JPH0144084B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to an improved regenerated cellulose blood purification membrane and a method for producing the same. More specifically, the present invention relates to a regenerated cellulose blood purification membrane with improved compatibility with blood and a method for producing the same. [Prior Art] As is well known, in recent years, artificial dialysis therapy for patients with renal failure has made rapid progress supported by advances in dialysis machines, dialysis equipment, and dialysis technology, and has contributed to prolonging the lives of patients with renal failure and reintegrating them into society. It plays a big role. In the development of artificial dialysis therapy, regenerated cellulose membranes, especially copper ammonium regenerated cellulose membranes, have played a major role, and in the past and present, the majority of dialysis treatments have been performed using these copper ammonium regenerated cellulose membranes. ing. This is because the membrane has excellent dialysis performance and high safety backed by many years of experience. However, despite this development of dialysis therapy, there are problems such as various side effects thought to be caused by long-term high-dose administration of anticoagulants used during dialysis, and problems related to the clinical symptoms of dialysis patients. Although the countermeasures are not clear, it has been pointed out that the white blood cell count temporarily decreases during dialysis (leucopenia) and that complement components are activated and partially consumed. These phenomena are thought to be caused by blood components coming into contact with the membrane material itself, and this phenomenon is observed in regenerated cellulose membranes and some synthetic membranes. To address these problems and phenomena, attempts have been made to develop new anticoagulants, improve dialysis therapy, and research on dialysis membranes with excellent blood compatibility. For example, it has been proposed to modify the surface of a regenerated cellulose membrane using heparin, vitamins, etc., but satisfactory results have not been obtained in terms of film stability and cost. In addition, certain types of synthetic membranes and cellulose acetate membranes are relatively resistant to blood coagulation or leukopenia, but these membranes have poor balance in physical properties such as dialysis performance, mechanical strength, and heat resistance. , it also has the disadvantage of being relatively expensive in terms of cost. [Problems to be Solved by the Invention] An object of the present invention is to provide a regenerated cellulose blood purification membrane that has improved compatibility with blood without impairing its excellent dialysis performance. The present inventors speculate that when the regenerated cellulose membrane comes into contact with blood components, the β-1,4-glucoside-bonded glucose on the membrane surface may be recognized as a foreign substance, inducing a reaction in the blood components. As a result of extensive research into modifying the surface of regenerated cellulose membranes, it was discovered that a regenerated cellulose membrane to which basic functional groups and acidic functional groups were added by coating the surface with a polymer satisfies the objectives of the present invention. , completed the invention. [Means for Solving the Problems] The present invention is characterized in that the surface of the regenerated cellulose membrane that comes into contact with blood is provided with basic functional groups and acidic functional groups by coating with a synthetic polymer. The present invention relates to a regenerated cellulose blood purification membrane. The present invention also relates to the following three methods of manufacturing blood purification membranes made of regenerated cellulose. The first production method involves applying a solution containing a synthetic polymer having basic functional groups and acidic functional groups to a regenerated cellulose membrane, and then removing excess polymer solution.
The method is then characterized in that the polymer is fixed to the regenerated cellulose membrane. In the second production method, a solution containing a synthetic polymer having a basic functional group and a synthetic polymer having an acidic functional group is applied to a regenerated cellulose membrane, and then the excess polymer solution is removed. It is characterized by fixing. In the third production method, a solution containing either a synthetic polymer having basic functional groups or a synthetic polymer having acidic functional groups is applied to a regenerated cellulose membrane, excess polymer solution is removed, and then the polymer is After fixation, a solution containing the other synthetic polymer is applied to the regenerated cellulose membrane, excess polymer solution is removed, and the polymer is fixed. The "regenerated cellulose" used in the present invention is natural cellulose that has been chemically or physically changed and then regenerated, and includes cuprammonium regenerated cellulose (called Kyupra, Bemberg, etc.), In addition to viscose rayon, it includes saponified cellulose esters, etc., but regenerated cellulose produced by the copper ammonia method is preferred because of its dialysis performance and high safety backed by many years of experience. Regarding the shape of regenerated cellulose, those molded into flat membranes or hollow fiber membranes are used, and hollow fiber membranes are preferred as blood purification membranes. In the present invention, basic functional groups and acidic functional groups are imparted to the regenerated cellulose membrane by coating the surface with a synthetic polymer. A combination of a polymer or a synthetic polymer having a basic functional group and a synthetic polymer having an acidic functional group is used. These synthetic polymers can be prepared using known polymerization methods such as radical polymerization, ionic polymerization, etc. using polymerizable monomers having basic functional groups, polymerizable monomers having acidic functional groups, and/or other polymerizable monomers It can be prepared by condensation polymerization or the like. It is also possible to use a monomer, such as chloromethylstyrene, into which a basic functional group can be introduced by amination after polymerization. The "basic functional group" used in the present invention is a functional group that has a positive charge and can become a cation in an acidic aqueous solution. Examples of such functional groups include primary amino groups, secondary amino groups, tertiary amino groups, quaternary ammonium groups, and nitrogen-containing aromatic ring groups such as pyridyl groups and imidazolinyl groups. Therefore, examples of the polymerizable monomer having a basic functional group used in the present invention include ethyleneimine; vinylamine; 2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine, and 4-vinylpyridine. Vinyl derivatives of nitrogen-containing aromatic ring compounds such as vinylimidazole, N-vinyl-2-ethylimidazole, and N-vinyl-2-methylimidazole; dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, dimethylaminopropyl ( Acrylic acid and methacrylic acid derivatives such as meth)acrylate, 3-dimethylamino-2-hydroxypropyl (meth)acrylate; N-dimethylaminoethyl (meth)acrylic acid amide, N-diethylaminoethyl (meth)acrylic acid amide, etc. acrylic acid amide and methacrylic acid amide derivatives; styrene derivatives such as p-dimethylaminomethylstyrene and p-diethylaminoethylstyrene; and derivatives in which the above vinyl compounds are made into quaternary ammonium salts with alkyl halides, etc. It will be done. Furthermore, the term "acidic functional group" used in the present invention refers to a functional group that can release hydrogen ions and become anions in a basic aqueous solution. Examples of such functional groups include carboxyl groups, sulfonic acid groups, and phosphoric acid groups. Therefore, examples of the polymerizable monomer having an acidic functional group used in the present invention include acrylic acid, methacrylic acid, p-styrenecarboxylic acid, p-styrenesulfonic acid, allylsulfonic acid, and sulfoethyl (meth)acrylate. ,ω
