JPS6260122B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is capable of concentrating and concentrating aqueous solutions such as ultrafiltration and dialysis.
The present invention relates to a novel semipermeable membrane suitable for separating substances, in particular to a semipermeable membrane suitable for use in artificial kidneys. A membrane composed of a hydrous methyl methacrylate polymer having an isotactic part and a syndiotactic part was already proposed (Japanese Patent Publication No.
3616). This membrane has a higher moisture content than conventionally used membranes for the same purpose, and has excellent mechanical properties despite its high moisture content. It has features such as greater water permeability than other materials. However, this membrane is used for purposes of obtaining relatively low water permeability (e.g., for dialysis therapy in regular artificial kidneys).
It is not suitable for cases where water removal is less than 500ml/hr.). Methods for improving this are a method of adding a hydrophilic vinyl monomer as a copolymerization component (Japanese Patent Application No. 53-36722), and a method of adding a vinyl monomer containing a group that can be dissociated into ions in water as a copolymerization component (Patent Application 1973-54736). However, although the water permeability of these membranes can be adjusted, the solute dialysis performance tends to change accordingly, and there are some problems in the balance between water permeability and dialysis performance. In other words, in order to obtain a high therapeutic effect by removing water through ultrafiltration and removing solutes from the blood through dialysis, as with artificial kidneys, appropriate water removal performance and balanced removal of solutes are required. Through repeated research, we have arrived at the present invention. In the present invention, there are basically two types of polymers used as membrane materials: a methyl methacrylate copolymer containing a polymerizable monomer having an alkali metal base of sulfonic acid as one of the polymerization components, and an amino or alkylamino copolymer. This method is characterized by using a mixture of a methyl methacrylate copolymer containing methacrylates as one of the polymerization components. In addition, the semipermeable membrane material of the present invention may contain polymethyl methacrylate of various degrees of polymerization, and even isomethyl It goes without saying that adding tactical polymethyl methacrylate is also a preferred method and is included in the present invention. Examples of polymerizable monomers having an alkali metal base of sulfonic acid include p-styrene sulfonic acid, allyl sulfonic acid, methallyl sulfonic acid, 3
-methacryloxypropanesulfonic acid, vinylsulfonic acid, 3-acryloxypropanesulfonic acid, or 2-acrylamide-2-methylpropanesulfonic acid, and their salts such as sodium salts and potassium salts. These monomers are used as one of the membrane material components as a copolymer with methyl methacrylate, and the amount added at that time is 0.1 to 20 mol%, preferably 0.5% as a constituent of the material polymer.
Used in amounts of ~10 mol%. The other polymer to be mixed as one of the membrane material components is a methyl methacrylate copolymer containing 0.2 to 40 mol%, preferably 1 to 20 mol% of amino or alkylamino methacrylate as one of the polymerization components. . Examples of monomers containing these amino groups are dimethylaminoethyl methacrylate, monomethylaminoethyl methacrylate, aminoethyl methacrylate, t-butylaminoethyl methacrylate, diethylaminoethyl methacrylate, t-butylaminoethyl methacrylate, dimethylaminopropyl methacrylate. ，
These include 3-(dimethylaminoethyl)-2-hydroxypropyl methacrylate and 2-aminoethyl methacrylate. Next, the ratio of mixing the above two polymers, that is, the methyl methacrylate copolymer containing a monomer having a sulfonic acid group and the methyl methacrylate copolymer containing (alkyl) amino methacrylates, is determined by weight. The ratio ranges from 1:9 to 9:1, preferably 1:1. In addition, it is also possible to add and mix atactic polymethyl methacrylate or even isotactic polymethyl methacrylate in order to improve viscosity control, mechanical strength, etc. In that case, these polymethyl methacrylate The proportion of the total mixture should be 80% or less, preferably
40% or less. The average molecular weight of these raw material polymers can be changed in consideration of the mechanical properties required depending on the membrane forming or spinning method and the intended use of the membrane, but in general, the average molecular weight of the raw material polymers is 100,000 or more. It is desirable that Next, the solvent for forming a membrane or preparing a spinning dope needs to be a solvent that can dissolve the raw material polymer and be capable of displacing water. Examples of preferred solvents include dimethyl sulfoxide,
dimethylformamide, dimethylacetamide,
Examples include N-methylpyrrolidone, dioxane, acetonitrile, acetone, methyl ethyl ketone, methyl cellosolve, and methyl carbitol. It is also possible to use a mixture of these.
