Medical coating agent and medical device

Abstract

To provide a medical coating agent which can impart excellent antithrombogenicity to the surface of a hardly coating base material such as a fluorine resin base material.SOLUTION: A medical coating agent contains a polymer containing a structural unit (M1) derived from an ethylenic unsaturated monomer having an urethane bond or an urea bond, and a structural unit (M2) derived from an ethylenic unsaturated monomer having a fluorine atom.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a medical coating agent and a medical device, and more particularly to a technique for imparting biocompatibility to a medical device that is used in contact with biological components or biological tissues. [Background technology]

[0002] Various materials, such as synthetic polymers, ceramics, glass, and metals, are used for medical devices. However, when a medical device comes into contact with biological components or biological tissues, the body may recognize the medical device as a foreign body, which may impair the function of the medical device or affect the body. For example, in applications where a medical device is used in contact with blood, components in the blood may recognize the medical device as a foreign body, activating the biological defense functions of those components and leading to the formation of a blood clot. Therefore, attention has been focused on imparting biocompatibility to the surface of a medical device using biocompatible synthetic polymers (see, for example, Patent Document 1).

[0003] Patent Document 1 discloses the use of a polymer having structural units derived from 2-methoxyethyl acrylate as a biocompatible medical material. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 04-152952 Summary of the Invention [Problem to be solved by the invention]

[0005] Various resin substrates are used as the substrate for medical devices, and substrates that are difficult to coat on the surface, such as fluororesin substrates (hereinafter also referred to as "difficult-to-coat substrates"), are sometimes used. However, when attempting to impart biocompatibility to the surface of a fluororesin substrate by coating it with a biocompatible synthetic polymer, the biocompatible synthetic polymer may not adhere to the substrate surface, making it impossible to impart biocompatibility to the surface of the medical device. Furthermore, in order to improve the adhesion between the substrate surface and the synthetic polymer, surface modification of the substrate surface by corona treatment, plasma treatment, etc. may be considered. However, in this case, a step of surface modification treatment of the substrate is required, which may complicate the manufacturing process of the medical device.

[0006] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a medical coating agent that can impart excellent antithrombogenicity to the surface of a hard-to-coat substrate such as a fluororesin substrate. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have found that by introducing a specific structural unit into a biocompatible polymer, it is possible to improve the adhesion of the polymer to a hard-to-coat substrate such as a fluororesin substrate while maintaining the antithrombogenicity of the polymer, thereby completing the present invention. Specifically, the present invention provides the following means.

[0008] [1] A medical coating agent containing a polymer including a structural unit (M1) derived from an ethylenically unsaturated monomer having a urethane bond or a urea bond and a structural unit (M2) derived from an ethylenically unsaturated monomer having a fluorine atom. [2] The medical coating agent according to [1], wherein the structural unit (M2) is a structural unit derived from an ethylenically unsaturated monomer having a CF2 group or a CF3 group. [3] The structural unit (M2) is a perfluoroalkyl group (-(CF2) nThe medical coating agent according to [1] or [2], wherein the structural unit is derived from an ethylenically unsaturated monomer having —CF3, where n≧1. [4] The medical coating agent according to any one of [1] to [3], wherein the content of the structural unit (M2) is 10 mass % or more based on all structural units contained in the polymer. [5] The medical coating agent according to any one of [1] to [4], wherein the glass transition temperature of the polymer in a saturated water-containing state is −30° C. or lower, when the water-containing state of the polymer is defined as a saturated water-containing state when the endothermic peak top due to ice melting appears at 0° C. in a DSC curve obtained by adding water to the polymer and raising the temperature at a rate of 5° C. / min using a differential scanning calorimeter (DSC). [6] The medical coating agent according to any one of [1] to [5], wherein when a film made of the polymer formed on a fluororesin substrate by spin coating is immersed in water for 5 minutes and then air bubbles are brought into contact with the film in water, the contact angle of the air bubbles is 120 degrees or more. [7] The medical coating agent according to any one of [1] to [6], wherein the polymer is a (meth)acrylic polymer. [8] A medical device having a substrate coated with the medical coating agent according to any one of [1] to [7]. [9] The medical device according to [8], wherein the substrate is a fluororesin substrate. [Effects of the Invention]

[0009] The medical coating agent of the present invention can impart excellent antithrombogenicity to the surface of a substrate that is difficult to coat, such as a fluororesin substrate. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a diagram showing an example of a DSC curve of a polymer containing intermediate water during hydration in a saturated water-containing state. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described in detail below. In this specification, "(meth)acrylic" means acrylic and / or methacrylic, and "(meth)acrylate" means acrylate and / or methacrylate. In the numerical ranges described in stages in this specification, the upper or lower limit value described in one numerical range may be replaced with the upper or lower limit value of another numerical range described in stages, and the upper or lower limit value of that numerical range may be replaced with a value shown in the examples.

[0012] <Medical coating agent> The medical coating agent of the present invention (hereinafter also referred to as "the coating agent") contains a polymer (hereinafter also referred to as "polymer (P)") containing a structural unit (M1) derived from an ethylenically unsaturated monomer having a urethane bond or a urea bond and a structural unit (M2) derived from an ethylenically unsaturated monomer having a fluorine atom. Each component contained in the coating agent will be described below.

[0013] <Polymer (P)> The polymer (P) may contain the structural unit (M1) and the structural unit (M2). The polymer (P) is preferably a (meth)acrylic polymer, because it can easily increase the reaction rate of the monomers and is easy to produce industrially. Specifically, the proportion of structural units derived from (meth)acrylic monomers in the polymer (P) among all structural units derived from the monomers constituting the polymer (P) is preferably more than 50% by mass, more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0014] (Structural unit (M1)) The structural unit (M1) contained in the polymer (P) is a structural unit derived from an ethylenically unsaturated monomer having a urethane bond or a urea bond (hereinafter also referred to as "monomer (A1)"). By containing the structural unit (M1), the polymer (P) becomes in a state containing a large amount of intermediate water upon hydration, which is thought to result in good antithrombotic properties.

[0015] Specifically, when a polymer (P) is soaked in water, the water interacting with the polymer (P) (i.e., hydrated water) can take three forms: "free water," "non-freezing water," and "intermediate water," depending on the strength of the interaction with the polymer. Of these, "free water" refers to water that has a weak interaction with the polymer and a freezing point of 0°C. "Non-freezing water" refers to water that has a strong interaction with the polymer and no detectable freezing point. "Intermediate water" refers to water that has an interaction with the polymer that is intermediate between free water and non-freezing water (i.e., that interacts relatively slowly with the polymer) and a freezing point below 0°C. It is believed that the biocompatibility of a polymer is related to the presence of intermediate water in the hydrated polymer (see, for example, paragraphs 0003 and 0004 of JP 2016-35000 A).

[0016] In other words, when cells recognize foreign substances in the body, the body's defense mechanisms are activated, resulting in a rejection reaction. Therefore, when a medical device comes into contact with biological components or tissues during treatment or surgery, if the body recognizes the medical device as a foreign body, the body's defense mechanisms are activated, which may interfere with treatment. For example, when a medical device comes into contact with blood, the body's defense mechanisms are activated, resulting in the formation of blood clots, which may inhibit the function of the medical device or affect the body. On the other hand, polymers with intermediate water on their surfaces are less likely to be recognized as foreign bodies by the body and are therefore thought to exhibit excellent antithrombotic properties.

