Medical instrument and method for producing same

Abstract

Provided is a medical instrument having a lubricating layer capable of achieving both excellent lubricity and durability (especially sliding durability) through a means different from the prior art.　A medical instrument according to the present invention comprises a substrate having a resin layer on the surface thereof, and a lubricating layer formed on at least a portion of the resin layer. The lubricating layer contains a hydrophilic copolymer of N-(2-hydroxyethyl) acrylamide and at least one monofunctional monomer selected from monomers represented by formula (1) and 2-methoxyethyl acrylate. In formula (1), each of R1 and R2 independently represents a methyl group or an ethyl group. The resin layer has, on the lubricating-layer side, a permeation layer in which the hydrophilic copolymer and a resin material forming the resin layer are mixed.

Description

Medical device and its manufacturing method

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

[0002] Medical devices inserted into living bodies, such as catheters and guidewires, 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 for coating the substrate surface of medical devices with a hydrophilic material having lubricity have been developed and put into practical use. Meanwhile, in order to maintain the operability of such medical devices, it is also important that the hydrophilic material having lubricity on the substrate surface can be maintained during use by the surgeon. Therefore, coatings with hydrophilic materials are required to have not only excellent lubricity but also durability against loads such as abrasion and abrasion.

[0003] From this perspective, Japanese Patent Laid-Open Publication No. 8-33704 (corresponding to the specification of U.S. Pat. No. 5,670,558) discloses a medical device in which a surface lubricating layer is formed on the surface of a substrate by dissolving a water-soluble or water-swellable polymer in a solvent that swells the substrate of the medical device to prepare a polymer solution, immersing the substrate of the medical device in this polymer solution to cause it to swell, and then crosslinking or polymerizing the polymer on the surface of the substrate.

[0004] According to the above-mentioned conventional techniques, a medical device having a lubricating layer exhibiting good lubricity can be obtained by fixing a hydrophilic material to the surface of a substrate. However, there remains a need for other means for obtaining a medical device having a lubricating layer exhibiting good lubricity and durability, in order to at least partially alleviate issues such as the affinity between the material constituting the substrate and the hydrophilic material, the coating time required to fix the hydrophilic material to the surface of the substrate, and the environmental impact of the coating process.

[0005] Therefore, the present invention has been made in consideration of the above circumstances, and an object of the present invention is to provide a medical device having a lubricating layer that can achieve both good lubricity (sliding property) and durability (particularly, sliding durability) by a means different from the above-mentioned conventional techniques. Another object of the present invention is to provide a method for producing a medical device having a lubricating layer that can achieve both good lubricity (sliding property) and durability (particularly, sliding durability) by a means different from the conventional techniques.

[0006] The present inventors have conducted extensive research and have found that a medical device having a lubricating layer that is capable of achieving both good lubricity (sliding properties) and durability (particularly sliding durability) can be obtained by providing a layer on a substrate that contains a mixture of a resin material constituting the substrate and a hydrophilic copolymer formed using a monomer having a specific structure, and this finding led to the completion of the present invention.

[0007] The above object can be achieved by the present invention having the following configuration, and the present invention includes the following aspects and configurations.

[0008] One aspect of the present invention is a medical device comprising: 1. a substrate having a resin layer on a surface thereof; and a lubricating layer formed on at least a portion of the resin layer, wherein the lubricating layer comprises a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from a monomer represented by the following formula (1) and 2-methoxyethyl acrylate:

[0009]

[0010] In the above formula (1), R １ and R ２are each independently a methyl group or an ethyl group, and the resin layer has a penetration layer on the lubricating layer side, in which the hydrophilic copolymer and the resin material that forms the resin layer are mixed; 2. In the medical device described in 1. above, when the total number of moles of the N-(2-hydroxyethyl)acrylamide-derived structural unit a1 and the monofunctional monomer-derived structural unit a2 in the hydrophilic copolymer is taken as 100 mole %, the content of the structural unit a1 is preferably 20 mole % or more and 80 mole % or less; 3. In the medical device described in 1. or 2. above, the monofunctional monomer is preferably N,N-dimethylacrylamide; 4. In the medical device described in 3. above, In the medical device described in any one of items 1. to 4., when the total number of moles of the N-(2-hydroxyethyl)acrylamide-derived structural unit a1 and the N,N-dimethylacrylamide-derived structural unit a2 in the hydrophilic copolymer is taken as 100 mole %, the content of the structural unit a1 is preferably 25 mole % or more and 60 mole % or less; 5. In the medical device described in any one of items 1. to 4. above, the thickness of the lubricating layer is preferably greater than the thickness of the penetration layer; 6. In the medical device described in item 5. above, the thickness of the lubricating layer is preferably at least twice the thickness of the penetration layer; 7. In the medical device described in any one of items 1. to 6. above, the hydrophilic copolymer preferably does not substantially contain structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides; 8. In the medical device described in any one of items 1. to 7. above, the hydrophilic copolymer preferably does not substantially contain structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides; 8. In the medical device described in any one of above, the hydrophilic copolymer is preferably composed of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the monomer represented by formula (1) above and 2-methoxyethyl acrylate; 9. In the medical device described in any one of above 1. to 8., the lubricating layer is preferably free of a polymerization initiator and its residue; 10. The medical device described in any one of above 1. to 9. is preferably a catheter, a stent delivery system, or a guidewire.

[0011] Another aspect of the present invention is to provide a coating liquid containing N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the group consisting of a monomer represented by the following formula (1) and 2-methoxyethyl acrylate,

[0012]

[0013] In the above formula (1), R １ and R ２ each independently represent a methyl group or an ethyl group, applying the coating liquid to at least a portion of a surface of a resin layer of a substrate having a resin layer on its surface, thereby causing the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer to penetrate into the resin layer and forming a precursor layer on at least a portion of the resin layer, and irradiating the precursor layer with an electron beam to polymerize the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer, thereby forming a lubricating layer formed on the surface of the resin layer and containing a hydrophilic copolymer of the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer, and a permeation layer located in at least a portion of the resin layer on the lubricating layer side, wherein the resin material that forms the resin layer and the hydrophilic copolymer are mixed together; 12. In the method for producing a medical device described in 11 above, it is preferable to irradiate the precursor layer with an electron beam at an exposure dose of more than 0 kGy and less than 200 kGy.

[0014] Figure 1A is a cross-sectional TEM image of Sample 3 obtained in Example 3. Figure 1B is a further enlarged image of the cross-sectional TEM image of Figure 1A. Figure 2 is a schematic diagram of a lubrication maintenance evaluation test device (friction tester). In Figure 2, 1 represents water, 2 represents a Petri dish, 3 represents an evaluation sample, 4 represents a thermoplastic elastomer terminal, 5 represents a load, 6 represents a moving table, and 10 represents a friction tester.

[0015] One aspect of the present invention is a medical device comprising: a substrate having a resin layer on a surface thereof; and a lubricating layer formed on at least a portion of the resin layer, wherein the lubricating layer comprises a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from a monomer represented by the following formula (1) and 2-methoxyethyl acrylate:

[0016]

[0017] In the above formula (1), R １ and R ２ each independently represents a methyl group or an ethyl group, and the resin layer has a penetration layer on the lubricating layer side, in which the hydrophilic copolymer and the resin material that forms the resin layer are mixed.

[0018] Another aspect of the present invention relates to a method for producing a medical device, comprising: preparing a coating liquid containing N-(2-hydroxyethyl)acrylamide, a monomer represented by formula (1) above, and at least one monofunctional monomer selected from 2-methoxyethyl acrylate; applying the coating liquid to at least a portion of a surface of a resin layer of a substrate having a resin layer on its surface, thereby causing the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer to penetrate into the resin layer and form a precursor layer on at least a portion of the resin layer; and irradiating the precursor layer with an electron beam to polymerize the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer, thereby forming a lubricating layer formed on the surface of the resin layer and containing a hydrophilic copolymer of the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer; and a permeation layer located on at least a portion of the resin layer on the lubricating layer side, in which the resin material forming the resin layer and the hydrophilic copolymer are mixed.

[0019] With this configuration, it is possible to provide a medical device having a lubricating layer that can achieve both good lubricity (sliding properties) and durability (lubrication maintenance) (particularly sliding durability).

[0020] In this specification, a medical device having the above configuration is also simply referred to as a "medical device" or a "medical device according to the present invention." In this specification, a "substrate having a resin layer on its surface" is also simply referred to as a "substrate" or a "substrate according to the present invention." In this specification, a "permeation layer containing a mixture of a hydrophilic copolymer and a resin material forming the resin layer" is also simply referred to as a "permeation layer" or a "permeation layer according to the present invention." In this specification, a "resin material forming the resin layer" is also simply referred to as a "resin material" or a "resin material according to the present invention." In this specification, a "monomer represented by formula (1)" is also simply referred to as a "monomer of formula (1)." In this specification, a "monofunctional monomer selected from a monomer represented by formula (1) and 2-methoxyethyl acrylate" is also simply referred to as a "monofunctional monomer."

[0021] In this specification, the "hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the monomer represented by formula (1) and 2-methoxyethyl acrylate" is also referred to simply as the "hydrophilic copolymer" or the "hydrophilic copolymer according to the present invention."

[0022] As used herein, the term "X to Y" indicating a range includes X and Y and means "X or greater and Y or less." Furthermore, "X and / or Y" means at least one of X and Y, and encompasses X alone, Y alone, and a combination of X and Y. 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. Furthermore, the term "(meth)acrylamide" encompasses both acrylamide and methacrylamide.

[0023] In this specification, when a certain structural unit is defined as being "derived from" or "derived from" a certain monomer, it means that the structural unit is generated by the reaction of a reactive group possessed by the corresponding monomer and / or is generated by the cleavage of a polymerizable unsaturated double bond (ethylenically unsaturated group) possessed by the corresponding monomer.

[0024] Unless otherwise specified, the operations and measurements of physical properties are carried out at room temperature (20 to 25° C.) and a relative humidity of 40 to 60% RH.

[0025] <Medical Device> A medical device according to one embodiment of the present invention comprises a substrate having a resin layer on its surface and a lubricating layer formed on at least a portion of the resin layer. The lubricating layer contains a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the monomer represented by formula (1) above and 2-methoxyethyl acrylate. By including this hydrophilic copolymer, the lubricating layer according to the present invention exhibits excellent lubricity when wet (e.g., when in contact with body fluids such as blood or aqueous liquids such as physiological saline; the same applies hereinafter). In addition, the medical device according to the present invention has a penetration layer on the lubricating layer side (in contact with the lubricating layer) of the resin layer, in which the hydrophilic copolymer and the resin material forming the resin layer are mixed. Here, in the penetration layer, not only are the molecular chains of the hydrophilic copolymer entangled with each other, but also the molecular chains of the hydrophilic copolymer and the molecular chains of the resin material are entangled. Furthermore, in this case, the hydrophilic copolymer may partially straddle both the lubricating layer and the penetration layer. Therefore, the resin layer and the lubricating layer are firmly bonded via the permeation layer, and the medical device having the above structure can exhibit excellent durability (especially sliding durability).

[0026] Therefore, a medical device having the above configuration can exhibit excellent lubricity and durability (particularly sliding durability) in a good balance. That is, the present invention provides a medical device having a lubricating layer that can achieve both excellent lubricity (sliding property) and durability (particularly sliding durability).

