JPH10165774A - Permselective hollow yarn membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a permselective hollow yarn membrane enhancing efficiency for removing a harmful substance such as β2 -MB and preventing the outflow of a useful substance such as albumin in blood dialysis by respectively setting voids at a time of wetness and an albumin sieve coefficient after the one-hr perfusion of bovine serum to specific values. SOLUTION: In a permselective hollow yarn membrane composed of a cellulose derivative, it is desirable that the occupying ratio of pores in the vol., that is, void vol. of a membrane wall from an aspect of the permeability of a substance through the membrane wall is high in relation to the structure of the membrane wall and the void ratio is 75% or more, desirably, about 78% or more. The albumin sieve coefficient of this hollow yarn membrane measured after bovine serum is perfused for one hr is 0.04 or less, pref., about 0.02 or less and, though the permeability of water, a low molecular substance and a substance with a mol.wt. is good, the permeability of albumin with a mol.wt. of about 66,000 through the hollow yarn membrane is sufficiently prevented and this membrane has sharp fractionation characteristics between these mol.wts.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a selectively permeable hollow fiber membrane. More specifically, it has a specific wet porosity, and a specific albumin sieving coefficient, and has selective permeability exhibiting excellent separation performance, and is suitable for blood treatment such as hemodialysis and hemofiltration dialysis. In particular, the present invention provides a selectively permeable hollow fiber membrane suitable for removing harmful substances in a medium-high molecular weight region.

[0002]

2. Description of the Related Art Permselective hollow fiber membranes have been practically used in reverse osmosis and hemodialysis. In particular, hollow fiber hemodialyzers are often used at present for purifying blood of patients with renal failure. In this case, a dialysis membrane, for example, a large number of hollow fiber membranes, is housed in a housing, a patient's blood is allowed to flow inside the hollow, and a dialysate is allowed to flow outside, that is, a hollow fiber gap portion, and a hollow fiber membrane wall is formed. The dialysis removes wastes in the blood and corrects the electrolyte concentration, and applies a pressure difference between the inside and outside of the hollow fiber to remove excess water in the blood by ultrafiltration. Furthermore, hollow fibers are sometimes used to separate plasma alone from blood or to remove specific components from the plasma to treat autoimmune diseases and the like. Recently, it has been confirmed that a therapeutic effect can be obtained by using hollow fibers in protein-permeable hemodialysis or protein-permeable hemofiltration dialysis.

As described above, a hollow fiber for blood treatment must selectively allow a specific substance to permeate according to the purpose. The performance is determined by the material of the hollow fiber, the porosity (the size and number of holes), the film thickness, and the like.

[0004] In recent years, β which is considered to be a causative substance of dialysis amyloidosis is associated with long-term complications of dialysis patients.
_2- microglobulin (β ₂ -MG, molecular weight 11,80
0), parathyroid hormone (molecular weight of about 9,500) considered to be associated with pruritus, hyperlipidemia, erythroblast inhibitory factor involved in anemia, molecular weight of 2 to 4 considered to be associated with arthralgia and bone pain The necessity of removing harmful substances in a relatively medium-high molecular weight region, such as thousands of substances, has been called for. On the other hand, loss of albumin (molecular weight: 66,000), which is essential for the human body, must be avoided as much as possible. That is, there is a demand for a permselective membrane having excellent permeability for substances having a molecular weight of 40,000 to 50,000 or less and good cutoff of the molecular weight of the fraction having good blocking properties for substances having a molecular weight of 60,000 or more.

[0005] However, conventionally, synthetic polymers such as polysulfone are disclosed in, for example, Japanese Patent Publication No.
As shown in JP-A-54373, those which relatively satisfy the above requirements have been obtained. However, in the case of cellulose derivatives, particularly triacetate, for example, as shown in JP-B-58-24165, when a hollow fiber is wet-spun. In order to use non-coagulable triacetate spinning solution, such as liquid paraffin, higher alcohol, isopropyl myristate, etc., as the core agent, the concentration of triacetate in the spinning solution should be increased to improve spinning during spinning. Not get. In addition, a layer having a dense structure is formed on the outer surface of the hollow fiber in order to solidify the spinning stock solution from the nozzle and then solidify the outer surface of the hollow fiber with the coagulating liquid.

[0006] For these reasons, conventionally, a cellulose derivative hollow fiber has a smaller difference in density between a dense layer and a porous layer in structure than a synthetic polymer membrane, and is close to a uniform layer as a whole.
The permeability of the substance was not sufficient. For this purpose, the thickness of the film has been reduced and the permeability has been improved, but this is not sufficient. Furthermore, since the density difference between the dense layer and the porous layer having a membrane structure is unclear, there is room for improvement in the fractionation characteristics of the permeated substance.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to solve such problems of the prior art, and to use a polymer of a cellulose derivative to approximate the structure of a conventional synthetic polymer. The purpose is to provide a dense and dense structure and to impart high molecular weight fractionation characteristics. In particular, it is an object of the present invention to provide a selectively permeable hollow fiber membrane capable of removing harmful substances in the medium-high molecular weight region such as β ₂ -MG and preventing outflow of useful substances such as albumin in hemodialysis and hemofiltration dialysis. I have.

[0008]

Means for Solving the Problems The inventors of the present invention have made intensive studies to achieve the above object, and as a result, a blood purifier using a hollow fiber having a specific porosity when wet and a sieving coefficient of albumin has been developed. The present inventors have found that a dramatically improved separation performance is exhibited, and reached the present invention.

That is, according to the present invention, in a hollow fiber having selective permeability, the porosity of the hollow fiber membrane in a wet state is 75% or more, and the albumin sieving coefficient (SC) after perfusing bovine plasma for 1 hour. ) Is 0.04 or less, and provides a selectively permeable hollow fiber membrane substantially composed of a cellulose derivative.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The hollow fiber membrane of the present invention has a selective permeability, and is made of a cellulose derivative, particularly acetylcellulose. It is a polymer consisting essentially of cellulose diacetate and cellulose triacetate. Note that “substantially” means that other polymers, additives, and the like may be contained as long as the properties of the cellulose derivative are not impaired.

Regarding the structure of the membrane wall of the hollow fiber membrane of the present invention, it is desirable that the proportion of the pores in the volume of the membrane wall, that is, the porosity, is high from the viewpoint of the permeability of the substance through the membrane wall. In the hollow fiber membrane according to the present invention, the porosity is 75% or more, preferably 78% or more.

However, in general, when the porosity is high, molecules having a high molecular weight can easily pass therethrough. In hemodialysis, which is the main object of the present invention, the sieving coefficient of albumin, which is essential for the human body, is 0.04 or less. , A substance having a molecular weight smaller than albumin and imparting selectivity to the permeability of albumin.

In general, it is difficult to realize such a membrane with a uniform porous structure, and it is difficult to realize the separation and permeation characteristics and the mechanical properties of a material, that is, an ultrathin dense layer for defining the separation, Such as having a porous layer that can withstand fluid pressure but has little effect on the permeation resistance of a substance.
Conventionally, a two-layer or multilayer structure realized by a synthetic polymer is preferable. In particular, when blood is processed through the inner surface of the hollow fiber membrane, it is desirable that there is a dense layer at least on the inner surface of the hollow fiber. If there is a porous layer on the inner surface, there is a concern that blood proteins may adhere to that portion or penetrate into the pores, thereby impeding the permeation of substances.

The hollow fiber membrane according to the present invention is characterized in that the albumin sieving coefficient measured after perfusing bovine plasma for one hour is 0.04 or less. It is preferably 0.02 or less, and water, a low molecular weight substance and a molecular weight of 10,000-2.
Despite the good material permeability of 000, the permeability of albumin with a molecular weight of about 66,000 through the hollow fiber membrane is well inhibited and there is a sharp difference between these molecular weights. It has excellent fractionation characteristics.

Generally, the thickness of the hollow fiber membrane is desirably small in view of the permeability of the substance. However, in the case of the high porosity according to the present invention, the thickness is preferably 30 μm or more from the viewpoint of mechanical strength. The inner diameter of the hollow fiber membrane is 100 to 300 μm.
m, more preferably 150 to 250 μm.

As described above, when the hollow fiber membrane of the present invention is used in a hemodialyzer or hemofiltration dialysis, it has a high ability to remove harmful substances in a medium-high molecular weight region such as β ₂ -MG and has a low molecular weight region. In addition to the excellent performance of removing harmful substances, the selective permeation of albumin, which is beneficial to the human body, is small.

Although the method for producing the hollow fiber membrane of the present invention is not particularly limited, a tube-in-orifice-shaped nozzle is preferably prepared by using an undiluted spinning solution obtained by dissolving a cellulose derivative in an organic solvent and using an aqueous solution as a core agent. A method is adopted in which the liquid is discharged more, passes through a gas, and then passes through a water-soluble coagulating liquid and solidifies.

The hollow fiber membrane according to the present invention can be generally subjected to high-pressure steam sterilization, and includes those after high-pressure steam sterilization.

Since the porosity and the sieving coefficient of albumin are somewhat reduced by high-pressure steam sterilization, it is necessary to set each value to a high value before sterilization.

