JP2000198845A - Production of polyalkyl ether/polyaryl ether sulfone copolymer excellent in antithrombogenic property - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a polyalkyl ether/polyaryl ether sulfone-based copolymer practically usable from the aspects of cost, productivity, moldability, etc., and excellent in blood compatibility, especially antithombogenic properties. SOLUTION: A bis (haloaryl) sulfone is thermally reacted with a dihydroxyaryl compound and an α,ω-bishydroxypolyoxyalkylene compound [hereinafter referred to as a polyalkylene glycol (PAG)] in the absence of a solvent or preferably in a small amount of an amide-based solvent in the presence of a weak or a medium basic catalyst. Thereby, a polyalkyl ether/polyaryl ether sulfone copolymer can efficiently be produced.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a polysulfone copolymer having excellent antithrombotic properties. More specifically, the present invention relates to a method for efficiently producing a specific polyalkyl ether / polyaryl ether sulfone copolymer which can be used as a medical material for use in contact with blood.

[0002]

2. Description of the Related Art In recent years, synthetic polymer materials have been widely used for medical materials such as artificial organs and catheters. Typical examples of the polymer materials for medical use include hydrophobic polymers such as polyester, polysulfone, polyvinyl chloride, polystyrene, silicone resin, polymethacrylate and fluorine-containing resin, polyvinyl alcohol, polyether urethane ( Hydrophilic polymers such as segmented polyurethane, SPU), poly (2-hydroxyethyl methacrylate) and polyacrylamide. While most of these conventional materials have been used mainly focusing on their physical and mechanical properties, SPU
Is known to have relatively excellent antithrombotic properties. Among them, BiomerR, CardiothaneR, etc. have been tried to be applied to artificial hearts, but they have not yet achieved sufficient effects (E. Nylas, RCReinbach, JBCaulfield, N. et al.
H. Buckley, WGAusten; J. Biomed. Mater. Res. Symp., 3,
129 (1972), LPJoyce, MCDevries, WSHastings, DB
Olsen, RKJarvik, WJKolff; Trans.ASAIO, 29, 81 (198
3)).

[0003] On the other hand, with the advancement of medical technology, the chances of contact between living tissue and blood and materials are increasing,
Biocompatibility of materials is becoming a major problem. Absorbing and denaturing biological components such as proteins and blood cells on the material surface not only causes unusual adverse effects such as thrombus formation and inflammatory reaction on the living body side,
This leads to deterioration of the material and is an important issue that must be solved fundamentally and urgently for medical materials. Regarding the prevention of blood coagulation on the material surface, continuous administration of a blood anticoagulant typified by heparin has conventionally been performed, but the effect of heparin administration over a long period has recently become a problem, and in particular, hemodialysis, With respect to hemodialysis therapy for patients with chronic renal failure who undergo blood purification such as hemofiltration, the development of a blood contact material that does not require an anticoagulant has been strongly desired. At present, more than 100,000 patients have been applied to the blood purification law in Japan.

Several methods have been proposed for suppressing the activation of complement or improving the antithrombotic properties of a medical material when it comes into contact with blood. For example, regarding the inhibition of complement activation, methods of fixing the surface of a polymer having a tertiary amino group, grafting a hydrophilic polymer such as a polyethylene oxide chain to the surface by a covalent bond, and the like have been reported. Although the effect of inhibiting complement activation has been confirmed, it was insufficient to suppress blood coagulation (antithrombotic). Regarding the improvement of the antithrombotic properties, the antithrombotic effect of the membrane surface by heparinization (JP-A-51-194) or the surface modification with a prostaglandin E1-cellulose derivative adsorption layer (JP-A-54-77497). A method of graft-polymerizing 2-methacryloyloxyethylphosphocholine (MPC), which is a polymer having excellent antithrombotic properties, on the surface of cellulose and immobilizing it (BIO INDUSTRY, 8 (6), 412-420 (1991) ) Or immobilization of chemically modified MPC-grafted cellulose derivatives on hollow fibers (JP-A-5-220218 and JP-A-5-220218).
-345802) and the like. But,
There are many problems in terms of insufficient effect, such as the problem of low stability of the physiologically active substance, or high cost due to the complexity of the immobilization method, and difficulty in obtaining a uniform immobilized surface layer. Not. Originally, dialysis performance of regenerated cellulose membrane was low, and surface coating method was complicated,
Not at a practical level.

