Medical device

Abstract

To provide a medical device that allows variation in the lubricity of a coating layer under biological conditions with a small temperature change, enables smooth and low-invasive removal from the body, and prevents unintended movement during in-body retention.SOLUTION: A medical device includes a base material layer and a coating layer formed on at least part of the base material layer, the coating layer having, at a proximal end portion, a temperature-responsive region which contains a copolymer (A), the copolymer (A) comprising: a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature; a structural unit (A-2) derived from a hydrophilic monomer; and a structural unit (A-3) derived from a reactive monomer. The temperature-responsive region has a phase transition temperature that exceeds 35.0°C and is lower than 38.0°C.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a medical device. [Background technology]

[0002] In the medical field, various procedures using medical devices with long, hollow tubes are performed. For example, a procedure is performed in which various catheters or the like are percutaneously introduced into a living body using an introducer sheath with a sheath tube.

[0003] The introducer sheath is percutaneously introduced into a biological lumen (e.g., a blood vessel) from the distal end of the sheath tube. The hollow portion formed inside the sheath tube is used as an access path connecting the inside and outside of the living body, with the distal end introduced into the living body and the proximal end exposed to the outside of the living body for a predetermined length. In this case, it is desirable to be able to smoothly insert and remove the sheath tube into the living body and to prevent inadvertent movement of the sheath tube during use (while the sheath tube is indwelling in the living body).

[0004] For the above purpose, Patent Document 1 reports an introducer sheath in which a hydrophilic lubricating coating layer that exhibits lubricity when wet is disposed on the outer surface of a tubular body, and a temperature-responsive lubricating coating layer that exhibits lubricity below a critical temperature and exhibits non-lubricity above the critical temperature is disposed on the proximal side of the hydrophilic lubricating coating layer. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2017 / 057389 Summary of the Invention [Problem to be solved by the invention]

[0006] In the introducer sheath described in Patent Document 1, the temperature-responsive lubricating coating layer exhibits good lubricity at around room temperature (25°C) while decreasing its lubricity at the body's ambient temperature (37°C). Therefore, by decreasing the temperature of the temperature-responsive lubricating coating layer during insertion into the body and removal from the body, the surgeon can smoothly insert the sheath tubing into the body and smoothly remove it from the body. Additionally, by increasing the temperature of the temperature-responsive lubricating coating layer by the body's ambient temperature or by heating the sheath tubing in the body, the surgeon can prevent the sheath tubing from moving unintentionally during placement in the body.

[0007] On the other hand, in the case of the temperature-responsive lubricating layer described in Patent Document 1, if the temperature difference between the critical temperature of the temperature-responsive lubricating layer and the body's environmental temperature (37°C) is large, when removing the sheath tube placed in the body, the surgeon must lower the temperature of the temperature-responsive lubricating layer from the body's environmental temperature to a temperature below the critical temperature of the temperature-responsive lubricating layer via the patient's skin around the puncture site. Therefore, if the temperature difference between the critical temperature of the temperature-responsive lubricating layer and the body's environmental temperature (37°C) is large, the temperature lowering operation of the temperature-responsive lubricating layer may increase the burden on the body due to the temperature change and may increase the surgeon's working time. For this reason, the introducer sheath described in Patent Document 1 may increase the burden on the body and reduce the surgeon's operability when lowering the temperature of the temperature-responsive lubricating layer in the body's environment. Therefore, from the perspective of reducing the burden on the body associated with the temperature lowering operation of the temperature-responsive lubricating layer and improving the surgeon's operability, a medical device that can change the lubricity of the temperature-responsive lubricating layer with a smaller temperature change in the body's environment is desired.

[0008] Therefore, the present invention has been made in consideration of the above circumstances, and aims to provide a medical device that can change the lubricity of a coating layer with a small change in temperature, can be smoothly and minimally invasively removed from the body, and can prevent inadvertent movement when left in the body. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the above problems can be solved by providing a temperature-responsive region containing a copolymer having specific structural units and having a specific phase transition temperature at the proximal end of a medical device, thereby completing the present invention.

[0010] That is, the above-mentioned object can be achieved by (1) a medical device comprising a base layer and a coating layer formed on at least a part of the base layer, wherein the coating layer has a temperature-responsive region at its base end, the temperature-responsive region including a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer, and the phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C. (2) In the medical device of (1) above, the structural unit (A-1) is preferably derived from at least one monomer selected from the group consisting of N-isopropylacrylamide, Nn-propylacrylamide, Nn-propylmethacrylamide, N-vinylpropionamide, vinyl methyl ether, N,N-diethylacrylamide, and N-methyl-N-isopropylacrylamide. (3) In the medical device of (1) or (2) above, the structural unit (A-2) is selected from the group consisting of N,N-dimethylacrylamide, acrylamide, acrylic acid, methacrylic acid, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone, 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acrylamido)methyl]propionate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio ...

[0033] It is preferable that the monomer is derived from at least one monomer selected from the group consisting of [2-(methacryloyloxy)ethyl]dimethylammonio]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate. (4) In the medical device of any one of (1) to (3) above, the structural unit (A-3) is preferably derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, methyl glycidyl methacrylate, allyl glycidyl ether, acryloyl isocyanate, acryloyloxymethyl isocyanate, acryloyloxyethyl isocyanate, methacryloyl isocyanate, methacryloyloxymethyl isocyanate, methacryloyloxyethyl isocyanate, crotonaldehyde, acrolein, and methacrolein. (5) In the medical device of any one of (1) to (4) above, it is preferred that the structural units (A-1) and (A-2) are arranged randomly, and the structural unit (A-3) is arranged in a block pattern. (6) In the medical device of any one of (1) to (5) above, it is preferred that the structural unit (A-1) is derived from N-isopropylacrylamide, the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the structural unit (A-2) is present in a proportion of 10 mol % or more and less than 20 mol % of the total composition of the structural units (A-1) and (A-2). (7) The medical device according to any one of (1) to (6) above is preferably an introducer sheath, a guiding sheath, or an indwelling needle. [Effects of the Invention]

[0011] The medical device of the present invention can change the lubricity of the coating layer with a small change in temperature, allowing for smooth and minimally invasive removal from the body and preventing inadvertent movement when placed in the body. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a schematic diagram of the device (friction measuring device) used to measure the phase transition temperature. [Figure 2] FIG. 2 is a graph showing the temperature dependence of frictional resistance of the samples of the example and comparative example. [Figure 3] FIG. 3 is a graph showing the relationship between the ratio of the composition of dimethylacrylamide (DMAAm) to the total composition of N-isopropylacrylamide (NIPAAm) and dimethylacrylamide (DMAAm) and the phase transition temperature (° C.). [Figure 4] FIG. 4 is a diagram showing an introducer sheath that is one embodiment of the medical device according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0013] One aspect of the present invention relates to a medical device comprising a substrate layer and a coating layer formed on at least a portion of the substrate layer, wherein the coating layer has a temperature-responsive region at a proximal end thereof, the temperature-responsive region comprising a copolymer (A) having a constituent unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a constituent unit (A-2) derived from a hydrophilic monomer, and a constituent unit (A-3) derived from a reactive monomer, and the phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C.

[0014] As described above, in the medical device of Patent Document 1, when the temperature difference between the critical temperature (phase transition temperature) of the temperature-responsive lubricating layer (temperature-responsive region) and the body's environmental temperature (37°C) is large, the temperature-responsive region cannot switch its lubricity between placement in the body and removal outside the body with a small temperature change in the body's environment. Therefore, the medical device of Patent Document 1 leaves room for improvement in terms of reducing the burden on the body associated with the temperature-lowering operation (temperature change) of the temperature-responsive region and improving the surgeon's operability. In contrast, the phase transition temperature of the temperature-responsive region of the present invention is in the range of more than 35.0°C and less than 38.0°C, which is close to the body's environmental temperature (37°C). Therefore, the temperature-responsive region of the present invention can change its lubricity with a small temperature change in the body's environment (particularly within a blood vessel). Therefore, the medical device of the present invention can change the lubricity of the temperature-responsive region with a small temperature change in a living body environment, and can switch the lubricity between when removed from the body (and when inserted into the body) and when left in the body. Therefore, by changing the lubricity of the temperature-responsive region with a small temperature change, the medical device of the present invention can be smoothly and minimally invasively removed from the body and can prevent inadvertent movement when left in the body. The medical device of the present invention can reduce the load on the living body caused by temperature changes and improve operability for the surgeon.

[0015] Preferred embodiments of the present invention will be described below. Note that the present invention is not limited to the following embodiments, and various modifications can be made within the scope of the claims. Furthermore, the embodiments described in this specification can be arbitrarily combined to form other embodiments.

[0016] In this specification, the "structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature" is also referred to simply as the "structural unit (A-1)" or the "structural unit (A-1) according to the present invention." The "structural unit (A-2) derived from a hydrophilic monomer" is also referred to simply as the "structural unit (A-2)" or the "structural unit (A-2) according to the present invention." The "structural unit (A-3) derived from a reactive monomer" is also referred to simply as the "structural unit (A-3)" or the "structural unit (A-3) according to the present invention." The "copolymer (A) having the structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, the structural unit (A-2) derived from a hydrophilic monomer, and the structural unit (A-3) derived from a reactive monomer" is also referred to simply as the "copolymer (A)" or the "copolymer (A) according to the present invention." A "temperature-responsive region containing copolymer (A) and having a phase transition temperature greater than 35.0°C and less than 38.0°C" is also simply referred to as a "temperature-responsive region" or a "temperature-responsive region according to the present invention."

[0017] In this specification, when the structural units constituting a copolymer or polymer have two or more types of structural units, the content (composition) of the structural units is the total content (composition) of the two or more types of structural units constituting the copolymer or polymer.

[0018] In this specification, the term "distal end" refers to the end of a medical device that is inserted into a living body, and the term "proximal end" refers to the hand side of the medical device.

[0019] As used herein, the term "X to Y" indicating a range includes X and Y and means "X or more and Y or less." As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups.

[0020] In this specification, when a certain structural unit is defined as being "derived from" a certain monomer, it means that the structural unit is a structural unit that is generated by cleavage of one of the polymerizable unsaturated double bonds of the corresponding monomer.

[0021] Unless otherwise specified, operations and measurements of physical properties are performed at room temperature (20-25°C) and a relative humidity of 40-60%RH.

[0022] Hereinafter, embodiments of the present invention will be described. However, the present invention is not limited to the following embodiments. Furthermore, the dimensional proportions in the drawings are exaggerated for the sake of explanation and may differ from the actual proportions.

