Medical instrument and method for producing same

Abstract

Provided is a medical instrument having a lubricating layer that can exhibit both good lubricity and good durability (and especially sliding durability) using means different from the prior art.　This medical instrument comprises: a substrate having a resin layer on the surface thereof; and a lubricating layer formed on at least a part of the resin layer. The lubricating layer contains a hydrophilic copolymer of acrylamide and at least one monofunctional monomer selected from among monomers represented by formula (1). The resin layer has, on the lubricating layer side, an interpenetrating layer in which the hydrophilic copolymer and a resin material that forms 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 surgeons. 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 contains a hydrophilic copolymer of acrylamide and at least one monofunctional monomer selected from monomers represented by the following formula (1):

[0009]

[0010] In the above formula (1), R １ and R ２each independently represent 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, it is preferable that the monofunctional monomer is at least one selected from the group consisting of N,N-dimethylacrylamide and N,N-diethylacrylamide; 3. In the medical device described in 1. or 2. above, it is preferable that the hydrophilic copolymer contains more structural units a2 derived from the monofunctional monomer than structural units a1 derived from acrylamide; 4. In the medical device described in 3. above, it is preferable that the ratio of the number of moles of structural units a2 contained in the hydrophilic copolymer to the number of moles of structural units a1 contained in the hydrophilic copolymer is more than 1 and less than 3; 5. In the medical device described in any of 1. to 4. above, it is preferable that the thickness of the lubricating layer is greater than the thickness of the penetration layer; 6. In the medical device described in 5. above, it is preferable that the thickness of the lubricating layer is greater than the thickness of the penetration layer; In the medical device described in any one of items 1. to 6. 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)acrylamide; 8. In the medical device described in any one of items 1. to 7. above, the hydrophilic copolymer preferably comprises acrylamide and at least one monofunctional monomer selected from the monomers represented by formula (1) above; 9. In the medical device described in any one of items 1. to 8. above, the lubricating layer preferably does not contain a polymerization initiator or residue thereof; 10. The medical device described in any one of items 1. to 9. above is preferably a catheter, a stent delivery system, or a guidewire.

[0011] Another aspect of the present invention is to provide a coating solution comprising: 11. a coating solution containing acrylamide and at least one monofunctional monomer selected from monomers represented by the following formula (1);

[0012]

[0013] In the above formula (1), R １ and R ２each independently represent a methyl group or an ethyl group, applying the coating liquid to at least a part of the surface of a resin layer of a substrate having a resin layer on its surface, causing the 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 acrylamide and the monofunctional monomer and form a lubricating layer formed on the surface of the resin layer and containing a hydrophilic copolymer of the acrylamide and the monofunctional monomer, and a penetration layer located in at least a part of the resin layer on the lubricating layer side, containing a mixture of the resin material that forms the resin layer and the hydrophilic copolymer; 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] Fig. 1 is a cross-sectional TEM image of the sample obtained in Example 2. Fig. 2 is a schematic diagram of a lubrication maintenance evaluation test device (friction tester). In Fig. 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 the 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 acrylamide and at least one monofunctional monomer selected from monomers represented by the following formula (1):

[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 permeation layer on the lubricating layer side, in which the hydrophilic copolymer and the resin material forming 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 acrylamide and at least one monofunctional monomer selected from the group consisting of monomers represented by formula (1) above; 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 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 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 acrylamide and the monofunctional monomer; and a penetration 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 "hydrophilic copolymer of acrylamide and at least one monofunctional monomer selected from the monomers represented by formula (1)" is also simply referred to as a "hydrophilic copolymer" or a "hydrophilic copolymer according to the present invention."

[0021] As used herein, the range "X to Y" 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)acrylamide" encompasses both acrylamide and methacrylamide.

[0022] 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.

[0023] 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.

[0024] <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 acrylamide and a monomer represented by formula (1). 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 permeation 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 permeation 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 resin material are entangled. Furthermore, in this case, the hydrophilic copolymer may partially straddle the lubricating layer and the permeation layer. Therefore, the resin layer and the lubricating layer are firmly bonded via the permeation layer. Therefore, a medical device having the above configuration can exhibit excellent durability (especially sliding durability).

[0025] 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).

[0026] The above mechanism is speculation and does not limit the technical scope of the present invention.

[0027] 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.

[0028] 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.

[0029] [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.

[0030] 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.

[0031] 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).

[0032] The lubricating layer contains a hydrophilic copolymer of acrylamide and at least one monofunctional monomer selected from monomers represented by the following formula (1): That is, the hydrophilic copolymer contained in the lubricating layer according to the present invention contains a structural unit derived from acrylamide and a structural unit derived from at least one monofunctional monomer selected from monomers represented by the following formula (1): Hereinafter, acrylamide and the monofunctional monomer are collectively referred to as "raw material monomers."

[0033]

[0034] In the above formula (1), R １ and R ２ each independently represents a methyl group or an ethyl group.

[0035] Acrylamide has very high hydrophilicity. Therefore, a hydrophilic copolymer having a structural unit a1 derived from acrylamide (hereinafter also referred to simply as "structural unit a1") has high hydrophilicity. Therefore, a lubricating layer containing this hydrophilic copolymer can exhibit excellent lubricity (sliding property) when wet. In contrast, when the hydrophilic (co)polymer forming the lubricating layer does not contain the structural unit a1, good lubricity (sliding property) cannot be obtained (see Comparative Example 2 described below).

