JP3495802B2 - Medical materials and polyvinyl alcohol polymers having phosphorylcholine groups - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medical material and / or medical product having excellent blood compatibility, and a polymer useful as the medical material and / or medical product. INDUSTRIAL APPLICABILITY The medical material and medical product of the present invention have excellent blood compatibility, and since the excellent blood compatibility is maintained for a long period of time, they are used as various medical materials and / or medical products including artificial organs. Extremely useful.

[0002]

2. Description of the Related Art In recent years, active development of artificial organs and the like has occurred, but in this technical field, there is a problem of biocompatibility, and in particular, it does not cause blood coagulation and activates the complement system. There is a demand for the development of a medical material having excellent blood compatibility that does not occur. As methods for obtaining medical materials and / or medical products having excellent blood compatibility, the following four types of methods have been mainly tried. A method of molding or spinning using a synthetic polymer material having excellent blood compatibility as a raw material, or coating a surface of a medical material or a medical product with a synthetic polymer material having excellent blood compatibility. A method of binding a blood-compatible chemical substance to the surface of a medical synthetic polymer material or a medical product made of the same. 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 a medical material or a medical product. A method using a biomaterial such as collagen or a biovalve as a raw material.

Of the above-mentioned methods (1) to (3), the physiologically active substances and biomaterials used as raw materials are natural products and are difficult to obtain in large quantities.
In addition to being expensive, there is a problem that blood compatibility is lost depending on the manufacturing conditions and storage conditions of medical materials and medical products. Therefore, it is possible to mass-produce relatively inexpensively, the above method using a synthetic polymer material having excellent blood compatibility, the above method of bonding a chemical substance having blood compatibility to the surface of the synthetic polymer material is actively used. It has been studied, and in that case, there is a strong demand for the development of a synthetic polymer having better blood compatibility and capable of maintaining the blood compatibility for a long period of time.

[0004] By the way, phospholipids are major constituents of biological membranes, are specifically present in the membrane-like structure of cells, and are involved in the function of biological membranes through phospholipids alone or through interaction with membrane proteins. It is known that 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 conventional techniques include (i) excellent biocompatibility by the applicant 2
-Development of methacryloyloxyethylphosphorylcholine (hereinafter sometimes referred to as "MPC") (JP-A-54-6)
3025), (ii) development of a copolymer of methacrylic acid ester such as ethyl methacrylate and MPC (JP-A-3-39309), and (iii) a sugar derivative having a phosphorylcholine group or a functional derivative thereof. Examples of the antithrombogenic regenerated cellulose-based membrane in which is immobilized and a method for producing the same (Japanese Patent Laid-Open No. 5-220218).

M of the above (i) developed by the applicant
PC has good blood compatibility and is biocompatible with methyl methacrylate polymer and polystyrene by copolymerizing MPC with methyl methacrylate or grafting MPC onto polymethylmethacrylate or polystyrene. It is possible to impart sex. However, even if MPC is graft-polymerized to polymethylmethacrylate or polystyrene, the reactivity of the graft polymerization is low,
It is difficult to obtain a graft polymer having remarkably improved blood compatibility, and improvement in blood compatibility is still insufficient even in the examples described in JP-A-54-63025. .

Also in the case of the copolymer of MPC and methacrylic acid ester of the above (ii), the reactivity between the copolymer and the surface of the base material is low and it is difficult to stably fix it to the base material. Therefore, the above-mentioned copolymer is easily peeled off from the surface of the substrate during use, and is easily detached from the surface of the substrate during the sterilization treatment. And if it is peeled from the base material or the copolymer eluted from the medical material may enter the body, it may cause an unexpected danger. Something is required.

The antithrombogenic regenerated cellulose membrane of the above (iii) has its blood compatibility because the carbohydrate derivative having a phosphorylcholine group or its functional derivative immobilized on the cellulose membrane is less likely to fall off from the cellulose membrane. It is said that it can be maintained over a long period of time to some extent, but it is not yet completely satisfactory. Moreover, in order to obtain the antithrombogenic regenerated cellulose membrane of (iii), an operation of graft-polymerizing a monomer having a phosphorylcholine group onto a sugar derivative or a functional derivative thereof, and a sugar having a phosphorylcholine group obtained thereby The process is complicated because a two-step operation for fixing the derivative or its functional derivative to the regenerated cellulose membrane is required. In particular, the operation of the second step is carried out by a method of dissolving a sugar derivative having a phosphorylcholine group or a functional derivative thereof in a solvent and fixing it on a regenerated cellulose membrane. The remaining unfixed sugar derivative having a phosphorylcholine group or its functional derivative must be removed from the regenerated cellulose membrane surface by centrifugation or suction, and the remaining solvent must be removed at a relatively low temperature. The operation is very complicated.

[0008]

The object of the present invention is that it can be easily produced without complicated steps, and that it has excellent blood compatibility, and its excellent blood compatibility is long-term. It is an object of the present invention to provide a medical material and / or a medical product that is retained over a period of time, and a synthetic polymer that can be effectively used for manufacturing such a medical material and a medical product.

[0009]

Means for Solving the Problems As a result of intensive investigations by the present inventors to solve the above problems, a compound having a phosphorylcholine group is bonded as a side chain group to a main chain composed of a polyvinyl alcohol polymer. Polymer, or a material or product having at least the polymer as a constituent element,
It has been found that it has excellent blood compatibility, and that excellent blood compatibility is maintained for a long period of time. Furthermore, the present inventors have found that such a medical material and / or medical product in which a compound having a phosphorylcholine group is bound to a polyvinyl alcohol-based polymer as a side chain group is obtained by using the polyvinyl alcohol-based polymer. A product having a predetermined shape and / or structure is prepared in advance, and a compound having a phosphorylcholine group is bonded to the surface of the product by graft polymerization or another suitable method, which can be easily manufactured without complicated steps. The present invention has been completed based on these findings.

