Medical tool and method for producing same

Abstract

The present invention provides a means capable of suppressing a deterioration of lubricity due to abrasion in a medical tool. A medical tool according to one embodiment of the present invention is provided with a base material layer, and a surface lubricating layer supported on at least a part of the base material layer. The surface lubricating layer contains a block copolymer having a constituent unit (A) derived from a reactive monomer having an epoxy group and a constituent unit (B) derived from a hydrophilic monomer. The number of fine particles having a particle diameter of 10 μm or more and less than 25 μm, detected by a fine particle test for the surface lubricating layer, is less than 2000.

Description

Medical devices and methods for manufacturing the same

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

[0002] Medical devices inserted into the body, such as catheters, guidewires, indwelling needles, and sheaths, are required to exhibit excellent lubricity in order to reduce tissue damage, such as blood vessels, and to improve the operator's operability. For this reason, medical devices coated with hydrophilic polymers that have lubricating properties on the surface of the base layer have been developed and put into practical use.

[0003] For example, Japanese Patent Publication No. 8-33704 (corresponding to U.S. Patent 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 causes the substrate of the medical device to swell, immersing the substrate of the medical device in this polymer solution to swell it, and further crosslinking or polymerizing the polymer on the surface of the substrate. The above document also discloses that it is preferable to use a block copolymer consisting of hydrophilic parts that exhibit lubricity and parts having epoxy groups as the water-soluble or water-swellable polymer. When such a block copolymer is used, the epoxy groups of the block copolymer can be crosslinked by heating, and a surface lubricating layer that is relatively difficult to peel off can be formed.

[0004] However, the inventors have found that when the medical devices described in the above-mentioned literature are rubbed against the body (for example, when passing a catheter through a narrowed or blocked blood vessel, the surface of the catheter rubs against the inner wall of the blood vessel or substances blocking the blood vessel (such as thrombi or plaque)), the lubricity (sliding properties) may decrease.

[0005] This invention has been made in view of the above circumstances, and aims to provide a means that can suppress the decrease in lubricity (sliding properties) due to friction in medical devices.

[0006] The inventors diligently conducted research to solve the above problems. In the process, they coated the surface of a substrate with a coating liquid containing the aforementioned block copolymer, formed a coating film by crosslinking the epoxy groups of the block copolymer through heat treatment, and then performed a cleaning treatment. Surprisingly, they found that medical devices that had undergone a cleaning treatment using a specific organic solvent exhibited excellent lubricity (sliding properties) even after abrasion. In subsequent investigations, they found that such a cleaning treatment reduced the number of fine particles detected in a fine particle test; furthermore, they found that the reduction in fine particles suppressed the decrease in lubricity (sliding properties) due to abrasion, thus completing the present invention.

[0007] The above problems can be solved by the present invention having the following configuration, and the present invention encompasses the following aspects and forms.

[0008] One aspect of the present invention is: 1. A medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer comprises a block copolymer having a reactive monomer having an epoxy group (A) and a hydrophilic monomer having a hydrophilic monomer (B), and the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubricating layer is less than 2000; 2. In the medical device described in 1. above, it is preferable that the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by the fine particle test is less than 900; 3. In the medical device described in 1. or 2. above, it is preferable that the number of fine particles with a particle size of 25 μm or more and less than 400 μm detected by the fine particle test is less than 20; 4. In the medical device described in 1. to 3. above, it is preferable that the number of fine particles with a particle size of 25 μm or more and less than 400 μm detected by the fine particle test is less than 20; 4. In the medical device described in any of the above, the reactive monomer having the epoxy group preferably comprises at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether; 5. In the medical device described in any of the above 1 to 4, the hydrophilic monomer preferably comprises at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone; 6. In the medical device described in any of the above 1 to 5, the molar ratio of constituent unit (A) to constituent unit (B) in the block copolymer is preferably 1:2 to 1:100; 7. In the medical device described in any of the above 1 to 6, the sliding resistance value in the sliding test of the surface lubricating layer is preferably less than 50 gf; 8. In the medical device described in any of the above, the medical device is preferably a catheter, a guidewire, an indwelling needle, or a sheath.

[0009] Another aspect of the present invention is: 9. A method for manufacturing a medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, comprising: preparing a coating liquid containing a block copolymer having a reactive monomer (A) having an epoxy group and a constituent unit (B) having a hydrophilic monomer, and a solvent; applying the coating liquid onto the base layer to form a coating film on the base layer; heating the coating film at a temperature of 110°C to 160°C for 1 hour or more; and washing the coating film after heating with a cleaning liquid containing at least one organic solvent selected from acetone, tetrahydrofuran, and N,N-dimethylformamide, or a cleaning liquid containing the organic solvent and water; 10. In the method for manufacturing a medical device described in 9. above, it is preferable to further heat the coating film after washing at a temperature of 110°C to 160°C for 1 hour or more.

[0010] This is a partial cross-sectional view of a catheter as a typical embodiment of the medical device according to the present invention. This is a partial cross-sectional view schematically showing an example of a different surface lamination configuration as an application example of the embodiment in Figure 1. This is a diagram showing the configuration of each part of a test apparatus for performing a particulate matter test of the medical device according to this embodiment. This is a diagram showing the operating state when the test method shown in the example is carried out. This is a diagram showing the operating state when the test method shown in the example is carried out. This is a schematic diagram showing a test apparatus for performing a sliding test of the medical device according to this embodiment.

[0011] Embodiments of the present invention will be described below. However, the present invention is not limited to the embodiments described below, and can be modified in various ways within the scope of the claims. Furthermore, the embodiments described herein can be combined in any way to form other embodiments. The dimensional ratios in the drawings are exaggerated for illustrative purposes and may differ from actual ratios. Also, when describing embodiments of the present invention with reference to the drawings, the same elements are denoted by the same reference numerals in the description of the drawings, and redundant explanations are omitted.

[0012] <Medical Device> A medical device according to one embodiment of the present invention comprises a base layer and a surface lubricating layer supported on at least a portion of the base layer. The surface lubricating layer contains a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubricating layer is less than 2000. The medical device according to this embodiment can suppress the decrease in lubricity (sliding properties) due to friction. A medical device having the above configuration will also be referred to as "medical device according to the present invention" or "medical device" below.

[0013] In this specification, a constituent unit (A) derived from a reactive monomer having an epoxy group is also simply referred to as "constituent unit (A) according to the present invention" or "constituent unit (A)". In this specification, a constituent unit (B) derived from a hydrophilic monomer is also simply referred to as "constituent unit (B) according to the present invention" or "constituent unit (B)". In this specification, a block copolymer having constituent units (A) and (B) is also simply referred to as "block copolymer according to the present invention" or "block copolymer". In this specification, the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubrication layer is also simply referred to as "number of fine particles with a particle size of 10 μm or more and less than 25 μm". In this specification, the number of fine particles with a particle size of 25 μm or more and less than 400 μm detected by a fine particle test is also simply referred to as "number of fine particles with a particle size of 25 μm or more and less than 400 μm".

[0014] In this specification, when a constituent unit is defined as "derived from" a monomer, it means that the constituent unit is produced by a condensation reaction of the reactive groups of the corresponding monomer, by the cleavage of the epoxy groups of the corresponding monomer, and / or by the cleavage of the ethylenically unsaturated groups (polymerizable unsaturated double bonds) of the corresponding monomer.

