Method for manufacturing medical instrument, and medical instrument

Abstract

Provided is a medical instrument having a coating layer (surface lubricating layer) having excellent lubricity (slidability) and durability (in particular, sliding durability).　A method for manufacturing a medical instrument according to the present invention is a method for manufacturing a medical instrument including a substrate layer and a surface lubricating layer supported on at least a portion of the substrate layer, the method comprising: preparing a coating liquid that contains a block copolymer having a reactive monomer-derived constitutional unit (A) having an epoxy group and a hydrophilic monomer-derived constitutional unit (B), a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent; and bringing the coating liquid into contact with the substrate layer.

Description

Method for manufacturing medical device and medical device

[0001] The present invention relates to a method for manufacturing a medical device and a medical device.

[0002] Medical devices (medical devices) inserted into the body such as catheters, guidewires, and indwelling needles are required to exhibit excellent lubricity in order to reduce tissue damage such as blood vessels and improve the operability of the operator. For this reason, a method of coating a hydrophilic polymer having lubricity on the surface of the base material layer has been developed and put into practical use. In such a medical device, the elution and peeling of the hydrophilic polymer from the surface of the base material layer is a problem in terms of maintaining safety and operability. Therefore, the coating with the hydrophilic polymer requires not only excellent lubricity but also durability against loads such as wear and rubbing.

[0003] From such a viewpoint, Japanese Patent Application Laid-Open No. 8-33704 (corresponding to US Patent No. 5670558) discloses a method of dissolving a water-soluble or water-swellable polymer in a solvent in which the base material of the medical device swells to prepare a polymer solution, immersing the base material of the medical device in this polymer solution to swell it, and further crosslinking or polymerizing this polymer on the surface of the base material to form a surface lubricating layer on the surface of the base material. According to the technique disclosed in the above document, a surface lubricating layer showing relatively good lubricity can be fixed to the base material.

[0004] The above document discloses that it is preferable to use a block copolymer composed of a hydrophilic moiety that exhibits lubricity and a moiety 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 a heating operation, and a surface lubricating layer that is relatively difficult to peel off can be formed.

[0005] However, good lubricity and excellent durability are in a trade-off relationship, and a technique that achieves both good lubricity and excellent durability is required.

[0006] The present invention has been made in view of the above circumstances, and aims to provide a medical device having a coating layer (surface lubrication layer) that is excellent in lubricity (sliding properties) and durability (especially sliding durability).

[0007] The inventors diligently conducted research to solve the above problems. As a result, they discovered that the above objectives could be achieved by forming a surface lubricating layer using a coating solution containing a hydrophilic block copolymer having epoxy groups, a water-soluble chlorine-containing compound, and a solvent, and thus completed the present invention.

[0008] The above objective can be achieved by the present invention having the following configuration, and the present invention encompasses the following aspects and forms.

[0009] One aspect of the present invention is: 1. A method for manufacturing a medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, comprising: preparing a coating solution containing a block copolymer having a reactive monomer having an epoxy group (A) and a hydrophilic monomer having a hydrophilic monomer (B), a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent; and contacting the coating solution onto the base layer; 2. In the method for manufacturing a medical device according to 1. above, it is preferable that the molecular weight of the chlorine-containing compound is 150 to 600; 3. In the method for manufacturing a medical device according to 1. or 2. above, it is preferable that the chlorine-containing compound is a chlorine derivative of a disaccharide; 4. In the method for manufacturing a medical device according to any of 1. to 3. above, it is preferable that the chlorine-containing compound is sucralose; 5. In the method for producing a medical device described in any of the above, the solvent preferably contains at least one selected from the group consisting of acetone, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, chloroform, dichloromethane, dioxane, benzene, methanol, ethanol, isopropyl alcohol, and butanol; 6. In the method for producing a medical device described in any of the above 1 to 5, the coating solution preferably contains 5 to 150 parts by mass of the chlorine-containing compound per 100 parts by mass of the block copolymer; 7. In the method for producing a medical device described in any of the above 1 to 6, the coating solution preferably contains the chlorine-containing compound in an amount of 0.1 to 20% by mass; 8. In the method for producing a medical device described in any of the above 1 to 6, In the method for manufacturing a medical device as described in any of the above, it is preferable that the reactive monomer having the epoxy group comprises at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allylglycidyl ether;9. In the method for manufacturing a medical device described in any of items 1 to 8 above, it is preferable that the hydrophilic monomer includes at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

[0010] Another aspect of the present invention is: 10. A medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer comprises a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and a chlorine-containing compound having a chlorine atom and being water-soluble; 11. In the medical device described in 10. above, it is preferable that the molecular weight of the chlorine-containing compound is 150 to 600; 12. In the medical device described in 10. or 11. above, it is preferable that the chlorine-containing compound is a chlorine derivative of a disaccharide; 13. In the medical device described in any of 10. to 12. above, it is preferable that the chlorine-containing compound is sucralose; 14. In 10. to 13. above In the medical device described in any of the above, the reactive monomer having the epoxy group preferably comprises at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether; 15. In the medical device described in any of the above 10 to 14, the hydrophilic monomer preferably comprises at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone; 16. The medical device described in any of the above 10 to 15 is preferably a catheter, a guidewire, or an indwelling needle.

[0011] This is a partial cross-sectional view of a catheter as a typical embodiment of the medical device according to the present invention. This is a partial cross-sectional view schematically showing an example of a different surface lamination configuration as an application example of the embodiment in Figure 1. This is a schematic diagram showing a test apparatus for performing a sliding test of the medical device according to this embodiment, showing the medical device being sandwiched between a pair of contact members. This is a schematic diagram showing a test apparatus for performing a sliding test of the medical device according to this embodiment, showing the medical device separated from a pair of contact members. This is a graph showing the durability evaluation results (sliding resistance value at the 50th test - sliding resistance value at the 5th test (increase)) for each sample in Examples 2 and 4-6 and Comparative Example 2.

[0012] A method for manufacturing a medical device according to one aspect of the present invention is a method for manufacturing a medical device comprising a base layer and a surface lubricating layer supported on at least a part of the base layer, comprising preparing a coating liquid containing a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent, and bringing the coating liquid into contact with the base layer. The method for manufacturing a medical device having the above configuration will hereinafter also be referred to as "the manufacturing method according to the present invention" or "the manufacturing method".

[0013] In this specification, a constituent unit (A) derived from a reactive monomer having an epoxy group is also referred to simply as "constituent unit (A) according to the present invention" or "constituent unit (A)". In this specification, a constituent unit (B) derived from a hydrophilic monomer is also referred to simply as "constituent unit (B) according to the present invention" or "constituent unit (B)". In this specification, a block copolymer having constituent units (A) and (B) is also referred to simply as "block copolymer according to the present invention" or "block copolymer". In this specification, a chlorine-containing compound having a chlorine atom and being water-soluble is also referred to simply as "chlorine-containing compound according to the present invention" or "chlorine-containing compound".

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

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

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

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

[0018] The present invention relates to a method for manufacturing a medical device, which involves preparing a coating solution containing a block copolymer having a reactive monomer (A) having an epoxy group and a constituent unit (B) having a hydrophilic monomer, a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent, and then bringing the coating solution into contact with a substrate layer. The coating layer (surface lubrication layer) formed by such a manufacturing method has excellent lubricity (sliding properties) and durability (especially sliding durability).

[0019] The manufacturing method according to the present invention is characterized by forming a surface lubricating layer using a chlorine-containing compound that has chlorine atoms and is water-soluble, in addition to a block copolymer having epoxy groups. The chlorine-containing compound according to the present invention is electron-withdrawing due to the chlorine atoms. Therefore, when the chlorine-containing compound comes into contact with the block copolymer, electrons are stripped from the epoxy groups (crosslinkable groups), the bonds are broken, and the epoxy groups become more easily ring-opened. When the epoxy groups open, crosslinking (bonding) between the block copolymers progresses, and the film strength of the surface lubricating layer increases. As a result, it is presumed that the medical device obtained by the manufacturing method according to the present invention will have higher flexibility and be able to maintain its strong coating layer well even after sliding in biological lumens such as narrow blood vessels, and will have excellent sliding durability.

[0020] Furthermore, the chlorine-containing compound according to the present invention is water-soluble and therefore has excellent water retention properties. Here, the sliding properties of the surface lubricating layer depend on the amount of water incorporated into it (i.e., water retention). Specifically, when the amount of water incorporated into the surface lubricating layer is large (i.e., the swelling rate is high), the sliding properties are good. In addition to the block copolymer making it easy to retain water, the chlorine-containing compound further enhances water retention in the surface lubricating layer according to the present invention. As a result, a surface lubricating layer formed using a coating solution that further contains the chlorine-containing compound according to the present invention in addition to the block copolymer exhibits superior sliding properties compared to a surface lubricating layer formed by the block copolymer alone.

