JPH1057476A - Membrane separator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To control the leakage of the useful materials dissolved in liquid to a min. level and to enable the removal if the materials having the mol.wt. large than the mol.wt. of these useful materials by combining separating membranes having specific sieving coeffts. varying with respect to the useful materials. SOLUTION: The ratios of the areas of the membranes of the different sieving coeffts. constituting a blood purifying device vary by judgment of to what extent a patient is able to withstand albumin which is the useful material or whether the patient is replenished with albumin pharmaceuticals or not. In general, the sieving coefft. is preferably set at 0.01 to 0.03 in order to attain a medical treatment effect and to minimized the side-effect by the loss of the albumin. In a method for setting the sieving coeff. of albumin in such range, the respective hollow fiber membrane are mixed at a ratio at which the area of the membrane having the sieving coefft. of 0.5 to 1 of the albumin is <=1/10 of the area of the membrane having the sieving coefft. >=0 to <0.5 of the albumin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a separation apparatus using a membrane for removing unnecessary substances from a liquid in which useful substances are dissolved. More specifically, the present invention relates to a separation apparatus having a characteristic that the fractionation characteristic is broad, comprising a membrane having a high rejection rate of a useful substance and a membrane having a high sieving coefficient of the useful substance. In particular, it is an object of the present invention to provide a blood purification apparatus capable of efficiently removing a harmful component having a higher molecular weight than albumin while controlling leakage of albumin in a blood purification treatment using a membrane.

[0002]

2. Description of the Related Art As a method for selectively separating a substance from a solution mainly based on the size of the substance, a membrane separation method has been put to practical use in the industrial and medical fields. In general, the problem in the membrane separation method is to improve the selectivity, and in order to achieve the problem, a high-performance membrane and an apparatus have been developed. Regarding the performance enhancement of the membrane, there have been established a method of making the pore size of the membrane uniform to sharpen the fractionation characteristics, and a method of forming a thin film with an asymmetric membrane or a composite membrane to reduce the permeation resistance of the solute. Regarding the apparatus, selectivity is improved by combining several membrane separation apparatuses in multiple stages and repeating the separation operation many times.
A membrane separation device is widely used in the medical field, particularly in blood purification therapy for patients with chronic renal failure or acute renal failure. The problem with this device is that it can remove uremic substances having a molecular weight smaller than albumin to the maximum while suppressing the leakage of albumin, which is a useful substance for living organisms. Polysulfone membrane, one of the most widely used membranes in recent years, has an asymmetric structure and sharp pore size distribution as described above, and is considered to be an ideal membrane that almost completely meets this need. I have.

With respect to obtaining sharp fractionation performance,
New attempts have also been made on symmetric membranes having a uniform membrane structure, which were considered to be inferior to asymmetric membranes (Jin Ohno: artificial dialysis membrane, new material: P30-35, 1994.
3). This symmetric membrane has the same function as an asymmetric membrane by making the membrane pore size sufficiently large compared to the permeable substance, and adsorbing the protein only to the membrane surface so that the useful substance cannot penetrate. Things. Due to the asymmetric structure formed by the adsorbed proteins, it has become possible to efficiently remove uremic proteins such as β2-microglobulin without leaking albumin, which has been conventionally difficult to remove by dialysis. It has been reported.

[0004] Further, attempts have been made to improve the efficiency of removing uremic substances by a new treatment method. One is hemofiltration dialysis. In this treatment method, by combining filtration and diffusion, a low molecular weight substance such as urea can be diffused to efficiently remove a large molecular weight substance such as β2-microglobulin by filtration. Since this treatment involves a large amount of water removal, an asymmetric membrane having excellent water permeability is widely used.

