JP7660447B2 - Medical devices and methods for manufacturing medical devices - Google Patents

Description

The present invention relates primarily to medical devices suitable for insertion or placement inside a living body and methods for manufacturing the same.

Medical devices that are inserted into the body, such as guidewires, stents, and catheters, are required to have lubricity with respect 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.

For this reason, a lubricating layer made of a hydrophilic polymer or the like is formed on the surface of such medical devices. A typical example of a hydrophilic polymer is polyvinyl alcohol, but this hydrophilic polymer alone tends to collapse in layer structure and is easily detached from the medical device, which is problematic from the standpoint of safety. Furthermore, it tends to swell and increase in volume, which is problematic from the standpoint of operability of the medical device.

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, with the ends of the hydrophilic polymer blocks being capped with phosphorylcholine moieties.

Re-table No. 2014-162872 Patent No. 6066366

However, both Patent Documents 1 and 2 require block polymers with complex structures.

The present invention was made in consideration of these circumstances, and aims to provide a medical device with a surface structure that does not require a block polymer with a complex structure, has lubricity, is strong, changes in volume little due to swelling, and does not dissolve or wash away in water, and a method for manufacturing the same.

In order to achieve the above object, first, the present invention provides a medical device comprising a substrate, a cross-linked gel layer provided on the substrate, and a lubricating layer provided on the cross-linked gel layer on the side opposite the substrate, the cross-linked gel layer being made of a cross-linked product of polyvinyl alcohol having a carboxy group or a salt thereof, and the lubricating layer being made of an epoxy group-containing hydrophilic polymer (Invention 1).

In the above invention (Invention 1), it is preferable that the cross-linked product of the polyvinyl alcohol is a product of chemically cross-linking the polyvinyl alcohol (Invention 2).

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

In the above inventions (Inventions 1 to 3), it is preferable that the epoxy group-containing hydrophilic polymer 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).

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).

Secondly, the present invention provides a method for manufacturing a medical device, which comprises 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).

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

In the above invention (Invention 7), it is preferable that the chemical crosslinking is performed by forming an acetal bond between the polyvinyl alcohol and the polyvinyl alcohol using a polyfunctional aldehyde compound (Invention 8).

The surface 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 of the medical device according to the present invention, it is possible to manufacture a medical device having a surface 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.

FIG. 1 is a schematic cross-sectional view of a medical device according to one embodiment of the present invention. 1 is a graph showing the results of a slip durability test performed in Test Example 2.

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 to 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.

The cross-linked gel layer 12 in the medical device 1 having the above configuration is made of a cross-linked product of polyvinyl alcohol, and is therefore strong and does not easily crumble even in the body. Therefore, it is difficult to detach from the base material 11, and the generation of fine particles and the like can be suppressed, resulting in high safety. In addition, since the cross-linked gel layer 12 is made of a cross-linked product of polyvinyl alcohol, there is little change in volume due to swelling, and even if it swells, it has excellent flexibility, so the operability of the medical device 1 is not hindered. For example, if the medical device 1 is a guidewire, if the cross-linked 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 cross-linked gel layer 12 can prevent such a decrease in operability.

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 in 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 from the substrate 11. It is preferable that a reaction product between the carboxy group or its salt in the polyvinyl alcohol and the epoxy group in the epoxy group-containing hydrophilic polymer is present at the interface between the crosslinked gel layer 12 and the lubricating layer 13.

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

1. Each Element (1) Medical Device The type of medical device 1 according to the present embodiment is not particularly limited as long as it requires lubricity for biological tissue, but it is generally preferable that the medical device be a medical device that is inserted or placed inside a living body.

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, endoscope overtubes, etc.), artificial blood vessels, artificial heart valves, and artificial organs.

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 surface made of a polymeric material such as urethane as a substrate on which a crosslinked gel layer 12 is formed is preferable. Particularly suitable forms of the long medical device include a guidewire and a catheter.

The catheter is not particularly limited, and any catheter can be used, such as 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.

As more specific configuration examples of the above-mentioned elongated medical device, various configurations such as those shown in (a) to (e) below 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.

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, as long as at least a portion of the surface of the medical device is provided with the above-mentioned crosslinked gel layer and lubricating layer.

(2) Substrate The structure and shape of the substrate 11 in this embodiment are appropriately selected depending on the type of medical device 1. The material constituting the substrate 11 is also appropriately selected depending on 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.

Metal materials are not particularly limited as long as they are used in medical devices, particularly medical devices that are inserted or placed in a living body, and examples 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.

When the material constituting the substrate 11 is a metal material, the surface of the substrate 11 on which the cross-linked gel layer 12 is provided may be subjected to a treatment to enhance the adhesion of the cross-linked 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.

