JP2002186667A - Hollow fiber type hemodialyzer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hemodialyzer capable of being also used safely for an undernourished patient and an aged patient by suppressing a rapid increase in the leakage quantity of albumin when a β2-microglobulin clearance is taken as 50 or more so as to enhance the elimination of low molecular weight protein. SOLUTION: The hollow fiber type hemodialyzer, using a hollow fiber membrane whose water permeability is taken as 150-280 ml/m2/hr/mmHg, is characterized as follows: a membrane area is taken as 1.1 m2 or more; total protein leakage quantity is taken as 0.6-3 g when 3-liter bovine blood is filtered at a filtration flow rate of 20 ml/min; and the water permeability of the hemodialyzer is taken as 300-500 ml/hr/mmHg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hollow fiber hemodialyzer excellent in safety and efficiency for use in treating chronic renal failure.

[0002]

BACKGROUND OF THE INVENTION Hemodialysis has become widespread as a treatment for end-stage renal failure. According to statistics as of the end of 1999, approximately 190,000 people in Japan have received this treatment. It is known that long-term dialysis treatment accumulates low molecular weight proteins of 10,000 to 20,000, which are difficult to remove by dialysis, causing many complications. In particular, beta-2 microglobulin having a molecular weight of 11,700 (hereinafter abbreviated as β2MG) was found to be a causative substance of dialysis amyloidosis seen in long-term dialysis patients.
Identified in 1980, it has since gained attention as a removal target for dialysis treatment. At present, many dialysers are generally called high-performance membranes, which have increased water permeability and pore size to increase β2MG removal performance.However, increasing the pore size increases β2MG removal performance. Leakage of albumin (molecular weight 67000), which is a useful protein necessary for the protein, also increases.

[0003] As a result of examination by the present inventors using a dialysis machine currently on the market, β2M which is an index of β2MG removal performance is obtained.
Until the G clearance is less than 50, there is already a dialyzer that can be safely used with substantially no albumin leakage (about 0.2 g or less), but with β2MG clearance of 50 or less.
In the above cases, it was found that the amount of albumin leakage increased rapidly and exceeded 3 g, which is said to be clinically problematic.
This is because the molecular weight of β2MG is large and the diffusion coefficient is low, so that the pore size of the membrane becomes large in order to enhance the β2MG removal performance, and as a result, the leakage amount of albumin also increases at the same time.

[0004] Although a treatment method called hemodiafiltration, which enhances the removal efficiency by combining filtration as well as diffusion of β2MG, has become widespread, hemodiafiltration is only a complicated procedure compared to hemodialysis. In addition, there is a problem that a replenisher and a special device are required, and the treatment cost is increased.

[0005] In the case of a patient whose body is large and who can take a sufficient amount of nutrients by diet, even if the leakage of albumin is large, β2M
Removal of large amounts of G has been shown to improve clinical symptoms.However, in older patients and small patients, high levels of albumin leakage can reduce plasma protein levels and reduce nutritional deficiencies and infections. May cause hypoproteinemia such as reduced resistance. Because of this, all patients
Β that can be used safely without hypoproteinemia
There is no dialyzer with high 2MG removal performance at present. In particular, high β2MG with β2MG clearance of 50 or more
Shows removal performance and is suitable for elderly and small dialysis patients.
Without special equipment, normal hemodialysis has a small amount of albumin leakage and there is no safe dialyzer.

[0006]

In order to enhance the performance of removing low molecular weight proteins such as β2MG, the membrane area of a hollow fiber membrane used in a dialyzer, the pore size, the number of pores, , The porosity, the film thickness, and the like. These means are all the same as those for improving the water permeability of the dialyzer. In addition, it is extremely difficult to increase the water permeability without increasing the pore diameter of the hollow fiber membrane, and when the water permeability of the hollow fiber membrane is increased to increase the β2MG removal performance, the amount of albumin leak increases rapidly. The problem was to increase. The present invention suppresses the problem of a rapid increase in albumin leakage, especially when the removal of low-molecular-weight proteins is enhanced with a β2MG clearance of 50 or more, and is safe for patients with poor nutrition and elderly patients. An object of the present invention is to provide a dialysis machine that can be used for the dialysis.

