Medical instrument

Abstract

The present invention provides a medical instrument that can be removed from the body by a surgeon by appropriate force when necessary while ensuring smooth insertion into the body and stable retention (fixation) within the body. A medical instrument according to the present invention is equipped with a base material layer and a coating layer formed on at least part of the base material layer, wherein the coating layer includes a copolymer (A), having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer, and a polymer (B) having a structural unit (B-1) derived from a hydrophilic monomer, the ratio (molar ratio) of structural units (A-1) to the structural units (B-1) is from 1.5 to 9.0, and the phase transition temperature of the coating layer is less than 37.0° C.

Description

medical equipment

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

[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 by a predetermined length. In this case, it is desirable to be able to smoothly insert the sheath tube into the living body and to be able 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, WO 2017 / 057389 (corresponding to EP 3 357 532 A1) 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 at or above the critical temperature is disposed proximal to the hydrophilic lubricating coating layer.

[0005] In the introducer sheath described in International Publication No. 2017 / 057389 (equivalent to EP 3 357 532 A1), 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, the sheath tube can be smoothly inserted into the body. Additionally, by increasing the temperature of the temperature-responsive lubricating coating layer at the body's ambient temperature during placement in the body, unintended movement of the sheath tube can be prevented.

[0006] On the other hand, in medical settings, there are cases where it is necessary to quickly remove a sheath tube from a living body in an emergency or other situation. In such cases, with the introducer sheath described in WO 2017 / 057389 (equivalent to EP 3 357 532 A1), the lubricity of the temperature-responsive lubricating coating layer decreases at the body's environmental temperature (37°C) during placement of the sheath tube in the living body, causing the frictional force of the temperature-responsive region to increase significantly. As a result, it may be difficult for the surgeon to remove the sheath tube from the living body without cooling the temperature-responsive lubricating region. Therefore, the introducer sheath described in WO 2017 / 057389 (equivalent to EP 3 357 532 A1) may reduce the surgeon's operability when work must be performed quickly, such as in an emergency.

[0007] Therefore, the present invention has been made in consideration of the above circumstances, and aims to provide a medical device that can be smoothly inserted into a living body and stably placed (fixed) in the living body by adjusting the frictional force (lubricity) of the coating layer of the medical device at the temperature of the living body's environment, while also allowing the surgeon to remove the medical device from the living body with an appropriate force when necessary.

[0008] 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 using a specific composition of a thermoresponsive copolymer and a hydrophilic polymer in a coating layer of a medical device, which has led to the completion of the present invention.

[0009] 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 comprises a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer, and a polymer (B) having a structural unit (B-1) derived from a hydrophilic monomer, wherein the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) is 1.5 or more and 9.0 or less, and the phase transition temperature of the coating layer is less than 37.0°C. (2) In the medical device of (1) above, it is preferable that 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) In the medical device of (1) or (2) above, it is preferable that the structural unit (B-1) 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-acrylamidomethyl]methyl ...

[0033] It is preferable that the monomeric component 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-2) 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, the polymer (B) preferably further has a structural unit (B-2) derived from a reactive monomer. (6) In the medical device of (5) above, the structural unit (B-2) 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. (7) In the medical device of any of (1) to (6) above, the copolymer (A) preferably further comprises a structural unit (A-3) derived from a monomer for adjusting the lower critical solution temperature. (8) The medical device of any of (1) to (7) above is preferably an introducer sheath, a guiding sheath, or an indwelling needle.

[0010] FIG. 1 is a diagram showing an introducer sheath, one embodiment of a medical device according to the present invention. In FIG. 1, 100 represents the introducer sheath; 110 represents the sheath tube; 120 represents the sheath hub; 130 represents the strain relief; 140 represents the coating layer; 150 represents the lubricating layer; 160 represents the side port; 170 represents the side tube; and 180 represents the three-way stopcock. FIG. 2 is a schematic diagram of an apparatus (friction force tester) used to evaluate lubricity. In FIG. 2, 300 represents the friction force tester; 310 represents the sheath tube; 311 represents water; 312 represents a container; and 313 and 314 represent silicone pads. FIG. 3 is a graph showing the friction forces of examples and comparative examples at 25°C and 37°C.

[0011] One aspect of the present invention relates to a medical device comprising a base layer and a coating layer formed on at least a portion of the base layer. The coating layer comprises a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer, and a polymer (B) having a structural unit (B-1) derived from a hydrophilic monomer, wherein the molar ratio of the structural unit (A-1) to the structural unit (B-1) is 1.5 or more and 9.0 or less, and the phase transition temperature of the coating layer is less than 37.0°C. With this configuration, the coating layer exhibits lubricity below the phase transition temperature and reduces its lubricity at temperatures equal to or higher than the phase transition temperature. Since the phase transition temperature of the coating layer is less than 37.0°C, the lubricity of the coating layer is reduced by heating to the temperature of a living lumen, such as the temperature inside a blood vessel (37°C). This allows the medical device to be smoothly inserted into a living body and, after insertion, can be stably retained (immobilized) in a predetermined position. In addition, this configuration allows the frictional force (lubricity) of the coating layer at temperatures above the phase transition temperature of the coating layer to be adjusted, allowing the surgeon to remove the medical device from the living body with an appropriate force when necessary (e.g., in an emergency).

[0012] Specifically, a medical device having such a configuration can be smoothly (easily) inserted into a living body (e.g., a biological lumen such as a blood vessel or ureter) by adjusting the temperature of the coating layer to a temperature below the phase transition temperature of the coating layer. Here, "smooth (easily) inserting a medical device" refers to the frictional force of the coating layer being 50 gf or less in the <Lubricity Evaluation of Coated Samples> described below. Preferably, the frictional force at 25°C (below the phase transition temperature of the coating layer) in the <Lubricity Evaluation of Coated Samples> described below is 45 gf or less, more preferably 40 gf or less (lower limit: 0 gf). Furthermore, a medical device having such a configuration can be stably placed (immobilized) in a living body by heating the coating layer to a temperature equal to or higher than the phase transition temperature of the coating layer. Here, "stably placing (immobilizing) a medical device" refers to the frictional force being 100 gf or more at 37°C (above the phase transition temperature of the coating layer) in the <Lubricity Evaluation of Coated Samples> described below. Preferably, the frictional force of the coating layer at 37°C (above the phase transition temperature of the coating layer) in the <Lubricity Evaluation of Coated Samples> described below is 110 gf or more, more preferably 120 gf or more, and particularly preferably 130 gf or more. From the viewpoint of enabling the surgeon to remove the medical device with an appropriate force without any special operation (e.g., cooling operation), the upper limit of the frictional force is, for example, 500 gf or less, preferably 490 gf or less, more preferably 450 gf or less, particularly preferably 400 gf or less, and most preferably 300 gf or less. Furthermore, from the viewpoint of balancing smooth insertion into the body and stable placement in the body, the difference between the frictional force at 25°C (below the phase transition temperature of the coating layer) and the frictional force at 37°C (above the phase transition temperature of the coating layer) in the <Lubricity Evaluation of Coated Samples> described below (=frictional force of the coating layer at 37°C - frictional force of the coating layer at 25°C) is, for example, 50 gf or more. Preferably, in the <Lubricity Evaluation of Coated Samples> below, the difference between the frictional force at 25°C (below the phase transition temperature of the coating layer) and the frictional force at 37°C (above the phase transition temperature of the coating layer) is 60 gf or more, more preferably 70 gf or more, particularly preferably 100 gf or more, and most preferably 130 gf or more.In addition, in the <Lubricity Evaluation of Coated Samples> below, the difference between the frictional force at 25°C (below the phase transition temperature of the coating layer) and the frictional force at 37°C (above the phase transition temperature of the coating layer) is, for example, 500 gf or less, preferably 450 gf or less, more preferably 350 gf or less, and even more preferably 250 gf or less.

[0013] In this specification, the frictional force is a value measured according to the method described in "Evaluation of Lubricity of Coated Samples" in the Examples below, except that the temperature is changed.

[0014] 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 reactive monomer" is also referred to simply as the "structural unit (A-2)" or the "structural unit (A-2) according to the present invention." The "copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer" is also referred to simply as the "copolymer (A)" or the "copolymer (A) according to the present invention."

[0015] In this specification, the "structural unit (B-1) derived from a hydrophilic monomer" is also referred to simply as the "structural unit (B-1)" or the "structural unit (B-1) according to the present invention." The "structural unit (B-2) derived from a reactive monomer" is also referred to simply as the "structural unit (B-2)" or the "structural unit (B-2) according to the present invention." The "polymer (B) having a structural unit (B-1) derived from a hydrophilic monomer" is also referred to simply as the "polymer (B)" or the "polymer (B) according to the present invention."

[0016] 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.

[0017] Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to be used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will prevail.

[0018] As used herein, the range "X to Y" includes X and Y and means "at least X and at most Y." As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups.

[0019] 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 a polymerizable unsaturated double bond of the corresponding monomer.

[0020] Unless otherwise specified, the operations and measurements of physical properties are carried out at room temperature (20 to 25°C) and a relative humidity of 40 to 60% RH.

[0021] 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.

[0022] <Medical Device> A medical device according to one aspect 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 contains a copolymer (A) and a polymer (B). The copolymer (A) has a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer. The polymer (B) has a structural unit (B-1) derived from a hydrophilic monomer. In this case, the copolymer (A) and the polymer (B) are contained in the coating layer such that the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) is 1.5 or more and 9.0 or less. The phase transition temperature of the coating layer is less than 37.0°C. The medical device of the present invention ensures smooth insertion into a living body and stable placement (immobilization) in the living body, while allowing the surgeon to remove it from the living body with an appropriate force when necessary.

[0023] Hereinafter, preferred embodiments of the medical device according to the present invention will be described.

