JPH0611317B2 - 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 renal failure patients has made great strides in development, supported by advances in dialysis machines, dialysis machines, and dialysis technology, playing a major role in prolonging the life of renal failure patients and returning to society. There is. In the development of such artificial dialysis therapy, the regenerated cellulose membrane and the copper ammonium method regenerated cellulose membrane play a large role. Over the past and present, the majority of dialysis therapy has been performed using these copper ammonium method regenerated cellulose membrane. Has been. This is because the membrane is excellent in dialysis performance and has high safety as evidenced by many years of experience.

However, in spite of the development of such dialysis therapy, there are problems such as various side effects that are considered to be caused by long-term large-dose administration of an anticoagulant used during dialysis, and the clinical symptoms of dialysis patients. The correspondence is not clear,
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.

For 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 presume that the β-1,4-glucoside-bonded glucose on the surface of the membrane is recognized as a foreign substance when the regenerated cellulose membrane comes into contact with the blood component, and the reaction of the blood component is induced, and regeneration is performed. As a result of earnest researches on modifying the surface of a cellulose membrane, the present invention was achieved by coating the surface with a copolymer of 2-hydroxyethyl methacrylate (hereinafter, abbreviated as “HEMA”) and a vinyl compound having a carboxyl group. It was found that the object of (1) was achieved, and the present invention was 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 vinyl compound having a carboxyl group and a carboxyl group, and a solution containing the copolymer of HEMA and a vinyl compound having a carboxyl group was applied to the regenerated cellulose membrane. After that, the excess polymer solution is removed, and then the polymer is fixed to the regenerated cellulose membrane, which comprises 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 laceration, saponified cellulose ester and the like are included, but copper ammonia method regenerated cellulose is usually used from the viewpoint of high dialysis performance and high safety for living body 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 vinyl compound having HEMA and a carboxyl group as described above,
For example, it is a copolymer with acrylic acid, methacrylic acid, vinyl acetic acid, or the like.

The copolymer composition of HEMA and the vinyl compound is 1 to 99% by weight of the HEMA and 99 to 1% by weight of the vinyl compound in consideration of the influence of the regenerated cellulose membrane dialysis performance at the time of coating and the effect on the compatibility with blood. It is possible to select appropriately within the range. It is also possible to use a copolymer containing HEMA and a vinyl compound other than the vinyl compound as the third component.

The solvent of the polymer when the polymer is applied 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 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 thereof 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 it is difficult to obtain the homogeneity of the polymer layer formed on the contrary, which causes variations in performance and the loss of the polymer during use. In the present invention, the polymer concentration is preferably in the range of 0.005 to 5% by weight / volume (hereinafter referred to as "W / V%"), and 0.01
The range of 1 W / V% is more preferable.

The reason why such a low polymer concentration can be adopted is that the polymer in the present invention has a low coating amount and gives a good blood compatibility improving effect without inhibiting the dialysis performance. The object of the present invention is sufficiently achieved even in the case of several hundred ppm with respect to regenerated cellulose. 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 film, applied, or applied to the cellulose film 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 draining operation is not performed properly, there is a risk of uneven thickness of the coating layer, which causes variations in performance and loss of the polymer 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 if necessary, and then washed with a volatile organic solvent having a good compatibility with the solvent, and the same as above. 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 a dialyzer. Especially when the morphological change of the regenerated cellulose membrane is brought about by the coating solvent, it is desirable to apply the above-mentioned production method in a state where it is incorporated in a dialyzer, and at this time, the removal of the coating solvent does not depend on drying, It is natural to adopt the method of washing and removing with water.

〔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 )
The concentration in the dialysate is obtained from the absorbance by a spectrophotometer in the same manner as in (1) using a 00 ppm aqueous solution, and the clearance is calculated by the following formula.

(3) Complement consumption rate The membrane was added to serum so that the surface area was 80 cm ² per 1 mml serum, and the complement value in serum after shaking at 37 ° C for 1 hour was determined by the method of Mayer et al. (Experimental immunochemistry,
50% hemolytic complement value (CH
The decrease in complement value from the blank measured in 50) 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) (100 hollow fibers)
0 piece, length 30 cm) was immersed in a 0.05 W / V% ethanol solution of a copolymer of HEMA and methacrylic acid (HEMA content 90 mol%) at room temperature for about 10 minutes, and then the excess solution was removed by a centrifuge. Then in a vacuum oven at 40 ° C-75
It was dried for 1 hour under the condition of 0 mmHg. 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.

Examples 2, 3 HEMA content of 50 mol% (Example 2) and 10 mol%
Coating was performed in the same manner as in Example 1 using the copolymer of HEMA and methacrylic acid of Example 3. Table 2 shows the results of dialysis performance and complement consumption rate of each of the obtained hollow fibers.

Example 4 The hollow fiber obtained in each of Examples 1 to 3 and an untreated hollow fiber were incorporated into a dialyzer, and extracorporeal circulation was performed by a dog. As a dog, a beagle dog having a weight of about 10 kg was used. 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 6000 U / heparin, and then blood circulation was started.

Except for the case of untreated hollow fiber, no change in arterial pressure was observed and stable extracorporeal circulation was possible. FIG. 1 shows changes in pressure on the artery side when the coated hollow fiber and the untreated hollow fiber prepared in Example 1 were used. As is clear from the graph, when untreated, blood pressure increased due to the initiation of blood clotting in the middle, but with the hollow fiber coated, stable extracorporeal circulation was possible.

〔The invention's effect〕

As is clear from the above explanation,
By coating a copolymer of HEMA and a vinyl compound having a carboxyl group, the regenerated cellulose membrane is modified to reduce blood coagulation and activation of complement components. It is also clear that the regenerated cellulose membrane is modified without impairing the excellent dialysis performance because the coating amount of the polymer is small.

[Brief description of drawings]

FIG. 1 is a graph showing changes over time in arterial pressure when extracorporeal circulation is performed by a dog. In the figure, 1 shows the results when the coated hollow fiber prepared in Example 1 was used, and 2 shows the results when the untreated hollow fiber was used.

Claims (2)

[Claims] 1. A blood purification membrane made of regenerated cellulose, characterized in that the surface of the regenerated cellulose membrane which comes into contact with blood is coated with a copolymer of 2-hydroxyethyl methacrylate and a vinyl compound having a carboxyl group. 2. A solution containing a copolymer of 2-hydroxyethyl methacrylate and a vinyl compound having a carboxyl group is applied 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 regenerated cellulose blood purification membrane, comprising: