Porous membrane and purification method

Abstract

This porous membrane has a structure that is nonuniform in the thickness direction, and for which a first surface is sparse and a second surface is dense. The porous membrane has a first capture layer (20-nm gold colloid capture layer), and this first capture layer is a layer that, when a gold colloid having an average particle diameter of 20 nm is permeated from the first surface side of the porous membrane to the second surface side, captures the gold colloid having an average particle diameter of 20 nm. The thickness of the first capture layer is at least 16.5 µm.

Description

Porous membrane and purification method

[0001] The present invention relates to a porous membrane and a purification method.

[0002] For example, in the production of antibody drugs, porous membranes are used to remove viruses in the process of purifying antibodies (e.g., IgG) by removing contaminants from cultured cells. These porous membranes are required to have a structure that allows antibodies to pass through while fractionating and removing viruses.

[0003] For example, Japanese Patent No. 5403444 (JP 2014-097465 A (Patent Document 1)) discloses a porous membrane used to remove viruses from biological materials such as blood. The porous membrane (porous hollow fiber membrane) disclosed in Patent Document 1 contains a polysulfone polymer and a copolymer of vinylpyrrolidone and vinyl acetate, and its surface and porous portion are coated with a cellulose polymer or the like (a polysaccharide or a polysaccharide derivative).

[0004] Japanese Patent No. 5403444 (JP 2014-097465 A)

[0005] A virus inactivation treatment is usually performed before the virus removal treatment. In this virus inactivation treatment, viruses are inactivated, for example, by lowering the pH of a liquid containing a biological material. It is known that the virus removal performance of a porous membrane decreases when using a liquid containing a biological material with a low pH. For this reason, in the past, a low-pH liquid containing a biological material after the virus inactivation treatment was neutralized to raise the pH before the virus removal treatment using a porous membrane was performed.

[0006] However, from the viewpoint of production efficiency, it is desirable to perform virus removal treatment directly on a low pH solution containing a biological material without carrying out the neutralization treatment described above.

[0007] Therefore, an object of the present invention is to provide a porous membrane that can be used to directly remove viruses from a liquid containing a biological material and having a low pH, that has high virus blocking ability, and that maintains a high filtration flow rate for a long period of time.

[0008] (1) A porous membrane having a non-uniform structure in the thickness direction, with a first surface being sparse and a second surface being dense, the porous membrane having a first trapping layer (20 nm gold colloid trapping layer), the first trapping layer being a layer that traps gold colloids having an average particle size of 20 nm when the gold colloids are passed through the porous membrane from the first surface side to the second surface side, and the thickness of the first trapping layer is 16.5 μm or more.

[0009] (2) The porous membrane described in (1) has a second capture layer, which is a layer that captures gold colloids having an average particle size of 30 nm when the gold colloids are passed through from the first surface side toward the second surface side, and the porous membrane satisfies the relationship a / b is 1.5 or greater, where a is the distance from the first surface to the position of the first capture layer closest to the second surface, and b is the distance from the first surface to the position of the second capture layer closest to the second surface.

[0010] (3) The porous membrane according to (1) or (2), wherein the porous membrane contains a hydrophobic polymer and a first hydrophilic polymer, and the surface of the porous membrane is coated with a second hydrophilic polymer.

[0011] (4) The porous membrane according to (3), wherein the hydrophobic polymer is a polysulfone-based polymer.

[0012] (5) The porous membrane according to (3) or (4), wherein the first hydrophilic polymer is at least one of polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate.

[0013] (6) The porous membrane according to any one of (3) to (5), wherein the second hydrophilic polymer is a cellulose-based polymer.

[0014] (7) The porous membrane according to any one of (1) to (6), which has the shape of a hollow fiber membrane, the inner surface of the hollow fiber membrane being the first surface, and the outer surface of the hollow fiber membrane being the second surface.

[0015] (8) The porous membrane according to any one of (1) to (7), which is used for removing viruses.

[0016] (9) A purification method using the porous membrane according to any one of (1) to (8).

[0017] According to the present invention, it is possible to provide a porous membrane that can be used to directly perform virus removal treatment on a low-pH liquid containing a biological material, has high virus blocking ability, and maintains a high filtration flow rate for a long period of time.

[0018] One reason why the virus removal performance of a porous membrane decreases in a low-pH liquid is that the higher-order structure of viruses collapses in a low-pH liquid, causing the viruses to become linear, making them more likely to pass through the pores of the porous membrane. In the porous membrane of the present invention, the thickness of the first trapping layer (20-nm gold colloid trapping layer), which is the part with relatively small pores, is 16.5 μm or more, so that even viruses that have become more likely to pass through can be captured, and it is thought that virus removal treatment can be performed directly on a low-pH liquid.

[0019] FIG. 1 is a schematic diagram illustrating an example of a method for producing a porous membrane. FIG. 2 is a schematic diagram illustrating depth filtration. FIG. 3 is a schematic diagram illustrating surface filtration. FIG. 4 is a schematic diagram illustrating dead-end filtration in each measurement method. FIG. 5A is an SEM image of a cross section of the porous membrane of Example 1. FIG. 5B is a binarized image of 20 nm gold colloid of a cross section of the porous membrane of Example 1. FIG. 6 is an SEM image of a cross section of the porous membrane of Example 4.

[0020] Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to these.

[0021] <Porous Membrane> [Materials Constituting the Porous Membrane] The porous membrane of this embodiment contains a hydrophobic polymer and a first hydrophilic polymer. The surface of the porous membrane (including the inner surfaces of the pores) is coated with a second hydrophilic polymer.

[0022] The porous membrane can be prepared, for example, by adsorbing (attaching) and immobilizing a second hydrophilic polymer, which is different from the first hydrophilic polymer, onto the surface (including the inner surface of the pores) of a base membrane containing a hydrophobic polymer and a first hydrophilic polymer. For example, the base membrane can be prepared from a blend polymer of a mutually compatible hydrophobic polymer and a first hydrophilic polymer, and can be prepared from a solution of both polymers in a common solvent.

[0023] (Hydrophobic Polymer) Examples of hydrophobic polymers include polysulfone-based polymers such as polysulfone and polyethersulfone, cellulose-based polymers such as cellulose acetate and cellulose derivatives, and polyolefin-based polymers such as polyethylene.

[0024] Polyethersulfone is a compound containing a structural unit represented by the following formula (1).

[0025]

[0026] Specific examples of polyethersulfone include Ultrason (registered trademark) E2020P and E6020P manufactured by BASF, and Sumikaexcel (registered trademark) 3600P, 4100P, 4800P, 5200P, and 7600P manufactured by Sumitomo Chemical Co., Ltd., with E6020P, 4800P, and 5200P being preferred. These may be used alone or in combination.

