JPH09131397A - Polymer material for medical use, and manufacture thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide excellent blood compatibility, and stably maintain the blood compatibility for a long period. SOLUTION: In this polymer material for medical use, copolymer comprising vinyl monomer units including phosphoryl choline radicals by 5-90mol%, vinyl monomer units including at least one sort of functional groups selected among epoxy radicals isocyanate radicals, hydroxyl groups, amino groups, carboxyl groups, and melcapt groups by 0.1-50mol%, and hydrophobic vinyl monomer units by 5-90mol% is coated on the surface of thermoplastic resin base material. The copolymer and the thermoplastic resin base material are coupled with each other by noncovalent coupling, and copolymer is coupled with each other by covalent crosslink.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medical polymer material and a method for producing the same. INDUSTRIAL APPLICABILITY The medical polymer material of the present invention has excellent blood compatibility and is stably retained for a long period of time, and thus is useful as a material for medical devices such as artificial organs.

[0002]

2. Description of the Related Art In recent years, medical materials such as artificial organs have been actively developed, but in this technical field, there is a problem of biocompatibility, in particular, it does not cause blood coagulation.
It is desired to develop a medical material having excellent blood compatibility that does not activate the complement system. As a method for obtaining a medical material having excellent blood compatibility, the following three types of methods have been mainly tried. (1) A method of molding using a synthetic polymer having excellent blood compatibility as a raw material, or coating the surface of a medical material with the synthetic polymer. (2) A method of adding an anticoagulant physiologically active substance such as heparin or urokinase to a medical material or binding it to the surface of the medical material. (3) A method using a biomaterial such as collagen or a bioprosthetic valve as a raw material. In the methods of (2) and (3) above, the anticoagulant physiologically active substance or biomaterial used as a raw material is a natural product, so it is expensive and, depending on the manufacturing conditions and storage conditions of medical materials, blood compatibility Is lost. Therefore, the above method (1) using a synthetic polymer having excellent blood compatibility, which can be mass-produced relatively inexpensively, has been actively researched.

By the way, phospholipids are the major constituents of biological membranes, and are specifically present in the membrane-like structure of cells.
It is known that phospholipids are involved in the function of biological membranes by themselves or through interactions with membrane proteins.
From this fact, not only phospholipids but also compounds similar to phospholipids are considered to have excellent blood compatibility and eventually biocompatibility, and have been actively studied in recent years. Examples of such a conventional technique include (i) 2-methacryloyloxyethylphosphorylcholine (hereinafter, may be abbreviated as MPC) by the present applicant, which is excellent in biocompatibility.
(See JP-A-54-63025), (ii)
A medical material having a base material coated with a copolymer of MPC and a methacrylic acid ester such as ethyl methacrylate
39309), (iii) poly-2-hydroxyethyl methacrylate having a hydroxyl group, which is a copolymer of MPC, n-butyl methacrylate, and glycidyl methacrylate having an epoxy group (hereinafter referred to as PHEM.
(A may be abbreviated as “A”) Covalently immobilized material [31st Annual Meeting of the Japanese Society for Artificial Organs (1993),
177], (iv) MPC, a vinyl chloride resin tube coated with a copolymer of methacryloyloxypropyltrichlorosilane, n-butyl methacrylate and 2-hydroxyethyl methacrylate, or MPC, 11
Examples thereof include polysulfone hollow fiber membranes (JP-A-7-51355) coated with a copolymer of methacryloyloxyundecyltrimethoxysilane, methyl methacrylate and 2-hydroxypropyl methacrylate.

[0004]

However, the MPC of (i) above has good blood compatibility, and
PC homopolymers have excellent biocompatibility, but MPC homopolymers are water-soluble and cannot be used as medical materials because they dissolve easily when they come into contact with body fluids such as blood. The medical material of the above (ii), in which the base material surface is coated with a copolymer of MPC and a methacrylic acid ester which is a hydrophobic monomer, is problematic when used for a short period of time under the condition of being in contact with blood. However, when used for a long time, there is a drawback that the copolymer coated on the surface of the base material is gradually eluted into blood and blood compatibility does not last for a long time. Furthermore, the dissolved copolymer may enter the body and cause an unexpected risk. The material of (iii) above is MPC
Although the copolymer and PHEMA are covalently bonded, they can be coated only on the surface of a special resin having a functional group such as a hydroxyl group capable of covalently bonding with an epoxy group. In the example in which the MPC copolymer of the above (iv) is coated on the inner surface of the vinyl chloride resin tube, it is treated with a 40% sulfuric acid aqueous solution containing 2% potassium permanganate before coating to give a vinyl chloride resin with a hydroxyl group,
A functional group that is covalently bonded to the MPC copolymer such as a carboxyl group is introduced, and the tube is covered by covalently bonding with the functional group. Such treatment uses a strong acid to ensure worker safety and process. Considering the complexity of wastewater treatment and wastewater treatment, it is preferable that the coating can be performed without such treatment. In addition, in the above polysulfone hollow fiber membrane, the MPC copolymer impregnated in the small pores present in the hollow fiber membrane is
The copolymers are crosslinked, and are hardly bonded to the hollow fiber membrane. In this case, the hollow fiber membrane was relatively stable because it was porous, and when the shape of the resin substrate was a tube or plate, it was not possible to stably coat the copolymer. . The processing temperature here is 100 ° C., which is considerably lower than the glass transition temperature of polysulfone (about 180 ° C.).

