JPH035208B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a blood processing membrane suitable for concentrating and separating blood components by ultrafiltration, dialysis, etc., and particularly a semipermeable blood processing membrane suitable for use in artificial kidneys. Artificial kidneys flow blood and dialysate through a dialysis membrane, and utilize the concentration and pressure differences between the two to remove harmful components and water. It is necessary to remove only waste products such as urea, uric acid, and creatinine without removing substances. Various synthetic membranes, including cellulose-based membranes, have been developed as membranes suitable for such purposes, but some problems remain in the balance between water permeability and dialyzability, and in blood compatibility. For example, cellulose-based membranes are slightly more hemolytic. Synthetic membranes generally have lower dialysis properties than water permeability, resulting in a poor balance between the two. In other words, in blood treatment using such conventional membranes, if the water permeability is high but the dialysis property is low, urea from the blood will not be removed sufficiently at the end of the treatment, while even if the dialysis property is high, the water permeability is low. Otherwise, the water content cannot be removed sufficiently. Ethylene-vinyl alcohol (EVA) copolymers have good blood compatibility, good antithrombotic and antihemolytic properties, and are also excellent in durability and chemical stability, so they are suitable for use in hemodialysis membranes. It is suitable as a material and has already been proposed as a dialysis membrane for artificial kidneys in JP-A-52-152877. This membrane has a hollow fiber shape and has excellent permeability for so-called medium molecular weight substances, which are around 300 to 6000 molecular weight, which are a problem for long-term dialysis patients. Not suitable for sexual purposes. A membrane that has sufficient dialysability with a relatively low water permeability, that is, a membrane that has an excellent balance between water permeability and dialysability, is a membrane that has a water permeation rate of 1 to 1 in 5 hours, which is the practical goal in this field. 5. The membrane is said to have a dialysis rate of 4×10 ^-4 cm/sec or more in terms of the overall mass transfer coefficient of urea. The present inventors conducted research on a method for producing a blood treatment membrane with an excellent balance between water permeability and dialysability, and arrived at the present invention. That is, the present invention prepares a membrane made of a saponified ethylene-vinyl acetate copolymer containing at least 25 mol% of vinyl alcohol residues and at least 10 mol% of ethylene residues, and then injects alcohol into the membrane. A maleic acid ester is contacted with a solution in which maleic anhydride is dissolved, and a carboxyl group and/or its salt is added to a vinyl alcohol residue by an esterification reaction or a salt or base treatment following the esterification reaction.
This is a method for producing a blood treatment membrane characterized by introducing 10 mol% of the membrane. The hemodialysis membrane produced by the method of the present invention exhibits excellent dialysis performance despite its relatively low water permeability, as is clear from the Examples described below. Therefore, it has excellent water permeability and dialysate balance, and is suitable for blood processing membranes, especially hemodialysis membranes and hemofiltration membranes.
This shows that it is highly effective. As the material for the membrane in the present invention, it is necessary to use a saponified ethylene-vinyl acetate copolymer containing at least 25 mol% of vinyl alcohol residues and at least 10 mol% of ethylene residues. Ethylene residues are preferably 20 to 50 mol%. The vinyl alcohol residue in the polymer is at least
It needs to be 25 mol%. If it is less than 25 mol%, affinity with blood decreases. The reason for this is not clear, but the balance between hydrophilicity and hydrophobicity of the polymer, which is one of the important factors for anticoagulation,
It is thought that the hydration of the hydroxyl group exerts a gradual adjustment effect. The preferred content of vinyl alcohol residues is 50 to 95 mol%. The content of the carboxyl group and/or its salt in the polymer is 0.5 to 10 mol% based on the vinyl alcohol residue. If it is less than 0.5 mol%, the effect of the present invention of increasing dialysis property compared to water permeability will not be fully exhibited, while if it exceeds 10 mol%, the membrane will tend to become wet and the pressure resistance will decrease. In order to impart mechanical strength to the membrane, it is desirable and practically safe to carry out a slight crosslinking reaction. The main mechanical strength that is a guideline for blood treatment membranes is pressure resistance, which must be able to withstand at least 500 mmHg when circulating blood at 37°C. Generally, when the content of carboxyl groups and/or their salts in the membrane-forming polymer is 0.5 to 10 mol%, good blood treatment results can be obtained without crosslinking. For the crosslinking reaction, known general methods can be used. Examples include crosslinking reactions caused by radiation and light such as rays and electron beams. A crosslinked structure can be introduced by copolymerization with a polymer having a crosslinked structure in advance. Further, a crosslinking reaction can also be carried out during polymerization and film formation. In particular, a step in which only a crosslinking reaction is performed may be performed. If necessary, a crosslinking reaction can be carried out after film formation. Various reactions including acetalization, esterification, and etherification can also be carried out at any time. Although these are not crosslinks, they are meaningful in adjusting the hydrophilicity and hydrophobicity of the membrane. A carboxyl group and/or a salt thereof is introduced after film formation. Introduction after film formation has the advantage of being able to control the distribution of ion charge, especially in the thickness direction of the film, and in extreme cases, carboxyl groups and/or their salts may be introduced only to the surface of the film. Alternatively, it is also possible to introduce different types of carboxyl groups and/or their salts on both sides of the membrane.
