Medical device

Abstract

To provide a technique that improves fixation of a medical device at a target site while maintaining the deliverability of the medical device through a biological lumen.SOLUTION: A medical device includes a base material layer and a coating layer formed on at least part of the base material layer, the coating layer having, at a distal end portion, a temperature-responsive region which contains a copolymer (A), the copolymer (A) comprising: a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature; a structural unit (A-2) derived from a hydrophilic monomer; and a structural unit (A-3) derived from a reactive monomer. The temperature-responsive region has a phase transition temperature that exceeds 37.0°C.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] In recent years, balloon catheters have been used to treat lesions (e.g., stenoses) that have occurred in biological lumens. Balloon catheters typically include a long shaft and a radially expandable balloon located at the distal end of the shaft. The surgeon can deliver the deflated balloon through the biological lumen to the lesion, and then expand the balloon to expand the lesion. The outer surface of the balloon is treated with a hydrophilic coating to improve slipperiness within the body, thereby enhancing smooth access to the lesion (e.g., Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 9-164191 Summary of the Invention [Problem to be solved by the invention]

[0004] Catheters such as balloon catheters, microcatheters, and contrast catheters require the tip of the catheter to be fixed at a predetermined position in a biological lumen in order to treat or diagnose a lesion. However, because catheters are treated with a hydrophilic coating near the tip to improve delivery through the biological lumen, it is sometimes difficult to properly fix the tip at a predetermined position in the biological lumen. For example, when a balloon catheter is used to treat a lesion by inflating the balloon, the balloon must be positioned (fixed) at the lesion. However, even if a surgeon attempts to dilate the lesion with the balloon located at the tip of the balloon catheter, the hydrophilic coating can cause the balloon to slip at the lesion during inflation (balloon slippage).

[0005] Therefore, the present invention has been made in consideration of the above circumstances, and aims to provide a technology that improves the fixation of a medical device at a desired position while maintaining the deliverability of the medical device in a biological lumen. [Means for solving the problem]

[0006] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that the above-mentioned problems can be solved by providing a temperature-responsive region, which contains a copolymer having specific structural units and has a phase transition temperature above body temperature, at the tip of a medical device, thereby completing the present invention.

[0007] That is, the above-mentioned object can be achieved by (1) a medical device comprising a base layer and a coating layer formed on at least a part of the base layer, wherein the coating layer has a temperature-responsive region at a tip portion, the temperature-responsive region including a copolymer (A) having a constituent unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a constituent unit (A-2) derived from a hydrophilic monomer, and a constituent unit (A-3) derived from a reactive monomer, and the phase transition temperature of the temperature-responsive region exceeds 37.0°C. (2) In the medical device of (1) above, the structural unit (A-1) is preferably derived from at least one monomer selected from the group consisting of N-isopropylacrylamide, N-isopropylmethacrylamide, Nn-propylacrylamide, Nn-propylmethacrylamide, N-vinylpropionamide, vinyl methyl ether, N-vinylisopropionamide, N,N-diethylacrylamide, and N-methyl-N-isopropylacrylamide. (3) In the medical device of (1) or (2), the structural unit (A-2) is selected from the group consisting of N,N-dimethylacrylamide, acrylamide, acrylic acid, methacrylic acid, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone, 2-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acryla Preferably, the copolymer is derived from at least one monomer selected from the group consisting of [[2-(methacryloyloxy)ethyl]dimethylammonio]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate. (4) In the medical device of any one of (1) to (3) above, the structural unit (A-3) is preferably derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, glycidyl ether, methyl glycidyl methacrylate, allyl glycidyl ether, acryloyl isocyanate, acryloyloxymethyl isocyanate, acryloyloxyethyl isocyanate, methacryloyl isocyanate, methacryloyloxymethyl isocyanate, methacryloyloxyethyl isocyanate, crotonaldehyde, acrolein, and methacrolein. (5) In the medical device of any one of (1) to (4) above, it is preferred that the structural units (A-1) and (A-2) are arranged randomly, and the structural unit (A-3) is arranged in a block pattern. (6) In the medical device of any one of (1) to (5) above, it is preferred that the structural unit (A-1) is derived from N-isopropylacrylamide, the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the structural unit (A-2) is present in a proportion of 20 mol % or more and 30 mol % or less based on the total composition of the structural units (A-1) and (A-2). (7) In any of the medical devices (1) to (6) above, the coating layer preferably has a lubricating region proximal to the temperature-responsive region, the lubricating region containing a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer, and the copolymer (B) is preferably configured so that the total composition of the structural units (B-1) and (B-2) is 50 mol % or more of all the structural units constituting the copolymer (B). (8) The medical device according to any one of (1) to (7) above is preferably a catheter. [Effects of the Invention]

[0008] According to the present invention, it is possible to improve fixation of a medical device at a desired position while maintaining the deliverability of the medical device in a biological lumen. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic diagram of the device (friction measuring device) used to measure the phase transition temperature. [Figure 2] FIG. 2 is a graph showing the temperature dependence of frictional resistance of the samples of the example and comparative example. [Figure 3] FIG. 3 is a graph showing the relationship between the ratio of the composition of dimethylacrylamide (DMAAm) to the total composition of N-isopropylacrylamide (NIPAAm) and dimethylacrylamide (DMAAm) and the phase transition temperature (° C.). [Figure 4] FIG. 4 is a partial cross-sectional view schematically illustrating the layered structure on the surface of a representative embodiment of a medical device according to the present invention. [Figure 5]FIG. 5 is a partial cross-sectional view showing a schematic example of a configuration in which the surface layer structure is different, as an application example of the embodiment of FIG. [Figure 6] FIG. 6 is a schematic view showing a medical device (balloon catheter) according to the present invention. [Figure 7] FIG. 7 is a schematic diagram of the tortuous blood vessel model used in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0010] One aspect of the present invention provides 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 has a temperature-responsive region at a tip portion, the temperature-responsive region including a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer, and the phase transition temperature of the temperature-responsive region exceeds 37.0°C.

[0011] Preferred embodiments of the present invention will be described below. Note that the present invention is not limited to the following embodiments, and various modifications can be made within the scope of the claims. Furthermore, the embodiments described in this specification can be arbitrarily combined to form other embodiments.

[0012] In this specification, the "structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature" is also referred to simply as the "structural unit (A-1)" or the "structural unit (A-1) according to the present invention." The "structural unit (A-2) derived from a hydrophilic monomer" is also referred to simply as the "structural unit (A-2)" or the "structural unit (A-2) according to the present invention." The "structural unit (A-3) derived from a reactive monomer" is also referred to simply as the "structural unit (A-3)" or the "structural unit (A-3) according to the present invention." The "copolymer (A) having the structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, the structural unit (A-2) derived from a hydrophilic monomer, and the structural unit (A-3) derived from a reactive monomer" is also referred to simply as the "copolymer (A)" or the "copolymer (A) according to the present invention." The "temperature-responsive region containing copolymer (A) and having a phase transition temperature of more than 37.0°C" is also simply referred to as the "temperature-responsive region" or the "temperature-responsive region according to the present invention."

[0013] 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.

[0014] As used herein, the term "X to Y" indicating a range includes X and Y and means "X or more and Y or less." As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" encompasses both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" encompasses both acryloyl and methacryloyl groups.

[0015] In this specification, when a certain structural unit is defined as being "derived from" a certain monomer, it means that the structural unit is a structural unit that is generated by cleavage of one of the polymerizable unsaturated double bonds of the corresponding monomer.

[0016] Unless otherwise specified, operations and measurements of physical properties are performed at room temperature (20-25°C) and a relative humidity of 40-60%RH.

[0017] 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.

[0018] <Medical equipment> A medical device according to one embodiment of the present invention comprises a substrate layer and a coating layer formed on at least a portion of the substrate layer, the coating layer having a temperature-responsive region at a tip portion thereof, the temperature-responsive region containing copolymer (A). The copolymer (A) comprises a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer. The phase transition temperature of the temperature-responsive region exceeds 37.0°C.

[0019] The temperature of the biological environment (e.g., blood vessels) is usually below 37.0°C. Therefore, the temperature-responsive region exhibits hydrophilicity and lubricity in biological lumens such as blood vessels because the temperature is below the phase transition temperature. Therefore, medical devices can be easily inserted to the desired location without damaging the biological tissue (e.g., the blood vessel wall) with which they come into contact. Meanwhile, by heating the distal end to a temperature equal to or higher than the phase transition temperature of the temperature-responsive region, the temperature-responsive region located at the distal end of the medical device becomes hydrophobic, thereby eliminating or reducing the lubricity of the temperature-responsive region. Therefore, for example, after inserting a medical device to a predetermined location (e.g., a location for introducing a contrast agent or a location for fixing a balloon), the lubricity of the temperature-responsive region can be reduced by heating the temperature-responsive region located at the distal end of the medical device to a temperature equal to or higher than the phase transition temperature. Therefore, the surgeon can perform a procedure while the medical device is firmly fixed in the desired position (the medical device can be stably maintained in the predetermined position). Therefore, according to the present invention, the medical device can be smoothly delivered to the desired location without damaging the biological lumen, and once it has reached the desired location, the surgeon can stably fix the tip of the medical device at that location by heating the temperature-responsive region to a temperature above the phase transition temperature.

[0020] Hereinafter, preferred embodiments of the medical device according to the present invention will be described with reference to the accompanying drawings.