Therefore, an object of the present invention is to provide a medical polymer material in which the coated copolymer having a phosphorylcholine group is stably retained without being dissolved in blood, that is,
It is an object of the present invention to provide a medical polymer material having excellent blood compatibility and being stably maintained for a long period of time, and a method for producing the same.

[0006]

According to the present invention, the above-mentioned object is 5 to 90 mol% of a vinyl monomer unit having a phosphorylcholine group; an epoxy group, an isocyanate group, a hydroxyl group, an amino group, a carboxyl group, A copolymer containing 0.1 to 50 mol% of a vinyl monomer unit having at least one functional group selected from the group consisting of mercapto groups; In the medical polymer material coated on the surface of the plastic resin base material, the copolymer and the thermoplastic resin base material are bound to each other by a non-covalent bond, and the copolymers are covalently crosslinked. 5 to 90 mol% of a vinyl polymer unit having a phosphorylcholine group, and a medical polymer material characterized by: an epoxy group, an isocyanate group, a hydroxyl group, an amino group, a carboxyl group, a merca The vinyl monomer unit having at least one functional group selected from the group consisting of preparative group 0.1
˜50 mol%; a thermoplastic resin substrate surface is coated with a copolymer containing a hydrophobic vinyl monomer unit in an amount of 5 to 90 mol%, and the thermoplastic resin is then optionally added in the presence of a crosslinking agent. It is achieved by providing a method for producing a medical polymer material, which comprises heating the substrate to a temperature not lower than the glass transition temperature.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The copolymer of the present invention needs to contain a vinyl monomer unit having a phosphorylcholine group in an amount of 5 to 90 mol% based on all structural units, which further improves blood compatibility. It is preferable that the content is 20 to 70 mol% from the viewpoint of being expressed. When the content of the vinyl monomer unit containing a phosphorylcholine group is less than 5 mol%, the blood compatibility is not sufficiently expressed, and when it exceeds 90 mol%, the water solubility becomes too high and the coating is performed. The copolymer is easily detached from the medical polymer material.

Examples of the vinyl monomer having a phosphorylcholine group include MPC, 2-methacryloyloxyethoxyethylphosphorylcholine, 6-methacryloyloxyhexylphosphorylcholine, 9-methacryloyloxynonylphosphorylcholine, allylphosphorylcholine, butenylphosphorylcholine, hexenylphosphorylcholine, Examples thereof include octenylphosphorylcholine and decenylphosphorylcholine. Among them, MPC is preferable because it has excellent polymerizability and is easily available. These vinyl monomers having a phosphorylcholine group are used alone or in combination of two or more.

The copolymer in the present invention is an epoxy group,
At least one selected from the group consisting of an isocyanate group, a hydroxyl group, an amino group, a carboxyl group, and a mercapto group.
It is necessary to contain 0.1 to 50 mol% of vinyl monomer units having various functional groups with respect to all structural units, and from the viewpoint of stably coating the surface of the thermoplastic resin substrate with the copolymer. , 1 to 25 mol% is preferable. As the functional group contained in the copolymer, an epoxy group having good reactivity is preferable.

Examples of the vinyl monomer having an epoxy group include glycidyl acrylate, glycidyl methacrylate, allyl glycidyl ether and the like.
Glycidyl methacrylate is preferable from the viewpoint of easy synthesis of the copolymer. These vinyl monomers having an epoxy group are used alone or in combination of two or more. As the vinyl monomer having an isocyanate group,
Examples thereof include methacryloyl isocyanate. As the vinyl monomer having a hydroxyl group, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate,
2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, allyl alcohol and the like are exemplified. As the vinyl monomer having an amino group, allylamine,
2-Methylallylamine and the like are exemplified. Examples of the vinyl monomer having a carboxyl group include methacrylic acid, acrylic acid, 3-allyloxypropionic acid and the like. Examples of the vinyl monomer having a mercapto group include methacrylic acid 3-mercaptopropyl ester and allyl mercaptan.