In addition, hydrophobic polymer materials such as polyvinyl chloride and polymethacrylate, and hydrophilic polymer materials such as polyvinyl alcohol and poly (2-hydroxyethyl methacrylate), all have mechanical strength, It is not satisfactory in terms of biocompatibility. In addition, segmented polyurethanes such as Biomer® and Cardiothane® suppress platelet adhesion due to a microphase separation structure between a rigid aromatic urethane binding site and a flexible polyether binding site, but their effects are not necessarily sufficient. In particular, a hydrogen-bonding partial structure such as a urethane bond or a urea bond contributes to the improvement of the rigidity of the molecular chain, but because of strong interaction between polar groups of the main chain, water that can reduce hydrophobic interaction is used. The hydration of the molecule is inhibited. Therefore, it has been reported that when blood proteins adsorb, they induce protein denaturation and promote platelet adhesion. In the first place a hydroxyl group,
Polar sites, such as amino groups, induce complement activation (alternate pathway) upon blood contact and also contribute to thrombus formation by promoting fibrin formation. Among other polyester polymers, PEO (polyethylene oxide) / PBT (polybutylene terephthalate) copolymer is known as a biocompatible polymer having excellent blood compatibility (Japanese Patent Application Laid-Open No. 60-2383).
No. 15), which also has a drawback in terms of chemical stability, such as high hydrolyzability and associated leakage of low-molecular-weight eluted substances into the body, and poses a serious problem in practical use.

On the other hand, HEMA (2-hydroxyethylmet) is a material design in which a polymer surface has a hydrophilic / hydrophobic microdomain structure to suppress platelet adhesion and exhibit antithrombotic properties.
hacrylate) -Styrene-HEMA block copolymer, etc. (C. Nojiri, T. Okano, D. Grainger, KDPark, S. Nak
ahama, K.Suzuki, SWKim, Trans.ASAIO, 33,596 (198
7)), however, is also expensive, brittle, and difficult to melt-mold and wet-mold, and poses a serious practical problem. Recently, by adapting a fluoroalkyl group with low surface energy (high hydrophobicity) to the hydrophobic domain of the microdomain structure, the phase separation state with the hydrophilic domain with high surface energy is stabilized, and more blood compatibility is obtained. Attempts have been made to improve the workability, but the problem of workability has not yet been solved. MPC (2-me
thacryloyloxyethylphosphoryl choline) -BMA (buthylm
ethacrylate) copolymer was shown to have excellent antithrombotic properties (K. Ishihara, R. Aragaki, T. Ueda, A. Watanabe, NN
akabayashi, J. Biomed. Mater. Res., 24, 1069 (1990)), which also has problems in moldability, price, and the like. In this sense, in considering the antithrombotic effect of a medical material, the combination with a polymer material having excellent antithrombotic properties has not actually reached a practical level.

The present inventors have proposed that a polyalkyl ether / polyaryl ether sulfone copolymer has excellent antithrombotic properties and that it be used as an antithrombotic material. As a polymerization method of such a polyalkyl ether / polyaryl ether sulfone copolymer, a dichlorodiphenyl sulfone derivative and a bisphenol compound, which are raw materials of polysulfone, and a polyoxyalkylene glycol having halogenated both terminals are used as a suitable base catalyst. A method of performing polycondensation by a nucleophilic substitution reaction by heating in the presence is employed. However, in this method, it is necessary to secure a halogenated polyoxyalkylene glycol which is not commercially available at present as a monomer raw material, and it is difficult to reduce the cost and mass-produce it to practical use.

That is, in order to produce a large amount of a polyalkyl ether / polyaryl ether sulfone copolymer at a low cost, a polyoxyalkylene component other than the halogenated polyoxyalkylene glycol at both ends is used in a large amount at a low cost. It is necessary to use what is supplied as the monomer material. A candidate that can be substituted in this sense is a polyoxyalkylene glycol having hydroxyl groups at both ends, and this raw material is widely and widely used as a monomer component for polyester and polyurethane.

