JP2000198846A - Polymer material excellent in antithrombogenic property and medical material comprising the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a cellulose diacetate composition practically usable from the aspects of cost, moldability, etc., capable of improving antithrombogenic properties and further excellent in dialytic performances, a medical antithrombogenic polymeric material comprising the composition and a medical dialytic material using the polymeric material. SOLUTION: This polymeric composition is composed of (A) 1-50 pts.wt. of a specific poly(alkyl aryl ether)sulfone copolymer having the content of a polyoxyalkylene unit within the range of 10-90 wt.% expressed in terms of weight ratio and based on the whole and (B) 99-50 pts.wt. of a cellulose diacetate. The polymeric composition is useful as a material for a medical material for use in contact with blood.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a polymer composition having excellent antithrombotic properties and a medical material using the same. More specifically, a polymer composition having excellent antithrombotic properties comprising a specific polyalkyl ether / polyalkyl ether sulfone copolymer and cellulose diacetate, and using the same in contact with blood using the same Related to medical materials. The medical material is suitable for a medical hemodialysis membrane obtained by, for example, melt-spinning a molten composition of the polymer composition or dry / wet spinning a dope solution.

[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.

[0004] The principle of blood purification is that blood and dialysate are brought into contact via a membrane, waste and metabolites in blood are diffused and removed into the dialysate, and excess water is removed by utilizing a pressure difference. By removing. When purifying blood, a blood purifier is used. In this case, a blood circuit in which hollow fibers are bundled is housed in a housing, and has a structure in which blood flows inside the hollow fibers and dialysate flows outside. Conventionally, regenerated cellulose membranes, especially regenerated cellulose membranes using the copper ammonium method, have been widely used as materials for dialysis membranes for blood purifiers. Play.
This is because the regenerated cellulose membrane has excellent dialysis performance and mechanical strength, and also has high safety backed by many years of experience. However, despite the progress of hemodialysis therapy, it is true that various problems associated with dialysis are still unsolved. The main ones are
One is transient leukopenia associated with complement activation in the blood by cellulosic polymers, and the second is various side effects that may occur due to long-term, high-dose administration of anticoagulants. As mentioned above, when performing hemodialysis,
Continuous administration of a blood anticoagulant typified by heparin has been performed in order to suppress a blood coagulation reaction in a blood purifier. However, as the solute removal performance of the blood purifier has been improved and a long life span of about 20 years has become possible, problems caused by the use of heparin have been pointed out one after another. In particular, it has been recognized that long-term administration of heparin is accompanied by side effects such as liver disorders such as abnormal lipid metabolism, prolonged bleeding time, and allergic reactions. From such a viewpoint, the development of a blood purifier having an antithrombotic property that does not cause blood coagulation even if the amount of the anticoagulant is reduced during the blood purification therapy or that is not used at all is required. It has become strongly desired. In addition, the antithrombotic blood purifier also makes the entire device portable, promotes rehabilitation of patients detained in hospitals for about 5 hours for 2-3 days a week, and improves the quality of life. Will also lead to

[0005] Without impairing the dialysis performance of the regenerated cellulose membrane,
Several methods have also been proposed for inhibiting complement activation or improving antithrombotic properties. For example, regarding suppression of complement activation,
Methods such as surface immobilization of a polymer having a tertiary amino group and grafting of a hydrophilic polymer such as a polyethylene oxide chain to the surface by a covalent bond have also been reported, and the effect of suppressing some degree of complement activation has been confirmed. However, it was insufficient to suppress blood coagulation (antithrombotic). Regarding the improvement of antithrombotic properties, heparinization of the membrane surface (Japanese Patent Laid-Open No.
194), or surface modification with a prostaglandin E1-cellulose derivative adsorption layer (JP-A-54-7).
No. 7497), a method of graft-polymerizing and immobilizing 2-methacryloyloxyethylphosphocholine (MPC), a polymer having excellent antithrombotic properties, on a cellulose surface (BIO INDUSTRY, 8 (6)). , 412- 420 (1
991)) or fixation of chemically modified MPC grafted cellulose derivatives to hollow fibers (JP-A-5-220218 and 5-345802). However, 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 converted. The dialysis performance of the regenerated cellulose membrane is originally low, and the surface coating method is complicated, so that it has not reached a practical level. Furthermore, it has recently been reported that membranes made of synthetic polymers such as polysulfone and polyethersulfone are superior in blood compatibility such as inhibition of complement activation compared to regenerated cellulose, but their antithrombotic properties are insufficient. However, the use of anticoagulants has not been reduced.

On the other hand, recently, acetylated cellulose acetate, which is an ester derivative of cellulose, has been mainly used as a membrane material for dialysis instead of regenerated cellulose. It has been reported to show dialysis performance far superior to membranes. However, it is not antithrombotic and has poor blood compatibility.

