Medical instrument

Abstract

Provided is a medical instrument having a lubrication layer that is further improved in lubricity and durability (especially sliding durability).　The medical instrument according to the present invention includes a base material layer and a lubrication layer that is formed on at least a portion of the base material layer. The lubrication layer comprises a copolymer which has a constituent unit (A) that includes a constituent unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and a constituent unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and a constituent unit (B) that is derived from a hydrophobic monomer having an epoxy group, wherein the content of the constituent unit (A) is 10-90 moles per mole of the constituent unit (B), and the content of the constituent unit (A-2) is 3-40 mol% with respect to the total amount of the constituent unit (A-1) and the constituent unit (A-2).

Description

medical equipment

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

[0002] Medical devices inserted into living bodies, such as catheters and guidewires, are required to exhibit excellent lubricity in order to reduce tissue damage to blood vessels and improve operability for the surgeon. For this reason, medical devices with a lubricious hydrophilic polymer layer on the surface of a substrate layer have been developed and put into practical use. Meanwhile, in order to maintain the operability for the surgeon, it is also important for such medical devices to be able to maintain the lubricious hydrophilic polymer on the surface of the substrate layer during use by the surgeon. Therefore, hydrophilic polymer coatings are required to have not only excellent lubricity but also durability against loads such as abrasion and abrasion.

[0003] From this perspective, Japanese Patent Laid-Open Publication No. 8-33704 (corresponding to the specification of U.S. Pat. No. 5,670,558) discloses a medical device in which a water-soluble or water-swellable polymer is dissolved in a solvent that swells the substrate of the medical device to prepare a polymer solution, the substrate of the medical device is immersed in this polymer solution to cause it to swell, and the polymer is crosslinked or polymerized on the surface of the substrate layer, thereby forming a surface lubricating layer on the surface of the substrate layer.

[0004] According to the technology disclosed in the above document, a surface lubricating layer exhibiting good lubricity can be fixed to a substrate.

[0005] The above-mentioned document discloses that it is preferable to use a block copolymer consisting of a hydrophilic portion that exhibits lubricity and a portion having an epoxy group as the water-soluble or water-swellable polymer. When such a block copolymer is used, the epoxy group of the block copolymer can be crosslinked by heating, thereby forming a surface lubricating layer that is relatively difficult to peel off.

[0006] Meanwhile, medical devices have become significantly smaller and thinner in recent years, and medical procedures that involve approaching narrow lesions through highly tortuous biological lumens with medical devices are becoming more common. Furthermore, as medical procedures become more complex, the manipulation of medical devices can take longer. Therefore, in order to maintain good operability of medical devices for a longer period of time, even when treating lesions through extremely complex biological lumens, there is a need for a technology that further enhances the lubricity and lubricity maintenance (durability) of medical device surfaces compared to conventional technologies. More specifically, in order to maintain good operability of medical devices even when the medical device repeatedly slides against the wall of a biological lumen to deliver the medical device to a lesion through a complex biological lumen (e.g., when delivering a medical device to a lesion through a portion of the biological lumen with a small bending radius, a portion of the biological lumen with a continuous bending portion, a portion of the biological lumen with a narrow inner diameter, etc.), there is a need for a technology that further enhances the lubricity and durability (especially sliding durability) of the device surface compared to conventional technologies.

[0007] Therefore, there is a demand for technology that can further improve the lubricity and durability (especially sliding durability) of the surface lubricating layer of medical devices and support increasingly complex and sophisticated medical procedures.

[0008] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a medical device having a lubricating layer with further improved lubricity and durability (particularly sliding durability).

[0009] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the above problems can be solved by using a copolymer having specific structural units in a specific composition in a lubricating layer, which has led to the completion of the present invention.

[0010] That is, the above-mentioned object can be achieved by (1) a medical device comprising a base layer and a lubricating layer formed on at least a portion of the base layer, wherein the lubricating layer comprises a copolymer having a structural unit (A) containing a structural unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and a structural unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and a structural unit (B) derived from a hydrophobic monomer having an epoxy group, wherein the content of the structural unit (A) is 10 to 90 moles per mole of the structural unit (B), and the content of the structural unit (A-2) is 3 to 40 mole% relative to the total amount of the structural unit (A-1) and the structural unit (A-2). (2) In the medical device of (1), the content of the structural unit (A) is preferably 25 to 70 moles per mole of the structural unit (B). (3) In the medical device of (1) or (2) above, the content of the structural unit (A-2) is preferably 6 mol % or more and 30 mol % or less, based on the total amount of the structural unit (A-1) and the structural unit (A-2). (4) In the medical device of any of (1) to (3) above, the structural unit (A-1) is preferably a structural unit derived from at least one monomer selected from the group consisting of acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacrylamide, N,N-diethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminopropylmethacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-(2-hydroxybutyl)acrylamide. (5) In the medical device of any one of (1) to (4) above, the structural unit (A-2) is preferably a structural unit derived from at least one monomer selected from the group consisting of acrylic acid, methacrylic acid, and alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts thereof.(6) In the medical device of any one of (1) to (5) above, the structural unit (B) is preferably a structural unit derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate. (7) In the medical device of any one of (1) to (6) above, the structural unit (A) is preferably configured so that the structural units (A-1) and (A-2) are randomly arranged. (8) In the medical device of any one of (1) to (6) above, the structural unit (B) is preferably configured so that it is arranged in a block form. (9) In the medical device of any one of (1) to (6) above, it is preferable that the structural unit (A) is configured so that the structural units (A-1) and (A-2) are randomly arranged, and the structural unit (B) is arranged in a block form. (10) It is preferable that the medical device of any one of (1) to (9) above is a catheter, a stent, or a guidewire.

[0011] FIG. 1 is a graph showing the gel fractions of copolymers 6 and 12, and the sliding resistance values ​​at the 20th time of sample 6 having a lubricating layer containing copolymer 6 and sample 12 having a lubricating layer containing copolymer 12.

[0012] One aspect of the present invention relates to a medical device comprising a base layer and a lubricating layer formed on at least a portion of the base layer, wherein the lubricating layer comprises a copolymer having structural units (A) including structural units (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and structural units (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and structural units (B) derived from a hydrophobic monomer having an epoxy group, wherein the content of structural units (A) is 10 to 90 moles per mole of structural unit (B), and the content of structural units (A-2) is 3 to 40 mole% relative to the total amount of structural units (A-1) and (A-2). This configuration can provide a medical device having a lubricating layer with further improved lubricity and durability (particularly, sliding durability).

[0013] In this specification, a "hydrophilic monomer having an acrylamide group or a methacrylamide group" is also referred to simply as a "hydrophilic monomer (A-1)" or a "hydrophilic monomer (A-1) according to the present invention." A "structural unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group" is also referred to simply as a "structural unit (A-1)" or a "structural unit (A-1) according to the present invention." A "hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group" is also referred to simply as a "hydrophilic monomer (A-2)" or a "hydrophilic monomer (A-2) according to the present invention." A "carboxy group and at least one of a salt of a carboxy group" is also referred to simply as a "carboxy group (salt)." A "structural unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group" is also referred to simply as a "structural unit (A-2)" or a "structural unit (A-2) according to the present invention." The "hydrophobic monomer having an epoxy group" is also referred to simply as the "hydrophobic monomer" or the "hydrophobic monomer according to the present invention." The "structural unit (B) derived from a hydrophobic monomer having an epoxy group" is also referred to simply as the "structural unit (B)" or the "structural unit (B) according to the present invention." The "copolymer having a structural unit (A) comprising a structural unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and a structural unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and a structural unit (B) derived from a hydrophobic monomer having an epoxy group" is also referred to simply as the "copolymer" or the "copolymer according to the present invention."

[0014] As used herein, the range "X to Y" includes X and Y and means "at least X and at most Y." As used herein, the term "(meth)acrylic" encompasses both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" encompasses both acrylic acid and methacrylic acid. Similarly, the term "(meth)acrylate" encompasses both acrylate and methacrylate. Thus, for example, the term "glycidyl (meth)acrylate" encompasses both glycidyl acrylate and glycidyl methacrylate.

[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 a polymerizable unsaturated double bond of the corresponding monomer.

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

[0017] <Medical Device> A medical device according to one embodiment of the present invention comprises a substrate layer and a lubricating layer formed on at least a portion of the substrate layer. The lubricating layer comprises a copolymer having a structural unit (A) including a structural unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and a structural unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and a structural unit (B) derived from a hydrophobic monomer having an epoxy group. The content of the structural unit (A) is 10 to 90 moles per mole of the structural unit (B). The content of the structural unit (A-2) is 3 to 40 mole% relative to the total amount of the structural unit (A-1) and the structural unit (A-2). The lubricating layer having the above structure contains the structural unit (A-2) in a proportion of 3 mol% to 40 mol% relative to the total amount of the structural unit (A-1) and the structural unit (A-2), and therefore can improve lubricity (sliding properties).Furthermore, the lubricating layer having the above structure contains the structural unit (A) in a proportion of 3 mol% to 40 mol% relative to the total amount of the structural unit (A-1) and the structural unit (A-2), and the copolymer contains 10 mol to 90 mol of the structural unit (A) per mol of the structural unit (B), and therefore can exhibit excellent lubricity (sliding properties) and durability (particularly sliding durability). Therefore, a medical device having the above configuration can exhibit excellent lubricity and lubrication maintenance (sliding durability) even when the medical device is repeatedly slid against the wall of a biological lumen in order to deliver it to a lesion site through a complex biological lumen (for example, when delivering a medical device to a lesion site through a portion of the biological lumen with a small bending radius, a portion of the biological lumen with continuous bending portions, a portion of the biological lumen with a narrow inner diameter, etc.). Therefore, according to the present invention, a medical device having a lubricating layer with further improved lubricity and durability (particularly sliding durability) can be provided.

[0018] 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.

[0019] Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept, unless otherwise specified. Furthermore, terms used in this specification should be understood to be used in the sense commonly used in the art, unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will prevail.