[0017] Platelets and fibrinogen are known to be blood components involved in thrombus formation. Platelets are blood cells that are activated by foreign substances and aggregate on the foreign substances to form thrombi (platelet thrombi), contributing to primary hemostasis in the hemostasis process. Fibrinogen, a coagulation factor I, is a protein that is converted to fibrin in the final stage of blood coagulation to form coagulated thrombi, contributing to secondary hemostasis in the hemostasis process. Fibrinogen is one of the main blood components involved in thrombus formation, and its resistance to adsorption onto polymers is considered to be an important factor for imparting biocompatibility (more specifically, antithrombogenicity) to medical devices. In this regard, the inventors' studies have shown that polymers containing the structural unit (M1) easily retain intermediate water during hydration, which can sufficiently suppress adsorption of fibrinogen onto the polymer. The specific structure of the monomer (A1) constituting the structural unit (M1) is described in detail below.

[0018] The monomer (A1) is preferably a compound capable of introducing a structure having a urethane bond or a urea bond into the side chain of a polymer, and is preferably a (meth)acrylic monomer having a urethane bond or a urea bond. When the monomer (A1) is a (meth)acrylic monomer, it is preferable because the reaction rate of the monomer can be easily increased. Below, the ethylenically unsaturated monomer having a urethane bond and the ethylenically unsaturated monomer having a urea bond will be described. Note that, as the monomer (A1), one type may be used alone, or two or more types may be used.

[0019] Ethylenically unsaturated monomers with urethane bonds The ethylenically unsaturated monomer having a urethane bond (hereinafter also referred to as "monomer (A1-1)") is advantageous over (methoxycarbonyl)aminoalkyl(meth)acrylate and a monomer having the following general formula (I): CH2=CR 1 -COO-R 2-NH-COO-R 3 -R 4 …(I) (In general formula (I), R 1 is a hydrogen atom or a methyl group, and R 2 is an alkylene group having 1 to 5 carbon atoms or "-(R 5 O) m -R 6 -" (where R 5 is an alkylene group having 1 to 3 carbon atoms, and R 6 is an alkylene group having 1 to 3 carbon atoms, and m is an integer of 1 to 3, and R 3 is an alkylene group having 1 to 3 carbon atoms, any hydrogen atom of which may be substituted with an alkoxy group having 1 to 10 carbon atoms, and R 4 is an alkoxy group having 1 to 10 carbon atoms. Compounds represented by the following formula (I) can be preferably used.

[0020] Furthermore, from the viewpoint of sufficiently increasing the anti-adsorption property of fibrinogen, R 3 In the case of R in general formula (I), any hydrogen atom of the alkylene group is more preferably substituted with an alkoxy group having 1 to 4 carbon atoms, and even more preferably with an alkoxy group having 1 or 2 carbon atoms. 4 is more preferably an alkoxy group having 1 to 4 carbon atoms, and even more preferably an alkoxy group having 1 or 2 carbon atoms.

[0021] Specific examples of the (methoxycarbonyl)aminoalkyl(meth)acrylate include (methoxycarbonyl)aminomethyl(meth)acrylate, 2-((methoxycarbonyl)amino)ethyl(meth)acrylate, 3-((methoxycarbonyl)amino)propyl(meth)acrylate, etc. Among these, 2-((methoxycarbonyl)amino)ethyl acrylate is preferably used because it can sufficiently lower the glass transition temperature of the polymer (P) in a saturated water-containing state.

[0022] Specific examples of the compound represented by the general formula (I) include 2-(((2-methoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-(((2-ethoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-(((2-propoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1,3-dimethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 2-( Examples of such acrylates include (((1,3-diethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1-methoxy-3-ethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 6-oxo-2,5,10-trioxa-7-azadodecan-12-yl (meth)acrylate, and 7-oxo-3,6,11-trioxa-8-azatridecan-13-yl (meth)acrylate.

[0023] Ethylenically unsaturated monomers with urea bonds The ethylenically unsaturated monomer having a urea bond (hereinafter also referred to as "monomer (A1-2)") is selected from the following general formula (II): from the viewpoints of obtaining a water-insoluble polymer (P), increasing the amount of water of hydration that the polymer (P) retains when the polymer (P) is brought into contact with water, and sufficiently lowering the glass transition temperature of the polymer (P) in a saturated water-containing state. CH2=CR 7 -COO-R 8 -NH-CO-NH-(R 9 O)nR 10 …(II) (In general formula (II), R 7 is a hydrogen atom or a methyl group, and R 8 is an alkylene group having 2 to 5 carbon atoms, and R 9 is an alkylene group having 1 to 3 carbon atoms, and R 10 is an alkyl group having 1 to 12 carbon atoms, and n is an integer of 0 to 2, provided that "-(R 9 The total number of carbon atoms in the 9 (number of carbon atoms multiplied by n) and R 10 and the total number of carbon atoms is 4 or more) It is preferable that the compound is represented by the following formula:

[0024] Furthermore, from the viewpoint of sufficiently increasing the anti-adsorption property of fibrinogen and obtaining a polymer exhibiting excellent biocompatibility, n in general formula (II) is preferably 1 or 2, and more preferably 1. From the same viewpoint, R 10 is more preferably an alkyl group having 1 to 5 carbon atoms, and even more preferably an alkyl group having 1 or 2 carbon atoms.

[0025] Specific examples of the compound represented by the general formula (II) include 2-(3-(2-ethoxyethyl)ureido)ethyl (meth)acrylate, 2-(3-(3-methoxypropyl)ureido)ethyl (meth)acrylate, 2-(3-(3-ethoxypropyl)ureido)ethyl (meth)acrylate, 2-(3-(4-methoxybutyl)ureido)ethyl (meth)acrylate, 3-(3-(2-ethoxyethyl)ureido) propyl (meth)acrylate, 3-(3-(3-methoxypropyl)ureido)propyl (meth)acrylate, 4-(3-(2-ethoxyethyl)ureido)butyl (meth)acrylate, 2-(3-(n-butyl)ureido)ethyl (meth)acrylate, 2-(3-(n-octyl)ureido)ethyl (meth)acrylate, 2-(3-(n-dodecyl)ureido)ethyl (meth)acrylate, and the like.

[0026] Among the above, the monomer (A1-2) is a monomer represented by the general formula (II) in which n is 1 and R 10 is an alkyl group having 1 to 5 carbon atoms, and in general formula (II), n is 1 and R 10 is an alkyl group having 1 or 2 carbon atoms. Of these, at least one selected from the group consisting of 2-(3-(2-ethoxyethyl)ureido)ethyl(meth)acrylate, 2-(3-(3-methoxypropyl)ureido)ethyl(meth)acrylate, 3-(3-(2-ethoxyethyl)ureido)propyl(meth)acrylate, and 3-(3-(3-methoxypropyl)ureido)propyl(meth)acrylate is particularly preferred.