The above-mentioned hydrophobic polymer materials such as polyvinyl chloride and polymethacrylate, and hydrophilic polymer materials such as polyvinyl alcohol and poly (2-hydroxyethyl methacrylate) are all mechanically strong and biocompatible. It is not satisfactory in terms of properties. Biomer
Segmented polyurethanes such as R and Cardiothane® suppress platelet adhesion due to the microphase-separated structure between the rigid aromatic urethane binding site and the flexible polyether binding site, but their effect is not always sufficient. In particular, hydrogen bonding partial structures such as urethane bonds and urea bonds,
Although it contributes to the improvement of the rigidity of the molecular chain, the interaction between polar groups of the main chain is strong, so that the hydration of water molecules that can reduce the hydrophobic interaction 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 polar site such as a hydroxyl group or an amino group generally induces complement activation (second pathway) at the time of blood contact, and also causes thrombus formation by promoting fibrin formation. For 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. 60-238315). There are drawbacks related to chemical stability, such as leakage of low-molecular eluates into the body accompanying this, and this 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.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide a cellulose diacetate composition which is practical in terms of cost, moldability, etc., has improved antithrombotic properties, and furthermore has excellent dialysis performance. Medical antithrombotic polymer material consisting of this,
Another object of the present invention is to provide a medical dialysis material using the same. By the way, the present inventors have proposed that a polyether / polysulfone copolymer has excellent antithrombotic properties and that it is used as an antithrombotic material. Therefore, it is considered that the dialysis performance can be improved and the antithrombotic property can be improved by compounding the polyether / polysulfone copolymer on the existing cellulose diacetate membrane by any method.

[0010]

DISCLOSURE OF THE INVENTION The present inventors have improved the antithrombotic properties of cellulose diacetate in consideration of blood compatibility (particularly antithrombotic properties), biosafety, economy, solvent solubility, and the like. Considered to do. As a result, the cellulose diacetate composition obtained by mixing a small amount of the specific polyether / polyarylethersulfone copolymer is effectively segregated on the membrane surface obtained by spinning the composition. It has been found that cellulose diacetate can be provided with antithrombotic properties. That is, excellent antithrombotic properties, in the copolymer of polyoxyalkylene glycol as a soft segment and polyaryl ether sulfone as a hard component, the number of polyoxyalkylene glycol units,
As a result of a detailed study of the type of the hydrophobic hard component and the control of the copolymer composition thereof, the polyalkyl ether / polyaryl obtained from the polyoxyalkylene glycol having an appropriate chain length and the aryl ether sulfone monomer was obtained. The cellulose diacetate composition obtained by blending a small amount of the ether sulfone copolymer with cellulose diacetate maintains the mechanical properties and dialysis performance by melt film formation or dry / wet film formation and spinning. As it was, it was found that a hemodialysis hollow fiber membrane comprising a cellulose diacetate composition having good antithrombotic properties was obtained, and the present invention was achieved.

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

[0012]

-(-Ar-X-Ar ¹ -O-)-... (1)-(-Ar ² -Y-Ar ³ -O-)-... (2)-(-RO- ) _K -... (3)

(Here, Ar and Ar ¹ are each independently a divalent aromatic hydrocarbon group which may be nucleus-substituted. Ar ² and Ar ³ may be each independently a nucleus-substituted aromatic hydrocarbon group. A good divalent aromatic hydrocarbon group, R is an alkylene group having 2 to 3 carbon atoms, and k is-(-RO-) _k
The polyoxyalkylene structure represented by-has a molecular weight of 40
The number of unit repetitions is 0 to 20,000. X is —SO ₂ —, and Y is an optionally hetero-substituted alkyl group or hetero atom or atomic group. ), And containing the repeating unit represented by the formula (3) based on the total amount of the repeating units represented by the formulas (1), (2) and (3). The amount is in the range of 10 to 90% by weight in a weight ratio, and a concentration of 1.2 g / dl, 3 in a mixed solvent of phenol / 1,1,2,2-tetrachloroethane 6/4 (weight ratio).
It is composed of 1 to 50 parts by weight of a polyalkyl ether / polyaryl ether sulfone copolymer (A) having a reduced viscosity of 0.5 or more measured at 5 ° C, and 99 to 50 parts by weight of cellulose diacetate (B). It is a polymer composition having excellent antithrombotic properties.

The present invention also relates to the above polyalkyl ether / polyaryl ether sulfone copolymers (A)
0 parts by weight, and cellulose diacetate (B) 99-
50 parts by weight of the polymer composition is to be used as a raw material for producing a medical material for use in contact with blood.

Further, the present invention relates to a medical material to be used in contact with blood, wherein at least a portion having a surface used in contact with blood contains the polyalkyl ether / polyaryl ether sulfone as described above. Polymer (A) 1
50 parts by weight and cellulose diacetate (B) 99
This is a medical material formed using a polymer composition composed of 50 to 50 parts by weight as a raw material.

Further, the present invention is a hemodialysis membrane produced by melt-spinning the above-mentioned polymer composition or by dry / wet spinning a dope solution.

The polyalkyl ether / polyaryl ether sulfone copolymer (A) used in the present invention is mainly composed of the partial structures represented by the above formulas (1) to (3).

