Medical instrument and method for manufacturing medical instrument

Abstract

[Problem] To provide a method for manufacturing a medical instrument having a surface lubrication layer exhibiting excellent durability even in a heat treatment at a low temperature. [Solution] This method is for manufacturing a medical instrument provided with a base material layer, and a surface lubrication layer supported by at least a portion of the base material layer, the method comprising: preparing a coating liquid containing a solvent, a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, and an isocyanate compound having at least two isocyanate groups; and applying the coating liquid on the base material layer.

Description

Medical device and method for manufacturing medical device

[0001] The present invention relates to a medical device and a method for manufacturing a medical device.

[0002] Medical devices inserted into living bodies, such as catheters, guidewires, and indwelling needles, are required to exhibit excellent lubricity in order to reduce tissue damage to blood vessels and improve operability for the surgeon. For this reason, methods of coating the surface of a substrate layer with a hydrophilic polymer having lubricity have been developed and put into practical use. In such medical devices, elution or peeling of the hydrophilic polymer from the surface of the substrate layer poses problems in terms of maintaining safety and operability. Therefore, coatings with hydrophilic polymers are required to have not only excellent lubricity but also durability against loads such as abrasion and abrasion.

[0003] From this point of view, Patent Document 1 discloses a medical device in which a water-soluble or water-swellable polymer is dissolved in a solvent that swells the substrate of the medical device to prepare a polymer solution, the substrate of the medical device is immersed in this polymer solution to swell, and the polymer is crosslinked or polymerized on the surface of the substrate, thereby forming a surface lubricating layer on the surface of the substrate. According to the technology disclosed in Patent Document 1, a surface lubricating layer that shows relatively good lubricity can be fixed to the substrate.

[0004] JP 2015-57081 A

[0005] However, in the case of conventional surface lubricating layers, in order to obtain high durability, heating at high temperatures is required. In this case, it is difficult to perform high-temperature heat treatment on substrates with low heat resistance, and it has been difficult to form a surface lubricating layer with sufficient durability.

[0006] Therefore, there is a demand for a technology that can achieve high durability (especially sliding durability) in medical devices having a surface lubricating layer even when heat treated at a low temperature of less than 100°C.

[0007] The present invention has been made in consideration of the above circumstances, and aims to provide a method for manufacturing a medical device having a surface lubricating layer that exhibits excellent durability (particularly sliding durability) even when heated at low temperatures.

[0008] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that the above-mentioned object can be achieved by combining an isocyanate compound having two or more isocyanate groups with a hydrophilic block copolymer having an epoxy group, and applying the two together as a one-component system, thereby completing the present invention.

[0009] The above object can be achieved by the present invention having the following configuration, and the present invention includes the following aspects and embodiments.

[0010] One aspect of the present invention has the following configuration: 1. A method for manufacturing a medical device comprising a base layer and a surface lubricating layer carried on at least a portion of the base layer, the method comprising: preparing a coating liquid containing a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, an isocyanate compound having two or more isocyanate groups, and a solvent; and applying the coating liquid onto the base layer.

[0011] 2. In the manufacturing method described in 1 above, the coating liquid preferably contains the block copolymer and the isocyanate compound in a mass ratio of 100:0.5 or more and 100:8 or less.

[0012] 3. In the manufacturing method described in 1. or 2. above, the isocyanate compound is preferably an aliphatic or aromatic isocyanate compound having 6 to 20 carbon atoms.

[0013] 4. In the manufacturing method according to any one of the above 1. to 3., the isocyanate compound preferably includes at least one selected from the group consisting of hexamethylene diisocyanate, toluene diisocyanate, and 4,4'-diphenylmethane diisocyanate.

[0014] 5. In the manufacturing method described in any one of 1. to 4. above, it is preferable that after the coating liquid is applied to the substrate to form a coating film, the coating film is heat-treated at a temperature of 80°C or higher but lower than 100°C for 1 hour or longer and 10 hours or shorter.

[0015] 6. In the production method according to any one of 1. to 5. above, the reactive monomer having an epoxy group preferably includes at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether.

[0016] 7. In the production method described in any one of 1. to 6. above, the hydrophilic monomer preferably includes at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

[0017] 8. In the production method according to any one of the above 1. to 7., the solvent preferably contains at least one selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and acetone.

[0018] 9. In the manufacturing method described in any one of the above 1. to 8., the base layer preferably contains at least one material selected from the group consisting of metal, polyamide resin, polyolefin resin, polyester resin, and polyurethane resin.

[0019] Another aspect of the present invention has the following configuration: 10. A medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer comprises a crosslinked reaction product of an epoxy group of a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, and an isocyanate group of an isocyanate compound having two or more isocyanate groups.

[0020] 11. In the medical device of 10. above, the reactive monomer having an epoxy group preferably includes at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether.

[0021] 12. In the medical device of 10. or 11. above, the hydrophilic monomer preferably includes at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

[0022] 13. In the medical device according to any one of the above items 10 to 12, the isocyanate compound preferably includes at least one selected from the group consisting of hexamethylene diisocyanate, toluene diisocyanate, and 4,4'-diphenylmethane diisocyanate.

[0023] 14. In the medical device according to any one of the above items 10 to 13, the base layer preferably contains at least one material selected from the group consisting of metal, polyamide resin, polyolefin resin, polyester resin, and polyurethane resin.

[0024] 1 is a partial cross-sectional view schematically showing the surface layer structure of a representative embodiment of a medical device according to the present invention. 2 is a partial cross-sectional view schematically showing an example of a different surface layer structure as an application example of the embodiment of FIG. 1. 3 is a graph evaluating the sliding durability of a surface lubricating layer provided on a stainless steel substrate (Example 1 and Comparative Example 1). 4 is a graph evaluating the sliding durability of a surface lubricating layer provided on a nylon elastomer substrate (Example 2 and Comparative Example 2). 5 is a graph evaluating the sliding durability of a surface lubricating layer provided on a polyester elastomer substrate (Example 3 and Comparative Example 3). 6 is a graph evaluating the sliding durability of a surface lubricating layer provided on a polyethylene substrate (Example 4 and Comparative Example 4). 7 is a graph evaluating the sliding durability of a surface lubricating layer provided on a stainless steel substrate (Example 1 and Comparative Example 5).

[0025] The following describes embodiments of the present invention, but the present invention is not limited to these embodiments and can be modified in various ways within the scope of the claims. The embodiments described herein can be arbitrarily combined to create other embodiments. In other words, a combination of two or more of the individual preferred embodiments of the present invention described below is also a preferred embodiment of the present invention and is considered to be disclosed in this specification (i.e., serves as a legal basis for amendment). In this specification, the range "X to Y" includes X and Y and means "X or more and Y or less." Unless otherwise specified, operations and measurements of physical properties are performed at room temperature (20-25°C) and a relative humidity of 40-50% RH. A and / or B refer to A, B, or a combination thereof.

[0026] A method for manufacturing a medical device according to one embodiment of the present invention is a method for manufacturing a medical device comprising a base layer and a surface lubrication layer supported on at least a portion of the base layer, and includes preparing a coating liquid containing a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, an isocyanate compound having two or more isocyanate groups, and a solvent, and applying the coating liquid onto the base layer.

[0027] According to the method for manufacturing a medical device of the present invention, it is possible to manufacture a medical device having a surface lubricating layer that exhibits excellent durability (particularly sliding durability) even when heated at a low temperature (e.g., less than 100°C).

[0028] Herein, the structural unit (A) derived from a reactive monomer having an epoxy group is also referred to simply as the "structural unit (A) according to the present invention" or "structural unit (A)." Herein, the structural unit (B) derived from a hydrophilic monomer is also referred to simply as the "structural unit (B) according to the present invention" or "structural unit (B)." Herein, a block copolymer having structural units (A) and (B) is also referred to simply as the "block copolymer according to the present invention" or "block copolymer."

[0029] In this specification, an isocyanate compound having two or more isocyanate groups is also simply referred to as "the isocyanate compound according to the present invention" or "the isocyanate compound."

[0030] In this specification, when a certain structural unit is defined as being "derived from" a certain monomer, it means that the structural unit is a divalent structural unit generated by cleavage of one of the polymerizable unsaturated double bonds of the corresponding monomer.

[0031] As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups. Similarly, the term "(meth)acrylate" encompasses both acrylate and methacrylate. For example, the term "alkoxyalkyl(meth)acrylate" encompasses both alkoxyalkylacrylate and alkoxyalkylmethacrylate.

[0032] In the present invention, a coating liquid containing a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, an isocyanate compound having two or more isocyanate groups, and a solvent is prepared, and the coating liquid is applied to the substrate layer. That is, the present invention is characterized in that a surface lubricating layer is formed using the block copolymer and the isocyanate compound as a one-component system.