[0020] [Substrate Layer (Substrate)] The substrate layer (substrate) used in the present invention may be made of any material and can be appropriately selected depending on the application. Specifically, materials constituting (forming) the substrate layer include metal materials, polymer materials, ceramics, etc. Here, the substrate layer may be entirely made of any of the above materials, or may have a structure in which the surface of a substrate layer core made of any of the above materials is coated with any of the other materials by an appropriate method to form a substrate surface layer. Examples of the latter include those in which the surface of a substrate core layer made of a resin material or the like is coated with a metal material by an appropriate method (conventionally known methods such as plating, metal vapor deposition, sputtering, etc.) to form a substrate surface layer; those in which the surface of a substrate core layer made of a hard reinforcing material such as a metal or ceramic material is coated with a polymeric material that is softer than the metal reinforcing material by an appropriate method (conventionally known methods such as dipping, spraying, coating, printing, etc.), or those in which the reinforcing material of the substrate core layer and the polymeric material of the substrate surface layer are combined (appropriate reaction treatment) to form a substrate surface layer. The substrate core layer may be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components formed of different materials are joined for each portion of the medical device. In addition, a separate middle layer may be formed between the substrate core layer and the substrate surface layer. Furthermore, the substrate surface layer may also be a multilayer structure formed by laminating different materials in multiple layers, or a structure (composite) in which components formed of different materials are joined for each portion of the medical device.

[0021] Among the materials constituting (forming) the base layer, the metal material is not particularly limited, and metal materials commonly used for medical devices such as catheters, stents, and guidewires can be used. Specific examples include various stainless steels (SUS) such as SUS304, SUS316, SUS316L, SUS420J2, and SUS630, as well as gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, and various alloys such as nickel-titanium (Ni-Ti) alloys, nickel-cobalt (Ni-Co) alloys, cobalt-chromium (Co-Cr) alloys, and zinc-tungsten (Zn-W) alloys. These may be used alone or in combination of two or more. The metal material may be appropriately selected from those optimal for the base layer of the intended use, such as a catheter, stent, or guidewire.

[0022] Furthermore, among the materials constituting (forming) the base layer, the polymeric material (resin material or elastomer material) is not particularly limited, and polymeric materials commonly used in medical devices such as catheters, stents, and guidewires can be used. Specific examples of the resin include polyamide resin (nylon), polyethylene resins such as linear low-density polyethylene (LLDPE), low-density polyethylene (LDPE), high-density polyethylene (HDPE), and modified polyethylene, polyolefin resins such as polypropylene resin, modified polyolefin resin, cyclic polyolefin resin, epoxy resin, polyurethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluororesins such as polytetrafluoroethylene (PTFE) and ethylene tetrafluoroethylene (ETFE), amino resins (urea resin, melamine resin, benzoguanamine resin), polyester resins such as polyethylene terephthalate resin and polybutylene terephthalate resin, styrene resins such as polystyrene, acrylic resin, polyacetal resin, vinyl acetate resin, phenolic resin, vinyl chloride resin (polyvinyl chloride (PVC)), silicone resin, polyether resins such as polyether ether ketone (PEEK), and polyimide resin. Thermoplastic elastomers such as polyurethane elastomer, polyester elastomer, and polyamide elastomer (nylon elastomer) can also be used as the material for the base layer. These may be used alone or in combination of two or more. The polymer material may be appropriately selected from those that are most suitable for the substrate layer of the intended use, such as a catheter, stent, guide wire, etc.

[0023] 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 wire, or a tube.

[0024] [Lubricating layer] The lubricating layer is formed (carried) on at least a part of the substrate layer (substrate).Here, the reason why the lubricating layer is formed (carried) on at least a part of the surface of the substrate layer is that in medical devices such as catheters, stents, guide wires, etc., which are used, the entire surface (whole surface) of these medical devices does not necessarily need to have lubricity when wet, and only the surface part (sometimes a part or sometimes the whole) that is required to have lubricity when wet is provided with the lubricating layer.Therefore, the lubricating layer includes the form of being formed to cover only one entire side of the substrate layer; the form of being formed to cover both sides of the substrate layer; the form of being formed to cover parts of both sides of the substrate layer in the same or different forms; the form of being formed to cover part of one side of the substrate layer, etc.

[0025] The lubricating layer contains a copolymer having a structural unit (A) which includes a structural unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and a structural unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and a structural unit (B) derived from a hydrophobic monomer having an epoxy group.

[0026] The acrylamide group (formula: CH ２ ═CH—C(═O)—N=) or methacrylamide group (formula: CH ２ =C(CH ３ The structural unit (A-1) derived from a hydrophilic monomer (hydrophilic monomer (A-1)) having a group represented by the formula (II)-C(=O)-N=) swells when in contact with body fluids (e.g., blood, urine) or aqueous solvents, and imparts slipperiness (lubricity) to the lubricating layer. Therefore, by introducing a structural unit derived from such a hydrophilic monomer into a copolymer, a lubricating layer formed using the copolymer exhibits excellent slipperiness (lubricity), and can reduce friction when the medical device comes into contact with a lumen wall such as a blood vessel wall.

[0027] The hydrophilic monomer (A-1) may be any monomer having an acrylamide group or a methacrylamide group and exhibiting lubricity in body fluids or aqueous solvents. Examples of such a hydrophilic monomer (A-1) include acrylamide, methacrylamide, N-methylacrylamide, N-methylmethacrylamide, N,N-dimethylacrylamide, N,N-dimethylmethacrylamide, N-ethylacrylamide, N-ethylmethacrylamide, N,N-diethylacrylamide, N,N-diethylmethacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminopropylmethacrylamide, N,N-dimethylaminoethylacrylate, N,N-dimethylaminoethylmethacrylate, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-(2-hydroxybutyl)acrylamide. Among these, from the viewpoints of further imparting lubricity and ease of synthesis, the hydrophilic monomer (A-1) preferably contains at least one selected from the group consisting of acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacrylamide, N,N-diethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminopropylmethacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-(2-hydroxybutyl)acrylamide, more preferably contains at least one selected from the group consisting of acrylamide, N,N-dimethylacrylamide, and N,N-diethylacrylamide, further preferably acrylamide or N,N-dimethylacrylamide, and particularly preferably N,N-dimethylacrylamide. The hydrophilic monomer-derived structural unit (A-1) may be composed of only one type of hydrophilic monomer (A-1), or may be composed of two or more types of hydrophilic monomers (A-1) in combination.

[0028] That is, in one embodiment of the present invention, the hydrophilic monomer-derived structural unit (A-1) is a structural unit derived from at least one monomer selected from the group consisting of acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacrylamide, N,N-diethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminopropylmethacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-(2-hydroxybutyl)acrylamide. In one embodiment of the present invention, the hydrophilic monomer-derived structural unit (A-1) is a structural unit derived from at least one monomer selected from the group consisting of acrylamide, N,N-dimethylacrylamide, and N,N-diethylacrylamide. In one embodiment of the present invention, the hydrophilic monomer-derived structural unit (A-1) is derived from acrylamide or N,N-dimethylacrylamide. In one embodiment of the present invention, the structural unit (A-1) derived from a hydrophilic monomer is derived from N,N-dimethylacrylamide.

[0029] The structural unit (A) has, in addition to the structural unit (A-1), a structural unit (A-2) derived from a hydrophilic monomer (hydrophilic monomer (A-2)) having at least one of a carboxy group (—COOH) and a salt of a carboxy group. The structural unit (A-2) may be composed of a structural unit derived from a hydrophilic monomer having a carboxy group and a structural unit derived from a hydrophilic monomer having a salt of a carboxy group. Furthermore, the number (total number) of carboxy groups and carboxy salts present in one hydrophilic monomer (A-2) is preferably 1 or 2, and more preferably 1.

[0030] The effects of adding the structural unit (A-2) to the structural unit (A) are described in detail below.

[0031] The epoxy group present in structural unit (B) interacts with other structural units (B) in copolymer or adjacent structural units (B) in copolymer during heat treatment, and forms inter-molecular cross-linking points, thereby forming a lubricating layer.However, when the proportion of structural unit (B) in the entire copolymer is small (particularly when the content of structural unit (B) is less than 5 mol% relative to the total structural units constituting copolymer), the proportion of other structural units (B) present around the epoxy group present in structural unit (B) becomes small, and the inter-molecular cross-linking point formation rate between epoxy group and other structural units (B) decreases.Therefore, when the proportion of structural unit (B) in the entire copolymer is small (particularly when the content of structural unit (B) is less than 5 mol% relative to the total structural units constituting copolymer), copolymer can increase the number of epoxy groups that contribute to the formation of cross-linking points, thereby improving the durability of lubricating layer. In addition, when the proportion of structural unit (B) that occupies in the whole copolymer is increased, and the durability of lubricating layer is improved (particularly, when the content of structural unit (B) is more than 5 mol% relative to the total structural units that constitute copolymer), the copolymer, along with the increase in the proportion of structural unit (B), the slipperiness of lubricating layer is reduced.Therefore, even in this case, by increasing the swelling property of structural unit (A), while maintaining the durability of lubricating layer, there is also room to improve the lubricity of lubricating layer.

[0032] The copolymer according to the present invention is designed so that the structural unit (A) has a structural unit (A-1) and a structural unit (A-2). The structural unit (A-2) is hydrophilic and has a carboxy group (salt). The carboxy group (salt) present in this structural unit (A-2) acts as a catalyst upon heat treatment, ring-opening the epoxy group present in the structural unit (B), and can promote chemical crosslinking between epoxy groups and between the epoxy group and the carboxy group (salt). Therefore, a portion of the carboxy group (salt) present in the structural unit (A-2) can promote chemical crosslinking between epoxy groups and between the epoxy group and the carboxy group (salt) in the lubricating layer, thereby improving the durability of the lubricating layer. Furthermore, when the carboxy group (salt) of the structural unit (A-2) does not form a chemical bond with the epoxy group, it contributes to the lubricity (swellability) of the lubricating layer as a hydrophilic material. Therefore, the lubricating layer containing the copolymer of the present invention can further improve the lubricity and durability (particularly sliding durability) due to the presence of the structural unit (A-2).

[0033] In addition, in copolymer, structural unit (A) contributes to lubricity, and structural unit (B) contributes to durability.Therefore, the lubricity and durability of copolymer are in a trade-off relationship.Therefore, in the past, it was difficult to achieve the enhancement of lubricity while maintaining durability by adjusting the ratio of structural unit (A) and structural unit (B) of copolymer.

[0034] The copolymer according to the present invention is configured such that the structural unit (A) is hydrophilic and includes a structural unit (A-2) having a carboxy group (salt). Therefore, even if the composition ratio of the structural unit (A) is increased to enhance lubricity, the carboxy group (salt) present in the structural unit (A-2) promotes chemical crosslinking of the epoxy group present in the structural unit (B), thereby improving the durability of the lubricating layer. Therefore, the lubricating layer containing the copolymer according to the present invention can further improve lubricity while maintaining durability (particularly sliding durability) due to the presence of the structural unit (A-2).

[0035] It should be noted that the above is merely speculation, and the present invention is not limited to the above.