[0005] More recently, data have been reported which indicate that albumin or higher uremic proteins are involved in various complications in patients undergoing long-term hemodialysis. Was. For example, substances that increase anemia by inhibiting the production of red blood cells, substances that lower the function of platelets and cause bleeding, and other substances that cause itching, bone / arthralgia, and irritability. These substances cannot be removed by a conventional membrane separation apparatus that does not allow albumin to pass. Therefore, a blood purification apparatus using a membrane having an increased pore size or a broad pore size distribution has been developed. It has been reported that this membrane separation device slightly increases albumin leakage as compared with the conventional device, but is effective in reducing complications in dialysis patients.

[0006]

SUMMARY OF THE INVENTION The present invention relates to a membrane separation apparatus for minimizing the leakage of a useful substance and efficiently removing a substance larger than the useful substance in a wide molecular weight range. It is. The object of the present invention cannot be achieved with an apparatus that improves the selectivity in the above-mentioned conventional membrane separation method, that is, sharpens the fractionation performance. For example, in blood purification, if a substance with a higher molecular weight than albumin, which is a useful substance, is to be removed, the higher the selectivity of the membrane separation device, the larger the difference in the sieving coefficient between albumin and its removal target substance. become. That is, in order to increase the sieving coefficient of the removed substance having a higher molecular weight than albumin, it is necessary to increase the sieving coefficient of albumin itself, so that the leakage of albumin, which is a useful substance, inevitably increases.

[0007] A membrane separation apparatus in which the membrane pore size is enlarged or the pore size distribution is broadened is effective to some extent in widening the range of the molecular weight of the permeating substance. Regarding blood purification devices, clinical performance evaluation of dialysis membranes with large pore diameters has been reported (Koji Nakajima, Akiko Saito, et al .: Performance evaluation of various large-pore high performance membranes. Kidney and dialysis vol.3)
6 separate high performance membranes 94: 132, 1
994). The report shows the pore diameter and the sieving coefficient of plasma proteins for three types of blood purification devices using each of a regenerated cellulose membrane, a cellulose triacetate membrane, and a polymethyl methacrylate membrane. Regarding the average pore radius, the regenerated cellulose membrane is 70 A, the cellulose triacetate membrane is 75 A, and the polymethyl methacrylate membrane is 100 A. Each membrane has a pore diameter larger than the pore diameter of 40 to 70 A of the conventional blood purification membrane. Has been The sieving coefficient of albumin of these large-diameter membranes is about 0.03, which is designed to be the maximum value allowed as a blood purification membrane. Among these membranes, it is described that the polymethyl methacrylate membrane having the largest pore diameter also transmits plasma proteins such as transferrin having a molecular weight of 90,000 and albumin having a molecular weight of 150,000, which are larger than albumin. However, the sieving coefficient of IgG is as low as 0.004, which is one of the values of albumin.
It is only about 0%. It is conceivable to further broaden the pore size distribution to broaden the range of the molecular weight that permeates and increase the sieving coefficient.However, a membrane-forming technology that freely controls the pore size distribution without increasing the amount of albumin leakage. Does not currently exist.

The present invention focuses on the above-mentioned problems of the prior art, and controls the leakage of a useful substance dissolved in a liquid to a minimum, and enables the removal of a substance having a higher molecular weight than the useful substance. In particular, it is an object of the present invention to provide a blood purification apparatus capable of efficiently removing a harmful component having a higher molecular weight than albumin while controlling the leakage of albumin in a blood purification treatment using a membrane. .

[0009]

The above objects can be achieved by the present invention described below. That is, the present invention provides “(1) a film having a sieving coefficient of 0 to less than 0.5 for a useful substance, and a film having a sieving coefficient of 0.5 to 1 for the useful substance. A membrane separation device. (2) A blood purification device comprising a membrane having a sieving coefficient of 0 to 0.5 for albumin and a membrane having a sieving coefficient of 0.5 to 1 for albumin. " Become.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Here, in the apparatus of the present invention,
The sieving coefficient (Sc) is Sc = (2 × Cf) / (Ci +
Calculated using the equation defined in (Co). Here, the concentration of the solute in the filtrate is Cf, and the concentration at the inlet of the membrane separation device is Cf.
i, the concentration at the outlet of the membrane separator was represented as Co. The sieving coefficient does not depend only on the characteristics of the membrane constituting the separation device, but also on the shear rate, temperature,
It also depends on the operating conditions of the apparatus, such as the filtration flow rate, and the solute concentration of the processing solution. Therefore, the sieving coefficient defined in the present invention must be determined so as to depend only on the characteristics of the film under the same operating conditions and processing solution conditions.