[0036] Furthermore, when methacrylamide is used instead of acrylamide, the film-forming properties of the hydrophilic copolymer and the durability of the lubricating layer are reduced (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 acrylamide and a monomer of formula (1) 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. In this method of electron beam polymerization, the progress of radical polymerization is presumed to be related to the film-forming properties of the hydrophilic copolymer and the durability of the lubricating layer. The acryloyl group (CH ２ ═CH—C(═O)—) has a conjugated structure that stabilizes radicals, so when acrylamide is used, electron beam polymerization proceeds easily. ２ =C(CH ３While the )-C(=O)-) group stabilizes radicals, its radical polymerization reaction rate constant is much smaller than that of an acryloyl group, making electron beam polymerization difficult when methacrylamide is used. Furthermore, while polyacrylate structures generally undergo crosslinking rather than degradation (decomposition) upon electron beam irradiation, polymethacrylate structures are more likely to undergo degradation (decomposition) rather than crosslinking upon electron beam irradiation. Therefore, it is presumed that polymethacrylamides, which have a structure similar to polymethacrylate, are more likely to undergo degradation (decomposition) rather than crosslinking upon electron beam irradiation. Therefore, when methacrylamide monomers are used, even if electron beam polymerization of methacrylamide proceeds upon electron beam irradiation, the decomposition reaction of polymethacrylamide simultaneously proceeds, resulting in insufficient polymerization and crosslinking upon electron beam irradiation, which may result in a decrease in the film-forming properties of the hydrophilic copolymer and the durability of the lubricating layer. Therefore, the hydrophilic copolymer according to the present invention essentially contains a structural unit a1 derived from acrylamide in order to form a lubricating layer with excellent lubricity and durability. For the reasons mentioned above, it is preferable that the hydrophilic copolymer is substantially free of methacrylamide-derived structural units. Here, "the hydrophilic copolymer is substantially free of methacrylamide-derived structural units" means that the content of methacrylamide-derived structural units 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 methacrylamide-derived structural units).

[0037] On the other hand, although acrylamide contributes to good lubricity (and even durability) as described above, acrylamide monomer alone has poor film-forming properties upon electron beam irradiation, making it impossible to form a lubricating layer with a uniform surface. Therefore, even if a polymer containing only the structural unit a1 derived from acrylamide can form a lubricating layer, its durability is insufficient (see Comparative Example 1 described below). In particular, as described above, in the method of forming a lubricating layer by applying a coating liquid containing raw material monomers to a resin layer and then irradiating it with an electron beam (electron beam polymerization), if a coating liquid containing only acrylamide as the raw material monomer is applied, acrylamide is a solid substance at room temperature, so it precipitates on the resin layer, making it impossible to form a uniform lubricating layer. In contrast, it has been found that the use of a monomer of the above formula (1) in combination with acrylamide improves the film-forming properties of the hydrophilic copolymer and makes it possible to form a lubricating layer with a uniform surface.

[0038] The present inventors speculate on this mechanism as follows. The monomer of formula (1) has an amide structure similar to acrylamide, and therefore has a high affinity with acrylamide, while being liquid at room temperature. Therefore, when the monomer of formula (1) and acrylamide are applied to a resin layer, the monomer of formula (1) functions as a solvent, suppressing the precipitation of acrylamide. As a result, a uniform coating film can be formed, and subsequent electron beam irradiation polymerizes these monomers to form a uniform lubricating layer. From the above, the monomer of formula (1) acts as a solvent for acrylamide when applied to a resin layer, and is randomly copolymerized with acrylamide during polymerization. It is speculated that the structure derived from the monomer of formula (1) acts as a crosslinking point that maintains the hydrophilic copolymer of the monomer of formula (1) and acrylamide within 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, in addition to the structural unit a1 derived from acrylamide, a structural unit a2 derived from the monomer of the above formula (1) (hereinafter also simply referred to as "structural unit a2").

[0039] As shown in formula (1), the monomer of formula (1) is monofunctional (having 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 of the lubricating layer. As a result, the swelling (slipperiness) of the lubricating layer is significantly reduced (see Comparative Examples 6 to 8 below). For this reason, it is preferable that the hydrophilic copolymer does not substantially contain structural units derived from polyfunctional (meth)acrylamide. Here, "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)acrylamide" means that the content of structural units derived from polyfunctional (meth)acrylamide 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)acrylamide). 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 no polyfunctional (meth)acrylamide (e.g., N,N'-methylenebis(acrylamide)) is charged to the coating liquid, the content of structural units derived from polyfunctional (meth)acrylamide 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 acrylamide-derived structural units, the structural units derived from the monomer of formula (1), 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).

[0040] In the above formula (1), R １ and R２ 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 (e.g., N-butylacrylamide) is used in which at least one of the substituents is a larger substituent (e.g., an alkyl group having 3 or more carbon atoms), it is not possible to improve lubricity and durability in a balanced manner (Comparative Example 5 described below).

[0041] Specific examples of the monomer (monofunctional monomer) of formula (1) include N,N-dimethylacrylamide, N,N-diethylacrylamide, and N-ethyl-N-methylacrylamide. These monofunctional monomers may be used alone or in combination of two or more. In one embodiment, the monomer (monofunctional monomer) of formula (1) is preferably at least one selected from the group consisting of N,N-dimethylacrylamide and N,N-diethylacrylamide.