[0024] [Substrate Layer] The substrate layer used in the present invention may be made of any material and can be appropriately selected depending on the application. Specifically, materials constituting (forming) the substrate layer include metal materials, polymer 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 reinforcing material, such as a metal 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 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 for each portion of the medical device.

[0025] Among the materials constituting (forming) the base layer, the metal material is not particularly limited, and metal materials commonly used for medical devices such as catheters, stents, and guidewires can be used. Specific examples 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) alloys, nickel-cobalt (Ni-Co) alloys, cobalt-chromium (Co-Cr) alloys, and zinc-tungsten (Zn-W) alloys. These may be used alone or in combination of two or more. The metal material may be appropriately selected from those optimal for the base layer of the intended use, such as a catheter, stent, or guidewire.

[0026] 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. Specific examples of the resin include polyamide resin, polyethylene resins such as 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), 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 elastomer, polyester elastomer, and polyamide elastomer (nylon elastomer) can also be used as the material for 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.

[0027] 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 line (wire), or a tube.

[0028] [Coating layer] The coating layer is formed (carried) on at least a part of the substrate layer (substrate).Here, the reason why the coating layer is formed (carried) on at least a part of the surface of the substrate layer is that in medical devices such as introducer sheaths, guiding sheaths, and indwelling needles, which are used, the entire surface (whole surface) of these medical devices does not necessarily have the desired effect (for example, lubricity when wet and stable placement), but only the surface part (sometimes a part or the whole) where the desired effect is required is coated with the coating layer.Therefore, as mentioned above, the coating layer includes the form of being formed to cover both sides of the substrate layer entirely; the form of being formed to cover only one side of the substrate layer entirely; the form of being formed to cover parts of both sides of the substrate layer in the same or different forms; the form of being formed to cover part of one side of the substrate layer, etc.

[0029] For example, 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 coating layer be formed so as to cover the entire outer surface of the tubular object, or (b) the coating layer be 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 coating layer be formed so as to cover the outer surface on the proximal side of the tubular object, from the viewpoint that, when the elongated medical body is placed in a living body, the coating layer 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). 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 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) at the base end of the medical device.

[0030] In the above embodiment (b), the length of the coating layer is appropriately selected taking into consideration the position where the medical device (elongated medical body) is to be fixed. For example, the coating layer is provided so that its leading end 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. That is, the coating layer is configured so that its leading end is located within a range of less than 0.5 of the effective length of the medical device from the base of the medical device in the longitudinal direction of the medical device. Below, the medical device according to the present invention will be described in the case of the introducer sheath 100 shown in FIG. 1. The introducer sheath 100 is placed in a blood vessel and is used to insert an elongated body, such as a catheter or guidewire, into the vessel. The introducer sheath 100 includes a sheath tube 110 having a hollow portion extending axially from the distal end to the proximal end, a sheath hub 120 connected to the proximal end of the sheath tube 110, and a strain relief 130 supported on the distal end of the sheath hub 120 and surrounding a predetermined area on the proximal end of the sheath tube 110. The sheath hub 120 also includes a side port 160 that communicates with the interior of the sheath tube 110. One end of a flexible side tube 170 made of, for example, polyvinyl chloride is liquid-tightly connected to the side port 160. The other end of the side tube 170 is attached to, for example, a three-way stopcock 180. A liquid such as saline can be injected into the hollow portion of the sheath tube 110 from the port of the three-way stopcock 180 via the side tube 170. The sheath tube 110 is a part that is percutaneously introduced into a blood vessel, and a coating layer 140 according to the present invention is formed on at least a part of the outer surface of the sheath tube 110. In this case, the coating layer 140 is formed, for example, at the proximal end position of the sheath tube 110 ("X" in FIG. 1). ０ 1), the tip position of the strain relief 130) toward the tip side of the sheath tube 110.

[0031] In the above-mentioned embodiment (b), in addition to the coating layer, a lubricating layer as described below may be disposed on the distal end side.

[0032] The phase transition temperature of the coating layer is less than 37.0°C. Therefore, the coating layer exhibits lubricity at temperatures below the phase transition temperature and reduces its lubricity when heated to or above the phase transition temperature at the temperature of a biological lumen, such as within a blood vessel (37°C). This allows the medical device to be smoothly inserted into the living body and stably retained (fixed) in a predetermined position after insertion. Here, the phase transition temperature of the coating layer is preferably 25°C or higher and 35°C or lower, more preferably 30°C or higher and 35°C or lower, and particularly preferably 32°C or higher and 35°C or lower. When the phase transition temperature of the coating layer is within this temperature range, the coating layer is more reliably heated to or above the phase transition temperature at the temperature of a biological lumen (37°C) to reduce its lubricity, allowing the medical device to be stably retained (fixed) in a predetermined position in a biological lumen. In addition, this prevents the lubricity of the coating layer from unexpectedly changing due to temperature changes in a biological environment, such as within a blood vessel. This allows the medical device to be more easily and stably retained (fixed) in a biological lumen, improving the operator's operability.

[0033] The coating layer comprises a copolymer (A) and a polymer (B). The copolymer (A) has a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer. The polymer (B) has a structural unit (B-1) derived from a hydrophilic monomer. The copolymer (A) and the polymer (B) are contained in the coating layer such that the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) is 1.5 or more and 9.0 or less. A medical device having a coating layer of such a composition can be smoothly inserted into a biological lumen in an environment below the phase transition temperature of the coating layer, and can be stably placed (immobilized) in the biological lumen in an environment above the phase transition temperature of the coating layer. In addition, in a medical device having a coating layer of such a composition, the frictional force (lubricity) of the coating layer at temperatures equal to or higher than the phase transition temperature of the coating layer is adjusted by the polymer (B), and therefore, when necessary (e.g., in an emergency), the surgeon can remove the medical device from the biological lumen by applying an appropriate force.

[0034] [Copolymer (A)] Copolymer (A) has a structural unit (A-1) derived from a temperature-responsive monomer and a structural unit (A-2) derived from a reactive monomer. The temperature-responsive monomer that constitutes structural unit (A-1) has a lower critical solution temperature (Lower Critical Solution Temperature, LCST). Copolymer (A) also has a lower critical solution temperature. Note that the lower critical solution temperature of copolymer (A) does not necessarily coincide with 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 a temperature environment below the lower critical solution temperature of copolymer (A), and exhibits hydrophobicity and non-lubricity in a temperature environment above the lower critical solution temperature of copolymer (A). The phase transition temperature of the coating layer is controlled by copolymer (A).

[0035] The temperature-responsive material contained in the coating layer is preferably composed solely of copolymer (A) (i.e., the polymer comprising the temperature-responsive monomer-derived structural unit (A-1) that constitutes the coating layer is copolymer (A) only). When the temperature-responsive material contained in the coating layer is composed solely of copolymer (A), the lower critical solution temperature of copolymer (A) is the same as the phase transition temperature of the coating layer (lower critical solution temperature of copolymer (A) = phase transition temperature of the coating layer). However, the coating layer may contain other polymers to the extent that the phase transition temperature of the coating layer is substantially the same as the lower critical solution temperature of copolymer (A). For example, the coating layer may contain, as the temperature-responsive material (polymer comprising the temperature-responsive monomer-derived structural unit (A-1)), in addition to copolymer (A) (i.e., a copolymer comprising structural units (A-1) and (A-2)), a polymer of a temperature-responsive monomer (e.g., a copolymer comprising structural unit (A-1) but not structural unit (A-2) or a homopolymer of structural unit (A-1)) (another temperature-responsive polymer). When the coating layer contains a temperature-responsive polymer other than copolymer (A) as a temperature-responsive material, the content of the other temperature-responsive polymer in the coating layer (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, relative to all components (i.e., the temperature-responsive material contained in the coating layer is composed solely 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 coating layer.

[0036] The lower critical solution temperature of the copolymer (A) is, for example, less than 37° C., preferably 25° C. or higher and 35° C. or lower, more preferably 30° C. or higher and 35° C. or lower, and particularly preferably 32° C. or higher and 35° C. or lower. At such a lower critical solution temperature, the coating layer containing the copolymer (A) is heated in the biological lumen to a temperature equal to or higher than the lower critical solution temperature of the copolymer (A), and the lubricity of the coating layer is reduced, allowing the medical device to be stably placed (fixed) in the biological lumen.

[0037] (Structural Unit (A-1)) The structural unit (A-1) constituting the copolymer (A) is derived from a temperature-responsive monomer having 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 (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.

[0038] 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 randomly within the segment of the structural unit (A-1), but a random pattern is preferred.

[0039] Examples of the temperature-responsive monomer include N-isopropylacrylamide (lower critical solution temperature: 32°C), N-n-propylacrylamide (lower critical solution temperature: 22°C), N-n-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). In the above, the lower critical solution temperature refers to the lower critical solution temperature of a homopolymer of each monomer. The structural unit (A-1) may be composed of only one type of the above-mentioned temperature-responsive monomer, or may be composed of two or more types of the above-mentioned temperature-responsive monomers in combination.

[0040] Among these, 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, from the viewpoint that the lower critical solution temperature of the homopolymer of the monomer is lower than the temperature of the living body environment and is sufficiently higher than room temperature. Furthermore, from the viewpoint that the lower critical solution temperature of the homopolymer of the temperature-responsive monomer is close to the temperature of the living body environment and exhibits good lubricity at temperatures lower than the lower critical solution temperature, it is particularly preferable that the temperature-responsive monomer is derived from N-isopropylacrylamide.

[0041] 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, N-n-propylacrylamide, N-n-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.

