JP2002172159A - Medical care appliance for body embedding - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical care appliance for body embedding which is excellent in an antithrombotic property and histocompatibility and is capable of exhibiting these excellent characteristics stably for a long period after indwelling in the body. SOLUTION: This medical care appliance is constituted by coating at least portions of the surface of a medical care appliance body 1 with a high-molecular film material 2 consisting of a polymer having at least one functional group selected from carboxylic group and carboxylic acid anhydride group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an implantable medical device having excellent antithrombotic properties and histocompatibility.

[0002]

2. Description of the Related Art In medical surgery in recent years, various medical instruments are implanted in the body as a substitute for a malfunctioning organ, or for protecting a postoperative site or maintaining its function. . In these medical devices, blood, tissue fluid,
It is required to be compatible with body fluids such as lymph, and organs and sites to be implanted. For example, in the case of a medical device embedded in a site that comes into contact with blood flow, such as a stent, an artificial blood vessel, or a catheter that is indwelled for a long period of time, blood adheres to the surface or coagulates the blood and does not hinder blood flow. It is required to have excellent antithrombotic properties and histocompatibility so as to be incompatible with living tissues and not to cause stenosis due to the formation of neointima, phenotypic change of fibroblasts and the like. In addition, similar characteristics are required for medical instruments to be implanted in the ureter, urethra, lymph vessels, and the like. Furthermore, medical devices that are placed in the body to hold a drug that exerts a sustained release effect and that are implanted in the body also have antithrombotic properties and tissue compatibility, and the characteristics of the device that hold the drug. Is required to be stably and continuously displayed.

When a stenosis occurs in a blood vessel of a living body, particularly a blood vessel such as a coronary artery, a balloon catheter is inserted into the stenosis, and the balloon is inflated to expand the blood vessel to secure the inner lumen and obtain a blood flow. Percutaneous coronary angioplasty (PTCA) has been performed to improve the quality of life. However, it is estimated that approximately 40% of patients undergo restenosis of coronary arteries within three months after surgery.

[0004] In order to solve the above problems, treatment with a stent attached to a balloon has been performed. By inserting a stent into a stenosis site and expanding it with a balloon, it is possible to achieve a desired appropriate blood vessel diameter. Conventionally, this stent is made of a metal such as stainless steel or tantalum, and has a problem that a thrombus easily adheres and a foreign body reaction that causes restenosis is easily stimulated. Therefore, in order to solve this problem, a stent is coated with a polymer material to provide antithrombotic properties, tissue compatibility with blood vessels, and a drug for preventing restenosis after stent placement. Stent coatings and compositions capable of sustained release have been disclosed, but none have been satisfactory.

[0005] Such problems with respect to antithrombotic properties and histocompatibility are not limited to stents, but are common to various medical devices to be implanted in the body. In the medical device, it is required that the antithrombotic property and histocompatibility are continuously and stably exhibited. However, conventional stents coated with a polymer material cannot stably maintain excellent antithrombotic properties and tissue compatibility over a long period of time after being placed in the body. In addition, there is a problem that blood flow is obstructed due to thickening of blood vessels, vascular stenosis and the like, and as a result, the restenosis rate does not decrease.

[0006]

SUMMARY OF THE INVENTION Accordingly, the present invention has been made to solve the above problems, and has excellent antithrombotic properties and tissue compatibility.
Moreover, an object of the present invention is to provide an implantable medical device capable of stably exhibiting its excellent properties for a long period of time after being placed in the body.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve this object and found that a polymer comprising a polymer having at least one functional group selected from a carboxyl group and a carboxylic anhydride group. It has been found that the film formed by the film material is effective. That is, the present invention
Based on the above knowledge, the present invention provides the following implantable medical devices (1) to (8).

(1) A body formed by coating at least a part of the surface of a medical device body with a polymer film material comprising a polymer having at least one functional group selected from a carboxyl group and a carboxylic anhydride group. Implantable medical device.