The copolymer of the present invention must contain the hydrophobic vinyl monomer unit in an amount of 5 to 90 mol%, which is to increase the bonding force between the copolymer and the thermoplastic resin substrate. , 25 to 7 from the viewpoint of ease of synthesis of the copolymer, etc.
It is preferable to contain 5 mol%. The hydrophobic vinyl monomer unit is an alkyl group, a vinyl monomer unit having a hydrophobic group such as a phenyl group, and as the hydrophobic vinyl monomer that induces the unit, for example, methyl methacrylate, Ethyl methacrylate, n-butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate, stearyl methacrylate, methyl acrylate, ethyl acrylate, n-butyl acrylate, hexyl acrylate, 2-acrylic acid Examples include ethylhexyl, alkyl (meth) acrylates such as dodecyl acrylate, styrene, etc. Among them, separation and purification of the resulting copolymer and unpolymerized monomers are easy, and a thermoplastic resin substrate is also used. A (meth) acryl having an alkyl group with 4 or more carbon atoms, such as having good bondability with Alkyl esters are preferred, hexyl methacrylate,
More preferred are (meth) acrylic acid alkyl esters having 6 or more carbon atoms in the alkyl group such as 2-ethylhexyl methacrylate, dodecyl methacrylate, stearyl methacrylate, hexyl acrylate, 2-ethylhexyl acrylate, dodecyl acrylate. These monomers are used alone or in combination of two or more.

The number average molecular weight of the copolymer in the present invention is preferably 5,000 or more from the viewpoint of facilitating separation and purification of the resulting copolymer and unpolymerized monomer.
000 or more is more preferable. The upper limit of the number average molecular weight of the copolymer is preferably 1,000,000 or less.

The copolymer in the present invention is, for example, at least one selected from the group consisting of a vinyl monomer having a phosphorylcholine group; an epoxy group, an isocyanate group, a hydroxyl group, an amino group, a carboxyl group and a mercapto group.
A vinyl monomer having various functional groups; and a monomer composition obtained by mixing a required amount of a hydrophobic vinyl monomer, are produced by radical polymerization in a solvent in the presence of a polymerization initiator. be able to.

As the polymerization initiator, a polymerization initiator generally used in radical polymerization, for example, 2,
2'-azobisisobutyronitrile (hereinafter referred to as AI
BN), azo compounds such as 1,1′-azobis (cyclohexanecarbonitrile), and organic peroxides such as benzoyl peroxide and lauryl peroxide.

The solvent is not particularly limited as long as it dissolves the above-mentioned monomer and does not denature the monomer. For example, methanol, ethanol, t-butyl alcohol, benzene, toluene, tetrahydrofuran, dioxane, Examples thereof include dichloromethane and chloroform. These solvents are used alone or in combination of two or more.

By coating the surface of the thermoplastic resin substrate with the copolymer thus obtained to form a copolymer layer on the surface of the thermoplastic resin substrate, the glass of the thermoplastic resin substrate is formed. The medical polymer material of the present invention can be produced by heating to a temperature above the transition temperature.

As the thermoplastic resin base material, a thermoplastic resin base material usually used for medical purposes can be used.
Polyolefins such as polyethylene, polypropylene, poly-4-methylpentene-1, vinyl chloride resin, vinylidene chloride resin, polystyrene, ABS resin, acrylic resin, polycarbonate, thermoplastic polyurethane, vinylidene chloride-vinyl chloride copolymer, ethylene- Vinyl alcohol copolymer, thermoplastic polyester, thermoplastic fibrin derivative resin, polysulfone, polyether sulfone, polyvinyl butyral, acrylonitrile-styrene resin, styrene-isoprene (block) copolymer, hydrogenated styrene-isoprene ( block)
Examples include base materials made of thermoplastic resins such as copolymers, styrene-olefin (block) copolymers, and mixtures thereof. Examples of the shape of the thermoplastic resin base material include tubes, containers, bags, and membranes.

The coating of the thermoplastic resin substrate with the copolymer is
It can be carried out by applying a coating solution obtained by dissolving the copolymer in a solvent to the thermoplastic resin substrate, spraying it, or immersing the thermoplastic resin substrate in the coating solution. As the solvent used as described above, an organic solvent is usually used, and the concentration of the copolymer in the coating solution is preferably in the range of 0.1 to 30% by weight. As the organic solvent, one that does not modify the copolymer and does not modify the surface of the thermoplastic resin substrate is used, and examples thereof include methanol, ethanol, dioxane, and acetone. These are used alone or as a mixed solvent of two or more kinds. Of these, methanol and ethanol are preferable because they do not modify the surface of the thermoplastic resin substrate, have a low boiling point, and are easily dried. However, when the copolymer contains an isocyanate group, acetone is usually used because the solvent reacts with the isocyanate group when alcohol is used.