[0027] Polysulfone-based polymers are advantageous for obtaining membranes with high water permeability and are excellent materials for processing into uniform membranes, asymmetric membranes, etc. Polysulfone-based polymers may contain functional groups or substituents such as alkyl groups, and hydrogen atoms in the hydrocarbon skeleton may be substituted with other atoms or substituents such as halogens. These polymers are preferably used alone, and those with a relatively high molecular weight are preferably used.

[0028] The content of the hydrophobic polymer in the entire porous membrane is preferably 60 to 90% by mass.

[0029] (First Hydrophilic Polymer) Examples of the first hydrophilic polymer include polyvinyl alcohol, polyethylene glycol, vinylpyrrolidone-based polymers (polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, etc.), polyacrylic acid, cellulose, methylcellulose, chitosan, etc. The vinylpyrrolidone-based polymer is a polymer of a monomer containing at least N-vinylpyrrolidone.

[0030] The vinylpyrrolidone polymer preferably contains a structural unit represented by the following formula (2).

[0031]

[0032] Examples of vinylpyrrolidone polymers include Kollidon (registered trademark) 30 and 90, and Luvitec (registered trademark) K30, K80, K85, K90, and VA64, all of which are commercially available from BASF.

[0033] The copolymer of vinylpyrrolidone and vinyl acetate is a copolymer using vinylpyrrolidone as the hydrophobic unit and vinyl acetate as the hydrophilic unit (hereinafter sometimes abbreviated as VA copolymer). As the VA copolymer, a copolymer having a weight ratio of vinylpyrrolidone to vinyl acetate of 6:4 (hereinafter sometimes abbreviated as VA6 / 4) or VA65 / 35 having a weight ratio of 65:35 is preferred from the viewpoints of imparting hydrophilicity to polysulfone-based membranes and excellent compatibility with polysulfone-based polymers.

[0034] The content of the first hydrophilic polymer in the porous membrane is preferably 5 to 15% by mass, more preferably 6 to 10% by mass. If the content of the first hydrophilic polymer in the membrane exceeds the upper limit, swelling in the membrane increases, causing instability of the pore size and a decrease in pressure resistance, which can have a significant impact on virus blocking and protein permeability. Furthermore, if the content of the first hydrophilic polymer in the membrane is too high, inconveniences such as the first hydrophilic polymer eluting during use and contaminating the recovered liquid may occur. If the content is lower than the lower limit, the virus removal ability may decrease, possibly due to insufficient contribution to membrane structure control.

[0035] The content of the first hydrophilic polymer and the second hydrophilic polymer can be measured by nuclear magnetic resonance (hereinafter sometimes abbreviated as NMR), and the content in a limited area near the surface of the membrane can be measured by surface infrared spectroscopy (hereinafter sometimes abbreviated as IR).

[0036] (Second Hydrophilic Polymer) The second hydrophilic polymer is a polysaccharide or a polysaccharide derivative. The second hydrophilic polymer is preferably a cellulose-based polymer.

[0037] The cellulose-based polymer is preferably a hydroxyalkyl cellulose, such as hydroxyethyl cellulose or hydroxypropyl cellulose (HPC).

[0038] Examples of polysaccharides other than cellulose include starch, dextran, and curdlan.

[0039] The weight-average molecular weight of the second hydrophilic polymer is preferably 140,000 or less in order to avoid an increase in solution viscosity and to improve the efficiency of penetration into the membrane. It is also preferable to appropriately reduce the molecular weight depending on the target pore size of the membrane.

[0040] In this embodiment, after producing a base membrane containing a hydrophobic polymer and a first hydrophilic polymer, it is preferable to attach the second hydrophilic polymer to the surface of the base membrane by, for example, immersing the base membrane in a solution or dispersion containing the second hydrophilic polymer. In this case, it is preferable to wash away excess first hydrophilic polymer from the polysulfone-based membrane containing the first hydrophilic polymer, and then attach the second hydrophilic polymer to the membrane surface and pore surfaces.

[0041] Coating a polysulfone membrane containing a first hydrophilic polymer with a second hydrophilic polymer has the effect of maintaining stable and high hydrophilicity and suppressing elution of the first hydrophilic polymer.

[0042] The weight ratio (IR / NMR) of the content (IR) of the second hydrophilic polymer present in the vicinity of the outer surface as determined by IR measurement to the content (NMR) of the second hydrophilic polymer present in the entire membrane as determined by NMR measurement is preferably 0.90 or more and 1.10 or less, more preferably 0.93 or more and 1.05 or less.

[0043] The content of the second hydrophilic polymer in the entire porous membrane is preferably 0.5 to 2.5% by mass, more preferably 0.7 to 2.2% by mass. If the content of the second hydrophilic polymer (e.g., a cellulose-based polymer) in the porous membrane exceeds the upper limit, the membrane is saturated with hydrophilicity and an excessive amount is added. Excessive content can cause swelling within the pores, blocking the pores and reducing water permeability and protein permeability. Furthermore, if the content is below the lower limit, adsorption of the hydrophilic-imparting protein can occur, significantly reducing the throughput of the protein solution. The coating with the second hydrophilic polymer also has the effect of suppressing elution of the first hydrophilic polymer. Here, the content of the cellulose-based polymer, which is the second hydrophilic polymer, can be measured by NMR as the content in the entire membrane.

[0044] [Porous membrane structure, etc.] The porous membrane of this embodiment has a non-uniform structure (asymmetric structure) in the thickness direction. Examples of porous membranes with an asymmetric structure include porous membranes whose density, porosity, cross-sectional porosity, average pore size, etc. vary in the thickness direction.

[0045] The porous membrane having an asymmetric structure of this embodiment may be in the form of a flat membrane or a hollow fiber membrane. A preferred structure is one in which the first surface side of the cross section (transverse section: cross section in the thickness direction) of the porous membrane is sparse and the second surface side is dense. For example, the porous membrane of this embodiment has an asymmetric structure in which the upstream side (first surface side) is sparser than the downstream side (second surface side) during use (filtration) for virus removal treatment, etc. That is, it is preferred to pass the liquid to be treated through the sparse structure side (first surface side) and perform filtration toward the dense structure side (second surface side).

[0046] When the porous membrane is a hollow fiber membrane, it may have either a structure in which the inner surface side is coarse and the outer surface side is dense (having a dense layer on the outer surface side), or a structure in which the inner surface side is dense (having a dense layer on the inner surface side) and the outer surface side is coarse, but a structure in which the inner surface side is coarse and the outer surface side is dense (having a dense layer on the outer surface side) is preferred. For example, when the inner surface (first surface) side of the hollow fiber membrane is the upstream side of filtration and filtration is performed from the inside to the outside, it is preferred that the inner surface side of the hollow fiber membrane is coarse and the outer surface side is dense.