(2) The implant according to (1), wherein the polymer is a copolymer of a hydrophobic vinyl monomer and a monomer having at least one functional group selected from a carboxyl group and a carboxylic anhydride group. Medical instruments.

(3) The implantable medical device according to (1), wherein the polymer is a copolymer of a hydrophobic vinyl monomer and maleic anhydride.

(4) The implantable medical device according to (2) or (3), wherein the hydrophobic vinyl monomer is at least one selected from styrene, ethylene and methyl vinyl ether.

(5) The polymer is a styrene-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer,
(1) an implantable medical device which is at least one selected from a methyl vinyl ether-maleic anhydride copolymer and a partially esterified copolymer obtained by partially esterifying the copolymer with a monohydric alcohol; .

(6) The monohydric alcohol is at least one selected from methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, 2-methoxyethyl alcohol and polyethylene glycol monoalkyl ether ( 5) An implantable medical device in the body.

(7) The polymer is at least one selected from 4-methacryloyloxyethylene trimellitic anhydride and methacryloyloxyethylene phthalic acid.
The implantable medical device according to (2), which is a vinyl polymer containing a structural unit derived from a seed.

(8) The medical device for implantation in the body according to any one of (1) to (7), wherein the medical device main body is a stent.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The medical device to be implanted in the present invention (hereinafter referred to as "the medical device of the present invention") will be described in detail below. The medical device of the present invention is obtained by coating at least a part of the surface of the medical device main body with a polymer film material.

In the medical device of the present invention, the material, shape, size, form, etc. of the medical device main body are not particularly limited, and may be determined according to the size, compliance, tissue, cell type, etc. of the site where the medical device is to be placed. It is determined as appropriate. For example, the material may be either a metal material or a polymer material, and has a required property according to a site to be placed, that is, a blood vessel, a ureter, a blood vessel such as a lymph vessel, a tissue such as a muscle, or the like. The material is not particularly limited as long as the material is biocompatible.

Examples of the metal material include stainless steel, titanium or a titanium alloy, tantalum or a tantalum alloy, platinum or a platinum alloy, gold or a gold alloy, and a cobalt-based alloy. SUS316L, which has the best corrosion resistance as stainless steel
Is preferred. This SUS316L is actually used as a stent material.

As the polymer material, for example, polyesters such as polyethylene terephthalate and polybutylene terephthalate or polyester-based elastomers having the same as a constituent unit, polyamides such as nylon 6, nylon 12, nylon 66, nylon 610 and the like, or the like. Polyolefins such as polyamide-based elastomers, polyurethanes, polyethylene, polypropylene, and polyolefin-based elastomers containing them as constituent units are exemplified. For example, polyethylene terephthalate is used as the material of the artificial blood vessel, polyurethane is used as the material of the catheter, and ultrahigh molecular weight polyethylene is used as the material of the artificial joint.

In the medical device of the present invention, the medical device main body has basic characteristics such as antithrombotic properties and tissue compatibility, and characteristics required for the medical device, for example,
A plurality of materials are appropriately combined according to rigidity, mechanical compliance with living tissue, followability, and the like.

Further, on the surface of the medical device main body covered with the polymer film material, a film is formed at required positions on the inner surface and the outer surface of the medical device main body. The location is, for example, a portion where the medical device is embedded and indwelled, a portion that comes into contact with body fluids such as blood, tissue fluid, and lymph fluid, or a portion that requires antithrombotic properties and tissue compatibility, etc., as appropriate. It is determined. For example, in the case of a stent as a medical device, it is preferable that at least a part, more preferably the entire surface of the inner surface and the outer surface is coated with a polymer film material.

In the present invention, the polymer film material comprises a polymer having at least one functional group selected from a carboxyl group and a carboxylic anhydride group. This polymer may have a structure in which the functional group is bonded to the polymer main chain in the molecule, or a low molecular compound or a polymer having the functional group is bonded to the polymer main chain as a side chain. It may have a structure. In this polymer, the carboxyl group or carboxylic anhydride is
It has good adhesion and adhesion to metals, and has excellent exfoliation resistance, so it is very stable even in blood.