In the above formulas (1) and (2), Ar, Ar
¹ , Ar ² and Ar ³ each independently represent a divalent aromatic hydrocarbon group which may be nuclear-substituted, and specifically, p-phenylene, m-phenylene, 2,6-naphthylene, 7-naphthylene, 1,4-naphthylene, 1,5
-Naphthylene, 4,4'-biphenylene, 2,2'-biphenylene, 4,4'-oxydiphenylene, 4,4 '
-Isopropylidene diphenylene, 4,4'-isopropylidene-2,2 ', 6,6'-tetramethyldiphenylene, 4,4'-sulfonyldiphenylene, and the like, and mono, di, tri, and tetra nuclei thereof Substituents can be exemplified. Examples of the nuclear substituent include an alkyl group having 1 to 8 carbon atoms such as methyl, ethyl and phenyl, an aryl group, fluorine,
Examples include a halogen group such as chlorine, a nitro group, and an alkoxy group having 1 to 8 carbon atoms. Among them, p-phenylene is Ar and Ar ¹ , and 4 is Ar ² and Ar ³ .
4′-oxydiphenylene, 4,4′-isopropylidene diphenylene, 4,4′-isopropylidene-2,
2 ', 6,6'-tetramethyldiphenylene, 4,4'
-Sulfonyldiphenylene and the like are preferred.

In the above formula (1), X is -SO
_2- , and in the above formula (2), Y is an alkyl group or a hetero atom or an atomic group which may be hetero-substituted. Specific examples of the structure of Y include an alkyl group such as methylene, ethylene, methylmethine, and isopropylidene;
1,3, -difluoroisopropylidene, 1,1,3
3-tetrafluoroisopropylidene, 1,1,1,
Halogenated alkyl groups such as 3,3,3-hexafluoroisopropylidene and trifluoromethylmethylene, as well as heteroatoms such as ether bonds by oxygen, thioether bonds by sulfur, amino groups, amide groups, sulfone groups, and sulfoxide groups; Examples of the bonding structure include a heteroatom group. Of these, Y is preferably methylene, isopropylidene, 1,1,1,3,3,3-hexafluoroisopropylidene, ether-type oxygen, an amino group, a sulfone group, or the like.

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 400 to 20,000. The molecular weight of the polyoxyalkylene structure is preferably from 600 to 15000, more preferably from 800 to 10
000, particularly preferably 1,000 to 6,000.

The polyalkyl ether / polyaryl ether sulfone copolymer (A) has a polyoxyalkylene structure represented by the above formula (3) in a content of the polyalkyl ether / polyaryl ether sulfone copolymer. It is in the range of 10-90% 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. If the content is more than 90%, the hydrophilicity is too high.
Elution 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.

In the poly (alkylaryl ether) sulfone copolymer (A), the molar ratio of the repeating unit represented by the above formula (1) based on the repeating unit represented by the above formula (2) is from 30 to 30. It is within the range of 60%.
By being in this range, better antithrombotic properties are exhibited. Such a ratio is preferably 40 to 55 in molar ratio.
%, More preferably 43.5 to 49.9%.

The polyalkylether / polyarylethersulfone copolymer (A) of the present invention includes, for example, bis (haloaryl) sulfone having a halogenated end of the aryl skeleton represented by the above formula (1); ) Wherein the terminal of the aryl skeleton represented by the formula (3) is hydroxylated, and α, ω wherein the terminal of the alkyl ether skeleton represented by the formula (3) is halogenated.
A -bis (2-haloalkoxy) polyoxyalkylene compound can be efficiently produced by a heating reaction in the presence of an alkali.

The polyalkylether / polyarylethersulfone copolymer (A) of the present invention comprises bis (haloaryl) sulfone having a halogenated end of the aryl skeleton represented by the above formula (1); A) .omega.-bishydroxypolyoxyalkylene compound having a hydroxyl-terminated alkyl ether skeleton represented by the formula (3) and a dihydroxyaryl compound having a hydroxyl-terminated aryl skeleton represented by the formula (3) In the same manner, the compound can be efficiently produced by a heating reaction.

In the reaction, these raw materials are charged and mixed in a molar ratio suitable for polymerizing the copolymer having a desired composition, and reacted with an alkali in the presence of a suitable solvent. At this time, polyalkyl ether / polyaryl ether sulfone copolymers of various compositions can be obtained by changing the molar ratio in the charging of the respective raw materials. The heating reaction temperature is preferably from 120 to 400C, more preferably from 160 to 350C. If the reaction temperature is higher than 400 ° C., side reactions may occur or the raw materials may be easily decomposed. If the reaction temperature is lower than 120 ° C., the reaction may be delayed.

The alkali used in the reaction is preferably an alkali metal carbonate or hydroxide, for example, lithium carbonate, potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydrogen carbonate, sodium hydrogen carbonate. , Potassium bicarbonate and the like. Of these, carbonates, particularly potassium carbonate, are preferred. It is necessary that the amount of alkali is an amount that substantially neutralizes the hydrogen halide generated during the reaction. it can. A suitable plasticizer for the reaction,
Solvents can also be used. To illustrate a suitable solvent,
Diphenylsulfone, N-methylpyrrolidone, N, N
-Dimethylacetamide, dimethylsulfoxide and the like can be used, and among them, N, N-dimethylacetamide and diphenylsulfone are preferable.

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 polyalkyl ether / polyaryl ether sulfone copolymer of the present invention thus obtained has the repeating units represented by the above formulas (1) to (3). In other words, in other words, the polyoxyalkylene structure Is an aromatic polyaryl ether sulfone copolymerized by the following formulas (4) and (5), or the following formulas (4) and (6)

[0029]

## STR3 ## _{- (- Ar-SO 2 -Ar} 1 -O-Ar 2 -Y-Ar 3 -O -) - (4) ( where Y is the Y synonymous with the aforementioned equation (2) .)

[0030]

Embedded image — (— RO—) _k —Ar ² —Y—Ar ³ —O— (5) (where Y has the same meaning as Y in the aforementioned formula (2).)

[0031]

Embedded image — (— RO—) _k —Ar—SO ₂ —Ar ¹ —O— (6)

(Where Y is synonymous with Y in the above formula (2)
It is. ) Is mainly composed of repeating units
A polymer and represented by the above formulas (4) and (5)
Repetition unit or the repetition represented by the above formulas (4) and (6)
Of the total weight of the repeating unit, the polyoxyalkylene structure
Structure (-(-R O-)_k-) Weight ratio of 10 to 90 weight
%, That is, the polyoxyalkylene structure (-(-RO-))
_k-) Is 10 to 90% by weight of the whole polymer).

The polyalkyl ether / polyaryl ether sulfone copolymer (A) of the present invention has a reduced viscosity of 0.5 or more, preferably 1.0 to 3.0. If the reduced viscosity is less than 0.5, the mechanical strength of the polymer becomes insufficient, which is not preferable. In addition, the reduced viscosity mentioned here is
Phenol / 1,1,2,2-tetrachloroethane mixed solvent (weight ratio 6/4), polymer concentration 1.2 g / d
1, a value measured at a temperature of 35 ° C.

In the polyalkyl ether / polyaryl ether sulfone copolymer of the present invention, the molecular weight and copolymer composition of the polyoxyalkylene structure 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.

The polyalkyl ether / polyaryl ether sulfone copolymer (A) of the present invention contains 3
The protein adsorption amount measured by the MicroBCA method when contacted at 7 ° C. for 1 hour is very small, and is 0.7 μg / cm ^2.
It has an excellent adsorption-suppressing effect on blood protein and platelet adhesion when in contact with a plasma solution. The reason is considered as follows. The polyalkyl ether / polyaryl ether sulfone copolymer is composed of a polyaryl sulfone having a large hydrophobicity at a rigid portion (hard component) and a hydrophilic polyoxyalkylene unit (soft component) fixed in a polymer main chain.
Both the hydrophilic segment and the hydrophobic polyarylsulfone segment are characterized by a surface structure macroscopically phase-separated as well as thermodynamically. 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 is in a state where normal protein is adsorbed on the surface of the monolayer, and further adhesion of biological components (red blood cells, white blood cells, and platelets) is suppressed. In addition, harmful biological reactions such as complement activation, thrombus formation, and cell membrane damage can be avoided. The smaller the amount of protein adsorption, the better.
A range of 7 μg / cm ² is practically sufficient.

In such a polyether / polyarylethersulfone copolymer, a rigid and highly hydrophobic polyarylethersulfone segment easily forms a stable domain structure, and is advantageous in expressing blood compatibility.
Furthermore, due to such a fine domain structure, the polyalkyl ether / polyaryl ether sulfone copolymer also changes wettability, solvent solubility, and miscibility with other polymers, resulting in various characteristics in terms of molding processing. There is a possibility that it can be provided.

The polyalkyl ether thus prepared /
The polyaryl ether sulfone copolymer (A) is mixed with cellulose diacetate (B) by various methods to provide the polymer composition having excellent antithrombotic properties of the present invention.

As the cellulose diacetate (B) in which the copolymer (A) is mixed, the number average molecular weight obtained by acetylating cellulose is 30,000 to 150,0.
00, a material having a degree of acetylation of 47.5% to 57.5% may be used. Of course, these cellulose diacetates (B) are not uniformly mixed with the above-mentioned copolymer (A) at the molecular level, and form a blend in which the polyalkyl ether / polyaryl ether sulfone copolymer (A) is surface-segregated. .

With respect to the blend ratio of the polyalkyl ether / polyaryl ether sulfone copolymer (A) to the cellulose diacetate (B), the weight ratio of the copolymer (A) should be at least 1%. And preferably 1 to 50% by weight, and 10 to 30% by weight.
It is more preferable to set the weight%. The above copolymer (A)
If the blending ratio is 1% by weight or less, the surface segregation absolute amount of the copolymer (A) is too small, so that a sufficient antithrombotic effect cannot be obtained, and if it is 50% by weight or more,
Depending on the shape of the material, there is a possibility that the original physical characteristics and usage conditions may change significantly.

In the blending method, various methods can be considered depending on the physical properties of the polymer. For example, the polymer composition is obtained by mixing the copolymer (A) and the cellulose diacetate (B) at the above-mentioned predetermined ratio. It can be prepared by dissolving in a solvent and then removing the organic solvent, or by melt-mixing the copolymer (A) and cellulose diacetate (B) at the above-mentioned predetermined ratio.

In the above polymer composition, the copolymer (A) and the cellulose diacetate (B) do not mix uniformly at the molecular level, but form separate phases,
Exists in phase separation.