[0015] In this specification, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Therefore, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Therefore, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups. Furthermore, similarly, the term "(meth)acrylate" encompasses both acrylate and methacrylate. For example, the term "alkoxyalkyl (meth)acrylate" encompasses both alkoxyalkyl acrylate and alkoxyalkyl methacrylate.

[0016] In this specification, the range "X to Y" includes X and Y and means "X or greater and Y or less". Furthermore, "X and / or Y" means at least one of X and Y and includes X alone, Y alone, and combinations of X and Y.

[0017] Unless otherwise specified, measurements of operation and physical properties are performed under room temperature (20-25°C) / relative humidity of 40-50% RH.

[0018] The medical device according to the present invention comprises a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer contains a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and is characterized in that the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubricating layer is less than 2000. The medical device having the above configuration exhibits excellent lubricity (sliding properties) even after friction.

[0019] The mechanism by which the medical device according to the present invention achieves the effects described above is not fully understood and is not bound by any theory, but the following mechanism is hypothesized. One of the features of the medical device according to the present invention is that the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubrication layer is less than 2000. Here, "the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubrication layer" refers to the number of fine particles with a particle size of 10 μm or more and less than 25 μm that are generated by performing the fine particle test described in the examples below on the medical device. In this fine particle test, the use of the medical device in a living body is simulated, and a predetermined sliding operation is performed on the medical device using a predetermined test apparatus. At this time, among the part of the surface lubrication layer peeled off from the base material layer of the medical device, those with a particle size of 10 μm or more and less than 25 μm are the fine particles with a particle size of 10 μm or more and less than 25 μm.

[0020] As mentioned above, with conventional medical devices, when the medical device was rubbed in the body (for example, when a catheter was passed through a narrowed or blocked blood vessel), the lubricity (sliding properties) sometimes decreased (the sliding resistance increased). It is thought that the cause of such a decrease in lubricity (sliding properties) was that some of the surface lubricating layer (fine particles) peeled off from the base material layer, and these fine particles became trapped between the medical device and the biological tissue, resulting in decreased lubricity (sliding properties) and increased sliding resistance. In particular, when rubbing was performed frequently at the same location, the lubricity (sliding properties) sometimes decreased significantly, and it is presumed that this was due to the accumulation of fine particles between the medical device and the biological tissue due to repeated rubbing. The medical device according to the present invention has a small number of fine particles, less than 2000, that are between 10 μm and 25 μm in size, and is less prone to generating fine particles, so the situation in which fine particles become trapped or accumulate between the medical device and the biological tissue is less likely to occur. As a result, the medical device according to the present invention is considered less susceptible to a decrease in lubricity (sliding properties) due to friction.

[0021] As described in Japanese Patent Publication No. 2024-172039, even before the filing of this application, medical devices were required to have durability that reduces peeling during use, in order to meet the approval standards outlined in USP <787> and <788>, etc. Conventionally, improvements in the durability of the surface lubricating layer could be achieved, for example, by prolonged heating and drying, but it was known that this came at the expense of reduced lubricity. The manufacturing method of the medical device according to the present invention, described later, is characterized by applying a coating liquid containing a block copolymer onto a substrate layer, performing a heat treatment, and then cleaning the coating film with a cleaning solution containing a specific solvent. According to this manufacturing method, it is possible to provide a medical device according to the present invention with a reduced number of microparticles, which was impossible to achieve with conventional technology. Furthermore, according to this manufacturing method, it is possible to provide a medical device according to the present invention that maintains good lubricity, which had to be sacrificed in conventional technology, while also having a reduced number of microparticles.

[0022] A preferred embodiment of the medical device according to the present invention will be described below with reference to the attached drawings.

[0023] Figure 1 is a partial cross-sectional view of a catheter as a typical embodiment of the medical device according to the present invention. Here, Figure 1 is a cross-sectional view of the catheter cut parallel to the axial direction. Figure 2 is a schematic partial cross-sectional view showing an example of a different configuration of the surface layered structure as an application example of the embodiment (catheter) shown in Figure 1.

[0024] As shown in Figures 1 and 2, the catheter as a medical device 200 in this embodiment is composed of a tubular body, and as shown in Figures 1 and 2, a lumen 203 is formed in the approximate center of the catheter body, extending along its entire length. In this embodiment, the medical device 200 comprises a base layer 201 and a surface lubricating layer 202 containing a block copolymer, which is provided on at least a part of the base layer 201 (in the figures, an example is shown where it is provided on the entire surface of the base layer 201 in the drawing). In Figures 1 and 2, the surface lubricating layer 202 is formed on the outer surface of the tubular base layer 201, but the present invention is not limited to the above embodiment, and may take any form, such as being formed on the inner surface of the base layer 201; being formed on both the outer and inner surfaces of the base layer 201; or being formed on a part of the outer surface, inner surface, or both of these surfaces of the base layer 201. Furthermore, if the base layer is planar (plate-shaped), the surface lubrication layer may take any form, such as being formed on one side of the base layer; being formed on both sides of the base layer; or being formed on part of one or both sides of the base layer.

[0025] The following provides a detailed explanation of each component of the medical device.

[0026] (Base Layer (Base Material)) The base layer used in this embodiment may be composed of any material, and the material is not particularly limited. Specifically, the materials constituting the base layer 201 include metal materials, polymer materials, and ceramics.

[0027] The metal material used to constitute the base layer is not particularly limited, and metal materials commonly used in medical devices such as catheters, guidewires, indwelling needles, and sheaths can be used. Specifically, examples include various stainless steels such as SUS304, SUS314, SUS316, SUS316L, SUS420J2, and SUS630, as well as gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, and various alloys such as nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, and zinc-tungsten alloys. These may be used individually or in combination of two or more. From the above metal materials, the most suitable metal material for the base layer of the catheter, guidewire, indwelling needle, sheath, etc., should be appropriately selected.

[0028] Furthermore, the polymer material (resin material or elastomer material) that constitutes the base layer is not particularly limited, and polymer materials commonly used in medical devices such as catheters, introducers, guidewires, indwelling needles, and sheaths are used. Specifically, examples include polyamide resins, polyolefin resins such as polyethylene resin and polypropylene resin, modified polyolefin resins, cyclic polyolefin resins, epoxy resins, polyurethane resins, diallyl phthalate resins (allyl resins), polycarbonate resins, fluororesins, amino resins (urea resins, melamine resins, benzoguanamine resins), polyester resins such as polyethylene terephthalate resin and polybutylene terephthalate resin, styrene resins, acrylic resins, polyacetal resins, vinyl acetate resins, phenolic resins, vinyl chloride resins, silicone resins (silicon resins), polyether resins, and polyimide resins.

[0029] Furthermore, thermoplastic elastomers such as polyurethane elastomers, polyester elastomers, and polyamide elastomers (nylon elastomers) can also be used as materials for the base layer.

[0030] These polymer materials may be used individually, as a mixture of two or more, or as a copolymer of two or more monomers constituting any of the above resins or elastomers. For the polymer material, the most suitable polymer material for the intended use as a base layer for catheters, guidewires, indwelling needles, sheaths, etc., should be appropriately selected. Among these, polyethylene resin, polyurethane resin, polyethylene terephthalate resin, polyamide resin, polyamide elastomer, or polyester elastomer are preferred polymer materials, with polyester elastomer being more preferred.

[0031] Furthermore, the shape of the base material layer is not particularly limited and can be appropriately selected depending on the intended use, such as in the form of a sheet, wire, rod, or tube.