[0036] The hydrophilic monomer (A-2) may be any one that is hydrophilic and has a carboxy group (salt). Examples of such hydrophilic monomer (A-2) include acrylic acid, methacrylic acid, maleic anhydride, aspartic acid, glutamic acid, polyalginic acid, adipic acid, glutaric acid, and hyaluronic acid; and alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts thereof (preferably NH ４ ＋ ) etc.

[0037] From the viewpoint of improving the water absorption of the structural unit (A-2), the salt of the carboxy group is preferably an alkali metal salt, an alkaline earth metal salt, or a quaternary ammonium salt (preferably, NH ４ ＋ ) is preferable. Examples of the alkali metal salt include lithium salt, potassium salt, and sodium salt of the carboxy group. Examples of the alkaline earth metal salt include magnesium salt, calcium salt, strontium salt, and barium salt. When the hydrophilic monomer (A-2) has an alkaline earth metal salt of the carboxy group, the alkaline earth metal salt bonds to two adjacent carboxy groups in one molecule of the hydrophilic monomer (A-2) or in two different hydrophilic monomers (A-2) (forming -C(=O)-O-X-O-C(=O)- (X=alkaline earth metal salt)). The hydrophilic monomer-derived structural unit (A-2) may be composed of only one type of hydrophilic monomer (A-2), or may be composed of two or more types of hydrophilic monomers (A-2).

[0038] Among these, the hydrophilic monomer (A-2) is selected from acrylic acid, methacrylic acid, and alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts thereof (preferably NH ４ ＋). The hydrophilic monomer (A-2) has excellent water absorption and functions as an acid that catalyzes the ring-opening of the epoxy group present in the structural unit (B). Therefore, the copolymer according to the present invention, due to the presence of the structural unit (A-2) derived from the hydrophilic monomer, can enhance the swelling property of the lubricating layer and further increase the number of epoxy groups (number of ring-opened epoxy groups) that contribute to the crosslinking reaction on the lubricating layer. Therefore, a lubricating layer containing a copolymer having the structural unit (A-2) derived from the hydrophilic monomer can improve lubricity, exhibit higher film strength (crosslink density), and further improve durability.

[0039] The hydrophilic monomer (A-2) is more preferably acrylic acid or an alkali metal salt thereof. As described above, in the structural unit derived from acrylic acid or the structural unit derived from an alkali metal salt of acrylic acid, the carboxy group catalyzes the ring-opening of the epoxy group present in the structural unit (B), and can promote chemical crosslinking between epoxy groups and between carboxy groups and epoxy groups. Therefore, the structural unit derived from acrylic acid or the structural unit derived from an alkali metal salt of acrylic acid can increase the number of epoxy groups in the copolymer that contribute to the crosslinking reaction on the lubricating layer, and can further improve the film strength (crosslink density) (and therefore durability) of the lubricating layer.

[0040] In addition, copolymers having structural units derived from acrylic acid or structural units derived from sodium acrylate that do not form chemical crosslinks with the epoxy groups present in the structural unit (B) are hydrophilic and also have excellent water absorption.For this reason, copolymers having structural units derived from acrylic acid or structural units derived from sodium acrylate exhibit swelling properties when in contact with body fluids (e.g., blood, urine) or aqueous solvents, and impart superior slip properties (lubricity) to the lubricating layer.Therefore, when the copolymer has a structural unit derived from acrylic acid or a structural unit derived from an alkali metal salt of acrylic acid as the structural unit (A-2), the lubricating layer formed using the copolymer exhibits superior slip properties (lubricity), and can further reduce friction when the medical device comes into contact with a lumen wall such as a blood vessel wall.

[0041] Therefore, a lubricating layer containing the copolymer according to the present invention can further improve the excellent lubricity and durability (especially sliding durability).

[0042] That is, in one embodiment of the present invention, the structural unit (A-2) is a structural unit derived from at least one monomer selected from the group consisting of acrylic acid, methacrylic acid, and alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts thereof. In one embodiment of the present invention, the structural unit (A-2) is a structural unit derived from at least one monomer selected from the group consisting of acrylic acid and alkali metal salts of acrylic acid. In one embodiment of the present invention, the structural unit (A-2) has at least one of a structural unit derived from acrylic acid and a structural unit derived from sodium acrylate.

[0043] Furthermore, when the structural unit (A-2) contains a structural unit derived from a hydrophilic monomer having a carboxy group and a structural unit derived from a hydrophilic monomer having a salt of a carboxy group, the proportion (mol %) of the structural unit derived from the hydrophilic monomer having a salt of a carboxy group in the entire structural unit (A-2) (hereinafter, also simply referred to as the "substitution rate") is preferably from 20 mol % to 100 mol %, and more preferably from 50 mol % to 80 mol %.

[0044] The structural unit (A) has a structural unit (A-1) and a structural unit (A-2). Here, the structural unit (A-1) and the structural unit (A-2) are preferably arranged randomly (the structural unit (A-1) and the structural unit (A-2) constitute a random copolymer). As a result, the carboxy group (salt) present in the structural unit (A-2) is dispersed within the segment of the structural unit (A). Therefore, the carboxy group (salt) present in the structural unit (A-2) is likely to form chemical crosslinks with the epoxy group present in the structural unit (B) at various sites in the structural unit (A). This increases the film strength (crosslink density) of the lubricating layer, further improving durability. That is, in one embodiment of the present invention, the structural unit (A) is configured so that the structural unit (A-1) and the structural unit (A-2) are arranged randomly.

[0045] The phrase "the structural units (A-1) and (A-2) form a random copolymer" means that the hydrophilic monomer (A-1) that forms the structural unit (A-1) and the hydrophilic monomer (A-2) that forms the structural unit (A-2) form a random copolymer. For example, when the structural unit (A-1) is composed of one type of hydrophilic monomer (A-1) and the structural unit (A-2) is composed of one type of hydrophilic monomer (A-2), this means that these two types of hydrophilic monomers form a random copolymer. Furthermore, when the structural unit (A-1) is composed of two types of hydrophilic monomers (A-1) and the structural unit (A-2) is composed of one type of hydrophilic monomer (A-2), this means that these three types of hydrophilic monomers form a random copolymer. Furthermore, when the structural unit (A-1) is composed of one type of hydrophilic monomer (A-1) and the structural unit (A-2) is composed of two types of hydrophilic monomers (A-2), this means that the three types of hydrophilic monomers constitute a random copolymer.

[0046] The structural unit (A) has structural units (A-1) and (A-2). The ratio of the structural unit (A-1) to the structural unit (A-2) is such that the content of the structural unit (A-2) is 3 mol% or more and 40 mol% or less relative to the total amount of the structural unit (A-1) and the structural unit (A-2). If the content of the structural unit (A-2) is less than 3 mol% relative to the total amount of the structural unit (A-1) and the structural unit (A-2), the composition of the structural unit (A-2) is too small, and there is not enough of the carboxy group (salt) of the hydrophilic monomer (A-2) involved in chemical crosslinking with the epoxy group present in the structural unit (B). For this reason, the lubricating layer exhibits excellent lubricity, but is inferior in durability (crosslink density). On the other hand, if the content of the structural unit (A-2) exceeds 40 mol% relative to the total amount of the structural unit (A-1) and the structural unit (A-2), the polymerization reaction product will turn yellow, and it will be impossible to obtain a polymer that can be used in a lubricating layer. From the standpoint of the balance between lubricity and durability (crosslink density) and operability in production, the content of the structural unit (A-2) is preferably 6 mol% or more and 30 mol% or less relative to the total amount of the structural unit (A-1) and the structural unit (A-2), and the content of the structural unit (A-2) is preferably 6.5 mol% or more and 20.0 mol% or less relative to the total amount of the structural unit (A-1) and the structural unit (A-2).

[0047] The copolymer according to the present invention has, in addition to the structural unit (A), a structural unit (B) derived from a hydrophobic monomer having an epoxy group.

[0048] The structural unit (B) has a structural unit derived from a hydrophobic monomer having an epoxy group. The hydrophobic monomer having an epoxy group has an epoxy group as a reactive group. The epoxy group present in the structural unit (B) interacts with other structural units (B) in the copolymer or with structural units (B) in adjacent copolymers during heat treatment, forming intermolecular crosslinking points. Furthermore, the epoxy group present in the structural unit (B) is ring-opened by heat treatment using a carboxy group (salt) in the copolymer or a carboxy group (salt) in an adjacent copolymer as a catalyst, and can also form chemical crosslinks with other epoxy groups or carboxy groups (salts). This increases the film strength of the lubricating layer and improves its durability. Furthermore, if the surface of the substrate layer has a functional group capable of reacting with an epoxy group, the epoxy group present in the structural unit (B) can also form a crosslinked structure with that functional group in the substrate layer, further improving the durability of the lubricating layer.

[0049] The hydrophobic monomer constituting the copolymer is not particularly limited as long as it has an epoxy group, and known compounds can be used. Among these, the hydrophobic monomer having an epoxy group preferably includes at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate, due to ease of crosslinking and control of polymerization. Among these, glycidyl (meth)acrylate is more preferred, and glycidyl methacrylate is particularly preferred, due to its ability to further promote the crosslinking reaction and ease of production. The hydrophobic monomer-derived structural unit (B) may be composed of only one type of hydrophobic monomer, or may be composed of two or more types of hydrophobic monomers.

[0050] That is, in one embodiment of the present invention, the structural unit (B) is a structural unit derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate. In one embodiment of the present invention, the structural unit (B) is a structural unit derived from glycidyl acrylate or glycidyl methacrylate. In one embodiment of the present invention, the structural unit (B) is a structural unit derived from glycidyl methacrylate.

[0051] The copolymer has a structural unit (A) and a structural unit (B). Here, the structural unit (A) and the structural unit (B) may be arranged randomly in the copolymer, or the structural unit (A) and the structural unit (B) may be arranged in a block form. In the copolymer, the structural unit (A) and the structural unit (B) are preferably arranged in a block form. That is, the copolymer is preferably a block copolymer in which the end of the copolymer composed of the structural unit (A) and the end of the polymer of the structural unit (B) are covalently linked, and a block composed of the structural unit (A) and a block composed of the structural unit (B) are linked. If it is a block copolymer, better results can be obtained in terms of the film strength (crosslink density) and lubricity of the lubricating layer.

[0052] Here, in the "block composed of the structural unit (A)", the structural units (A-1) and (A-2) may be arranged randomly, or the structural units (A-1) and (A-2) may be arranged in block form. However, in the "block composed of the structural unit (A)", as mentioned above, it is preferable that the structural units (A-1) and (A-2) are arranged randomly.