Next, the thermoplastic resin base material coated with the copolymer is treated with a glass transition temperature (hereinafter,
This may be abbreviated as Tg). By heating the copolymer to a temperature higher than or equal to Tg, the copolymer and the thermoplastic resin substrate are bonded by a non-covalent bond, and the copolymer is crosslinked with each other. The medical polymer material can be obtained. That is, by heating the thermoplastic resin base material to a temperature equal to or higher than the glass transition temperature, the thermoplastic resin base material becomes in an amorphous state, the thermoplastic resin base material and the copolymer are hydrogen-bonded, van der Waals force, etc. Stable non-covalent bond due to the intermolecular force of.

On the other hand, the crosslinking between the copolymers is carried out between the functional groups of the copolymer. When the copolymer has at least one functional group of an epoxy group and an isocyanate group, these functional groups react with water contained in the air or the solvent by heating and can be crosslinked. . When using a copolymer having at least one functional group selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group and a mercapto group and at least one functional group of an epoxy group and an isocyanate group, and a hydroxyl group , A copolymer having at least one functional group selected from the group consisting of an amino group, a carboxyl group and a mercapto group, and a copolymer having at least one functional group of an epoxy group and an isocyanate group. In some cases, cross-linking can be achieved by reaction between these functional groups.

In the present invention, when a copolymer having only at least one functional group selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group and a mercapto group is used, covalent cross-linking is carried out using a cross-linking agent. It is necessary to. As the cross-linking agent, a cross-linking agent having two or more functional groups of at least one of an epoxy group and an isocyanate group is used, and, for example, 1,4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, 1, Examples thereof include 6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, 1,3-butadiene diepoxide, 1,7-octadiene diepoxide, hexamethylene diisocyanate, and 4,4′-diphenylmethane diisocyanate. These compounds may be used alone or
Used in combinations of more than one species.

When the copolymer has at least one functional group of an epoxy group and an isocyanate group, at least one selected from the group consisting of an amino group, a hydroxyl group, a carboxyl group and a mercapto group. It is also possible to crosslink with a crosslinking agent having two or more functional groups. As the cross-linking agent, bis (3-aminopropyl) ether, 1,2-bis (2-aminoethoxy) ethane,
N, N'-bis (2-aminoethyl) -1,3-propanediamine, 1,4-butanediol bis (3-aminopropyl) ether, ethylene glycol bis (3-aminopropyl) ether, diethylene glycol bis (3 -Aminopropyl) ether, bis (3-aminopropyl) ether, ethylenediamine, hexamethylenediamine, ethylene glycol, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyethylene glycol, ethylene glycol bis (4-carboxyphenyl) ether, 1 , 10-bis (4-carboxyphenoxy) decane, 1,6-hexanedithiol and the like. These compounds are used alone or in combination of two or more.

The amount of the cross-linking agent used is the epoxy group, isocyanate group, hydroxyl group, amino group,
It is preferably within the range of 0.01 to 50 mol% with respect to the total number of moles of the carboxyl group and the mercapto group. When a cross-linking agent is used, it is preferable to dissolve the cross-linking agent in the coating solution.

The above heating is carried out at a temperature within the range from Tg of the thermoplastic resin substrate to the melting point of the thermoplastic resin substrate in order to bond the copolymer and the thermoplastic resin substrate by non-covalent bond. Is preferable, and it is more preferable that the temperature is not lower than Tg + 5 ° C. and not higher than the temperature at which the thermoplastic resin substrate is modified. At the same time, it is preferable to adopt a temperature at which the crosslinking reaction of the copolymer also proceeds. The temperature at which the thermoplastic resin base material is modified means the temperature at which the thermoplastic resin base material becomes unusable due to deformation, coloring, etc., and varies depending on the type and usage form of the thermoplastic resin base material. The heating time varies depending on the type and ratio of structural units of the copolymer, the type of thermoplastic resin substrate, etc., but is preferably the time shown by the following mathematical formula (1) or more. The upper limit of the heating time is preferably 200 hours or less from the viewpoint of productivity.

[0025]

(Equation 1)

For example, in the case of coating the surface of a thermoplastic resin substrate with a copolymer of MPC, glycidyl methacrylate and hexyl methacrylate, when the thermoplastic resin substrate is a vinyl chloride resin (Tg: about 70 ° C.), The heating temperature is preferably in the range of 75 to 120 ° C, more preferably in the range of 80 to 100 ° C from the viewpoint that the thermoplastic resin substrate is not denatured by heat and the copolymer can be firmly coated. As for the heating time, if the heating temperature is 80 ° C,
It is preferably in the range of 6 to 100 hours, and in the case of 120 ° C., preferably in the range of 0.4 to 24 hours. Further, the thermoplastic resin base material is poly-4-methylpentene-1 resin (Tg:
When the heating temperature is about 50 ° C, the heating temperature is 55 to 80 ° C.
Is preferably within the range. As for the heating time, the heating temperature is 6
In the case of 0 ° C, it is preferably within the range of 24 to 200 hours,
In the case of 80 ° C., the range of 6 to 100 hours is preferable.

