Medical devices and methods for manufacturing medical devices

Abstract

To provide a medical instrument equipped with a surface layer structure that does not require a block polymer of a complicated structure, has lubricity, is robust and causes less change of volume by swelling, and is not be dissolved / washed away under water, and a method for manufacturing thereof.SOLUTION: A medical instrument 1 comprises: a base material 11; a crosslinked gel layer 12 provided on the base material 11; and a lubricant layer 13 provided on the opposite side of the base material 11 in the crosslinked gel layer 12, where the crosslinked gel layer 12 consists of a crosslinked product of polyvinyl alcohol having carboxy group or salt thereof, and the lubricant layer 13 consists of epoxy group-containing hydrophilic polymers.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a medical device that is suitable for insertion or placement primarily within a living body, and a method for manufacturing the same. [Background technology]

[0002] Medical devices that are inserted into the living body, such as guidewires, stents, and catheters, are required to have lubricity relative to biological tissue in order to prevent damage to the biological tissues, such as blood vessels, with which they come into contact, and to improve the operability of the medical device.

[0003] Therefore, a lubricating layer made of hydrophilic polymers is formed on the surface of the above-mentioned medical devices. A representative example of a hydrophilic polymer is polyvinyl alcohol, but this hydrophilic polymer alone is prone to collapse in layer structure, and is therefore prone to detachment from the medical device, which is problematic from the viewpoint of safety. Furthermore, it is prone to swelling and increasing in volume, which is problematic from the viewpoint of operability of the medical device.

[0004] Therefore, Patent Document 1 proposes providing a surface lubricating layer formed of a block copolymer consisting of a hydrophilic portion and a hydrophobic portion having a reactive functional group on the base layer of a medical device.In addition, Patent Document 2 proposes coating the surface of an implantable medical device with an amphiphilic triblock copolymer that includes a hydrophobic polymer block and hydrophilic polymer blocks arranged on both sides of the hydrophobic polymer block, and the ends of the hydrophilic polymer blocks are capped with phosphorylcholine moieties. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Re-table No. 2014-162872 [Patent Document 2] Patent No. 6066366 Summary of the Invention [Problem to be solved by the invention]

[0006] However, both of Patent Documents 1 and 2 require a block polymer with a complex structure.

[0007] The present invention has been made in consideration of the above-mentioned circumstances, and aims to provide a medical device having a surface structure that does not require a block polymer with a complex structure, has lubricity, is tough, changes in volume little due to swelling, and does not dissolve or wash away in water, and a method for manufacturing the same. [Means for solving the problem]

[0008] In order to achieve the above-mentioned object, firstly, the present invention provides a medical device comprising a substrate, a crosslinked gel layer provided on the substrate, and a lubricating layer provided on the crosslinked gel layer on the opposite side of the substrate, wherein the crosslinked gel layer is made of a crosslinked product of polyvinyl alcohol having a carboxy group or a salt thereof, and the lubricating layer is made of an epoxy group-containing hydrophilic polymer (Invention 1).

[0009] In the above invention (Invention 1), the crosslinked product of the polyvinyl alcohol is preferably obtained by chemically crosslinking the polyvinyl alcohol (Invention 2).

[0010] In the above invention (Invention 2), it is preferable that the polyvinyl alcohols are bonded to each other via acetal bonds (Invention 3).

[0011] In the above inventions (Inventions 1 to 3), the epoxy group-containing hydrophilic polymer preferably contains polymerization units based on at least one monomer selected from the group consisting of an acrylamide monomer, a betaine monomer, an alkoxy group-containing (meth)acrylate, (meth)acrylic acid, vinyl sulfonic acid, and vinylpyrrolidone (Invention 4).

[0012] In the above inventions (Inventions 1 to 4), it is preferable that the device is a medical device that is inserted or placed inside a living body (Invention 5).

[0013] Secondly, the present invention provides a method for producing a medical device, comprising the steps of forming a coating film of polyvinyl alcohol having a carboxy group or a salt thereof on a substrate, crosslinking the polyvinyl alcohol while leaving the carboxy group or the salt thereof to form a crosslinked gel layer, forming a lubricating layer made of an epoxy group-containing hydrophilic polymer on the crosslinked gel layer, and reacting the carboxy group or the salt thereof of the polyvinyl alcohol with the epoxy group of the epoxy group-containing hydrophilic polymer (Invention 6).

