JPS6137963B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel ion-selective adsorption composite semipermeable membrane that can be particularly suitably used as a dialysis membrane for blood purification, and a method for producing the same. In recent years, in the field of medical equipment, research has been actively conducted on the development and improvement of various artificial organs using dialysis membranes. For example, in the field of artificial kidneys, large-scale devices that dialyze blood using large amounts of water have been developed.
Diafiltration liquid purifiers using adsorbents have been developed to make them smaller and lighter. Although the advent of this purifier has made it possible to significantly reduce the amount of diafiltration fluid required, it is difficult to realize a wearable device or even an implantable device, which is the ultimate goal, due to the volume and weight. However, it is still insufficient. In order to achieve these goals, it is desired to complete a so-called direct blood perfusion method in which waste products in blood are removed using an adsorbent. In response to these demands, the present inventors have previously proposed an adsorption water removal type blood purification device using a special semipermeable membrane and a direct blood perfusion method using a small amount of a highly concentrated aqueous solution. However, subsequent research has revealed that although this device smoothly removes excess water from the blood, it is still insufficient in removing electrolytes from the blood. In other words, the main electrolytes in the blood include cations such as sodium, potassium, calcium, magnesium, and protons, and anions such as chlorine, inorganic phosphorus, bicarbonate, and hydroxide ions, and these are always at constant concentrations. and PH is
Although it remains constant at around 7.4±0.1, it is said that patients with chronic renal failure generally tend to have excess sodium, potassium, and inorganic phosphorus and a deficiency in calcium and bicarbonate. Therefore, as an electrolyte adsorbent, it does not adsorb calcium or bicarbonate, but selectively adsorbs sodium, potassium, inorganic phosphorus, chlorine, etc.
It is necessary to have the ability to minimize PH fluctuations. By the way, rapid changes in water and other electrolytes are unfavorable for living organisms, and in some cases can be fatal, so it is expected that it will be extremely difficult to develop materials suitable for this purpose. . On the other hand, ion exchangers have been used as electrolyte adsorbents since ancient times and have been widely used in various industries including water treatment, and are also used in the pharmaceutical field as oral preparations as disintegrants and acid-base regulators.
In the field of artificial organs, changes in pH due to contact with blood have been previously investigated (for example, Genichi Hori et al., "Polymers", Vol. 9, p. 129). Furthermore, as part of the regenerating adsorbent for the filtration fluid of an artificial kidney, it is known that an ion exchanger such as zirconium phosphate or zirconium oxide is used for ammonium adsorption. However, in general, when ion exchangers come into direct contact with blood, they tend to selectively adsorb electrolytes with high ionic valences, leading to the undesirable result of preferential removal of calcium. When blood passes through a layer filled with a spherical material such as exchange resin, blood clot formation, hemolysis,
There is a risk of protein adsorption. The present inventors have conducted various studies to overcome these difficulties and develop a semipermeable membrane with low calcium adsorption, sufficient mechanical strength, and high water permeability. degree of 45% or more, especially 50
%, the permeability of calcium chloride is significantly lower than that of sodium chloride and potassium chloride, and it is possible to suppress the adsorption of calcium ions by coating the ion exchange resin with this membrane. We have discovered that when dispersed in polyhydroxyethyl methacrylate, mechanical strength can be improved and the destruction of cellulose acetate membranes, which is often observed when wet, can be prevented.Based on this knowledge, we have developed the present invention. Ivy. That is, the present invention has a multilayer structure in which the upper and lower sides of a polyhydroxyethyl methacrylate layer in which strongly acidic ion exchange resin powder and basic ion exchange resin powder are uniformly dispersed are covered with cellulose acetate membranes having a degree of acetylation of 45% or more. The present invention provides an ion-selective adsorption composite semipermeable membrane having the following properties. As the strongly acidic ion exchange resin in the present invention, those commonly used for removing alkali metal ions present in various aqueous solutions, such as ion exchange resins having sulfonic acid groups or sulfuric acid groups, are used.
As the basic ion exchange resin, those commonly used for removing halogen ions and other anions, such as ion exchange resins having a quaternary ammonium base, are used. These ion exchange resins are used as powders with a particle size of 100 μm or less.