[0032] Here, the base layer 201 may be composed entirely of any of the above materials. The base layer 201 may be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which members formed of different materials are joined together for each part of the medical device. Alternatively, as shown in Figure 2, it may have a structure in which a base layer core portion 201a composed of any of the above materials is coated with any of the other above materials in an appropriate manner to form a base surface layer 201b. Examples of the latter case include a substrate layer core portion 201a made of a resin material or the like, on which a metal material is coated by an appropriate method (such as plating, metal deposition, sputtering, or other conventionally known methods) to form a substrate surface layer 201b; or a substrate layer core portion 201a made of a hard reinforcing material such as a metal material, on which a polymer material that is more flexible than the reinforcing material such as a metal material is coated by an appropriate method (such as dipping, spraying, coating, printing, or other conventionally known methods), or a substrate surface layer 201b is formed by compounding the reinforcing material that forms the substrate layer core portion 201a with the polymer material. Furthermore, the substrate layer core portion 201a may be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which members made of different materials are joined together for each part of the medical device. In addition, another middle layer (not shown) may be formed between the substrate layer core portion 201a and the substrate surface layer 201b. Furthermore, the substrate surface layer 201b may also be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which components made of different materials are joined together for each part of the medical device.

[0033] (Surface Lubrication Layer (Coating Layer)) The surface lubrication layer is supported on at least a portion of the base material layer 201. The reason why the surface lubrication layer 202 is supported on at least a portion of the surface of the base material layer 201 is that, in medical devices such as catheters, guidewires, indwelling needles, and sheaths, which are the intended applications, it is not necessarily required that all surfaces (the entire surface) of these medical devices be lubricated when wet. It is sufficient for the surface lubrication layer to be supported only on the surface portion (which may be a portion or the entire surface) where lubrication is required when wet. For this reason, as described above, when the base material layer is tubular as shown in Figures 1 and 2, the surface lubrication layer can be formed to cover the entire outer surface of the base material layer; to cover the entire outer and inner surfaces of the base material layer; to cover a portion of the outer and inner surfaces of the base material layer in the same or different form; or to cover a portion of the outer or inner surface of the base material layer. Furthermore, when the base layer is planar (plate-shaped), the surface lubrication layer includes forms formed on one side of the base layer; forms formed on both sides of the base layer; and forms formed on one or part of both sides of the base layer.

[0034] In the medical device according to the present invention, the area of ​​the surface lubrication layer can be appropriately set by those skilled in the art depending on the type and size of the medical device to be used. From the viewpoint of providing sufficient lubrication to the medical device, the area of ​​the surface lubrication layer is preferably 450 mm². ２ That is all, more preferably 900 mm ２ The above, and more preferably 1350 mm ２ The above is the most preferred, and is particularly 1780 mm. ２ That's all.

[0035] (Block Copolymer) The block copolymer according to the present invention has a constituent unit (A) derived from a reactive monomer having an epoxy group and a constituent unit (B) derived from a hydrophilic monomer.

[0036] In the present invention, the block copolymer forms a surface lubricating layer supported on at least a portion of the substrate layer. That is, in the medical device according to the present invention, the surface lubricating layer includes the block copolymer. "Supported" means a state in which the surface lubricating layer is fixed in a state in which it does not easily detach from the surface of the substrate layer, and includes not only a form in which the entire surface of the substrate layer is completely covered by the surface lubricating layer, but also a form in which only a portion of the surface of the substrate layer is covered by the surface lubricating layer, that is, a form in which the surface lubricating layer is attached only to a portion of the surface of the substrate layer.

[0037] Reactive monomers having epoxy groups that constitute block copolymers possess epoxy groups as reactive groups. By introducing such reactive monomer-derived constituent units (A) into the block copolymer, the epoxy groups open their rings, promoting crosslinking (bonding) between block copolymers and increasing the film strength of the surface lubrication layer. Furthermore, if the substrate layer is a resin material, crosslinking (bonding) between the block copolymer and the substrate layer may also occur due to the reaction between the ring-opened epoxy groups and the reactive groups on the surface of the resin material (e.g., amino groups, carboxyl groups, etc.).

[0038] The reactive monomers constituting the block copolymer are not particularly limited as long as they have an epoxy group, and known compounds can be used. In particular, because it is easier to control the crosslinking or polymerization of the block copolymer, it is preferable that the reactive monomer having an epoxy group contains at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allylglycidyl ether.

[0039] Among these, glycidyl (meth)acrylate is more preferred, and glycidyl methacrylate is particularly preferred, in consideration of factors such as being able to further promote the crosslinking reaction and ease of production. That is, in a more preferred embodiment of the present invention, the reactive monomer having an epoxy group is at least one of glycidyl acrylate and glycidyl methacrylate. Furthermore, in a particularly preferred embodiment of the present invention, the reactive monomer having an epoxy group is glycidyl methacrylate.

[0040] The above reactive monomers may be used alone singly, or two or more thereof may be used in combination. That is, the reactive site derived from a reactive monomer may be of a homopolymer type composed of a single type of reactive monomer, or may be of a copolymer type composed of two or more of the above reactive monomers. When two or more types are used, the form of the structural unit (A) may be the form of a block copolymer (block form) or the form of a random copolymer (random form).

[0041] The hydrophilic monomer constituting the block copolymer has swelling properties when in contact with body fluids (e.g., blood, urine) and aqueous solvents, and thus imparts lubricity (surface lubricity) to medical devices. Therefore, by introducing such a structural unit (B) derived from a hydrophilic monomer into the block copolymer, the lubricity (surface lubricity) of the medical device is improved, and friction when the medical device contacts a luminal wall such as a blood vessel wall can be reduced.

[0042] The hydrophilic monomers constituting the block copolymer are not particularly limited as long as they possess the above-mentioned properties, and known compounds can be used. Examples include acrylamide and its derivatives, vinylpyrrolidone, acrylic acid and methacrylic acid and their derivatives, polyethylene glycol acrylate and its derivatives, monomers having sugars or phospholipids in their side chains, and water-soluble monomers such as maleic anhydride. More specifically, acrylic acid, methacrylic acid, N-methylacrylamide, N,N-dimethylacrylamide (DMAA), acrylamide, acryloylmorpholine, N,N-dimethylaminoethyl acrylate, N-vinylpyrrolidone, 2-methacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, vinyl methyl ether, 2-hydroxyethyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, 1,4-cyclohexanedimethanol mono(meth)acrylate, 1-chloro-2-hydroxypropyl (meth)acrylate, diethylene Examples include glycol mono(meth)acrylate, 1,6-hexanediol mono(meth)acrylate, pentaerythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropanedi(meth)acrylate, trimethylolethanedi(meth)acrylate, 2-hydroxy-3-phenyloxypropyl(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, 2-hydroxy-3-phenyloxy(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, cyclohexanedimethanol mono(meth)acrylate, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate.From the viewpoints of imparting excellent lubricity, ease of synthesis and operability, the hydrophilic monomer preferably includes at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

[0043] Among the above, in consideration of imparting excellent lubricity, ease of synthesis and operability, N,N-dimethylacrylamide, acrylamide, or 2-hydroxyethyl methacrylate is more preferred, and N,N-dimethylacrylamide is particularly preferred. That is, in a more preferred embodiment of the present invention, the hydrophilic monomer is at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate. Furthermore, in a particularly preferred embodiment of the present invention, the hydrophilic monomer is N,N-dimethylacrylamide.

