JPS58116361A - Blood treating membrane - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood processing membrane suitable for concentrating and separating blood components by ultraviolet filtration, dialysis, etc., and particularly to 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 toxic components and water. Various synthetic membranes, including cellulose-based membranes, have been developed as membranes suitable for various purposes, where it is necessary to remove only waste products such as urea, uric acid, and creatinine without removing substances. , leaving a slight gap in the balance between water permeability and dialysability, and 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.

Ethylene-vinyl alcohol (CEVA) based co-M combination has good blood compatibility, good anti-thrombotic and anti-hemolytic properties, as well as excellent durability and chemical stability, making it a suitable material for hemodialysis membranes. It is suitable as
No. 2877, it is proposed as a dialysis membrane for artificial kidneys. This membrane has a hollow fiber shape and has excellent permeability to so-called medium molecular weight substances with a molecular fi of 500 to 6000, which is a problem for long-term dialysis patients. Not suitable for sexual purposes.

The present inventors conducted research on the balance between hydrophilicity and hydrophobicity of membrane materials, and the correlation between water permeability and dialysis performance, and arrived at the present invention.

That is, the present invention has at least two vinyl alcohol residues.
Contains 5 mol% and 0.3 ionizable groups in water.
It is a blood treatment membrane consisting of a polymer containing ~45 mol%.

As is clear from the examples described below, the hemodialysis membrane of the present invention exhibits excellent dialysis performance despite its relatively low water permeability. Therefore, it has an excellent balance of water permeability and dialysis properties, and is highly effective as a blood processing membrane, particularly as a hemodialysis membrane and a hemofiltration membrane.

As the material for the membrane in the present invention, it is necessary to use a polymer containing at least 25 mol% of vinyl alcohol residues. Such polymers include polyvinyl alcohol or vinyl alcohol copolymers, such as at least one of olefins such as ethylene and propylene, styrene, vinyl chloride, acrylonitrile, acrylic acid and derivatives thereof, and vinyl such as vinyl acetate. Examples include copolymers with esters and saponified products.

Among these polymers, the best is an ethylene-vinyl alcohol copolymer that has a good balance between hydrophilicity and hydrophobicity and has excellent anticoagulant properties. Furthermore, this ethylene-vinyl alcohol copolymer has an excellent balance of water permeability and dialysis properties, as is clear from the examples described below. The ethylene residue in the ethylene-vinyl alcohol copolymer is at least 10 mol%, preferably 20 to 50 mol%.

It is necessary that the vinyl alcohol residues in the polymer be at least 25 mole percent. When the amount is less than 25 mol%, affinity with blood decreases. The reason for this is not clear, but it is thought that the hydration of the hydroxyl groups has the effect of gently adjusting the balance between hydrophilicity and hydrophobicity of the polymer, which is one of the important factors for anticoagulant properties. It will be done. The preferred content of vinyl alcohol residues is 50 to 95 mol%.

The content of groups that can be ionized into ions in water (hereinafter referred to as ionic groups) in the polymer is 0.5 mol% to 45%.
It is mole%. If it is less than 0.3 mol %, the effect of the present invention of increasing dialysability compared to water permeability will not be fully exhibited. On the other hand, the upper limit is 45 mol%, but if it exceeds this, the membrane will swell to a large extent and the pressure resistance will drop significantly, requiring many crosslinks, which will reduce both water permeability and dialysability. I don't like it. Generally, the ionic group is 15
When the amount exceeds mol%, it is practically safer to perform a slight crosslinking reaction to impart mechanical strength to the membrane.

The main mechanical strength that is used as a guideline for blood treatment membranes is pressure resistance, which is at least 50% when circulating blood at 37°C.
It is necessary to be able to withstand 0 mvI'Hl9 Usually, the content of ionic groups in the polymer forming the membrane is 0.
．． In the case of 5 to 10 mol%, good blood treatment results can be obtained without crosslinking.

For the crosslinking reaction, known general methods can be used, but for example, organic crosslinking agents such as divinyl compounds, formaldehyde, dialdehyde, diisocyanate, boron, etc.
Examples include crosslinking using an inorganic crosslinking agent such as a compound, and crosslinking reaction using radiation or light such as r-rays or 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. Also acetalization and esterification.

Various reactions including 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.