That is, the present invention provides a compound having a phosphorylcholine group in the polyvinyl alcohol polymer is a component of the polymer attached as side groups, predetermined
A medical material or a medical product comprising an article having the shape and / or structure of Here, in this specification
The "article having a predetermined shape and / or structure" means
Articles shaped into a predetermined shape and / or structure
Say. Therefore, a compound having a phosphorylcholine group
Polymer itself in which the substance is bonded as a side chain group, the polymerization
Mere powder of the body, the polymer dispersed or dissolved in a liquid
Liquid substances are not included in the above-mentioned “article”. Then, the above-mentioned medical material or medical product of the present invention is obtained by binding a compound having a phosphorylcholine group to an article having a predetermined shape and / or structure manufactured in advance using a polyvinyl alcohol-based polymer. Or a polyvinyl alcohol-based polymer having a main chain to which a side chain having a phosphorylcholine group is bonded, which is an article manufactured using a polymer as a raw material, or polyvinyl alcohol A base material may be coated with a polymer in which a main chain made of a system polymer has a side chain having a phosphorylcholine group bonded thereto.

Further, the present invention is characterized by graft-polymerizing an unsaturated monomer having a phosphorylcholine group onto an article having a predetermined shape and / or structure manufactured in advance using a polyvinyl alcohol-based polymer to obtain the above-mentioned medical use. Includes methods of manufacturing materials or medical products.

And, the present invention is a polyvinyl alcohol
Having phosphorylcholine group in the main chain composed of polymer
The unsaturated monomers were formed by graft polymerization include polymeric side chains is bonded having a phosphorylcholine group in the main chain of polyvinyl alcohol polymer. Change
In addition, the present invention includes a method for producing the polymer by graft-polymerizing an unsaturated monomer having a phosphorylcholine group to a polyvinyl alcohol-based polymer.

The medical material or medical product of the present invention is
It can be produced by binding a compound having a phosphorylcholine group to an article having a predetermined shape and / or structure produced in advance using a polyvinyl alcohol polymer (hereinafter referred to as "PVA polymer"). Then, in the case of this method of bonding a compound having a phosphorylcholine group to an article made of a PVA-based polymer produced in advance, a predetermined amount and a large amount of phosphorylcholine group can be bound to the surface of the article more reliably. , Medical materials with excellent blood compatibility and /
Or medical products can be obtained. In that case, P
The article previously manufactured from the VA polymer may be in a final product form, a semi-finished product form, a material form before being made into a product, or the like. Also, PVA
The article made of the system-based polymer may be wholly formed of the PVA-based polymer or may be partially formed of the PVA-based polymer. In short, the PVA-based polymer is at least a part of the article. On the surface of which the compound having a phosphorylcholine group is bonded to that portion. But not limited to
Examples of the PVA-based polymer article here include:
Films, sheets, membranes, hollow fiber membranes, artificial blood vessels, catheters and other tubular materials, bag-like materials such as blood bags, containers,
Examples thereof include fibers, cloth-like materials, beads, and other various medical products and materials, and the shape, structure, size, etc. of the article are not particularly limited.

An article made of a PVA polymer is a homopolymer made of only vinyl alcohol (hereinafter referred to as "PVA homopolymer"), or 60% by mol or more of vinyl alcohol units and other copolymerization of less than 40% by mol. It is preferably a copolymer of a PVA unit having a component unit and another copolymerization component unit (hereinafter referred to as "PVA copolymer"). If the article is formed from a PVA copolymer, the PVA
The other copolymerization component unit in the copolymer may be any copolymerization component unit derived from a monomer copolymerizable with vinyl alcohol (vinyl acetate), for example, ethylene, propylene, butylene, pentene, hexene, heptene. Examples thereof include copolymerization component units derived from monomers such as methacrylic acid, vinyl chloride, methyl methacrylate, ethyl methacrylate, propyl methacrylate, acrylonitrile, vinylpyrrolidone and styrene.
The PVA copolymer may have only one type of these copolymerization component units, or may have two or more types. P
The ratio of the other copolymerization unit in the VA copolymer is 40
If it exceeds mol%, the amount of the side chain having a phosphorylcholine group introduced into the main chain made of the PVA copolymer is reduced, and a PVA polymer excellent in blood compatibility cannot be obtained, which is not preferable.

PVA homopolymers or PVA copolymers having other copolymer component units in a proportion of less than 40 mol% are:
Usually, after homopolymerizing a carboxylic acid ester of vinyl alcohol typified by vinyl acetate or copolymerizing a carboxylic acid ester of vinyl alcohol with another copolymerizable monomer, the carboxylic acid ester group of vinyl alcohol is PVA-based polymers (PVA homopolymers and P
The VA copolymer) has a saponification degree of preferably 50% or more, and more preferably 85 to 100%.

Particularly, as the PVA-based polymer constituting the article, a PVA homopolymer or an ethylene-vinyl alcohol copolymer containing an ethylene unit in a proportion of 20 mol% or more and less than 40 mol% (hereinafter referred to as "EVAL resin"). Say)
Is preferable from the viewpoints of blood compatibility of the finally obtained medical material or medical product, easy availability, cost, and the like. The degree of polymerization of the PVA-based polymer that constitutes the article is preferably 500 to 16000, from the viewpoints of moldability and the strength of the molded article, and more preferably 900 to 4000.

The medical material or medical product of the present invention in which a compound having a phosphorylcholine group is bonded to the surface of an article made of a PVA-based polymer having a predetermined shape and / or structure in advance has a phosphorylcholine group. By having it on the surface, it exhibits good blood compatibility, but it is preferable that the density (number) of phosphorylcholine groups per unit area on the surface is 8 × 10 ¹⁵ / cm ² or more, More preferably, it is 40 × 10 ¹⁵ pieces / cm ² or more. If the density of phosphorylcholine groups per unit area on the surface is less than 8 × 10 ¹⁵ groups / cm ² , blood compatibility will not be sufficiently exhibited.

