Hollow fiber membrane and plasma separation method

Abstract

A hollow fiber membrane containing a polyethersulfone, the hollow fiber membrane having a non-uniform structure in the thickness direction, and the inclination index, which is the ratio of the average pore diameter on the inner surface side to the average pore diameter on the outer surface side in the cross section of the hollow fiber membrane, being 2.00 or more.

Description

Technical Field

[0001] The invention relates to a hollow fiber membrane and a plasma separation method. Background Art

[0002] In recent years, equipment for apheresis treatment has been developed that uses dialysis, filtration, adsorption, etc. to remove pathogenic substances and excess water from the patient's blood or body fluid and return them to the patient's body. In particular, plasma exchange therapy is known, which uses hollow fiber membranes to separate blood into blood cells, platelets, etc. and plasma for patients with liver failure, blood diseases, autoimmune diseases, etc., discards plasma containing pathogenic substances (IgG, cytokines, etc.), and replaces it with fresh frozen plasma, etc.

[0003] For example, Patent Document 1 (Japanese Patent No. 5290168) and Patent Document 2 (International Publication No. 2020 / 203716) disclose hollow fiber membranes (e.g., hollow fiber membranes made of polyethersulfone) used for separation of plasma from blood (plasma separation) as described above. It should be noted that polyethylene and the like are known as other materials suitable for hollow fiber membranes used in plasma separation and the like.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent No. 5290168

[0007] Patent Document 2: International Publication No. 2020 / 203716 Summary of the invention

[0008] Problems to be solved by the invention

[0009] When such a hollow fiber membrane (hollow fiber membrane made of polyethersulfone) is used to perform plasma separation, clogging of the hollow fiber membrane is likely to occur. Therefore, it is desired to provide a hollow fiber membrane which can suppress the occurrence of clogging and can be used continuously and stably.

[0010] Therefore, an object of the present invention is to suppress the occurrence of clogging of a hollow fiber membrane when performing plasma separation using the hollow fiber membrane.

[0011] Means for solving problems

[0012] (1) A hollow fiber membrane comprising polyethersulfone, wherein

[0013] The hollow fiber membrane has a non-uniform structure in the thickness direction.

[0014] The ratio of the average pore size on the inner surface side of the cross section of the hollow fiber membrane to the average pore size on the outer surface side, that is, the tilt index is 2.00 or more.

[0015] (2) The hollow fiber membrane according to (1), wherein a pore mode diameter in a cross section of the hollow fiber membrane is 0.090 μm or more.

[0016] (3) The hollow fiber membrane according to (1) or (2), further comprising a vinyl pyrrolidone-based polymer.

[0017] (4) The hollow fiber membrane according to any one of (1) to (3), which is used for plasma separation.

[0018] (5) A method for separating plasma using the hollow fiber membrane according to any one of (1) to (4).

[0019] Effects of the Invention

[0020] According to the present invention, when plasma separation is performed using a hollow fiber membrane made of polyethersulfone, the occurrence of clogging of the hollow fiber membrane can be suppressed. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a schematic diagram for explaining an example of a method for producing a hollow fiber membrane.

[0022] Figure 2 is a schematic diagram for explaining depth filtration.

[0023] Figure 3 This is a diagram for explaining surface filtration (screen filtration).

[0024] Figure 4 These are SEM images of a cross section (a) of the hollow fiber membrane of Example 1, an inner surface side (b) of (a), and an outer surface side (c) of (a).

[0025] Figure 5 This is a SEM image of a cross section of a hollow fiber membrane of Plasmaflo (reference).

[0026] Figure 6 This is a SEM image of a cross section of the hollow fiber membrane of Comparative Example 1.

[0027] Figure 7 This is a graph for explaining the method of measuring the most frequent pore diameter.

[0028] Figure 8 is a schematic diagram of a ring-shaped micromodule. DETAILED DESCRIPTION

[0029] Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to these embodiments.

[0030] <Hollow fiber membrane>

[0031] (Polyethersulfone)

[0032] The hollow fiber membrane of this embodiment contains polyethersulfone. The ratio of polyethersulfone in the material constituting the hollow fiber membrane is preferably 90 mass % or more, more preferably 93 mass % or more, and further preferably 95 mass % or more. The hollow fiber membrane may be composed only of polyethersulfone.

