JPH0366380A - Hollow fiber type plasma separating membrane - Google Patents

Abstract

PURPOSE:To obtain the hollow fiber type plasma separating membrane which is improved in safety and more particularly hemolysis resistance and is excellent in adaptability to a living organism by forming the projecting parts of semicircular cylindrical tablets on the inside surface, in contact with blood, of the hollow fiber type plasma separating membrane and specifying the spacing between the projecting parts and the height thereof. CONSTITUTION:The projecting parts of the semicircular cylindrical tablets in parallel with the major axis direction of the hollow fiber are formed on the membrane surface in order to control the capturing of red blood cells on the membrane surface. The area where the red blood cells come into contact with the membrane decreases and the flow in the major axis direction in the hollow fiber is regulated, by which the stagnation of the flow near the membrane surface is decreased and the red blood cells are hardly captured on the membrane surface. The spacings between the peaks of the projecting parts of the semicircular cylindrical tablets is set smaller than 3 times the max. diameter (about 8.5mum) of the red blood cells to lower the probability that the red blood cells enter the valleys. The contact points increase and the red blood cells are liable to be captured if the spacing is set too small. The spacing L between the peaks is, therefore, required to be 1(mum)<=L<=20(mum). The height of the peaks is required to be 1(mum)<=H<=10(mum) in order to provide the effect of regulating the flow in the major axis direction of the hollow fiber.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a medical hollow fiber plasma separation membrane used for the purpose of separating plasma components from blood. [I A medium-density plasma with excellent biocompatibility, no hemolysis, and improved hemolysis resistance, used in medical fields such as plasma exchange therapy and component collection 1111 for collecting plasma from healthy individuals. It relates to separation membranes.

(Conventional technical field) 1111 Separation of plasma components excluding blood cell components from blood
Serum separation has been developed as a medical method for treatment such as plasma exchange therapy, which aims to remove pathogenic substances and toxic substances.

However, in order to compensate for the absolute shortage of plasma raw material supply within the region in response to the increase in the amount of plasma preparations used due to recent advances in medical technology, the 1m component donation from plasma separation has been institutionalized. As a result, this plasma separation method was expanded to include healthy individuals. The Kll serous separation membrane used for such component +fn is used for healthy people, and has a much higher level of safety and non-biocompatibility than the conventional therapeutic single serous separation membrane. required. The material for the width l plasma separation membrane is cellulose acetate, polyethylene 1/
However, conventional open separation membranes have reached a level where they can be used in 7.1 minutes due to their compatibility and safety. There was nothing. For example, in terms of biocompatibility, cellulose-based membranes, which have traditionally been widely used as blood purification membranes, are activated when complement components in the blood come into contact with the membrane, causing an immune system response. It has been known. In addition, polyolefin membranes, which are said to have relatively good biocompatibility, cannot be formed by phase separation, and the pores are made microporous by stretching, which reduces the pores. When blood cells are captured in the pores, strong stress is applied locally to the red blood cell membrane due to the parallel strand-shaped polymer fibrils.
There was a problem that it easily caused hemolysis.

(Problems to be Solved by the Invention) The present invention provides a hollow fiber plasma separation membrane that is safe and biocompatible and can be used for healthy donors (donors + fn persons). Safety here refers to membrane strength that does not cause leaks, no membrane defects such as pinholes, and that does not generate dissolved [1n] when it comes into contact with blood and performs plasma separation. Biocompatibility numerically refers to the reaction between the blood coagulation system and the immune system, but in plasma separation, since the reaction of the coagulation system is blocked by an anticoagulant, it mainly refers to the reaction of the immune system. Refers to a reaction. The present invention provides safety and
In particular, the present invention aims to provide a hollow fiber plasma separation membrane with improved hemolysis resistance and excellent biocompatibility rh.

(Means for Solving the Problems) In order to solve the above problems, the present invention has been arrived at as a result of intensive research. That is, semicylindrical protrusions are formed on the inner surface of the hollow fiber separation membrane that comes into contact with blood, and the distance (L) between the protrusions is
This is a hollow fiber plasma separation membrane with improved resistance to hemolysis, in which the height (H) is expressed by the formula 1 and the height (H) is expressed by the formula 2.

1/jj: aL ≦ 20 pm −<1) 1
Door ≦ H ≦ 10u...121 The materials of the separation membrane to which the present invention is applied are cellulose-based, cellulose acetate-based, polyvinyl chloride, polyvinyl alcohol, polyolefin-based, polycarbonate-based, and polysulfone-based polymers. Polycarbonate is preferable in terms of compatibility.

