Elongated medical device, and method for producing elongated medical device

Abstract

To form a hydrophilic coating film with a simple structure having excellent adhesion.SOLUTION: A coating film on an elongated medical device is composed of a polymeric material that has been crosslinked by a structure given by any of formulas (1) to (3): -CH(OH)-CH(R1)-O-C(=O)-NH-R2-NH-C(=O)-O-CH(R1)-CH(OH)- (1); -CH(OH)-CH(R1)-O-C(=O)-NH-R2-NH-C(=O)-O-CH(CH(R1)-OH)- (2); and -CH(CH(R1)-OH)-O-C(=O)-NH-R2-NH-C(=O)-O-CH(CH(R1)-OH)- (3).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to coated elongated medical devices and methods of making elongated medical devices. [Background technology]

[0002] Conventionally, medical devices with various hydrophilic coatings have been known. For example, long medical devices such as catheters and guidewires that are inserted into living bodies and used are coated with a hydrophilic coating agent to impart lubricity to the surface of the long medical device. Specifically, Patent Document 1, for example, discloses a configuration in which a hydrophilic epoxy resin coating is formed on a medical device using a hydrophilic polymer having a hydrophilic monomer and a reactive functional group such as an epoxy group. Patent Document 2 also discloses a guidewire in which a thin-film primer containing functional groups is formed on a substrate, and a hydrophilic compound is immobilized on the substrate by reacting the functional group of the thin-film primer with the hydrophilic compound. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015 / 137259 [Patent Document 2] Japanese Patent Application Laid-Open No. 2011-110392 Summary of the Invention [Problem to be solved by the invention]

[0004] However, the present inventors have discovered a new problem: for example, when forming a coating using an epoxy resin on a metal substrate, mixing a hydrophilic substance into the coating material as described in Patent Document 1 can make it relatively difficult to achieve sufficient adhesion. In such cases, to achieve more sufficient adhesion, it is necessary to separately provide a layer containing the hydrophilic substance and a layer for adhering the hydrophilic substance to the substrate, as described in Patent Document 2. Therefore, a technology that improves adhesion while simplifying the structure of the hydrophilic coating is desired. Furthermore, for example, long medical instruments that are inserted into the body include those made of metal and those with urethane surfaces. When a coating is formed on such long medical instruments using an epoxy resin, it can be relatively difficult to achieve high adhesion between the coating and the substrate. Therefore, a technology that can reduce the above-mentioned disadvantages and improve adhesion between the hydrophilic coating and the substrate is desired for long medical devices equipped with a hydrophilic coating. [Means for solving the problem]

[0005] The present disclosure can be realized in the following forms. (1) According to one aspect of the present disclosure, there is provided a long medical device, which has a coating formed on the surface of a substrate, and the coating is made of a polymeric material in which a copolymer containing polymerization units with a hydrophilic structure is crosslinked by a structure represented by any one of the following formulas (1) to (3): -CH(OH)-CH(R 1 )-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(R 1 )-CH(OH)- … (1) -CH(OH)-CH(R 1 )-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)- … (2) -CH(CH(R 1 )-OH)-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)- … (3) (In each formula, R 1 R may be the same or different and represent a hydrogen atom, a linear alkyl group having one or more carbon atoms, or a branched alkyl group having one or more carbon atoms. 2 represents an alkylene group having one or more carbon atoms, a divalent alicyclic hydrocarbon group containing an alicyclic structure having three or more carbon atoms, or a divalent aromatic group containing an aromatic ring structure having six or more carbon atoms, and the alkylene group, the alicyclic hydrocarbon group, and the aromatic group do not have an -NR 3 -(R 3 may have a divalent group represented by a hydrogen atom or an alkyl group having 1 to 8 carbon atoms). According to the elongated medical device of this embodiment, the coating formed on the surface of the elongated medical device can improve adhesion between the substrate and the device, and hydrophilicity. (2) In the elongated medical device of the above embodiment, the hydrophilic structure may be electrically neutral. With this configuration, the biocompatibility of the coating of the elongated medical device can be improved. (3) In the elongated medical device of the above embodiment, the hydrophilic structure may include at least one structure selected from the group consisting of a betaine structure, an amide structure, a lactam structure, and a polyalkylene oxide structure. With this configuration, the elongated medical device can be provided with a hydrophilic coating that is electrically neutral. (4) In the elongated medical device of the above embodiment, the hydrophilic structure may include at least one of a betaine structure having a quaternary ammonium as a positively charged functional group and an amide structure having a tertiary ammonium. With this configuration, when a coating film is formed on a substrate using a coating agent including a copolymer containing polymerization units having the hydrophilic structure, the tertiary ammonium or quaternary ammonium can act as a catalyst for a crosslinking reaction of the coating agent. This makes it possible to form a hydrophilic coating by a simpler method without adding other catalysts during coating formation, and further simplifies the composition of the coating. (5) In the elongated medical device of the above embodiment, the substrate may include at least one of a metal, a polymeric material having a group capable of forming a hydrogen bond, and polyurethane on the surface of the substrate, which can further enhance the adhesion between the substrate and the coating. (6) In the elongated medical device of the above embodiment, the elongated medical device may be a guidewire or a catheter. In this configuration, the guidewire or catheter can be provided with a coating that has high adhesion to the substrate and sufficient hydrophilicity. The present disclosure can be realized in various forms other than those described above, and can be realized in the form of, for example, a method for manufacturing an elongated medical device. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 is an explanatory diagram showing how a coating agent is crosslinked. [Figure 2] FIG. 1 is an explanatory diagram showing the principle of adhesion of a hydrophilic coating to a metal substrate. [Figure 3] FIG. 1 is an explanatory diagram showing the principle of adhesion of a hydrophilic coating to a urethane substrate. [Figure 4] FIG. 10 is an explanatory diagram showing the results of a cross-cut test. [Figure 5] FIG. 10 is an explanatory diagram showing the evaluation results of adhesion. [Figure 6] FIG. 2 is an explanatory diagram showing the change in viscosity of a coating agent over time. DETAILED DESCRIPTION OF THE INVENTION

[0007] The elongated medical device of this embodiment has a hydrophilic coating formed on the surface of the substrate. First, the coating provided on the elongated medical device of this embodiment will be described below.

[0008] The coating provided on the elongated medical device of this embodiment is composed of a polymeric material in which a copolymer containing polymerization units with a hydrophilic structure is crosslinked by a structure represented by any one of the following formulas (1) to (3):

[0009] -CH(OH)-CH(R 1 )-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(R 1 )-CH(OH)- … (1) -CH(OH)-CH(R 1 )-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)- … (2) -CH(CH(R 1 )-OH)-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)- … (3)

[0010] Here, in each formula, R 1 may be the same or different and represent a hydrogen atom, a linear alkyl group having 1 or more carbon atoms, or a branched alkyl group having 1 or more carbon atoms. More specifically, R 1 may each independently be a hydrogen atom or an alkyl group having 1 or more carbon atoms. The number of carbon atoms in the alkyl group is not limited, but is preferably 1 to 4, for example. 2 represents an alkylene group having one or more carbon atoms, a divalent alicyclic hydrocarbon group containing an alicyclic structure having three or more carbon atoms, or a divalent aromatic group containing an aromatic ring structure having six or more carbon atoms, and the alkylene group, the alicyclic hydrocarbon group, and the aromatic group do not have an -NR bond between carbon atoms. 3 -(R 3 may have a divalent group represented by a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. The alkylene group preferably has 1 to 5 carbon atoms. The alicyclic structure preferably has 3 to 6 carbon atoms, and the alicyclic hydrocarbon group preferably has 3 to 12 carbon atoms. The aromatic ring structure preferably has 6 to 10 carbon atoms, and the aromatic group preferably has 6 to 20 carbon atoms. -NR which may be present between the carbon atoms of each of the alkylene group, alicyclic hydrocarbon group, and aromatic group 3 The number of - is preferably 1 or 2. 2is preferably an alkylene group having 1 to 6 carbon atoms, and particularly preferably an alkylene group having 4 to 6 carbon atoms.