In practice, the method of introducing carboxyl groups and/or their salts after membrane formation is a suitable technique for producing ionic blood treatment membranes in small quantities and in many varieties, especially by introducing ionic groups after modularization. be. In the present invention, after introducing carboxyl groups into the membrane using maleic anhydride, it can be converted into a desired carboxyl group salt by treating with various salts and bases. In the present invention, the average molecular weight of the polymer forming the membrane is approximately 30,000 or more. Normally, it is preferably about 60,000 to 200,000. The higher the average molecular weight, the better the mechanical properties of the membrane, but as the molecular weight increases, the viscosity of the stock solution increases, making it difficult to form a membrane with performance suitable for blood treatment. be. Next, a method for manufacturing the blood treatment membrane of the present invention will be described. As the solvent for the polymer, a solvent is selected from among water and organic solvents that can completely dissolve the raw material polymer and can be quickly dissolved in the coagulation bath. For example, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, pyrrolidone, N-methylpyrrolidone, monohydric alcohols such as methanol, ethanol, isopropanol, polyhydric alcohols such as ethylene glycol, propylene glycol, glycerin, phenol, metacresol, formic acid. , water or a mixture thereof. If necessary, it may contain a substance that can be dissolved or dispersed in the solvent of the polymer. These substances include inorganic or organic salts, various acids, alkalis, polyethylene glycols, colloidal silica, and the aforementioned crosslinking agents, but other than substances added for the purpose of crosslinking, , it is necessary that substantially no substance remains in the final film. If they remain, these substances may leak into the blood, making it unsafe. The concentration of the polymer in the membrane forming stock solution is in the range of 5 to 50% by weight, preferably 10 to 35% by weight. At a concentration lower than this, the viscosity is too low, and at a concentration higher than this, the viscosity is too high, making it difficult to stably obtain a uniform film. The temperature of the membrane forming stock solution is 0°C to 120°C, preferably 5°C.
~95℃ is good. If the temperature is lower than this, the viscosity becomes too high and film formation becomes difficult, and if the temperature is higher than this, the polymer may be decomposed or deteriorated. The membrane-forming stock solution obtained in this way is formed into a membrane by various known wet coagulation methods. A few examples include a method of extruding a film-forming stock solution through a die with elongated slit-shaped holes and solidifying it by contacting or immersing it in a coagulation bath to form a flat film, and a method of forming a film from a die with annular holes. Examples include a method of extruding a stock solution to form a tubular or hollow fiber membrane. If necessary, an irregularly shaped cap with a hole of a more complex shape may be used.
Alternatively, the film may be formed by casting the film-forming stock solution into a desired shape, or by contacting or immersing it in a coagulation bath while casting. Applying the so-called Leob film forming technology, the film is discharged, expanded, and
Alternatively, by evaporating an appropriate amount of solvent from the surface of the cast membrane-forming stock solution, an asymmetric membrane having a dense structure only on the surface can be obtained. An asymmetric membrane can also be formed by bringing coagulation baths having different coagulation rates into contact with each side of the discharged, spread, or cast membrane-forming solution. As the coagulation bath, one is used that has high compatibility with the solvent of the membrane-forming stock solution and has substantially no compatibility with the components forming the membrane. Generally, water, monohydric alcohols such as methanol and ethanol, polyhydric alcohols such as ethylene glycol, diethylene glycol, and glycerin, acetone, or mixtures thereof are used. In order to control the coagulation rate, a miscible organic solvent, or an inorganic salt such as mirabilite or calcium chloride may be added to the coagulation bath. In special cases, only one side of the film is in contact with the coagulation bath, and the other side is exposed to a gas such as air or nitrogen, or to the solvent of the film forming stock solution such as benzene, toluene, hexane, or mercury, or to the coagulation bath. It is carried out in contact with immiscible liquids. In some cases, as in JP-A-55-148209, the material is passed through a gas phase immediately before contacting the coagulation bath. Generally, the solidification rate of water or a mixture of water and the solvent used in the membrane forming stock solution is suitable for forming membranes. The temperature of the coagulation bath is an important factor in obtaining membranes with performance suitable for blood processing, and is generally between -15℃ and 50℃.