[0053] The phrase "the structural units (A) and (B) are arranged randomly" means that the hydrophilic monomer (A-1) that constitutes the structural unit (A), the hydrophilic monomer (A-2) that constitutes the structural unit (A), and the hydrophobic monomer that constitutes the structural unit (B) constitute a random copolymer.

[0054] That is, in one embodiment of the present invention, the structural unit (B) is configured to be arranged in a block form. Also, in one embodiment of the present invention, the structural unit (A) is configured so that the structural units (A-1) and (A-2) are arranged randomly, and the structural unit (B) is arranged in a block form.

[0055] As used herein, the phrase "structural unit (B) is arranged in a block form" means that a block consisting of only the structural unit (B) is present in the main chain of the copolymer, i.e., -[structural unit (B) ｎ ]-(n is an integer of 2 or greater) is intended to be present in the main chain of the copolymer. In this embodiment, when the structural unit (B) is composed of two or more types of hydrophobic monomers, two or more types of hydrophobic monomers are present in one block. For example, when the structural unit (B) is composed of two different types of structural unit (Y-1) and structural unit (Y-2), -[structural unit (Y-1) ｍ１ -Structural unit (Y-2) ｍ２ ] ｍ - (m1 and m2 are each independently an integer of 1 or greater, m is an integer of 2 or greater, and the structural units (Y-1) and (Y-2) may be arranged in a block or random manner) are present in the main chain of the copolymer.

[0056] The copolymer has a structural unit (A) having a structural unit (A-1) and a structural unit (A-2), and a structural unit (B). The content of the structural unit (A) is 10 moles or more and 90 moles or less per mole of the structural unit (B). If the content of the structural unit (A) per mole of the structural unit (B) is less than 10 moles, the composition of the structural unit (A) derived from a hydrophilic monomer is too small, and the lubricating layer has poor lubricity (sliding properties, swelling ratio). If the content of the structural unit (A) per mole of the structural unit (B) is more than 90 moles, the composition of the structural unit (B) derived from a hydrophobic monomer is too small, and the lubricating layer does not exhibit sufficient film strength (crosslink density) and has poor durability. From the viewpoint of achieving a better balance between durability (crosslink density) and lubricity (sliding properties, swelling ratio), the content of the structural unit (A) is preferably 25 mol or more and 70 mol or less per mol of the structural unit (B), and more preferably 30 mol or more and 60 mol or less per mol of the structural unit (B).

[0057] The content (composition) of the structural unit (B) is preferably 0.8 mol% or more, more preferably 1 mol% or more, and particularly preferably 1.5 mol% or more, based on all structural units constituting the copolymer. Furthermore, the content (composition) of the structural unit (B) is preferably 13 mol% or less, more preferably 10 mol% or less, even more preferably 5 mol% or less, and particularly preferably 3.0 mol% or less, based on all structural units constituting the copolymer. In one embodiment of the present invention, the content (composition) of the structural unit (B) is 0.8 mol% or more and 13 mol% or less, based on all structural units constituting the copolymer. In one embodiment of the present invention, the content (composition) of the structural unit (B) is 1 mol% or more and 10 mol% or less, based on all structural units constituting the copolymer. In one embodiment of the present invention, the content (composition) of the structural unit (B) is 1 mol% or more and 5 mol% or less, based on all structural units constituting the copolymer. In one embodiment of the present invention, the content (composition) of the structural unit (B) is 1.5 mol% or more and 3.0 mol% or less, based on all structural units constituting the copolymer. Within this range, the lubricating layer exhibits sufficient film strength (crosslink density) and can exhibit excellent durability.

[0058] (Other Structural Units) The copolymer according to the present invention essentially contains the structural units (A) and (B), but may contain other structural units in addition to these structural units. When the copolymer contains other structural units, examples of the monomers constituting the other structural units (other monomers) include 4-hydroxybutyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, 2-hydroxybutyl(meth)acrylate, 6-hydroxyhexyl(meth)acrylate, 1,4-cyclohexanedimethanol mono(meth)acrylate, 1-chloro-2-hydroxypropyl(meth)acrylate, diethylene glycol mono(meth)acrylate, and 1,6-hexanediol mono(meth)acrylate. , pentaerythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropane di(meth)acrylate, trimethylolethane di(meth)acrylate, 2-hydroxy-3-phenyloxypropyl(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, 2-hydroxy-3-phenyloxy(meth)acrylate, triethylene glycol, tripropylene glycol, etc. The other constituent units may be composed of only one type of other monomer, or may be composed of two or more types of other monomers.

[0059] When the copolymer according to the present invention has other structural units, it is preferable that the copolymer according to the present invention is substantially composed of structural unit (A) and structural unit (B) (content of other structural units = more than 0 mol% and less than 5 mol%).In this form, the copolymer according to the present invention can achieve a good balance between the lubricity (surface lubricity) due to the structural unit (A) derived from the hydrophilic monomer and the durability due to the structural unit (B) derived from the hydrophobic monomer having an epoxy group.More preferably, the copolymer according to the present invention (preferably a block copolymer of structural unit (A) and structural unit (B)) is composed only of structural unit (A) and structural unit (B) (content of other structural units = 0 mol%).

[0060] The copolymer having the above composition can be controlled by adjusting the charge ratio (molar ratio) of each monomer so that it falls within the above range. Therefore, the charge ratio (molar ratio) of the hydrophilic monomer to the hydrophobic monomer in the copolymer production stage is preferably within the above range.

[0061] The composition (molar ratio) of each structural unit of the copolymer can be determined, for example, by NMR measurement of the copolymer ( １ H-NMR measurement, １３ For example, the composition of each structural unit can be confirmed by measuring the composition of the copolymer solution. １ The composition (molar ratio) of each structural unit can be determined by measuring the integral ratio of the intensity of each signal in the H-NMR spectrum. １３ The composition (molar ratio) of each structural unit can be determined by measuring the integral ratio of the intensity of each signal in the C-NMR spectrum.

[0062] In one embodiment of the present invention, the copolymer according to the present invention comprises a structural unit (A-1) derived from at least one monomer selected from the group consisting of acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacrylamide, N,N-diethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminopropylmethacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-(2-hydroxybutyl)acrylamide, and a structural unit (A-2) derived from acrylic acid, methacrylic acid, and and a structural unit (A) consisting solely of a structural unit (A-2) derived from at least one monomer selected from the group consisting of alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts of these, and a structural unit (B) derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate, or alternatively, the polymer is composed solely of the structural unit (A) and the structural unit (B). In one embodiment of the present invention, the copolymer according to the present invention is essentially composed of a structural unit (A) consisting only of a structural unit (A-1) derived from at least one monomer selected from the group consisting of acrylamide, N,N-dimethylacrylamide, and N,N-diethylacrylamide, and a structural unit (A-2) derived from at least one monomer selected from the group consisting of acrylic acid and alkali metal salts of acrylic acid, and a structural unit (B) derived from glycidyl acrylate or glycidyl methacrylate, or is composed only of the structural unit (A) and the structural unit (B).In one embodiment of the present invention, the copolymer according to the present invention is essentially composed of a structural unit (A) consisting only of a structural unit (A-1) derived from acrylamide or N,N-dimethylacrylamide and a structural unit (A-2) derived from at least one monomer selected from the group consisting of acrylic acid and alkali metal salts of acrylic acid, and a structural unit (B) derived from glycidyl acrylate or glycidyl methacrylate, or is composed only of the structural unit (A) and the structural unit (B).

[0063] The weight average molecular weight of the copolymer according to the present invention is preferably 10,000 to 10,000,000 from the viewpoint of solubility. The weight average molecular weight of the copolymer is more preferably 100,000 to 5,000,000 from the viewpoint of ease of preparation of a coating liquid. In this specification, the "weight average molecular weight" is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance.

[0064] The thickness (dry film thickness) of the lubricating layer is, for example, 0.1 to 10 μm, preferably 0.5 to 5 μm, and more preferably about 1 to 3 μm.

[0065] The method for producing the copolymer according to the present invention is not particularly limited, and known methods can be applied in the same manner or with appropriate modifications. For example, when the copolymer according to the present invention is a block copolymer of the structural unit (A) and the structural unit (B), it can be produced by applying a conventionally known polymerization method such as a living radical polymerization method, a polymerization method using a macroinitiator, or a polycondensation method. Among these, living radical polymerization methods or polymerization methods using a macroinitiator are preferably used because they allow for easy control of the molecular weight and molecular weight distribution of the structural units (portions) derived from hydrophobic monomers and the structural units (portions) derived from hydrophilic monomers. The living radical polymerization method is not particularly limited, and, for example, methods described in JP-A-11-263819, JP-A-2002-145971, JP-A-2006-316169, etc., as well as atom transfer radical polymerization (ATRP), etc., can be applied in the same manner or with appropriate modifications. Furthermore, in a polymerization method using a macroinitiator, for example, a macroinitiator having a hydrophobic monomer having an epoxy group and a radically polymerizable group such as a peroxide group is prepared, and then the macroinitiator, hydrophilic monomers (A-1) and (A-2), and, if necessary, other monomers are polymerized in a polymerization solvent, thereby producing a block copolymer having the structural unit (A) and the structural unit (B) (if necessary, structural units derived from other monomers).

[0066] In the above polymerization, the mixing ratio of the hydrophilic monomer (A-1), the hydrophilic monomer (A-2), and the hydrophobic monomer is preferably controlled so as to obtain the composition of each structural unit as described above. The polymerization solvent is appropriately selected from solvents in which each monomer can be dissolved. For example, water, dimethyl sulfoxide, chlorobenzene, tetrahydrofuran, etc. are used, with dimethyl sulfoxide and chlorobenzene being preferred from the viewpoint of monomer solubility. The above polymerization solvents may be used alone or as a mixture of two or more. In the above 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 24 hours, more preferably 3 to 15 hours. The polymerization is carried out in an inert atmosphere such as a nitrogen atmosphere or an argon atmosphere.

