JPH03173572A - Porous hollow yarn film for plasma separation - Google Patents

Abstract

PURPOSE:To provide a porous hollow yarn type plasma separating film excellent in living body adaptability which has a rapid plasma permeating rate and can suppress the activation of a complement by making a hollow yarn film formed of a specified polycarbonate have macrovoids of specified diameters in a specified ratio to the film sectional area. CONSTITUTION:A plasma separating porous hollow thread film used at the time of separating a plasma from a blood is formed of one or two or more of polycarbonates represented by the formula (I), (II), or (III), and the film thickness is 10-100mum. In the hollow yarn film, macrovoids of 0.5-30mum in diameter are present in 5-70% to the film sectional area. In the formulae, R1 and R2 are selected from the radials of H, CH3, C2H5, C3H7, C6H12 and C6H5, K from H, F, Cl and Br, and Y from O, SO2, and CO2.

Description

[Detailed Description of the Invention] (Industrial Application Field) This invention relates to a plasma separation membrane that separates plasma from blood, and more specifically to blood exchange therapy and plasma collection for collecting plasma from healthy individuals. The present invention relates to plasma separation membranes used in the medical field.

(Prior art) Plasma separation, which separates plasma from blood using a membrane, was developed with the aim of medical treatment such as plasma exchange therapy, which aims to remove pathogenic substances and malignant substances from plasma. It is what was done. However, in recent years, the demand for plasma preparations has increased dramatically, and as an alternative to conventional whole blood donation, component blood donation (plasma collection) in which only plasma is collected has come to be performed. The plasma fraction jiI membrane used for component blood donation is used for healthy individuals, and safety in plasma collection has become very important. In particular, requirements regarding the biocompatibility of plasma separation membranes, which play a central role in plasma separation methods, have become extremely strict.

Conventionally, cellulose-based membranes widely used as blood purification membranes are known to activate complement components in the blood when they come into contact with the membrane, triggering an immune system response. Furthermore, polyolefin membranes, which are said to have relatively good biocompatibility, are difficult to form using a phase separation method, and the pores are formed by a stretching method. The problem is that it has a slat-like shape, and if blood cells become trapped in the pores, it tends to cause hemolysis.

Separation membranes using polysulfone have relatively good plasma separation properties due to their finger-like structure, but their biocompatibility as a material is not sufficient, and
Since the wall surface of the finger-like pore has considerable irregularities, the contact area with separated plasma components is extremely large, which tends to be a factor that promotes complement activation.

Regarding polycarbonate membranes, there is a technology for using them as flat membranes in industrial water treatment (Japanese Patent Publication No. 15549/1983), but there is no example of their use as hollow fibers for plasma separation. Technology using polyether polycarbonate hollow fiber membranes for plasma separation (JP-A-57-52461, JP-A-5
9-22559), but the effect of suppressing complement activity is not sufficient.

In this way, at present, the physiological relationship between blood components and separation membranes,
In addition, even a high level of biocompatibility related to physical interaction has come to be required.

It is known that when a living body and a plasma separation membrane come into contact, the living body recognizes the plasma separation membrane as a foreign substance to itself, and a reaction is caused based on some kind of interaction.

Biocompatibility means that the degree of such foreign body recognition reaction is slight. Particular problems that arise when artificial organs are used can be broadly divided into the blood coagulation system and the immune system.

In plasma separation, the reaction of the coagulation system is inhibited by the use of an anticoagulant, so that only the reaction of the immune system is a problem in terms of biocompatibility. Since plasma separation itself involves short-term extracorporeal circulation, complement activity is particularly problematic for the immune system.

In other words, in order to improve the biocompatibility of a plasma separation membrane, it is necessary to suppress this complement activity.

(Problems to be Solved by the Invention) An object of the present invention is to provide a porous hollow fiber plasma separation membrane that has a high plasma permeation rate, suppresses complement activation, and has excellent biocompatibility.

(Means for Solving the Problems) As a result of intensive research to provide an excellent plasma separation membrane that solves the above-mentioned problems, the present invention has been achieved. That is, the present invention provides: (1) The following general formula (I) for separating plasma from blood.

A porous hollow fiber membrane with a membrane thickness of 10 to 100 u made of one or more polycarbonates having (n) or (III), the hollow fiber membrane has a macroscopic membrane with a diameter of 0.5 to 30 IU. A porous hollow fiber membrane for plasma separation, characterized in that voids exist in an amount of 5 to 70% of the cross-sectional area of the membrane.

(III) ■ The porous intermediate fiber membrane for plasma separation according to claim 1, wherein the hollow fiber membrane has pores with a diameter of 0.5 to 30μ in the outermost layer and the innermost layer of the hollow fiber.
There are macrovoid layers m4 and m2 containing m macrovoids, and the thickness of both layers m+ +m2 is 30% of the film thickness.
This is a porous hollow fiber membrane for blood stain separation characterized by the above characteristics.