[0021] Fig. 4 is a partial cross-sectional view schematically showing the surface layer structure of a representative embodiment of a medical device according to the present invention (hereinafter also simply referred to as "medical device"). Fig. 5 is a partial cross-sectional view schematically showing a different example of the surface layer structure as an application example of this embodiment.

[0022] 4 and 5, the medical device 100 of this embodiment is an elongated body (medical elongated body) including a base layer 101 and a coating layer 102 (the figure shows an example in which the coating layer 102 is fixed to the entire surface (whole surface) of the base layer 101) formed on at least a part of the base layer 101. A temperature-responsive region (not shown) having a phase transition temperature exceeding 37.0°C is disposed at least at the tip of the coating layer 102.

[0023] Each component of the medical device of this embodiment will be described below.

[0024] [Base material layer (base material)] The substrate layer used in the present invention may be made of any material, and a suitable material can be selected depending on the application. Specifically, materials constituting (forming) the substrate layer 101 include metal materials, polymeric materials, ceramics, and the like. Here, the substrate layer 101 may be entirely made of any of the above materials, as shown in FIG. 4, or may have a structure in which a substrate surface layer 101b is formed by coating a substrate layer core portion 101a made of any of the above materials with another of the above materials by an appropriate method, as shown in FIG. 5. Examples of the latter case shown in Figure 5 include a substrate core layer 101a made of a resin or other material, coated with a metal material by an appropriate method (such as plating, metal vapor deposition, or sputtering), to form a substrate surface layer 101b; a substrate core layer 101a made of a hard reinforcing material such as a metal or ceramic material, coated with a polymeric material that is softer than the metal or other reinforcing material by an appropriate method (such as dipping, spraying, coating, or printing), or a substrate surface layer 101b formed by combining the reinforcing material of the substrate core layer 101a and the polymeric material of the substrate surface layer 101b (by an appropriate reaction process). Therefore, the substrate core layer 101a may be a multilayer structure formed by laminating different materials, or a structure (composite) in which components made of different materials are joined together for different parts of the medical device. Furthermore, another middle layer (not shown) may be formed between the base material layer core portion 101a and the base material surface layer 101b. Furthermore, the base material surface layer 101b may also be a multilayer structure formed by laminating multiple layers of different materials, or a structure (composite) in which members formed of different materials for different parts of the medical device are joined together.

[0025] Among the materials constituting (forming) the base layer 101, 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, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, and various alloys such as nickel-titanium (Ni-Ti) alloy, nickel-cobalt (Ni-Co) alloy, cobalt-chromium (Co-Cr) alloy, and zinc-tungsten (Zn-W) alloy. These may be used alone or in combination of two or more. The metal material may be appropriately selected based on the optimum metal material 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 101, 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 base material include polyethylene resins such as polyamide resin, linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), high-density polyethylene (HDPE), and modified polyethylene, polyolefin resins such as polypropylene resin, modified polyolefin resin, cyclic polyolefin resin, epoxy resin, polyurethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluororesin, 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)), polytetrafluoroethylene (PTFE), 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 base material. These may be used alone or in combination of two or more. The polymer material may be appropriately selected from those that are most suitable for the substrate layer of the intended use, such as a catheter, stent, guide wire, etc.

[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 linear (wire), or a tubular shape.

[0028] [Coating layer] The coating layer 102 is formed (carried) on at least a portion of the substrate layer (substrate) 101. The reason why the coating layer 102 is formed (carried) on at least a portion of the surface of the substrate layer 101 is that, in medical devices such as catheters and guidewires, which are intended for use, it is not necessary for the entire surface (entire surface) of these medical devices to have the desired effect (e.g., lubricity when wet), and it is sufficient that the coating layer is carried only on the surface portion (which may be a portion or the entire surface) where the desired effect is desired. For this reason, as described above, the coating layer may be formed so as to entirely cover both surfaces of the substrate layer as shown in FIGS. 4 and 5; so as to entirely cover only one surface of the substrate layer; so as to partially cover both surfaces of the substrate layer in the same or different forms; so as to partially cover one surface of the substrate layer, and the like.

[0029] A temperature-responsive region having a phase transition temperature exceeding 37.0° C. is disposed at least in the tip portion of the coating layer 102. Specifically, the coating layer 102 may be composed solely of a temperature-responsive region having a phase transition temperature exceeding 37.0° C., or may have a lubricating region, as described below, in addition to the temperature-responsive region having a phase transition temperature exceeding 37.0° C.

[0030] The temperature-responsive region is formed at least in the distal portion of the coating layer 102. In this specification, the coating layer 102 is formed in a region including the distal end of the medical device (elongated medical body) so that the temperature-responsive region is located at least on the distal side of the medical device (elongated medical body). Here, the "distal end" of the medical device (elongated medical body) refers to the portion located on the distal side of the medical device (elongated medical body). That is, the coating layer 102 is formed from the portion located on the distal side of the medical device (elongated medical body) toward the proximal end, and includes a temperature-responsive region at least in the distal end. Note that the coating layer may be formed in a region of the medical device (elongated medical body) that is to be fixed in a biological lumen (for example, in the case of a balloon catheter, the balloon located on the distal side of the balloon catheter). Therefore, the coating layer 102 does not have to be formed from the distal end of the medical device (elongated medical body) toward the proximal end.

[0031] The length of the temperature-responsive region can be appropriately selected taking into consideration the shape and length of the medical device to improve fixation of the medical device in a biological lumen in an environment above the phase transition temperature of the temperature-responsive region. For example, the temperature-responsive region is provided in a portion of the medical device located distal to the midpoint of the effective length of the medical device in the longitudinal direction. That is, the temperature-responsive region is provided in a range of less than 0.5 of the effective length of the medical device from the most distal end of the medical device in the longitudinal direction of the medical device (e.g., in a range of less than 65 cm from the most distal end of the medical device when the effective length of the catheter is 130 cm). When the medical device is a balloon catheter, at least a portion of the temperature-responsive region is preferably provided in the balloon located at the distal end of the balloon catheter. Furthermore, when the medical device is a microcatheter or an angiography catheter, at least a portion of the temperature-responsive region is preferably provided in a range of 25 cm from the most distal end of the microcatheter or angiography catheter in the longitudinal direction of the microcatheter or angiography catheter.

[0032] The temperature-responsive region includes a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer. The phase transition temperature of the temperature-responsive region exceeds 37.0°C. In this specification, the term "phase transition temperature" refers to the temperature at which the temperature-responsive region (particularly the copolymer (A) contained in the temperature-responsive region) switches from water-soluble to water-insoluble, reducing the lubricity of the temperature-responsive region. That is, the temperature-responsive region exhibits lubricity in a biological environment (e.g., a biological lumen) below 37.0°C. On the other hand, the lubricity of the temperature-responsive region decreases when heated to a temperature above the phase transition temperature (above 37.0°C). Therefore, the lubricity of the temperature-responsive region allows the surgeon to smoothly insert the medical device to the desired location in a biological lumen in an environment below the phase transition temperature of the temperature-responsive region. Furthermore, after the medical device reaches the desired location, the surgeon can perform treatment while the medical device is firmly fixed at the desired location in the biological lumen by heating the temperature-responsive region to a temperature above the phase transition temperature, thereby reducing the lubricity of the temperature-responsive region. After treatment is completed at the desired location in the biological lumen, the surgeon can stop heating the temperature-responsive region and return the temperature to a temperature close to the original biological environment (a temperature below the phase transition temperature of the temperature-responsive region), thereby restoring the lubricity of the temperature-responsive region. Therefore, the surgeon can smoothly remove the medical device after treatment.

[0033] The phase transition temperature of the temperature-responsive region is preferably close to the temperature of the biological environment in order to reduce the burden on the living body associated with the heating operation of the temperature-responsive region. On the other hand, the phase transition temperature of the temperature-responsive region is preferably somewhat different from the temperature of the biological environment in order to prevent a decrease in the lubricity of the temperature-responsive region in the biological environment (to maintain good operability for the surgeon). From the viewpoints of the surgeon's operability, reducing the burden on the living body, and balancing both, the phase transition temperature of the temperature-responsive region is preferably 37.5°C or higher and lower than 45.0°C, more preferably 38.0°C or higher and lower than 43.0°C, and particularly preferably 38.5°C or higher and lower than 42.0°C. In particular, when the phase transition temperature of the temperature-responsive region is lower than 45.0°C, the surgeon can switch the lubrication performance of the temperature-responsive region with a small temperature change while minimizing the burden of temperature changes on the living body. In this specification, "phase transition temperature" is measured according to the method described in the Examples.

[0034] [Copolymer (A)] Copolymer (A) has a structural unit (A-1) derived from a temperature-responsive monomer, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer. The temperature-responsive monomer constituting 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 constituting 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 temperature-responsive region is controlled by copolymer (A).

[0035] The temperature-responsive region is preferably composed only of copolymer (A). When the temperature-responsive region is composed only of copolymer (A), the lower critical solution temperature of copolymer (A) is the same as the phase transition temperature of the temperature-responsive region (the lower critical solution temperature of copolymer (A) = the phase transition temperature of the temperature-responsive region). However, the temperature-responsive region may contain other copolymers to the extent that the phase transition temperature of the temperature-responsive region is substantially the same as the lower critical solution temperature of copolymer (A). For example, the temperature-responsive region may contain, in addition to copolymer (A), a polymer of a temperature-responsive monomer (e.g., a copolymer containing structural unit (A-1) but not structural unit (A-2) or (A-3), or a homopolymer of structural unit (A-1)) (another copolymer). When the temperature-responsive region contains a copolymer other than copolymer (A), the content of the other copolymer in the temperature-responsive region (in terms of solid content) is, for example, less than 5% by mass, preferably less than 3% by mass, more preferably less than 1% by mass (lower limit: 0% by mass), and particularly preferably 0% by mass (i.e., the temperature-responsive material contained in the temperature-responsive region is composed only of copolymer (A).) With such a composition, the lower critical solution temperature of copolymer (A) is substantially the same as the phase transition temperature of the temperature-responsive region.