Since the polymerization reaction group is an alcoholic hydroxyl group, various devises have been made on the reaction conditions for copolymerization with polyaryl ether sulfone in which the polymerization active group is a phenolate anion. For example EP 422933 A2
Now, the chlorine group at the end of polyethersulfone (PES)
It has been reported that PES is hydrophilized by reacting with polyethylene glycol under a strong base such as sodium metal or sodium hydride and coupling. Vysokomol.S
oedin., Ser.A (1984), 26 (1), 97-103, block by connecting polysulfone and polyethylene glycol, whose ends are hydroxyl groups of bisphenol A, using hexamethylene isocyanate as a crosslinking agent. Methods for preparing copolymers have been reported. These methods are effective for introducing a small or partial amount of a polyoxyalkylene chain into the polysulfone skeleton. However, as in the polyalkyl ether / polyaryl ether sulfone-based copolymer of the present invention, the main chain skeleton is not effective. It is not suitable for introducing a polyoxyalkylene chain homogeneously and in a large amount (especially, 30% by weight or more in a polymer by weight). In the polymerization using a strong base such as sodium hydride, a sufficiently high molecular weight copolymer cannot be obtained due to the formation of by-products due to the elimination reaction of the raw material or polymerization active group, and a method using isocyanate as a crosslinking agent In such a case, since a considerable amount of urethane bonds are generated in the main chain, the influence of the urethane skeleton is inevitable from the viewpoint of physical properties and blood compatibility of the polymer.

In this sense, the production of the polyalkyl ether / polyaryl ether sulfone copolymer of the present invention is carried out under mild conditions using a catalyst having a moderate basicity under mild conditions. Nucleophilic substitution polymerization of monomer raw materials is desired. In fact, US57009
02 and Macromolecules (1996), 29, 7619-7621 and J. Appl. Po.
In lym. Sci (1997), 66 (7), 1353-1358, etc., potassium chloride was used as a base catalyst to allow the chlorine atom at the polysulfone end and the methoxylated polyethylene glycol at one end (Me
MeO-PEG to polysulfone by nucleophilic substitution reaction of O-PEG)
Grafting of ABA-type block copolymers has been reported. This polymerization is a grafting of PEG onto polysulfone similar to the above-mentioned report, and the introduction ratio of polyoxyethylene chains into polysulfone is as low as 30 wt% or less. However, it may be applicable to the production of the polyalkylether / polyarylethersulfone copolymer of the present invention by controlling and optimizing the polymerization conditions using PEG which is a hydroxyl group at both ends.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a polyalkyl ether / polyaryl ether which is practical in terms of cost, productivity, moldability, etc., and has excellent blood compatibility, especially excellent antithrombotic properties. An object of the present invention is to provide a sulfone copolymer, a method for producing the same, and a medical material using the same.

[0012]

Means for Solving the Problems The present inventors, as a copolymer component of a polyalkyl ether / polyaryl ether sulfone copolymer, use a raw material monomer of polyoxyalkylene glycol which is a soft segment having excellent antithrombotic properties. Using a low-cost polyalkylene glycol (PAG) having an average molecular weight in the range of 2,000 to 20,000, a diphenylsulfone dichloro derivative and a bisphenol compound as raw materials of a polyarylethersulfone as a hard component are mixed with or without a solvent. Medium, by polycondensation using a basic catalyst, the number of polyoxyalkylene glycol units in the copolymer, the type of hydrophobic hard component,
The present inventors have also found that a blood-compatible polyalkyl ether / polyaryl ether sulfone copolymer having a controlled copolymer composition can be prepared inexpensively and in large quantities, and the present invention has been achieved.

That is, the present invention provides the following formulas (1) to
(3)

[0014]

Embedded image Cl—Ar—X—Ar ¹ —Cl (1) HO—Ar ² —OH (2) HO— (RO) _k —OH (3) In 1), X is —SO ₂ —, and Ar is
And Ar ¹ are each independently a divalent aromatic group which may be nucleus-substituted. In the above formula (2), Ar
² is a divalent aromatic group which may be substituted with a nucleus. In the above formula (3), R is an alkylene group having 2 to 3 carbon atoms, and k is a number of unit repeats such that the molecular weight of the polyoxyalkylene structure represented by (RO) k becomes 2000 to 20,000. A) a phenol / 1,1,2,2-tetrachloroethane 6/4 (weight ratio) mixture comprising polycondensation of the raw material monomer represented by the formula (1) in the absence or in a solvent using a basic catalyst. 1.2g concentration in solvent
/ Dl, a method for producing a polyalkyl ether / polyaryl ether sulfone copolymer excellent in antithrombotic properties, having a reduced viscosity of 0.5 or more measured at 35 ° C.