[0047] This structure moderately disrupts the flow of the filtrate, making it difficult for clogging-causing components such as aggregates to adsorb to the membrane surface, thereby mitigating the decrease in filtration rate caused by clogging of the inner membrane surface and shortening the processing time for target liquids such as relatively high-concentration protein solutions.

[0048] Here, the effect of filtration using a porous membrane having an asymmetric structure according to this embodiment will be described. Referring to Fig. 3, in filtration using a porous membrane 3, small components 5 such as antibodies (IgG) in the cell culture solution pass through the pores of the porous membrane 3 from the extrusion side (upper side of Fig. 3: the first surface side of the porous membrane; the inner surface side in the case of a hollow fiber membrane) and are separated to the second surface side of the porous membrane (lower side of Fig. 2: the outer surface side in the case of a hollow fiber membrane). Meanwhile, components 4 (viruses, etc.) contained in the cell culture solution that are larger than component 5 cannot pass through the pores of the porous membrane and are removed from the filtrate. In the case of filtration (surface filtration: screen filtration) using a (conventional) porous membrane 3 having a uniform structure in the thickness direction shown in Fig. 3, large components 4 tend to concentrate and accumulate near the outermost surface of the extrusion side of the porous membrane 3 (upper side of Fig. 3: the first surface side of the porous membrane (the inner surface side in the case of a hollow fiber membrane)), which can easily cause clogging. In contrast, as shown in Figure 2, in filtration (depth filtration) using a porous membrane 3 having an asymmetric structure (in this embodiment), large-sized components 4 are dispersed and captured in the thickness direction of the porous membrane 3 (clogging occurs sequentially in the thickness direction). Therefore, clogging is less likely to occur.

[0049] It is preferable that the hollow fiber membrane has an asymmetric structure with the densest part (dense layer) in the cross-sectional direction of the membrane on the outside. The membrane structure can be easily confirmed, for example, by observation with an electron microscope. Since hollow fiber membranes are intended to highly remove microscopic substances such as viruses, these microscopic substances must be reliably captured at some part of the membrane thickness. Substances to be captured, such as viruses, are captured as they pass through the pore channels in the membrane thickness (called deep layer filtration). However, the presence of the smallest pores in the dense layer at the outlet can ensure nearly 100% removal. If a dense layer is present at the inlet, it is possible to capture them at that part (called screen filtration). However, in this case, localized capture at the inlet results in a decrease in the permeability of the solute to be passed due to narrowing of the pore size and accumulation of captured substances as filtration progresses, leading to a decrease in the permeate volume due to blockage. For this reason, it is undesirable for a dense layer to be present at the inlet.

[0050] (Thickness of the first trapping layer) In the porous membrane of this embodiment, when gold colloids having an average particle size of 20 nm are passed through the porous membrane from the first surface side (inner surface side) to the second surface side (outer surface side), the layer in which the gold colloids having an average particle size of 20 nm are trapped is defined as the first trapping layer. In other words, the porous membrane has a first trapping layer. Similarly, the layer in which gold colloids having an average particle size of 30 nm are trapped is defined as the second trapping layer (30 nm gold colloid trapping layer). It is preferable that the porous membrane has a second trapping layer.

[0051] The thickness of the first trapping layer (20 nm gold colloid trapping layer) is 16.5 μm or more, and preferably 17 μm or more, thereby achieving the above-mentioned effects of the present invention.

[0052] The ratio of the thickness of the first trapping layer to the thickness of the entire porous membrane is preferably 10 to 55%, and more preferably 25 to 45%.

[0053] In the porous membrane of the present invention, the LRV (log reduction value), which indicates the virus blocking performance (removal performance), is preferably 3.5 or more, more preferably 4.0 or more (removal rate of 99.99% or more), and even more preferably 4.7 or more.

[0054] For example, "LRV≧5" means 10 ５ This means that when a liquid containing 100,000 viruses is filtered, the number of viruses leaking into the filtrate is 1 or less. Thus, the higher the LRV of a porous membrane, the higher the blocking performance (removal performance) of the porous membrane against the object to be filtered (viruses, etc.).

[0055] In general, an LRV of about 4 is considered preferable from the standpoint of safety (reference: Oda Masahiro et al., "Challenges and Case Studies of Virus Clearance Tests," PDA Journal of GMP and Validation in Japan, Vol. 7, No. 1, 2005), and a hollow fiber membrane module with an LRV of 4.7 or higher is considered to have good virus removal performance.

[0056] The smallest virus found in nature is parvovirus, which has a diameter of approximately 20 nm. Therefore, the permeability of the 20 nm gold colloid can serve as a reference index for virus permeability (blocking ability).

[0057] The average particle size of the gold colloid mentioned above means the average particle size described in the instruction manual for the gold colloid product.

[0058] (Ratio a / b) When the distance from the first surface of the porous membrane to the position of the first trapping layer (20 nm gold colloid trapping layer) closest to the second surface is defined as a, and the distance from the first surface of the porous membrane to the position of the second trapping layer (30 nm gold colloid trapping layer) closest to the second surface is defined as b, the ratio a / b is preferably 1.5 or more, more preferably 1.6 or more, and even more preferably 2.0 or more. In other words, it is preferable that the porous membrane satisfy the relationship a / b is 1.5 or more. The a is the distance from the first surface to the position of the first trapping layer closest to the second surface. The b is the distance from the first surface to the position of the second trapping layer closest to the second surface. In this case, the decrease in filtration flow rate through the porous membrane over time is suppressed. This is thought to be because the greater the distance between the 30-nm gold colloid capture layer (the outermost position) and the 20-nm gold colloid capture layer (the outermost position) (the greater the ratio a / b), the thicker the clogging layer becomes and the longer it takes for impurities to fill the pores in the porous membrane, thereby suppressing the decrease in filtration flow rate over time.This prevents a decrease in the throughput of the virus removal process and increases the amount of processing before clogging occurs.

[0059] The thickness (membrane thickness) of the porous membrane is preferably 30 to 200 μm, more preferably 40 to 100 μm. The membrane thickness of a hollow fiber membrane can be calculated by "(outer diameter - inner diameter) / 2". In the case of a hollow fiber membrane, the inner diameter is preferably 150 μm or more and 400 μm or less, more preferably 200 μm or more and 350 μm or less.

[0060] In the case of a hollow fiber membrane, the hollow ratio is preferably 15 to 60%, more preferably 20 to 50%. The hollow ratio is the ratio of the area 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(%)." By setting the hollow ratio within the above range, it is possible to achieve both filtration performance and strength against filtration pressure.

