JPH0611316B2 - Improved blood purification membrane and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to an improved regenerated cellulose blood purification membrane and a method for producing the same. More specifically, it relates to a regenerated cellulose blood purification membrane having improved compatibility with blood and a method for producing the same.

[Conventional technology]

As is well known, in recent years, artificial dialysis therapy for patients with mental deficiency has made a long progress, supported by advances in dialysis machines, dialysis machines, and dialysis technology, and plays a major role in prolonging the lives of patients with mental deficiency and returning to society. . In the development of such artificial dialysis therapy, regenerated cellulose membranes, particularly copper ammonium method regenerated cellulose membranes, play a large role. Over the past and present, the majority of dialysis therapy is performed using these copper ammonium method regenerated cellulose membranes. Has been. This is because the membrane is excellent in dialysis performance and has high safety as evidenced by many years of experience.

However, despite such development of dialysis therapy, for example, problems such as various side effects that are considered to be due to long-term massive administration of anticoagulants used during dialysis, and clinical symptoms of dialysis patients. Is not clear, but
It has also been pointed out that the number of white blood cells temporarily decreases during dialysis (leukopenia) and the complement component is activated and partially consumed. It is considered that these phenomena are caused by the contact of the blood component with the membrane material itself, and this phenomenon is observed in the regenerated cellulose membrane and some synthetic membranes.

With respect to such problems and phenomena, attempts have been made to develop new anticoagulants, improve dialysis therapy, and develop dialysis membranes having excellent blood compatibility.

For example, it has been proposed to modify the surface of the regenerated cellulose membrane with heparin, vitamins, etc., but satisfactory results have not been obtained in terms of stability and cost of the coating. Also, certain synthetic membranes and cellulose triacetate membranes
Although the blood coagulation or leukopenia phenomenon is relatively slight, these membranes have the drawbacks of poor balance in physical properties such as dialysis performance, mechanical strength, and heat resistance, and a high cost.

[Problems to be solved by the invention]

An object of the present invention is to provide a regenerated cellulose blood purification membrane which has improved compatibility with blood without impairing excellent dialysis performance.

The present inventors presumed that the β-1,4-glucoside-bonded glucose on the membrane surface of the regenerated cellulose membrane when contacted with blood components is recognized as a foreign substance, and the reaction of blood components may be induced. As a result of earnest research on modifying the surface of the regenerated cellulose membrane, 2-hydroxyethyl methacrylate (hereinafter referred to as “HEMA”) and a third
It has been found that the object of the present invention can be achieved by coating a copolymer of a vinyl compound having a primary amino group, and the present invention has been completed.

[Means for solving problems]

The present invention uses HEMA on the surface of the regenerated cellulose membrane that is in contact with blood.
A blood purification membrane made of regenerated cellulose characterized by being coated with a copolymer of a vinyl compound having a tertiary amino group and a solution containing the copolymer of HEMA and a vinyl compound having a tertiary amino group. Is applied to the regenerated cellulose membrane, excess polymer solution is removed, and then the polymer is fixed to the regenerated cellulose membrane, which is a method for producing a regenerated cellulose blood purification membrane.

The "regenerated cellulose" used in the present invention is a natural cellulose that has been chemically or physically changed and then regenerated, and includes a copper-ammonia method regenerated cellulose (called cupra, bemberg, etc.), In addition to viscose rayon and the like, saponified cellulose ester and the like are included, but copper-ammonia method regenerated cellulose is preferable from the viewpoint of dialysis performance and safety supported by many years of experience.

Regarding the shape of the regenerated cellulose, a flat membrane or a hollow fiber membrane is used, and the hollow fiber membrane is preferable as the blood purification membrane.

The polymer used for coating in the present invention is a copolymer of HEMA and a vinyl compound having a tertiary amino group as described above. Examples of the vinyl compound having a tertiary amino group include 2-vinylpyridine, 4-vinylpyridine, 4-vinylimidazole, N-vinyl-2.
-Vinyl derivatives of nitrogen-containing aromatic ring compounds such as methylimidazole; dimethylaminoethyl (meth) acrylate,
Derivatives of acrylic acid and methacrylic acid such as diethylaminoethyl (meth) acrylate and 3-dimethylamino-2-hydroxypropyl (meth) acrylate; N-dimethylaminoethyl (meth) acrylic acid amide, N-diethylaminoethyl (meth) acrylic Examples thereof include acrylic acid amide and methacrylic acid amide derivatives such as acid amide; and styrene derivatives such as p-dimethylaminomethylstyrene and p-diethylaminoethylstyrene.

