JPH0611326B2 - Porous hollow fiber filtration membrane - Google Patents

Description

TECHNICAL FIELD The present invention relates to a blood purification membrane for selectively removing harmful substances such as bilirubin in plasma.

[Prior Art] Recently, plasma exchange therapy has been clinically applied to the treatment of intractable diseases, and its effect is being gained. However, this removes all plasma components and replenishes supplemental fluids such as fresh plasma, plasma preparations, albumin, etc., and not only the active ingredients in plasma cannot be recovered, but also the lack of plasma or plasma preparations as supplemental fluids. ,
Many problems such as the occurrence of serum hepatitis and allergies have been pointed out.

For this reason, a two-stage separation method and a low temperature filtration method have been devised as a method for removing a polymer substance (hereinafter referred to as a harmful substance) that causes a disease from the plasma obtained by separating blood cells by membrane separation. However, it is very difficult to selectively remove only harmful substances depending on the pore size of the membrane because the molecular weight of the harmful substances differs depending on the disease, and it is very difficult to control the pore size to a specified size. There are limits because of this.

On the other hand, a method for removing harmful substances using an adsorbent has also been investigated, and as a method for removing harmful substances such as bilirubin by adsorption, JP-A-57-64059 and JP-A-55-106165.
Anion exchange resins, polyamine-based adsorbents, etc. have been proposed in the publication. Although this adsorbs bilirubin and the like in plasma, its ability is not yet sufficient, and it has not yet been put to practical use.

[Problems to be Solved by the Invention] An object of the present invention is to provide a porous hollow fiber filtration membrane capable of selectively removing harmful substances such as bilirubin only by filtering plasma or serum.

[Means for Solving the Problem] That is, the gist of the present invention is that the amino group or the quaternary ammonium group is introduced into the surface of the micropores, and the film thickness is 5 μm to 300
A porous hollow fiber filtration membrane having a specific surface area of at least 10 m ² / g, a large number of micropores penetrating from the inner wall surface to the outer wall surface, and a human serum albumin permeability of 80% or more. is there.

When the thickness of the membrane of the present invention is less than 5 μm, the adsorption area is small, and when it exceeds 300 μm, the plasma permeability is lowered. The material of the porous film is not particularly limited,
An amino group or a quaternary ammonium group must be introduced on the surface of the micropores. Amino groups are primary, secondary, and 3
It may be any of the primary amino groups. Of these, a tertiary amino group and a quaternary ammonium group are preferred. As a method of introducing an amino group or a quaternary ammonium group, the amino group or the quaternary ammonium group may be introduced into the surface of the hollow fiber micropores by a chemical reaction, or a polymer having an amino group or a quaternary ammonium group may be formed on the surface of the hollow fiber micropores. . Specifically, for example, a method in which styrene, acrylamide, acrylonitrile, etc. are graft-copolymerized on a polyethylene porous hollow fiber, and an amino group or a quaternary ammonium group is introduced into this, after polystyrene is chloromethylated on the polystyrene porous hollow fiber membrane. Examples thereof include a method of reacting an amine to introduce an amino group and a method of converting a cyano group of a polyacrylonitrile porous hollow fiber into a reduced amino group. Further, an addition polymer composed of a polyvalent amine and a polyvalent epoxy compound may be formed on the surface of the porous hollow fiber membrane.

As a material for the porous hollow fiber membrane, polyvinyl alcohol,
Cellulose acetate, polyolefin and the like can be exemplified, but the porous hollow fiber filtration membrane obtained by stretching a highly oriented crystalline unstretched hollow fiber made of polyolefin or the like at a relatively low temperature has a large micropore internal surface area. It is preferably used.

The porous membrane used in the present invention has a specific surface area of at least 10 m ²
/ G or more. If the specific surface area is less than 10 m ² / g, the removal efficiency of harmful substances in blood is not sufficient. This specific surface area can be measured by a nitrogen gas adsorption method. The porous membrane has a human serum albumin permeability of 80.
% Or more is required. As for the human serum albumin permeability, a hollow fiber having an effective length of 7 cm is used when the membrane is a hollow fiber, and a physiological saline solution of 0.1% human serum albumin serum is circulated inside the hollow fiber under the condition that the transmembrane pressure difference is 50 mmHg. The concentration of human serum albumin contained in the filtrate was
It can be calculated by the following formula using the value obtained by measuring the absorbance at 0 nm.