The spacing (L) and height (H) of the semicylindrical convex portions provided on the inner surface of the hollow fiber plasma separation membrane according to the present invention are shown in FIG. It is desirable that the convex portion be formed parallel to the long sleeve direction of the hollow fiber, and that the pores opened on the membrane surface have a smooth FI shape or an oval shape.

Hemolysis in the present invention refers to the destruction of the cell membrane of red blood cells, the collapse of the cells, and the release of cytoplasm.Hemoglobin (Hb) in the cells is released, so the concentration of Hb released into the blood is The degree of hemolysis can be determined by this (usually 3■/rlQ or less). The mechanism by which hemolysis occurs in plasma separation by transmembrane is due to the 1 g pressure difference (Trans Me
mbrane Pressure.

A flow perpendicular to the membrane surface is formed by TMP), and a so-called cross flow occurs between it and the flow in the axial direction of the hollow fiber. Blood cell components reach the membrane surface with the flow of filtrate (plasma), but cannot pass through the narrowed pores, so they are either captured on the membrane surface or rolled on the surface by the flow in the axial direction of the hollow fibers. Seeds, once again flowing in the axial direction. At this time, the captured red blood cells are subjected to the force of being drawn into the pores by TMP and the shear force due to the axial flow of blood. The cell membrane will be destroyed and hemolysis will occur.

In this mechanism of generation of melt [m], melt 1fT
1. The key points for this occurrence are: - red blood cells are captured on the membrane surface; There are two points: the cell membrane is destroyed.

Therefore, it is necessary to consider measures for preventing hemolysis in two stages. One is to provide a membrane structure that prevents red blood cells from being captured on the membrane surface, and the other is to reduce the force applied to the red blood cell membrane so that the cell membrane of the red cell that is captured on the membrane surface is not destroyed. A possible method is to prevent hemolysis by dispersing it. As a result of careful consideration of these points, the researchers of the present invention have created a hollow membrane with improved hemolysis resistance that has an effective effect on these two points by creating a membrane shape as shown above. It has been found that it is possible to make a thread-type plasma separation membrane. That is, in order to suppress the capture of red blood cells on the membrane surface, by forming a semicircular protrusion parallel to the long sleeve direction of the hollow fibers on the membrane surface, the area in which the red blood cells come into contact with the membrane is reduced. In addition, the flow in the long sleeve direction within the hollow fibers is rectified, reducing flow stagnation near the membrane surface.
Red blood cells become trapped on the membrane surface. At this time, the distance between the peaks of the semicircular protrusions is equal to the maximum diameter of the red blood cells (approximately 8.57 JJ).
By making it smaller than 3 times I), the probability of entering the valley is lowered, and if it is too small, there will be many contact points (and it will be easier to be captured), so the distance between the vertices (L) is
1 (p)! It is necessary that L≦20 (units),
In addition, the height of the apex is f(p)! in order to have a rectifying effect on the flow in the long-sleeve direction of all the hollow fibers of somen noodles.
It is necessary that H≦10(u). In addition, in order to prevent hemolysis of red blood cells trapped in the pores on the membrane surface, the pores are smooth circular or smooth oval shapes formed by phase separation, and the red blood cell membrane has fibrillar or linear slits. It is necessary that the structure does not cause local stress concentration.

The method for producing a hollow fiber plasma separation membrane having such a structure by spinning is to use a spinning dope with a high coagulation rate, increase the coagulation value of the inner solution, and draw the inner surface while slowly coagulating the outer surface. This is achieved by

In other words, the inner surface has already solidified due to stretching,
A semicylindrical protrusion is formed on the inner surface due to the difference in shrinkage in the diameter direction of the hollow fiber with the outer surface, which solidifies slowly (small inner shrinkage, large outer shrinkage). What is important at this time is to lower the draft ratio during spinning membrane formation in order to increase the contraction force in the diameter direction of the medium yarn, and to lower the coagulation bath temperature to slow coagulation from the outside to reduce the coagulation value. It is desirable to use a high coagulation bath with low solvent concentration.

When polycarbonate is used as the hollow fiber membrane material, the concentration of polycarbonate is 15 to 25%, and 25%
After that, no convex portions will be formed on the inner surface. It is important to make the internal solution and coagulation bath different so that the coagulation rate is faster inside and slower outside.For example, when using water as a coagulant, the inner solution has more water, and the outer solution has less water. Control by reducing.