[0011] The thickness of the coating is not particularly limited and may be set appropriately depending on the application, but may be, for example, about 1 μm to 1000 μm. The coating may be formed, for example, from a hydrophilic coating agent. Below, a description is given of coating agents suitable for forming the coating provided on the elongated medical device of this embodiment.

[0012] A coating agent suitable for forming a coating on the elongated medical device of this embodiment contains a solvent as well as a copolymer (C) containing polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure. That is, the coating agent used to form a coating on the elongated medical device of this embodiment contains a copolymer (C) produced by copolymerizing a material containing a monomer (a) for obtaining polymerization units (A) having a cyclic carbonate structure and a monomer (b) for obtaining polymerization units (B) having a hydrophilic structure. Each of the above-mentioned polymerization units will be described below.

[0013] (1) Polymerized unit (A) having a cyclic carbonate structure: The polymerization unit (A) having the cyclic carbonate structure described above has at least one cyclic carbonate group of at least one kind. The polymerization unit (A) having the cyclic carbonate structure of this embodiment can have, for example, 1 to 3 cyclic carbonate groups, preferably 1 or 2 cyclic carbonate groups, and more preferably 1 cyclic carbonate group.

[0014] The "cyclic carbonate group" can have the structure shown in the following formula (4). (4) In the formula, R 1 represents a hydrogen atom, a linear alkyl group having 1 to 4 carbon atoms, a branched alkyl group having 1 to 4 carbon atoms, a linear alkenyl group having 1 to 4 carbon atoms, or a branched alkenyl group having 1 to 4 carbon atoms. 1At least one hydrogen atom of R may be substituted with a halogen atom, and at least one carbon atom (-C-) of R may be substituted with -O-, -S-, or -P-. 1 In the formula, examples of the linear or branched alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, etc. Examples of the linear or branched alkenyl group having 1 to 4 carbon atoms include groups in which at least one, preferably one, of the direct carbon-carbon bonds of the above alkyl groups is replaced with an unsaturated double bond. From the viewpoint of easily improving water resistance, R 1 is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom. (4) In the formula, R 2 represents a linear or branched alkylene or alkenylene group having 1 to 4 carbon atoms. 2 At least one hydrogen atom of R may be substituted with a halogen atom, and at least one carbon atom (-C-) of R may be substituted with -O-, -S-, or -P-. 2 In the formula, examples of the linear or branched alkylene group having 1 to 4 carbon atoms include a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, a methylmethylene group, a methylethylene group, a dimethylethylene group, and a methylpropylene group. Examples of the linear or branched alkenylene group having 1 to 4 carbon atoms include groups in which at least one, preferably one, of the direct carbon-carbon bonds of the alkylene group is replaced with an unsaturated double bond. From the viewpoint of easily improving water resistance, R 2 is preferably a linear or branched alkylene group having 1 to 4 carbon atoms, and more preferably a linear alkylene group having 1 carbon atom. Specifically, it is desirable that the cyclic carbonate group has a 2-oxo-1,3-dioxolane structure. More specifically, it is desirable that the cyclic carbonate group be a (2-oxo-1,3-dioxolan-4-yl) group.

[0015] [ka]

[0016] The monomer (a) for forming the polymerization unit (A) having a cyclic carbonate structure is preferably a (meth)acrylate having a cyclic carbonate group, and the R of the cyclic carbonate group of the above-mentioned formula (4) is preferably added to the group represented by the following formula (5): 2 More preferably, it is a monomer directly bonded to

[0017] CH2=CR 1 -R 4 -(CH2) n - … (5) (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 4 represents -COO- or -CO-NH-, and n represents an integer of 1 to 4.

[0018] Specific examples of the monomer (a) that can be used include (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) and (2-oxo-1,3-dioxolan-4-yl)methyl acrylate (GCA), with (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) being more preferred.

[0019] (2) Polymer unit (B) having a hydrophilic structure The hydrophilic polymerized units (B) in this embodiment have a hydrophilic structure that imparts hydrophilicity to the polymerized units. The hydrophilic structure is preferably a charge-neutral structure. Examples of charge-neutral hydrophilic structures include a betaine structure, an amide structure, an alkylene oxide structure, and a lactam structure. However, the polymerized units (B) may have a hydrophilic structure other than the above-mentioned betaine structure, amide structure, alkylene oxide structure, or lactam structure. For example, it is also possible to use polymerized units having a charged hydrophilic structure that is not charge-neutral.

[0020] A betaine structure refers to a structure in which a positive charge and a negative charge are not adjacent to each other in the same molecule, and the positively charged atom is not bound to a dissociable hydrogen atom, resulting in a neutral (non-charged) structure overall. In the betaine structure, the positively charged functional group can be, for example, quaternary ammonium, sulfonium, or phosphonium, and the negatively charged functional group can be, for example, sulfonic acid, carboxylic acid, or phosphonic acid. That is, the betaine structure can be, for example, sulfobetaine, carboxybetaine, or phosphobetaine.

[0021] The betaine structure of this embodiment can have various combinations of the positively charged functional group and the negatively charged functional group described above. Suitable betaine structures of this embodiment include, for example, structures derived from N-methacryloylaminopropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (MAMCMB), N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CMB), 2-methacryloyloxyethyl-phosphorylcholine (MPC), or 3-methacryloylaminopropyl-dimethyl-3-sulfobetaine (SMB). The coating agent used to form the coating on the elongated medical device of this embodiment is cured by ring-opening the cyclic carbonate structure of the polymerized unit (A) and crosslinking with a crosslinking agent, as described below. However, if the positively charged functional group of the betaine structure has a quaternary ammonium, this is desirable because the quaternary ammonium can act as a catalyst for the crosslinking reaction. As an example of the polymerized unit (B) having a betaine structure as a hydrophilic structure, the polymerized unit obtained when N-methacryloylaminopropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (MAMCMB) is used as the monomer (b) is shown in the following formula (6).