Further, the present invention is to use the above-mentioned polyalkyl ether / polyaryl ether sulfone copolymer as a material for a medical material for use in contact with blood.

According to the present invention, the monomer raw materials represented by the above formulas (1) to (3) are polycondensed with or without a solvent in a solvent using a basic catalyst, thereby providing excellent antithrombotic properties. A polyalkyl ether / polyaryl ether sulfone copolymer is provided.

In the above formulas (1) to (3), Ar, Ar
¹ and Ar ² each independently represent a divalent aromatic group which may be nuclear-substituted, and specifically, p-phenylene, m-phenylene, 2,6-naphthylene, 2,7-naphthylene, 1,4-naphthylene, 1,5-naphthylene,
4,4′-biphenylene, 2,2′-biphenylene,
4,4′-oxydiphenylene, 4,4′-isopropylidene diphenylene, 4,4 ′-(1,1,1,3,
3,3-hexafluoroisopropylidene) diphenylene, 4,4′-isopropylidene-2,2 ′, 6,6 ′
-Tetramethyldiphenylene, 4,4'-sulfonyldiphenylene and the like, and mono-, di-, tri- and tetra-nuclear substituents thereof can be exemplified. Examples of the nucleus substituent include an alkyl group having 1 to 8 carbon atoms such as methyl, ethyl and phenyl, an aryl group, a halogen group such as fluorine and chlorine, a nitro group, and an alkoxy group having 1 to 8 carbon atoms. Among them, Ar and Ar ^′ are p-phenylene;
Examples of r ^″ include 4,4′-isopropylidene diphenylene, 4,4 ′-(1,1,1,3,3,3-hexafluoroisopropylidene) diphenylene, 4,4′-sulfodiphenylene and the like. preferable.

In the above formula (1), X is -SO
_2- .

In the above formula (3), R represents a group having 2 to 3 carbon atoms.
And specific examples thereof include ethylene, propylene and the like. Of these, ethylene is preferred as R. R may have a single structure,
It may be composed of two or more types of structures. K represents the number of repeating units such that the molecular weight of the polyoxyalkylene structure represented by (RO) k is 2000 to 20,000. For example, when R is a polyoxyethylene chain, K
Takes a value of 45 to 450. The molecular weight of the polyoxyalkylene structure is preferably 2,000 to 15,000, more preferably 3,000 to 10,000, and particularly preferably 300.
0 to 6000.

The polyalkyl ether / polyaryl ether sulfone copolymer obtained by the above method has a polyoxyalkylene structure represented by the above formula (3) having a content relative to that of the polyalkyl ether / polyaryl ether sulfone copolymer. , 10 to 85% by weight. When the content of the polyoxyalkylene structure is 10% or less by weight, the hydrophobicity of the polyalkyl ether / polyaryl ether sulfone copolymer is too high, and the wettability with water in a dry film state is not sufficient. On the other hand, if the content is 85% or more, the hydrophilicity is too high, so that the dissolution into water and remarkable swelling occur, resulting in insufficient mechanical strength. The content of the polyoxyalkylene structure is preferably 30 to 80% by weight, and more preferably 30 to 70% by weight.

The polyalkyl ether / polyaryl ether sulfone copolymer obtained by the present invention is mainly composed of repeating units represented by the following formulas (4) and (5).

[0022]

-[(-RO-) k-(-Ar-X-Ar ¹ -O-)] _y ·· (4)-[(-Ar ² -O-)-(-Ar-X-Ar ¹ -O-)] _1-y- ··· (5) X, Ar, Ar ¹ , A in the above formulas (4) and (5)
r ² , R, k and y are the same as described above.

The copolymer is phenol / 1,1,1,
The reduced viscosity measured at 35 ° C. at a concentration of 1.2 g / dl in a mixed solvent of 2,2-tetrachloroethane 6/4 (weight ratio) is 0.5 or more.

In the above equations (4) and (5), Y
Represents the molar fraction of the polymer chain, and the value of X is 10 to 10% of the content of the polyoxyalkylene structure represented by the above formula (4) with respect to the polyalkyl ether / polyaryl ether sulfone copolymer. The number is in the range of 85% by weight. The specific value of Y varies depending on the chemical structure and composition of the Ar group and R group to be introduced, but specific examples include, for example, phenylene as Ar, Ar ¹ and Ar ² , and a molecular weight of 2000 to 20000 as R. When introducing 10 to 85 wt% of the polyoxyethylene chain, Y is 0.00176 to
Take a value in the range of about 0.95200.