°C, preferably in the range of 0 °C to 25 °C. If the temperature is lower than this, solidification is slow and film forming properties are deteriorated. A temperature higher than this cannot be used in the present invention because the coagulation temperature becomes too high and tends to result in a film with extremely high water permeability or a non-uniform film. The draft provided from the time of discharge from the die to the time of solidification is also an important factor determining membrane performance. In order to obtain a thin film of uniform thickness, it is desirable that the draft be large, but if it is too large, pinhole-like or slit-like cracks are likely to occur in the film. If it is too small, the permeability of the membrane will be insufficient. In the case of the present invention
It is good to give a draft of 1.5 to 30 times, preferably 2 to 15 times. After leaving the coagulation bath, the membrane is further stretched and stretched as necessary.
Membrane performance and mechanical performance can be adjusted by heat treatment, washing, drying, etc. The heat treatment is carried out under tension or without tension. The temperature is usually below 120°C. Either dry heat or wet heat methods can be used, but in the case of drying, the film performance can also be adjusted by humidity. Even during drying, the membrane performance can be adjusted by adjusting the humidity. Examples of membranes used in the present invention include the aforementioned asymmetric membranes (those with a dense structure on one or both sides), homogeneous structure membranes (those with a dense cross-sectional structure), microporous structure membranes, etc. However, homogeneous structure membranes and asymmetric hollow fiber membranes having a dense structure on one side (especially the inner surface) are particularly preferred. In the case of such an asymmetric hollow fiber membrane having a dense structure on one side, it is sufficient to achieve the object of the present invention by introducing carboxyl groups and/or their salts only into the dense structure portion of the inner surface that comes into contact with blood. . The outer diameter of hollow fiber membrane is 50~
3000μ, preferably 100~800μ, film thickness 5~200μ,
Preferably it is 10-100μ. The best shape for the module is a hollow fiber type, but other known shapes such as a flat membrane type, spiral type, tubular type, coil type, and keel type can also be used. As described above, the carboxyl group and/or its salt is introduced after film formation, but it may also be introduced after forming into a module as described above. In the present invention, a carboxyl group and/or a salt thereof is introduced into a saponified ethylene-vinyl acetate copolymer by an esterification reaction or a salt or base treatment following the esterification reaction. The solvents, reactants, catalysts, etc. used must be thoroughly removed before blood treatment. From this point of view, it is advantageous to use a water-soluble organic solvent as the solvent for maleic anhydride, especially a water-soluble organic solvent that contains a small number of hydroxyl groups relative to its molecular weight. In the present invention, for example, a carboxyl group and/or a salt thereof can be introduced into the membrane by preparing an alcoholic maleate solution containing excess maleic anhydride and bringing it into contact with the membrane. Also, in the present invention, the membrane can be used as a wet or dry membrane. Drying methods include airflow, heat rays,
In addition to direct drying using electromagnetic waves, for example, the water contained in the film can be replaced with an organic solvent that is water-miscible and does not dissolve the polymer (e.g., acetone, methanol, tetrahydrofuran, etc.), and then the organic solvent can be removed by reducing pressure, heating, etc. a method of removing it, a method of treating it with an aliphatic polyhydric alcohol such as glycerin, ethylene glycol, polyethylene glycol, etc. during or after film formation, and then drying it;
Furthermore, a method of freezing the water-containing film with liquid nitrogen or carbon dioxide gas and freeze-drying it can be used. In particular, when using the membrane obtained by the method of the present invention for applications such as artificial kidneys, it is desirable to sterilize it with formalin, ethylene oxide gas, autoclave, gamma rays, etc. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 and Comparative Example 1 Ethylene content 33 mol%, saponification degree 99.8 mol%
A saponified ethylene-vinyl acetate copolymer was heated and dissolved in dimethyl sulfoxide to give a concentration of 22% by weight.
A membrane forming stock solution was obtained. After leaving this at 70℃ overnight to degas it, it is discharged from an annular nozzle with a nozzle hole diameter of 650 μm, a needle outer diameter of 250 μm, and a needle inner diameter of 90 μm, and nitrogen gas flows out from the needle at a rate of 0.42 ml/min. 20 of dimethyl sulfoxide while
% coagulated in aqueous solution. The solidification temperature is 4°C. The coagulant was thoroughly removed by washing with hot water, followed by replacement with acetone, and then drying in a stream of air at 25°C. The obtained hollow fibers have an inner diameter of 220μ in the dry state,
The outer diameter was 320μ, the film thickness was 50μ, and the membrane structure was homogeneous. 5,680 of these hollow fibers were bundled and both ends thereof were fixed to a cylindrical housing with polyurethane resin to produce a module (effective membrane area: 0.8 m ² ). A maleate solution of polyethylene glycol (molecular weight 400) containing 15% maleic anhydride was introduced into the hollow fibers of this module, and
After esterification was carried out for a period of time to bond carboxyl groups, the mixture was washed with warm water for 2 hours to remove excess reaction solution. The esterified vinyl alcohol residue was 2.5 mol%. Using this module, 500 ml/min of dialysate was applied to the outside of the hollow fiber, and 200 ml/min of bovine blood was applied to the inside.
