Polymer composition and antithrombotic coating agent

Abstract

Provided is a polymer composition that achieves both substrate adhesion properties and antithrombogenicity. The polymer composition is characterized by containing a polymer having a monomer unit represented by chemical formula (1). m represents a natural number of 2-12; n represents the number of repetitions of the monomer unit; R1 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms; R2 represents an oxygen atom, a sulfur atom, SO, SO2, or NR3; and X1, X2 and X3 each independently represent (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 1-12 carbon atoms, a substituted or unsubstituted alkenyl group having 2-10 carbon atoms, or a substituted or unsubstituted alkynyl group having 2-10 carbon atoms, or (IV) a methoxy group, an ethoxy group, or a 2-hydroxyethoxy group. Provided that X1, X2 and X3 are not all hydrogen atoms.

Description

Polymer composition and antithrombogenic coating agent

[0001] The present invention relates to a polymer composition characterized by being unlikely to cause a foreign body reaction in a living body or biological substances such as biological tissues including blood, cells, and proteins, when the polymer composition comes into contact with the living body, and to an antithrombotic coating agent using the polymer composition.

[0002] In general, medical materials are required to have antithrombogenicity (i.e., the property of inhibiting platelet adhesion to the surface of the material). 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, resulting in, for example, nonspecific adsorption of proteins to the surface, causing denaturation, and consequent activation of the coagulation system, complement system, and platelet system. For this reason, for example, in the case of surfaces 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 to prevent the device from being recognized as a foreign body and causing a foreign body reaction in the biological substance during use. Various biocompatible materials have been proposed, and their practical use in medical settings and the like is progressing.

[0003] To impart antithrombotic properties to medical materials, hydrophilic groups are imparted to the polymers that make up the medical material. 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 made by polymerizing a unit structure in which a structure (phospholipid polar group) that mimics a substance that makes up the body is bonded to a polymerizable group such as a vinyl group as a monomer. By applying a composition containing this MPC polymer to the surface of a medical device, biocompatibility is imparted, platelet adhesion and other problems are suppressed, and excellent antithrombotic properties are exhibited. Furthermore, polyethylene glycol (PEG) has a chain ether structure -(C ２ H ４ It is a polymer with a repeating unit of -O-, and is known to have excellent biocompatibility despite having a structure dissimilar to the substances that constitute living organisms (Non-Patent Document 1, Patent Document 1).

[0004] On the other hand, medical materials also require substrate adhesion. To provide substrate adhesion to medical materials, hydrophobic groups are added to the polymer that makes up the medical material. The hydrophobic groups of the polymer prevent the polymer from leaching out into blood and also improve 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 MPC polymer, since MPC homopolymer is water-soluble and difficult to use as a medical material, a technique has been used in which MPC is copolymerized with a hydrophobic structural unit (butyl methacrylate, etc.) to achieve both biocompatibility and water insolubility (Patent Document 2). Furthermore, since the above PEG is also water-soluble, efforts have been made to improve water resistance by copolymerizing it with other structural units (Patent Document 3) or by forming a crosslinked structure (Patent Document 4).

[0007] The above examples involve the use of techniques such as adding hydrophobic structural units that do not exhibit biocompatibility or modifying part of the structure of the original biocompatibility polymer in order to impart hydrophobicity to the biocompatibility polymer in order to make it insoluble in water, which raises concerns from the perspective of biocompatibility.

[0008] Poly(2-methoxyethyl acrylate) (PMEA) is a coating material with excellent antithrombotic properties. A specially structured water barrier layer exists at the interface between PMEA and blood components. Precise electronic state analysis 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 due to the interaction between PMEA and water. A small amount of water molecules adsorbed to specific sites in this phase-separated structure act as a scaffold for the subsequent growth of the barrier layer (Non-Patent Document 2).

[0009] However, PMEA's adhesion to substrates is insufficient, leaving room for improvement. Therefore, an inorganic / organic hybrid material called an SQ / PMEA hybrid has been proposed by combining it with the inorganic compound SQ (silsesquioxane) (Patent Document 5). Furthermore, Non-Patent Document 3 describes the synthesis of an SQ / PMEA hybrid by thiol-initiated radical polymerization of 2-methoxyethyl acrylate (MEA) from a thiol-containing random silsesquioxane (SQ-SH) using 2,2'-azobisisobutyronitrile as an initiator. SQ / PMEA hybrids offer superior substrate adhesion compared to PMEA homopolymers. However, inorganic / organic hybrid materials are disadvantageous compared to homopolymer materials in terms of production cost and manufacturing procedure. Furthermore, SQ / PMEA hybrids have the problem of reduced antithrombogenicity depending on the amount of SQ used in the hybridization.