[0027] The polymer (P) preferably contains a structural unit derived from the monomer (A1-1) as the structural unit (M1), in that a polymer having superior anti-adsorption properties to fibrinogen can be obtained.

[0028] The polymer (P) preferably contains 10% by mass or more of the structural unit (M1) relative to the total structural units of the polymer (P). When the proportion of the structural unit (M1) in the polymer (P) is within the above range, the coating agent can be sufficiently effective in inhibiting fibrinogen adsorption to a substrate, which is advantageous in that a medical device with excellent antithrombotic properties can be obtained. From this perspective, the proportion of the structural unit (M1) in the polymer (P) is preferably 20% by mass or more, more preferably 30% by mass or more, and even more preferably 40% by mass or more, relative to the total structural units of the polymer (P). Furthermore, from the perspective of ensuring adhesion to difficult-to-coat substrates, the proportion of the structural unit (M1) in the polymer (P) is preferably 95% by mass or less, more preferably 90% by mass or less, relative to the total structural units of the polymer (P).

[0029] (Structural unit (M2)) The structural unit (M2) is a structural unit derived from an ethylenically unsaturated monomer having a fluorine atom (hereinafter also referred to as "monomer (A2)"), and the monomer (A2) may be any monomer that is copolymerizable with the monomer (A1).

[0030] The monomer (A2) is not particularly limited, but is preferably an ethylenically unsaturated monomer having a CF2 group or a CF3 group, from the viewpoint of enhancing the adhesion of the polymer (P) to a hard-to-coat substrate (for example, a fluororesin substrate), and further preferably a perfluoroalkyl group (-(CF2) n More preferably, it is an ethylenically unsaturated monomer having —CF3, where n≧1.

[0031] Specific examples of the monomer (A2) include (meth)acrylic monomers having a (meth)acryloyl group, such as trifluoromethyl (meth)acrylate, pentafluoroethyl (meth)acrylate, heptafluoropropyl (meth)acrylate, nonafluorobutyl (meth)acrylate, undecafluoropentyl (meth)acrylate, tridecafluorohexyl (meth)acrylate, pentadecafluoroheptyl (meth)acrylate, and monomers represented by the following general formula (1): fluoroethylenes such as monofluoroethylene, difluoroethylene, trifluoroethylene, chlorotrifluoroethylene, and tetrafluoroethylene; vinylidene fluoride, vinyl fluoride, and hexafluoropropylene. The monomer (A2) may be used singly or in combination of two or more.

[0032] Among these, (meth)acrylic monomers are preferred from the viewpoints of copolymerizability and ease of handling, and monomers represented by the following general formula (1) are more preferred from the viewpoints of availability and cost, and from the viewpoints of sufficiently increasing the adhesion of polymer (P) to hard-to-coat substrates such as fluororesin substrates and improving the coatability of the present coating agent. Furthermore, from the viewpoint of ensuring resistance to adsorption of fibrinogen, acrylic monomers are more preferred than methacrylic monomers as the ethylenically unsaturated monomer. When an acrylic monomer and a methacrylic monomer are used in combination, it is preferable to use a larger amount of the acrylic monomer than the amount of the methacrylic monomer.

[0033] CH2=C(R 1 )-COO-(CH2) m -(CF2) n -Z (1) [In the formula, R1 represents a hydrogen atom or a methyl group, Z represents a hydrogen atom or a fluorine atom, m represents an integer of 1 to 4, and n represents an integer of 1 to 20.]

[0034] Z in the above general formula (1) is preferably a fluorine atom because the properties of fluorine are prominent. Regarding m, m=1 or 2 is preferred from the viewpoint of availability. Regarding n, n=1 to 20 is preferable, but if n is small, the polymer (P) may not exhibit sufficient adhesion to a hard-to-coat substrate such as a fluororesin substrate, and if n is too large, the solubility in solvents and compatibility with other compounds may decrease. From these viewpoints, n=2 to 15 is more preferable, n=3 to 10 is even more preferable, and n=3 to 7 is even more preferable.

[0035] Commercially available preferred monomers (A2) include Cheminox FAAC-4, Cheminox FAAC-6, Cheminox FAMAC-4, and Cheminox FAMAC-6 (all manufactured by Unimatec Corporation), R-1110, R-1210, R-1420, R-1620, R-5210, R-5410, R-5610, M-1110, M-1210, M-1420, M-1620, M-5210, M-5410, and M-5610 (all manufactured by Daikin Corporation), Light Acrylate FA-108 (manufactured by Kyoeisha Chemical Co., Ltd.), Viscoat-3F, Viscoat-3FM, Viscoat-4F, Viscoat-8F, and Viscoat-8FM (all manufactured by Osaka Organic Chemical Industry Ltd.), and the like.

[0036] The polymer (P) preferably contains the structural unit (M2) in an amount of 5% by mass or more relative to the total structural units contained in the polymer (P). The proportion of the structural unit (M2) in the polymer (P) within the above range is advantageous in that it can further enhance the adhesion of the polymer (P) to difficult-to-coat substrates. From this perspective, the proportion of the structural unit (M2) in the polymer (P) is more preferably 10% by mass or more, and even more preferably 20% by mass or more, relative to the total structural units contained in the polymer (P). Furthermore, from the perspective of ensuring that the polymer (P) exhibits good antithrombogenicity, the proportion of the structural unit (M2) in the polymer (P) is preferably 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less, relative to the total structural units contained in the polymer (P).

[0037] The mass ratio ((M1) / (M2)) of the structural unit (M1) to the structural unit (M2) contained in the polymer (P) is preferably in the range of 95 / 5 to 10 / 90, more preferably in the range of 90 / 10 to 20 / 80, even more preferably in the range of 80 / 20 to 20 / 80, and even more preferably in the range of 80 / 20 to 30 / 70, from the viewpoint of obtaining a polymer that has a good balance between resistance to fibrinogen adsorption and adhesion to difficult-to-coat substrates.

[0038] (Other structural units) The polymer (P) may be composed of a structural unit (M1) and a structural unit (M2). Furthermore, the polymer (P) may further contain structural units different from the structural units (M1) and (M2) (hereinafter also referred to as "other structural units"), for example, to adjust the glass transition temperature of the polymer (P), within the scope of the present invention. The monomer constituting the other structural units may be any monomer copolymerizable with the monomers (A1) and (A2). Examples of such monomers include (meth)acrylic acid, methyl acrylate, ethyl acrylate, 2-methoxyethyl acrylate, hydroxyethyl (meth)acrylate, acrylonitrile, and styrene. The monomer constituting the other structural units may be used alone or in combination of two or more.

[0039] When polymer (P) contains other structural units, the proportion of the other structural units in polymer (P) is preferably 20% by mass or less, more preferably 10% by mass or less, even more preferably 5% by mass or less, and even more preferably 1% by mass or less, of the total structural units contained in polymer (P), from the viewpoint of ensuring resistance to fibrinogen adsorption and adhesion to difficult-to-coat substrates.

[0040] The polymer (P) may be a random copolymer, a block copolymer, a graft copolymer, etc. Among these, a random copolymer is preferred, since it can provide the polymer (P) with better resistance to fibrinogen adsorption and better adhesion to difficult-to-coat substrates.

