Medical instrument and method for producing same

Abstract

Provided is a medical instrument having a lubricating layer capable of achieving excellent good lubricity and durability (especially sliding durability) using a means different from the prior art.　A medical instrument according to the present invention comprises a substrate having a resin layer on the surface thereof, and a lubricating layer formed on at least a portion of the resin layer. The lubricating layer contains a hydrophilic polymer formed by irradiating a monomer represented by formula (1) with an electron beam. The resin layer has, on the lubricating-layer side thereof, a permeation layer in which the hydrophilic polymer and a resin material forming the resin layer are mixed.

Description

Medical device and its manufacturing method

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

[0002] Medical devices inserted into living bodies, such as catheters and guidewires, are required to exhibit excellent lubricity in order to reduce tissue damage to blood vessels and improve operability for 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 polymer formed by irradiating a monomer having a specific structure with an electron beam, thereby completing 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 part of the resin layer, wherein the lubricating layer contains a hydrophilic polymer formed by irradiating a monomer represented by the following formula (1) with an electron beam:

[0009]

[0010] 1. A medical device in which, in the formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents the average number of moles of ethylene oxide added and is 3 to 15, and the resin layer has, on the side of the lubricating layer, a penetration layer in which the hydrophilic polymer and the resin material forming the resin layer are mixed; 2. In the medical device described in 1. above, in the formula (1), n ​​is preferably 3 or more and less than 9; 3. In the medical device described in 1. or 2. above, in the formula (1), R is preferably a methyl group or an ethyl group; 4. In the medical device described in any of 1. to 3. above, it is preferable that the hydrophilic polymer is substantially free of structural units derived from polyfunctional (meth)acrylate; 5. In the medical device described in any of 1. to 4. above, it is preferable that the hydrophilic polymer is composed of a monomer represented by the formula (1); 6. In the medical device described in 1. to 5. above, it is preferable that the hydrophilic polymer is composed of a monomer represented by the formula (1); 7. In the medical device described in any one of above 1. to 6., the lubricating layer preferably does not contain a polymerization initiator or its residue; 7. The medical device described in any one of above 1. to 6. is preferably a catheter, a stent delivery system, or a guidewire.

[0011] Another aspect of the present invention is a method for producing a coating liquid comprising: 8. preparing a coating liquid containing a monomer represented by the following formula (1);

[0012]

[0013] 8. A method for producing a medical device, comprising: in the above formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents the average number of moles of ethylene oxide added and is 3 to 15; 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 penetrating the monomer 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 monomer and form a lubricating layer formed on the surface of the resin layer and containing a hydrophilic polymer of the monomer; and a permeation layer located in at least a portion of the resin layer on the lubricating layer side, in which the resin material forming the resin layer and the hydrophilic polymer are mixed; 9. In the method for producing a medical device described in above 8, it is preferable to irradiate the precursor layer with an electron beam at an exposure dose of more than 0 kGy and less than 300 kGy.

[0014] 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 contains a hydrophilic polymer formed by irradiating a monomer represented by the following formula (1) with an electron beam:

[0015]

[0016] In the above formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents the average number of moles of ethylene oxide added, which is 3 to 15. The above resin layer relates to a medical device having, on the side of the above lubricating layer, a penetration layer in which the above hydrophilic polymer and a resin material forming the above resin layer are mixed.

[0017] Another aspect of the present invention relates to a method for manufacturing a medical device, comprising: preparing a coating liquid containing a monomer 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 penetrating the monomer 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 monomer, thereby forming a lubricating layer formed on the surface of the resin layer and containing a hydrophilic polymer of the 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 polymer are mixed.

[0018] 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).

[0019] 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 polymer 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)" or a "monomer according to the present invention." In this specification, a "hydrophilic polymer formed by irradiating a monomer represented by formula (1) with an electron beam" is also simply referred to as a "hydrophilic polymer" or a "hydrophilic polymer according to the present invention."

[0020] As used herein, the term "X to Y" indicating a range includes X and Y and means "X or greater and Y or less." Furthermore, "X and / or Y" means at least one of X and Y, and encompasses X alone, Y alone, and a combination of X and Y. As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups. Similarly, the term "(meth)acrylate" encompasses both acrylate and methacrylate.

[0021] 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.

[0022] 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.

[0023] <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 polymer formed by irradiating a monomer represented by the above formula (1) with an electron beam. This hydrophilic polymer exhibits excellent lubricity when wet (e.g., when in contact with a body fluid such as blood or an aqueous liquid such as physiological saline; the same applies hereinafter). Therefore, a lubricating layer containing the hydrophilic polymer can exhibit excellent lubricity (sliding properties) when wet. Furthermore, electron beam irradiation polymerizes the monomer represented by the above formula (1) to form a hydrophilic polymer, and crosslinking between the hydrophilic polymers also progresses. Therefore, electron beam irradiation results in more crosslinking within the lubricating layer (e.g., crosslinking between hydrophilic polymers) than other methods (e.g., UV radical polymerization). Therefore, a lubricating layer containing the hydrophilic polymer can exhibit excellent durability (e.g., sliding durability) due to increased crosslinking within the lubricating layer.