[0022] [ka]

[0023] The amide structure is a structure having an amide bond, and can be, for example, a structure obtained when any of N,N-dimethylacrylamide (DMAAm), N-isopropylacrylamide (NiPPAM), acrylamide (AAm), methylacrylamide (MAAm), 2-acrylamido-2-methylpropylsulfonic acid (AMPS), methacrylamide, N-vinylformamide, N-vinylacetamide, and N-vinylpyrrolidone is used as monomer (b). Among these monomers (b), N,N-dimethylacrylamide (DMAAm), N-isopropylacrylamide (NiPPAM), acrylamide (AAm), methylacrylamide (MAAm), and 2-acrylamido-2-methylpropylsulfonic acid (AMPS) are preferably used as monomer (b). Such an amide structure has no charge imbalance and is neutral overall. The coating agent used to form the coating film on the elongated medical device of this embodiment is cured by opening the cyclic carbonate structure of the polymerized unit (A) and crosslinking it with a crosslinking agent, as described below. The tertiary ammonium of the amide structure is desirable because it can act as a catalyst for the crosslinking reaction. As an example of the polymerized unit (B) having an amide structure as a hydrophilic structure, the polymerized unit obtained when N,N-dimethylacrylamide (DMAAm) is used as a monomer is shown in the following formula (7).

[0024] [ka]

[0025] The alkylene oxide structure is a structure having an alkylene oxide group (-RO-; where R is an alkylene group and R preferably has 1 to 5 carbon atoms). The alkylene oxide structure of this embodiment can be, for example, a structure obtained when any of alkoxypolyalkylene glycol acrylate, alkoxypolyalkylene glycol methacrylate, alkoxyalkyl acrylate, and alkoxyalkyl methacrylate is used as the monomer (b). Specifically, for example, methoxypolyethylene glycol acrylate, methoxypolyethylene glycol methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, methoxypolypropylene glycol acrylate, methoxypolypropylene glycol methacrylate, methoxymethyl acrylate, methoxymethyl methacrylate, ethoxymethyl acrylate, ethoxymethyl methacrylate, ethoxyethyl acrylate, ethoxyethyl methacrylate, ethoxypropyl acrylate, and ethoxypropyl methacrylate can be used. Such an alkylene oxide structure has no bias in charge and is neutral as a whole. As an example of the polymerized unit (B) having an alkylene oxide structure as a hydrophilic structure, the polymerized unit obtained when methoxypolyethylene glycol methacrylate (M90G) is used as the monomer (b) is shown in the following formula (8). Furthermore, as another example of the polymerized unit (B) having an alkylene oxide structure as a hydrophilic structure, the polymerized unit obtained when methoxyethyl acrylate (MEA) is used as the monomer (b) is shown in the following formula (9).

[0026] [ka]

[0027] [ka]

[0028] The lactam structure can be a β-lactam (4-membered ring) structure, a γ-lactam (5-membered ring) structure, a δ-lactam (6-membered ring) structure, or an ε-lactam (7-membered ring) structure, with a γ-lactam (5-membered ring) structure being preferred. Examples of the monomer (b) used to obtain the lactam structure of this embodiment include vinyl monomers having a 5-membered ring lactam structure, such as N-vinylpyrrolidone, N-vinyl-5-methylpyrrolidone, N-vinyl-5-ethylpyrrolidone, N-vinyl-5-propylpyrrolidone, N-vinyl-5-butylpyrrolidone, and 1-(2-propenyl)-2-pyrrolidone; vinyl monomers having a 6-membered ring lactam structure, such as N-vinylpiperidone; and vinyl monomers having a 7-membered ring lactam structure, such as N-vinylcaprolactam. Such lactam structures are not biased in charge and are neutral overall. As an example of the polymerized unit (B) having a lactam structure as a hydrophilic structure, the polymerized unit obtained when N-vinylpyrrolidone (NVP) is used as the monomer (b) is shown in the following formula (10).

[0029] [ka]

[0030] The hydrophilic polymerized units (B) may be formed using various hydrophilic monomers (b) other than those mentioned above. Other usable hydrophilic monomers (b) include, for example, acrylic acid, acrylates such as sodium acrylate, methacrylic acid, methacrylates such as sodium methacrylate, maleic anhydride, 2-hydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate (2HEA), 2-hydroxypropyl acrylate (2HPA), 2-hydroxypropylmethyl acrylate (2HPMA), 4-hydroxybutyl acrylate (4HBA), 4-hydroxybutyl methacrylate (4HBMA), 1,4-cyclohexanedimethanol monoacrylate (CHDMA), lactic acid and other amino acids, acryloylmorpholine (AMP), and N,N-dimethylaminoethyl acrylate.

[0031] (3) Copolymer (C): As described above, the coating agent used to form the coating film on the elongated medical device of this embodiment contains a copolymer (C) containing polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure. As described above, the copolymer (C) contained in the coating agent can be produced by copolymerizing a material containing a monomer (a) for obtaining polymerization units (A) having a cyclic carbonate structure and a monomer (b) for obtaining polymerization units (B) having a hydrophilic structure.

[0032] The copolymer (C) may have, as the polymerization unit (A) having a cyclic carbonate structure, structural units derived from one or more types of monomers (a) selected from the monomers (a) described above. The copolymer (C) may have, as the polymerization unit (B) having a hydrophilic structure, structural units derived from one or more types of monomers (b) selected from the monomers (b) described above. The copolymer (C) may be a random copolymer or a block copolymer containing the polymerization unit (A) having a cyclic carbonate structure and the polymerization unit (B) having a hydrophilic structure, or a mixture thereof.

[0033] Copolymer (C) may further contain structural units different from the polymerized units (A) having a cyclic carbonate structure and the polymerized units (B) having a hydrophilic structure. For example, when preparing copolymer (C), a monomer having a long-chain aliphatic structure, such as n-butyl methacrylate or n-lauryl methacrylate, may be added in addition to monomers (a) and (b). This lowers the glass transition temperature (Tg) of copolymer (C) and softens it. Furthermore, when preparing copolymer (C), a monomer having a functional group capable of forming crosslinks upon irradiation with light, such as 4-methacryloyloxybenzophenone (MBP) or 4-methacryloyloxy-2-hydroxybenzophenone (MHP), may be added in addition to monomers (a) and (b).

[0034] In the copolymer (C), the content of the polymerized units (A) having a cyclic carbonate structure is preferably 2 mol% or more, more preferably 3 mol% or more, and even more preferably 5 mol% or more, from the viewpoint of ensuring adhesion between the coating agent and the substrate to be coated with the coating agent. The content of the polymerized units (A) having a cyclic carbonate structure may be, for example, 50 mol% or less, preferably 30 mol% or less, more preferably 20 mol% or less, and even more preferably 15 mol% or less. In the copolymer (C), the content of the polymerized units (B) having a hydrophilic structure may be, for example, 50 mol% or more, from the viewpoint of ensuring hydrophilicity in the coating. In particular, from the viewpoint of obtaining a long medical device with excellent lubricity, the content of the polymerized units (B) having a hydrophilic structure is preferably 70 mol% or more, more preferably 80 mol% or more, and even more preferably 85 mol% or more. In the copolymer (C), the content of the polymerized units (B) having a hydrophilic structure is preferably 98 mol% or less, more preferably 97 mol% or less, and even more preferably 95 mol% or less. When producing the copolymer (C), for example, the monomer (a) may be mixed in the proportion of the polymerization unit (A) having the above-mentioned cyclic carbonate structure, and the monomer (b) may be mixed in the proportion of the polymerization unit (B) having the above-mentioned hydrophilic structure. The copolymer (C) preferably contains at least a polymerized unit (B1) having a betaine structure as the polymerized unit (B) having a hydrophilic structure, and the amount of the polymerized unit (B1) having a betaine structure is preferably 10 mol% or more, more preferably 20 mol% or more, even more preferably 30 mol% or more, and even more preferably 40 mol% or more based on the amount of all polymerized units contained in the copolymer (C) in order to easily improve the lubricity of the coating. The copolymer (C) containing a polymerized unit having a betaine structure also preferably contains at least one polymerized unit (B) having a hydrophilic structure selected from the group consisting of an amide structure, an alkylene oxide structure, and a lactam structure. The copolymer (C) also preferably has at least a polymerized unit (B2) having an amide structure as the polymerized unit (B) having a hydrophilic structure, and the amount of the polymerized unit (B2) having an amide structure may be 10 mol% or more, preferably 30 mol% or more, more preferably 50 mol% or more, even more preferably 70 mol% or more, even more preferably 80 mol% or more, and particularly preferably 85 mol% or more, based on the amount of all polymerized units contained in the copolymer (C), from the viewpoint of easily increasing the lubricity of the coating and easily increasing crosslinkability at low temperatures. In addition, the copolymer (C) containing a polymerized unit having an amide structure also preferably contains at least one polymerized unit (B) having a hydrophilic structure selected from the group consisting of a betaine structure, an alkylene oxide structure, and a lactam structure.