-sulfobutyl (meth)acrylate, 3-sulfo-2-hydroxypropyl (meth)acrylate, 2-acrylamido-2-methylpropanesulfonic acid, and the like. Moreover, the polymerizable monomer having a basic functional group and/or an acidic functional group can be copolymerized with other polymerizable monomers. Such other polymerizable monomers include, for example, alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl (meth)acrylate, and n-butyl (meth)acrylate; 2-hydroxyethyl methacrylate; Amides such as (meth)acrylamide, N-methyl (meth)acrylamide, and N-butoxy(meth)acrylamide; N-vinylpyrrolidone; acrylonitrile; vinyl acetate; and styrene. By combining these polymerizable monomers, a large number of polymers can be used in the present invention, considering the copolymer composition, but the effects on dialysis performance, blood compatibility, affinity for cellulose, coating It is possible to select it appropriately by taking into consideration the solubility in the solvent and the like. Generally, the ratio of basic functional groups to acidic functional groups is about 1 to
9: Can be appropriately selected within the range of about 9 to 1 (molar ratio). As described above, using the above polymerizable monomer, (A) a polymer having a basic functional group and an acidic functional group, (B) a polymer having a basic functional group, and (C) a polymer having an acidic functional group are easily obtained. In the present invention, in order to impart basic functional groups and acidic functional groups to a regenerated cellulose membrane, (1) a method of coating (A), (2) a method of coating (B) and (C) at the same time, and (3) ) The method of coating one of (B) and (C) and then coating the other is adopted, but in (2) and (3), (A) and (B) or
A combination of polymers (A) and (C) is also possible. Polymer solvent when applying the polymer to the regenerated cellulose membrane (hereinafter referred to as "coating solvent")
is a solvent that uniformly dissolves the polymer and facilitates impregnation or application of the polymer onto the membrane surface. In the present invention, basically any solvent that can dissolve the above polymer is used as described below. All are available. A suitable solvent must be selected in consideration of ease of removal, safety if a trace amount remains, etc. In the present invention, as such a solvent, lower alcohols such as methanol and ethanol, acetone and dimethylformamide, and mixtures of these with water are preferred, and ethanol is particularly preferred. The polymers dissolved in these coating solvents are sufficiently effective at low concentrations. A high concentration is undesirable because it is difficult to obtain uniformity in the polymer layer formed, resulting in variations in performance and the polymer falling off during use. In the present invention, the polymer concentration is 0.005 to 5% by weight/solute amount (hereinafter referred to as
(denoted as “w/v%”) is preferably in the range of 0.01 to
A range of 1 w/v% is more preferred. The reason why such a low polymer concentration can be adopted is that in the present invention, the coating amount of the polymer is low and provides a good effect of improving blood compatibility without interfering with the dialysis performance. hundreds for regenerated cellulose
Even in the case of ppM, the purpose of the present invention is satisfactorily achieved. Such a fact was something that could never have been predicted. In the present invention, the amount of coated polymer is preferably in the range of 50 ppM to 5000 ppM, particularly preferably in the range of 70 ppM to 1000 ppM, particularly preferably in the range of 70 ppM to 1000 ppM. Coating the blood purification membrane with a polymer can be performed as follows. First, the polymer is dissolved in a coating solvent, and the resulting polymer solution is applied to the cellulose membrane by impregnation, coating, or other methods. Next, in order to form a uniform coating film, centrifugal removal,
Excess polymer solution is removed from the membrane surface by a method such as suction. If this draining operation is not performed properly, there is a risk of uneven thickness of the coating layer, which causes performance variations and polymer shedding during use. After draining, the polymer is fixed by removing the coating solvent. Removal of the coating solvent is carried out by conventional methods such as vacuum drying, ventilation drying, heat drying, etc. if the solvent is volatile, and if necessary, a polymer-free solvent is used if the solvent has a relatively high boiling point. After washing with a volatile organic solvent having good compatibility with the solvent, drying is carried out in the same manner as above. Furthermore, if the solvent is soluble in water, a method of incorporating a regenerated cellulose membrane into a dialyzer and washing it with water can also be adopted. In order to improve the uniformity of the coating layer, it is preferable to repeat the steps of applying the polymer solution to the membrane surface, draining the liquid, and fixing the polymer. Furthermore, it is even more preferable to repeat the process including the heat treatment described below. After removing the coating solvent, it is preferable to perform a heat treatment. Heat treatment is effective to prevent the coating layer from falling off and to obtain higher blood compatibility. The heat treatment is preferably carried out at a temperature range of 50 to 150°C, more preferably 70 to 130°C. As a heat treatment method, both dry heating and steam heating can be used, and methods such as high frequency heating and far infrared heating are also effective. The heat treatment time must be set in consideration of the effect to be obtained, but is usually from several tens of seconds to several hours, preferably from 1 minute to 1 hour.
When steam sterilization is performed, sufficient effects may be obtained without further performing the above heat treatment. The above manufacturing method can be similarly applied regardless of whether the surface of the membrane to be coated that comes into contact with blood is the inner or outer surface of a hollow fiber or the like. The above manufacturing method can also be applied when a hollow fiber or the like is incorporated into a dialyzer. Especially when the coating solvent causes a change in the morphology of the regenerated cellulose membrane,
It is desirable to apply the above manufacturing method, and in this case, the coating solvent is removed without drying.
It is natural to adopt a method of washing and removing with water. [Example] Next, the content of the present invention will be described in more detail with reference to Examples. Note that the measurement items described in the following examples were each measured by the following methods. (1) Water permeability Make a module by fixing both ends of a bundle of 100 hollow fiber filaments with adhesive, fill the inside of the fibers with water, close one end, and extend 200mm from the open end.
Add water while applying Hg pressure, and measure the water permeation rate per unit time. The membrane area of the filament is calculated by measuring the inner diameter and the effective length of the module. (2) Clearance Make a module similar to (1), and use a 1000 ppm aqueous solution of urea or vitamin B-12 instead of water.
Using a 100 ppm aqueous solution of (VB ₁₂ ), determine the concentration in the dialysate from the absorbance using a spectrophotometer in the same manner as in (1), and calculate the clearance using the following formula. Clearance = (Concentration in dialysate) x (Volume of dialysate per minute) / (Concentration before dialysis) (3) Complement consumption rate Add the membrane to serum so that the surface area is 80 cm ² per 1 ml of serum. After shaking at 37°C for 1 hour, the complement value in the serum was measured using the method of Mayer et al.
Thomas, 1961) as a 50% hemolytic complement value (CH50), and the decrease in complement value from a blank is expressed as the percentage of complement consumption. Example 1 A bundle of dried hollow fibers (inner diameter 200 μm, membrane thickness 13 μm) made of regenerated cellulose using the cuprammonium method (number of hollow fibers
1000 pieces, length 30cm) with a molar ratio of 80:10:10 [N-vinylpyrrolidone].
After immersing the [dimethylaminoethyl methacrylate]-[methacrylic acid] copolymer in a 0.05 w/v% methanol solution at room temperature for about 10 minutes, excess solution was removed using a centrifuge, and then 40 minutes in a vacuum dryer. It was dried for 1 hour at -750 mHg. The bundle was then treated in a dry heat dryer at 120°C for 10 minutes. Table 1 shows the results of measuring the dialysis performance and complement consumption rate of coated hollow fibers and untreated hollow fibers.