[0033] Polyethersulfone is a compound containing a structural unit represented by the following formula (1).

[0034] [Chemical formula 1]

[0035]

[0036] Examples of polyethersulfone include Ultrason (registered trademark) E2020P and E6020P manufactured by BASF or SUMIKAEXCEL (registered trademark) 3600P, 4100P, 4800P, 5200P, and 7600P manufactured by Sumitomo Chemical Co., Ltd., and preferably E6020P, 4800P, or 5200P. These may be used alone or in combination.

[0037] (Vinyl pyrrolidone polymer)

[0038] The hollow fiber membrane of the present embodiment may further contain a vinyl pyrrolidone polymer. The vinyl pyrrolidone polymer can suppress the adsorption of components in the blood such as platelets and proteins to the hollow fiber membrane.

[0039] The vinyl pyrrolidone-based polymer refers to a polymer containing at least a monomer of N-vinyl pyrrolidone.

[0040] The vinyl pyrrolidone polymer preferably contains a structural unit represented by the following formula (2). Examples of the vinyl pyrrolidone polymer include Kollidon (registered trademark) 30, 90 or Luvitec (registered trademark) K30, K80, K85, K90, and VA64 sold by BASF. These may be used alone or in combination.

[0041] [Chemical formula 2]

[0042]

[0043] The content of the vinyl pyrrolidone polymer in the entire hollow fiber membrane is preferably 1 to 10% by mass, and more preferably 1.5 to 5% by mass.

[0044] (Structure of hollow fiber membrane, etc.)

[0045] The hollow fiber membrane of this embodiment has a non-uniform structure in the thickness direction (asymmetric structure). It should be noted that examples of hollow fiber membranes having an asymmetric structure include hollow fiber membranes having density, porosity, cross-sectional opening ratio, etc. that are different in the thickness direction.

[0046] In the hollow fiber membrane having an asymmetric structure of the present embodiment, the average pore size on the inner surface side of the cross section (cross section: cross section in the thickness direction) is larger than the average pore size on the outer surface side. The hollow fiber membrane of the present embodiment has a structure in which the inner surface side is sparse and the outer surface side is dense.

[0047] In this embodiment, the tilt index of the hollow fiber membrane is greater than 2.00. The tilt index refers to the ratio of the average pore size on the inner surface side of the cross section of the hollow fiber membrane to the average pore size on the outer surface side. It should be noted that the average pore size and the tilt index can be measured using the method described in the embodiments described below.

[0048] Reference Figure 2 In the case of plasma separation using the hollow fiber membrane 3, the plasma in the blood is separated from the extrusion side ( Figure 2 The upper side: the inner surface side of the hollow fiber membrane) passes through the hollow fiber membrane 3. Among the components contained in the plasma (albumin, fibrinogen, or IgG or IgM of autoimmune antibodies, cytokines that can be pathogenic substances, etc.), smaller components 51 and 52 (cytokines, etc.) easily pass through the pores of the hollow fiber membrane, but larger components 4 (IgG, IgM, etc.) sometimes block the pores of the hollow fiber membrane. Here, Figure 2 As shown, in filtration (depth filtration) using the hollow fiber membrane 3 having an asymmetric structure, the components 4 with large molecular weight are dispersed and attached in the thickness direction of the hollow fiber membrane 3 (clogging occurs sequentially in the membrane thickness direction). Therefore, clogging is less likely to occur.

[0049] On the other hand, Figure 3 As shown, when filtration (surface filtration: mesh filtration) is performed using a hollow fiber membrane 3 having a uniform structure in the thickness direction, components 4 with large molecular weights contained in the plasma tend to aggregate and accumulate on the extrusion side of the hollow fiber membrane 3 ( Figure 3 The upper side: the inner surface side of the hollow fiber membrane) is near the outermost surface, so it is easy to be clogged.

[0050] The pore mode diameter of the cross section of the hollow fiber membrane of the present embodiment is preferably 0.090 μm or more. In addition, the pore mode diameter is preferably 0.5 μm or less, and more preferably 0.3 μm or less.

[0051] It should be noted that the pore mode diameter can be measured by the method described in Examples described later.