[0027] The above mechanism is speculation and does not limit the technical scope of the present invention.

[0028] Preferred embodiments of the present invention will be described below. Note that the present invention is not limited to the following embodiments, and various modifications can be made within the scope of the claims. Furthermore, the embodiments described in this specification can be arbitrarily combined to form other embodiments.

[0029] Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to be used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will prevail.

[0030] [Lubricating layer] The lubricating layer is formed (carried) on at least a part of the resin layer. Here, the reason why the lubricating layer is formed (carried) on at least a part of the surface of the resin layer is that in medical devices such as catheters, stent delivery systems, and guidewires, which are preferred uses, it is not necessary for all surfaces (the entire surface) of these medical devices to have lubricity when wet, and it is sufficient that the lubricating layer is carried only on the surface portion (sometimes a part or sometimes all) that is required to have lubricity when wet. Therefore, for example, when the resin layer is tubular (tube-shaped), the lubricating layer includes a form formed to cover the entire outer surface of the resin layer; a form formed to cover the entire inner surface of the resin layer; a form formed to cover a part of the outer surface and inner surface of the resin layer in the same or different forms; a form formed to cover a part of the outer surface or inner surface of the resin layer, etc. Furthermore, when the resin layer is linear (wire-shaped), the lubricating layer includes a form formed to cover the entire outer surface of the resin layer; a form formed to cover a part of the outer surface of the resin layer, etc. Furthermore, when the resin layer is in the form of a sheet, the lubricating layer may be formed so as to cover the entire one side of the resin layer; so as to cover the entire both sides of the resin layer; so as to cover a portion of both sides of the resin layer in the same or different forms; or so as to cover a portion of one side of the resin layer.

[0031] The lubricating layer exhibits lubricity when wet, improving the operator's operability when inserting a medical device into a biological lumen such as a blood vessel, and also functions to reduce tissue damage caused by friction with the biological lumen tissue. For this reason, the lubricating layer constitutes the outermost layer of the medical device that comes into contact with the inner surface of the biological lumen.

[0032] The lubricating layer is substantially free of the resin material that forms the resin layer. Here, "the lubricating layer is substantially free of the resin material that forms the resin layer" means that the content of the resin material (in terms of solid content) relative to the total mass of the lubricating layer is less than 0.5 mass%, preferably 0.1 mass% or less (lower limit: 0 mass%), and more preferably 0 mass% (the lubricating layer does not contain the resin material).

[0033] The lubricating layer contains a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from a monomer represented by the following formula (1) and 2-methoxyethyl acrylate. That is, the hydrophilic copolymer contained in the lubricating layer according to the present invention contains a structural unit derived from N-(2-hydroxyethyl)acrylamide and a structural unit derived from at least one monofunctional monomer selected from a monomer represented by the following formula (1) and 2-methoxyethyl acrylate. Hereinafter, N-(2-hydroxyethyl)acrylamide and the monofunctional monomer will also be collectively referred to as the "raw material monomer."

[0034]

[0035] In the above formula (1), R １ and R ２ each independently represents a methyl group or an ethyl group.

[0036] N-(2-hydroxyethyl)acrylamide has high hydrophilicity. Therefore, a hydrophilic copolymer having a structural unit a1 derived from N-(2-hydroxyethyl)acrylamide (hereinafter also simply referred to as "structural unit a1") has high hydrophilicity. Therefore, a lubricating layer containing this hydrophilic copolymer can exhibit excellent lubricity (sliding properties) when wet. In contrast, when the hydrophilic (co)polymer forming the lubricating layer does not contain the structural unit a1, good lubricity (sliding properties) cannot be obtained (see Comparative Example 2 described below).

[0037] Furthermore, when N-(2-hydroxyethyl)methacrylamide is used instead of N-(2-hydroxyethyl)acrylamide, the durability of the lubricating layer decreases (Comparative Examples 3 and 4 described below). Here, as described below, in one embodiment, the lubricating layer according to the present invention is preferably formed by applying a coating liquid containing N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the monomer of formula (1) and 2-methoxyethyl acrylate onto a resin layer, followed by electron beam irradiation (electron beam polymerization). This method makes it possible to easily form a permeation layer in which the hydrophilic copolymer and the resin material forming the resin layer are mixed. Furthermore, in this method of electron beam polymerization, it is presumed that the progress of radical polymerization is related to the durability of the lubricating layer. The acryloyl group (CH ２ Since N-(2-hydroxyethyl)acrylamide has a conjugated structure that stabilizes radicals, electron beam polymerization proceeds easily when N-(2-hydroxyethyl)acrylamide is used. On the other hand, the methacryloyl group (CH ２ =C(CH ３)-C(=O)-) stabilizes radicals, but has a much smaller reaction rate constant for radical polymerization than an acryloyl group, making electron beam polymerization difficult when N-(2-hydroxyethyl)methacrylamide is used. Generally, a polyacrylate structure undergoes a crosslinking reaction rather than breakdown (decomposition) upon electron beam irradiation, whereas a polymethacrylate structure is more likely to undergo breakdown (decomposition) rather than crosslinking upon electron beam irradiation. Therefore, it is presumed that poly-N-(2-hydroxyethyl)methacrylamide, which has a structure similar to polymethacrylate, is more likely to undergo breakdown (decomposition) rather than crosslinking upon electron beam irradiation. Therefore, when N-(2-hydroxyethyl)methacrylamide is used, even if electron beam polymerization of N-(2-hydroxyethyl)methacrylamide proceeds upon electron beam irradiation, the decomposition reaction of poly-N-(2-hydroxyethyl)methacrylamide proceeds simultaneously, resulting in insufficient polymerization and crosslinking upon electron beam irradiation, potentially reducing the durability of the lubricating layer. Therefore, in order to form a lubricating layer having excellent lubricity and durability, the hydrophilic copolymer according to the present invention essentially contains structural units a1 derived from N-(2-hydroxyethyl)acrylamide. Furthermore, for the reasons described above, it is preferable that the hydrophilic copolymer is substantially free of structural units derived from N-(2-hydroxyethyl)methacrylamide. Here, "the hydrophilic copolymer is substantially free of structural units derived from N-(2-hydroxyethyl)methacrylamide" means that the content of structural units derived from N-(2-hydroxyethyl)methacrylamide is less than 5 mol% of all structural units constituting the hydrophilic copolymer, preferably less than 1 mol% (lower limit: 0 mol%), and particularly preferably 0 mol% (the hydrophilic copolymer does not contain structural units derived from N-(2-hydroxyethyl)methacrylamide).

[0038] On the other hand, N-(2-hydroxyethyl)acrylamide contributes to good lubricity (and durability) as described above. However, a polymer containing only the structural unit a1 derived from N-(2-hydroxyethyl)acrylamide has relatively good film-forming properties but insufficient durability (Comparative Example 1 described below). In contrast, it has been found that by using the above monofunctional monomer in combination with N-(2-hydroxyethyl)acrylamide, a lubricating layer with sufficient durability can be formed.

[0039] The present inventors speculate that this mechanism is as follows. The monofunctional monomer has high affinity and compatibility with N-(2-hydroxyethyl)acrylamide. Furthermore, a polymer containing only the structural unit a2 derived from the monofunctional monomer does not have sufficient slipperiness (lubricity) because the monofunctional monomer is less hydrophilic than N-(2-hydroxyethyl)acrylamide, but the film-forming properties and durability of the lubricating layer are good. From the above, the monofunctional monomer appropriately mixes with N-(2-hydroxyethyl)acrylamide when applied to the resin layer, and randomly copolymerizes with N-(2-hydroxyethyl)acrylamide during polymerization. Furthermore, it is speculated that the structures derived from the monofunctional monomer tend to be adjacent to each other in the lubricating layer as sites less hydrophilic than (2-hydroxyethyl)acrylamide, and therefore act as crosslinking points that maintain the copolymer of N-(2-hydroxyethyl)acrylamide and the monofunctional monomer within the lubricating layer. Therefore, the hydrophilic copolymer according to the present invention can form a lubricating layer that is superior in lubricity and durability. Accordingly, the hydrophilic copolymer according to the present invention essentially contains, in addition to the structural unit a1 derived from N-(2-hydroxyethyl)acrylamide, the structural unit a2 derived from the monofunctional monomer (hereinafter also simply referred to as "structural unit a2").

[0040] The monofunctional monomer has one acryloyl group. When a hydrophilic copolymer is formed using a polyfunctional monomer having two or more (meth)acryloyl groups, polymerization proceeds through multiple (meth)acryloyl groups, resulting in a denser three-dimensional network structure of the hydrophilic copolymer in the lubricating layer, reducing the swelling property of the lubricating layer. As a result, the swelling property (slipperiness) of the lubricating layer is significantly reduced (see Comparative Example 5 below). For this reason, it is preferable that the hydrophilic copolymer does not substantially contain structural units derived from polyfunctional (meth)acrylates or polyfunctional (meth)acrylamides. Here, "polyfunctional (meth)acrylate" refers to a (meth)acrylate compound having two or more (meth)acryloyl groups. Furthermore, "polyfunctional (meth)acrylamide" refers to an amide compound having two or more (meth)acryloyl groups. Furthermore, the phrase "the hydrophilic copolymer is substantially free of structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides" means that the content of structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides is less than 5 mol% relative to all structural units constituting the hydrophilic copolymer, preferably less than 1 mol% (lower limit: 0 mol%), and particularly preferably 0 mol% (the hydrophilic copolymer does not contain structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides). The composition can be controlled by adjusting the charge ratio (molar ratio) of each monomer so that it falls within the above range. For example, if a polyfunctional (meth)acrylate (e.g., triethylene glycol diacrylate) and a polyfunctional (meth)acrylamide (e.g., N,N'-methylenebis(acrylamide)) are not added to the coating liquid, the content of structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides in the resulting hydrophilic copolymer will be 0 mol%. The composition (molar ratio) of the hydrophilic copolymer can be confirmed, for example, by subjecting the hydrophilic copolymer to Fourier transform infrared absorption spectroscopy (FT-IR) or time-of-flight secondary ion mass spectrometry (TOF-SIMS).For example, the composition (molar ratio) of the hydrophilic copolymer can be calculated from the absorption peak values ​​corresponding to the N-(2-hydroxyethyl)acrylamide-derived structural units, the monofunctional monomer-derived structural units, the polyfunctional (meth)acrylate-derived structural units, and the polyfunctional (meth)acrylamide-derived structural units by measuring the FT-IR spectrum of the hydrophilic copolymer. Furthermore, each of the structural units contained in the hydrophilic copolymer can be identified by pyrolysis GC-MS (gas chromatography-mass spectrometry).

[0041] In the above formula (1), R １ and R ２ are each independently a methyl group or an ethyl group. １ and R ２ may be the same or different from each other. １ and R ２ When a monomer (such as N-butylacrylamide) is used in which at least one of the substituents is a larger substituent (such as an alkyl group having 3 or more carbon atoms), the slipperiness is reduced (see Comparative Example 7 below). Also, when an acrylate having a hydroxyalkyl group having 3 or more carbon atoms (such as 4-hydroxybutyl acrylate) is used, the slipperiness is reduced (see Comparative Example 6 below).

[0042] Specific examples of the monomer of formula (1) include N,N-dimethylacrylamide, N,N-diethylacrylamide, and N-ethyl-N-methylacrylamide.