[0010] It is known that some polymers having a 2-pyrrolidone structure with a five-membered ring 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 level of antithrombotic properties and is water-soluble like the above-mentioned MPC polymer and PEG. For example, Patent Document 6 describes a technique for crosslinking this polyvinylpyrrolidone by irradiation.

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

[0012] The common feature of the various polymers described above is that the phenomenon of the polymer's biocompatibility and the phenomenon of the polymer's water solubility are essentially similar, suggesting the existence of a kind of trade-off relationship between biocompatibility and water resistance. The aforementioned 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.

[0014] JP 2016-63801 JP 3-39309 JP 2005-23108 JP 2005-255875 JP 2021-80323 JP 2-86838 JP 4-28705

[0015] Tanaka, M. et al., Journal of Biomaterials Science Polymer Edition, 2010, 21, p. 1849-1863 Murakami, D. et al., Langmuir, 2022, p. 1090-1098 Nishimura, S. et. al., ACS Applied Polymer Materials, 2020, 2, p. 4790-4801

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

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

[0018]

[0019] In the chemical formula (1), m is a natural number between 2 and 12, and n represents the number of repeating monomer units. １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ２ are oxygen atoms, sulfur atoms, SO, SO ２ , or NR ３ (However, R ３ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

[0020] X １ , X ２ , or X ３ are each independently selected from the group represented by the following (I), (II), (III) or (IV) (provided that X１ , X ２ , and X ３are 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 which case the alkyl group, alkenyl group, or alkynyl group, when substituted, 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, and 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 , a 3-pyrrolidinopropoxy group, a 3-tetrahydrofuryloxy group, a 4-tetrahydropyranyloxy group, a 4-(N-methylpiperidyl)methoxy group, a 2-hydroxy-2-methylpropoxy group, a carbamoylmethoxy group, a piperidino group, a morpholino group, a piperazino group, a 4-cyanopiperidino group, a 4-methoxycarbonylpiperazino group, a 3,5-dimethylmorpholino group, a 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;

[0021] According to the present invention, a polymer composition can be obtained that has both substrate adhesion and antithrombogenicity.

[0022] 1 is a photograph showing the adhesion of each polymer to a polycarbonate substrate, 2 is a photograph showing the adhesion of each polymer to a glass substrate, and 3 is a graph showing the number of platelets adhered to a polycarbonate substrate for each polymer.

[0023] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these embodiments are intended to facilitate understanding of the principles of the present invention, and the scope of the present invention is not limited to the following embodiments. Other embodiments in which a person skilled in the art appropriately replaces the configuration of the following embodiments 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 containing a polymer having a monomer unit represented by chemical formula (1).

[0025]

[0026] Polymers having a pyrrolidone ring in the side chain have excellent antithrombogenicity but poor adhesion to substrates. The present inventors have newly discovered that by adding a substituent to the pyrrolidone ring that enables interaction with the substrate, adhesion and uniformity to the substrate during coating can be improved without impairing antithrombogenicity, 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 connecting the main chain portion of the polymer and 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 insufficient, making it difficult to sufficiently suppress the elution of the polymer into blood. However, when m is any natural number from 2 to 12, the hydrophobicity is sufficient, making it possible to suppress the elution of the polymer into blood. Preferably, m is any natural number from 2 to 6, more preferably 2, 3, or 4, and most preferably 2. Note that if m is a natural number of 13 or greater, the hydrophobicity becomes strong, which may impair the antithrombotic properties.

[0028] In chemical formula (1), n ​​represents the number of repeating monomer units. Specifically, the polymer composition of 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 strength may be insufficient, making it impossible to form a strong coating. Furthermore, from the viewpoint of operability, the weight-average molecular weight of the polymer composition of 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] X １ , X ２ , or X ３ are each independently selected from the group consisting of (I), (II), (III) and (IV) below. １ , X ２ , and X ３are 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 which case the alkyl group, alkenyl group, or alkynyl group, when substituted, 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, and 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 , a 3-pyrrolidinopropoxy group, a 3-tetrahydrofuryloxy group, a 4-tetrahydropyranyloxy group, a 4-(N-methylpiperidyl)methoxy group, a 2-hydroxy-2-methylpropoxy group, a carbamoylmethoxy group, a piperidino group, a morpholino group, a piperazino group, a 4-cyanopiperidino group, a 4-methoxycarbonylpiperazino group, a 3,5-dimethylmorpholino group, a 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] Substituent X in chemical formula (1) １ , X ２ , or X ３ The presence of at least one of the substituents X at the α-position can provide adhesion to the substrate. １ The presence of a substituent X at only the α-position is preferable for exhibiting adhesion to a substrate. １ is most preferably present.