[0052] The inner diameter of the hollow fiber membrane is preferably 150 μm or more and 400 μm or less, and more preferably 200 μm or more and 350 μm or less.

[0053] The thickness of the hollow fiber membrane is preferably 50 to 200 μm, more preferably 60 to 150 μm. It should be noted that the membrane thickness can be calculated by “(outer diameter-inner diameter) / 2”.

[0054] The hollow fiber membrane (hollow fiber type membrane) is preferably composed of a semipermeable membrane.

[0055] The hollow ratio of the hollow fiber membrane is preferably 15 to 60%, more preferably 20 to 50%. It should be noted that the hollow ratio is the area ratio of the hollow portion in the cross section of the hollow fiber membrane, and is expressed as "hollow portion cross-sectional area / (membrane portion cross-sectional area+hollow portion cross-sectional area)×100 (%)".

[0056] (use)

[0057] The hollow fiber membrane of the present embodiment can be suitably used for separation of biological materials and the like that are prone to clogging (plasma separation, etc.), for example.

[0058] It should be noted that in plasma separation, plasma is separated from blood. Plasma is a liquid component obtained by removing blood cells (white blood cells and red blood cells), platelets and other cellular components from blood. Plasma contains water, protein, inorganic salts, sugars, fats, nitrogen compounds, etc., as well as albumin, fibrinogen, IgG, cytokines, etc.

[0059] <Method for producing hollow fiber membrane>

[0060] Hereinafter, one embodiment of the method for producing the above-mentioned hollow fiber membrane will be described.

[0061] The method for producing the hollow fiber membrane according to the present embodiment is, for example, the following method.

[0062] The manufacturing method is the manufacturing method of the above-mentioned hollow fiber membrane, comprising:

[0063] The spinning step comprises discharging a spinning solution and an inner solution from a double-layer tubular nozzle through an air-running portion into a coagulation liquid, coagulating the spinning solution in the coagulation liquid, and then pulling out the coagulated product of the spinning solution from the coagulation liquid, thereby obtaining a hollow fiber membrane.

[0064] The spinning solution comprises: a resin raw material containing polyethersulfone, a solvent, and a non-solvent.

[0065] The internal liquid contains water,

[0066] The total concentration of the components other than water in the internal solution (internal solution concentration) is 70 to 90% by mass.

[0067] The nozzle stretch ratio is 1.5 to 6.5.

[0068] 〔Spinning process〕

[0069] Reference Figure 1 In the spinning process, the spinning dope 10a and the inner liquid 10b are discharged from the double-layer tubular nozzle 11 through the air travel portion (air gap) 20 into the coagulation liquid 21, the spinning dope is coagulated in the coagulation liquid 21, and the coagulated product of the spinning dope is pulled out from the coagulation liquid 21, thereby obtaining the hollow fiber membrane 3. The pulling out of the hollow fiber membrane is performed, for example, using the in-liquid guides 12, 13 and the rollers 14, 15, 16. It should be noted that the hollow fiber membrane 3 pulled out from the coagulation liquid 21 is, for example, immersed in a water bath 22 and then wound up by a winder 23.

[0070] The nozzle 11 is a double-layered tube, comprising an outer tube and an inner tube disposed inside the outer tube. The spinning solution is discharged from the gap (slit) between the outer tube and the inner tube, and the inner solution is discharged from the inner tube. The inner diameter of the outer tube is preferably 500 to 1500 μm, more preferably 600 to 1200 μm. The outer diameter of the inner tube is preferably 150 to 700 μm, more preferably 150 to 600 μm. It should be noted that the outer diameter of the inner tube is preferably the same as the inner diameter of the hollow fiber membrane.

[0071] By using such a nozzle, the discharge linear velocity of the spinning solution and the drawing velocity can be made equivalent, so that the interface friction between the discharged spinning solution and the internal solution can be reduced, and the inner surface of the hollow fiber membrane can be prevented from being roughened.

[0072] It should be noted that the linear velocity of the spinning solution discharge is obtained by dividing the amount of spinning solution discharged by the cross-sectional area of ​​the slit (see the following formula), wherein the cross-sectional area of ​​the slit is obtained from the inner diameter (a) of the outer tube and the outer diameter (b) of the inner tube [π(a / 2) 2 -π(b / 2) 2 〕.