[Table] Examples 2 and 3 The copolymer composition of the copolymer used in Example 1 as the coating polymer was changed, and the molar ratio of each was 80:15:5 (Example 2) and
Coating treatment was carried out in the same manner as in Example 1, except that a [N-vinylpyrrolidone]-[dimethylaminoethyl methacrylate]-[methacrylic acid] copolymer of 80:5:15 (Example 3) was used. Table 2 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers. Example 4 As a polymer solution, each content is expressed as a molar ratio.
80:10:10 [2-hydroxyethyl methacrylate]-[dimethylaminoethyl methacrylate]-[2-acrylamide-2-methylpropanesulfonic acid] copolymer with 0.05 w/v% ethanol-water (90:10 ) The coating treatment was carried out in the same manner as in Example 1, except that the solution was used. Table 2 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

[Table] Examples 5, 6, 7 Copolymer A of [2-hydroxyethyl methacrylate]-[dimethylaminoethyl methacrylate] (each content in molar ratio 90:10) and [2-hydroxyethyl methacrylate] were used as polymer solutions. Copolymer B of xyethyl methacrylate and methacrylic acid
(each content is 90:10 in molar ratio) was dissolved in ethanol, and the respective concentrations were Example 5 (Copolymer A 0.025w/v%, Copolymer B 0.025w/v%), Example 6 (copolymer
A0.01w/v%, copolymer B0.04w/v%) and Example 7 (copolymer A0.04w/v%), copolymer B0.01w/v%). Coating treatment was performed in the same manner as in Example 1 using these polymer solutions. The results of measuring the dialysis performance and complement consumption rate of each hollow fiber obtained were
Shown in the table.