[0024] The resin layer has a permeation layer on the lubricating layer side (in contact with the lubricating layer) containing a mixture of a hydrophilic polymer and a resin material forming the resin layer. The permeation layer is formed by irradiating a coating liquid containing a monomer in a state in which the resin layer is partially permeated with the monomer and polymerizing the monomer. The monomer easily permeates the resin layer due to its small molecular size. When the monomer is irradiated with an electron beam in a state in which the monomer has permeated the resin layer, polymerization of the monomer (electron beam polymerization) occurs, and in the permeation layer, the molecular chains of the hydrophilic polymer and the molecular chains of the resin material are entangled with each other. Therefore, the medical device has a permeation layer on the lubricating layer side (in contact with the lubricating layer) of the resin layer containing a mixture of a hydrophilic polymer and a resin material forming the resin layer. Furthermore, when the portion of the resin layer where the monomer has permeated (the permeation precursor layer) is irradiated with an electron beam, the monomer polymerizes to form a hydrophilic polymer, and crosslinking (electron beam crosslinking) between the hydrophilic polymers and between the hydrophilic polymer and the resin material also proceeds. Therefore, in the permeation layer, crosslinks (chemical bonds) are formed not only between the hydrophilic polymers in the permeation layer but also between the hydrophilic polymers and the resin material. Therefore, in the permeation layer, the molecular chains of the hydrophilic polymers and the molecular chains of the hydrophilic polymer and the resin material are entangled and exist in a partially crosslinked state.

[0025] In addition, because electron beam irradiation polymerization is highly reactive, electron beam irradiation causes hydrophilic polymers to polymerize and their chain length to increase. Therefore, the hydrophilic polymer partially exists across both the lubricating layer and the penetration layer, and crosslinks (chemical bonds) are formed between the hydrophilic polymer in the penetration layer and the resin material. In addition to these crosslinks (chemical bonds), crosslinks (chemical bonds) are also formed between the hydrophilic polymers existing across the lubricating layer and the penetration layer, and between the hydrophilic polymer existing across the lubricating layer and the penetration layer and the hydrophilic polymer 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).

[0026] Therefore, a medical device having the above configuration can exhibit excellent lubricity and durability (particularly sliding durability) in a good balance. That is, according to the present invention, it is possible to provide a medical device having a lubricating layer that can achieve both excellent lubricity and durability (particularly sliding durability), and a method for producing the same.

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

[0028] Furthermore, in polymerization by electron beam irradiation, the monomer itself is radicalized by electron beam irradiation, and this radicalized monomer becomes a polymerization initiating radical, causing a successive reaction. Therefore, polymerization of monomers by electron beam irradiation does not require a polymerization initiator (e.g., a benzophenone-based photoinitiator or an acetophenone-based photoinitiator). Furthermore, because the polymerization of monomers by electron beam irradiation has a high polymerization rate (reaction rate), the amount of residual monomer (residual monomer amount) in the lubricating layer and the permeation layer can be reduced. This is also highly desirable from a safety perspective. Furthermore, because the electron beam irradiation process is completed in a short time, the temperature of the substrate is unlikely to rise, and the process is carried out at a relatively low temperature (e.g., below 50°C). Therefore, it can be used even on heat-sensitive substrates.

[0029] 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.

[0030] 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.

[0031] [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.

[0032] The lubricating layer exhibits lubricity when wet, improving the operator's operability when inserting the 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.

[0033] 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).

[0034] Furthermore, as described above, polymerization of monomers by electron beam irradiation does not require a polymerization initiator (e.g., a benzophenone-based photoinitiator, an acetophenone-based photoinitiator). For this reason, in one embodiment, the hydrophilic polymer preferably does not contain any residues of the polymerization initiator. That is, the content of the residues of the polymerization initiator present in the hydrophilic polymer is preferably 0 mol% relative to all structural units constituting the hydrophilic polymer. 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 the total content (in terms of solids content) of unreacted polymerization initiator and post-reaction polymerization initiator residue relative to the total mass of the lubricating layer being 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 any polymerization initiator or its residue can be confirmed, for example, by pyrolysis GC-MS (gas chromatography-mass spectrometry).

[0035] The lubricating layer contains a hydrophilic polymer formed by irradiating a monomer represented by the following formula (1) with an electron beam. That is, the hydrophilic polymer according to the present invention is formed by irradiating a raw material monomer containing a monomer represented by the following formula (1) with an electron beam.

[0036]