The polymeric material is not particularly limited as long as it is used in medical devices, particularly medical devices that are 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, and fluororesins. These may be used alone or in combination of two or more.

Even when the material constituting the substrate 11 is a polymeric material, the surface of the substrate 11 on which the cross-linked gel layer 12 is provided may be subjected to a treatment to enhance the adhesion of the cross-linked gel layer 12. Examples of such treatments include primer treatment, oxidation, and roughening. Examples of oxidation methods include corona discharge treatment, chromic acid treatment, flame treatment, hot air treatment, ozone/ultraviolet light treatment, and the like, and examples of roughening methods include sandblasting and solvent treatment.

(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.

In the present embodiment, the polyvinyl alcohol preferably contains 2 mol % or more of carboxyl groups or their salts, more preferably 3 mol % or more, and even more preferably 4 mol % or more. This allows the polyvinyl alcohol having the carboxyl groups or their salts to react sufficiently with the epoxy group-containing hydrophilic polymer constituting the lubricating layer 13, and allows the lubricating layer 13 to be firmly adhered to the crosslinked gel layer 12. In addition, the polyvinyl alcohol preferably contains 10 mol % or less of carboxyl groups or their salts, more preferably 8 mol % or less, and even 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.

In the present embodiment, the polyvinyl alcohol preferably has a degree of saponification of 90 mol% or more, particularly preferably 96 mol% or more, and even 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 degree of saponification is not particularly limited and may be 100 mol%, but is usually preferably 99 mol% or less.

In this embodiment, the number average molecular weight (Mn) of the polyvinyl alcohol containing a carboxy group or a salt thereof 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.

In this embodiment, the cross-linked polyvinyl alcohol is preferably a chemically cross-linked polyvinyl alcohol. Although a physically cross-linked cross-linked product may be used, a chemically cross-linked cross-linked product has a stronger cross-linked gel layer 12, is less likely to crumble in vivo, and undergoes less volume change due to swelling.

In the cross-linked polyvinyl alcohol, it is preferable that the polyvinyl alcohol molecules are bonded together via acetal bonds. This makes the cross-linked gel layer 12 stronger and reduces the volume change due to swelling.

In the above-mentioned crosslinked polyvinyl alcohol, it is preferable that the polyvinyl alcohol is crosslinked by a polyfunctional aldehyde compound. The polyfunctional aldehyde compound can effectively form acetal bonds between the polyvinyl alcohols, and therefore the resulting crosslinked gel layer 12 is stronger and undergoes less volume change due to swelling. In addition, the polyfunctional aldehyde compound reacts with the hydroxyl groups of the polyvinyl alcohol but does not react with the carboxyl groups or salts thereof, and therefore can selectively crosslink only through the hydroxyl groups of the polyvinyl alcohol while leaving the carboxyl groups or salts thereof in the polyvinyl alcohol.

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, and the like. These may be used alone or in combination of two or more. Among the above, glutaraldehyde, which has excellent biological safety, is particularly preferred.

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

When the cross-linked gel layer 12 contains polyvinyl alcohol that does not have either a carboxy group or a salt thereof, the ratio of the polyvinyl alcohol to the total polyvinyl alcohol present in the cross-linked 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 cross-linked gel layer 12 is further improved.

The thickness of the cross-linked gel layer 12 is preferably 1 μm or more as a lower limit, particularly 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 thickness of the cross-linked gel layer 12 is preferably 8 μm or less as an upper limit, particularly preferably 6 μm or less, and even more preferably 4 μm or less. This allows the volume change due to swelling of the cross-linked gel layer 12 to be kept to a minimum.

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

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 methoxypolyethylene glycol acrylate, and alkoxy group-containing alkyl (meth)acrylates such as methoxyethyl acrylate; maleic anhydride-based monomers such as maleic anhydride; (meth)acrylic acid, vinyl sulfonic acid, vinyl pyrrolidone, and the like. Among these, the hydrophilic polymer preferably contains a polymerization unit 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, vinyl sulfonic acid, and vinyl pyrrolidone.

Epoxy group-containing hydrophilic polymers may also be hydrophilic polymers having a basic skeleton such as acrylamide-based polymers, such as polyacrylamide and glycidyl methacrylate-dimethylacrylamide copolymer; maleic anhydride-based polymers, such as methyl vinyl ether-maleic anhydride copolymer; polyalkylene glycols, such as polyethylene glycol and polypropylene glycol; betaine-based polymers, such as polycarboxybetaine, polyphosphobetaine, and polysulfobetaine; polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, polyvinylsulfonic acid, and derivatives thereof, and having epoxy groups introduced into the basic skeleton by copolymerizing a monomer containing an epoxy group, for example.