The copolymer composition of HEMA and the above vinyl compound is 1 to 99% by weight of HEMA, the above vinyl compound 99 to 1 in consideration of the effect on the regenerated cellulose membrane dialysis performance when coated, the effect on the compatibility with blood, and the like. It is possible to select appropriately within the range of weight%. It is also possible to use a multi-dimensional copolymer in which HEMA and two or more of the above vinyl compounds are combined, and a copolymer containing HEMA and a vinyl compound other than the vinyl compound having a tertiary amino group as a third component is used. It is also possible to use.

The solvent of the polymer (hereinafter, referred to as “coating solvent”) when the polymer is applied to the regenerated cellulose membrane is a solvent that uniformly dissolves the polymer and facilitates impregnation or coating of the polymer on the membrane surface. In general, as described below, any solvent that can dissolve the above-mentioned polymer can be basically used. Appropriate solvent must be selected in consideration of ease of removal and safety when a trace amount remains. 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 preferable, and ethanol is particularly preferable.

Polymers that can be dissolved in these coating solvents are fully effective at low concentrations. In the case of a high concentration, it is not preferable because the polymer layer formed on the contrary is difficult to obtain uniformity, which causes variations in performance and loss of the polymer during use. In the present invention, the polymer concentration is preferably in the range of 0.05 to 5% by weight / volume (hereinafter referred to as “w / v%”), and 0.01
The range of up to 1 w / v% is more preferable.

The reason why such a low polymer concentration can be adopted is that in the present invention, the polymer has a low coating amount and gives a good blood compatibility improving effect without impairing the dialysis performance. For example, even when the amount of coated polymer is several hundred ppm based on the regenerated cellulose, the object of the present invention is sufficiently achieved. This fact is something we could never have expected. In the present invention, the coated polymer amount is preferably in the range of 50 ppm to 5000 ppm, particularly preferably in the range of 70 ppm to 1000 ppm.

The coating of the polymer on the blood purification membrane can be performed as follows. First, the polymer is dissolved in a coating solvent, and the obtained polymer solution is impregnated into the membrane, applied, or applied to the cellulose membrane by another method. Then, in order to form a uniform coating film, the excess polymer solution is removed from the film surface by a method such as centrifugal removal or suction. If this drainage operation is not performed properly, there is a risk of variations in performance and unevenness in the thickness of the coating layer that causes the polymer to fall off during use.

After draining, the polymer is fixed by removing the coating solvent. The coating solvent can be removed by vacuum drying, ventilation drying, if the solvent is volatile,
It is carried out by a usual method such as heating and drying, and when the solvent has a relatively high boiling point, it is washed with a solvent containing no polymer as necessary, and then washed with a volatile organic solvent having a good compatibility with the solvent. Similarly, it is carried out by the method of drying. Further, when the solvent is soluble in water, a method of incorporating the regenerated cellulose membrane in a dialyzer and washing with water can also be adopted.

In order to enhance the uniformity of the coating layer, it is preferable to repeat the processes of applying the polymer solution to the film surface, draining the solution, and fixing the polymer. Furthermore, it is more preferable to repeat the process including the heat treatment described below.

It is preferable to perform heat treatment after removing the coating solvent. The heat treatment prevents the coating layer from falling off,
It is effective for obtaining higher blood compatibility. The heat treatment is preferably performed in a temperature range of 50 to 150 ° C, more preferably 70 to 130 ° C. As the heat treatment method, either dry heating or steam heating can be used, and methods such as high frequency heating and far infrared heating are also effective. The heat treatment time has to be set in consideration of the effect to be obtained, but is usually several tens of seconds to several hours, and preferably 1 minute to 1 hour.
When steam sterilization is performed, sufficient effects may be obtained without further heat treatment.

The above-described manufacturing method can be similarly applied regardless of whether the membrane surface to be coated which comes into contact with blood is the inner surface or the outer surface of the hollow fiber or the like.

The above manufacturing method can be applied to the case where a hollow fiber or the like is incorporated in the dialyzer. Especially when the morphological change of the regenerated cellulose membrane is caused by the coating solvent,
It is desirable to apply the above-mentioned manufacturing method in a state where it is incorporated in a dialyzer, and in this case, it is natural that the method of removing the coating solvent by washing without water is adopted.

〔Example〕

Next, the contents of the present invention will be described in more detail by way of examples.

The measurement items described in the following examples were measured by the following methods.

(1) Water permeation amount Make a module in which both ends of a bundle of 100 hollow fiber filaments are fixed with an adhesive, fill the inside of the yarn with water, close one end, and apply water at a pressure of 200 mmHg from the open end. Put it in and measure the amount of water 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 10% urea instead of water.
00ppm aqueous solution or 1 of vitamin B-12 (VB ₁₂ )
Using a 00 ppm aqueous solution, the concentration in the dialysate is obtained from the absorbance by a spectrophotometer in the same manner as in (1), and the clearance is calculated from the following formula.

(3) Complement consumption rate A membrane was added to serum so that the surface area was 80 cm ² per 1 ml serum, and the complement value in the serum after shaking at 37 ° C for 1 hour was determined by the method of Mayer et al. (Experimental immunochemistry, P13
3 Thomas, 1961), the decrease in complement value from the blank measured by 50% hemolytic complement value (CH50) is expressed as the complement consumption rate.

Example 1 A bundle of dried hollow fiber made of regenerated cellulose with a copper-ammonia method (inner diameter: 200 μm, film thickness: 13 μm) (the number of hollow fibers: 1000)
Book, length 30 cm) of a copolymer of HEMA and dimethylaminoethylmethacrylate (HEMA content 90 mol%).
After soaking in a 05w / v% ethanol solution at room temperature for about 10 minutes, the excess solution was removed by a centrifuge and then dried in a vacuum dryer at 40 ° C-750 mmHg for 1 hour.
Then, this bundle was processed at 120 ° C. for 10 minutes in a dry heat dryer.

Table 1 shows the results of dialysis performance and complement consumption rate of the coated hollow fiber and the untreated hollow fiber.

Example 2 Coating was performed in the same manner as in Example 1 except that a copolymer of HEMA and 3-dimethylamino-2-hydroxypropyl methacrylate (HEMA content 90 mol%) was used as the polymer to be coated. Table 2 shows the results of dialysis performance and complement consumption rate of the obtained hollow fibers.

Example 3 Coating was performed in the same manner as in Example 1 except that HEMA and p-diethylaminoethylstyrene (HEMA content 95 mol%) were used as the coating polymer. Table 2 shows the results of dialysis performance and complement consumption rate of the obtained hollow fibers.

Examples 4, 5 HEMA content of 50 mol% (Example 4) and 10 mol%
A coating was performed in the same manner as in Example 1 using the copolymer of HEMA of Example 5 and dimethylaminoethyl methacrylate. Table 3 shows the results of the dialysis performance and the complement consumption rate of each of the obtained hollow fibers.

Example 6 The hollow fiber obtained in each of Examples 1 to 5 and the untreated hollow fiber were incorporated into a dialyzer, and extracorporeal circulation was performed by a dog. As a dog, a beagle dog having a body weight of about 10 kg was used, and a blood flow of 100 ml / min was taken from a shunt built in the neck and allowed to flow to the dialyzer blood flow side. Before the extracorporeal circulation, the inside of the dialyzer was washed with physiological saline, and then the inside of the dialyzer and the blood circuit were filled with physiological saline containing 600 U / l of heparin, and then blood circulation was started. No matter which dialyzer is used, the white blood cell count takes a minimum value within about 5 to 30 minutes after the start of dialysis. The results of this minimum value are shown in Table 4 with the value immediately before dialysis taken as 100%.

[Effects of the Invention] As is clear from the above description, by coating the surface of the regenerated cellulose membrane with a copolymer of HEMA and a vinyl compound having a tertiary amino group, the regenerated cellulose membrane is modified and leukocyte The effect of the present invention that the phenomenon of transient reduction and the activation phenomenon of complement components are reduced can be achieved. Further, it is clear that since the coating amount of the polymer is small, the regenerated cellulose membrane can be modified without impairing the excellent dialysis performance.

Claims (2)

[Claims] 1. A regenerated cellulose membrane is provided with 2 on the membrane surface in contact with blood.
-A blood purification membrane made of regenerated cellulose, which is coated with a copolymer of hydroxyethyl methacrylate and a vinyl compound having a tertiary amino group. 2. A solution containing a copolymer of 2-hydroxyethyl methacrylate and a vinyl compound having a tertiary amino group is applied to a regenerated cellulose membrane, excess polymer solution is removed, and then the polymer is regenerated cellulose. A method for producing a regenerated cellulose blood purification membrane, which comprises fixing to a membrane.