The concentration of the membrane-forming or spinning dope varies depending on the water content of the membrane, the type of solvent used, the membrane-forming method, etc., but is usually in the range of 10 to 40%. The homogeneous solution obtained in this way can be brought into contact with a coagulating liquid to form a film or spin by a wet method using various known methods. For example, the stock solution can be cast onto a flat plate such as a glass plate or a metal plate, and then immersed in a coagulation bath to solidify it, or it can be extruded into a coagulation bath through a nozzle with elongated holes and formed into a film. In addition to flat plates, membranes of various shapes can be formed by spinning them from spindles with concentric circular holes and forming them into cylindrical or hollow fiber shapes, or by spreading them on convex, concave, or other irregularly shaped surfaces and solidifying them. Obtainable. Note that depending on the composition of the polymer, the stock solution in the method of the present invention may need to be heated at around room temperature in order to cause gelation. As the coagulation bath, water, aliphatic lower alcohols, or a mixture thereof is generally used. Furthermore, in order to adjust the coagulation ability, it is also possible to use a mixture in which a solvent used in the stock solution, an inorganic salt, an acid, an alkali, etc. are added to the above-mentioned water or alcohol. Alcohols used include methanol, ethanol, n-propanol, isopropanol, butanols, ethylene glycol, and glycerin. The membrane of the present invention does not undergo significant changes in permeation performance and mechanical properties over long periods of time when kept in a wet state. It is also possible to store it in a dry state by attaching a suitable wetting agent such as hydrous glycerin. In addition to the above, examples of wetting agents include ethylene glycol, polyethylene glycol, and various surfactants. Furthermore, it is also possible to change the permeability and mechanical properties of the membrane by heat treatment after membrane formation. The heat treatment is carried out under tension or without tension, and in either case it is carried out in water, in a hydrophilic liquid or in a wet state. Temperatures typically range from 50 to 110°C. Next, the present invention will be specifically explained using examples. Example 1 Copolymerization of methyl methacrylate and dimethylaminoethyl methacrylate was carried out in dimethyl sulfoxide using a radical initiator, the content of the latter in the copolymer was 6.1 mol %, and the viscosity formula of polymethyl methacrylate was Weight average molecular weight calculated using
4.8×10 ⁵ copolymers were obtained. Copolymerization of methyl methacrylate and sodium p-styrene sulfonate was carried out in water-methanol using a radical initiator, and the content of the latter in the copolymer was 2.6 mol% and the weight average molecular weight was 1.8 ×
A copolymer of 10 ⁵ was obtained. In addition, to adjust the viscosity, the weight average molecular weight is 1.4×
Atactic polymethyl methacrylate of 10 ⁵ and 1.5×10 ⁶ was prepared. Furthermore, to improve mechanical strength, the isotactic degree is 95% by triad display measured by NMR with a weight average molecular weight of 6.0 × ¹⁰⁵ .
An isotactic polymethyl methacrylate was prepared. 2 parts of the copolymer, 2 parts of the copolymer, 1 part of isotactic polymethyl methacrylate, and 1 part of polymethyl methacrylate with a weight average molecular weight of 4.5×10 ⁵
The mixture was mixed and heated to dissolve in dimethyl sulfoxide. The solution polymer concentration at that time was 20%. Spread this solution between 125 μl of glass at approximately 100°C.
Cast the film while adjusting the film thickness by placing a spacer, and solidify it in ice water to form a film with a thickness of 123μ and a water content of 68.5.