[0043] The monofunctional monomer may be used alone or in combination of two or more. In one embodiment, the monofunctional monomer is preferably at least one selected from the group consisting of N,N-dimethylacrylamide, N,N-diethylacrylamide, and 2-methoxyethyl acrylate. From the viewpoint of forming a lubricating layer having superior lubricity while maintaining good durability, the monofunctional monomer is more preferably at least one selected from the group consisting of N,N-dimethylacrylamide and N,N-diethylacrylamide, and even more preferably N,N-dimethylacrylamide.

[0044] The hydrophilic copolymer has a structural unit a1 derived from N-(2-hydroxyethyl)acrylamide and a structural unit a2 derived from the monofunctional monomer. Here, the content of the structural unit a1 in the hydrophilic copolymer is not particularly limited. In consideration of further improvements in lubricity (sliding properties) and durability (particularly sliding durability), when the total number of moles of the structural unit a1 and the structural unit a2 in the hydrophilic copolymer is taken as 100 mol%, the content of the structural unit a1 in the hydrophilic copolymer is preferably 20 mol% or more, more preferably 23 mol% or more, even more preferably 25 mol% or more, and particularly preferably 30 mol% or more. Furthermore, when the total number of moles of the structural unit a1 and the structural unit a2 in the hydrophilic copolymer is taken as 100 mol %, the content of the structural unit a1 is preferably 80 mol % or less, more preferably 75 mol % or less, even more preferably 70 mol % or less, even more preferably 60 mol % or less, and particularly preferably 50 mol % or less.

[0045] That is, when the total number of moles of the structural unit a1 contained in the hydrophilic copolymer and the number of moles of the structural unit a2 contained in the hydrophilic copolymer is taken as 100 mole%, the content of the structural unit a1 in the hydrophilic copolymer is preferably 20 mole% or more and 80 mole% or less, more preferably 23 mole% or more and 75 mole% or less, even more preferably 23 mole% or more and 70 mole% or less, even more preferably 25 mole% or more and 60 mole% or less, and particularly preferably 25 mole% or more and 50 mole% or less.If the content (composition) of the structural unit a1 in the hydrophilic copolymer is within the above range, the lubricating layer can exhibit high lubricity.

[0046] As described above, in a more preferred embodiment of the present invention, the monofunctional monomer is N,N-dimethylacrylamide. Even when the monofunctional monomer is N,N-dimethylacrylamide, when the total number of moles of the structural unit a1 and the structural unit a2 in the hydrophilic copolymer is taken as 100 mol%, the content of the structural unit a1 in the hydrophilic copolymer is preferably 20 mol% to 80 mol%, more preferably 23 mol% to 75 mol%, even more preferably 23 mol% to 70 mol%, still more preferably 25 mol% to 60 mol%, and particularly preferably 25 mol% to 50 mol%.

[0047] The method for measuring the content of the structural unit a1 contained in the hydrophilic copolymer is as described above. The content can be controlled, for example, by adjusting the charge ratio (content ratio) of each monomer contained in the coating liquid used to form the lubricating layer so that it falls within the above range.

[0048] In one embodiment of the present invention, when the total mole number of the molar content of the structural unit a1 and the molar content of the structural unit a2 in the hydrophilic copolymer is 100 mol%, the content of the structural unit a2 in the hydrophilic copolymer is preferably 20 mol% or more and 80 mol% or less, more preferably 25 mol% or more and 77 mol% or less, even more preferably 30 mol% or more and 77 mol% or less, even more preferably 40 mol% or more and 75 mol% or less, and particularly preferably 50 mol% or more and 75 mol% or less.It should be noted that, when two or more kinds of structural unit a2 exist, the content of the structural unit a2 refers to the total amount.If the content of the structural unit a2 in the hydrophilic copolymer is within the above range, the lubricating layer can exhibit high durability.

[0049] The hydrophilic copolymer may be formed solely from the structural unit a1 derived from N-(2-hydroxyethyl)acrylamide and the structural unit a2 derived from the monofunctional monomer, or may further contain, in addition to the structural units a1 and a2, structural units derived from a monomer (other monomer) other than N-(2-hydroxyethyl)acrylamide and the monofunctional monomer. Examples of the other monomer include N-methylacrylamide, N-ethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminoethyl acrylate, 2-acrylamido-2-methylpropanesulfonic acid, acrylamide, N-(2-hydroxypropyl)acrylamide, N-(2-hydroxybutyl)acrylamide, N-vinyl-2-pyrrolidone (1-vinyl-2-pyrrolidone), polyethylene glycol monoacrylate, polyethylene glycol alkyl ether monoacrylate; glycidyl acrylate, 3,4-epoxycyclohexylmethyl acrylate, 2 ... acrylate, β-methylglycidyl acrylate; 4-hydroxybutyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxybutyl acrylate, 6-hydroxyhexyl acrylate, 1,4-cyclohexanedimethanol monoacrylate, 1-chloro-2-hydroxypropyl acrylate, 1,6-hexanediol monoacrylate, 2-hydroxy-3-phenyloxypropyl acrylate, 4-hydroxycyclohexyl acrylate, 2-hydroxy-3-phenyloxyacrylate, 4-hydroxycyclohexyl acrylate, etc. The other monomers may be used alone or in combination of two or more.

[0050] When the hydrophilic copolymer according to the present invention further contains, in addition to the structural units a1 and a2, a structural unit b derived from another monomer (hereinafter also referred to simply as "structural unit b"), the content of structural unit b is preferably greater than 0 mol% and less than 5 mol% relative to the total (100 mol%) of structural units a1, a2, and b. The hydrophilic copolymer having the above composition can be controlled by adjusting the charge ratio (molar ratio) of each monomer so that it falls within the above range. Particularly preferably, the hydrophilic copolymer according to the present invention is composed of the structural units a1 and a2 (the content of structural unit b derived from another monomer = 0 mol%). That is, in a preferred embodiment, the hydrophilic copolymer is composed of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from a monomer represented by formula (1) and 2-methoxyethyl acrylate.

[0051] The hydrophilic copolymer according to the present invention is preferably a random copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the monomer represented by the above formula (1) and 2-methoxyethyl acrylate. The fact that the hydrophilic copolymer is a random copolymer can be confirmed by nuclear magnetic resonance ( １３ This can be confirmed by, for example, C-NMR spectrum.

[0052] The lubricating layer essentially contains a hydrophilic copolymer, but may also contain other components. When the lubricating layer contains other components, the other components are not particularly limited. For example, when the medical device is intended for insertion into a body cavity or a biological lumen, such as a catheter, the other components may include drugs (biologically active substances) such as anticancer drugs, immunosuppressants, antibiotics, antirheumatic drugs, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic drugs, integrin inhibitors, antiallergic drugs, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid-improving drugs, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, vascular smooth muscle proliferation inhibitors, anti-inflammatory drugs, biomaterials, interferons, and NO production promoters. The amount of the other components added is not particularly limited, and commonly used amounts are used in the same manner. Ultimately, the amount of the other components added is appropriately selected by the attending physician, taking into account the severity of the disease being treated, the patient's weight, and the like. Preferably, the lubricating layer is substantially free of other components (i.e., the lubricating layer is substantially composed of a hydrophilic copolymer). Specifically, the content of other components (in terms of solid content) relative to the total mass of the lubricating layer is preferably less than 10% by mass, more preferably less than 5% by mass, and even more preferably less than 1% by mass (lower limit: 0% by mass), and it is particularly preferred that the lubricating layer is free of other components (i.e., the lubricating layer is composed of a hydrophilic copolymer).

[0053] As described below, the medical device according to the present invention can be produced by applying a coating liquid containing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer onto a resin layer, followed by electron beam irradiation (electron beam polymerization). Such polymerization of raw material monomers by electron beam irradiation does not require a polymerization initiator (e.g., a benzophenone-based photoinitiator or an acetophenone-based photoinitiator). Therefore, in one embodiment, the hydrophilic copolymer preferably does not contain any residues of the polymerization initiator. That is, the content of the residues of the polymerization initiator present in the hydrophilic copolymer is preferably 0 mol % relative to the total structural units constituting the hydrophilic copolymer. Furthermore, the lubricating layer preferably does not substantially contain any polymerization initiator or its residues. Here, "the lubricating layer is substantially free of polymerization initiators and their residues" means that the total content (in terms of solids content) of unreacted polymerization initiators and residues of polymerization initiators after reaction relative to the total mass of the lubricating layer is less than 0.5% by mass (lower limit: 0% by mass), preferably 0.1% by mass or less (lower limit: 0% by mass), and more preferably 0% by mass (the lubricating layer is free of polymerization initiators and their residues). Note that the fact that the lubricating layer is substantially free of polymerization initiators and their residues can be confirmed, for example, by pyrolysis GC-MS (gas chromatography mass spectrometry).

[0054] In order to obtain better lubrication, the thickness of the lubricating layer (dry film thickness) is preferably larger than the thickness of the penetration layer (dry film thickness) described later. From the same viewpoint as above, the thickness of the lubricating layer is more preferably 2 times or more than the thickness of the penetration layer, even more preferably 5 times or more, even more preferably 10 times or more, particularly preferably 30 times or more, and most preferably 40 times or more. On the other hand, the thickness of the lubricating layer is, for example, 100 times or less than the thickness of the penetration layer, may be 80 times or less, or may be 60 times or less. Therefore, in one embodiment, the thickness of the lubricating layer relative to the thickness of the penetration layer is more preferably 2 times or more and 100 times or less, more preferably 2 times or more and 80 times or less, 2 times or more and 60 times or less, 5 times or more and 60 times or less, 10 times or more and 60 times or less, 30 times or more and 60 times or less, and 40 times or more and 60 times or less are more preferred in this order.

[0055] The thickness of the lubricating layer (dry film thickness) is, for example, 0.3 to 15 μm, preferably 1 to 10 μm, and more preferably about 2 to 5 μm. With such a thickness, the lubricating layer can fully exhibit lubricity. Furthermore, it is preferable that the relationship (ratio) between the thickness of the penetration layer and the thickness of the lubricating layer described above is satisfied. The thickness of the lubricating layer and the relationship (ratio) between the thickness of the lubricating layer and the thickness of the penetration layer described above can be controlled by adjusting the amount of coating liquid applied, as described below. In this specification, the thickness of the lubricating layer is a value measured by observation with a transmission electron microscope (TEM).

[0056] As described in detail below, in a preferred embodiment, the hydrophilic copolymer is formed by applying a coating liquid containing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer onto a resin layer, followed by electron beam irradiation to polymerize and crosslink the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer. In this case, the hydrophilic copolymer can be defined as one formed by irradiating N-(2-hydroxyethyl)acrylamide and the monofunctional monomer with an electron beam (a random copolymer formed by electron beam irradiation). The electron beam irradiation not only extends the polymer chains of N-(2-hydroxyethyl)acrylamide and the monofunctional monomer (polymerization reaction), but also crosslinks the polymer chains to each other (crosslinking reaction), thereby forming a hydrophilic copolymer. Furthermore, because the crosslinking positions in this crosslinking reaction are random, the crosslinking positions of the hydrophilic copolymer cannot be identified or are very difficult to identify, and it is either impossible to represent the hydrophilic copolymer by a general formula (structure) or very difficult to represent the hydrophilic copolymer by a general formula (structure). Therefore, at the time of filing, it was impossible or impractical to directly identify the hydrophilic copolymer obtained by electron beam irradiation based on its structure or properties ("impossible / impractical circumstances"). Therefore, it may be appropriate to identify the hydrophilic random copolymer as a "product" by stating "a hydrophilic random copolymer formed by irradiating raw material monomers containing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer with an electron beam."