According to the present invention, bis (haloaryl) sulfones represented by the above formulas (1) to (3), dihydroxyaryl compounds and α, ω-bishydroxypolyoxyalkylene compounds (hereinafter referred to as polyalkylene glycol, PAG) Described below) in the presence of a weak to moderate basic catalyst in the absence of a solvent or, preferably, in a small amount of an amide-based solvent, to thereby efficiently produce a polyalkyl ether / polyaryl ether sulfone copolymer. Can be.

In the reaction, the sum of the number of moles of the dihydroxyaryl compound represented by the above formulas (2) and (3) and PAG is equal to the number of moles of the bis (haloaryl) sulfone represented by the above formula (1). The reaction mixture is mixed and mixed in an appropriate amount, and reacted with an alkali in the presence of a suitable solvent. By changing the molar ratio of the dihydroxyaryl compound and PAG, polyalkyl ether / polyaryl ether sulfone copolymers having various compositions can be obtained. Heating reaction temperature is 1
20-400 degreeC is preferable, More preferably, it is 160-3.
50 ° C. If the reaction temperature is higher than 400 ° C, side reactions may occur or the raw materials may be easily decomposed.
Lower values result in slower response.

The basic catalyst used in the reaction is preferably an alkali metal carbonate, and examples thereof include lithium carbonate, potassium carbonate, sodium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. Of these, potassium carbonate is particularly preferred. It is necessary that the amount of the basic catalyst is an amount that substantially neutralizes the hydrogen halide generated during the reaction. Can be done. A small amount of an appropriate solvent (about 0 to the same weight based on the total weight of the raw material monomers) can be used for the reaction. Illustrative of suitable solvents are N-methylpyrrolidone,
Amide solvents such as N, N-dimethylacetamide and dimethylsulfoxide can be used.
N-dimethylacetamide is preferred. The reaction may be performed using a plasticizer. Examples of such a plasticizer include diphenyl sulfone and dialkyl ether of ethylene glycol.

Additives can be added during the reaction to accelerate the reaction. Examples of such additives include metals or salts thereof, clathrate compounds, chelating agents, and organometallic compounds.

The above polyalkyl ether / polyaryl ether sulfone copolymer has a reduced viscosity of 0.5 or more,
Preferably it is 1.0-3.0. If the reduced viscosity is less than 0.5, the mechanical strength of the polymer becomes insufficient, which is not preferable. The reduced viscosity referred to here is phenol /
In a 1,1,2,2-tetrachloroethane mixed solvent (weight ratio: 6/4), polymer concentration: 1.2 g / dl, temperature: 35 ° C.
Means the value measured in

The molecular weight and copolymer composition of the polyoxyalkylene structure of the polyalkyl ether / polyaryl ether sulfone copolymer can be arbitrarily changed according to the purpose.

In the present invention, the above-mentioned polyalkyl ether / polyaryl ether sulfone copolymer is used in such a range that its properties are not substantially changed (for example, the polymer 2).
(0% by weight or less, preferably 10% by weight or less), and other components may be contained as copolymer components. As other components to be copolymerized, for example, a polyester containing an ethylene terephthalate unit as a main repeating unit,
Polyester containing butylene terephthalate unit as a main repeating unit, polyether sulfone containing diphenyl sulfone as a main repeating unit, polysulfone containing a condensate of diphenyl sulfone and bisphenol A as a main repeating unit, and a carbonate of bisphenol A are mainly repeated. Polycarbonate and the like contained as a unit can be mentioned.