[0021] Therefore, medical devices manufactured according to the manufacturing method of the present invention have excellent durability (surface lubrication retention and sliding durability) as well as excellent lubricity. Thus, the present invention provides a medical device having a coating layer (surface lubrication layer) with excellent lubricity (sliding properties) and durability (especially sliding durability). Note that the above mechanism is speculative and does not limit the technical scope of the present invention.

[0022] Embodiments of the present invention will be described below. However, the present invention is not limited to the embodiments described below, and can be modified in various ways within the scope of the claims. Furthermore, the embodiments described herein can be combined in any way to form other embodiments. The dimensional ratios in the drawings are exaggerated for illustrative purposes and may differ from actual ratios. Also, when describing embodiments of the present invention with reference to the drawings, the same elements are denoted by the same reference numerals in the description of the drawings, and redundant explanations are omitted.

[0023] Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0024] [Method for Manufacturing Medical Devices] The method for manufacturing medical devices according to the present invention includes preparing a coating solution containing a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent ((I) coating solution preparation step); and bringing the coating solution into contact with a substrate layer ((II) contact step). By using a solution containing a chlorine-containing compound together with the block copolymer as a coating solution, a medical device can be obtained having a coating layer (surface lubrication layer) with excellent lubricity (sliding properties) and durability (especially sliding durability).

[0025] After step (II) above, further steps such as a solvent removal step ((III) solvent removal step) and a washing step ((IV) washing step) may be performed as needed. Of these, it is preferable to perform at least a (III) solvent removal step (preferably a drying / heat treatment step) after step (II) above. In the method of the present invention, the chlorine-containing compound is stably maintained in the surface lubrication layer. Furthermore, the epoxy group of the block copolymer opens its ring without the need to add an acid or base. For this reason, in the method of the present invention, it is not particularly necessary to perform the (IV) washing step, which is advantageous for mass production.

[0026] (I) Coating Solution Preparation Step In this step, a coating solution containing a block copolymer, a chlorine-containing compound, and a solvent is prepared. Here, in this step, the coating solution may be prepared by mixing the block copolymer, the chlorine-containing compound, and the solvent. Alternatively, a coating solution containing a block copolymer, a chlorine-containing compound, and a solvent may be purchased and used.

[0027] In the following, preferred embodiments for preparing the coating solution by mixing a block copolymer, a chlorine-containing compound, and a solvent will be described in detail.

[0028] (Block Copolymer) The block copolymer according to the present invention has a constituent unit (A) derived from a reactive monomer having an epoxy group and a constituent unit (B) derived from a hydrophilic monomer.

[0029] In the present invention, the block copolymer forms a surface lubricating layer supported on at least a portion of the substrate layer. That is, in the medical device according to the present invention, the surface lubricating layer includes the block copolymer. "Supported" means a state in which the surface lubricating layer is fixed in a state in which it does not easily detach from the surface of the substrate layer, and includes not only a form in which the entire surface of the substrate layer is completely covered by the surface lubricating layer, but also a form in which only a portion of the surface of the substrate layer is covered by the surface lubricating layer, that is, a form in which the surface lubricating layer is attached only to a portion of the surface of the substrate layer.

[0030] Reactive monomers having epoxy groups that constitute block copolymers possess epoxy groups as reactive groups. By introducing such reactive monomer-derived constituent units (A) into the block copolymer, the epoxy groups open their rings, promoting crosslinking (bonding) between block copolymers and increasing the film strength of the surface lubrication layer. Furthermore, if the substrate layer is a resin material, crosslinking (bonding) between the block copolymer and the substrate layer may also occur due to the reaction between the ring-opened epoxy groups and the reactive groups on the surface of the resin material (e.g., amino groups, carboxyl groups, etc.).

[0031] The reactive monomers constituting the block copolymer are not particularly limited as long as they have an epoxy group, and known compounds can be used. In particular, because it is easier to control the crosslinking or polymerization of the block copolymer, it is preferable that the reactive monomer having an epoxy group contains at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate (GMA), 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allylglycidyl ether.

[0032] In particular, considering factors such as the ability to further promote the crosslinking reaction and ease of manufacture, glycidyl (meth)acrylate is more preferred, and glycidyl methacrylate is especially preferred. That is, in a more preferred embodiment of the present invention, the reactive monomer having an epoxy group is at least one of glycidyl acrylate and glycidyl methacrylate. Furthermore, in a particularly preferred embodiment of the present invention, the reactive monomer having an epoxy group is glycidyl methacrylate.

[0033] The above-mentioned reactive monomers may be used individually or in combination of two or more. That is, the reactive site derived from the reactive monomer may be a homopolymer composed of a single reactive monomer, or a copolymer composed of two or more of the above-mentioned reactive monomers. When two or more are used, the form of the constituent unit (A) may be a block copolymer (block-like) or a random copolymer (random-like).

[0034] The hydrophilic monomers constituting the block copolymer swell upon contact with bodily fluids (e.g., blood, urine) or aqueous solvents, thus imparting lubricity (surface lubricity) to the medical device. Therefore, by introducing such hydrophilic monomer-derived constituent units (B) into the block copolymer, the lubricity (surface lubricity) of the medical device can be improved, and friction when the medical device comes into contact with the lumen walls of blood vessels or other tubular structures can be reduced.

[0035] The hydrophilic monomers constituting the block copolymer are not particularly limited as long as they possess the above-mentioned properties, and known compounds can be used. Examples include acrylamide and its derivatives, vinylpyrrolidone, acrylic acid and methacrylic acid and their derivatives, polyethylene glycol acrylate and its derivatives, monomers having sugars or phospholipids in their side chains, and water-soluble monomers such as maleic anhydride. More specifically, acrylic acid, methacrylic acid, N-methylacrylamide, N,N-dimethylacrylamide (DMAA), acrylamide, acryloylmorpholine, N,N-dimethylaminoethyl acrylate, N-vinylpyrrolidone, 2-methacryloyloxyethyl phosphorylcholine, 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, vinyl methyl ether, 2-hydroxyethyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, 1,4-cyclohexanedimethanol mono(meth)acrylate, 1-chloro-2-hydroxypropyl (meth) Examples include acrylates, diethylene glycol mono(meth)acrylate, 1,6-hexanediol mono(meth)acrylate, pentaerythritol tri(meth)acrylate, dipentaerythritol penta(meth)acrylate, neopentyl glycol mono(meth)acrylate, trimethylolpropanedi(meth)acrylate, trimethylolethanedi(meth)acrylate, 2-hydroxy-3-phenyloxypropyl(meth)acrylate, 4-hydroxycyclohexyl(meth)acrylate, 2-hydroxy-3-phenyloxy(meth)acrylate, cyclohexanedimethanol mono(meth)acrylate, poly(ethylene glycol) methyl ether acrylate, and poly(ethylene glycol) methyl ether methacrylate. From the viewpoint of providing excellent lubricity, ease of synthesis, and operability, it is preferable that the hydrophilic monomer includes at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

[0036] In particular, considering the imparting of excellent lubricity, ease of synthesis, and ease of handling, N,N-dimethylacrylamide, acrylamide, or 2-hydroxyethyl methacrylate are more preferred, and N,N-dimethylacrylamide is particularly preferred. That is, in a more preferred embodiment of the present invention, the hydrophilic monomer is at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate. Furthermore, in a particularly preferred embodiment of the present invention, the hydrophilic monomer is N,N-dimethylacrylamide.

[0037] The hydrophilic monomers described above may be used individually or in combination of two or more. That is, the hydrophilic moiety derived from the hydrophilic monomer may be a homopolymer composed of a single hydrophilic monomer, or a copolymer composed of two or more of the hydrophilic monomers. When two or more types are used, the hydrophilic moiety may be in the form of a block copolymer (block-like) or a random copolymer (random-like).