[0042] The content (composition) of the structural unit (A-1) is preferably 80 mol% or more, and more preferably more than 85 mol%, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-1) is preferably 99 mol% or less, and more preferably 97 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 80 mol% or more and 99 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 more than 85 mol% and 97 mol% or less, based on all structural units constituting the copolymer (A).

[0043] (Structural Unit (A-2)) The structural unit (A-2) 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-2) 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, improving the durability of the coating layer. Furthermore, to further improve the durability of the coating layer, the reactive functional group may be selected to be a functional group that bonds with the base layer. The presence of the structural unit (A-2) in the copolymer (A) can improve the durability of the coating layer.

[0044] The structural unit (A-2) 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-2) is composed of two or more types of reactive monomers, the two or more types of reactive monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (A-2).

[0045] 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 the copolymer (A), and the like. Specifically, it can be a functional group such as an epoxy group, an acid halide group, an aldehyde group, an isocyanate group, or an acid anhydride group. From the viewpoint of more firmly fixing the copolymer (A) (and therefore the coating layer) to the base layer and further improving the film strength of the 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-2) may be one type, or two or more types may coexist.

[0046] Examples of such structural unit (A-2) 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; monomers having an acid halide group, such as (meth)acrylic acid chloride, (meth)acrylic acid bromide, and (meth)acrylic acid iodide; monomers having an aldehyde group in the molecule, such as (meth)acrolein ((meth)acrylaldehyde) and crotonaldehyde; monomers having an isocyanate group in the molecule, such as (meth)acryloyl isocyanate, (meth)acryloyloxymethyl isocyanate, (meth)acryloyloxyethyl isocyanate and (meth)acryloyloxypropyl isocyanate; and monomers having an acid anhydride group in the molecule, such as maleic anhydride, itaconic anhydride and citraconic anhydride. Of these, the structural unit (A-2) is preferably derived from a monomer having at least one of an epoxy group, an aldehyde group and an isocyanate group, and more preferably derived from a monomer having an epoxy group. Among these, from the viewpoint of further firmly fixing the copolymer (A) (and therefore the coating layer) to the substrate layer and further improving the film strength of the 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, and glycidyl acrylate and glycidyl methacrylate, which react by heat or the like and are relatively easy to handle, are more preferred, and glycidyl methacrylate is particularly preferred. These reactive monomers may be used alone or in combination of two or more.

[0047] 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 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-2) is derived from at least one monomer of glycidyl acrylate and glycidyl methacrylate. In one embodiment of the present invention, the structural unit (A-2) is derived from glycidyl methacrylate.

[0048] The content (composition) of the structural unit (A-2) is preferably 1 mol% or more, and more preferably 3 mol% or more, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-2) is preferably 20 mol% or less, and more preferably 15 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 1 mol% or more 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-2) is 3 mol% or more and 15 mol% or less, based on all structural units constituting the copolymer (A).

[0049] (Other Structural Units) The copolymer (A) according to the present invention essentially contains the structural unit (A-1) and the structural unit (A-2), 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 include a lower critical solution temperature adjusting monomer and a monomer other than the lower critical solution temperature adjusting monomer (also referred to as other monomers). The other structural units may be composed of only one of the above-mentioned monomers, or may be composed of two or more of the above-mentioned monomers. When the other structural unit is composed of two or more of the above-mentioned monomers, the two or more of the above-mentioned monomers may be arranged in a block form or a random form within the segment of the other structural unit.

[0050] Among these, it is preferable that the copolymer (A) further contains a structural unit derived from a monomer for adjusting the lower critical solution temperature. For example, when the copolymer (A) further contains a structural unit derived from a hydrophilic monomer for adjusting the lower critical solution temperature as the structural unit (A-3), the lower critical solution temperature of the copolymer (A) containing the structural units (A-1), (A-2), and (A-3) will be higher than the lower critical solution temperature of the copolymer (A) consisting only of the structural units (A-1) and (A-2). Therefore, this configuration makes it possible to easily adjust the lower critical solution temperature of the copolymer (A) depending on the usage environment, for example by reducing the gap between the lower critical solution temperature of the copolymer (A) and the temperature of the biological environment.

[0051] That is, in one embodiment of the present invention, the copolymer (A) further includes a structural unit (A-3) derived from a monomer for adjusting the lower critical solution temperature. In this specification, the "structural unit (A-3) derived from a monomer for adjusting the lower critical solution temperature" is also referred to simply as the "structural unit (A-3)."

[0052] Hereinafter, an embodiment (Embodiment 1) in which the copolymer (A) further contains a structural unit (A-3) will be described.

[0053] In embodiment 1, the structural unit (A-3) may be composed of only one type of lower critical solution temperature controlling monomer, or may be composed of two or more types of lower critical solution temperature controlling monomers. When the structural unit (A-3) is composed of two or more types of lower critical solution temperature controlling monomers, the two or more types of lower critical solution temperature controlling monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (A-3).

[0054] In the first embodiment, the lower critical solution temperature adjusting monomer may be any monomer capable of adjusting the lower critical solution 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-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[ Suitable examples include 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 lower critical solution temperature, ease of synthesis, etc., 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] [[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 are preferred, N,N-dimethylacrylamide and acrylamide are more preferred, and N,N-dimethylacrylamide is particularly preferred. These lower critical solution temperature adjusting monomers may be used alone or in combination of two or more.

[0055] 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 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-3) 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-3) is derived from N,N-dimethylacrylamide.

[0056] For example, when N-isopropylacrylamide is selected as the structural unit (A-1) and N,N-dimethylacrylamide is selected as the structural unit (A-3), in embodiment 1, the content (composition) of the structural unit (A-3) can be adjusted to at least 0 mol % and not more than 15 mol % (preferably more than 0 mol % and not more than 15 mol %) of all structural units constituting the copolymer (A), thereby making it possible to appropriately adjust the lower critical solution temperature of the copolymer (A) within a preferred range of 32°C to 35°C.

[0057] In embodiment 1, the structural units (A-1) and (A-3) are preferably arranged randomly. That is, the structural units (A-1) and (A-3) preferably constitute a random copolymer. This allows the lower critical solution temperature of the copolymer (A) to be more effectively adjusted. Furthermore, the structural units (A-2) are preferably arranged in blocks. That is, in the copolymer (A), the end of the copolymer composed of the structural units (A-1) and (A-3) is preferably linked to the end of the structural unit (A-2) by a covalent bond, and a region (block) composed of the structural units (A-1) and (A-3) is preferably linked to a region (block) composed of the structural unit (A-2). In this case, the structural unit (A-2) has little or no effect on the lower critical solution temperature of the copolymer (A). For this reason, the copolymer (A) can be firmly fixed to the base layer via the structural unit (A-2) while maintaining the lower critical solution temperature adjusted by the structural units (A-1) and (A-3). Therefore, a medical device having a coating layer containing the copolymer (A) having such a structure can further improve the durability of the coating layer. That is, in one embodiment of the present invention, the copolymer (A) has the structural units (A-1), (A-2), and (A-3), wherein the structural units (A-1) and (A-3) are arranged randomly and the structural unit (A-2) is arranged in a block pattern.

[0058] The phrase "the structural units (A-1) and (A-3) form a random copolymer" means that when the structural unit (A-1) is composed of two types of temperature-responsive monomers and the structural unit (A-3) is composed of one type of lower critical solution temperature-controlling monomer, these three monomers form a random copolymer. Furthermore, when the structural unit (A-1) is composed of one type of temperature-responsive monomer and the structural unit (A-3) is composed of two types of lower critical solution temperature-controlling monomers, these three monomers form a random copolymer. Furthermore, when the structural unit (A-1) is composed of two types of temperature-responsive monomers and the structural unit (A-3) is composed of two types of lower critical solution temperature-controlling monomers, these four monomers form a random copolymer.

[0059] As used herein, the phrase "structural unit (A-2) is arranged in the form of a block" means that a block consisting of only the structural unit (A-2) is present in the main chain of the copolymer (A), that is, -[structural unit (A-2) ｎ ]-(n is an integer of 2 or greater) is intended to be present in the main chain of copolymer (A). In this embodiment, when the structural unit (A-2) is composed of two or more types of reactive monomers, two or more types of reactive monomers are present in one block. For example, when the structural unit (A-2) 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 -Structural 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) is present in the main chain of copolymer (A).

[0060] Hereinafter, an embodiment (Embodiment 2) will be described in which the copolymer (A) further contains a structural unit (structural unit (A-4)) derived from a monomer (another monomer) other than the structural units (A-1), (A-2), and (A-3).

[0061] In embodiment 2, the structural unit (A-4) may be composed of only one type of other monomer, or may be composed of two or more types of other monomers. When the structural unit (A-4) is composed of two or more types of other monomers, the two or more types of other monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (A-4).

[0062] In embodiment 2, examples of the 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 tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, and the like. Examples of such acrylates include 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, 4-hydroxycyclohexyl(meth)acrylate, cyclohexanedimethanol mono(meth)acrylate, adipic acid, glutaric acid, triethylene glycol, and tripropylene glycol.

[0063] In embodiment 2, copolymer (A) is preferably composed of only the structural unit (A-1) and the structural unit (A-2), or only the structural unit (A-1), the structural unit (A-2), and the structural unit (A-3) (the content of the structural unit (A-4) = 0 mol %). However, copolymer (A) may contain structural unit (A-4) in an amount substantially equal to the lower critical solution temperature of copolymer (A) composed only of structural unit (A-1) and structural unit (A-2), or the lower critical solution temperature of copolymer (A) composed only of structural unit (A-1), structural unit (A-2), and structural unit (A-3). When copolymer (A) contains structural unit (A-4), a block composed only of structural unit (A-4) is arranged in the main chain of copolymer (A). With such an arrangement, the lower critical solution temperature of copolymer (A) does not change. In this case, the content of the structural unit (A-4) is preferably 0 mol% or more and less than 10 mol% relative to all structural units constituting the copolymer (A). Particularly preferably, the copolymer (A) is substantially composed of the structural unit (A-1) and the structural unit (A-2), or substantially composed of the structural unit (A-1), the structural unit (A-2), and the structural unit (A-3) (the content of the structural unit (A-4) = 0 mol% or more and less than 5 mol%). Most preferably, the copolymer (A) is composed only of the structural unit (A-1) and the structural unit (A-2), or composed only of the structural unit (A-1), the structural unit (A-2), and the structural unit (A-3) (the content of the structural unit (A-4) = 0 mol%).

[0064] In this specification, the content (composition) of each structural unit (structural units (A-1), (A-2), (A-3), and (A-4)) can be measured by a known method. For example, １The 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 an N-isopropylacrylamide-derived structural unit (A-1) and a glycidyl methacrylate-derived structural unit (A-2), or when it is composed of an N-isopropylacrylamide-derived structural unit (A-1), a glycidyl methacrylate-derived structural unit (A-2), and an N,N-dimethylacrylamide-derived structural unit (A-3), the composition of each structural unit (copolymer composition) is measured by the method described in the Examples. When the copolymer (A) has structural units other than those described above, the composition (molar ratio) of each structural unit can be measured by appropriately modifying the following method.

[0065] 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. In this specification, the molecular weight of the copolymer (A) can also be calculated from the type and number of repeating units.

[0066] The method for producing the copolymer (A) is not particularly limited, and conventionally known polymerization methods such as living radical polymerization and polymerization using a macroinitiator can be appropriately adopted. Among these, living radical polymerization and polymerization using a macroinitiator are preferably used because they allow the structural unit (A-2) to be arranged in a block form. The living radical polymerization method is not particularly limited, and examples thereof include the methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, and the like, as well as atom transfer radical polymerization (ATRP), which 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-2)) 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, if necessary, a monomer for forming the structural unit (A-3) and the like are polymerized in a polymerization solvent to prepare the copolymer (A).

[0067] In the above polymerization, the amounts of the macroinitiator and the monomers for forming each structural unit added may be such that each structural unit has the composition described above.

[0068] The polymerization solvent is appropriately selected from solvents capable of dissolving the macroinitiator, the monomers for forming the structural unit (A-1), and the monomers for forming the structural unit (A-3). 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-3), dimethyl sulfoxide and chlorobenzene are preferably used.

[0069] 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.

[0070] Furthermore, in 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 appropriately, if necessary.

[0071] After copolymerization, the copolymer (A) is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0072] [Polymer (B)] The polymer (B) has a structural unit (B-1) derived from a hydrophilic monomer. In the coating layer, the copolymer (A) and the polymer (B) are present such that the ratio of the structural unit (A-1) to the structural unit (B-1) (structural unit (A-1) / structural unit (B-1) (molar ratio)) is 1.5 or more and 9.0 or less. If the ratio of the structural unit (A-1) to the structural unit (B-1) is less than 1.5, the amount of the structural unit (A-1) in the coating layer is too small relative to the amount of the structural unit (B-1), and therefore the coating layer cannot sufficiently increase frictional force even at temperatures equal to or higher than the phase transition temperature. Therefore, even if the coating layer is heated to a temperature equal to or higher than the phase transition temperature in a biological lumen, the medical device cannot be stably placed (immobilized). On the other hand, when the ratio of the structural unit (A-1) to the structural unit (B-1) exceeds 9.0, the amount of the structural unit (A-1) in the coating layer is excessive relative to the amount of the structural unit (B-1), resulting in an unnecessarily high frictional force at temperatures above the phase transition temperature. Therefore, when a medical device is placed in a biological lumen and the coating layer is heated to a temperature above the phase transition temperature, the surgeon will need to use excessive force to remove the medical device from the biological lumen, necessitating special procedures such as cooling the coating layer to a temperature below the phase transition temperature before removing the medical device from the biological lumen. This reduces the operability of the medical device.

[0073] The ratio of the structural unit (A-1) to the structural unit (B-1) (structural unit (A-1) / structural unit (B-1) (molar ratio)) is preferably 1.9 or more and 9.0 or less, and more preferably 2.3 or more and 5.7 or less. Such a ratio makes it possible to achieve a better balance between smooth insertion of the medical device into a biological lumen in a temperature environment below the phase transition temperature of the coating layer, stable placement of the medical device in a biological lumen in a temperature environment at or above the phase transition temperature of the coating layer, and operability of the medical device in a temperature environment at or above the phase transition temperature of the coating layer (ease of removal of the medical device from a biological lumen in a temperature environment at or above the phase transition temperature of the coating layer). In this specification, the ratio of the structural unit (A-1) to the structural unit (B-1) (structural unit (A-1) / structural unit (B-1) (molar ratio)) is calculated by dividing the content (composition) of the structural unit (A-1) in the copolymer (A) by the content (composition) of the structural unit (B-1) in the polymer (B), obtaining the result to two decimal places, and rounding off to one decimal place.

[0074] In addition, when the copolymer (A) has structural units (A-1), (A-2), and (A-3) (Embodiment 1 above), the structural unit (A-3) may overlap with the structural unit (B-1). In this embodiment, the structural unit (A-3) of the copolymer (A) acts to change the lower critical solution temperature of the copolymer (A) (and therefore the phase transition temperature of the coating layer). On the other hand, the structural unit (B-1) of the polymer (B) does not change the lower critical solution temperature of the copolymer (A) (and therefore the phase transition temperature of the coating layer). For this reason, the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) can be calculated by the following method. In particular, the composition of the structural unit (A-1) in the coating layer (composition Y0) and the total composition of the structural units (A-3) and (B-1) in the coating layer (composition Y1) are measured. The content (composition Y2) of the structural unit (A-3) in the copolymer (A) is estimated by measuring the lower critical solution temperature of the copolymer (A). The value obtained by subtracting the composition Y2 from the composition Y1 (= composition Y1 - composition Y2) corresponds to the structural unit (B-1) in the polymer (B). Based on these values, the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) [= (composition Y0) / (composition Y1 - composition Y2)] can be calculated.

[0075] (Structural Unit (B-1)) The structural unit (B-1) constituting the polymer (B) has a structural unit (B-1) derived from a hydrophilic monomer. The polymer (B) exhibits hydrophilicity and lubricity when wet. Therefore, the polymer (B) containing the structural unit (B-1) can reduce the frictional force of the coating layer in a temperature environment at or above the phase transition temperature. Therefore, in the medical device of the present invention, the polymer (B) reduces the frictional force of the coating layer in a temperature environment at or above the phase transition temperature of the coating layer, allowing the surgeon to remove the medical device from the living body with an appropriate force when necessary (for example, in an emergency).

[0076] The structural unit (B-1) 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 (B-1) 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 (B-1).

[0077] The hydrophilic monomer may be any one that can exhibit lubricity in body fluids or aqueous solvents. Specific examples thereof 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, 2-hydroxyethyl methacrylate, 2-[[2-(methacryloyloxy)ethyl]dimethyl] 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 imparting excellent lubricity and ease of synthesis, 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 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.

[0078] That is, in one embodiment of the present invention, the structural unit (B-1) 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 (B-1) 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 (B-1) is derived from N,N-dimethylacrylamide.

[0079] (Other Structural Units) The polymer (B) according to the present invention essentially contains the structural unit (B-1), but may also contain other structural units in addition to these structural units. When the polymer (B) contains other structural units, examples of the monomers constituting the other structural units include the reactive monomers having a reactive functional group described above in (Structural Unit (A-2)); and the other monomers described above in (Other Structural Units) in [Copolymer (A)]. The other structural unit may be composed of only one of the above monomers, or may be composed of two or more of the above monomers. When the other structural unit is composed of two or more of the above monomers, the two or more of the above monomers may be arranged in a block or random manner within the segment of the other structural unit.

[0080] Of these, it is preferred that polymer (B) further contains a structural unit derived from a reactive monomer having a reactive functional group. According to this configuration, the reactive functional group present in polymer (B) interacts with copolymer (A) (particularly the reactive functional group of structural unit (A-2) in copolymer (A)) or the substrate layer (particularly when the substrate layer is a resin material), forming a crosslinked structure with copolymer (A) or the substrate layer. Furthermore, the reactive functional groups in polymer (B) react with each other, further increasing the film strength of the coating layer. Therefore, it is possible to further improve the durability of the coating layer of the medical device. That is, in one embodiment of the present invention, polymer (B) further contains a structural unit (B-2) derived from a reactive monomer.

[0081] Hereinafter, an embodiment (Embodiment 3) in which the polymer (B) further contains a structural unit (B-2) will be described.

[0082] In embodiment 3, examples of the reactive monomer that constitutes the structural unit (B-2) include the same monomers as the reactive monomer having a reactive functional group described above (structural unit (A-2)). Of these, from the viewpoints of the interaction between the polymer (B) and the copolymer (A) and further strengthening the fixation of the polymer (B) to the base layer, the reactive monomer that constitutes the structural unit (B-2) is preferably 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. Glycidyl acrylate and glycidyl methacrylate are more preferred, and glycidyl methacrylate is particularly preferred, as the reaction is accelerated by heat or the like and they are relatively easy to handle. These reactive monomers may be used alone or in combination of two or more.

[0083] That is, in one embodiment of the present invention, the structural unit (B-2) 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 (B-2) is derived from at least one monomer of glycidyl acrylate and glycidyl methacrylate. In one embodiment of the present invention, the structural unit (B-2) is derived from glycidyl methacrylate.