When the phosphorylcholine group is subsequently introduced into the surface of the PVA polymer article to produce the medical material and / or medical product of the present invention, (a) a phosphorylcholine group-containing compound is used. A method in which a saturated monomer is graft-polymerized on the surface of an article made of a PVA polymer in the presence of a catalyst; (b) an unsaturated monomer having a phosphorylcholine group is made of a PVA polymer by using energy rays such as ultraviolet rays and radiation. (C) A prepolymer is formed by previously polymerizing an unsaturated monomer having a phosphorylcholine group, and the prepolymer is coated with a spacer such as an epoxy compound, an isocyanate compound or a halogenated triazine. Through P
A method of binding to the surface of an article made of a VA polymer; (d) a compound having a phosphorylcholine group and having active hydrogen is attached to the surface of an article made of a PVA polymer through a spacer such as an epoxy compound or an isocyanate compound. A method of binding; and the like can be adopted.

Among the above-mentioned methods (a) to (d), the method (a) has a relatively simple reaction operation and can be carried out under mild polymerization conditions. It is preferably carried out from the viewpoint that the damage of the is small.
The unsaturated monomer having a phosphorylcholine group used in the above methods (a) to (c) is PVA.
Any unsaturated monomer having a phosphorylcholine group that can be bonded to the surface of the polymer based on graft polymerization or other functional groups can be used. For example, MP
C, 2-methacryloyloxyethoxyethylphosphorylcholine, 6-methacryloyloxyhexylphosphorylcholine, 10-methacryloyloxynonylphosphorylcholine, allylphosphorylcholine, butenylphosphorylcholine, hexenylphosphorylcholine, octenylphosphorylcholine, decenylphosphorylcholine and the like can be mentioned. These unsaturated monomers may be used alone or in combination of two or more kinds. Among them, MPC is more preferably used in terms of price, availability, polymerization reactivity and the like.

In the case of the graft polymerization of (a) above, the density of phosphorylcholine groups on the surface of the PVA-based polymer article is preferably 8 × 10 ¹⁵ above.
The unsaturated monomer having a phosphorylcholine group is graft-polymerized on the surface of the PVA-based polymer article at a rate of not less than 1 / cm ² . Then, in graft-polymerizing the unsaturated monomer having a phosphorylcholine group on the surface of the PVA-based polymer article, when the graft polymerization is performed in the presence of nitric acid using a tetravalent cerium compound as a catalyst, It can be done smoothly. In that case, as a catalyst composed of a tetravalent cerium compound,
For example, cerium (IV) ammonium nitrate, cerium (IV) ammonium sulfate dihydrate, cerium (IV) ammonium sulfate tetrahydrate, cerium (IV) sulfate tetrahydrate, cerium (IV) hydroxide, cerium oxide ( IV) and the like can be used. Moreover, the amount of the catalyst composed of a tetravalent cerium compound is usually preferably about 1 to 100% based on the total weight of the unsaturated monomer having a phosphorylcholine group.

In graft-polymerizing an unsaturated monomer having a phosphorylcholine group on the surface of a PVA-based polymer article, an unsaturated monomer having a phosphorylcholine group, a tetravalent cerium compound and nitric acid are dissolved, while a PVA-based polymer is dissolved. Combined articles are preferably water, lower alcohols such as methanol, ethanol, propanol, butanol, etc., DMSO, etc., which are less harmful to living organisms, and DMSO and the like are used. These solvents may be used alone or in combination of two or more kinds. You may.

The above graft polymerization of the unsaturated monomer onto the surface of the PVA-based polymer article is carried out when the concentration of the unsaturated monomer having a phosphorylcholine group in the solution is about 0.1 to 50% by weight and tetravalent cerium. Surfaces which form a homogeneous solution having a compound catalyst concentration of about 0.001 to 50% by weight and a nitric acid concentration of about 0.001 to 10% by weight, and which are intended to impart blood compatibility to a PVA-based polymer article. At least 25 ~ 45 ℃ under this solution and oxygen-free atmosphere
It can be carried out by contacting at a temperature of 1 to 5 hours, and then removing unreacted unsaturated monomer, nitric acid, and tetravalent cerium compound remaining on the surface of the PVA-based polymer article by washing with water or the like.

The molar ratio of the phosphorylcholine groups present on the surface of the PVA-based polymer article obtained above (the molar ratio of vinyl alcohol units on the surface of the article having the graft-polymerized phosphorylcholine group) is ESCA (Electron
By performing surface analysis by Spectroscopy for Chemical Analysis, the atomic percentage of oxygen and phosphorus can be obtained, and can be obtained according to the following mathematical formula (1).

[0024]

## EQU1 ## A = B / (C-6B) (1) In the above formula, A = the number of moles of phosphorylcholine group per 1 mole of the monomer unit constituting the PVA polymer, B = the number of phosphorus atoms determined by ESCA Percentage (mol%) C = percentage of oxygen atoms determined by ESCA (mol%)

Further, according to the present invention, PVA manufactured in advance is used.
In place of the above method of binding a compound having a phosphorylcholine group to the surface of an article made of a polymer to obtain a medical material and / or medical product having excellent blood compatibility,
A PVA-based polymer having a main chain to which a side chain having a phosphorylcholine group is bonded is produced, and a medical material or medical product having blood compatibility by molding, spinning, or other method using the polymer. Alternatively, the surface of a substrate used as a medical material or a medical product may be coated or fixed with the above-mentioned polymer having a side chain having a phosphorylcholine group bonded to a main chain made of a PVA-based polymer. It may be used as a medical material or a medical product having blood compatibility. Therefore, as described above, the present invention provides a phosphorylcholine group in the main chain composed of these medical material and medical product, and the PVA polymer. A polymer having a side chain bonded with is included in the scope of the present invention.