[0014] In the above invention (Invention 6), it is preferable that the polyvinyl alcohol is chemically crosslinked to form the crosslinked gel layer (Invention 7).

[0015] In the above invention (Invention 7), the chemical crosslinking is preferably performed by forming an acetal bond between the polyvinyl alcohol and the polyvinyl alcohol using a polyfunctional aldehyde compound (Invention 8). Effect of the Invention

[0016] The surface layer structure of the medical device according to the present invention does not require a block polymer with a complex structure, and is lubricating, tough, and undergoes little volume change due to swelling. Furthermore, according to the manufacturing method for a medical device according to the present invention, it is possible to manufacture a medical device having a surface layer structure that is lubricating, tough, undergoes little volume change due to swelling, and does not dissolve or wash away in water, without using a block polymer with a complex structure. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 is a schematic cross-sectional view of a medical device according to one embodiment of the present invention. [Diagram 2] 1 is a graph showing the results of a slippage durability test carried out in Test Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Hereinafter, an embodiment of the present invention will be described. FIG. 1 shows a schematic cross-sectional view of a medical device according to one embodiment of the present invention. 1, the medical device 1 according to this embodiment includes a substrate 11, a crosslinked gel layer 12 provided on the substrate 11, and a lubricating layer 13 provided on the crosslinked gel layer 12 on the side opposite the substrate 11. The crosslinked gel layer 12 is made of a crosslinked product of polyvinyl alcohol having a carboxy group or a salt thereof, and the lubricating layer 13 is made of an epoxy group-containing hydrophilic polymer.

[0019] The crosslinked gel layer 12 in the medical device 1 having the above configuration is made of a crosslinked product of polyvinyl alcohol, and is therefore strong and does not easily crumble even in a living body. Therefore, it is difficult to detach from the base material 11, and the generation of fine particles and the like can be suppressed, and safety is high. In addition, since the crosslinked gel layer 12 is made of a crosslinked product of polyvinyl alcohol, the volume change due to swelling is small, and even if it swells, it has excellent flexibility, so the operability of the medical device 1 is not hindered. For example, when the medical device 1 is a guidewire, if the crosslinked gel layer 12 swells in a blood vessel and increases in volume or becomes hard, the operation of the guidewire deteriorates and the operability decreases, but the crosslinked gel layer 12 can prevent such a decrease in operability.

[0020] In addition, the lubricating layer 13 in the medical device 1 according to this embodiment is made of an epoxy group-containing hydrophilic polymer, and therefore has excellent lubricity in the living body. Furthermore, since the lubricating layer 13 is made of an epoxy group-containing hydrophilic polymer, the epoxy group reacts with the carboxy group or its salt of the polyvinyl alcohol in the crosslinked gel layer 12 to form a chemical bond. As a result, a strong chemically crosslinked hydrogel layer is constructed, and the lubricating layer 13 adheres firmly to the crosslinked gel layer 12 and is difficult to detach from the crosslinked gel layer 12 and, in turn, from the substrate 11. It is preferable that a reaction product between the carboxy group or its salt of the polyvinyl alcohol and the epoxy group of the epoxy group-containing hydrophilic polymer exists at the interface between the crosslinked gel layer 12 and the lubricating layer 13.

[0021] In the medical device 1 having the above configuration, a tough surface layer structure that is not easily broken down in vivo can be formed without the need for a block polymer with a complex configuration, although the present invention does not exclude the use of a block polymer with a complex configuration.

[0022] 1. Each element (1) Medical devices The type of medical device 1 according to this embodiment is not particularly limited as long as it requires lubricity for biological tissue, but it is generally preferable that the medical device is one that is inserted or placed inside a living body.

[0023] Examples of the medical device 1 according to this embodiment include guidewires, catheters, indwelling needles, stents, balloons, cannulas, cardiopulmonary bypass circuits, endogenous vascular monitoring devices, tissue patch devices, blood pumps, pacemaker electrodes, drug delivery devices, various tubes (angiography tubes, endotracheal tubes, feeding tubes, urological tubes, endoscopic overtubes, etc.), artificial blood vessels, artificial heart valves, and artificial organs.