Examples of ionic groups include carboxyl groups, sulfonic acid groups, sulfinic acid groups, phosphonic acid groups, phosphinic acid groups,
and their salts, phenolic hydroxyl groups and their salts, esters such as sulfates and phosphates, and their salts, various amino groups and their salts, basic-containing heterocyclic compounds such as pyridine, and the like. Examples include onium salts such as 94-grade ammonium salts, sulfonium salts, and phosphonium salts. These groups have 2 groups in the same residue.
There may be more than s, or two or more types may be present in the polymer forming the waist. ≠Ionic groups can be introduced into the polymer forming the membrane by copolymerizing vinyl monomers, polymers, or multicomponent copolymers containing them with other monomers. Alternatively, it can also be introduced by a chemical reaction after polymerization. An ionic group may be introduced by light, radiation, or the like. Moreover, if necessary, it can be introduced after film formation. The introduction after film formation is carried out to determine the distribution of ion charge,
In particular, it has the advantage of being able to adjust the distribution in the thickness direction of the membrane, and in extreme cases, it is possible to introduce ionic groups only to the surface of the membrane.
Alternatively, it is also possible to introduce different types of ionic groups onto both sides of the membrane. The method of introducing ionic groups after membrane formation is actually a suitable technique for producing ionic blood treatment membranes in small quantities and in many varieties.

In the present invention, the average molecular weight of the polymer forming the membrane is approximately 30,000 or more. Usually, about 60,000 to 200,000 is preferable.

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 (which makes it difficult to form a membrane with performance suitable for blood treatment). It is.

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 an aifrI agent that can completely dissolve the polymer used as the fiber and can be rapidly dissolved in the coagulation bath. Dimethyl sulfoxide, dimethylformamide, dimethylacetamide,
Tetrahydrofuran, pyrrolidone.

N-methylpyrrolidone, and monohydric alcohols such as methanol, ethanol, and isopropanol.

Polyhydric alcohols such as ethylene glycol, propylene glycol, and glycerin, phenol, metacresol,
Mention may be made of formic acid, water or mixtures 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 and various acids.

These include alkalis, polyethylene glycols, colloidal silica, and the crosslinking agents mentioned above, but it is necessary that substantially no substances other than those added for the purpose of crosslinking remain in the final film. be. If it remains,
These substances may leak into the bloodstream, making it unsafe.

The concentration of the polymer in the membrane forming stock solution is in the range of 5 to 501% 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.

Il! The temperature of the l-layer film is 0°C to 120°C, preferably 5°C to
A temperature of 95° C. is preferable; at a temperature lower than this, the viscosity becomes too high and it becomes difficult to form a film, and at a temperature higher than this, decomposition and deterioration of the polymer may occur.

The film-forming stock solution obtained in this manner is used to form a film by various known wet coagulation methods. To name a few examples, there are methods for extruding a film-forming stock solution through a nozzle with elongated slit-like holes and assimilation by contacting or immersing it in a coagulation bath, forming a flat film, and using a nozzle with an annular hole. Examples include a method of extruding a membrane forming stock solution to form a tubular or hollow fiber membrane. If necessary, an irregularly shaped die with holes of more complicated shape may be used.Also, after casting the membrane forming stock solution into the desired shape, or while casting it, it may be brought into contact with or immersed in a coagulation bath. A film may be used.

Applying the so-called Leob membrane film forming technology, if an appropriate amount of solvent is evaporated from the surface of the discharged, spread, or cast film forming solution just before contacting or immersing in the coagulation bath, only the surface An asymmetric membrane with a dense structure can be obtained. An asymmetric membrane can also be formed by bringing coagulation baths having different coagulation rates into contact with one side of a discharged, spread, or cast membrane-forming stock 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 and methanol.

Monohydric alcohols such as ethanol, polyhydric alcohols such as ethylene glycol, diethylene glycol, and glycerin, acetone, or mixtures thereof are used. A miscible organic solvent in the coagulation bath to control the coagulation rate;
Inorganic salts such as mirabilite and calcium chloride may also be added. In special cases, only one side of the membrane is in contact with the coagulation bath, and the other side is exposed to a gas such as air, nitrogen, or benzene.

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It is carried out in contact with a liquid that is immiscible with the bath. In some cases, as in JP-A No. 55-148209, the material is passed through a gaseous phase immediately before contacting the coagulation bath.

Usually, the solidification rate of water or a mixture of water and the solvent used in the membrane forming stock solution is suitable for forming the membrane.

The temperature of the coagulation bath is an important factor in obtaining membranes with suitable performance for blood processing, and is generally in the range -15°C to 50°C, preferably between 0°C and 25°C.