[0033] Medical devices with a surface lubricating layer require a highly durable surface lubricating layer. One approach to achieving a highly durable surface lubricating layer is to increase the degree of crosslinking of the polymer that constitutes the surface lubricating layer, and to use a crosslinking aid during the crosslinking reaction. For example, a method using an acid or base as a crosslinking aid can be used to crosslink a block copolymer having structural units derived from a reactive monomer with an epoxy group. However, there is a risk that the crosslinking aid (acid or base) will remain in the formed surface lubricating layer, causing further reaction within the surface lubricating layer. This will result in poor stability over time and, as a result, reduced durability of the surface lubricating layer. Therefore, when using such a crosslinking aid, it is necessary to remove the crosslinking aid remaining in the surface lubricating layer after the crosslinking reaction, which is a cumbersome process. Therefore, methods to maintain or improve the durability of the surface lubricating layer have been used to ensure the reactivity of the polymer, such as by heating at high temperatures or extending the heating time. However, in such cases, there is a problem that substrates with low heat resistance cannot be used.

[0034] Therefore, the inventors have investigated a method that allows crosslinking at low temperatures. As a result, the inventors have found that by mixing a block copolymer and an isocyanate compound in one liquid (one-liquid system), and carrying out a crosslinking reaction while the epoxy group of the block copolymer and the isocyanate compound are in contact with each other, a highly durable surface lubricating layer can be obtained even when the crosslinking reaction is carried out at low temperatures. That is, the present invention has found that by using a coating liquid that is a one-liquid system of a block copolymer and an isocyanate compound, a highly durable surface lubricating layer can be formed by heat treatment at low temperatures (for example, below 100 ° C).

[0035] The mechanism by which such effects can be achieved by using a coating solution containing a block copolymer and an isocyanate compound as a one-component system is believed to be as follows: The isocyanate compound according to the present invention is electrophilic. Therefore, when the isocyanate compound comes into contact with the block copolymer, electrons from the epoxy groups (crosslinking moieties) are removed, severing the bond and ring-opening the epoxy groups. The ring-opened epoxy groups react with each other, crosslinking (bonding) the block copolymers. Alternatively, the ring-opened epoxy groups of the block copolymer react with the isocyanate groups of the isocyanate compound, crosslinking (bonding) the block copolymers via the isocyanate compound. This increases the film strength of the surface lubricating layer. Because this ring-opening reaction of the epoxy group is a molecule-to-molecule electron transfer, the isocyanate compound and the block copolymer (hydrophilic polymer molecule) must approach each other until their molecular electron orbitals overlap. However, because a solvent is present between the isocyanate compound and the block copolymer in the coating solution, the isocyanate compound and the block copolymer do not come into close contact and exist apart. As a result, the isocyanate compound does not attract electrons from the epoxy groups (crosslinking moieties), and the ring-opening (crosslinking reaction) of the epoxy groups in the coating liquid hardly or not occurs at all. Because the ring-opening of the epoxy groups in the block copolymer does not occur, the coating liquid does not become viscous or gel, and the solution form is maintained. Therefore, the coating liquid can be uniformly applied to the substrate layer. After the coating liquid is applied to the substrate layer, when the solvent is removed from the coating liquid film, the isocyanate compound comes into contact with the block copolymer and attracts electrons (the molecular electron orbitals overlap), initiating and promoting the ring-opening (crosslinking reaction) of the epoxy groups. According to the method of the present invention, the coating liquid can be uniformly applied to the substrate layer, and the ring-opening (crosslinking reaction) of the epoxy groups proceeds evenly and densely on the substrate layer surface, thereby increasing the film strength of the surface lubrication layer and more firmly immobilizing the block copolymer on the substrate layer surface.As a result, it is presumed that a surface lubricating layer (a strong coating layer) with high film strength is formed, and the strong coating layer can be well maintained even after sliding against a biological lumen such as a more flexible and narrow blood vessel, and high lubricity (surface lubricity) can be maintained for a longer period of time (i.e., excellent surface lubricity can be maintained and sliding durability can be improved). Note that the above mechanism is presumed and does not limit the technical scope of the present invention.

[0036] Therefore, the medical device produced according to the method of the present invention has excellent durability (sliding durability). In addition, the medical device produced according to the method of the present invention also has excellent lubricity, and since the lubricity is highly durable, it also has excellent surface lubrication maintenance properties.

[0037] <Method for Manufacturing Medical Device> The method for manufacturing a medical device according to the present invention includes preparing a coating liquid containing a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, an isocyanate compound having two or more isocyanate groups, and a solvent ((I) preparation step); and applying the coating liquid to the substrate layer ((II) application step). In this way, by using a solution containing a specific isocyanate compound together with the block copolymer as the coating liquid, a medical device having a surface lubrication layer (coating layer) that exhibits excellent durability can be obtained.

[0038] After the above step (II), if necessary, further steps such as a drying and / or heat treatment step ((III) drying / heat treatment step), and a washing step ((IV) washing step) may be carried out. Of these, it is preferable to carry out at least the (III) drying / heat treatment step after the above step (II). Furthermore, if necessary, the (III) drying / heat treatment step may be followed by the (IV) washing step, but in the method of the present invention, the isocyanate compound used in forming the surface lubrication layer is covalently bonded to the block copolymer or becomes a water-insoluble polyurea, so there is no particular need to carry out the (IV) washing step, which is advantageous for mass production.

[0039] (I) Preparation Step In this step, a coating liquid containing a block copolymer, an isocyanate compound, and a solvent is prepared. Here, in this step, the coating liquid may be prepared by mixing the block copolymer, the isocyanate compound, and the solvent to prepare the coating liquid. Alternatively, the coating liquid may be prepared by mixing the isocyanate compound and the solvent to prepare a liquid containing the isocyanate compound, and then further mixing the block copolymer with the liquid containing the isocyanate compound to prepare the coating liquid. Alternatively, the coating liquid may be prepared by mixing the block copolymer and the solvent to prepare a liquid containing the block copolymer, and then further mixing the isocyanate compound with the liquid containing the block copolymer to prepare the coating liquid. Furthermore, the coating liquid containing the block copolymer, the isocyanate compound, and the solvent may be purchased and used.

[0040] A preferred embodiment of preparing a coating liquid by mixing a block copolymer, an isocyanate compound, and a solvent will be described in detail below.

[0041] (Block copolymer) In the present invention, the block copolymer forms a surface lubricating layer supported on at least a part of the base layer. That is, in the medical device obtained by the method of the present invention, the surface lubricating layer comprises a block copolymer. Note that "supported" means that the surface lubricating layer is fixed in a state that it is not easily separated from the surface of the base layer, and includes not only the form in which the entire surface of the base layer is completely covered with the surface lubricating layer, but also the form in which only a part of the surface of the base layer is covered with the surface lubricating layer, that is, the form in which the surface lubricating layer is attached to only a part of the surface of the base layer.

[0042] The block copolymer according to the present invention has a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer.

[0043] The reactive monomer having epoxy group that constitutes block copolymer has epoxy group as reactive group.By introducing the structural unit (A) derived from this reactive monomer into block copolymer, epoxy group ring-opens, and the cross-linking (bonding) between block copolymers progresses, and the film strength of surface lubrication layer increases.In addition, when base layer is made of resin material, the cross-linking (bonding) between block copolymer and base layer also occurs due to the open epoxy group.

[0044] The reactive monomer constituting the block copolymer is not particularly limited as long as it has an epoxy group, and known compounds can be used. Among these, the reactive monomer having an epoxy group preferably includes at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether, because this facilitates control of the crosslinking or polymerization of the block copolymer. Among these, glycidyl (meth)acrylate is more preferred, and glycidyl methacrylate is particularly preferred, in consideration of the ability to further promote the crosslinking reaction and ease of production.

[0045] The reactive monomers may be used alone or in combination of two or more. That is, the reactive site derived from the reactive monomer may be a homopolymer type composed of one type of reactive monomer alone, or a copolymer type composed of two or more types of the reactive monomers. When two or more types are used, the reactive site may be in the form of a block copolymer or a random copolymer.

[0046] That is, in a preferred embodiment of the present invention, the reactive monomer having an epoxy group includes at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether, or is at least one selected from the above group. In a more preferred embodiment of the present invention, the reactive monomer having an epoxy group is at least one of glycidyl acrylate and glycidyl methacrylate. In a particularly preferred embodiment of the present invention, the reactive monomer having an epoxy group is glycidyl methacrylate.

[0047] The hydrophilic monomers constituting the block copolymers swell when in contact with body fluids or aqueous solvents, thereby imparting lubricity (surface lubricity) to medical devices. Therefore, by introducing the structural unit (B) derived from such a hydrophilic monomer into the block copolymer, the lubricity (surface lubricity) of the medical device can be improved, thereby reducing friction when the medical device comes into contact with a lumen wall such as a blood vessel wall.