[0067] Furthermore, when producing the copolymer, 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 salt pH buffers), inorganic acids, inorganic acid salts, organic acids, organic acid salts, and other additives may be used as needed. After polymerization, the copolymer is preferably purified by a common purification method such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0068] The structural unit (A-2) is a structural unit derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group. A copolymer having a structural unit (A-2) derived from a hydrophilic monomer having a salt of a carboxy group may be obtained by substituting all or part of the structural units derived from the hydrophilic monomer having a carboxy group with structural units derived from a hydrophilic monomer having a salt of a carboxy group through alkali treatment. The alkali treatment can be carried out, for example, by mixing a solution containing a copolymer containing a hydrophilic structural unit (A-2) derived from a carboxy group (e.g., a copolymer containing a structural unit (A-2) derived from acrylic acid) with an aqueous solution containing a basic substance (e.g., sodium bicarbonate or calcium hydroxide). When forming a lubricating layer containing a copolymer having a structural unit (A-2) derived from a hydrophilic monomer having a salt of a carboxy group, the copolymer obtained as described above can be used to prepare a coating liquid for forming the lubricating layer.

[0069] When forming a lubricating layer containing a copolymer having a structural unit (A-2) derived from a hydrophilic monomer having a salt of a carboxy group, as described in WO 2015 / 029625, a lubricating precursor layer may be formed using a coating liquid containing a copolymer having a structural unit (A-2) derived from a hydrophilic monomer having a carboxy group, and then this lubricating precursor layer may be formed by treating the lubricating precursor layer with an aqueous solution containing a basic substance (for example, by immersing the lubricating precursor layer in an aqueous sodium bicarbonate solution).

[0070] The alkali treatment simply converts the carboxy groups in the structural unit (A-2) into salts of the carboxy groups, and therefore the treatment does not change the content (mol %) of the structural unit (A-2) relative to the total amount of the structural unit (A-1) and the structural unit (A-2), or the content (mol) of the structural unit (A) per mole of the structural unit (B).

[0071] (Other Components) The lubricating layer essentially contains the copolymer. In addition to the copolymer, the lubricating layer may contain other components. 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 anticancer drugs, immunosuppressants, antibiotics, antirheumatic drugs, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium channel blockers, antihyperlipidemic drugs, integrin inhibitors, antiallergic drugs, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid-improving drugs, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet drugs, vascular smooth muscle proliferation inhibitors, anti-inflammatory drugs, biomaterials, interferons, and NO production promoters (biologically active substances). The amount of the other components added is not particularly limited, and commonly used amounts are used in the same manner. Ultimately, the amount of the other components added is appropriately selected by the attending physician, taking into account the severity of the disease to be treated, the patient's weight, and the like. Preferably, the lubricating layer is substantially free of other components (i.e., the lubricating layer is substantially composed of the copolymer). Specifically, the content of other components is preferably less than 10% by mass (solid content equivalent) of the mass of the lubricating layer, more preferably less than 5% by mass (solid content equivalent), and it is particularly preferable that the lubricating layer is free of other components (i.e., the lubricating layer is composed of the copolymer).

[0072] <Method for manufacturing medical devices> The method for manufacturing medical devices according to the present invention is not particularly limited except for forming a lubricating layer using the copolymer described above and, if necessary, other components, and known methods can be used in the same way or with appropriate modifications. The method for manufacturing medical devices according to the present invention is preferably a method in which the copolymer according to the present invention and, if necessary, other components are added to and mixed with a solvent to prepare a solution containing the copolymer (also simply referred to as a "coating liquid" in this specification) ((I) coating liquid preparation step); this coating liquid is applied to a substrate layer to form a coating film on the substrate layer ((II) coating film formation step); and the coating film is heat-treated to form a lubricating layer on the substrate layer ((III) lubricating layer formation step).

[0073] A preferred embodiment of each step will be described below.

[0074] (I) Coating Solution Preparation Step In this step, a solution (coating solution) containing the copolymer, a solvent, and, if necessary, other components is prepared. The solvent used to prepare the coating solution is not particularly limited and is appropriately selected depending on the type of copolymer (and other components, if used). Specific examples of the solvent include water, alcohols such as methanol, ethanol, isopropanol, and ethylene glycol, ketones such as acetone, methyl ethyl ketone, and cyclohexanone, esters such as ethyl acetate, halides such as chloroform, alkanes such as hexane, ethers such as tetrahydrofuran and butyl ether, aromatics such as benzene and toluene, amides such as N,N-dimethylformamide, and sulfoxides such as dimethyl sulfoxide, but are not limited thereto. The above solvents may be used alone or in combination of two or more.

[0075] After the copolymer and, if necessary, other components have been added to the solvent, stirring may be carried out if necessary to promote dissolution or dispersion.

[0076] The concentration of the copolymer in the coating solution is not particularly limited. The concentration of the copolymer in the coating solution is, for example, 0.5% by mass or more and 50% by mass or less, and preferably 1% by mass or more and 10% by mass or less. If the concentration of the copolymer is within the above range, the resulting lubricating layer can fully exhibit the effects of the present invention. In addition, a lubricating layer of the desired thickness can be easily obtained with a single coating, and the viscosity of the solution is within an appropriate range, which is preferable in terms of operability (e.g., coatability of the coating solution) and production efficiency. However, even if the concentration is outside the above range, it can be fully used as long as it does not affect the effects of the present invention.

[0077] (II) Coating film forming step In this step, the coating liquid prepared in (I) above is applied onto a substrate layer to form a coating film on the substrate layer. Here, the substrate layer is the same as described above, so its description will be omitted here.

[0078] The method for applying (coating) the copolymer solution (coating liquid) to the surface of the substrate layer is not particularly limited, and any conventionally known method can be used, such as coating / printing, immersion (dipping, dip coating), spraying (spraying), spin coating, mixed solution-impregnated sponge coating, bar coating (e.g., wire bar method), die coating, reverse coating, comma coating, gravure coating, doctor knife method, etc. Of these, immersion (dipping, dip coating), spraying (spraying), and bar coating are preferably used.

[0079] When forming a coating film (hence, lubricating layer; the same applies hereinafter) on a thin and narrow inner surface of a catheter or the like, the substrate layer may be immersed in the coating liquid and the system may be depressurized to degas the solution. By depressurizing and degassing the solution, the solution can be quickly penetrated into the thin and narrow inner surface, facilitating the formation of the coating film. When forming a coating film only on a portion of the substrate layer, the substrate layer may be immersed only in the coating liquid and the coating liquid may be coated on that portion, thereby forming a coating film on the desired surface portion of the substrate layer.

[0080] If it is difficult to immerse only a portion of the substrate layer in the coating liquid, the surface portion of the substrate layer that does not require the formation of a coating film can be protected (coated, etc.) with a suitable removable (attachable) member or material, and then the substrate layer can be immersed in the coating liquid to coat the substrate layer with the coating liquid. After that, the protective member (material) on the surface portion of the substrate layer that does not require the formation of a lubricating layer can be removed, thereby forming a coating film on the desired surface portion of the substrate layer. However, the present invention is not limited to these formation methods, and conventionally known methods can be used as appropriate to form a coating film. For example, if it is difficult to immerse only a portion of the substrate layer in the coating liquid, other coating methods (e.g., methods of applying the coating liquid to a predetermined surface portion of a medical device using an application device such as a sprayer, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor knife) can be used instead of the immersion method. In addition, when the structure of a cylindrical medical device requires that both the outer and inner surfaces of the device have a lubricating layer, the immersion method (dipping method) is preferably used because it allows both the outer and inner surfaces to be coated at the same time.

[0081] The amount of coating liquid to be applied is preferably selected so that the thickness of the resulting lubricating layer (dry film thickness) falls within the above range.

[0082] Before applying the coating liquid, the surface of the substrate layer may be pre-treated by ultraviolet irradiation treatment, plasma treatment, corona discharge treatment, flame treatment, oxidation treatment, silane coupling treatment, phosphoric acid coupling treatment, surfactant treatment, etc. If the solvent of the coating liquid is only water, it is difficult to apply the coating liquid to the hydrophobic surface of the substrate layer. However, by subjecting the substrate layer surface to plasma treatment or surfactant treatment, the substrate layer surface becomes hydrophilic. This improves the wettability of the coating liquid to the substrate layer surface, allowing the formation of a uniform lubricating layer.

[0083] (III) Lubricating Layer Forming Step In this step, the coating film formed in (II) above is heat-treated to form a lubricating layer on the substrate layer. During the heat treatment, the epoxy groups present in the structural unit (B) interact with other structural units (B) in the copolymer or with structural units (B) in adjacent copolymers, forming intermolecular crosslinks. In addition to the above interaction, some of the epoxy groups present in the structural unit (B) are ring-opened by the heat treatment using a carboxy group (salt) in the copolymer or a carboxy group (salt) in an adjacent copolymer as a catalyst, forming chemical crosslinks with other epoxy groups or carboxy groups (salts). In addition, if the surface of the substrate layer has a functional group that can react with an epoxy group, the epoxy group present in the structural unit (B) can also form crosslinks with that functional group in the substrate layer.

[0084] The heat treatment conditions can be appropriately selected depending on the types of monomers constituting the copolymer (particularly the hydrophilic monomer (A-2) and the hydrophobic monomer). The heat treatment temperature is preferably 60°C or higher and 170°C or lower, more preferably 80°C or higher and 150°C or lower. The heat treatment time is preferably 10 minutes or higher and 24 hours or lower, more preferably 30 minutes or higher and 5 hours or lower. Under these conditions, aggregation of the structural units (B) is promoted during the heat treatment, and the carboxy groups of the structural units (A-2) function as catalysts to promote chemical crosslinking between epoxy groups and between carboxy groups and epoxy groups. The pressure conditions during the heat treatment are not particularly limited, and the heat treatment can be carried out under normal pressure (atmospheric pressure), or under increased pressure or reduced pressure. Examples of heat treatment means (apparatus) that can be used include ovens (heat treatment furnaces) and reduced-pressure heat treatment machines. The heat treatment step can be carried out once, or can be repeated multiple times using different heat treatment conditions.

[0085] As a result of the above, a lubricating layer is formed on the substrate layer. After the heat treatment step, the lubricating layer provided on the substrate layer may be washed.

[0086] The lubricating layer obtained by the above method can exhibit excellent lubricity and durability (lubrication maintenance and sliding durability) even under severe conditions. Therefore, medical devices equipped with such a lubricating layer can be applied to complex lesions.

