WO2016072409A1 - 中空糸濾過膜 - Google Patents
中空糸濾過膜 Download PDFInfo
- Publication number
- WO2016072409A1 WO2016072409A1 PCT/JP2015/081000 JP2015081000W WO2016072409A1 WO 2016072409 A1 WO2016072409 A1 WO 2016072409A1 JP 2015081000 W JP2015081000 W JP 2015081000W WO 2016072409 A1 WO2016072409 A1 WO 2016072409A1
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- WIPO (PCT)
- Prior art keywords
- hollow fiber
- membrane
- hydrophilic polymer
- filtration
- mass
- Prior art date
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- 239000012528 membrane Substances 0.000 title claims abstract description 189
- 239000012510 hollow fiber Substances 0.000 title claims abstract description 118
- 238000001914 filtration Methods 0.000 title claims abstract description 117
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 107
- 239000011148 porous material Substances 0.000 claims abstract description 73
- 229920000642 polymer Polymers 0.000 claims abstract description 42
- 229920002492 poly(sulfone) Polymers 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 13
- 239000004695 Polyether sulfone Substances 0.000 claims description 10
- 229920006393 polyether sulfone Polymers 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 8
- 230000004907 flux Effects 0.000 abstract description 32
- 230000007423 decrease Effects 0.000 abstract description 19
- 241000700605 Viruses Species 0.000 description 49
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 45
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- 102000004169 proteins and genes Human genes 0.000 description 27
- 108090000623 proteins and genes Proteins 0.000 description 27
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- 239000012460 protein solution Substances 0.000 description 23
- 239000011550 stock solution Substances 0.000 description 23
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 23
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 239000012466 permeate Substances 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 239000002033 PVDF binder Substances 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
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- 239000000047 product Substances 0.000 description 3
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 3
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- 230000000007 visual effect Effects 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 241000991587 Enterovirus C Species 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
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- 230000000274 adsorptive effect Effects 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
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- 125000003118 aryl group Chemical group 0.000 description 1
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
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Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
- B01D71/68—Polysulfones; Polyethersulfones
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0016—Coagulation
- B01D67/00165—Composition of the coagulation baths
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
- B01D69/087—Details relating to the spinning process
-
- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
- D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
- D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
- D01F6/76—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from other polycondensation products
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/08—Specific temperatures applied
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/08—Specific temperatures applied
- B01D2323/081—Heating
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/10—Specific pressure applied
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/18—Pore-control agents or pore formers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/20—Plasticizers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/218—Additive materials
- B01D2323/2182—Organic additives
- B01D2323/21839—Polymeric additives
- B01D2323/2187—Polyvinylpyrolidone
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
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- B01D2323/219—Specific solvent system
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/02—Details relating to pores or porosity of the membranes
- B01D2325/022—Asymmetric membranes
- B01D2325/023—Dense layer within the membrane
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/36—Hydrophilic membranes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0081—After-treatment of organic or inorganic membranes
- B01D67/0095—Drying
Definitions
- the present invention relates to a hollow fiber filtration membrane.
- Hollow fiber membranes intended for filtration treatment of solutions containing physiologically active substance solutions such as proteins are widely used in industrial applications such as microfiltration and ultrafiltration, and medical applications such as hemodiafiltration.
- physiologically active substance solutions such as proteins
- virus removal / inactivation methods include heat treatment, optical treatment, chemical treatment, etc., but due to problems such as protein denaturation, inactivation efficiency, chemical contamination, etc.
- Membrane filtration methods that are effective for all viruses, regardless of their nature, are drawing attention.
- the smallest types of viruses are parvoviruses with a diameter of 18 to 24 nm and polioviruses with a diameter of 25 to 30 nm, and relatively large types include HIV viruses with a diameter of 80 to 100 nm.
- virus removal membranes used in the purification process of plasma fractionation preparations and biopharmaceuticals are efficient for proteins such as 5 nm albumin and 10 nm globulin from the viewpoint of productivity as well as virus removal performance. Recovery is required. For this reason, ultrafiltration membranes, hemodialysis membranes having a pore size of several nanometers, and reverse osmosis membranes having a small pore size are not suitable as virus removal membranes because proteins block the pores during filtration. In particular, when aiming at removal of small viruses such as parvovirus, it is difficult to achieve both virus removal performance and efficient protein recovery.
- contaminants such as protein aggregates are always present in a protein solution filtered using a membrane for the purpose of purification of the preparation. Since this contaminant clogs the pores during filtration, it is more difficult to achieve both virus removal performance and efficient protein recovery when filtration is performed under conditions where there are many contaminants.
- Patent Document 1 discloses a virus removal method using a hollow fiber membrane made of regenerated cellulose.