[0038] The block copolymer has a constituent unit (A) derived from the reactive monomer and a constituent unit (B) derived from the hydrophilic monomer. Here, the ratio of constituent unit (A) to constituent unit (B) is not particularly limited as long as the above effects are achieved. Considering good lubricity, lubricity retention, strength of the coating layer, and bonding with the substrate layer, the ratio of constituent unit (A) to constituent unit (B) (molar ratio of constituent unit (A):constituent unit (B)) is preferably 1:2 to 1:100, more preferably 1:2 to 1:50, even more preferably 1:5 to 1:50, and particularly preferably 1:10 to 1:30. Within this range, the surface lubrication layer can exhibit sufficient lubricity due to constituent unit (B), and sufficient coating layer strength, bonding with the substrate layer (in the case of a resin material), and durability due to constituent unit (A). The molar ratio of the above constituent unit (A) to constituent unit (B) can be controlled by adjusting the charging ratio (molar ratio) of each monomer during the production of the block copolymer. Therefore, the charging ratio (molar ratio) of the reactive monomer having an epoxy group and the hydrophilic monomer during the production of the block copolymer is preferably 1:2 to 1:100, more preferably 1:2 to 1:50, even more preferably 1:5 to 1:50, and particularly preferably 1:10 to 1:30.

[0039] The block copolymer according to the present invention essentially contains structural unit (A) and structural unit (B), but may also have other structural units in addition to these structural units. When the block copolymer has other structural units, examples of other structural units include adipic acid, glutaric acid, triethylene glycol, and tripropylene glycol. The monomers constituting the other structural units may be used individually or in combination of two or more. That is, the other structural units may be a homopolymer type composed of a single structural unit, or a copolymer type composed of two or more structural units. When two or more monomers constituting the above-mentioned other structural units are used, the segments composed of these monomers may be in the form of a block copolymer, a random copolymer, or an alternating copolymer.

[0040] When the block copolymer according to the present invention has other constituent units, the content of the other constituent units is preferably greater than 0 mol% and less than or equal to 5 mol% of the total constituent units constituting the block copolymer. That is, in the block copolymer according to the present invention, when the total of all constituent units constituting the block copolymer is taken as 100 mol%, the sum of the content of constituent unit (A) and constituent unit (B) is preferably 95 mol% or more (upper limit: less than 100 mol%). More preferably, the block copolymer according to the present invention is substantially composed of constituent unit (A) and constituent unit (B) (content of other constituent units = greater than 0 mol% and less than 5 mol%). In this form, the block copolymer according to the present invention can achieve a good balance between durability due to constituent unit (A) and lubricity (surface lubricity) due to constituent unit (B). Preferably, the block copolymer according to the present invention does not contain the above-mentioned other constituent units (content of other constituent units = 0 mol%).

[0041] The composition of each constituent unit (constituent units (A) and (B), other constituent units) in the block copolymer is determined by known methods, for example, NMR measurement of the copolymer. １ H-NMR measurement, １３ It can be measured by performing a 1C-NMR measurement, etc. Specifically, the block copolymer solution １ By measuring the integral ratio of the intensities of each signal in the H-NMR spectrum, the composition (molar ratio) of the constituent units can be determined.

[0042] In one embodiment of the present invention, the block copolymer according to the present invention is substantially composed of a constituent unit (A) derived from at least one reactive monomer selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allyl glycidyl ether, and a constituent unit (B) derived from at least one hydrophilic monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone, or is composed solely of the constituent unit (A) and the constituent unit (B).

[0043] In one embodiment of the present invention, the block copolymer according to the present invention is substantially composed of a structural unit (A) derived from at least one reactive monomer of glycidyl acrylate and glycidyl methacrylate, and a structural unit (B) derived from at least one hydrophilic monomer selected from the group consisting of N,N-dimethylacrylamide, acrylamide, and 2-hydroxyethyl methacrylate, or is composed only of the above structural unit (A) and the above structural unit (B).

[0044] In one embodiment of the present invention, the block copolymer according to the present invention is substantially composed of a structural unit (A) derived from glycidyl methacrylate (a reactive monomer having an epoxy group) and a structural unit (B) derived from N,N-dimethylacrylamide (a hydrophilic monomer), or is composed only of the above structural unit (A) and the above structural unit (B).

[0045] The weight average molecular weight of the block copolymer is preferably 10,000 to 10,000,000 from the viewpoint of solubility. The weight average molecular weight of the block copolymer is more preferably 100,000 to 5,000,000 from the viewpoint of ease of preparation of the coating solution. In the present specification, the "weight average molecular weight" shall be the value measured by gel permeation chromatography (Gel Permeation Chromatography, GPC) using polystyrene as a standard substance.

[0046] The method for producing block copolymers is not particularly limited, and conventionally known polymerization methods such as living radical polymerization, polymerization using macroinitiators, and polycondensation methods can be applied. Of these, living radical polymerization or polymerization using macroinitiators are preferred because they allow for easy control of the molecular weight and molecular weight distribution of constituent units (parts) derived from reactive monomers and constituent units (parts) derived from hydrophilic monomers. The living radical polymerization method is not particularly limited, but methods described in, for example, Japanese Patent Publication No. 11-263819, Japanese Patent Publication No. 2002-145971, Japanese Patent Publication No. 2006-316169, and atomic transfer radical polymerization (ATRP) can be applied in a similar manner or with appropriate modifications. Furthermore, in polymerization using macroinitiators, for example, a macroinitiator having a reactive site with a reactive functional group and a radically polymerizable group such as a peroxide group can be prepared, and then a block copolymer having hydrophilic sites and reactive sites can be produced by polymerizing the macroinitiator with monomers to form hydrophilic sites.

[0047] Furthermore, the polymerized block copolymer is preferably purified by general purification methods such as reprecipitation, dialysis, ultrafiltration, or extraction.

[0048] (Chlorine-containing compound) The chlorine-containing compound according to the present invention has a chlorine atom and is water-soluble. In this specification, "water-soluble" means that the solubility in water at 20°C is 1 g / 100 mL or more. Preferably, the chlorine-containing compound has a solubility of 10 g / 100 mL or more under the above conditions.

[0049] In the manufacturing method according to the present invention, the water-soluble nature of the chlorine-containing compound improves the lubricity (sliding properties) of the coating layer (surface lubrication layer) containing it. Furthermore, because the chlorine-containing compound has electron-withdrawing properties due to its chlorine atoms, it promotes ring-opening of epoxy groups contained in block copolymers adjacent to the chlorine-containing compound. As a result, cross-linking (bonding) between block copolymers progresses, increasing the film strength of the surface lubrication layer, thus improving the durability of the coating layer (surface lubrication layer). In this specification, "electron-withdrawing properties" refer to the property of attracting electrons more easily from the bonded atom compared to a hydrogen atom.

[0050] A chlorine-containing compound has at least one chlorine atom per molecule. From the viewpoint of promoting the above-mentioned crosslinking reaction, it is preferable that the number of chlorine atoms contained in the chlorine-containing compound is two or more per molecule. Furthermore, there is no particular upper limit, but for example, it is 10 or less, preferably 8 or less, more preferably 5 or less, and even more preferably 4 or less. Accordingly, the number of chlorine atoms contained in the chlorine-containing compound is, for example, 2 to 10, preferably 2 to 8, more preferably 2 to 5, even more preferably 2 to 4, and particularly preferably 3 per molecule.

[0051] The molecular weight of the chlorine-containing compound is not particularly limited, but is preferably 100 or more, more preferably 150 or more, even more preferably 200 or more, and particularly preferably 300 or more. Furthermore, although the molecular weight of the chlorine-containing compound is not particularly limited, it is preferably less than 1,000, more preferably 600 or less, even more preferably 500 or less, and particularly preferably 450 or less. In other words, the molecular weight of the chlorine-containing compound is preferably 100 or more and less than 1,000, more preferably 150 to 600, even more preferably 200 to 500, and particularly preferably 300 to 450.

[0052] The molecular weight of chlorine-containing compounds can be determined by determining their structure using NMR or similar methods, and then calculating the molecular weight based on the resulting molecular formula. If the above method is not feasible, analytical techniques such as gel permeation chromatography (GPC) may be used.

[0053] From the viewpoint of having moderate water solubility and being able to further improve the lubricity (sliding properties) of the surface lubricating layer, the chlorine-containing compound is preferably a chlorine derivative of a sugar, more preferably a chlorine derivative of a disaccharide, and particularly preferably sucralose. Furthermore, these sugars are also suitable in terms of safety.

[0054] (Preparation of coating solution) The coating solution is prepared using the block copolymer, chlorine-containing compound, and solvent (and other components if other components are used). Here, the chlorine-containing compound is stable in the coating solution and is therefore preferred in terms of safety and ease of operation. In the coating solution, the solvent is interposed between the chlorine-containing compound and the block copolymer, so the chlorine-containing compound and the block copolymer exist at a distance from each other, rather than in close contact. On the other hand, ring-opening of the epoxy group (crosslinking reaction) is initiated and proceeds when the block copolymer and the chlorine-containing compound approach each other until the electron orbitals of their respective molecules overlap, and electrons are exchanged. For this reason, ring-opening of the epoxy group (crosslinking reaction) does not proceed easily in the coating solution, so the viscosity of the coating solution due to the above crosslinking reaction does not change much or at all. In addition, gelation of the coating solution is suppressed, so the coating solution can maintain its solution form. Thus, in the manufacturing method according to the present invention, the coating solution can be uniformly brought into contact with (coated) the substrate layer, and workability is excellent.

