JPH03173571A - Hollow yarn type plasma separating film - Google Patents

Abstract

PURPOSE:To obtain excellent living body adaptability and high plasma permeating performance by using a hollow yarn type plasma separating film formed of one or two kinds or more of specified polycarbonates. CONSTITUTION:A hollow yarn plasma separating film used in the separation of plasma from blood is formed of one, or two or more of polycarbonates represented by the formula (I), (II), or (II). The average pore diameter present in the surface and inner part of the hollow yarn film is 0.075-0.3mum, the mercury press-fit quantity ratio (K) determined by the mercury press-fit method represented by the formula (IV) is 0.05 or less, and the porosity is 0.4 to 0.8. In the formulae, R1 and R2 are selected from the radials of H, CH3, C2H5, C3H7, C6H12 and C6H5, X from H, F, Cl and Br, and Y from O, SO2 and CO2.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a hollow fiber plasma separation membrane that separates plasma that does not contain blood cell components from blood. The present invention relates to a hollow fiber plasma separation membrane with excellent biocompatibility that can be used for blood collection (donor plasmapheresis) and plasma exchange therapy applied to patients with autoimmune diseases.

(Prior Art) Recent improvements in analysis technology have made it possible to expand and investigate the response of living organisms to foreign substances to the molecular level. As a result, detailed studies are underway on biocompatibility, particularly biocompatibility with blood. In particular, research is progressing on hemodialysis membranes for artificial kidneys, and the reaction when they come into contact with blood has been studied in detail. According to this, reactions in living organisms are triggered by contact with membranes that are foreign to the living body, and various reactions occur due to the interaction between proteins and cells in the blood and membranes. This reaction can be broadly divided into 1) blood coagulation system reaction and 2) immune system reaction. However, in plasma separation, anticoagulants are used to block the coagulation system reaction (■), and the reaction is relatively short (30 minutes to 2 hours), so it is one of the short-term reactions of the immune system (■). The problem is the activation of complement, which is a reaction. The complement system reaction recognizes and attacks foreign substances at the earliest stage of the immune system reaction, and originally functions as a defense system against bacteria that have invaded the body. However, this activation of complement causes anaphylatoxin shock and other unfavorable effects on the living body, so a membrane with low complement activation is desired as a plasma separation membrane. Complement activation is greatly influenced by the physical and chemical properties of the membrane surface. It is known that materials that are less susceptible to complement activation include hydrophobic surface characteristics and the absence of polar groups such as OH groups, NH groups, and SH groups. Known examples of such materials include polycarbonate, polyethylene, polyvinyl chloride, polyether sulfone, and the like. However, it is not possible to obtain a plasma separation membrane with completely low complement activity using membrane materials alone.

In other words, the fine structure of the membrane influences complement activation. When plasma passes through the pores of a plasma separation membrane, the complement system proteins in the plasma come into contact with the membrane material, and the larger the contact area at this time, the greater the opportunity for complement activation. No matter how low complement activation the material is,
There was a problem that complement in the filtered plasma was activated.

Regarding polycarbonate membranes, there is a technology (Japanese Patent Publication No. 53-15549) related to flat membranes for filtration of industrial water in the food industry, pharmaceutical industry, etc. The technology used for plasma separation as a D\°゛I hollow fiber membrane is do not have.

There is also a technology that uses hollow fiber membranes made from polyether polycarbonate for plasma separation (Japanese Patent Laid-Open No. 57-5
No. 2481, JP-A No. 59-22559) do not have sufficient complement activation suppressing effects. Regarding polycarbonate membranes, there is a technology for flat membranes for filtration of industrial water in the food and pharmaceutical industries (Japanese Patent Publication No. 15549/1983), but no technology has been found for applying hollow fiber membranes to plasma separation.

(Problems to be Solved by the Invention) One object of the present invention is to provide a hollow fiber plasma separation membrane that is biocompatible, in particular has low complement activation, and has an appropriate plasma separation rate. In the conventional plasma separation group, an attempt is made to provide a plasma-based plasma separation membrane that separates blood from blood by filtration.

(Means for Solving the Problems) In order to solve the above problems, as a result of intensive research, the present invention has been completed. That is, a hollow fiber plasma separation membrane composed of one or more polycarbonates having the following general formula (I), (n), or (III) that separates plasma from blood, the hollow fiber membrane The pore radius existing on the surface and inside of is 0.075-0.31U,', -
Tosusenji The mercury intrusion amount ratio (K) determined by the mercury intrusion method shown by the following formula (IV) is 0.05 or less, and the porosity is 0.4 or more and 0.8 or less. Hollow fiber plasma separation membrane.

J is selected from the same SO2 and CO□.

The polycarbonate of the present invention has the general formula (I), (n
) or (III), in which R,, R2 is CH
3. Polycarbonates in which X is H are preferred. The molecular weight is 15,000 to 40,000, and if it is less than 15,000, it is difficult to spin into a hollow fiber membrane (III) The hollow fiber membrane of the present invention is porous, and the average pore radius existing on the inner surface and surface of the membrane is 0.075 to 0-3 /jJ
s is preferably 0.1 to 0.25u.