The material of the membrane used in the apparatus of the present invention may be regenerated cellulose, polyacrylonitrile, polysulfone, modified cellulose, polymethyl methacrylate, polyethylene, polyvinyl alcohol, polyamide, polypropylene, ceramic, or the like. Appropriate ones are used depending on the state of the processing liquid and the purpose of the operating conditions. As the form of the film, a film shape, a tubular shape, a hollow fiber shape, and the like are used, and the hollow fiber shape is practically preferable.

Further, the membranes having different sieving coefficients used in the present invention may be contained in one container, or may be incorporated in separate containers. However, when incorporated in separate containers, it is preferable that the containers are installed in parallel so that the processing liquid is distributed at the ratio of the respective membrane areas.

When the device of the present invention is used for purifying blood, particularly for treating patients with acute renal failure or chronic renal failure, the membrane having a sieving coefficient of 0 or more and less than 0.5 with respect to albumin is used as a membrane. The one having a radius of 30 to 120A is preferable, and the one having a radius of 50 to 80A is more preferable. On the other hand, a film having a sieving coefficient of 0.5 or more and 1 or less with respect to albumin is preferably 150 A to 0.3 μm, and more preferably 250 A to 0.1 μm. If the membrane pore radius is larger than 0.3 μm, blood cell components such as red blood cells and platelets tend to leak. Also, the membrane pore radius is 0.
If the filtration pressure is increased even at 6 μm or less, there is a possibility that red blood cells may be destroyed, that is, hemolysis may occur due to the effect of shear stress generated when a part of the cell membrane of the red blood cells enters the inside of the membrane pore and the blood flows. On the other hand, when the membrane pore radius is smaller than 150 A, the transmittance of albumin or higher molecular weight is reduced, and the efficiency of removing harmful components having large molecular weight is reduced. At the same time, if the permeation of proteins such as albumin and fibrinogen is hindered, these proteins accumulate near the membrane surface, forming a concentration-polarized layer and deteriorating the filtration performance. Therefore, it is even more preferable to set the membrane pore size to a size that allows most plasma proteins to pass through.

In the case where the present invention is used as a blood purification apparatus, the membrane is not particularly limited by the material, shape, size, etc., and an appropriate one is selected according to the purpose, such as water permeability and solute diffusion performance. Just do it.

Examples of the material include polymers such as regenerated cellulose, polyacrylonitrile, polysulfone, modified cellulose, polymethyl methacrylate, polyethylene, polyvinyl alcohol, polyamide, and polypropylene.

As described above, the hollow fiber is preferable, but the size is preferably 1 to 200 μm, more preferably 5 to 100 μm. The inner diameter is 50-600 μm, and even 10
0 to 300 μm can be more preferably used. In particular, a membrane having a sieve coefficient of 0 or more and less than 0.5 with respect to albumin preferably has excellent diffusion performance of substances such as urea, creatinine, electrolyte, and β2-microglobulin. Further, a membrane having a sieving coefficient of 0.5 or more and 1 or less with respect to albumin preferably has high water permeability and excellent blood filtration performance.