[0087] [Uses of Medical Devices] The lubricating layer of the medical device according to the present invention has excellent lubricity and durability. The medical device according to the present invention is used in contact with body fluids, blood, etc., and the surface of the lubricating layer has lubricity in body fluids and aqueous liquids such as physiological saline, improving operability and reducing damage to tissue mucosa, while maintaining lubricity for a long period of time. Therefore, the medical device can be suitably used in catheters, stents, guidewires, etc. used in blood vessels. That is, in one embodiment of the present invention, the medical device is a catheter, stent, or guidewire. Other examples of the medical device include the following:

[0088] (a) Catheters inserted or left in the digestive tract via the mouth or nose, such as gastric catheters, nutritional catheters, and tube feeding tubes; (b) Catheters inserted or left in the airway or trachea via the mouth or nose, such as oxygen catheters, oxygen cannulas, endotracheal tube tubes and cuffs, tracheostomy tube tubes and cuffs, and endotracheal suction catheters; (c) Catheters inserted or left in the urethra or ureter, such as urethral catheters, urinary catheters, and urethral balloon catheter catheters and balloons; (d) Catheters inserted or left in various body cavities, organs, and tissues, such as suction catheters, drainage catheters, and rectal catheters; (e) Catheters inserted or left in blood vessels, such as indwelling needles, IVH catheters, thermodilution catheters, angiography catheters, vasodilator catheters, and dilators or introducers, or guide wires, stylets, etc. for these catheters; (f) artificial tracheas, artificial bronchi, etc. (g) Medical devices for extracorporeal circulation therapy (artificial lungs, artificial hearts, artificial kidneys, etc.) and their circuits.

[0089] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples, and examples obtained by appropriately combining the technical means disclosed in each example are also included in the scope of the present invention. In the following examples, unless otherwise specified, operations were performed at room temperature (25°C). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

[0090] Synthesis Example 1: Synthesis of Copolymer 1 29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50° C., and the mixture was then heated at 50° C. for 3 hours to remove the hydrochloric acid under reduced pressure. To the resulting oligoester (22.5 g), 4.5 g of methyl ethyl ketone was added, and the mixture was added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% aqueous hydrogen peroxide, 0.44 g of surfactant dioctyl phosphate, and 120 g of water, followed by a reaction at −5° C. for 20 minutes. The resulting product was repeatedly washed with water and methanol and then dried to obtain a polyperoxide (PPO) having multiple peroxide groups in the molecule. Subsequently, 0.5 g of this PPO was polymerized with 0.5 g of a polymerization initiator and 9.5 g of glycidyl methacrylate (GMA) as a hydrophobic monomer in benzene as a solvent at 65° C. for 2 hours with stirring under reduced pressure. The reaction product was reprecipitated with diethyl ether to obtain polyGMA having peroxide groups in the molecule (PPO-GMA).

[0091] Subsequently, 0.83 g of the obtained PPO-GMA (corresponding to 5.81 mmol of GMA) was used as a polymerization initiator to dissolve 6.33 g (63.88 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 0.42 g (5.81 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO = 1:1 (mass ratio)), and the solution was heated to 75°C for 3 hours under a nitrogen atmosphere to polymerize. The reaction product was reprecipitated with tert-butyl methyl ether and recovered to obtain Copolymer 1 consisting of DMAA, AA, and GMA. The DMAA:AA:GMA ratio of the obtained Copolymer 1 was １３Measurement by C-NMR revealed that the molar ratio of DMAA:AA:GMA was 11:1:1.

[0092] Synthesis Example 2: Synthesis of Copolymer 2 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0093] Subsequently, 0.71 g of the obtained PPO-GMA (corresponding to 4.98 mmol of GMA) was used as a polymerization initiator to dissolve 4.93 g (49.76 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 1.79 g (24.88 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75°C for 3 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 2. The DMAA:AA:GMA ratio of the obtained Copolymer 2 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 9:4:1.

[0094] Synthesis Example 3: Synthesis of Copolymer 3 Poly-GMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0095] Subsequently, 0.45 g of the obtained PPO-GMA (corresponding to 3.14 mmol of GMA) was used as a polymerization initiator to dissolve 6.22 g (62.73 mmol) of N,N-dimethylacrylamide (DMAA) and 0.45 g (6.27 mmol) of acrylic acid (AA) as hydrophilic monomers in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 3. The DMAA:AA:GMA ratio of the obtained Copolymer 3 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 20:2:1.

[0096] Synthesis Example 4: Synthesis of copolymer 4 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0097] Subsequently, 0.28 g of the obtained PPO-GMA (corresponding to 1.99 mmol of GMA) was used as a polymerization initiator to dissolve 5.92 g (59.71 mmol) of N,N-dimethylacrylamide (DMAA) and 0.72 g (9.95 mmol) of acrylic acid (AA) as hydrophilic monomers in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 4. The DMAA:AA:GMA ratio of the obtained Copolymer 4 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 29:5:1.

[0098] Synthesis Example 5: Synthesis of copolymer 5 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0099] Subsequently, 0.20 g of the obtained PPO-GMA (corresponding to 1.44 mmol of GMA) was used as a polymerization initiator to dissolve 6.41 g (64.68 mmol) of N,N-dimethylacrylamide (DMAA) and 0.21 g (2.87 mmol) of acrylic acid (AA) as hydrophilic monomers in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 5. The DMAA:AA:GMA ratio of the obtained Copolymer 5 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 44:2:1.

[0100] Synthesis Example 6: Synthesis of Copolymer 6 Poly-GMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0101] Subsequently, 0.20 g of the obtained PPO-GMA (corresponding to 1.37 mmol of GMA) was used as a polymerization initiator to dissolve 6.12 g (61.76 mmol) of N,N-dimethylacrylamide (DMAA) and 0.50 g (6.86 mmol) of acrylic acid (AA) as hydrophilic monomers in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 6. The DMAA:AA:GMA ratio of the obtained Copolymer 6 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 43:4:1.

[0102] Synthesis Example 7: Synthesis of copolymer 7 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0103] Subsequently, 0.18 g of the obtained PPO-GMA (corresponding to 1.28 mmol of GMA) was used as a polymerization initiator to dissolve 5.70 g (57.45 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 0.92 g (12.77 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 7. The DMAA:AA:GMA ratio of the obtained Copolymer 7 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 41:8:1.

[0104] Synthesis Example 8: Synthesis of copolymer 8 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0105] Subsequently, 0.15 g of the obtained PPO-GMA (corresponding to 1.05 mmol of GMA) was used as a polymerization initiator to dissolve 6.23 g (62.85 mmol) of N,N-dimethylacrylamide (DMAA) and 0.38 g (5.24 mmol) of acrylic acid (AA) as hydrophilic monomers in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 8. The DMAA:AA:GMA ratio of the obtained Copolymer 8 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 54:4:1.

[0106] Synthesis Example 9: Synthesis of copolymer 9 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0107] Subsequently, 0.12 g of the obtained PPO-GMA (corresponding to 0.85 mmol of GMA) was used as a polymerization initiator to dissolve 6.30 g (63.52 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 0.31 g (4.23 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 8 hours under a nitrogen atmosphere to polymerize, thereby obtaining Copolymer 9. The DMAA:AA:GMA ratio of the obtained Copolymer 9 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 70:4:1 (molar ratio).

[0108] Synthesis Example 10: Synthesis of Copolymer 10 Poly-GMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0109] Subsequently, 0.10 g of the obtained PPO-GMA (corresponding to 0.71 mmol of GMA) was used as a polymerization initiator to dissolve 6.34 g (63.97 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 0.26 g (3.55 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 8 hours under a nitrogen atmosphere to polymerize, thereby obtaining copolymer 10. The DMAA:AA:GMA ratio of the obtained copolymer 10 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 82:4:1 (molar ratio).

[0110] Synthesis Example 11: Synthesis of copolymer 11 Poly-GMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0111] Subsequently, 1.68 g of the obtained PPO-GMA (corresponding to 11.84 mmol of GMA) was used as a polymerization initiator to dissolve 5.87 g (59.19 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 0.85 g (11.84 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 5 hours under a nitrogen atmosphere to polymerize, thereby obtaining copolymer 11. The DMAA:AA:GMA ratio of the obtained copolymer 11 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 5:1:1 (molar ratio).

[0112] Synthesis Example 12: Synthesis of copolymer 12 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0113] Subsequently, 0.54 g of the obtained PPO-GMA (corresponding to 3.79 mmol of GMA) was used as a polymerization initiator, and 4.51 g (45.45 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer was dissolved in a chlorobenzene solvent, and the solution was heated to 80° C. for 7 hours under a nitrogen atmosphere to polymerize, thereby obtaining copolymer 12. The DMAA:GMA ratio of the obtained copolymer 12 was １Measurement by H-NMR revealed that the ratio (molar ratio) of DMAA to GMA was 12:1.

[0114] Synthesis Example 13: Synthesis of copolymer 13 Poly-GMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0115] Subsequently, 0.10 g of the obtained PPO-GMA (corresponding to 0.72 mmol of GMA) was used as a polymerization initiator to dissolve 6.44 g (64.98 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer and 0.16 g (2.17 mmol) of acrylic acid (AA) in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 8 hours under a nitrogen atmosphere to polymerize, thereby obtaining copolymer 13. The DMAA:AA:GMA ratio of the obtained copolymer 13 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 80:2:1.

[0116] Synthesis Example 14: Synthesis of copolymer 14 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0117] Subsequently, 0.09 g of the obtained PPO-GMA (corresponding to 0.64 mmol of GMA) was used as a polymerization initiator to dissolve 6.36 g (64.20 mmol) of N,N-dimethylacrylamide (DMAA) and 0.23 g (3.21 mmol) of acrylic acid (AA) as hydrophilic monomers in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 8 hours under a nitrogen atmosphere to polymerize, thereby obtaining copolymer 14. The DMAA:AA:GMA ratio of the obtained copolymer 14 was measured according to the same method as in Synthesis Example 1, and the DMAA:AA:GMA ratio (molar ratio) was found to be 87:4:1.

[0118] Synthesis Example 15: Synthesis of copolymer 15 PolyGMA (PPO-GMA) was obtained in the same manner as in Synthesis Example 1.

[0119] Subsequently, 0.91 g of the obtained PPO-GMA (corresponding to 6.38 mmol of GMA) was used as a polymerization initiator, and 3.80 g (38.30 mmol) of N,N-dimethylacrylamide (DMAA) and 2.76 g (38.30 mmol) of acrylic acid (AA) as hydrophilic monomers were dissolved in a mixed solvent of chlorobenzene and dimethyl sulfoxide (DMSO) (chlorobenzene:DMSO=1:1 (mass ratio)), and the solution was heated to 75° C. for 3 hours under a nitrogen atmosphere. After completion of the reaction, the polymerization solution turned yellow, and Copolymer 15 (DMAA:AA:GMA ratio (molar ratio)=6:6:1 (charge ratio)) was not obtained.