The polyalkylether / polyarylethersulfone copolymer (A) has a hydrophilic polyoxyethylene chain and can be basically uniformly mixed with a conventional hydrophobic polymer material at the molecular level. There is no. Accordingly, the resulting polymer composition (hereinafter sometimes referred to as a blend)
Has a structure in which both blend components, that is, a polyalkyl ether / polyaryl ether sulfone copolymer (A) and a cellulose diacetate (B) are phase-separated.
In this phase separation state, the copolymer (A) segregates preferentially on the surface of the blend (strictly speaking, a bulk interface near the polymer such as an air interface at the time of forming a cast film). As a driving force for segregation, in addition to the low compatibility of the polyaryl ether sulfone unit itself with cellulose diacetate, if the interface is a contact surface with water, it is a hydrophilic unit of the copolymer. The hydrophilicity of the polyoxyethylene chain and the hydrophobicity and oleophobicity of the polyarylethersulfone unit having a small surface free energy mainly work at the interface with air. Since the obtained blend has the copolymer (A) segregated on the surface, it is presumed that the blend exhibits blood compatibility at the time of blood contact by the mechanism described above. For the development of antithrombotic properties, it is preferable that the above copolymer is segregated at a high concentration so as to be 50% by weight or more with respect to the surface composition of the blend. % Is more preferable. The surface composition referred to here means the vicinity of the surface of the polymer, specifically, a depth of 1 from the surface.
It refers to the fraction of the polymer in the region up to about 00 ° and does not refer to the bulk blend composition of both polymers as a whole.

According to the present invention, a medical material to be used in contact with blood by utilizing such properties of the polymer composition, and at least a surface to be used in contact with blood Is formed using a polymer composition comprising a polyalkyl ether / polyaryl ether sulfone copolymer (A) and cellulose diacetate (B) as a raw material, and the above-mentioned copolymer near the surface of the portion is formed. A medical material is provided, wherein the concentration of (A) is higher than the concentration of the copolymer (A) in the entire polymer composition forming the portion.

The proportion of the copolymer (A) in the vicinity of the surface can be determined by manufacturing a medical material from an organic solvent solution of the polymer composition or by molding and cooling the melted composition in melt molding. When producing a material for use, the ratio (concentration) of the copolymer (A) in the entire polymer composition becomes higher. That is, in the former processing method, phase separation occurs near the surface as the organic solvent scatters from the solution, and in the latter, during cooling, and finally, a medical material having a high concentration of the copolymer (A) near the surface. Is obtained. The vicinity of the surface is not strict, but is a region from the surface to a depth of about 100 °.

According to the present invention, a medical material having a thin thickness at a portion used in contact with blood is advantageously produced by the following method.

That is, according to the present invention, in the case of the melt spinning method, a polyalkyl ether / polyaryl ether sulfone copolymer (A) and a cellulose diacetate (B)
Is melt-molded, and when the molding method is a wet or dry molding method using a solvent, in addition to this, the above (A) is dissolved in an aprotic polar organic solvent (C) which can dissolve them.
A dope having a total concentration of the component and the component (B) of 1 to 30% by weight is prepared, and the dope is formed into a thin film, and the thin film is subjected to a wet or dry molding method, so that each of the thin films has a thickness of 1 mm or less. A method for producing a medical material having blood and a portion used in contact with blood.

The aprotic polar organic solvent to be used is a solvent in which both of the polymers (A) and (B) are dissolved, for example, aliphatic cyclic ethers such as tetrahydrofuran and 1,3-dioxolan, N-methylpyrrolidone , N,
N'-dimethylformamide, N, N'-dimethylacetamide, amide-based aprotic polar solvents such as N-methylmorpholine, methylene chloride, halogen-based nonpolar solvents such as chloroform, and halogen-based solvents and methanol;
A mixed solvent with ethanol or the like or dimethyl sulfoxide is suitably used.

The dope can be formed into a thin film by, for example, casting the dope on a substrate to form a film or spinning to form a hollow fiber. The total concentration of the component (A) and the component (B) in the dope is preferably 5 to 20% by weight, more preferably 10 to 15% by weight during casting, and preferably when spinning into a hollow fiber. Is 5 to 30% by weight, more preferably 1
It is 0 to 20% by weight, particularly preferably 13 to 14% by weight.

After the dope is formed into a thin film, the aprotic polar organic solvent is removed by a wet or dry method to give a medical material as a self-supporting molded article.

Further, in the wet method here, the thin film of the dope is treated with water /
This is a method of removing the aprotic organic solvent in the dope by treating in an aprotic organic solvent and then in water. In the dry method, a thin film of the dope is at room temperature, under normal pressure or at 40 to 50 ° C., about 1 to 30 mmHg. The aprotic organic solvent in the dope is similarly removed by treating under reduced pressure.

The thin film, which is the part of the medical material to be used in contact with blood, preferably has a thickness of 1 μm to 1 mm, and in particular, preferably has a thickness of 10 to 50 μm for hollow fibers. .

The polymer composition thus obtained has a concentration of 5
Weight of human platelet poor plasma (PPP) in a phosphate buffer at 37 ° C. for 1 hour at a protein adsorption of 0.8 μg / cm ² or less (albumin by MicroBCA method) (Converted), preferably 0.6 μg
/ Cm ² or less. 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.