% transparent semipermeable membrane A was obtained. Table 1 shows the permeation characteristics of this membrane. Here, P ₁ (g ^-1・cm ³・sec) is the pressure permeation constant, which represents the unit area of the membrane, the unit pressure difference per unit membrane thickness, and the volume of permeate per unit time, and P ₂
(cm ² /sec) represents the solute permeation constant due to the concentration gradient per unit area of the membrane and unit membrane thickness when there is no volumetric flow of liquid. Comparative Example 1 5 parts of the atactic polymethyl methacrylate prepared in Example 1 and 1 part of the isotactic polymethyl methacrylate were mixed so that the weight average molecular weight was 4.5×10 ⁵ , and the same mixture as in Example 1 was prepared. A semipermeable membrane B having a membrane thickness of 112 μm and a water content of 68.8% was obtained by the method. The transmission characteristics are shown in Table 1. Comparative Example 2 4 parts of the copolymer prepared in Example 1 and 1 part of each polymethyl methacrylate were mixed to have a weight average molecular weight of 4.5×10 ⁵ , and a film thickness of 134
A semipermeable membrane C with μ and a water content of 68.2% was obtained. The transmission characteristics are shown in Table 1. Comparative Example 3 4 parts of the copolymer prepared in Example 1 and 1 part of each polymethyl methacrylate were mixed to have a weight average molecular weight of 4.5×10 ⁵ , and a film thickness of 125
A semipermeable membrane D with a water content of 70.2% was obtained. The transmission characteristics are shown in Table 1.

[Table] Note that the membrane of Comparative Example 1 had too high water permeability (P ₁ ),
When hollow fibers are spun using this membrane material polymer to create a hollow fiber artificial kidney, two to three times the amount of water required will be removed under normal dialysis treatment conditions, requiring a controller. Note that the desirable water permeability (P ₁ ) value is around 1.5. That is, only the membrane of Example 1 of the present invention has moderate water permeability and high urea, phosphate ion, and vitamin content.
This shows that it is possible to provide a semipermeable membrane for artificial kidneys with balanced B ₁₂ permeability. Example 2 Copolymerization of methyl methacrylate and diethylaminoethyl methacrylate was carried out in a mixed solvent of methanol and water using a radical initiator, and the content of the latter in the copolymer was 4.8 mol% and the weight average molecular weight was 6.6. A copolymer of ×10 ⁵ was obtained. 2.5 parts of this copolymer, 2.5 parts of the copolymer prepared in Example 1, and 1 part of isotactic polymethyl methacrylate were mixed, and a film was formed in the same manner as in Example 1. A semipermeable membrane E with a rate of 69.5% was obtained. The water permeability P ₁ of this membrane is 1.3×10 ^-12
(g ^-1・cm ³・sec), and the permeation constant P ₂ of urea is
7.1×10 ^-6 (cm ² /sec), permeation constant of phosphate ion
P ₂ was 3.1×10 ⁻⁶ (cm ² /sec), and the permeation constant P ₂ of vitamin B ₁₂ was 1.2×10 ⁻⁶ (cm ² /sec). Example 3 Copolymerization of methyl methacrylate and sodium 3-methacryloxypropylsulfonate in Example 1
A copolymer having a weight average molecular weight of 2.4×10 ⁵ and a content of 1.8 mol % in the latter copolymer was obtained. 2 parts of this copolymer, 2 parts of the copolymer prepared in Example 1, and 2 parts of polymethacrylic acid were mixed so that the weight average molecular weight was 4.5 × 10 ⁵ , and the mixture was heated and dissolved in dimethylacetamide. A semipermeable membrane F having a membrane thickness of 102 μm and a water content of 66.8% was obtained in the same manner as in Example 1. The water permeability P ₁ of this membrane is 0.9×10 ^-12 (g ^-1・
cm ³ sec), and the permeation constant P ₂ of urea is 6.9×10 ^-6
(cm ² /sec), the permeation constant P ₂ of phosphate ion is 3.0×
10 ^-6 (cm ² /sec), the permeability constant P ₂ of vitamin B ₁₂ is 1.2
×10 ^-6 (cm ² /sec). Example 4 2 parts of the copolymer prepared in Example 1, 2 parts of the copolymer, 1 part of isotactic polymethyl methacrylate, and 1 part of polymethyl methacrylate were mixed to have a weight average molecular weight of 5.5×10 ⁵ The mixture was mixed and heated and dissolved in dimethyl sulfoxide to prepare a spinning stock solution. The polymer concentration was 26%. The viscosity of this stock solution was approximately 2100 poise at 110°C. This stock solution is spun while quantitatively injecting air into the hollow fiber through the annular spinning hole, and dimethyl sulfoxide is added to approximately 20%.