[0023] <Medical equipment> A medical device according to one embodiment of the present invention comprises a base layer and a coating layer formed on at least a portion of the base layer. The coating layer has a temperature-responsive region containing a copolymer (A) at its proximal end. The copolymer (A) comprises a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer. The temperature-responsive region has a phase transition temperature greater than 35.0°C and less than 38.0°C. A medical device according to the present invention comprising a temperature-responsive region containing such a copolymer (A) exhibits good lubricity in an environment below the phase transition temperature of the temperature-responsive region. Therefore, by lowering the temperature of the temperature-responsive region to a temperature below the phase transition temperature of the temperature-responsive region, the medical device can be inserted into a biological lumen without damaging the biological tissue (e.g., a blood vessel wall) that comes into contact with the temperature-responsive region. Furthermore, the medical device of the present invention has a temperature-responsive region whose phase transition temperature is in the temperature range of greater than 35.0°C and less than 38.0°C, and its lubricity can be eliminated or reduced by heating to a temperature equal to or higher than the phase transition temperature of the temperature-responsive region. Therefore, a surgeon can eliminate or reduce the lubricity with a small temperature change in a living body environment (e.g., within a blood vessel), thereby placing the medical device in a living body lumen. Furthermore, because the medical device of the present invention exhibits good lubricity in an environment below the phase transition temperature of the temperature-responsive region, the medical device placed in a living body lumen can be removed from the living body by cooling the temperature of the temperature-responsive region below the phase transition temperature of the temperature-responsive region, without damaging the contacting living tissue (e.g., the blood vessel wall). Since the phase transition temperature of the temperature-responsive region is close to the living body temperature (37°C), the lubricity of the temperature-responsive region can be changed with a small temperature change, minimizing the stress on the living body associated with temperature changes. Furthermore, the ease of operation for the surgeon can be improved.

[0024] Hereinafter, preferred embodiments of the medical device according to the present invention will be described.

[0025] [Base material layer] The substrate layer used in the present invention may be made of any material, and can be appropriately selected depending on the application. Specific examples of materials constituting (forming) the substrate layer include metal materials, polymeric materials, ceramics, etc. Here, the substrate layer may be entirely made of any of the above materials, or may have a structure in which the surface of a substrate layer core made of any of the above materials is coated with any of the other materials by an appropriate method to form a substrate surface layer. Examples of the latter include a substrate surface layer formed by coating the surface of a substrate core made of a resin material or the like with a metal material by an appropriate method (conventionally known methods such as plating, metal vapor deposition, sputtering, etc.); a substrate surface layer formed by coating the surface of a substrate core made of a hard reinforcing material such as a metal or ceramic material with a polymer material that is softer than the metal reinforcing material by an appropriate method (conventionally known methods such as dipping, spraying, coating, printing, etc.); or a substrate surface layer formed by combining the reinforcing material of the substrate core and the polymer material of the substrate surface layer (by an appropriate reaction treatment). Thus, the substrate core may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components formed of different materials are joined together for each portion of the medical device. Furthermore, a separate middle layer may be formed between the substrate core and the substrate surface layer. Furthermore, the substrate surface layer may also be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components formed of different materials are joined together for each portion of the medical device.

[0026] Among the materials constituting (forming) the substrate layer, the metallic material is not particularly limited, and metallic materials commonly used for medical devices such as catheters, stents, and guidewires can be used. Examples of metallic materials include various stainless steels (SUS) such as SUS304, 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 (Ni-Ti) alloy, nickel-cobalt (Ni-Co) alloy, cobalt-chromium (Co-Cr) alloy, and zinc-tungsten (Zn-W) alloy. These may be used alone or in combination. The metallic material may be appropriately selected based on the intended use, such as an introducer sheath, guiding sheath, or indwelling needle.

[0027] Furthermore, among the materials constituting (forming) the base layer, the polymeric material (resin material or elastomer material) is not particularly limited, and polymeric materials commonly used in medical devices such as catheters, introducers, stents, and guidewires can be used. Examples of polymeric materials include polyethylene resins such as polyamide resin, linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), high-density polyethylene (HDPE), and modified polyethylene; polyolefin resins such as polypropylene resin, modified polyolefin resin, cyclic polyolefin resin, epoxy resin, polyurethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluororesins such as polytetrafluoroethylene (PTFE) and ethylene tetrafluoroethylene (ETFE; Ethylene Tetra Fluoro Ethylene); amino resins (urea resin, melamine resin, benzoguanamine resin), polyester resins such as polyethylene terephthalate resin and polybutylene terephthalate resin; styrene resins such as polystyrene; acrylic resin, polyacetal resin, vinyl acetate resin, phenolic resin, vinyl chloride resin (polyvinyl chloride (PVC)), silicone resin, polyether resins such as polyether ether ketone (PEEK); and polyimide resin. Thermoplastic elastomers such as polyurethane elastomers, polyester elastomers, and polyamide elastomers (nylon elastomers) can also be used as the polymer material constituting the base layer. These may be used alone or in combination of two or more. The polymer material may be appropriately selected from those that are optimal for the base layer of the intended use, such as an introducer sheath, a guiding sheath, or an indwelling needle.

[0028] The shape of the substrate layer is not particularly limited, and may be selected appropriately depending on the mode of use, such as a sheet, a linear (wire), or a tubular shape.

[0029] [Coating layer] The coating layer is formed (carried) on at least a portion of the substrate layer (substrate). Here, the reason why the coating layer is formed (carried) on at least a portion of the surface of the substrate layer is that in medical devices such as introducer sheaths, guiding sheaths, and indwelling needles, which are intended for use, it is not necessary for the entire surface (entire surface) of these medical devices to have the desired effect (for example, lubricity during insertion and withdrawal, and stable placement), and it is sufficient for the coating layer to be carried only on the surface portion where the desired effect is required. Therefore, as described above, the coating layer includes a form formed to cover both sides of the substrate layer entirely; a form formed to cover only one side of the substrate layer entirely; a form formed to cover parts of both sides of the substrate layer in the same or different forms; a form formed to cover part of one side of the substrate layer, etc.

[0030] The coating layer has, at least at the base end, a temperature-responsive region having a phase transition temperature of greater than 35.0° C. and less than 38.0° C. Specifically, the coating layer may consist solely of a temperature-responsive region having a phase transition temperature of greater than 35.0° C. and less than 38.0° C., or may have a lubricating region (described below) in addition to the temperature-responsive region having a phase transition temperature of greater than 35.0° C. and less than 38.0° C.

[0031] The temperature-responsive region is formed at least in the proximal end of the coating layer. The coating layer is formed in a region including the proximal end of the medical device (elongated medical body) so that the temperature-responsive region is located at least on the proximal side of the medical device (elongated medical body). Here, the "proximal end" of the medical device (elongated medical body) refers to the portion located on the proximal side of the medical device (elongated medical body). That is, the coating layer is formed from the portion located on the proximal side of the medical device (elongated medical body) toward the distal end, and includes a temperature-responsive region at least in the proximal end. Note that the coating layer may be formed at a position where the medical device (elongated medical body) is inserted into a living body when the medical device (elongated medical body) is used. Therefore, the coating layer does not have to be formed on the very proximal end of the medical device (elongated medical body) (for example, the position of the sheath hub 220 or the strain relief 230 in FIG. 4). For example, as shown in FIG. 4, the coating layer is formed so that the most distal end of the temperature-responsive region is located closer to the base end than the middle position of the effective length of the medical device in the longitudinal direction of the medical device.

[0032] When the medical device according to the present invention is a tubular object (elongated medical body) such as an introducer sheath, a guiding sheath, an indwelling needle, etc., it is preferable that (a) the temperature-responsive region is formed so as to cover the entire outer surface of the tubular object, or (b) the temperature-responsive region is formed so as to cover the outer surface on the proximal side of the tubular object. In particular, when the medical device according to the present invention is a tubular object (elongated medical body) such as an introducer sheath, a guiding sheath, an indwelling needle, etc., it is more preferable that (b) the temperature-responsive region is formed so as to cover the outer surface on the proximal side of the tubular object, from the viewpoint that the temperature-responsive region can be formed only around the position where the elongated medical body will come into contact with biological tissue (biological tissue located between a biological lumen and the body surface, which is the puncture site connecting the biological lumen with the outside of the body) when the elongated medical body is placed in a living body. By configuring the medical device in this manner, the tip end of the medical device can be smoothly inserted into the biological lumen and fixed at the base end of the medical device to the biological tissue (the biological tissue located between the biological lumen and the body surface, at the puncture site connecting the biological lumen to the outside of the body).

[0033] In the above embodiment (b), the length of the temperature-responsive region is appropriately selected taking into consideration the position where the medical device (elongated medical body) is to be fixed. For example, the temperature-responsive region is provided so that the most distal end of the temperature-responsive region is located closer to the base end than the middle position of the effective length of the medical device in the longitudinal direction of the medical device.

[0034] The following describes a medical device according to the present invention, which is an introducer sheath 200 shown in FIG. 4. The introducer sheath 200 is placed in a blood vessel and is used to insert an elongated object, such as a catheter or a guidewire, into the blood vessel. The introducer sheath 200 includes a sheath tube 210 having a hollow portion extending axially from its distal end to its proximal end, a sheath hub 220 connected to the proximal end of the sheath tube 210, and a strain relief 230 supported on the distal end of the sheath hub 220 and surrounding a predetermined area on the proximal end of the sheath tube 210. The sheath hub 220 also includes a side port 270 that communicates with the interior of the sheath tube 210. One end of a flexible side tube 280 made of, for example, polyvinyl chloride is liquid-tightly connected to the side port 270. The other end of the side tube 280 is attached to, for example, a three-way stopcock 290. A liquid such as physiological saline can be injected into the hollow portion of the sheath tube 210 from the port of this three-way stopcock 290 via the side tube 280. The sheath tube 210 is a portion that is percutaneously introduced into a blood vessel, and a temperature-responsive region 240 according to the present invention is formed at least on the proximal end of the outer surface of the sheath tube 210. In this case, the temperature-responsive region 240 can be provided, for example, in a range of 5 to 50 mm (range of "X" in FIG. 4) from the proximal end position of the sheath tube 210 ("X0" in FIG. 4, the distal end position of the strain relief 230) toward the distal end of the sheath tube 210.

[0035] In the above-mentioned form (b), a lubricating region ("250" in FIG. 4) as described below may be disposed on the tip side in addition to the temperature-responsive region to form the coating layer 260.

[0036] The temperature-responsive region includes a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer. The phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C. In this specification, the term "phase transition temperature" refers to the temperature at which the temperature-responsive region (particularly the copolymer (A) contained in the temperature-responsive region) switches from water-soluble to water-insoluble, resulting in a decrease in the lubricity of the temperature-responsive region. In other words, the temperature-responsive region exhibits hydrophilicity and lubricity in an environment below the phase transition temperature, and its lubricity decreases in an environment above the phase transition temperature. In this specification, the "phase transition temperature" is measured according to the method described in the Examples.

[0037] The phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C, which is close to the temperature of the biological environment (particularly the temperature inside blood vessels). Therefore, the surgeon can change the lubricity of the temperature-responsive region with a small change in temperature in the biological environment, and can switch the lubricity between when the device is removed outside the body (and when inserted into the body) and when it is left in the body.