(Effect) The polyalkyl ether / polyaryl ether sulfone copolymer obtained by the method of the present invention has a Mic when exposed to human plasma at 37 ° C. for 1 hour.
The protein adsorption amount measured by the roBCA method is very small, 0.7 μg / cm ² or less, and has an excellent adsorption suppressing effect on adhesion of blood proteins and platelets when in contact with a plasma solution. The reason is considered as follows. The polyalkyl ether / polyaryl sulfone copolymer has a polyaryl sulfone (hard component) having large hydrophobicity at a rigid portion and a hydrophilic polyoxyalkylene unit (soft component) fixed in a polymer main chain. Thus, both the hydrophilic segment and the hydrophobic polyarylsulfone segment are characterized not only by thermodynamics but also by a macroscopically phase-separated surface structure. In such a polymer, since there is no hydrogen bond donor group in the main chain, the interaction between the main chains is small, and the domain of the hydrophilic polyoxyalkylene unit is in contact with water molecules that can reduce the hydrophobic interaction. Happens easily. Therefore, selective adsorption of the biological protein to the surface based on the domain pattern occurs, and the adsorbed protein is not denatured on the surface. As a result, the surface of the polymer becomes a state in which normal protein is adsorbed on the surface of the monolayer, and further biological components (red blood cells,
Leukocytes and platelets) are suppressed. In addition, harmful biological reactions such as complement activation, thrombus formation, and cell membrane damage can be avoided. The smaller the protein adsorption amount, the better, but
In the range of 0.3 to 0.7 μg / cm ^2, the effect is practically sufficient. As described above, such a highly hydrophobic and rigid polyarylethersulfone segment easily forms a stable domain structure, and is advantageous in expressing blood compatibility. Further, a polyalkyl ether / polyaryl ether sulfone copolymer obtained by block copolymerization with a hydrophilic polyoxyalkylene unit has wettability and solvent solubility,
As a result of the change in miscibility with other polymers, there is a possibility that various characteristics can be imparted from the viewpoint of molding processing.

The thus prepared polyalkyl ether /
The polyarylethersulfone copolymer (A) is used alone or in combination or mixed with a general-purpose medical polymer material by various methods to provide the polymer composition having excellent antithrombotic properties of the present invention.

As the medical polymer material for compounding or mixing the above copolymer, polyester, polyamide, polyurethane, polyvinyl chloride, polymethacrylate, polyolefin, polyarylsulfone, rubber-based elastomer and the like are preferably used. These general-purpose medical materials may be medical-grade polymers containing no impurities or the like and having a number average molecular weight of 10,000 to 1,000,000. The above-mentioned copolymer is complexed by directly coating or laminating on the blood contact surface of these materials,
Alternatively, these materials may be compounded as a composition blended by an appropriate method.

The medical material thus obtained has an amount of protein adsorbed on the surface of the above-mentioned copolymer when exposed to a phosphate buffer of 5% by weight of human platelet poor plasma (PPP) at 37 ° C. for 1 hour. Is preferably 0.8 μg / cm ² or less (in terms of albumin by the MicroBCA method), and 0.6 μg / cm ² or less.
More preferably, it is not more than cm ² . If the amount of protein adsorbed at the time of blood contact is 0.8 μg / cm ² or more, subsequent adhesion of platelets and activation cannot be sufficiently suppressed, and thrombus formation proceeds.

[0036]

According to the present invention, the above formulas (1) to (3)
By using the compound represented by the formula as a starting material, a polyalkyl ether / polyaryl ether sulfone copolymer having excellent antithrombotic properties can be easily produced, has high productivity, and can be produced at low cost. . Such a copolymer has little adsorption of biological components such as proteins and blood cells, and can suppress denaturation of the adsorbed protein and adhesion and activation of the contacted platelets. Furthermore, the activation of complement and damage to cell membranes can be avoided because the number of free terminal chains of oxyethylene and free hydroxyl groups in the copolymer is small. Therefore, the field of application of the polyalkylether / polyarylethersulfone copolymer of the present invention is useful as a medical material whose main purpose is to use it directly in contact with blood components. It can be used for artificial blood vessels, heart-lung machines, hemodialysis membranes, blood bags, catheters, plasma separation membranes and the like. When the polyalkyl ether / polyaryl ether sulfone copolymer of the present invention is used as such a material, it is not only coated and laminated by itself, but also formed as a hollow fiber, sheet, film, tube, Blend with various general-purpose medical materials, apply the blend on the surface of various materials, modify only the blood contact surface, or mold the blend itself into a material,
Processing is also possible.

[0037]

The present invention will be described below in more detail by reference examples and examples. However, the following examples do not limit the present invention. 1. “Parts” in the examples represent “parts by weight” unless otherwise specified.