[0120] Reference Example 1 The gel fraction of copolymer 6 and copolymer 12 obtained in Synthesis Examples 6 and 12 was measured according to the following method. Note that gel fraction is an index of the degree of crosslinking (crosslink density) of a copolymer under specific conditions. In detail, gel fraction refers to the ratio of the weight of the insoluble portion obtained when the copolymer is reacted under specific conditions and then dissolved in a specific solvent, and the weight of this gel to the weight of the copolymer after the reaction before dissolution. That is, the gel fraction shown here indicates the ease of hardening of the copolymer when the copolymer is hardened under the same temperature conditions (130 ° C, 2 hours) (the crosslink density of the copolymer in the lubricating layer). For example, when the gel fraction is high, the hardening of the copolymer is easily progressed by heat treatment, suggesting that the durability of the lubricating layer is high.

[0121] [Measurement of gel fraction] (Preparation of cured film) Copolymer 6 or Copolymer 12 was added to dimethylformamide (DMF) and stirred for 1 hour to obtain a coating solution with a concentration of 8% by mass. Next, about 5 ml of this coating solution was uniformly spread on a PFA dish with a diameter of 75 mm, and then heated at 130°C for 2 hours to form a cured film on the dish.

[0122] (Measurement of Gel Fraction) The cured film obtained above was cut into 3 to 5 mm squares to prepare samples.

[0123] 50 mg of this sample was placed in a 50 ml sample tube, followed by the addition of 10 g of dimethylformamide (DMF). The sample tube was then heated on a hot plate at 100 °C for 1 hour. The heated contents were passed through a pleated metal mesh (#150, diameter 100 mm) to separate the solid components from the DMF. The mesh with the attached solid components was immersed in approximately 50 ml of acetone for 10 minutes, and the solvent was replaced from DMF to acetone. The mesh was then dried under reduced pressure at 130 °C for 3 hours. After drying, the metal mesh was weighed, and the difference between this and the mass of the metal mesh alone, which had been measured previously, was taken as the dried mass (mg) of the sample. The gel fraction (%) was calculated by dividing the dried mass (mg) of the sample by the initial mass (50 mg) [= (dried mass (mg) of the sample (mg) × 100) / initial mass (50 mg)].

[0124] The results are shown in Figure 1. The above measurement was performed three times (N=3) for each sample, and the average value is shown as the gel fraction in Figure 1. In addition to the gel fraction (white areas in Figure 1), Figure 1 also shows the sliding resistance values ​​(gf) at the 20th time (black areas in Figure 1) of Samples 6 and 12, measured as described below.

[0125] From FIG. 1, it can be seen that Copolymer 6 (DMAA:AA:GMA=43:4:1 (molar ratio)) (gel fraction=79.0%) exhibits a significantly higher gel fraction than Copolymer 12 (DMAA:GMA=12:1 (molar ratio)) (gel fraction=57.7%).

[0126] The ratio of the structural unit (B) to all structural units constituting copolymer 6 (ratio of GMA-derived structural units to all structural units constituting copolymer 6 = approximately 2.1 mol%) is lower than the ratio of the structural unit (B) to all structural units constituting copolymer 12 (ratio of GMA-derived structural units to all structural units constituting copolymer 12 = approximately 7.7 mol%). Therefore, in general, compared to copolymer 12, copolymer 6 has a smaller ratio of other structural units (B) present around the epoxy groups present in structural unit (B), which should result in a lower rate of intermolecular crosslinking and a lower gel fraction.

[0127] However, as shown in the results of Figure 1, Copolymer 6 exhibits a significantly higher gel fraction than Copolymer 12. From these results, it is presumed that the carboxy group (salt) (carboxy group present in acrylic acid) present in the structural unit (A-2) of the copolymer acts as a catalyst upon heat treatment, ring-opening the epoxy group present in the structural unit (B), and promoting chemical crosslinking between epoxy groups and between the epoxy group and the carboxy group (salt).

[0128] Therefore, by introducing the structural unit (A-2) having a carboxy group (salt), the copolymer according to the present invention can be expected to promote chemical crosslinking between epoxy groups and between epoxy groups and carboxy groups (salts), thereby improving the film strength (crosslink density) of the lubricating layer, and therefore further improving the sliding durability (lubrication maintenance) of the lubricating layer.

[0129] In addition to the above, the sliding resistance value (5.5 gf) at the 20th stroke of Sample 6, which has a lubricating layer containing Copolymer 6 having the structural unit (A-2), is significantly lower than the sliding resistance value (19.2 gf) at the 20th stroke of Sample 12, which has a lubricating layer containing Copolymer 12 not having the structural unit (A-2). That is, Sample 6 exhibits superior lubricity compared to Sample 12. Here, the sliding resistance value (19.2 gf) at the 20th stroke of Sample 12, which has a lubricating layer containing Copolymer 12, is also significantly higher than the sliding resistance value (13.1 gf) at the 20th stroke of Sample 1, which has a lubricating layer containing Copolymer 1. Therefore, it is presumed that one factor contributing to this improvement in lubricity is the presence in the copolymer of the structural unit (A-2), particularly the structural unit (A-2) having a carboxy group (salt) that does not form a chemical bond with the epoxy group, which further imparts hydrophilicity and water absorption to the lubricating layer. Therefore, it is expected that the lubricity of the copolymer according to the present invention can be further improved by introducing the structural unit (A-2) having a carboxy group (salt).

[0130] Example 1 0.5 g of copolymer 1 was added to 12.3 g of acetone, and then 6.19 g of a 0.52% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain coating liquid 1.

[0131] Next, the coating liquid 1 was dip-coated onto a 0.4 mm diameter tube substrate made of nylon 12 (Diamid L1940W, manufactured by Polypla Evonik Co., Ltd.) at a speed of 50 mm / sec, and then heat-treated at 120°C for 2 hours to obtain Sample 1, in which a lubricating layer (dry film thickness: approximately 1 μm) was formed on the tube substrate.

[0132] Example 2 0.5 g of copolymer 2 was added to 12.3 g of acetone, and then 6.29 g of a 2.02 mass % aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain coating liquid 2.

[0133] Sample 2, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 2 was used instead of Coating Liquid 1 in Example 1.

[0134] Example 3 0.5 g of Copolymer 3 was added to 12.3 g of acetone, and then 6.19 g of a 0.60% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 3.

[0135] Sample 3, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 3 was used instead of Coating Liquid 1 in Example 1.

[0136] Example 4 0.5 g of Copolymer 4 was added to 12.3 g of acetone, and then 6.22 g of a 1.00 mass % aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 4.

[0137] Sample 4, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 4 was used instead of Coating Liquid 1 in Example 1.

[0138] Example 5 0.5 g of Copolymer 5 was added to 12.3 g of acetone, and then 6.19 g of a 0.29% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 5.

[0139] Sample 5, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 5 was used instead of Coating Liquid 1 in Example 1.

[0140] Example 6 0.5 g of Copolymer 6 was added to 12.3 g of acetone, and then 6.20 g of a 0.58% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 6.

[0141] Sample 6, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 6 was used instead of Coating Liquid 1 in Example 1.

[0142] Example 7 0.5 g of Copolymer 7 was added to 12.3 g of acetone, and then 6.24 g of a 1.13 mass % aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 7.

[0143] Sample 7, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 7 was used instead of Coating Liquid 1 in Example 1.

[0144] Example 8 0.5 g of Copolymer 8 was added to 12.3 g of acetone, and then 6.18 g of a 0.47% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 8.

[0145] Sample 8, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 8 was used instead of Coating Liquid 1 in Example 1.

[0146] Example 9 0.5 g of Copolymer 9 was added to 12.3 g of acetone, and then 6.19 g of a 0.37% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain Coating Liquid 9.

[0147] Sample 9, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 9 was used instead of Coating Liquid 1 in Example 1.

[0148] Example 10 0.5 g of copolymer 10 was added to 12.3 g of acetone, and then 6.19 g of a 0.32 mass % aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain coating liquid 10.

[0149] Sample 10 having a lubricating layer formed on a tube substrate was obtained in the same manner as in Example 1, except that Coating Liquid 10 was used instead of Coating Liquid 1 in Example 1.

[0150] Comparative Example 1 0.5 g of copolymer 11 was added to 12.3 g of acetone, and then 6.23 g of a 0.95% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain coating liquid 11.

[0151] Sample 11, in which a lubricating layer was formed on a tube substrate, was obtained in the same manner as in Example 1, except that Coating Liquid 11 was used instead of Coating Liquid 1 in Example 1.

[0152] Comparative Example 2 Coating liquid 12 was obtained by dissolving 0.6 g of copolymer 12 in 19.4 g of dimethylformamide (DMF).

[0153] In Example 1, the coating liquid 12 was used instead of the coating liquid 1, and the heating temperature was changed to 130°C. In the same manner as in Example 1, a sample 12 having a lubricating layer formed on a tube substrate was obtained.

[0154] Comparative Example 3 0.5 g of copolymer 13 was added to 12.3 g of acetone, and then 6.16 g of a 0.17 mass % aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain coating liquid 13.

[0155] Sample 13 having a lubricating layer formed on a tube substrate was obtained in the same manner as in Example 1, except that Coating Liquid 13 was used instead of Coating Liquid 1 in Example 1.

[0156] Comparative Example 4 0.5 g of copolymer 14 was added to 12.3 g of acetone, and then 6.18 g of a 0.30% by mass aqueous solution of sodium hydrogen carbonate was added thereto, followed by stirring for 1 hour, to obtain coating liquid 14.

[0157] Sample 14 having a lubricating layer formed on a tube substrate was obtained in the same manner as in Example 1, except that coating liquid 14 was used instead of coating liquid 1 in Example 1.

[0158] The lubricity and sliding durability (lubrication maintenance ability) of Samples 1 to 14 obtained above were evaluated according to the following methods. The results are shown in Table 1. Note that for Copolymer 15 of Synthesis Example 15, a sample could not be prepared because Copolymer 15 could not be synthesized.

[0159] Table 1 below shows the ratio of N,N-dimethylacrylamide (structural unit (A-1)), acrylic acid (salt) (structural unit (A-2)), and glycidyl methacrylate (structural unit (B)) for each copolymer ("DMAA:AA:GMA (molar ratio)" in Table 1 below), the total composition of N,N-dimethylacrylamide and acrylic acid (salt) and the ratio of glycidyl methacrylate ("(DMAA+AA):GMA (molar ratio)" in Table 1 below), and the ratio of acrylic acid (salt) to the total composition of N,N-dimethylacrylamide and acrylic acid (salt) ("AA / (DMAA+AA) (mol %)" in Table 1 below). In Table 1 below, for Comparative Example 5 (copolymer 15), no copolymer was obtained, so the charge ratio at the time of polymerization is shown.