Further, these strongly acidic ion exchange resins and basic ion exchange resins are used in a mixed manner at a ratio showing approximately equal exchange capacity. Even if these ion exchange resins are carefully coated with cellulose acetate during drying, the film will be destroyed when wet due to its low wet elongation and the calcium ion adsorption suppressing effect will be lost. This is used by dispersing it in polyhydroxyethyl methacrylate, which is a hydrophilic and permeable polymer compound. The polyhydroxyethyl methacrylate suitably has an intrinsic viscosity [η] in the range of 1 to 1.5 in methyl cellosolve. Cross-linked polyvinyl alcohol and cross-linked polyacrylamide are known as hydrophilic polymer compounds similar to polyhydroxyethyl methacrylate, but the former has insufficient flexibility, and the latter has too much swelling and It cannot be used in the present invention because of its low adhesiveness. In the present invention, in order to suppress the removal of calcium ions, it is necessary to cover the above-mentioned ion exchange resin-containing polyhydroxyethyl methacrylate layer with a cellulose acetate membrane. or more, preferably 50%
The above materials are used, and the appropriate film thickness is in the range of 12 to 30 μm. Furthermore, hemolysis when blood is passed through the polyhydroxyethyl methacrylate layer containing ion exchange resin,
Prevention of thrombus formation, etc., reduction of the probability of contact between blood and adsorbent to avoid sudden changes in electrolyte concentration, increase of mechanical strength and workability due to composite lamination of adsorbent on semipermeable membrane, Furthermore, as a result of examining the conditions for combining the cellulose acetate semipermeable membrane and the ion exchange resin-containing polyhydroxyethyl methacrylate layer in relation to the effects of integrating adsorption and semipermeability, we found that in the present invention, polyhydroxyethyl methacrylate It has been found that it is preferable to adjust the mixing ratio of the powder and the powdered ion exchange resin to a weight ratio of 1:1 to 1:2. In this way, the mechanical strength of the semipermeable membrane of the present invention can be increased, and the adhesion of the composite membrane can be improved to the extent that it does not peel off even when wet. Next, the structure of the ion selective adsorption composite semipermeable membrane of the present invention will be explained according to the accompanying drawings. Figure 1 is a schematic diagram of the cross section of this semipermeable membrane.
A polyhydroxyethyl methacrylate layer 5 in which a strongly acidic ion exchange resin powder 3 and a basic ion exchange resin powder 4 are dispersed is provided on top of the polyhydroxyethyl methacrylate layer 5, and the layer is further covered with a cellulose acetate membrane 2. According to the present invention, an ion selective adsorption composite semipermeable membrane having such a structure can be manufactured by the following method. That is, in a solution obtained by dissolving polyhydroxyethyl methacrylate in a suitable solvent such as 2-methoxyethanol, a mixture of strongly acidic ion exchange resin powder and basic ion exchange resin powder with a particle size of 100 μm or less was added to polyhydroxyethyl methacrylate 1. It is added at a ratio of 1 to 2 parts by weight per part by weight to prepare a stock solution with a solid content concentration of 20 to 35% by weight. Separately, a predetermined cellulose acetate is dissolved in a suitable solvent such as acetone at a concentration of 15 to 20% by weight, and this solution is cast on a flat surface and dried to form semipermeable cellulose acetate with a thickness of 12 to 30 μm. After forming a membrane and casting the stock solution on top of it, the temperature is 50~60°C.
Dry at temperature and cool to room temperature. The surface is then coated with a cellulose acetate membrane by casting a cellulose acetate solution with a concentration of 1 to 2% by weight and drying. The ion-selective adsorption composite semipermeable membrane obtained in this way exhibits the advantages of low adsorption of calcium ions and high water permeation rate, and in particular, the water permeation rate rapidly disperses as the ratio of ion exchange resin increases. do. Next, the present invention will be explained in more detail with reference to Examples. Reference example 1 1 g of powdered strongly acidic ion exchange resin and 1 g of basic ion exchange resin were mixed into an aqueous solution (Na ⁺ : 160 meq/, K ⁺ : 6 meq/,
Ca ²⁺ : 5.5meq/, Mg ²⁺ : 2.4meq/, Cl ^- :
Contains 141meq/, acetate ion: 33meq/, inorganic phosphorus: 1.3mmol/, and small amounts of other non-electrolytes.
Hereinafter, this will be referred to as the test solution. ) 0.1 and 37℃
Changes in the concentration of each electrolyte in the solution over time and changes in pH were measured using the batch method. Table 1 shows Na ⁺ ,
Shows Ca ²⁺ and PH changes. Electrolyte concentration is expressed as a percentage of the stock solution.