[0057] Therefore, in one embodiment, the present invention can provide a medical device comprising a substrate having a resin layer on its surface and a lubricating layer formed on at least a portion of the resin layer, wherein the lubricating layer contains a hydrophilic random copolymer formed by irradiating raw material monomers containing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer with an electron beam, and the resin layer has a permeation layer on the lubricating layer side in which the hydrophilic random copolymer and the resin material that forms the resin layer are mixed.

[0058] [Substrate] The substrate used in the present invention may be any substrate having at least a resin layer on its surface. For example, the substrate may be composed of only a resin layer (i.e., the resin layer is the substrate), or may be composed of a layer (substrate layer) made of a material other than the resin material constituting the resin layer and a resin layer, which can be appropriately selected depending on the application. Hereinafter, the "layer made of a material other than the resin material constituting the resin layer" will also be simply referred to as the "substrate layer." Furthermore, the resin layer may be composed of a single resin layer or a laminate of multiple resin layers, which can be appropriately selected depending on the application.

[0059] The resin layer has a penetration layer on the lubricating layer side, which contains a mixture of a hydrophilic copolymer and a resin material forming the resin layer. A penetration layer having such a configuration is preferably formed by applying a coating liquid containing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer onto the resin layer, allowing these raw material monomers to penetrate the resin layer, and then performing electron beam irradiation (electron beam polymerization). Therefore, the resin layer must be permeable to N-(2-hydroxyethyl)acrylamide and the monofunctional monomer (raw material monomer). Specifically, the resin material constituting (forming) the resin layer is a material in which, after applying a coating liquid containing raw material monomers to the surface of a resin layer made of the resin material at room temperature (25°C) and waiting three minutes, the raw material monomers contained in the coating liquid penetrate 50 nm or more from the surface of the resin layer. That is, the resin material is a material in which a coating liquid containing raw material monomers is applied to the surface of a resin layer made of the resin material to form a coating film, and after 3 minutes, an electron beam is irradiated onto the coating film to form a penetration layer having a thickness of 50 nm or more from the surface of the resin layer.

[0060] As such a resin material, amorphous polymers are preferably used. Specific examples include fluororesins such as amorphous polyolefin resins, epoxy resins, amorphous polyurethane resins, diallyl phthalate resins (allyl resins), polycarbonate resins, polytetrafluoroethylene (PTFE), and ethylene-tetrafluoroethylene copolymers (ETFE; Ethylene Tetra Fluoro Ethylene), amino resins (urea resins, melamine resins, benzoguanamine resins), amorphous polyester resins, styrene resins such as polystyrene, acrylic resins, polymethyl methacrylate, polyacetal resins, vinyl acetate resins, phenolic resins, vinyl chloride resins (polyvinyl chloride), silicone resins (silicon resins), polysulfone resins such as polyethersulfone resins, amorphous polyamide resins, polyamideimide resins, and amorphous polyimide resins. Thermoplastic elastomers such as olefin elastomers, polyurethane elastomers, polyester elastomers, and polyamide elastomers (nylon elastomers) are also preferably used. Among these, from the viewpoint of allowing the raw material monomer to penetrate more easily (facilitating the formation of a penetration layer), the resin material is preferably selected from amorphous polymers (e.g., polycarbonate resin, vinyl chloride resin, polymethyl methacrylate, polystyrene, polyamide-imide resin, amorphous polyester resin, etc.); thermoplastic elastomers (e.g., olefin elastomer, polyester elastomer, polyamide elastomer, etc.), and more preferably selected from polyamide elastomers and amorphous polyester resins. These resin materials may be used alone or in combination of two or more. When the resin layer is a laminate of multiple resin layers, the resin materials constituting each resin layer may be the same or different.

[0061] The substrate may further include a substrate layer that supports the resin layer depending on its intended use and required strength. Materials constituting (forming) the substrate layer include crystalline polymer materials, metal materials, glass materials, ceramics, etc. Here, the substrate layer may be entirely composed (formed) of any of the above materials, or the surface of a substrate layer core formed from the above resin material or the like may be coated with any of the above materials by an appropriate method (conventionally known method such as plating, metal vapor deposition, sputtering, etc.). Examples of crystalline polymer materials include polyethylene resins such as high-density polyethylene (HDPE) and modified polyethylene, polyolefin resins such as polypropylene resin, modified polyolefin resins, cyclic polyolefin resins, crystalline polyester resins such as polyethylene terephthalate resin and polybutylene terephthalate resin, liquid crystal polyester, crystalline polyamide resins such as nylon 6 and nylon 66, polyphthalamide, polyphenylene sulfide, polyether ether ketone, etc. These crystalline polymer materials may be used alone or in combination of two or more.

[0062] The metallic material is not particularly limited, and metallic materials generally used for medical devices such as catheters, stent delivery systems, guidewires, etc. Specific examples include various stainless steels (SUS) such as SUS304, SUS316, SUS316L, SUS420J2, and SUS630, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, and various alloys such as nickel-titanium (Ni-Ti) alloy, nickel-cobalt (Ni-Co) alloy, cobalt-chromium (Co-Cr) alloy, and zinc-tungsten (Zn-W) alloy. These metallic materials may be used alone or in combination of two or more.

[0063] When the substrate has a substrate layer and a resin layer, the substrate layer is substantially free of a hydrophilic copolymer. Here, the phrase "substantially free of a hydrophilic copolymer" means that the content of the hydrophilic copolymer (in terms of solid content) relative to the total mass of the substrate layer is less than 0.5% by mass (lower limit: 0% by mass), preferably 0.1% by mass or less (lower limit: 0% by mass), and more preferably 0% by mass (the substrate layer does not contain a hydrophilic copolymer).

[0064] The method for forming the resin layer on the substrate layer is not particularly limited. For example, a method of coating the substrate layer with a resin material by an appropriate means (conventionally known methods such as dipping, spraying, coating, printing, etc.), or a method of combining the substrate layer with a resin material can be used. Alternatively, a commercially available product may be used as the substrate consisting of the substrate layer and the resin layer. Examples of such commercially available products include COSMOSHINE (registered trademark) A4360 and A4160 (biaxially stretched PET films, both manufactured by Toyobo Co., Ltd.).

[0065] The shape of the substrate is not particularly limited, and may be selected appropriately depending on the intended use, such as a sheet, a wire, or a tube.

[0066] The permeation layer constitutes at least a part of the resin layer and is adjacent to the lubricating layer, being located on the lubricating layer side of the resin layer. The permeation layer contains a mixture of a hydrophilic copolymer and a resin material. The structure (layer structure) can be confirmed using known observation means such as a scanning electron microscope (SEM) or a transmission electron microscope (TEM). The compounds contained in each layer (e.g., the types of hydrophilic copolymer and resin material, as well as other components, polymerization initiators, and types of polymerization initiator residues) can be analyzed by time-of-flight secondary ion mass spectrometry (TOF-SIMS), pyrolysis GC-MS (gas chromatography-mass spectrometry), NMR (e.g., １The layer structure (e.g., the number of layers and layer thickness) constituting the medical device can be evaluated using a transmission electron microscope (TEM). Furthermore, the compounds contained in each layer can be evaluated in the thickness direction of the layer using time-of-flight secondary ion mass spectrometry (TOF-SIMS) or pyrolysis GC-MS (gas chromatography-mass spectrometry).

[0067] In the penetration layer, not only are the molecular chains of the hydrophilic copolymer entangled with each other, but also the molecular chains of the hydrophilic copolymer and the molecular chains of the resin material. Furthermore, the hydrophilic copolymer may partially exist across both the lubricating layer and the penetration layer. Therefore, the resin layer and the lubricating layer are firmly bonded via the penetration layer. Therefore, a medical device having the above configuration can exhibit excellent durability (especially sliding durability).

[0068] The thickness of the penetration layer (dry film thickness) is preferably within a range that satisfies the relationship (ratio) between the thickness of the lubricating layer and the thickness of the penetration layer described above. The thickness of the penetration layer (dry film thickness) is, for example, 0.01 μm or more, may be 0.05 μm or more, 0.1 μm or more, 0.5 μm or more, or 1 μm or more. On the other hand, the upper limit of the thickness of the penetration layer is, for example, 10 μm or less, may be 5 μm or less, may be 3 μm or less, or may be 1 μm or less. In one embodiment, the thickness of the penetration layer (dry film thickness) is, for example, 0.01 μm or more and 10 μm or less, may be 0.01 μm or more and 5 μm or less, may be 0.05 μm or more and 3 μm or less, or may be 0.1 μm or more and 1 μm or less. Such a thickness can achieve sufficient durability (especially sliding durability). The thickness of the penetration layer can be controlled by appropriately selecting the amount of coating liquid applied, the application temperature, the penetration time, the type of resin material forming the resin layer, etc., as described below. In this specification, the thickness of the permeation layer is a value measured by observation with a transmission electron microscope (TEM).

[0069] The penetration layer may be formed on the lubricating layer side of the resin layer. For example, the resin layer may be composed solely of a penetration layer containing a hydrophilic copolymer and a resin material (the resin material forming the resin layer) (i.e., the penetration layer may be a resin layer), or it may be composed of a layer (base layer) and a penetration layer that is substantially free of the hydrophilic copolymer. As described above, when a coating liquid containing a raw material monomer is applied to penetrate the resin layer, there may be a region deep within the resin layer where the raw material monomer does not penetrate. In this form, since the hydrophilic copolymer is not formed in this region, the resin layer may have a penetration layer and a base layer that is not permeated with the hydrophilic copolymer. That is, in one embodiment, the resin layer may have a base layer that contains the resin material forming the resin layer and is substantially free of the hydrophilic copolymer, and a penetration layer formed on the base layer and containing a mixture of the hydrophilic copolymer and the resin material. In this form, the penetration layer is formed on the lubricating layer side (in contact with the lubricating layer). That is, the medical device according to the present invention may have a base layer, a penetration layer, and a lubricating layer, in this order.

[0070] In the above, the base layer "substantially does not contain a hydrophilic copolymer" means that the content of the hydrophilic copolymer (in terms of solid content) relative to the total mass of the base layer is less than 0.5% by mass (lower limit: 0% by mass), preferably 0.1% by mass or less (lower limit: 0% by mass), and more preferably 0% by mass (the base layer does not contain a hydrophilic copolymer).

[0071] <Method for manufacturing medical device> As described above, one of the features of the medical device according to the present invention is that a permeation layer containing a mixture of a hydrophilic copolymer and a resin material is provided on the lubricating layer side of a resin layer. Such a medical device can be manufactured by applying a coating liquid containing raw material monomers to the resin layer of a substrate, allowing the raw material monomers to permeate into the resin layer, and then polymerizing the raw material monomers by electron beam irradiation.