[0048] The hydrophilic monomer constituting the block copolymer is not particularly limited as long as it has the above-mentioned properties, and known compounds can be used, such as acrylamide and its derivatives, vinylpyrrolidone, acrylic acid, methacrylic acid and their derivatives, polyethylene glycol acrylate and its derivatives, monomers having sugars or phospholipids in the side chains, and water-soluble monomers such as maleic anhydride. More specifically, acrylic acid, methacrylic acid, N-methylacrylamide, N,N-dimethylacrylamide (DMAA), acrylamide, acryloylmorpholine, N,N-dimethylaminoethyl acrylate, N-vinylpyrrolidone, 2-methacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, vinyl methyl ether, 2-hydroxyethyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, 1,4-cyclohexanedimethanol mono(meth)acrylate, 1-chloro-2-hydroxypropyl (meth)acrylate, diethylene glycol mono(meth)acrylate, 1,6-hexanediol mono(meth)acrylate, pentaerythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropane di(meth)acrylate, trimethylolethane di(meth)acrylate, 2-hydroxy-3-phenyloxypropyl(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, 2-hydroxy-3-phenyloxy(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, cyclohexanedimethanol mono(meth)acrylate, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate.From the viewpoints of imparting excellent lubricity, ease of synthesis, and operability, the hydrophilic monomer preferably includes at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone, and more preferably at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate. Of these, from the viewpoint of excellent lubricity, N,N-dimethylacrylamide is particularly preferred as the hydrophilic monomer.

[0049] The above hydrophilic monomers may be used alone or in combination of two or more. That is, the hydrophilic moiety derived from the hydrophilic monomer may be a homopolymer type composed of one hydrophilic monomer alone, or a copolymer type composed of two or more of the above hydrophilic monomers. When two or more types are used, the form of the hydrophilic moiety may be a block copolymer or a random copolymer.

[0050] That is, in a preferred embodiment of the present invention, the hydrophilic monomer includes or is at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone. In a more preferred embodiment of the present invention, the hydrophilic monomer is at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate. In a particularly preferred embodiment of the present invention, the hydrophilic monomer is N,N-dimethylacrylamide.

[0051] The block copolymer has the above-mentioned structural unit (A) and structural unit (B). Here, the ratio of the structural unit (A) to the structural unit (B) is not particularly limited as long as the above-mentioned effects are achieved. In consideration of good lubricity, lubrication maintenance, coating layer strength, and bonding with the base layer, the ratio of the structural unit (A) to the structural unit (B) (molar ratio of the structural unit (A): the structural unit (B)) is preferably 1:2 to 1:100, more preferably 1:2 to 1:50, even more preferably 1:5 to 1:50, and particularly preferably 1:10 to 1:30. Within such a range, the surface lubricating layer can exhibit sufficient lubricity due to the structural unit (B), and can exhibit sufficient coating layer strength, bonding with the base layer (in the case of a resin material), and durability due to the structural unit (A). The molar ratio of the structural unit (A): the structural unit (B) can be controlled by adjusting the feed ratio (molar ratio) of each monomer during the production stage of the block copolymer. Therefore, the charging ratio (molar ratio) of the reactive monomer having an epoxy group to the hydrophilic monomer in the production stage of the block copolymer is preferably 1:2 to 1:100, more preferably 1:2 to 1:50, even more preferably 1:5 to 1:50, and particularly preferably 1:10 to 1:30. The molar ratio of the structural unit (A):structural unit (B) can be determined, for example, by NMR measurement ( １ H-NMR measurement, １３ This can be confirmed by performing spectroscopy (e.g., C-NMR measurement).

[0052] The block copolymer according to the present invention essentially contains the structural unit (A) and the structural unit (B), but may contain other structural units in addition to these structural units. When the block copolymer contains other structural units, examples of such other structural units include adipic acid, glutaric acid, triethylene glycol, and tripropylene glycol. The monomers constituting the other structural units may be used alone or in combination of two or more. That is, the other structural units may be homopolymers composed of a single structural unit, or copolymers composed of two or more structural units. When two or more monomers are used to constitute the other structural units, the segments composed of the monomers may be in the form of a block copolymer, a random copolymer, or an alternating copolymer.

[0053] When the block copolymer according to the present invention contains other structural units, the content of the other structural units is preferably more than 0 mol% and less than 5 mol% relative to the total structural units constituting the block copolymer. That is, in the block copolymer according to the present invention, when the total of all structural units constituting the block copolymer is taken as 100 mol%, the total content of the structural units (A) and (B) is preferably 95 mol% or more (upper limit: less than 100 mol%). More preferably, the block copolymer according to the present invention is substantially composed of the structural units (A) and (B) (the content of the other structural units is more than 0 mol% and less than 5 mol%). In this form, the block copolymer according to the present invention can achieve a good balance between the durability provided by the structural unit (A) and the lubricity (surface lubricity) provided by the structural unit (B). Preferably, the block copolymer according to the present invention does not contain the other structural units (the content of the other structural units is 0 mol%).

[0054] The composition of each structural unit (structural units (A) and (B) and other structural units) can be measured by a known method. For example, １ The composition (molar ratio) of the structural units can be determined by measuring the integral ratio of the intensities of each signal in the H-NMR spectrum.

[0055] In one embodiment of the present invention, the block copolymer according to the present invention is composed essentially of, or consists of, a structural unit (A) derived from at least one reactive monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether, and a structural unit (B) derived from at least one hydrophilic monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

[0056] In one embodiment of the present invention, the block copolymer according to the present invention is composed essentially of, or consists of, a structural unit (A) derived from at least one reactive monomer of glycidyl acrylate and glycidyl methacrylate, and a structural unit (B) derived from at least one hydrophilic monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate.

[0057] In one embodiment of the present invention, the block copolymer according to the present invention is composed essentially of, or consists of, a structural unit (A) derived from glycidyl methacrylate (a reactive monomer having an epoxy group) and a structural unit (B) derived from N,N-dimethylacrylamide (a hydrophilic monomer).

[0058] The weight average molecular weight of the block copolymer is preferably 10,000 or more and 10,000,000 or less from the viewpoint of solubility. The weight average molecular weight of the block copolymer is more preferably 100,000 or more and 5,000,000 or less from the viewpoint of ease of preparation of the coating liquid. In this specification, the "weight average molecular weight" is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance.

[0059] The method for producing the block copolymer is not particularly limited, and can be prepared by applying conventional polymerization methods such as living radical polymerization, polymerization using a macroinitiator, and polycondensation. Among these, living radical polymerization or polymerization using a macroinitiator is preferred because it allows for easy control of the molecular weight and molecular weight distribution of the structural units (portions) derived from reactive monomers and the structural units (portions) derived from hydrophilic monomers. The living radical polymerization method is not particularly limited, and examples include methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, and the like, as well as atom transfer radical polymerization (ATRP), which can be applied in the same manner or with appropriate modifications. Furthermore, in polymerization using a macroinitiator, for example, a macroinitiator having a reactive moiety with a reactive functional group and a radically polymerizable group such as a peroxide group can be prepared, followed by polymerizing the macroinitiator with a monomer for forming the hydrophilic moiety, thereby preparing a block copolymer having a hydrophilic moiety and a reactive moiety.

[0060] After polymerization, the block copolymer is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0061] (Isocyanate Compound Having Two or More Isocyanate Groups) In the present invention, the isocyanate compound has two or more isocyanate groups. The isocyanate compound is electrophilic. Therefore, when the isocyanate compound comes into contact with the block copolymer, it pulls electrons from the epoxy groups (crosslinking moieties) of the block copolymer, thereby inducing ring-opening of the epoxy groups. The ring-opened epoxy groups react with each other, crosslinking (bonding) the block copolymers. Alternatively, the ring-opened epoxy groups of the block copolymer react with the isocyanate groups of the isocyanate compound, crosslinking (bonding) the block copolymers with each other via the isocyanate compound. This increases the film strength of the surface lubricating layer. Furthermore, when the base layer is made of a resin material, the ring-opened epoxy groups also crosslink (bond) the block copolymer with the base layer. Therefore, the medical device obtained by the method of the present invention can further improve durability (sliding durability) and maintain its shape well even after sliding.

[0062] The above-mentioned crosslinking of the block copolymer can also be promoted by adding an acid or base to the coating liquid. However, in such cases, the acid or base present in the coating liquid may rapidly crosslink or polymerize the block copolymers in the coating liquid, increasing the viscosity of the coating liquid (or causing gelation), making it difficult to apply the coating liquid uniformly. In contrast, the solvent in the coating liquid prevents isocyanate compounds from contacting the block copolymers, making crosslinking or polymerizing the block copolymers less likely to occur in the coating liquid. Furthermore, when the solvent is removed by heating or drying, the isocyanate compound promotes the crosslinking reaction when it comes into contact with the block copolymer. Therefore, the increase in viscosity (gelation) of the coating liquid due to the crosslinking of the block copolymers in the coating liquid can be suppressed. Therefore, the method of the present invention allows the coating liquid to be uniformly applied to the substrate layer. In addition, when an acid or base is added to the coating liquid, after forming the surface lubricating layer, a cleaning process to remove any remaining acid or base from the surface lubricating layer or a neutralization process to neutralize any remaining acid or base from the surface lubricating layer is required. In contrast, in the method of the present invention, the compound used in forming the surface lubricating layer is an isocyanate compound such as hexamethylene diisocyanate, toluene diisocyanate, 4,4'-diphenylmethane diisocyanate, etc. Therefore, since the above-mentioned separate process is not required, the work efficiency can be improved.