[0024] In particular, the medical device 1 according to this embodiment is preferably a long medical device that is inserted into the body. For example, a long medical device having a metal surface or a long medical device having a polymeric material such as urethane as a substrate on which a crosslinked gel layer 12 is formed is preferably used. Particularly preferred forms of the long medical device include a guidewire and a catheter.

[0025] The catheter is not particularly limited, and any catheter can be used, for example, a guiding catheter, a penetration catheter, a microcatheter, a balloon catheter, a dilator, etc. The guidewire is also not particularly limited, and any guidewire can be used.

[0026] As more specific configuration examples of the above-mentioned elongated medical device, various configurations such as those shown in the following (a) to (e) can be adopted. (a) A guide wire comprising: a linear core wire; a coating layer provided on at least a portion of the outer periphery of the core wire; and the above-mentioned crosslinked gel layer and a lubricating layer formed on the surface of the coating layer. (b) A guide wire comprising: a linear core wire; a coil layer in which wire is spirally wound around at least a portion of the outer periphery of the core wire; and the above-mentioned crosslinked gel layer and lubricating layer formed on the surface of the coil layer. (c) A guide wire comprising: a linear core wire; a coil layer in which wire is spirally wound around at least a portion of the outer periphery of the core wire; a coating layer provided on the outer periphery of the coil layer; and the above-mentioned crosslinked gel layer and a lubricating layer formed on the surface of the coating layer. (d) A catheter comprising a tubular member and the above-mentioned crosslinked gel layer and lubricating layer formed on the surface of the tubular member. (e) A catheter comprising a tubular member, a balloon disposed at one end of the tubular member, and the crosslinked gel layer and the lubricating layer formed on the surface of the balloon.

[0027] However, the medical device 1 according to this embodiment may have a configuration different from those described above in (a) to (e), and may be a medical device other than a guidewire or a catheter, provided that at least a portion of the surface of the medical device is provided with the above-mentioned crosslinked gel layer and lubricating layer.

[0028] (2) Base material The structure and shape of the substrate 11 in this embodiment are appropriately selected according to the type of medical device 1. The material constituting the substrate 11 is also appropriately selected according to the type of medical device 1, and examples of the material include metal materials, polymeric materials, and ceramic materials, and a combination of multiple types of materials may be used.

[0029] The metal material is not particularly limited as long as it is used for medical devices, particularly medical devices to be inserted or placed in a living body, and examples thereof include stainless steels such as SUS302, SUS304, and SUS316; gold, platinum, titanium, nickel, chromium, cobalt, tungsten, and alloys thereof (e.g., nickel-titanium alloy, nickel-chromium alloy, platinum-nickel alloy, nickel-cobalt alloy, cobalt-chromium alloy, etc.). These may be used alone or in combination of two or more.

[0030] When the material constituting the substrate 11 is a metal material, the surface of the substrate 11 on which the crosslinked gel layer 12 is to be provided may be subjected to a treatment for enhancing the adhesion of the crosslinked gel layer 12. Examples of such treatments include phosphoric acid treatment, ethylene-acrylic acid coating treatment, epoxy adhesive coating treatment, ozone / ultraviolet light treatment, plasma treatment, corona discharge treatment, and flame treatment.

[0031] The polymeric material is not particularly limited as long as it is used for medical devices, particularly medical devices to be inserted or placed in a living body, and examples thereof include polyamide, polyolefins such as polyethylene and polypropylene, polyesters such as polyethylene terephthalate and polybutylene terephthalate, polyurethane, polycarbonate, polyacetal, polyethersulfone, silicone resins, fluororesins, etc. These may be used alone or in combination of two or more.