[0072] That is, another aspect of the present invention is a method for preparing a coating liquid containing N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from a monomer represented by the following formula (1) and 2-methoxyethyl acrylate,

[0073]

[0074] In the above formula (1), R １ and R ２ each independently represent a methyl group or an ethyl group, and a method for producing a medical device includes the steps of: applying the coating liquid to at least a portion of a surface of a resin layer of a substrate having a resin layer on its surface, thereby causing the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer to penetrate into the resin layer and forming a precursor layer on at least a portion of the resin layer (a precursor layer forming step); and irradiating the precursor layer with an electron beam to polymerize the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer and thereby forming a lubricating layer formed on the surface of the resin layer and containing a hydrophilic copolymer of the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer, and a permeation layer located in at least a portion of the resin layer on the lubricating layer side, in which the resin material forming the resin layer and the hydrophilic copolymer are mixed (an electron beam irradiation step).

[0075] When a coating liquid containing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer is applied to the surface of a resin layer, a portion of these raw material monomers penetrates into the resin layer, while the remaining raw material monomers remain on the surface of the resin layer (collectively referred to as a precursor layer). The precursor layer is then irradiated with an electron beam, causing radical polymerization of the raw material monomers to form a hydrophilic copolymer. As described above, the hydrophilic copolymer obtained by polymerizing N-(2-hydroxyethyl)acrylamide and a monofunctional monomer exhibits excellent lubricity when wet. Therefore, a lubricating layer containing this hydrophilic copolymer can exhibit excellent lubricity (sliding properties) when wet.

[0076] Furthermore, the medical device obtained by the above method can exhibit extremely excellent durability (especially sliding durability), and the mechanism behind this is presumed to be as follows: In electron beam irradiation, raw material monomers are polymerized to form a hydrophilic copolymer, and crosslinking between the hydrophilic copolymers also progresses. Therefore, electron beam irradiation results in more crosslinking within the lubricating layer (e.g., crosslinking between hydrophilic copolymers) than other methods (e.g., UV radical polymerization). Therefore, a lubricating layer containing the hydrophilic copolymer can exhibit excellent durability (especially sliding durability) due to increased crosslinking within the lubricating layer.

[0077] According to the above method, a permeation layer is formed by irradiating the raw material monomers after they have partially permeated the resin layer with electron beam irradiation. The raw material monomers used to form the hydrophilic copolymer have small molecular sizes, which allow them to easily permeate the resin layer. When the raw material monomers are irradiated with electron beams after they have permeated the resin layer, a polymerization reaction (electron beam polymerization) of the raw material monomers occurs. Therefore, in the permeation layer, the molecular chains of the hydrophilic copolymers are entangled with each other, and with the molecular chains of the resin material. Therefore, the medical device obtained by the above method has a permeation layer on the lubricating layer side of the resin layer (in contact with the lubricating layer), in which the hydrophilic copolymer and the resin material that forms the resin layer are mixed. Furthermore, when the raw material monomers are irradiated with electron beams to the portion of the resin layer where they have permeated (the permeation precursor layer), the raw material monomers polymerize to form hydrophilic copolymers, and crosslinking between the hydrophilic copolymers (electron beam crosslinking) and between the hydrophilic copolymers and the resin material (electron beam crosslinking) also occurs. Therefore, in the penetration layer, crosslinks (chemical bonds) are formed not only between the hydrophilic copolymers in the penetration layer but also between the hydrophilic copolymers and the resin material, so that in the penetration layer, the molecular chains of the hydrophilic copolymers are entangled with each other and with the molecular chains of the resin material, and exist in a partially crosslinked state.

[0078] In addition, since the polymerization by electron beam irradiation has high reactivity, the hydrophilic copolymer is polymerized and the chain length of the hydrophilic copolymer is increased. Therefore, the hydrophilic copolymer is partially present across both the lubricating layer and the penetration layer, and crosslinks (chemical bonds) are formed between the hydrophilic copolymers in the penetration layer and between the resin material. In addition to these crosslinks (chemical bonds), crosslinks (chemical bonds) are also formed between the hydrophilic copolymers present across the lubricating layer and the penetration layer, and between the hydrophilic copolymers present across the lubricating layer and the penetration layer and the hydrophilic copolymer in the lubricating layer. Therefore, the resin layer and the lubricating layer are firmly bonded via the penetration layer. Therefore, the medical device obtained by the above method can exhibit excellent durability (especially sliding durability).

[0079] Therefore, the medical device obtained by the above method has excellent lubricity and extremely excellent durability (especially sliding durability). Note that the above mechanism is speculation and does not limit the technical scope of the present invention.

[0080] Furthermore, when raw material monomers are polymerized by electron beam irradiation, the raw material monomers themselves are radicalized by electron beam irradiation, and these radicalized raw material monomers become polymerization initiating radicals, causing a sequential reaction. Therefore, polymerization of raw material monomers by electron beam irradiation does not require a polymerization initiator (e.g., a benzophenone-based photoinitiator or an acetophenone-based photoinitiator). Furthermore, because polymerization by electron beam irradiation has a high polymerization rate (reaction rate), it can reduce the amount of residual monomer in the lubricating layer and the penetration layer. This makes it highly desirable from a safety perspective. Furthermore, because the electron beam irradiation process is completed in a short time, it is unlikely to cause a temperature rise in the substrate, and it is performed at a relatively low temperature (e.g., below 50°C). Therefore, it can be used on heat-sensitive substrates.

[0081] A preferred embodiment of each step will be described below.

[0082] (I) Precursor Layer Formation Step In this step, first, a coating liquid (also referred to simply as "coating liquid" in this specification) containing (2-hydroxyethyl)acrylamide, at least one monofunctional monomer selected from the monomer of formula (1) and 2-methoxyethyl acrylate, and other monomers used as needed is prepared. If the other components used as needed do not react (are not denatured) when irradiated with an electron beam, these other components may be mixed into the coating liquid. The other monomers when the coating liquid contains a monomer other than the raw material monomer, and the other components when the coating liquid contains other components, are the same as those described above, and therefore will not be described here.

[0083] The coating solution can be prepared by mixing the raw material monomer and other optional monomers and components with a solvent. Because the monofunctional monomer is liquid at the temperature during preparation (e.g., 20-25°C), a separate solvent is not required (the coating solution may consist only of N-(2-hydroxyethyl)acrylamide and the monofunctional monomer). This method of not using a separate solvent is preferable because it eliminates the need for a solvent removal step, which is environmentally friendly and reduces the number of steps required for mass production. If necessary, a separate solvent may be used in preparing the coating solution, for example, when it is desirable to adjust the viscosity of the coating solution. The solvent to be used is appropriately selected depending on the type of raw material monomer (and, if used, the other monomers and components). Examples of solvents that can be used include water, acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. The above solvents may be used alone or in the form of a mixed solvent of two or more. When a solvent is used to prepare the coating solution, the concentration of the raw material monomer in the coating solution is not particularly limited. The concentration of the raw material monomer in the coating solution may be, for example, 0.05% by mass or more and 20% by mass or less, or 1% by mass or more and 15% by mass or less, or 5% by mass or more and 10% by mass or less. If the concentration of the raw material monomer is within the above range, the resulting lubricating layer can exhibit sufficient lubricity. Furthermore, a lubricating 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 the concentration is outside the above range, it can be sufficiently used as long as it does not affect the effects of the present invention.

[0084] Next, the coating liquid prepared as above is applied to the desired portion of the resin layer surface of the substrate. As a result, a portion of the raw material monomer penetrates into the resin layer, and a coating film containing the remaining raw material monomer is formed on the surface of the resin layer, forming a precursor layer. That is, the precursor layer is composed of a permeation precursor layer, in which the raw material monomer penetrates into the resin layer and becomes a permeation layer in the subsequent electron beam irradiation process, and a lubricating precursor layer, which is formed on the surface of the resin layer and becomes a lubricating layer in the subsequent electron beam irradiation process.

[0085] In this process, the substrate, resin layer, and coating portion of the resin layer are the same as those described above, and therefore will not be described here. Before applying the coating liquid, the surface of the resin layer may be pre-treated (pre-treatment process) by electron beam irradiation, plasma irradiation, ultraviolet irradiation, corona discharge treatment, oxidation, or the like. In particular, it is preferable to hydrophilize the resin layer surface by electron beam irradiation or plasma irradiation. This improves the wettability of the coating liquid to the resin layer surface, further promoting the penetration of the raw material monomer into the resin layer. That is, the precursor layer formation process preferably includes performing electron beam irradiation or plasma irradiation on at least a portion of the resin layer of a substrate having a resin layer on its surface. Furthermore, the precursor layer formation process preferably includes performing electron beam irradiation on at least a portion of the resin layer of a substrate having a resin layer on its surface.

[0086] When electron beam irradiation treatment is performed as a pretreatment step, the dose of electron beams irradiated onto the substrate (resin layer) is preferably 10 to 200 kGy, more preferably 30 to 100 kGy. The acceleration voltage is preferably 20 to 100 kV, more preferably 40 to 70 kV. The irradiation temperature is preferably 10 to 80°C, more preferably 20 to 40°C. The electron beam irradiation treatment may be performed in an inert gas atmosphere such as a nitrogen gas atmosphere or an argon gas atmosphere.

[0087] The method for applying (coating) the coating liquid to the surface of the resin layer is not particularly limited, and conventionally known methods can be applied, such as coating / printing, immersion (dipping, dip coating), spraying (spraying), spin coating, mixed solution impregnated sponge coating, bar coating (e.g., wire bar method), die coating, reverse coating, comma coating, gravure coating, doctor knife method, etc. Of these, immersion (dipping, dip coating), spraying (spraying), die coating, and bar coating are preferably used.

[0088] When it is difficult to apply the coating liquid only to the desired portion (part of the resin layer), the portion that does not need to form the precursor layer can be protected (coated, etc.) with a suitable removable (attachable) member or material, and then the coating liquid can be applied to the resin layer to form the precursor layer on the resin layer. After that, the protective member (material) of the portion that does not need to form the lubricating layer can be removed, thereby forming the precursor layer in the desired portion of the resin layer. However, the present invention is not limited to these formation methods, and the precursor layer can be formed by appropriately using a conventionally known method.

[0089] The amount of coating liquid to be applied is preferably selected so that the thickness (dry film thickness) of the resulting lubricating layer and permeation layer falls within the above range.

[0090] Next, the precursor layer formed above is dried if necessary to form the precursor layer into a resin layer. It is preferable to perform a drying process when the coating liquid further contains a solvent. The drying process includes natural drying or heat treatment, but natural drying is preferable. When natural drying is performed, the drying time is, for example, 1 minute to 5 hours, preferably 2 to 60 minutes, and more preferably 3 to 20 minutes.

[0091] Furthermore, when heat treatment is performed to remove the solvent, the conditions for the heat treatment can be appropriately selected depending on the type of solvent, etc. For example, the heat treatment temperature is preferably 10 to 50°C. The heat treatment time can be 10 seconds to 5 hours. Under the above conditions, the solvent can be efficiently removed and a precursor layer can be formed in the resin layer. Furthermore, by performing heat treatment, it is possible to promote the penetration of the raw material monomer into the resin layer. In this case, the heat treatment temperature can be about 40 to 60°C. The heat treatment time can be about 10 seconds to 5 minutes. Under these conditions, the raw material monomer can be efficiently penetrated into the resin layer.

[0092] The pressure conditions in the drying step are not particularly limited, and the drying step may be carried out under normal pressure (atmospheric pressure), or may be under increased or reduced pressure. As the drying means (apparatus), for example, an oven or a reduced-pressure dryer can be used, but in the case of natural drying, no particular drying means (apparatus) is required.