[0042] From the viewpoint of forming a lubricating layer having superior lubricity while maintaining good durability, R １ and R ２ It is preferable that at least one of the groups is a methyl group, and it is particularly preferable that all of them are methyl groups (that is, the monomer of formula (1) is N,N-dimethylacrylamide).

[0043] The hydrophilic copolymer has a structural unit a1 derived from acrylamide and a structural unit a2 derived from the monomer (monofunctional monomer) of the above formula (1). Here, the ratio of the structural unit a1 to the structural unit a2 is not particularly limited. Considering further improvements in lubricity (sliding properties) and durability (particularly sliding durability), the hydrophilic copolymer contains the structural unit a2 in a ratio of, for example, 0.5 moles or more, preferably 1 mole or more, per mole of the structural unit a1. From the viewpoint of further improving the durability of the lubricating layer, it is preferable that the hydrophilic copolymer contains more of the structural unit a2 than the structural unit a1 (i.e., the number of moles of the structural unit a1 is less than the number of moles of the structural unit a2). Therefore, the hydrophilic copolymer contains the structural unit a2 in a ratio of more than 1 mole, even more preferably 1.5 moles or more, particularly preferably 1.8 moles or more, and most preferably 2 moles or more, per mole of the structural unit a1. Furthermore, the hydrophilic copolymer contains the structural unit a2 in a ratio of, for example, 4 moles or less, preferably 3 moles or less, more preferably less than 3 moles, particularly preferably 2.5 moles or less, and most preferably 2.3 moles or less, per mole of the structural unit a1.

[0044] In one embodiment of the present invention, the hydrophilic copolymer contains, for example, 0.5 moles or more and 4 moles or less, preferably 1 mole or more and 3 moles or less, more preferably more than 1 mole and 3 moles or less, even more preferably more than 1 mole and less than 3 moles, even more preferably 1.5 moles or more and 2.5 moles or less, particularly preferably 1.8 moles or more and 2.3 moles or less, and most preferably 2 moles or more and 2.3 moles or less, relative to 1 mole of the structural unit a1. That is, in one embodiment of the present invention, the ratio of the number of moles of the structural unit a2 contained in the hydrophilic copolymer to the number of moles of the structural unit a1 contained in the hydrophilic copolymer is, for example, 0.5 or more and 4 or less, preferably 1 or more and 3 or less, more preferably more than 1 and 3 or less, even more preferably more than 1 and less than 3, even more preferably 1.5 or more and 2.5 or less, particularly preferably 1.8 or more and 2.3 or less, and most preferably 2 or more and 2.3 or less. The method for measuring the ratio (molar ratio) of the number of moles of the structural unit a1 and the structural unit a2 contained in the hydrophilic copolymer is as described above. When two or more types of structural unit a2 are present, the molar number of the structural unit a2 refers to the total amount. The molar ratio can be controlled, for example, by adjusting the charge ratio (molar ratio) of each monomer contained in the coating liquid used to form the lubricating layer so that it falls within the above range. When the hydrophilic copolymer contains the structural unit a2 relative to the structural unit a1 at the above molar ratio, the lubricating layer has excellent sliding durability and can exhibit high lubricity.

[0045] In one embodiment of the present invention, the content (composition) of structural unit a1 in hydrophilic copolymer is, for example, 20 mol% or more and 65 mol% or less, preferably 25 mol% or more and 50 mol% or less, more preferably 25 mol% or more and less than 50 mol%, even more preferably more than 25 mol% and less than 50 mol%, even more preferably 28 mol% or more and 40 mol% or less, particularly preferably 30 mol% or more and 35 mol% or less, and most preferably 30 mol% or more and 34 mol% or less.If the content (composition) of structural unit a1 in hydrophilic copolymer is within the above range, the lubricating layer can exhibit high lubricity.

[0046] In one embodiment of the present invention, the content (composition) of the structural unit a2 in the hydrophilic copolymer is, for example, 35 mol% or more and 80 mol% or less, preferably 50 mol% or more and 75 mol% or less, more preferably more than 50 mol% and 75 mol% or less, even more preferably more than 50 mol% and 75 mol% or less, even more preferably more than 50 mol% and 75 mol% or less, even more preferably 60 mol% or more and 72 mol% or less, particularly preferably 65 mol% or more and 70 mol% or less, and most preferably 66 mol% or more and 70 mol% or less.In addition, when two or more structural units a2 are present, the content (composition) of the structural unit a2 refers to the total amount.If the content (composition) of the structural unit a2 in the hydrophilic copolymer is within the above range, the lubricating layer can exhibit high durability.

[0047] The hydrophilic copolymer may be formed solely from the structural unit a1 derived from acrylamide and the structural unit a2 derived from the monomer of formula (1), or may further contain, in addition to the structural unit a1 and the structural unit a2, a structural unit derived from a monomer (other monomer) other than acrylamide and the monomer of formula (1). Examples of the other monomer include N-methylacrylamide, N-ethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminoethyl acrylate, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)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-epoxycyclohexyl acrylate, 2,4-epoxy-2,4-dimethyl ... 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.