[Table] Example 8 Using a bundle of regenerated cellulose hollow fibers similar to Example 1, [N-vinylpyrrolidone]-[dimethylaminoethyl methacrylate] copolymer (each content in molar ratio) was prepared as a polymer solution.
Prepare a 90:10 0.05 w/v% ethanol solution,
After immersing the hollow fiber bundle in the solution at room temperature for about 10 minutes,
Excess solution was removed with a centrifuge, and then dried in a vacuum dryer at 40°C-750mmHg for 1 hour. Next, as a polymer solution, 0.05 w/v% of a copolymer of [N-vinylpyrrolidone]-[methacrylic acid] (each content is 90:10 in molar ratio).
An ethanol solution was prepared, and the hollow fiber bundle was coated under the same conditions as above. Finally, this hollow fiber bundle was treated in a dry heat dryer at 120°C for 10 minutes. Table 4 shows the results of measuring the dialysis performance and complement consumption rate of the hollow fibers obtained. Example 9 In Example 8, a 0.05 w/v% ethanol solution of [2-hydroxyethyl methacrylate]-[dimethylaminoethyl methacrylate] copolymer with a molar ratio of 90:10) was used as a polymer solution. 0.05w/v% of a copolymer of [2-hydroxyethyl methacrylate]-[2-acrylamide-2-methylpropanesulfonic acid] with a molar ratio of 90:10 as a polymer solution.
Example 8 using ethanol-water (90:10) solution
It was carried out in the same way. Table 4 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers. Example 10 In Example 8, 0.05w of [N-vinylpyrrolidone]-[2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride] copolymer with a molar ratio of 90:10) was used as a polymer solution. v% ethanol-
A water (70:30) solution was used as a polymer solution [N-
The same procedure as in Example 8 was carried out using a 0.05 w/v % ethanol solution of vinylpyrrolidone]-[methacrylic acid] copolymer. Table 4 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