[0038] Furthermore, the phase transition temperature of the temperature-responsive region is preferably 35.1°C or higher but lower than 37.0°C, and more preferably 35.3°C or higher but lower than 36.9°C. Within this range, when the medical device is placed in a living body, the temperature of the temperature-responsive region can be raised to near the phase transition temperature at the body's environmental temperature, thereby changing the lubricity of the temperature-responsive region, thereby improving the operability of the surgeon. Furthermore, since the temperature difference between the phase transition temperature of the temperature-responsive region and the body's environmental temperature is reduced, the burden on the living body associated with the temperature-lowering operation of the temperature-responsive region can be further reduced when the medical device is removed from the living body.

[0039] [Copolymer (A)] Copolymer (A) has a structural unit (A-1) derived from a temperature-responsive monomer, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer. The homopolymer of the temperature-responsive monomer that constitutes structural unit (A-1) has a lower critical solution temperature (LCST). Copolymer (A) also has a lower critical solution temperature. Note that the lower critical solution temperature of copolymer (A) is different from the lower critical solution temperature of the homopolymer of the temperature-responsive monomer that constitutes structural unit (A-1). Copolymer (A) exhibits hydrophilicity and lubricity in temperature environments below the lower critical solution temperature of copolymer (A), and hydrophobicity and non-lubricity in temperature environments above the lower critical solution temperature of copolymer (A). The phase transition temperature of the temperature-responsive region can be controlled by copolymer (A).

[0040] The temperature-responsive region is preferably composed only of copolymer (A). When the temperature-responsive region is composed only of copolymer (A), the lower critical solution temperature of copolymer (A) is the same as the phase transition temperature of the temperature-responsive region (the lower critical solution temperature of copolymer (A) = the phase transition temperature of the temperature-responsive region). However, the temperature-responsive region may contain other copolymers to the extent that the phase transition temperature of the temperature-responsive region is substantially the same as the lower critical solution temperature of copolymer (A). For example, the temperature-responsive region may contain, in addition to copolymer (A), a polymer of a temperature-responsive monomer (e.g., a copolymer containing structural unit (A-1) but not structural unit (A-2) or (A-3), or a homopolymer of structural unit (A-1)) (another copolymer). When the temperature-responsive region contains a copolymer other than copolymer (A), the content of the other copolymer in the temperature-responsive region (in terms of solid content) is, for example, less than 5% by mass, preferably less than 3% by mass, more preferably less than 1% by mass (lower limit: 0% by mass), and particularly preferably 0% by mass (i.e., the temperature-responsive material contained in the temperature-responsive region is composed only of copolymer (A).) With such a composition, the lower critical solution temperature of copolymer (A) is substantially the same as the phase transition temperature of the temperature-responsive region.

[0041] In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is greater than 35.0°C and less than 38.0°C. In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is 35.1°C or more and less than 37.0°C. In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is 35.3°C or more and 36.9°C or less. A medical device comprising a coating layer having a temperature-responsive region containing such copolymer (A) at its proximal end allows the surgeon to change the lubricity of the temperature-responsive region with small temperature changes in a biological environment, and enables switching of lubricity between removal from the body (and insertion into the body) and placement in the body.

[0042] Each structural unit constituting the copolymer (A) will be described in detail below. Note that, although the following describes an embodiment in which the lower critical solution temperature of the copolymer (A) is substantially the same as or equal to the phase transition temperature of the temperature-responsive region, the present invention is not limited to the following embodiment.

[0043] (Structural unit (A-1)) The structural unit (A-1) constituting the copolymer (A) is derived from a temperature-responsive monomer, the homopolymer of which has a lower critical solution temperature. A polymer composed solely of the structural unit (A-1) (homopolymer of the temperature-responsive monomer) has a specific lower critical solution temperature (LCST). A polymer composed solely of the structural unit (A-1) (homopolymer of the temperature-responsive monomer) exhibits hydrophilicity and lubricity in a temperature environment below the lower critical solution temperature of the polymer, and exhibits hydrophobicity and non-lubricity in a temperature environment above the lower critical solution temperature of the polymer.

[0044] The structural unit (A-1) may be composed of only one type of temperature-responsive monomer, or may be composed of two or more types of temperature-responsive monomers. When the structural unit (A-1) is composed of two or more types of temperature-responsive monomers, the two or more types of temperature-responsive monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (A-1).

[0045] Examples of temperature-responsive monomers include N-isopropylacrylamide (lower critical solution temperature: 32°C), Nn-propylacrylamide (lower critical solution temperature: 22°C), Nn-propylmethacrylamide (lower critical solution temperature: 28°C), N-vinylpropionamide (lower critical solution temperature: 32°C), vinyl methyl ether (lower critical solution temperature: 34°C), N,N-diethylacrylamide (lower critical solution temperature: 34°C), and N-methyl-N-isopropylacrylamide (lower critical solution temperature: 22°C). The lower critical solution temperature is the lower critical solution temperature of the homopolymer of each monomer. The structural unit (A-1) may be composed of only one of the above-mentioned temperature-responsive monomers, or may be composed of two or more of the above-mentioned temperature-responsive monomers in combination.

[0046] Among these, from the viewpoint that the lower critical solution temperature of the homopolymer of the temperature-responsive region monomer is closer to the biological environment temperature, the temperature-responsive monomer is preferably at least one monomer selected from the group consisting of N-isopropylacrylamide, N-vinylpropionamide, vinyl methyl ether, and N,N-diethylacrylamide.Furthermore, from the viewpoint that the lower critical solution temperature of the homopolymer of the temperature-responsive monomer is closer to the biological environment temperature and exhibits good lubricity at temperatures below the lower critical solution temperature, the temperature-responsive monomer is particularly preferably derived from N-isopropylacrylamide.

[0047] That is, in one embodiment of the present invention, the structural unit (A-1) is derived from at least one monomer selected from the group consisting of N-isopropylacrylamide, Nn-propylacrylamide, Nn-propylmethacrylamide, N-vinylpropionamide, vinyl methyl ether, N,N-diethylacrylamide, and N-methyl-N-isopropylacrylamide. In one embodiment of the present invention, the structural unit (A-1) is derived from at least one monomer selected from the group consisting of N-isopropylacrylamide, N-vinylpropionamide, vinyl methyl ether, and N,N-diethylacrylamide. In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide.

[0048] The content (composition) of the structural unit (A-1) is preferably greater than 65 mol%, more preferably 70 mol% or greater, and particularly preferably 75 mol% or greater, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-1) is preferably 90 mol% or less, more preferably 85 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-1) is greater than 65 mol% and 90 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-1) is 70 mol% or more and 85 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-1) is 75 mol% or more and 85 mol% or less, based on all structural units constituting the copolymer (A). Within these ranges, the effects of the present invention can be achieved.

[0049] (Structural unit (A-2)) The structural unit (A-2) according to the present invention is derived from a hydrophilic monomer. The presence (composition) of the structural unit (A-2) and the structural unit (A-1) can adjust the phase transition temperature of the temperature-responsive region. For example, the lower critical solution temperature of a homopolymer of the temperature-responsive monomer N-isopropylacrylamide (NIPAAm) is 32°C. When a NIPAAm homopolymer is applied to a temperature-responsive region, the temperature-responsive region must be used in a temperature environment below 32°C in order to exhibit lubricity. Therefore, when a NIPAAm homopolymer is applied to a temperature-responsive region, in order to exhibit lubricity in a biological environment (e.g., a biological lumen such as a blood vessel), the temperature of the temperature-responsive region must be significantly lowered from the biological environment temperature (37°C). In contrast, the copolymer (A) according to the present invention can increase the lower critical solution temperature of the copolymer (A) (and therefore the phase transition temperature of the temperature-responsive region containing the copolymer (A)) by introducing the structural unit (A-2) in addition to the structural unit (A-1). Therefore, by combining the structural unit (A-1) and the structural unit (A-2), it is possible to reduce the temperature difference between the phase transition temperature of the temperature-responsive region and the biological environment temperature (37°C), which allows the surgeon to change the lubricity of the temperature-responsive region with small temperature changes in the biological environment, and switch the lubricity between when the device is removed outside the body (and inserted into the body) and when it is left in the body.

[0050] The structural unit (A-2) may be composed of only one type of hydrophilic monomer, or may be composed of two or more types of hydrophilic monomers. When the structural unit (A-2) is composed of two or more types of hydrophilic monomers, the two or more types of hydrophilic monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (A-2).

[0051] The hydrophilic monomer may be any one that exhibits lubricity in body fluids or aqueous solvents and can adjust the phase transition temperature of the copolymer (A).Specific examples include N-methylacrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, acrylamide, acrylic acid, methacrylic acid, acryloylmorpholine, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone (N-vinyl-2-pyrrolidone), 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate, 2-[[2-(methacryloyloxy)ethyl]dimethacrylate, 2-hydroxyethyl ... Suitable examples include 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acrylamidopropyl)dimethylammonio]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate.Among these, from the viewpoints of ease of adjusting the phase transition temperature, imparting excellent lubricity, ease of synthesis, etc., N,N-dimethylacrylamide (DMAAm), acrylamide, acrylic acid, methacrylic acid, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone, 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acrylamidopropyl) [dimethylammonio]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate are preferred, N,N-dimethylacrylamide and acrylamide are more preferred, and N,N-dimethylacrylamide is particularly preferred. These hydrophilic monomers may be used alone or in combination of two or more.

[0052] That is, in one embodiment of the present invention, the structural unit (A-2) is derived from at least one monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, acrylic acid, methacrylic acid, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone, 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acrylamidopropyl)dimethylammonio]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate. In one embodiment of the present invention, the structural unit (A-2) is derived from at least one monomer selected from the group consisting of N,N-dimethylacrylamide and acrylamide. In one embodiment of the present invention, the structural unit (A-2) is derived from N,N-dimethylacrylamide.

[0053] The content (composition) of the structural unit (A-2) is preferably greater than 3 mol%, more preferably 5 mol% or greater, and particularly preferably 10 mol% or greater, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-2) is preferably 30 mol% or less, more preferably 25 mol% or less, and particularly preferably 20 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-2) is greater than 3 mol% and 30 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-2) is 5 mol% or more and 25 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-2) is 10 mol% or more and 20 mol% or less, based on all structural units constituting the copolymer (A). When the content (composition) of the structural unit (A-2) is within the above range, the phase transition temperature of the temperature-responsive region can be more effectively controlled to be within a preferred range. Furthermore, the temperature-responsive region can exhibit good lubricity in an environment below the phase transition temperature of the temperature-responsive region. Therefore, the surgeon can change the lubricity of the temperature-responsive region with a small temperature change in the living body environment, and the temperature-responsive region can exhibit good lubricity when removing the medical device from the living body (and when inserting the medical device into the living body).