Furthermore, the ratio of the areas of the membranes having different sieving coefficients constituting the blood purification apparatus differs depending on how much albumin loss the patient can endure or whether the patient is replenished with an albumin preparation or the like. . Generally, since the amount of albumin leakage of the blood purification device needs to be set low, the sieving coefficient of albumin as the whole device is set to 0.05 or less, more preferably, due to the therapeutic effect and the loss of albumin. It is preferable to set the sieving coefficient to 0.01 to 0.03 in order to minimize side effects. As one method for setting the sieving coefficient of albumin in the above range, the area of a membrane having a sieving coefficient of 0 or more and less than 0.5 with respect to albumin is 20,000, and the area of the membrane with 0. 5 or more,
It is preferable to mix each hollow fiber membrane in the apparatus so that the area of the membrane having a sieving coefficient of 1 or less is 2 to 200.

A method for manufacturing the above-described blood purification apparatus is, for example, as follows. That is, the area of the membrane having a sieving coefficient of 0 or more and less than 0.5 with respect to albumin is 200
On the other hand, the hollow fiber membranes are mixed so that the area of the membrane having a sieving coefficient of 0.5 or more and 1 or less with respect to albumin is 1 to 200, and the total is about 5,000 to 20,000. It is manufactured by bundling and filling a cylindrical plastic container having a dialysate inlet / outlet and fixing both ends to the container with a potting material such as polyurethane. Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

[0019]

【Example】

Examples 1 to 5, Comparative Examples 1 to 5 Average membrane pore radii 50A, 70A, 90A, 100A, 12
Seven types of blood purification devices having an effective membrane area of 1.72 m ² were produced using polymethyl methacrylate hollow fiber membranes of 0 A, 200 A, 400 A, 600 A, and 800 A. As comparative examples, 14,000 hollow fiber membranes having an average membrane pore radius of 50 A were filled (Comparative Example 1), 14,000 hollow fiber membranes having an average membrane pore radius of 70 A were filled (Comparative Example 2), and 90 A of average membrane pore radii were filled. 14,000 hollow fiber membranes (Comparative Example 3), 14,000 hollow fiber membranes with an average membrane pore radius of 100A (Comparative Example 4), and 14,000 hollow fiber membranes with an average membrane pore radius of 120A (Comparative Example) Example 5) was prepared. Further, as examples, 13870 hollow fiber membranes having an average membrane pore radius of 50 A and hollow fiber membranes 130 having an average membrane pore radius of 100 A are used.
130 hollow fiber membranes were mixed and filled (Example 1), 13980 hollow fiber membranes having an average membrane pore radius of 50A and 20 hollow fiber membranes having an average membrane pore radius of 200A were filled (Example 1). 2), hollow fiber membrane 1385 having an average membrane pore radius of 50A
0 and 150 hollow fiber membranes having an average membrane pore radius of 400A (Example 3), 13998 hollow fiber membranes having an average membrane pore radius of 50A and two hollow fiber membranes having an average membrane pore radius of 600A were filled. (Example 4) 13999 hollow fiber membranes having an average membrane pore radius of 50A and hollow fiber membranes 1 having an average membrane pore radius of 800A
A filled book (Example 5) was prepared. Table 1 shows the contents of the above Examples and Comparative Examples. The pore diameter and porosity of each hollow fiber membrane shown in Table 1 were measured using a high-precision fully automatic gas adsorption device (BELSORP 36: Japan Bell).
It is obtained by measuring an adsorption / desorption isotherm at a temperature of -196 ° C.