[0037] The monomer shown in the above formula (1) has hydrophilicity due to the polyethylene oxide chain. Therefore, a hydrophilic polymer formed using such a hydrophilic monomer has hydrophilicity, and a lubricating layer containing the hydrophilic polymer exhibits lubricity (sliding property). On the other hand, a monomer in which the polyethylene oxide chain in the above formula (1) is another polyalkylene oxide chain (for example, a polypropylene oxide chain) is less hydrophilic than the monomer of formula (1). Therefore, a lubricating layer containing a hydrophilic polymer formed from a monomer having such another polyalkylene oxide chain is inferior in lubricity (sliding property). In addition, as shown in the above formula (1), the monomer has an acryloyl group (CH ２ =CH-C(=O)-). The acryloyl group has a conjugated structure that stabilizes radicals. Therefore, when a monomer represented by formula (1) is used, polymerization by electron beam irradiation proceeds easily. In contrast, the methacryloyl group (CH ２ =C(CH ３)-C(=O)-) stabilizes the radical, but has a much smaller reaction rate constant for radical polymerization than the acryloyl group. Therefore, when the monomer contains a methacryloyl group, polymerization by electron beam irradiation is difficult. Generally, polyacrylate structures containing acryloyl groups undergo crosslinking rather than breakdown (decomposition) upon electron beam irradiation, whereas polymethacrylate structures containing methacryloyl groups undergo breakdown (decomposition) rather than crosslinking upon electron beam irradiation. Therefore, it is presumed that polymers of monomers containing methacryloyl groups undergo breakdown (decomposition) rather than crosslinking upon electron beam irradiation. Therefore, when a monomer containing a methacryloyl group is used, even if electron beam polymerization of the monomer proceeds upon electron beam irradiation, the decomposition reaction of the polymer of the monomer also proceeds simultaneously. As a result, polymerization and crosslinking do not proceed sufficiently even upon electron beam irradiation, and a lubricating layer cannot be formed (Comparative Examples 3 to 6). Furthermore, as shown in the above formula (1), the monomer is monofunctional (the number of acryloyl groups is one). When the hydrophilic polymer is formed using a polyfunctional monomer having two or more (meth)acryloyl groups, polymerization proceeds through multiple (meth)acryloyl groups. As a result, the hydrophilic polymer in the lubricating layer forms a denser three-dimensional network structure, reducing the swelling property of the lubricating layer. As a result, the swelling property (slipperiness) of the lubricating layer is significantly reduced (Comparative Example 2). For this reason, it is preferable that the hydrophilic polymer does not substantially contain structural units derived from polyfunctional (meth)acrylates. Here, "polyfunctional (meth)acrylate" refers to an acrylate compound having two or more (meth)acryloyl groups. Furthermore, the phrase "the hydrophilic polymer is substantially free of structural units derived from polyfunctional (meth)acrylate" means that the content of structural units derived from polyfunctional (meth)acrylate is less than 5 mol% relative to all structural units constituting the hydrophilic polymer, preferably less than 1 mol% (lower limit: 0 mol%), and particularly preferably 0 mol% (the hydrophilic polymer does not contain structural units derived from polyfunctional (meth)acrylate). The above composition can be controlled by adjusting the charge ratio (molar ratio) of each monomer so that it falls within the above range.For example, if a polyfunctional (meth)acrylate (e.g., methoxypolyethylene glycol diacrylate) is not added to the coating liquid, the content of polyfunctional (meth)acrylate-derived structural units in the resulting hydrophilic polymer will be 0 mol%. The composition (molar ratio) of the hydrophilic polymer can be confirmed, for example, by subjecting the hydrophilic polymer 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 polymer can be calculated by measuring the FT-IR spectrum of the hydrophilic polymer and calculating the absorption peak value corresponding to the structural unit derived from the monomer of formula (1). Furthermore, each structural unit contained in the hydrophilic polymer can be identified by pyrolysis GC-MS (gas chromatography-mass spectrometry).

[0038] In the above formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, and a 2-ethylhexyl group. Of these, R is preferably an alkyl group (i.e., the monomer is a polyethylene glycol alkyl ether acrylate). Furthermore, from the viewpoint of wetting of the resin layer (e.g., ease of penetration of the monomer into the resin layer, reduction of repelling), R is more preferably an alkyl group having 1 to 4 carbon atoms, even more preferably a methyl group or an ethyl group (i.e., the monomer is polyethylene glycol methyl ether acrylate (methoxypolyethylene glycol acrylate) or polyethylene glycol ethyl ether acrylate (ethoxypolyethylene glycol acrylate)), and particularly preferably a methyl group.

[0039] In the above formula (1), n ​​represents the ethylene oxide (—O—CH ２ CH ２n represents the average number of moles of ethylene oxide (-) added. n is 3 to 15. Here, if n is less than 3, the resulting polymer is highly hydrophobic, and the lubricating layer cannot absorb a sufficient amount of water. As a result, the lubricating layer has poor lubricity (Comparative Example 7). On the other hand, if n exceeds 15, the ethylene oxide chain length becomes too long, and the steric hindrance makes it difficult for radical polymerization between the monomers to proceed (resulting in reduced film strength). Furthermore, the monomer becomes too large, reducing the permeability of the monomer into the resin layer. As a result, the formation of the permeation layer becomes difficult to proceed, and the adhesion between the lubricating layer and the resin layer decreases, resulting in reduced durability of the lubricating layer (Comparative Example 1). From the viewpoint of achieving a better balance between lubricity and durability, n is preferably 3 to 13, more preferably 3 to less than 9, even more preferably 3 to 5, and particularly preferably 3.

[0040] The monomer of formula (1) may be synthesized by a known method, or a commercially available product may be used. Examples of commercially available products include methoxytriethylene glycol acrylate (Viscoat #MTG, manufactured by Osaka Organic Chemical Industry Co., Ltd.) (in formula (1), n ​​= 3, R = methyl group), methoxypolyethylene glycol (n = 9) acrylate monomer (product name: AM-90G, manufactured by Shin-Nakamura Chemical Co., Ltd., chemical name: methoxypolyethylene glycol #400 acrylate) (in formula (1), n ​​= 9, R = methyl group), and methoxypolyethylene glycol (n = 13) acrylate monomer (product name: AM-130G, manufactured by Shin-Nakamura Chemical Co., Ltd., chemical name: methoxypolyethylene glycol #400 acrylate) (in formula (1), n ​​= 9, R = methyl group). Examples of suitable hydroxyl group-terminated polyalkylene glycol monoacrylates include AME-400 (manufactured by NOF Corporation, product name: AME-400, n≈9) (in formula (1), n≈9, R=methyl), hydroxyl-terminated polyalkylene glycol monoacrylate Blemmer (registered trademark) AP-D series (manufactured by NOF Corporation) (in formula (1), R=hydrogen atom), and methoxypolyethylene glycol (n=9) acrylate (manufactured by Kyoeisha Chemical Co., Ltd., Light Acrylate 130A).