[0073] The linear velocity of the spinning solution [m / min] = the amount of spinning solution discharged / the cross-sectional area of ​​the slit

[0074] The discharge rate of the spinning solution is preferably 1.0 to 5.0 cc / min, more preferably 1.5 to 4.0 cc / min.

[0075] The pulling speed is the rotation speed (surface speed) of the roller 14 provided at the outlet of the coagulation bath (refer to Figure 1 ).

[0076] The ratio of the discharge linear velocity to the pulling velocity (pulling velocity / discharge linear velocity), i.e., the nozzle draw ratio, is preferably 1.5 to 6.5, and more preferably 2.0 to 6.0. Thus, by making the discharge linear velocity faster than the pulling velocity of the spinning solution, the characteristic membrane structure of the hollow fiber of the present invention can be obtained.

[0077] The linear distance of the aerial traveling portion 20 (the distance between the tip of the nozzle 11 and the liquid surface of the coagulation liquid 21 ) is preferably 10 to 200 mm, and more preferably 10 to 100 mm.

[0078] It should be noted that the hollow fiber membrane obtained by the spinning process can be further subjected to a cleaning process (water washing process) using pure water. The water flow in the water washing process is preferably a flow in the opposite direction to the moving direction of the hollow fiber membrane (countercurrent), but can also be a flow in the same direction as the moving direction of the hollow fiber membrane (downstream).

[0079] (Spinning solution)

[0080] The spinning solution 10a includes, for example, the above-mentioned resin raw material containing polyethersulfone, a solvent, and a non-solvent.

[0081] The temperature (set temperature) of the spinning solution in the nozzle 11 is preferably 50 to 110°C, more preferably 60 to 100°C.

[0082] The concentration of polyethersulfone in the spinning solution is preferably 10 to 30% by mass, more preferably 10 to 25% by mass. If the concentration of polyethersulfone is too low, the strength of the hollow fiber membrane may be reduced. On the other hand, if the concentration of polyethersulfone is too high, the viscosity of the spinning solution may be too high, making it difficult to perform spinning.

[0083] When a vinyl pyrrolidone polymer is added to the spinning solution, the concentration of the vinyl pyrrolidone polymer in the spinning solution is preferably 3 to 20% by mass, more preferably 5 to 15% by mass. If the concentration of the vinyl pyrrolidone polymer is too low, proteins in the blood are easily accumulated and blocked when used for plasma separation, and sometimes the performance decreases faster over time. On the other hand, if the concentration of the vinyl pyrrolidone polymer is too high, the viscosity of the spinning solution sometimes becomes too high and it is difficult to implement spinning.

[0084] The solvent is a liquid that can dissolve polyethersulfone. The solvent is preferably a polar solvent, preferably soluble in water. The polar solvent is preferably an aprotic polar solvent. Examples of the aprotic polar solvent include N-methylpyrrolidone (NMP), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile, and the like.

[0085] The non-solvent is a liquid (excluding water) that does not dissolve polyethersulfone. Examples of the non-solvent include glycol esters, glycerol, and alcohols, and glycol esters are preferred. Examples of glycol esters include ethylene glycol, triethylene glycol (TEG), polyethylene glycol (polyethylene glycol 200, polyethylene glycol 400, etc.), and propylene glycol.

[0086] In the spinning solution, the ratio of the amount of solvent (S) to the amount of non-solvent (NS) (S / NS ratio) is preferably 35 / 65 to 55 / 45, and more preferably 40 / 60 to 50 / 50. If the S / NS ratio in the spinning solution becomes too small, the dissolution of polyethersulfone becomes unstable, so that the spinning stability is sometimes reduced, or an asymmetric structure suitable for the use of the present invention cannot be obtained. If the S / NS ratio becomes large, a hollow fiber membrane with an asymmetric structure may not be obtained, or the spinning stability is reduced.

[0087] It should be noted that the spinning solution may contain water in addition to the solvent and the non-solvent.

[0088] When mixing the resin raw material containing polyethersulfone, the solvent, and the non-solvent to be the constituent material of the hollow fiber membrane, the order of adding the materials and the mixing method are not particularly limited.