Specific examples of the polymer include a copolymer of a hydrophobic vinyl monomer and a monomer having a carboxyl group or a carboxylic anhydride group. Examples of the hydrophobic vinyl monomer include styrene, α-methylstyrene, ethylene, propylene, methyl vinyl ether, 2-methoxyethyl acrylate, or butyl,
Examples include acrylic or methacrylic monomers having a long-chain alkyl group such as pentyl, hexyl, octyl, dodecyl, and stearyl, and other acrylic monomers.

Examples of the monomer containing a carboxyl group or a carboxylic anhydride group include maleic anhydride, maleic acid, 4-methacryloyloxyethylene trimellitic anhydride, methacryloyloxyethylene phthalic acid, N-methacryloyloxyglutamic acid, N-
Examples include methacryloyl-ε-caproic acid, N-methacryloyl-γ-butyric acid, N-methacryloyl-5-aminosalicylic acid, and N-acryloylphenylglycine. Also, the copolymerizable hydrophobic vinyl monomer is
For example, in the case of a monomer having a styrene-based aromatic ring or an acrylic or methacrylic monomer having a long-chain alkyl group, acrylic acid, methacrylic acid and the like can also be used.

In the present invention, the hydrophobic vinyl monomer and the monomer containing a carboxyl group or a carboxylic acid anhydride group may be those obtained by copolymerizing only one kind of each of these monomers. Copolymers obtained by combining species may be used.

Examples of the copolymerization method include radical polymerization, cationic polymerization, coordination polymerization and the like. At this time, in order to efficiently perform the copolymerization, an appropriate polymerization solvent may be used. Examples of the polymerization solvent include solvents such as toluene, benzene, chlorobenzene, methanol, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and dimethylsulfoxide.

In the present invention, among the above copolymers,
A copolymer of a hydrophobic vinyl monomer and maleic anhydride is preferred. The maleic anhydride unit has a carboxylic acid anhydride group, and has a carboxyl group in the main chain of the copolymer by partially hydrolyzing or forming a partially esterified product with a monohydric alcohol. A polymer can be obtained. The polymer film material can be made hydrophobic by copolymerizing with a hydrophobic monomer.
On the other hand, maleic anhydride is known as a monomer that does not homopolymerize, and can be copolymerized with only an electron-donating monomer.

Specific examples of the copolymer of the hydrophobic vinyl monomer and maleic anhydride include styrene-maleic anhydride copolymer, methyl vinyl ether-maleic anhydride copolymer and ethylene-maleic anhydride copolymer. And the like. The molar fraction (mol%) of maleic anhydride in the copolymer is preferably 10 mol% or more.
If it is less than 10 mol%, sufficient compatibility with a living body cannot be obtained. On the other hand, maleic anhydride is known as a monomer that does not homopolymerize, and is generally said to be polymerized by alternate copolymerization with an electron-donating monomer.
It is impossible to make it contain 0 mol% or more. Therefore, the molar fraction of maleic anhydride in the copolymer is 10 to 5
0 mol% is preferable, and 20-50 m is more preferable.
ol%.

Further, a monohydric alcohol is chemically grafted for the purpose of modifying the material such as making the polymer more hydrophobic or hydrophilic, or increasing the mobility of the surface of the polymer material upon contact with body fluid. Is also good. Thus, by treating the polymer,
It is possible to alleviate the biological reaction with each cell or tissue, further alleviate the foreign body reactivity in the living body, and maintain the compatibility for a long time.

The monohydric alcohol is selected from methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, 2-methoxyethyl alcohol, polyethylene glycol monoalkyl ether or a mixture thereof. In addition, lauryl alcohol, stearyl alcohol, oleyl alcohol, polypropylene glycol monoalkyl ether and the like, or a mixture thereof can also be used.