In the PVA-based polymer of the present invention to which side chains having a phosphorylcholine group are bound, P constituting the main chain
The VA polymer is a PVA homopolymer, or 60 mol% as in the case of the article made of the PVA polymer described above.
It is preferably a PVA copolymer having the above vinyl alcohol units and less than 40 mol% of other copolymerization component units. When the main chain is a PVA copolymer, vinyl alcohol (vinyl acetate) is used as the other copolymerization component unit.
As long as it is a copolymerization component unit derived from the above-mentioned monomer that is copolymerizable with, the PVA copolymer may have only one kind of those copolymerization component units, or may have two or more kinds. You may have. When the proportion of the other copolymerization component units in the PVA copolymer exceeds 40 mol%, PVA
It is not preferable because the introduction amount of the side chain having a phosphorylcholine group in the main chain of the copolymer is reduced, and a PVA polymer excellent in blood compatibility cannot be obtained. Also, PVA
The homopolymer or PVA copolymer preferably has a degree of saponification of vinyl alcohol units of 50% or more, and 85
It is preferably ˜100%.

As the PVA-based polymer constituting the main chain, P
When the VA homopolymer or the above-mentioned EVAL resin containing ethylene units in a proportion of 20 mol% or more and less than 40 mol% is used, the blood compatibility, availability, price, etc. of the polymer finally obtained can be improved. It is preferable from the point. The PVA-based polymer constituting the main chain has a degree of polymerization of 500 to 16
From the viewpoint of moldability and strength of the molded product, it is preferably 000, and more preferably 900 to 4000.

The polymer of the present invention has the above-mentioned PV content.
A compound having a phosphorylcholine group is bonded as a side chain to the main chain composed of an A-based polymer, but monomer units constituting the PVA-based polymer (for example, P having a saponification degree of 100%) are used.
In the case of a VA homopolymer, a vinyl alcohol unit, and in the case of a PVA copolymer having a saponification degree of 100%, the phosphorylcholine group is 0. It is preferable that the compound is bonded at a ratio of 004 to 0.01 mol from the viewpoint of blood compatibility, easiness of bonding a compound having a phosphorylcholine group to a PVA-based polymer, and physical properties of the PVA-based polymer. . Further, the chemical structure, length, molecular weight, etc. of the side chain having a phosphorylcholine group are compounds having a phosphorylcholine group used for forming the side chain (having a polymerizable monomer having a phosphorylcholine group, a prepolymer, and other functional groups). Compound), a method for binding a compound having a phosphorylcholine group to the main chain composed of a PVA-based polymer,
Depending on the amount of bonding, etc., when a side chain is formed by graft-polymerizing an unsaturated monomer having a phosphorylcholine group to a main chain composed of a PVA-based polymer, one side chain has about 1 It may be formed by a polymer of about 5 to about the unsaturated monomer.

The content of the phosphorylcholine group in the polymer of the present invention can be quantified by a wet decomposition-molybdenum blue absorptiometer method. That is, this method is a method for quantifying phosphorus in an organic matter, in which sulfuric acid, nitric acid and perchloric acid are added to an organic matter containing phosphorus to decompose the organic matter, and phosphorus in the organic matter is converted into phosphate ions. After shaping, ammonium molybdate,
It is a method of adding tin chloride and tin chloride to make it blue, and measuring the absorbance at 700 nm to obtain the amount of phosphorus from a calibration curve prepared in advance. For details, refer to "Analytical Chemistry Handbook 17-2-6 Optical analysis method ”.

As a method for bonding a side chain having a phosphorylcholine group to a main chain composed of a PVA polymer, (a ') an unsaturated monomer having a phosphorylcholine group is added to the PVA polymer in the presence of a catalyst. Method of graft polymerization; (b ′) PVA of an unsaturated monomer having a phosphorylcholine group using energy rays such as ultraviolet rays and radiation.
(C ') unsaturated polymer having a phosphorylcholine group is preliminarily polymerized to form a prepolymer, and the prepolymer is, for example, a spacer such as an epoxy compound, an isocyanate compound or a halogenated triazine. (D ') A compound having a phosphorylcholine group and having active hydrogen is bonded to the PVA-based polymer via a spacer such as an epoxy compound or an isocyanate compound, or PVA-based polymer or PVA A method of causing a condensation reaction with the hydroxyl group of the polymer to be bonded to the PVA polymer; and the like.

Among the above methods (a ') to (d'), the method (a ') has a relatively simple reaction operation,
Moreover, it can be carried out under mild polymerization conditions and is preferably used from the viewpoint that the PVA-based polymer is less damaged.
When the side chain having a phosphorylcholine group is bound by the above methods (a ') to (c'), does the unsaturated monomer having a phosphorylcholine group have a phosphorylcholine group and is graft polymerization possible? Alternatively, any monomer having a polymerizable unsaturated group for forming a prepolymer can be used. For example, the same MPC, 2-methacryloyloxyethoxyethylphosphorylcholine, 6-methacryloyloxyhexylphosphorylcholine, and 10 as described above can be used. -Methacryloyloxynonylphosphorylcholine, allylphosphorylcholine, butenylphosphorylcholine, hexenylphosphorylcholine, octenylphosphorylcholine, decenylphosphorylcholine, etc., and these monomers may be used alone. It may be used in combination of two or more thereof. Among them, MPC is preferably used because it has an excellent graft-polymerizability to a PVA-based polymer, is easily available, and has excellent blood compatibility.

When the polymer of the present invention is produced by the method (a ′), the amount of the unsaturated monomer having a phosphorylcholine group is about 0.01 to 1 mol per mol of the PVA polymer. Graft polymerization is preferably carried out at a ratio of 1.0 mol because a polymer excellent in blood compatibility can be obtained. In addition, the method of the above (a '), using a tetravalent cerium compound as a catalyst in the presence of nitric acid,
When performed by a method of graft-polymerizing an unsaturated monomer having a phosphorylcholine group in the PVA polymer can be carried out the graft polymerization very smoothly. Examples of the catalyst composed of a tetravalent cerium compound in that case include, for example, cerium (IV) ammonium nitrate, cerium (IV) ammonium sulfate dihydrate, cerium (IV) ammonium tetrahydrate, and sulfuric acid as described above. Cerium (IV) tetrahydrate, cerium (IV) hydroxide, cerium (IV) oxide and the like can be mentioned. Further, in the graft polymerization, it is usually preferable to use the catalyst composed of a tetravalent cerium compound in a proportion of about 1 to 100% based on the total weight of the unsaturated monomer having a phosphorylcholine group.