[0061] The porosity of the porous membrane is preferably 70% or more and 95% or less, more preferably 85% or more and 95% or less, and even more preferably 90% or more and 95% or less. By making the porosity 70% or more, the recovery rate of antibodies (such as IgG) can be increased. On the other hand, if the porosity is too high, the strength of the porous membrane may be insufficient. By making the porosity within the above range, both filtration performance and strength against filtration pressure can be achieved. The porosity of the porous membrane can be calculated, for example, from the mass of water when the pores of the porous membrane are saturated with water and the mass of the dried porous membrane.

[0062] The pure water permeation rate of the porous membrane at 25°C (hereinafter referred to as pure water flux) is 50 to 500 L / (m ２ ·h·bar). If the pure water flux is smaller than the above-mentioned value, efficient treatment becomes difficult due to problems such as a longer filtration time and a larger membrane area being required. If the pure water flux is larger than the above-mentioned value, the pore size becomes excessively large, which may cause problems such as difficulty in separating and removing substances such as viruses to a high degree, or a decrease in membrane strength and poor handling. The pure water flux should be 80 to 400 L / (m ２ ·h·bar) is more preferable, and 100 to 350 L / (m ２ ·h·bar) is more preferred.

[0063] (Uses) The porous membrane of this embodiment can be used, for example, in purifying a target liquid by removing viruses (a purification method). That is, the porous membrane of this embodiment is for removing viruses. The porous membrane of this embodiment is suitably used, for example, in the production of antibody drugs, to remove viruses and the like contained in a cell culture solution in a process of purifying an antibody (e.g., IgG) by removing impurities and the like from the cell culture solution.

[0064] From the viewpoint of durability of the hollow fiber membrane against pressure applied during filtration, it is preferable to perform filtration from the inside to the outside, with the inner surface of the hollow fiber membrane as the upstream side of filtration.Furthermore, for ease and simplicity of operation, dead-end filtration is preferred.

[0065] <Method for producing porous membrane (hollow fiber membrane)> Hereinafter, a method for producing a hollow fiber membrane, which is an example of the porous membrane, will be described.

[0066] The method for producing a hollow fiber membrane of this embodiment includes, in this order: a spinning step in which a spinning dope and an inner liquid are discharged from a double-tube nozzle through an air-travel section into a coagulation liquid, the spinning dope is coagulated in the coagulation liquid, and the coagulated product of the spinning dope is pulled out of the coagulation liquid, thereby obtaining a hollow fiber membrane; and a coating step in which the surface (including the inner surface of the porous section) of the hollow fiber membrane (porous membrane) is coated with a second hydrophilic polymer.

[0067] 1 , in the spinning process, a spinning dope 10a and an inner liquid 10b are discharged from a double-tube nozzle 11 through an air gap 20 into a coagulation liquid 21, where the spinning dope is coagulated in the coagulation liquid 21. The coagulated product of the spinning dope is then pulled out of the coagulation liquid 21 to obtain a hollow fiber membrane. The hollow fiber membrane is pulled out by, for example, submerged guides 12 and 13 and rollers 14, 15 and 16. The hollow fiber membrane pulled out of the coagulation liquid 21 is immersed in, for example, a water washing bath 22 and then wound up by a winder 23.

[0068] The nozzle 11 has a double-tube shape and includes an outer tube and an inner tube provided inside the outer tube. The spinning dope is discharged from the gap (slit) between the outer tube and the inner tube, and the inner solution is discharged from the inside of 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 is preferable that the outer diameter of the inner tube is approximately the same as the inner diameter of the hollow fiber membrane.

[0069] The air gap length (AG length), which is the linear distance of the air travel section 20 (the distance between the tip of the nozzle 11 and the liquid surface of the solidifying liquid 21), is preferably 10 to 100 mm, and more preferably 10 to 80 mm.

[0070] The hollow fiber membrane obtained by the spinning step may be further subjected to a washing step with pure water (water-washing step). In the water-washing step, the water preferably flows in the opposite direction to the movement direction of the hollow fiber membrane (countercurrent), but may also flow in the same direction as the movement direction of the hollow fiber membrane (co-current).

[0071] (Spinning Dope) The spinning dope 10a contains, for example, the above-mentioned polysulfone-based polymer and resin raw material containing a vinylpyrrolidone-based polymer, a solvent, and a non-solvent.

[0072] The spinning dope (membrane-forming solution) is obtained by mixing, stirring, and dissolving the above-mentioned components. Heating may be performed for dissolution. However, excessive heating may lead to decomposition of the polymer or high-temperature phase separation of the spinning solution specific to the present invention, so the heating temperature is preferably 30 to 80°C. Furthermore, the spinning dope is preferably prepared under an inert gas atmosphere.

[0073] The temperature of the spinning dope discharged from the nozzle 11 (nozzle temperature) is preferably 40 to 80° C., more preferably 45 to 60° C. If the nozzle temperature is low, coagulation tends to proceed, and the membrane structure becomes too dense, resulting in a decrease in permeability. If the nozzle temperature is high, the progress of phase separation is excessively suppressed, and large pores tend to be generated, which may lead to a decrease in separation characteristics and strength.

[0074] The concentration of the polysulfone-based polymer in the spinning dope is preferably 20 to 40% by mass, more preferably 25 to 35% by mass. A low polysulfone-based polymer concentration is preferable to achieve high permeability, but an excessively low concentration can result in reduced strength and poor separation characteristics. On the other hand, to reliably trap minute substances such as viruses, it is necessary to reduce the porosity of the dense layer as much as possible to ensure their capture. Therefore, a high polysulfone-based polymer concentration is preferable. However, if the polysulfone-based polymer concentration is increased, the entire membrane may have an overly dense structure, regardless of how the membrane-forming conditions are controlled. Furthermore, if the polysulfone-based polymer concentration is too high, the viscosity of the spinning dope may become too high, making spinning difficult.

[0075] The concentration of the vinylpyrrolidone polymer in the spinning dope is preferably 0.5 to 20% by mass, more preferably 1 to 15% by mass. If the concentration is too low, the control of the membrane structure and the amount remaining in the membrane will be insufficient, resulting in a decrease in performance. If the concentration is too high, phase separation (coagulation) of the spinning dope will tend to proceed excessively, which will deteriorate the operability (filter filtration of the spinning dope and fiber breakage) when producing a hollow fiber membrane. In addition, the diffusion of the polymer during phase separation will be significantly reduced, which may prevent the formation of a desired membrane structure.

[0076] The solvent is a liquid capable of dissolving the polysulfone polymer. The solvent is preferably a polar solvent, and is preferably soluble in water. The polar solvent is preferably an aprotic polar solvent. Examples of aprotic polar solvents include N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile, and ε-caprolactam. NMP, DMF, and DMAc are particularly preferred, with NMP being more preferred.