[0041] The polymerization method for producing the polymer (P) is not particularly limited. The polymer (P) can be obtained by polymerizing monomers using known radical polymerization methods such as solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization. In the case of solution polymerization, for example, an organic solvent and monomers are charged into a reactor, a polymerization initiator (e.g., an azo compound) is added, and the mixture is heated to 40 to 250°C to polymerize, thereby obtaining the target polymer. When the polymer (P) obtained by the polymerization reaction is subjected to isolation and / or purification treatment, known methods can be used for these treatments. When the polymer (P) is isolated and / or purified by a reprecipitation method, a water-insoluble polymer may be recovered at a high purity by using an aqueous solvent.

[0042] (Polymer properties) ·Molecular weight characteristics The weight-average molecular weight (Mw) of the polymer (P) is preferably in the range of 2,000 to 2,000,000. An Mw of 2,000 or more ensures sufficient mechanical strength of the coating film formed on a substrate using the coating agent. Furthermore, an Mw of 2,000,000 or less can prevent the viscosity of the coating agent from becoming too high, making it easier to ensure good coatability and handleability. The Mw of the polymer (P) is more preferably 5,000 or more, even more preferably 10,000 or more, even more preferably 30,000 or more, and even more preferably 50,000 or more. The upper limit of the Mw of the polymer (P) is more preferably 1,500,000 or less, and even more preferably 1,000,000 or less. In this specification, the Mw of the polymer is a standard polystyrene-equivalent value obtained using gel permeation chromatography (GPC).

[0043] -About saturated water content According to the findings of the present inventors, when a polymer containing intermediate water upon hydration is sufficiently hydrated, i.e., saturated with water, the peak top of the endothermic heat due to ice melting appears at 0°C. Figure 1 shows an example of a DSC curve for a polymer containing intermediate water upon hydration in a saturated state. Note that water that melts around 0°C during the heating process is defined as "free water." Furthermore, water that has a different crystallization temperature from free water, forms crystals at a lower temperature than free water, and melts below 0°C during the heating process is defined as "intermediate water." Figure 1 shows DSC curves for a sufficiently hydrated polymer, measured using a differential scanning calorimeter (DSC) when the temperature was increased and decreased over a temperature range from -100°C to 40°C at a heating rate of 5°C / min.

[0044] During the temperature drop from 40°C to -100°C, a crystallization peak due to supercooling of free water is first observed, and then, at lower temperatures, a low-temperature crystallization peak due to intermediate water (the exothermic peak P1 in Figure 1) is observed. During the subsequent temperature rise from -100°C to 40°C, a low-temperature crystallization peak due to intermediate water (more specifically, intermediate water that did not freeze during the temperature drop) (the exothermic peak P2 in Figure 1) is observed. Note that the low-temperature crystallization peak during the temperature drop is due to the low-temperature crystal formation of intermediate water that is close to free water, and the low-temperature crystallization peak during the temperature rise is due to intermediate water that did not freeze during the temperature drop; both are classified as intermediate water.

[0045] Furthermore, an endothermic peak with a peak top at 0°C is observed due to the melting of ice crystallized from free water and intermediate water (see P3 in Figure 1). The temperature lower than 0°C of the endothermic peak of P3 is the melting peak due to the melting of ice crystallized from intermediate water, and the temperature higher than 0°C is the melting peak due to the melting of ice crystallized from free water. Based on this behavior of a polymer containing intermediate water upon hydration, this specification defines the hydrated state of a polymer when the endothermic peak top due to ice melting appears at 0°C in a DSC curve obtained by heating a hydrated polymer at a rate of 5°C / min. However, "when the endothermic peak top due to ice melting appears at 0°C" means that a margin of error in the endothermic peak top appearing near 0°C (e.g., 0°C ± 0.2°C) is acceptable as long as the polymer contains enough water to be considered saturated.

[0046] Glass transition temperature in saturated water state The polymer (P) preferably has a glass transition temperature of -30°C or lower in a saturated water-containing state. When the polymer (P) has a glass transition temperature of -30°C or lower in a saturated water-containing state, the polymer (P) can have better resistance to fibrinogen adsorption. From the viewpoint of obtaining a polymer with sufficiently high resistance to fibrinogen adsorption, the glass transition temperature of the polymer (P) in a saturated water-containing state is preferably -35°C or lower, more preferably -40°C or lower. The lower limit of the glass transition temperature of the polymer (P) in a saturated water-containing state is not particularly limited, but is, for example, -100°C or higher.

[0047] ·Bubble contact angle in water The polymer (P) exhibits high adhesion to difficult-to-coat substrates (e.g., fluororesin substrates), thereby exhibiting good coatability. Furthermore, when the polymer (P) coats the surface of a difficult-to-coat substrate, it maintains adhesion to the substrate surface while exhibiting high hydrophilicity at the contact surface with water (water interface) upon contact with water. The coatability of the polymer (P) can be evaluated, for example, by the degree of coating (whether coating is possible or not and the coating rate) when a film is formed on the surface of the difficult-to-coat substrate by spin coating. The hydrophilicity of the polymer (P) at the water interface when coating the surface of the difficult-to-coat substrate (hereinafter also referred to as "surface hydrophilicity") can be evaluated, for example, by measuring the bubble contact angle (hereinafter also referred to as "bubble contact angle θ") when bubbles are brought into contact with the polymer (P) coating the substrate surface in water. The closer the bubble contact angle θ is to 180 degrees, the higher the hydrophilicity of the bubble contact surface (i.e., the water interface of the polymer (P)).

[0048] Specifically, when air bubbles are brought into contact with a film made of polymer (P) formed on a fluororesin substrate by spin coating in water, the bubble contact angle θ is preferably 120° or greater. From the viewpoint of making the fluororesin substrate coated with this coating agent less likely to be recognized as a foreign body by the living body and thereby imparting better antithrombotic properties to the surface of the fluororesin substrate, the bubble contact angle θ is more preferably 125° or greater, even more preferably 130° or greater, even more preferably 135° or greater, even more preferably 140° or greater, and even more preferably 145° or greater. There is no particular upper limit to the bubble contact angle θ, but it may be, for example, 160° or less, 155° or less, or 150° or less.

[0049] In this specification, the bubble contact angle θ is a value measured by the air-bubble method. Specifically, a 1.0 (w / v)% polymer solution prepared by dissolving a polymer to be evaluated in a solvent (more specifically, a good solvent for the polymer to be evaluated) is applied by spin coating to a fluororesin substrate, and the solvent is removed from the fluororesin substrate to form a polymer film on the fluororesin substrate. The polymer film is then immersed in water for 5 minutes, and air bubbles are then brought into contact with the polymer film in water to measure the bubble contact angle θ. Details of the method for measuring the bubble contact angle θ follow the method described in the Examples below.

[0050] In the present coating agent, the content of polymer (P) is preferably 50 parts by mass or more, more preferably 70 parts by mass or more, even more preferably 80 parts by mass or more, even more preferably 90 parts by mass or more, and even more preferably 95 parts by mass or more, relative to 100 parts by mass of the total solids content (i.e., components other than the solvent in the medical coating agent) contained in the present coating agent. By setting the content of polymer (P) within the above range, excellent antithrombogenicity is exhibited, and stable biocompatibility can be imparted to the substrate, which is advantageous.