In graft-polymerizing the unsaturated monomer having a phosphorylcholine group on the main chain of the PVA polymer, the PVA polymer, the unsaturated monomer having a phosphorylcholine group, the tetravalent cerium compound and nitric acid are dissolved in a solvent. It is preferable to form a uniform solution to carry out the polymerization. As the solvent in that case, any solvent can be used as long as it can dissolve the four, but from the viewpoint of safety, water, methanol,
Lower alcohols such as ethanol, propanol, butanol, dimethyl sulfoxide (DMSO), acetone,
Cyclohexanol, phenol and the like are preferably used, and these solvents may be used alone or in combination of two or more kinds.

In the above graft polymerization, about 5 to 300 parts by weight of an unsaturated monomer having a phosphorylcholine group, 5 to 300 parts by weight of a tetravalent cerium compound catalyst, and about 300 parts by weight of nitric acid per 100 parts by weight of a PVA polymer. 1-50
It is advisable to dissolve 1 part by weight in about 300 to 3000 parts by weight of a solvent to form a uniform solution, and to perform this in an oxygen-free atmosphere at a temperature of 25 to 45 ° C. for 1 to 5 hours. Then, an operation such as reprecipitation is performed using a mixed solvent of a good solvent and a poor solvent (for example, DMSO / methanol, dimethylformamide / methanol, water / methanol, etc.) to purify the polymer obtained by graft polymerization. The polymer of the present invention in which a side chain having a phosphorylcholine group is bonded to the main chain composed of a PVA-based polymer is recovered. The graft polymerization ratio of the unsaturated monomer having a phosphorylcholine group in the polymer of the present invention thus obtained is determined by the above-mentioned wet decomposition-molybdenum blue absorptiometry to determine the phosphorus content in the polymer, and based on that. It can be obtained by calculating.

The polymer having a main chain composed of a PVA-based polymer to which a side chain having a phosphorylcholine group is bonded is a polymer obtained by graft polymerization of the above-mentioned unsaturated monomer having a phosphorylcholine group, and further a graft polymerization. In any case of a polymer obtained by bonding a prepolymer having a phosphorylcholine group or another compound to a PVA-based polymer by any other method, the side chain having a phosphorylcholine group is a PVA-based polymer. It has excellent blood compatibility because it is pendantly attached to the main chain. Moreover, since the main chain of the polymer is composed of a PVA-based polymer, it has a blood compatibility higher than that of the above-mentioned conventional polymer having a phosphorylcholine group having a main chain composed of polymethylmethacrylate or polystyrene. It is excellent in that it is extremely useful as a medical material.

[0036] In the use of the polymer side chain is attached having a phosphorylcholine group in the main chain of PVA polymer as a medical material and / or medical products, preferably the polymer is DMSO, dimethyl formamide, It is dissolved in a solvent such as dimethylacetamide or propanol, and the solution is used to prepare a conventional method such as dry method or wet method.
Using the same molding method and spinning method as those used for VA polymers, flat film, film, sheet, hollow fiber film, tubular, various molded products, fibers, etc. Various medical materials and / or medical products having excellent blood compatibility can be manufactured by manufacturing the various articles and products. Further, polymerization in which a side chain having a phosphorylcholine group is bonded to a main chain made of a PVA-based polymer
The body is dissolved in a solvent to form a solution, and the solution is used for various base materials that have already been manufactured (for example, sheet, film, film,
Molded articles, fabrics, tubes, and other products) the coating is subjected by dipping, by forming a coating layer of the polymer over those products, various medical materials excellent in blood compatibility and Medical products can be manufactured.

The medical material and / or medical product of the present invention in which a compound having a phosphorylcholine group is bonded to the surface of an article made of a PVA polymer, and a side chain having a phosphorylcholine group in the main chain of the PVA polymer is used. The medical material and / or medical product of the present invention obtained by molding or spinning using the bound polymer as a raw material or used as a coating material all have good blood compatibility. Therefore, even when it comes into contact with blood, thrombus is unlikely to occur, and complement activation is also unlikely to occur. Moreover, since the phosphorylcholine group bonded to the surface is not easily released from the PVA-based polymer article, its blood compatibility is maintained for a long period of time. Moreover, any of the above-mentioned medical materials and medical products of the present invention may be detached even when subjected to a sterilization method for medical devices such as γ-ray sterilization, high-pressure steam sterilization, and sterilization with ethylene oxide gas. It does not change. Therefore, the medical material and the medical product of the present invention include an artificial dialysis membrane, a plasma separation membrane, a medical material and a medical product that come into contact with blood in a unit of several hours such as a blood adsorbent,
Catheters, artificial blood vessels that are in contact with blood for a long time,
Respiratory Assist Circulator, Continuous Hemofiltration [eg CAV
H (Continuous Arteriovenous Hemofiltration) etc.]
It can also be effectively used for.

In the present invention, the blood compatibility of a medical material or a medical product is evaluated by measuring the blood compatibility of the medical material as whole blood, as will be specifically described in the following examples. A method of observing the change over time of the clot weight by contact (kinetic method), and a method of contacting a medical material with platelet-rich plasma and using a calcium ion (Ca ²⁺ ) sensitive fluorescent dye (Fura2) It was carried out by a method of measuring the change in free calcium ion concentration in platelet cells due to stimulation.