[0032] Even when the material constituting the substrate 11 is a polymeric material, the surface of the substrate 11 on which the crosslinked gel layer 12 is to be provided may be subjected to a treatment for enhancing the adhesion of the crosslinked gel layer 12. Examples of such treatments include a primer treatment, an oxidation method, a roughening method, etc. Examples of the oxidation method include a corona discharge treatment, a chromic acid treatment, a flame treatment, a hot air treatment, an ozone / ultraviolet light treatment, etc., and examples of the roughening method include a sandblasting method, a solvent treatment method, etc.

[0033] (3) Crosslinked gel layer As described above, the crosslinked gel layer 12 in this embodiment is made of a crosslinked product of polyvinyl alcohol having a carboxy group or a salt thereof. As the salt of the carboxy group (carboxylate), an alkali metal salt or an alkaline earth metal salt is preferable, among which an alkali metal salt is particularly preferable, and a sodium salt is further preferable.

[0034] The polyvinyl alcohol in this embodiment preferably contains 2 mol % or more of a carboxy group or its salt, particularly preferably 3 mol % or more, and more preferably 4 mol % or more. This allows the polyvinyl alcohol having a carboxy group or its salt to react sufficiently with the epoxy group-containing hydrophilic polymer constituting the lubricating layer 13, and allows the lubricating layer 13 to be firmly attached to the crosslinked gel layer 12. The polyvinyl alcohol also preferably contains 10 mol % or less of a carboxy group or its salt, particularly preferably 8 mol % or less, and more preferably 6 mol % or less. This allows a predetermined amount of hydroxyl groups in the polyvinyl alcohol to remain, and a good crosslinked product can be formed.

[0035] The polyvinyl alcohol in this embodiment preferably has a saponification degree of 90 mol% or more, particularly preferably 96 mol% or more, and more preferably 98 mol% or more. This allows a good crosslinked product to be formed via the hydroxyl groups of the polyvinyl alcohol. The upper limit of the saponification degree is not particularly limited and may be 100 mol%, but is usually preferably 99 mol% or less.

[0036] The number average molecular weight (Mn) of the polyvinyl alcohol containing a carboxy group or a salt thereof in this embodiment is preferably 20,000 or more, and more preferably 40,000 or more. The number average molecular weight (Mn) is preferably 1,000,000 or less, and more preferably 200,000 or less. The most preferable number average molecular weight (Mn) is about 100,000.

[0037] The crosslinked polyvinyl alcohol in this embodiment is preferably a chemically crosslinked polyvinyl alcohol. Although a physically crosslinked crosslinked product may be used, a chemically crosslinked crosslinked product has a stronger crosslinked gel layer 12, is less likely to collapse in vivo, and has less volume change due to swelling.

[0038] In the crosslinked product of polyvinyl alcohol, it is preferable that the polyvinyl alcohol molecules are bonded together via acetal bonds, which makes the crosslinked gel layer 12 stronger and reduces the volume change due to swelling.

[0039] In the crosslinked product of polyvinyl alcohol, it is preferable that polyvinyl alcohol is crosslinked by a polyfunctional aldehyde compound. The polyfunctional aldehyde compound can form acetal bonds between polyvinyl alcohols well, so that the crosslinked gel layer 12 obtained is stronger and has less volume change due to swelling. In addition, the polyfunctional aldehyde compound reacts with the hydroxyl group of polyvinyl alcohol but does not react with the carboxyl group or its salt, so that it can selectively crosslink only through the hydroxyl group of polyvinyl alcohol while leaving the carboxyl group or its salt of polyvinyl alcohol.

[0040] The polyfunctional aldehyde compound is not particularly limited as long as it contains two or more aldehyde groups in one molecule, and examples thereof include glutaraldehyde, glyoxal, malondialdehyde, adipic dialdehyde, maleic dialdehyde, phthalaldehyde, isophthalaldehyde, etc. These may be used alone or in combination of two or more. Among the above, glutaraldehyde, which has excellent biological safety, is particularly preferred.