(Function) In the polymer composition having excellent antithrombotic properties of the present invention, the above-mentioned polyalkyl ether / polyaryl ether sulfone copolymer (A) is coated with cellulose diamine at the part of the material which comes into contact with blood. It is characterized by being blended with acetate (B). Here, the portion that comes into contact with blood refers to the surface of the material that comes into contact with blood and the vicinity thereof. As described above, in the material, the polyalkyl ether / polyaryl ether sulfone copolymer (A) is in a state where it is macroscopically phase-separated from cellulose diacetate (B) which is a component of another blend. It is in. The polyoxyethylene unit of the polyether / polysulfone copolymer is used to stabilize the interfacial free energy in the blend during solvent removal, so that the interface between the blend and the bulk (blood / blend (Body interface). Therefore, it is considered that the copolymer (A) orients over most of the contact interface with blood in the presence of water (which is a main component of blood), thereby suppressing adsorption of plasma proteins and platelet adhesion.
For example, when actually used as a hollow fiber for artificial dialysis, the copolymer (A) may be mixed at least on the surface of the porous membrane through which blood flows. Therefore, the entire material may be formed by the blend of the present invention itself, or a method of compounding with another material may be preferably implemented.

[0055]

Industrial Applicability The polymer composition having excellent antithrombotic properties of the present invention has low adsorption of biological components such as proteins and blood cells, and suppresses denaturation of the adsorbed protein and adhesion and activation of contacted platelets. Can be. Furthermore, because the number of free end chains of oxyethylene and free hydroxyl groups in the blend is small,
Complement activation and cell membrane damage can be avoided. Therefore, as a field of application of the polymer composition of the present invention, it is useful as a medical material whose main purpose is to use it in direct contact with blood components, for example, artificial kidney, artificial blood vessel, heart-lung machine,
It can be used for hemodialysis membranes, blood bags, catheters, plasma separation membranes and the like. When the polymer composition of the present invention is used as such a material, not only the blend itself is used as a material to form a hollow fiber, a sheet, a film, and a tube, but also the blend is dissolved in a solvent. Can be applied to these various material surfaces to modify only the blood contact surface.

[0056]

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. Rain r1. “Parts” in the examples represent “parts by weight” unless otherwise specified.

2. Preparation of Polymer Composition and Surface Composition Analysis by ESCA A polymer composition was prepared by wet blending cellulose diacetate with the above-mentioned polyether / polyarylethersulfone copolymer (A), and the surface composition was prepared. Was analyzed by ESCA. Preparation of the polymer composition
The procedure was as follows. The copolymer (A) produced in Reference Example
To control cellulose diacetate (CD
A, a number-average molecular weight of 100,000, a degree of acetylation of 55%, manufactured by Teijin) and heat dissolution in tetrahydrofuran (THF) to obtain a dope solution of the antithrombotic medical polymer composition. The solution was formed into a film on a Teflon support substrate by a casting method, and the solvent was removed under reduced pressure to obtain a film made of a polymer composition having a thickness of about 0.5 mm by a dry method. As a comparative example, a polyether / polysulfone copolymer (R) was similarly used in place of the copolymer (A) as another copolymer having blood compatibility, and a polymer blend with cellulose diacetate was used. Was prepared.

For the measurement of ESCA, a membrane was cut out on a disk having a diameter of 1 cm, equilibrated in a phosphate buffer overnight, and then freeze-dried to obtain a measurement sample. The equipment is VG ESC
Using ALAB-200, MgKα radiation was irradiated and scanned so that the photoelectron extraction angle was 45 °. The measurement was performed on the surface that was in contact with the air interface during casting.

3. Evaluation of Protein Adsorption Amount of protein adsorbed on the membrane was quantitatively evaluated by the MicroBCA method. This is shown by the copper ion and B
This is a protein quantification method using a kit using a CA protein detection reagent. Only the copper ion monovalently reduced by the protein present in the sample undergoes a chelate reaction with this reagent to form a color (57
0 nm), the protein concentration (in terms of albumin) can be quantified by measuring the absorbance of the sample.

[0060]

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In the evaluation, cellulose diacetate (CD) having no antithrombotic properties was used as a control polymer.
A) was used as a comparative experiment.

For the preparation of a sample, a blend film of the copolymer (A) and cellulose diacetate (B) prepared in the same manner as in Example 1 was cut out to a diameter of 15 mm to obtain an evaluation sample. As a comparative example, the above copolymer (R) was similarly used, and a polymer blend film with cellulose diacetate was prepared and evaluated. In the measurement, human membrane platelet poor (PPP) was used for these membranes, and the amount of protein adsorbed when the membrane was brought into contact with the plasma solution was spectrally quantified. Upon evaluation,
A PPP prepared at a predetermined concentration (5% by weight 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% aqueous sodium dodecyl sulfate solution. The color was developed by a conventional method, and the amount of adsorption was estimated from the absorbance.

4. 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, using platelet-rich plasma (PRP), platelet adhesion behavior on the membrane surface after contact with PRP was observed by SEM. PRP is obtained by adding 3.5 wt% trisodium citrate aqueous solution to fresh blood collected from human brachial vein.
9 volumes, 1000 r. p. m. The supernatant was prepared by centrifugation at for 10 minutes. As a sample, a blend film of the above-mentioned polyether / polyaryl ether sulfone copolymer (A) and cellulose diacetate (B), and a control cellulose diacetate flat film as a comparative example were used. These were cultured in Petri dishes (Falcon, 24we)
11)), and contacted with 0.7 ml of PRP at 37 ° C. for 3 hours. 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.