[0044] The above hydrophilic monomers may be used alone, or two or more thereof may be used in combination. That is, the hydrophilic portion derived from a hydrophilic monomer may be a homopolymer type composed of a single hydrophilic monomer, or a copolymer type composed of two or more of the above hydrophilic monomers. When two or more hydrophilic monomers are used, the form of the hydrophilic portion may be a block copolymer form (block form) or a random copolymer form (random form).

[0045] The block copolymer has a constituent unit (A) derived from the reactive monomer and a constituent unit (B) derived from the hydrophilic monomer. Here, the ratio of constituent unit (A) to constituent unit (B) is not particularly limited as long as the above effects are achieved. Considering good lubricity, lubricity retention, strength of the coating layer, and bonding with the substrate layer, the ratio of constituent unit (A) to constituent unit (B) (molar ratio of constituent unit (A):constituent unit (B)) is preferably 1:2 to 1:100, more preferably 1:2 to 1:50, even more preferably 1:5 to 1:50, and particularly preferably 1:10 to 1:30. Within this range, the surface lubrication layer can exhibit sufficient lubricity due to constituent unit (B), and sufficient coating layer strength, bonding with the substrate layer (in the case of a resin material), and durability due to constituent unit (A). The molar ratio of the above constituent unit (A) to constituent unit (B) can be controlled by adjusting the charging ratio (molar ratio) of each monomer during the production of the block copolymer. Therefore, the charging ratio (molar ratio) of the reactive monomer having an epoxy group and the hydrophilic monomer during the production of the block copolymer is preferably 1:2 to 1:100, more preferably 1:2 to 1:50, even more preferably 1:5 to 1:50, and particularly preferably 1:10 to 1:30.

[0046] The block copolymer according to the present invention essentially contains structural unit (A) and structural unit (B), but may also have other structural units in addition to these structural units. When the block copolymer has other structural units, examples of other structural units include adipic acid, glutaric acid, triethylene glycol, and tripropylene glycol. The monomers constituting the other structural units may be used individually or in combination of two or more. That is, the other structural units may be a homopolymer type composed of a single structural unit, or a copolymer type composed of two or more structural units. When two or more monomers constituting the above-mentioned other structural units are used, the segments composed of these monomers may be in the form of a block copolymer, a random copolymer, or an alternating copolymer.

[0047] When the block copolymer according to the present invention has other constituent units, the content of the other constituent units is preferably greater than 0 mol% and less than or equal to 5 mol% of the total constituent units constituting the block copolymer. That is, in the block copolymer according to the present invention, when the total of all constituent units constituting the block copolymer is taken as 100 mol%, the sum of the content of constituent unit (A) and constituent unit (B) is preferably 95 mol% or more (upper limit: less than 100 mol%). More preferably, the block copolymer according to the present invention is substantially composed of constituent unit (A) and constituent unit (B) (content of other constituent units = greater than 0 mol% and less than 5 mol%). In this form, the block copolymer according to the present invention can achieve a good balance between durability due to constituent unit (A) and lubricity (surface lubricity) due to constituent unit (B). Preferably, the block copolymer according to the present invention does not contain the above-mentioned other constituent units (content of other constituent units = 0 mol%).

[0048] The composition of each constituent unit (constituent units (A) and (B), other constituent units) in the block copolymer is determined by known methods, for example, NMR measurement of the copolymer. １ H-NMR measurement, １３ It can be measured by performing a 1C-NMR measurement, etc. Specifically, the block copolymer solution １ By measuring the integral ratio of the intensities of each signal in the H-NMR spectrum, the composition (molar ratio) of the constituent units can be determined.

[0049] In one embodiment of the present invention, the block copolymer according to the present invention is substantially composed of a constituent unit (A) derived from at least one reactive monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether, and a constituent unit (B) derived from at least one hydrophilic monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone, or is composed solely of the constituent unit (A) and the constituent unit (B).

[0050] In one embodiment of the present invention, the block copolymer according to the present invention is substantially composed of a constituent unit (A) derived from at least one reactive monomer of glycidyl acrylate and glycidyl methacrylate, and a constituent unit (B) derived from at least one hydrophilic monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate, or is composed solely of the constituent unit (A) and the constituent unit (B).

[0051] In one embodiment of the present invention, the block copolymer according to the present invention is substantially composed of a constituent unit (A) derived from glycidyl methacrylate (a reactive monomer having an epoxy group) and a constituent unit (B) derived from N,N-dimethylacrylamide (a hydrophilic monomer), or is composed solely of the above constituent unit (A) and the above constituent unit (B).

[0052] The weight-average molecular weight of the block copolymer is preferably 10,000 to 10,000,000 from the viewpoint of solubility. More preferably, the weight-average molecular weight of the block copolymer is 100,000 to 5,000,000 from the viewpoint of ease of preparation of the coating solution. In this specification, "weight-average molecular weight" refers to the value measured by gel permeation chromatography (GPC) using polystyrene as the standard substance.

[0053] The method for producing block copolymers is not particularly limited, and conventionally known polymerization methods such as living radical polymerization, polymerization using macroinitiators, and polycondensation methods can be applied. Of these, living radical polymerization or polymerization using macroinitiators are preferred because they allow for easy control of the molecular weight and molecular weight distribution of constituent units (parts) derived from reactive monomers and constituent units (parts) derived from hydrophilic monomers. The living radical polymerization method is not particularly limited, but methods described in, for example, Japanese Patent Publication No. 11-263819, Japanese Patent Publication No. 2002-145971, Japanese Patent Publication No. 2006-316169, and atomic transfer radical polymerization (ATRP) can be applied in a similar manner or with appropriate modifications. Furthermore, in polymerization using macroinitiators, for example, a macroinitiator having a reactive site with a reactive functional group and a radically polymerizable group such as a peroxide group can be prepared, and then a block copolymer having hydrophilic sites and reactive sites can be produced by polymerizing the macroinitiator with monomers to form hydrophilic sites.

[0054] Furthermore, the polymerized block copolymer is preferably purified by general purification methods such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0055] (Number of microparticles) The medical device according to this embodiment is characterized in that the number of microparticles with a particle size of 10 μm or more and less than 25 μm detected by a microparticle test of the surface lubrication layer is less than 2000. If the number of microparticles with a particle size of 10 μm or more and less than 25 μm is 2000 or more, there is a risk that the decrease in lubricity (sliding properties) due to friction cannot be sufficiently suppressed. From the viewpoint of further suppressing the decrease in lubricity (sliding properties) due to friction, the number of microparticles with a particle size of 10 μm or more and less than 25 μm is preferably less than 900, more preferably less than 500, and even more preferably less than 400 (lower limit: 0). The number of microparticles with a particle size of 10 μm or more and less than 2000 may be 0 or more and less than 2000, 1 or more and less than 900, 10 or more and less than 500, 100 or more and less than 400, or 150 or more and less than 400. The number of fine particles between 10 μm and 25 μm can be controlled by the conditions of the cleaning process in the manufacturing method of the medical device according to the present invention, as described later. More specifically, the number of fine particles can be reduced by selecting an organic solvent that increases the solubility of the block copolymer in the cleaning solution; increasing the contact time between the coating film and the cleaning solution; or by stirring the cleaning solution or irradiating it with ultrasound when the coating film and the cleaning solution are in contact.