Among the above, acrylamide-based polymers are preferred from the viewpoint of ease of introduction of epoxy groups and excellent lubricity, 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.

In the present embodiment, the epoxy group-containing hydrophilic polymer preferably contains 1 mol % or more of epoxy groups, more preferably 2 mol % or more, and even 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 salt thereof 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, more preferably 15 mol % or less, and even more preferably 10 mol % or less. This allows the lubricity of the lubricating layer 13 to be well maintained without interfering with the hydrophilicity of the hydrophilic polymer.

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.

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 even 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 even more preferably 4 μm or less. This effectively prevents the hydrophilic polymer that is not bonded to the crosslinked product of polyvinyl alcohol in the crosslinked gel layer 12 from falling off the lubricating layer 13.

2. Manufacturing Method A preferred manufacturing method for 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, so that an arbitrary film thickness can be applied by setting an optimal withdrawal speed for each layer.

Next, the polyvinyl alcohol is crosslinked to form a crosslinked gel layer 12 while leaving the carboxyl groups or salts 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.

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 a salt thereof 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 in a conventional manner, 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.

The above-described embodiments are described to facilitate understanding of the present invention, and are not described to limit the present invention. Therefore, each element disclosed in the above embodiments is intended to include all design modifications and equivalents that fall within the technical scope of the present invention.

For example, other layers may be provided between the substrate 11 and the cross-linked gel layer 12.

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

Example 1
1. Formation of polyvinyl alcohol coating film As polyvinyl alcohol having a carboxy group or a salt thereof, 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 -OCOCH ₃ 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 polyvinyl alcohol coating film.

2. Formation of crosslinked gel layer The substrate having the polyvinyl alcohol coating film obtained in step 1 above 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 dried by heating 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.

3. Formation of 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 withdrawing the substrate at a constant speed of 10 mm/sec. Thereafter, the substrate was dried by heating at 120°C for 60 minutes 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 having a layer structure of substrate/crosslinked gel layer/lubricating layer was obtained.

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, containing 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 does not contain either a carboxy group or a salt thereof, and therefore the polyvinyl alcohol is not chemically crosslinked.

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.

[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.

As a result, the laminate of Example 1 had a thickness of 3.00 μm when dry and 3.25 μm when swollen. In other words, it was revealed that the laminate expanded slightly when immersed in saline, but the difference was small.

On the other hand, in the laminates of Comparative Example 1 and Comparative Example 2, the lubricating layer was washed away after immersion in saline solution, and the thickness of the lubricating layer could not be observed. This is thought to be because the gel strength of the lubricating layer in these examples was weak, and it dissolved and diffused in the saline solution.

[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.

Figure 2 shows the results of the above measurements. In the graph shown in Figure 2, the horizontal axis represents the number of measurements, and the vertical axis represents the resistance value (gf). As shown in the graph, in the laminate of Example 1, the resistance value does not change much from the initial value, even if the laminate is repeatedly pulled out. Therefore, it can be seen that the lubricating layer of the laminate of Example 1 is well maintained and the laminate can continue to exhibit excellent lubricity, even if the laminate is repeatedly pulled out.

In contrast, in Comparative Example 1, which does not contain polyvinyl alcohol containing a carboxy group or 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 as a result, lubricity cannot be maintained.

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 less likely to flow out. Furthermore, the laminate obtained in the examples showed excellent lubricity even when used repeatedly.

The medical device of the present invention is suitable as, for example, a guidewire, a catheter, an artificial blood vessel, etc.

1... medical device 11... substrate 12... crosslinked gel layer 13... lubricating layer

Claims (8)

A substrate;
A crosslinked gel layer provided on the substrate;
a lubricating layer provided on the opposite side of the crosslinked gel layer to the substrate,
the crosslinked gel layer is made of a crosslinked product of polyvinyl alcohol having a carboxy group or a salt thereof,
A medical device characterized in that the lubricating layer is made of an epoxy group-containing hydrophilic polymer. The medical device according to claim 1, characterized in that the cross-linked polyvinyl alcohol is obtained by chemically cross-linking the polyvinyl alcohol. The medical device according to claim 2, characterized in that the polyvinyl alcohol molecules are bonded together by acetal bonds. 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. The medical device according to any one of claims 1 to 4, characterized in that it is a medical device to be inserted or placed inside a living body. 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 method for manufacturing a medical device, comprising forming a lubricating layer made of an epoxy group-containing hydrophilic polymer on the crosslinked gel layer, and reacting a carboxy group or a salt thereof of the polyvinyl alcohol with an epoxy group of the epoxy group-containing hydrophilic polymer. The method for manufacturing a medical device according to claim 6, characterized in that the polyvinyl alcohol is chemically crosslinked to form the crosslinked gel layer. The method for manufacturing 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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