Phosphorylcholine groups are present on the surface of the medical polymer material of the present invention at 1 × 10 ⁻¹⁰ to 1 × 10 ⁻⁵ mol / c.
It is preferably present at a density of m ² and is from 1 × 10 ⁻⁹ to
More preferably, it is present at a density of 1 × 10 ^-5 mol / cm ² . Surface density of phosphorylcholine group is 1 × 10
When it is less than ^-10 mol / cm ² , blood compatibility is difficult to be expressed.

The medical polymer material of the present invention is excellent in blood compatibility, hardly causes thrombus even when it comes into contact with blood, and does not activate complement. Since the copolymer having blood compatibility does not easily desorb from the surface of the thermoplastic resin substrate, the polymer material for medical use maintains blood compatibility for a long period of time. Therefore, the medical polymer material of the present invention is suitable as a material for all medical devices such as catheters, blood circuits, blood bags, and artificial blood vessels that are used in contact with blood for a long period of time.

[0029]

EXAMPLES The present invention will be described below with reference to Examples and the like.
The present invention is not limited to these. The number average molecular weight of the copolymer was determined by the GPC method, and the content ratio of structural units in the copolymer was determined by the ¹ H-NMR method.

Reference Example 1 MPC [manufactured by NOF CORPORATION] 3.13 g (55 mol%), glycidyl methacrylate 0.14 g (5 mol%), n-butyl methacrylate 1.10 g (40 mol%) and AIBN0. 0.04 g was dissolved in 28 ml of ethanol, and the inside of the reaction vessel was sufficiently replaced with argon gas.
The polymerization reaction was carried out by immersing the reaction container in a warm bath at 60 ° C. for 24 hours. After cooling, the polymerization solution was poured into chloroform to precipitate the copolymer. After the precipitate separated by filtration was dissolved in methanol and poured again into chloroform to precipitate the copolymer, the operation was repeated twice, and finally, precipitation was performed with ethyl ether instead of chloroform, and the precipitate of the copolymer was separated by filtration. , Dried in vacuum. The yield was 65%. The content of MPC units in the obtained copolymer (hereinafter, sometimes abbreviated as Copolymer 1) is 54 mol%, and the content of glycidyl methacrylate units is 4.5.
Mol%, the content of n-butyl methacrylate unit is 41.
It was 5 mol% and the number average molecular weight of the copolymer 1 was 140,000.

Reference Example 2 In Reference Example 1, the types and proportions of the monomers used were MPC 2.3 g (40 mol%), glycidyl methacrylate 0.55 g (20 mol%), and methacrylic acid n-.
A copolymer was obtained in the same manner as in Reference Example 1 except that 1.31 g (40 mol%) of hexyl was used. The yield was 82%. The content of MPC unit in the obtained copolymer (hereinafter, sometimes abbreviated as copolymer 2) was 38.
Mol%, content of glycidyl methacrylate unit is 18
Mol%, the content of n-hexyl methacrylate unit is 44
The copolymer 2 had a number average molecular weight of 120,000.

Reference Example 3 In Reference Example 1, the types and proportions of the monomers used were MPC 2.0 g (35 mol%), glycidyl methacrylate 0.55 g (20 mol%), and methacrylic acid 2-.
A copolymer was obtained in the same manner as in Reference Example 1 except that 1.72 g (45 mol%) of ethylhexyl was used. Yield 75
%Met. The content of MPC unit in the obtained copolymer (hereinafter, this may be abbreviated as Copolymer 3) is 32 mol%, the content of glycidyl methacrylate unit is 19 mol%, and 2-ethylhexyl methacrylate unit. Was 49 mol% and the number average molecular weight of the copolymer 3 was 150,000.

Example 1 The copolymer 1 obtained in Reference Example 1 was dissolved in ethanol to a concentration of 5% to prepare a copolymer solution. Fill the inside of a soft vinyl chloride resin medical tube with an inner diameter of 10 mm with the copolymer solution, and after 10 minutes, remove the solution,
Heat at 100 ° C. for 24 hours. The tube was washed with ethanol to obtain a tube coated with the copolymer. Whole blood added with heparin to a concentration of 2 U / ml,
After filling this copolymer-coated tube at 37 ° C. for 30 minutes, blood was taken out and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that proteins and platelets were scarcely attached. Further, after washing the above copolymer-coated tube with distilled water, one end of the tube was closed with forceps, whole blood immediately after blood collection was put therein, and the time until coagulation was measured. As a result, it was 21 minutes. The glass transition temperature of the vinyl chloride resin used at this time was about 70 ° C.