[0036] In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is greater than 37.0°C. In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is greater than or equal to 37.5°C and less than 45.0°C. In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is greater than or equal to 38.0°C and less than 43.0°C. In one embodiment of the present invention, the lower critical solution temperature of copolymer (A) is greater than or equal to 38.5°C and less than 42.0°C. A medical device having a coating layer with a temperature-responsive region containing copolymer (A) at its distal end exhibits hydrophilicity and lubricity in a biological lumen, allowing the medical device to be easily inserted to a desired location without damaging biological tissue. Furthermore, after reaching a desired location in a biological lumen (e.g., a lesion site), the temperature-responsive region located at the distal end of the coating layer can be heated to a temperature above the phase transition temperature to reduce the lubricity of the temperature-responsive region, thereby stably maintaining the medical device in a predetermined position.

[0037] Each of the structural units constituting the copolymer (A) will be described in detail below.

[0038] (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) (a homopolymer of the temperature-responsive monomer) has a specific lower critical solution temperature (LCST). A polymer composed solely of the structural unit (A-1) (a 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.

[0039] 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.

[0040] Examples of temperature-responsive monomers include N-isopropylacrylamide (lower critical solution temperature: 32°C), N-isopropylmethacrylamide (lower critical solution temperature: 44°C), Nn-propylacrylamide (lower critical solution temperature: 22°C), Nn-propylmethacrylamide (lower critical solution temperature: 28°C), N-vinylpropionamide (lower critical solution temperature: 32°C), vinyl methyl ether (lower critical solution temperature: 34°C), N-vinylisopropionamide (lower critical solution temperature: 39°C), N,N-diethylacrylamide (lower critical solution temperature: 32°C), and N-methyl-N-isopropylacrylamide (lower critical solution temperature: 22°C). In the above, the lower critical solution temperature is the lower critical solution temperature of the homopolymer of each temperature-responsive 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 a combination of two or more types of the above-mentioned temperature-responsive monomer.

[0041] 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, N-vinylisopropionamide, and N,N-diethylacrylamide, from the viewpoint that the lower critical solution temperature of the homopolymer of the temperature-responsive monomer is closer to the temperature of the biological environment.Furthermore, the temperature-responsive monomer is particularly preferably N-isopropylacrylamide, from the viewpoint that the lower critical solution temperature of the homopolymer of the temperature-responsive monomer is closer to the biological environment and exhibits good lubricity at temperatures below the lower critical solution temperature.

[0042] 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-isopropylmethacrylamide, Nn-propylacrylamide, Nn-propylmethacrylamide, N-vinylpropionamide, vinyl methyl ether, N-vinylisopropionamide, 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, N-vinylisopropionamide, and N,N-diethylacrylamide. In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide.

[0043] The content (composition) of the structural unit (A-1) is preferably 55 mol% or more, and more preferably more than 60 mol%, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-1) is preferably 98 mol% or less, and more preferably less than 80 mol%, 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 55 mol% or more and 98 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 60 mol% and less than 80 mol%, based on all structural units constituting the copolymer (A). Within these ranges, the effects of the present invention can be achieved.

[0044] (Structural unit (A-2)) The structural unit (A-2) according to the present invention is derived from a hydrophilic monomer. The presence (composition) of the structural unit (A-2) and the structural unit (A-1) can adjust the phase transition temperature of the temperature-responsive region. For example, the lower critical solution temperature of a homopolymer of the temperature-responsive monomer N-isopropylacrylamide (NIPAAm) is 32°C. When a NIPAAm homopolymer is applied to a temperature-responsive region, it must be used in a temperature environment below 32°C in order for the temperature-responsive region to exhibit lubricity. For this reason, when a NIPAAm homopolymer is applied to a temperature-responsive region, it is unable to exhibit lubricity in a biological environment (e.g., a biological lumen such as a blood vessel). In contrast, by introducing the structural unit (A-2) in addition to the structural unit (A-1), the lower critical solution temperature of the copolymer (A) (and therefore the phase transition temperature of the temperature-responsive region containing the copolymer (A)) can be increased. Therefore, by combining the structural units (A-1) and (A-2) so that the phase transition temperature of the temperature-responsive region is higher than the temperature in the biological environment (i.e., a temperature above 37.0 ° C), the temperature-responsive region containing copolymer (A) can exhibit lubricity in the biological environment (e.g., a biological lumen such as a blood vessel). Furthermore, if the lower critical solution temperature of copolymer (A) (and therefore the phase transition temperature of the temperature-responsive region containing copolymer (A)) is higher than the temperature in the biological environment, it is possible to prevent the lubrication performance from being unexpectedly switched due to temperature changes in the biological environment. In particular, by combining structural units (A-1) and (A-2) so that the lower critical solution temperature of copolymer (A) is less than 45.0 ° C, it becomes possible to switch the lubrication function with small temperature changes while minimizing the temperature change burden on the living body when the surgeon switches the lubrication performance of the temperature-responsive region.

[0045] The structural unit (A-2) may be composed of only one type of hydrophilic monomer, or may be composed of two or more types of hydrophilic monomers. When the structural unit (A-2) is composed of two or more types of hydrophilic monomers, the two or more types of hydrophilic monomers may be arranged in a block pattern or random pattern within the segment of the structural unit (A-2).

[0046] The hydrophilic monomer may be any one that exhibits lubricity in body fluids or aqueous solvents and can adjust the phase transition temperature of the copolymer (A).Specific examples include N-methylacrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, acrylamide, acrylic acid, methacrylic acid, acryloylmorpholine, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, vinylpyrrolidone (N-vinyl-2-pyrrolidone), 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate, 2-[[2-(methacryloyloxy)ethyl]dimethacrylate, 2-hydroxyethyl ... Suitable examples include 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]acetate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate, 3-[(3-acrylamidopropyl)dimethylammonio]propanoate, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonic acid, 4-[[2-(methacryloyloxy)ethyl]dimethylammonio]butane-1-sulfonic acid, 2-methacryloyloxyethyl phosphorylcholine, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate.Among these, from the viewpoints of ease of adjusting the phase transition temperature, imparting excellent lubricity, ease of synthesis, etc., the following were selected: 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] Preferred are 2-(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, with N,N-dimethylacrylamide and acrylamide being more preferred, and N,N-dimethylacrylamide being particularly preferred. The structural unit (A-2) may be composed of only one of the above hydrophilic monomers, or may be composed of two or more of the above hydrophilic monomers in combination.

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

[0048] The content (composition) of the structural unit (A-2) is preferably 1 mol% or more, more preferably 5 mol% or more, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-2) is preferably 45 mol% or less, more preferably 40 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 45 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-2) is 5 mol% or more and 40 mol% or less, based on all structural units constituting the copolymer (A). When the content (composition) of the structural unit (A-2) is within the above range, the phase transition temperature of the temperature-responsive region can be more effectively controlled to fall within a preferred range. Therefore, the lubricity of the temperature-responsive region can be further enhanced, while minimizing the temperature change that occurs when an operator switches the lubricity of the temperature-responsive region with a small temperature change in a living body environment.

[0049] For example, when N-isopropylacrylamide is selected as the structural unit (A-1) and N,N-dimethylacrylamide is selected as the structural unit (A-2), from the viewpoint of setting the lower critical solution temperature of the copolymer (A) higher than the temperature of the biological environment (greater than 37.0 ° C.) and less than 45.0 ° C., the content (composition) of the structural unit (A-2) is preferably 20 mol% or more, more preferably more than 20 mol%, particularly preferably 25 mol% or more, based on the total composition of the structural unit (A-1) and the structural unit (A-2) (based on 100 mol% of the total of the structural unit (A-1) and the structural unit (A-2)). In this embodiment, the content (composition) of the structural unit (A-2) is preferably 40 mol% or less, more preferably 30 mol% or less, particularly preferably less than 30 mol%, based on the total composition of the structural unit (A-1) and the structural unit (A-2) (based on 100 mol% of the total of the structural unit (A-1) and the structural unit (A-2)).

[0050] In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide, and the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the content (composition) of the structural unit (A-2) is from 20 mol% to 40 mol% relative to the total composition of the structural units (A-1) and (A-2) (based on a total of 100 mol% of the structural units (A-1) and (A-2)). In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide, and the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the content (composition) of the structural unit (A-2) is from 20 mol% to 30 mol% relative to the total composition of the structural units (A-1) and (A-2) (based on a total of 100 mol% of the structural units (A-1) and (A-2)). In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide, the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the content (composition) of the structural unit (A-2) is greater than 20 mol% and not greater than 30 mol% relative to the total composition of the structural units (A-1) and (A-2) (relative to a total of 100 mol% of the structural units (A-1) and (A-2)). This configuration allows the phase transition temperature of the temperature-responsive region to be controlled to greater than 37.0°C and not greater than 42.0°C.