[0056] Furthermore, from the viewpoint of further suppressing the decrease in lubricity (sliding properties) due to friction, the number of fine particles with a particle size of 25 μm or more and less than 400 μm detected by the fine particle test is preferably less than 20, more preferably less than 15, and even more preferably less than 10 (lower limit: 0). The number of fine particles with a particle size of 25 μm or more and less than 400 μm may be 0 or more and less than 20, 1 or more and less than 15, or 2 or more and less than 10. The number of fine particles with a particle size of 25 μm or more and less than 400 μm can be controlled by the conditions of the heating process in the manufacturing method of the medical device according to the present invention, which will be described later. More specifically, the number of fine particles can be reduced by making the heating time longer or increasing the heating temperature.

[0057] In this embodiment, the sliding resistance value in a sliding test of the surface lubrication layer is preferably less than 50 gf (lower limit: 0 gf). Here, "sliding resistance value in a sliding test" refers to the value obtained by performing the sliding test described in the examples below on the medical device. The sliding resistance value can be adjusted as appropriate depending on the type and application of the medical device, but for example, it may be 5 to 40 gf, 10 to 35 gf, or 15 to 30 gf. The above sliding resistance value can be controlled by the conditions of the cleaning process, the presence or absence of a reheating process, the conditions of the reheating process, etc., in the manufacturing method of the medical device according to the present invention described below.

[0058] <Method for Manufacturing Medical Devices> The method for manufacturing medical devices according to the present invention described above is not particularly limited, but can be easily manufactured by the following method. That is, another aspect of the present invention is a method for manufacturing medical devices comprising a base layer and a surface lubricating layer supported on at least a part of the base layer, comprising: preparing a coating solution containing a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and a solvent ((I) coating solution preparation step); applying the coating solution onto the base layer to form a coating film on the base layer ((II) coating film formation step); heating the coating film at a temperature of 110°C to 160°C for 1 hour or more ((III) heating step); and washing the coating film after heating with a cleaning solution containing at least one organic solvent selected from acetone, tetrahydrofuran (THF), and N,N-dimethylformamide (DMF), or a cleaning solution containing the organic solvent and water ((IV) cleaning step). The manufacturing method for a medical device having the above configuration provides a medical device that exhibits excellent lubricity (sliding properties) even after friction. Furthermore, the manufacturing method for a medical device having the above configuration provides a medical device with a reduced number of microparticles. The medical device having the above configuration will also be referred to below as "the manufacturing method according to the present invention" or "the manufacturing method."

[0059] The mechanism by which the manufacturing method according to the present invention produces the effects described above is not fully clear and is not bound by any theory, but the following mechanism is hypothesized. The manufacturing method according to this embodiment is characterized by providing a (IV) washing step after the (III) heating step, in which the heated coating film is washed with a washing solution containing at least one organic solvent selected from acetone, THF, and DMF, or a washing solution containing the above organic solvent and water. In the (III) heating step, the epoxy groups of the block copolymers having epoxy groups (uncrosslinked block copolymers) contained in the coating film open up rings, and crosslinking (bonding) between block copolymers proceeds. At this point, the heated coating film contains a mixture of block copolymers that have been sufficiently crosslinked and polymerized, and low-molecular-weight block copolymers that have not been sufficiently crosslinked and remain. In the (IV) washing step, when such a heated coating film is washed with a washing solution, the low-molecular-weight block copolymers are selectively dissolved into the washing solution, while the polymerized block copolymers remain in the coating film. Low-molecular-weight block copolymers, due to insufficient crosslinking, can detach from the coating (surface lubrication layer) during use of medical devices, potentially leading to the generation of fine particles between 10 μm and 25 μm in size. According to the manufacturing method of the present invention, the low-molecular-weight block copolymer is removed from the coating in the (IV) cleaning step, making it less likely for fine particles to be generated during use of medical devices. As a result, situations where fine particles become trapped or accumulate between the medical device and biological tissue, as described above, are less likely to occur. Consequently, medical devices produced by the manufacturing method of the present invention are less likely to experience a decrease in lubricity (sliding properties) due to friction. Furthermore, by employing the (IV) cleaning step, the number of fine particles can be reduced while minimizing the decrease in lubricity (sliding properties), making it possible to provide medical devices with excellent lubricity (sliding properties) and suppressed decrease in lubricity (sliding properties) due to friction.

[0060] The following describes preferred embodiments of the manufacturing method according to the present invention.

[0061] (I) Coating Solution Preparation Step In this step, a coating solution containing a block copolymer and a solvent is prepared. Here, the coating solution may be prepared by mixing the block copolymer and the solvent. Alternatively, a coating solution containing a block copolymer and a solvent may be purchased and used.

[0062] In the following, preferred embodiments for preparing the coating solution by mixing the block copolymer and a solvent will be described in detail. The preferred form of the block copolymer has been described above, so its explanation will be omitted here.

[0063] The solvent used in preparing the coating solution is not particularly limited as long as it can dissolve the block copolymer (and other components, if any) and is appropriately selected depending on the type of block copolymer (and other components, if any). From the viewpoint of high solubility, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and butanol; ketone solvents such as acetone, methyl ethyl ketone, and cyclohexanone; halogenated solvents such as dichloromethane, chloroform, and carbon tetrachloride; and organic solvents such as tetrahydrofuran (THF), dimethyl sulfoxide, N,N-dimethylformamide (DMF), dioxane, and benzene are preferably used. These may be used individually or in combination of two or more (in the form of a mixed solvent).

[0064] The order and method of adding the block copolymer and solvent are not particularly limited. Each of the above components may be added together or separately, in stages or sequentially. The mixing method is also not particularly limited, and known methods can be used. Methods for preparing the coating solution include adding the block copolymer to the solvent, or adding the solvent to the block copolymer. The above additions may be carried out while stirring if necessary. Alternatively, the mixture may be stirred after the above additions.

[0065] The concentration of the block copolymer in the coating solution is not particularly limited. From the viewpoint of further improving the applicability, lubricity, and durability of the surface lubricating layer, the concentration of the block copolymer in the coating solution is preferably 0.5 to 20% by mass, more preferably 1 to 15% by mass, and particularly preferably 3 to 10% by mass. If the concentration of the block copolymer is within the above range, the lubricity and durability of the resulting surface lubricating layer can be fully exhibited. Furthermore, a uniform surface lubricating layer of the desired thickness can be easily obtained with a single coating, and the viscosity of the solution is within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, even if it is outside the above range, it can still be used as long as it does not affect the effects of the present invention.

[0066] The coating liquid for forming the surface lubricating layer may contain other components in addition to the block copolymer and solvent. These other components are not particularly limited and, for example, when the medical device is intended for insertion into a body cavity or lumen such as a catheter, may include drugs (bioactive substances) such as anticancer agents, immunosuppressants, antibiotics, antirheumatic drugs, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic drugs, integrin inhibitors, antiallergic agents, antioxidants, GPIIb / IIIa antagonists, retinoids, flavonoids, carotenoids, lipid-improving agents, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle proliferation inhibitors, anti-inflammatory drugs, bio-derived materials, interferon, and NO production promoters. The amount of other components added is not particularly limited, and the amounts typically used are applied in the same manner. Ultimately, the amount of other components added should be appropriately selected considering the severity of the disease being treated, the patient's weight, etc.