[0084] In embodiment 3, the content (composition) of the structural unit (B-2) is preferably 1 mol% or more, and more preferably 3 mol% or more, relative to all structural units constituting the polymer (B). Furthermore, the content (composition) of the structural unit (B-2) is preferably 20 mol% or less, and more preferably 15 mol% or less, relative to all structural units constituting the polymer (B). In one embodiment of the present invention, the content (composition) of the structural unit (B-2) is 1 mol% or more and 20 mol% or less, relative to all structural units constituting the polymer (B). In one embodiment of the present invention, the content (composition) of the structural unit (B-2) is 3 mol% or more and 15 mol% or less, relative to all structural units constituting the polymer (B). Within these ranges, durability can be further improved.

[0085] In this specification, the content (composition) of each structural unit (structural units (B-1) and (B-2)) can be measured by a known method. For example, １ The composition (molar ratio) of the structural units can be determined by measuring the integral ratio of the intensities of each signal in the H-NMR spectrum, and the composition (molar ratio) of each structural unit can be determined by appropriately modifying the method described in the examples below.

[0086] In embodiment 3, the structural unit (B-2) 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 (B-2) is composed of two or more types of reactive monomers, the two or more types of reactive monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (B-2).

[0087] In addition, in embodiment 3, the structural unit (B-1) and the structural unit (B-2) are preferably arranged in a block form. In other words, the structural unit (B-1) and the structural unit (B-2) preferably constitute a block copolymer.

[0088] It is preferable that the polymer (B) is composed solely of the structural unit (B-1), or that it is composed solely of the structural unit (B-1) and the structural unit (B-2) (the content of structural units other than the structural unit (B-1) and the structural unit (B-2) = 0 mol %). However, the polymer (B) may contain structural units other than the structural units (B-1) and (B-2) as long as the effects of the present invention are not impaired. When the polymer (B) contains structural units other than the structural units (B-1) and (B-2), the content of structural units other than the structural units (B-1) and (B-2) is preferably more than 0 mol % and less than 10 mol % relative to all structural units constituting the polymer (B). More preferably, the polymer (B) is composed essentially of the structural unit (B-1), or is composed essentially of the structural unit (B-1) and the structural unit (B-2) (the content of structural units other than the structural units (B-1) and (B-2) = 0 mol % or more and less than 5 mol %). Particularly preferably, the polymer (B) is composed solely of the structural unit (B-1), or solely of the structural unit (B-1) and the structural unit (B-2) (the content of structural units other than the structural units (B-1) and (B-2) = 0 mol %). Most preferably, the polymer (B) is composed solely of the structural unit (B-1) and the structural unit (B-2) (the content of structural units other than the structural units (B-1) and (B-2) = 0 mol %). With such a composition, the copolymer (B) reduces the frictional force of the coating layer in a temperature environment equal to or higher than the phase transition temperature of the coating layer, and can improve the durability of the coating layer.

[0089] The weight-average molecular weight of polymer (B) 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. In this specification, the molecular weight of polymer (B) can also be calculated from the type and number of repeating units.

[0090] The method for producing the polymer (B) is not particularly limited, and known methods can be used or known methods can be appropriately modified and applied.

[0091] (Other Components) The coating layer essentially contains the copolymer (A) and the polymer (B). The coating layer may contain other components in addition to the copolymer (A) and the polymer (B). The other components are not particularly limited. For example, when the medical device is intended for insertion into a body cavity or blood vessel, such as an introducer sheath, a guiding sheath, or an indwelling needle, examples of the other components include 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 (biologically active substances). The amount of the other components added is not particularly limited, and commonly used amounts are used in the same manner. Ultimately, the amounts of the other components added are appropriately selected taking into consideration the severity of the disease to be treated, the patient's weight, etc. Preferably, the coating layer does not contain any other components. That is, in a preferred embodiment of the present invention, the coating layer is composed of the copolymer (A) and the polymer (B).

[0092] (Other Regions) The medical device of the present invention essentially has a coating layer containing the copolymer (A) and the polymer (B) on at least a portion of the base layer. The medical device may further have regions (other regions) other than the coating layer. The other regions may be regions (lubricating layers) that can exhibit lubricity regardless of the temperature environment. When a lubricating layer is further provided on the base layer, the lubricating layer is preferably formed closer to the distal end than the coating layer, and more preferably formed closer to the distal end than the coating layer while in contact with the coating layer.

[0093] As described above, the lubricating layer is preferably provided in the region of the medical device that is distal to the coating layer in the longitudinal direction and that is inserted into a biological lumen. The lubricating layer exhibits lubricity regardless of temperature. Therefore, in the above-described configuration, the lubricating layer is located distal to the coating layer. Therefore, when inserting the medical device into a biological lumen, the medical device can be smoothly inserted to a desired position in the biological lumen via the lubricating layer without worrying 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 a desired position in the biological lumen, the medical device can be fixed to biological tissue (biological tissue located between the biological lumen and the body surface, at a puncture site connecting the biological lumen and the outside of the body) via the coating layer located proximal to the lubricating layer.

[0094] In the following, the medical device according to the present invention will be described in the case of an introducer sheath 100 shown in Fig. 1. The introducer sheath 100 has a coating layer 140 located on the proximal side of the outer surface of the sheath tube 110, and a lubricating layer 150 located distal to the coating layer while in contact with the coating layer 140. Note that the lubricating layer 150 does not need to be formed on the entire surface distal to the coating layer 140 as shown in Fig. 1, 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.

[0095] That is, in one embodiment of the present invention, the medical device has a base layer, a coating layer formed on at least a portion of the base layer, and a lubricating layer formed on at least a portion of the base layer and provided distally of the coating layer, the lubricating layer comprising a copolymer (C) having a structural unit (C-1) derived from a hydrophilic monomer and a structural unit (C-2) derived from a reactive monomer. In one embodiment of the present invention, the medical device has a base layer, a coating layer formed on at least a portion of the base layer, and a lubricating layer formed on at least a portion of the base layer and provided distally of the coating layer in contact with the coating layer, the lubricating layer comprising a copolymer (C) having a structural unit (C-1) derived from a hydrophilic monomer and a structural unit (C-2) derived from a reactive monomer.

[0096] In this embodiment, the lubricating layer 150 may include a copolymer (C) having a structural unit (C-1) derived from a hydrophilic monomer and a structural unit (C-2) derived from a reactive monomer. In this case, the copolymer (C) is preferably a block copolymer having a structural unit (C-1) derived from a hydrophilic monomer and a structural unit (C-2) derived from a reactive monomer. The structural unit (C-1) (hence, the hydrophilic monomer) and the structural unit (C-2) (hence, the reactive monomer) are the same as the structural unit (B-1) and the structural unit (B-2) described above in [Copolymer (B)], respectively, and therefore will not be described here.

[0097] The content of the structural unit (C-1) in the copolymer (C) 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 all structural units constituting the copolymer (C). With such a composition, good lubricity and lubrication maintenance can be achieved.

[0098] The content of the structural unit (C-2) in the copolymer (C) is, for example, from 1 mol % to 20 mol %, and preferably from 3 mol % to 15 mol %, relative to all structural units constituting the copolymer (C). With such a composition, good lubricity, sliding durability, coating layer strength, adhesion to the substrate layer, and the like can be achieved.

[0099] The copolymer (C) according to the present invention may contain other structural units in addition to the structural units (C-1) and (C-2). When the polymer (C) contains other structural units, examples of the monomers constituting the other structural units 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, 1,4-cyclohexanedimethanol mono(meth)acrylate, and 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, 4-hydroxycyclohexyl(meth)acrylate, cyclohexanedimethanol mono(meth)acrylate, adipic acid, glutaric acid, triethylene glycol, tripropylene glycol, etc. The other structural unit may be composed of only one of the above monomers, or may be composed of two or more of the above monomers. Note that when composed of two or more of the above monomers, the two or more of the above monomers may be arranged in a block or random manner within the segment of the other structural unit.

[0100] When copolymer (C) contains other structural units, the content of the other structural units is preferably more than 0 mol% and less than 10 mol% relative to all structural units constituting copolymer (C). More preferably, copolymer (C) is substantially composed of structural units (C-1) derived from a hydrophilic monomer and structural units (C-2) derived from a reactive monomer (content of other structural units = more than 0 mol% and less than 5 mol%). More preferably, copolymer (C) is composed only of structural units (C-1) and structural units (C-2) (content of other structural units = 0 mol%).

[0101] That is, in one embodiment of the present invention, a medical device has a base layer, a coating layer formed on at least a portion of the base layer, and a lubricating layer formed on at least a portion of the base layer and provided distally of the coating layer, wherein the lubricating layer contains a copolymer (C) essentially composed of a structural unit (C-1) derived from a hydrophilic monomer and a structural unit (C-2) derived from a reactive monomer. In one embodiment of the present invention, a medical device has a base layer, a coating layer formed on at least a portion of the base layer, and a lubricating layer formed on at least a portion of the base layer and provided distally of the coating layer in contact with the coating layer, wherein the lubricating layer contains a copolymer (C) composed only of a structural unit (C-1) derived from a hydrophilic monomer and a structural unit (C-2) derived from a reactive monomer.

[0102] The weight average molecular weight of the copolymer (C) 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 (C) solution (coating liquid).

[0103] The method for producing the copolymer (C) is not particularly limited, and can be produced by applying conventionally known polymerization methods such as living radical polymerization, polymerization using a macroinitiator, and polycondensation. Among these, living radical polymerization or polymerization using a macroinitiator is preferably used 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 applied 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.

[0104] (Method for manufacturing a medical device) The method for manufacturing a medical device according to the present invention includes applying a solution (coating liquid A) containing a copolymer (A), a polymer (B), and a solvent to at least a portion of a substrate layer ((I) solution application step). If necessary, the coating layer A formed on at least a portion of the substrate layer in the above step (I) may be heat-treated ((II) heat treatment step). Furthermore, after the above step (II), the heat-treated coating layer A may be washed ((III) washing step).