[0051] In one embodiment of the present invention, the structural unit (A-1) is derived from N-isopropylacrylamide, the structural unit (A-2) is derived from N,N-dimethylacrylamide, and the content (composition) of the structural unit (A-2) is 25 mol% or more and less than 30 mol% of the total composition of the structural units (A-1) and (A-2) (wherein the total of the structural units (A-1) and (A-2) is 100 mol%). With this configuration, the temperature-responsive region can be controlled to have a phase transition temperature of 42.0°C or less, and a large difference can be ensured between the phase transition temperature of the temperature-responsive region and the temperature of the biological environment (37°C). This minimizes the temperature change burden on the living body when switching the lubricating performance of the temperature-responsive region, and more reliably expresses lubricity in the biological environment (for example, biological lumen such as blood vessels).

[0052] Additionally or alternatively, the total content (composition) of the structural units (A-1) and (A-2) is preferably 80 mol% or more, more preferably 90 mol% or more, and particularly preferably 95 mol% or more, based on all structural units constituting the copolymer (A). Furthermore, the total content (composition) of the structural units (A-1) and (A-2) is preferably 99 mol% or less, more preferably 98 mol% or less, and particularly preferably 97 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the total content (composition) of the structural units (A-1) and (A-2) is greater than 80 mol% and less than 99 mol% based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the total content (composition) of the structural units (A-1) and (A-2) is 90 mol% or more and less than 98 mol% based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the total content (composition) of the structural units (A-1) and (A-2) is 95 mol % or more and 97 mol % or less of all structural units constituting the copolymer (A).Within this range, the temperature-responsive region can exhibit good lubricity below the phase transition temperature.

[0053] (Structural unit (A-3)) The structural unit (A-3) according to the present invention is derived from a reactive monomer having a reactive functional group. The reactive functional groups present in the structural unit (A-3) react with each other to form a crosslinked structure within the same copolymer (A) or between different copolymers (A). This increases the film strength of the temperature-responsive region (coating layer) and improves the durability of the temperature-responsive region (coating layer). Furthermore, to further enhance the durability of the temperature-responsive region (coating layer), the reactive functional group may be selected to bond with the substrate layer. The presence of the structural unit (A-3) in the copolymer (A) can improve the durability of the temperature-responsive region (coating layer). The structural unit (A-3) may be composed of only one type of reactive monomer, or two or more types of reactive monomers.

[0054] The reactive functional group is not particularly limited and can be appropriately selected depending on the type of material constituting the base layer, the desired degree of crosslinking (film strength) of copolymer (A), and the like. Specifically, 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 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-3) may be one type, or two or more types may coexist.

[0055] Examples of such structural unit (A-3) include monomers having an epoxy group in the molecule, such as glycidyl acrylate, glycidyl methacrylate, glycidyl ethers (for example, aliphatic glycidyl ethers such as butyl glycidyl ether, 4-hydroxybutyl acrylate glycidyl ether, cetyl glycidyl ether), methyl glycidyl methacrylate, and allyl glycidyl ether; (meth)acrylic acid chloride, (meth)acrylic acid bromide, and (meth)acrylic acid iodide; The structural unit (A-3) may be derived from a monomer having an acid halide group in the molecule, such as a methyl acrylate; a monomer having an aldehyde group in the molecule, such as (meth)acrylaldehyde; a monomer having an isocyanate group in the molecule, such as (meth)acryloyl isocyanate, (meth)acryloyloxymethyl isocyanate, (meth)acryloyloxyethyl isocyanate, or (meth)acryloyloxypropyl isocyanate; or a monomer having an acid anhydride group in the molecule, such as maleic anhydride, itaconic anhydride, or citraconic anhydride. Of these, the structural unit (A-3) is preferably derived from a monomer having at least one of an epoxy group, an aldehyde group, or an isocyanate group, and more preferably derived from a monomer having an epoxy group. Among these, from the viewpoints of further firmly fixing the copolymer (A) (and therefore the coating layer) to the base 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, with glycidyl acrylate and glycidyl methacrylate being more preferred, as their reaction is accelerated by heat or the like and they are relatively easy to handle, and glycidyl methacrylate being particularly preferred. These reactive monomers may be used alone or in combination of two or more.

[0056] That is, in one embodiment of the present invention, the structural unit (A-3) is derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, methyl glycidyl methacrylate, allyl glycidyl ether, acryloyl isocyanate, acryloyloxymethyl isocyanate, acryloyloxyethyl isocyanate, methacryloyl isocyanate, methacryloyloxymethyl isocyanate, methacryloyloxyethyl isocyanate, crotonaldehyde, acrolein, and methacrolein. In one embodiment of the present invention, the structural unit (A-3) is derived from at least one monomer of glycidyl acrylate and glycidyl methacrylate. In one embodiment of the present invention, the structural unit (A-3) is derived from glycidyl methacrylate.

[0057] The content (composition) of the structural unit (A-3) is preferably 1 mol% or more, more preferably 2 mol% or more, and particularly preferably 3 mol% or more, based on all structural units constituting the copolymer (A). Furthermore, the content (composition) of the structural unit (A-3) is preferably 20 mol% or less, more preferably 15 mol% or less, and particularly preferably 10 mol% or less, based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-3) is 1 mol% or more and less than 20 mol% based on all structural units constituting the copolymer (A). In one embodiment of the present invention, the content (composition) of the structural unit (A-3) is 2 mol% or more and 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-3) is 3 mol% or more and 10 mol% or less, based on all structural units constituting the copolymer (A). Within this range, the temperature-responsive region can exhibit good durability.

[0058] Copolymer (A) has structural units (A-1), (A-2), and (A-3). Preferably, structural units (A-1) and (A-2) are arranged randomly. That is, structural units (A-1) and (A-2) preferably constitute a random copolymer. This allows the lower critical solution temperature of copolymer (A) to be adjusted. Preferably, structural units (A-3) are arranged in blocks. That is, in copolymer (A), the end of a copolymer composed of structural units (A-1) and (A-2) is covalently linked to the end of structural unit (A-3), and a region (block) composed of structural units (A-1) and (A-2) is linked to a region (block) composed of structural unit (A-3). In this case, structural unit (A-3) has little or no effect on the lower critical solution temperature of copolymer (A). Therefore, the temperature-responsive region containing the copolymer (A) can be firmly fixed to the base layer via the structural unit (A-3) while maintaining the phase transition temperature adjusted by the structural units (A-1) and (A-2). Therefore, the coating layer of a medical device containing a copolymer (A) having such a structure exhibits excellent lubricity below the phase transition temperature of the temperature-responsive region, but the lubricity decreases when heated above the phase transition temperature of the temperature-responsive region. Furthermore, the coating layer of a medical device containing a copolymer (A) having such a structure also has excellent durability. Note that the above is an assumption, and the present invention is not limited by this assumption.

[0059] That is, in one embodiment of the present invention, the structural units (A-1) and (A-2) are arranged randomly, and the structural unit (A-3) is arranged in a block pattern.

[0060] As used herein, the phrase "structural unit (A-3) is arranged in the form of a block" means that a block consisting of only the structural unit (A-3) is present in the main chain of the copolymer (A), i.e., -[structural unit (A-3) n]-(n is an integer of 2 or more) is intended to be present in the main chain of the copolymer (A). In this embodiment, when two or more types of structural units (A-3) are present, two or more types of structural units (A-3) are present in one block. For example, when the structural unit (A-3) is composed of a structural unit (Y-1) having a reactive functional group (y1) and a structural unit (Y-2) having a reactive functional group (y2) different from the reactive functional group (y1), -[structural unit (Y-1) m1 -Constituent unit (Y-2) m2 ] m - (m1 and m2 are each independently an integer of 1 or greater, m is an integer of 2 or greater, and the structural units (Y-1) and (Y-2) may be arranged in a block or random manner) are present in the main chain of the copolymer (A).

[0061] (other building blocks) The copolymer (A) according to the present invention essentially contains the structural unit (A-1), the structural unit (A-2), and the structural unit (A-3), but may contain other structural units in addition to these structural units. When the copolymer (A) contains other structural units, examples of the monomers constituting the other structural units 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 tri(meth)acrylate, and the like. Examples of the other structural units include tetramethylpenta(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, and tripropylene glycol. The other structural units may be composed of only one type of structural unit, or two or more types of structural units. When the other structural units are composed of two or more types of structural units, the two or more types of structural units may be arranged in a block or random pattern.

[0062] Copolymer (A) is preferably composed solely of structural units (A-1), (A-2), and (A-3) (content of other structural units = 0 mol%). However, copolymer (A) may contain other structural units within a range that is substantially the same as the lower critical solution temperature of copolymer (A) composed solely of structural units (A-1), (A-2), and (A-3). When copolymer (A) contains other structural units, blocks consisting solely of the other structural units are arranged in the main chain of copolymer (A). In this arrangement, the lower critical solution temperature of copolymer (A) does not change due to the other structural units. In this case, the content of the other structural units is preferably greater than 0 mol% and less than 10 mol% of the total structural units constituting copolymer (A). Particularly preferably, copolymer (A) is substantially composed of structural units (A-1), (A-2), and (A-3) (content of other structural units = greater than 0 mol% and less than 5 mol%). Most preferably, the copolymer (A) is composed solely of the structural unit (A-1), the structural unit (A-2), and the structural unit (A-3) (content of other structural units=0 mol %).

[0063] In this specification, the content (composition) of each structural unit (structural units (A-1), (A-2), (A-3), etc.) can be measured by a known method. For example, 1 The composition (molar ratio) of the structural units can be measured by measuring the integral ratio of the intensity of each signal in the H-NMR spectrum. When the copolymer (A) is composed of a structural unit (A-1) derived from N-isopropylacrylamide, a structural unit (A-2) derived from N,N-dimethylacrylamide, and a structural unit (A-3) derived from glycidyl methacrylate, the structural unit composition (copolymer composition) is measured by the method described in the Examples. When the copolymer (A) contains structural units other than those mentioned above, the composition (molar ratio) of each structural unit can be measured by appropriately modifying the method described in the Examples.