[0067] (II) Coating Film Formation Process In this process, the coating liquid prepared in (I) Coating Liquid Preparation Process is applied to the substrate layer to form a coating film on the substrate layer. The preferred form of the substrate layer has been described above, so its explanation is omitted here.

[0068] The method for applying the coating liquid to the surface of the substrate layer is not particularly limited. Methods for applying (coating) the coating liquid are not particularly limited and include coating / printing, immersion (dipping method, dip coating method), spraying method, spin coating method, mixed solution impregnation sponge coating method, bar coating method, die coating method, reverse coating method, comma coating method, gravure coating method, and doctor knife method. Of these, the immersion method (dipping method, dip coating method) is preferred.

[0069] Furthermore, when forming a surface lubrication layer on the inner surface of a narrow tube such as a catheter, the base layer may be immersed in the coating solution, and the system may be degassed by reducing the pressure. By reducing the pressure and degassing, the solution can be quickly penetrated into the inner surface of the narrow tube, promoting the formation of the surface lubrication layer.

[0070] Furthermore, when forming a surface lubrication layer on only a portion of the base layer, the surface lubrication layer can be formed on the desired surface portion of the base layer by immersing only a portion of the base layer in the coating liquid and coating that portion of the base layer with the coating liquid.

[0071] If it is difficult to immerse only a portion of the substrate layer in the coating solution, the surface portion of the substrate layer that does not require the formation of a surface lubrication layer can be protected (covered, etc.) in advance with a suitable removable member or material, then the substrate layer can be immersed in the coating solution to coat the substrate layer with the coating solution, the protective member (material) on the surface portion of the substrate layer that does not require the formation of a surface lubrication layer can be removed, and then the block copolymer can be crosslinked by heat treatment to form a surface lubrication layer on the desired surface portion of the substrate layer. However, the present invention is not limited in any way to these formation methods, and the surface lubrication layer can be formed by appropriately using conventionally known methods. For example, if it is difficult to immerse only a portion of the substrate layer in the coating solution, other coating methods may be applied instead of the immersion method (for example, a method of applying the coating solution to a predetermined surface portion of a medical device using an application device such as a spray device, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor's knife). Furthermore, in cases where the structure of a medical device requires both the outer and inner surfaces of a cylindrical device to have a surface lubrication layer, the dipping method is preferred because it allows both the outer and inner surfaces to be coated at once.

[0072] The amount of coating liquid applied is preferably such that the thickness (dry film thickness) of the resulting film (surface lubrication layer) is 0.1 to 10 μm, more preferably 0.3 to 5 μm, and even more preferably 0.5 to 3 μm. If the application amount results in a film (surface lubrication layer) thickness of 0.1 μm or more, sufficient durability of the resulting film (surface lubrication layer) can be achieved. Furthermore, if the application amount results in a film (surface lubrication layer) thickness of 10 μm or less, the surface of the film (surface lubrication layer) becomes less sticky, making handling during manufacturing easier.

[0073] (III) Heating Process In this process, the coating film formed on the substrate layer in the (II) coating film formation process is heated at a temperature of 110°C to 160°C for at least one hour. This heating process causes the epoxy groups of the block copolymers (uncrosslinked block copolymers) contained in the coating film to open up, and crosslinking (bonding) between the block copolymers progresses. As a result, the block copolymers become polymerized, and a strong surface lubrication layer is formed. Therefore, high lubricity (surface lubricity) can be maintained for a longer period of time. If the heating temperature in the heating process is less than 110°C or the heating time is less than one hour, the crosslinking may not progress sufficiently. Low-molecular-weight block copolymers that remain because crosslinking has not progressed sufficiently are removed in the subsequent washing process (IV), so it may not be possible to support the desired amount of surface lubrication layer (block copolymer) on the surface of the substrate layer, and good lubricity (surface lubricity) may not be maintained. Furthermore, if the heating temperature exceeds 160°C, the crosslinking may proceed excessively, potentially leading to a decrease in swelling due to the surface lubrication layer becoming too hard. The heating temperature in the heating process can be appropriately set by those skilled in the art depending on the type of block copolymer and the type and size of the medical device to be used. Similarly, the upper limit of the heating time in the heating process varies depending on the type of block copolymer and the type and size of the medical device to be used, so it cannot be stated definitively, but it is generally 30 hours or less. The heating time can be 1 to 30 hours, 1 to 25 hours, or 1 to 12 hours. In addition, a drying process ((A) drying process) to remove the solvent from the coating film by heating at a temperature near room temperature (20 to 30°C) or at a temperature above room temperature but below 110°C may be provided after the (II) coating film formation process and before the (III) heating process. The drying process can be carried out under normal pressure (atmospheric pressure), or it may be carried out under pressurized or reduced pressure. As for drying methods (devices), for example, a vacuum dryer can be used, but in the case of natural drying, no special drying method (device) is necessary.

[0074] In the heating process, heating may be performed only once at a single temperature between 110°C and 160°C; it may be performed multiple times at a single temperature; or it may be performed once or multiple times at a single temperature followed by one or more times at another temperature (either lower or higher than the first temperature). If heating is performed over multiple stages, (III) the heating time in the heating process refers to the sum of the times for each heating treatment.

[0075] The heating means (device) used in the heating process can, for example, be an oven, but is not limited to this. The heating process can be carried out under normal pressure (atmospheric pressure), or it may be carried out under pressurized or reduced pressure.

[0076] (IV) Cleaning Step In this step, the coating film heated in the (III) heating step is cleaned with a cleaning solution containing at least one organic solvent selected from acetone, THF, and DMF, or a cleaning solution containing the organic solvent and water. As described above, this cleaning step selectively dissolves the low-molecular-weight block copolymer contained in the heated coating film into the cleaning solution. As a result of removing the low-molecular-weight block copolymer from the coating film, it becomes less likely for fine particles caused by the low-molecular-weight block copolymer to be generated when the medical device is used.

[0077] The cleaning solution used in the cleaning process must contain at least one organic solvent selected from acetone, THF, and DMF, or the organic solvent and water. The inclusion of the above organic solvent in the cleaning solution allows for the selective elution of low molecular weight block copolymers into the cleaning solution. From the viewpoint of more effectively removing low molecular weight block copolymers, the above organic solvent is preferably at least one selected from acetone and THF, and is preferably acetone.

[0078] Furthermore, it is also preferable to use a cleaning solution containing the organic solvent and water. By using a cleaning solution containing water, the coating film after crosslinking swells with water, which can further promote the elution of low-molecular-weight block copolymers. When the cleaning solution contains an organic solvent and water, the proportion of water in the cleaning solution is not particularly limited, but is preferably 5 to 95% by mass, more preferably 10 to 90% by mass, even more preferably 20 to 80% by mass, particularly preferably 30 to 70% by mass, and most preferably 40 to 60% by mass. With such a configuration, the elution of low-molecular-weight block copolymers is further promoted, and the number of fine particles generated when the medical device is used can be further reduced.

[0079] The cleaning method in the cleaning process is not particularly limited as long as it can dissolve the low-molecular-weight block copolymer contained in the coating film into the cleaning solution, but a method of immersing the coating film in the cleaning solution is preferably used. The immersion time of the coating film in the cleaning solution is not particularly limited, but is preferably 10 seconds to 5 hours, and more preferably 30 seconds to 1 hour. In order to promote the dissolution of the low-molecular-weight block copolymer and shorten the cleaning time, the cleaning solution may be stirred or ultrasonic waves may be irradiated into the cleaning solution while the coating film is immersed in it. The temperature of the cleaning solution in the cleaning process is also not particularly limited, but may be around room temperature (20 to 30°C), or it may be heated up to about 50°C.