[0105] In addition, when a coating layer containing copolymer (A) and polymer (B) is provided on the base end side of the substrate layer, and a lubricating layer containing copolymer (C) is provided on the substrate layer distal to the coating layer, for example, a solution containing copolymer (C) and a solvent (coating liquid B) may be applied to the substrate layer distal to the coating layer (preferably so as to be in contact with the coating layer) ((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).

[0106] Each step will be described below. The present invention can be applied in the same manner as known methods for producing medical devices or by appropriately modifying such methods, except that copolymer (A) and polymer (B) or copolymer (A), polymer (B) and copolymer (C) according to the present invention are used, and is not limited to the following forms.

[0107] (I) Coating Liquid A Application Step (Coating Layer A Formation Step) In this step, first, a solution containing the copolymer (A), polymer (B), and solvent, as well as other components if necessary (also referred to simply as "coating liquid A" in this specification) is prepared, and the coating liquid A is applied to at least a portion 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 coating layer containing copolymer (A) and polymer (B) on at least a portion of the surface of the substrate layer (preferably the surface of the base end side of the substrate layer). In this specification, "supported" means a state in which the layer to be formed (in this embodiment, the coating layer) is fixed so that it does not easily separate from the surface of the substrate layer. This includes not only a state in which the entire surface of the substrate layer is completely covered with the layer, but also a state in which only a portion of the substrate surface is covered with the layer, i.e., a state in which the coating layer is attached to only a portion of the substrate surface. Therefore, the method of applying the solution is not particularly limited except for the use of coating liquid A containing copolymer (A), polymer (B), and solvent, and can be applied in the same manner as known methods or by appropriately modifying them. When the coating liquid A contains other components, the other components are the same as those described above, and therefore, a description thereof will be omitted here.

[0108] Specifically, in this step, the copolymer (A), the polymer (B), and, if necessary, other components are dissolved in a solvent to prepare a solution (coating liquid A), and the coating liquid A is then coated on a desired portion of the substrate layer to form the coating layer A. Here, the copolymer (A), the polymer (B), and (if used, other components) may be added to the solvent all at once, or each component may be added to a separate solvent and then mixed. Before applying the coating liquid A, the substrate layer may be subjected to a hydrophilization treatment (e.g., plasma irradiation) in advance.

[0109] Here, the solvent used to dissolve the copolymer (A) and the polymer (B) is not particularly limited as long as it can dissolve the copolymer (A) and the polymer (B) (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. Note that, when the copolymer (A) and the polymer (B) are each dissolved in a solvent and then these solutions are mixed to prepare the coating liquid A, the solvents for dissolving the copolymer (A) and the polymer (B) may be the same or different, but are preferably the same.

[0110] When coating solution A or copolymer (A) and polymer (B) are added to another solvent, the concentration of copolymer (A) in the solution is not particularly limited. For example, the concentrations of copolymer (A) and polymer (B) in the solution are each independently preferably 0.01 to 20% by mass, more preferably 0.05 to 15% by mass, and particularly preferably 1 to 10% by mass. The concentrations of copolymer (A) and polymer (B) in the solution may be the same or different. When the concentrations of copolymer (A) and polymer (B) are within the above ranges, a uniform coating layer of the desired thickness can be easily obtained in a single coating run, and the viscosity of the solution is within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, concentrations outside the above ranges are also fully usable as long as they do not affect the effects of the present invention.

[0111] The mixing ratio of the copolymer (A) and the polymer (B) in the coating solution A is such that the ratio (molar ratio) of the structural unit (A-1) of the copolymer (A) to the structural unit (B-1) of the polymer (B) is 1.5 or more and 9.0 or less, and the preferred ratio is the same as that for the polymer (B) above.

[0112] The coating solution A prepared as described above is applied to a predetermined region (preferably the surface on the base end side) of the substrate layer. Here, the substrate layer is the same as that described above, and therefore a description thereof will be omitted here.

[0113] The method for applying (coating) the coating liquid A onto the surface of the base layer is not particularly limited, and any conventionally known method can be applied, such as a coating / printing method, a dipping method (dipping method, dip coating method), a spraying method (spray method), a spin coating method, a mixed solution impregnated sponge coating method, a bar coating method, a die coating method, a reverse coating method, a comma coating method, a gravure coating method, a doctor knife method, etc. Of these, the dipping method (dipping method, dip coating method) is preferably used.

[0114] Furthermore, when forming coating layer A only on a part of the base layer, coating layer A can be formed on the desired part of the base layer by immersing only a part of the base layer in coating liquid A and coating part of the base layer with coating liquid A.

[0115] When it is difficult to immerse only a portion of the substrate layer in the coating liquid A, the surface portion of the substrate layer that does not require a coating layer can be protected (coated, etc.) with a suitable detachable (attachable) member, and then the substrate layer can be immersed in the coating liquid A to coat the substrate layer with the coating liquid A. After that, the protective member (material) on the surface portion of the substrate layer that does not require a coating layer can be removed, and then the substrate can be reacted by heat treatment or the like to form a coating layer on the desired surface portion of the substrate layer. However, the present invention is not limited to these formation methods, and conventionally known methods can be used as appropriate to form a coating layer. For example, when it is difficult to immerse only a portion of the substrate layer in the coating liquid A, other coating methods (e.g., a method of applying the coating liquid A to a predetermined 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.

[0116] The amount of coating solution A to be applied is preferably an amount such that the thickness of the resulting coating layer (dry film thickness) is 0.1 to 10 μm, more preferably an amount such that the thickness is 0.5 to 5 μm, and even more preferably an amount such that the thickness is 1 to 3 μm.

[0117] (II) Heat Treatment Step In this step, if necessary, the coating layer A formed in step (I) 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 group of the copolymer (A), the reactive functional group of the copolymer (A) reacts with the material constituting the substrate layer to firmly fix the coating layer A to the substrate layer. Therefore, the durability of the coating layer A can be improved. For this reason, it is preferable to heat-treat the coating layer A formed in step (I). Furthermore, when the polymer (B) further contains a structural unit (B-2) derived from a reactive monomer, the reactive functional group of the polymer (B) reacts with the reactive functional group of the copolymer (A), thereby further improving the film strength. Furthermore, when the substrate layer forms a chemical bond with the reactive functional group of the polymer (B), the reactive functional group of the polymer (B) reacts with the material constituting the substrate layer to firmly fix the coating layer A to the substrate layer. Furthermore, the reactive functional groups of the polymer (B) react with each other, thereby increasing the film strength of the coating layer A. This further improves the durability of the coating layer A. For this reason, it is preferable to heat-treat the coating layer A formed in the above step (I).

[0118] 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) and polymer (B) 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 the copolymer (A) in the coating layer A react more efficiently, further 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) in the coating layer A react more effectively with the material constituting the substrate layer, thereby allowing the coating layer A to be sufficiently firmly fixed to the substrate layer. Therefore, a high-strength coating layer A can be formed that does not easily peel off from the substrate layer. Furthermore, when the polymer (B) further contains a structural unit (B-2) derived from a reactive monomer, under the above conditions, the reactive functional groups of the polymer (B) in the coating layer A react with each other, or the reactive functional groups of the polymer (B) in the coating layer A react with the reactive functional groups of the copolymer (A) more efficiently, thereby further increasing the film strength of the coating layer A. Furthermore, when the substrate layer forms a chemical bond with the reactive functional group of the polymer (B), the reactive functional group of the polymer (B) in the coating layer A reacts more effectively with the material constituting the substrate layer, thereby allowing the 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. Therefore, the durability of the coating layer A can be improved. For this reason, it is preferable to heat-treat the coating layer A formed in the above step (I) under the above conditions.

[0119] The pressure conditions in the heat treatment step are not particularly limited, and the heat treatment step may be carried out under normal pressure (atmospheric pressure), or may be carried out under increased or reduced pressure.

[0120] 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.

[0121] (III) Washing Step 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.

[0122] The washing method is not particularly limited, but may include a method of immersing layer A containing copolymer (A) and polymer (B) (coating layer A or covering layer A; the same applies hereinafter) in a washing solvent, a method of pouring a washing solvent over layer A containing copolymer (A) and polymer (B), or a combination of these. The washing solvent used in this case is not particularly limited as long as it does not dissolve covering layer A containing copolymer (A) and polymer (B), 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 layer A containing copolymer (A)) is not particularly limited, but is preferably 1 to 60 minutes, more preferably 5 to 30 minutes.

[0123] 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.

[0124] (I') Coating liquid B application step (coating layer B formation step) This step can be performed when a lubricating layer is formed on the base layer in addition to the coating layer. Therefore, when no lubricating layer is formed (i.e., when only the coating layer is formed on the base layer), this step and the following steps (II') and (III') are not performed.

[0125] In this step, a solution containing the copolymer (C), a solvent, and, if necessary, 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 no coating layer is formed (particularly, the distal side of the coating layer) ((I') coating liquid B application step, coating layer B formation step). This step is carried out for the purpose of supporting (or coating) the coating layer B containing copolymer (C) in the region distal to the coating layer 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 lubricating layer.

[0126] This step is the same as the above-mentioned (I) Coating Liquid A Application Step (Coating Layer A Formation Step) except that copolymer (C) is used instead of copolymer (A) and polymer (B) (coating liquid B is used instead of coating liquid A) and the area to be coated is different, and therefore a description thereof will be omitted here.

[0127] (II') Heat Treatment Step (Coating Layer B Formation Step) 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 (C) 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 group of the copolymer (C), the reactive functional group of the copolymer (C) reacts with the material constituting the substrate layer, thereby firmly fixing the coating layer B to the substrate layer. Therefore, the durability of the coating layer B can be improved. For this reason, it is preferable to heat-treat the coating layer B formed in step (I') above.