The graft reaction of the monohydric alcohol can be easily performed in a solvent system in which the polymer is dissolved. In order to carry out the reaction well, it is advisable to add tertiary amines such as pyridine and triethylamine as heating and a catalyst.

Further, in the medical device of the present invention, the polymer film material may contain various drugs as necessary in order to suppress thickening and inflammation after placing the medical device in the body. Drugs contained as necessary include anticancer agents, anti-inflammatory agents, antithrombotic agents, antioxidants, and the like, and are appropriately determined according to the indwelling site of the medical device, the intended medical effect, complications to be prevented, and the like. Selected.

In the manufacture of the medical device of the present invention, the method of coating the medical device body with the polymer film material is not particularly limited. For example, a desired amount of the polymer film material and other components contained as required may be contained. A drug is dissolved or dispersed in a solvent to prepare a coating solution, and using the coating solution, a method of coating a medical device body, a medical device body coated only with a polymer film material,
Further, it can be performed by a method such as coating a coating solution containing a desired amount of a drug in a solution of a polymer film material. In the case of the latter method, the respective polymer coating materials may not be the same. Further, the coating method is not particularly limited, and may be any method such as a spray method and a dipping method.

The solvent used for preparing the coating solution is preferably one having a boiling point of 100 ° C. or less.
The above may be used. Suitable solvents include acetone,
Examples include chloroform, dichloromethane, hexane, tetrahydrofuran, methanol, ethanol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and the like. The concentration of the polymer film material in the coating solution is preferably adjusted to 0.01 to 10%, more preferably 0.1 to 5%, from the viewpoint that a uniform film can be formed on the surface of the medical device body. %.

The thickness of the coating covering the surface of the medical device body of the present invention is desirably 0.1 to 100 μm. Within this range, even when the implantable medical device is expanded, the polymer film material does not generate cracks and the like, and has followability. Further, it is possible to secure a sufficient amount of the drug or the like contained as required.

The present invention provides implantable medical devices which can be placed in the body to exhibit desired medical effects, such as stents, stent grafts, artificial blood vessels, catheters, artificial heart valves, pacemaker leads, bone screws, artificial bones. , Artificial trachea, sutures and the like. Above all, a stent used to be placed in a blood vessel such as a stenosis of a living body, a ureter, a urethra, a lymph vessel or the like to secure a sufficient lumen is a specific example of the medical device of the present invention. It is suitable as an embodiment.

Hereinafter, an example of the overall structure of the indwelling stent according to the present invention will be described with reference to FIGS. FIG. 1 is a front view of a stent formed in a tubular shape, and FIG. 2 is a developed view of the stent of FIG. 1 cut and developed along the axial direction.

In the stent 1 shown in FIGS. 1 and 2, a plurality (five in this example) of components 2 (2 in this example) each having a substantially rhombic shape and having an open central portion are provided so as to surround the central axis.
a, 2b, 2c, 2d, 2e) are arranged, and the side of each component 2 is connected by a connecting portion 3 to form an annular unit 4
Is composed. Each component 2 has an axial dimension longer than a circumferential dimension. The shape of the component 2 is not limited to the diamond shape, but may be a substantially elliptical shape or a polygonal shape other than the diamond shape. All the components 2 are arranged so as to be substantially equidistant from the central axis of the stent 1 and are curved in the circumferential direction so as to form a circle with the five components 2. In the axial direction of the stent 1, a plurality (eight in this example) of annular units 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4
h are arranged, and the annular units 4 adjacent to each other are connected at one place by a connecting portion 5 connecting the connecting portions 3 to each other to form a tubular body as a whole. The connecting portions 5 extend slightly obliquely (about 12 degrees in this example) with respect to the central axis of the stent 1, and each connecting portion 5 is spirally arranged along the circumferential direction of the stent 1. I have.

The components 2 constituting the annular units 4 at both ends of the stent 1 have a substantially expanded end in order to obtain a sufficient expanding force at the end and to reduce damage to the inner wall of the blood vessel and the balloon. It has a semi-elliptical shape.