[0031]

[0032] X １ 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] X １ is more preferably an unsubstituted alkyl group having 1 to 12 carbon atoms, even more preferably an ethyl group, an n-propyl group, or an n-butyl group, and most preferably X １ is an ethyl group.

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

[0035] R ２ are oxygen atoms, sulfur atoms, SO, SO ２ , or NR ３ (However, R ３ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and preferably R ２is an oxygen atom or -NH-. As shown in the following chemical formula (3), R ２ is an oxygen atom.

[0036]

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

[0038]

[0039] The polymer composition of the present invention has a unique structure in which a substituent that enables interaction with a substrate is provided on the pyrrolidone ring in the monomer unit. Therefore, it can be synthesized as a homopolymer derived from one type of monomer unit, and is therefore 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, various properties can be imparted 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 that constitute 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; alkyl acrylates such as methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, hexyl acrylate, and 2-ethylhexyl acrylate. alkyl methacrylates such as alkyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, and hexyl methacrylate; alkoxy(meth)acrylates such as methoxy(meth)acrylate; alkoxyalkyl(meth)acrylates such as methoxyethyl(meth)acrylate; glycidyl methacrylate; alkyl acrylamides such as acrylamide, t-butylacrylamide, n-butylacrylamide, i-butylacrylamide, hexyl acrylamide, and heptyl acrylamide; N,N-dialkyl acrylamides such as N,N-dimethylacrylamide and N,N-diethylacrylamide; N,N-dialkyl methacrylamides such as methacrylamide, N,N-dimethylmethacrylamide, and N,N-diethylmethacrylamide; 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, as needed.

[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 solution, and then carry out the polymerization reaction.

[0044] The polymerization solvent is not particularly limited, but examples thereof include dimethylformamide, dimethylacetamide, dimethyl sulfoxide, 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 concentration of the monomer unit 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. The upper limit of the monomer unit concentration is not particularly limited, but is, for example, below the saturated concentration, 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 known initiators can be used. Preferably, a radical polymerization initiator is used in view of excellent polymerization stability. Specific examples thereof include 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, and 2,2'-azobis(2-methylpropionyl)propane. Examples of the polymerization initiator 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-dimethylbutylperoxyneodecanoate, α-cumylperoxyneodecanoate, 1,1,3,3-tetrabutylperoxyneodecanoate, t-butylperoxyneodecanoate, t-butylperoxyneoheptanoate, t-butylperoxypivalate, t-amylperoxyneodecanoate, t-amylperoxypivalate, 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, and more preferably 0.01 to 2 parts by mass, per 100 parts by mass of the monomer units.

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

[0047] The atmosphere 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. The reaction solution may be stirred during the polymerization reaction.

[0048] The polymer after polymerization can be purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, extraction, etc. Among the above methods, purification by reprecipitation 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 of the present invention contains a solvent in addition to the polymer composition of the present invention. The solvent is not particularly limited, but may include, for example, at least one of water or alcohol, and preferably the solvent is alcohol. The alcohol is not particularly limited, but may be, for example, 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, for example, 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 of the present invention in the antithrombotic coating agent is not particularly limited, but is preferably 0.1 to 20 wt %, more preferably 0.2 to 10 wt %.

[0051] Medical devices for which the antithrombotic coating agent can be 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-like artificial skin, and artificial pericardium, which are inserted into 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 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, 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, enteral 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 polymeric 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), and ethylene-tetrafluoroethylene copolymer (ETFE), glass, metal, ceramic, carbon, and composite materials thereof.

[0053] In medical devices, a coating layer consisting of a coating film of the antithrombotic coating agent according to the present invention is formed on the surface of a substrate. The coating layer is formed on the surface of a substrate by applying the antithrombotic coating agent according to the present invention to cover the surface of the substrate. The method for applying the antithrombotic coating agent according to the present invention to the surface of a substrate can be any known method, and is not particularly limited, and examples 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 can be adjusted appropriately depending on the application of the medical device, and is not particularly limited, but is formed to be thinner than 1000 μm, for example.