When the human serum albumin permeability is less than 80%, when blood is filtered, harmful substances can be removed, but useful plasma components are not sufficiently permeated, which is not preferable.

The size of the fine pores of the membrane is preferably 1 to 10 kg / cm ² when expressed in terms of valve points, from the viewpoint of plasma permeability. The bubble point can be measured by a method according to ASTM F316-80 using ethanol as a test solution. The porous membrane may be a flat membrane, but is preferably a hollow fiber because the device can be made compact. In the case of hollow fibers, the inner diameter is preferably 150 to 500 μm. Further, the porosity is preferably 30% or more from the viewpoint of plasma or serum filtration, and more preferably 40% or more.

[Examples] The present invention will be described in more detail with reference to the following examples.

Example 1 As a porous membrane having a large number of micropores penetrating from the inner wall surface to the outer wall surface, an inner diameter of 270 μm, a film thickness of 60 μm, a porosity of 60 vol%, a bubble point measured in ethanol of 3.2 kg / cm ² , Internal surface area 3 measured by N ₂ adsorption method
Using 2 m ² / g polyethylene porous hollow fiber membrane EHF (trade name, manufactured by Mitsubishi Rayon Co., Ltd.), styrene was subjected to electron beam graft copolymerization by an air pre-irradiation method. The amount of styrene added was about 38% with respect to the polyethylene hollow fiber. Next, this hollow fiber membrane was chloromethylated and then aminated with trimethylamine. Using this hollow fiber, a plasma filtration mini-module having an effective length of 7 cm and a membrane area of 200 cm ² (hollow fiber inner diameter standard) was prepared. When the transmittance of human serum albumin of this mini module was measured in a circle, it was 95
%Met. With this mini module,
Plasma containing 19.5 mg / d was placed inside the hollow fiber at 37 ℃.
It was made to flow at a rate of ml / min, and filtered through the hollow fiber membrane surface at a rate of 0.3 ml / min for 60 minutes. The unfiltered plasma was recirculated to the unfiltered plasma by a circulation filtration method.
The bilirubin concentration in plasma after filtration was 7.8 mg / dl. In contrast, the loss of total protein, albumin and immunoglobulin was slight.

Comparative Example 1 Using the same polyethylene porous hollow fiber membrane as that used in Example 1, a mini module was prepared without graft copolymerization, and after hydrophilizing treatment with ethyl alcohol, the same conditions as in Example 1 were applied. Then, the same plasma as in Example 1 was filtered. Bilirubin concentration in plasma after filtration is 15.6 mg / d
It was l.

Comparative Example 2 Tertiary amine type anion exchange resin Amberlyte A-21
0.4 g (Rohm and Haas) and 18 ml of the same plasma as used in Example 1 were incubated at 37 ° C. for 2 hours. The plasma bilirubin concentration in the supernatant was 16.8 mg / d.
It was l. When the amount of the ion exchange resin was 4 g and the incubation was performed in the same manner, the plasma bilirubin concentration in the supernatant was 12.3 mg / dl.

[Effects of the Invention] The porous hollow fiber membrane of the present invention has an amino group or a quaternary ammonium group introduced on the surface of its micropores, so that the active surface area is remarkably large, and the surface of an anion-type anion exchange resin-like surface is improved. Compared with the granular adsorbent having an amino group, the treatment efficiency when treating plasma is far superior and the loss of useful substances is small.

Claims (1)

[Claims] 1. An amino group or a quaternary ammonium group is introduced on the surface of micropores, and the film thickness is 5 μm to 300 μm.
A porous hollow fiber filtration membrane having a specific surface area of at least 10 m ² / g, a large number of micropores penetrating from an inner wall surface to an outer wall surface, and a human serum albumin permeability of 80% or more.