[0063] As used herein, "electrophilicity" refers to the property of a side that receives or takes away electrons in a reaction that involves the transfer of electrons between different chemical species to form a chemical bond.

[0064] The isocyanate compound according to the present invention may have two or more isocyanate groups. For example, an aliphatic or aromatic isocyanate compound having 4 to 30 carbon atoms is preferred, an aliphatic or aromatic isocyanate compound having 5 to 25 carbon atoms is more preferred, an aliphatic or aromatic isocyanate compound having 8 to 22 carbon atoms is even more preferred, an aliphatic or aromatic isocyanate compound having 10 to 20 carbon atoms is particularly preferred, and an aliphatic or aromatic isocyanate compound having 12 to 18 carbon atoms is most preferred. Compounds having 4 to 30 carbon atoms have sufficient solvent solubility and therefore excellent coating properties. Aromatic isocyanate compounds have higher electrophilicity, which can further promote crosslinking by the structural unit (A) of the block copolymer (particularly during heat treatment) (further improving durability). In one embodiment, the isocyanate compound is an aliphatic or aromatic isocyanate compound having 6 to 20 carbon atoms. In one embodiment, the isocyanate compound is an aromatic isocyanate compound having 8 to 20 carbon atoms (preferably 10 to 18 carbon atoms). In another embodiment, the isocyanate compound is an aliphatic isocyanate compound having 4 to 20 carbon atoms (preferably 6 to 16 carbon atoms). In one embodiment, the isocyanate compound is an aromatic isocyanate compound having 10 to 20 carbon atoms. The number of carbon atoms in the isocyanate compound includes the carbon atoms of the two isocyanate groups contained in the isocyanate compound.

[0065] The isocyanate compound according to the present invention preferably has 2 or more and 5 or less, more preferably 2 or more and 4 or less, even more preferably 2 or more and 3 or less, and particularly preferably 2 isocyanate groups.

[0066] Examples of the isocyanate compound according to the present invention include aliphatic diisocyanate compounds such as ethylene diisocyanate, hexamethylene diisocyanate, cyclohexylene diisocyanate, methylenebis(4,1-cyclohexylene)diisocyanate, 1,3-bis(isocyanatomethyl)cyclohexane, bis(isocyanatomethyl)benzene, and 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethylcyclohexane (isophorone diisocyanate); and xylene. and aromatic diisocyanate compounds such as diisocyanate, toluene diisocyanate, diphenylmethane diisocyanate, naphthalene diisocyanate, 2,2'-diphenylmethane diisocyanate (2,2'-MDI), 2,4'-diphenylmethane diisocyanate (2,4'-MDI), 4,4'-diphenylmethane diisocyanate (4,4'-MDI), phenylene diisocyanate, tris(4-isocyanatophenyl)methane, and toluene triisocyanate. In this specification, when the group to which the isocyanate group is directly bonded is aliphatic, it is referred to as an "aliphatic isocyanate compound," and when the group to which the isocyanate group is directly bonded is an aromatic ring, it is referred to as an "aromatic diisocyanate." For example, bis(isocyanatomethyl)benzene is classified as an "aliphatic isocyanate compound" because the isocyanate group is bonded to the benzene ring via an aliphatic group (methylene group).

[0067] The isocyanate compound preferably includes at least one selected from the group consisting of hexamethylene diisocyanate, toluene diisocyanate, and 4,4'-diphenylmethane diisocyanate, and more preferably at least one selected from the group consisting of hexamethylene diisocyanate, toluene diisocyanate, and 4,4'-diphenylmethane diisocyanate.

[0068] (Preparation of Coating Liquid) A coating liquid is prepared using the block copolymer, isocyanate compound, and solvent. The isocyanate compound is stable in the coating liquid, making it preferable in terms of safety and ease of operation. Furthermore, in the coating liquid, a solvent is present between the isocyanate compound and the block copolymer, so the isocyanate compound and the block copolymer are not in close contact but are separated from each other. Meanwhile, the ring-opening (crosslinking reaction) of the epoxy group is initiated and progresses when the electron orbitals of the block copolymer and the isocyanate compound molecules approach each other until they overlap, resulting in electron exchange. Therefore, the ring-opening (crosslinking reaction) of the epoxy group hardly or not at all progresses in the coating liquid, and the viscosity of the coating liquid hardly or not changes at all. Therefore, the process is easy to work with.

[0069] The order and method of adding the block copolymer, isocyanate compound, and solvent are not particularly limited. The components may be added all at once or separately, stepwise, or continuously. The mixing method is also not particularly limited, and known methods can be used. Methods for preparing the coating liquid include sequentially adding the isocyanate compound and block copolymer to a solvent, sequentially adding the block copolymer and isocyanate compound to a solvent, or simultaneously adding the isocyanate compound and block copolymer to a solvent. Preferably, the isocyanate compound and block copolymer are sequentially added to a solvent, or the block copolymer and isocyanate compound are sequentially added to a solvent. The addition may be performed with stirring, if necessary. Alternatively, the mixture may be stirred after the addition. In one embodiment, the coating liquid is prepared by adding and mixing the isocyanate compound to a solvent, and then further adding and mixing the block copolymer.

[0070] The solvent used to prepare the coating liquid is not particularly limited as long as it can dissolve the block copolymer and the isocyanate compound (and other components, if used), and is appropriately selected depending on the type of the block copolymer and the isocyanate compound (and other components, if used). From the viewpoint of high solubility, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and organic solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran (THF), dimethyl sulfoxide, N,N-dimethylformamide (DMF), dioxane, and benzene are preferably used. In one embodiment, the solvent preferably contains at least one selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and acetone. These solvents may be used alone or in combination (in the form of a mixed solvent).

[0071] The concentration of the block copolymer in the coating solution is not particularly limited. From the viewpoint of further improving the coatability, lubricity, and durability of the surface lubrication layer, the concentration of the block copolymer in the coating solution is preferably 0.5% by mass or more and 20% by mass or less, more preferably 1% by mass or more and 15% by mass or less, even more preferably 2% by mass or more and 12% by mass or less, and particularly preferably 3% by mass or less and 10% by mass or less. 3% by mass or more and 8% by mass or less is particularly preferred. If the concentration of the block copolymer is within the above range, the lubricity and durability of the resulting surface lubrication layer can be fully exhibited. In addition, a uniform surface lubrication layer of the desired thickness can be easily obtained with a single coating, and the viscosity of the solution is within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, even if it is outside the above range, it can be fully used as long as it does not affect the effects of the present invention.

[0072] The concentration of the isocyanate compound in the coating liquid is also not particularly limited. From the viewpoint of the lubricity (slidability) of the surface lubrication layer, it is preferable to add a small amount of isocyanate compound. On the other hand, from the viewpoint of the durability (sliding durability) of the surface lubrication layer, it is preferable to add a certain amount of isocyanate compound. From the above points of view, the concentration of the isocyanate compound in the coating liquid is preferably 0.001% by mass or more and 12% by mass or less, more preferably 0.005% by mass or more and 5.0% by mass or less, even more preferably 0.01% by mass or more and less than 3.0% by mass, particularly preferably 0.01% by mass or more and 1.0% by mass or less, and most preferably 0.05% by mass or more and 0.8% by mass or less. If the concentration of the isocyanate compound is within the above range, the lubricity (slidability) of the surface lubrication layer is sufficiently ensured, while the crosslinking of the block copolymer is sufficiently promoted without excessively progressing (crosslinking can be moderately promoted). Therefore, the lubricity and durability of the obtained surface lubrication layer can be fully exhibited. However, even if the amount is outside the above range, it is still usable as long as it does not affect the effects of the present invention.

[0073] Furthermore, from the viewpoints of further improving durability (sliding durability), coatability, and lubricity of the surface lubricating layer, the mixing ratio of the block copolymer and the isocyanate compound in the coating liquid is preferably such that the content of the isocyanate compound in the coating liquid is equal to or less than the content of the block copolymer in the coating liquid, and from the viewpoint of further improving durability (sliding durability), it is more preferable that the content of the isocyanate compound in the coating liquid is less than the content of the block copolymer in the coating liquid. More specifically, the mixing ratio of the block copolymer and the isocyanate compound in the coating liquid (block copolymer: isocyanate compound (mass ratio)) is, for example, 100:0.01 or more and 100:30 or less, preferably 100:0.02 or more and 100:25 or less, more preferably 100:0.1 or more and 100:20 or less, even more preferably 100:0.2 or more and 100:10 or less, even more preferably 100:0.3 or more and 100:9 or less, particularly preferably 100:0.5 or more and 100:8 or less, and most preferably 100:1 or more and 100:5 or less. If the mass ratio of the block copolymer and the isocyanate compound is within the above range, the durability and lubricity of the obtained surface lubricating layer can be fully exhibited.

