy group; (IV) Methoxy group, ethoxy group, 2-hydroxyethoxy group, 2-methoxyethoxy group, carboxymethoxy group, 5-tetrazolylmethoxy group, cyanomethoxy group, 4-piperidylmethoxy group, 2-(N,N-dimethylamino)ethoxy group, 3-oxetanylmethoxy group, 2-morpholinoethoxy group, 2-(N-methylpiperazino)ethoxy group, 2-pyrrolidinoethoxy group, 2-piperidinoethoxy group , 3-pyrrolidinopropoxy group, 3-tetrahydrofuryloxy group, 4-tetrahydropyranyloxy group, 4-(N-methylpiperidyl)methoxy group, 2-hydroxy-2-methylpropoxy group, carbamoylmethoxy group, piperidino group, morpholino group, piperazino group, 4-cyanopiperidino group, 4-methoxycarbonylpiperazino group, 3,5-dimethylmorpholino group, 3,5-dimethylpiperazino group, 4 -methoxypiperidino group, 4-carboxypiperidino group, N-methylsulfonylpiperazino group, 4-methylsulfonylpiperidino group, N-2-hydroxy-2-methylpropylpiperazino group, N-hydroxyacetylpiperazino group, N-acetylpiperazino group, N-methylpiperazino group, N-(3-oxetanyl)piperazino group, 4-hydroxycyclohexyl group, 1-methylpyrazol-4-yl group, 4-(N,N-dimethylamino)phenyl group, 4-ethoxycarbonyloxazol-2-yl group, 4-(N-methylpiperazino)phenyl group, ethoxycarbonyl group, N-(2-morpholinoethyl)carbamoyl group, 2-oxazolyl group, 4-morpholinocarbonyloxazol-2-yl group, 4-pyrrolidinomethyloxazol-2-yl group, or 4-carboxyoxazol-2-yl group;). 【Chemistry 1】

2. A polymer composition comprising a polymer having a monomer unit represented by chemical formula (2) However, in the chemical formula (2), m is a natural number from 2 to 12, n means the number of repeating monomer units, R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ２ is an oxygen atom, a sulfur atom, SO, SO ２ , or NR ３ (However, R ３ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; X １ are each independently selected from the group represented by (I), (II) or (III) below. (I) a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; (II) a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms; In the case where the alkyl group, alkenyl group, and alkynyl group are substituted, they are substituted with one or more groups independently selected from the group consisting of the following (a) to (c): (a) a halogen atom, a hydroxyl group, a carboxy group, a mercapto group, an oxo group, a haloalkyl group having 1 to 6 carbon atoms, and a haloalkoxy group having 1 to 6 carbon atoms; (b) an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 2 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms; (c) an amino group, a carbamoyl group, a sulfamoyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkoxy group, a 4- to 8-membered saturated heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryloxy group, and a 5- to 10-membered heteroaryloxy group; (III) Methoxy group, ethoxy group, 2-hydroxyethoxy group, 2-methoxyethoxy group, carboxymethoxy group, 5-tetrazolylmethoxy group, cyanomethoxy group, 4-piperidylmethoxy group, 2-(N,N-dimethylamino)ethoxy group, 3-oxetanylmethoxy group, 2-morpholinoethoxy group, 2-(N-methylpiperazino)ethoxy group, 2-pyrrolidinoethoxy group, 2-piperidinoethoxy group , 3-pyrrolidinopropoxy group, 3-tetrahydrofuryloxy group, 4-tetrahydropyranyloxy group, 4-(N-methylpiperidyl)methoxy group, 2-hydroxy-2-methylpropoxy group, carbamoylmethoxy group, piperidino group, morpholino group, piperazino group, 4-cyanopiperidino group, 4-methoxycarbonylpiperazino group, 3,5-dimethylmorpholino group, 3,5-dimethylpiperazino group, 4 -methoxypiperidino group, 4-carboxypiperidino group, N-methylsulfonylpiperazino group, 4-methylsulfonylpiperidino group, N-2-hydroxy-2-methylpropylpiperazino group, N-hydroxyacetylpiperazino group, N-acetylpiperazino group, N-methylpiperazino group, N-(3-oxetanyl)piperazino group, 4-hydroxycyclohexyl group, 1-methylpyrazol-4-yl group, 4-(N,N-dimethylamino)phenyl group, 4-ethoxycarbonyloxazol-2-yl group, 4-(N-methylpiperazino)phenyl group, ethoxycarbonyl group, N-(2-morpholinoethyl)carbamoyl group, 2-oxazolyl group, 4-morpholinocarbonyloxazol-2-yl group, 4-pyrrolidinomethyloxazol-2-yl group, or 4-carboxyoxazol-2-yl group;). 【Chemistry 2】

3. A polymer composition comprising a polymer having a monomer unit represented by chemical formula (3) ( However, in the chemical formula (3), m is a natural number from 2 to 12, n means the number of repeating monomer units, X １ represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2 to 10 carbon atoms; Here, when the alkyl group, alkenyl group, and alkynyl group are substituted, they are substituted with one or more groups independently selected from the group consisting of the following (a) to (c): (a) a halogen atom, a hydroxyl group, a carboxy group, a mercapto group, an oxo group, a haloalkyl group having 1 to 6 carbon atoms, and a haloalkoxy group having 1 to 6 carbon atoms; (b) an alkoxy group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 2 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms; (c) an amino group, a carbamoyl group, a sulfamoyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered cycloalkoxy group, a 4- to 8-membered saturated heterocyclic group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryloxy group, and a 5- to 10-membered heteroaryloxy group. 【Chemistry 3】

4. A polymer composition comprising a polymer having a monomer unit represented by chemical formula (4) (wherein n represents the number of repeating monomer units). 【Chemistry 4】

5. 5. An antithrombotic coating agent for a medical device, comprising the polymer composition according to claim 1 and a solvent containing at least one of water and an alcohol.

6. 6. The antithrombotic coating agent according to claim 5, wherein the medical device is any one of an artificial organ, a therapeutic device, an artificial organ, a catheter, a guide wire, and a stent.

7. 6. The antithrombotic coating agent according to claim 5, wherein the alcohol is at least one selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, and 2-methyl-2-propanol.

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