[0128] This step is the same as the heat treatment step (II) above except that coating layer B is used instead of coating layer A, and therefore a description thereof will be omitted here.

[0129] (III') Washing Step In this step, the coating layer B formed in the above step (I') or the covering layer B obtained in the above step (II') is washed, if necessary.

[0130] This step is the same as the above-mentioned (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.

[0131] In the above, steps (I), (II), (III), (I'), (II') and (III') are carried out in this order, but either step (I) or step (I') may be carried out first. For example, steps (I), (II), and (III) may be followed by steps (I'), (II'), and (III'); steps (I), (II), and (III) may be followed by 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')).

[0132] (Method of Using the Medical Device) The medical device according to the present invention comprises a coating layer on at least a portion of a base layer. The coating layer contains a copolymer (A) and a polymer (B). The copolymer (A) has a lower critical solution temperature. Therefore, in an environment below the phase transition temperature of the coating layer, the surgeon can smoothly insert the medical device into a biological lumen.

[0133] Here, when a coating layer is formed over the entire substrate layer, it is preferable for the surgeon to cool the coating layer to a temperature below the phase transition temperature of the coating layer before inserting the medical device into a biological lumen so that the coating layer exhibits hydrophilicity and lubricity. For example, the coating layer of the medical device can be cooled to a temperature below the phase transition temperature by immersing it in physiological saline solution below the phase transition temperature of the coating layer. This allows the surgeon to insert the cooled portion of the coating layer more smoothly to 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 coating layer can reduce tissue damage and the burden on the patient. Meanwhile, after inserting the distal end of the medical device to a predetermined position in the biological lumen and placing the medical device in the biological lumen, the coating layer of the medical device is heated to a temperature above the phase transition temperature by heat transmitted from the surface of the biological lumen, biological tissue, and body fluids such as blood. For example, when a medical device is placed in a biological lumen, a portion of the coating layer 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 coating layer, making it hydrophobic and non-lubricating (resistant). This increases the frictional force between the coating layer 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 coating layer may be actively heated to a temperature above the phase transition temperature of the coating layer. Furthermore, the coating layer contains, in addition to the copolymer (A), a polymer (B) such that the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) is a predetermined ratio. Therefore, the coating layer is configured so that the frictional force does not increase in a temperature environment above the phase transition temperature, compared to the frictional force of a coating layer composed only of copolymer (A). Therefore, when removing the medical device from the biological lumen, the surgeon can remove the medical device from the biological lumen without requiring special operations such as cooling the coating layer with physiological saline or the like below the phase transition temperature of the coating layer.

[0134] Furthermore, when the coating layer and the lubricating layer are formed on the base layer, the medical device may have a lubricating layer formed on the base layer distal to the coating layer in the longitudinal direction of the medical device. The lubricating layer exhibits lubricity regardless of temperature. Therefore, when inserting the medical device into a biological lumen, the medical device can be smoothly inserted to a desired position in the biological lumen via the lubricating layer without worrying 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, when inserting the medical device into a biological lumen, the hydrophilicity and lubricity of the lubricating layer reduce tissue damage and reduce the burden on the patient. Meanwhile, after inserting the distal end of the medical device into a predetermined position in the biological lumen and inserting the medical device into the biological lumen to the position where the coating layer is located, the coating layer of the medical device is heated to a temperature above the phase transition temperature by heat transmitted from the surface of the biological lumen, biological tissue, and body fluids such as blood. For example, when a medical device is placed in a biological lumen, a portion of the coating layer 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 coating layer, making it hydrophobic and non-lubricating (resistant). This increases the frictional force at the contact site between the coating layer and the living body, allowing the medical device to be held (fixed) in place. The coating layer may also be heated to a temperature above the phase transition temperature of the coating layer by actively heating the coating layer 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. Furthermore, the coating layer contains, in addition to the copolymer (A), a polymer (B) such that the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) is a predetermined ratio. Therefore, the coating layer is configured such that the frictional force does not increase in a temperature environment above the phase transition temperature compared to the frictional force of a coating layer composed solely of the copolymer (A). Therefore, when removing the medical device from the biological lumen, the surgeon can remove the medical device from the biological lumen without having to perform any special operations such as cooling the coating layer with saline solution that is below the phase transition temperature of the coating layer.

[0135] Here, the method for cooling the coating layer of a medical device to a temperature below the phase transition temperature of the coating layer is not particularly limited. For example, before 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 coating layer, thereby cooling the coating layer 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. 1, 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 coating layer 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.

[0136] The cooling conditions are not particularly limited as long as they can cool the coating layer to a temperature below the phase transition temperature of the coating layer and allow the medical device to move smoothly through the biological lumen. Specifically, it is more preferable to use a liquid whose temperature is adjusted to be preferably 20 to 1°C lower, and more preferably 15 to 2°C lower, than the phase transition temperature of the coating layer. A liquid at such a temperature can sufficiently reduce the lubricity of the coating layer.

[0137] [Uses of Medical Devices] The medical device according to the present invention is used in contact with body fluids, blood, etc., 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 coating layer, thereby improving operability and reducing damage to tissue mucosa. On the other hand, in a temperature environment above the phase transition temperature of the coating layer, the lubricity of the copolymer (A) is reduced or lost, allowing the medical device to be firmly fixed in the desired position. Specific examples of medical devices suitable for such uses 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.

[0138] 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.

[0139] [Method for measuring the composition of each structural unit] The composition (molar ratio) of each structural unit constituting the copolymer was measured by measuring the molar ratio of the copolymer solution according to the following conditions. １ Quantitation was performed by measuring the integral ratio of the intensity of each signal in the H-NMR spectrum (integral ratio of chemical shifts).

[0140] (Measurement conditions) Device name: FT NMR device JNM ECZ500R (JEOL RESONANCE Co., Ltd.) Resonance frequency: １ H; 500MHz Measurement mode: １ H NMR Dissolution solvent: deuterated chloroform Number of measurements: 64 Measurement temperature: room temperature (25°C) Sample preparation method: 10 mg of copolymer (sample) was dissolved in 0.75 mL of dissolution solvent.

[0141] 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.

[0142]

[0143] 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.

[0144]

[0145] obtained １In 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.

[0146]

[0147] <Synthesis of Copolymers> Synthesis Example 1: Synthesis of Temperature-Responsive Block Copolymer 1 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 mixture was allowed to react 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.

[0148] 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.

[0149] Using 0.355 g of the polyglycidyl methacrylate (PPO-GMA) obtained above as a polymerization initiator, 5.658 g of N-isopropylacrylamide (NIPAAm) (temperature-responsive monomer) was dissolved in 30 g of chlorobenzene and polymerized under a nitrogen atmosphere at 75° C. for 6 hours. The reaction product was recovered by reprecipitation with hexane, yielding a temperature-responsive block copolymer 1 having a temperature-responsive moiety consisting of NIPAAm and a reactive moiety consisting of GMA.

[0150] The composition (molar ratio) of each structural unit of the temperature-responsive block copolymer 1 obtained above was determined according to the above-mentioned method. As a result, the ratio of NIPAAm to GMA (NIPAAm:GMA (molar ratio)) in the temperature-responsive block copolymer 1 was 20:1. The lower critical solution temperature of the temperature-responsive block copolymer 1 was 32°C.

[0151] Synthesis Example 2: Synthesis of temperature-responsive block copolymer 2 In the same manner as in Synthesis Example 1, polyglycidyl methacrylate (PPO-GMA) having a peroxide group in the molecule was obtained.

[0152] Using 0.356 g of the polyglycidyl methacrylate (PPO-GMA) obtained above as a polymerization initiator, 5.658 g of N-isopropylacrylamide (NIPAAm) (temperature-responsive monomer) and 0.502 g of N,N-dimethylacrylamide (DMAAm) (monomer for adjusting the lower critical solution temperature) were dissolved in 30 g of chlorobenzene, and polymerization was carried out at 75°C for 6 hours under a nitrogen atmosphere. The reaction product was recovered by reprecipitation with hexane, yielding a temperature-responsive block copolymer 2 having a temperature-responsive moiety consisting of NIPAAm and DMAAm and a reactive moiety consisting of GMA.

[0153] The composition (molar ratio) of each structural unit of the obtained temperature-responsive block copolymer 2 was determined according to the above-mentioned method. As a result, the ratio of NIPAAm, DMAAm, and GMA (NIPAAm:DMAAm:GMA (molar ratio)) of the temperature-responsive block copolymer 2 was 20:2:1. The lower critical solution temperature of the temperature-responsive block copolymer 2 was 34°C.

[0154] Synthesis Example 3: Synthesis of hydrophilic block copolymer 1 In the same manner as in Synthesis Example 1, polyglycidyl methacrylate having a peroxide group in the molecule (PPO-GMA) was obtained.

[0155] Using 0.404 g of the polyglycidyl methacrylate (PPO-GMA) obtained above as a polymerization initiator, 3.378 g of N,N-dimethylacrylamide (DMAAm) (hydrophilic monomer) was dissolved in 30 g of chlorobenzene, and polymerization was carried out under a nitrogen atmosphere at 80° C. for 4 hours. The reaction product was recovered by reprecipitation with hexane, yielding a hydrophilic block copolymer 1 having a hydrophilic moiety consisting of DMAAm and a reactive moiety consisting of GMA.

[0156] The composition (molar ratio) of each structural unit of the obtained hydrophilic block copolymer 1 was determined by the above-mentioned method, and the ratio of DMAAm to GMA (DMAAm:GMA (molar ratio)) of the hydrophilic block copolymer 1 was found to be 12:1.