[0041] The hydrophilic polymer may be formed solely from the monomer of formula (1), or may be formed from the monomer of formula (1) and a monomer (another monomer) other than the monomer of formula (1). Examples of the other monomer include acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacrylamide, N,N-diethylacrylamide, 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); glycidyl acrylate, 3,4-epoxycyclohexyl methyl acrylate, β-methylglycidyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxybutyl acrylate, 6-hydroxyhexyl acrylate, 1,4-cyclohexanedimethanol monoacrylate, 1-chloro-2-hydroxypropyl acrylate, 1,6-hexanediol monoacrylate, 2-hydroxy-3-phenyloxypropyl acrylate, 4-hydroxycyclohexyl acrylate, 2-hydroxy-3-phenyloxyacrylate, 4-hydroxycyclohexyl acrylate, etc. The other monomers may be used alone or in combination of two or more.

[0042] When the hydrophilic polymer according to the present invention is formed from the monomer of formula (1) and other monomers, the content of the other monomers is preferably more than 0 mol% and less than 5 mol% relative to the total of the monomer of formula (1) and other monomers. The hydrophilic polymer 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 polymer according to the present invention is formed from the monomer represented by formula (1) (the content of the other monomers = 0 mol%).

[0043] The lubricating layer essentially contains a hydrophilic polymer, 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 typically 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 does not substantially contain other components (i.e., the lubricating layer is substantially composed of a hydrophilic polymer). 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 mass%, more preferably less than 5 mass%, and even more preferably less than 1 mass% (lower limit: 0 mass%), and it is particularly preferable that the lubricating layer does not contain other components (i.e., the lubricating layer is composed of a hydrophilic polymer).

[0044] 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. The thickness of the lubricating layer can be controlled by adjusting the amount of coating liquid applied, which will be described later. In this specification, the thickness of the lubricating layer is a value measured by observation with a transmission electron microscope (TEM).

[0045] A hydrophilic polymer can be defined as a polymer formed by irradiating a monomer represented by formula (1) with an electron beam (a polymer formed by electron beam irradiation). Upon irradiation with an electron beam, the monomer represented by formula (1) not only undergoes extension of its polymer chains (polymerization reaction) but also crosslinks between the polymer chains (crosslinking reaction), thereby becoming a hydrophilic polymer. Because the crosslinking positions in this crosslinking reaction are random, the crosslinking positions of the hydrophilic polymer cannot be identified or are extremely difficult to identify, making it impossible or extremely difficult to represent the hydrophilic polymer by a general formula (structure). Therefore, at the time of filing, it is impossible or impractical to directly identify the hydrophilic polymer obtained by electron beam irradiation based on its structure or properties ("impossible / impractical circumstances"). Therefore, it may be appropriate to identify the hydrophilic polymer as a "product" by the definition of "a hydrophilic polymer formed by irradiating a monomer represented by formula (1) with an electron beam."

[0046] [Substrate] The substrate used in the present invention may have 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 may be 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.

[0047] The resin layer has a penetration layer on the lubricating layer side, which contains a mixture of a hydrophilic polymer and a resin material forming the resin layer. A penetration layer having such a configuration is formed by applying a coating liquid containing a monomer of formula (1) onto the resin layer, allowing the monomer to penetrate the resin layer, and then polymerizing (electron beam polymerization) and crosslinking (electron beam crosslinking) the resin layer by irradiating it with an electron beam. Therefore, the resin layer must be one through which the monomer can penetrate. Specifically, the resin material constituting (forming) the resin layer refers to a material in which, at room temperature (25°C), a coating liquid containing a monomer is applied to the surface of a resin layer made of the resin material, and after 3 minutes, the monomer contained in the coating liquid penetrates 50 nm or more from the surface of the resin layer. In other words, the resin material refers to a material in which a coating liquid containing a monomer 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.

[0048] As such a resin material, amorphous polymers are preferably used. Specific examples include fluororesins such as amorphous polyolefin resins, epoxy resins, amorphous polyurethane resins, diallyl phthalate resins (allyl resins), polycarbonate resins, polytetrafluoroethylene (PTFE), and ethylene-tetrafluoroethylene copolymers (ETFE; Ethylene Tetra Fluoro Ethylene), amino resins (urea resins, melamine resins, benzoguanamine resins), amorphous polyester resins, styrene resins such as polystyrene, acrylic resins, polymethyl methacrylate, polyacetal resins, vinyl acetate resins, phenolic resins, vinyl chloride resins (polyvinyl chloride), silicone resins (silicon resins), polysulfone resins such as polyethersulfone resins, amorphous polyamide resins, polyamideimide resins, and amorphous polyimide resins. Thermoplastic elastomers such as olefin elastomers, polyurethane elastomers, polyester elastomers, and polyamide elastomers (nylon elastomers) are also preferably used. Among these, from the viewpoint of easier penetration of the monomer (easier 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.), more preferably selected from polyamide elastomers and amorphous polyester resins, and particularly preferably polyamide elastomers. 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.

[0049] 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 methods such as plating, metal vapor deposition, sputtering, etc.). Here, examples of crystalline polymer materials include polyethylene resins such as high-density polyethylene (HDPE) and modified polyethylene, polyolefin resins such as polypropylene resin, modified polyolefin resin, cyclic polyolefin resin, 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.

[0050] 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.

[0051] 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.).

[0052] 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.

[0053] 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 polymer 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 polymer 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., １ The 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).

[0054] In the penetration layer, not only the molecular chains of the hydrophilic polymers but also the molecular chains of the hydrophilic polymers and the resin material are entangled, and partial cross-linking (chemical bonding) is formed between the hydrophilic polymers and between the hydrophilic polymers and the resin material. In addition, the hydrophilic polymers are partially present across both the lubricating layer and the penetration layer, and cross-linking (chemical bonding) is also formed between the hydrophilic polymers present across the lubricating layer and the penetration layer, between the hydrophilic polymers present across the lubricating layer and the penetration layer and the hydrophilic polymer in the lubricating layer, between the hydrophilic polymers present across the lubricating layer and the penetration layer and the hydrophilic polymer in the penetration layer, and between the hydrophilic polymers present across the lubricating layer and the penetration layer and the resin material in 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).