[0064] The weight-average molecular weight of the copolymer (A) is several thousand to several million, preferably 10,000 to 5 million. In this specification, the "weight-average molecular weight" is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance. The molecular weight of the copolymer (A) can also be calculated from the type and number of repeating units.

[0065] In addition, the method for producing copolymer (A) is not particularly limited, and can be suitably adopted conventionally known polymerization methods such as living radical polymerization and polymerization using a macroinitiator. Among these, living radical polymerization or polymerization using a macroinitiator is preferably used because it allows the structural unit (A-3) to be arranged in a block form. The living radical polymerization method is not particularly limited, and for example, the methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, etc., as well as atom transfer radical polymerization (ATRP) can be applied in the same manner or with appropriate modifications. Furthermore, in a polymerization method using a macroinitiator, for example, a macroinitiator having a reactive site (structural unit (A-3)) with a reactive functional group and a radically polymerizable group such as a peroxide group is prepared, and then the macroinitiator, a monomer for forming the structural unit (A-1), and a monomer for forming the structural unit (A-2) are polymerized in a polymerization solvent to prepare the copolymer (A).

[0066] In the above polymerization, the mixing ratio of the macroinitiator, the monomer for forming the structural unit (A-1), and the structural unit (A-2) can be such that each structural unit has the composition described above.

[0067] The polymerization solvent is appropriately selected from solvents that can dissolve the macroinitiator, the monomers for forming the structural unit (A-1), and the monomers for forming the structural unit (A-2). For example, water, dimethyl sulfoxide, chlorobenzene, methyl ethyl ketone, benzene, etc. are used. From the viewpoint of the solubility of the macroinitiator, the monomers for forming the structural unit (A-1), and the monomers for forming the structural unit (A-2), dimethyl sulfoxide and chlorobenzene are preferably used.

[0068] 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.

[0069] Furthermore, when producing the copolymer (A), chain transfer agents, polymerization rate modifiers, surfactants, water-soluble polymers, water-soluble inorganic compounds (such as alkali metal salts, alkali metal hydroxides, polyvalent metal salts, and non-reducing alkali metal salts), inorganic acids, inorganic acid salts, organic acids, organic acid salts, and other additives may be used as needed.

[0070] After copolymerization, the copolymer (A) is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0071] (Other ingredients) The temperature-responsive region essentially contains copolymer (A). The temperature-responsive region may contain other components in addition to copolymer (A), as long as the phase transition temperature remains unchanged. The other components are not particularly limited. For example, when the medical device is intended for insertion into a body cavity or lumen, such as a catheter, examples of the other components include drugs (biologically active substances) such as anticancer drugs, immunosuppressants, antibiotics, antirheumatic drugs, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic drugs, integrin inhibitors, antiallergic drugs, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid-improving drugs, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, vascular smooth muscle proliferation inhibitors, anti-inflammatory drugs, biomaterials, interferons, and NO production promoters. The amounts of the other components added are 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 account the severity of the disease to be treated, the patient's weight, and other factors. Preferably, the temperature-responsive region does not contain any other components, that is, in a preferred embodiment of the present invention, the temperature-responsive region is composed of the copolymer (A).

[0072] (Other areas) The coating layer has a temperature-responsive region at least in its distal end. The coating layer may further have a region (other region) other than the temperature-responsive region. The other region may be a region (lubrication region) that exhibits lubricity regardless of the temperature environment. When the coating layer further has a lubrication region, the lubrication region is preferably formed proximally of the temperature-responsive region, and more preferably formed proximally of the temperature-responsive region while in contact with the temperature-responsive region. The lubrication region of the coating layer can exhibit lubricity regardless of temperature. Therefore, the lubrication region of the coating layer can maintain its lubrication performance even at temperatures above the phase transition temperature of the temperature-responsive region. Therefore, when the coating layer is heated to a temperature above the phase transition temperature of the temperature-responsive region, the lubrication performance of only the temperature-responsive region located at the distal end of the coating layer can be switched, allowing the medical device to be more reliably fixed at the desired position in the biological lumen. Furthermore, it is possible to reliably prevent the lubrication performance of regions of the coating layer other than the temperature-responsive region from unexpectedly switching in the biological lumen, allowing the medical device to be inserted more smoothly into the desired position.

[0073] Hereinafter, an embodiment in which the coating layer has a lubricating region will be described with reference to Fig. 6. Note that Fig. 6 describes an embodiment in which the medical device is a balloon catheter, but the present invention is not limited to this embodiment. The lubricating region of the coating layer can be appropriately changed depending on the application of the medical device.

[0074] Fig. 6 is a schematic diagram showing a medical device (balloon catheter) according to the present invention. As shown in Fig. 6, the medical device (balloon catheter) 200 includes a hollow outer tubular shaft 250, an inner tubular shaft 280 disposed inside the outer tubular shaft 250, a distal tip 270 disposed at the distal end of the inner tubular shaft 280, and a balloon 260 disposed radially outward from the inner tubular shaft 280. The balloon 260 is connected to the distal end of the outer tubular shaft 250 and the distal end of the inner tubular shaft 280 on the distal side of the medical device (balloon catheter) 200. The coating layer 210 includes a temperature-responsive region 212 disposed on the balloon 260 and a lubricating region 211 disposed on the outer tubular shaft 250 so as to contact the proximal end of the temperature-responsive region 212.

[0075] As shown in Figure 6, the lubricating region 211 does not need to be formed on all surfaces (the entire surface) other than the temperature-responsive region of the medical device, but only on the surface portion (which may be part or all) that is required to have lubricity when wet.

[0076] In this embodiment, the lubricating region 211 may include a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer. In this case, the copolymer (B) is preferably a block copolymer having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer. The structural unit (B-1) (hence, the hydrophilic monomer) and the structural unit (B-2) (hence, the reactive monomer) are the same as the structural unit (A-2) and the structural unit (A-3) described above in [Copolymer (A)], respectively, and therefore will not be described here.

[0077] The content of the structural unit (B-1) in the copolymer (B) is, for example, 80 mol % to 98 mol %, preferably 85 mol % to 97 mol %, of all structural units constituting the copolymer (B). With such a composition, good lubricity and lubrication maintenance can be achieved.

[0078] The content of the structural unit (B-2) in the copolymer (B) is, for example, 2 mol % to 20 mol % and preferably 3 mol % to 15 mol % of all structural units constituting the copolymer (B). With such a composition, good sliding durability, coating layer strength, and adhesion to the substrate layer can be achieved.

[0079] The copolymer (B) according to the present invention may contain other structural units in addition to the structural units (B-1) and (B-2). When the copolymer (B) contains other structural units, the other structural units may be the other monomers described above in [Copolymer (A)]. In this case, the total content (total composition) of the structural units (B-1) and (B-2) is, for example, 50% or more by mole, preferably 70% or more but less than 100% by mole, and more preferably 90% or more but less than 100% by mole, based on all structural units constituting the copolymer (B). It is particularly preferred that the copolymer (B) is substantially composed of the structural units (B-1) and (B-2) (the content of other structural units is greater than 0% by mole and less than 5% by mole). More preferably, the copolymer (B) is composed only of the structural units (B-1) and (B-2) (the content of other structural units is 0% by mole).

[0080] That is, in one embodiment of the present invention, the coating layer has a lubricating region on the proximal side of the temperature-responsive region, which contains a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer, and the copolymer (B) is configured so that the total composition of the structural units (B-1) and (B-2) is 50 mol% or more relative to all structural units constituting the copolymer (B). In one embodiment of the present invention, the coating layer has a lubricating region on the proximal side of the temperature-responsive region, which contains a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer, and the copolymer (B) is configured so that the total composition of the structural units (B-1) and (B-2) is 70 mol% or more but less than 100 mol% relative to all structural units constituting the copolymer (B). In one embodiment of the present invention, the coating layer has a lubrication region on the proximal side of the temperature-responsive region, the lubrication region containing a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer, and the copolymer (B) is configured so that the total composition of the structural units (B-1) and (B-2) is 90 mol % or more and 100 mol % or less of all structural units constituting the copolymer (B). In one embodiment of the present invention, the coating layer has a lubrication region on the proximal side of the temperature-responsive region, the lubrication region containing a copolymer (B) composed only of the structural unit (B-1) derived from a hydrophilic monomer and the structural unit (B-2) derived from a reactive monomer.

[0081] The weight-average molecular weight of copolymer (B) is not particularly limited, but is preferably 10,000 to 10,000,000 from the viewpoint of solubility, and more preferably 100,000 to 5,000,000 from the viewpoint of ease of preparation of a copolymer (B) solution (coating liquid).