[0051] <Other ingredients> The present coating agent may further contain components other than the polymer (P) (hereinafter also referred to as "other components") depending on the purpose of use, etc. When the present coating agent is a liquid, one embodiment of the present coating agent is a polymer composition in which the polymer (P) is dissolved or dispersed in a solvent as necessary.

[0052] When the coating agent contains a solvent, a solvent capable of dissolving the polymer (P) is preferably used. The solvent contained in the coating agent is preferably an organic solvent. Specific examples include alcohols such as methanol, ethanol, n-propanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as ethylene glycol monomethyl ether, propylene glycol monomethyl ether, tetrahydrofuran, and dioxane; esters such as ethylene glycol monomethyl ether acetate and ethyl acetate; amide solvents such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; hydrocarbons such as n-hexane, cyclohexane, toluene, and xylene; and dimethyl sulfoxide. The solvent may be used alone or in combination.

[0053] Other components that may be blended into the coating agent include solvents as well as various drugs such as antibacterial agents, anti-inflammatory agents, and antioxidants. One or more of these other components may be used. The content of the other components may be appropriately selected depending on each component, as long as the effects of the present invention are not impaired.

[0054] When the present coating agent is in a solution state, the solids concentration of the medical coating agent (here, the mass ratio of components other than the solvent in the medical coating agent to the volume of the solvent used to prepare the medical coating agent) is not particularly limited, but is preferably 0.001 to 30 (w / v)%. By setting the solids concentration to 0.001 (w / v)% or more, a coating film with sufficient thickness and mechanical strength can be formed on the substrate. A solids concentration of 30 (w / v)% or less ensures good coatability and makes it easy to form a coating film with a uniform thickness. The solids concentration of the present coating agent is more preferably 0.01 to 25 (w / v)%, and even more preferably 0.05 to 20 (w / v)%.

[0055] The present coating agent contains a polymer (P) that has good adhesion to difficult-to-coat substrates (for example, fluororesin substrates), and as a result, the present coating agent exhibits excellent coatability to difficult-to-coat substrates. The reason why the polymer (P) contained in the present coating agent can impart excellent antithrombogenicity to the surface of a difficult-to-coat substrate despite having the structural unit (M2) with a relatively high hydrophobicity is not clear, but the following may be considered: When the present coating agent is applied to the surface of a difficult-to-coat substrate to form a coating film on the substrate surface, the structural unit (M2) contained in the polymer (P) gives the polymer (P) good affinity with the difficult-to-coat substrate. Therefore, even when the present coating agent is applied to the surface of the difficult-to-coat substrate by, for example, spin coating, the polymer (P) easily adheres to the substrate surface, ensuring good coatability, and it is thought that this is why a coating film can be formed on the substrate surface. Furthermore, when a coating film is formed by applying this coating agent to the surface of a difficult-to-coat substrate (coated substrate), and the substrate is then brought into contact with water, the polymer (P) that constitutes the coating film changes, for example, by reorientation at the water interface, making it easier for the structural unit (M1) to appear at the water interface where it has a higher affinity. This causes the polymer (P) to contain a large amount of intermediate water on its surface upon hydration, and it is thought that this results in the imparting of excellent antithrombogenicity to the substrate surface. Furthermore, the coating film formed on a difficult-to-coat substrate by this coating agent is resistant to peeling even when contacted with water, making it useful in that it can impart sustained antithrombogenicity to difficult-to-coat substrates.

[0056] Medical Devices The medical device of the present invention is formed by coating a substrate with the above-described coating agent. The medical device of the present invention has a surface partially or entirely coated with the polymer (P) contained in the coating agent. Therefore, the medical device of the present invention has high anti-adsorption properties for fibrinogen and excellent antithrombogenic properties.

[0057] The substrate of the medical device to which the coating agent is applied is not particularly limited. Examples of materials constituting the substrate of the medical device include various materials such as resin, rubber, metal, glass, and ceramic. Examples of resins include various resin materials such as polycarbonate, polyethylene terephthalate, polyvinyl chloride, polyolefin, polyurethane, poly(meth)acrylate, polystyrene, polyacetal, polysulfone, polyethersulfone, fluorine-based resins (such as polyvinylidene fluoride and polyethylene tetrafluoride), acrylonitrile-butadiene-styrene (ABS) resin, polyamide, ethylene-vinyl acetate resin, and silicone resin. Examples of rubbers include silicone rubber and urethane rubber. Examples of metals include various metal materials such as stainless steel, titanium, and aluminum. The material constituting the substrate of the medical device may be a mixture of two or more materials.

[0058] Because the present coating agent contains polymer (P), it exhibits good coatability even on difficult-to-coat substrates. Among the above, highly hydrophobic substrates are preferred as substrates to which the present coating agent is applied, with fluororesin substrates being particularly preferred. Examples of fluororesin substrates include polytetrafluoroethylene, expanded polytetrafluoroethylene, polyvinylidene fluoride, tetrafluoroethylene, and trifluorochloroethylene-ethylene copolymer resins. Among these, substrates primarily composed of polytetrafluoroethylene are sometimes used as substrates for medical devices. The present coating agent is suitable for imparting excellent antithrombogenic properties to such general-purpose substrates. The fluororesin substrate may also be a substrate in which a fluororesin layer is provided on the surface of a substrate other than a fluororesin.

[0059] The method for coating the surface of a substrate with the present coating agent is not particularly limited. For example, when the present coating agent is in a solution state, the coating agent is applied to the surface of a substrate, and the solvent is removed by heating or other means, thereby obtaining a medical device in which at least a portion of the surface of the substrate is coated with the polymer (P).

[0060] The coating method can be appropriately selected depending on the shape of the substrate, the intended use, etc. Examples of coating methods include bar coating, applicator coating, doctor blade coating, dip coating, roll coating, spin coating, flow coating, knife coating, comma coating, reverse coating, die coating, lip coating, gravure coating, microgravure coating, and ink jet coating. The amount of coating of the present coating agent can be appropriately selected depending on the intended use and material of the medical device, etc., so that the thickness of the coating film formed by the present coating agent falls within the desired range. Of the above coating methods, spin coating, dip coating, and flow coating are preferred because they allow for relatively easy adjustment to a practical film thickness (for example, a film thickness of about 20 to 200 nm).

[0061] The medical devices whose substrate surfaces are coated with the present coating agent are not particularly limited, and can be applied to a variety of medical devices. Specific examples include various medical devices such as stents, catheters, blood bags, transfusion instruments, surgical instruments, dental instruments, blood circulation devices, blood purification devices, plasma separation devices, artificial blood vessels, and artificial organs (e.g., heart-lung machines, artificial kidneys, etc.). Furthermore, when applying the present coating agent to medical devices, the purpose and use thereof are not particularly limited. For example, the present coating agent may be used as an antibacterial and antifouling coating agent. Considering that the present coating agent can impart excellent antithrombogenic properties to the substrate surface, the present coating agent is particularly suitable as a material for coating the substrate of medical devices that come into direct contact with blood. [Example]

[0062] The present invention will be specifically described below based on examples. However, the present invention is not limited to these examples. In the following, "parts" and "%" mean "parts by mass" and "% by mass", respectively, unless otherwise specified.