[0055] The order and method of adding the block copolymer, chlorine-containing compound, and solvent are not particularly limited. Each component may be added together or separately, in stages or sequentially. The mixing method is also not particularly limited, and known methods can be used. Methods for preparing the coating solution include sequentially adding the chlorine-containing compound and block copolymer to the solvent, sequentially adding the block copolymer and chlorine-containing compound to the solvent, or adding the chlorine-containing compound and block copolymer to the solvent together. Preferably, the chlorine-containing compound and block copolymer are added sequentially to the solvent, or the block copolymer and chlorine-containing compound are added sequentially to the solvent. The above additions may be carried out while stirring if necessary. Alternatively, the mixture may be stirred after the above additions.

[0056] The solvent used in preparing the coating solution is not particularly limited as long as it can dissolve the block copolymer and the chlorine-containing compound (and other components if used), and is appropriately selected depending on the type of block copolymer, chlorine-containing compound (and other components if used). From the viewpoint of high solubility, alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and butanol; ketone-based solvents such as acetone, methyl ethyl ketone, and cyclohexanone; halogen-based solvents such as dichloromethane, chloroform, and carbon tetrachloride; and organic solvents such as tetrahydrofuran (THF), dimethyl sulfoxide, N,N-dimethylformamide (DMF), dioxane, and benzene are preferably used. These may be used individually or in combination of two or more (in the form of a mixed solvent). According to the manufacturing method of the present invention, a wide variety of solvents can be used in preparing the coating solution as described above. Therefore, the manufacturing method of the present invention can be said to be a highly versatile method.

[0057] In particular, from the viewpoint of further improving the lubricity and durability (especially sliding durability) of the surface lubrication layer, in one embodiment, the solvent preferably contains at least one selected from the group consisting of acetone, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, chloroform, dichloromethane, dioxane, benzene, methanol, ethanol, isopropyl alcohol, and butanol; more preferably contains at least one selected from the group consisting of acetone, N,N-dimethylformamide, and tetrahydrofuran; even more preferably contains N,N-dimethylformamide and / or tetrahydrofuran; and particularly preferably contains N,N-dimethylformamide. Furthermore, these preferred solvents are preferably present in an amount of 50% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and particularly preferably 95% by mass or more, based on the total mass (100% by mass) of the solvent used in the coating solution. In other embodiments, the solvent is preferably at least one selected from the group consisting of acetone, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, chloroform, dichloromethane, dioxane, benzene, methanol, ethanol, isopropyl alcohol, and butanol; more preferably at least one selected from the group consisting of acetone, N,N-dimethylformamide, and tetrahydrofuran; even more preferably N,N-dimethylformamide and / or tetrahydrofuran; and particularly preferably N,N-dimethylformamide.

[0058] The concentration of the block copolymer in the coating solution is not particularly limited. From the viewpoint of further improving the applicability, lubricity, and durability of the surface lubricating layer, the concentration of the block copolymer in the coating solution is preferably 0.5 to 20% by mass, more preferably 1 to 15% by mass, and particularly preferably 3 to 10% by mass. If the concentration of the block copolymer is within the above range, the lubricity and durability of the resulting surface lubricating layer can be fully exhibited. Furthermore, a uniform surface lubricating layer of the desired thickness can be easily obtained with a single coating, and the viscosity of the solution is within an appropriate range, which is preferable in terms of operability (e.g., ease of coating) and production efficiency. However, even if it is outside the above range, it can still be used as long as it does not affect the effects of the present invention.

[0059] The concentration of the chlorine-containing compound in the coating solution is also not particularly limited. From the viewpoint of further improving the lubricity (sliding properties) and durability (sliding durability) of the surface lubrication layer, it is preferable to add a certain amount of the chlorine-containing compound. Therefore, the concentration of the chlorine-containing compound in the coating solution is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0.3% by mass or more and 10% by mass or less, even more preferably 0.4% by mass or more and less than 10% by mass, even more preferably more than 0.4% by mass and 8% by mass or less, even more preferably 0.5% by mass or more and 6% by mass or less, and particularly preferably more than 0.5% by mass and 5% by mass or less. The concentration of the chlorine-containing compound in the coating solution may also be 2.0% by mass or more and less than 5% by mass. If the concentration of the chlorine-containing compound is within the above range, the lubricity (sliding properties) of the surface lubrication layer is further improved, and the crosslinking of the block copolymer is sufficiently advanced without excessive advancement (crosslinking can be moderately promoted). Thus, the lubricity and durability of the resulting surface lubrication layer are further improved. However, even if the range falls outside the above range, it is still perfectly usable as long as it does not affect the effects and benefits of the present invention.

[0060] Furthermore, the mixing ratio (mass ratio) of the block copolymer and the chlorine-containing compound in the coating liquid is preferably as follows, from the viewpoint of further improving the durability (sliding durability) and lubricity of the surface lubricating layer and the applicability. That is, when the block copolymer in the coating liquid is 100 parts by mass, the content of the chlorine-containing compound is, for example, 1 to 200 parts by mass, preferably 5 to 150 parts by mass, more preferably 8 parts by mass or more and less than 150 parts by mass, even more preferably more than 8 parts by mass and 120 parts by mass or less, even more preferably 10 to 100 parts by mass, even more preferably more than 10 parts by mass and 100 parts by mass or less, and particularly preferably more than 10 parts by mass and less than 100 parts by mass. Alternatively, when the block copolymer in the coating liquid is 100 parts by mass, the content of the chlorine-containing compound may be 40 parts by mass or more and less than 100 parts by mass. If the content (mass) of the chlorine-containing compound relative to 100 parts by mass of block copolymer in the coating liquid is within the above range, the durability and lubricity of the resulting surface lubricating layer will be further improved.

[0061] (II) Contact process (coating liquid contact process) In this process, the coating liquid prepared in the above (I) preparation process is brought into contact with the substrate layer to form a coating (coated layer) on the substrate layer.

[0062] The base layer may be composed of any material, including, for example, metal materials, polymer materials, and ceramics.

[0063] The metal material used to constitute the base layer is not particularly limited, and metal materials commonly used in medical devices such as catheters, guidewires, and indwelling needles can be used. Specifically, examples include various stainless steels such as SUS304, SUS314, SUS316, SUS316L, SUS420J2, and SUS630, as well as gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, or various alloys such as nickel-titanium alloys, nickel-cobalt alloys, cobalt-chromium alloys, and zinc-tungsten alloys. These may be used individually or in combination of two or more. From the above metal materials, the most suitable metal material for the base layer of the catheter, guidewire, or indwelling needle should be appropriately selected.

[0064] Furthermore, the polymer material (resin material or elastomer material) that constitutes the base layer is not particularly limited, and polymer materials commonly used in medical devices such as catheters, introducers, guidewires, and indwelling needles are used. Specifically, examples include polyamide resin, polyolefin resins such as polyethylene resin and polypropylene resin, modified polyolefin resin, cyclic polyolefin resin, epoxy resin, polyurethane resin, diallyl phthalate resin (allyl resin), polycarbonate resin, fluororesin, amino resin (urea resin, melamine resin, benzoguanamine resin), polyester resins such as polyethylene terephthalate resin and polybutylene terephthalate resin, styrene resin, acrylic resin, polyacetal resin, vinyl acetate resin, phenolic resin, vinyl chloride resin, silicone resin (silicon resin), polyether resin, and polyimide resin.

[0065] Furthermore, thermoplastic elastomers such as polyurethane elastomers, polyester elastomers, and polyamide elastomers (nylon elastomers) can also be used as materials for the base layer.

[0066] These polymer materials may be used individually, as a mixture of two or more, or as a copolymer of two or more monomers constituting any of the above resins or elastomers. For the polymer material, the most suitable polymer material for the intended use as a base layer for catheters, guidewires, indwelling needles, etc., should be appropriately selected. Among these, polyethylene resin, polyurethane resin, polyethylene terephthalate resin, polyamide resin, or polyamide elastomer are preferred polymer materials, with polyamide resin or polyamide elastomer being more preferred.

[0067] Furthermore, the shape of the base material layer is not particularly limited and can be appropriately selected depending on the intended use, such as in the form of a sheet, wire, rod, or tube.