[0089] (internal fluid)

[0090] The inner liquid contains water. The content of water in the inner liquid is preferably 10 to 30% by mass, more preferably 15 to 25% by mass.

[0091] The internal solution may contain a solvent, a non-solvent, etc. in addition to water. Examples of the non-solvent include ethylene glycol, triethylene glycol (TEG), polyethylene glycol 200 or 400, glycerol, propylene glycol, etc. Examples of the solvent include N-methylpyrrolidone (NMP), dimethylacetamide, dimethylformamide, dimethyl sulfoxide, etc.

[0092] In order to obtain the hollow fiber membrane of the present embodiment having an asymmetric structure in which the average pore diameter on the inner surface side is large and the average pore diameter on the outer surface side is small, it is preferred that the concentration of components other than water (solvent, non-solvent, etc.) contained in the inner liquid is increased relative to the concentration of the coagulation liquid (inner liquid concentration ratio). The inner liquid concentration is preferably 70 to 90% by mass, and more preferably 75 to 85% by mass.

[0093] In order to obtain the hollow fiber membrane of the present embodiment, it is preferable to adjust the nozzle stretch ratio to a specific range. The nozzle stretch ratio is preferably 1.5 to 6.5, and more preferably 2.0 to 6.0.

[0094] When the spinning solution 10a and the internal solution 10b are discharged from the double-tube-shaped nozzle 11, a temperature difference may be provided between the spinning solution and the internal solution.

[0095] (Coagulation liquid)

[0096] The coagulation liquid preferably contains a solvent and a non-solvent (excluding water). It should be noted that, in this case, the coagulation liquid may contain water in addition to the solvent and the non-solvent.

[0097] The ratio of the total amount of the solvent and the non-solvent in the coagulation liquid (concentration of the coagulation liquid: CB concentration) is preferably 60 to 90% by mass, and more preferably 65 to 90% by mass.

[0098] The ratio of the amount of the solvent to the amount of the non-solvent in the coagulation liquid is, for example, 40 / 60 to 50 / 50.

[0099] The temperature of the coagulation liquid is preferably 30 to 80°C, more preferably 40 to 70°C.

[0100] Example

[0101] Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

[0102] [Example 1]

[0103] The hollow fiber membrane of Example 1 was produced by a method basically similar to the method for producing the hollow fiber membrane described in the embodiment. Specific conditions and the like are as follows.

[0104] (Preparation of spinning solution)

[0105] 17.0 mass % of PES (6020P manufactured by BASF), 10.0 mass % of PVP (Kollidon (registered trademark) K30 manufactured by BASF), 32.85 mass % of N-methylpyrrolidone (NMP manufactured by Mitsubishi Chemical Corporation, solvent), and 40.15 mass % of triethylene glycol (TEG manufactured by Mitsubishi Chemical Corporation, non-solvent) were mixed and dissolved to obtain a spinning stock solution.

[0106] (Composition of internal fluid)

[0107] A mixed solution of 37.8% by mass of NMP (solvent), 46.2% by mass of TEG (non-solvent) and 16.0% by mass of reverse osmosis (RO) water. The total concentration of the solvent and the non-solvent in the internal liquid (IL) (internal liquid concentration: IL concentration) is 84% ​​by mass.

[0108] (Composition of coagulation liquid)

[0109] A mixed solution of 26.1% by mass of NMP (solvent), 31.9% by mass of TEG (non-solvent), and 42.0% by mass of RO water. The total concentration of the solvent and the non-solvent in the coagulation liquid (CB) (CB concentration) was 58% by mass.

[0110] (Conditions of the spinning process)

[0111] Spinning solution discharge temperature (set temperature): 67°C

[0112] Distance of air travel part (air gap length: AG length): 30mm

[0113] Pull-out speed (spinning speed): 15 m / min (winding onto the reel (winder 23))

[0114] Nozzle stretch ratio: 4.05

[0115] (Conditions of the water washing process)

[0116] Flow in the washing tank (bath): Countercurrent

[0117] Temperature: 30℃

[0118] The bundle of hollow fiber membranes obtained in the above steps was cut into a predetermined length, wrapped with gauze, washed with RO water at 80° C., and dried at 60° C. using a hot air dryer.