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

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

[0056]

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

[0060] 6.10 g of N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-pyrrolidone was dissolved in 90 mL of anhydrous tetrahydrofuran and cooled to −35° C. under a nitrogen atmosphere. 22 mL of a 1.3 M solution of lithium bis(trimethylsilyl)amide (LHMDS) in tetrahydrofuran was slowly added dropwise thereto, and the mixture was stirred for 90 minutes. 7.12 g of iodoethane dissolved in 30 mL of anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred overnight. The reaction solution was placed in an ice bath, and distilled water was added dropwise thereto to quench the reaction. The separated organic layer was recovered, and the aqueous layer was further extracted three times with 100 mL of chloroform. All 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]

[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 a nitrogen atmosphere. 29.5 mL of a 1.3 M solution of lithium bis(trimethylsilyl)amide (LHMDS) in tetrahydrofuran was slowly added dropwise thereto, and the mixture was stirred for 90 minutes. 13.5 g of iodopropane dissolved in 60 mL of dehydrated tetrahydrofuran was added dropwise thereto, and the mixture was stirred overnight. The reaction solution was placed in an ice bath, and distilled water was added dropwise thereto to quench the reaction. The separated organic layer was recovered, and the aqueous layer was further extracted three times with 100 mL of chloroform. All 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]

[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 a nitrogen atmosphere. 45.0 mL of a 1.3 M solution of lithium bis(trimethylsilyl)amide (LHMDS) in tetrahydrofuran was slowly added dropwise thereto, and the mixture was stirred for 90 minutes. 21.6 g of iodobutane dissolved in 60 mL of dehydrated tetrahydrofuran was added dropwise thereto, and the mixture was stirred overnight. The reaction solution was placed in an ice bath, and distilled water was added dropwise thereto to quench the reaction. The separated organic layer was recovered, and the aqueous layer was further extracted three times with 100 mL of chloroform. All 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]

[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 thereto, followed by stirring at room temperature overnight. Thereafter, the reaction solution was filtered to remove Amberlyst (registered trademark) 15, and the solvent was evaporated under reduced pressure to obtain the target product.

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

[0071]

[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 thereto, followed by stirring at room temperature overnight. Thereafter, the reaction solution was filtered to remove Amberlyst (registered trademark) 15, and the solvent was evaporated under reduced pressure to obtain the target product.

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

[0074]

[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 thereto, followed by stirring at room temperature overnight. Thereafter, the reaction solution was filtered to remove Amberlyst (registered trademark) 15, and the solvent was evaporated under reduced pressure to obtain the target product.

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

[0077]

[0078] 1.68 g of N-(2-hydroxyethyl)-3-ethyl-2-pyrrolidone and 1.22 g of triethylamine were dissolved in 30 mL of dehydrated dichloromethane and stirred under ice cooling. 0.981 g of acryloyl chloride dissolved in 20 mL of dehydrated dichloromethane was added dropwise to the solution under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was then washed three times with 100 mL of 1 M hydrochloric acid, three times with 100 mL of 5% aqueous potassium carbonate, and three times with 100 mL of saturated saline. The organic layer was recovered and dehydrated over anhydrous magnesium sulfate. The solvent was removed 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]

[0081] 1.69 g of N-(2-hydroxyethyl)-3-propyl-2-pyrrolidone and 0.893 g of triethylamine were dissolved in 30 mL of dehydrated dichloromethane and stirred under ice cooling. 0.865 g of acryloyl chloride dissolved in 20 mL of dehydrated dichloromethane was added dropwise to the solution under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was then washed three times with 100 mL of 1 M hydrochloric acid, three times with 100 mL of 5% aqueous potassium carbonate, and three times with 100 mL of saturated saline. The organic layer was recovered and dehydrated over anhydrous magnesium sulfate. The solvent was evaporated 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]

[0084] 2.43 g of N-(2-hydroxyethyl)-3-butyl-2-pyrrolidone and 1.56 g of triethylamine were dissolved in 50 mL of dehydrated dichloromethane and stirred under ice cooling. 1.20 g of acryloyl chloride dissolved in 35 mL of dehydrated dichloromethane was added dropwise to the solution under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was then washed three times with 100 mL of 1 M hydrochloric acid, three times with 100 mL of 5% aqueous potassium carbonate, and three times with 100 mL of saturated saline. The organic layer was recovered and dehydrated over anhydrous magnesium sulfate. The solvent was removed 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]

[0087] 0.23 g of N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone and 1.8 mg of 2,2'-azobisisobutyronitrile (AIBN) were dissolved in 0.86 mL 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, yielding the target product (weight average molecular weight: 50,300).