[0068] The method for bringing the coating liquid into contact with the surface of the substrate layer is not particularly limited. Here, as a specific method of "contact," conventionally known methods such as applying the coating liquid to the surface of the substrate layer can be appropriately adopted.

[0069] The method of applying the coating solution is not particularly limited and includes methods such as coating / printing, immersion (dipping method, dip coating method), spraying method, spin coating method, mixed solution impregnation sponge coating method, bar coating method, die coating method, reverse coating method, comma coating method, gravure coating method, and doctor knife method. Of these, the immersion method (dipping method, dip coating method) is preferred.

[0070] Furthermore, when forming a surface lubrication layer on a narrow inner surface such as a catheter, the base layer may be immersed in the coating solution, and the system may be degassed by reducing the pressure. By reducing the pressure and degassing, the solution can be quickly penetrated into the narrow inner surface, promoting the formation of the surface lubrication layer.

[0071] Furthermore, when forming a surface lubrication layer on only a portion of the base layer, the surface lubrication layer can be formed on the desired surface portion of the base layer by immersing only a portion of the base layer in the coating liquid and coating that portion of the base layer with the coating liquid.

[0072] If it is difficult to immerse only a portion of the substrate layer in the coating solution, the surface portion of the substrate layer that does not require the formation of a surface lubrication layer may be protected (covered, etc.) in advance with a suitable removable member or material, then the substrate layer may be immersed in the coating solution to coat the substrate layer with the coating solution, after which the protective member (material) on the surface portion of the substrate layer that does not require the formation of a surface lubrication layer may be removed, and then the solvent may be removed by heat treatment or the like to allow the reaction to proceed, thereby forming a surface lubrication layer on the desired surface portion of the substrate layer. However, the present invention is not limited in any way to these formation methods, and the surface lubrication layer may be formed by appropriately using conventionally known methods. For example, if it is difficult to immerse only a portion of the substrate layer in the coating solution, other coating methods may be applied instead of the immersion method (for example, a method of applying the coating solution to a predetermined surface portion of a medical device using an application device such as a spray device, bar coater, die coater, reverse coater, comma coater, gravure coater, spray coater, or doctor's knife). Furthermore, in cases where the structure of a medical device requires both the outer and inner surfaces of a cylindrical device to have a surface lubrication layer, the dipping method is preferred because it allows both the outer and inner surfaces to be coated at once.

[0073] The amount of coating liquid applied is preferably such that the thickness (dry film thickness) of the resulting film (surface lubrication layer) is 0.1 to 10 μm, more preferably 0.3 to 5 μm, and even more preferably 0.5 to 3 μm. If the application amount results in a film (surface lubrication layer) thickness of 0.1 μm or more, sufficient durability of the resulting film (surface lubrication layer) can be achieved. Furthermore, if the application amount results in a film (surface lubrication layer) thickness of 10 μm or less, the surface of the film (surface lubrication layer) becomes less sticky, making handling during manufacturing easier.

[0074] (III) Solvent Removal Step In the method for manufacturing a medical device according to the present invention, it is preferable to perform a step to remove the solvent in the coating (coating layer) after bringing the coating liquid into contact with the substrate layer in the (II) Contact Step (Coating Liquid Contact Step) above to form a coating (coated layer). That is, in a preferred embodiment, the method for manufacturing a medical device according to the present invention is a method for manufacturing a medical device comprising a substrate layer and a surface lubricating layer supported on at least a part of the substrate layer, and includes preparing a coating liquid containing a block copolymer having a reactive monomer having an epoxy group (A) and a hydrophilic monomer having a constituent unit (B), a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent ((I) Coating Liquid Preparation Step), bringing the coating liquid into contact with the substrate layer to form a coating ((II) Contact Step), and removing the solvent from the coating ((III) Solvent Removal Step).

[0075] The solvent removal step is a step to remove the solvent contained in the coating liquid from the film (coating layer), and is preferably carried out by drying and / or heat treatment. That is, in the method for manufacturing medical devices according to the present invention, it is preferable to further perform a drying / heat treatment step after the above (II) contact step (coating liquid contact step). By performing the solvent removal step (preferably a drying / heat treatment step), a stronger surface lubricating layer can be formed.

[0076] As described above, in the coating solution used to form the film (coating layer), a solvent is interposed between the chlorine-containing compound and the block copolymer, so the chlorine-containing compound and the block copolymer do not come into close contact but exist at a distance from each other. For this reason, in the coating solution, the chlorine-containing compound does not readily attract electrons from the epoxy group (crosslinking group), and the ring-opening (crosslinking reaction) of the epoxy group does not proceed easily. On the other hand, after the coating solution is brought into contact with the substrate layer, when the solvent is removed from the coating solution film (coating layer), the chlorine-containing compound comes into contact with the block copolymer and readily attracts electrons (the electron orbitals of the molecules overlap more easily), and the ring-opening (crosslinking reaction) of the epoxy group is promoted. Therefore, by performing a solvent removal step (preferably a drying / heating step) after the contact step (coating solution contact step), the coating solution can be uniformly brought into contact with (coated) the substrate layer, and the ring-opening (crosslinking reaction) of the epoxy group proceeds evenly and densely on the surface of the substrate layer, thereby increasing the film strength of the surface lubrication layer. As a result, a surface lubrication layer with high film strength (a robust coating layer) is formed, and it is presumed that this robust coating layer can be well maintained even after sliding in a more flexible and narrow biological lumen such as a blood vessel, and that high lubricity (surface lubricity) can be maintained for a longer period of time (i.e., excellent surface lubricity can be maintained and sliding durability can be improved). In particular, when the solvent is removed by heat treatment (applying thermal energy) to the coating liquid film (coating layer), electron movement occurs more actively due to the expansion and contraction of molecules due to thermal energy, and ring opening (crosslinking reaction) of epoxy groups is further promoted, so the durability of the surface lubrication layer can be further improved. For this purpose, in the method for manufacturing medical devices according to the present invention, it is preferable to perform a drying step and / or a heat treatment step as a solvent removal step, and it is more preferable to perform a drying step and a heat treatment step.

[0077] Here, "drying treatment" and "heating treatment" are not strictly distinguished, but for the sake of explanation, "drying treatment" refers to keeping the substrate layer in contact with the above coating liquid at or below room temperature (20-30°C), and "heating treatment" refers to keeping it at a temperature above room temperature (20-30°C).

[0078] The conditions during drying or heat treatment are not particularly limited, as long as they allow for the formation of a surface lubricating layer containing a block copolymer on the substrate layer.

[0079] In other words, it is more preferable to maintain the coating (coating layer) at 10 to 200°C after contacting the coating liquid containing the block copolymer onto the substrate layer (after forming the coating layer). Maintaining it at such a temperature effectively promotes the crosslinking or polymerization of the block copolymer, forming a strong coating layer (surface lubrication layer). Therefore, high lubricity (surface lubricity) can be maintained for a longer period of time. Furthermore, maintaining it at such a temperature can suppress excessive crosslinking or polymerization. Therefore, it is possible to suppress the decrease in swelling caused by the surface lubrication layer becoming too hard, and as a result, good lubricity (surface lubricity) can be maintained.

[0080] Furthermore, after contacting the coating liquid containing the block copolymer onto the substrate layer (after forming the coating layer), it is more preferable to maintain the coating layer at 200°C or below, even more preferable to maintain it at 20 to 150°C, and most preferable to maintain it at 50 to 140°C. Maintaining it at such temperatures further promotes the crosslinking reaction, allowing for the formation of a surface lubricating layer with higher durability. The surface lubricating layer can also exhibit excellent lubricity. In particular, maintaining the temperature at 150°C or below can suppress excessive crosslinking or polymerization of the block copolymer. It can also prevent and suppress a decrease in the hydrophilicity of the constituent units (B) of the block copolymer. Therefore, it is possible to suppress a decrease in swelling caused by the surface lubricating layer becoming too hard, and to more easily control the lubricity. Note that the above temperatures may be changed during the drying or heat treatment.