[0093] (II) Electron Beam Irradiation Step: In this step, the precursor layer formed in (I) above is irradiated with an electron beam. This polymerizes and crosslinks the raw material monomers in the precursor layer, and the lubricating precursor layer and penetrating precursor layer that make up the precursor layer become a lubricating layer and a penetrating layer, respectively. Furthermore, electron beam irradiation randomly copolymerizes N-(2-hydroxyethyl)acrylamide and a monofunctional monomer. Specifically, electron beam irradiation causes excitation and ionization of the raw material monomer, generating radicals. These radicals in the raw material monomer act as polymerization initiation radicals, undergoing a sequential reaction, resulting in polymerization and the formation of a hydrophilic random copolymer. That is, this step forms a hydrophilic random copolymer with N-(2-hydroxyethyl)acrylamide. Hereinafter, the "hydrophilic random copolymer" formed in this step will also be referred to simply as "hydrophilic copolymer." Furthermore, it is possible to determine whether the hydrophilic copolymer formed is a copolymer of the raw material monomers by analysis using infrared spectrum analysis, pyrolysis GC-MS (gas chromatography-mass spectrometry), or time-of-flight secondary ion mass spectrometry (TOF-SIMS).

[0094] The hydrophilic copolymer formed by electron beam irradiation of the raw material monomers present in the lubricating precursor layer exhibits excellent lubricity when wet. Therefore, a lubricating layer containing this hydrophilic copolymer can exhibit excellent lubricity (sliding properties). Furthermore, electron beam irradiation simultaneously causes crosslinking between hydrophilic copolymers in the lubricating precursor layer. Therefore, the lubricating layer has high film density and can also exhibit excellent durability (especially sliding durability). In the permeation precursor layer, electron beam irradiation of the raw material monomers present in the permeation precursor layer produces a hydrophilic copolymer, and crosslinking (chemical reaction) occurs between the hydrophilic copolymers and between the hydrophilic copolymer and the resin material. In addition, because electron beam irradiation polymerization is highly reactive, the hydrophilic copolymer is polymerized, increasing the chain length of the hydrophilic copolymer. Therefore, the raw material monomers present in the lubricating precursor layer and the permeation precursor layer are easily polymerized across both layers to form a hydrophilic copolymer. The hydrophilic copolymer present across both layers forms crosslinks (chemical bonds) with the hydrophilic copolymer present across both layers, the hydrophilic copolymer present only in the lubricating layer or the permeation layer, and even the resin material present in the permeation layer. Therefore, this process firmly bonds the resin layer and the lubricating layer via the permeation layer. Therefore, medical devices having the above configuration can exhibit excellent durability (especially sliding durability). The polymerization rate (reaction rate) can be evaluated by using FTIR (Fourier Transform Infrared Spectroscopy) to evaluate the structural changes (specifically, the CH stretching at the C forming the double bond) that occur when the double bonds of the raw material monomer disappear due to polymerization by electron beam irradiation.

[0095] In this process, in order to achieve both good lubricity and durability, it is important to appropriately adjust the irradiation dose of the electron beam irradiated to the precursor layer. Specifically, the irradiation dose of the electron beam irradiated to the precursor layer is preferably more than 0 kGy and less than 200 kGy. That is, in a preferred embodiment of the present invention, the precursor layer is irradiated with the electron beam at an irradiation dose of more than 0 kGy and less than 200 kGy. The irradiation dose of the electron beam irradiated to the precursor layer is preferably 10 kGy or more and less than 200 kGy, more preferably more than 10 kGy and less than 200 kGy, even more preferably 20 kGy or more and less than 100 kGy, and particularly preferably 20 kGy or more and less than 100 kGy. With such an irradiation dose, the electron beam polymerization of the raw material monomer and the crosslinking between the hydrophilic copolymer or between the hydrophilic copolymer and the resin material can be carried out in an appropriate balance.

[0096] Other conditions for electron beam irradiation are appropriately selected taking into consideration the types of raw material monomers and resin materials used, etc. For example, the irradiation temperature is preferably 10 to 80°C, more preferably 20 to 40°C. The acceleration voltage is preferably 30 to 200 kV, more preferably 30 to 100 kV.

[0097] Electron beam irradiation is performed at room temperature and does not require heating. Therefore, it can be used suitably even on substrates with low heat resistance. Furthermore, since it does not require the use of a polymerization initiator, it is also highly preferable in terms of the biological safety required for medical devices. Note that polymerization and crosslinking by electron beam irradiation terminates when the radicals are deactivated by recombination of two radicals (recombination termination) or hydrogen transfer between two radicals (disproportionation termination).

[0098] If the lubricating layer contains other components in addition to the hydrophilic copolymer, a step of applying a coating liquid containing the other components to the lubricating layer may be further performed after the electron beam irradiation step (II). This step can prevent the loss of functionality of the other components, compared to the method of forming a lubricating layer using a coating liquid containing the other components together with the raw material monomers described in the precursor layer formation step (I). The other components used in this step are the same as those described above, so their description is omitted here. The solvent contained in the coating liquid containing the other components is not particularly limited as long as it does not dissolve the lubricating layer, but it is preferable that it be able to sufficiently dissolve or disperse the other components. The method for preparing the coating liquid containing the other components is not particularly limited, and known methods such as mixing the other components and solvents can be used. The concentration is also not particularly limited, and is appropriately selected depending on the function of the other components used. Furthermore, the method for applying the coating liquid containing the other components to the lubricating layer is not particularly limited, and the same application methods as those described in the precursor layer formation step (I) can be used.

[0099] [Uses of Medical Devices] The lubricating layer of the medical device according to the present invention has excellent lubricity and durability. Therefore, when the lubricating layer of the medical device according to the present invention comes into contact with body fluids such as blood or aqueous liquids such as physiological saline, it exhibits lubricity, improving the operator's operability and reducing damage to tissue mucosa. Specific examples of medical devices include catheters, stent delivery systems, and guidewires used to improve stenoses or obstructions in biological lumens such as blood vessels (e.g., cerebral blood vessels, coronary arteries, etc.), bile ducts, tracheas, esophagus, and urethra. That is, in one embodiment of the present invention, the medical device is a catheter, stent delivery system, or guidewire. Other examples of medical devices include the following:

[0100] (a) Catheters inserted or left in the digestive tract via the mouth or nose, such as gastric catheters, nutritional catheters, and tube feeding tubes; (b) Catheters inserted or left in the airway or trachea via the mouth or nose, such as oxygen catheters, oxygen cannulas, endotracheal tube tubes and cuffs, tracheostomy tube tubes and cuffs, and endotracheal suction catheters; (c) Catheters inserted or left in the urethra or ureter, such as urethral catheters, urinary catheters, and urethral balloon catheter catheters and balloons; (d) Catheters inserted or left in various body cavities, organs, and tissues, such as suction catheters, drainage catheters, and rectal catheters; (e) Catheters inserted or left in blood vessels, such as indwelling needles, IVH catheters, thermodilution catheters, angiography catheters, vasodilator catheters, and dilators or introducers, or guide wires, stylets, etc. for these catheters; (f) artificial tracheas, artificial bronchi, etc. (g) Medical devices for extracorporeal circulation therapy (artificial lungs, artificial hearts, artificial kidneys, etc.) and their circuits.

[0101] 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, and examples obtained by appropriately combining the technical means disclosed in each example are also included in the scope of the present invention. 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.

[0102] Example 1 A 1 mm thick press sheet (nylon elastomer sheet; hereinafter also referred to as "ELG5660") made of polyamide elastomer (Grilflex (registered trademark) ELG5660, manufactured by EMS) was prepared as a substrate. One side of the nylon elastomer sheet was subjected to pretreatment (hydrophilization treatment) by irradiating it with an electron beam under a nitrogen gas atmosphere at an acceleration voltage of 50 kV and an irradiation dose of 70 kGy.

[0103] N-(2-hydroxyethyl)acrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter also referred to as "HEAA") and N,N-dimethylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter also referred to as "DMAA") were mixed and stirred so that the molar ratio (HEAA / DMAA) of N-(2-hydroxyethyl)acrylamide and N,N-dimethylacrylamide was 8 / 2, to obtain a coating liquid. The coating liquid was applied to the electron beam irradiated surface of the nylon elastomer sheet using a wire bar (number: OSP-04). The coating liquid was in a liquid state at room temperature (25°C).

[0104] Next, using an electron beam irradiation device (I-Compact EB (registered trademark) manufactured by Iwasaki Electric Co., Ltd.), the coated surface was irradiated with electron beams under conditions of an acceleration voltage of 50 kV and an irradiation dose of 20 kGy in a nitrogen gas atmosphere 3 minutes after the coating, thereby obtaining Sample 1.

[0105] Observation of the cross section of the obtained Sample 1 with a transmission electron microscope (TEM) confirmed that Sample 1 had a three-layer structure. Furthermore, analysis of Sample 1 in the thickness direction from the coated surface side using time-of-flight secondary ion mass spectrometry (TOF-SIMS) confirmed that only the hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide was present in the layer on the coated surface side (first layer), that the hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide and the resin (polyamide elastomer) constituting the substrate (resin layer) were mixed in the middle layer (second layer), and that only the resin constituting the substrate (resin layer) was present in the layer furthest from the coated surface (third layer). These results confirmed that Sample 1 has a structure in which a penetration layer (second layer) containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, and a lubricating layer (first layer) composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide are sequentially formed on a substrate (a nylon elastomer sheet serving as a resin layer) (third layer). Furthermore, the presence of the penetration layer (second layer) indicates that the polyamide elastomer constituting the substrate functions as the resin layer in the present invention.

[0106] Example 2 Sample 2 was obtained in the same manner as in Example 1, except that the coating solution was prepared by changing the molar ratio of the monomers (HEAA / DMAA) contained in the coating solution to 6 / 4. The coating solution was in a liquid state at room temperature (25°C).

[0107] The obtained Sample 2 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 2 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, and a lubrication layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0108] Example 3 Sample 3 was obtained in the same manner as in Example 1, except that the molar ratio (HEAA / DMAA) of the monomers contained in the coating solution was changed to 4 / 6. The coating solution was in a liquid state at room temperature (25°C).

[0109] The obtained Sample 3 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. Cross-sectional TEM images obtained by TEM observation of Sample 3 are shown in FIGS. 1A and 1B. As a result, it was confirmed that Sample 3 has a structure in which a permeation layer (thickness (dry film thickness): approximately 1.4 μm) containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, and a lubrication layer (thickness (dry film thickness): approximately 3.5 μm) composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, are sequentially formed on the substrate (a nylon elastomer sheet serving as a resin layer), respectively. It was also confirmed that Samples 4 to 5 obtained in the following Examples 4 to 5 have the same structure (layer configuration) as described above.

[0110] Example 4 Sample 4 was obtained in the same manner as in Example 3, except that the electron beam irradiation conditions after application of the coating liquid were changed to a dose of 50 kGy.

[0111] Example 5 Sample 5 was obtained in the same manner as in Example 3, except that the electron beam irradiation conditions after application of the coating liquid were changed to a dose of 150 kGy.