[0048] When the hydrophilic copolymer according to the present invention further contains a structural unit b (hereinafter simply referred to as "structural unit b") derived from another monomer in addition to the structural units a1 and a2, the content of the structural unit b is preferably more than 0 mol% and less than 5 mol% relative to the total (100 mol%) of the 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 the structural unit b derived from another monomer = 0 mol%). That is, in a preferred embodiment, the hydrophilic copolymer is composed of acrylamide and at least one monofunctional monomer selected from the monomers represented by formula (1).

[0049] The hydrophilic copolymer according to the present invention is preferably a random copolymer of acrylamide and at least one monofunctional monomer selected from the monomers represented by the above formula (1). 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.

[0050] 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).

[0051] As described below, the medical device according to the present invention can be produced by applying a coating liquid containing acrylamide and a monomer of formula (1) to 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 polymerization initiator residues present in the hydrophilic copolymer is preferably 0 mol% relative to all structural units constituting the hydrophilic copolymer. Furthermore, the lubricating layer preferably does not substantially contain any polymerization initiator or its residue. Here, the phrase "the lubricating layer is substantially free of any polymerization initiator or its residue" refers to a total content (in terms of solids) of unreacted polymerization initiator and post-reaction polymerization initiator residue relative to the total mass of the lubricating layer of 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 does not contain any polymerization initiator or its residue). 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).

[0052] 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.

[0053] 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).

[0054] As described in detail below, in a preferred embodiment, the hydrophilic copolymer is formed by applying a coating liquid containing acrylamide and a monomer of formula (1) to a resin layer, followed by irradiation with an electron beam, thereby polymerizing and crosslinking the acrylamide and the monomer of formula (1). In this case, the hydrophilic copolymer can be defined as a copolymer formed by irradiating the acrylamide and the monomer of formula (1) with an electron beam (a random copolymer formed by electron beam irradiation). The electron beam irradiation not only extends the polymer chains of the acrylamide and the monomer of formula (1) (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 therefore cannot be represented by a general formula (structure), or are very difficult to represent by a general formula (structure). Therefore, at the time of filing, it is 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 copolymer as a "product" by the provision that "a hydrophilic random copolymer formed by irradiating raw material monomers containing acrylamide and a monomer of formula (1) with an electron beam."

[0055] 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 comprises a hydrophilic random copolymer formed by irradiating raw material monomers containing acrylamide and at least one monofunctional monomer selected from the monomers represented by formula (1) with an electron beam, and the resin layer has a penetration layer on the lubricating layer side in which the hydrophilic random copolymer and the resin material that forms the resin layer are mixed.

[0056] [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.

[0057] The resin layer has a penetration layer on the lubricating layer side, which contains a hydrophilic copolymer and a resin material that forms the resin layer. A penetration layer having such a configuration is preferably formed by applying a coating liquid containing acrylamide and a monomer of formula (1) onto the resin layer, allowing these raw material monomers to penetrate the resin layer, and then irradiating the resin layer with an electron beam (electron beam polymerization). Therefore, the resin layer must be permeable to acrylamide and the monomer of formula (1) (raw material monomer). Specifically, the resin material that constitutes (forms) the resin layer refers to a material that, at room temperature (25°C), a coating liquid containing raw material monomers is applied to the surface of a resin layer made of the resin material, and after 3 minutes, the raw material monomers contained in the coating liquid penetrate 50 nm or more from the surface of the resin layer. In other words, the resin material refers to a material that, when 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, the coating film is irradiated with an electron beam, forming a penetration layer having a thickness of 50 nm or more from the surface of the resin layer.

[0058] 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, etc.), 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.

[0059] 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), modified polyethylene, polyolefin resins such as polypropylene, 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.

[0060] The metallic material is not particularly limited, and metallic materials commonly used for medical devices such as catheters, stent delivery systems, guidewires, etc. can be used. 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.

[0061] 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).

[0062] 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.).

[0063] 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.

[0064] 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).

[0065] 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).

[0066] 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, 3 μm or less, 2 μm or less, or 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, 0.01 μm or more and 5 μm or less, 0.05 μm or more and 3 μm or less, or 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).

[0067] 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.

[0068] 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).

[0069] <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.

[0070] That is, another aspect of the present invention is to provide a coating liquid containing acrylamide and at least one monofunctional monomer selected from the group consisting of monomers represented by the following formula (1),

[0071]

[0072] In the above formula (1), R １ and R ２ each independently represent a methyl group or an ethyl group, and the coating liquid is applied to at least a portion of a surface of a resin layer of a substrate having a resin layer on its surface, causing the acrylamide and the monofunctional monomer to penetrate into the resin layer, thereby forming a precursor layer on at least a portion of the resin layer (precursor layer forming step), and irradiating the precursor layer with an electron beam to polymerize the 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 acrylamide and the monofunctional monomer, and a permeation layer located in at least a portion of the resin layer on the lubricating layer side, containing a mixture of the resin material that forms the resin layer and the hydrophilic copolymer (electron beam irradiation step).

[0073] When a coating liquid containing acrylamide and the monomer of formula (1) 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). Next, the precursor layer is 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 acrylamide and the monomer of formula (1) exhibits excellent lubricity when wet. Therefore, a lubricating layer containing this hydrophilic copolymer can exhibit excellent lubricity (sliding properties) when wet.

[0074] 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.

[0075] Furthermore, 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 permeate the resin layer and are irradiated with electron beams, 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 permeate the resin layer (permeation precursor layer), electron beam irradiation polymerizes the raw material monomers 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.