Reference Example 1 (Synthesis of α, ω-bis (2-chloroethoxy) polyoxyethylene (number average molecular weight 3000)) 30 parts of polyethylene glycol (# 3000), 2.4 parts of pyridine, 150 parts of dehydrated chloroform The part was charged into a conical flask equipped with a pick and stirred to obtain a homogeneous solution. To this, a mixed solution of 1.8 parts of thionyl chloride and 15 parts of dehydrated chloroform was added dropwise over 30 minutes under ice-cooling. Then, the ice-cooling was removed and the liquid temperature was raised to room temperature. Then, stirring was continued for another 8 hours. After the chloroform was distilled off under reduced pressure, another 15 parts of fresh thionyl chloride was further added, followed by heating to dryness for 24 hours. Thereafter, excess thionyl chloride was distilled off under reduced pressure, and the residue was washed with fresh chloroform 3
Dissolved in 00 parts, washed three times with 200 parts of saturated saline, then once with 200 parts of pure water, and separated the chloroform layer.
Dry over anhydrous sodium sulfate overnight. Chloroform was distilled off and the resulting oil solidified immediately at room temperature. This was dissolved by heating in 40 parts of acetone, and reprecipitated from 200 parts of diethyl ether to obtain 28.8 parts of white powdery crystals.
The melting point of the product was between 50.5 ° C and 53.5 ° C. IR
(Infrared spectroscopy) measurement showed that this compound was α, ω-bis (2-
Chloroethoxy) polyoxyethylene (number average molecular weight 3
000).

[Examples 1 to 3] A1. Production of polymer 4,4-hexafluoroisopropylidene diphenol 16.8
0 parts, 11.90 parts of bis (4-chlorophenyl) sulfone, and 25.95 parts of α, ω-bis (2-chloroethoxy) polyoxyethylene (number-average molecular weight: 3035) from which coexisting water was removed by azeotropic distillation with toluene. 200 ml of toluene, N, N-
100 ml of dimethylacetamide, 8.625 parts of potassium carbonate,
The flask was placed in a three-necked flask having a nitrogen inlet and an outlet, and the flask was guided to a Dean-Starks trap to replace with nitrogen, and heated to reflux at 115 to 125 ° C. for 16 hours. After confirming that the outflow of water accompanying the reaction was completed, toluene was distilled off over 8 hours, and N, N-dimethylacetamide was newly added to make a total of 200 ml in a form to make up for the reduced amount of toluene.
In addition, the atmosphere in the flask was replaced with nitrogen,
The mixture was heated and stirred for an hour to react. After the reaction, the whole is opened and washed with 3000 ml of ion-exchanged water while stirring, and then washed with 3000 ml of fresh ion-exchanged water for 2 hours.
Repeated times. Next, the polymer was dissolved in a 0.1 wt% hydrochloric acid aqueous solution 3000.
The mixture was washed with stirring for 8 hours with ml, and the remaining alkaline catalyst was completely deactivated and eluted in water. This is replaced with new ion-exchanged water
The operation of stirring and washing with 3000 ml for 2 hours and removing hydrochloric acid was repeated three times. The obtained polymer was dried under reduced pressure at 80 ° C. for 24 hours, extracted with chloroform, filtered and dried. Finally, about 92% of the theoretical yield (about 48 g) of a dried polymer was obtained. This polymer has a polyoxyethylene component of 50
% By weight of a polysulfone component and 50% by weight of a polysulfone component, which is referred to as PEO3000 (50) -co-PF.
Abbreviated as S (50).

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 0.85. The number average molecular weight of this polymer was about 25,000 (in terms of polystyrene). Table 1 shows the results.

In a similar manner, P having different copolymer composition ratios
EO3000 (60) -co-PFS (40) (Example 2), PEO3000 (60) -co-PES (4
0) (Example 3) was synthesized.

Example 4 A2. Production of polymer 4,4-hexafluoroisopropylidene diphenol 12.8
48 parts, bis (4-chlorophenyl) sulfone part, and α, from which coexisting water was removed by azeotropic distillation with toluene,
ω-bis (2-hydroxy) polyoxyethylene # 40
0035.37 parts, 15 ml of toluene, 20 ml of N, N-dimethylacetamide and 8.28 parts of potassium carbonate were put into a three-necked flask having a nitrogen inlet and an outlet, and this was introduced into a Dean-Starks trap and replaced with nitrogen. And 115 to 12
Heat reflux was performed at 5 ° 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 for 80 hours to react. After the reaction, the operation of opening and washing the whole with 3000 ml of ion-exchanged water while stirring, and then washing with 3000 ml of fresh ion-exchanged water for 2 hours was repeated three times. Then, the polymer was added to a 0.1 wt% hydrochloric acid aqueous solution 30
The mixture was washed with stirring in 00 ml for 8 hours, and the remaining alkaline catalyst was completely deactivated and eluted in water. This was further washed with 3000 ml of fresh ion-exchanged water under stirring for 2 hours, followed by dehydrochlorination.
Repeated times. The obtained polymer was dried under reduced pressure at 80 ° C. for 24 hours, extracted with chloroform, 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
0% by weight and 40% by weight of a polysulfone component. This is a copolymer of PEO3000 (60) -co-P
Abbreviated as SFS (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 1.55. Further, the number average molecular weight of this polymer was about 32,000 (in terms of polystyrene). Table 1 shows the results.

The molecular weights and viscosities of these polymers polymerized in Examples 1 to 4 are collectively shown in Table 1. The structure of the polymer is also shown.

[0072]

[Table 1]

1) The abbreviations respectively correspond to the following structural formulas. 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).