The stent 1 has a diameter suitable for insertion into a living body, and expands when a force spreading outward from the inside of the tubular body is applied. In the stent 1, the end of the component 2 of the adjacent annular unit 4 is placed in a substantially V-shaped or trapezoidal space formed between two adjacent components 2 included in one annular unit 4. Invading.
Since the ends of the components 2 are overlapped along the circumferential direction of the stent 1 in this manner, many annular units 4 are arranged along the axial direction of the stent 1 having a predetermined length. Can be. Therefore, even when the length of each component 2 along the axial direction of the stent 1 is reduced when the stent 1 is expanded, the increase in the gap on the side surface of the stent 1 is small, and the stenosis portion of the blood vessel is more reliably obtained. Can be extended,
And the state can be maintained favorably. Further, the connecting portion 5 is spirally arranged along the circumferential direction of the stent 1,
Since it does not extend so as to form a continuous straight line, the load when one annular unit 4 changes so as to follow a blood vessel can be suppressed from being transmitted to non-adjacent annular units 4. The unit 4 can be expanded independently.

The non-expanded diameter of the stent 1 is 1.2 to
About 1.8 mm is preferable, and especially 1.3 to 1.6 mm
Is more preferred. The axial length of one component 2 is preferably about 1.5 to 4.0 mm, particularly 2.0 to 4.0 mm.
3.0 mm is more preferable. The length of the portion where the components 2 of the annular unit 4 adjacent to each other overlap in the axial direction is preferably 0.5 to 1 mm. The distance between the centers of the adjacent components 2 included in the annular units 4 adjacent to each other is preferably 1.3 to 2.5 mm. The connecting portion 5 is positioned at 0 ° with respect to the central axis of the stent 1.
It is preferable that the inclination is about 30 degrees, especially 5 to 2 degrees.
More preferably, it is inclined at 5 degrees. The length of the connecting portion 5 is preferably from 1.4 to 2.7 mm. The number of the annular units 4 is preferably 6 to 10.

The thickness of the component 2 constituting the annular unit 4 at the center of the stent 1 is preferably about 0.05 to 0.12 mm, particularly preferably 0.06 to 0.10 mm. The thickness of the component 2 constituting the annular unit 4 at both ends of the stent 1 is the thickness of the component 2 constituting the annular unit 4 at the center.
About 3/5 to 4/5 of the wall thickness, specifically 0.05 to
About 0.07 mm is preferable.

As the material of the stent base material, a material having a certain degree of biocompatibility is preferable. For example, a metal material such as stainless steel, titanium or a titanium alloy, tantalum or a tantalum alloy, platinum or a platinum alloy, gold or a gold alloy, or a cobalt-based alloy is used. As stainless steel, SUS316L, which has the best corrosion resistance, is preferable.

The stent having the shape shown in FIGS. 1 and 2 can be manufactured by processing a pipe made of the above-mentioned material by a method such as laser processing. It is preferable to anneal after obtaining a stent having a final shape by processing. By performing the annealing, the flexibility and plasticity of the entire stent are improved, and the indwellability in the bent blood vessel is improved. As a result, the force for restoring the stent to its pre-expanded shape after expansion, particularly the force for restoring to a linear shape after expanding at a bent blood vessel site, is reduced, and the physical force applied to the bent blood vessel inner wall is reduced. As the stimulation decreases, the cause of restenosis can be reduced. The annealing is preferably performed in an atmosphere of an inert gas (for example, argon gas) or a hydrogen gas so that an oxide film is not formed on the surface of the stent, and it is preferable that the stent be heated to 900 to 1200 ° C. and then cooled slowly. After processing into a stent shape, a noble metal plating such as gold or platinum may be applied.

As described above, the medical device of the present invention has been described with reference to FIGS. 1 and 2 by taking a balloon expandable stent as an example. However, the present invention is not limited to these. Applicable.

[0046]

The present invention will be described in more detail with reference to the following examples.