At lower temperatures, solidification is slow <, IJ! M property decreases.

A temperature higher than this cannot be used in the present invention because the solidification rate becomes too fast, resulting 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 with a uniform thickness, it is desirable to have a large draft, but if it is too large, pinhole-like or slit-like cracks may occur in the film. If it is too small, the permeability of the membrane will be insufficient. In the case of the present invention, 1.5 to 30 times, preferably 2 to 30 times
It is better to give 15x draft.

After leaving the coagulation bath, the membrane is further stretched as necessary.

Heat treatment, cleaning. It is possible to adjust the membrane performance 2 mechanical performance by drying, etc. The heat treatment is carried out under tension or without tension. The temperature is usually below 120°C. dry heat, moist heat,
Either method can be used, but in the case of dry heat, the membrane performance can also be adjusted by humidity. During drying, membrane performance can be similarly adjusted by humidity.

In addition to the above-mentioned asymmetric membrane (having a dense structure on one or both sides), membranes used in the present invention include homogeneous structure membranes (
(having a dense cross-sectional structure), microporous membranes, etc. can be used, but homogeneous membranes and asymmetric hollow delicate 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 ionic groups only into the dense structure portion of the inner surface that comes into contact with blood. The outer diameter of the hollow fiber membrane is 50-3000μ, preferably 100-800μ, and the membrane thickness is 5-200μ, preferably 10-100μ.

The best module shape is the hollow fiber type, but
Other types include flat membrane type, spiral type, and tubular type.

Known forms such as a coil type and a keel type can also be used.

As mentioned above, the introduction of ionic groups can be carried out after film formation, but
It can also be introduced after being formed into a module like the one above.
Acetalization, esterification, etherification, sulfonation,
Oxidation, reduction, addition, substitution.

Known reactions such as exchange and grafting can be used. The solvent-free reactants, catalysts, etc. used must be thoroughly removed before blood treatment.

The membrane according to the invention can also be used as a wet or dry membrane. Drying methods include air current, heat rays, etc. [In addition to direct drying using magnetic waves, etc., for example, water contained in the film can be removed by drying with a water-miscible polymer that does not dissolve the polymer [solution 11 (e.g., atom-9 methanol, tetrahydrofuran, etc.)]. #5 method of replacing the organic solvent and then applying pressure reduction, heating, etc. Glycerin, ethylene glyfur at %li or after film formation.

A method of treating with an aliphatic polyhydric alcohol such as polyethylene glycol and subsequent drying, or a method of freezing the water-containing film with liquid nitrogen or carbon dioxide gas and freeze-drying it, etc. can be used.

In particular, when using the membrane of the present invention for applications such as artificial kidneys, formalin and ethylene oxide gas are used. It is desirable to perform sterilization using an autoclave, R-rays, etc.

Hereinafter, the present invention will be specifically explained using examples.

Example 1 and Comparative Example 1 A saponified ethylene-vinyl acetate copolymer with an ethylene content of 35 mol% and a degree of saponification of 99.8 mol% was heated and dissolved in dimethyl sulfoxide, and a film-forming stock solution with a concentration of 122711% by weight was prepared. Obtained. After leaving this at 70°C overnight to defoam,
Nozzle hole diameter is 650μm, 1 needle outer diameter is 250μm,
It was discharged from an annular nozzle with a needle inner diameter of 90 μm, and was coagulated in a 20% aqueous solution of dimethyl sulfoxide while 42 ml of nitrogen gas was flowing out from the needle. The solidification temperature is 4°C. The coagulant was thoroughly removed by washing with hot water, then replaced with acetone, and then
It was dried in an air stream at 5°C. The obtained hollow fiber had a homogeneous structure with an inner diameter of 220 μm, an outer diameter of 320 μm, and a film thickness of s o p and H in a dry state. This hollow wire #! 5,680 pieces are bundled together, and both ends are made of polyurethane resin into a cylindrical shape of 7 pieces.
1 housing, module (effective membrane area 0.8 d)
) was created. A 15% polyethylene glycol (molecular weight 400) maleate solution of maleic anhydride was introduced into the hollow fibers in this module, and esterification was performed at 70°C for 4 hours to bond carboxyl groups, followed by washing with warm water for 2 hours. , excess reaction solution was removed. The esterified vinyl alcohol residue was 2.5 mol%.

Using this module, the dialysate was applied to the outside of the hollow fiber at 5Ω.
Q ml, min, 200mj/f of bovine blood inside
Water permeability and urea permeability were measured under a pressure difference of IQ Omml. The results are shown in Table 1.

Comparative Example 1 shows the results of dialysis using hollow fibers containing no ionic groups, which were produced in the same manner. Here, the ultrafiltration rate (U
FR) is the unit time and unit area of the membrane.

It represents the volume of permeate per unit pressure, and k is the overall mass transfer coefficient when there is no volumetric flow of liquid, and is calculated by equation (1).

Here, QB is the blood flow rate, 9A is the membrane area, and Dp is the dialysance, which is calculated by equation (2).

However, QB1n+QBout are each module entrances.

The blood flow rate at the outlet, CBt*, CBoa+, is the urea concentration in the blood at the module inlet side and the outlet steel, respectively, and CD1n is the urea concentration in the dialysate on the inlet side.

Examples 2 to 6 and Comparative Example 2 Ethylene content 44 mol%, Kenl! Using 99.8 mol% saponified ethylene-vinyl acetate copolymer, the concentration of the membrane-forming stock solution was 24%, the coagulation bath temperature was 12°C, and the other conditions were the same as in Example 1. A module consisting of a homogeneous membrane was fabricated.

1 of maleic anhydride inside the hollow fibers in this module.
A solution of 596 polyethylene glycol (molecular weight 400) maleate was introduced, and esterification was carried out at 70° C. while changing the reaction time in the range of 2 to 10 hours to introduce carboxyl groups. After the reaction was completed, one reaction solution was removed by washing with warm water for 2 hours.

Using this module, a 0.1% urea solution was applied inside the hollow fiber at a rate of 200 mJ/min, and distilled water was applied at a rate of 50 mJ/min to the outside.
The water permeability and urea permeability were measured under a pressure difference of 100 mmHf at a flow rate of 0 mjAnin.The experimental humidity was 37°C. The results are shown in Table-2.

Comparative Example 2 shows the results of dialysis using a hollow fiber containing no ionic groups produced in the same manner.

Example 7 and Comparative Example 3 Chips of a saponified ethylene-vinyl acetate copolymer with an ethylene content of 32 mol% and a saponification degree of 99.8 mol% were soaked in sulfuric acid 1
0%, nitric acid 10%, and sodium benzaldehyde sulfonate 596, and 1.5% at 60°C.
Acetalization reaction was carried out for a period of time to obtain a polymer having an average molecular weight of 84,000 and containing 3.4 moles and 96 acetalized vinyl alcohol residues (1.7 mole % as sulfone groups). After thoroughly washing with water, replacing with acetone, and drying,
This polymer was dissolved in dimethylsulfonate at 80°C,
The mixture was left to stand overnight to defoam and obtain a 22% concentrated stock solution.

After lowering the stock solution temperature to 40℃, the nozzle hole diameter was 65℃.
0μm1 Needle outer diameter is 250μm1 Needle inner diameter is 90μm Discharge from an annular nozzle, 0
．． While nitrogen gas of 42 mj/f[]in was flowing out, it was solidified with 1 minute of cold water at 0.2°C. Thereafter, in the same manner as in Example 1, a 0.7 m' module consisting of 5000 hollow wires Ia (homogeneous structure IA) was produced. Example 2~
Urea permeability and water permeability were measured in the same manner as in 6. The results are shown in Table 3.

Comparative Example 3 is the result of dialysis using a hollow fiber containing no ionic groups produced in the same manner.

Table 6 Table 19 Tables 2 and 3 show that the blood treatment membrane of the present invention has low water permeability (UFR) but is dialyzable (k).
It can be seen that the membrane has excellent water permeability and dialysis performance.

Claims (1)

[Scope of Claims] (1) Contains at least 25 mol% of vinyl alcohol residues and contains 0.3 to 4 groups that can be dissociated into ions in water.
A blood treatment membrane made of a polymer containing 5 mol%. (2) The blood treatment membrane according to claim IN1, which contains 50 to 95 mol% of vinyl alcohol residues. (3) The blood treatment membrane according to claims 1 and 2, which contains 0.5 to 10 mol% of groups that can be dissociated into ions in water. (4) The blood treatment membrane according to claims 1 to 3, which contains at least 10 mol% of ethylene residues. (6) The blood treatment membrane according to claims 1 to 4, which contains 20 to 50 mol% of ethylene residue. The blood treatment membrane according to items 1 to 5.