[0077] The non-solvent is a liquid (excluding water) that does not dissolve the polysulfone polymer. Examples of non-solvents include glycol esters, glycerin, and alcohols, with glycol esters being preferred. Examples of glycol esters include ethylene glycol (EG), diethylene glycol (DEG), triethylene glycol (TEG), polyethylene glycol (PEG: polyethylene glycol 200, polyethylene glycol 400, etc.), propylene glycol (PG), glycerin, and water. When using a polysulfone polymer and a vinylpyrrolidone polymer, ether polyols such as DEG, TEG, and PEG are preferred, with TEG being more preferred. In this specification, ether polyol refers to a substance having at least one ether bond and two or more hydroxyl groups in its structure.

[0078] In the spinning dope, the mass ratio of the solvent (S) to the non-solvent (NS) (S / NS ratio) is preferably 25 / 75 to 55 / 45, more preferably 40 / 60 to 50 / 50. If the solvent content is lower than this, coagulation tends to proceed, the membrane structure becomes too dense, and permeability decreases, making it impossible to obtain the desired flux or protein permeability. Furthermore, if the solvent content is higher than this, the progression of phase separation is excessively suppressed, and large pores tend to form, which is undesirable because it may lead to a decrease in separation characteristics and strength.

[0079] When mixing the resin raw material, solvent, and non-solvent that are the constituent materials of the hollow fiber membrane, the order in which the materials are added and the mixing method are not particularly limited.

[0080] (Inner Liquid) The inner liquid preferably has a solvent and / or non-solvent contained in the spinning dope as its main component. However, using only the solvent contained in the spinning dope excessively suppresses coagulation on the lumen wall surface, making it impossible to obtain a desirable surface structure. Therefore, it is preferable to use a mixture of a solvent and a non-solvent, a non-solvent only, a mixture of a solvent and water, a mixture of a non-solvent and water, or a mixture of a solvent, a non-solvent, and water. When the inner liquid (core liquid) contains water, the water content in the inner liquid is preferably 5 to 30% by mass, more preferably 10 to 25% by mass. If the amount of organic component is small, coagulation tends to proceed easily, and the inner structure of the membrane becomes too dense, resulting in reduced permeability.

[0081] The internal liquid may contain a solvent, a non-solvent, etc. Non-solvents include ethylene glycol, triethylene glycol (TEG), polyethylene glycol 200 or 400, glycerin, propylene glycol, etc. Solvents include N-methylpyrrolidone (NMP), dimethylacetamide, dimethylformamide, dimethyl sulfoxide, etc.

[0082] When the water content of the internal liquid is low and the solvent content is high, the coagulation rate on the inside of the hollow fiber membrane slows, the phase separation time is extended, and a sparse structure is formed on the inside of the hollow fiber membrane. Furthermore, when the water content is high and the solvent content is low, the coagulation rate on the inside of the hollow fiber membrane increases, the phase separation time is shortened, and a dense structure is formed on the inside of the hollow fiber membrane. To obtain a hollow fiber membrane of this embodiment that exhibits a sparse structure on the inside of the membrane, it is preferable to increase the concentration of components other than water (solvent, non-solvent, etc.) contained in the internal liquid (internal liquid concentration). The internal liquid concentration is preferably 70 to 95% by mass, more preferably 75 to 90% by mass. The mass ratio of the solvent to the non-solvent in the internal liquid (solvent / non-solvent) is, for example, 40 / 60 to 50 / 50.

[0083] When the spinning dope 10a and the inner liquid 10b are discharged from the double-tube nozzle 11, a temperature difference may be provided between the spinning dope and the inner liquid.

[0084] (Coagulation Liquid) The coagulation liquid preferably contains a solvent and a non-solvent. The solvent and non-solvent may each be a single type, or a mixture of multiple types. If the content of each solvent is too high, the coagulation rate on the outside of the hollow fiber membrane slows, the phase separation time is extended, and a sparse structure is formed on the outside of the hollow fiber membrane. On the other hand, if the content of the solvent is too low, the coagulation rate on the outside of the hollow fiber membrane increases, the phase separation time is shortened, and a dense structure is formed on the outside of the hollow fiber membrane. To obtain a hollow fiber membrane of this embodiment with a dense outside, the ratio of the total amount of solvent and non-solvent in the coagulation liquid (concentration of the coagulation liquid) is preferably 20 to 60% by mass, more preferably 30 to 45% by mass. The mass ratio of the solvent to the non-solvent in the coagulation liquid (solvent / non-solvent) is, for example, 40 / 60 to 50 / 50.

[0085] The temperature of the coagulation liquid also has a significant effect on the coagulation time of the membrane. If the temperature of the coagulation liquid is high, the coagulation rate on the outside of the hollow fiber membrane slows, the phase separation time is extended, and a sparse structure is formed on the outside of the hollow fiber membrane. If the temperature of the coagulation liquid is low, the coagulation rate on the outside of the hollow fiber membrane increases, the phase separation time is shortened, and a dense structure is formed on the outside of the hollow fiber membrane. To obtain the hollow fiber membrane of this embodiment with a dense outside, the temperature of the coagulation liquid is preferably 30 to 70°C, more preferably 40 to 60°C.

[0086] If the coagulation rate on the outside of the hollow fiber membrane, which is determined by the concentration and temperature of the coagulation liquid, is faster than the coagulation rate on the inside of the hollow fiber membrane, which is determined by the concentration of the internal liquid, the inner surface will have a sparse structure and the outer surface will be dense. If the coagulation rate on the outside of the membrane is too fast compared to the inner surface, the outer surface will be excessively dense, which may excessively suppress the permeation of useful components such as IgG, or the thickness of the clogging layer will be reduced, making it easier for the filtration rate to decrease over time. Conversely, if the coagulation rate is too slow, the pore size on the outer surface of the membrane will be large, or the thickness of the virus capture layer will be reduced, allowing viruses and other impurities to pass through. If the coagulation rate is too slow, the inner surface will be dense and the outer surface will be sparse, preventing liquid from penetrating into the membrane from the inner surface. Therefore, in order to obtain the hollow fiber membrane of this embodiment, which has a sparse structure on the inner surface and a dense structure on the outer surface, and which has an asymmetric structure that allows useful components to pass through and blocks impurities, it is important to balance the concentration of the internal liquid, the concentration of the coagulation liquid, and the temperature.

[0087] After membrane production and washing, the resulting hollow fiber membranes are cut to an appropriate length and bundled together. The bundle is left standing for 30 minutes to 2 hours to remove any internal liquid present in the hollow spaces.

[0088] In a further washing step, the bundle from which the internal liquid has been removed is immersed in hot water poured from below while the bundle is standing upright, and then the water is drained, and this process is repeated to completely wash away the solvent and non-solvent from the inside and outside of the hollow portion and the inside of the hollow fiber membranes. The temperature of the hot water is preferably 70°C to 95°C, more preferably 75°C to 90°C.