[0054] For example, when N-isopropylacrylamide is selected as the structural unit (A-1) and N,N-dimethylacrylamide as the structural unit (A-2), the content (composition) of the structural unit (A-2) is preferably 9.5 mol% or more, more preferably 10 mol% or more, based on the total composition of the structural unit (A-1) and the structural unit (A-2) (based on 100 mol% of the total of the structural unit (A-1) and the structural unit (A-2)). In this embodiment, the content (composition) of the structural unit (A-2) is preferably less than 23 mol%, more preferably less than 20 mol%, based on the total composition of the structural unit (A-1) and the structural unit (A-2) (based on 100 mol% of the total of the structural unit (A-1) and the structural unit (A-2)). In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide, and the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the content (composition) of the structural unit (A-2) is 9.5 mol% or more and less than 23 mol% relative to the total composition of the structural units (A-1) and (A-2) (based on a total of 100 mol% of the structural units (A-1) and (A-2)). In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide, and the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the content (composition) of the structural unit (A-2) is 10 mol% or more and less than 20 mol% relative to the total composition of the structural units (A-1) and (A-2) (based on a total of 100 mol% of the structural units (A-1) and (A-2)). According to this embodiment, the surgeon can switch the lubricity of the temperature-responsive region with small temperature changes while minimizing the temperature change load on the living body in a living body environment. Therefore, the surgeon can switch the lubricity of the temperature-responsive region between when the medical device is removed from the living body (and when the medical device is inserted into the living body) and when the medical device is indwelling in the living body, while minimizing the temperature change load on the living body. Furthermore, with this composition, the temperature-responsive region can exhibit better lubricity in a living body environment (e.g., a living body lumen such as a blood vessel).

[0055] (Structural unit (A-3)) The structural unit (A-3) according to the present invention is derived from a reactive monomer having a reactive functional group. The reactive functional groups present in the structural unit (A-3) react with each other to form a crosslinked structure within the same copolymer (A) or between different copolymers (A). This increases the film strength of the coating layer and improves the durability of the coating layer. Furthermore, to further enhance the durability of the coating layer, the reactive functional group may be selected to be a functional group that bonds with the substrate layer. The presence of the structural unit (A-3) in the copolymer (A) can improve the durability of the coating layer.

[0056] The structural unit (A-3) may be composed of only one type of reactive monomer, or may be composed of two or more types of reactive monomers. When the structural unit (A-3) is composed of two or more types of reactive monomers, the two or more types of reactive monomers may be arranged in a block form or random form within the segment of the structural unit (A-3).

[0057] The reactive functional group is not particularly limited and can be appropriately selected depending on the type of material constituting the base layer, the desired degree of crosslinking (film strength) of copolymer (A), and the like. Specifically, the reactive functional group can be an epoxy group, an acid halide group, an aldehyde group, an isocyanate group, an acid anhydride group, or other functional group. From the viewpoint of more firmly immobilizing copolymer (A) (and thus the temperature-responsive region) on the base layer and further improving the film strength of the temperature-responsive region (coating layer), the reactive functional group is preferably an epoxy group, an aldehyde group, or an isocyanate group, and more preferably an epoxy group. In this case, the reactive functional group present in the structural unit (A-3) may be one type, or two or more types may coexist.

[0058] Examples of such structural unit (A-3) include monomers having an epoxy group in the molecule, such as glycidyl acrylate, glycidyl methacrylate, glycidyl ethers (for example, aliphatic glycidyl ethers such as butyl glycidyl ether, 4-hydroxybutyl acrylate glycidyl ether, cetyl glycidyl ether), methyl glycidyl methacrylate, and allyl glycidyl ether; (meth)acrylic acid chloride, (meth)acrylic acid bromide, and (meth)acrylic acid iodide; The structural unit (A-3) may be derived from a monomer having an acid halide group in the molecule, such as a methyl acrylate; a monomer having an aldehyde group in the molecule, such as (meth)acrylaldehyde; a monomer having an isocyanate group in the molecule, such as (meth)acryloyl isocyanate, (meth)acryloyloxymethyl isocyanate, (meth)acryloyloxyethyl isocyanate, or (meth)acryloyloxypropyl isocyanate; or a monomer having an acid anhydride group in the molecule, such as maleic anhydride, itaconic anhydride, or citraconic anhydride. Of these, the structural unit (A-3) is preferably derived from a monomer having at least one of an epoxy group, an aldehyde group, or an isocyanate group, and more preferably derived from a monomer having an epoxy group. Among these, from the viewpoints of further firmly fixing the copolymer (A) (and therefore the temperature-responsive region) to the base layer and further improving the film strength of the temperature-responsive region (coating layer), glycidyl acrylate, glycidyl methacrylate, methyl glycidyl methacrylate, allyl glycidyl ether, acryloyl isocyanate, acryloyloxymethyl isocyanate, acryloyloxyethyl isocyanate, methacryloyl isocyanate, methacryloyloxymethyl isocyanate, methacryloyloxyethyl isocyanate, crotonaldehyde, acrolein, and methacrolein are preferred, with glycidyl acrylate and glycidyl methacrylate being more preferred, as their reaction is accelerated by heat or the like and they are relatively easy to handle, and glycidyl methacrylate being particularly preferred. These reactive monomers may be used alone or in combination of two or more.

[0059] That is, in one embodiment of the present invention, the structural unit (A-3) is derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, methyl glycidyl methacrylate, allyl glycidyl ether, acryloyl isocyanate, acryloyloxymethyl isocyanate, acryloyloxyethyl isocyanate, methacryloyl isocyanate, methacryloyloxymethyl isocyanate, methacryloyloxyethyl isocyanate, crotonaldehyde, acrolein, and methacrolein. In one embodiment of the present invention, the structural unit (A-3) is derived from at least one monomer of glycidyl acrylate and glycidyl methacrylate. In one embodiment of the present invention, the structural unit (A-3) is derived from glycidyl methacrylate.

[0060] The content (composition) of the structural unit (A-3) is preferably greater than 1 mol %, more preferably greater than 2 mol %, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-3) is preferably 20 mol % or less, more preferably 18 mol % or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-3) is greater than 1 mol % and 20 mol % or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-3) is 2 mol % or more and 18 mol % or less, based on all structural units constituting the copolymer (A). Within this range, the temperature-responsive region can exhibit good durability.

[0061] Copolymer (A) has structural units (A-1), (A-2), and (A-3). Preferably, structural units (A-1) and (A-2) are randomly arranged. That is, structural units (A-1) and (A-2) preferably constitute a random copolymer. This allows the lower critical solution temperature of copolymer (A) to be adjusted. Therefore, the temperature difference between the lower critical solution temperature of copolymer (A) and the body temperature (37°C) can be adjusted to be small. Furthermore, structural units (A-3) are preferably arranged in blocks. That is, in copolymer (A), the end of the copolymer composed of structural units (A-1) and (A-2) is covalently linked to the end of structural unit (A-3), and a region (block) composed of structural units (A-1) and (A-2) is linked to a region (block) composed of structural unit (A-3). The structural unit (A-3) has little or no effect on the lower critical solution temperature of the copolymer (A). Therefore, a temperature-responsive region containing the copolymer (A) can be firmly fixed to the base layer via the structural unit (A-3) while maintaining the phase transition temperature adjusted by the structural units (A-1) and (A-2). This improves the durability of the temperature-responsive region. Therefore, a temperature-responsive region containing a copolymer (A) having such a structure can change its lubricity with small temperature changes in a biological environment. It exhibits excellent lubricity below the phase transition temperature of the temperature-responsive region, and its lubricity decreases when heated above the phase transition temperature of the temperature-responsive region. Furthermore, a temperature-responsive region containing a copolymer (A) having such a structure also has excellent durability. The above is a conjecture, and the present invention is not limited by it.

[0062] In one embodiment of the present invention, the structural units (A-1) and (A-2) are arranged randomly, and the structural unit (A-3) is arranged in a block pattern.

[0063] As used herein, the phrase "structural unit (A-3) is arranged in the form of a block" means that a block consisting of only the structural unit (A-3) is present in the main chain of the copolymer (A), i.e., -[structural unit (A-3) n ]-(n is an integer of 2 or more) is intended to be present in the main chain of the copolymer (A). In this embodiment, when the structural unit (A-3) is composed of two or more types of reactive monomers, the two or more types of reactive monomers are present in one block. For example, when the structural unit (A-3) is composed of a structural unit (Y-1) having a reactive functional group (y1) and a structural unit (Y-2) having a reactive functional group (y2) different from the reactive functional group (y1), -[structural unit (Y-1) m1 -Constituent unit (Y-2) m2 ] m - (m1 and m2 are each independently an integer of 1 or greater, m is an integer of 2 or greater, and the structural units (Y-1) and (Y-2) may be arranged in a block or random manner) are present in the main chain of the copolymer (A).

[0064] (other building blocks) The copolymer (A) according to the present invention essentially contains the structural unit (A-1), the structural unit (A-2), and the structural unit (A-3), but may contain other structural units in addition to these structural units. When the copolymer (A) contains other structural units, examples of the monomers constituting the other structural units (other monomers) include 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 glycol mono(meth)acrylate, 1,6-hexanediol mono(meth)acrylate, pentaerythritol acrylate, methyl meth ... Examples of the other structural units include erythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropane di(meth)acrylate, trimethylolethane di(meth)acrylate, 2-hydroxy-3-phenyloxypropyl(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, 2-hydroxy-3-phenyloxy(meth)acrylate, adipic acid, glutaric acid, triethylene glycol, and tripropylene glycol. The other structural units may be composed of only one other monomer, or two or more other monomers. When the other structural units are composed of two or more other monomers, the two or more other monomers may be arranged in a block or random configuration within the segments of the other structural units.

[0065] Copolymer (A) is preferably composed solely of structural units (A-1), (A-2), and (A-3) (content of other structural units = 0 mol%). However, copolymer (A) may contain other structural units within a range that is substantially the same as the lower critical solution temperature of copolymer (A) composed solely of structural units (A-1), (A-2), and (A-3). When copolymer (A) contains other structural units, blocks consisting solely of the other structural units are arranged in the main chain of copolymer (A). In this arrangement, the lower critical solution temperature of copolymer (A) does not change due to the other structural units. In this case, the content of the other structural units is preferably greater than 0 mol% and less than 10 mol% of the total structural units constituting copolymer (A). Particularly preferably, copolymer (A) is substantially composed of structural units (A-1), (A-2), and (A-3) (content of other structural units = greater than 0 mol% and less than 5 mol%). Most preferably, copolymer (A) is composed solely of structural units (A-1), (A-2), and (A-3) (content of other structural units = 0 mol%). With this composition, the lower critical solution temperature of copolymer (A) will be substantially the same as the lower critical solution temperature of a copolymer composed solely of structural units (A-1), (A-2), and (A-3).