[0035] The weight-average molecular weight of the copolymer (C) is preferably 10,000 or more, more preferably 40,000 or more, and is preferably 1,000,000 or less, more preferably 90,000 or less.

[0036] When producing the copolymer (C), the method for polymerizing the material containing the monomer (a) and the monomer (b) is not particularly limited, and examples thereof include solution polymerization, bulk polymerization, emulsion polymerization, suspension polymerization, etc. Among these, solution radical polymerization is preferred.

[0037] (4) Formation of a hydrophilic coating The hydrophilic coating of the elongated medical device of this embodiment can be formed by coating a substrate with a coating agent containing the aforementioned copolymer (C) and a solvent. Specifically, a crosslinking agent such as a diamine or polyamine is further mixed with the coating agent, and the cyclic carbonate structure of the polymerized unit (A) is reacted with the crosslinking agent to open the cyclic carbonate ring, thereby forming a polyhydroxyurethane. By allowing this reaction to proceed on the substrate to which the coating agent has been applied, a hydrophilic coating that adheres closely to the substrate can be formed.

[0038] The crosslinking agent used to form the polyhydroxyurethane is not particularly limited as long as it contains two or more primary amines in the molecule. For example, amine-based crosslinking agents such as aliphatic polyamines, alicyclic polyamines, and aromatic polyamines are suitable. Specifically, for example, hexamethylenediamine (HMDA), 1,4-butanediamine (BDA), diethylenetriamine (DETA), and triethylenetetramine (TETA) are suitable as aliphatic polyamines. For example, menthenediamine (MDA) and isophoronediamine (IPDA) are suitable as alicyclic polyamines. For example, metaxylenediamine (m-XDA), diaminodiphenylmethane (DDM), and m-phenylenediamine (m-PDA) are suitable as aromatic polyamines. In particular, hexamethylenediamine (HMDA) is a long-chain aliphatic compound with high structural reactivity and flexibility, making it suitable as a crosslinking agent. In addition, it has lower toxicity than other diamine compounds with shorter chain lengths, making it suitable for use in medical devices.

[0039] When applying the coating agent to a substrate, the coating agent and crosslinking agent may be dissolved in a solvent so that the concentration and viscosity of the coating agent are within the appropriate range. The amount of the solvent is not particularly limited as long as it is an amount that can dissolve the copolymer (C) and the crosslinking agent and can be adjusted appropriately to facilitate application. For example, it may be 10 to 99% by mass based on the total amount of the resulting coating agent. The solvent is not particularly limited as long as it can dissolve the copolymer (C). For example, various hydrophilic polar solvents can be used, such as alcohols such as ethanol, methanol, propanol, 2-propanol, butanol, and benzyl alcohol, as well as N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and dimethylacetamide (DMA). A polymerization initiator or catalyst may also be added to the coating agent, if necessary. The coating agent containing the crosslinking agent can be cured by heating, for example, to 70 to 150°C to promote the ring-opening reaction of the cyclic carbonate.

[0040] FIG. 1 is an explanatory diagram showing how the copolymer (C) contained in the coating agent is crosslinked by a crosslinking agent to form polyhydroxyurethane. FIG. 1 shows the cyclic carbonate structure derived from the polymerization unit (A) contained in the copolymer (C) when (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) is used as the monomer (a). In the copolymer (C) shown in FIG. 1, R 1 is a hydrogen atom (H) or a methyl group (CH3), but when (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) is used as the monomer (a), R 1 becomes H. Also, FIG. 1 shows the use of hexamethylenediamine as a crosslinking agent. Note that in the part after the ring-opening reaction in FIG. 1 and in FIGS. 2 and 3 described later, the "part representing the polymerization site of the polymerized units (A) and (B)" is simplified and indicated by a wavy line, and the "hydrophilic structure R derived from the polymerized unit (B)" is also indicated by a wavy line. 2 " has been omitted.

[0041] As shown in Figure 1, when the coating agent hardens, urethane bonds are formed and hydroxyl groups are generated as the cyclic carbonate ring opens. In Figure 1, hydroxyl groups are indicated by dashed lines, and urethane bonds are indicated by dashed lines. When the cyclic carbonate ring opens, the resulting crosslinked structure can vary depending on the site attacked by the amine crosslinker. Specifically, when the structure derived from (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) is ring-opened as shown in Figure 1, three types of crosslinked structures can be generated, as shown in formulas (1) to (3), depending on whether the amine crosslinker attacks the oxygen atom at position 1 or 3 of the five-membered ring. Figure 1 shows the case where the crosslinked structure of formula (1) is obtained.

[0042] -CH(OH)-CH(R 1 )-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(R 1 )-CH(OH)- … (1) -CH(OH)-CH(R 1 )-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)- … (2) -CH(CH(R 1 )-OH)-OC(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)- … (3) (In each formula, R 1 R may be the same or different and represent a hydrogen atom, a linear alkyl group having one or more carbon atoms, or a branched alkyl group having one or more carbon atoms. 2 represents an alkylene group having one or more carbon atoms, a divalent alicyclic hydrocarbon group containing an alicyclic structure having three or more carbon atoms, or a divalent aromatic group containing an aromatic ring structure having six or more carbon atoms, and the alkylene group, the alicyclic hydrocarbon group, and the aromatic group do not have an -NR 3 -(R 3 may have a divalent group represented by a hydrogen atom or an alkyl group having 1 to 8 carbon atoms).

[0043] In this embodiment, the material constituting the substrate to be coated with the coating agent is not particularly limited and can be, for example, a metal or a polymeric material (resin). From the viewpoint of further enhancing the adhesion of the coating agent, it is preferable that the surface of the substrate contains at least one of a metal, a polymeric material having a group capable of forming a hydrogen bond, and a polyurethane. For example, by applying and curing the aforementioned coating agent to a metal substrate, a substrate containing a polymeric material having a group capable of forming a hydrogen bond, or a polyurethane substrate, the adhesion between the resulting hydrophilic coating (hydrogel layer) and the substrate can be further enhanced.