2. Evaluation of Protein Adsorption Amount of protein adsorbed on the membrane was quantitatively evaluated by the MicroBCA method. This is a protein quantification method using a kit using copper ions and a BCA protein detection reagent. Only the copper ion monovalently reduced by the protein present in the sample undergoes a chelate reaction with this reagent to develop color (570 nm), so that the protein concentration (in terms of albumin) can be quantified by measuring the absorbance of the sample. For the preparation of the sample, the copolymer prepared in the same manner as in Example 1 was dissolved in methylene chloride so as to have a concentration of 1 wt%, and the solution was used to obtain a sample having a diameter of 15 mm.
A thin film layer of the copolymer was prepared by casting on a PET disk. In the evaluation, polyethersulfone (PES,
Mitsui Chemicals, casts polymer from NMP and processes it into a disc, polyethylene terephthalate (PET, diameter 15m)
m, 0.5 mm thick disk, Wako Pure Chemical Industries) flat membrane was used for the comparative experiment. In the measurement, these samples were used for human platelet poor plasma (PP
Using P), the amount of protein adsorbed when brought into contact with this plasma solution was spectrally quantified. At the time of evaluation, PPP prepared at a predetermined concentration (5 wt% phosphate buffer solution) with a phosphate buffer was brought into contact with the polymer membrane at 37 ° C. for 1 hour, and the adsorbed protein was extracted with a 1 wt% sodium dodecyl sulfate aqueous solution. , Micr
Using an oBCA kit, the color was developed by a conventional method, and the amount of adsorption was estimated from the absorbance.

3. Evaluation of adhesion of platelets adsorbed on membrane surface by SEM observation In general, platelet adhesion, which is a stage before severe thrombus formation,
It is known that the type of protein adsorbed on the material surface and the orientation on the surface are greatly involved in aggregation. And activation of adherent platelets (deformation, granule release)
Affects subsequent aggregation, platelet thrombus formation, and promotion of coagulation factor system reactions. Therefore, by observing the adhesion state of platelets on the surface of the material after contact with blood (whole blood or component blood), the degree of blood compatibility of the polymer can be roughly estimated. Here, human platelet-rich plasma (PR
Using P), the platelet adhesion behavior of the membrane surface after PRP contact was observed by SEM. PRP is prepared by adding 1/9 volume of a 3.5 wt% aqueous solution of trisodium citrate to fresh blood collected from a human upper arm vein, and adding 1000 r. p. m. The supernatant was prepared by centrifugation at for 10 minutes. As the samples, the aforementioned polyalkyl ether / polyaryl ether sulfone copolymer thin film coated PET flat film and control PES and PET flat films were used. These were cultured in a Petri dish (Falcon, 24w).
), and contacted with 0.7 ml of PRP for 3 hours at 37 ° C. The polymer sample after the contact was thoroughly washed with distilled water, fixed with a 2.5 wt% glutaraldehyde aqueous solution at room temperature for 2 hours, freeze-dried, and then gold-deposited to obtain an observation sample.

Examples 1 to 3 A. Production of polymer 4,4-hexafluoroisopropylidene diphenol 12.8
48 parts (central glass), 14.358 parts of bis (4-chlorophenyl) sulfone (manufactured by Lancaster), and α, ω-bis (2-hydroxy) polyoxyethylene # 4000 from which coexisting water has been removed by azeotropic distillation with toluene. (Polyethylene glycol, number average molecular weight 3000, manufactured by NOF Corporation) 35.37 parts, toluene 15 parts, N, N-dimethylacetamide 20 parts, potassium carbonate 8.28 parts (Kanto Chemical), three with nitrogen inlet and outlet Into a Dean-Starks trap and purge with nitrogen.
Heat reflux was performed at 15-125 ° C for 20 hours. After confirming that the outflow of water accompanying the reaction was completed, toluene was distilled off over 8 hours, and the atmosphere in the flask was replaced with nitrogen.
The mixture was heated and stirred at 145 ° C. for 80 hours to be reacted. Sampling was performed at regular intervals, and the progress of the reaction was evaluated by GPC. After the reaction, the whole was opened with stirring in 2000 ml of ion-exchanged water, washed, and then further washed with 2000 ml of fresh ion-exchanged water.
The operation of washing with stirring under time was repeated three times. Then, the polymer was stirred and washed with 3000 ml of a 0.1 wt% hydrochloric acid aqueous solution for 8 hours,
The remaining potassium carbonate catalyst was completely deactivated and eluted in water. This operation was further repeated three times with stirring and washing with 2000 ml of fresh ion-exchanged water for 2 hours, followed by dehydrochlorination. The obtained polymer was dried under reduced pressure at 60 ° C. for 24 hours, extracted with tetrahydrofuran, filtered and dried. Finally, about 95% of the theoretical yield (about 56 g) of a dried polymer was obtained.