[0157] Synthesis Example 4: Synthesis of hydrophilic polymer 2 0.07 g of 2,2'-azobisisobutyronitrile (polymerization initiator) and 4.198 g of N,N-dimethylacrylamide (DMAAm) (hydrophilic monomer) were dissolved in 30 g of chlorobenzene and polymerized at 75°C for 6 hours under a nitrogen atmosphere. The reaction product was reprecipitated with hexane and recovered to obtain hydrophilic polymer 2 composed of DMAAm.

[0158] <Preparation of Samples> Examples 1 to 6 and Comparative Examples 1 to 4 The temperature-responsive block copolymers 1 and 2 obtained in Synthesis Examples 1 and 2, the hydrophilic block copolymer 1 obtained in Synthesis Example 3, and the hydrophilic polymer 2 obtained in Synthesis Example 4 were each dissolved in tetrahydrofuran to a concentration of 5% by mass to prepare solutions (1) to (4). These solutions (1) to (4) were mixed at the mass ratios shown in Table 1 below (referred to as "mixing ratio (mass ratio)" in Table 1 below) to prepare coating solutions (1) to (10). Table 1 below also shows the molar ratio of the structural unit (A-1) (N-isopropylacrylamide) to the structural unit (B-1) (N,N-dimethylacrylamide) (referred to as "(A-1) / (B-1) mixing ratio (molar ratio)" in Table 1 below).

[0159] A sample sheath tube was obtained by subjecting the outer surface of an ethylene tetrafluoroethylene (ETFE) sheath tube (French: 6 Fr., length: 130 mm) to plasma treatment under atmospheric pressure.

[0160] Each sample sheath tube was immersed in each of the coating solutions prepared above so that the entire length of the sample sheath tube was completely immersed, and then pulled up at a speed of 15 mm / sec to dip-coat the sample tube with each coating solution, forming a coating film on the sample sheath tube. The sample sheath tube with the coating film formed thereon was then heated in an oven at 160°C for 3 hours, thereby forming a coating layer (thickness: 1 μm) containing a predetermined (co)polymer on the sample sheath tube, thereby obtaining sheath tubes (1) to (10). The phase transition temperature of the coating layer of sheath tubes (1) to (5) was 32°C. The phase transition temperature of the coating layer of sheath tubes (6) and (10) was 34°C.

[0161] The sheath tubes (1) to (10) obtained in Examples 1 to 6 and Comparative Examples 1 to 4 were evaluated for lubricity according to the following method.

[0162] <Lubricity Evaluation of Coated Samples> The lubricity of the coated surface of each sheath tube was evaluated using a friction tester (DL-1000, manufactured by Oak River Technology). Specifically, as shown in FIG. 2 , a sheath tube 310 was immersed in a container 312 filled with water 311 adjusted to each temperature (25°C or 37°C), and set between silicone pads (grippers) 313 and 314 of a friction tester 300 with a gripping force of 500 g. While applying a gripping force of 500 g to the silicone pads 313 and 314, the friction force (gf) was measured when the sheath tube was pulled up at a test speed (pulling speed) of 5 mm / sec and a test stroke (pulling distance) of 40 mm. The water temperatures were 25°C and 37°C, and the friction force was measured at each temperature. The friction force at each temperature was measured for a total of five sheath tubes (N = 5), and the average value was used as the result.

[0163] The results are shown in Table 1 below and Figure 3. In this evaluation, a frictional force of 50 gf or less was deemed to indicate good lubricity and ease of insertion into the body (although poor stability during placement in the body). A frictional force of 100 gf or more was deemed to indicate stable placement in the body. A frictional force of 500 gf or less was deemed to indicate that the sheath tube could be removed from the body with an appropriate force when necessary without cooling the coating layer to a temperature below the phase transition temperature of the coating layer during placement in the body.

[0164]

[0165] The results in Table 1 and Figure 3 show that the surface friction force in a temperature environment of 37°C can be controlled by adjusting the mixing ratio of the temperature-responsive block copolymers 1 and 2 as copolymer (A) to the hydrophilic block copolymer 1 or hydrophilic polymer 2 as polymer (B). Furthermore, Examples 1 to 6, in which the molar ratio of NIPAAm, the temperature-responsive monomer of the temperature-responsive block copolymer, to DMAAm, the hydrophilic monomer of hydrophilic block copolymer 1 or hydrophilic polymer 2 (i.e., structural unit (A-1) / structural unit (B-1) (molar ratio)) is in the range of 1.5 to 9.0, exhibit lubricity in a temperature environment below the phase transition temperature of the coating layer (25°C), while exhibiting a moderate friction force in a temperature environment near body temperature (37°C), which is a temperature above the phase transition temperature of the coating layer. Therefore, the combination of copolymer (A) and polymer (B) according to the present invention is expected to be suitable as a coating for sheath tubes.

[0166] On the other hand, the sheath tubes (7) and (10) of Comparative Examples 1 and 4 exhibit good lubricity in a temperature environment of 25°C, but exhibit significantly high frictional force in a temperature environment close to body temperature (37°C). Therefore, these sheath tubes exhibit high frictional force when placed in a living body in a temperature environment of 37°C, making removal from the living body difficult or impossible without cooling. Furthermore, the sheath tubes (8) and (9) of Comparative Examples 2 and 3 exhibit lubricity both in a temperature environment of 25°C and a temperature environment close to body temperature (37°C), and therefore exhibit insufficient frictional force when placed in a living body in a temperature environment of 37°C.

[0167] The durability of the sheath tubes (1) to (10) obtained in Examples 1 to 6 and Comparative Examples 1 to 4 was evaluated according to the following method.

[0168] <Durability evaluation of coated samples> After the above <Lubricity evaluation of coated samples>, the sheath tubes (1) to (10) were each pinched between two fingers in warm water at 37°C and slid 10 times to evaluate the lubricity (durability) of the coating layer.

[0169] As a result, the sheath tube (5) of Example 5 showed a gradual increase in friction force with repeated sliding, compared with the sheath tubes (1) to (4) and (6) to (10) of Examples 1 to 4 and 6 and Comparative Examples 1 to 4. That is, the sheath tube (5) of Example 5 showed increased resistance to the fingers at an early stage. This is considered to be because the hydrophilic polymer 2 used in the sheath tube (5) of Example 5 did not contain a constitutional unit derived from GMA, which is a reactive monomer, and therefore the hydrophilic polymer 1 was not sufficiently fixed to the surface of the ETFE sheath tube, which is the base layer, compared with Examples 1 to 4 and 6 and Comparative Examples 1 to 4.

[0170] Introducer sheaths (1) to (10) were obtained by attaching a sheath hub, a strain relief, a side tube, and a three-way stopcock to the sheath tubes (1) to (10) obtained in Examples 1 to 6 and Comparative Examples 1 to 4. The introducer sheaths (1) to (10) were evaluated for insertability, placement, and removability according to the following methods.

[0171] <Evaluation of Insertion, Placement, and Removal of Coated Samples> A silicone artery model and a 37°C thermostatic bath were prepared. Warm water was poured from the 37°C thermostatic bath into the artery of the silicone artery model, allowing 37°C warm water to flow through the interior of the model. Each introducer sheath was immersed in physiological saline at room temperature (25°C), then quickly inserted into the artery model and inserted near the proximal end of the sheath tube. After retaining the introducer sheath in the artery model for one minute, the sheath tube of each introducer sheath was withdrawn from the artery model. As a result, the sheath tube of each introducer sheath (1) to (10) could be inserted into the artery model without significant resistance. Furthermore, the sheath tubes of introducer sheaths (1) to (7) and (10) were sufficiently retained in the artery model after insertion. When removing the sheath tubes of introducer sheaths (2) to (5) from the artery model, they could be removed with moderate force without any cooling procedures. Furthermore, when removing the sheath tubes of introducer sheaths (1) and (6) from the artery model, although greater resistance was felt compared to introducer sheaths (2) to (5), they could also be removed without any cooling procedures. On the other hand, when removing the sheath tubes of introducer sheaths (7) and (10) from the artery model, they could not be easily removed even when attempts were made to pull them out forcefully. Therefore, introducer sheaths (7) and (10) were removed from the artery model by flushing room temperature (25°C) saline into the inside of the sheath tubes through the side tubes of the introducer sheaths placed in the artery model, thereby performing a cooling procedure. Furthermore, the sheath tubes of the introducer sheaths (8) and (9) could unintentionally slip out of the artery model with a slight force without any cooling operation, and were therefore less stable when placed.

[0172] This application is based on Japanese Patent Application No. 2024-022641, filed on February 19, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0173] 100...introducer sheath, 110...sheath tube, 120...sheath hub, 130...strain relief, 140...coating layer, 150...lubricating layer, 160...side port, 170...side tube, 180...three-way stopcock, 300...friction force tester, 310...sheath tube, 311...water, 312...container, 313, 314...silicone pads.

Claims

1. A medical device comprising a base layer and a coating layer formed on at least a portion of the base layer, wherein the coating layer comprises a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature and a structural unit (A-2) derived from a reactive monomer, and a polymer (B) having a structural unit (B-1) derived from a hydrophilic monomer, wherein the ratio (molar ratio) of the structural unit (A-1) to the structural unit (B-1) is 1.5 or more and 9.0 or less, and the phase transition temperature of the coating layer is less than 37.0°C.

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 (B-1) is 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. The medical device according to claim 1, wherein the structural unit (A-2) 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. The medical device according to claim 1, wherein the polymer (B) further comprises a structural unit (B-2) derived from a reactive monomer.

6. The medical device according to claim 5, wherein the structural unit (B-2) 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.

7. The medical device according to claim 1, wherein the copolymer (A) further comprises a structural unit (A-3) derived from a monomer for adjusting the lower critical solution temperature.

8. 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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