[0044] The metal constituting the metal substrate may be, for example, an element that forms a metallic bond, such as iron (Fe), chromium (Cr), nickel (Ni), molybdenum (Mo), cobalt (Co), titanium (Ti), tungsten (W), platinum (Pt), gold (Au), silver (Ag), or tin (Sn), either alone or in the form of an alloy. More specifically, stainless steel alloys, nickel-titanium alloys, cobalt-chromium alloys, platinum alloys, tungsten, or tin-silver alloys are suitable.

[0045] The "group capable of forming a hydrogen bond" may be any group containing a hydrogen atom and in which the hydrogen atom forms a covalent bond with an atom that is more electronegative than the hydrogen atom. Examples of the atom that forms a covalent bond with a hydrogen atom include an oxygen atom (O), a nitrogen atom (N), a sulfur atom (S), and a carbon atom (C). More specifically, examples of the "group capable of forming a hydrogen bond" include a hydroxyl group (-OH), an amino group (-NH), and an imino group (=NH). Furthermore, examples of the "polymer material having a group capable of forming a hydrogen bond" include polyvinyl alcohol (PVA) and modified polyolefin resins having a group capable of forming a hydrogen bond.

[0046] As the polyurethane substrate, a wide variety of synthetic resins having urethane bonds can be used. Specifically, for example, aromatic ether urethane, aromatic carbonate urethane, aromatic ester urethane, aliphatic ether urethane, aliphatic carbonate urethane, aliphatic ester urethane, polyhydroxyurethane, urea urethane partially containing urea bonds, etc. can be used. In particular, aromatic ether urethane and polyhydroxyurethane are preferably used because of their superior flexibility, reactivity, and adhesion.

[0047] Below, as examples of forming a hydrophilic coating, we will explain the formation of a hydrophilic coating using a substrate whose surface is made of metal, a substrate whose surface is made of a polymeric material having groups capable of forming hydrogen bonds, and a substrate whose surface is made of polyurethane.

[0048] FIG. 2 is an explanatory diagram schematically illustrating the principle by which a hydrophilic coating according to this embodiment adheres to a substrate 10 whose surface is made of metal. As shown in FIG. 2, when the coating agent of this embodiment hardens, hydroxyl groups are generated as the cyclic carbonate ring opens. The hydroxyl groups thus generated form hydrogen bonds with the hydroxyl groups on the surface of the metal substrate, adhering to the substrate surface. That is, the reaction in which the cyclic carbonate ring opens and crosslinks, hardening the coating agent, and the reaction in which hydrogen bonds are formed with the substrate surface proceed simultaneously, resulting in the hydrophilic coating being adhered to the substrate 10. Based on a similar principle, a hydrophilic coating can also be firmly adhered to a substrate 10 whose surface is made of a polymeric material having groups capable of forming hydrogen bonds.

[0049] FIG. 3 is an explanatory diagram schematically illustrating the principle by which a hydrophilic coating according to this embodiment adheres to a substrate 10 whose surface is made of polyurethane. As shown in FIG. 3, when the coating agent of this embodiment hardens, urethane bonds are generated as the cyclic carbonate ring opens. The urethane bonds thus generated form a compatible adhesion with the urethane that forms the substrate surface. That is, the reaction in which the cyclic carbonate ring opens and crosslinks, causing the coating agent to harden, and the reaction in which the urethanes form a compatible adhesion with the substrate surface described above proceed simultaneously, resulting in the hydrophilic coating being adhered to the substrate 10.

[0050] However, the substrate included in the elongated medical device of this embodiment may be a substrate other than a substrate containing at least one of metal, polymeric material having groups capable of forming hydrogen bonds, and polyurethane on its surface. For example, if a bonding force due to hydrogen bonding or the like occurs between the coating and the substrate when the coating agent is cured on the substrate to form a coating, a similar high adhesion can be obtained in the hydrophilic coating.

[0051] (5) Long medical devices: The elongated medical device of this embodiment can be a medical device that is inserted into the body. Specifically, the elongated medical device of this embodiment can be a long medical device that uses, as the substrate 10, a long medical device made of metal, a long medical device made of urethane, or a long medical device in which metal is coated with a polymeric material having groups capable of forming hydrogen bonds or polyurethane, and forms the hydrophilic coating described above on the surface of the substrate 10. Particularly suitable forms of the elongated medical device of this embodiment include, for example, a guidewire or a catheter. Specifically, the substrate can be, for example, a metal guidewire, a guidewire with a urethane coating layer on the surface of a coil layer at the tip (urethane-jacketed guidewire), or a catheter with a hollow polyurethane shaft.

[0052] The catheter of the present disclosure is not particularly limited, and can be applied to any catheter, for example, a guiding catheter, a penetration catheter, a microcatheter, a balloon catheter, a foreign body removal catheter, an angiography catheter, a bile duct catheter, a urethral catheter, an endoscope, a dilator, etc. The guidewire of the present disclosure is also not particularly limited, and can be applied to any guidewire, for example, a PCI guidewire for coronary artery treatment, a PTA guidewire for lower limb vascular treatment, an IVR guidewire for peripheral vascular treatment, an INR guidewire for cerebrovascular treatment, a CAG guidewire for angiography, etc.

[0053] More specifically, the elongated medical device of this embodiment can employ various configurations, for example, as shown in the following (a) to (e). The coating layer of the guidewires of (a) and (c) below preferably comprises at least one of metal, polymeric material having groups capable of forming hydrogen bonds, and polyurethane, as explained above as the configuration of the surface of the substrate 10.

[0054] (a) A guide wire comprising: a linear core wire; a coating layer provided on at least a portion of the outer periphery of the core wire; and a coating formed on the surface of the coating layer, the coating being formed from a polymer material in which a copolymer (C) containing a polymer unit (B) having a hydrophilic structure is crosslinked by a structure represented by any one of the above-mentioned formulas (1) to (3). (b) A guide wire comprising: a linear core wire; a coil layer in which a wire is spirally wound around at least a portion of the outer periphery of the core wire; and a coating formed on the surface of the coil layer, the coating being made of a polymer material in which a copolymer (C) containing a polymer unit (B) having a hydrophilic structure is crosslinked by a structure represented by any one of the above-mentioned formulas (1) to (3). (c) A guide wire comprising: a linear core wire; a coil layer in which a wire is spirally wound around at least a portion of the outer periphery of the core wire; a coating layer provided on the outer periphery of the coil layer; and a coating formed on the surface of the coating layer, the coating being made of a polymer material in which a copolymer (C) containing a polymer unit (B) having a hydrophilic structure is crosslinked by a structure represented by any one of the above formulas (1) to (3). (d) A catheter comprising a tubular member and a coating formed on the surface of the tubular member, the coating being made of a polymeric material in which a copolymer (C) containing a polymer unit (B) having a hydrophilic structure is crosslinked by a structure represented by any one of the above formulas (1) to (3). (e) A catheter comprising a tubular member, a balloon disposed at one end of the tubular member, and a coating formed on the surface of the balloon, the coating being formed from a polymer material in which copolymer (C) containing polymerization units (B) having a hydrophilic structure is crosslinked by a structure represented by any one of the above formulas (1) to (3).

[0055] However, the elongated medical device of this embodiment may have a configuration different from those described above in (a) to (e), and may be a elongated medical device other than a guidewire or catheter. It is sufficient that at least a portion of the surface of the elongated medical device is provided with a hydrophilic coating formed using the coating agent according to this embodiment.