[0041] It is also preferable that the crosslinked gel layer 12 contains polyvinyl alcohol having neither a carboxy group nor a salt thereof, in addition to the above-mentioned polyvinyl alcohol having a carboxy group or a salt thereof. By containing polyvinyl alcohol having neither a carboxy group nor a salt thereof, the crosslinked gel layer 12 is likely to have a desired strength, and it is easy to form a crosslinked gel layer 12 having superior durability. When the crosslinked gel layer 12 contains polyvinyl alcohol having neither a carboxy group nor a salt thereof, the polyvinyl alcohol may form a crosslinked product together with polyvinyl alcohol having a carboxy group or a salt thereof, or may have a structure in which the polyvinyl alcohol is entangled with the crosslinked product formed by polyvinyl alcohol having a carboxy group or a salt thereof.

[0042] When the crosslinked gel layer 12 contains polyvinyl alcohol having neither a carboxy group nor a salt thereof, the ratio of the polyvinyl alcohol to the total polyvinyl alcohol present in the crosslinked gel layer 12 is preferably 5% by mass or more, more preferably 10% by mass or more, and even more preferably 20% by mass or more. Moreover, the ratio is preferably 100% by mass or less, more preferably 80% by mass or less, and even more preferably 60% by mass or less. By having the ratio within these ranges, the durability of the crosslinked gel layer 12 is further improved.

[0043] The lower limit of the thickness of the crosslinked gel layer 12 is preferably 1 μm or more, more preferably 1.5 μm or more, and even more preferably 2 μm or more. This allows the layer to function well as a hydrogel and provide good lubricity to the medical device 1. The upper limit of the thickness of the crosslinked gel layer 12 is preferably 8 μm or less, more preferably 6 μm or less, and even more preferably 4 μm or less. This allows the volume change due to swelling of the crosslinked gel layer 12 to be further reduced.

[0044] (4) Lubricating layer As described above, the lubricating layer 13 in this embodiment is made of an epoxy group-containing hydrophilic polymer.

[0045] The epoxy group-containing hydrophilic polymer preferably contains at least one hydrophilic monomer as a polymerization unit constituting the polymer. Examples of the hydrophilic monomer include acrylamide-based monomers such as dimethylacrylamide; betaine-based monomers such as carboxybetaine, phosphobetaine, and sulfobetaine; alkoxy group-containing (meth)acrylates such as alkoxy group-containing polyether (meth)acrylates such as methoxypolyethyleneglycol acrylate, and alkoxy group-containing alkyl (meth)acrylates such as methoxyethyl acrylate; maleic anhydride-based monomers such as maleic anhydride; (meth)acrylic acid, vinylsulfonic acid, and vinylpyrrolidone. Among these, the hydrophilic polymer preferably contains polymerization units based on at least one monomer selected from the group consisting of acrylamide-based monomers, betaine-based monomers, alkoxy group-containing (meth)acrylates, (meth)acrylic acid, vinylsulfonic acid, and vinylpyrrolidone.

[0046] In addition, the epoxy group-containing hydrophilic polymer may have, as its basic skeleton, an acrylamide-based polymer such as polyacrylamide or a glycidyl methacrylate-dimethylacrylamide copolymer; a maleic anhydride-based polymer such as a methyl vinyl ether-maleic anhydride copolymer; a polyalkylene glycol such as polyethylene glycol or polypropylene glycol; a betaine-based polymer such as polycarboxybetaine, polyphosphobetaine, polysulfobetaine; polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, polyvinylsulfonic acid, or derivatives thereof; or the like, and an epoxy group is introduced into the basic skeleton by, for example, copolymerizing a monomer containing an epoxy group.

[0047] Among the above, from the viewpoints of ease of introduction of epoxy groups and excellent lubricity, acrylamide-based polymers are preferred, and in particular, acrylamide-based polymers having dimethylacrylamide as a monomer unit are preferred, and further, copolymers of 4-hydroxybutyl acrylate glycidyl ether and dimethylacrylamide are preferred.

[0048] In the present embodiment, the epoxy group-containing hydrophilic polymer preferably contains 1 mol % or more of epoxy groups, particularly preferably 2 mol % or more, and more preferably 4 mol % or more, based on 100 mol % of all polymerized units constituting the polymer. This allows the epoxy group-containing hydrophilic polymer to fully react with the carboxyl group or its salt of the polyvinyl alcohol in the crosslinked gel layer 12, and the lubricating layer 13 can be firmly attached to the crosslinked gel layer 12. In addition, the epoxy group-containing hydrophilic polymer preferably contains 20 mol % or less of epoxy groups, particularly preferably 15 mol % or less, and more preferably 10 mol % or less. This allows the lubricating property of the lubricating layer 13 to be well maintained without impeding the hydrophilicity of the hydrophilic polymer.