[0081] Furthermore, while there are no particular restrictions on the drying or heat treatment time, it is preferably 10 minutes to 30 hours, more preferably 30 minutes to 25 hours, even more preferably 1 to 12 hours, and most preferably 1 to 10 hours. By setting the time to such an extent, crosslinking or polymerization in the block copolymer is effectively promoted, and a strong coating layer (surface lubrication layer) is formed. As a result, high lubricity (surface lubricity) can be maintained for a longer period of time. In addition, by setting the time to such an extent, it is possible to suppress the excessive progression of the above-mentioned crosslinking or polymerization. As a result, a decrease in swelling caused by the surface lubrication layer becoming too hard can be suppressed, and as a result, good lubricity (surface lubricity) can be maintained. In particular, by setting the heat treatment time to 30 hours (more preferably 25 hours, even more preferably 12 hours, and most preferably 10 hours) or less, a decrease in the hydrophilicity of the constituent units (B) of the block copolymer can be prevented and suppressed, making it easier to control the lubricity. Furthermore, if the base layer is composed of the above-mentioned polymer material (resin material or elastomer material), the drying or heat treatment time may be shorter, for example, 15 minutes to 5 hours or 30 minutes to 3 hours. With such a short time, damage to the hydrophilic groups within the constituent unit (B) (decrease in the hydrophilicity of the constituent unit (B) of the block copolymer) can be further suppressed, allowing the surface lubrication layer to exhibit better lubricity. In addition, there is the advantage that even polymer materials that are easily deformed or plasticized by heat can be used as the base layer. Therefore, according to the present invention, the selectivity of materials is broadened, and medical devices for a variety of applications can be manufactured. Moreover, since it is possible to form a surface lubrication layer with excellent durability at low temperatures, it is also preferable from the viewpoint of energy cost when manufacturing medical devices.

[0082] In this process, from the viewpoint of particularly effectively (efficiently) promoting the crosslinking or polymerization of the block copolymer, it is preferable to perform a heat treatment after the drying treatment. By going through drying and heat treatment in this way, the solvent is removed (i.e., the block copolymer and chlorine-containing compound are in a state where they can easily come into contact), and the effect of promoting the crosslinking or polymerization of the block copolymer by the chlorine-containing compound is further improved. In addition, since the heat treatment can be performed for a shorter time, even polymer materials that are easily deformed or plasticized by heat can be used as the base layer.

[0083] The conditions for drying and heat treatment (temperature, time, etc.) are not particularly limited, but from the viewpoint of efficiently manufacturing medical devices, if the base layer is made of polymer material, it is preferable to perform a drying treatment at 10-30°C for 15 minutes to 5 hours, followed by a heat treatment at 40-200°C for 30 minutes to 10 hours. Furthermore, from the same viewpoint, it is more preferable to perform a drying treatment at 15-30°C for 20 minutes to 3 hours, followed by a heat treatment at 45-150°C for 30 minutes to 6 hours, and it is particularly preferable to perform a drying treatment at 20-25°C for 20 minutes to 1.5 hours, followed by a heat treatment at 50-130°C for 1 to 3 hours.

[0084] From a similar viewpoint, when the base layer is made of a metal material, it is preferable to perform a drying treatment at 10 to 30°C for 15 minutes to 5 hours, followed by a heat treatment at 40 to 200°C for 5 to 20 hours. Furthermore, from a similar viewpoint, it is more preferable to perform a drying treatment at 15 to 30°C for 30 minutes to 3 hours, followed by a heat treatment at 80 to 150°C for 8 to 18 hours, and it is particularly preferable to perform a drying treatment at 20 to 25°C for 30 minutes to 1.5 hours, followed by a heat treatment at 100 to 130°C for 10 to 15 hours. Under these conditions, medical devices with a highly durable surface lubrication layer can be manufactured. Note that a further drying treatment may be performed after the above heat treatment.

[0085] Under the above-mentioned conditions (temperature, time, etc.), a strong surface lubricating layer (coating layer) can be supported on the surface of the substrate layer. Furthermore, depending on the type of substrate layer, a crosslinking reaction occurs via the epoxy groups in the block copolymer within the surface lubricating layer, forming a high-strength surface lubricating layer that does not easily peel off from the substrate layer. Therefore, the above drying / heating treatment process can effectively suppress and prevent the peeling of the surface lubricating layer from the substrate layer.

[0086] Furthermore, there are no restrictions on the pressure conditions during drying; it can be carried out under normal pressure (atmospheric pressure), or under pressurized or reduced pressure.

[0087] For drying or heating, an oven or vacuum dryer can be used, but in the case of natural drying, no special drying equipment is necessary.

[0088] By going through the (I) coating liquid preparation step and (II) contact step (coating liquid contact step) described above, as well as the (III) solvent removal step (preferably a drying / heat treatment step) which is performed as needed, a medical device having a surface lubricating layer (coating layer) with excellent lubricity (sliding properties) and durability (especially sliding durability) can be manufactured.

[0089] In other words, according to the method of the present invention, after forming a coating layer containing a block copolymer and a chlorine-containing compound on the surface of the substrate layer, a strong surface lubrication layer that does not easily peel off from the substrate layer can be formed by crosslinking epoxy groups. Furthermore, the medical device obtained by the method of the present invention exhibits excellent lubricity and durability (lubricity retention) because a surface lubrication layer is formed on the surface not only by the block copolymer but also by a water-soluble chlorine-containing compound.

[0090] [Medical Devices] The medical devices manufactured by the method of the present invention described above have a structure in which the surface lubricating layer is supported on the substrate layer by bringing a coating liquid containing a block copolymer and a chlorine-containing compound that forms the surface lubricating layer into contact with the substrate layer. In the coating liquid, the chlorine-containing compound and the block copolymer are dissolved in the solvent (the chlorine-containing compound and the block copolymer are uniformly mixed in the coating liquid). Therefore, in the surface lubricating layer, the chlorine-containing compound is considered to exist surrounded by the polymer chains of the block copolymer.

[0091] Accordingly, in another aspect of the present invention, a medical device is provided comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer comprises a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and a chlorine-containing compound having a chlorine atom and being water-soluble. The medical device having the above configuration will hereinafter also be referred to as "the medical device according to the present invention" or "medical device".

[0092] In the above embodiment, the explanations of terms such as block copolymer and chlorine-containing compound are the same as those described in the above [Method for Manufacturing Medical Devices], and therefore the explanations are omitted here. In this case, the preferred ratio (content ratio) of block copolymer and chlorine-containing compound present in the surface lubrication layer is the same as the preferred mixing ratio of block copolymer and chlorine-containing compound in the coating liquid described above (chlorine-containing compound).

[0093] In one embodiment, the medical device according to the present invention comprises a base layer and a surface lubricating layer supported on at least a portion of the base layer, and can be obtained by preparing a coating solution containing a block copolymer having a reactive monomer having an epoxy group (A) and a hydrophilic monomer having a hydrophilic monomer (B), a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent, and bringing the coating solution into contact with the base layer.

[0094] Hereinafter, preferred embodiments of medical devices manufactured by the method according to the present invention will be described with reference to the attached drawings.

[0095] Figure 1 is a partial cross-sectional view of a catheter as a typical embodiment of a medical device manufactured by the method according to the present invention. Here, Figure 1 is a cross-sectional view of the catheter cut parallel to the axial direction. Figure 2 is a partial cross-sectional view schematically showing an example of a different configuration of the surface laminated structure as an application example of the embodiment (catheter) shown in Figure 1. In Figures 1 and 2, each reference numeral represents the following: Reference numeral 1 represents the base material layer; reference numeral 1a represents the core portion of the base material layer; reference numeral 1b represents the base material surface layer; reference numeral 2 represents the surface lubrication layer; reference numeral 3 represents the lumen; and reference numeral 10 represents the medical device according to the present invention.

[0096] As shown in Figures 1 and 2, the catheter as a medical device 10 in this embodiment is composed of a tubular body, and as shown in Figures 1 and 2, a lumen 3 is formed in the approximate center of the catheter body, extending along its entire length. In this embodiment, the medical device 10 comprises a base layer 1 and a surface lubricating layer 2 containing a block copolymer, which is provided on at least a part of the base layer 1 (in the figures, an example is shown where it is provided on the entire surface of the base layer 1 in the drawing). In Figures 1 and 2, the surface lubricating layer 2 is formed on the outer surface of the tubular base layer 1, but the present invention is not limited to the above embodiment, and may take any form, such as being formed on the inner surface of the base layer 1; being formed on both the outer and inner surfaces of the base layer 1; or being formed on a part of the outer surface, inner surface, or both of these surfaces of the base layer 1. Furthermore, if the base layer is planar (plate-shaped), the surface lubricating layer may take any form, such as being formed on one side of the base layer; being formed on both sides of the base layer; or being formed on a part of one or both sides of the base layer.

[0097] The following provides a detailed explanation of each component of the medical device.

[0098] (Base Layer (Base Material)) The base layer used in this embodiment may be composed of any material, and the material is not particularly limited. Specifically, the materials constituting the base layer 1 include metal materials, polymer materials, and ceramics. Specific examples of the materials constituting the base layer 1 are as described in (II) Contact Process (Coating Liquid Contact Process) above.