[0082] The method for producing the copolymer (B) is not particularly limited, and can be produced by applying conventional polymerization methods such as living radical polymerization, polymerization using a macroinitiator, and polycondensation. Among these, living radical polymerization or polymerization using a macroinitiator is preferred because it is easy to control the molecular weight and molecular weight distribution of the structural units (portions) derived from reactive monomers and the structural units (portions) derived from hydrophilic monomers. The living radical polymerization method is not particularly limited, and for example, methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, etc., as well as atom transfer radical polymerization (ATRP), etc., can be used in the same manner or with appropriate modifications. In addition, in a polymerization method using a macroinitiator, for example, a macroinitiator having a reactive moiety with a reactive functional group and a radically polymerizable group such as a peroxide group is prepared, and then the macroinitiator is polymerized with a monomer for forming a hydrophilic moiety to prepare a block copolymer having a hydrophilic moiety and a reactive moiety. After polymerization, the product is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0083] (Manufacturing method of medical devices) The method for producing a medical device according to the present invention includes applying a solution (coating solution A) containing copolymer (A) and a solvent to at least the tip of the substrate layer ((I) solution application step). If necessary, the coating layer A formed on at least the tip of the substrate layer in step (I) may be heat-treated ((II) heat treatment step). Furthermore, after step (II), the heat-treated coating layer A may be washed ((III) washing step).

[0084] Furthermore, when a temperature-responsive region containing copolymer (A) is provided only at the tip of the base layer, another region (for example, a lubrication region containing copolymer (B)) may be provided on the base end side of the temperature-responsive region. In an embodiment in which the coating layer has a temperature-responsive region and another region, for example, a solution containing copolymer (B) and a solvent (coating liquid B) may be applied to the base layer located on the base end side of the temperature-responsive region ((I') solution application step), the coating layer B formed in the above step (I') may be heat-treated ((II') heat treatment step), and after the above step (II'), the heat-treated coating layer B may be washed ((III') washing step).

[0085] Each step will be explained below. The present invention is not limited to the following embodiments, and known methods for producing medical devices can be applied in the same manner or with appropriate modifications, except that the copolymer (A) or the copolymer (A) and the copolymer (B) according to the present invention are used.

[0086] (I) Coating liquid A application process (coating layer A formation process) In this step, a solution containing the copolymer (A), a solvent, and, if necessary, other components (also referred to simply as "coating liquid A" in this specification) is first prepared, and the coating liquid A is applied to at least the tip of the substrate layer ((I) coating liquid A application step, coating layer A formation step). This step is carried out for the purpose of supporting (or coating) a temperature-responsive region containing copolymer (A) on at least the tip surface of the substrate layer. In this specification, "supported" refers to a state in which the layer (temperature-responsive region, coating layer) to be formed is fixed so that it does not easily separate from the substrate layer surface. This term includes not only a state in which the entire surface of the substrate layer is completely covered by the layer, but also a state in which only a portion of the substrate surface is covered by the layer, i.e., a state in which the temperature-responsive region or coating layer is attached to only a portion of the substrate surface. Therefore, the method of applying the solution is not particularly limited except for the use of coating liquid A containing copolymer (A) and a solvent, and can be applied in the same manner as known methods or with appropriate modifications. In addition, if coating liquid A contains other components, the other components are the same as those described above, and therefore will not be described here.

[0087] Specifically, in this step, the copolymer (A) and, if necessary, other components are dissolved in a solvent to prepare a solution (coating liquid A).

[0088] The solvent used to dissolve the copolymer (A) is not particularly limited as long as it can dissolve the copolymer (A) (and other components, if used). From the viewpoint of higher solubility, acetone, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone are used.

[0089] The concentration of copolymer (A) in coating solution A is not particularly limited. For example, the concentration of copolymer (A) in coating solution A is preferably 0.01 to 20% by mass, more preferably 0.05 to 15% by mass, and particularly preferably 1 to 10% by mass. When the concentration of copolymer (A) is within the above range, the resulting temperature-responsive region (coating layer) exhibits adequate lubricity below the phase transition temperature of the temperature-responsive region, and the lubricity can be reduced above the phase transition temperature of the temperature-responsive region. Furthermore, a uniform temperature-responsive region (coating layer) of the desired thickness can be easily obtained with a single coating, and the viscosity of the solution falls within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, even if the concentration is outside the above range, it can be used as long as it does not affect the effects of the present invention.

[0090] Next, the coating liquid A prepared above is applied to a predetermined area of ​​the base layer (at least the surface of the tip portion). Here, the base layer is the same as that described above, so a description thereof will be omitted here.

[0091] The method for applying (coating) the copolymer (A) solution (coating liquid A) to the surface of the substrate layer is not particularly limited, and any conventionally known method can be used, such as coating / printing, dipping, spraying, spin coating, mixed solution-impregnated sponge coating, bar coating, die coating, reverse coating, comma coating, gravure coating, doctor knife coating, etc. Of these, the dipping method (dipping or dip coating) is preferably used.

[0092] Furthermore, when forming a temperature-responsive region (coating layer) only on a portion of the substrate layer, the temperature-responsive region (coating layer) can be formed in the desired portion of the substrate layer by immersing only a portion of the substrate layer in coating liquid A and coating the coating liquid A onto that portion of the substrate layer.

[0093] If it is difficult to immerse only a portion of the substrate layer in the coating liquid A, the surface portion of the substrate layer where no temperature-responsive region (coating layer) is required can be protected (e.g., coated) with a suitable detachable member. The substrate layer can then be immersed in the coating liquid A to coat the substrate layer with the coating liquid A. After that, the protective member (material) covering the surface portion of the substrate layer where no temperature-responsive region (coating layer) is required can be removed, and the substrate can be reacted by heat treatment or the like to form a temperature-responsive region (coating layer) on the desired surface portion of the substrate layer. However, the present invention is not limited to these formation methods, and a temperature-responsive region (coating layer) can be formed using any conventionally known method. For example, if it is difficult to immerse only a portion of the substrate layer in the coating liquid A, other coating techniques (e.g., applying the coating liquid A to a desired surface portion of a medical device using an application device such as a sprayer, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor knife) can be used instead of the immersion method.

[0094] The amount of coating liquid A (copolymer (A) solution) to be applied is preferably such that the thickness (dry film thickness) of the resulting temperature-responsive region (coating layer) is 0.1 to 10 μm, more preferably 0.5 to 5 μm, and even more preferably 1 to 3 μm.

[0095] (II) Heat treatment process In this step, if necessary, the coating layer A formed in step (I) above is heat-treated. This allows the reactive functional groups of the copolymer (A) to react with each other, thereby increasing the film strength of the coating layer A. Furthermore, if the substrate layer forms a chemical bond with the reactive functional groups of the copolymer (A), the reactive functional groups of the copolymer (A) can react with the material constituting the substrate layer to firmly fix the coating layer A to the substrate layer. This can improve the durability of the coating layer (temperature-responsive region). For this reason, it is preferable to heat-treat the coating layer A formed in step (I) above.

[0096] The conditions for the heat treatment are not particularly limited, as long as they allow the formation of a coating layer A containing copolymer (A) on the substrate layer. For example, the heat treatment temperature is preferably 40 to 200°C, more preferably 50 to 180°C, and particularly preferably 90 to 150°C. The heat treatment time is preferably 30 minutes to 15 hours, more preferably 1 to 10 hours, and particularly preferably 2 to 5 hours. Under the above conditions, the reactive functional groups of copolymer (A) in coating layer A react more efficiently with each other, further increasing the film strength of coating layer A. Furthermore, when the substrate layer forms a chemical bond with the reactive functional groups of copolymer (A), the reactive functional groups of copolymer (A) in coating layer A react more effectively with the material constituting the substrate layer, thereby allowing coating layer A to be sufficiently firmly fixed to the substrate layer. Therefore, a high-strength coating layer A that does not easily peel off from the substrate layer can be formed.

[0097] The pressure conditions in the heat treatment step are not particularly limited, and the heat treatment step can be carried out under normal pressure (atmospheric pressure), or under increased or reduced pressure.

[0098] 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.

[0099] (III) Cleaning process In this step, if necessary, the coating layer A formed in the above step (I) or the covering layer A obtained in the above step (II) is washed.

[0100] The washing method is not particularly limited, but may include a method of immersing the layer A containing copolymer (A) (coating layer A or covering layer A; the same applies hereinafter) in a washing solvent, a method of pouring the washing solvent over the layer A containing copolymer (A), or a combination of these. The washing solvent used here is not particularly limited as long as it does not dissolve the covering layer A containing copolymer (A), but water or warm water is preferably used. The temperature of the washing solvent is not particularly limited, but is preferably 20°C to 100°C, more preferably 25 to 80°C. The washing time (the time during which the washing solvent is brought into contact with the layer A containing copolymer (A)) is not particularly limited, but is preferably 1 to 60 minutes, more preferably 5 to 30 minutes.

[0101] 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.

[0102] (I') Coating liquid B application process (coating layer B formation process) This step can be performed when the coating layer has a lubricating region in addition to the temperature-responsive region. Therefore, when the coating layer does not include a lubricating region (i.e., when the coating layer is composed only of a temperature-responsive region), this step and the following steps (II') and (III') are not performed.

[0103] In this step, a solution containing the copolymer (B) and a solvent, and optionally other components (also referred to simply as "coating liquid B" in this specification) is prepared, and the coating liquid B is applied to at least a portion of the region of the medical device obtained in step (I), (II), or (III) where no temperature-responsive region is formed (particularly the proximal side of the temperature-responsive region) ((I') coating liquid B application step, coating layer B formation step). This step is carried out for the purpose of supporting (or coating) a coating layer B containing copolymer (B) on (or covering) the proximal side region of the temperature-responsive region of the base layer. Here, the portion to which coating liquid B is applied is a region that requires lubricity but does not need to be fixed in a biological lumen. Specifically, it is the region corresponding to the lubrication region.