The hollow fibers were introduced into a coagulation bath of 2 to 5 DEG C. containing an aqueous solution, then passed through a glycerin bath, and wound into a skein at a speed of about 30 m/min. The medium diameter of this hollow fiber was approximately 220μ, and the film thickness was approximately 40μ. 9,000 of these hollow fibers were housed in a hollow fiber artificial kidney case with an effective length of 190 mm using the usual method to create a module with an effective area of about 1.2 m ² . Table 2 shows the transmission performance of this module. Comparative Example 4 Hollow fibers with an inner diameter of about 220μ and a film thickness of about 40μ were prepared in the same manner as in Example 4 using 5 parts of the atactic polymethyl methacrylate prepared in Example 1 and 1 part of the isotactic polymethyl methacrylate. A module with an effective area of approximately 1.2 m ² was produced by spinning.
Table 2 shows the transmission performance of this module. Comparative Example 5 As a representative example of a cellulose-based hollow fiber artificial kidney, Table 2 shows the permeation performance catalog values (partially measured values) of a module with an effective area of approximately 1.3 m ² , Cordis Dow's C-DAK model 1.3.

[Table] Comparative Example 4 has no problem with solute permeability, but water permeability (ultrafiltration) is too high. Note that the desirable water permeability value is around 3.0. In addition, Comparative Example 5 had poor permeability to phosphate ions and vitamin _B12 ;
Furthermore, water permeability is also lacking. On the other hand, the module of Example 4 of the present invention has appropriate water permeability and high dialysance, and enables well-balanced dialysis therapy. Comparative Example 6 Membrane A of Example 1 and membrane A of Comparative Example 1 were added to 3 c.c. each of platelet-rich plasma (PRP) obtained by centrifuging fresh blood collected from a rabbit carotid artery with 3.8% sodium citrate added. Disc-shaped sections, each 14 mm in diameter, cut from membrane B were immersed and shaken at 37°C for 1 hour. As a control, PRP without a membrane was used. The platelets in each PRP were measured using a Coulter counter to obtain the following values. Control 4.80×10 ⁵ /mm ³ Membrane A impregnated 4.08×10 ⁵ /mm ³ Membrane B 3.31×10 ⁵ /mm ³ In other words, the decrease rate of platelets in Membrane A is small and blood compatibility is good. Comparative Example 7 200 units of heparin was added to 100 ml of fresh blood collected from the carotid artery of a rabbit, and the mixture was centrifuged to obtain platelet-rich plasma (PRP). Disc-shaped sections with a diameter of 43 mm cut from membrane A of Example 1, membrane B of Comparative Example 1, and membrane D of Comparative Example 3 were each placed in a physiological saline solution containing 500 units of heparin.
It was soaked in 100 ml for 30 minutes, and then thoroughly washed with physiological saline. Each of these membranes was brought into contact with PRP at 37°C for 1 hour, then washed with phosphate buffer and fixed with 3% glutaraldehyde solution. Next, the adhesion of platelets to these membranes was observed using an electron microscope.

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Claims (1)

[Claims] 1. A methyl methacrylate copolymer containing a polymerizable monomer having an alkali metal base of sulfonic acid,
A hydrous semipermeable membrane made of a mixture with a methyl methacrylate copolymer containing (alkyl)aminomethacrylates.