[0056] In addition, when the elongated medical device of this embodiment includes a substrate made of a resin that is difficult to heat, it is desirable to be able to form a hydrophilic coating on the substrate at a lower temperature. Therefore, in such cases, it is desirable to use, as the copolymer (C) constituting the coating, a copolymer (C) that acts as a catalyst for the crosslinking reaction by ring-opening the cyclic carbonate structure of the polymerized units (A) even under relatively low temperature conditions. As described above, for example, when the copolymer (C) has a betaine structure containing a quaternary ammonium or an amide structure containing a tertiary ammonium as the polymerized units (B) having a hydrophilic structure, these quaternary ammonium and tertiary ammonium can act as catalysts for the crosslinking reaction. In particular, tertiary ammonium, especially tertiary ammonium that does not form a ring structure, is desirable because it has high activity in promoting the crosslinking reaction even under low-temperature conditions such as room temperature. From the viewpoint of efficiently promoting crosslinking of the copolymer (C) at low temperatures, the copolymer (C) is preferably a random copolymer of the polymerized units (A) and the above-mentioned polymerized units (B).

[0057] The elongated medical device of the present embodiment configured as described above includes a coating formed using a coating agent containing a copolymer (C) containing polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure. Therefore, the coating formed on the surface of the elongated medical device can enhance adhesion to the substrate and hydrophilicity. By applying the coating agent to the substrate and forming the coating through a curing reaction involving ring-opening of the cyclic carbonate, a hydrophilic coating can be formed while maintaining adhesion to the substrate, without the need for a separate layer to enhance adhesion to the substrate.

[0058] Hydroxyl groups are generated upon ring-opening of the cyclic carbonate contained in the polymerization unit (A) of the coating agent. Therefore, when a metal component having hydroxyl groups on its surface is used as the substrate, the hydroxyl groups generated upon ring-opening of the cyclic carbonate form hydrogen bonds with the hydroxyl groups on the surface of the metal substrate. As a result, the formation of a hydrophilic coating allows the hydrophilic coating to adhere well to the substrate. Furthermore, urethane bonds are formed upon ring-opening of the cyclic carbonate in the polymerization unit (A) of the coating agent. Therefore, when the substrate surface is made of a urethane resin, the urethane bonds formed upon ring-opening of the cyclic carbonate are compatible with the urethane structure on the substrate surface. As a result, the formation of a hydrophilic coating allows the hydrophilic coating to adhere well to the substrate.

[0059] Thus, after the coating agent is applied to a substrate, a reaction occurs on the substrate surface, generating hydroxyl groups and urethane bonds on the substrate surface, facilitating interactions between the hydrophilic coating and the substrate surface, making it easier to achieve high adhesion. Furthermore, by using the coating agent according to this embodiment, a hydrophilic coating that adheres well to the substrate can be formed, whether the substrate surface is made of metal, a polymeric material having groups capable of forming hydrogen bonds, or a urethane resin. This coating agent can be widely used for polymeric materials, including metals and urethane resins, that are commonly used for the surface structure of long medical instruments. Therefore, the coating agent according to this embodiment can be used as a more versatile coating agent than conventional hydrophilic coating agents for long medical devices.

[0060] In particular, when the coating agent is used to coat a long medical device, the biocompatibility of the long medical device can be improved by making the hydrophilic structure of the polymerized unit (B) having a hydrophilic structure a neutrally charged hydrophilic structure. In contrast, for example, if the coating agent has a non-neutral, charged structure as the hydrophilic structure, biocompatibility may be insufficient. Specifically, for example, proteins in the blood may be attracted to the charge and easily adsorbed, which may promote thrombus formation or cause allergic reactions due to the adsorption of complement proteins. As an example, the polymerized unit obtained when methacrylic acid having a carboxylic acid, which is a negatively charged hydrophilic structure, is used as a monomer is shown in formula (11) below. In the long medical device of this embodiment coated with the coating agent of this embodiment, the hydrophilic structure of the coating is neutrally charged, which suppresses such reactions and improves biocompatibility.

[0061] [ka]

[0062] Furthermore, when forming a hydrophilic coating on a long medical device, the ring-opening reaction of the cyclic carbonate structure of the polymerized unit (A) can be utilized to promote the urethane reaction while reducing the use of harmful substances such as isocyanates. Therefore, even when a long medical device is used as a substrate, post-treatment of the coating process with a coating agent can be eliminated or simplified, thereby simplifying the entire manufacturing process involving the coating process using a coating agent. Furthermore, the ring-opening reaction of the cyclic carbonate structure generally proceeds under relatively mild conditions, at around 70°C, thereby reducing the manufacturing costs of devices equipped with a hydrophilic coating. [Example]

[0063] The following describes the elongated medical device of the present disclosure based on examples. Here, elongated medical devices (S1 to S7) were prepared and compared by coating a substrate with a coating agent that varied the conditions for the hydrophilic polymerized unit (B) and the conditions for curing (gelation).

[0064] <Explanation of each sample> The copolymer used to prepare the elongated medical device of Sample S1 contains structural units derived from (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) as the polymerized units (A) having a cyclic carbonate structure. The copolymer used to prepare Sample S1 also contains structural units derived from N-methacryloylaminopropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (MAMCMB) and methoxypolyethylene glycol methacrylate (M90G) as the polymerized units (B) having a hydrophilic structure. Specifically, the copolymer used to prepare Sample S1 contains 10 mol% structural units derived from GCMA, 40 mol% structural units derived from MAMCMB, and 50 mol% structural units derived from M90G. Hereinafter, the copolymer used to prepare Sample S1 is also referred to as "Poly(MAMCMB-M90G-GCMA) 40:50:10." "Poly(MAMCMB-M90G-GCMA)40:50:10" is shown in the following formula (12). "Poly(MAMCMB-M90G-GCMA)40:50:10" is a random copolymer, but formula (12) shows the site where the above three structural units are polymerized consecutively. In formula (12), the cyclic carbonate is shown surrounded by a dashed line.

[0065] [ka]

[0066] The elongated medical device, Sample S1, was fabricated by using a medical guidewire with a metal coil as the substrate and coating the portion of the substrate containing the metal coil with "Poly(MAMCMB-M90G-GCMA) 40:50:10." Specifically, the copolymer was dissolved in ethanol to a concentration of 20 wt %. Just before application to the substrate, the coating agent containing the dissolved copolymer was mixed with a 5% ethanol solution of hexamethylenediamine (HMDA) as a crosslinker in a weight ratio of 5:3, and thoroughly dissolved. The coating agent containing the crosslinker was applied to the substrate by dip coating. After application, the coating agent was dried for 1 hour in a hot air circulating oven at 120°C, producing Sample S1.

[0067] The long medical device of sample S2 was fabricated in the same manner as sample S1, except that a guidewire (urethane-jacketed guidewire) having a urethane coating layer on the surface of the metal coil portion was used as the base material, and the portion including the urethane coating layer was coated with a coating agent.