[Table] Examples 11, 12, 13 In Example 8, the molar ratio of the polymer solution content was 85:15 (Example 11), 90:10 (Example 12),
A 0.05 w/v% ethanol solution of [2-hydroxyethyl methacrylate]-[dimethylaminoethyl methacrylate] copolymer which is 95:5 (Example 13) was prepared as a polymer solution with a molar ratio of 95:5 ( Example 11) 90:10 (Example 12), 85:
Example 8 using a 0.05 w/v% ethanol solution of [2-hydroxyethyl methacrylate]-[methacrylic acid] copolymer which is 15 (Example 13)
It was carried out in the same way. Table 5 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

〔Effect of the invention〕

As is clear from the above explanation, by coating the regenerated cellulose membrane with a polymer and imparting basic and acidic functional groups to the surface of the regenerated cellulose membrane, the activation phenomenon of complement components and the leucopenia phenomenon become slight, and the anticoagulant The compatibility with blood is also improved. Furthermore, such improvements do not impair the excellent dialysis performance of the regenerated cellulose membrane.

【table】 [Brief explanation of drawings]

FIG. 1 is a graph showing changes in arterial pressure over time when a dog performs extracorporeal circulation. In the figure, 1 shows the results when the coated hollow fibers were used in Example 12, and 2 shows the results when untreated hollow fibers were used.

Claims (1)

[Claims] 1. A blood purification membrane made of regenerated cellulose, characterized in that a basic functional group and an acidic functional group are imparted to the surface of the regenerated cellulose membrane that comes into contact with blood by coating it with a synthetic polymer. . 2. After applying a solution containing a synthetic polymer having a basic functional group and an acidic functional group to a regenerated cellulose membrane, excess polymer solution is removed, and then the polymer is fixed to the regenerated cellulose membrane. A method for producing a blood purification membrane made of regenerated cellulose. 3. After applying a solution containing a synthetic polymer having a basic functional group and a synthetic polymer having an acidic functional group to a regenerated cellulose membrane, the excess polymer solution is removed, and then both of the polymers are fixed. A method for producing a regenerated cellulose blood purification membrane. 4 A solution containing either a synthetic polymer having basic functional groups or a synthetic polymer having acidic functional groups is applied to the regenerated cellulose membrane, excess polymer solution is removed, and the polymer is fixed, after which the other one is applied. A method for producing a regenerated cellulose blood purification membrane, comprising applying a solution containing a synthetic polymer to the regenerated cellulose membrane, removing excess polymer solution, and fixing the polymer.