Example 1 A styrene-maleic anhydride copolymer (maleic anhydride content: 50 mol%) was dissolved in acetone to prepare a coating solution having a concentration of 1% by weight. This coating liquid was used for an outer diameter of 1.44 mm,
The inner and outer surfaces of a cylindrical stent (material: SUS316L) having an inner diameter of 1.24 mm and a length of 20 mm were coated by a spray method. The inner and outer surfaces of the stent were uniformly coated with a styrene-maleic anhydride copolymer, and the thickness of the coating film was about 100 μm.

Example 2 A partially esterified product of styrene-maleic anhydride copolymer (maleic anhydride content: 50 mol%) with methyl alcohol (esterification ratio with methyl alcohol: 50%) was 1% by weight in acetone.
To prepare a coating solution. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The inner and outer surfaces of the stent are uniformly coated with the partially esterified product, and the thickness of the coating film is about 50 μm.
Met.

Example 3 A partially esterified product of styrene-maleic anhydride copolymer (maleic anhydride content: 30 mol%) with isobutyl alcohol (esterification ratio with isobutyl alcohol: 50%) was added to acetone at 1% by weight. To prepare a coating solution. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The inner and outer surfaces of the stent were uniformly coated with the partially esterified product, and the thickness of the coating film was about 110 μm.

Example 4 Partial esterification of styrene-maleic anhydride copolymer (maleic anhydride content: 50 mol%) with methyl alcohol and isobutyl alcohol (esterification rate with methyl alcohol: 25)
%, Esterification rate with isobutyl alcohol 25%)
Was dissolved in acetone at a concentration of 1% by weight to prepare a coating solution. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The partial esterified product was uniformly coated on the inner and outer surfaces of the stent, and the thickness of the coating film was about 100 μm.

Example 5 Partial esterification of styrene-maleic anhydride copolymer (maleic anhydride content: 40 mol%) with methyl alcohol and isobutyl alcohol (esterification ratio with methyl alcohol: 25)
%, Esterification rate with isobutyl alcohol 25%)
Was dissolved in acetone at a concentration of 5% by weight to prepare a coating solution. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The partial esterified product was uniformly coated on the inner and outer surfaces of the stent, and the thickness of the coating film was about 100 μm.

Example 6 A coating solution was prepared by dissolving an ethylene-maleic anhydride copolymer (maleic anhydride content: 30 mol%) in acetone at a concentration of 0.5% by weight. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The partial esterified product was uniformly coated on the inner and outer surfaces of the stent, and the thickness of the coating film was about 100 μm.

Example 7 Partial esterified product of styrene-maleic anhydride copolymer (maleic anhydride content: 20 mol%) with methyl alcohol and isobutyl alcohol (esterification ratio with methyl alcohol: 25)
%, Esterification rate with isobutyl alcohol: 25
%) Was dissolved in acetone at a concentration of 5% by weight to prepare a coating liquid. The same stent as that used in Example 1 was immersed and dried in this coating solution to perform coating. The inner and outer surfaces of the obtained stent were uniformly coated with the partial esterified product, and the thickness of the coating film was about 100 μm.

Example 8 A copolymer was synthesized by radical polymerization of methacryloyloxyethylene phthalic acid and 2-methoxyethyl acrylate in dioxane at a weight ratio of 2: 3. This copolymer was purified by a reprecipitation method, and dissolved in chloroform at a concentration of 1% by weight to prepare a coating solution. This coating solution was used in Example 1
The inner and outer surfaces of the same stent as those used in the above were coated by a spray method. The inner and outer surfaces of the stent were uniformly coated with the copolymer, and the thickness of the coating film was about 100 μm.

Example 9 A copolymer was synthesized by radical polymerization of 4-methacryloyloxyethylene trimellitic anhydride and 2-methoxyethyl acrylate in dioxane at a weight ratio of 1: 1. This copolymer was purified by a reprecipitation method, and dissolved in chloroform at a concentration of 1% by weight to prepare a coating solution. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The inner and outer surfaces of the stent are uniformly coated with the copolymer,
The thickness of the coating film was about 100 μm.