[0020]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

[Examples 1 to 4] A solution prepared by uniformly dissolving 13 parts of cellulose triacetate and 20 parts of triethylene glycol in 67 parts of dimethyl sulfoxide was used as a spinning solution, and an aqueous solution of dimethyl sulfoxide was supplied through a tube-in orifice type nozzle. After being discharged into the air as a core agent, it was guided into a coagulating liquid to be solidified, washed with water, glycerin-adhering treatment, and then wound up. The obtained hollow fiber membranes are dried, bundled, inserted and filled in a cylindrical container, and both ends are adhered and fixed with polyurethane to prepare a hemodialyzer having an effective area of about 1.5 m ^2. The water permeability in vitro (ultrafiltration, UFR), the overall mass transfer coefficient (K ₀ ) of dextran 10,000 and the sieving coefficient (SC) of albumin using bovine plasma were measured.

The evaluation items were measured by the following methods. The method for measuring UFR is described in "I. In vitro performance evaluation in water system, 3. Ultrafiltration" in "Chemical Purifier" Evaluation Criteria (Draft) of the Scientific Committee of the Japanese Society for Dialysis Therapy (May 10, 1994). by.

The method of measuring the overall mass transfer coefficient K ₀ of dextran 10,000 is as follows, using a hemodialyzer having an effective membrane surface area of 1.5 m ² filled with hollow fiber bundles in a cylindrical container.
At 0 ° C., a 0.1% by weight aqueous solution of 10,000 dextran was flowed at 200 ml / min to the blood side, that is, the hollow side, and 500 ml of water was flown to the dialysate side, that is, the hollow fiber gap side.
By measuring the concentration in the effluent on the blood side at a flow rate of / min, K ₀ is obtained by the following equation. The dextran concentration in the sampling solution is measured by, for example, an anthrone-sulfuric acid method.

[0024]

(Equation 1)

Q _B : flow rate on the blood side [ml / sec] Q _D : flow rate on the dialysate side [ml / sec] DA: dextran 10,000 dialysance
The measurement method is in vitro by the Japanese Dialysis Medical Association Scientific Committee
o Based on the evaluation working group evaluation method. A: Effective membrane area of hollow fiber membrane [cm ² ]: Membrane area based on the inner diameter of the hollow fiber membrane in a wet state.

The method of measuring the sieving coefficient (SC) of albumin is based on the in vitro evaluation protocol and functional classification (draft) ('94 .11.12) of bovine plasma in blood purifiers by the Scientific Committee of the Japanese Society for Dialysis Therapy. The measurement of albumin concentration was performed by A / GB-Test Wako (Wako Pure Chemical Industries, Ltd.).

[Comparative Examples 1 and 2] A hollow fiber was prepared by uniformly dissolving 25 parts of cellulose triacetate and 20 parts of triethylene glycol in 55 parts of N-methylpyrrolidone as a stock solution for spinning. A membrane was obtained, and a hemodialyzer having an effective area of about 1.5 m ² was prepared. Evaluation items were measured in the same manner as in Examples 1 to 4.

[Comparative Examples 3 and 4] A solution prepared by uniformly dissolving 20 parts of cellulose triacetate and 20 parts of triethylene glycol in 60 parts of N-methylpyrrolidone was used as a stock solution for spinning, and liquid paraffin was used as a core agent. A hollow fiber membrane was obtained in the same manner and assembled into a hemodialyzer having an effective area of about 1.5 m ² . After sufficiently washing and removing the liquid paraffin as the core agent, evaluation items were measured in the same manner as in Examples 1 to 4. Table 1 shows the results.

[0029]

[Table 1]

Table 1 shows spinning conditions of Examples 1 to 4 and Comparative Examples 1 to 4, characteristic values in vitro and evaluation items.

The hollow fiber of the present invention has high water-removing performance, high permeation performance of dextran 10,000, and good molecular weight fractionation characteristics in which albumin permeation is suppressed.

[0032]

According to the hollow fiber membrane of the present invention, when a blood purifier is assembled by using the bundle, the performance of removing harmful substances in the medium high molecular weight region is high and the amount of albumin leaking into the dialysate is small. This is an excellent effect.

Claims (4)

[Claims] 1. A hollow fiber membrane having permselectivity,
Substantially cellulose, wherein the porosity of the hollow fiber membrane in a wet state is 75% or more, and the albumin sieving coefficient (SC) after perfusing bovine plasma for 1 hour is 0.04 or less. A permselective hollow fiber membrane made of a derivative. 2. The permselective hollow fiber membrane according to claim 1, wherein the permselective hollow fiber membrane has a dense layer at least on an inner surface. 3. The permselective hollow fiber membrane according to claim 1, wherein the permselective hollow fiber membrane substantially consists of cellulose triacetate. 4. The permselective hollow fiber membrane according to claim 1, wherein said permselective hollow fiber membrane is obtained by high-pressure steam sterilization.