[0089] After the above-mentioned washing treatment, the hollow fiber membrane is preferably treated with high-pressure hot water. Specifically, it is preferable to set the membrane submerged in water in a high-pressure steam sterilizer and treat it under normal high-pressure steam sterilization conditions, such as a treatment temperature of 120 to 150°C and a treatment time of 20 to 120 minutes.

[0090] After the high-pressure hot water treatment, the hollow fiber membrane is dried and sent to the next cellulose polymer coating treatment process. A wide variety of commonly used drying methods can be used, including air drying, reduced-pressure drying, hot air drying, and microwave drying. The temperature of the hot air used for hot air drying is preferably lower than that used in the hot water heating treatment.

[0091] [Coating Step] In the coating step, the surface of the hollow fiber membrane (porous membrane) (including the inner surface of the porous portion) is coated with a second hydrophilic polymer.

[0092] For example, the hollow fiber membrane obtained as described above is then immersed in a coating solution consisting of a lower alcohol aqueous solution in which a cellulose-based polymer, which is a second hydrophilic polymer, is dissolved, to adhere the cellulose-based polymer to the membrane surface, including the pore surfaces. Examples of lower alcohols include ethanol and 2-propanol. The lower alcohol aqueous solution also contributes to cleaning the hollow fiber membrane, making it possible to remove the vinylpyrrolidone-based polymer that is not completely removed by the high-pressure hot water treatment. In other words, the use of a lower alcohol aqueous solution has the advantage of allowing the removal of excess vinylpyrrolidone-based polymer and the coating treatment to be performed simultaneously.

[0093] The coating solution is preferably an aqueous solution containing 0.1 to 1.0% by mass, more preferably 0.3 to 0.7% by mass, of a cellulose-based polymer and 10 to 30% by mass, more preferably 15 to 25% by mass, of 2-propanol. If the cellulose-based polymer concentration is lower than the above range, the hollow fiber membrane will not be sufficiently hydrophilized. On the other hand, if the concentration is higher than the above range, the viscosity of the aqueous solution will increase, making it difficult to uniformly hydrophilize the entire membrane. Furthermore, by adjusting the lower alcohol concentration to the above range, excessive detachment of the VA copolymer due to the coating solution can be suppressed. Furthermore, immersing the hollow fiber membrane in the above aqueous solution for about 30 minutes is sufficient as a treatment time.

[0094] After the above treatment, the hollow fiber membrane is removed and immersed in warm water for heat treatment. This treatment is performed under reduced pressure conditions of -0.06 to -0.08 MPa (normal pressure), allowing the warm water to penetrate deep into the pores. This treatment stabilizes the cellulose-based polymer coating. In aqueous solutions of cellulose-based polymers at room temperature, the hydroxyl groups in the cellulose form hydrogen bonds between water molecules and cellulose molecules, resulting in weak interactions with the substrate to be coated. Therefore, hot water treatment breaks these hydrogen bonds, causing a conformational change that enhances interactions with the hydrophobic substrate and the first hydrophilic polymer, resulting in rearrangement, thereby forming a stable coating. The temperature of the warm water is preferably 60°C to 95°C, more preferably 80°C to 95°C. The immersion time is preferably 10 to 90 minutes, more preferably 30 to 60 minutes. The hollow fiber membrane of this embodiment can be obtained by again subjecting the hollow fiber membrane obtained in this manner to a drying treatment under the conditions described above.

[0095] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0096] [Example 1] A hollow fiber membrane (porous membrane) of Example 1 was produced by a method basically similar to the hollow fiber membrane production method described in the embodiment. Specific production conditions etc. are as follows.

[0097] (Preparation of spinning dope) 28.5% by mass of polyethersulfone (PES: Ultrason (registered trademark) 6020P manufactured by BASF), 9% by mass of polyvinylpyrrolidone (PVP, Kollidon VA64 manufactured by BASF), 28.125% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 34.375% by mass of triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were mixed and heated to dissolve uniformly, thereby preparing a spinning dope. The spinning dope was degassed by sealing under reduced pressure.

[0098] (Preparation of Internal Solution) An internal solution was prepared by mixing 42.75 mass % of NMP (solvent), 52.25 mass % of TEG (non-solvent), and 5 mass % of water (RO water: water treated with reverse osmosis).

[0099] (Preparation of Coagulation Liquid) A coagulation liquid was prepared by mixing 26 mass % of NMP (solvent), 31 mass % of TEG (non-solvent), and 43 mass % of water (RO water).

[0100] (Coating Liquid) A coating liquid was prepared by mixing 7.5 mass % of 2-propanol (manufactured by Nacalai Tesque, Inc.), 0.5 mass % of hydroxypropyl cellulose (HPC, weight average molecular weight: 50,000, manufactured by Nippon Soda Co., Ltd.), and 92 mass % of water (RO water).

[0101] <Spinning Process> The spinning dope (membrane forming solution) was discharged from the annular portion of a double-tube nozzle (tube-in-orifice nozzle), and the inner liquid (core liquid) was discharged from the center of the double-tube nozzle. Both liquids passed through a dry section (air gap section 20) isolated from the outside air, and then passed through a coagulation liquid 21 and a water washing bath 22, and were taken up at a predetermined speed (spinning speed: take-up speed). The nozzle temperature (discharge temperature) was set to 50°C. The air gap length was 10 mm. The spinning speed was 19 m / min. The spinning speed was the winding speed. The temperature of the coagulation liquid was set to 30°C. The temperature of the water washing bath was set to 55°C. The filamentous material (hollow fiber membrane) pulled up from the coagulation liquid was washed in the water washing bath and then wound up at a predetermined speed (winding speed) by a winder 23. The discharge rates of the dope and the inner solution from the nozzle were adjusted so that the hollow fiber membrane after the spinning process had an inner diameter of 205 μm and a membrane thickness of 65 μm.

[0102] The wound filamentous material (hollow fiber membrane) was cut into 40 cm lengths, and a bundle consisting of 5,000 cut hollow fiber membranes was produced. To remove the internal liquid, the bundle was left standing for 30 minutes. The bundle was then immersed upright in 85°C warm water for a cleaning treatment. The warm water was replaced five times, and the cleaning treatment was repeated. The wet bundle was then quickly submerged in a high-pressure steam sterilizer filled with 40°C warm water, and subjected to high-pressure hot water treatment at 140°C for 20 minutes. Microwave drying was then performed at an internal temperature of 35°C. This high-pressure steam treatment and drying were repeated a total of three times.