[0055] The thickness of the penetration layer (dry film thickness) is, for example, 0.01 μm or more, 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, 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 to 10 μm or less, 0.01 μm or more to 5 μm or less, 0.05 μm or more to 3 μm or less, or 0.1 μm or more to 1 μm or less. Such a thickness can achieve sufficient durability (particularly 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, and the like. In this specification, the thickness of the penetration layer is a value measured by observation with a transmission electron microscope (TEM).

[0056] When the substrate has a substrate layer and a resin layer, the substrate layer is substantially free of a hydrophilic polymer. Here, the phrase "substantially free of a hydrophilic polymer" means that the content of the hydrophilic polymer (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 polymer).

[0057] <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 polymer 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 a monomer to the resin layer of a substrate, allowing the monomer to permeate into the resin layer, and then polymerizing the monomer by electron beam irradiation.

[0058] That is, another aspect of the present invention provides a coating solution containing a monomer represented by the following formula (1),

[0059]

[0060] In the above formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents the average number of moles of ethylene oxide added, which is 3 to 15. The present invention provides a method for producing a medical device, comprising: 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 penetrating the monomer into the resin layer and 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 monomer and form a lubricating layer formed on the surface of the resin layer and containing a hydrophilic polymer of the monomer, and a permeation layer located in at least a portion of the resin layer on the lubricating layer side, in which the resin material forming the resin layer and the hydrophilic polymer are mixed (electron beam irradiation step).

[0061] A preferred embodiment of each step will be described below.

[0062] (I) Precursor Layer Formation Step In this step, first, a coating liquid (also referred to simply as "coating liquid" in this specification) containing the monomer of formula (1) and other monomers used as needed is prepared. If the other components used as needed do not react (do not denature) when irradiated with an electron beam, these other components may be mixed into the coating liquid. The monomer of formula (1), the other monomers when the coating liquid contains a monomer other than the monomer of formula (1), 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.

[0063] A coating liquid can be prepared by mixing the monomer of formula (1) and other monomers and components, if necessary, with a solvent, if necessary. 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 solely of 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 in this case is appropriately selected depending on the type of monomer (and, if used, other monomers and components). For example, 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 monomer concentration in the coating solution is not particularly limited. The monomer concentration in the coating solution may be, for example, 0.05% by mass or more and 20% by mass or less, 1% by mass or more and 15% by mass or less, or 5% by mass or more and 10% by mass or less. If the monomer concentration 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 falls 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.

[0064] Next, the coating liquid prepared above is applied to a desired portion of the resin layer surface of the substrate. As a result, a portion of the monomer penetrates into the resin layer, and a coating film containing the remaining monomer is formed on the surface of the resin layer, forming a precursor layer. That is, the precursor layer is composed of a penetration precursor layer, in which the monomer penetrates into the resin layer and becomes a penetration 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.

[0065] 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 substrate (resin layer) may be pre-treated by electron beam irradiation, plasma irradiation, ultraviolet irradiation, corona discharge treatment, oxidation, or the like (pretreatment process). 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 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 more 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.

[0066] When electron beam irradiation treatment is performed as a pretreatment step, the dose of electron beams irradiated onto the substrate (resin layer) is, for example, 10 to 300 kGy, preferably 10 to 200 kGy, and more preferably 30 to 100 kGy. The acceleration voltage is preferably 20 to 100 kV, and more preferably 40 to 70 kV. The irradiation temperature is preferably 10 to 80°C, and 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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 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 monomer can efficiently penetrate into the resin layer.

[0072] 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.

[0073] (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 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. Specifically, electron beam irradiation causes excitation and ionization of the monomer, generating radicals, and the radicals generated in the monomer act as polymerization initiation radicals, undergoing successive reactions, resulting in polymerization and forming a hydrophilic polymer. It is possible to determine whether the formed hydrophilic polymer has a structural unit derived from the monomer of formula (1) by analysis using infrared spectrum analysis, pyrolysis GC-MS (gas chromatography-mass spectrometry), or time-of-flight secondary ion mass spectrometry (TOF-SIMS).

[0074] Hydrophilic polymers formed by electron beam irradiation of monomers present in the lubricating precursor layer exhibit excellent lubricity when wet. Therefore, lubricating layers containing such hydrophilic polymers can exhibit excellent lubricity (sliding properties). Furthermore, electron beam irradiation simultaneously causes crosslinking between hydrophilic polymers 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 monomers present in the permeation precursor layer produces hydrophilic polymers, and crosslinking (chemical reactions) occurs between hydrophilic polymers and between the hydrophilic polymer and the resin material. In addition, because polymerization by electron beam irradiation is highly reactive, the hydrophilic polymers are polymerized, and the chain length of the hydrophilic polymer increases. Therefore, the monomers present in the lubricating precursor layer and the permeation precursor layer are easily polymerized across both layers to form hydrophilic polymers. The hydrophilic polymer present across both layers forms crosslinks (chemical bonds) with the hydrophilic polymer present across both layers, the hydrophilic polymer 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 bond of the monomer (raw material monomer) disappears due to polymerization by electron beam irradiation.

[0075] In this process, in order to achieve both good lubricity and durability, it is important to appropriately adjust the dose of electron beam irradiated to the precursor layer. Specifically, the dose of electron beam irradiated to the precursor layer is preferably more than 0 kGy and less than 300 kGy. That is, in a preferred embodiment of the present invention, the precursor layer is irradiated with electron beam at a dose of more than 0 kGy and less than 300 kGy. The dose of electron beam irradiated to the precursor layer is preferably 10 kGy or more and 200 kGy or less, more preferably 20 kGy or more and 150 kGy or less, even more preferably 25 kGy or more and less than 150 kGy, and particularly preferably 30 kGy or more and 100 kGy or less. With such a dose, electron beam polymerization of the monomer and crosslinking between hydrophilic polymers or between the hydrophilic polymer and the resin material can be performed in an appropriate balance.