[0074] (II) Coating Step In this step, the coating liquid prepared in the above (I) Preparation Step is applied onto the substrate layer to form a coating film (coating layer) on the substrate layer.

[0075] The substrate layer may be made of any material, including, for example, metal materials, polymer materials (resin materials), and ceramics.

[0076] The metal material constituting the substrate layer is not particularly limited, and metal materials commonly used for medical devices such as catheters, guidewires, and indwelling needles can be used. Specific examples include various stainless steels (SUS) such as SUS304, SUS314, SUS316, SUS316L, SUS420J2, and SUS630, as well as gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, and various alloys such as nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, and zinc-tungsten alloys. These may be used alone or in combination of two or more. The metal material may be appropriately selected from those optimal for the substrate layer of the intended use, such as a catheter, guidewire, or indwelling needle.

[0077] Furthermore, among the materials constituting the substrate layer, the polymer material (resin material or elastomer material) is not particularly limited, and polymer materials commonly used in medical devices such as catheters, introducers, guidewires, and indwelling needles can be used. Specific examples include polyamide resin (nylon), polyolefin resins such as polyethylene resin and polypropylene resin, modified polyolefin resin, cyclic polyolefin resin, epoxy resin, polyurethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluororesin, amino resin (urea resin, melamine resin, benzoguanamine resin), polyester resins such as polyethylene terephthalate resin and polybutylene terephthalate resin, styrene resin, acrylic resin, polyacetal resin, vinyl acetate resin, phenolic resin, vinyl chloride resin, silicone resin (silicon resin), polyether resin, and polyimide resin. The above resins also include elastomers. Therefore, thermoplastic elastomers such as polyurethane elastomers as polyurethane resins, polyester elastomers as polyester resins, and polyamide elastomers (nylon elastomers) as polyamide resins (nylon) can also be used as materials for the base layer.

[0078] These polymer materials may be used alone, as a mixture of two or more types, or as a copolymer of two or more monomers constituting any of the above resins or elastomers. Among these, polyamide resins, polyolefin resins, polyester resins, and polyurethane resins are preferred, with polyethylene resins, polyester resins, polyester elastomers, polyurethane resins, polyethylene terephthalate resins, polyamide resins, and polyamide elastomers being more preferred, and polyethylene resins, polyester resins, polyester elastomers, polyamide resins, and polyamide elastomers being even more preferred. The carboxyl and amino groups contained as terminal groups in polyamide resins and polyamide elastomers can undergo crosslinking reactions with epoxy groups in block copolymers. Furthermore, these polymer materials (particularly polyamide resins and polyamide elastomers) are relatively soft, allowing the block copolymers constituting the surface lubricating layer to easily penetrate them. This enhances the bonding between the polymer material (particularly polyamide resins and polyamide elastomers) and the block copolymer, resulting in the formation of a more durable surface lubricating layer. The polymer material may be appropriately selected from the polymer materials optimal for the substrate layer of the intended use, such as catheters, guidewires, and indwelling needles.

[0079] According to the manufacturing method of the present invention, a surface lubricating layer with excellent durability can be formed by low-temperature heat treatment, so that even if the substrate layer has low solubility, a surface lubricating layer with excellent durability can be formed.Such substrate layers include metals, polyamide resins, polyolefin resins, polyester resins, polyurethane resins, etc., and among these, metals, polyethylene resins, polyester elastomers, polyamide elastomers, etc. are preferred.Therefore, according to one embodiment, the substrate layer is one or more selected from the group consisting of metals, polyethylene resins, polyester elastomers, and polyamide elastomers.

[0080] The shape of the substrate layer is not particularly limited, and may be appropriately selected depending on the mode of use, such as a sheet, a line (wire), a rod, or a tube.

[0081] The method for applying (coating) the coating liquid to the surface of the substrate layer is not particularly limited, and any conventionally known method can be used, such as a coating / printing method, a dipping method (dipping method, dip coating method), a spraying method (spray method), a spin coating method, a mixed solution impregnated sponge coating method, a bar coating method, a die coating method, a reverse coating method, a comma coating method, a gravure coating method, a doctor knife method, etc. Of these, the dipping method (dipping method, dip coating method) is preferably used.

[0082] Furthermore, when forming a surface lubricating layer only on a portion of the substrate layer, only a portion of the substrate layer can be immersed in a coating liquid and the coating liquid can be coated onto that portion of the substrate layer, thereby forming a surface lubricating layer on the desired surface portion of the substrate layer.

[0083] The amount of coating liquid applied is preferably such that the thickness (dry film thickness) of the resulting coating (surface lubricating layer) is 0.1 to 10 μm, more preferably 0.5 to 5 μm, and even more preferably 1 to 3 μm. If the amount of coating is such that the thickness of the coating (surface lubricating layer) is 0.1 μm or more, the durability of the resulting coating (surface lubricating layer) can be sufficiently achieved. Furthermore, if the amount of coating is such that the thickness of the coating (surface lubricating layer) is 10 μm or less, the surface of the coating (surface lubricating layer) becomes less sticky, making it easier to handle during production.

[0084] (III) Drying / heat treatment step In the manufacturing method of the medical device according to the present invention, if necessary, after the coating liquid is applied to the substrate layer in the above (II) coating step to form a coating film (coating layer), a drying step and / or a heat treatment step may be carried out. For the purpose of removing the solvent and forming a strong surface lubrication layer, it is preferable to carry out the drying step and / or the heat treatment step, and it is more preferable to carry out the drying step and the heat treatment step.

[0085] Here, the "drying treatment" and the "heating treatment" are not strictly distinguished from each other, but for the sake of convenience, the "drying treatment" refers to maintaining the substrate layer coated with the coating liquid at a temperature close to room temperature (20 to 30°C) or lower, and the "heating treatment" refers to maintaining the substrate layer at a temperature higher than a temperature close to room temperature (20 to 30°C).

[0086] In the production method of the present invention, it is preferable to carry out a drying treatment before the heat treatment, which is carried out in order to volatilize the solvent to a certain extent before the heat treatment in the next step, in order to improve the handleability of the coating film formed on the substrate layer.

[0087] The conditions for the drying treatment before the heat treatment are not particularly limited, but are preferably conditions under which the solvent volatilizes to an extent that the coating film formed on the substrate layer can maintain a certain shape. For example, the temperature for the drying treatment before the heat treatment is preferably 10°C or higher and 30°C or lower. The time for the drying treatment before the heat treatment is preferably 0.5 hours or higher and 3 hours or lower. That is, it is more preferable to maintain the coating film formed by applying the block copolymer solution to the substrate layer at 10°C or higher and 30°C or lower for 0.5 hours or higher and 3 hours or lower. The above temperature may be changed during the drying treatment.

[0088] The heating temperature is preferably less than 100°C, more preferably greater than 30°C and less than 100°C, even more preferably 35°C to 95°C, particularly preferably 40°C to 90°C, and most preferably 50°C to 85°C. In one embodiment, the heating temperature is 80°C to 100°C. By maintaining the temperature at such a temperature (applying thermal energy), the thermal energy causes the molecules to expand and contract, resulting in more active electron migration, which further promotes the ring-opening (crosslinking reaction) of the epoxy groups, forming a surface lubricating layer with higher durability, and the surface lubricating layer can exhibit excellent lubricity. In addition, damage to the hydrophilic groups in the base layer constituent unit (B) (decreased hydrophilicity of the block copolymer constituent unit (B)) can be suppressed, allowing the surface lubricating layer to exhibit better lubricity. In particular, by setting the heating temperature to less than 100°C, when the base layer is made of the above-mentioned polymer material (resin material or elastomer material), deformation or plasticization of the base layer due to heat can be suppressed. Therefore, according to the present invention, the selection of materials is broader, and medical devices for a variety of uses can be manufactured. In addition, since a surface lubricating layer with excellent durability can be formed at low temperatures, it is also preferable from the viewpoint of energy costs when manufacturing medical devices. The above temperature may be changed during the heat treatment.

[0089] When the substrate layer is made of metal, the heat treatment time is preferably 10 hours or less, more preferably 9 hours or less, even more preferably 8 hours or less, particularly preferably 6 hours or less, and most preferably 5 hours or less. When the substrate layer is made of metal, the heat treatment time may be 0.5 hours or more, may be 1 hour or more, and preferably 3 hours or more. When the substrate layer is made of resin, the heat treatment time is preferably 10 hours or less, more preferably 8 hours or less, even more preferably 6 hours or less, particularly preferably 5 hours or less, and most preferably 2 hours or less. When the substrate layer is made of resin, the heat treatment time may be 0.5 hours or more, may be 1 hour or more. By setting the heat treatment time to such a time, crosslinking or polymerization in the block copolymer is effectively promoted, and a strong coating layer (surface lubrication layer) is formed. Therefore, high lubricity (surface lubricity) can be maintained for a longer period of time. Furthermore, by setting the heat treatment time to such a time, excessive crosslinking or polymerization can be suppressed. Therefore, the decrease in swelling caused by the surface lubrication layer becoming too hard can be suppressed, and as a result, good lubricity (surface lubricity) can be maintained. Furthermore, by setting the heat treatment time in this range, it is possible to prevent or suppress a decrease in the hydrophilicity of the structural unit (B) of the block copolymer, and it becomes possible to more easily control the lubricity. In particular, when the base layer is composed of the above-mentioned polymer material (resin material or elastomer material), a short heat treatment time of 5 hours or less can suppress the base layer from being deformed or plasticized by heat.