[0039]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Example 1 [Experiment 1] (1) EVAL resin [manufactured by Kuraray Co., Ltd .; ethylene content = 32 mol%, polymerization degree Pv = 1100] 85 g was DM
It was added to SO so that the total amount would be 500 g, and heated and dissolved in a warm water bath at 80 ° C. while stirring. The obtained solution of EVAL resin is poured onto a glass plate, immersed in a water bath together with the glass plate to solidify the solution, and further washed with running water overnight to obtain a porous EVAL resin having a thickness of about 100 μm. A flat membrane was obtained. (2) A piece of 5 cm × 5 cm was cut out from the EVAL resin porous flat membrane obtained in (1) above, and MPC (manufactured by NOF Corporation) 0.33 g (1.1 × 10 ⁻³ mol), sulfuric acid Tetraammonium cerium (IV) dihydrate 0.03g
(5.0 × 10 ⁻⁵ mol), 5.0 × 10 ⁻⁴ mol of nitric acid and 10 ml of distilled water were placed in a reaction vessel for polymerization, and the inside of the vessel was replaced with argon gas. The reaction vessel containing the above reaction liquid containing EVAL resin porous flat membrane and MPC was immersed in a hot water bath at 35 ° C., and the inside of the vessel was stirred for 4 hours to carry out a polymerization reaction. After completion of the reaction, the EVAL resin porous flat membrane was taken out of the container and thoroughly washed with water to obtain an EVAL resin porous flat membrane on which MPC was graft-polymerized.

(3) MPC in EVAL resin porous flat membrane obtained by graft-polymerizing the MPC obtained in (2) above
Was quantified by the above-mentioned wet decomposition-absorptiometry to calculate the density (number / cm ² ) of phosphorylcholine groups graft-polymerized on the surface of the EVAL resin porous flat membrane. In addition, the surface analysis by ESCA is performed and MPC
The surface density of the phosphorylcholine group present on the surface of the EVAL resin porous flat membrane graft-polymerized with was calculated and compared with the result by the wet decomposition-absorptiometry. The results are shown in Table 1 below.

[Experiment 2] The amount of MPC used was 0.15.
An EVAL resin porous flat membrane in which MPC was graft-polymerized on the surface was produced in the same manner as in Experiment 1 except that g (0.5 × 10 ⁻³ mol) was changed. The density of phosphorylcholine groups in the obtained flat film was calculated by the wet decomposition-absorptiometry and ESCA in the same manner as in Experiment 1, and the results are shown in Table 1 below.

[Experiment 3] The amount of MPC used was 0.01
EVAL with MPC graft-polymerized on the surface in the same manner as in Experiment 1 except that the amount was changed to 5 g (0.05 × 10 ^-3 mol)
A resin porous flat membrane was manufactured. The surface density of phosphorylcholine groups in the obtained flat film was calculated by the wet decomposition-absorptiometry and ESCA in the same manner as in Experiment 1, and the results are shown in Table 1 below.

[Experiment 4] The amount of MPC used was 0.00
EVAL graft-polymerized with MPC on the surface in the same manner as in Experiment 1 except that the amount was changed to 9 g (0.03 × 10 ^-3 mol)
A resin porous flat membrane was manufactured. The surface density of phosphorylcholine groups in the obtained flat film was calculated by the wet decomposition-absorptiometry and ESCA in the same manner as in Experiment 1, and the results are shown in Table 1 below.

[Blood Compatibility Test (Blood Coagulation Test)] (1) The EVAL resin porous flat membrane graft-polymerized with MPC obtained in the above Experiments 1 to 4 was sized 3 cm × 3 cm for the same sample. Four pieces each cut into pieces were prepared, and each piece was placed on another glass watch glass. A watch glass with a porous flat membrane of EVAL resin graft-polymerized with MPC was placed in a constant temperature bath at 37 ° C., and ACD (anticoagulant: sodium citrate 2.
2g, citric acid 0.8g, glucose 2.2g to 100ml by adding distilled water) was added at a rate of 13% by weight, and 0.20ml of human blood was added, and 0.1g was added.
Coagulation was started by adding 0.020 ml of an aqueous calcium chloride solution of 1 / liter. (2) Four watch glasses were covered with glass plates, and distilled water was added at 3 minutes, 5 minutes, 7 minutes, and 9 minutes after the addition of the aqueous solution of calcium chloride to stop coagulation. The formed clot was immersed in water for 5 minutes and then in formalin for 10 minutes and then washed with water. The clot was lightly held down by a filter paper to sufficiently remove water, and then weighed. As a control, EVAL
The same test was carried out on a glass watch glass on which no resin porous flat membrane was placed to measure the weight of the clot on the watch glass, and the weight of the clot when the contact time was 9 minutes was 100%, The percentage of clot weight at each contact time for each sample was calculated and was as shown in Table 1 below (Experiment 5). Further, when a blood coagulation test similar to the above was performed on a polystyrene flat film as another control sample (Experiment 6), the results are shown in Table 1 below.

[0046]

[Table 1]

From the results shown in Table 1 above, the flat EVAL resin membranes of Experiments 1 to 4 having a phosphorylcholine group on the surface did not cause blood coagulation at all when contacted with blood or had very little blood compatibility, and were excellent in blood compatibility. In particular, the EVAL resin porous flat membranes of Experiments 1 to 3 in which the density of phosphorylcholine groups on the flat membrane surface is 8 × 10 ¹⁵ pieces / cm ² or more does not cause blood coagulation at all when contacted with blood. It can be seen that there is very little occurrence, and the blood compatibility is extremely excellent.

[Sterilization Test] The EVAL resin porous flat membrane graft-polymerized with MPC on the surface obtained in the above Experiment 2 was sterilized by irradiating it with 25 KGy of γ-ray in the presence of distilled water. Phosphorus derived from MPC was quantified in distilled water that coexisted with the porous flat membrane, but no phosphorus was detected, and the graft-polymerized MPC was treated with γ-rays for sterilization to obtain a substrate. Was not detached from the surface of the EVAL resin porous flat membrane.