[0068] The copolymer used to prepare the elongated medical device of Sample S3 contains structural units derived from (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) as polymerization units (A) having a cyclic carbonate structure. The copolymer used to prepare Sample S3 also contains structural units derived from N,N-dimethylacrylamide (DMAAm) as polymerization units (B) having a hydrophilic structure. Specifically, the copolymer used to prepare Sample S3 contains 10 mol% structural units derived from GCMA and 90 mol% structural units derived from DMAAm. Hereinafter, the copolymer used to prepare Sample S3 will also be referred to as "Poly(DMAAm-GCMA)90:10." "Poly(DMAAm-GCMA)90:10" is shown in formula (13) below. "Poly(DMAAm-GCMA)90:10" is a random copolymer, and formula (13) shows the site where the two structural units described above are polymerized consecutively. In formula (13), the cyclic carbonate is shown surrounded by a dashed line, and the tertiary ammonium is shown surrounded by a dotted line. The weight-average molecular weight of the copolymer of sample S3 was approximately 90,000. The weight-average molecular weight of the copolymer of sample S3 and the weight-average molecular weight of the copolymers of the other samples described below were measured by gel permeation chromatography (GPC).

[0069] [ka]

[0070] The long medical device of Sample S3 was fabricated in the same way as Sample S1, by using a medical guidewire equipped with a metal coil portion as the substrate and coating the portion of the substrate containing the metal coil portion with "Poly(DMAAm-GCMA) 90:10." The method for coating the substrate with the coating agent when fabricating Sample S3 was the same as that for Sample S1, except that the solvent used to dissolve the copolymer to prepare the coating agent was changed from ethanol to dimethylformamide.

[0071] The long medical device of sample S4 was fabricated in the same manner as sample S3, except that a guidewire (urethane-jacketed guidewire) having a urethane coating layer on the surface of the metal coil portion was used as the base material, and the portion including the urethane coating layer was coated with a coating agent.

[0072] The elongated medical device of Sample S5, like Sample S4, uses "Poly(DMAAm-GCMA) 90:10" as the copolymer and a guidewire (urethane-jacketed guidewire) with a urethane coating layer on the surface of the metal coil portion as the substrate. However, the copolymer used to manufacture the elongated medical device of Sample S5 has a different weight-average molecular weight from the copolymer used to manufacture Sample S4 (and Sample S3) because the conditions for producing the copolymer were different. The weight-average molecular weight of the copolymer for Sample S5 was approximately 40,000.

[0073] The elongated medical device of Sample S6, like Sample S1, used "Poly(MAMCMB-M90G-GCMA) 40:50:10" as the copolymer, and a medical guidewire with a metal coil portion as the substrate. However, in Sample S6, HDMA was not added as a crosslinking agent to the coating agent, and a hydrophilic coating was formed on the substrate using the coating agent under the same conditions as Sample S1. Sample S6 corresponds to a comparative example.

[0074] The long medical device of Sample S7, like Sample S3, uses "Poly(DMAAm-GCMA) 90:10" as the copolymer and a medical guidewire with a metal coil portion as the substrate. However, in Sample S7, HDMA as a crosslinking agent was not added to the coating agent, and the other conditions were the same as for Sample S1, and a hydrophilic coating was formed on the substrate using the coating agent. Sample S7 corresponds to a comparative example.

[0075] <Lubricity evaluation> To evaluate lubricity, each of the prepared samples S1 to S7 was immersed in saline and then rubbed with a fingertip to compare the feel. The evaluation results are summarized in Table 1 below. In Table 1, samples with good slipperiness results are rated "A," while samples with poor slipperiness results are rated "B." As shown in Table 1, samples S1 to S5 exhibited good lubricity, unlike samples S6 and S7. Specifically, by promoting the crosslinking reaction of the coating agent on the substrate, a hydrophilic coating was formed that adhered to the substrate and exhibited sufficient lubricity. Furthermore, even when the molecular weight of the copolymer used to form the hydrophilic coating was different, as in samples S4 and S5, hydrophilic coatings with good lubricity were formed over a wide range of weight-average molecular weights, for example, from 40,000 to 90,000.

[0076] [Table 1]

[0077] <Evaluation of film strength> To evaluate film strength, each of the prepared samples S1 to S7 was placed underwater between a urethane roller (AXFM-D25-L15-V8-N, manufactured by Misumi Corporation) and a stainless steel plate (SUS304 plate, 30 x 30 mm). A load of 0.981 N was applied, and the resistance value was measured when one end connected to the load cell was pulled out. Similar measurements were performed 50 times in a row, and the initial resistance value after the first measurement was compared with the resistance value after the 50th measurement to evaluate film strength. A lower resistance value indicates better film strength. The evaluation results are summarized in Table 2 below. As shown in Table 2, samples S1 to S5, unlike samples S6 and S7, exhibited low resistance values ​​even after the 50th measurement. This confirms that by promoting the crosslinking reaction of the coating agent on the substrate, a hydrophilic coating that adheres to the substrate and exhibits good film strength is formed. Furthermore, even when the molecular weight of the copolymer used to form the hydrophilic coating is different, as in the case of samples S4 and S5, it was confirmed that a hydrophilic coating that adheres to the substrate and exhibits good film strength can be formed over a wide range of weight-average molecular weights, for example, from 40,000 to 90,000.

[0078] [Table 2]

[0079] <Evaluation of adhesion to metal substrates> To evaluate adhesion to metal substrates, a model using a stainless steel plate as the substrate was used instead of the elongated medical devices described for Samples S1 to S7. Specifically, a stainless steel plate was used as the metal substrate, and adhesion was compared between a coating formed from a copolymer comprising polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure and a polyurethane coating (Comparative Example). Similar to Sample S1, "Poly(MAMCMB-M90G-GCMA) 40:50:10" was used as the copolymer comprising polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure. Additionally, hexamethylenediamine (HMDA) was used as a curing agent. A coating was formed on the substrate under the same conditions as Sample S1. The polyurethane coating of the Comparative Example was formed by a dipping method using Pellethane 2360-80AE (manufactured by Lubrizol), a known medical polyurethane.

[0080] Adhesion to metal substrates was evaluated by a cross-cut test (JIS K5600-5-6, 1999). Specifically, a grid-like cut was made in the formed coating at 1 mm intervals using a cutter knife, transparent adhesive tape was applied and then peeled off, and the state of the grid was observed to confirm the state of peeling of the coating.

[0081] FIG. 4 is an explanatory diagram showing the results of the cross-cut test. As shown in FIG. 4, in the case of a coating similar to sample S1 ((MAMCMB-M90G-GCMA) + HMDA), no peeling of the coating was observed in any of the grids (evaluation result: 0 (no peeling)). In contrast, in the coating of the comparative example, peeling was observed widely in the area where the test was conducted (evaluation result: 4 (large peeling)). As such, it was confirmed that the coating formed using a coating agent including polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure exhibits superior adhesion to metal substrates compared to the coating of the comparative example formed using a polyol resin and an isocyanate curing agent.