The meaning of being below is that it increases the contact area with plasma proteins, and in these pores, plasma proteins are more likely to interact with each other due to flow, protein adsorption, etc., and complement is activated. easy to become That is, from the viewpoint of biocompatibility, it is necessary to minimize the area with a pore radius of 0.051 U or less, and to make the ratio of the pore volume to the total pore volume 0.05 or less. The porosity is a measure of the filtration characteristics of a membrane, and if the porosity is less than 0.4, the filtration rate is too low to be used in practice. Further, if the porosity is 0.8 or more, the membrane strength becomes weak and problems such as leakage occur. As a material, polycarbonate is suitable because it has excellent biocompatibility and can be spun into a membrane using a phase separation method suitable for controlling pore size distribution.

The pore size distribution of the hollow fiber membrane was measured using the mercury intrusion method. If a membrane pore retaining agent such as glycerin is attached to the sample, the attached material is removed by washing with water, water is removed by freeze drying or vacuum drying, and the sample is completely dried. A sample of a certain weight is taken and the pore system distribution is measured by mercury intrusion. This pressure and the amount of mercury injected were plotted to determine the pore size distribution. The relationship between the pressure and hole radius at this time was expressed by the following equation.

R=2TCO8θ/P P: Pressure (kg/c!) T: Surface tension of mercury (480dyn/C11i) θ: Contact angle of mercury (140°C) R: Pore radius (c-) The measured pressure range is: 1 kg/cii! From 20
00 kg/d, and the ratio of the pore volume of 0.05- or less to the total pore volume is the amount of mercury injected from a pressure of 150 kg/ctft to a pressure of 2000 kg/c+lt divided by the total amount of mercury injected. did. The porosity was calculated using the following formula from the total mercury intrusion amount and the sample weight.

ε=v/(v+w/p) ε: Porosity (-) v: Total mercury intrusion amount (cIll) W: Sample weight (g) p: Polymer density (g/ad) Such pore distribution characteristics In order to form a membrane by spinning, the spinning stock solution (dope) and coagulation conditions must be set so that uniform polymer particles are formed when the polymer coagulates.
There is a point. With doped composition, polycarbonate (PC) i
i11 degrees should be between 18% and 25%.

That is, in PC, since the dope viscosity is extremely low, PC7! If C is less than 16%, the strength of the hollow fiber is weak;
It cannot be spun into a hollow fiber membrane. Also, from 15% to 1
Between 8% and 8%, minute pores are likely to be formed and the requirements of the present invention are not met. On the other hand, if it exceeds 25%, the filtration rate will be extremely low and it will not be practical as a plasma separation membrane. The solvent used is a mixed solvent system consisting of a good solvent that has good solubility with PC and a poor solvent that has somewhat low solubility. The solvent used in the mixed solvent system is preferably an aprotic polar solvent with a boiling point of 150° C. or higher. Examples of such solvents include good solvents such as N-methyl-2-pyrrolidone (NMP) and dimethylacetamide (DMAC), and poor solvents such as 2-pyrrolidone (2-PN) and γ-butyrolactone ( GBL), N,N-dimethylformamide (D
MF) There is. The solubility parameters of these solvents are 10 (cal/(i)”2~! 12 (cal
/CIfl)”2 preferably 11 (cal/cIll
)'' to 12 (cal/cil)''2.The reason for this solubility parameter is that if it is less than 10, it will have good solubility with PC, but there will be no formation of polymer particles and porous If it is 12 or more, the solubility will be poor, and even if it is dissolved, the strength of the coagulated polymer will be very weak (spinning film cannot be formed.Solubility in mixed solvent system The value of the parameter is the solubility parameter of the mixed solvent δmix, where the solubility parameter of solvent 1 is δ□, the solubility parameter of solvent 2 is 62, the volume fraction of solvent 1 is φ1, and the volume fraction of solvent 2 is φ2. can be calculated as δmlX = φ1·δ1+φ2·δ2.The volume fraction was determined from the molar fraction X(−) and the molecular volume V(c1il/1DQ).

φ,=x,−V,/Σx,−V.

Solubility parameter values were determined by Barton, A.F.
M.

Chemical Reviews -Lj-(8)
731 (1975) was used. Furthermore, as a coagulation condition during spinning and film formation, 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. ,
During the coagulation bath temperature (T2), 0≦(T1-T2)
It is necessary to satisfy the relationships of ≦50 ('CL) and T2≦50 (''C), and the concentration of water in the coagulable core liquid and the concentration of water in the coagulation bath must both be 50% or less. By doing so, the formation of polymer particles is progressed by slow twisting, and a hollow fiber membrane that satisfies the requirements of the present invention can be obtained.