[0076] In addition, because the polymerization by electron beam irradiation has high reactivity, the hydrophilic copolymer is polymerized by electron beam irradiation, and the chain length of the hydrophilic copolymer increases. Therefore, the hydrophilic copolymer partially exists across both the lubricating layer and the penetration layer, and crosslinks (chemical bonds) are formed between the hydrophilic copolymer in the penetration layer and the resin material. In addition to these crosslinks (chemical bonds), crosslinks (chemical bonds) are also formed between the hydrophilic copolymers existing across the lubricating layer and the penetration layer, and between the hydrophilic copolymer existing 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).

[0077] 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.

[0078] 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.

[0079] A preferred embodiment of each step will be described below.

[0080] (I) Precursor Layer Formation Step In this step, first, a coating liquid (also referred to simply as "coating liquid" in this specification) containing acrylamide and a monomer of formula (1) (raw material monomer), as well as 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.

[0081] The coating liquid can be prepared by mixing the above-mentioned raw material monomer and other optional monomers and components with an optional solvent. When the monomer of formula (1) is liquid at the temperature during preparation (e.g., 20-25°C), there is no need to use a separate solvent (the coating liquid may consist only of acrylamide and the monomer of formula (1)). 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 the monomer of formula (1) is solid at the temperature during preparation (e.g., 20-25°C), or if it is desirable to adjust the viscosity of the coating liquid, a separate solvent may be used to prepare the coating liquid as needed. The solvent to be used is appropriately selected depending on the type of raw material monomer (and, if used, 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 to 20% by mass or less, or 1% by mass or more to 15% by mass or less, or 5% by mass or more to 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 used as long as it does not affect the effects of the present invention.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] (II) Electron Beam Irradiation Step In this step, the precursor layer formed in (I) above is irradiated with an electron beam. As a result, the raw material monomers in the precursor layer are polymerized and crosslinked, and the lubricating precursor layer and the penetrating precursor layer that constitute the precursor layer become a lubricating layer and a penetrating layer, respectively. Furthermore, electron beam irradiation causes random polymerization of acrylamide and the monomer of formula (1). Specifically, electron beam irradiation causes excitation and ionization of the raw material monomer, generating radicals. The radicals generated in the raw material monomer act as polymerization initiation radicals, reacting sequentially, causing polymerization and forming a hydrophilic random copolymer. That is, this step forms a hydrophilic random copolymer of acrylamide and the monomer of formula (1). Hereinafter, the "hydrophilic random copolymer" formed in this step will also be simply referred to as "hydrophilic copolymer." Furthermore, it is possible to determine whether the hydrophilic copolymer formed is a copolymer of 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).

[0092] 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, electron beam polymerization is highly reactive, which causes the hydrophilic copolymer to polymerize and increase its chain length. 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.

[0093] 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 an 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, particularly preferably 20 kGy or more and less than 100 kGy, and most preferably 20 kGy or more and 60 kGy or less. 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 performed in an appropriate balance.

[0094] 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.

[0095] 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).

[0096] 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 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 can 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.

[0097] [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:

[0098] (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.

[0099] 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.

[0100] 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.

[0101] A coating liquid was obtained by dissolving acrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter also referred to as "AA") in N,N-dimethylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter also referred to as "DMAA") so that the molar ratio (AA / DMAA) of acrylamide was 1 / 1. 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).

[0102] 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 30 kGy in a nitrogen gas atmosphere 3 minutes after the coating, thereby obtaining Sample 1.

[0103] Observation of a slice 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 the layer on the coated surface side (first layer) contained only a hydrophilic copolymer of acrylamide-N,N-dimethylacrylamide, the middle layer (second layer) contained a mixture of a hydrophilic copolymer of acrylamide-N,N-dimethylacrylamide and the resin (polyamide elastomer) constituting the substrate (resin layer), and the layer furthest from the coated surface (third layer) contained only the resin constituting the substrate (resin layer). These results confirmed that Sample 1 has a structure in which a permeation layer (second layer) containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of acrylamide-N,N-dimethylacrylamide, and a lubricating layer (first layer) composed of a hydrophilic copolymer of 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 permeation layer (second layer) indicates that the polyamide elastomer constituting the substrate functions as the resin layer in the present invention. Samples 3 and 4 obtained in Examples 3 and 4 below were also confirmed to have the same structure (layer configuration) as described above.

[0104] Example 2 Sample 2 was obtained in the same manner as in Example 1, except that the molar ratio (AA / DMAA) of the monomers contained in the coating solution was changed to 1 / 2. The coating solution was in a liquid state at room temperature (25°C).

[0105] The obtained Sample 2 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. A cross-sectional TEM image obtained by TEM observation of Sample 2 is shown in FIG. 1. As a result, it was confirmed that Sample 2 had a structure (layer configuration) similar to that of Sample 1 of Example 1. Furthermore, the thicknesses of the first and second layers (both dry film thicknesses) were measured using TEM images and found to be approximately 3.5 μm and approximately 1.5 μm, respectively. From these results, it was confirmed that Sample 2 has a structure in which a permeation layer (thickness (dry film thickness): approximately 1.5 μm) containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of acrylamide-N,N-dimethylacrylamide, and a lubrication layer (thickness (dry film thickness): approximately 3.5 μm) composed of a hydrophilic copolymer of acrylamide-N,N-dimethylacrylamide are sequentially formed on the substrate (a nylon elastomer sheet serving as a resin layer).