[0099] Here, the base layer 1 may be composed entirely of any of the above materials. The base layer 1 may be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which members made of different materials are joined together for each part of the medical device. Alternatively, as shown in Figure 2, it may have a structure in which a base layer core portion 1a made of any of the above materials is coated with another of the above materials in an appropriate manner to form a base surface layer 1b. Examples of the latter case include a base layer core portion 1a made of a resin material, etc., on which a metal material is coated in an appropriate manner (a conventionally known method such as plating, metal deposition, sputtering, etc.) to form a base surface layer 1b; a base layer core portion 1a made of a hard reinforcing material such as a metal material, on which a polymer material that is more flexible than the reinforcing material such as a metal material is coated in an appropriate manner (a conventionally known method such as dipping, spraying, coating / printing, etc.), or a reinforcing material forming the base layer core portion 1a and a polymer material are composited to form a base surface layer 1b. Furthermore, the base layer core portion 1a may be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which members formed of different materials for each part of the medical device are joined together. Also, another middle layer (not shown) may be formed between the base layer core portion 1a and the base surface layer 1b. Furthermore, the base surface layer 1b may also be a multilayer structure formed by laminating different materials in multiple layers, or a structure in which members formed of different materials for each part of the medical device are joined together.

[0100] (Surface Lubrication Layer (Coating Layer)) The surface lubrication layer is supported on at least a portion of the base material layer 1. The reason why the surface lubrication layer 2 is supported on at least a portion of the surface of the base material layer 1 is that, in medical devices such as catheters, guidewires, and indwelling needles, which are the intended applications, it is not necessarily required that all surfaces (the entire surface) of these medical devices be lubricated when wet. It is sufficient for the surface lubrication layer to be supported only on the surface portion (which may be a portion or the entire surface) where lubrication is required when wet. For this reason, as described above, when the base material layer is tubular as shown in Figures 1 and 2, the surface lubrication layer can be formed to cover the entire outer surface of the base material layer; to cover the entire outer and inner surfaces of the base material layer; to cover a portion of the outer and inner surfaces of the base material layer in the same or different form; or to cover a portion of the outer or inner surface of the base material layer. Furthermore, when the base layer is planar (plate-shaped), the surface lubrication layer includes forms formed on one side of the base layer; forms formed on both sides of the base layer; and forms formed on one or part of both sides of the base layer.

[0101] <Applications of Medical Devices> Examples of medical devices according to the present invention include devices used in contact with bodily fluids such as body fluids and blood. These devices have lubricating surfaces in aqueous liquids such as bodily fluids and physiological saline, enabling improved operability and reduced damage to tissue mucosa. Specific examples of medical devices according to the present invention include, but are not limited to, catheters, guidewires, and indwelling needles used within blood vessels. In one embodiment, the medical device according to the present invention is a catheter, guidewire, or indwelling needle. In another embodiment, the medical device according to the present invention may be a microcatheter, balloon catheter, or guiding catheter.

[0102] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, unless otherwise specified, the operations were carried out at room temperature (25°C). Unless otherwise specified, "%" and "parts" mean "mass%" and "parts by mass," respectively.

[0103] Synthesis Example 1 The following reaction was carried out to produce block copolymer (1).

[0104]

[0105] 72.3 g of adipic acid dichloride was mixed with 29.7 g of triethylene glycol at 50°C, and the mixture was then incubated at 50°C for 3 hours to remove the hydrochloric acid under reduced pressure and obtain an oligoester. Next, 22.5 g of the obtained oligoester was mixed with 4.5 g of methyl ethyl ketone, which was then added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of the surfactant dioctyl phosphate, and 120 g of water. The mixture was reacted at -5°C for 20 minutes. The resulting product was washed with water and methanol, and then dried to obtain a polyperoxide (PPO) having multiple peroxide groups in its molecule. Subsequently, 0.5 g of this PPO and 9.5 g of glycidyl methacrylate (GMA) were polymerized with benzene as the solvent at 65°C for 2 hours under reduced pressure with stirring. The reaction product obtained after polymerization was reprecipitated with diethyl ether to obtain poly-GMA (PPO-GMA) having peroxide groups in its molecule.

[0106] Next, 1.35 g of the obtained PPO-GMA (equivalent to 9.5 mmol of GMA) was dissolved in chlorobenzene with 11.2 g (113 mmol) of N,N-dimethylacrylamide (DMAA) as a hydrophilic monomer, and polymerization was carried out by heating at 80°C for 7 hours under a nitrogen atmosphere. The reaction product was reprecipitated with cyclohexane and recovered to obtain block copolymer (1). The DMAA:GMA ratio of the obtained block copolymer (1) was １ Measurement by H-NMR confirmed that the DMAA:GMA ratio was 12:1 (molar ratio). Furthermore, regarding the obtained block copolymer (1), １ Analysis using 1H-NMR and ATR-IR confirmed the presence of an epoxy group within the molecule.

[0107] Example 1 The block copolymer (1) obtained in Synthesis Example 1 and sucralose (manufactured by Tokyo Chemical Industry Co., Ltd., solubility in water at 20°C: 28.3 g / 100 mL) were dissolved in acetone as a solvent to prepare coating solution (1). At this time, the concentration of block copolymer (1) was set to 5.0% by mass and the concentration of sucralose to 0.5% by mass (block copolymer (1): sucralose (mass ratio) = 100:10).

[0108] A tube with an outer diameter of 2.37 mm, molded from polyamide elastomer (Shore hardness 60D, (Vestamid E62, manufactured by EVONIK)), was immersed in the above coating solution (1), pulled up at a pulling speed of 5 mm / sec, and dried at room temperature (25°C) for 30 minutes to form a coating layer (tube (1)). This tube (1) was stored in an oven at 130°C for 1 hour to heat-treat the coating layer, and then cooled to room temperature. In this way, a sample (coated tube) (1) having a coating layer (surface lubrication layer) containing block copolymer (1) and sucralose on the tube surface was prepared.

[0109] Example 2 Sample (coated tube) (2) was prepared in the same manner as in Example 1, except that the solvent was changed to N,N-dimethylformamide (DMF) when preparing the coating solution to prepare coating solution (2), and a coated layer was formed using coating solution (2).

[0110] Example 3 Sample (coated tube) (3) was prepared in the same manner as in Example 1, except that the solvent was changed to tetrahydrofuran (THF) when preparing the coating solution (3), and a coating layer was formed using the coating solution (3).

[0111] Comparative Example 1 A comparative sample (comparative coated tube) (1) was prepared in the same manner as in Example 1, except that a comparative coated solution (1) was prepared without adding sucralose during the preparation of the coating solution, and a coated layer was formed using the comparative coated solution (1).

[0112] Comparative Example 2 A comparative sample (comparative coated tube) (2) was prepared in the same manner as in Example 2, except that a comparative coated solution (2) was prepared without adding sucralose during the preparation of the coating solution, and a coated layer was formed using the comparative coated solution (2).

[0113] Comparative Example 3 A comparative sample (comparative coated tube) (3) was prepared in the same manner as in Example 3, except that the comparative coated solution (3) was prepared without adding sucralose during the preparation of the coating solution, and a coating layer was formed using the comparative coated solution (3).

[0114] Example 4 Sample (coated tube) (4) was prepared in the same manner as in Example 2, except that, when preparing the coating solution, the concentration of block copolymer (1) was set to 5.0% by mass and the concentration of sucralose to 0.4% by mass (block copolymer (1): sucralose (mass ratio) = 100:8) to prepare the coating solution (4), and a coated layer was formed using the coating solution (4).

[0115] Example 5 A sample (coated tube) (5) was prepared in the same manner as in Example 2, except that, when preparing the coating solution, the concentration of block copolymer (1) was set to 5.0% by mass and the concentration of sucralose to 2.0% by mass (block copolymer (1): sucralose (mass ratio) = 100:40) to prepare the coating solution (5), and a coated layer was formed using the coating solution (5).

[0116] Example 6 A sample (coated tube) (6) was prepared in the same manner as in Example 2, except that, when preparing the coating solution, the concentration of block copolymer (1) was set to 5.0% by mass and the concentration of sucralose to 5.0% by mass (block copolymer (1): sucralose (mass ratio) = 100:100) to prepare the coating solution (6), and a coated layer was formed using the coating solution (6).

[0117] [Evaluation of sliding resistance] The sliding properties and durability of the surface lubrication layer were evaluated for the samples (1) to (6) prepared in Examples 1 to 6 above, and the comparative samples (1) to (3) prepared in Comparative Examples 1 to 3 above, according to the following method.