Comparative Example 1 Whole blood to which heparin was added at a concentration of 2 U / ml was filled in a soft vinyl chloride resin tube just washed with distilled water for 30 minutes at 37 ° C. Was taken out and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that many platelets were attached. Also, after washing the soft vinyl chloride resin tube with distilled water, one end of the tube was closed with forceps, whole blood immediately after blood collection was placed in it, and the time until coagulation was measured.
5 minutes. From the above results, it can be seen that the tube obtained in Example 1 has a good antithrombotic property.

Example 2 The copolymer 2 obtained in Reference Example 2 was dissolved in ethanol to a concentration of 10% to prepare a copolymer solution. A vinyl chloride resin film (thickness 1 mm) was immersed in the copolymer solution, taken out 5 minutes later, and heated at 80 ° C. for 12 hours. This was washed with ethanol to obtain a film coated with the copolymer. This copolymer-coated film is
After autoclave sterilization at ℃ for 30 minutes, a part of
It was immersed in a 1% o-toluidine blue aqueous solution. After washing with water, visual observation showed that the dye was uniformly dyed, and it was confirmed that the copolymer was uniformly coated even after sterilization. In addition, when observing the stained area with a microscope, the thickness was about 1 μm.
Since the dyed layer of No. 2 was present, it was confirmed that the coated copolymers were crosslinked. Next, the autoclave-sterilized copolymer-coated film was immersed in whole blood containing heparin at a concentration of 2 U / ml at 37 ° C. for 30 minutes, and then the blood was taken out and fixed with glutaraldehyde. . Observation of the blood contact surface with an electron microscope revealed that proteins and platelets were scarcely attached.

Example 3 The copolymer 3 obtained in Reference Example 3 was dissolved in ethanol to a concentration of 5% to prepare a copolymer solution. The inside of a soft vinyl chloride resin tube having an inner diameter of 8 mm was filled with the copolymer solution, and after 5 minutes, the solution was taken out and the temperature was adjusted to 2 at 80 ° C.
After heating for 4 hours, it was washed with distilled water to obtain a tube coated with the copolymer. A part of this copolymer-coated tube was immersed in a 0.01% o-toluidine blue aqueous solution for 5 minutes, washed with water, and visually observed to find that it was uniformly dyed and the copolymer was uniformly coated. It was confirmed. Next, whole blood to which heparin was added so that the concentration thereof was 2 U / ml was added to the copolymer-coated tube to give 37
After filling at 30 ° C. for 30 minutes, blood was taken out and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that proteins and platelets were scarcely attached. In addition, the above copolymer-coated tube (length 8
cm) was stopped with forceps, whole blood immediately after blood collection was put therein, and the time until coagulation was measured was 22 minutes. The glass transition temperature of the vinyl chloride resin used at this time was about 70 ° C.

Comparative Example 2 Treatment was carried out under the same conditions as in Example 3 except that the heating temperature was changed to 60 ° C. in Example 3. That is, the copolymer 3 obtained in Reference Example 3 was dissolved in ethanol to a concentration of 5% to prepare a copolymer solution. The inside of a soft vinyl chloride resin tube having an inner diameter of 8 mm was filled with the copolymer solution, and after 5 minutes, the solution was drained, heated at 60 ° C. for 24 hours, and washed with distilled water to obtain a tube. A part of this tube was immersed in a 0.01% o-toluidine blue aqueous solution for 5 minutes, washed with water, and visually observed.
It was confirmed that the tube was not coated with the copolymer. Next, whole blood to which heparin was added at 2 U / ml was filled in this tube at 37 ° C. for 30 minutes, and then the blood was taken out and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that many proteins and platelets were attached. In addition, one end of the above-mentioned tube (length 8 cm) was stopped with forceps, whole blood immediately after blood collection was put therein, and the result of measuring the time until coagulation was obtained.
It was 15 minutes. From these results, it is found that the copolymer is not coated when the heat treatment is performed at a temperature lower than the glass transition temperature.

Reference Example 4 In Reference Example 1, the ratio of the monomers used was changed to MPC.
2.0 g (35 mol%), glycidyl methacrylate 0.14 g (5 mol%), n-butyl methacrylate 1.
A copolymer was obtained in the same manner as in Reference Example 1 except that 7 g (60 mol%) was used. The yield was 83%. The content of MPC unit in the obtained copolymer (hereinafter, may be abbreviated as Copolymer 4) is 35 mol%, the content of glycidyl methacrylate unit is 4 mol%, and n-butyl methacrylate unit. And the number average molecular weight of the copolymer 4 was 120,000.