[0103] <Coating step with second hydrophilic molecules> Hydroxypropyl cellulose (HPC, manufactured by Nippon Soda Co., Ltd.) was used as the second hydrophilic polymer to coat the surfaces of the hollow fiber membranes (including the inner surfaces of the pores). Specifically, the bundle of hollow fiber membranes obtained above was immersed in the coating solution in a container at 25°C. After sealing the container, the pressure was quickly reduced to -0.07 MPa and the container was left standing for 20 minutes. After that, the container was returned to normal pressure, and the bundle was removed and left standing for 5 minutes in an upright position to remove the treatment solution. Thereafter, the bundle was immersed in an upright position in RO water at 80°C to perform a gelation (insolubilization) treatment of the HPC for 1 hour. Thereafter, microwave drying was performed at an internal temperature of 35°C.

[0104] In this way, a bundle of hollow fiber membranes whose surfaces were coated with HPC was obtained. The inner diameter, outer diameter, and membrane thickness of the hollow fiber membranes measured before drying (as spun) and after drying after the gelation treatment are shown in Table 2.

[0105] [Examples 2 to 5 and Comparative Examples 1 to 3] In Examples 2 to 5 and Comparative Examples 1 to 3, as shown in Tables 1 and 2, at least one of the nozzle temperature, the composition ratio of the coagulation liquid, and the membrane thickness of the hollow fiber membrane after the spinning process was changed from that of Example 1. In Table 1, "%" means "% by mass." For example, in Example 2 and Comparative Example 1, only the membrane thickness of the hollow fiber membrane after the spinning process was changed compared to Example 1. Otherwise, the hollow fiber membranes of Examples 2 to 5 and Comparative Examples 1 to 3 were produced in the same manner as in Example 1. Note that Comparative Examples 2 and 3 correspond to Examples 1 and 2 of Patent Document 1, respectively, and Comparative Examples 2 and 3 used Luvitec VA64 (manufactured by BASF) as the vinylpyrrolidone-based polymer, the same as that used in Examples 1 and 2 of Patent Document 1.

[0106]

[0107] The porous membranes (hollow fiber membranes) of the above Examples and Comparative Examples were subjected to the following measurements. The measurement results are shown in Table 2.

[0108] <Inner Diameter, Outer Diameter, and Membrane Thickness of Hollow Fiber Membranes> The inner diameter (ID), outer diameter (OD), and membrane thickness (Δd) of the hollow fiber membranes (after drying) in the above Examples and Comparative Examples were measured using the following method. An appropriate number of hollow fiber membranes were threaded through a 3 mm diameter hole drilled in the center of a glass slide, ensuring that none of the hollow fiber membranes would fall out. The hollow fiber membranes were then cut with a razor along the top and bottom surfaces of the glass slide to obtain cross-sectional samples of the hollow fiber membranes. The inner and outer diameters of the obtained cross-sectional samples of the hollow fiber membranes were measured using a projector (Nikon PROFILE PROJECTOR V-12). Specifically, the dimensions of the outer surface of each hollow fiber membrane cross section were measured in the X-X and Y-Y directions (two perpendicular directions on the cross section), and the arithmetic mean of these values ​​was used as the outer diameter of each hollow fiber membrane cross section. Furthermore, the dimensions of the hollow portion in the X-X direction and the Y-Y direction (two perpendicular directions on the cross section) were measured for each hollow fiber membrane cross section, and the arithmetic average was taken as the inner diameter of one hollow fiber membrane cross section. Similar measurements were performed on 10 cross sections, and the average values ​​were taken as the inner diameter and outer diameter. The membrane thickness (average value) was calculated using the formula "(outer diameter - inner diameter) / 2" based on the measurement results (average value) of the inner and inner diameters of the hollow fiber membrane.

[0109] <SEM Image> SEM images of the cross section of the hollow fiber membrane were obtained using the following procedure. (1) The hollow fiber membrane was lightly washed with water, and the sample was frozen in liquid nitrogen and cut. (2) The obtained sample was fixed to a sample stage so that the cut surface could be observed, and carbon deposition was performed by sputtering. (3) The carbon-deposited sample was observed using a scanning electron microscope (Hitachi S-2500) at an accelerating voltage of 10 kV, and an SEM image was obtained.

[0110] Figure 5A shows an SEM image of a cross section of the porous membrane (hollow fiber membrane) of Example 1. Figure 6 shows an SEM image of a cross section of the porous membrane (hollow fiber membrane) of Example 4. Figures 5A and 6 confirm that the hollow fiber membranes of Examples 1 and 4 have an asymmetric structure, with the inner surface being sparse and the outer surface being dense.

[0111] <Preparation of hollow fiber membrane module> A hollow fiber membrane bundle was inserted into a cylindrical container, and both ends were fixed with adhesive. The ends were cut to obtain a module equipped with a hollow fiber membrane bundle with both ends open. The number of hollow fiber membranes was appropriately determined. In addition, ports were provided at two locations on the cylindrical surface of the cylindrical container, allowing fluid to perfuse both the outer and inner surfaces of the hollow fiber membranes.

[0112] <Gold Colloid Filtration Test> (Preparation of Gold Colloid Dispersion) 6 mL of a 20 nm gold colloid homogeneous solution (Gold Colloid, manufactured by BBI Solutions) was mixed with 3 mL of a 2.0 mass% aqueous solution of bovine serum albumin (Albumin, Bovine Serum, F-V, pH 5.2, manufactured by Nacalai Tesque, Inc.), and then 3 mL of a 0.4 mass% aqueous solution of glutathione (reduced form) (manufactured by Nacalai Tesque, Inc.) was added to prepare a 20 nm gold colloid dispersion. Similarly, a 30 nm gold colloid dispersion was also prepared separately.

[0113] (Filtration Test) Using the hollow fiber membrane module prepared above, the above-mentioned gold colloid dispersion (20 nm gold colloid dispersion or 30 nm gold colloid dispersion) was subjected to dead-end filtration at a pressure of 1000 hPa for 5 minutes (see FIG. 4).