[0076] Other conditions for electron beam irradiation are appropriately selected taking into consideration the types of 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 50 to 200 kV, more preferably 50 to 100 kV.

[0077] 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).

[0078] If the lubricating layer contains other components in addition to the hydrophilic polymer, a step of applying a coating liquid containing the other components to the lubricating layer may be further performed after the electron beam irradiation step (II). This step can prevent the loss of functionality of the other components, compared to the method of forming a lubricating layer using a coating liquid containing other components together with the monomer, as described in the precursor layer formation step (I). The other components used in this step are similar to those described above, and therefore will not be described here. The solvent contained in the coating liquid containing the other components is not particularly limited as long as it does not dissolve the lubricating layer, but it is preferable that it be able to sufficiently dissolve or disperse the other components. The method for preparing the coating liquid containing the other components is not particularly limited, and known methods such as mixing the other components and solvents can be used. The concentration is also not particularly limited, and is appropriately selected depending on the function of the other components used. Furthermore, the method for applying the coating liquid containing the other components to the lubricating layer is not particularly limited, and the same application methods as those described in the precursor layer formation step (I) can be used.

[0079] [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:

[0080] (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.

[0081] 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.

[0082] Example 1 Methoxytriethylene glycol acrylate monomer (Viscoat #MTG, manufactured by Osaka Organic Chemical Industry Ltd.) was applied to a 1 mm thick press sheet (nylon elastomer sheet) (substrate) made of polyamide elastomer (Grilflex (registered trademark) ELG5660, manufactured by EMS) using a wire bar (number: OSP-04). Note that methoxytriethylene glycol acrylate monomer is liquid at room temperature (25°C).

[0083] Next, using an electron beam irradiation device (I-Compact EB (registered trademark) manufactured by Iwasaki Electric Co., Ltd.), the coated surface was irradiated with an electron beam in a nitrogen gas atmosphere under conditions of an acceleration voltage of 90 kV and an irradiation dose of 30 kGy, 3 minutes after the above coating, to obtain Sample 1.

[0084] Observation of the cross section of the obtained Sample 1 using a transmission electron microscope (TEM) confirmed that Sample 1 had a three-layer structure. Furthermore, analysis of Sample 1 in the thickness direction from the coated surface side using time-of-flight secondary ion mass spectrometry (TOF-SIMS) confirmed that only poly(methoxytriethylene glycol acrylate) was present in the layer on the coated surface side (Layer 1), that poly(methoxytriethylene glycol acrylate) and a polyamide-based elastomer were present in the middle layer (Layer 2), and that only polyamide-based elastomer was present in the layer furthest from the coated surface (Layer 3). These results confirmed that Sample 1 has a structure in which a penetration layer (Layer 2) containing a mixture of nylon elastomer sheet and poly(methoxytriethylene glycol acrylate), and a lubrication layer (Layer 1) composed of poly(methoxytriethylene glycol acrylate) are sequentially formed on a substrate (Layer 3) (a nylon elastomer sheet serving as a resin layer).

[0085] Example 2 Sample 2 was obtained in the same manner as in Example 1, except that methoxypolyethylene glycol (n=9) acrylate (manufactured by Shin-Nakamura Chemical Co., Ltd., product name: AM-90G, chemical name: methoxypolyethylene glycol #400 acrylate) was used instead of the methoxytriethylene glycol acrylate monomer in Example 1. Note that methoxypolyethylene glycol (n=9) acrylate is liquid at room temperature (25°C).

[0086] The obtained Sample 2 was subjected to TEM observation and TOF-SIMS analysis in the same manner as in Example 1. As a result, it was confirmed that Sample 2 had a structure in which a permeation layer in which a nylon elastomer sheet and poly(methoxypolyethylene glycol (n=9) acrylate) were mixed, and a layer composed of poly(methoxypolyethylene glycol (n=9) acrylate) were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0087] Example 3 Sample 3 was obtained in the same manner as in Example 2, except that the dose of electron beam irradiation was changed to 150 kGy.

[0088] The obtained Sample 3 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 3 had a structure in which a permeation layer containing a mixture of a nylon elastomer sheet and poly(methoxypolyethylene glycol (n=9) acrylate), and a lubricating layer composed of poly(methoxypolyethylene glycol (n=9) acrylate) were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0089] Example 4 Sample 4 was obtained in the same manner as in Example 1, except that methoxypolyethylene glycol (n=13) acrylate (manufactured by Shin-Nakamura Chemical Co., Ltd., product name: AM-130G, chemical name: methoxypolyethylene glycol #600 acrylate) was used instead of the methoxytriethylene glycol acrylate monomer in Example 1. Note that methoxypolyethylene glycol (n=13) acrylate is liquid at room temperature (25°C).

[0090] The obtained Sample 4 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 4 had a structure in which a permeation layer containing a mixture of a nylon elastomer sheet and poly(methoxypolyethylene glycol (n=13) acrylate), and a lubricating layer composed of poly(methoxypolyethylene glycol (n=13) acrylate) were sequentially formed on a substrate (a nylon elastomer sheet that is a resin layer).

[0091] Comparative Example 1 Methoxypolyethylene glycol (n=23) acrylate (manufactured by Shin-Nakamura Chemical Co., Ltd., product name: AM-230G, chemical name: methoxypolyethylene glycol #1000 acrylate) was dissolved in ethanol to a mass concentration of 5 mass %, and the solution was stirred to obtain a coating liquid.