[0066] In this specification, the content (composition) of each structural unit (structural units (A-1), (A-2), (A-3), etc.) can be measured by a known method. For example, 1 The composition (molar ratio) of the structural units can be measured by measuring the integral ratio of the intensity of each signal in the H-NMR spectrum. When the copolymer (A) is composed of a structural unit (A-1) derived from N-isopropylacrylamide, a structural unit (A-2) derived from N,N-dimethylacrylamide, and a structural unit (A-3) derived from glycidyl methacrylate, the structural unit composition (copolymer composition) is measured by the method described in the Examples. When the copolymer (A) contains structural units other than those mentioned above, the composition (molar ratio) of each structural unit can be measured by appropriately modifying the method described in the Examples.

[0067] The weight-average molecular weight of the copolymer (A) is several thousand to several million, preferably 10,000 to 5 million. In this specification, the "weight-average molecular weight" is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance. The molecular weight of the copolymer (A) can also be calculated from the type and number of repeating units.

[0068] In addition, the method for producing copolymer (A) is not particularly limited, and can be suitably adopted conventionally known polymerization methods such as living radical polymerization and polymerization using a macroinitiator. Among these, living radical polymerization or polymerization using a macroinitiator is preferably used because it allows the structural unit (A-3) to be arranged in a block form. The living radical polymerization method is not particularly limited, and for example, the methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, etc., as well as atom transfer radical polymerization (ATRP) can be applied in the same manner or with appropriate modifications. Furthermore, in a polymerization method using a macroinitiator, for example, a macroinitiator having a reactive site (structural unit (A-3)) with a reactive functional group and a radically polymerizable group such as a peroxide group is prepared, and then the macroinitiator, a monomer for forming the structural unit (A-1), and a monomer for forming the structural unit (A-2) are polymerized in a polymerization solvent to prepare the copolymer (A).

[0069] In the above polymerization, the mixing ratio of the macroinitiator, the monomer for forming the structural unit (A-1), and the structural unit (A-2) can be such that each structural unit has the composition described above.

[0070] The polymerization solvent is appropriately selected from solvents that can dissolve the macroinitiator, the monomers for forming the structural unit (A-1), and the monomers for forming the structural unit (A-2). For example, water, dimethyl sulfoxide, chlorobenzene, methyl ethyl ketone, benzene, etc. are used. From the viewpoint of the solubility of the macroinitiator, the monomers for forming the structural unit (A-1), and the monomers for forming the structural unit (A-2), dimethyl sulfoxide and chlorobenzene are preferably used.

[0071] In the polymerization, the polymerization conditions are also not particularly limited as long as the copolymerization proceeds. For example, the polymerization temperature is preferably 30 to 150°C, more preferably 40 to 100°C. The polymerization time is preferably 30 minutes to 30 hours, more preferably 3 to 24 hours. The polymerization is carried out in an inert atmosphere such as a nitrogen atmosphere or an argon atmosphere.

[0072] Furthermore, when producing the copolymer (A), chain transfer agents, polymerization rate modifiers, surfactants, water-soluble polymers, water-soluble inorganic compounds (such as alkali metal salts, alkali metal hydroxides, polyvalent metal salts, and non-reducing alkali metal salts), inorganic acids, inorganic acid salts, organic acids, organic acid salts, and other additives may be used as needed.

[0073] After copolymerization, the copolymer (A) is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0074] (Other ingredients) The temperature-responsive region essentially contains copolymer (A). The temperature-responsive region may contain other components in addition to copolymer (A), as long as the phase transition temperature of the temperature-responsive region is not altered. The other components are not particularly limited. For example, when the medical device is intended for insertion into a body cavity or lumen, such as a catheter, examples of the other components include drugs (biologically active substances) such as anticancer drugs, immunosuppressants, antibiotics, antirheumatic drugs, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic drugs, integrin inhibitors, antiallergic drugs, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid-improving drugs, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, vascular smooth muscle proliferation inhibitors, anti-inflammatory drugs, biomaterials, interferons, and NO production promoters. The amount of the other components added is not particularly limited, and commonly used amounts are used. Ultimately, the amount of the other components added is appropriately selected taking into consideration the severity of the disease to which the composition is applied, the patient's weight, etc. Preferably, the temperature-responsive region does not contain any other components. That is, in a preferred embodiment of the present invention, the temperature-responsive region is composed of the copolymer (A) described above.

[0075] (Other areas) The coating layer has a temperature-responsive region at least at the base end. The coating layer may further have a region (other region) other than the temperature-responsive region. The other region may be a region (lubrication region) that can exhibit lubricity regardless of the temperature environment. When the coating layer further has a lubrication region, the lubrication region is preferably formed further distally than the temperature-responsive region, and more preferably formed distally than the temperature-responsive region while in contact with the temperature-responsive region. This allows the lubrication region of the coating layer to exhibit lubricity regardless of temperature. Therefore, the lubrication region of the coating layer can maintain lubricity regardless of the environmental temperature.

[0076] The lubricating region is preferably located in the distal region of the coating layer in the longitudinal direction of the medical device, in the region that will be inserted into the biological lumen. The lubricating region exhibits lubricity regardless of temperature. Therefore, in the above-described configuration, the lubricating region is located closer to the distal end of the medical device than the coating layer. Therefore, when inserting the medical device into the biological lumen, the medical device can be smoothly inserted to the desired position in the biological lumen via the lubricating region without having to worry about the temperature rise of the coating layer due to the temperature environment of the biological lumen. This improves the operability of the medical device. Furthermore, after inserting the medical device to the desired position in the biological lumen, the medical device can be fixed to the biological tissue (the biological tissue located between the biological lumen and the body surface, at the puncture site connecting the biological lumen and the outside of the body) via the temperature-responsive region located on the proximal side of the lubricating region.

[0077] In the following, the medical device according to the present invention will be described in the case of an introducer sheath 200 shown in Fig. 4. The introducer sheath 200 has a temperature-responsive region 240 located on the proximal side of the outer surface of the sheath tube 210, and a lubricating region 250 located distal to the temperature-responsive region while in contact with the temperature-responsive region 240. Note that the lubricating region 250 does not need to be formed on the entire surface distal to the temperature-responsive region 240 as shown in Fig. 4, but may be formed only on the surface portion (which may be a part or the entire surface) that is required to have lubricity when wet.

[0078] Here, the material used in the lubricating region is not particularly limited. Preferably, the material used in the lubricating region includes a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer.

[0079] That is, in one embodiment of the present invention, the coating layer has a temperature-responsive region formed at least at the base end of the substrate layer, and a lubricating region formed in at least a portion of the substrate layer and provided distally of the temperature-responsive region, the lubricating region comprising a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer. In one embodiment of the present invention, the medical device has a coating layer having a temperature-responsive region formed at least at the base end of the substrate layer, and a lubricating region formed in at least a portion of the substrate layer and provided distally of the temperature-responsive region while in contact with the temperature-responsive region, the lubricating region comprising a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer.

[0080] In this embodiment, the lubricating region 250 may include a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer. In this case, the copolymer (B) is preferably a block copolymer having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer. The structural unit (B-1) (hence, the hydrophilic monomer) and the structural unit (B-2) (hence, the reactive monomer) are the same as the structural unit (A-2) and the structural unit (A-3) described above in [Copolymer (A)], respectively, and therefore will not be described here.

[0081] The content of the structural unit (B-1) in the copolymer (B) is, for example, 80 mol % or more and 99 mol % or less, and preferably 85 mol % or more and 97 mol % or less, based on the total structural units constituting the copolymer (B). With such a composition, good lubricity in the lubrication range can be achieved.

[0082] The content of the structural unit (B-2) in the copolymer (B) is, for example, 1 mol% to 20 mol%, preferably 3 mol% to 15 mol%, based on the total structural units constituting the copolymer (B). With such a composition, the film strength of the lubricating area and adhesion to the substrate are improved, and good sliding durability of the lubricating area can be achieved.

[0083] The copolymer (B) according to the present invention may have other structural units in addition to the structural units (B-1) and (B-2). When the polymer (B) has other structural units, examples of the monomers constituting the other structural units (other monomers) include acrylic acid, methacrylic acid, acryloylmorpholine, 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, and 1,4-cyclohexanedimethanol mono(meth)acrylate. Examples of other structural units include 1-chloro-2-hydroxypropyl (meth)acrylate, 1,6-hexanediol mono(meth)acrylate, pentaerythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropane di(meth)acrylate, trimethylolethane di(meth)acrylate, 2-hydroxy-3-phenyloxypropyl (meth)acrylate, 4-hydroxycyclohexyl (meth)acrylate, 2-hydroxy-3-phenyloxy (meth)acrylate, adipic acid, glutaric acid, triethylene glycol, and tripropylene glycol. The other structural units may be composed of only one other monomer, or two or more other monomers. When the other structural units are composed of two or more other monomers, the two or more other monomers may be arranged in a block or random configuration within the segments of the other structural units.

[0084] When copolymer (B) contains other structural units, the content of the other structural units is preferably more than 0 mol% and less than 10 mol% of all structural units constituting copolymer (B). More preferably, copolymer (B) is substantially composed of structural units (B-1) derived from a hydrophilic monomer and structural units (B-2) derived from a reactive monomer (content of other structural units = more than 0 mol% and less than 5 mol%). More preferably, copolymer (B) is composed only of structural units (B-1) and structural units (B-2) (content of other structural units = 0 mol%).

[0085] That is, in one embodiment of the present invention, the coating layer has a temperature-responsive region formed at least at the base end of the substrate layer, and a lubricating region formed in at least a portion of the substrate layer and provided distally of the temperature-responsive region, the lubricating region containing a copolymer (B) substantially composed of a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer. In one embodiment of the present invention, the medical device has a coating layer having a temperature-responsive region formed at least at the base end of the substrate layer, and a lubricating region formed in at least a portion of the substrate layer and provided distally of the temperature-responsive region while in contact with the temperature-responsive region, the lubricating region containing a copolymer (B) composed only of a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer.

[0086] The weight-average molecular weight of copolymer (B) is not particularly limited, but is preferably 10,000 to 10,000,000 from the viewpoint of solubility, and more preferably 100,000 to 5,000,000 from the viewpoint of ease of preparation of a copolymer (B) solution (coating liquid).

[0087] The method for producing the copolymer (B) is not particularly limited, and can be produced by applying conventional polymerization methods such as living radical polymerization, polymerization using a macroinitiator, and polycondensation. Among these, living radical polymerization or polymerization using a macroinitiator is preferred because it is easy to control the molecular weight and molecular weight distribution of the structural units (portions) derived from reactive monomers and the structural units (portions) derived from hydrophilic monomers. The living radical polymerization method is not particularly limited, and for example, methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, etc., as well as atom transfer radical polymerization (ATRP), etc., can be used in the same manner or with appropriate modifications. In addition, in a polymerization method using a macroinitiator, for example, a macroinitiator having a reactive moiety with a reactive functional group and a radically polymerizable group such as a peroxide group is prepared, and then the macroinitiator is polymerized with a monomer for forming a hydrophilic moiety to prepare a block copolymer having a hydrophilic moiety and a reactive moiety. After polymerization, the product is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0088] (Manufacturing method of medical devices) The method for producing a medical device according to the present invention includes applying a solution (coating solution A) containing copolymer (A) and a solvent to at least the base end of the substrate layer ((I) solution application step). If necessary, the coating layer A formed on at least the base end of the substrate layer in step (I) may be heat-treated ((II) heat treatment step). Furthermore, after step (II), the heat-treated coating layer A may be washed ((III) washing step).