Example 2 [Experiment 1] (1) EVAL resin [manufactured by Kuraray Co., Ltd .; ethylene content = 32 mol%, degree of polymerization Pv = 1100] spun using a porous hollow for a hemodialyzer Thread film (inner diameter 175 μm)
Using, a mini module having an inner surface area of about 50 cm ² was produced. On the inner surface of the hollow fiber membrane of this mini module, M
PC (manufactured by NOF Corporation) 0.33 g (1.1 x 10)
^-3 mol), tetraammonium cerium (IV) sulfate dihydrate 0.032 g (5.0 × 10 ^-5 mol) and nitric acid 5.0
After degassing, the reaction liquid prepared by dissolving 10 ⁻⁴ mol of 10 ⁻⁴ mol in distilled water was contacted by circulating for 4 hours in an atmosphere of 35 ° C., and then thoroughly washed with water to form a hollow fiber membrane surface. A mini module obtained by graft-polymerizing MPC was obtained. (2) The graft polymerization amount of MPC per unit area on the inner surface of the hollow fiber membrane of the mini-module obtained by graft-polymerizing the MPC obtained in (1) above was determined in the same manner as in Example 1, and the results are shown in Table 2 below. It was as shown in. (3) Further, the density of phosphorylcholine groups on the inner surface of the hollow fiber membrane of the mini-module graft-polymerized with the MPC obtained in (1) above was calculated by the wet decomposition-absorptiometry method and ESCA in the same manner as in Example 1. However, it was as shown in Table 2 below.

[Blood compatibility test (blood coagulation test)] Regarding the mini-module (inner surface area: 50 cm ² ) graft-polymerized with the MPC obtained in the above (1) of Experiment 1, a closed circuit containing the mini-module was covered with a silicon tube. Was manufactured using. Human platelet-rich plasma is ^subjected to Ca ²⁺ by a predetermined method.
Platelet suspension obtained by loading with a sensitive fluorescent dye (Fura2) [platelet concentration = 2 × 10 ⁸ cells / m
1; HEPES buffer solution (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid)] to which calcium chloride was added so as to be 1 mmol / liter, and then the above-mentioned closing was performed under an atmosphere of 37 ° C. It was circulated in the circuit for 10 minutes and brought into contact with the inner surface of the EVAL resin porous hollow fiber membrane. The time-dependent change in the fluorescence intensity ratio of two-wavelength-excited one-wavelength of the circulating Fura2-loaded platelet suspension was measured, and further, Triton X-100 (polyethylene glycol-mono-p-
Octyl phenyl ether) and EGTA (glycol ether diamine tetraacetic acid) were sequentially added to measure the fluorescence intensity at the maximum Ca ²⁺ concentration and at zero. By substituting these measured values into the formula of Tsien et al. Represented by the following formula (2) and calculating the Ca ²⁺ concentration [Ca ²⁺ ] (nmol / l), the results shown in Table 2 below are obtained. Got

[0051]

[Ca ²⁺ ] = {(R-Rmin) / (Rmax-R)} × (sf ₃₈₀ / sb ₃₈₀ ) × Kd (2) where R = fluorescence intensity ratio (when excited at 340 nm Value divided by fluorescence intensity when excited at 380 nm) Rmin = minimum value of fluorescence intensity ratio when Ca ²⁺ concentration is made zero using EGTA Rmax = Platelet using Triton X-100 Break 1
Maximum fluorescence intensity ratio observed when mM Ca ²⁺ and Fura 2 are bound sf ₃₈₀ = fluorescence intensity when excited at 380 nm when Ca ²⁺ concentration is zero using EGTA sb ₃₈₀ = triton Use X-100 to destroy platelets 1
Fluorescence intensity when excited at 380 nm when mM Ca ²⁺ and Fura 2 are bound Kd = Ca ²⁺ and Fura 2 dissociation constant

The details of the equation of Tsien et al. Expressed by the above equation (2) are described in J. Biol. Chem. 260, 3440 (1985) by Tsien et al., “A new generation of Ca ²⁺ indica.
tionwith greatly improved fluorescence propertie
s ”and the method for evaluating the biocompatibility of artificial dialysis membranes using Ca ²⁺ concentration as an index, see“ Artificial Organs ”18 (3), 1185.
-1190 (1989), "Development of biocompatibility evaluation method of new artificial dialysis membrane using intracellular Ca ion dynamics as an index" by Takemoto et al.

[Experiment 2] A porous hollow fiber membrane (inner diameter: 175 μm) for a hemodialyzer obtained by spinning using the same EVAL resin as in (1) above (inner surface area: about 50 cm).
² ) was used to prepare a mini-module, and using this mini-module as it was, a closed circuit in which MPC was not graft-polymerized on the surface was prepared in the same manner as in Experiment 1. The platelet suspension was circulated for 10 minutes in the closed circuit in which MPC was not graft-polymerized in the same manner as in Experiment 1 above, and the fluorescence intensity was measured in the same manner as in Experiment 1 to determine the Ca ²⁺ concentration from the measured value. Upon calculation, the results shown in Table 2 below were obtained.

[Experiment 3] Further, a closed circuit was formed using only a silicon tube without using a mini module composed of an EVAL resin porous hollow fiber membrane, and a platelet suspension was prepared in the same manner as in Experiments 1 and 2 above. Was circulated for 10 minutes, the fluorescence intensity was measured, and the Ca ²⁺ concentration was calculated from the measured value. The results shown in Table 2 below were obtained (control).

[0055]

[Table 2]

At the initial stage of a series of platelet activation processes involved in the formation of thrombus, free calcium ion Ca ²⁺ plays a very important role in transmitting an external stimulus to the inside of the platelet. The activation of platelets is governed by the concentration of calcium ions Ca ²⁺ inside the cells. Therefore, an increase in the concentration of free calcium ion Ca ²⁺ in the cytoplasm due to contact with a foreign substance is an index that reflects the activation of platelets. Therefore, looking at the results in Table 2 above based on this point, a closed circuit made using a mini-module consisting of EVAL resin porous hollow fiber membrane with MPC immobilized (graft polymerization) on the surface is used. Experiment 1 is EVA in which MPC is not fixed on the surface.
Calcium in the platelet suspension after circulating the platelet suspension in the closed circuit for 10 minutes, as compared to Experiment 2 in which a closed circuit prepared using a mini-module made of L resin porous hollow fiber membrane was used It can be seen that the concentration of ions Ca ²⁺ is significantly low and that it exhibits good antithrombotic properties.