The temperature of the coagulation bath is usually 30"C or higher, but in the present invention it is lowered to 5 to 20C.

(Example) Manufacturing method and evaluation measurement method of hollow fiber type separation membrane A hollow fiber type plasma separation membrane is manufactured by spinning a spinning stock solution in which a polymer is dissolved in a mixed solvent of a solvent and a non-solvent into a coagulable solution consisting of a solvent, a non-solvent and water. After being discharged from a double-pipe nozzle together with the core liquid and running in the air, it was coagulated in a coagulation bath containing the same components as the core liquid, and then coagulated to form a film by dry-wet spinning. After washing this medium-spicy membrane with water,
The hollow fibers were subjected to hot water treatment at 121° C. in an autoclave, and then immersed in a 50% glycerin aqueous solution and dried to obtain a plasma separation membrane. The inner diameter of the hollow fiber was 280u, and the membrane thickness was 40u. The method for evaluating the PL performance of this plasma separation membrane is to modularize it using the usual urethane resin adhesion method, with a length of 20 cm and an effective membrane area of 0.2 mm. / form a plasma separation module. Using bovine blood containing ACD solution as an anticoagulant, plasma separation performance was evaluated while supplying bovine blood at 5 om&/-1n.
, LL, P, 1902-1910. (1985), Hakuju, Banno Sukei, Ikeda Fuyuki et al.'s reports, etc., used general evaluation methods.

The evaluation items are the maximum plasma separation rate Q F wax and the sieving coefficient of plasma fluorescent matter SC Total Protei.
It was set as n. Note that SCTotal Protein is defined by the following formula.

SCTotalProte1n='cll'cold'
-,.

Regarding hemolysis resistance, the transmembrane pressure difference (T
MP). i.e. O-) Plasma bone ti! measured colorimetrically with luidine! The TMP at which the difference in free hemoglobin concentration in the collected plasma was 3-g/(112 or more) with respect to the free hemoglobin concentration in the blood supplied to the device was determined.

Example 1 Polycarbonate resin (Mitsubishi Kasei Novarex) 20
1 ht part, N-methylpyrrolidone (NMP) as solvent
using a dope prepared by mixing and dissolving 72 parts by weight of
From a double pipe nozzle having a 5 IUI annular slit and an internal liquid supply hole, the liquid was discharged along with an internal liquid having a weight ratio of water/NMP/γ-butyrolactone of 35158.5/8.5, and the air travel was 2 cm. After that, the coagulated liquid with the same components as the internal liquid and the composition of 30/83/7 was passed through the nozzle draft 17.
After running the membrane in such a manner that the hollow fiber membrane was washed with water, a hollow fiber membrane having convex portions on the inner surface of the membrane was obtained. After this membrane was subjected to the above treatment, it was made into a module and evaluated.

Comparative Example 1 Polycarbonate resin (Noparex) 30 weight tjl1
parts, 63 parts by weight of N-methylpyrrolidone as a solvent, γ
- A hollow fiber membrane was prepared in the same manner as in Example 1 using a dope prepared by mixing and dissolving 7 parts by weight of butyrolactone.
No convex portions were formed on the inner surface. This membrane was also subjected to the same treatment as in Example 1, and after being made into a module, it was evaluated.

The following margins The plasma separation membrane of the present invention is TMP 300 nus
Even with Hg, no solution of 1 m was observed. On the other hand, in a comparative example in which no convex portions are formed on the inner surface of the hollow fiber membrane, TMP200
Melting +fn was observed below mmHg.

(Effects of the Invention) According to the present invention, it is possible to obtain an I'll serum separation membrane having excellent +, In serum separation performance and excellent hemolysis resistance.

[Brief explanation of drawings]

FIG. 1 is a diagram showing a semicircular convex portion existing on the inner surface of the hollow fiber membrane, and FIG. 2 is a diagram showing the height (H) of the convex portion and the interval (L) between the convex portions. . Patent m1 person Tokanbo Co., Ltd.

Claims (1)

[Scope of Claims] A hollow fiber plasma separation membrane, in which semicylindrical protrusions are formed on the inner surface of the separation membrane that comes into contact with blood, and the distance (L) between the protrusions is expressed by formula 1, A hollow fiber plasma separation membrane having improved hemolysis resistance and having convex portions on the inner surface of the hollow fiber membrane, characterized in that the height (H) is expressed by formula 2. 1μm≦L≦20μm...(1) 1μm≦H≦10μm...(2)