[0092] Next, the coating liquid was applied to a 1 mm thick press sheet (nylon elastomer sheet) (substrate) made of polyamide elastomer (Grilflex (registered trademark) ELG5660, manufactured by EMS) using a wire bar (number #36). After air drying for 1 minute and confirming that the ethanol had evaporated, the coated surface was irradiated with an electron beam in a nitrogen gas atmosphere at an acceleration voltage of 90 kV and an irradiation dose of 30 kGy to obtain Sample 5.

[0093] Comparative Example 2 Sample 6 was obtained in the same manner as in Example 1, except that polyethylene glycol (n=9) diacrylate (manufactured by Shin-Nakamura Chemical Co., Ltd., product name: A-400, chemical name: polyethylene glycol #400 diacrylate) was used instead of the methoxytriethylene glycol acrylate monomer in Example 1.

[0094] Comparative Example 3 Sample 7 was obtained in the same manner as in Example 1, except that methoxypolyethylene glycol (n=4) methacrylate (manufactured by Shin-Nakamura Chemical Co., Ltd., product name: M-40G, chemical name: methoxytetraethylene glycol methacrylate) was used instead of the methoxytriethylene glycol acrylate monomer in Example 1.

[0095] Comparative Example 4 Sample 7 was obtained in the same manner as in Comparative Example 3. The coated surface of Sample 7 was irradiated with an electron beam in a nitrogen gas atmosphere under conditions of an acceleration voltage of 90 kV and an irradiation dose of 420 kGy, to obtain Sample 8 (total irradiation dose: 30 kGy + 420 kGy = 450 kGy).

[0096] Comparative Example 5 Sample 9 was obtained in the same manner as in Example 1, except that methoxypolyethylene glycol (n=9) methacrylate (manufactured by Shin-Nakamura Chemical Co., Ltd., product name: M-90G, chemical name: methoxypolyethylene glycol methacrylate) was used instead of the methoxytriethylene glycol acrylate monomer in Example 1.

[0097] Comparative Example 6 Sample 9 was obtained in the same manner as in Comparative Example 5. The coated surface of Sample 9 was irradiated with an electron beam in a nitrogen gas atmosphere under conditions of an acceleration voltage of 90 kV and an irradiation dose of 420 kGy, to obtain Sample 10 (total irradiation dose: 30 kGy + 420 kGy = 450 kGy).

[0098] Comparative Example 7 Sample 11 was obtained in the same manner as in Example 1, except that 2-methoxyethyl acrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of the methoxytriethylene glycol acrylate monomer.

[0099] Comparative Example 8 Sample 12 was obtained in the same manner as in Example 1, except that a SUS plate (manufactured by Misumi Corporation: length 20 mm × width 50 mm × thickness 0.5 mm) was used instead of the nylon elastomer sheet.

[0100] The film-forming properties of Samples 1 to 12 obtained above were evaluated according to the following method. The results are shown in Table 1 below. The substrate materials and lubricating layer formation conditions (type of monomer, electron beam irradiation conditions) of Samples 1 to 12 obtained above are also shown in Table 1 below. In Table 1 below, "irradiation conditions (kV-kGy)" indicates the acceleration voltage (kV) and irradiation dose (kGy) during electron beam irradiation. For example, the electron beam irradiation conditions in Example 1 indicate an acceleration voltage of 90 kV and an irradiation dose of 30 kGy.

[0101] [Film-forming property evaluation] For each sample, the coated surface after electron beam irradiation was observed. When the coating liquid was cured and the coating surface was uniform, the film-forming property was judged to be good ("A" in Table 1 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 coated surface is visually inspected and no repelling or bumps are observed. For samples 7 to 10, the coating liquid did not harden after electron beam irradiation, and the liquid adhered to the hand when touched (a lubricating layer could not be formed), so they were rated "B" in Table 1 below.

[0102]

[0103] Examples 1 to 4 use acrylate-based monomers (monomers having an acryloyl group), while Comparative Examples 3 to 6 use methacrylate-based monomers (monomers having a methacryloyl group). In particular, Example 2 and Comparative Example 5 are similar except that they use acrylate-based monomers and methacrylate-based monomers, respectively. As is clear from Table 1, when a methacrylate-based monomer was used, the coating liquid did not harden and a lubricating layer could not be formed. In particular, in Comparative Examples 4 and 6, additional electron beam irradiation was performed to the point where the substrate discolored (the electron beam irradiation dose was increased), but the coating liquid did not harden. This is thought to be because the radical polymerization of the monomer did not proceed sufficiently when a methacrylate-based monomer was used. This is presumably because the reaction rate constant of methacrylate-based monomers (monomers having a methacryloyl group) is small during polymerization by electron beam irradiation, and 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 the above results, it is considered that the monomer must be an acrylate-based monomer (a monomer having an acryloyl group).

[0104] Next, for Samples 1 to 6 and 11 to 12, which were confirmed to have good film-forming properties as described above, the lubricity and lubrication maintenance (durability) were evaluated according to the following method. The results are shown in Table 3 below. The substrate materials and lubrication layer formation conditions (type of monomer, electron beam irradiation conditions) for Samples 1 to 6 and 11 to 12 obtained above are also listed in Table 3 below. In Table 3 below, "irradiation conditions (kV-kGy)" indicates the acceleration voltage (kV) and irradiation dose (kGy) during electron beam irradiation. For example, the electron beam irradiation conditions in Example 1 indicate an acceleration voltage of 90 kV and an irradiation dose of 30 kGy.