The water permeability and urea permeability were measured under a pressure difference of 100 mmHg. When examining the hollow fibers for clogged blood (residual blood) after a 5-hour evaluation of bovine blood, residual blood was found in only three fibers, which is clinically considered to have a large amount of residual blood. It was far less than 0.5% of the total number of fibers. The results are shown in Table 1. Comparative Example 1 is the result of dialysis using a hollow fiber containing no carboxyl group, which was produced in the same manner.
Here, the ultraviolet rate (UFR) represents the volume of permeate per unit time, unit area, and unit pressure of the membrane,
k is the overall mass transfer coefficient when there is no volumetric flow of liquid, and is calculated by equation (1). k=Q _B /0.6Aln0.4(D _B /Q _B )−1/(D _B /Q _B )−1…(
1) Here, Q _B is blood volume, A is membrane area, and D _B is dialysance, which is calculated by equation (2). D _B = Q _Bio ×C _Bio −Q _Bput ×C _Bput /C _Bio −C _Dio …(2) However, Q _Bio and Q _Bput are the blood flow rates at the module inlet and outlet, respectively, and C _Bio and C _Bput are the blood flow rates at the module inlet, respectively. The urea concentration in the blood on the side and outlet side, C _Dio is the urea concentration in the dialysate on the inlet side.

[Table] Examples 2 to 7 and Comparative Examples 2 to 3 Using a saponified ethylene-vinyl acetate copolymer with an ethylene content of 44 mol% and a degree of saponification of 99.8 mol%, membrane forming stock solution concentration was 24% and coagulation bath temperature. A module consisting of a hollow fiber homogeneous membrane having an effective area of 0.8 m ² was prepared at 12° C. in the same manner as in Example 1 except for the following conditions. 15% maleic anhydride inside the hollow fibers in this module
A maleate solution of polyethylene glycol (molecular weight: 400) containing polyethylene glycol (molecular weight: 400) was introduced, and esterification was carried out at 70°C for varying reaction times in the range of 2 to 10 hours to introduce carboxyl groups. After the reaction was completed, the reaction solution was removed by washing with warm water for 2 hours. Using this module, 0.1
%, urea solution at 200ml/min, and distilled water on the outside.
The water permeability and urea permeability were measured under a pressure difference of 100 mmHg at a flow rate of 500 ml/min. Experiment temperature was 37℃
It is. When the hollow fibers were examined for clogged blood (residual blood) after 5 hours of bovine blood evaluation, residual blood was observed in Examples 2 to 7 in 6, 3, 4, 2, and 2, respectively.
and 9 fibers, which were far less than 0.5% of the total number of hollow fibers that are clinically considered to have a large amount of residual blood. The results are shown in Table 2.

[Table] Comparative Example 2 shows the results of dialysis using a hollow fiber containing no carboxyl group produced in the same manner. Comparative Example 3 is the result of dialysis using a hollow fiber containing no carboxyl group prepared in the same manner using a saponified ethylene-vinyl acetate copolymer having an ethylene content of 32 mol% and a degree of saponification of 99.8 mol%. From Tables 1 and 2, it can be seen that the blood treatment membrane of the present invention has excellent dialysis performance (k) despite its low water permeability (UFR), and is a membrane with a good balance between water permeability and dialysis performance. Recognize. Comparative Example 4 A hollow fiber membrane was prepared in the same manner as in Example 1, except that a 25% solution of saponified ethylene-vinyl acetate copolymer containing 77 mol% ethylene (23 mol% vinyl alcohol residue content) was used. , inner diameter 220μ, outer diameter
A 330μ hollow fiber membrane was obtained. Using this membrane, a module was assembled in the same manner as in Example 1, carboxyl groups were introduced, and evaluation was performed using bovine blood. After 5 hours of bovine blood evaluation, the hollow fiber membrane was checked for clogged blood (residual blood)32
It was warm with books.

Claims (1)

[Claims] 1. A membrane made of a saponified ethylene-vinyl acetate copolymer containing at least 25 mol% of vinyl alcohol residues and at least 10 mol% of ethylene residues is prepared, and then the membrane is coated with maleic ester of alcohol. Contact with a solution in which maleic anhydride is dissolved, and introduce 0.5 to 10 mol% of carboxyl groups and/or their salts to vinyl alcohol residues by esterification reaction or salt or base treatment following esterification reaction. A method for producing a blood treatment membrane, characterized by: