JPH01111404A - Hollow yarn-type membrane for blood plasma separation - Google Patents

Abstract

PURPOSE:To attain a membrane for blood plasma separation with excellent suitability to living bodies and low complement activity, by selecting a vinyl chloride resin as a hollow yarn membrane with a defined inner diameter and thickness. CONSTITUTION:A dope comprising a plastisizer-free vinyl chloride resin dissolved in a ternary soln. contg. solvents and non-solvents and an inner soln. contg. solvents and non-solvents are sprayed through a double-tube nozzle, introduced into a coagulation bath, and spun by dry/wet process to give a hollow yarn. Then, thus prepd. yarn is washed, treated with glycerin, and dried to obtain a hollow yarn-type membrane for blood plasma separation with inner diameter 150-450mum and thickness at 100mum.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a membrane that separates plasma from blood, and more specifically, it is used in medical fields such as plasma exchange therapy and plasma sampling to collect plasma from normal people. The present invention relates to a plasma separation membrane that is used for plasma separation.

(Prior art) The plasma separation method, which separates plasma from blood using a membrane, is used to treat intractable diseases such as fulminant hepatitis, chronic RYJ syndrome, systemic erythromatosus, and collagen disease. This technology was developed in Japanese Patent Application Laid-Open No. 1986-
This is already clear in JP-A No. 11065, JP-A-58-41883, and the like. In recent years, the demand for plasma preparations has increased dramatically due to advances in this type of plasma purification technology.In order to meet this demand, component blood donation (plasma collection), in which only plasma is collected, is currently being used as an alternative to conventional whole blood donation. ) has come to be carried out.

As described above, plasma separation membranes have now been applied to the point of collecting plasma from healthy people, so it has become necessary to further improve the safety of plasma collection methods. There are very high expectations regarding the biocompatibility of plasma membranes, which account for a large proportion of the human body.

In contrast, biocompatibility in the prior art field has centered on the requirement that there be no toxicity, etc., and no functional defects, as seen in artificial kidney standards. In addition to this, for plasma separation membranes, an important requirement for biocompatibility is not to damage blood cell components during plasma separation. Although these requirements are very important, they are only the minimum requirements that must be met.
Current expectations regarding biocompatibility have extended to the reaction of living organisms to plasma separation membranes and the interaction between living organisms and membranes.

It is well known that when a living body comes into contact with a membrane, the living body recognizes the membrane as a foreign substance, and a reaction based on some kind of interaction always occurs there. Good biocompatibility means that the degree of foreign body recognition reaction is slight. When artificial organs are used, the biological reactions that are particularly problematic can be roughly divided into (1) the coagulation system and (2) the immune system.

In the plasma separation method that is the object of the present invention, the coagulation system (1) is blocked by the use of an anticoagulant, and therefore, the biological reaction that becomes a problem during plasma separation is the immune system (2). Since plasma separation itself involves short-term extracorporeal circulation, its biocompatibility targets humoral immunity (complement activity) within the immune system (2).

(Problems to be Solved by the Invention) The purpose of the present invention is to suppress complement activation, which has been considered a problem during conventional hemodialysis and plasma separation. The present invention aims to provide plasma separation with superior biocompatibility by minimizing complement activation caused by living organisms during separation.

(Means for Solving the Invention) Complement activation generally depends on the chemical structure of the material, and in particular, the chemical structure includes many hydroxyl groups. It is known that cellulose and polyvinyl alcohol exhibit significantly large activation. For this reason, conventional methods such as chemical modification of membranes are currently being used (for example, University of Texas R.C., Eberhat
Trans A
n+ Sac Artlf Intern Organ
s vol 29P242-244 1983), but due to their novelty, more careful consideration will be given to their stability in the future.

In order to ensure maximum safety for blood donors, the researchers selected vinyl chloride resin, which is chemically stable and has a long track record in blood purification technology as a material for blood bags, etc., and developed a membrane structure. We conducted extensive research into ways to suppress complement activation without impairing its excellent blood compatibility by modifying it. As a result, the complement activation reaction, which is the main body of the humoral immune response in living organisms, is determined by the characteristics of the material forming the membrane, the contact area when plasma passes through the membrane surface, and the hydrodynamics when plasma passes through the membrane. It has been found that complement activation occurs immediately upon contact with a living body, and that the degree of complement activation is determined by all three factors, leading to the present invention.

That is, the present invention is a hollow fiber membrane made of vinyl chloride resin, which has an inner diameter of 150 to 450 μm and a membrane thickness of 100 μm or less, and is a plasma separation membrane with excellent biocompatibility.

As for the material, the present inventors selected vinyl chloride resin, which is a hydrophobic polymer and is stable. In view of this, the first point of the present invention is that unplasticized vinyl chloride is particularly used.

In other words, when vinyl chloride resins and chloride compounds containing plasticizers, which have been widely used for medical purposes up until now, are molded into membranes, plasticity that has an adverse effect on the human body is generated from the membrane surface. This is because we found that not only the agent elutes, but also the degree of complement activation is significant.

Therefore, although the present invention uses unplasticized vinyl chloride resin as a raw material, when this is then formed into a membrane, the thickness of the membrane must be kept as low as possible in order to keep the contact area with blood plasma low. I discovered that.

That is, if the film thickness exceeds 100 μm, it becomes extremely difficult to suppress complement activation.

However, due to its structure, plasma separation membranes have an average of about 0.
Very poro with pore radius around 0.05~0.5μm
Since the membrane itself is made of US, it tends to have structural disturbances and is actually weak in terms of strength. Therefore, from the viewpoint of mechanical properties, the membrane thickness of the plasma separation membrane should be as thick as possible. Desirably, therefore, realistically, the plasma separation membrane according to the present invention needs to have a thickness of 30 to 100 μm.

The most important point of the present invention is that the biocompatibility of the membrane surface is controlled by the hydrodynamics of membrane plasma separation.

In other words, the plasma separation membrane hydrodyna Ics is
It relates to how smoothly plasma flows through a membrane during plasma separation, and has traditionally been used when discussing membrane structure.
This is achieved by reducing the actor (curvature rate). As a result of extensive research into the complement activation mechanism, the present inventors found that the complement activation flow is c.
As is widely known in the lassical pathway, a certain amount of time is required for C1compv to develop, and complement activation only occurs when local stagnation occurs during the passage of plasma proteins. I found out what I could get.

Furthermore, membrane structure and hydrodynamics during plasma separation
As a result of further investigation between cs, that is, complement activation phenomenon,
The vinyl chloride resin we selected as the membrane material is generally formed by a melting method, but in the present invention, the largest Pa1nt of the present invention is to dissolve the vinyl chloride resin in a solvent and dry spin it using a double tube nozzle. Alternatively, wet spinning is used. When forming a membrane using this spinning method, a coagulating liquid is also used for the core liquid of the hollow fiber membrane, and as a result of coagulating from the inside and outside of the hollow fiber, the resulting continuous pore structure provides a good biological They found that compatibility was achieved and completed the present invention by forming a new PVC film.

That is, the most preferable membrane is a hollow fiber membrane of 100 .mu.m or less, preferably 30 to 100 .mu.m, prepared by dissolving a vinyl chloride resin containing no plasticizer in a solvent to prepare a spinning bath.

Moreover, the membrane structure obtained by the present invention not only has excellent biocompatibility in terms of complement activity, but also has excellent blood compatibility.
It also has the property of being less likely to cause hemolysis during plasma separation.

Hereinafter, the effects of the present invention will be explained with reference to Examples.
Prior to that, the evaluation method implemented in the present invention and its details will be explained.

The hollow fiber obtained according to the present invention was made into a module by the usual urethane welding method and had a length of 20 cm.

was molded into a plasma separation module with an effective membrane area of 0.2/ml.

The obtained plasma separation module contains ACD as an anticoagulant.
Bovine blood was added to 50 mff1/
A method for evaluating plasma separation performance was performed under conditions of min.

Evaluation methods include, for example, artificial organs 141902-1910 1
This is a general evaluation method as seen in reports by 985 Japanese Red Cross, Jokei Banno, Hiroyuki Ikeda, and others. Maximum plasma separation rate QP,
□, plasma protein sieving coefficient (Sieving Coe
(abbreviated as SC) SCTotal
It was conducted for protein.

Incidentally, SCTotal Protein refers to the total protein concentration in separated plasma.

The biocompatibility of the obtained plasma separation membrane was evaluated in terms of (I) complement activation and (2) blood compatibility (hemolysis).

(ri) Complement activation surface: Hollow fiber membrane 100c113 (membrane area in terms of inner diameter) was cut into small pieces, 1mff1 of gelatin veronal buffer solution was added, and after immersion, human total complement (Cord
ls If) was added to CH3 at 37℃ for 1 hour.
0 was measured to evaluate the degree of complement activation.

■ Hemolysis characteristics: Hemolysis was evaluated by monitoring the free hemoglobin concentration in plasma in plasma separation performance evaluation using bovine blood.

(Example) Example 1 An unplasticized vinyl chloride resin is dissolved in a ternary system of a solvent and a non-solvent to make Dope, and then a solvent and a non-solvent are used as the internal liquid.
Using a mixed solvent of solvent and water, discharge it from a double tube nozzle,
After taking a 1 cm llr gap, the fibers were introduced into a coagulation bath consisting of a solvent and non-solvent water to form hollow fibers, washed with water, treated with glycerin as a membrane structure retaining agent, dried, and formed into hollow fibers. A plasma separation membrane was obtained. Also, its inner diameter is 3
00 μm1 film thickness was 50 μm.

This plasma separation membrane was modularized by the method described above, and the results of evaluation are shown in Table 1.

Table-1 * Trans Membrane Pressur
e (Transmembrane pressure difference) Good results were obtained. In addition, in terms of complement activation, it was 32CH50, whereas the plasma separation membrane showed good biocompatibility with no significant difference from 29C)(50).

Comparative example 1 The inner diameter of the hollow fiber is 300 μm and the film thickness is 150 μm.
The film was formed under the same conditions as in Example 1, except that
Table 2 shows the results of evaluation using the same method as in Examples.

Table 2 Again, good results were obtained. This complement activation resulted in poor biocompatibility.

Comparative Example 2 Using cellulose acetate (CA) as the polymer, a membrane was formed in the same manner as in Example 1 to obtain a hollow fiber plasma separation membrane with an inner diameter of 300 μm and a membrane thickness of 50 μm, and the results were evaluated in the same manner as in Example. It is shown in Table 3.

Table 3 Again, good results were obtained. However, it exhibited complement activation and was significantly inferior in terms of biocompatibility.

(Effects of the Invention) According to the present invention, a hollow fiber plasma separation membrane having excellent plasma separation performance and low complement activity can be provided.

Patent applicant: Toyobo Co., Ltd.

Claims (2)

[Claims] (1) A plasma separation membrane with excellent biocompatibility, which is a hollow fiber membrane made of vinyl chloride resin and has an inner diameter of 150 to 450 μm or less and a membrane thickness of 100 μm. (2) The plasma separation membrane according to claim 1, wherein the hollow fiber membrane made of vinyl chloride resin is formed by a dry-wet method.