[0114] (Measurement of the Thickness of the 20-nm Gold Colloid Capture Layer) For the hollow fiber membrane after the filtration test, the thickness of the layer (capture layer) capturing 20-nm gold colloid (or 30-nm gold colloid) was measured as follows. (1) The filtration hollow fiber membrane (sample) was positioned under a microscope at a magnification of 100 × 1000 so that the inner surface of the membrane's thickness portion (cross section) was captured from the outer surface side, and an image of the cross section was then taken at an image size of 1600 × 1200 pixels. Note that the cross-sectional image taken with the microscope for Example 1 is shown in Figure 5B. (2) The captured image was binarized using binarization software (WinROOF 2013) using the following procedure to determine the thickness of the gold colloid capture layer. a. The image was imported into the binarization software, and the "monochrome image" option was selected from the image processing options to convert the captured cross-sectional image to black and white. b. A rectangular area with one side equal to or greater than the film thickness and the other side 1 μm long was selected from the inner surface to the outer surface of the membrane thickness. c. "Automatic binarization" was performed, and a histogram was displayed with density values ​​on the horizontal axis and pixel counts on the vertical axis. d. "Discrimination analysis" was selected to separate the binary image of the cross section photographed with a microscope (the above histogram) into peaks stained by the captured gold colloid and peaks unstained. e. In the above histogram, the distance between the peaks stained with gold colloid and the peaks unstained was divided into thirds, and the density value at one-third of the way from the stained area was set as the binarization threshold. f. The area where gold colloid was captured was determined as a continuous area with two or more adjacent pixels displayed in color by binarization within the membrane cross section. g. The distance in the film thickness direction between the innermost and outermost areas where gold colloid was captured was measured, and this was determined as the thickness of the gold colloid capture layer. In FIG. 5B, the thickness of the gold colloid capturing layer is the length of the arrow in the figure.

[0115] (Measurement of the ratio a / b) For the hollow fiber membrane after the filtration test, a [the distance from the inner surface of the hollow fiber membrane to the outermost position of the first trapping layer (20 nm gold colloid trapping layer)] and b [the distance from the inner surface of the hollow fiber membrane to the outermost position of the second trapping layer (30 nm gold colloid trapping layer)] were measured in the same manner as in the binarization of the photographed image of the hollow fiber membrane cross section. The ratio a / b was calculated from the measured values ​​of a and b.

[0116] <Virus removal performance: LRV at low pH> The LRV was measured for the virus removal performance of a hollow fiber membrane for a low pH (pH: 5.2) solution using the following procedure. (Preparation of measurement solution) The measurement solution was prepared by adjusting the pH of an aqueous solution containing phage to 5.2. (Procedure) (1) Using the hollow fiber membrane module, the measurement solution was subjected to dead-end filtration (see Figure 4), and the filtrate was collected. (2) Pseudomonas aeruginosa was cultured in a medium to which the collected filtrate had been added. If the filtrate contained phage, the number of Pseudomonas aeruginosa plaques would increase. (3) After culturing for a predetermined time, the number of plaques was counted. The bacterial titer was determined from the number of plaques, and the log reduction value (LRV) was calculated using the following formula: LRV = log １０ (1-potency of filtrate / potency of test solution)

[0117] <Filtration Flow Rate: Throughput> The filtration flow rate (throughput) per membrane area of ​​the hollow fiber membrane module was measured using the following procedure. (Preparation of Measurement Solution) An aqueous solution containing 0.5% by mass of IVIG (an antibody plasma fraction preparation) and phage was prepared as the measurement solution. (Calculation of Membrane Area) The total surface area (membrane area) of the hollow fiber membrane module was calculated using the following formula based on the inner diameter of the hollow fiber membrane: Membrane Area = n × π × ID × L, where n is the number of hollow fiber membranes in the module, π is the ratio of the circumference of a circle to its diameter, ID is the inner diameter of the hollow fiber membrane [m], and L is the effective length of the hollow fiber membrane in the module [m]. (Procedure) (1) The measurement solution was subjected to dead-end filtration using the hollow fiber membrane module (see Figure 4), and the filtrate was continuously collected. (2) The total weight of the continuously collected filtrate was continuously measured (monitored). (3) From the difference between the total weight of the filtrate at 59 minutes and 60 minutes after the start and the above membrane area, the filtration flow rate (throughput) per membrane area at 60 minutes was calculated using the following formula: Filtration flow rate = (total weight of the filtrate at 60 minutes - total weight of the filtrate at 59 minutes) / membrane area

[0118] Table 2 shows the inner diameter, outer diameter, and membrane thickness of the hollow fiber membrane, the thickness of the 20 nm gold colloid capture layer, the ratio a / b, the LRV at low pH, and the filtration flow rate after 60 minutes, all of which were measured as described above.

[0119]

[0120] The results shown in Table 2 indicate that the LRV of the hollow fiber membrane module increases significantly when the thickness of the 20 nm gold colloid capture layer is 16.5 μm or greater. Furthermore, it is believed that an LRV of 4.7 or greater, which is desirable for virus removal performance, can be achieved if the thickness of the 20 nm gold colloid capture layer is 20 μm or greater.

[0121] Furthermore, from the values ​​of a / b and filtration flow rate shown in Table 2, it can be seen that when the value of a / b is 1.5 or more, the decrease in throughput over time is suppressed and a larger amount of liquid can be processed before clogging occurs.

[0122] 10a Spinning dope, 10b Inner liquid, 11 Nozzle, 12, 13 Submerged guide, 14, 15, 16 Roller, 20 Air-borne running section, 21 Coagulation liquid, 22 Water washing bath, 23 Winder, 3 Porous membrane (hollow fiber membrane), 4 Large component, 5 Small component.

Claims

1. A porous membrane having a non-uniform structure in the thickness direction where the first surface is hydrophobic and the second surface is hydrophilic, the porous membrane has a first capture layer (20 nm gold colloid capture layer), when the first capture layer allows gold colloids with an average particle size of 20 nm to permeate from the first surface side to the second surface side of the porous membrane, the first capture layer is a layer that captures the gold colloids with an average particle size of 20 nm, the thickness of the first capture layer is 16.5 μm or more, the porous membrane.

2. the porous membrane has a second capture layer, when the second capture layer allows gold colloids with an average particle size of 30 nm to permeate from the first surface side to the second surface side, the second capture layer is a layer that captures the gold colloids with an average particle size of 30 nm, the porous membrane satisfies the relationship where a / b is 1.5 or more, where a is the distance from the first surface to the position on the second surface side of the first capture layer that is the farthest, where b is the distance from the first surface to the position on the second surface side of the second capture layer that is the farthest, the porous membrane according to Claim 1.

3. the porous membrane contains a hydrophobic polymer and a first hydrophilic polymer, the surface of the porous membrane is coated with a second hydrophilic polymer, the porous membrane according to Claim 1 or Claim 2.

4. the hydrophobic polymer is a polysulfone-based polymer, the porous membrane according to Claim 3.

5. the first hydrophilic polymer is at least one of polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate, the porous membrane according to Claim 3.

6. the second hydrophilic polymer is a cellulose-based polymer, the porous membrane according to Claim 3.

7. having the shape of a hollow fiber membrane, where the inner surface of the hollow fiber membrane is the first surface and the outer surface of the hollow fiber membrane is the second surface, the porous membrane according to Claim 1 or Claim 2.

8. for virus removal, the porous membrane according to Claim 1 or Claim 2.

9. A purification method using the porous membrane according to Claim 1 or Claim 2.