The polycarbonate of the present invention has the general formula (I), (If
) or (III), in which R11R2 is CH
3, X or H polycarbonate is preferred. Molecular weight is 15,000 to 40,000, preferably 20,000 to 30
000, if it is less than 15,000, it is difficult to spin into a hollow fiber membrane, and if it is more than 40,000, it is impossible to form a porous membrane with an appropriate pore size.

The hollow fiber membrane of the present invention has a thickness of 10 to 100 pm, preferably 20 to 60 pm. If the membrane thickness is less than 10u, the fiber strength as a hollow fiber is insufficient, and problems remain in handling such as modularization.If the membrane thickness is greater than 100pJ, the resistance when plasma permeates becomes large, and other requirements are met. It is difficult to create a plasma separation membrane in which complement activation is suppressed even when the membrane is filled with this condition.

The term "macrovoid" as used in the present invention refers to a cavity existing inside the membrane, and the cavity has a diameter of 0.5 to 30u, and the total area of the air conditioning part is preferably 5 to 70% of the cross-sectional area of the membrane. is 10 to 50%, more preferably 20 to 40%. If the diameter of the macrovoid is less than 0.5% and the area ratio is less than 10%, the permeation of plasma will be slow and the frequency of contact will be increased, making it difficult for plasma proteins to flow in this macrovoid region. Interaction is likely to occur due to adsorption, etc., and complement activation is likely to occur.

If the size of the macrovoids is 30% or more and the area ratio is 70% or more, the shape retention as a support layer will be insufficient, and problems will arise in terms of maintaining the film strength.

In the plasma separation membrane of the present invention, it is further preferable that the inner wall surface of the macrovoid present in the membrane is smooth. Macrovoids with uneven parts inhibit the passage of plasma,
Plasma proteins become difficult to flow, and as mentioned above, complement activity is insufficiently suppressed.

Here, the macrovoid wall surface being smooth means that there are no irregularities as shown in FIG. 2 of the drawing.

In addition, the thickness of the macrovoid layer present in the outermost layer and the innermost layer of the hollow fiber membrane, m l + m 2, is 30% or more of the total membrane thickness, and if it is less than 30%, the shape retention as a support layer is poor. It is insufficient and the membrane strength maintenance property is unsatisfactory.

Among the macrovoid layers, the macrovoid layer on the inner surface side of the hollow fiber (indicated by ■ in Figure 1) has an opening with a pore diameter of 0.15 to 0.5 μm facing the hollow portion of the hollow fiber membrane (in the position indicated in ■ in Figure 1). It has the function of separating blood cells and plasma.

Depending on the film formation conditions, a homogeneous layer having a smaller pore diameter than the macrovoids may exist between the macrovoid layers.

The size and area ratio of the macrovoids were determined by image analysis based on electron micrographs.

The hollow fiber membrane having the structure of the present invention has a dope composition of 15 to 30% of the silica polymer. If it is less than 15%, no pores will be formed, or even if they are formed, minute pores will be likely to be formed, and the fiber strength as a hollow fiber will be reduced. On the other hand, if it exceeds 30%, the blood filtration rate becomes extremely small.

The polymer solvent used is a mixed solvent of a good solvent with excellent solubility of polycarbonate and a poor solvent with low solubility. The solvent used is an aprotic polar solvent with a boiling point of 150°C or higher, and N-methyl-2-pyrrolidone (NMP) is a good solvent.
), dimethylacetamide (DMAC), poor solvents such as 2-pyrrolidone (2-PN), γ-butyrolactone (GBL), dimethylformamide (DMF), and polyalkylene glycol (PAG).

The coagulation conditions during spinning and membrane production are as follows: This dope is discharged from a double pipe nozzle together with a coagulable core liquid, allowed to travel in the air, and then coagulated in a coagulation bath. It is preferable to use a mixed system of. The coagulation bath temperature (T2) is a maximum of 70°C, and the relationship with the nozzle temperature (T1) is O≦T, -T2≦70°C, and the concentration of water in the coagulating core liquid and water in the coagulating bath is are both below 60%.

After spinning and coagulation, the formation of polymer particles is advanced by washing with water and wet heat treatment at 100 to 130°C (autoclave treatment is preferred), followed by immersion in a 50% glycerin aqueous solution and drying to form a porous hollow fiber type. Obtain a plasma separation membrane.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but first, a method for evaluating plasma separation membranes carried out in Examples and Comparative Examples will be explained.

The hollow fiber membrane is modularized by a conventional urethane resin bonding method to form a plasma separation module with a length of 20 cm and an effective membrane area of 0.2I. Using bovine blood to which ACD solution was added as an anticoagulant, plasma separation performance was evaluated while supplying bovine blood at 50-/1n. The evaluation method is, for example, artificial organ kl, P.