(Example) Manufacturing method and evaluation measurement method of hollow fiber plasma separation membrane After coagulating the hollow fiber plasma separation membrane by the method described above,
The membrane was washed with water, subjected to hot water treatment at 121° C. in an autoclave, and further immersed in a 50% aqueous glycerin solution and dried to obtain a hollow fiber plasma separation membrane. The inner diameter of the hollow fiber is 2
The 80pJ1 film thickness was 140pxp. The method for evaluating the performance of this plasma separation membrane is to modularize it using a conventional urethane resin adhesion method to form a plasma separation module with a length of 20 cm and an effective membrane area of 0.2 cm. Using fresh bovine blood to which ACD solution was added as an anticoagulant, 50 m (!/w) of bovine blood was used.
The plasma separation performance is evaluated while being supplied in the blood, and the method is described, for example, in Artificial Organs, 14.1902-1910, (
1985), the Japan Red Cross, Jokei Banno, Hiroyuki Ikeda, et al., a general evaluation method was used.

The evaluation items were the maximum plasma filtration rate Q f wax and the plasma protein sieving coefficient S Ctotal-pr. te＋□
And so.

In addition, 5Cto□1-9r. te+. is defined by the following formula.

S Ctotal-protein = (total protein concentration in separated plasma) / (total protein concentration in supplied blood) Biocompatibility was evaluated using fresh human blood with ACD solution added as an anticoagulant. The membrane area of the module was as small as 0.0211Il' (1/10 scale of live blood evaluation). Activation of complement in filtered plasma is due to the activation of C3, one of the complement components. , activated form C
This was done by measuring the concentration of 3a. C3,1 degree was measured by radioimmunoassay method.

Example 1 Polycarbonate resin (R, , R in general formula (I)
2 is CH3,
(cat/c1il)"") 70, 2 parts by weight, and γ-butyrolactone (GBL) (solubility parameter 12
．． 9 (cal/c1i1)"") 7.8 parts by weight of mixed solvent (solubility parameters 11, 4 (cal/c1
il) ""), temperature controlled at 60°C, and discharged from a double pipe nozzle together with a coagulable core liquid having a composition of water/NMP/GBL = 50/4515, and the air travel was 2 Cm. After that, the temperature was controlled at 10℃.
It was coagulated in a coagulation bath having a composition of water/NMP/GBL=35158.5/6.5, and subjected to the water washing, autoclave treatment (121° C.) and glycerin treatment to obtain the hollow fiber membrane shown in Table 1. After modularization, evaluation was performed.

Example 2 20 parts by weight of the same polycarbonate resin (Mitsubishi Kasei Tubarex, Mw, approximately 30,000) as in Example 1 was added to N
72 parts by weight of MP and N,N-dimethylformamide (DM
FH solubility harameter 12.1 (callod)””
) 8 parts by weight of mixed solvent (Solubility Harameter 11,
3 (cat/c1il)""), e o'
Water/NMP/DMF=40 with temperature control at c.
Water/N MP/DMF = 35 was discharged from a double pipe nozzle together with a coagulable core liquid having a composition of 154/8, and after traveling in the air for 2 cm, the temperature was controlled at 10 ° C.
It was coagulated in a coagulation bath having a composition of 158.5/8.5, subjected to the above treatment, and after being made into a module, it was evaluated.

Example 3 30 parts by weight of the same polycarbonate resin (Mitsubishi Kasei Tuvalex, molecular weight 22,000) as in Example 1 was added to NMP.
It was dissolved in a mixed solvent of 63 parts by weight and 7 parts by weight of GBL, and evaluated in the same manner as in Example 1.

Comparative Example 1 One part of the same 15 weight polycarbonate resin (Mitsubishi Kasei Tuvalex, Mw, approximately 30,000) as in Example 1 was added to NMP.
Comparative Example 2 A commercially available cellulose triacetate hollow fiber membrane was similarly evaluated and compared.

As shown in Table 1, the hollow fiber plasma separation membrane of the present invention is
The activation of C3 was small (it had excellent biocompatibility, and in terms of performance, it had a high plasma filtration rate and plasma protein permeation performance.

Margins below (Effects of the Invention) According to the present invention, it is possible to provide a hollow fiber plasma separation membrane having excellent biocompatibility and high plasma source permeability.

Claims (1)

[Claims] One or two polycarbonates having the following general formula (I), (II) or (III) for separating plasma from blood.
A hollow fiber plasma separation membrane composed of at least 1 species, wherein the average pore radius existing on the surface and inside of the hollow fiber membrane is 0.0.
75 to 0.3 μm, and the mercury intrusion amount ratio (K) determined by the mercury intrusion method shown by the following formula (IV) is 0.0
5 or less and a porosity of 0.4 or more and 0.8 or less. ▲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 and CO_2. ] K=Amount of mercury intrusion at a pressure of 150 to 2000 kg/cm^2/Amount of mercury intrusion at a pressure of 1 to 2000 kg/cm^2 (IV)