[0106] Example 3 Sample 3 was obtained in the same manner as in Example 1, except that the molar ratio (AA / DMAA) of the monomers contained in the coating solution was changed to 3 / 7. The coating solution was in a liquid state at room temperature (25°C).

[0107] Example 4 Sample 4 was obtained in the same manner as in Example 1, except that the molar ratio (AA / DMAA) of the monomers contained in the coating solution was changed to 1 / 3. The coating solution was in a liquid state at room temperature (25°C).

[0108] Example 5 Sample 5 was obtained in the same manner as in Example 1, except that the composition of the coating liquid and the conditions for electron beam irradiation after application of the coating liquid were changed as follows: A coating liquid was obtained by dissolving acrylamide in N,N-diethylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter also referred to as "DEAA") so that the molar ratio of acrylamide to N,N-diethylacrylamide (AA / DEAA) was 3 / 7. The coating liquid was in a liquid state at room temperature (25°C).

[0109] The electron beam irradiation conditions after the application of the coating liquid were a nitrogen gas atmosphere, an acceleration voltage of 50 kV, and an irradiation dose of 10 kGy.

[0110] The obtained Sample 5 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 5 has a structure in which a permeation layer containing a mixture of the resin constituting the substrate (resin layer) and a hydrophilic copolymer of acrylamide-N,N-diethylacrylamide, and a lubricating layer composed of a hydrophilic copolymer of acrylamide-N,N-diethylacrylamide are sequentially formed on a substrate (a nylon elastomer sheet serving as a resin layer). It was also confirmed that Samples 6 to 8 obtained in the following Examples 6 to 8 have the same structure (layer configuration) as described above.

[0111] Example 6 Sample 6 was obtained in the same manner as in Example 5, except that the electron beam irradiation conditions after application of the coating liquid were changed to a dose of 30 kGy.

[0112] Example 7 Sample 7 was obtained in the same manner as in Example 5, except that the electron beam irradiation conditions after application of the coating liquid were changed to a dose of 60 kGy.

[0113] Example 8 Sample 8 was obtained in the same manner as in Example 5, except that the electron beam irradiation conditions after application of the coating liquid were changed to a dose of 100 kGy.

[0114] Example 9 Sample 9 was obtained in the same manner as in Example 2, except that the substrate was changed as follows: 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 the substrate. In addition, the pretreatment (hydrophilization treatment) performed in Example 2 was not performed, and the coating liquid was applied onto the primer layer.

[0115] The obtained Sample 9 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, Sample 9 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 acrylamide-N,N-dimethylacrylamide, and a lubricating layer (thickness (dry film thickness): about 4.5 μm) composed of a hydrophilic copolymer of acrylamide-N,N-dimethylacrylamide were 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. Furthermore, it was confirmed that Samples 10 to 11 obtained in the following Examples 10 to 11 also have the same structure (layer configuration) as described above.

[0116] Example 10 Sample 10 was obtained in the same manner as in Example 9, except that the coating solution was prepared by changing the molar ratio (AA / DMAA) of the monomers contained in the coating solution to 3 / 7.

[0117] Example 11 Sample 11 was obtained in the same manner as in Example 9, except that the coating solution was prepared by changing the molar ratio (AA / DMAA) of the monomers contained in the coating solution to 1 / 3.

[0118] Example 12 Sample 12 was obtained in the same manner as in Example 10, except that the monomer contained in the coating solution was changed, and the coating solution was prepared by replacing DMAA with DEAA.

[0119] 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 11 had a structure in which a permeation layer containing a mixture of the resin constituting the primer layer and a hydrophilic copolymer of acrylamide-N,N-diethylacrylamide, and a lubricating layer composed of a hydrophilic copolymer of acrylamide-N,N-diethylacrylamide were sequentially formed on a base layer (polyester film).

[0120] Comparative Example 1 Sample C1 was obtained in the same manner as in Example 1, except that the composition of the coating liquid and the application conditions of the coating liquid were changed as follows: The molar ratio of the monomers contained in the coating liquid (AA / DMAA) was changed to 1 / 0, and AA was dissolved in ethanol to prepare a coating liquid with a concentration of 8 mass % (i.e., the coating liquid was prepared without using DMAA). Note that the coating liquid was in a liquid state at room temperature (25°C).

[0121] In addition, when applying the coating liquid, a wire bar (number: #20) 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.

[0122] Comparative Example 2 Sample C2 was obtained in the same manner as in Example 1, except that the molar ratio of the monomers (AA / DMAA) contained in the coating solution was changed to 0 / 1 (i.e., the coating solution was prepared without using AA). The coating solution was in a liquid state at room temperature (25°C).

[0123] Comparative Example 3 Sample C3 was obtained in the same manner as in Example 2, except that the monomer contained in the coating solution was changed, and that the coating solution was prepared by changing AA to methacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.) The coating solution was in a liquid state at room temperature (25°C).

[0124] 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 120 kGy.

[0125] Comparative Example 5 Sample C5 was obtained in the same manner as in Example 2, except that the monomer contained in the coating solution was changed, and DMAA was replaced with N-butylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd.; hereinafter, also referred to as "N-butyl AA") to prepare the coating solution. The coating solution was in a liquid state at room temperature (25°C).