[0007]

The present invention has the following arrangement to achieve the above object. Water permeability using a hollow fiber membrane of ^{150 ~280mL / m 2 / hr /} mmHg, and the membrane area 1.1 m ² or more, the bovine blood filtration flow rate 20 mL /
Total protein leak when filtering 3L with min 0.6 ~ 3
g and the permeability of the dialyzer is 300-500 mL / hr / mmHg
A hollow fiber hemodialyzer characterized by the following. The hollow fiber hemodialyzer according to the above, wherein the hollow fiber membrane is made of cellulose triacetate.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors studied the water permeability of a hollow fiber membrane used in a hemodialyzer, the membrane area of the dialyzer, the total amount of protein leak, the water permeability of the dialyzer, and the clearance which is the β2MG removal performance. As a result of studying in detail, the present inventors have found means for solving the above-mentioned problems, and have reached the present invention.

In the present invention, the water permeability of the hollow fiber membrane is 150
It needs to be in the range of 280280 mL / m ² / hr / mmHg. 15
Is less than ^{0mL / m 2 / hr / mmHg} , it is possible to reduce the leakage of albumin to 2g or less regardless of the membrane area of the dialyzer, it increased much membrane area very, film in consideration of the present inventors Even with an area of 3 m ² , the β2MG clearance is not preferable because it does not reach 50 or more at which the effect of improving clinical symptoms is observed. When the water permeability exceeds 280 mL / m ² / hr / mmHg, a high β
Although 2MG clearance occurs, the amount of albumin leakage cannot be suppressed to 3 g or less, which does not cause hypoproteinemia, regardless of the membrane area, and it is not preferable because a dialyzer that can be safely used for all patients cannot be obtained.

In the present invention, when assembling a hemodialyzer using the above hollow fiber membrane, the membrane area of the dialyzer must be at least 1.1 m ² . If the membrane area is less than this, the diffusion of β2MG itself will be rate-determining,
High β2MG clearance cannot be obtained. Increasing the membrane area increases the clearance of β2MG, but at the same time increases the volume of the dialyzer and increases the amount of blood drawn out of the body, which is a problem. Generally when the hollow fiber inner diameter 200 [mu] m, dialyzer membrane area that can safely treat calculated from extracorporeally circulating blood flow is 3m ² or less, preferably increased more secure if 2.1 m ² or less, all patients Thus, a dialyzer that can be used safely can be obtained. However, if the inner diameter of the hollow fiber is different, the blood volume of the dialyzer changes even if the membrane area is the same. For example, if the inner diameter of the hollow fiber increases, the blood volume increases even with the same membrane area, and if the inner diameter decreases, the blood volume decreases. Therefore, the upper limit of the membrane area cannot be determined unconditionally.

In the present invention, in order to sufficiently remove β2MG and perform safe dialysis treatment, it is necessary to set the total protein leak amount when filtering 3 L of bovine blood at a filtration flow rate of 20 mL / min to 0.6 to 3 g. In our study, no matter how the fractionation properties of the membrane were improved, a certain amount of albumin leakage was necessary to sufficiently remove β2MG, and the total protein leakage was less than 0.6 g. Cannot achieve a β2MG clearance of 50 or more, and although the β2MG removal performance is improved, if the total protein leak exceeds 3 g, the albumin leak exceeds 3 g, and hypoproteinemia, a clinical problem, may occur. This is a problem that is easy to cause.

In the present invention, it is necessary to use the above-mentioned hollow fiber membrane, to set the membrane area and the total amount of protein leak within the above range, and to set the water permeability of the dialyzer within the range of 300 to 500 mL / hr / mmHg. . According to the study of the present inventors, this cause is not well understood. However, the above water permeability is 150-280 mL / m ² /
Even when using a hollow fiber membrane of hr / mmHg, if the water permeability as a dialyzer is less than 300 mL / hr / mmHg, even if the total protein leak is kept low, the β2MG clearance cannot obtain 50 or more, The water permeability as a dialyzer is 500mL /
When it exceeds hr / mmHg, it was found that total protein leak could not be kept low even if β2MG clearance of 50 or more could be obtained. According to the study of the present inventors, the hollow fiber membrane water permeability is 280 mL / m ² / hr / near the upper limit of the present invention
For mmHg, membrane area water permeability as 1.7 m ² (dialyzer
Up to 500 mL / hr / mmHg), it was possible to suppress the total protein creep to a low level, but it was found that the total protein leak suddenly increased when it exceeded 1.9 m ² . When the water permeability of the hollow fiber is 150 mL / m ² / hr / mmHg, which is close to the lower limit, if the membrane area is 1.9 m ² (the water permeability of the dialyzer is 289 mL / hr / mmHg), β2M
The G clearance was 45, but the β2MG clearance was 51 at 2.1 m ² (dialyzer permeability: 319 mL / hr / mmHg), which was a sufficient value.