[0063] 1. Synthesis of ethylenically unsaturated monomers having urethane or urea bonds [Synthesis Example 1: Synthesis of 2-(((2-methoxyethoxy)carbonyl)amino)ethyl acrylate] A 300 mL three-neck flask was equipped with a stirrer, 50 mL of tetrahydrofuran (hereinafter also referred to as "THF") (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a solvent, 0.09 g of dibutyltin dilaurate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst, and 6.28 g of 2-methoxyethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a raw material alcohol, and was equipped with a thermometer, a 50 mL dropping funnel, and a three-way cock. Then, 10.58 g of 2-acryloyloxyethyl isocyanate (manufactured by Showa Denko K.K., trade name: Karenz AOI, hereinafter also referred to as "AOI") was added to the dropping funnel. Next, nitrogen was flowed through the three-way stopcock at 100 mL / min for 10 minutes. After the nitrogen flow, a nitrogen-filled rubber balloon was attached to the three-way stopcock, and the flask was cooled to 5°C or below in an ice bath. AOI was then added dropwise from the dropping funnel while maintaining the internal temperature at 10°C or below. After the dropwise addition was completed, the temperature was raised to room temperature (25°C), and stirring was continued overnight. Then, 10 mL of saturated aqueous sodium bicarbonate solution was added dropwise to the flask to terminate the reaction. 200 mL of the resulting solution was transferred to a separatory funnel, and the organic and aqueous layers were separated. 30 mL of ethyl acetate (Fujifilm Wako Pure Chemical Industries, Ltd., special grade) was added to the aqueous layer and shaken to extract the aqueous layer. This shaking and aqueous layer extraction procedure was repeated twice. 30 mL of saturated saline was added to the recovered organic layer and shaken to wash it. This shaking and organic layer washing procedure was repeated twice. 30 mg of anhydrous sodium sulfate (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the washed organic layer and stirred for 1 hour to dehydrate it. The mixture was filtered using fluted filter paper to remove the sodium sulfate, and paramethoxyphenol was added to a theoretical yield of 250 ppm. Next, the solvent was removed using a rotary evaporator while the sample was immersed in a 40°C water bath. After the solvent was removed, the sample was left standing under reduced pressure for 1 hour using a vacuum pump, and the remaining solvent was removed again. The collected sample was purified by silica gel column chromatography using a solvent mixture of hexane and ethyl acetate in a 1:1 volume ratio to obtain 2-(((2-methoxyethoxy)carbonyl)amino)ethyl acrylate (hereinafter also referred to as "MEOCNA").

[0064] Synthesis Example 2: Synthesis of 2-(3-(2-ethoxyethyl)ureido)ethyl acrylate A stirrer was added to a 300 mL three-neck flask, and 50 mL of THF (Fujifilm Wako Pure Chemical Industries, Ltd.) as a solvent and 10.58 g of AOI as an isocyanate compound were added. A thermometer, a 100 mL dropping funnel, and a three-way cock were then attached. 4.41 g of 2-ethoxyethylamine (Fujifilm Wako Pure Chemical Industries, Ltd.) as a raw material amine and 50 mL of THF as a solvent were added to the attached dropping funnel. Next, nitrogen was flowed at 100 mL / min via the three-way stopcock for 10 minutes. After the nitrogen flow, a nitrogen-filled rubber balloon was attached to the three-way stopcock. Subsequently, the amine solution was added dropwise from the dropping funnel. After that, stirring was continued overnight at room temperature (25°C). The reaction was terminated by adding 10 mL of 1 N dilute hydrochloric acid dropwise to the flask. The liquid was transferred to a 200 mL separatory funnel, and the organic and aqueous layers were separated. 30 mL of ethyl acetate (Fujifilm Wako Pure Chemical Industries, Ltd., special grade) was added to the aqueous layer and shaken to extract the aqueous layer. This procedure was repeated twice. 30 mL of saturated saline was added to the recovered organic layer and shaken to wash it. This procedure was repeated twice. 30 mg of anhydrous sodium sulfate (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the washed organic layer, and the mixture was stirred for 1 hour to dehydrate it. The mixture was filtered using fluted filter paper to remove the sodium sulfate, and paramethoxyphenol was added to a theoretical yield of 250 ppm. The solvent was removed using a rotary evaporator while the mixture was immersed in a water bath at 40°C. After the solvent was removed, the mixture was left standing under reduced pressure for 1 hour using a vacuum pump, and the remaining solvent was removed again to obtain 2-(3-(2-ethoxyethyl)ureido)ethyl acrylate (hereinafter also referred to as "EEA-UA").

[0065] 2. Polymer production and analysis Each polymer was produced according to the following Production Examples 1 to 6 and Comparative Production Examples 1 and 2. Furthermore, the weight average molecular weight (Mw) and the bubble contact angle in water of each of the obtained polymers were measured by the following methods.

[0066] <Measurement of polymer weight average molecular weight (Mw)> The weight average molecular weight (Mw) of the polymer was measured by gel permeation chromatography (GPC) under the following measurement conditions. (GPC analysis conditions) Equipment: Tosoh Corporation, model number HLC-8320GPC Detector: RI detector Column: Tosoh TSKgel SuperMultiporeHZ-M x 3 Column temperature: 40℃ Eluent: THF (containing 0.03% sulfur as an internal standard) ·Flow rate: 350μL / min Calibration curve: Standard polystyrene

[0067] <Measurement of the glass transition temperature (Tg) of polymers in a saturated water-containing state> Each polymer was immersed in a large excess of pure water (10 g of pure water per 30 mg of polymer) and allowed to stand at room temperature (25°C) for 3 days to allow hydration. The hydrated polymer was removed from the water using tweezers, and water adhering to each hydrated polymer was removed using a medical paper. After that, 0.003 to 0.005 g of each hydrated polymer was weighed into an aluminum pan. Using a differential scanning calorimeter (NETZSCH DSC214Polymer, measurement atmosphere: air), the polymer was cooled from 40°C to -100°C at a rate of 5°C / min, held at -100°C for 5 minutes, and then heated back up to 40°C to determine the glass transition temperature (Tg) of the polymer in the saturated hydrated state. In the DSC curve obtained by DSC measurement at a heating rate of 5°C / min, the water content state of the polymer when the peak top of the endothermic heat due to ice melting appears at 0°C was defined as the "saturated water content state," and the glass transition temperature (Tg) of the polymer in the saturated water content state was determined from the DSC curve when the peak top of the endothermic heat due to ice melting appears at 0°C. In the following Production Examples and Comparative Production Examples, the glass transition temperature of the polymer in the saturated water content state will be simply referred to as "Tg."