[0088] 12) Synthesis of poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone)

[0089]

[0090] 0.237 g of N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone and 1.7 mg of 2,2'-azobisisobutyronitrile (AIBN) were dissolved in 0.81 mL 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, yielding the target product (weight average molecular weight: 48,100).

[0091] 13) Synthesis of poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone)

[0092]

[0093] 0.715 g of N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone and 4.36 mg of 2,2'-azobisisobutyronitrile (AIBN) were dissolved in 1.94 mL 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 polymer was purified by precipitation using methanol as a good solvent and water as a poor solvent, yielding the target product (weight average molecular weight: 48,300).

[0094] 14) Substrate Adhesion Test Coating was carried out on polycarbonate (φ14 mm) as follows: The polymer was dissolved in methanol to a concentration of 0.20 wt % to prepare a coating solution.

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

[0096]

[0097] As a reference example, the following polymer PNAHxP (where n represents the number of repeating monomer units) was prepared.

[0098]

[0099] 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.

[0100] The coating liquid was applied to the substrate surface at 40.8 μL / cm ２ The solution was dropped so that the concentration became 0.01% and spin-coated at 4500 rpm for 30 seconds in the cases of PMEA, PNAHxP, and poly(N-(2-acryloyloxyethyl)-3-ethyl-2-pyrrolidone). The solution was spin-coated at 4000 rpm for 40 seconds in the cases of poly(N-(2-acryloyloxyethyl)-3-propyl-2-pyrrolidone) and poly(N-(2-acryloyloxyethyl)-3-butyl-2-pyrrolidone).

[0101] 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 was exposed and the adhesion to the substrate was 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, the substrate surface was not exposed and the adhesion to the substrate was excellent.

[0102] Next, the substrate was changed to a glass substrate (φ14 mm) and coating was carried out in the same manner as in the case of polycarbonate.

[0103] 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 was exposed and the adhesion to the substrate was 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, the substrate surface was not exposed and the adhesion to the substrate was excellent.

[0104] 15) Platelet Adhesion Test The platelet adhesion test was performed as follows. First, in the same manner as in 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, in the same manner as in the above-mentioned 13) Substrate Adhesion Test, a polycarbonate substrate was coated with the polymers.

[0105] The blood samples were purchased from the Japanese Red Cross Society and were collected in Japan for experiments. Immediately after arrival, they were dispensed into vacuum blood collection tubes and stored in a refrigerator. After dispensing, they were used in experiments within two days. The tubes were left to stand at room temperature for 30 minutes before use, and then returned to room temperature. After slow inversion five times, the tubes were centrifuged at 400 rcf for 5 minutes. 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 platelets in PRP diluted 800-fold with phosphate-buffered saline using a hemocytometer, and the concentration was found to be 1.28 x 10 ８ PRP was diluted with PPP to give a concentration of 100 cells / mL.

[0106] The platelet suspension was then applied to each substrate sample at 313 μL / cm ２ (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 adhered to the substrate surface, the substrate was immersed in a 1% glutaraldehyde aqueous solution and incubated at 37°C for 2 hours. After immobilization, the substrate was washed 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.

[0107] The results are shown in Figure 3. Figure 3 shows the number of platelets adhering to the polycarbonate substrate for each polymer. Suppression of platelet adhesion means excellent antithrombogenicity. As shown in Figure 3, in the case of PMEA, platelets adhered to the substrate surface, and the antithrombogenicity was 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 the antithrombogenicity was excellent.

[0108] 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) (wherein, in chemical formula (1), m is a natural number from 2 to 12, n is the number of repeating monomer units, and 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; 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 which, when the alkyl group, the alkenyl group, or the 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, and 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;); 2. A polymer composition comprising a polymer having a monomer unit represented by chemical formula (2) (wherein, in chemical formula (2), m is a natural number from 2 to 12, n is the number of repeating monomer units, and 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; 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 which, when the alkyl group, the alkenyl group, or the 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;(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;); 3. A polymer composition comprising a polymer having a monomer unit represented by chemical formula (3) (wherein, in chemical formula (3), m is a natural number from 2 to 12, n is the number of repeating monomer units, and 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; in this case, 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.

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).

5. An antithrombotic coating agent for medical devices, comprising the polymer composition according to any one of claims 1 to 4 and a solvent containing at least one of water and alcohol.

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. 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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