[0090] That is, in a preferred embodiment of the present invention, after applying the coating liquid to a substrate to form a coating film, the coating film is heat-treated at a temperature of more than 30°C and less than 100°C for 10 hours or less (i.e., maintained as a coating film). In a more preferred embodiment, after applying the coating liquid to a substrate to form a coating film, the coating film is heat-treated at a temperature of 80°C or higher and less than 100°C for 1 hour or more and 10 hours or less (i.e., maintained as a coating film). By maintaining the coating film under such conditions (time and temperature), crosslinking or polymerization of the block copolymer is effectively promoted, and a strong coating layer (surface lubrication layer) is formed. Therefore, high lubricity (surface lubricity) can be maintained for a longer period of time. Furthermore, by maintaining the coating film under such conditions (time and temperature), excessive crosslinking or polymerization can be prevented. Therefore, the decrease in swelling caused by the surface lubrication layer becoming too hard can be suppressed, and as a result, good lubricity (surface lubricity) can be maintained.

[0091] The conditions for the drying treatment after the heat treatment are not particularly limited, as long as the surface lubricating layer containing the block copolymer on the base layer is cooled to room temperature.

[0092] By carrying out the drying / heating treatment process under the above-mentioned conditions (temperature, time, etc.), it is possible to make a strong surface lubricating layer (coating layer) on the surface of the substrate layer.In addition, depending on the type of substrate layer, crosslinking reaction occurs via the epoxy group in the block copolymer in the surface lubricating layer, and it is possible to form a high-strength surface lubricating layer that is not easily peeled off from the substrate layer.Therefore, by the above-mentioned drying / heating treatment process, it is possible to effectively suppress and prevent the peeling off of the surface lubricating layer from the substrate layer.

[0093] The pressure conditions during drying are not particularly limited, and drying can be carried out under normal pressure (atmospheric pressure), or under increased or reduced pressure.

[0094] As the drying or heating means (device), for example, an oven, a vacuum dryer, etc. can be used, but in the case of natural drying, no particular drying means (device) is required.

[0095] (IV) Cleaning step In the manufacturing method of the medical device according to the present invention, if necessary, a coating liquid is applied to the substrate layer in the above (II) coating step to form a coating film (coating layer), and after the above (II) drying / heat treatment step, the surface lubricating layer formed on the substrate layer may be washed ((IV) cleaning step). The cleaning step is carried out for the purpose of efficiently removing impurities and unreacted substances contained in the surface lubricating layer and imparting better lubricity (low friction) to the surface lubricating layer.

[0096] The cleaning method is not particularly limited, but may be a method of immersing the surface lubricating layer made of a block copolymer in a cleaning solvent, a method of pouring the cleaning solvent over, or a combination of these. The cleaning solvent used here is not particularly limited as long as it does not dissolve the surface lubricating layer made of a block copolymer and can efficiently remove impurities and unreacted substances, but water (e.g., ion-exchanged water, distilled water, reverse osmosis membrane water, filtered water, sterilized water, purified water) or warm water is preferably used. The temperature of the cleaning water is not particularly limited, but is preferably 20°C to 100°C, more preferably 25 to 80°C. The cleaning time (the time the cleaning solvent is in contact with the coating) is not particularly limited, but is preferably 30 seconds to 60 minutes, more preferably 1 to 30 minutes.

[0097] After the washing step, a drying step may be further carried out. The drying method and drying conditions (temperature, time, etc.) are not particularly limited, and any conventionally known method can be used.

[0098] The medical device manufactured by the method of the present invention has a structure in which a surface lubricating layer is supported on a substrate layer by applying a solution (coating liquid) containing a block copolymer and an isocyanate compound that form the surface lubricating layer onto the substrate layer. Whether or not the surface lubricating layer contains an isocyanate compound can be confirmed by the following method. That is, the surface lubricating layer is extracted using an organic solvent such as deuterated chloroform, and the obtained extracted solution is analyzed by NMR ( １ H-NMR measurement, １３The isocyanate compound can be analyzed by C-NMR measurement, LC-MS (liquid chromatography mass spectrometry), or GC (gas chromatography) to detect a peak derived from the isocyanate group of the isocyanate compound.

[0099] <Medical Device> By undergoing the above-described (I) preparation step and (II) application step, and optionally the (III) drying / heat treatment step and / or (IV) cleaning step, a medical device having a surface lubricating layer (coating layer) that exhibits excellent durability can be manufactured.

[0100] According to the method of the present invention, a coating film containing a block copolymer and an isocyanate compound is formed on the surface of a substrate layer, and then the epoxy groups are crosslinked to form a strong surface lubricating layer that does not easily peel off from the substrate layer. In this case, the epoxy groups of the block copolymer crosslink with the isocyanate groups of the isocyanate compound, resulting in a crosslinked reaction product between the epoxy groups of the block copolymer and the isocyanate groups of the isocyanate compound having two or more isocyanate groups. The medical device obtained by the method of the present invention exhibits excellent lubricity and durability (lubrication retention) because a surface lubricating layer formed on the surface is a crosslinked reaction product between the block copolymer and the isocyanate compound.

[0101] The medical device manufactured by the method of the present invention has a structure in which a surface lubricating layer is supported on a substrate layer by applying a coating liquid containing a block copolymer and an isocyanate compound that form the surface lubricating layer to the substrate layer. In the coating liquid, the isocyanate compound and the block copolymer are dissolved in a solvent (the isocyanate compound and the block copolymer are uniformly mixed in the coating liquid). Therefore, the block copolymer and the isocyanate compound are mutually entangled (crosslinked) in the surface lubricating layer.

[0102] Therefore, in another aspect of the present invention, a medical device is provided that includes a substrate layer and a surface lubricating layer supported on at least a portion of the substrate layer, wherein the surface lubricating layer contains a crosslinked reaction product of an epoxy group of a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, and an isocyanate group of an isocyanate compound having two or more isocyanate groups. In this aspect, terms such as block copolymer and isocyanate compound are the same as those described above in the <Method for Manufacturing a Medical Device>, and therefore will not be described here. As described above, the block copolymer and isocyanate compound in the coating liquid are preferably contained in a mass ratio of 100:0.5 or more and 100:8 or less. Therefore, the block copolymer and isocyanate compound present in the surface lubricating layer are preferably contained in a mass ratio of 100:0.5 or more and 100:8 or less. In this case, the preferred ratio (mass ratio) of the block copolymer and the isocyanate compound present in the surface lubrication layer is the same as the preferred mass ratio of the block copolymer and the isocyanate compound in the coating liquid.

[0103] Hereinafter, preferred embodiments of a medical device manufactured by a method according to the present invention will be described with reference to the accompanying drawings. Note that the dimensional proportions in the drawings have been exaggerated for the sake of convenience and may differ from the actual proportions. Furthermore, when describing embodiments of the present invention with reference to the drawings, identical elements will be designated by the same reference numerals, and duplicate explanations will be omitted.

[0104] Figure 1 is a partial cross-sectional view schematically illustrating the surface layer structure of a representative embodiment of a medical device (also abbreviated as "medical device" in this specification) manufactured by the method of the present invention. Figure 2 is a partial cross-sectional view schematically illustrating a different example of the surface layer structure as an application example of this embodiment. Note that the symbols in Figures 1 and 2 represent the following: Symbol 1 represents the substrate layer; symbol 1a represents the substrate layer core; symbol 1b represents the substrate surface layer; symbol 2 represents the surface lubricating layer; and symbol 10 represents the medical device manufactured by the method of the present invention.

[0105] As shown in Figures 1 and 2, the medical device 10 of this embodiment comprises a base layer 1 and a surface lubricating layer 2 containing a block copolymer provided on at least a portion of the base layer 1 (the figures show an example in which the surface lubricating layer 2 is provided on the entire (whole) surface of the base layer 1 in the drawings). In Figures 1 and 2, the surface lubricating layer 2 is formed on both sides of the base layer 1, but the present invention is not limited to the above form, and may be any form, such as a form in which the surface lubricating layer 2 is formed on one side of the base layer 1; a form in which the surface lubricating layer 2 is formed on part of one or both sides of the base layer 1, etc.

[0106] Below, the medical device will be described in detail for each of its constituent parts.

[0107] (Substrate Layer (Substrate)) The substrate layer used in this embodiment may be made of any material, and the material is not particularly limited. Specific examples of materials constituting the substrate layer 1 include metal materials, polymeric materials, and ceramics. Specific examples of materials constituting the substrate layer 1 are as described in the above (II) Coating step.