[Table 1] Next, dextran having an average molecular weight of 512000 (Sig
ma) at a flow rate of 200 ml / min to these blood purification devices, and at a temperature of 37 ° C. and a filtration flux of 2 cm / sec, the molecular weight of dextran in the inlet, outlet and filtrate of the device. By analyzing and measuring the concentration, the fractionation characteristics of each device were examined. Gel filtration chromatography (GPC) was used to measure the molecular weight distribution and concentration of dextran. The devices that make up GPC are:
Differential refractometer (RI-8010: Toso), chromatogram data processing (Chromatocoder 21: Toso), high-performance liquid chromatography pump (CCPE-II: Toso), autosampler (AS-8020: Toso) , Deaerator (S
D8022: Toso, column oven (CTO-6: Shimadzu Corporation), separation column (GMPWXL: Toso), computer for data collection and analysis (PC9801RA:
NEC). Water was used as a solvent, the separation temperature was set at 40 ° C., and the flow rate was set at 0.5 ml / min. Dextran standard solution (molecular weight 1000, 5000, 12000, 50,000, 1
Using 50,000: Fluka), a calibration curve showing the relationship between the elution time and the molecular weight value was obtained, the dextran molecular weight of the sample was determined from the calibration curve, and the respective concentrations were obtained as peak heights. The data obtained as described above was substituted into the above-described equation, the sieving coefficient was calculated, and the fractionation characteristics of each device were obtained. Table 2 shows the sieving coefficients of dextran having a molecular weight of 100,000 to 1,000,000 and their values divided by the sieving coefficient of dextran having a molecular weight of 100,000 in percentage.

In Table 2, dextran having a molecular weight of 100,000 is assumed to be a useful substance, and the effects of the present invention will be described based on measured values of Examples and Comparative Examples in the table. First, consider the case where the amount of loss of useful substances can be increased to some extent. In order to make the sieving coefficient of dextran having a molecular weight of 200,000 according to the conventional technique 0.1 or more, it is necessary to use a membrane having an average membrane pore radius of at least 100 A as in Comparative Examples 4 and 5. However, at the same time, as can be seen from the tables, in Comparative Examples 4 and 5, the sieving coefficient of dextran having a molecular weight of 100,000, which is assumed to be a useful substance, becomes 0.5 or more, and the loss becomes excessive. On the other hand, in Example 3 prototyped based on the present invention, the molecular weight was 1
The value of the sieving coefficient of dextran of 100,000
0.35 which is the same as that of Comparative Example 3 using the membrane of A and is suppressed to 0.35, and the sieving coefficient of the molecular weight of 200,000 is larger than 0.33 obtained in Comparative Example 5 having an average membrane pore radius of 120A.
6 can be maintained. Moreover, in Example 3, the value of the sieving coefficient of dextran having a molecular weight of 1,000,000 was maintained at 50% or more of the value of 100,000 in molecular weight, and it was possible to remove substances in the high molecular weight region which could not be achieved in the comparative example. ing.

[0021]

[Table 2] Next, consider the case where it is necessary to reduce the amount of loss of useful substances. In order to set the sieving coefficient of dextran having a molecular weight of 100,000 to 0.1 or less using the conventional technique, it is necessary to use a membrane having an average pore radius of 70 A or more as in Comparative Examples 1 and 2. However, in these comparative examples, the sieving coefficient of a substance having a molecular weight of 200,000 or more, that is, twice or more the molecular weight of the useful substance, is reduced to a value of less than 10% of the sieving coefficient of the useful substance. It is not possible to remove substances having a molecular weight more than twice that of the substance. Example 1,
As shown in 2, 4, and 5, according to the present invention, the sieving coefficient of a useful substance is reduced by a membrane separation apparatus including a membrane having a sieving coefficient of less than 0.5 and a membrane having a value of 0.5 or more. While keeping the value low, it became possible to maintain the sieving coefficient of a substance having a higher molecular weight than a useful substance at a high value. Moreover, as shown in Example 5, by increasing the average pore radius of the membrane having high permeability to useful substances, the molecular weight range of the substances to be removed is widened, and the sieving of those substances is performed. It is possible to keep the coefficient higher. Furthermore, the range of the molecular weight to be removed and the sieving coefficient can be arbitrarily set by appropriately changing the average membrane pore diameter of the hollow fiber membrane constituting the membrane separation device and the number thereof.

FIGS. 1 and 2 show the effect of the present invention according to the above-described embodiment as a fractionation curve together with a comparative example.