[0089] Furthermore, when a temperature-responsive region containing copolymer (A) is provided only at the base end of the substrate layer, the coating layer may have another region (e.g., a lubrication region containing copolymer (B)) further distal than the temperature-responsive region. In an embodiment in which the coating layer has a temperature-responsive region and another region, for example, a solution containing copolymer (B) and a solvent (coating liquid B) may be applied to the substrate layer located distal to the temperature-responsive region ((I') solution application step), the coating layer B formed in the above step (I') may be heat-treated ((II') heat treatment step), and after the above step (II'), the heat-treated coating layer B may be washed ((III') washing step).

[0090] Each step will be explained below. The present invention is not limited to the following embodiments, and known methods for producing medical devices can be applied in the same manner or with appropriate modifications, except that the copolymer (A) or the copolymer (A) and the copolymer (B) according to the present invention are used.

[0091] (I) Coating liquid A application process (coating layer A formation process) In this step, a solution containing the copolymer (A), a solvent, and, if necessary, other components (also referred to simply as "coating liquid A" in this specification) is first prepared, and the coating liquid A is applied to at least the base end of the substrate layer ((I) coating liquid A application step, coating layer A formation step). This step is carried out for the purpose of supporting (or coating) a temperature-responsive region containing copolymer (A) on at least the base end surface of the substrate layer. In this specification, "supported" refers to a state in which the layer to be formed (temperature-responsive region, coating layer) is fixed so that it does not easily separate from the surface of the substrate layer. This term includes not only a state in which the entire surface of the substrate layer is completely covered by the layer, but also a state in which only a portion of the substrate surface is covered by the layer, i.e., a state in which the temperature-responsive region or coating layer is attached to only a portion of the substrate surface. Therefore, the method for applying the solution is not particularly limited except for the use of coating liquid A containing copolymer (A) and a solvent, and can be applied in the same manner as known methods or with appropriate modifications. In addition, if coating liquid A contains other components, the other components are the same as those described above, and therefore will not be described here.

[0092] First, the copolymer (A) and, if necessary, other components are dissolved in a solvent to prepare a solution (coating liquid A). Before applying the coating liquid A, the substrate layer may be subjected to a hydrophilization treatment (for example, plasma irradiation).

[0093] The solvent used to dissolve the copolymer (A) is not particularly limited as long as it can dissolve the copolymer (A) (and other components, if used). From the viewpoint of higher solubility, acetone, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone are used.

[0094] The concentration of copolymer (A) in coating solution A is not particularly limited. For example, the concentration of copolymer (A) in coating solution A is preferably 0.01 to 20% by mass, more preferably 0.05 to 15% by mass, and particularly preferably 1 to 10% by mass. When the concentration of copolymer (A) is within the above range, the resulting temperature-responsive region (coating layer) exhibits adequate lubricity at temperatures below the phase transition temperature, and the lubricity can be reduced at temperatures above the phase transition temperature. In addition, a uniform temperature-responsive region (coating layer) of the desired thickness can be easily obtained with a single coating, and the viscosity of the solution falls within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, even if the concentration is outside the above range, it can be used as long as it does not affect the effects of the present invention.

[0095] Next, the coating liquid A prepared as above is applied to a predetermined region of the substrate layer (at least the surface of the base end of the substrate layer). Here, the substrate layer is the same as that described above, so a description thereof will be omitted here.

[0096] The method for applying (coating) the copolymer (A) solution (coating liquid A) to the surface of the substrate layer is not particularly limited, and any conventionally known method can be used, such as coating / printing, dipping, spraying, spin coating, mixed solution-impregnated sponge coating, bar coating, die coating, reverse coating, comma coating, gravure coating, doctor knife coating, etc. Of these, the dipping method (dipping or dip coating) is preferably used.

[0097] Furthermore, when forming a temperature-responsive region (coating layer) only on a portion of the substrate layer, the temperature-responsive region (coating layer) can be formed in the desired portion of the substrate layer by immersing only a portion of the substrate layer in coating liquid A and coating the coating liquid A onto that portion of the substrate layer.

[0098] If it is difficult to immerse only a portion of the substrate layer in the coating liquid A, the surface portion of the substrate layer where no temperature-responsive region (coating layer) is required can be protected (e.g., coated) with a suitable detachable member. The substrate layer can then be immersed in the coating liquid A to coat the substrate layer with the coating liquid A. After that, the protective member (material) covering the surface portion of the substrate layer where no temperature-responsive region (coating layer) is required can be removed, and the substrate can be reacted by heat treatment or the like to form a temperature-responsive region (coating layer) on the desired surface portion of the substrate layer. However, the present invention is not limited to these formation methods, and a temperature-responsive region (coating layer) can be formed using any conventionally known method. For example, if it is difficult to immerse only a portion of the substrate layer in the coating liquid A, other coating techniques (e.g., applying the coating liquid A to a desired surface portion of a medical device using an application device such as a sprayer, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor knife) can be used instead of the immersion method.

[0099] The amount of coating liquid A (copolymer (A) solution) to be applied is preferably such that the thickness (dry film thickness) of the resulting temperature-responsive region (coating layer) is 0.1 to 10 μm, more preferably 0.5 to 5 μm, and even more preferably 1 to 3 μm.

[0100] (II) Heat treatment process In this step, if necessary, the coating layer A formed in step (I) above is heat-treated. This allows the reactive functional groups of the copolymer (A) to react with each other, thereby increasing the film strength of the coating layer A. Furthermore, when the substrate layer forms a chemical bond with the reactive functional groups of the copolymer (A), the reactive functional groups of the copolymer (A) react with the material constituting the substrate layer, thereby firmly fixing the coating layer A to the substrate layer. This improves the durability of the coating layer A. For this reason, it is preferable to heat-treat the coating layer A formed in step (I) above.

[0101] The conditions for the heat treatment are not particularly limited, as long as they allow the formation of a coating layer A containing copolymer (A) on the substrate layer. For example, the heat treatment temperature is preferably 40 to 200°C, more preferably 50 to 180°C, and particularly preferably 90 to 160°C. The heat treatment time is preferably 30 minutes to 15 hours, more preferably 1 to 10 hours, and particularly preferably 2 to 5 hours. Under the above conditions, the reactive functional groups of copolymer (A) in coating layer (A) react more efficiently with each other, thereby further increasing the film strength of coating layer (A). Furthermore, when the substrate layer forms a chemical bond with the reactive functional groups of copolymer (A), the reactive functional groups of copolymer (A) in coating layer (A) react more effectively with the material constituting the substrate layer, thereby allowing coating layer (A) to be sufficiently firmly fixed to the substrate layer. Therefore, a high-strength coating layer (A) that does not easily peel off from the substrate layer can be formed (the durability of coating layer (A) can be improved).

[0102] The pressure conditions in the heat treatment step are not particularly limited, and the heat treatment step can be carried out under normal pressure (atmospheric pressure), or under increased or reduced pressure.

[0103] As the drying or heating means (device), for example, an oven, a vacuum dryer, etc. can be used, but in the case of natural drying, no particular drying means (device) is required.

[0104] (III) Cleaning process In this step, if necessary, the coating layer A formed in the above step (I) or the covering layer A obtained in the above step (II) is washed.

[0105] The washing method is not particularly limited, but may include a method of immersing the layer A containing copolymer (A) (coating layer A or covering layer A; the same applies hereinafter) in a washing solvent, a method of pouring the washing solvent over the layer A containing copolymer (A), or a combination of these. The washing solvent used here is not particularly limited as long as it does not dissolve the covering layer A containing copolymer (A), but water or warm water is preferably used. The temperature of the washing solvent is not particularly limited, but is preferably 20°C to 100°C, more preferably 25 to 80°C. The washing time (the time during which the washing solvent is brought into contact with the layer A containing copolymer (A)) is not particularly limited, but is preferably 1 to 60 minutes, more preferably 5 to 30 minutes.

[0106] After the washing step, a drying step may be further carried out. The drying method and drying conditions (temperature, time, etc.) are not particularly limited, and any conventionally known method can be used.

[0107] (I') Coating liquid B application process (coating layer B formation process) This step can be performed when the coating layer has a lubricating region in addition to the temperature-responsive region. Therefore, when the coating layer does not include a lubricating region (for example, when the coating layer is composed only of a temperature-responsive region), this step and the following steps (II') and (III') are not performed.

[0108] In this step, a solution containing the copolymer (B) and a solvent, and optionally other components (also referred to simply as "coating liquid B" in this specification) is prepared, and the coating liquid B is applied to at least a portion of the region of the medical device obtained in step (I), (II), or (III) where the temperature-responsive region is not formed (particularly the distal side of the temperature-responsive region) ((I') coating liquid B application step, coating layer B formation step). This step is carried out for the purpose of supporting (or coating) a coating layer B containing copolymer (B) on (or covering) the distal side region of the temperature-responsive region of the base layer. Here, the portion to which coating liquid B is applied is a region that requires lubricity but does not need to be fixed in a biological lumen. Specifically, it is the region corresponding to the lubrication region.

[0109] This step is the same as the above-mentioned (I) Coating Liquid A Application Step (Coating Layer A Formation Step) except that copolymer (B) is used instead of copolymer (A) (coating liquid B is used instead of coating liquid A) and the area to be coated is different, so a detailed explanation will be omitted here.

[0110] (II') Heat treatment process In this step, if necessary, the coating layer B formed in step (I') above is heat-treated. This allows the reactive functional groups of the copolymer (B) to react with each other, thereby increasing the film strength of the coating layer B. Furthermore, when the substrate layer forms a chemical bond with the reactive functional groups of the copolymer (B), the reactive functional groups of the copolymer (B) react with the material constituting the substrate layer, thereby firmly fixing the coating layer B to the substrate layer. This improves the durability of the coating layer B. For this reason, it is preferable to heat-treat the coating layer B formed in step (I') above.

[0111] This step is the same as the above-mentioned (II) heat treatment step except that coating layer B is used instead of coating layer A, and therefore a description thereof will be omitted here.

[0112] (III') Cleaning step In this step, if necessary, the coating layer B formed in the above step (I') or the covering layer B obtained in the above step (II') is washed.

[0113] This step is the same as the above (III) cleaning step except that the coating layer B or the covering layer B is used instead of the coating layer A or the covering layer A, respectively, and therefore a description thereof will be omitted here.