Example 3 [Experiment 1] (1) EVAL resin [manufactured by Kuraray Co., Ltd .; ethylene content = 32 mol%, degree of polymerization Pv = 1100] spun using a porous material for plasma component separator Hollow fiber membrane (inner diameter 175μ
m) was used to produce a mini-module having an inner surface area of about 450 cm ² . MPC (manufactured by NOF Corporation) 0.97 g (3.3
X 10 ^-3 mol), tetraammonium cerium (IV) sulfate dihydrate 0.96 g (1.5 x 10 ^-4 mol) and nitric acid 1.5 x 10 ^-3 mol in 30 ml of distilled water. After being degassed, they were contacted by circulating for 4 hours in an atmosphere of 35 ° C., and then sufficiently washed with water to obtain a mini-module in which MPC was graft-polymerized on the surface of the hollow fiber membrane. (2) The graft polymerization amount of MPC per unit area on the inner surface of the hollow fiber membrane of the mini-module graft-polymerized with the MPC obtained in (1) above was determined in the same manner as in Example 1, and the results are shown in Table 3 below. It was as shown in. (3) Further, the density of phosphorylcholine groups on the inner surface of the hollow fiber membrane of the mini-module graft-polymerized with the MPC obtained in (1) above was calculated by the wet decomposition-absorptiometry method and ESCA in the same manner as in Example 1. However, the results are shown in Table 3 below.

[Blood compatibility test] (1) of Experiment 1 above
Ex-vivo evaluation was performed using the mini-module (internal surface area 450 cm ² ) obtained by graft-polymerizing the MPC obtained in the above. That is, the weight of the mini module is 14
Infuse an arteriovenous cannula for blood transfusion into the right femoral arteriovenous of a mixed-breed dog of kg, and use a roller pump to draw blood at 5 ml /
When it was introduced into the mini-module and circulated in minutes, as shown in Table 3 below, thrombus formation was not observed in the mini-module even after 48 hours from the start of circulation. After the test, take out the mini module and wash it with saline.
A 1.25% glutaraldehyde physiological saline solution was sealed inside the hollow fiber membrane and left for 2 hours. Next, after displacing the inside of the hollow fiber membrane with pure water, freeze-drying and gold deposition were sequentially performed, and the inside surface of the hollow fiber membrane was observed with a scanning electron microscope (SEM). As a result, the adherence of blood cell components and plasma proteins was observed. Was not observed. As the circuit for circulation, a polyvinyl chloride tube having heparin immobilized on its surface was used.

[Experiment 2] A porous hollow fiber membrane (inner diameter: 175 μm) for a plasma component separator obtained by spinning using the same EVAL resin as in (1) above was used, in which MPC was not fixed. A mini module having a surface area of about 450 cm ² was prepared. This mini module weighs 12k
When a blood transfusion arteriovenous cannula was intubated in the right femoral arteriovenous of a mixed-breed dog of g, and a circulation test was performed in the same manner as in Experiment 1 above, 4 hours after the start of circulation as shown in Table 3 below. Blood began to clot in the mini-module and a thrombus formed.

[0060]

[Table 3]

[0061]

[Effects of the Invention] The medical material and medical product of the present invention obtained by bonding a compound having a phosphorylcholine group to the surface of an article made of a PVA polymer, and a phosphorylcholine group in the main chain made of a PVA polymer. The medical material and medical product of the present invention obtained by molding, spinning, coating a base material, etc. using a polymer having side chains bonded as a raw material or a coating material are both excellent in blood compatibility. Moreover, since its excellent blood compatibility is maintained for a long period of time, it is extremely useful as various medical materials and / or medical products including artificial organs.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61M 1/18 500 A61L 33/00 T (72) Inventor Tatsuhiko Higaki 1-12-39 Umeda, Kita-ku, Osaka-shi, Osaka Within Kuraray Co., Ltd. (72) ) Inventor Koji Inai, 1621 Sakata, Kurashiki City, Okayama Prefecture Claret Co., Ltd. (56) Reference JP 62-259063 (JP, A) JP 8-723 (JP, A) JP 7- 268038 (JP, A) JP-A-6-65265 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61L 33/00-33/18 A61L 29/00-29/18 C08F 8/40 C08L 29/04 A61M 1/16-1/18 CAPLUS (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A predetermined shape and / or composition comprising a polyvinyl alcohol polymer having a compound having a phosphorylcholine group bonded as a side chain group, as a constituent element.
A medical material or medical product consisting of an article having a structure . 2. The medical material or medical material according to claim 1, which is obtained by binding a compound having a phosphorylcholine group to an article having a predetermined shape and / or structure manufactured in advance using a polyvinyl alcohol-based polymer. Product. 3. The medical material or medical product according to claim 2, wherein the density of phosphorylcholine groups on the surface of the article is 8 × 10 ¹⁵ / cm ² or more. 4. A polymer prepared by using as a raw material a polymer in which a side chain having a phosphorylcholine group is bonded to a main chain made of a polyvinyl alcohol polymer, or a substrate coated with the polymer. The medical material or medical product according to claim 1. 5. An unsaturated monomer having a phosphorylcholine group is graft-polymerized to an article having a predetermined shape and / or structure manufactured in advance using a polyvinyl alcohol-based polymer.
Of manufacturing medical materials or medical products of. 6. A polyvinyl alcohol-based polymer
Group unsaturated monomers with phosphorylcholine groups in the main chain.
Was formed by RAFT polymerization, a polymer side chain is attached having a phosphorylcholine group in the main chain of polyvinyl alcohol polymer. 7. A method for producing a polymer according to claim 6 , wherein the polyvinyl alcohol polymer is graft-polymerized with an unsaturated monomer having a phosphorylcholine group.