[0119] Thus, a dried hollow fiber membrane was obtained. The inner diameter (membrane inner diameter) of the obtained hollow fiber membrane was 300 μm and the thickness (membrane thickness) was 75 μm.

[0120] (Measurement of the inner diameter and membrane thickness of hollow fiber membranes)

[0121] In addition, the film inner diameter and film thickness were measured by the following method.

[0122] An appropriate number of hollow fiber membranes were passed through a hole with a diameter of 3 mm in the center of a glass slide to such an extent that the hollow fiber membrane would not fall off the hole, and the hollow fiber membrane was cut along the upper and lower surfaces of the glass slide using a razor to obtain a hollow fiber membrane cross-sectional sample. The inner diameter and outer diameter of the hollow fiber membrane were measured using a projector (Nikon PROFILE PROJECTOR V-12) for the obtained hollow fiber membrane cross-sectional sample.

[0123] Specifically, for one hollow fiber membrane cross section, the dimensions of the outer surface of the hollow fiber membrane in the XX direction and the YY direction (two orthogonal directions on the cross section) are measured, and the arithmetic mean of these values ​​is used as the outer diameter of one hollow fiber membrane cross section. In addition, for one hollow fiber membrane cross section, the dimensions of the hollow part in the XX direction and the YY direction (two orthogonal directions on the cross section) are measured, and the arithmetic mean is used as the inner diameter of one hollow fiber membrane cross section 1. It should be noted that 10 cross sections are measured in the same manner, and the average values ​​are used as the inner diameter and outer diameter.

[0124] Based on the inner diameter of the hollow fiber membrane and the measurement result (average value) of the inner diameter, the membrane thickness (average value) was calculated by the formula “(outer diameter−inner diameter) / 2”.

[0125] [Examples 2 to 5, Comparative Example 1]

[0126] The production conditions of the hollow fiber membranes were changed as shown in Table 1. Except for this, the hollow fiber membranes of Examples 2 to 5 and Comparative Example 1 were produced in the same manner as in Example 1. "%" in Table 1 means "mass %".

[0127] It should be noted that Figure 6 A cross-sectional SEM image of the hollow fiber membrane of Comparative Example 1 is shown in FIG.

[0128] <Evaluation of hollow fiber membrane performance>

[0129] The following measurements were performed on each of the hollow fiber membranes of the above-mentioned Examples and Comparative Examples. The measurement results are shown in Table 2. In addition, a scanning electron microscope (SEM) image of the hollow fiber membrane of Example 1 is shown in Figure 4 middle.

[0130] (Module production)

[0131] A bundle of multiple hollow fiber membranes cut into a length of about 30 cm is wrapped with a polyethylene film to form a hollow fiber membrane bundle. The hollow fiber membrane bundle is inserted into a cylindrical polycarbonate tubular container, and the two ends are fixed with a carbamate potting agent. The ends are cut off to obtain a module with two open ends. The number of hollow fiber membranes is appropriately set. It should be noted that an inlet and outlet (Japanese: ポート) is set at two locations of the cylindrical surface of the cylindrical tubular container so that the fluid can be perfused into the outer surface of the hollow fiber membrane, and an inner gate (Japanese: ヘッダー) is installed at both ends of the tubular container so that the fluid can be perfused into the inner surface of the hollow fiber membrane.

[0132] (Manufacturing of ring-shaped micromodules)

[0133] A bundle of multiple hollow fiber membranes cut into about 40 cm lengths was bent so that the ends overlapped, and the ends were inserted into a tube (casing) and fixed with a urethane potting agent. A portion of the adhesive fixing portion was cut off to obtain a ring-shaped micromodule ( Figure 8 ). The number of hollow fiber membranes is appropriately set.

[0134] It should be noted that, for ease of reference, the same measurement was also performed on a commercially available membrane-type plasma separator using a hollow fiber membrane, namely Plasmaflo (manufactured by Asahi Kasei Medical Corporation). The measurement results are shown in Table 2. It should be noted that the hollow fiber membrane used in Plasmaflo is a hollow fiber membrane composed of hydrophobic polyethylene, and an ethylene vinyl alcohol copolymer is coated on the surface (outer surface). The inner diameter of the hollow fiber membrane is 250 μm and the thickness is 50 μm. The scanning electron microscope (SEM) image of the hollow fiber membrane used in Plasmaflo is shown in Figure 5 middle.