[0080] After the above cleaning, a drying step ((B) drying step) may be provided to remove the cleaning solution from the coating film by heating it to a temperature near room temperature (20-30°C) or to a temperature above room temperature but below 110°C. The embodiment of the (B) drying step is the same as the (A) drying step described above, so the explanation is omitted here.

[0081] Through the above steps, the medical device according to the present invention can be obtained.

[0082] (V) Reheating step The method for manufacturing a medical device according to the present invention may further include a step ((V) reheating step) in which the coating film after cleaning is heated at a temperature of 110°C to 160°C for one hour or more, if necessary. Including such a step further promotes crosslinking (bonding) of the polymerized block copolymer, and the lubricity (surface lubricity) can be moderately reduced. This makes it easy to impart lubricity suitable for the type of medical device and its intended use. Conventionally, methods for controlling the lubricity of a surface lubrication layer have been known, such as reducing lubricity by increasing the heating temperature or extending the heating time, but in practice, there has been a problem in that it is difficult to achieve a reduction in lubricity that is commensurate with the increase in heating temperature or extension of heating time. In the manufacturing method according to one embodiment of the present invention, by performing the (V) reheating step after the (IV) cleaning step, it is possible to reduce lubricity more effectively than by increasing the heating temperature or extending the heating time in the (III) heating step. The mechanism by which these effects are obtained is presumed to be that (IV) the removal of low-molecular-weight block copolymers in the washing process makes it easier for the epoxy groups remaining in the high-molecular-weight block copolymers to come into close proximity, and (V) further crosslinking (bonding) proceeds in the reheating process.

[0083] (V) The heating method in the reheating process is the same as in (III) the heating process, so the explanation is omitted here.

[0084] <Applications of Medical Devices> Examples of medical devices according to the present invention include devices used in contact with bodily fluids such as body fluids and blood. These devices have lubricating surfaces in aqueous liquids such as bodily fluids and physiological saline, enabling improved operability and reduced damage to tissue mucosa. Specific examples of medical devices according to the present invention include, but are not limited to, catheters, guidewires, indwelling needles, or sheaths used within blood vessels. In one embodiment, the medical device according to the present invention is a catheter, guidewire, indwelling needle, or sheath. In another embodiment, the medical device according to the present invention may be a microcatheter, balloon catheter, or guiding catheter.

[0085] 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. In the following examples, unless otherwise specified, the operations were carried out at room temperature (25°C). Unless otherwise specified, "%" and "parts" mean "mass%" and "parts by mass," respectively.

[0086] <Example of sample preparation for evaluation> [Synthesis Example 1] The following reaction was carried out to produce block copolymer (1).

[0087]

[0088] 72.3 g of adipic acid dichloride at 50°C was mixed with 29.7 g of triethylene glycol dropwise, and the hydrochloric acid was removed under reduced pressure at 50°C for 3 hours to obtain an oligoester. Next, 22.5 g of the obtained oligoester was mixed with 4.5 g of methyl ethyl ketone, which was then added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of dioctyl phosphate as a surfactant, and 120 g of water, and the mixture was reacted at -5°C for 20 minutes. The resulting product was washed repeatedly with water and methanol, and then dried to obtain a polyperoxide (PPO) having multiple peroxide groups in its molecule.

[0089] Next, 0.5 g of PPO, 9.5 g of glycidyl methacrylate (GMA) as a reactive monomer, and 30 g of benzene as a solvent were polymerized under reduced pressure at 80°C for 2 hours with stirring. The reaction product obtained after polymerization was reprecipitated with diethyl ether to obtain polyglycidyl methacrylate (PPO-GMA) having multiple peroxide groups in its molecule.

[0090] Next, 1.0 g of the obtained PPO-GMA (equivalent to 7 mmol of GMA) was added to a mixture of 9.0 g (90.8 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 90 g of dimethyl sulfoxide as a solvent, and the mixture was reacted at 80°C for 18 hours. The resulting reaction product was reprecipitated with hexane and recovered to obtain a block copolymer (1) having epoxy groups in its molecule.１ Analysis by 1H-NMR confirmed that the molar ratio of GMA:DMAA (constituent unit (A):constituent unit (B)) was 1:12. Further, the obtained block copolymer (1) was １ analyzed by 1H-NMR and ATR-IR, and it was confirmed that epoxy groups existed in the molecule. In addition, the weight average molecular weight (Mw) of the block copolymer (1) measured by gel permeation chromatography (GPC, in terms of polystyrene) was approximately 1,500,000.

[0091] [Example 1] The block copolymer (1) obtained in the above Synthesis Example 1 was dissolved in N,N-dimethylformamide (DMF) to a concentration of 4.2% by mass to prepare a coating liquid (1). A part of a tube with an outer diameter of 1.4 mm (a range of 400 mm from the tip) molded from Perprene (registered trademark) (P-280B, polyester elastomer, manufactured by Toyobo MC) was immersed in the coating liquid (1), and DMF was removed by drying at room temperature (25°C) for 30 minutes to form a coating film on the tube surface (Tube (1a)). Furthermore, after this tube (1a) was stored in an oven at 125°C for 1 hour to heat treat the coating film, it was cooled to room temperature (25°C), thereby obtaining a coating layer (surface lubricating layer) containing the block copolymer (1) (dry film thickness: 1 μm, area: 1760 mm ２ ) to prepare Tube (1b). Next, after Tube (1b) was stored in an oven at 135°C for 1 hour to perform a second heat treatment, it was cooled to room temperature (25°C) (Tube (1c)). Furthermore, a cleaning liquid (1) in which RO water and acetone were mixed at a mass ratio of 50:50 was prepared. After immersing Tube (1c) in the cleaning liquid (1) at room temperature (25°C) for 30 minutes, it was dried at room temperature (25°C) to prepare Sample (1).

[0092] [Example 2] Following the same procedure as in Example 1, Tube (1b) was prepared. A cleaning liquid (1) in which RO water and acetone were mixed at a mass ratio of 50:50 was prepared. After immersing Tube (1b) in the cleaning liquid (1) for 30 minutes, it was dried at room temperature (25°C) (Tube (2c)). Next, after Tube (2c) was stored in an oven at 135°C for 1 hour to perform a second heat treatment, it was cooled to room temperature (25°C) to prepare Sample (2).

[0093] [Comparative Example 1] A tube (1b) was prepared using the same procedure as in Example 1. The tube (1b) was then heated again in an oven at 135°C for 1 hour, and then cooled to room temperature (25°C) to prepare comparative sample (1).

[0094] <Particulate Test> 1. Preparation of the Test Apparatus As shown in Figure 3, the test apparatus 1 has a retaining groove 21 formed on the upper surface of the mounting table 20, which has a groove shape in which straight paths (first straight section 21a, second straight section 21c, third straight section 21e) and meandering paths (first meandering section 21b, second meandering section 21d) are arranged alternately, and the tube 10 is fitted into the retaining groove 21. The tube 10 is a hose (E-PD-4 flexible fluorine hose (tube type), manufactured by Hakko Co., Ltd.) with an inner diameter of 4 mm, an outer diameter of 6 mm, and a total length of 1 m. The mounting table 20 was 230 mm in length, 380 mm in width, and 19 mm in thickness. The retaining groove 21 has a groove depth of 6.2 mm and a groove width of 6.2 mm. The first straight section 21a is 80 mm long, the second straight section 21c is 40 mm long, and the third straight section 21e is 60 mm long. The radius of curvature of the curved section at the base end (i.e., the side to which the injection device 40 is connected) of the first meandering section 21b is R50, and the radius of curvature of the curved section at the tip is R40. The radius of curvature of the curved section at the base end of the second meandering section 21d is R70, and the radius of curvature of the curved section at the tip is R40.