Examples of the material of the hollow fiber membrane used in the present invention include regenerated cellulose, cellulose based materials such as cellulose acetate and cellulose triacetate, polysulfone, polyether sulfone, polyacrylonitrile, polymethyl methacrylate, and ethylene vinyl alcohol copolymer. raising is but water permeability ^{150 ~280mL / m 2 / hr /} mm
Cellulose acetate, cellulose triacetate, polysulfone, and polyethersulfone, which are easy to obtain a hollow fiber membrane in the Hg range, are preferable, and the total protein leak is low.
Cellulose triacetate is particularly preferred because it is easy to obtain a hollow fiber membrane in the range of 0.6 to 2 g.

As a method for producing such a hollow fiber membrane for use in a hemodialyzer, when cellulose triacetate is used as a raw material, a membrane-forming solution in which a polymer is dissolved is discharged together with a hollow-forming agent and coagulated in a coagulation bath. After that, a method of removing the solvent remaining in the water washing step, applying glycerin, drying and winding up may be employed, but the following spinning conditions are particularly preferable.

In order to obtain a film having a high porosity, the polymer concentration of the film-forming solution is lower than usual, specifically, 20% or less, preferably 18% or less, more preferably 16% or less. However, when the polymer concentration is 12% or less, the water permeability of the hollow fiber membrane tends to be 300 mL / m ² / hr / mmHg or more, which is not preferable. In addition, as a hollow forming agent, liquid paraffin or isopropyl myristate, which is a non-coagulating liquid,
When nitrogen or air is used, the completed hollow fiber has a structure that is almost uniform, and the range of water permeability is 150 to 280 mL / m ² / hr / mmHg
It is preferable because it can be easily adjusted. It is not preferable to use a coagulating liquid as the hollow forming agent because the hollow fiber tends to have an asymmetric structure having a skin layer inside, and the water permeability of the hollow fiber membrane tends to be 300 mL / m ² / hr / mmHg or more. Further, in order to make the pore diameter inside the hollow fiber membrane uniform and to reduce the total protein to a size that is difficult to transmit, the nozzle discharge temperature is made lower than usual, specifically, 160 ° C. or less, preferably 140 ° C.
Hereinafter, the temperature is more preferably set to 120 ° C. or lower. In order to make the pore diameter outside the hollow fiber membrane uniform and as large as possible in order to reduce the membrane resistance, the temperature of the coagulation bath is made higher than usual, specifically 25 ° C. or more, preferably 3 ° C. or more.
5 ° C. or higher, more preferably 45 ° C. or higher. Furthermore, in order to suppress shrinkage of the film during drying, the glycerin concentration when applied before drying is higher than usual, specifically,
55% or more, preferably 65% or more, more preferably 75% or more.

The water permeability thus obtained is 150 to 280 m.
Using a hollow fiber membrane of ^{L / m 2 / hr / mmHg} , water permeability of the dialyzer membrane area in the range of 300-500 / hr / mmHg is 1.1 m ² or more, the total protein leakage 0.6 to 3.0 g of the blood Dialyzer is high β2M
A useful dialyzer having both G removal performance and safety can be obtained.

Hereinafter, the present invention will be described in detail with reference to examples.

[0018]

EXAMPLES [Measurement of Water Permeability of Hollow Fiber Membrane and Dialyzer] The blood outlet circuit of the dialyzer (outlet side from the pressure measurement point) is stopped with forceps to perform total filtration. Put pure water kept at 37 ° C in a pressurized tank, and while controlling the pressure with a regulator, send the pure water to a dialyzer kept in a 37 ° C constant temperature water bath,
The filtrate flowing out from the dialysate side is measured with a measuring cylinder. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2. Here, Pi is the dialyzer inlet pressure, and Po is the dialyzer outlet pressure. Change the TMP by 4 points, measure the filtration flow rate,
Calculate the water permeability from the slope. At this time, the correlation coefficient between TMP and filtration flow rate needs to be 0.999 or more. Also, to reduce the pressure loss error due to the circuit, set TMP within the range of 500mmHg or less. The water permeability of the hollow fiber membrane is determined as follows from the membrane area obtained by the measurement shown separately and the water permeability of the dialyzer. UFR (H) = UFR (D) / A where, UFR (H): water permeability of the hollow fiber membrane (mL / m ² / hr / mmH
g), UFR (D): Permeability of dialyzer (mL / hr / mmHg), A: Membrane area of dialyzer (m ² )