[0114] In the above, steps (I), (II), (III), (I'), (II'), and (III') are performed in this order, but step (I) and step (I') may be performed in any order. For example, steps (I), (II), and (III) may be followed by steps (I'), (II'), and (III'); steps (I), (II), and (III') may be performed after steps (I'), (II'), and (III'); steps (I) and (I') may be performed in this order, followed by step (II) (which also serves as step (II')) and step (III) (which also serves as step (III')); steps (I') and (I) may be performed in this order, followed by step (II) (which also serves as step (II')) and step (III) (which also serves as step (III')).

[0115] (How to use medical equipment) The medical device according to the present invention comprises a temperature-responsive region at least at the proximal end of the coating layer. The temperature-responsive region contains copolymer (A) and has a phase transition temperature greater than 35.0°C and less than 38.0°C. Therefore, by lowering the temperature to a temperature below the phase transition temperature of the temperature-responsive region and improving the lubricity of the temperature-responsive region, the surgeon can smoothly insert the medical device into a biological lumen via the coating layer (temperature-responsive region and, if present, a lubrication region). On the other hand, by heating the temperature to a temperature equal to or greater than the phase transition temperature of the temperature-responsive region and reducing the lubricity of the temperature-responsive region, the surgeon can stably maintain (place) the medical device at a predetermined position in a biological lumen via the coating layer (temperature-responsive region). The phase transition temperature of the temperature-responsive region according to the present invention is greater than 35.0°C and less than 38.0°C, which is close to the temperature of the living body environment (e.g., the temperature of a biological lumen). Therefore, the temperature-responsive region of the present invention can change its lubricity with a small temperature change in a living body environment, which reduces the burden on the living body associated with the temperature-lowering operation (temperature change) of the temperature-responsive region when the medical device of the present invention is removed from the living body lumen, and improves the operability of the surgeon.

[0116] Hereinafter, methods of using a medical device will be described for the case where a temperature-responsive region is formed over the entire substrate layer, and for the case where a temperature-responsive region and a lubricating region are formed in the substrate layer.

[0117] When the temperature-responsive region is formed over the entire base layer, the surgeon cools the temperature-responsive region below the phase transition temperature before inserting the medical device into a biological lumen so that the temperature-responsive region exhibits hydrophilicity and lubricity. This allows the surgeon to smoothly insert the cooled portion of the temperature-responsive region into the biological lumen to the desired position. Furthermore, when inserting the medical device into a biological lumen such as a blood vessel, the hydrophilicity and lubricity of the temperature-responsive region can reduce tissue damage and ease the burden on the patient. Meanwhile, after inserting the tip of the medical device to a predetermined position in the biological lumen and placing the medical device in the biological lumen, the temperature-responsive region of the medical device is heated to a temperature above the phase transition temperature by heat transferred from the surface of the biological lumen and biological tissue. For example, when a medical device is placed in a biological lumen, a portion of the temperature-responsive region of the medical device located at the puncture site connecting the biological lumen and the body surface is heated over time by the biological tissue surrounding the puncture site to a temperature above the phase transition temperature. This reduces or eliminates the hydrophilicity and lubricity of the temperature-responsive region, making it hydrophobic and non-lubricious (resistant). This increases the frictional resistance between the temperature-responsive region and the contact site with the living body, allowing the medical device to be held (fixed) in place. After inserting the tip of the medical device to a predetermined position in the biological lumen and placing the medical device in the biological lumen, the temperature-responsive region may be actively heated to a temperature above the phase transition temperature. Furthermore, when removing a medical device placed in the biological lumen from the biological lumen, the surgeon cools the temperature-responsive region below the phase transition temperature before removing the medical device from the biological lumen so that the temperature-responsive region remains hydrophilic and lubricious. This allows the surgeon to smoothly remove the cooled portion of the temperature-responsive region from the biological lumen while reducing damage to the biological tissue at the puncture site when removing the medical device from the biological lumen. The phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C, which is close to the temperature of the biological environment (e.g., the temperature of the biological lumen). This allows the surgeon to change the lubricity of the temperature-responsive region with a small temperature change in the biological environment. Therefore, when removing the medical device from the biological lumen, the surgeon can reduce the burden on the living body associated with the cooling process (temperature change) of the temperature-responsive region.

[0118] Furthermore, when the temperature-responsive region and the lubricating region are formed on the base layer, the coating layer has a lubricating region on the base layer distal to the temperature-responsive region in the longitudinal direction of the medical device. The lubricating region exhibits lubricity regardless of temperature. Therefore, when inserting the medical device into a biological lumen, the medical device can be smoothly inserted to the desired position in the biological lumen via the lubricating region without worrying about the temperature rise in the temperature-responsive region due to the temperature environment of the biological lumen. Therefore, it is possible to reliably prevent the lubricity of the coating layer in the biological lumen from unexpectedly changing in the region other than the temperature-responsive region, improving the operability of the medical device.

[0119] As in the case where the temperature-responsive region is formed over the entire base layer, the surgeon cools the temperature-responsive region below the phase transition temperature before inserting the medical device into a biological lumen so that the temperature-responsive region exhibits hydrophilicity and lubricity. This allows the surgeon to smoothly insert the cooled portion of the lubricated region and temperature-responsive region into the desired position when inserting the medical device into a biological lumen. Furthermore, when inserting the medical device into a biological lumen such as a blood vessel, the hydrophilicity and lubricity of the lubricated region and temperature-responsive region can reduce tissue damage and ease the burden on the patient. Meanwhile, after inserting the tip of the medical device into a predetermined position in the biological lumen and inserting the medical device into the biological lumen up to the position where the temperature-responsive region is located, the temperature-responsive region of the medical device is heated to a temperature above the phase transition temperature by heat transferred from the surface of the biological lumen or biological tissue. For example, when a medical device is placed in a biological lumen, a portion of the temperature-responsive region of the medical device located at the puncture site connecting the biological lumen to the body surface is heated over time by the biological tissue surrounding the puncture site to a temperature above the phase transition temperature. This reduces or eliminates the hydrophilicity and lubricity of the temperature-responsive region, making it hydrophobic and non-lubricious (resistant). This increases the frictional resistance between the temperature-responsive region and the contact point with the living body, allowing the medical device to be held (fixed) in place. Alternatively, after inserting the tip of the medical device to a predetermined position in the biological lumen and placing the medical device in the biological lumen, the temperature-responsive region may be actively heated to a temperature above the phase transition temperature. Furthermore, when removing a medical device placed in the biological lumen from the biological lumen, the surgeon cools the temperature-responsive region below the phase transition temperature before removing the medical device from the biological lumen so that the temperature-responsive region retains hydrophilicity and lubricity. This allows the surgeon to smoothly remove the portion of the temperature-responsive region that has been cooled from the biological lumen while reducing damage to the biological tissue at the puncture site when removing the medical device from the biological lumen. Here, the phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C, which is close to the temperature of the biological environment (e.g., the temperature of the biological lumen). Therefore, the surgeon can change the lubricity of the temperature-responsive region with small temperature changes in the biological environment.Therefore, when the surgeon removes the medical device from the body lumen, the surgeon can reduce the burden on the living body that accompanies the temperature lowering operation (temperature change) of the temperature-responsive region.

[0120] Here, the method for cooling the temperature-responsive region to a temperature below the phase transition temperature is not particularly limited. For example, when inserting a medical device such as an introducer sheath, a guiding sheath, or an indwelling needle into a biological lumen, the medical device may be immersed in a tray filled with a liquid such as physiological saline whose temperature is lower than the phase transition temperature of the temperature-responsive region before inserting the medical device into the biological lumen, thereby cooling the temperature-responsive region to a temperature below the phase transition temperature. Furthermore, in the case of an introducer sheath having a tubular member (sheath tube) as shown in FIG. 4, the outer surface of the medical device may be cooled from the lumen of the sheath tube by flowing a liquid (e.g., water or physiological saline) whose temperature is lower than the phase transition temperature of the temperature-responsive region through an opening communicating with the lumen of the sheath tube (e.g., a three-way stopcock connected to the sheath hub via a tube) before insertion into the biological lumen. Furthermore, when a medical device such as an introducer sheath, a guiding sheath, or an indwelling needle is removed from a biological lumen, the outer surface of the medical device may be cooled with a cooling agent or the like around the puncture site where the medical device is placed before the medical device is removed from the biological lumen, thereby cooling the outer surface of the medical device so that the temperature-responsive region reaches a temperature below the phase transition temperature. Similarly, there are no particular limitations on the method for heating the temperature-responsive region to a temperature equal to or higher than the phase transition temperature. For example, after inserting a medical device such as an introducer sheath, a guiding sheath, or an indwelling needle to a predetermined position in a biological lumen, the outer surface of the medical device may be heated with a heat insulator or the like around the puncture site where the medical device is placed, thereby heating the outer surface of the medical device so that the temperature-responsive region reaches a temperature equal to or higher than the phase transition temperature.

[0121] The cooling conditions for the temperature-responsive region are not particularly limited as long as they can cool the temperature-responsive region to a temperature below the phase transition temperature and allow the medical device to move smoothly through a biological lumen. However, from the viewpoint of reducing the burden on the living body associated with temperature changes in the temperature-responsive region, the cooling conditions for the temperature-responsive region are preferably temperature conditions close to the phase transition temperature of the temperature-responsive region. Specifically, the temperature is preferably at least 1°C but less than 5°C lower than the phase transition temperature of the temperature-responsive region, and more preferably 2 to 4°C lower than the phase transition temperature of the temperature-responsive region. Such a temperature reduces the burden on the living body associated with the temperature-lowering process of the temperature-responsive region, while allowing the temperature-responsive region to exhibit sufficient lubricity and allowing the medical device to move smoothly.

[0122] Furthermore, the heating conditions for the temperature-responsive region are not particularly limited as long as they can heat the temperature-responsive region to a temperature equal to or higher than the phase transition temperature and can hold (fix) the medical device at a predetermined position in the biological lumen. However, from the viewpoint of reducing the burden on the living body associated with temperature changes in the temperature-responsive region, the heating conditions for the temperature-responsive region are preferably temperature conditions close to the phase transition temperature of the temperature-responsive region. Specifically, a temperature that is 1°C or more but less than 5°C higher than the phase transition temperature of the temperature-responsive region is preferred, and a temperature that is 2 to 4°C higher than the phase transition temperature of the temperature-responsive region is more preferred. At such a temperature, the lubricity of the temperature-responsive region can be sufficiently reduced, allowing the medical device to be stably held (fixed) while reducing the burden on the living body associated with the heating operation of the temperature-responsive region.