[0095] 2. Test Method The test method was carried out as follows. First, as shown in Figure 4, the tube 10 was set in the holding groove 21 of the mounting base 20, the inside of the tube 10 was thoroughly washed with RO water, and then filled with RO water. Next, the washed recovery container 30 was placed at the tip end (distal end) of the tube 10, and 100 mL of RO water was injected from the proximal end (proximal end) of the tube 10 using an injection device 40 (syringe). Next, the 100 mL of RO water collected in the recovery container 30 was set in a particle counter (HIAC9703, manufactured by Beckman Coulter), and measured based on the measurement conditions (single sample volume: 10 mL, number of samples: 4, calculation method: the first sample was discarded, and the average value of the remaining 3 sample data was used, unit: particles / 10 mL). The measured value was then recorded as a blank.

[0096] Next, the inner and outer surfaces of each sample were washed with RO water, and the tip of each sample, with its inner lumen filled with RO water, was placed at the insertion start position S of the tube 10. Then, as shown in Figure 5, the tip of each sample was inserted from the insertion start position S to the insertion end position E, and then the tip was pulled back to the insertion start position S five times. This reciprocating motion ensured that when the tip of each sample reached the insertion end position E, the surface lubrication layer 110 formation area (the area from the tip to 400 mm) was located between the insertion start position S and the insertion end position E.

[0097] Next, as shown in Figure 6, 10 mL of RO water was injected with the tip of each sample positioned at the insertion start position S. Then, each sample was removed from the tube 10, and 90 mL of RO water was injected from the proximal end of the tube 10 to adjust the total volume of recovered liquid in the recovery container 30 to 100 mL.

[0098] Next, the recovered liquid in the recovery container 30 was placed in a particle counter (HIAC9703, Beckman Coulter) and measured according to the measurement conditions (single sample volume: 10 mL, number of samples: 4, calculation method: the first sample was discarded, and the average of the remaining 3 sample data was used, unit: particles / 10 mL). The recorded blank value was then subtracted from the measured value, multiplied by 10, and the value converted to the number of particles per 100 mL was recorded as the total number of particles. The number of particles between 10 μm and 25 μm and the number of particles between 25 μm and 400 μm were then determined. The measurement results for each sample are shown in Table 1.

[0099] <Sliding Test> A sliding test was performed on the above sample using the test apparatus 300 shown in Figure 7. First, a hole was made in a silicone rubber sheet 310 (thickness: 1.5 mm, hardness: Shore A50, manufactured by AS ONE Corporation) with an 18G hypodermic needle. This silicone rubber sheet 310 was fixed in water using a fixing jig 320. Sample 100 was inserted into the hole in the silicone rubber sheet 310. Sample 100 was fixed to a precision universal testing machine 330 (AGX series, manufactured by Shimadzu Corporation) at a point 50 mm from the silicone rubber sheet 310. The sample was slid back and forth 50 times at a test speed of 500 mm / min and a stroke of 40 mm, and the test force was recorded. The value obtained by adding the "maximum test force during indentation" and the "maximum test force during withdrawal" (if the "maximum test force" is a negative value, it is converted to a positive value) during the Xth reciprocating sliding was defined as the "sliding resistance value of the Xth reciprocating sliding." The "sliding resistance value of the 5th reciprocating sliding" was used to evaluate the sliding resistance value. To evaluate the increase in sliding resistance, the value obtained by subtracting the "sliding resistance value at the 5th measurement" from the "sliding resistance value at the 50th measurement" was used (if the resulting value was negative, it was treated as "0 gf"). The results are shown in Table 1 below.

[0100]

[0101] As shown in Table 1, in the medical devices of the examples where the number of fine particles between 10 μm and 25 μm was less than 2000, the increase in sliding resistance was reduced, and the decrease in lubricity due to friction was suppressed. Furthermore, it was confirmed that all example samples had good sliding resistance values.

[0102] Comparing Example 1 and Example 2, Example 1, in which washing was performed after two heat treatments, had a low sliding resistance value, while Example 2, in which washing was performed between the two heat treatments, had a high sliding resistance value. This is thought to be because, in Example 2, the low-molecular-weight uncrosslinked components (block copolymers with epoxy groups) that remained after the first heat treatment due to insufficient crosslinking were removed by washing, and the crosslinking of the high-molecular-weight uncrosslinked components proceeded more easily in the second heat treatment, resulting in a higher crosslinking density. In other words, it can be seen that the method of performing heat treatment after washing is useful as one of the control methods for intentionally increasing the sliding resistance value.

[0103] This application is based on Japanese Patent Application No. 2025-028660, filed on 26 February 2025, the disclosures of which are referenced and incorporated in whole.

[0104] 1 Test apparatus, 10 Tube, 20 Mounting platform, 21 Holding groove, 21a First straight section, 21b First meandering section, 21c Second straight section, 21d Second meandering section, 21e Third straight section, 30 Recovery container, 40 Injection device, 100 Sample, 110 Surface lubrication layer, 200 Medical device (catheter), 201 Base layer, 201a Base layer core, 201b Base surface layer, 202 Surface lubrication layer, 203 Lumen, 300 Test apparatus, 310 Silicone rubber sheet, 320 Fixing jig, 330 Precision universal testing machine, E Insertion end position, S Insertion start position.

Claims

1. A medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer contains a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by a fine particle test of the surface lubricating layer is less than 2000.

2. The medical device according to claim 1, wherein the number of fine particles with a particle size of 10 μm or more and less than 25 μm detected by the fine particle test is less than 900.

3. The medical device according to claim 1, wherein the number of fine particles with a particle size of 25 μm or more and less than 400 μm detected by the fine particle test is less than 20.

4. The medical device according to claim 1, wherein the reactive monomer having an epoxy group comprises at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allylglycidyl ether.

5. The medical device according to claim 1, wherein the hydrophilic monomer comprises at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

6. The medical device according to claim 1, wherein the molar ratio of constituent unit (A) to constituent unit (B) in the block copolymer is 1:2 to 1:

100.

7. The medical device according to claim 1, wherein the sliding resistance value in a sliding test of the surface lubrication layer is less than 50 gf.

8. The medical device according to claim 1, wherein the medical device is a catheter, a guidewire, an indwelling needle, or a sheath.

9. A method for manufacturing a medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, comprising: preparing a coating liquid containing a block copolymer having a reactive monomer (A) having an epoxy group and a constituent unit (B) having a hydrophilic monomer, and a solvent; applying the coating liquid onto the base layer to form a coating film on the base layer; heating the coating film at a temperature of 110°C to 160°C for 1 hour or more; and cleaning the heated coating film with a cleaning liquid containing at least one organic solvent selected from acetone, tetrahydrofuran, and N,N-dimethylformamide, or a cleaning liquid containing the organic solvent and water.

10. The method for manufacturing a medical device according to claim 9, further comprising heating the coating film after washing at a temperature of 110°C to 160°C for one hour or more.

Images