[0023]

According to the present invention, membrane separation characterized in that leakage of useful components can be minimized and substances having a wide range of molecular weights can be removed by simply combining conventionally used separation membranes having different fractionation characteristics. It became possible to provide a device. Particularly, in blood purification treatment using a membrane, it is possible to provide a blood purification device capable of efficiently removing harmful components having a higher molecular weight than albumin while controlling the leakage of albumin to a minimum. Was.
The device of the present invention enables removal of toxic substances having a molecular weight larger than albumin, which is considered to be a cause of anemia, bleeding, pruritus, bone / arthralgia, irritability, etc. in patients who have been undergoing long-term hemodialysis. Is what you do. These high molecular weight substances are not removed by conventional blood purification equipment,
It may have accumulated over a long period of time until it caused complications in the body. In a single treatment using the device of the present invention, toxic substances cannot be sufficiently removed to prevent excessive leakage of useful substances such as albumin, immune proteins, and blood coagulation factors. 2-3 weeks a week
The effect can be expected by continuing the treatments. Therefore, the device of the present invention is sufficiently effective for the continuous removal of high-molecular-weight toxic substances that have been accumulated over a long period of time and have a slow production rate in the body, which could not be removed by conventional blood purification devices. It can be demonstrated.

[Brief description of the drawings]

FIG. 1 shows a fractionation curve in an example of the present invention.

FIG. 2 shows a fractionation curve in an example of the present invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location B01D 69/02 B01D 69/02

Claims (10)

[Claims] 1. A membrane separation apparatus comprising a membrane having a sieving coefficient of 0 or more and less than 0.5 for a useful substance, and a membrane having a sieving coefficient of 0.5 or more and 1 or less for the useful substance. . 2. The area of a membrane having a sieving coefficient of 0.5 or more and 1 or less for the useful substance is 0 for the useful substance.
As described above, 1 / of the area of the film having a sieving coefficient of less than 0.5
2. The membrane separation device according to claim 1, wherein the number is 10 or less. 3. The sieve coefficient of a substance having a molecular weight more than twice that of the useful substance is 0.5 or less, and the value of the sieve coefficient is 70% or more of the sieve coefficient of the useful substance. The membrane separation device according to claim 1, wherein: 4. A substance having a molecular weight more than twice that of the useful substance has a sieving coefficient of 0.05 or less, and the value of the sieving coefficient is 20% or more of the sieving coefficient of the useful substance. The membrane separation device according to claim 1, wherein: 5. A substance having a molecular weight twice or more that of the useful substance has a sieving coefficient of 0.03 or less, and the value of the sieving coefficient is 10% or more of the sieving coefficient of the useful substance. The membrane separation device according to claim 1, wherein: 6. A blood purification apparatus comprising a membrane having a sieving coefficient of 0 or more and 0.5 or less for albumin, and a membrane having a sieving coefficient of 0.5 or more and 1 or less for albumin. 7. The area of the membrane having a sieving coefficient of 0.5 or more and 1 or less with respect to the albumin is 1 / the area of the membrane having a sieving coefficient of 0 or more and less than 0.5 with respect to the albumin. A blood purification apparatus characterized in that the number is 10 or less. 8. A substance having a molecular weight of at least twice that of albumin, wherein the sieving coefficient is 0.1 or less, and the value of the sieving coefficient is 70% or more of the sieving coefficient of albumin. The blood purification apparatus according to claim 6, wherein 9. The sieving coefficient of a substance having a molecular weight of at least twice that of albumin is 0.05 or less, and the value of the sieving coefficient is 20% or more of the sieving coefficient of albumin. The blood purification apparatus according to claim 6, wherein 10. A substance having a molecular weight five times or more that of albumin, wherein the sieving coefficient is 0.03 or less, and the value of the sieving coefficient is 10% or more of the sieving coefficient of albumin. The blood purification apparatus according to claim 6, wherein