[Table] The neutral salt decomposition and adsorption reaction proceeds rapidly, reaching equilibrium within 5 minutes, and nearly 80% of calcium ions are adsorbed. Therefore, such ion exchange resins cannot be brought into direct contact with blood. Reference Example 2 0.8g of a powdered strongly acidic ion exchange resin, 0.8g of a similarly basic ion exchange resin, and 3.2g of cellulose acetate (degree of acetylation: 55%) were mixed as an acetone solution and cast into a film. After drying, the adsorbent (E2-1) obtained by immersing and drying in a 2% by weight solution of cellulose acetate, 1.85 g each of powdered strong acidic and basic ion exchange resins, and 7.4 g of Regarding the adsorbent (E2-2), which was prepared by mixing polyhydroxyethyl methacrylate as a methyl cellosolve solution, casting it into a film, drying it, and then treating it in the same way as E2-1 above, 0.1% of each of the test solutions of Reference Example 1 was used. and 0.2
The same measurement as in Reference Example 1 was carried out using the batch method at 37°C. The results are shown in Table 2.

[Table] The cellulose acetate film treatment slightly suppressed calcium adsorption. However, since this adsorbent has low strength and lacks flexibility, it is likely to be damaged during operation and the surface coating film may be torn. In the case of E2-2, this phenomenon was particularly strong, and it is thought that calcium adsorption was increased. Example 1 A 15.5% by weight acetone solution of cellulose acetate with a degree of acetylation of 55% was made, and after filtering and defoaming, a 300μ thick solution was prepared on a substrate.
The cast film was cast at a speed of 8 cm/sec using a blade of 1.5 cm and dried. Powdered strong acidic ion exchange resin 1 is passed through a mesh onto this membrane so that the particle size is 100 μm or less.
Mix 1.2 parts by weight of a similarly treated basic ion exchange resin per part by weight, and mix this with a methyl cellosolve solution containing 0.7 parts by weight of polyhydroxyethyl methacrylate per 1 part by weight of the mixed ion exchange resin. Mixed stock solution with a solid content of 20% by weight
Cast through a 500 μm blade at a similar speed,
A 1% by weight acetone solution of cellulose acetate with a degree of acetylation of 55% was poured onto the surface of the laminated membrane dried at 50°C and dried to produce an ion-selective adsorption composite semipermeable membrane. This membrane was assembled into a flat plate in a frame with an effective area of 12 cm x 32 cm, the test solution 0.3 was further diluted to 0.9 with distilled water, and a roller pump was used to dilute this solution to 50
Changes in electrolyte concentration and pH of the test solution over time were measured when the test solution was brought into contact with circulation at a rate of ml/min. This experiment was conducted at room temperature and the temperature of the test solution was 20±1°C. The results are shown in Table 3.

[Table] The values in Table 3 are percentages of the test solution before treatment.
It is. Since the mixing ratio of the strongly acidic ion exchange resin and the basic ion exchange resin differs in exchange capacity ratio, the pH fluctuation is large, but the effect of suppressing calcium adsorption is evident. Since the surface coating contains 1% cellulose acetate, there may be defects in the membrane. Example 2 The same amount of mixed powder ion exchange resin as in Example 1 was applied to polyhydroxyethyl methacrylate.
The ratio is 0.6:1, and the casting blade is 1 mm.
Table 4 shows the results of the same measurements as in Example 1 performed on a composite semipermeable membrane whose surface was coated with cellulose acetate twice with a 1% solution.

[Table] Example 3 The surface coating treatment of Example 2 was carried out using a 2% by weight cellulose acetate acetone solution, and similar measurements were carried out. As a result, the PH decreased from 6.42 to 6.22 after secondary treatment.
Na ⁺ is 92%, K ⁺ is 86%, Ca2 ⁺ is 90%, ^Cl- is 88%
showed that. Example 4 Since the wet strength of the composite semipermeable membrane in the present invention strongly depends on the mixing ratio of polyhydroxyethyl methacrylate and powdered ion exchange resin, the strength and elongation of the composite semipermeable membrane were measured by changing this mixing ratio. First, measurements similar to those in Examples 2 and 3 were performed. The surface coating treatment in this case was carried out using the same 2% solution as in Example 3. The rate of water permeation through osmosis through the test solution and 3 mol/calcium chloride was also measured.
The time variation of electrolyte concentration was generally similar to Example 3. Table 5 shows the measurement results of strength, elongation, water permeation rate, etc.

[Table] In Table 5, C indicates a strongly acidic ion exchange resin, and A indicates a basic ion exchange resin. By the way, the strength of itself is 552 μm, which is made of polyhydroxyethyl methacrylate without a base film and a mixed resin ratio of 1/0.7.
The thickness was only 5 g per 5 mm width.

[Brief explanation of the drawing]

FIG. 1 is a schematic cross-sectional view of the ion-selective adsorption composite semipermeable membrane of the present invention, in which reference numeral 1 is a cellulose acetate semipermeable membrane, 2 is a cellulose acetate surface-coated thin film, and 3
4 is a strong acidic ion exchange resin powder, 4 is a basic ion exchange resin powder, and 5 is a polyhydroxyethyl methacrylate layer.

Claims (1)

[Scope of Claims] 1. A multilayer in which the upper and lower sides of a polyhydroxyethyl methacrylate layer in which strongly acidic ion exchange resin powder and basic ion exchange resin powder are uniformly dispersed are covered with cellulose acetate membranes having a degree of acetylation of 45% or more. Ion-selective adsorption composite semipermeable membrane for blood purification with a structured structure. 2. Add strongly acidic ion exchange resin powder and basic ion exchange resin powder with a particle size of 100 μm or less to a polyhydroxyethyl methacrylate solution, thoroughly disperse them, and then add this to a semipermeable cellulose acetate with an acetylation degree of 45% or more. A method for producing an ion-selective adsorption composite semipermeable membrane for blood purification, which comprises casting the membrane onto the membrane, drying it, and then covering the membrane with a cellulose acetate membrane.