[0108] Here, the entire substrate layer 1 may be made of any of the above materials. The substrate layer 1 may be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which components formed of different materials are joined together for each portion of the medical device. Alternatively, as shown in FIG. 2, the substrate may have a structure in which the surface of a substrate layer core portion 1a formed of any of the above materials is coated with any of the other materials by an appropriate method to form a substrate surface layer 1b. Examples of the latter case include a substrate in which the surface of a substrate layer core portion 1a formed of a resin material or the like is coated with a metal material by an appropriate method (conventionally known methods such as plating, metal vapor deposition, sputtering, etc.) to form a substrate surface layer 1b; a substrate in which the surface of a substrate layer core portion 1a formed of a hard reinforcing material such as a metal material or a ceramic material is coated with a polymer material that is softer than the metal reinforcing material by an appropriate method (conventionally known methods such as dipping, spraying, coating / printing, etc.); or a substrate in which the reinforcing material forming the substrate layer core portion 1a and the polymer material are combined to form a substrate surface layer 1b. The base layer core 1a may be a multilayer structure formed by laminating multiple layers of different materials, or a structure in which different parts of the medical device are joined together. A separate middle layer (not shown) may be formed between the base layer core 1a and the base surface layer 1b. The base surface layer 1b may also be a multilayer structure formed by laminating multiple layers of different materials, or a structure in which different parts of the medical device are joined together.

[0109] (Surface lubricating layer (coating layer)) The surface lubricating layer is supported on at least a portion of the substrate layer 1. Here, the reason why the surface lubricating layer 2 is supported on at least a portion of the surface of the substrate layer 1 is that in medical devices such as catheters, guide wires, and indwelling needles, which are used for these medical devices, it is not necessary for all surfaces (the entire surface) of these medical devices to have lubricity when wet, and the surface lubricating layer only needs to be supported on the surface portion (sometimes a portion or the entire surface) that is required to have lubricity when wet. For this reason, as described above, the surface lubricating layer includes a form formed to cover both sides of the substrate layer as shown in FIG. 1 and FIG. 2; a form formed to cover only one entire side of the substrate layer; a form formed to cover parts of both sides of the substrate layer in the same or different forms; a form formed to cover part of one side of the substrate layer, and the like.

[0110] <Uses of Medical Devices> The medical devices produced by the method of the present invention are devices used in contact with body fluids, blood, etc., and have a surface that is lubricious in body fluids, physiological saline, and other aqueous liquids, thereby enabling improved operability and reduced damage to tissue mucosa. Specific examples include catheters, guidewires, indwelling needles, etc. used in blood vessels, but other examples include the following medical devices:

[0111] (a) Catheters that are inserted or left in the digestive tract via the mouth or nose, such as gastric catheters, nutritional catheters, and enteral feeding tubes.

[0112] (b) Catheters that are inserted or placed in the airway or trachea via the mouth or nose, such as oxygen catheters, oxygen cannulas, endotracheal tubes and cuffs, tracheostomy tubes and cuffs, and endotracheal suction catheters.

[0113] (c) Catheters that are inserted or placed in the urethra or ureter, such as urethral catheters, urinary catheters, and urethral balloon catheters.

[0114] (d) Catheters such as suction catheters, drainage catheters, and rectal catheters that are inserted or left in various body cavities, organs, or tissues.

[0115] (e) Catheters that are inserted or placed in blood vessels, such as indwelling needles, IVH catheters, thermodilution catheters, angiography catheters, vasodilator catheters, and dilators or introducers, or guide wires and stylets for these catheters.

[0116] (f) Artificial trachea, artificial bronchi, etc.

[0117] (g) Medical devices for extracorporeal circulation therapy (artificial lungs, artificial hearts, artificial kidneys, etc.) and their circuits.

[0118] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, unless otherwise specified, operations were performed at room temperature (25°C). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

[0119] Synthesis Example 1 The following reaction was carried out to produce a block copolymer (1).

[0120]

[0121] 29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50°C, and the mixture was allowed to react at 50°C for 3 hours. The hydrochloric acid was then removed under reduced pressure to obtain an oligoester. Next, 4.5 g of methyl ethyl ketone was added to 22.5 g of the obtained oligoester, and this was added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of dioctyl phosphate as a surfactant, and 120 g of water, and the mixture was allowed to react at -5°C for 20 minutes. The obtained product was repeatedly washed with water and methanol and then dried to obtain a polyperoxide (PPO) having multiple peroxide groups in the molecule.

[0122] Next, 0.5 g of this PPO, 9.5 g of glycidyl methacrylate (GMA), and 30 g of benzene as a solvent were polymerized at 80°C for 2 hours with stirring under reduced pressure. The reaction product obtained after the polymerization was reprecipitated with diethyl ether to obtain polyglycidyl methacrylate (PPO-GMA) having multiple peroxide groups in the molecule.

[0123] Subsequently, 1.0 g of the obtained PPO-GMA (corresponding to 7 mmol of GMA) was added to 9.0 g of N,N-dimethylacrylamide (DMAA) and 90 g of dimethyl sulfoxide as a solvent, and the mixture was reacted at 80°C for 18 hours. The reaction product obtained after the reaction was reprecipitated with hexane and recovered to obtain a block copolymer (1) (structural unit (A):structural unit (B) = GMA:DMAA = 1:14 (molar ratio)) having an epoxy group in the molecule and exhibiting lubricity when wet. The block copolymer (1) thus obtained was １ H-NMR and ATR-IR analyses confirmed the presence of epoxy groups in the molecule. Furthermore, the weight-average molecular weight (Mw) of block copolymer (1) measured by gel permeation chromatography (GPC, polystyrene equivalent) was approximately 1.5 million.

[0124] Example 1 4,4'-Diphenylmethane diisocyanate (manufactured by Kanto Chemical, product name: 4,4'-methylenediphenyldiisocyanate) was added to N,N-dimethylformamide (DMF) so that the final concentration in the coating solution was 0.1% by mass, and the mixture was gently shaken to stir and dissolve. It was visually confirmed that no solids remained dissolved, thereby obtaining solution (1). Thereafter, the block copolymer (1) synthesized in Synthesis Example 1 above was added to solution (1) so that the final concentration in the coating solution was 4.5% by mass, and the mixture was stirred for 1 hour using a stirrer. It was visually confirmed that no solids remained dissolved, thereby preparing coating solution (1).

[0125] A rod (outer diameter: 3.00 mm) made of SUS (MISUMI, SUS304 polished rod RGOS3-200) was used as a substrate and immersed in the coating solution (1) and dip-coated (withdrawal speed: 8 mm / sec). The rod with the coating solution (1) attached was dried at room temperature (25 ° C) for 1 hour to form a coating film (1) on the rod surface (rod (1)). Furthermore, this rod (1) was stored in an oven at 80 ° C for 5 hours to heat-treat the coating film (1) (rod (1')). This rod (1') was dried at room temperature (25 ° C) for 1 hour to prepare a sample (coated rod) (1) having a coating layer (surface lubrication layer) (dry film thickness: 1 μm) containing a cross-linked copolymer derived from the block copolymer (1) on its surface.

[0126] Example 2 A sample (coated tube) (2) was produced in the same manner as in Example 1, except that the substrate was changed from SUS to a tube (outer diameter: 2.80 mm) made of nylon elastomer (Vestamid E47-S1, manufactured by Evonik).

[0127] Example 3 A sample (coated tube) (3) was produced in the same manner as in Example 1, except that the substrate was changed from SUS to a tube (outer diameter: 2.46 mm) made of polyester elastomer (Pelprene E-450B, manufactured by Toyobo Co., Ltd.).

[0128] Example 4 A sample (coated tube) (4) was produced in the same manner as in Example 1, except that the substrate was changed from SUS to a tube (outer diameter: 4.00 mm) made of polyethylene (manufactured by AS ONE Corporation, polyethylene tube hose 6-608-02).

[0129] Comparative Example 1 The block copolymer (1) synthesized in Synthesis Example 1 above was added to N,N-dimethylformamide (DMF) so that the final concentration in the coating solution was 4.5% by mass, and the mixture was stirred for 1 hour using a stirrer. After visually confirming that no solid remained undissolved, a comparative coating solution (1) was prepared.

[0130] A rod (outer diameter: 3.00 mm) made of SUS (manufactured by Misumi, SUS304 polished rod RGOS3-200) was used as a substrate, and the rod was dip-coated (withdrawal speed: 8 mm / sec). The rod with the comparative coating liquid (1) attached was dried at room temperature (25 ° C) for 1 hour to form a comparative coating film (1) on the rod surface (comparative rod (1)). Furthermore, this comparative rod (1) was stored in an oven at 80 ° C for 5 hours to heat-treat the comparative coating film (1) (comparative rod (1')). This comparative rod (1') was dried at room temperature (25 ° C) to prepare a comparative sample (comparative coated rod) (1) having a coating layer (surface lubrication layer) (dry film thickness: 1 μm) containing a cross-linked copolymer derived from the block copolymer (1) on the surface.