[0112] Example 6 Sample 6 was obtained in the same manner as in Example 1, except that the molar ratio (HEAA / DMAA) of the monomers contained in the coating solution was changed to 2 / 8. The coating solution was in a liquid state at room temperature (25°C).

[0113] The obtained Sample 6 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 6 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, and a lubrication layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0114] Example 7 Sample 7 was obtained in the same manner as in Example 1, except that N,N-diethylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter, also referred to as "DEAA") was used instead of N,N-dimethylacrylamide. The coating liquid in this example was in a liquid state at room temperature (25°C).

[0115] The obtained Sample 7 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 7 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide, and a lubrication layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0116] Example 8 Sample 8 was obtained in the same manner as in Example 7, except that the molar ratio (HEAA / DEAA) of the monomers contained in the coating solution was changed to 6 / 4. The coating solution was in a liquid state at room temperature (25°C).

[0117] The obtained Sample 8 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 8 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide, and a lubricating layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0118] Example 9 Sample 9 was obtained in the same manner as in Example 7, except that the molar ratio (HEAA / DEAA) of the monomers contained in the coating solution was changed to 4 / 6. The coating solution was in a liquid state at room temperature (25°C).

[0119] The obtained Sample 9 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 9 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide, and a lubrication layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0120] Example 10 Sample 10 was obtained in the same manner as in Example 1, except that 2-methoxyethyl acrylate (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter, also referred to as "MEA") was used instead of N,N-dimethylacrylamide. The coating liquid in this example was in a liquid state at room temperature (25°C).

[0121] The obtained Sample 10 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 10 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-2-methoxyethyl acrylate, and a lubricating layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-2-methoxyethyl acrylate were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0122] Example 11 Sample 11 was obtained in the same manner as in Example 10, except that the coating solution was prepared by changing the molar ratio (HEAA / MEA) of the monomers contained in the coating solution to 6 / 4. The coating solution was in a liquid state at room temperature (25°C).

[0123] The obtained Sample 11 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 11 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-2-methoxyethyl acrylate, and a lubricating layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-2-methoxyethyl acrylate were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0124] Example 12 Sample 12 was obtained in the same manner as in Example 10, except that the molar ratio (HEAA / MEA) of the monomers contained in the coating solution was changed to 4 / 6. The coating solution was in a liquid state at room temperature (25°C).

[0125] The obtained Sample 12 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 12 had a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-2-methoxyethyl acrylate, and a lubricating layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-2-methoxyethyl acrylate were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0126] Example 13 A polyester film with a primer layer (resin layer) (Cosmoshine (registered trademark) A4160, manufactured by Toyobo Co., Ltd.; hereinafter also referred to as "A4160") was prepared as a substrate.

[0127] N-(2-hydroxyethyl)acrylamide (HEAA, manufactured by Tokyo Chemical Industry Co., Ltd.) and N,N-dimethylacrylamide (DMAA, manufactured by Tokyo Chemical Industry Co., Ltd.) were mixed and stirred so that the molar ratio (HEAA / DMAA) of N-(2-hydroxyethyl)acrylamide and N,N-dimethylacrylamide was 7 / 3, to obtain a coating liquid. This coating liquid was applied onto the primer layer of the A4160 using a wire bar (number: OSP-04). The coating liquid was in a liquid state at room temperature (25°C).

[0128] Next, using an electron beam irradiation device (I-Compact EB (registered trademark) manufactured by Iwasaki Electric Co., Ltd.), the coated surface was irradiated with electron beams under conditions of an acceleration voltage of 50 kV and an irradiation dose of 20 kGy in a nitrogen gas atmosphere 3 minutes after the coating, thereby obtaining Sample 13.

[0129] The obtained Sample 13 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 13 has a structure in which a permeation layer containing a mixture of the resin constituting the primer layer and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, and a lubricating layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide are sequentially formed on a substrate layer (polyester film). Therefore, since the permeation layer is formed, it can be said that the primer layer functions as the resin layer in the present invention. Furthermore, it was confirmed that Sample 14 obtained in the following Example 14 has the same structure (layer configuration) as described above.

[0130] Example 14 Sample 14 was obtained in the same manner as in Example 13, except that the molar ratio of the monomers (HEAA / DMAA) contained in the coating solution was changed to 5 / 5. The coating solution was in a liquid state at room temperature (25°C).

[0131] Example 15 Sample 15 was obtained in the same manner as in Example 13, except that the molar ratio of the monomers (HEAA / DMAA) contained in the coating solution was changed to 3 / 7. The coating solution was in a liquid state at room temperature (25°C).

[0132] The obtained Sample 15 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, Sample 15 was confirmed to have a structure in which a penetration layer (thickness (dry film thickness): about 0.1 μm) containing a mixture of the resin constituting the primer layer and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide, and a lubricating layer (thickness (dry film thickness): about 4.5 μm) composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-dimethylacrylamide are sequentially formed on the base layer (polyester film). Therefore, since a penetration layer having the above thickness (about 0.1 μm) is formed, it can be said that the primer layer functions as the resin layer in the present invention.

[0133] Example 16 Sample 16 was obtained in the same manner as in Example 15, except that N,N-diethylacrylamide (DEAA, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of N,N-dimethylacrylamide. The coating liquid in this example was in a liquid state at room temperature (25°C).

[0134] The obtained Sample 16 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 16 had a structure in which a permeation layer containing a mixture of the resin constituting the primer layer and a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide, and a lubricating layer composed of a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide-N,N-diethylacrylamide were sequentially formed on a base layer (polyester film).

[0135] Comparative Example 1 Sample C1 was obtained in the same manner as in Example 1, except that the molar ratio (HEAA / DMAA) of the monomers contained in the coating solution was changed to 10 / 0 (i.e., the coating solution was prepared without using DMAA). The coating solution was in a liquid state at room temperature (25°C).

[0136] Comparative Example 2 Sample C2 was obtained in the same manner as in Example 1, except that the molar ratio of the monomers (HEAA / DMAA) contained in the coating solution was changed to 0 / 10 (i.e., the coating solution was prepared without using HEAA). Note that the coating solution was in a liquid state at room temperature (25°C).

[0137] Comparative Example 3 Sample C3 was obtained in the same manner as in Example 3, except that the coating solution was prepared using N-(2-hydroxyethyl)methacrylamide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; hereinafter also referred to as "HEMA") instead of N-(2-hydroxyethyl)acrylamide. The coating solution in this comparative example was liquid at room temperature (25°C).

[0138] Comparative Example 4 Sample C4 was obtained in the same manner as in Comparative Example 3, except that the electron beam irradiation conditions after application of the coating liquid were changed to a dose of 200 kGy.

[0139] Comparative Example 5 Sample C5 was obtained in the same manner as in Example 1, except that the composition of the coating liquid and the application conditions for the coating liquid were changed as follows: N-(2-hydroxyethyl)acrylamide and N,N'-methylenebis(acrylamide) (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter also referred to as "N,N'-methylenebisAA") were used as solutes, and a coating liquid was obtained by dissolving them in ethanol so that the total concentration was 5 mass%. At this time, the molar ratio of the above monomers (HEAA / N,N'-methylenebisAA) was adjusted to 9 / 1. The above coating liquid was in a liquid state at room temperature (25°C).

[0140] In addition, when applying the coating liquid, a wire bar (number: #36) was used, and after application, the coating was allowed to dry naturally for 1 minute. After confirming that the solvent ethanol had evaporated, the coated surface was irradiated with an electron beam 3 minutes later.

[0141] Comparative Example 6 Sample C6 was obtained in the same manner as in Example 3, except that 4-hydroxybutyl acrylate (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter, also referred to as "HBA") was used instead of N,N-dimethylacrylamide. The coating liquid in this comparative example was liquid at room temperature (25°C).

[0142] Comparative Example 7 Sample C7 was obtained in the same manner as in Example 3, except that N-butylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter, also referred to as "BAA") was used instead of N,N-dimethylacrylamide. The coating liquid was in a liquid state at room temperature (25°C).

[0143] Comparative Example 8 Sample C8 was obtained in the same manner as in Example 3, except that the substrate was changed to a SUS plate (manufactured by Misumi Corporation: length 20 mm × width 50 mm × thickness 0.5 mm) and pretreatment (hydrophilization treatment) was not performed.

[0144] The film-forming properties of Samples 1 to 16 and C1 to C8 obtained above were evaluated according to the following method. The results are shown in Table 2 below. Table 2 also lists the type of substrate for each sample obtained above, whether the substrate was pretreated, and the conditions for forming the lubricating layer (type and molar ratio of monomers, and electron beam irradiation conditions). In Table 2 below, the numbers in parentheses for "Pretreatment (kV-kGy)" indicate the acceleration voltage (kV) and dose (kGy) during electron beam irradiation as pretreatment. For example, the electron beam irradiation conditions for pretreatment in Example 1 indicate an acceleration voltage of 50 kV and a dose of 70 kGy. Furthermore, in Table 2 below, "Irradiation conditions (kV-kGy)" indicate the acceleration voltage (kV) and dose (kGy) during electron beam irradiation after application of the coating liquid. For example, the electron beam irradiation conditions in Example 1 indicate an acceleration voltage of 50 kV and a dose of 20 kGy.

[0145] [Film-forming property evaluation] The coated surface of each sample was observed after electron beam irradiation. When the coating liquid was cured and the coating surface was uniform, the film-forming property was judged to be good ("A" in Table 2 below). When the coating surface was uniform but the coating liquid was not sufficiently cured and the coating surface felt tacky (sticky), the result was judged to be "B" in Table 2 below. Here, "the coating liquid is cured" refers to a state in which the coating liquid does not adhere to the hand when the surface is touched. Furthermore, "the coating surface is uniform" refers to a state in which the coating surface was visually inspected and no repelling or bumps were observed.

[0146] All samples exhibited good film-forming properties.

[0147] [Sensory Evaluation] Each sample was evaluated for lubricity and lubrication maintenance (durability) according to the following method. The results are shown in Table 2 below: Each sample was immersed in water so that the lubricating layer (coated surface) was submerged. After 1 minute, while still immersed in water, the coated surface was rubbed with the pad of a finger 30 times in the longitudinal direction over a width of approximately 5 cm. The slipperiness was evaluated after the fifth rubbing stroke ("Slipperiness" in Table 2 below) and the 30th rubbing stroke ("Durability" in Table 2 below). The rubbing strength and speed were kept as similar as possible between samples. The slipperiness (lubricity) after the fifth rubbing stroke and the slipperiness (durability) after the 30th rubbing stroke were evaluated according to the criteria in Table 1 below. As a guideline for the evaluation criteria for slipperiness, the resistance value after the fifth rubbing stroke measured with a Tribomaster sliding tester in the "Sliding Durability Evaluation" section described below is also listed.

[0148]

[0149] [Sliding Durability Evaluation] For samples (example samples) that received an "A" or "B" rating for both sliding property and durability in the sensory evaluation, the sliding durability of the lubricating layer was evaluated according to the following method. The results are shown in Table 2 below. A friction tester (Handy Tribomaster TL201, manufactured by Trinity Lab Co., Ltd.) 10 shown in FIG. 2 was used. Each evaluation sample 3 was fixed in a petri dish 2 with the lubricating layer (coated surface) facing up, and immersed in water 1 to a height sufficient to completely immerse the evaluation sample 3. This petri dish 2 was placed on the moving table 6 of the friction tester 10 shown in FIG. 2. A terminal (φ10 mm) 4 made of hydrogenated styrene-based thermoplastic elastomer (SEBS) was brought into contact with the evaluation sample 3, and a load 5 of 100 g was applied to the terminal. At this time, the sliding distance was set to 15 mm, the sliding speed was set to 16.7 mm / sec, and the moving table 6 was moved back and forth horizontally 20 times, and the sliding resistance values ​​(gf) were measured on the first reciprocation (1st time), the fifth reciprocation (5th time), and the 20th reciprocation (20th time).