Reference Example 5 In Reference Example 1, the types and proportions of the monomers used were MPC 2.0 g (35 mol%), glycidyl methacrylate 0.14 g (5 mol%), and n-hexyl methacrylate 2.0 g (60%). A copolymer was obtained in the same manner as in Reference Example 1 except that the amount was changed to mol%). The yield was 81%. In the obtained copolymer (hereinafter, this may be abbreviated as copolymer 5), the content of MPC unit is 34 mol%, the content of glycidyl methacrylate unit is 5 mol%, n-hexyl methacrylate unit. Was 61 mol%, and the number average molecular weight of the copolymer 5 was 120,000.

Reference Example 6 In Reference Example 1, the types and proportions of the monomers used were 2.0 g (35 mol%) of MPC, 0.14 g (5 mol%) of glycidyl methacrylate, and 2.3 g (60% of 2-ethylhexyl methacrylate). Mol%), except that
A copolymer was obtained in the same manner as in Reference Example 1. The yield was 72%. The content of MPC unit in the obtained copolymer (hereinafter, sometimes abbreviated as copolymer 6) is 3
5 mol%, the content of glycidyl methacrylate unit is 4
Mol%, the content of 2-ethylhexyl methacrylate unit was 61 mol%, and the number average molecular weight of the copolymer 6 was 11
It was 10,000.

Examples 4 to 15 The copolymers obtained in Reference Examples 4 to 6 were each dissolved in ethanol to a concentration of 5% to prepare copolymer solutions. The inside of the soft vinyl chloride resin tube was filled with the copolymer solution, and after 5 minutes, the solution was drained and heated under the conditions of temperature and time shown in Table 1. Next, after washing with ethanol,
It was immersed in a 0.01% o-toluidine blue aqueous solution. After washing with water, the state of dyeing was visually observed, and the results are shown in Table 1.

[0042]

[Table 1]

From Table 1, it can be seen that all the tubes obtained in Examples 4 to 15 had the inner surface uniformly dyed, that is, the copolymer was uniformly coated.

Example 16 A solution prepared by dissolving the copolymer 2 obtained in Reference Example 2 in ethanol to a concentration of 5% was placed in a test tube made of poly-4-methylpentene-1, and taken out after 5 minutes. 2 at 60 ° C
Heat for 4 hours. After washing with ethanol, it was dyed with a 0.01% o-toluidine blue aqueous solution. As a result, it was confirmed that the inner surface of the test tube was uniformly dyed and the copolymer was uniformly coated. Next, in the same manner as in Example 1, after filling the whole blood with heparin added, the blood was taken out and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that proteins and platelets were scarcely attached.

Example 17 Example 1 was repeated except that hexamethylenediamine was added to the copolymer solution of Example 16 so that the final concentration was 0.01%.
It processed on the same conditions as No. 6. The inner surface of the test tube was uniformly dyed with an o-toluidine blue aqueous solution, and it was confirmed that the copolymer was uniformly coated.

Comparative Example 3 The procedure of Example 16 was repeated under the same conditions as in Example 16 except that the heating temperature was changed to 35 ° C. The inner surface of the test tube was not dyed with the o-toluidine blue aqueous solution and the copolymer was obtained. Was confirmed to be uncoated.

Comparative Example 4 Treatment was carried out under the same conditions as in Example 17, except that the heating temperature was changed to 35 ° C. At this time, the crosslinked product of the copolymer was dissolved in the ethanol used for washing, and the inner surface of the test tube made of poly-4-methylpentene-1 was not dyed with the o-toluidine blue aqueous solution. Therefore, the inner surface of the test tube was not coated with the copolymer.

Comparative Example 5 A polysulfone plate was immersed in a solution prepared by dissolving the copolymer 2 obtained in Reference Example 2 in ethanol to a concentration of 5% and heating at 100 ° C. for 24 hours. At this time, the crosslinked product of the copolymer was dissolved in the ethanol used for washing, and the polysulfone plate was not dyed with the o-toluidine blue aqueous solution. Therefore, the polysulfone plate was not coated with the copolymer. From these results, it can be seen that even under the condition that a crosslinked product of the copolymer is formed, the surface of the thermoplastic resin substrate cannot be coated with the copolymer when the heating temperature is lower than the glass transition temperature.

Example 18 The copolymer solution used in Example 3 had a final concentration of 0.00
The treatment was carried out under the same conditions as in Example 3 except that hexamethylenediamine was added so as to be 5%. That is, the copolymer 3 obtained in Reference Example 3 was dissolved in ethanol to a concentration of 5%, and hexamethylenediamine was further added so that the final concentration was 0.005% to prepare a copolymer solution. Prepared. Filling the inside of a soft vinyl chloride resin tube with an inner diameter of 8 mm with the copolymer solution, draining the solution after 5 minutes, heating at 80 ° C. for 24 hours, washing with distilled water, and a tube coated with the copolymer Got A part of this copolymer-coated tube was immersed in a 0.01% o-toluidine blue aqueous solution for 5 minutes, washed with water, and visually observed to find that the tube was uniformly dyed and the copolymer was uniformly coated. Was confirmed. In addition, one end of the above copolymer-coated tube (length 8 cm) was fixed with forceps, whole blood immediately after blood collection was put therein, and the result of measuring the time until coagulation was obtained.
It was 18 minutes.