[0131] Comparative Example 2 A comparative sample (comparative coated tube) (2) was produced in the same manner as in Comparative Example 1, except that the substrate was changed from SUS to a tube (outer diameter: 2.80 mm) made of nylon elastomer (Vestamid E47-S1, manufactured by Evonik).

[0132] Comparative Example 3 A comparative sample (comparative coated tube) (3) was produced in the same manner as in Comparative Example 1, except that the substrate was changed from SUS to a tube (outer diameter: 2.46 mm) made of polyester elastomer (Pelprene E-450B, manufactured by Toyobo Co., Ltd.).

[0133] Comparative Example 4 A comparative sample (comparative coated tube) (4) was produced in the same manner as in Comparative Example 1, except that the substrate was changed from SUS to a tube (outer diameter: 4.00 mm) made of polyethylene (manufactured by AS ONE Corporation, polyethylene tube hose 6-608-02).

[0134] Comparative Example 5 4,4'-Diphenylmethane diisocyanate (manufactured by Kanto Chemical, product name: 4,4'-methylenediphenyldiisocyanate) was added to N,N-dimethylformamide (DMF) so that the final concentration in the coating solution was 0.1% by mass, and the mixture was gently shaken and stirred to dissolve. It was visually confirmed that no solid remained undissolved, and a comparative coating solution (5a) was prepared.

[0135] Next, the block copolymer (1) synthesized in Synthesis Example 1 above was added to N,N-dimethylformamide (DMF) so that the final concentration in the coating solution was 4.5% by mass, and the mixture was stirred for 1 hour using a stirrer. After visually confirming that no solid remained dissolved, a comparative coating solution (5b) was prepared.

[0136] A rod (outer diameter: 3 mm) made of SUS (MISUMI, SUS304 polished rod RGOS3-200) was used as a substrate and immersed in the comparative coating liquid (5a) and dip-coated (withdrawal speed: 8 mm / sec). The rod with the comparative coating liquid (5a) attached was dried at room temperature (25°C) for 1 hour to form a comparative coating film (5a) on the rod surface (comparative rod (5a)). This comparative rod (5a) had a coating layer (dry film thickness: 0.2 µm) containing 4,4'-diphenylmethane diisocyanate on its surface as the comparative coating film (5a).

[0137] Next, the comparative rod (5a) was immersed in the comparative coating liquid (5b) and dip-coated (pull-up speed: 8 mm / sec). The rod with the comparative coating liquid (5b) attached was dried at room temperature (25 ° C) for 1 hour to remove DMF, and a comparative coating film (5b) was formed on the comparative coating film (5a) (comparative rod (5)). Furthermore, this comparative rod (5) was stored in an oven at 80 ° C for 5 hours, and the comparative coating film (5a) and comparative coating film (5b) were heat-treated (comparative rod (5')). This comparative rod (5') was dried at room temperature (25 ° C) for 1 hour to prepare a comparative sample (comparative coated rod) (5) having a coating layer (surface lubricating layer) (dry film thickness: 1.2 μm) containing a cross-linked copolymer derived from block copolymer (1) on the surface. The surface lubricating layer is the sum of the two layers formed by the comparative coating film (5a) and the comparative coating film (5b).

[0138] The sliding durability of Samples (1) to (4) prepared in Examples 1 to 4 and Comparative Samples (1) to (5) prepared in Comparative Examples 1 to 5 was evaluated according to the following method. The results are shown in Table 1 below.

[0139] [Evaluation of Sliding Durability] The sliding durability (durability of the surface lubricating layer) of each sample was evaluated according to the following method.

[0140] Each sample was immersed in tap water and set in a pinch tester (DL1000, manufactured by OAKRIVER TECHNOLOGY), and slid 50 times at a grip force of 500 gf, a test speed of 8.3 mm / s, and a test stroke of 25 mm (grip pad material: silicone, grip pad height: 12.35 mm).

[0141] The test force (tensile force) (gf) during each sliding test was measured, and the relationship between the number of sliding cycles and the resistance value is shown in Figures 3 to 7. Figure 3 is a graph showing the sliding durability against a stainless steel substrate, corresponding to Example 1 and Comparative Example 1. Figure 4 is a graph showing the sliding durability against a nylon elastomer substrate, corresponding to Example 2 and Comparative Example 2. Figure 5 is a graph showing the sliding durability against a polyester elastomer substrate, corresponding to Example 3 and Comparative Example 3. Figure 6 is a graph showing the sliding durability against a polyethylene substrate, corresponding to Example 4 and Comparative Example 4. Figure 7 is a graph showing the sliding durability against a stainless steel substrate, corresponding to Example 1 and Comparative Example 5. Each sample was slid 50 times, and the average values ​​were plotted in the graphs. One to three samples were prepared for each test, and measurements were performed with n = 1 to 3 (the plotted lines in the graphs represent the number n).

[0142] In addition, the test force after 50 sliding cycles was evaluated, and the overall sliding durability was evaluated based on the following criteria: The lower the test force, the better the sliding durability was judged to be.

[0143] [Overall evaluation of sliding durability] After 50 sliding cycles in the pinch test: ×: Test force at 50th cycle is 100 gf or more: peeling occurred; ○: Test force at 50th cycle is less than 100 gf: no peeling occurred.

[0144]

[0145] Table 1 above shows that by applying a coating liquid containing an isocyanate compound and a block copolymer to a substrate layer, a medical device having a surface lubricating layer with excellent sliding durability and sliding properties can be obtained. This is thought to be because the isocyanate compound and the block copolymer crosslink in the coating film formed by the coating liquid, promoting polymerization and forming a strong surface lubricating layer.

[0146] On the other hand, when a coating solution not containing an isocyanate compound (i.e., a coating solution containing only a block copolymer) was used, the sliding durability of the surface lubricating layer was poor (Comparative Examples 1 to 4). This is thought to be because crosslinking or polymerization of the block copolymer was not promoted, and a strong surface lubricating layer was not formed, so part of the surface lubricating layer peeled off within 50 sliding cycles.

[0147] In addition, in Comparative Example 5, the isocyanate compound and the block copolymer are coated with separate coating solutions, and the coating containing the block copolymer is formed on the coating containing the isocyanate compound.As a result, it is found that the obtained surface lubricating layer has low sliding durability.This is thought to be because the crosslinking or polymerization of the block copolymer is not promoted, and a strong surface lubricating layer is not formed, so that a part of the surface lubricating layer peels off after 50 sliding times.

[0148] This application is based on Japanese Patent Application No. 2023-166805, filed on September 28, 2023, the disclosure of which is hereby incorporated by reference in its entirety.

[0149] 10 Medical device, 1 Base material layer, 1a Base material layer core portion, 1b Base material surface layer, 2 Lubricating layer.

Claims

1. A method for manufacturing a medical device having a base layer and a surface lubricating layer supported on at least a portion of the base layer, comprising: preparing a coating liquid containing a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, an isocyanate compound having two or more isocyanate groups, and a solvent; and applying the coating liquid onto the base layer.

2. The method according to claim 1, wherein the coating liquid contains the block copolymer and the isocyanate compound in a mass ratio of 100:0.5 or more and 100:8 or less.

3. The method according to claim 1, wherein the isocyanate compound is an aliphatic or aromatic isocyanate compound having 6 to 20 carbon atoms.

4. The method of claim 1, wherein the isocyanate compound comprises at least one selected from the group consisting of hexamethylene diisocyanate, toluene diisocyanate, and 4,4'-diphenylmethane diisocyanate.

5. The method according to claim 1, further comprising, after applying the coating liquid onto the substrate to form a coating film, heat-treating the coating film at a temperature of 80° C. or higher and lower than 100° C. for 1 hour or longer and 10 hours or shorter.

6. The method according to claim 1, wherein the reactive monomer having an epoxy group comprises at least one member selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether.

7. The method of claim 1, wherein the hydrophilic monomer comprises at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

8. The method of claim 1, wherein the solvent comprises at least one selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and acetone.

9. The method according to claim 1, wherein the substrate layer comprises at least one selected from the group consisting of metal, polyamide resin, polyolefin resin, polyester resin, and polyurethane resin.

10. A medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer contains a crosslinked reaction product between an epoxy group of a block copolymer having a structural unit (A) derived from a reactive monomer having an epoxy group and a structural unit (B) derived from a hydrophilic monomer, and an isocyanate group of an isocyanate compound having two or more isocyanate groups.

11. The medical device according to claim 10, wherein the reactive monomer having an epoxy group includes at least one member selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether.

12. The medical device according to claim 10, wherein the hydrophilic monomer comprises at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

13. The medical device according to claim 10, wherein the isocyanate compound comprises at least one selected from the group consisting of hexamethylene diisocyanate, toluene diisocyanate, and 4,4'-diphenylmethane diisocyanate.

14. The medical device according to claim 10, wherein the substrate layer comprises at least one material selected from the group consisting of metal, polyamide resin, polyolefin resin, polyester resin, and polyurethane resin.

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