[Measurement of Membrane Area of Dialyzer] The membrane area of the dialyzer is determined by the following formula based on the inner diameter of the hollow fiber. A = n × π × d × L where n: number of hollow fibers in dialyzer, π: pi, d: inner diameter of hollow fiber, L: effective length of hollow fiber in dialyzer

[Measurement of total protein leak] Hematocrit was adjusted to 30% and total protein concentration was adjusted to 7.0 ± 0.5 g / dL.
The ACD-added bovine blood kept at ℃ is sent to the dialyzer at 200 mL / min. With the filtration flow rate kept constant at 20 ± 2 mL / min, a recycling circuit is used to return the filtrate and the dialyser outlet blood to the beaker containing the original blood. The filtrate is collected at intervals of 15 minutes from the start of filtration, and the total protein concentration in the filtrate is measured using Micro TP Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.). Continue to a total filtration volume of 3L, during which the average filtrate protein concentration and total filtration volume (3L)
From, the total amount of protein that has flowed out to the filtrate side is calculated.

[Measurement of β2MG Clearance] ACD-added bovine plasma adjusted to a total protein concentration of 7.0 ± 0.5 g / dL and kept at 37 ° C. was flowed at a blood-side flow rate of 200 mL / min.
Flow at 0 mL / min and a filtration flow rate of 15 mL / min. The plasma at the outlet of the dialyzer is returned to the beaker containing the original plasma together with the physiological saline containing ACD for the filtration flow rate. Bovine plasma is supplemented with human β2MG at a concentration of 0.05 to 0.1 mg / L. Blood inlet, 20min at 5min intervals from the start of dialysis
Measure the concentration of β2MG in the outlet and dialysate outlet. The clearance is calculated by the following formula. CL (β2MG) = 200 × [(200 × CBi)-(185 × CBo)] /
(200 × CBi) Here, CBi: blood inlet concentration, CBo: blood outlet concentration. Also, if% MBE calculated by the following formula exceeds ± 50%, it is not used as data.% MBE = 100 × (MB-MD) / MD where MB: (200 × CBi) − (185 × CBo) , MD: 515 x CDo.

Example 1 and Comparative Example 1 16% by weight of cellulose triacetate, 60.5% by weight of N-methylpyrrolidone and 23.5% by weight of triethylene glycol were added to 15% by weight.
It was melted at 0 ° C. and defoamed under reduced pressure to obtain a film forming solution. A film-forming solution was discharged from a tube-in-orifice nozzle heated to 120 ° C using liquid paraffin as a hollow forming agent, and after passing through an air gap, solidified in water at 45 ° C. After washing with water and removing the solvent, it is passed through a 75% aqueous glycerin solution,
Dried with a dryer and rolled up. The inner diameter of the selected hollow fiber membrane was 202.4 μm, and the film thickness was 14.8 μm. Using the hollow fiber membrane thus obtained, hemodialyzers having different membrane areas were assembled. At this time, the size of the case was adjusted so that the filling rate of the hollow fibers in the hemodialyzer was 52 to 55%. Table 1 shows the specifications and performance of the obtained hemodialyzer. That is, No.1-1 to No.1-6 have low total protein leak due to low water permeability of the dialyzer, but β2MG clearance is less than 50. On the other hand, 1-7 to 1-9 are highly safe with less than 2g of total protein leak, and β2MG clearance
It can be seen that a high β2MG removal performance of 50 or more is exhibited.

Example 2 and Comparative Example 2 14% by weight of cellulose triacetate, 62% by weight of N-methylpyrrolidone and 24% by weight of triethylene glycol were added at 150 ° C.
And degassed under reduced pressure to obtain a film forming solution. A film-forming solution was discharged from a tube-in-orifice nozzle heated to 110 ° C using liquid paraffin as a hollow forming agent, and after passing through an air gap, solidified in water at 50 ° C. After washing with water and removing the solvent, the mixture was passed through a 78% aqueous glycerin solution, dried with a drier and wound up. The inner diameter of the selected hollow fiber membrane is
The thickness was 197.8 μm and the film thickness was 15.2 μm. Using the hollow fiber membrane thus obtained, hemodialyzers having different membrane areas were assembled. At this time, the size of the case was adjusted so that the filling rate of the hollow fibers in the hemodialyzer was 52 to 55%. Table 2 shows the specifications and performance of the obtained hemodialyzer. That is, No. 2-3 to 2-6 have obtained dialysers with high safety and high β2MG removal performance. In Nos. 2-1 and 2-2, the membrane area is small and the permeability of the dialyzer is low, so the β2MG clearance is less than 50. Nos. 2-7 and 2-8 provided high β2MG clearance, but No. 2-6
In comparison, it can be seen that the total protein leak increases sharply with an increase in the membrane area.