[0049] The number average molecular weight (Mn) of the epoxy group-containing hydrophilic polymer in this embodiment is preferably 20,000 or more, and more preferably 40,000 or more. The number average molecular weight (Mn) is preferably 1,000,000 or less, and more preferably 200,000 or less. The most preferable number average molecular weight (Mn) is about 100,000.

[0050] The thickness of the lubricating layer 13 is preferably 1 μm or more as a lower limit, particularly preferably 1.5 μm or more, and more preferably 2 μm or more. This allows the lubricating layer 13 to fully exhibit lubricity to the living body. The thickness of the lubricating layer 13 is preferably 8 μm or less as an upper limit, particularly preferably 6 μm or less, and more preferably 4 μm or less. This allows the hydrophilic polymer that is not bonded to the crosslinked product of polyvinyl alcohol in the crosslinked gel layer 12 to be effectively prevented from falling off from the lubricating layer 13.

[0051] 2. Manufacturing method A preferred method for producing the medical device 1 according to this embodiment will be described. First, a coating film of polyvinyl alcohol having a carboxy group or a salt thereof is formed on the substrate 11. This coating film can be formed, for example, by immersing the substrate in an aqueous solution of polyvinyl alcohol having a carboxy group or a salt thereof and applying it onto the substrate 11 by a method of withdrawing the polyvinyl alcohol at a constant speed, or by immersing the substrate 11 in an aqueous solution of polyvinyl alcohol having a carboxy group or a salt thereof and then drying the substrate. In the case of a coating method of withdrawing at a constant speed, the coating film thickness can be controlled by changing the withdrawal speed. If the withdrawal speed is increased, the film thickness becomes thicker, and if the withdrawal speed is decreased, the film thickness becomes thinner. Therefore, by setting an optimal withdrawal speed for each layer, it is possible to apply a film of any thickness.

[0052] Next, the polyvinyl alcohol is crosslinked to form a crosslinked gel layer 12 while leaving the carboxyl group or salt of the polyvinyl alcohol. As described above, this crosslinking is preferably chemical crosslinking, and in particular, chemical crosslinking by a polyfunctional aldehyde compound is preferable. The chemical crosslinking of the polyvinyl alcohol by the polyfunctional aldehyde compound can be performed, for example, by immersing the substrate 11 on which the coating film of the polyvinyl alcohol is formed in a solution (preferably an aqueous solution) of the polyfunctional aldehyde compound with a hydrogen ion exponent (pH) of less than 2, and then drying the substrate. The polyfunctional aldehyde undergoes chemical crosslinking with any hydroxyl group at room temperature in an acidic environment. Any acid can be used for acidification, but acetic acid, citric acid, hydrochloric acid, etc. are preferably used because they are water-soluble.

[0053] Finally, a lubricating layer 13 made of an epoxy group-containing hydrophilic polymer is formed on the crosslinked gel layer 12, and the carboxy group or its salt of the polyvinyl alcohol is reacted with the epoxy group of the epoxy group-containing hydrophilic polymer. The lubricating layer 13 made of an epoxy group-containing hydrophilic polymer can be formed by applying an aqueous solution of the epoxy group-containing hydrophilic polymer onto the crosslinked gel layer 12 by a conventional method, or by immersing the substrate 11 on which the crosslinked gel layer 12 has been formed in an aqueous solution of the epoxy group-containing hydrophilic polymer, and then drying it.

[0054] The above-described embodiments are described for the purpose of facilitating understanding of the present invention, and are not described for the purpose of limiting the present invention. Therefore, each element disclosed in the above embodiment is intended to include all design modifications and equivalents that fall within the technical scope of the present invention.