This polymer is a polyoxyethylene component 6
It is a copolymer composed of 0% by weight and 40% by weight of a polysulfone component, and is abbreviated as PEO3000 (60) -co-PSFS (40).

120 mg of this polymer was mixed with phenol /
It was dissolved in 10 ml of a 1,1,2,2-tetrachloroethane mixed solvent (weight ratio 6/4), and the reduced viscosity was measured to be 1.25. Further, the number average molecular weight of this polymer was about 32,000 (in terms of polystyrene). Table 1 shows the results.

In a similar manner, PEs having different copolymer composition ratios
O3000 (60) -co-PSS (40) and PEO3000 (60) -co-PSPES (40) were synthesized. Table 1 also shows the molecular weight and viscosity of these polymers. The structure of the polymer used is also shown.

[0044]

[Table 1]

1) Abbreviations correspond to the following structural formulas, respectively. 2) Reduced viscosity measured at 35 ° C. by dissolving 120 mg in 10 ml of a phenol / 1,1,2,2-tetrachloroethane mixed solvent (weight ratio: 6/4).

As a result, it has been clarified that various polyalkyl ether / polyaryl ether sulfone copolymers shown below can be efficiently polymerized by using polyethylene glycol as a raw material monomer.

[0047]

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Examples 4 to 6 and Comparative Examples 1 and 2 Evaluation of Protein Adsorption Amount The protein adsorption on the membrane surface was measured according to the method described above. As shown in Table 2, the polyalkyl ether / polyaryl ether sulfone copolymer of the present invention showed a significant suppression of protein adsorption as compared with conventional medical materials such as polyether sulfone and polyethylene terephthalate.

C. SEM Observation of Platelet Adhesion to Polymer Surface Using Human PRP Table 2 also shows the platelet adhesion numbers of various polymer membrane surfaces after PRP contact. According to the above study, adhesion of a large amount of platelets to the surface was observed for polyethersulfone and polyethylene terephthalate, which are medical materials having low ability to inhibit protein adsorption. On the other hand, the membrane of the polyalkylether / polyarylethersulfone copolymer having a high ability to inhibit protein adsorption showed clear inhibition of platelet adhesion as compared with the control PES and PET.

From the above results, the polyalkylether / polyarylethersulfone copolymer excellent in the ability to suppress protein adsorption is more effective than the existing polyethersulfone.
It was found that platelet adhesion was significantly suppressed and blood compatibility was excellent.

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[Table 2]

Continued on the front page F-term (reference) 4C081 AB13 AB32 AB35 AC08 AC12 AC15 BA02 BA04 BB04 CA022 CA042 CA082 CA162 CA212 CA232 CA281 CA282 CB052 CC02 CC08 DA02 DA03 DA04 DC03 DC12 EA06 4J002 CN031 GB03 4J030 BA09 BA42 BA48 BB46 BB06 BB52 BF19 BG32

Claims (2)

[Claims] [Claim 1] the following formulas (1) to (3) ## STR1 ## ^{Cl-Ar-X-Ar 1} -Cl ··· (1) HO-Ar 2 -OH ··· (2) HO- (RO ) _k in -OH ··· (3) (the formula (1), X is -SO ₂ - is, Ar
And Ar ¹ are each independently a divalent aromatic group which may be nucleus-substituted. In the above formula (2), Ar
² is a divalent aromatic group which may be substituted with a nucleus. In the above formula (3), R is an alkylene group having 2 to 3 carbon atoms, and k is a number of unit repeats such that the molecular weight of the polyoxyalkylene structure represented by (RO) k becomes 2000 to 20,000. A) a phenol / 1,1,2,2-tetrachloroethane 6/4 (weight ratio) mixture comprising polycondensation of the raw material monomer represented by the formula (1) in the absence or in a solvent using a basic catalyst. 1.2g concentration in solvent
/ Dl, a method for producing a polyalkyl ether / polyaryl ether sulfone copolymer excellent in antithrombotic properties, having a reduced viscosity of 0.5 or more measured at 35 ° C. 2. Use of the above polyalkyl ether / polyaryl ether sulfone copolymer as a material for medical materials for use in contact with blood.