JPH0144083B2 - - 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 that are 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 response to this is not clear, it has been pointed out that there is a temporary decrease in white blood cells during dialysis (leucopenia) and a phenomenon in which 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 has been 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 develop 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 synthetic membranes and cellulose astate membranes have relatively minor blood coagulation or leukopenia phenomena;
It has a poor balance in terms of physical properties such as dialysis performance, mechanical strength, and heat resistance, and also has the disadvantage of being relatively expensive. [Problems to be Solved by the Invention] An object of the present invention is to provide a blood purification membrane made of regenerated cellulose 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, 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 regenerated cellulose membrane surface, it was discovered that the object of the present invention could be achieved by coating the membrane surface with a polymer and imparting basic functional groups, and the present invention was completed. [Means for solving the problem] The present invention provides a homopolymer of a polymerizable monomer having a nitrogen-containing basic functional group, or a homopolymer of a polymerizable monomer and other polymers having a nitrogen-containing basic functional group, on the surface of the regenerated cellulose membrane that comes into contact with blood. A regenerated cellulose blood purification membrane coated with a copolymer with a polymerizable monomer (excluding 2-hydroxyethyl methacrylate), and a homopolymer of a nitrogen-containing basic monomer or After applying a solution containing a copolymer of a polymerizable monomer and another polymerizable monomer (excluding 2-hydroxyethyl methacrylate) to the regenerated cellulose membrane, excess polymer solution is removed, and then the above-mentioned This method consists of a method for producing a regenerated cellulose blood purification membrane characterized by fixing a polymer to the regenerated cellulose membrane. 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. The "nitrogen-containing basic functional group" used in the present invention is a functional group that has a positive charge on a nitrogen atom and can become a cation in an acidic aqueous solution. Such functional groups include primary amino groups, secondary amino groups, and tertiary amino groups.
Examples include nitrogen-containing aromatic ring groups such as a class amino group, a quaternary ammonium group, a pyridyl group, and an imidazolinyl group. Therefore, the polymerizable monomer having a nitrogen-containing basic functional group used in the present invention includes, for example, vinylamine; 2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine, 4-vinylpyridine; imidazole, N-vinyl-2-
Vinyl derivatives of nitrogen-containing aromatic ring compounds such as ethylimidazole and N-vinyl-2-methylimidazole; dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, dimethylaminopropyl (meth)acrylate, 3-dimethylamino- Acrylic acid and methacrylic acid derivatives such as 2-hydroxypropyl (meth)acrylate; Acrylic acid amides and methacrylic acid amides such as N-dimethylaminoethyl (meth)acrylic acid amide and N-diethylaminoethyl (meth)acrylic acid amide Derivatives; styrene derivatives such as P-dimethylaminomethylstyrene and P-diethylaminoethylstyrene; and the above vinyl compounds with alkyl halides, etc.
Examples include derivatives in the form of ammonium salts. In addition, other polymerizable monomers (excluding 2-hydroxyethyl methacrylate) used in the copolymerization with the nitrogen-containing basic monomer in the present invention include, for example, methyl (meth)acrylate, ethyl (meth)acrylate, ) Acrylate, alkyl (meth)acrylates such as n-butyl (meth)acrylate; amides such as (meth)acrylamide, N-methyl (meth)acrylamide, N-butoxy (meth)acrylamide, N-vinylpyrrolidone; acrylonitrile ; vinyl acetate; styrene and the like. Many combinations of these polymerizable monomers can be used in the present invention, considering the copolymer composition. Select an appropriate copolymer composition from a wide range of copolymer compositions containing 1% or more of nitrogen-containing basic monomer units, taking into consideration the effects on dialysis performance, blood compatibility, affinity for cellulose, solubility in coating solvents, etc. It is possible to select. The polymer solvent used 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. Basically, any solvent that can dissolve the above polymer can be used as described below. An appropriate 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/volume (hereinafter referred to as
(denoted as “W/V%”) is preferably in the range of 0.01 to
A range of 1W/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 fully 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. Coating the blood purification membrane with a polymer can be carried out 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, excess polymer solution is removed from the film surface by centrifugation, suction, or other methods. If this liquid draining operation is not performed properly, there is a risk of uneven thickness of the coating layer, which causes variations in performance 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 a conventional method such as vacuum drying, ventilation drying, or heat drying if the solvent is volatile; if the solvent has a relatively high boiling point,
After washing with a polymer-free solvent as necessary, washing is performed with a volatile organic solvent having good compatibility with the solvent, and drying is carried out in the same manner as above. Furthermore, if the solvent is soluble in water, a method of incorporating the 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. The heat treatment is preferably performed at a temperature range of 50 to 150°C, more preferably 70 to 130°C, which is effective for preventing the coating layer from falling off and obtaining higher blood compatibility. Heat treatment methods include dry heating,
Any method of 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. In particular, when the coating solvent causes a change in the morphology of the regenerated cellulose membrane, it is desirable to apply the above manufacturing method while it is incorporated in a dialyzer.
Naturally, the coating solvent can be removed by washing with water instead of by drying. [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 measured by the following methods. (1) Water permeability A module is made by fixing both ends of a bundle of 100 hollow fiber filaments with adhesive, and after filling the inside of the fibers with water, close one end and insert 220 mm from the open end.
Add water while applying a pressure of mmHg, and measure the amount of water permeation 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), but 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 ^cm2 per 1 ml of serum, The complement value in the serum after shaking at ℃ for 1 hour was determined by the method of Mayer et al.
immunochemistry, P133 Thomas, 1961)
The 50% hemolytic complement value (CH50) was measured using the method, and the decrease in the complement value from the blank was expressed as the complement consumption rate. 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
After immersing 1,000 pieces (length 30 cm) in a 0.05 W/V% ethanol solution of poly(dimethylaminoethyl methacrylate) at room temperature for about 10 minutes, excess solution was removed using a centrifuge, and then they were placed in a vacuum dryer. 40 inside
It was dried for 1 hour at -750 mmHg. after that,
This bundle was 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] Example 2 Coating treatment was carried out in the same manner as in Example 1, except that a 0.05W/V% ethanol-aqueous solution (ethanol:water = 7:3) of poly(2-methacryloyloxyethyltrimethylammonium chloride) was used. I did it. Table 2 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers. Example 3 The coating treatment was carried out in the same manner as in Example 1, except that poly(P-diethylaminoethylstyrene) was used as the polymer. Table 2 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers. Example 4 The coating treatment was carried out in the same manner as in Example 2 except that poly(2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride) was used as the polymer. Table 2 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

[Table] Examples 5 and 6 Copolymers of dimethylaminoethyl methacrylate and methyl methacrylate as coating polymers (content of dimethylaminoethyl methacrylate: 10 mol% (Example 5) and 50 mol%)
(Example 6)) The coating treatment was carried out in the same manner as in Example 1, except that acetone was used as the coating solvent. Table 3 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

[Table] Examples 7 and 8 Copolymers of dimethylaminoethyl methacrylate and N-vinylpyrrolidone as coating polymers (content of dimethylaminoethyl methacrylate: 10 mol% (Example 7) and 50 mol%)
(Example 8)) The coating treatment was carried out in the same manner as in Example 1, except that (Example 8)) was used. Table 4 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

[Table] Example 9 Coating treatment was carried out in the same manner as in Example 1, except that a copolymer of dimethylaminoethyl methacrylate and acrylamide (content of dimethylaminoethyl methacrylate: 50 mol%) was used as the coating polymer. The results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers were
Shown in the table. Example 10 A copolymer of 2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride and N-vinylpyrrolidone (2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride content: 10 mol%) was used as the coating polymer. Coating treatment was performed in the same manner as in Example 1. Table 5 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers. Example 11 Copolymer of diethylaminoethylstyrene and N-vinylpyrrolidone as coating polymer (content of diethylaminoethylstyrene
The coating treatment was carried out in the same manner as in Example 1, except that 20 mol %) was used. Table 5 shows the results of measuring the dialysis performance and complement consumption rate of the obtained hollow fibers.

[Table] Example 12 The hollow fibers obtained in Examples 1, 5, 6, 7, and 10 and the untreated hollow fibers were each incorporated into a dialysis machine,
Extracorporeal circulation was performed using a dog. The dog used was a pegle dog weighing approximately 10 kg, and
A blood flow of 100 ml/min was collected and sent to the blood flow side of the dialyzer. Note that, prior to extracorporeal circulation, the inside of the dialyzer was washed with physiological saline, and then the dialyzer and blood circuit were filled with physiological saline containing 600 U of heparin, and then blood circulation was started. No matter which dialyzer is used, the white blood cell count reaches its minimum value approximately 5 to 30 minutes after the start of dialysis. Table 6 shows the results of determining the minimum value, setting the value immediately before dialysis as 100.

〔Effect of the invention〕

As is clear from the above explanation, by coating the surface of the regenerated cellulose membrane with a polymer and providing basic functional groups, the activation phenomenon of complement components and the leucopenia phenomenon are minimized, and the compatibility with blood is improved. Ru. Further, such improvements do not impair the excellent dialysis performance of the regenerated cellulose membrane.

Claims (1)

[Scope of Claims] 1. A homopolymer of a polymerizable monomer having a nitrogen-containing basic functional group, or a homopolymer of the polymerizable monomer and other polymerizable monomers ( (excluding 2-hydroxyethyl methacrylate). 2. A solution containing a homopolymer of a polymerizable monomer having a nitrogen-containing basic functional group or a copolymer of the polymerizable monomer and another polymerizable monomer (excluding 2-hydroxyethyl methacrylate). A method for producing a regenerated cellulose blood purification membrane, which comprises applying the polymer to the regenerated cellulose membrane, removing excess polymer solution, and then fixing the polymer to the regenerated cellulose membrane.