[0068] <Measurement of bubble contact angle in water> Each polymer was dissolved in a solvent to prepare a 1.0 (w / v)% polymer solution. The solvent used was methanol for the polymers obtained in Production Examples 1, 2, and 7, ethanol for the polymers obtained in Production Examples 3, 5, and 6, ethyl acetate for the polymer obtained in Production Example 4, and methanol for the polymers obtained in Comparative Production Examples 1 and 2. After thoroughly washing a PTFE resin substrate (3.0 cm square, 1 mm thick, AS ONE Corporation, PTFE sheet) with methanol, 235 μL of each polymer solution prepared above was applied to a PP substrate by spin coating. The spin coating conditions were 500 rpm, 5 s → 1,500 rpm, 10 s → 1,500 to 4,000 rpm (slope), 5 s → 4,000 rpm, 10 s → 4,000 to 0 rpm (slope), 5 s. The substrate was then air-dried at room temperature (25 °C) for 3 days to obtain a coated substrate for evaluation for each polymer solution. Each of the resulting coated substrates was fixed to the sample stage of a three-phase kit (Kyowa Interface Science Co., Ltd.) and immersed in a transparent cell filled with pure water at room temperature (25°C). Five minutes and 30 minutes after immersion, a contact angle meter (Kyowa Interface Science Co., Ltd., Model No. DropMaster DMO-501SA) was fitted with a reverse needle. 2 μL of air bubbles were dispensed from the tip of the syringe to attach to the surface of the coated substrate coated with the medical coating. The bubble contact angle (bubble contact angle) was then measured 30 seconds after the bubble was attached. The closer the bubble contact angle was to 180°, the more hydrophilic the surface of the bubble was.

[0069] [Production Example 1: Production of Polymer A] In a two-necked test tube, 4.5 g of MEOCNA as a monomer, 0.5 g of 2-(perfluorohexyl)ethyl acrylate (ChemiNox FAAC-6, manufactured by Unimatec Co., Ltd., hereinafter also referred to as "CF6AA"), 0.218 g of 2,2'-azobis(2,4-dimethylvaleronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., hereinafter also referred to as "V-65 initiator") as a radical initiator, and 20.0 g of ethyl acetate as a solvent were added. A stirrer was then placed in the test tube, a thermometer attached to the side tube, and a three-way stopcock attached to the main tube. A syringe needle was inserted through the three-way stopcock, and argon was blown into the solution at 100 mL / min for 30 minutes to deoxygenate it. The three-way stopcock was then closed, and the test tube was sealed. The test tube was placed in a heat block set at 60 °C to initiate polymerization. The temperature of the heat block was adjusted appropriately so that the internal temperature remained at 60 °C. After 3 hours, the test tube was cooled in an ice bath to terminate the polymerization. Reprecipitation purification was carried out twice using a solvent consisting of hexane and ethyl acetate in a 6:4 mass ratio. The recovered polymer was then reprecipitated and purified using pure water as the aqueous reprecipitation purification solvent, yielding Polymer A. GPC analysis of Polymer A revealed a weight-average molecular weight of 215,000. The Tg was -53 °C, and the bubble contact angle after 5 minutes of immersion in water was 134°.

[0070] [Production Example 2: Production of Polymer B] Polymer B was obtained by the same procedure as in Production Example 1, except that 4.0 g of MEOCNA and 1.0 g of CF6AA were used as monomers, 0.206 g of V-65 initiator as a radical initiator, and 20 g of ethyl acetate as a solvent were used. GPC measurement of Polymer B revealed that the weight-average molecular weight was 78,000. In addition, the Tg was −46° C., and the bubble contact angle 5 minutes after immersion in water was 144°.

[0071] [Production Example 3: Production of Polymer C] Polymer C was obtained by the same procedure as in Production Example 1, except that 3.0 g of MEOCNA and 2.0 g of CF6AA were used as monomers, 0.184 g of V-65 initiator as a radical initiator, and 20 g of ethyl acetate as a solvent were used. GPC measurement of Polymer C revealed that the weight-average molecular weight was 113,000. In addition, the Tg was −48° C., and the bubble contact angle 5 minutes after immersion in water was 137°.

[0072] [Production Example 4: Production of Polymer D] Polymer D was obtained by the same procedure as in Production Example 1, except that 4.25 g of MEOCNA was used as the monomer, 0.75 g of 2-(perfluorobutyl)ethyl acrylate (ChemiNox FAAC-4, manufactured by Unimatec Corporation, hereinafter also referred to as "CF4AA") was used instead of CF6AA, 0.0 g of V-65 initiator was used as the radical initiator, and 20 g of ethyl acetate was used as the solvent. GPC measurement of Polymer D revealed that the weight-average molecular weight was 91,000. The Tg was -58°C, and the bubble contact angle 5 minutes after immersion in water was 139°.

[0073] [Production Example 5: Production of Polymer E] Polymer E was obtained by the same procedure as in Production Example 1, except that 3.0 g of MEOCNA and 1.00 g of CF4AA were used as monomers, 0.168 g of V-65 initiator as a radical initiator, and 16.0 g of ethyl acetate as a solvent. GPC measurement of Polymer E revealed that the weight-average molecular weight was 119,000. The Tg was −58° C., and the bubble contact angle 5 minutes after immersion in water was 142°.

[0074] [Production Example 6: Production of Polymer F] Polymer F was obtained by the same procedure as in Production Example 1, except that 4.0 g of EEA-UA and 1.0 g of CF6AA were used as monomers, 0.184 g of V-65 initiator as a radical initiator, 20 g of ethyl acetate as a solvent, and reprecipitation purification was performed using only water. GPC measurement of Polymer F showed that the weight-average molecular weight was 82,000. The Tg was -51°C, and the bubble contact angle 5 minutes after immersion in water was 145°.

[0075] Comparative Production Example 1: Production of Polymer G Polymer G was obtained by the same procedure as in Production Example 1, except that 3 g of 2-methoxyethyl acrylate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the monomer, 0.555 g of 2,2'-azobis(2-methylbutyronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., hereinafter also referred to as "V-59 initiator") was used as the radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent for reprecipitation purification, a mixture of hexane and acetone in a mass ratio of 6:4, was used. GPC measurement of Polymer G revealed that the weight-average molecular weight was 84,000. Furthermore, the Tg was -60°C, and the bubble contact angle after 5 minutes of immersion in water was 89°.

[0076] Comparative Production Example 2: Production of Polymer H Polymer H was obtained by the same procedure as in Production Example 1, except that 3 g of MEOCNA was used as the monomer, 0.358 g of V-59 initiator as the radical initiator, 27 g of ethyl acetate as the solvent, and a solvent obtained by mixing hexane and acetone in a mass ratio of 4:6 as the reprecipitation purification solvent were used. GPC measurement of Polymer H showed that the weight-average molecular weight was 100,800. In addition, the Tg was -60°C, and the bubble contact angle 5 minutes after immersion in water was 99°.