[0104] This step is the same as the above-mentioned (I) Coating Liquid A Application Step (Coating Layer A Formation Step) except that copolymer (B) is used instead of copolymer (A) (coating liquid B is used instead of coating liquid A) and the area to be coated is different, so a detailed explanation will be omitted here.

[0105] (II') Heat treatment process In this step, if necessary, the coating layer B formed in step (I') is heat-treated. This allows the reactive functional groups of the copolymer (B) to react with each other, thereby increasing the film strength of the coating layer B. Furthermore, when the substrate layer forms a chemical bond with the reactive functional groups of the copolymer (B), the reactive functional groups of the copolymer (B) react with the material constituting the substrate layer, thereby firmly fixing the coating layer B to the substrate layer. This improves the durability of the coating layer (lubrication region). For this reason, it is preferable to heat-treat the coating layer B formed in step (I').

[0106] This step is the same as the above-mentioned (II) heat treatment step except that coating layer B is used instead of coating layer A, and therefore a description thereof will be omitted here.

[0107] (III') Cleaning step In this step, if necessary, the coating layer B formed in the above step (I') or the covering layer B obtained in the above step (II') is washed.

[0108] This step is the same as the above (III) cleaning step except that the coating layer B or the covering layer B is used instead of the coating layer A or the covering layer A, respectively, and therefore a description thereof will be omitted here.

[0109] In the above, steps (I), (II), (III), (I'), (II'), and (III') are performed in this order, but step (I) and step (I') may be performed in any order. For example, steps (I), (II), and (III) may be followed by steps (I'), (II'), and (III'); steps (I), (II), and (III') may be performed after steps (I'), (II'), and (III'); steps (I) and (I') may be performed in this order, followed by step (II) (which also serves as step (II')) and step (III) (which also serves as step (III')); steps (I') and (I) may be performed in this order, followed by step (II) (which also serves as step (II')) and step (III) (which also serves as step (III')).

[0110] (Fixing medical devices in biological lumens) The medical device according to the present invention comprises a coating layer at least in a portion located on the distal end. The coating layer comprises a temperature-responsive region in the distal end, the temperature of which exceeds 37.0°C. While the medical device (e.g., a balloon catheter) is inserted into a biological lumen such as a blood vessel, the temperature of the temperature-responsive region is below the phase transition temperature, since the temperature of the biological lumen such as a blood vessel is usually below 37.0°C. Therefore, the coating layer (the temperature-responsive region and, if present, the lubricating region) exhibits lubricity. After inserting the medical device into the desired position in the biological lumen, the surgeon heats the distal end (temperature-responsive region) of the medical device to a temperature equal to or higher than the phase transition temperature of the temperature-responsive region. This reduces or eliminates the lubricity of the temperature-responsive region, allowing the surgeon to stably maintain the medical device in the desired position. Therefore, the surgeon can treat or diagnose the lesion while the medical device is firmly fixed in the desired position. Furthermore, after treatment or diagnosis of the lesion has been completed, the surgeon can stop the heating operation and return the temperature of the temperature-responsive region to the temperature of the living lumen (37.0°C or less). This restores the lubricity of the temperature-responsive region. Therefore, the surgeon can smoothly remove the medical device after treatment or diagnosis of the lesion.

[0111] Here, the heating method is not particularly limited as long as it can heat the temperature-responsive region to a temperature above the phase transition temperature. For example, when the medical device is a balloon catheter, one method involves providing a temperature-responsive region on at least a portion of the outer surface of the balloon (preferably the entire outer surface of the balloon), and inflating the balloon with a liquid (e.g., water, saline, or contrast agent) heated to a temperature above the phase transition temperature of the temperature-responsive region, thereby heating the temperature-responsive region located on the outer surface of the balloon. Alternatively, when the medical device is a catheter such as a microcatheter, one method involves providing a temperature-responsive region on the outer surface of the tip of the catheter, and injecting a liquid (e.g., water, saline, or contrast agent) heated to a temperature above the phase transition temperature of the temperature-responsive region from an opening in the catheter tip, thereby transferring heat from the inner surface of the tip of the catheter to the outer surface of the tip of the catheter, thereby heating the temperature-responsive region.

[0112] The heating conditions are not particularly limited as long as they allow stable immobilization of the medical device via the temperature-responsive region. Specifically, it is preferable to use a liquid heated to a temperature 1 to 5°C higher than the phase transition temperature of the temperature-responsive region, and it is more preferable to use a liquid heated to a temperature 2 to 4°C higher than the phase transition temperature of the temperature-responsive region. With a liquid at such a temperature, the lubricity of the temperature-responsive region can be switched without causing protein denaturation (e.g., blood coagulation).

[0113] [Medical device uses] The medical device according to the present invention is used in contact with body fluids, blood, etc., and has a surface that is lubricious in body fluids or aqueous liquids such as physiological saline, thereby improving operability and reducing damage to tissue mucosa. Specific examples include catheters, stents, guidewires, etc. used in blood vessels. That is, the medical device according to one embodiment of the present invention is a catheter or a guidewire. The medical device according to one embodiment of the present invention is a catheter (e.g., a balloon catheter, an angiography catheter, or a microcatheter). The medical device according to one embodiment of the present invention is a balloon catheter, an angiography catheter, or a microcatheter. Other examples of the medical devices include the following:

[0114] (a) Catheters inserted or left in the digestive tract via the mouth or nose, such as gastric catheters, feeding catheters, and tube feeding tubes; (b) Catheters inserted or placed in the airway or trachea via the mouth or nose, such as oxygen catheters, oxygen cannulas, endotracheal tubes and cuffs, tracheostomy tubes and cuffs, and endotracheal suction catheters; (c) Catheters inserted or placed in the urethra or ureter, such as urinary catheters, urinary catheters, and urethral balloon catheters; (d) Catheters inserted or left in various body cavities, organs, or tissues, such as suction catheters, drainage catheters, and rectal catheters; (e) Catheters that are inserted or placed in blood vessels, such as indwelling needles, IVH catheters, thermodilution catheters, and dilators or introducers, or guide wires, stylets, etc. for these catheters; (f) Artificial trachea, artificial bronchi, etc. [Example]

[0115] 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).

[0116] <Synthesis of copolymer> Synthesis Example 1: Synthesis of polyperoxide PPO-GMA 29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50°C, and then the hydrochloric acid was removed under reduced pressure at 50°C for 3 hours to obtain an oligoester. Next, 4.5 g of methyl ethyl ketone was added to 22.5 g of the obtained oligoester, and this was added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% by mass hydrogen peroxide, 0.44 g of dioctyl phosphate as a surfactant, and 120 g of water, and the reaction was carried out at -5°C for 20 minutes. The obtained product was repeatedly washed with water and methanol and then dried to obtain a polyperoxide (PPO) having multiple peroxide groups in the molecule.

[0117] 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.

[0118] Synthesis Examples 2 to 7: Synthesis of Copolymers (1) to (6) Using the polyglycidyl methacrylate (PPO-GMA) obtained in Synthesis Example 1 as a polymerization initiator, N-isopropylacrylamide (NIPAAm) (temperature-responsive monomer) and N,N-dimethylacrylamide (DMAAm) (hydrophilic monomer) were dissolved in chlorobenzene as a solvent in the amounts (g) shown in Table 1 ("Synthesis Charge Amount [g]" in Table 1 below), and polymerization was carried out at 75°C for 6 hours under a nitrogen atmosphere. After polymerization for the specified time, the reaction product was reprecipitated with hexane and recovered to obtain copolymers (poly[(NIPAAm-r-DMAAm)-b-GMA]) (1) to (6) having a temperature-responsive portion in which NIPAAm and DMAAm were randomly copolymerized and a reactive portion made of GMA.

[0119] The compositions (molar ratios) of NIPAAm, DMAAm, and GMA in the copolymers (1) to (6) obtained in Synthesis Examples 2 to 7 were determined according to the following method: 1 Chemical analysis was performed by H-NMR, and the values ​​were determined from the integral ratio of chemical shifts. The results are shown in Table 1. In Table 1 below, the composition (mol) of each monomer calculated based on the synthetic charge amount (g) is referred to as "charge composition ratio" and 1 The composition (molar) of each monomer measured by chemical analysis using H-NMR is shown as "Analyzed Composition Ratio." In Table 1 below, 1 Regarding the composition of each monomer (analytical composition ratio) measured by chemical analysis using H-NMR, the compositions of NIPAAm, DMAAm, and GMA relative to the total composition of NIPAAm, DMAAm, and GMA are shown as NIPAAm / total structural units (mol%), DMAAm / total structural units (mol%), and GMA / total structural units (mol%), respectively. Similarly, the composition ratio of DMAAm relative to the total composition of NIPAAm and DMAAm is shown as DMAAm / (NIPAAm+DMAAm)(mol%), and the composition ratio of the total composition of NIPAAm and DMAAm relative to the total composition of NIPAAm, DMAAm, and GMA is shown as NIPAAm+DMAAm / total structural units (mol%).

[0120] [Method for measuring the composition of each structural unit] According to the following conditions, the copolymer solution 1The composition (molar ratio) of each structural unit was quantified by measuring the integral ratio of the intensity of each signal in the H-NMR spectrum (integral ratio of chemical shifts).

[0121] (Measurement conditions) Equipment name: FT NMR equipment JNM ECZ500R (JEOL RESONANCE Co., Ltd.) Resonant frequency: 1 H: 500MHz Measurement mode: 1 H NMR Dissolving solvent: deuterated chloroform Accumulation count: 64 times Measurement temperature: room temperature (25℃) Sample preparation method: Dissolve 10 mg of copolymer (sample) in 0.75 mL of dissolution solvent.