[0150]

[0151]

[0152] From the results in Table 2, it can be seen that the samples of the examples can achieve both lubricity (sliding properties) and durability compared to the samples of the comparative examples. In comparative example 1, a lubricating layer is formed without using a monofunctional monomer (at least one selected from the monomer of formula (1) and MEA). As a result, in comparative example 1, the film-forming properties of the lubricating layer were good, but the formed lubricating layer peeled off in the sensory evaluation of durability. In comparative example 2, a lubricating layer is formed without using HEAA. As a result, in comparative example 2, the film-forming properties of the lubricating layer were good, but sufficient slip properties (lubricity) could not be obtained. From the above, it can be said that both HEAA and a monofunctional monomer are essential as monomers constituting a hydrophilic copolymer in order to form a lubricating layer excellent in lubricity (sliding properties) and durability.

[0153] Furthermore, when N-(2-hydroxyethyl) methacrylamide (HEMA) was used instead of HEAA, as in Comparative Example 3, the durability of the lubricating layer deteriorated. In this case, the reason for the decreased durability of the lubricating layer in Comparative Example 3 was predicted to be insufficient curing of the raw material monomer. Therefore, in Comparative Example 4, the electron beam irradiation dose during curing was increased compared to Comparative Example 3, but sufficient durability of the lubricating layer was not obtained. This is thought to be because radical polymerization did not proceed sufficiently when HEMA was used. This is presumably because methacrylamide-based monomers (methacryloyl groups) have a smaller reaction rate constant for radical polymerization upon electron beam irradiation than acrylamide-based monomers (acryloyl groups), making electron beam polymerization less likely to proceed. From the above results, it is considered that HEAA is necessary as a monomer constituting the hydrophilic copolymer.

[0154] In Comparative Example 5, a sample was prepared using a bifunctional monomer (N,N'-methylenebis(acrylamide)) instead of a monofunctional monomer (at least one selected from the monomer of formula (1) and MEA). As a result, Comparative Example 5 had inferior slipperiness compared to Examples 1 to 12. This is presumably because electron beam polymerization proceeds via the acryloyl groups at both ends, resulting in the hydrophilic copolymer forming the lubricating layer having a denser three-dimensional network structure, reducing the swelling of the lubricating layer. From the above, it is considered that in order to improve the lubricity of the lubricating layer, the monomers constituting the hydrophilic copolymer must be monofunctional.

[0155] In Comparative Example 6, 4-hydroxybutyl acrylate was used instead of the monofunctional monomer (at least one selected from the monomer of formula (1) and MEA), but the slipperiness (lubricity) was reduced compared to Examples 10 to 12. In contrast, Examples 10 to 12, which used the same substrate as Comparative Example 6 but a monofunctional monomer, all resulted in excellent slipperiness (lubricity) and durability. Therefore, when the monofunctional monomer is an acrylic acid ester, it is considered that the monofunctional monomer is preferably 2-methoxyethyl acrylate (MEA), which does not have a hydroxyl group at the terminal of the ester group and has a small number of carbon atoms in the ester group.

[0156] In Comparative Example 7, N-butylacrylamide was used instead of the monofunctional monomer (at least one selected from the monomer of formula (1) and MEA), but the slipperiness (lubricity) was reduced compared to Examples 1 to 9. In contrast, Examples 1 to 9, which used the same substrate as Comparative Example 7 and DMAA or DEAA as the monofunctional monomer, all resulted in excellent slipperiness (lubricity) and durability. Therefore, it is considered that in the monomer of formula (1), the substituent on the nitrogen must be a methyl group or an ethyl group.

[0157] Examples 1, 7, and 10 used ELG5660 as the substrate and DMAA, DEAA, and MEA as the monomers, respectively. The molar ratio of HEAA was the same at 80 mol% in all cases. A comparison of these revealed that the sliding resistance values ​​decreased in the order of DMAA, DEAA, and MEA. A comparison of Examples 2, 8, and 11, in which the molar ratio of HEAA was 60 mol%, and Examples 3, 9, and 12, in which the molar ratio of HEAA was 40 mol%, also revealed that the sliding resistance values ​​decreased in the order of DMAA, DEAA, and MEA.

[0158] Furthermore, in Examples 15 and 16, A4160 was used as the base material and DMAA and DEAA were used as the monomers, respectively, but the molar ratio of HEAA was the same at 30 mol %. Comparing these, it was found that the sliding resistance value decreased in the order of DMAA and DEAA.

[0159] From the above, it can be said that in order to form a lubricating layer with better lubricity, the types of monomers that are most preferable are DMAA, DEAA, and MEA in that order.

[0160] Examples 1 to 3 and 6 were similar in condition except for the HEAA / DMAA molar ratio. From these comparisons, it is considered that when the content of DMAA-derived structural units in the hydrophilic copolymer is 25 mol% or more and 60 mol% or less, a lubricating layer with particularly excellent slip properties and durability can be formed. Among these, it was found that Example 3, in which the content of DMAA-derived structural units is 40 mol%, had the lowest sliding resistance value.

[0161] Examples 13 to 16 are examples in which A4160 was used as the substrate. Compared to when ELG5660 was used as the substrate, Examples 13 to 16 tended to have lower sliding resistance, i.e., improved slipperiness (lubricity). From a structural perspective, these examples differ in the thickness of the penetration layer and lubricating layer. Specifically, as described above, Example 3 (substrate: ELG5660) had a penetration layer thickness (dry film thickness) of approximately 1.4 μm and a lubricating layer thickness (dry film thickness) of approximately 3.5 μm (lubricating layer thickness / penetration layer thickness = 3.5 / 1.4 = 2.5 times), while Example 15 (substrate: A4160) had a lubricating layer thickness (dry film thickness) of approximately 4.5 μm and a penetration layer thickness (dry film thickness) of approximately 0.1 μm (lubricating layer thickness / penetration layer thickness = 4.5 / 0.1 = 45 times). From these comparisons, it can be inferred that the greater the lubricating layer thickness relative to the penetration layer thickness, the greater the improvement in lubricity. Therefore, it is considered that better lubrication can be obtained by making the thickness of the lubricating layer larger than that of the penetration layer (lubricating layer thickness > penetration layer thickness), and further by making the thickness of the lubricating layer at least twice that of the penetration layer. Furthermore, from Example 15, it is considered that excellent durability can be obtained by making the penetration layer at least 0.1 μm thick.

[0162] Examples 3 to 5 were tested under similar conditions except for the electron beam irradiation dose. As is clear from Table 2, in Examples 3 to 5, increasing the electron beam irradiation dose resulted in a decrease in slipperiness. This is presumably because increasing the electron beam irradiation dose increases the polymerization rate (reaction rate) of the raw material monomers and promotes crosslinking between hydrophilic copolymers, resulting in a denser three-dimensional network structure and a decrease in the swelling property of the lubricating layer. For this reason, from the perspective of improving the lubricity of the lubricating layer, it is considered preferable to use a low electron beam irradiation dose (particularly less than 200 kGy).

[0163] Example 3 and Comparative Example 8 were conducted under similar conditions except for the substrate. Comparative Example 8 showed inferior results in both slipperiness and durability compared to Example 3. This is presumably because the HEAA and DMAA did not penetrate into the SUS substrate used in Comparative Example 8, making it impossible to form a penetration layer, resulting in poor adhesion between the lubricating layer and the substrate. From the above, it is considered that the substrate needs to have a resin layer on at least the surface into which the monomer penetrates.

[0164] This application is based on Japanese Patent Application No. 2024-123428, filed on July 30, 2024, the disclosure of which is incorporated by reference in its entirety.

[0165] 1 Water, 2 Petri dish, 3 Evaluation sample, 4 Thermoplastic elastomer terminal, 5 Load, 6 Moving table, 10 Friction measuring device

Claims

1. A medical device comprising a substrate having a resin layer on its surface, and a lubricating layer formed on at least a portion of the resin layer, wherein the lubricating layer comprises a hydrophilic copolymer of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from a monomer represented by the following formula (1) and 2-methoxyethyl acrylate: In the formula (1), R １ and R ２ each independently represents a methyl group or an ethyl group, and the resin layer has a penetration layer on the lubricating layer side, in which the hydrophilic copolymer and the resin material that forms the resin layer are mixed.

2. The medical device according to claim 1, wherein the content of the structural unit a1 in the hydrophilic copolymer is 20 mol % or more and 80 mol % or less, when the total number of moles of the structural unit a1 derived from N-(2-hydroxyethyl)acrylamide and the number of moles of the structural unit a2 derived from the monofunctional monomer is taken as 100 mol %.

3. The medical device according to claim 1, wherein the monofunctional monomer is N,N-dimethylacrylamide.

4. The medical device according to claim 3, wherein the content of structural unit a1 in the hydrophilic copolymer is 25 mol % or more and 60 mol % or less, when the total number of moles of the structural unit a1 derived from N-(2-hydroxyethyl)acrylamide and the number of moles of the structural unit a2 derived from N,N-dimethylacrylamide is taken as 100 mol %.

5. The medical device according to claim 1, wherein the thickness of the lubricating layer is greater than the thickness of the permeation layer.

6. The medical device according to claim 5, wherein the thickness of the lubricating layer is at least twice the thickness of the permeation layer.

7. The medical device according to claim 1, wherein the hydrophilic copolymer is substantially free of structural units derived from polyfunctional (meth)acrylates and polyfunctional (meth)acrylamides.

8. The medical device according to claim 1, wherein the hydrophilic copolymer is composed of N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the monomer represented by formula (1) and 2-methoxyethyl acrylate.

9. The medical device according to claim 1, wherein the lubrication layer does not contain a polymerization initiator and its residue.

10. The medical device of claim 1, wherein the medical device is a catheter, a stent delivery system, or a guidewire.

11. A coating liquid containing N-(2-hydroxyethyl)acrylamide and at least one monofunctional monomer selected from the group consisting of a monomer represented by the following formula (1) and 2-methoxyethyl acrylate is prepared; In the formula (1), R １ and R ２ each independently represent a methyl group or an ethyl group; applying the coating liquid to at least a part of a surface of a resin layer of a substrate having a resin layer on its surface, thereby causing the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer to penetrate into the resin layer and forming a precursor layer on at least a part of the resin layer; and irradiating the precursor layer with an electron beam to polymerize the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer, thereby forming a lubricating layer formed on the surface of the resin layer and containing a hydrophilic copolymer of the N-(2-hydroxyethyl)acrylamide and the monofunctional monomer, and a permeation layer located on at least a part of the resin layer on the lubricating layer side, wherein the resin material forming the resin layer and the hydrophilic copolymer are mixed together.

12. The manufacturing method according to claim 11, wherein the precursor layer is irradiated with an electron beam at a dose of more than 0 kGy and less than 200 kGy.

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