[0123] [Medical device uses] The medical device according to the present invention is used in contact with body fluids, blood, and the like, and has a surface that exhibits lubricity in body fluids and aqueous liquids such as physiological saline in a temperature environment below the phase transition temperature of the temperature-responsive region, thereby improving operability and reducing damage to tissue mucosa. On the other hand, in a temperature environment above the phase transition temperature of the temperature-responsive region, the lubricity of the copolymer (A) decreases or disappears, allowing the surgeon to firmly fix the medical device in the desired position (allowing the medical device to be stably maintained (placed) in the predetermined position). Specific examples of medical devices suitable for such applications include introducer sheaths, guiding sheaths, and indwelling needles. That is, the medical device according to one embodiment of the present invention is an introducer sheath, guiding sheath, or indwelling needle. [Example]

[0124] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples, and examples obtained by appropriately combining the technical means disclosed in each example are also included in the scope of the present invention. In the following examples, unless otherwise specified, operations were performed at room temperature (25°C). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass," respectively.

[0125] <Synthesis of copolymer> Synthesis Example 1: Synthesis of polyperoxide PPO-GMA 29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50°C, and then the hydrochloric acid was removed under reduced pressure at 50°C for 3 hours to obtain an oligoester. Next, 4.5 g of methyl ethyl ketone was added to 22.5 g of the obtained oligoester, and this was 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 reaction was carried out at -5°C for 20 minutes. The obtained product was repeatedly washed with water and methanol and then dried to obtain a polyperoxide (PPO) having multiple peroxide groups in the molecule.

[0126] Subsequently, 0.5 g of this PPO (polymerization initiator), 9.5 g of glycidyl methacrylate (GMA), and 30 g of benzene (solvent) were polymerized at 65°C for 2 hours with stirring under reduced pressure. The reaction product obtained after the polymerization was reprecipitated with diethyl ether to obtain polyglycidyl methacrylate (PPO-GMA) having peroxide groups in the molecule.

[0127] Synthesis Examples 2 to 7: Synthesis of Copolymers (1) to (6) Using the polyglycidyl methacrylate (PPO-GMA) obtained in Synthesis Example 1 as a polymerization initiator, N-isopropylacrylamide (NIPAAm) (temperature-responsive monomer) and N,N-dimethylacrylamide (DMAAm) (hydrophilic monomer) were dissolved in chlorobenzene as a solvent in the amounts (g) shown in Table 1 ("Synthesis Charge Amount [g]" in Table 1 below), and polymerization was carried out at 75°C for 6 hours under a nitrogen atmosphere. After polymerization for the specified time, the reaction product was reprecipitated with hexane and recovered to obtain copolymers (poly[(NIPAAm-r-DMAAm)-b-GMA]) (1) to (6) having a temperature-responsive portion in which NIPAAm and DMAAm were randomly copolymerized and a reactive portion made of GMA.

[0128] The compositions (molar ratios) of NIPAAm, DMAAm, and GMA in the copolymers (1) to (6) obtained in Synthesis Examples 2 to 7 were determined according to the following method: 1 Chemical analysis was performed by H-NMR, and the values ​​were determined from the integral ratio of chemical shifts. The results are shown in Table 1. In Table 1 below, the composition (mol) of each monomer calculated based on the synthetic charge amount (g) is referred to as "charge composition ratio" and 1 The composition (molar) of each monomer measured by chemical analysis using H-NMR is shown as "Analyzed Composition Ratio." In Table 1 below, 1Regarding the composition of each monomer (analytical composition ratio) measured by chemical analysis using H-NMR, the compositions of NIPAAm, DMAAm, and GMA relative to the total composition of NIPAAm, DMAAm, and GMA are shown as NIPAAm / total structural units (mol%), DMAAm / total structural units (mol%), and GMA / total structural units (mol%), respectively. Similarly, the composition ratio of DMAAm relative to the total composition of NIPAAm and DMAAm is shown as DMAAm / (NIPAAm+DMAAm)(mol%), and the composition ratio of the total composition of NIPAAm and DMAAm relative to the total composition of NIPAAm, DMAAm, and GMA is shown as NIPAAm+DMAAm / total structural units (mol%).

[0129] [Method for measuring the composition of each structural unit] According to the following conditions, the copolymer solution 1 The composition (molar ratio) of each structural unit was quantified by measuring the integral ratio of the intensity of each signal in the H-NMR spectrum (integral ratio of chemical shifts).

[0130] (Measurement conditions) Equipment name: FT NMR equipment JNM ECZ500R (JEOL RESONANCE Co., Ltd.) Resonant frequency: 1 H: 500MHz Measurement mode: 1 H NMR Dissolving solvent: deuterated chloroform Accumulation count: 64 times Measurement temperature: room temperature (25℃) Sample preparation method: Dissolve 10 mg of copolymer (sample) in 0.75 mL of dissolution solvent.

[0131] obtained 1 In the H-NMR spectrum, a signal (signal A) near δ=3.9 ppm indicates the presence of the structure indicated by the arrow in the following structure of N-isopropylacrylamide (NIPAAm).

[0132] [ka]

[0133] obtained 1 In the H-NMR spectrum, a signal (signal B) near δ=2.9 ppm indicates the presence of the structure indicated by the arrow in the following structure of N,N-dimethylacrylamide (DMAAm).

[0134] [ka]

[0135] obtained 1 In the H-NMR spectrum, a signal (signal C) near δ=3.2 ppm indicates the presence of the structure indicated by the arrow in the following structure of glycidyl methacrylate (GMA).

[0136] [ka]

[0137] [Table 1]

[0138] <Sample Preparation> Example 1 Copolymer (1) obtained in Synthesis Example 2 was dissolved in tetrahydrofuran (THF) to a concentration of 5% by mass to prepare a coating solution. A sheet (size: 15 mm x 40 mm, thickness: 1 mm) made of nylon elastomer (Grilflex (registered trademark) ELG6260, M-Chemie Japan Co., Ltd.) was immersed in this coating solution and then pulled up at a speed of 15 mm / sec to form a coating film on the sheet. The sheet with the coating film formed thereon was then heated in an oven at 130°C for 3 hours to form a coating layer (thickness: 1 μm) containing copolymer (1) on the sheet, thereby obtaining sheet (1).

[0139] Example 2, Comparative Examples 1 to 4 Sheets (2) to (6) were obtained in the same manner as in Example 1, except that copolymers (2) to (6) obtained in Synthesis Examples 3 to 7 were used instead of copolymer (1).

[0140] [Measurement of phase transition temperature] For the sheets (1) to (2) and (3) to (6) (samples) obtained in Examples 1 to 2 and Comparative Examples 1 to 4, the temperature dependence of frictional resistance was evaluated using a friction force tester (Tribomaster TL201Ts, manufactured by Trinity Labs) shown in FIG. 1 according to the following method.

[0141] Specifically, each sheet (sample) 3 was placed on a temperature-controlled stage 2 with the coating layer (the surface coated with each copolymer) facing up. Stage 2 was then filled with PBS solution 1 (pH 7.4) at room temperature (25°C). A cylindrical SEBS terminal 4 (φ6 mm) was then placed in contact with the coating layer of sheet 3. A 50 g load 5 was applied to terminal 4, and the terminal 4 was moved horizontally (sliding) at a speed of 10 mm / sec and a distance of 15 mm. The frictional resistance (gf) was then measured. The temperature was then increased approximately 1°C increments up to 44°C using the temperature control function, and the frictional resistance (gf) was measured repeatedly under the same conditions at approximately 1°C intervals. The temperature dependence of the frictional resistance was evaluated. A frictional resistance of 20 gf or less was considered to be good lubricity, and the temperature at which the frictional resistance reached 20 gf was designated the phase transition temperature (°C). The results are shown in Table 2 and Figure 2. In Table 2, sheet (6) was marked with "-" because the friction resistance was 20 gf or less in the measurement temperature range.

[0142] Figure 3 shows the relationship between the ratio (mol %) of the DMAAm composition to the total composition of NIPAAm and DMAAm [=DMAAm (mol) × 100 / (NIPAAm (mol) + DMAAm (mol))] and the phase transition temperature (°C). Figure 3 shows that the phase transition temperature increases almost linearly with an increase in the DMAAm composition (molar ratio).

[0143] [Table 2]

[0144] From these results, the temperature-responsive region containing copolymers (1) and (2) has a phase transition temperature greater than 35.0°C and less than 38.0°C, which is close to the temperature of the biological environment. Therefore, it is considered that sheets (1) and (2) of Examples 1 and 2 exhibit good lubricity by cooling below the phase transition temperature of the temperature-responsive region (less than 36.9°C for sheet (1) and less than 35.3°C for sheet (2)). On the other hand, it is considered that the frictional resistance of sheets (1) and (2) of Examples 1 and 2 can be increased by stopping the cooling operation and returning them to the biological environment temperature (e.g., about 37°C). Therefore, it is expected that sheets (1) and (2) of Examples 1 and 2 can switch the lubricity of the temperature-responsive region with small temperature changes in the biological environment, thereby minimizing the load on the living body. [Explanation of symbols]

[0145] 1...PBS solution, 2...Temperature-controlled stage, 3...sheet (sample), 4...SEBS terminal, 5...Load (50g), 10...Friction measuring device (friction resistance temperature dependency evaluation system), 200...introducer sheath, 210...Sheath tube, 220...sheath hub, 230...Strain relief, 240...Temperature responsive region, 250...lubrication area, 260...Covering layer, 270...Side port, 280…Side tube, 290...Three-way stopcock.

Claims

1. A medical device comprising a base layer and a coating layer formed on at least a portion of the base layer, the coating layer has, at its base end, a temperature-responsive region including a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer; A medical device, wherein the phase transition temperature of the temperature-responsive region is greater than 35.0°C and less than 38.0°C.

2. 2. The medical device according to claim 1, wherein the structural unit (A-1) is derived from at least one monomer selected from the group consisting of N-isopropylacrylamide, N-n-propylacrylamide, N-n-propylmethacrylamide, N-vinylpropionamide, vinyl methyl ether, N,N-diethylacrylamide, and N-methyl-N-isopropylacrylamide.

3. The structural unit (A-2) is selected from the group consisting of N,N-dimethylacrylamide, acrylamide, acrylic acid, methacrylic acid, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone, 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acrylamidopropyl)dimethylammonio] ]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate.

4. 2. The medical device according to claim 1, wherein the structural unit (A-3) is derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, methyl glycidyl methacrylate, allyl glycidyl ether, acryloyl isocyanate, acryloyloxymethyl isocyanate, acryloyloxyethyl isocyanate, methacryloyl isocyanate, methacryloyloxymethyl isocyanate, methacryloyloxyethyl isocyanate, crotonaldehyde, acrolein, and methacrolein.

5. 2. The medical device according to claim 1, wherein the structural units (A-1) and (A-2) are arranged randomly, and the structural unit (A-3) is arranged in a block pattern.

6. The structural unit (A-1) is derived from N-isopropylacrylamide, The structural unit (A-2) is derived from N,N-dimethylacrylamide, The medical device according to claim 1, wherein the structural unit (A-2) is present in a proportion of 10 mol % or more and less than 20 mol % based on the total composition of the structural unit (A-1) and the structural unit (A-2).

7. The medical device according to claim 1 , wherein the medical device is an introducer sheath, a guiding sheath, or an indwelling needle.

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