[0055] For example, another layer may be provided between the substrate 11 and the crosslinked gel layer 12 . EXAMPLES

[0056] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0057] Example 1 1. Formation of polyvinyl alcohol coating As polyvinyl alcohol having a carboxy group or its salt, polyvinyl alcohol (saponification degree: about 99 mol%, number average molecular weight (Mn): 100,000) containing about 4 mol% of -COONa group, about 95 mol% of -OH group, and about 1 mol% of -OCOCH3 group was mixed and dissolved in a weight ratio of 4:1 to prepare an aqueous solution (concentration: 5 mass%). A metal guide wire made of SUS304 as a substrate was immersed in the aqueous solution and pulled out at a constant speed of 5 mm / sec, thereby applying the aqueous solution to the surface of the substrate. The substrate was then heated at 70°C for 60 minutes and dried to form a coating film of polyvinyl alcohol.

[0058] 2. Formation of cross-linked gel layer The substrate having the polyvinyl alcohol coating film obtained in step 1 was immersed in a glutaraldehyde aqueous solution having a concentration of 12.5% ​​by mass (further containing citric acid having a concentration of 1% by mass) for 60 minutes. Thereafter, the substrate having the polyvinyl alcohol coating film was taken out and heated and dried at 70°C for 60 minutes to form a crosslinked gel layer formed by chemically crosslinking the polyvinyl alcohol. The thickness of this crosslinked gel layer was about 1 μm.

[0059] 3. Formation of a lubricating layer As an epoxy group-containing hydrophilic polymer, an aqueous solution (concentration: 10% by mass) of a random copolymer of 4-hydroxybutyl acrylate glycidyl ether (4-HBAGE) and dimethylacrylamide (having epoxy groups derived from 4-HBAGE, epoxy group content: 10 mol%, number average molecular weight (Mn): 100,000) was prepared. The substrate after the formation of the crosslinked gel layer obtained in the above step 2 was immersed in the aqueous solution of the epoxy group-containing hydrophilic polymer, and the aqueous solution was applied to the exposed surface of the crosslinked gel layer by pulling it out at a constant speed of 10 mm / sec. Thereafter, the substrate was heated at 120°C for 60 minutes and dried to form a lubricating layer having a thickness of 3.00 μm. It is considered that the formation of this lubricating layer caused a reaction between the -COONa group of the polyvinyl alcohol in the crosslinked gel layer and the epoxy group of the epoxy group-containing hydrophilic polymer in the lubricating layer at the interface between the crosslinked gel layer and the lubricating layer. In this way, a laminate consisting of a layer structure of substrate / crosslinked gel layer / lubricating layer was obtained.

[0060] Comparative Example 1 A laminate having a layer structure of a substrate / crosslinked gel layer / lubricating layer according to Comparative Example 1 was obtained in the same manner as in Example 1, except that a lubricating layer having a thickness of 2.95 μm was formed using an aqueous solution (concentration: 5 mass%) in which polyvinyl alcohol (saponification degree: about 98%, number average molecular weight (Mn): 260,000, having neither a carboxy group nor a salt thereof) was dissolved. Note that in this laminate according to Comparative Example 1, the polyvinyl alcohol constituting the crosslinked gel layer has neither a carboxy group nor a salt thereof, and therefore the polyvinyl alcohol is not chemically crosslinked.

[0061] Comparative Example 2 Except for omitting step 2 and setting the thickness of the lubricating layer to 2.25 μm, a laminate having a layer structure of substrate / crosslinked gel layer / lubricating layer according to Comparative Example 2 was obtained in the same manner as in Example 1. Note that, in the laminate according to Comparative Example 2, since step 2 was omitted, the polyvinyl alcohol in the crosslinked gel layer was not chemically crosslinked.

[0062] [Test Example 1] (Evaluation of volume change due to swelling) The laminates produced in the examples and comparative examples were immersed in physiological saline for 20 seconds. After being removed from the physiological saline, the change in film thickness due to swelling of the lubricating layer was observed using a laser microscope.

[0063] As a result, the thickness of the laminate according to Example 1 was 3.00 μm when dry and 3.25 μm when swollen. In other words, it was revealed that the laminate expanded slightly by immersing in physiological saline, but the difference was small.