[0105] [Sensory Evaluation] Each sample was immersed in water so that the lubricating layer (coated surface) was 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 stroke ("Slipperiness" in Table 3 below) and the 30th stroke ("Durability" in Table 3 below). The rubbing strength and speed were kept as similar as possible between samples. The slipperiness (lubricity) after the fifth stroke and the slipperiness (durability) after the 30th stroke were evaluated according to the criteria in Table 2 below.

[0106]

[0107]

[0108] The results in Table 3 show that Samples 1 to 4 of the Examples are able to achieve both lubricity (slipperiness) and durability compared to Samples 5 to 6 and 11 to 12 of the Comparative Examples. Note that the durability of Sample 2 of Example 2 and Sample 4 of Example 4 were both rated "B", but Sample 4 had lower slipperiness after the 30th stroke.

[0109] Examples 1-4 and Comparative Examples 1-7 were similar in condition except for the average number of moles of ethylene oxide added to the monomer. As is clear from the above results, durability decreased as the average number of moles of ethylene oxide added to the monomer increased. This is presumably because, as the average number of moles of ethylene oxide added increased, radical polymerization of the monomer became more difficult due to steric hindrance (reduced film strength), and because, as the molecular weight increased, penetration of the monomer into the resin layer decreased (reduced adhesion to the substrate). On the other hand, Sample 11 of Comparative Example 7, which had a lubricating layer formed using a monomer with an average number of moles of ethylene oxide added of 1, showed no slippage from the first stroke (poor slipperiness (lubricity)). This is presumably because the hydrophobicity of polymethoxyethyl acrylate was too strong, preventing the lubricating layer from absorbing water. Sample 11 of Comparative Example 7 showed no slippage from the first stroke, making it impossible to measure durability. From the above, it is considered that the average number of moles of ethylene oxide added in the monomer greatly contributes to the lubricity and durability, and in order to achieve both the lubricity and durability of the lubricating layer, it is preferable that the average number of moles of ethylene oxide added in the monomer is 3 to 13. Furthermore, from a comparison of Examples 1, 2 and 4, it is considered that in order to achieve a better balance between the lubricity and durability of the lubricating layer, it is preferable that the average number of moles of ethylene oxide added in the monomer is 3 to 9 (particularly 3 or more and less than 9).

[0110] Examples 2 and 3 were under the same conditions except for the electron beam irradiation dose. As is clear from Table 3, increasing the electron beam irradiation dose reduces the slipperiness. This is presumably because increasing the electron beam irradiation dose increases the polymerization rate (reaction rate) of the monomer, and the three-dimensional network structure formed by the hydrophilic polymer becomes denser (reducing the swelling property of the lubricating layer). For this reason, from the viewpoint of improving the lubricity of the lubricating layer, it is considered that a low electron beam irradiation dose (particularly less than 300 kGy) is preferable.

[0111] Example 2 uses a monofunctional monomer having one acryloyl group, while Comparative Example 2 uses a bifunctional monomer having two acryloyl groups. Example 2 and Comparative Example 2 have similar conditions except for the number of acryloyl groups in the monomer. As is clear from Table 3, Comparative Example 2, which uses a bifunctional monomer, has inferior slip properties compared to Example 2. This is presumably because in Comparative Example 2, polymerization by electron beam irradiation proceeds through the acryloyl groups at both ends, resulting in a denser three-dimensional network structure of the lubricating layer and reduced swelling of the lubricating layer. From the above, it is considered that the monomer must be monofunctional in order to improve the lubricity of the lubricating layer.

[0112] Example 1 and Comparative Example 8 were conducted under similar conditions except for the substrate, but Sample 12 of Comparative Example 8 was inferior to Sample 1 of Example 1 in both slipperiness and durability. More specifically, Sample 12 slid well the first time, but by the fifth time, the lubricating layer peeled off from the substrate, resulting in poor slipperiness (poor both lubricity and durability). This is presumably because the monomer (methoxytriethylene glycol acrylate) did not penetrate the SUS substrate, making it impossible to form a permeated layer, resulting in poor adhesion between the lubricating layer and the substrate. From the above, it is considered that the substrate must have a resin layer on at least the surface through which the monomer can penetrate.

[0113] This application is based on Japanese Patent Application No. 2024-123429, filed on July 30, 2024, the disclosure of which is incorporated by reference in its entirety.

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 contains a hydrophilic polymer formed by irradiating a monomer represented by the following formula (1) with an electron beam: In the formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents the average number of moles of ethylene oxide added, which is 3 to 15. The medical device has a permeation layer on the lubricating layer side, in which the hydrophilic polymer and a resin material forming the resin layer are mixed.

2. The medical device according to claim 1, wherein in formula (1), n ​​is 3 or more and less than 9.

3. The medical device according to claim 1, wherein in formula (1), R is a methyl group or an ethyl group.

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

5. The medical device according to claim 1, wherein the hydrophilic polymer is composed of a monomer represented by formula (1).

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

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

8. A coating solution containing a monomer represented by the following formula (1) is prepared, in formula (1), R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and n represents the average number of moles of ethylene oxide added, which is 3 to 15; applying the coating liquid to at least a part of a surface of a resin layer of a substrate having a resin layer on its surface, thereby penetrating the monomer 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 monomer, thereby forming a lubricating layer formed on the surface of the resin layer and containing a hydrophilic polymer of the monomer, and a permeation layer located on at least a part of the resin layer on the lubricating layer side, in which the resin material forming the resin layer and the hydrophilic polymer are mixed.

9. The manufacturing method according to claim 8, wherein the precursor layer is irradiated with an electron beam at a dose of more than 0 kGy and less than 300 kGy.

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