[0074]

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Examples 5 to 7 Production of polymer composition, film comprising the same and ESCA
Surface composition analysis by ESCA Table 2 shows the results of surface composition analysis by ESCA of a polymer composition film composed of a blend of various polyether / polyaryl ether sulfone copolymers (A) and cellulose diacetate (B). In any of the blends, the fraction of the polyether / polyarylethersulfone copolymer (A) exceeds the value assuming uniform mixing at a surface composition within a depth of 100 ° from the surface, and the copolymer is effective. It was confirmed that the surface of the film was segregated.

[0076]

[Table 2]

Examples 8 to 10, Comparative Example 1 Evaluation of Protein Adsorption Amount of protein adsorbed on the surface of the membrane made of the blend was measured according to the method described above. The blending ratio of the copolymer (A) constituting the film is 10% by weight. As shown in Table 3, the polymer composition of the polyalkyl ether / polyaryl ether sulfone copolymer of the present invention and cellulose diacetate showed significant suppression of protein adsorption as compared with conventional cellulose diacetate. Was.

[0078]

[Table 3]

1) Value converted into albumin 2) Value quantifying the degree of deformation associated with activation of adherent platelets. The deformed state of the platelets is classified into four stages with the undeformed as the first stage, the number of platelets in each state is multiplied by the number of the stage, and the sum is divided by the total number of adherent platelets to obtain a morphological index. Therefore, if all of the adherent platelets are not deformed, the morphological index becomes 1, and if all of them undergo the fourth-stage deformation, the index becomes 4.

D. SEM observation of platelet adhesion to polymer surface using human PRP Table 3 also shows the platelet adhesion numbers of various polymer membrane surfaces after PRP contact. According to the above study, in the case of cellulose diacetate, which is a hydrophobic polymer having low suppression of protein adsorption, adhesion of many platelets was observed on the surface. On the other hand, a polyalkyl ether / polyaryl ether sulfone copolymer (A) having a high protein adsorption suppressing ability and cellulose /
The blender membrane with diacetate showed clear inhibition of platelet adhesion as compared to the original cellulose diacetate.

From the above results, it has been clarified that the polymer composition of the present invention, which has an excellent ability to inhibit protein adsorption, significantly inhibits platelet adhesion as compared with existing cellulose diacetate.

Thus, by melting or dry / wet spinning the polymer composition of the present invention, a medical membrane excellent in blood compatibility while maintaining excellent membrane properties inherent in cellulose diacetate can be maintained. It became clear that it could be provided.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Takeyuki Kawaguchi 2-1 Hinodemachi, Iwakuni-shi, Yamaguchi Pref. CD022 DA02 DA03 DA04 DC03 DC12 EA03 EA06 4J002 AB011 CN032 CN062 GB03 4J030 BA10 BA42 BB52 BB66 BF19 BG32

Claims (6)

[Claims] 1. The following formulas (1) to (3):-(-Ar-X-Ar ¹ -O-)-(1)-(-Ar ² -Y-Ar ³ -O -)-... (2)-(-RO-) _k -... (3) (where Ar and Ar ¹ are each independently a divalent aromatic hydrocarbon which may be nuclear-substituted. Ar
² and Ar ³ are each independently a divalent aromatic hydrocarbon group which may be substituted with a nucleus. R is an alkylene group having 2 to 3 carbon atoms, and k is a polyoxyalkylene structure represented by-(-RO-) _k- having a molecular weight of 400 to 2,000.
The number of unit repetitions is 0. X is -S
O ₂ —, and Y is an optionally hetero-substituted alkyl group or hetero atom or atomic group. ) And substantially consisting of the repeating unit represented by the formula (1),
The content of the repeating unit represented by the above formula (3) based on the total amount of the repeating units represented by (2) and (3) is in the range of 10 to 90% by weight by weight, and phenol / 1 Polyalkyl ether / polyaryl ether sulfone copolymer having a reduced viscosity of 0.5 or more measured at 35 ° C. at a concentration of 1.2 g / dl in a mixed solvent of 1,1,2,2-tetrachloroethane 6/4 (weight ratio). Combined (A) 1 to 50 parts by weight, and cellulose diacetate (B) 99 to 50
A polymer composition having excellent antithrombotic properties, characterized by comprising: 2. A polymer composition comprising 1 to 50 parts by weight of the polyalkyl ether / polyaryl ether sulfone copolymer (A) and 99 to 50 parts by weight of cellulose diacetate (B). Use as a material for manufacturing medical materials for use in contact with blood. 3. A medical material to be used in contact with blood, wherein at least a portion having a surface to be used in contact with blood contains the polyalkyl ether / polyaryl ether sulfone copolymer ( A) 1 to 50 parts by weight,
And a polymer composition comprising 99 to 50 parts by weight of cellulose diacetate (B). 4. The polymer composition forming a polyalkyl ether / polyaryl ether sulfone copolymer (A) in the vicinity of the surface of a portion having a surface used in contact with blood. The medical material according to claim 3, which is higher than the concentration of the copolymer (A) in the whole. 5. The medical material is a hemodialysis membrane.
5. The medical material according to any one of items 4 to 4. 6. The medical device according to claim 5, wherein the hemodialysis membrane is produced by melt-spinning a molten composition as the polymer composition or dry / wet spinning a dope solution of the polymer composition. Materials.