[0064] On the other hand, in the laminates according to Comparative Examples 1 and 2, the lubricating layer was washed away after immersion in physiological saline, and the thickness of the lubricating layer could not be observed. This is thought to be because the lubricating layers in these examples had weak gel strength and were dissolved and diffused in physiological saline.

[0065] [Test Example 2] (Slip durability test) A slip durability test was carried out on the laminates produced in the examples and comparative examples. Specifically, in an underwater environment, the laminate was sandwiched between a urethane roller (manufactured by Misumi Corporation, product name "AXFM-D25-L15-V8-N") and a stainless steel plate (SUS304 plate, 30 x 30 mm), and one end of the laminate was pulled out under a load of 0.981 N, and the resistance value (gf) at that time was measured using a load cell connected to the laminate. This series of measurements was then repeated 50 times using the same laminate.

[0066] The results of the above measurements are shown in Fig. 2. In the graph shown in Fig. 2, the horizontal axis indicates the number of measurements, and the vertical axis indicates the resistance value (gf). As shown in the graph, in the laminate according to Example 1, the resistance value does not change much from the initial value even if the laminate is repeatedly pulled out. Therefore, it is understood that the laminate according to Example 1 maintains the lubricating layer well and continues to exhibit excellent lubricity even if the laminate is repeatedly pulled out.

[0067] In contrast, in Comparative Example 1, which does not contain polyvinyl alcohol containing a carboxy group and its salt, and Comparative Example 2, which does not contain glutaraldehyde as a crosslinking agent, the resistance value increases with repeated pulling. Therefore, in Comparative Examples 1 and 2, the lubricating layer peels off due to abrasion with repeated pulling, and it is therefore impossible to maintain lubricity.

[0068] As is clear from the results of Test Examples 1 and 2, the laminate obtained in the Examples had little volume change due to swelling of the lubricating layer, and the crosslinked gel layer and the lubricating layer were unlikely to flow out. Furthermore, the laminate obtained in the Examples showed excellent lubricity even when used repeatedly. [Industrial Applicability]

[0069] The medical device according to the present invention is suitable as, for example, a guide wire, a catheter, an artificial blood vessel, and the like. [Explanation of symbols]

[0070] 1. Medical devices 11...Base material 12...Crosslinked gel layer 13...Lubricating layer

Claims

1. A substrate; A crosslinked gel layer provided on the substrate; a lubricating layer provided on the opposite side of the crosslinked gel layer from the substrate; It is equipped with the crosslinked gel layer is made of a crosslinked product of polyvinyl alcohol having a carboxy group or a salt thereof, The lubricating layer is made of an epoxy group-containing hydrophilic polymer. A medical device characterized by:

2. The medical device according to claim 1, characterized in that the cross-linked product of the polyvinyl alcohol is obtained by chemically cross-linking the polyvinyl alcohol.

3. The medical device according to claim 2, characterized in that the polyvinyl alcohol molecules are bonded to each other by acetal bonds.

4. The medical device according to any one of claims 1 to 3, characterized in that the epoxy group-containing hydrophilic polymer contains polymerization units based on at least one monomer selected from the group consisting of an acrylamide-based monomer, a betaine-based monomer, an alkoxy group-containing (meth)acrylate, (meth)acrylic acid, vinyl sulfonic acid, and vinylpyrrolidone.

5. 5. The medical device according to claim 1, which is a medical device inserted or placed inside a living body.

6. forming a coating film of polyvinyl alcohol having a carboxy group or a salt thereof on a substrate; crosslinking the polyvinyl alcohol to form a crosslinked gel layer while leaving the carboxy group or a salt thereof; A lubricating layer made of an epoxy group-containing hydrophilic polymer is formed on the crosslinked gel layer, and a carboxy group or a salt thereof of the polyvinyl alcohol is reacted with an epoxy group of the epoxy group-containing hydrophilic polymer. A method for manufacturing a medical device.

7. The method for producing a medical device according to claim 6, characterized in that the polyvinyl alcohol is chemically crosslinked to form the crosslinked gel layer.

8. The method for producing a medical device according to claim 7, characterized in that the chemical crosslinking is performed by forming an acetal bond between the polyvinyl alcohol and the polyvinyl alcohol using a polyfunctional aldehyde compound.

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