Comparative Example 3 Cellulose triacetate 21% by weight, N-methylpyrrolidone 57% by weight and triethylene glycol 22% by weight were heated at 150 ° C.
And degassed under reduced pressure to obtain a film forming solution. A film-forming solution was discharged from a tube-in-orifice nozzle heated to 165 ° C. using liquid paraffin as a hollow forming agent, and after passing through an air gap, solidified in water at 20 ° C. After washing with water and removing the solvent, the solution was passed through a 45% aqueous glycerin solution, dried with a drier and wound up. The inner diameter of the selected hollow fiber membrane is
The thickness was 199.4 μm and the film thickness was 15.0 μm. Using the hollow fiber membrane thus obtained, hemodialyzers having different membrane areas were assembled. At this time, the size of the case was adjusted so that the filling rate of the hollow fibers in the hemodialyzer was 52 to 55%. Table 3 shows the specifications and performance of the obtained hemodialyzer. Due to the low water permeability of the hollow fiber membrane, β2MG
Clearance is low.

Comparative Example 4 15% by weight of cellulose triacetate, 63.5% by weight of N-methylpyrrolidone and 24.5% by weight of triethylene glycol
It was melted at 0 ° C. and defoamed under reduced pressure to obtain a film forming solution. A film-forming solution was discharged from a tube-in-orifice nozzle heated to 105 ° C using liquid paraffin as a hollow forming agent, and after passing through an air gap, was coagulated in water at 58 ° C. After washing with water and removing the solvent, it is passed through a 78% glycerin aqueous solution,
Dried with a dryer and rolled up. The inner diameter of the selected hollow fiber membrane was 201.7 μm, and the film thickness was 15.6 μm. Using the hollow fiber membrane thus obtained, hemodialyzers having different membrane areas were assembled. At this time, the size of the case was adjusted so that the filling rate of the hollow fibers in the hemodialyzer was 52 to 55%. Table 4 shows the specifications and performance of the obtained hemodialyzer. Due to the high water permeability of the hollow fiber membrane, the β2MG clearance is high, but the total protein leak is high and a highly safe dialyzer cannot be obtained.

[0026]

[Table 1] Unit Membrane area (m ² ), UFR (D): Permeability of dialyzer (mL / hr /
mmHg), UFR (H): water permeability of hollow fiber membrane (mL / m ² / hr / mmHg),
TPL: Total protein leak (g), CLβ2MG: β2MG clearance (mL / min)

[0027]

[Table 2] Unit, membrane area (m ² ), UFR (D): Permeability of dialyzer (mL / hr /
mmHg), UFR (H): water permeability of hollow fiber membrane (mL / m ² / hr / mmHg),
TPL: total protein leak (g), CLβ2MG: β2MG clearance (mL / min)

[0028]

[Table 3] Unit, membrane area (m ² ), UFR (D): Permeability of dialyzer (mL / hr /
mmHg), UFR (H): water permeability of hollow fiber membrane (mL / m ² / hr / mmHg),
TPL: total protein leak (g), CLβ2MG: β2MG clearance (mL / min)

[0029]

[Table 4] Unit, membrane area (m ² ), UFR (D): Permeability of dialyzer (mL / hr /
mmHg), UFR (H): water permeability of hollow fiber membrane (mL / m ² / hr / mmHg),
TPL: total protein leak (g), CLβ2MG: β2MG clearance (mL / min)

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C077 AA05 BB01 KK11 LL05 LL12 LL17 LL21 NN14 PP03 PP08 PP10 PP15 4D006 GA13 MA01 MB02 MB06 MC18X MC38 MC39 MC62 NA10 NA13 PA01 PC47 4L035 BB04 BB20 DD03 EE20

Claims (2)

[Claims] 1. A method using a hollow fiber membrane having a water permeability of 150 to 280 mL / m ² / hr / mmHg, having a membrane area of 1.1 m ² or more, and filtering 3 L of bovine blood at a filtration flow rate of 20 mL / min. Total protein leak is 0.6-3g and dialyzer permeability is 300-500m
A hollow fiber hemodialyzer characterized by L / hr / mmHg. 2. The hollow fiber hemodialyzer according to claim 1, wherein the hollow fiber membrane is made of cellulose triacetate.