[0126] Comparative Example 6 Sample C6 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: 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 dissolved in ethanol so that the total concentration was 5 mass % to obtain a coating liquid. At this time, the molar ratio of the above monomers (AA / N,N'-methylenebisAA) was adjusted to 10 / 1. The above coating liquid was in a liquid state at room temperature (25°C).

[0127] 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.

[0128] Comparative Example 7 Sample C7 was obtained in the same manner as in Comparative Example 6, except that the molar ratio of the monomers (AA / N,N'-methylenebisAA) contained in the coating solution was changed to 1 / 1. The coating solution was in a liquid state at room temperature (25°C).

[0129] Comparative Example 8 Sample C8 was obtained in the same manner as in Comparative Example 6, except that the molar ratio of the monomers contained in the coating solution (AA / N,N'-methylenebisAA) was changed to 1 / 10. The coating solution was in a liquid state at room temperature (25°C).

[0130] Comparative Example 9 Sample C9 was obtained in the same manner as in Example 2, except that the substrate was changed to a SUS plate (manufactured by Misumi Corporation: length 20 mm × width 50 mm × thickness 0.5 mm). Note that pretreatment was performed under the same conditions as in Example 2 (electron beam irradiation), and a coating liquid was applied to the electron beam irradiated surface.

[0131] The film-forming properties of Samples 1 to 12 and C1 to C9 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 30 kGy.

[0132] [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.

[0133] Although the coating solution for sample C1 (Comparative Example 1) hardened after electron beam irradiation, many bumps were observed on the surface, and therefore the sample was marked with a "C" in Table 2 below. When preparing sample C1, acrylamide (AA), which is a solid material at room temperature, was dissolved in ethanol to prepare the coating solution. After applying this coating solution, the ethanol was dried and removed (natural drying), resulting in the precipitation of solid AA on the substrate surface. Therefore, even when the substrate surface was irradiated with an electron beam, a uniform coating surface was not formed.

[0134] [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 completely submerged. After 1 minute, with the lubricating layer (coated surface) of the sample 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 rub ("Slipperiness" in Table 2 below) and the 30th rub ("Durability" in Table 2 below). The rubbing strength and speed were kept as similar as possible between samples. The slipperiness (lubricity) after the fifth rub and the slipperiness (durability) after the 30th rub 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 rub measured with a Tribomaster sliding tester in the "Sliding Durability Evaluation" section described below is also listed.

[0135] In the evaluation of slipperiness, samples C1 (Comparative Example 1) and C9 (Comparative Example 9) showed slipperiness on the first stroke, but the lubricating layer peeled off on the fifth stroke, and they no longer showed any slipperiness, so they were rated "(D)."

[0136]

[0137] [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 Labs) 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 50 times, and the sliding resistance values ​​(gf) were measured on the 1st reciprocation (1st time), 5th reciprocation (5th time), 20th reciprocation (20th time), and 50th reciprocation (50th time).

[0138]

[0139]

[0140] From the results in Table 2, it can be seen that the samples of the examples can achieve both lubricity (sliding property) and durability compared to the samples of the comparative examples. In comparative example 1, a lubricating layer was formed without using DMAA (i.e., the monomer of formula (1)), but as described above, the film-forming properties were poor, and the formed lubricating layer peeled off in the sensory evaluation of slipperiness (lubricity). In comparative example 2, a lubricating layer was formed without using AA, but although the layer was formed, sufficient slipperiness (lubricity) could not be obtained. From the above, it can be said that in order to form a lubricating layer with excellent lubricity (sliding property) and durability, both AA and the monomer of formula (1) are essential as monomers constituting the hydrophilic copolymer.

[0141] Furthermore, when methacrylamide was used instead of AA, as in Comparative Examples 3 and 4, the film-forming properties of the hydrophilic copolymer were slightly reduced, and the durability of the lubricating layer deteriorated. In Comparative Example 3, the reduced film-forming properties of the hydrophilic copolymer and the durability of the lubricating layer were predicted to be due to insufficient curing of the raw material monomers. Therefore, in Comparative Example 4, the electron beam irradiation dose during curing was increased, but the film-forming properties of the hydrophilic copolymer were not good, and sufficient durability of the lubricating layer was not obtained. This is thought to be because radical polymerization did not proceed sufficiently when methacrylamide 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). Therefore, when electron beam irradiation is performed for a very short period of time, the radicals disappear (the reaction stops) before the sequential reaction has progressed sufficiently. From these results, it is considered that the monomer must be an acrylamide-based monomer (acryloyl group).

[0142] In Comparative Example 5, N-butylacrylamide was used instead of the monomer of formula (1), but the slipperiness (lubricity) was reduced compared to Examples 1 to 8. In contrast, Examples 1 to 8, which used the same substrate as Comparative Example 5 and DMAA or DEAA as the monomer of formula (1), 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.

[0143] In Comparative Examples 6 to 8, a bifunctional monomer (N,N'-methylenebis(acrylamide)) was used instead of the monomer of formula (1), and samples were prepared by varying the molar ratio. As a result, Comparative Examples 6 to 8 all had inferior slip properties compared to Examples 1 to 8. 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, which reduces 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.