[0077] 3. Manufacturing and evaluation of medical coating agents [Examples 1 to 6 and Comparative Examples 1 and 2] Each polymer produced in Production Examples 1 to 6 and Comparative Production Examples 1 and 2 was mixed with a solvent to prepare a 0.2 (w / v)% polymer solution, which was used as a medical coating agent. The same solvent was used to prepare each medical coating agent as the polymer solution prepared for measuring the bubble contact angle in water. Furthermore, a fibrinogen adsorption test (MicroBCA assay) was performed on the coated substrates coated with each medical coating agent by cast coating. The details of the evaluation method are as follows:

[0078] <Fibrinogen adsorption test for coated substrates using cast coating (MicroBCA assay)> In this test, to evaluate the anti-adsorption properties of each polymer against blood components, a coated substrate for evaluation was prepared using a "thick-film cast coating" method so that the surface coating rate of the medical coating agent was 100% by mass. 15 μL of each medical coating agent was dropped into each well of a 96-well plate (Corning Incorporated, General Assay Plate, Polypropylene 96-well Perfect Plate, Flat Bottom, Non-sterile) and allowed to dry for 3 days to obtain the coating substrate for evaluation. Subsequently, 50 μL of a solution prepared by dissolving fibrinogen in PBS(-) (Fujifilm Wako Pure Chemical Industries, Ltd.) to a concentration of 3 mg / mL was added to each well. The plates were then incubated at 37°C for 10 minutes. After incubation, the internal solution was removed, and each well was washed with 200 μL of PBS(-). This process was repeated seven times. After drying, 50 μL of extraction solution (a 1:1 volume mixture of 5% SDS aqueous solution and 0.1 N sodium hydroxide aqueous solution) was added to each well. The plates were then incubated at 37°C for 2 hours. After incubation, 50 μL of PBS(-) was added to each well, followed by 100 μL of Working Reagent prepared according to the instructions for the Micro BCA Protein Assay Kit (Thermo Scientific). The wells were then heated at 60°C for 1 hour. After heating, the absorbance at 540 nm was measured using a plate reader (Vmax Kinetic Microplate Reader, Fujifilm Wako Pure Chemical Industries, Ltd.). Based on the fibrinogen concentration of the resulting extract, the amount of fibrinogen adsorbed per unit area on the coating substrate for evaluation (μg / cm) was calculated. 2 ) (hereinafter also referred to as "FIB adsorption amount") was calculated. The smaller this value, the better the antithrombotic property. The benchmark lines for calculating the concentration were prepared using bovine serum albumin included with the Micro BCA Protein Assay Kit (manufactured by Thermo Scientific) according to the manufacturer's instructions.

[0079] Comparative Example 3 In the fibrinogen adsorption test, the test was carried out in the same manner as in Examples 1 to 6 and Comparative Examples 1 and 2, except that the 96-well plate was not coated with a medical coating agent.

[0080] The properties of the polymers used in Examples 1 to 6 and Comparative Examples 1 and 2, and the evaluation results of the medical coating agents, as well as the evaluation result of Comparative Example 3, are shown in Table 1.

[0081] [Table 1]

[0082] Details of the compounds used in Table 1 are shown below. MEOCNA: 2-(((2-methoxyethoxy)carbonyl)amino)ethyl acrylate Rate (Synthesis Example 1) EEA-UA: 2-(3-(2-ethoxyethyl)ureido)ethyl acrylate (synthetic Example 2) CF6AA: 2-(perfluorohexyl)ethyl acrylate (Unimatec Corporation, Cheminox FAAC-6) CF4AA: 2-(perfluorobutyl)ethyl acrylate (Unimatec Corporation, Cheminox FAAC-4) MEA: 2-Methoxyethyl acrylate, Fujifilm Wako Pure Chemical Industries, Ltd. 2-acrylic acid Methoxyethyl

[0083] 4. Evaluation Results As is clear from the results in Table 1, even when the medical coating agents of Examples 1 to 6 were applied to the surface of a difficult-to-apply fluororesin substrate, the films composed of polymers A to F had large air bubble contact angles of 120 degrees or more in water, demonstrating the effect of hydrophilizing the surface and suggesting high coatability. Furthermore, the substrate surfaces coated with the medical coating agents of Examples 1 to 6 had low adsorption of fibrinogen (FIB), a blood protein, demonstrating excellent anti-adsorption properties against blood components. These results suggest that polymers A to F contained in the medical coating agents of Examples 1 to 6 have improved affinity with the surface of the fluororesin substrate due to the inclusion of the structural unit (M2), thereby imparting a hydrophilic effect to the surface of the fluororesin substrate. Furthermore, when polymers A to F come into contact with water while coating the surface of a substrate, the structural units (M1) in polymers A to F are more likely to appear on the water interface side than on the substrate surface side, and it is presumed that the presence of structural units (M1) causes more intermediate water to cover the substrate surface, thereby exhibiting excellent anti-adsorption properties against fibrinogen (FIB). Furthermore, for polymers A to F, the measured bubble contact angle in water showed little change over time, suggesting that polymers A to F, which coat the substrate surface, are unlikely to peel off from the substrate surface even when in contact with water for a long period of time, and can provide the substrate surface with sustained anti-adsorption properties.

[0084] In contrast, the medical coating agent of Comparative Example 1, which used polymer G containing a structural unit derived from MEA instead of the structural unit (M1) but not containing the structural unit (M2), and the medical coating agent of Comparative Example 2, which used polymer H containing the structural unit (M1) but not containing the structural unit (M2), showed films composed of polymers G and H with air bubble contact angles in water of less than 120 degrees, which was smaller than the medical coating agents of Examples 1 to 6, confirming that the hydrophilicity of the fluororesin substrate surface was low. These results suggest that the medical coating agents of Comparative Examples 1 and 2 were difficult to coat on the substrate surface at a practical film thickness and therefore had poor practicality.

Claims

1. A medical coating agent containing a polymer including a structural unit (M1) derived from an ethylenically unsaturated monomer having a urethane bond or a urea bond, and a structural unit (M2) derived from an ethylenically unsaturated monomer having a fluorine atom.

2. The structural unit (M2) is CF ２ group or CF ３ 2. The medical coating agent according to claim 1, wherein the structural unit is derived from an ethylenically unsaturated monomer having a group.

3. The structural unit (M2) is a perfluoroalkyl group (-(CF ２ ) ｎ -CF ３ 2. The medical coating agent according to claim 1, wherein the structural unit is derived from an ethylenically unsaturated monomer having the formula:

4. 2. The medical coating agent according to claim 1, wherein the content of the structural unit (M2) is 10 mass % or more based on all structural units contained in the polymer.

5. 2. The medical coating agent according to claim 1, wherein the glass transition temperature of the polymer in a saturated water-containing state is −30° C. or lower, when the saturated water-containing state of the polymer is determined by absorbing water into the polymer and raising the temperature at a rate of 5° C. / min using a differential scanning calorimeter (DSC). The DSC curve is obtained by measuring the water content of the polymer at a DSC rate of 5° C. / min, and the glass transition temperature of the polymer in the saturated water-containing state is −30° C. or lower.

6. 2. The medical coating agent according to claim 1, wherein when a film made of the polymer formed on a fluororesin substrate by spin coating is immersed in water for 5 minutes and then air bubbles are brought into contact with the film in water, the contact angle of the air bubbles is 120 degrees or more.

7. The medical coating agent according to claim 1 , wherein the polymer is a (meth)acrylic polymer.

8. A medical device comprising a substrate coated with the medical coating agent according to any one of claims 1 to 7.

9. The medical device according to claim 8 , wherein the substrate is a fluororesin substrate.

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