JP3345260B2 - Permselective hollow fiber membrane - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a selectively permeable hollow fiber membrane. More specifically, it has a specific water permeation performance and an overall mass transfer coefficient of a specific dextran in a dialyzer, and a sieving coefficient of albumin, and has selective permeability exhibiting excellent separation performance, and hemodialysis,
It is an object of the present invention to provide a selectively permeable hollow fiber membrane suitable for blood treatment such as hemofiltration dialysis, and particularly 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 method, a dialysis membrane, for example, a large number of hollow fiber membranes, is housed in a housing, blood of a patient flows in the hollow, and a dialysate flows in the outside, that is, a hollow fiber gap, and a hollow fiber is formed. In addition to removing waste in blood and correcting electrolyte concentration by dialysis through the membrane wall, a pressure difference is applied inside and outside the hollow fiber to remove excess water in 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- MG (microglobulin) (molecular weight 11,800)
It is thought to be related to parathyroid hormone (molecular weight of about 9,500), which is thought to be associated with pruritus and hyperlipidemia, erythroblast inhibitory factor (molecular weight of about 1,000) involved in anemia, joint pain and bone pain The need to remove harmful substances in the relatively high molecular weight region, such as substances having a molecular weight of 20,000 to 40,000, has been avoided.
On the other hand, albumin essential for the human body (molecular weight 66,000)
Loss must be avoided as much as possible. That is, there is a demand for a permselective membrane which is excellent in permeability of substances having a molecular weight of 40,000 or less and 50,000 or less, and which has good rejection of substances having a molecular weight of 60,000 or more and a good sharp cut property of a cut molecular weight.

However, conventionally, synthetic polymers such as polysulfone are disclosed in, for example, Japanese Patent Publication No.
As can be seen in JP-A-54373, those relatively satisfying the above requirements have been obtained. However, in the case of cellulose derivatives, especially triacetate, for example, as shown in JP-B-58-24165, when a hollow fiber is wet-spun. For the core agent,
In order to use non-coagulable triacetate spinning solution such as liquid paraffin, higher alcohol, and isopropyl myristate, it is necessary to increase the concentration of triacetate in the spinning solution to increase spinnability during spinning. 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 provide a coarse-dense structure close to the structure of a conventional synthetic polymer using a polymer of a cellulose derivative. And high molecular weight fractionation properties. Especially in hemodialysis and hemofiltration dialysis, β ₂
-It is an object of the present invention to provide a selectively permeable hollow fiber membrane capable of removing harmful substances in a medium-high molecular weight region such as MG and preventing outflow of useful substances such as albumin.

[0008]

The present inventors have conducted intensive studies to achieve the above object, and as a result, a blood purifier using a hollow fiber having a specific water permeation performance, an overall mass transfer coefficient of dextran and a sieve 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, a water permeable performance at 37 ° C. (UF
R) is not less than 200 ml / Hr, mmHg, m ² , and the hollow fiber membrane was assembled and measured as a dialyzer. The dextran using an aqueous solution containing 0.1% by weight of dextran having a molecular weight of 10,000 was measured. The overall mass transfer coefficient (K ₀ ) is 6.7 × 10 ⁻⁵ cm / sec or more, and the sieving coefficient (SC) of albumin after perfusing bovine plasma for 1 hour is 0.02 or less. The present invention provides a selectively permeable hollow fiber membrane substantially consisting of a cellulose derivative.

Hereinafter, the present invention will be described in more detail.

That is, the hollow fiber membrane of the present invention has a selective permeability, and is made of a cellulose derivative, particularly acetylcellulose. And a polymer composed 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.

The structure of the membrane wall of the hollow fiber membrane of the present invention is characterized by an ultra-thin dense layer that functions to separate and permeate the separation and permeation characteristics of the substance and the mechanical properties, and is capable of mechanically withstanding fluid pressure. A two-layer or multi-layer structure conventionally realized by a synthetic polymer, which has a porous layer having almost no permeation resistance, 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 thickness of the hollow fiber membrane is generally desirably small in view of the permeability of the substance.
In the case of a structure having two or more layers, the thickness is preferably 30 μm or more from the viewpoint of mechanical strength because of having a porous layer. The inner diameter of the hollow fiber membrane is 100 to 300 μm, and more preferably 150 to 250 μm.
m is preferred.

The water permeability (UFR) at 37 ° C. of the hollow fiber membrane of the present invention is 200 ml / hr, mmHg,
m ² or more. It was difficult to obtain such a high level of water permeation performance with a conventional membrane having a relatively uniform structure. By providing such a UFR, TMP (differential pressure applied to both sides of the hollow fiber membrane) for removing a certain amount of water can be reduced, and adhesion of blood proteins to the hollow fiber membrane can be suppressed. . For example, in dialysis using bovine blood, the effective area 1.
When removing water of ² L (liter) in 4 hours with a dialyser of 5 m ^2, a dialyser using a conventional cellulose acetate hollow fiber requires a TMP of 20 to 30 mmHg. In the dialyzer used, about 1/2 of 20
A TMP of less than mmHg, for example, 10 mmHg or more and less than 20 mmHg is sufficient. Further, high water permeability means that not only water molecules but also low molecular substances such as urea, creatinine, uric acid and the like are permeable, which is desirable as a basic performance for a dialyzer.