[0122] obtained 1 In the H-NMR spectrum, a signal (signal A) near δ=3.9 ppm indicates the presence of the structure indicated by the arrow in the following structure of N-isopropylacrylamide (NIPAAm).

[0123] [ka]

[0124] obtained 1 In the H-NMR spectrum, a signal (signal B) near δ=2.9 ppm indicates the presence of the structure indicated by the arrow in the following structure of N,N-dimethylacrylamide (DMAAm).

[0125] [ka]

[0126] obtained 1 In the H-NMR spectrum, a signal (signal C) near δ=3.2 ppm indicates the presence of the structure indicated by the arrow in the following structure of glycidyl methacrylate (GMA).

[0127] [ka]

[0128] [Table 1]

[0129] <Sample Preparation> Example 1 Copolymer (1) obtained in Synthesis Example 2 was dissolved in tetrahydrofuran to a concentration of 5% by mass to prepare a coating solution. A sheet (size: 15 mm x 40 mm, thickness: 1 mm) made of nylon elastomer (Grilflex (registered trademark) ELG6260, M-Chemie Japan Co., Ltd.) was immersed in this coating solution and then pulled up at a speed of 15 mm / sec to form a coating film on the sheet. The sheet with the coating film formed thereon was then heated in an oven at 130°C for 3 hours to form a coating layer (thickness: 1 μm) containing copolymer (1) on the sheet, thereby obtaining sheet (1).

[0130] Examples 2 to 3, Comparative Examples 1 to 3 Sheets (2) to (6) were obtained in the same manner as in Example 1, except that copolymers (2) to (6) obtained in Synthesis Examples 3 to 7 were used instead of copolymer (1).

[0131] [Measurement of phase transition temperature] For the sheets (1) to (3) and (4) to (6) (samples) obtained in Examples 1 to 3 and Comparative Examples 1 to 3, the temperature dependence of frictional resistance was evaluated using a friction force tester (Tribomaster TL201Ts, manufactured by Trinity Labs) shown in FIG. 1 according to the following method.

[0132] Specifically, each sheet (sample) 3 was placed on a temperature-controlled stage 2 with the coating layer (the surface coated with each copolymer) facing up. Stage 2 was filled with phosphate-buffered saline (PBS) solution (pH 7.4) at room temperature (25°C). A cylindrical SEBS terminal 4 (φ6 mm) was then placed in contact with the coating layer of sheet 3. A 50 g load 5 was applied to terminal 4, and the terminal 4 was moved horizontally (sliding) at a speed of 10 mm / sec and a distance of 15 mm. The frictional resistance (gf) was then measured. The temperature was then raised to 44°C in approximately 1°C increments, and the frictional resistance (gf) was measured repeatedly at the same conditions every approximately 1°C. The temperature dependence of the frictional resistance was evaluated. A frictional resistance of 20 gf or less was considered to indicate good lubricity, and the temperature at which the frictional resistance reached 20 gf was designated the phase transition temperature (°C). The results are shown in Table 2 and Figure 2. In Table 2, sheet (6) was marked with "-" because the friction resistance was 20 gf or less in the measurement temperature range.

[0133] Figure 3 shows the relationship between the ratio (mol %) of the DMAAm composition to the total composition of NIPAAm and DMAAm [=DMAAm (mol) × 100 / (NIPAAm (mol) + DMAAm (mol))] and the phase transition temperature (°C). Figure 3 shows that the phase transition temperature increases almost linearly with an increase in the DMAAm composition (molar ratio).

[0134] From these results, it is considered that the sheets (1) to (3) of Examples 1 to 3 (particularly Examples 1 and 2), which have a phase transition temperature exceeding 37.0°C, exhibit good lubricity in the body environment, while being able to increase frictional resistance with a slight temperature rise. Therefore, it is expected that the sheets (1) to (3) of Examples 1 to 3 can switch their lubrication function with a small temperature change, making it possible to minimize the load on the living body.

[0135] In particular, by imparting such properties to the catheter surface, the position of the catheter can be temporarily fixed by introducing a heated contrast agent or the like. Similarly, by imparting such properties to the balloon surface, the position of the balloon catheter can be temporarily fixed by injecting a heated liquid during balloon inflation. Therefore, the medical device according to the present invention exhibits lubricity when inserted into a biological lumen, and is suitable for use in balloon catheters, microcatheters, contrast catheters, and the like, which require temporary fixation of the device during treatment or diagnosis of a lesion.

[0136] [Table 2]

[0137] Example 4 Copolymer (1) (phase transition temperature: 39.0°C) obtained in Synthesis Example 2 was dissolved in tetrahydrofuran to a concentration of 5% by mass to prepare a coating solution. This coating solution was dip-coated onto the outer surface of an uncoated microcatheter (coronary artery stenosis penetration catheter FINECROSS (registered trademark) MG (manufactured by Terumo Corporation), distal end outer diameter: 0.60 mm, distal end inner diameter: 0.45 mm, distal end wall thickness: 0.075 mm, effective length: 130 cm) in a 600 mm distal end (distance from the distal end to 600 mm; distal end) at a speed of 15 mm / sec to form a coating film at the distal end of the catheter. The microcatheter with the coating film formed thereon was then heated in an oven at 130°C for 3 hours to obtain a microcatheter (1) having a temperature-responsive region (thickness: 1 μm) containing copolymer (1) in the distal end portion extending 600 mm from the distal end.

[0138] The fixation of the tip of the microcatheter (1) obtained above was evaluated according to the following method. As a tortuous blood vessel model, a bent silicone tube (total length: 180 mm) with an inner diameter of 3 mm and filled with phosphate-buffered saline (PBS solution) was prepared, as shown in Figure 7. As shown in Figure 7, the tortuous blood vessel model (tube) had four wavy bends, from the base end to the tip end, with a 20 mm radius of curvature ("R20" in Figure 7), a 15 mm radius of curvature ("R15" in Figure 7), a 10 mm radius of curvature ("R10" in Figure 7), and an 8 mm radius of curvature ("R8" in Figure 7).

[0139] A microcatheter (1) was inserted from the base end of the tortuous blood vessel model, and positioned so that the temperature-responsive region containing copolymer (1) of the microcatheter was in contact with the four bends in the tortuous blood vessel model and the tip of the microcatheter was located distal to the bend with a curvature radius of 8 mm in the tortuous blood vessel model. A syringe was then used to flush 42°C warm water into the microcatheter, and the warm water was sprayed from the tip opening of the microcatheter, and the behavior of the tip of the microcatheter at this time was confirmed. As a result, the tip of the microcatheter (1) did not move, and it was possible to stably spray the contrast agent.

[0140] Comparative Example 4 A microcatheter (2) having a region (thickness: 1 μm) containing copolymer (6) at its tip was obtained in the same manner as in Example 4, except that copolymer (6) (DMAAm-GMA block copolymer) obtained in Synthesis Example 7 was used instead of copolymer (1).

[0141] A tortuous blood vessel model similar to that in Example 4 was prepared.

[0142] The obtained microcatheter (2) was inserted from the base end of the tortuous blood vessel model, and positioned so that the region of the microcatheter containing copolymer (6) was in contact with the four bends in the tortuous blood vessel model and the tip of the microcatheter was located distal to the bends with a curvature radius of 8 mm in the tortuous blood vessel model. After that, a syringe was used to flush the microcatheter with 42°C warm water, and the warm water was sprayed from the tip opening of the microcatheter, and the behavior of the tip of the microcatheter at that time was confirmed. As a result, the tip of the microcatheter (2) kicked back due to the reaction force from the flushing operation, and it was not possible to stably spray the contrast agent. [Explanation of symbols]

[0143] 1...PBS solution, 2...Temperature-controlled stage, 3...sheet (sample), 4...SEBS terminal, 5...Load (50g), 10...Friction measuring device (friction resistance temperature dependency evaluation system), 101...Base material layer, 101a...base material layer core portion, 101b...base material surface layer, 102...Covering layer, 100...Medical equipment, 200...Medical devices (balloon catheters), 210...Covering layer, 211...Lubrication area, 212...Temperature responsive region, 250...Outer tube shaft, 260...balloon, 270...tip, 280...Inner tube shaft.

Claims

1. A medical device comprising a base layer and a coating layer formed on at least a portion of the base layer, the coating layer has a temperature-responsive region at a tip portion, the temperature-responsive region including a copolymer (A) having a structural unit (A-1) derived from a temperature-responsive monomer having a lower critical solution temperature, a structural unit (A-2) derived from a hydrophilic monomer, and a structural unit (A-3) derived from a reactive monomer; A medical device, wherein the phase transition temperature of the temperature-responsive region exceeds 37.0°C.

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

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

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

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

6. The structural unit (A-1) is derived from N-isopropylacrylamide, The structural unit (A-2) is derived from N,N-dimethylacrylamide, The medical device according to claim 1, wherein the structural unit (A-2) is present in a proportion of 20 mol % or more and 30 mol % or less based on the total composition of the structural unit (A-1) and the structural unit (A-2).

7. 2. The medical device according to claim 1, wherein the coating layer has a lubricating region containing a copolymer (B) having a structural unit (B-1) derived from a hydrophilic monomer and a structural unit (B-2) derived from a reactive monomer, on the proximal side of the temperature-responsive region, and the copolymer (B) is configured so that the total composition of the structural units (B-1) and (B-2) is 50 mol % or more of all structural units constituting the copolymer (B).

8. The medical device of claim 1 , wherein the medical device is a catheter.

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