[0135] [Determination of the tilt index]

[0136] First, a cross section of the hollow fiber membrane (refer to Figure 4 (a) ) was photographed. In the obtained cross-sectional image, the inner surface side of the hollow fiber membrane (reference Figure 4 (b)) and the outer surface side (refer to Figure 4 (c) , the range of 5 μm in the membrane thickness direction (from the inner surface) and the range of 10 μm in the direction perpendicular to the membrane thickness direction were respectively used as the measurement range. For this measurement range, the image was binarized in white / black using image analysis software, and the pore size distribution of the pores on the inner surface side and the outer surface side of the hollow fiber membrane of the cross section was measured, and the equivalent circle diameter was measured. The average value of the equivalent circle diameters obtained was taken as the average pore size.

[0137] It should be noted that the threshold value was increased by 5 points at a time, and the number of pores determined at each threshold value was measured. Based on the result, the threshold value when the number of pores determined was the largest was adopted. Based on the threshold value thus adopted, the above-mentioned binarization was performed.

[0138] Based on the following formula, the cross section of the hollow fiber membrane (refer to Figure 4 (a)) The inner surface side (refer to Figure 4 (b)) and the outer surface side (refer to Figure 4 (c) The tilt index was calculated from the average pore size.

[0139] Tilt index = (average pore size on the inner surface side of the cross section of the hollow fiber membrane) / (average pore size on the outer surface side of the cross section of the hollow fiber membrane)

[0140] [Measurement of the most frequent pore diameter]

[0141] The average pore size (average pore size) was measured using a Perm-Porometer (through-pore size distribution measuring device) made by PMI using a ring-shaped micromodule. It should be noted that perfluoropolyester (trade name: Galwick) was used as a solvent for the Perm-Porometer. From the measurement results of the average pore size obtained in this way, the following were obtained: Figure 7 The average pore size distribution shown in the figure is taken as the average pore size with the largest number of distributions (highest pore distribution density) as the pore mode diameter (refer to Figure 7 ).

[0142] [Measurement of maximum pore diameter]

[0143] The whole of the annular micromodule is immersed in a sufficient amount of 2-propanol (hereinafter abbreviated as iPA) for 3 minutes, so that iPA is spread throughout the inner cavity and the membrane wall. Under the state where the hollow fiber membrane part of the annular micromodule is immersed in iPA as a whole, the annular micromodule is connected to a nitrogen pipeline and pressurized, and the nitrogen pipeline is designed to install a pressure gauge on the sleeve so that the pressurized pressure can be monitored. The point where bubbles continuously appear from the membrane wall of the hollow fiber membrane is recorded as the bubble point P [Pa]. For 1 sample, 3 measurements are implemented, and the average value of the measured value of the bubble point is used as the bubble point of the sample. Further, according to the following formula, the maximum pore size calculated by the bubble point (P [bar]) measured in iPA is obtained.

[0144] Maximum pore size [μm] = 4γCOSθ / P

[0145] γ represents the surface tension of the solvent (N / m), θ represents the contact angle between the membrane material and the solvent (°), and P represents the bubble point pressure (Pa). The calculation is based on the surface tension of iPA γ = 20.8, the contact angle 0°, and COSθ = 1.

[0146] [Measurement of Transmembrane Pressure Difference (TMP)]

[0147] Cow blood was added with citric acid to inhibit coagulation and adjusted to a hematocrit of 40±2% and a protein concentration of 6 to 7 g / dL. The blood flow rate (Qb) was 100 mL / min and the filtration flow rate (Qf) was 30 mL / min for 180 minutes. The inlet pressure, outlet pressure, and filtrate pressure were measured 30 minutes after the start of the circulation and 180 minutes after the start of the circulation. The transmembrane pressure difference (TMP) was calculated from the measured pressure values ​​according to the following formula.