[0160] [Evaluation of Sliding Resistance Value] The sliding resistance value of the lubricating layer of each sample was measured using an Oakriver sliding tester (DL1000, manufactured by OAKRIVER TECHNOLOGY A PaR Systems Company) according to the following procedure.

[0161] The container was filled with RO water, and each sample was fixed so that the measurement point was immersed. After immersing the sample for 1 minute, the sample was clamped with a silicone terminal (13 mm x 32 mm) under a load of 500 gf and set. While applying a grip force of 500 gf to the silicone terminal, the sample was moved vertically at a sliding distance of 50 mm and a sliding speed of 20 mm / sec, repeatedly sliding the same point of the sample 20 times. The sliding resistance (gf) was measured when the sample was pulled up vertically for the 5th, 10th, and 20th times. Note that before measuring the sliding resistance, a core was inserted into the inner cavity of the sample (tube substrate).

[0162] In this evaluation test, from the viewpoint of the lubricity (slidability) of the lubricating layer, a sliding resistance value of 15 gf or less at the 20th time is acceptable, preferably 14 gf or less, more preferably 10.0 gf or less, and particularly preferably less than 10.0 gf. Also, from the viewpoint of the sliding durability (lubrication maintenance) of the lubricating layer, a difference between the sliding resistance value at the 20th time and the sliding resistance value at the 5th time (= sliding resistance value at the 20th time - sliding resistance value at the 5th time) ("difference" in Table 1 below) of less than 6.0 gf is acceptable, preferably less than 2.0 gf, more preferably less than 1.0 gf, even more preferably 0.4 gf or less, and particularly preferably less than 0.4 gf.

[0163]

[0164] From the results in Table 1, it can be seen that the sliding resistance values ​​at the 20th time in the [Evaluation of Sliding Resistance Value] of Samples 1 to 10 of the Examples are significantly lower and have excellent lubricity (slidability) compared to the Comparative Examples, Samples 11 to 14. In particular, Samples 2 and 4 to 9 have sliding resistance values ​​at the 20th time in the [Evaluation of Sliding Resistance Value] of less than 10.0 gf, and therefore have particularly excellent lubricity (slidability).

[0165] Furthermore, in Samples 1 to 8, the difference between the sliding resistance value at the 20th time and the sliding resistance value at the 5th time in the [Evaluation of Sliding Resistance Value] was less than 1.0 gf, indicating that they had better sliding durability (lubrication maintenance ability) than Samples 9 to 10, in which the difference was 1.0 gf or more. In particular, Samples 1, 3-4, and 6-8 did not show an increase in sliding resistance value between the sliding resistance value at the 5th time and the sliding resistance value at the 20th time in the [Evaluation of Sliding Resistance Value], indicating that they had even better sliding durability (lubrication maintenance ability). From these findings, it is believed that by setting the total composition of DMAA and AA (structural unit (A)) to 60 moles or less per mole of GMA (structural unit (B)) and setting the ratio of acrylic acid (salt) (structural unit (A-2)) in the structural unit (A) (AA / (DMAA+AA)) to 6.5 mol% or more and 20.0 mol% or less, a better balance of lubricity and sliding durability can be achieved.

[0166] Furthermore, Sample 1 of Example 1 and Sample 12 of Comparative Example 2 have the same ratio of structural units derived from hydrophilic monomers (DMAA and AA, or DMAA only) to structural units derived from hydrophobic monomers (GMA). On the other hand, Sample 1 has significantly lower sliding resistance values ​​(significantly superior lubricity) at the 5th, 10th, and 20th times in the [Evaluation of Sliding Resistance Value] test compared to Sample 12. This is thought to be due to the fact that Copolymer 1 further contains structural units derived from acrylic acid (salt).

[0167] Furthermore, it can be seen that Sample 1 of Example 1 has significantly lower sliding resistance values ​​(significantly superior lubricity) at the 5th, 10th, and 20th times in the [Evaluation of Sliding Resistance Value] comparison with Sample 11 of Comparative Example 1. This is thought to be because Copolymer 1 has 10 or more moles of the total composition (structural unit (A)) of DMAA and AA per mole of GMA (structural unit (B)), and therefore the proportion of structural units derived from hydrophilic monomers (DMAA and AA, or DMAA only) in Copolymer 1 is high, thereby exhibiting excellent lubricity.

[0168] Sample 13 of Comparative Example 3 has 82 moles of structural units derived from hydrophilic monomers (DMAA and AA) per mole of structural units derived from hydrophobic monomers (GMA). Therefore, Sample 13 has a sliding resistance value of less than 10 gf at the fifth time in the [Evaluation of Sliding Resistance Value], and is therefore excellent in lubricity (smoothness). On the other hand, Sample 13 has a significant increase in sliding resistance between the fifth and tenth times in the [Evaluation of Sliding Resistance Value], and therefore has low sliding durability (lubrication maintenance). From this, it is considered that Sample 13 has a ratio (AA / (DMAA+AA)) of acrylic acid (salt) (structural unit (A-2)) in the structural unit (A) of less than 3 mol%, and therefore the film strength of the lubricating layer was not sufficiently improved, and the sliding durability of the lubricating layer was not sufficiently increased.

[0169] In Sample 14 of Comparative Example 4, the ratio of hydrophilic monomer (DMAA and AA)-derived structural units to hydrophobic monomer (GMA)-derived structural units was 91 moles, meaning that the ratio of hydrophilic monomer (DMAA and AA)-derived structural units to hydrophobic monomer (GMA)-derived structural units was very high. In Sample 14, the ratio (AA / (DMAA+AA)) of acrylic acid (salt) (structural unit (A-2)) in structural unit (A) was 3 mol% or more, but the sliding resistance value significantly increased between the 5th and 10th sliding resistance values ​​in the [Evaluation of Sliding Resistance Value], indicating low sliding durability (lubrication maintenance). From this, it is considered that Sample 14 had more than 90 moles of hydrophilic monomer (DMAA and AA)-derived structural units to 1 mole of hydrophobic monomer (GMA)-derived structural units, which resulted in insufficient improvement in the film strength of the lubricating layer and insufficient improvement in the sliding durability of the lubricating layer.

[0170] Here, Sample 10 of Example 10 has significantly lower sliding resistance values ​​at the 20th time and the difference between the sliding resistance value at the 20th time and the sliding resistance value at the 5th time in the [Evaluation of Sliding Resistance Values] (excellent lubricity and sliding durability) compared to Sample 13 of Comparative Example 3. Sample 10 has 86 moles of structural units derived from hydrophilic monomers (DMAA and AA) per mole of structural units derived from the hydrophobic monomer (GMA), and the ratio (AA / (DMAA+AA)) of acrylic acid (salt) (structural unit (A-2)) in structural unit (A) is 3% or more. For this reason, it is believed that the lubricity and sliding durability of the lubricating layer can be improved by setting the copolymer to have 90 moles or less of structural units derived from hydrophilic monomers (DMAA and AA) per mole of structural units derived from hydrophobic monomers (GMA) and by setting the ratio of acrylic acid (salt) (structural unit (A-2)) in structural unit (A) (AA / (DMAA+AA)) to 3 mol% or more.

[0171] Furthermore, compared to Sample 12 of Comparative Example 2, Sample 2 of Example 2 had a significantly lower sliding resistance value at the 20th time in the [Evaluation of Sliding Resistance Value] (excellent lubricity). Furthermore, Sample 2 also had a small difference between the sliding resistance value at the 20th time and the sliding resistance value at the 5th time, demonstrating sufficient sliding durability. Sample 2 contained 13 moles of structural units derived from hydrophilic monomers (DMAA and AA) per mole of structural units derived from the hydrophobic monomer (GMA), and the ratio of acrylic acid (salt) (structural unit (A-2)) in the structural unit (A) (AA / (DMAA+AA)) was 30.8 mol%. For this reason, taking into consideration the contents of Comparative Example 5, it is believed that the lubricity and sliding durability of the lubricating layer can be sufficiently improved by setting the copolymer to 90 moles or less of structural units derived from hydrophilic monomers (DMAA and AA) per mole of structural units derived from hydrophobic monomers (GMA) and setting the ratio of acrylic acid (salt) (structural unit (A-2)) in structural unit (A) (AA / (DMAA+AA)) to 40 mole % or less.

[0172] This application is based on Japanese Patent Application No. 2024-52931, filed on March 28, 2024, the disclosure of which is incorporated by reference in its entirety.

Claims

1. A medical device comprising a base layer and a lubricating layer formed on at least a portion of the base layer, wherein the lubricating layer comprises a copolymer having a structural unit (A) containing a structural unit (A-1) derived from a hydrophilic monomer having an acrylamide group or a methacrylamide group and a structural unit (A-2) derived from a hydrophilic monomer having at least one of a carboxy group and a salt of a carboxy group, and a structural unit (B) derived from a hydrophobic monomer having an epoxy group, wherein the content of the structural unit (A) is 10 to 90 moles per mole of the structural unit (B), and the content of the structural unit (A-2) is 3 to 40 mole% of the total amount of the structural unit (A-1) and the structural unit (A-2).

2. The medical device according to claim 1, wherein the content of said structural unit (A) is 25 moles or more and 70 moles or less per mole of said structural unit (B).

3. The medical device according to claim 1, wherein the content of the structural unit (A-2) is from 6 mol % to 30 mol % relative to the total amount of the structural unit (A-1) and the structural unit (A-2).

4. The medical device according to claim 1, wherein the structural unit (A-1) is a structural unit derived from at least one monomer selected from the group consisting of acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacrylamide, N,N-diethylacrylamide, N,N-dimethylaminopropylacrylamide, N,N-dimethylaminopropylmethacrylamide, 2-acrylamido-2-methylpropanesulfonic acid, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-(2-hydroxybutyl)acrylamide.

5. The medical device according to claim 1, wherein the structural unit (A-2) is a structural unit derived from at least one monomer selected from the group consisting of acrylic acid, methacrylic acid, and alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts thereof.

6. The medical device according to claim 1, wherein the structural unit (B) is a structural unit derived from at least one monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl acrylate, and β-methylglycidyl methacrylate.

7. The medical device according to claim 1, wherein the structural unit (A) is configured so that the structural units (A-1) and (A-2) are randomly arranged.

8. The medical device according to claim 1, wherein the structural units (B) are configured to be arranged in a block shape.

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

10. The medical device of claim 1, wherein the medical device is a catheter, a stent, or a guidewire.

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