[0144] In Examples 3 and 6, ELG5660 was used as the substrate, and DMAA and DEAA were used as the monomers of formula (1), respectively, but the slipperiness (lubricity) and durability were almost the same (slipperiness: B, durability: A in both cases). On the other hand, in Examples 10 and 12, A4160 was used as the substrate, and DMAA and DEAA were used as the monomers of formula (1), respectively, but the sample of Example 10 had better slipperiness (lubricity) than the sample of Example 12 (slipperiness of Example 10: A, slipperiness of Example 12: B). From this, it can be said that in order to form a lubricating layer with better lubricity, it is preferable to use DMAA as the monomer of formula (1).

[0145] Examples 1 to 4 were under similar conditions except for the molar ratio of AA / DMAA. From these comparisons, it is considered that when the number of moles of DMAA (i.e., the monomer of formula (1)) is greater than the number of moles of AA (number of moles of AA < number of moles of the monomer of formula (1)), a lubricating layer with superior durability can be formed. Furthermore, although the results of the sensory evaluation of slipperiness and durability were the same for Examples 2 to 4, a comparison of sliding resistance values ​​revealed that when the ratio of the number of moles of DMAA to the number of moles of AA is greater than 1 and less than 3, there is a tendency for particularly low sliding resistance values ​​to be exhibited. From this, it is considered that in order to form a lubricating layer with superior lubricity, it is preferable to set the ratio of the number of moles of the monomer of formula (1) to the number of moles of AA to be greater than 1 and less than 3.

[0146] Examples 2 and 9, Examples 3 and 10, Examples 4 and 11, and Examples 6 and 12 were all similar except for the substrate. Comparison of these revealed that when A4160 was used as the substrate, the slipperiness (lubricity) was improved. The results of the sensory evaluation were the same for Examples 6 and 12, but Example 12 had slightly better sliding resistance values. From a structural perspective, these examples differ in the thickness of the penetration layer and lubricating layer. Specifically, as described above, Example 2 (substrate: ELG5660) had a penetration layer thickness of approximately 3.5 μm and a lubricating layer thickness of approximately 1.5 μm (lubricating layer thickness / penetration layer thickness = 3.5 / 1.5 = 2.33 times), while Example 9 (substrate: A4160) had a penetration layer thickness of approximately 4.5 μm and a lubricating layer thickness of approximately 0.1 μm (lubricating layer thickness / penetration layer thickness = 4.5 / 0.1 = 45 times). From these comparisons, it is estimated that the greater the thickness of lubricating layer is relative to the thickness of penetration layer, the more improved the lubricity is.Therefore, it is considered that by making the thickness of lubricating layer larger than the thickness of penetration layer (thickness of lubricating layer>thickness of penetration layer), and even by making the thickness of lubricating layer more than twice the thickness of penetration layer, it can be obtained better lubricity.In addition, from Example 9, it is considered that by having the thickness of penetration layer at least 0.1 μm or more, it can be obtained good durability.

[0147] Examples 5 to 8 were conducted under similar conditions except for the electron beam irradiation dose. As is clear from Table 2, increasing the electron beam irradiation dose improved durability while decreasing slipperiness. This is presumably because increasing the electron beam irradiation dose increased the polymerization rate (reaction rate) of the raw material monomers, promoting crosslinking between hydrophilic copolymers, resulting in a denser three-dimensional network structure (reducing the swelling 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).

[0148] Examples 2 and 9 and Comparative Example 9 were operated under similar conditions except for the substrate. Comparative Example 9 was inferior to Examples 2 and 9 in both slipperiness and durability. More specifically, in Comparative Example 9, as described above, the lubricating layer peeled off after the fifth stroke, and slipperiness deteriorated (both lubricity and durability were poor). This is presumably because AA and DMAA did not penetrate the SUS substrate, 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, at least on the surface, into which the monomers penetrate.

[0149] This application is based on Japanese Patent Application No. 2024-123426, filed on July 30, 2024, the disclosure of which is incorporated by reference in its entirety.

[0150] 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 acrylamide and at least one monofunctional monomer selected from monomers represented by the following formula (1): In the formula (1), R １ and R ２ each independently represent a methyl group or an ethyl group, and the resin layer has a penetration layer on the lubricating layer side, the penetration layer containing a mixture of the hydrophilic copolymer and a resin material forming the resin layer.

2. The medical device according to claim 1, wherein the monofunctional monomer is at least one selected from the group consisting of N,N-dimethylacrylamide and N,N-diethylacrylamide.

3. The medical device according to claim 1, wherein the hydrophilic copolymer contains more of the structural unit a2 derived from the monofunctional monomer than the structural unit a1 derived from the acrylamide.

4. The medical device according to claim 3, wherein the ratio of the number of moles of the structural unit a2 to the number of moles of the structural unit a1 in the hydrophilic copolymer is greater than 1 and less than 3.

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)acrylamide.

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

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 acrylamide and at least one monofunctional monomer selected from the group consisting of monomers represented by the following formula (1) 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 a surface thereof to cause the acrylamide and the monofunctional monomer to penetrate into the resin layer and form a precursor layer on at least a part of the resin layer; and irradiating the precursor layer with an electron beam to polymerize the acrylamide and the monofunctional monomer to form a lubricating layer formed on the surface of the resin layer and containing a hydrophilic copolymer of the acrylamide and the monofunctional monomer, and a penetration layer located on at least a part of the resin layer on the lubricating layer side and containing a mixture of the resin material that forms the resin layer and the hydrophilic copolymer.

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.

Images