One of the features of the hollow fiber membrane of the present invention is that the total mass transfer coefficient K ₀ of dextran 10,000 in a dialyzer assembled using the hollow fiber bundle is 6.
It is 7 × 10 ⁻⁵ cm / sec or more.
The K ₀ can be measured by filling a cylindrical container with a bundle of hollow fibers at a filling rate of about 52%, solidifying both ends with an adhesive, cutting, and opening the hollow portion. Using a dialyzer assembled with an effective membrane surface area of 5 m ² , at 0 ° C. at 37 ° C., on the blood side, that is, on the hollow side.
A 1% by weight aqueous solution of 10,000 dextran was added to 200
K ₀ is obtained by the following equation by measuring the concentration in the effluent on the blood side when water is flowed at 500 ml / min on the dialysate side, that is, on the hollow fiber gap side, at 500 ml / min. The dextran concentration in the sampling solution is measured by, for example, an anthrone-sulfuric acid method.

[0016]

(Equation 1)

The K ₀ of the hollow fiber membrane of the present invention is 6.7 ×
10 ⁻⁵ cm / sec or more, more preferably 9.2 × 10
^-5 cm / sec or more is practically preferable.

Furthermore, in the hollow fiber membrane according to the present invention, the sieving coefficient of albumin measured after perfusing bovine plasma on the blood side for one hour in a dialyzer assembled using the hollow fiber bundle is 0.02 or less. It is characterized by: It is preferably 0.01 or less, and water, a low molecular weight substance and a molecular weight of 10,
Despite the good material permeability of dextran of 000, the permeability of albumin having a molecular weight of about 66,000 through the hollow fiber membrane is sufficiently inhibited,
It has sharp fractionation characteristics between these molecular weights.

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 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 a 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.

[0021]

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 8, Comparative Examples 1 to 3 13 parts of cellulose triacetate and triethylene glycol 20
Part was uniformly dissolved in 67 parts of dimethylsulfoxide as a spinning stock solution, and a tube-in orifice type nozzle was used as an aqueous solution of dimethylsulfoxide as a core agent.
After being discharged into the air, it is guided into the coagulating liquid and solidified,
After washing with water and glycerin adhesion treatment, it was 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 (UFR) in vitro, the overall mass transfer coefficient (K ₀ ) of dextran 10,000 and the sieving coefficient (SC) of albumin using bovine plasma were measured. On the other hand, β
₂ -Use a solution of 0.05% of MG, and
The blood was dialyzed at a flow rate of 00 ml / min and the dialysate was flowed at a flow rate of 500 ml / min for approximately 4 hours.

The removal rate of β ₂ -MG before and after dialysis, ie,

[0024]

(Equation 2)

After the calculation, the concentration effect of β ₂ -MG due to water removal was corrected.

The UFR reduction rate immediately after the start of dialysis and immediately before the end of dialysis for 4 hours, ie,

[0027]

(Equation 3)

Was calculated. Further, after the dialysis was completed, the amount of albumin in all the dialysate was measured and defined as the amount of albumin leakage.

Table 1 shows spinning conditions, in vitro characteristic values, and dialysis performance. The hollow fiber of the present invention has a large removal rate of β ₂ -MG, a small change in UFR with time, and a small amount of albumin leaked into the dialysate.

[0030]

[Table 1]

When the hollow fiber membrane of the present invention is used to assemble a blood purifier using the bundle, not only the removal rate of harmful substances in the medium-high molecular weight region such as β ₂ -MG is high, but also the water removal performance is improved. This is an excellent effect that changes over time during dialysis are small and the amount of albumin leaking into the dialysate is small.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-211229 (JP, A) JP-A-7-148252 (JP, A) JP-A-7-278948 (JP, A) JP-A 8- 38598 (JP, A) JP-A-8-970 (JP, A) JP-A-9-70525 (JP, A) JP-B3-76970 (JP, B2) JP-B 8-29231 (JP, B2) (58) Field surveyed (Int.Cl. ⁷ , DB name) A61M 1/16-1/18 B01D 69 / 02,69 / 08,71 / 16

Claims (2)

(57) [Claims] 1. A substantially permeable cellulose triacetate having a dense layer on the inner surface and a porous layer on the outer surface.
In the hollow fiber membrane made of bets, water permeability (UFR) is at 37 ° C., and the 200ml / Hr, mmHg, m ² or more and the hollow fiber membrane was assembled measured as dialyzer, a molecular weight of 10,000 dextran 0.1% by weight of
The mass transfer coefficient (K ₀ ) of the dextran using an aqueous solution containing 6.7 × 10 ⁻⁵ cm / sec or more, and the sieving coefficient of albumin (S.
C. ) Is not more than 0.02.
A permselective hollow fiber membrane for hemodialysis comprising cellulose triacetate . 2. The selectively permeable hollow fiber membrane has a thickness of 30 μm.
The selectively permeable hollow fiber membrane according to claim 1, comprising the above.