[0082] <Evaluation of adhesion to urethane substrate> A guidewire (urethane-jacketed guidewire) with a urethane coating layer on the surface of the metal coil was used as the urethane substrate, and the adhesion of the coating was evaluated. Specifically, the adhesion was compared between a coating formed from a copolymer containing polymerization units (A) with a cyclic carbonate structure and polymerization units (B) with a hydrophilic structure, and a coating formed from a copolymer containing structural units derived from a monomer containing an epoxy group instead of polymerization units (A) with a cyclic carbonate structure. Poly(MAMCMB-M90G-GCMA) 40:50:10 was used as the copolymer containing polymerization units (A) with a cyclic carbonate structure and polymerization units (B) with a hydrophilic structure, and the coated guidewire had the same configuration as the previously described sample S2. Furthermore, as a copolymer having structural units derived from a monomer containing an epoxy group instead of the polymerization units (A) having a cyclic carbonate structure, "Poly(MAMCMB-M90G-4HBAGE)40:50:10" was used, which is a copolymer having structural units derived from 4-hydroxybutyl acrylate glycidyl ether (4HBAGE). Adhesion to urethane substrates was evaluated using the same method as in the "Evaluation of film strength" described above.

[0083] FIG. 5 is an explanatory diagram showing the results of the adhesion evaluation. In FIG. 5, the horizontal axis represents the number of times the sample was pulled out and the resistance value was measured (number of slides), and the vertical axis represents the measured resistance value (slip resistance value). Three samples were prepared for each of the coated guidewires similar to sample S2, coated with a copolymer containing polymerization units (A) having a cyclic carbonate structure (referred to as "polymerization units (A)" in FIG. 5), and the coated guidewires coated with a copolymer containing polymerization units derived from a monomer containing an epoxy group (referred to as "polymerization units derived from an epoxy group-containing monomer" in FIG. 5). The above test was performed on each sample. As shown in FIG. 5, it was confirmed that when a coating agent containing polymerization units (A) having a cyclic carbonate structure and polymerization units (B) having a hydrophilic structure was used, a hydrophilic coating exhibiting superior adhesion to the urethane substrate was obtained compared to when a coating agent containing polymerization units derived from a monomer containing an epoxy group and polymerization units (B) having a hydrophilic structure was used.

[0084] <Evaluation of catalytic activity under low-temperature conditions> We evaluated the catalytic activity of various copolymers containing modified hydrophilic units (B) by forming hydrophilic coatings at relatively low temperatures. Specifically, we prepared copolymers containing structural units derived from N,N-dimethylacrylamide (DMAAm), N-vinylpyrrolidone (NVP), N-methacryloylaminopropyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (MAMCMB), and methoxyethyl acrylate (MEA) as the hydrophilic units (B). All copolymers contained structural units derived from (2-oxo-1,3-dioxolan-4-yl)methyl methacrylate (GCMA) as the cyclic carbonate units (A). Each copolymer contained 10 mol% of the polymerized units (A) and 90 mol% of the polymerized units (B). Among the copolymers described above, the copolymer having structural units derived from DMAAm as polymerization units (B) was the same as the copolymer used in the previously described sample S5, and had a weight-average molecular weight of approximately 40,000. The copolymer having structural units derived from NVP as polymerization units (B) had a weight-average molecular weight of approximately 55,000, the copolymer having structural units derived from MAMCMB had a weight-average molecular weight of approximately 100,000, and the copolymer having structural units derived from MEA had a weight-average molecular weight of approximately 40,000.

[0085] The substrate on which the hydrophilic coating was formed was a guidewire (urethane-jacketed guidewire) with a urethane coating layer on the surface of a metal coil. After preparing each of the copolymers described above, the copolymer was dissolved in dimethylformamide to a concentration of 20 wt%. Just before application to the substrate, the coating agent containing the dissolved copolymer was mixed with a 5% ethanol solution of hexamethylenediamine (HMDA) as a crosslinker in a weight ratio of 5:3, and thoroughly dissolved. The coating agent containing the crosslinker was applied to the substrate by dip coating. After application, the coating agent was left at room temperature (26°C) for 1 hour, 2 hours, 3 hours, and 4 hours, and the change in viscosity was measured. The viscosity of each coating agent left on the substrate as described above was measured using a rotational vibration viscometer (VISCOMETER VM-10A-L, manufactured by Sansho Co., Ltd.).

[0086] Figure 6 is an explanatory diagram showing the viscosity change over time of coating agents containing polymers with different polymerized units (B). Figure 6 distinguishes each copolymer by indicating the type of polymerized unit (B). As shown in Figure 6, the viscosity increased over time only in the case of coating agents containing DMAAm-derived structural units as the polymerized units (B), confirming that crosslinking proceeds even at room temperature. Generally, when the hydrophilic structure of the polymerized units (B) is a betaine structure containing a quaternary ammonium or an amide structure containing a tertiary ammonium, these quaternary ammonium and tertiary ammonium are thought to act as catalysts for the crosslinking reaction of the coating agent. The results in Figure 6 confirm that, particularly when the polymerized units (B) contain DMAAm-derived structural units, i.e., tertiary ammonium that does not form a ring structure, have high activity in promoting the crosslinking reaction of the coating agent, even at low temperatures such as room temperature.

[0087] The present disclosure is not limited to the above-described embodiments, and can be realized in various configurations without departing from the spirit thereof. For example, the technical features in each embodiment described in the Summary of the Invention section can be appropriately replaced or combined to solve some or all of the above-described problems or achieve some or all of the above-described effects. Furthermore, if a technical feature is not described as essential in this specification, it can be appropriately deleted. [Explanation of symbols]

[0088] 10...Base material

Claims

1. A long medical device, a coating is formed on the surface of the base material, the coating is composed of a polymer material in which a copolymer containing a polymerization unit having a hydrophilic structure is crosslinked by a structure represented by any of the following formulas (1) to (3). Long medical device. -CH(OH)-CH(R 1 )-O-C(=O)-NH-R 2 -NH-C(=O)-O-CH(R 1 )-CH(OH)- … (1) -CH(OH)-CH(R 1 )-O-C(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)-…(2) -CH(CH(R 1 )-OH)-O-C(=O)-NH-R 2 -NH-C(=O)-O-CH(CH(R 1 )-OH)-… (3) (In each formula, R 1 may be the same or different and represents a hydrogen atom, a linear alkyl group having 1 or more carbon atoms, or a branched alkyl group having 1 or more carbon atoms. R 2 is an alkylene group having 1 or more carbon atoms, a divalent alicyclic hydrocarbon group containing an alicyclic structure having 3 or more carbon atoms, or a divalent aromatic group containing an aromatic ring structure having 6 or more carbon atoms, and the alkylene group, the alicyclic hydrocarbon group, and the aromatic group have a divalent group represented by -NR ３ -(R ３ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms) may be included.)

2. The long medical device according to claim 1, the hydrophilic structure is electrically neutral Long medical device.

3. The long medical device according to claim 1, the hydrophilic structure includes at least one structure selected from the group consisting of a betaine structure, an amide structure, a lactam structure, and a polyalkylene oxide structure Long medical device.

4. The long medical device according to claim 3, the hydrophilic structure includes at least one of a betaine structure having a quaternary ammonium as a positively charged functional group and an amide structure having a tertiary ammonium Long medical device.

5. The long medical device according to claim 1, the base material includes at least one of metal, a polymer material having a group capable of forming a hydrogen bond, and polyurethane on the surface of the base material Long medical device.

6. The long medical device according to claim 1, the long medical device is a guide wire or a catheter Long medical device.

7. A method for manufacturing a long medical device, applying a coating agent containing a copolymer (C) containing a polymerization unit (A) having a cyclic carbonate structure and a polymerization unit (B) having a hydrophilic structure on a base material provided on the medical device, curing the coating agent on the base material Method for manufacturing a long medical device.

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