Example 10 Methacryloyloxyethylene phthalic acid and methyl vinyl ether were radically polymerized in a weight ratio of 2: 3 in toluene to synthesize a copolymer. This copolymer was purified by a reprecipitation method, and dissolved in chloroform at a concentration of 1% by weight to prepare a coating solution. This coating solution was coated on the inner and outer surfaces of the same stent as used in Example 1 by a spray method. The inner and outer surfaces of the stent were uniformly coated with the copolymer, and the thickness of the coating film was about 100 μm.

Next, the in vitro evaluation of antiplatelet activity was carried out using the stents obtained in Examples 1, 4 and 8 as Experimental Examples 1 to 3, and a coating film was prepared as a comparative example. Experimental Example 4 in which antiplatelet activity was evaluated for a stent having no stent was also performed. At this time, the evaluation of antiplatelet activity was performed by the following method. The results are shown below.

Evaluation of antiplatelet activity On the surface of the coating film formed on the stainless steel plate,
Platelet count is 10 × 10 ^FourMulti-blood adjusted to μl
100 μl of platelet plasma was added dropwise. Ink at room temperature for 30 minutes
After rinsing, rinse thoroughly with saline.
Was. After fixation, adsorbed on the film surface with an electron microscope
The platelets were observed at a 1000-fold image and evaluated. Any
Of platelets adsorbed on the surface of the membrane in five fields of view
Are classified into the following three groups according to their degree of activity.
Was counted. For comparison, stainless steel
A stainless steel plate (SUS316L) was used. type I type Almost no morphological change type II type Although prosthesis is put out, activity is moderate
Type III type Completely collapses form and adheres to material surface
And high activity

(Experimental Example 1) The number of platelets adsorbed on the surface of the film formed with the coating solution prepared in Example 1 was counted. As a result, two type I types and two type II
It was confirmed that the total number of platelets adsorbed as 5 types and 2 type III types was small, the number of activated platelets was small, and the anti-platelet activity of the coating film was high.

(Experimental Example 2) The number of platelets adsorbed on the surface of the film formed using the coating solution prepared in Example 4 was counted. As a result, three type I types, ty
Eight peII types and two typeIII types confirmed that the total number of platelets adsorbed was small, the number of activated platelets was also small, and the anti-platelet activity of the coating film was high.

(Experimental Example 3) The number of platelets adsorbed on the surface of the film formed using the coating solution prepared in Example 8 was counted. As a result, four type I types, t
With 6 ypeII types and 3 typeIII types, the number of adsorbed platelets was small and the number of activated platelets was also small, confirming that the anti-platelet activity of the coating film was high.

(Experimental Example 4) As a comparative example, the number of platelets adsorbed on the surface of a stainless steel SUS316L plate was counted. As a result, there were three type I types, ten type II types, and thirty type III types.
It was confirmed that the antiplatelet activity was inferior to that evaluated in 3.

Further, Experimental Examples 5 to 7 for evaluating the in vivo biocompatibility of the stents obtained in Examples 1, 4 and 8 were performed. At this time, the biocompatibility was evaluated by an experiment in which a stent was placed in the rabbit iliac artery according to the following method.

Evaluation of Biocompatibility The coated stent was mounted on a balloon catheter and subjected to EOG sterilization. JW rabbit (about 3k
g, male) was shaved under ketamine and xylazine anesthesia, and after disinfection with isodine, the right common carotid artery was detached from the tissue. After introducing about 150 U / kg of heparin from the auricular vein, a balloon catheter in which a stent pre-loaded on the detached right common carotid artery is selectively introduced into the iliac artery from the sheath introducer and defined at the indwelling site The stent was expanded by pressure. After removing the balloon, the right common carotid artery was ligated and locally sutured. 4 from stent placement
One week later, a sheath introducer was introduced into the left common carotid artery in the same manner as when the stent was placed. Under fluoroscopy, a contrast catheter is inserted into the blood vessel from the sheath introducer, and the catheter is selectively carried to the abdominal aorta (approximately 3 cm above the branch of the iliac artery). After injection, the left and right iliac arteries were contrasted from the right and left femoral arteries to confirm the state of blood flow. Next, after performing systemic perfusion with a heparinized diet, blood vessels near the stent placement site were fixed with a 10% neutral buffered formalin solution. After sufficient immobilization, target vessels were excised. The blood vessel in which the stent was placed was embedded in a resin by a conventional method, and a pathological specimen was prepared. The pathological specimen was stained with HE and observed with an optical microscope.