1902-1910, (1985) The general evaluation method taught in the reports of the Japan Red Cross, Jokei Banno, Hiroyuki Ikeda, etc. was used.

The evaluation items were the maximum plasma separation rate Q f , and the plasma protein sieving coefficient sc to□1-21°tei
It was set as n. SCtotal-protein is defined by the following formula.

Regarding biocompatibility, ■complement activation and
■Blood compatibility (hemolysis) was evaluated as follows.

■ Complement activation hollow fiber membrane 100c111 (membrane area in terms of inner diameter) was cut into thin pieces, gelatin veronal buffer 1- was added and immersed, and then human whole complement (manufactured by Cordis Inc.) was added for 37 hours. Incubate for 1 hour at °C. After that May
Serum complement value CH30 is measured by the ar method to evaluate the degree of complement activation.

■ In evaluating plasma separability using hemolyzed bovine blood, hemolysis is evaluated by monitoring the free hemoglobin concentration in plasma.

The presence of macrovoids was investigated by observing the cross section of the membrane using a microscope. The figure shows optical and electron micrographs of a cross section of the membrane.

Examples and comparative examples will be described below.

Examples 1 to 4 Polycarbonate resin in which X in formula (I) is H, R, and R2 is CH3 (Tubarex manufactured by Mitsubishi Kasei, MW2
2000), and using the polymer solvent, internal liquid, and coagulation bath as shown in Table 1, the internal liquid was passed through a double tube nozzle having an annular slit with an outer diameter of 11 mm and a width of 95 μm, and an internal liquid supply hole. After being discharged and running in the air for 20 minutes, it was run in a coagulation tank, washed with water, and autoclaved at 121°C to form a hollow fiber membrane.

This membrane was treated with glycerin to obtain a hollow fiber membrane for plasma separation.

The hollow fiber membranes each had an inner diameter of 280 u, and the membrane thicknesses are shown in Table 2. This membrane was modularized and plasma filtration rate and complement activation were evaluated. The results are shown in Table 2.

For complement activation, serum complement activation was evaluated in a blank case after incubation for 1 hour at 37° C. in gelatin veronal buffer without the presence of hollow fiber membranes. As a result, CH30 was 32.0 Comparative Examples 1 to 2 Using the same polycarbonate as in the example, spinning was carried out in the same manner as in the example using the polymer solvent, internal solution, coagulation bath, and coagulation conditions shown in Table 1. A hollow fiber membrane shown in Table 2 was obtained.

A hollow fiber membrane for plasma separation was modularized using the same method as in the example, and plasma filtration rate and complement activation were evaluated. The results are shown in Table 2.

Margins below (Effects of the Invention) According to the present invention, it is possible to provide a porous hollow fiber plasma separation membrane with suppressed complement activity, excellent biocompatibility, and high plasma filtration performance.

[Brief explanation of the drawing]

FIG. 1 is an overall cross-sectional photograph of the porous hollow fiber membrane of the present invention. FIG. 2 is a drawing obtained by tracing the photograph of FIG. 1 for explaining each part of FIG. 1. FIGS. 3 and 4 are partial electron micrographs of a cross section of a hollow fiber membrane, showing macrovoids. Figure 5 is the photo of Figure 3, and the 6th
The figure is a trace drawing for explanation based on FIG. 4. In the drawings, 1 is the innermost surface of the hollow fiber membrane, 2 is the macrovoid layer 3 on the inside of the hollow membrane, is a homogeneous layer 4 is the macrovoid layer 5 on the outside of the hollow fiber membrane, and macrovoid 6 is the hollow part of the hollow fiber membrane. shows. Quick map Figure 8

Claims (2)

[Claims] (1) The following general formula (I) for separating plasma from blood, (
A porous hollow fiber membrane having a thickness of 10 to 100 μm and composed of one or more polycarbonates having II) or (III), the hollow fiber membrane having macrovoids with a diameter of 0.5 to 30 μm. 1. A porous hollow fiber membrane for plasma separation, characterized in that 5 to 70% of the cross-sectional area of the membrane is present. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [Here, R_1, R_2 are H, CH_3, C_2H_5
, C_3H_7, C_6H_1_2, C_6H_5, X is H, F, Cl, Br, Y is O,
Selected from SO_2, CO_2] (2) The porous intermediate fiber membrane for plasma separation according to claim 1, wherein the hollow fiber membrane has pores having a diameter of 0.5 to 30 in the outermost layer and the innermost layer of the hollow fiber.
Macrovoid layers m_1 and m containing μm macrovoids
A porous hollow fiber membrane for plasma separation, characterized in that _2 exists, and the thickness of both layers (m_1+m_2) is 30% or more of the membrane thickness.