[0118] Referring to Figures 3 and 4, a test apparatus 100 for evaluating the sliding resistance (sliding test) of the medical device 10 according to this embodiment will be described. Figure 3 is a schematic diagram showing the test apparatus 100 for performing a sliding test of the medical device 10 according to this embodiment, showing the medical device 10 being sandwiched between a pair of contact members 91 and 92. Figure 4 is a schematic diagram showing the test apparatus 100 for performing a sliding test of the medical device 10 according to this embodiment, showing the medical device 10 being separated from the pair of contact members 91 and 92.

[0119] As shown in Figures 3 and 4, the test apparatus 100 has a pair of contact members 91 and 92. The pair of contact members 91 and 92 are configured to move closer to and further apart from each other, and when the pair of contact members 91 and 92 are close together, the medical device 10 can be gripped with a predetermined force. As the test apparatus 100, the DL1000 manufactured by Oak River Technology can be used.

[0120] Next, a method for measuring the sliding resistance value of a sample (coated tube) 10' as a medical device 10 using the test apparatus 100 will be described. Here, the sample (coated tube) 10' corresponds to the samples (1) to (6) prepared in Examples 1 to 6, and the comparative samples (1) to (3) prepared in Comparative Examples 1 to 3.

[0121] First, each sample 10' was immersed in tap water for 5 minutes. Then, the sample 10' was removed from the water and placed in a pinch tester (OAKRIVER TECHNOLOGY, DL1000), which served as the test apparatus 100. The pair of contact members 91 and 92 were brought close together, and the sample 10' was clamped with a grip force of 500 gf. For this purpose, the grip pads used as contact members 91 and 92 were made of silicone with a Shore A60 rating and a pad thickness of 12.35 mm.

[0122] Next, the resistance value was measured while the sample 10' was pulled up at a predetermined speed. In this case, the speed at which the sample 10' was pulled up (test speed) was 8.3 mm / sec, and the test stroke (distance pulled up) was 35 mm.

[0123] Afterward, the pair of contact members 91 and 92 were separated from each other to release the clamping state of the sample 10', and then the sample 10' was returned to its initial position.

[0124] The above process was repeated 50 times, and the sliding resistance value (sliding resistance value) at the 5th time was used as the sliding performance evaluation value. Furthermore, the sliding resistance value at the 5th time was subtracted from the sliding resistance value at the 50th time (sliding resistance value at the 50th time - sliding resistance value at the 5th time) to obtain the durability evaluation value. In other words, the increase in the sliding resistance value at the 50th time relative to the sliding resistance value at the 5th time was used as the durability evaluation value. If the calculated value was negative as a result of the above calculation, it was set to "0 gf". It is preferable for both the sliding performance evaluation value and the durability evaluation value to be small. For example, the sliding performance evaluation value is preferably 10 gf or less, more preferably 9 gf or less, and particularly preferably 8 gf or less (lower limit: 0 gf). Similarly, the durability evaluation value is preferably 150 gf or less, more preferably 100 gf or less, even more preferably 50 gf or less, particularly preferably 10 gf or less, and most preferably 5 gf or less (lower limit: 0 gf). Furthermore, from the viewpoint of achieving both good lubricity and excellent durability, it is preferable that the sliding performance evaluation value is 10 gf or less and the durability evaluation value is 150 gf or less, more preferably that the sliding performance evaluation value is 10 gf or less and the durability evaluation value is 100 gf or less, even more preferably that the sliding performance evaluation value is 9 gf or less and the durability evaluation value is 50 gf or less, particularly preferably that the sliding performance evaluation value is 8 gf or less and the durability evaluation value is 10 gf or less, and particularly preferably that the sliding performance evaluation value is 8 gf or less and the durability evaluation value is 5 gf or less.

[0125] The results obtained from the above evaluations are shown in Tables 1 and 2 and Figure 5 below. In the following tables, the sucralose / block copolymer addition concentration represents the addition concentration for each solvent (addition concentration in the coating solution).

[0126]

[0127] According to Table 1 above, all of the examples demonstrated excellent sliding properties (lubricity) and durability (sliding durability). Furthermore, comparing Examples 1 to 3, the sample using DMF as the solvent for the coating solution (Example 2) had the best sliding properties (lubricity), followed by THF (Example 3) and acetone (Example 1). This is thought to be due to differences in the solubility of the block copolymer depending on the type of solvent, and is specifically inferred as follows: The molecular chains (polymer molecular chains) of a block copolymer have a larger radius of rotation in the coating solution and can spread out more easily the solvent used in the coating solution is a good solvent. When a coating solution using such a good solvent is applied to a substrate layer, the polymer molecular chains are more likely to be arranged on the substrate layer in an expanded state. As a result, the gaps in the network structure of polymer chains in the formed coating layer (surface lubrication layer) become larger, so the surface lubrication layer formed using a coating solution containing a good solvent is more likely to contain water, and is thought to have improved sliding properties (lubricity).

[0128] Therefore, it is appropriate to compare evaluation results between samples using the same solvent. Below, we compared each sample in which the coating solution solvent was DMF and the mass ratio of block copolymer to sucralose was changed.

[0129]

[0130] Figure 5 shows the durability evaluation results (sliding resistance value at 50th trial - sliding resistance value at 5th trial) for each sample in Comparative Example 2, Examples 2 and 4-6.

[0131] As shown in Figure 5, the durability evaluation values ​​(increase in sliding resistance) for Examples 2, 5, and 6 were drastically reduced (i.e., durability was dramatically improved). This indicates that when the sucralose content in the coating solution is 10 parts by mass or more per 100 parts by mass of block copolymer, the durability of the surface lubrication layer is dramatically improved. This is presumed to be because when the amount of chlorine atoms in sucralose relative to the block copolymer exceeds a certain ratio, it can effectively promote crosslinking of the block copolymer.

[0132] According to the present invention, a coating layer (surface lubrication layer) with excellent lubricity (sliding properties) and durability (especially sliding durability) can be formed. Therefore, according to the present invention, a medical device having a coating layer (surface lubrication layer) with excellent lubricity (sliding properties) and durability (especially sliding durability) is provided.

[0133] This application is based on Japanese Patent Application No. 2025-017371, filed on February 5, 2025, the disclosures of which are referenced and incorporated as a whole.

[0134] 10 Medical device (catheter), 1 base layer, 1a base layer core, 1b base surface layer, 2 surface lubrication layer, 3 lumen, 100 test apparatus, 10' sample (tube), 91 contact member, 92 contact member.

Claims

1. A method for manufacturing a medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, comprising: preparing a coating solution containing a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, a chlorine-containing compound having a chlorine atom and being water-soluble, and a solvent, and bringing the coating solution into contact with the base layer.

2. The method according to claim 1, wherein the molecular weight of the chlorine-containing compound is 150 to 600.

3. The method according to claim 1, wherein the chlorine-containing compound is a chlorine derivative of a disaccharide.

4. The method according to claim 1, wherein the chlorine-containing compound is sucralose.

5. The method according to claim 1, wherein the solvent comprises at least one selected from the group consisting of acetone, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, chloroform, dichloromethane, dioxane, benzene, methanol, ethanol, isopropyl alcohol, and butanol.

6. The method according to claim 1, wherein the coating liquid contains 5 to 150 parts by mass of the chlorine-containing compound with respect to 100 parts by mass of the block copolymer.

7. The method according to claim 1, wherein the coating solution contains the chlorine-containing compound in an amount of 0.1 to 20% by mass.

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

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

10. A medical device comprising a base layer and a surface lubricating layer supported on at least a portion of the base layer, wherein the surface lubricating layer comprises a block copolymer having constituent units (A) derived from a reactive monomer having an epoxy group and constituent units (B) derived from a hydrophilic monomer, and a chlorine-containing compound having a chlorine atom and being water-soluble.

11. The medical device according to claim 10, wherein the molecular weight of the chlorine-containing compound is 150 to 600.

12. The medical device according to claim 10, wherein the chlorine-containing compound is a chlorine derivative of a disaccharide.

13. The medical device according to claim 10, wherein the chlorine-containing compound is sucralose.

14. The medical device according to claim 10, wherein the reactive monomer having an epoxy group comprises at least one selected from the group consisting of glycidyl acrylate, glycidyl methacrylate, 3,4-epoxycyclohexylmethyl acrylate, 3,4-epoxycyclohexylmethyl methacrylate, β-methylglycidyl methacrylate, and allylglycidyl ether.

15. The medical device according to claim 10, wherein the hydrophilic monomer comprises at least one selected from the group consisting of N,N-dimethylacrylamide, acrylamide, 2-hydroxyethyl methacrylate, and N-vinylpyrrolidone.

16. The medical device according to claim 10, wherein the medical device is a catheter, a guidewire, or an indwelling needle.

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