(Experimental Example 5) As a result of an angiographic examination of the site where the stent obtained in Example 1 was indwelled, it was confirmed that the indwelling portion was sufficiently patent and blood flow was secured.
Further, as a result of pathological observation, there was almost no thickening, no inflammatory reaction around the stent was observed, and the tissue compatibility was shown.

(Experimental Example 6) As a result of an angiographic examination of the site where the stent obtained in Example 4 was indwelled, it was confirmed that the indwelling portion was sufficiently patent and blood flow was secured.
Further, as a result of pathological observation, there was almost no thickening, no inflammatory reaction around the stent was observed, and the tissue compatibility was shown.

(Experimental Example 7) As a result of an angiographic examination of the site where the stent obtained in Example 8 was indwelled, it was confirmed that the indwelling portion was sufficiently patent and blood flow was secured.
Further, as a result of pathological observation, there was almost no thickening, no inflammatory reaction around the stent was observed, and the tissue compatibility was shown.

[0068]

The implantable medical device of the present invention has excellent antithrombotic properties and tissue compatibility, and can exhibit its excellent characteristics stably for a long period of time after being placed in the body. Therefore, the implantable medical device of the present invention is particularly suitable for a stent used for indwelling in a blood vessel such as a stenosis of a living body, a ureter, a urethra, a lymph vessel or the like to secure a sufficient lumen. It is suitable as.

[Brief description of the drawings]

FIG. 1 is a front view showing an example of a stent which is a specific example of the medical device for implantation within the body of the present invention.

FIG. 2 is a development view of the stent of FIG. DESCRIPTION OF SYMBOLS 1 Stent 2 Component 3 Connecting part 4 Annular unit 5 Connecting part

Claims (8)

[Claims] (1) At least a part of a surface of a medical device main body is
An implantable medical device coated with a polymer film material comprising a polymer having at least one functional group selected from a carboxyl group and a carboxylic anhydride group. 2. The method according to claim 1, wherein the polymer is a hydrophobic vinyl monomer,
The implantable medical device according to claim 1, which is a copolymer with a monomer having at least one functional group selected from a carboxyl group and a carboxylic anhydride group. 3. The polymer according to claim 1, wherein the polymer is a hydrophobic vinyl monomer,
2. The implantable medical device according to claim 1, which is a copolymer with maleic anhydride. 4. The method according to claim 1, wherein the hydrophobic vinyl monomer is styrene,
4. The implantable medical device according to claim 2, wherein the medical device is at least one selected from ethylene and methyl vinyl ether. 5. The polymer according to claim 1, wherein the copolymer is a styrene-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, a methyl vinyl ether-maleic anhydride copolymer, or a copolymer of these with a monohydric alcohol. 2. The implantable medical device according to claim 1, wherein the medical device is at least one member selected from partially esterified copolymers which are esterified in a targeted manner. 6. The monohydric alcohol is at least one selected from methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, 2-methoxyethyl alcohol and polyethylene glycol monoalkyl ether. 6. The medical device implantable in the body according to item 5. 7. The polymer according to claim 2, wherein the polymer is a vinyl polymer containing a structural unit derived from at least one selected from 4-methacryloyloxyethylene trimellitic anhydride and methacryloyloxyethylene phthalic acid. Implantable medical device. 8. The medical device according to claim 1, wherein the medical device body is a stent.