[0148] TMP = ([inlet pressure] + [outlet pressure]) / 2 - [filtrate pressure]

[0149] [Determination of sieving coefficient of fibrinogen (SCFib)]

[0150] The same test as the above TMP was performed, and the liquids at the inlet side, outlet side, and filtrate side were sampled 30 minutes after the start of the circulation and 180 minutes after the start of the circulation, and the concentrations were determined using ELISA-KIT (Fibrinogen ELISA Kit 96test (Cloud-Clone Corp.) manufactured by Cosmo Bio). The fibrinogen sieving coefficient (SCFib) was calculated from the obtained measured values ​​according to the following formula.

[0151] SCFib = 2 × [filtrate concentration] / ([inlet concentration] + [outlet concentration])

[0152] It should be noted that the retention rate of the fibrinogen sieving coefficient (SCFib) is an indicator of how much the fibrinogen sieving coefficient has changed 30 minutes after the start of the cycle and 180 minutes after the start of the cycle, and can be calculated using SCFib 30 minutes after the start of the cycle / SCFib 180 minutes after the start of the cycle. It should be noted that, for example, when 100% of fibrinogen permeates the membrane, the fibrinogen sieving coefficient is 1.

[0153]

[0154]

[0155] From the results shown in Table 2, it can be seen that in the hollow fiber membranes of Examples 1 to 5 having a tilt index of 2.00 or more, the increase in the transmembrane pressure difference (TMP) is suppressed to 50 mmHg or less, compared with the hollow fiber membrane of Comparative Example 1 having a tilt index of less than 2.00. It should be noted that if the TMP exceeds 50 mmHg, hemolysis is likely to occur during plasma separation, so it is important to maintain the TMP at 50 mmHg or less in treatment using plasma separation.

[0156] The suppression of the increase in TMP is mainly caused by the clogging of the hollow fiber membrane, so it is considered that the clogging is suppressed in the hollow fiber membranes of Examples 1 to 5. Therefore, in the hollow fiber membrane of Comparative Example 1, which is considered to be prone to clogging, the retention rate of the fibrinogen sieving coefficient (SCFib) is low, while in contrast, in the hollow fiber membranes of Examples 1 to 5, the retention rate of SCFib becomes high.

[0157] In addition, it can be seen that in the hollow fiber membrane of Example 5 with a tilt index of 2.00 or more and a pore mode diameter of less than 0.090 μm, the fibrinogen sieving coefficient is greatly reduced from the beginning. On the other hand, in the hollow fiber membranes of Examples 1 to 4 with a tilt index of 2.00 or more and a pore mode diameter of 0.090 μm or more, no particular reduction in the fibrinogen sieving coefficient is observed. It should be noted that even in the hollow fiber membrane of Comparative Example 1 with a tilt index of less than 2.00 and a pore mode diameter of less than 0.090 μm, no reduction in the fibrinogen sieving coefficient is observed at the beginning. Based on these results, it is believed that in a hollow fiber membrane with a high tilt index (more than 2.00), if the pore mode diameter is less than 0.090 μm, there is a tendency for the fibrinogen sieving coefficient to be greatly reduced. From the perspective of maintaining the fibrinogen sieving coefficient in the hollow fiber membrane of the present invention, it is desirable to maintain the pore mode diameter at 0.090 μm or more.

[0158] Description of Reference Numerals

[0159] 10a spinning solution, 10b internal solution, 11 nozzle, 12, 13 liquid guide, 14, 15, 16 roller, 20 aerial travel part, 21 coagulation solution, 22 water washing bath, 23 winder, 3 hollow fiber membrane, 4 large-sized component, 51, 52 small-sized component.

Claims

1. A hollow fiber membrane comprising polyethersulfone, wherein: The hollow fiber membrane has a non-uniform structure in the thickness direction. The ratio of the average pore size on the inner surface side of the cross section of the hollow fiber membrane to the average pore size on the outer surface side, that is, a tilt index, is 2.00 or more.

2. The hollow fiber membrane according to claim 1, wherein The hollow fiber membrane has a cross-sectional pore mode diameter of 0.090 μm or more. The hollow fiber membrane according to claim 1 or 2, further comprising a vinyl pyrrolidone-based polymer. 4 . The hollow fiber membrane according to claim 1 , which is used for plasma separation. 5 . A method for separating plasma using the hollow fiber membrane according to claim 1 .

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