Example 19 The copolymer 2 obtained in Reference Example 2 was dissolved in ethanol to a concentration of 2% to prepare a copolymer solution. A styrene-olefin block copolymer (styrene-isobutylene-styrene block copolymer; TS polymer manufactured by Kuraray; glass transition temperature of about -60 ° C) was used to prepare a tube having an inner diameter of 8 mm, and the inside thereof was filled with a copolymer solution, After 5 minutes, the solution was taken out, heated at 120 ° C. for 4 hours, and then washed with distilled water to obtain a tube coated with the copolymer.
A part of this copolymer-coated tube was immersed in a 0.01% o-toluidine blue aqueous solution for 5 minutes, washed with water, and visually observed to find that it was uniformly dyed and the copolymer was uniformly coated. It was confirmed. Next, whole blood to which heparin was added so that its concentration became 2 U / ml was filled in a copolymer-coated tube at 37 ° C. for 30 minutes, and then the blood was taken out and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that proteins and platelets were scarcely attached. In addition, one end of the above copolymer-coated tube (length 8 cm) was clamped with forceps, whole blood immediately after blood collection was put therein, and the time until coagulation was measured. As a result, it was 21 minutes.

Example 20 The copolymer 2 obtained in Reference Example 2 was dissolved in ethanol to a concentration of 2% to prepare a copolymer solution. Styrene-isoprene copolymer (Kuraray High Blur HVS
-3; a tube having an inner diameter of 8 mm was prepared at a glass transition temperature of about -20 ° C, the inside was filled with a copolymer solution, the solution was extracted after 5 minutes, heated at 120 ° C for 4 hours, and then washed with distilled water. Then, a tube coated with the copolymer was obtained.
A part of this copolymer-coated tube was immersed in a 0.01% o-toluidine blue aqueous solution for 5 minutes, washed with water, and visually observed to find that it was uniformly dyed and the copolymer was uniformly coated. It was confirmed. Next, heparin-added whole blood to a concentration of 2 U / ml was filled in the copolymer-coated tube at 37 ° C. for 30 minutes, and then,
Blood was removed and fixed with glutaraldehyde. Observation of the blood contact surface with an electron microscope revealed that proteins and platelets were scarcely attached. In addition, one end of the above copolymer-coated tube (length 8 cm) was clamped with forceps, whole blood immediately after blood collection was put therein, and the time until coagulation was measured. As a result, it was 22 minutes.

[0052]

EFFECTS OF THE INVENTION According to the present invention, a blood-compatible copolymer is not easily detached, is excellent in blood compatibility, and blood compatibility is stably maintained for a long period of time. Provided is a medical polymer material which is less likely to occur. Furthermore, according to the present invention, even when the functional group capable of covalently bonding to the copolymer coated on the surface is not present in the thermoplastic resin substrate, the copolymer is stably coated on the thermoplastic resin substrate. It is possible to easily manufacture the obtained medical polymer material.

Claims (4)

[Claims] 1. A vinyl monomer unit having a phosphorylcholine group in an amount of 5 to 90 mol%; at least one functional group selected from the group consisting of an epoxy group, an isocyanate group, a hydroxyl group, an amino group, a carboxyl group and a mercapto group. A polymer material for medical use in which the surface of a thermoplastic resin substrate is coated with a copolymer containing from 0.1 to 50 mol% of vinyl monomer units having from 5 to 90 mol% of hydrophobic vinyl monomer units. 2. The medical polymer material, wherein the copolymer and the thermoplastic resin substrate are bound to each other by a non-covalent bond, and the copolymers are covalently crosslinked. 2. The medical polymer material according to claim 1, wherein the vinyl monomer unit having a functional group is a vinyl monomer unit having an epoxy group. 3. The medical polymer material according to claim 1, wherein the hydrophobic vinyl monomer unit is a (meth) acrylic acid alkyl ester unit having an alkyl group having 4 or more carbon atoms. 4. A vinyl monomer unit having a phosphorylcholine group in an amount of 5 to 90 mol%; at least one functional group selected from the group consisting of an epoxy group, an isocyanate group, a hydroxyl group, an amino group, a carboxyl group and a mercapto group. After coating a copolymer containing 0.1 to 50 mol% of vinyl monomer units having a hydrophobic vinyl monomer unit of 5 to 90 mol% on the surface of the thermoplastic resin substrate, crosslinking is carried out if necessary. A method for producing a medical polymer material, which comprises heating in the presence of an agent to a temperature not lower than the glass transition temperature of the thermoplastic resin substrate.