- Patent Document 2 discloses a virus removal membrane having a surface hydrophilized by a graft polymerization method on a hollow fiber membrane made of polyvinylidene fluoride (PVDF) formed by a thermally induced phase separation method.
- PVDF polyvinylidene fluoride
- Patent Document 3 a membrane having a nominal pore diameter of 0.22 ⁇ m modified so that the surface has a negative charge is connected in series to the filtration upstream portion of the virus removal membrane. Disclosed is a method for suppressing a decrease in filtration performance of a virus removal membrane over time by adsorbing a protein aggregate that is a product.
- Patent Document 4 a polysaccharide derivative is coated on a hollow fiber membrane formed from a blend of a polysulfone polymer, a vinyl pyrrolidone, and a vinyl acetate copolymer, whereby vinyl pyrrolidone and acetic acid are coated from the hollow fiber membrane.
- a virus removal membrane in which elution of a vinyl copolymer is suppressed is disclosed.
- the amount of filtration until the filtration pressure is set to 3 bar by performing constant-rate filtration of the immunoglobulin solution at 120 L / (L ⁇ m 2 ⁇ bar) is disclosed.
- Patent No. 4024041 International Publication No. 2003/026779 International Publication No. 2010/098867 Japanese Patent No. 5403444
- the hollow fiber membranes described in Patent Documents 1 and 2 have a thick virus trapping region at the center in the film thickness direction, and can capture a large amount of contaminants, so that the permeation rate (Flux) decreases with time during filtration. It has the feature that does not cause.
- the cellulose membrane described in Patent Document 1 has low strength when wet with water, it is difficult to set a high filtration pressure, and high flux cannot be obtained, so that highly efficient protein recovery is possible. Is difficult.
- the PVDF membrane described in Patent Document 2 is formed by a thermally induced phase separation method. Thermally induced phase separation is difficult to produce an inclined asymmetric structure in which the pore diameter changes in the film thickness direction, and generally forms a homogeneous structure film. Therefore, a high flux cannot be obtained as compared with a film having an inclined asymmetric structure.
- Patent Document 4 describes the resistance to clogging of a membrane, which is evaluated based on a change in pressure of a protein solution at a constant speed, and the fact that the pressure rises during the constant speed filtration is substantially noticeable. Means clogging. Therefore, it is suggested that when the protein solution containing impurities is processed, clogging occurs and the filtration performance is lowered.
- An object of the present invention is to provide a hollow fiber filtration membrane that can suppress and efficiently recover useful components.
- the present inventors have solved the above-mentioned problems by making the content of the hydrophilic polymer in the hollow fiber membrane lower in the inner surface part than in other parts.
- the present invention has been completed.
- a hollow fiber filtration membrane comprising a polysulfone polymer and a hydrophilic polymer and having a large number of pores, An inclined asymmetric porous structure in which the average pore diameter of the pores increases from the outer surface portion to the inner surface portion of the membrane, The content of the hydrophilic polymer in the film is 6.0 to 10.0% by mass, A hollow fiber filtration membrane in which the ratio of the content of the hydrophilic polymer in the inner surface portion to the content of the hydrophilic polymer in the membrane is 0.50 to 0.80.
- [3] The hollow fiber filtration membrane according to [1] or [2], wherein the permeation rate of pure water is 80 to 240 L / (hr ⁇ m 2 ⁇ bar).
- [4] The hollow fiber filtration membrane according to any one of [1] to [3], which has a dense layer having a thickness of 2 to 10 ⁇ m.
- [5] The hollow fiber filtration membrane according to any one of [1] to [4], wherein the polysulfone-based polymer is polyethersulfone.
- [6] The hollow fiber filtration membrane according to any one of [1] to [5], wherein the hydrophilic polymer is a copolymer containing vinylpyrrolidone units.
- the hollow fiber filtration membrane of the present invention When the hollow fiber filtration membrane of the present invention is used, even when a filtration solution containing contaminants such as protein aggregates is filtered, a decrease in flux over time hardly occurs. Therefore, it is suitable as a membrane for removing pathogenic substances such as viruses from protein solutions in the purification process of plasma fractionated preparations and biopharmaceuticals.
- the hydrophilic hollow fiber filtration membrane of this embodiment contains a polysulfone polymer and a hydrophilic polymer.
- the polysulfone-based polymer is a polymer having a sulfone group (—SO 2 —) in its structure, and specific examples thereof include, for example, polyaryl ether sulfone having a repeating unit represented by the following formula 1, The polyether sulfone which has a repeating unit shown by following formula 2 is mentioned, Especially the polyether sulfone which has a repeating unit shown by Formula 2 is preferable.
- the aryl group may contain a substituent such as a functional group or an alkyl group, and the hydrogen atom of the hydrocarbon skeleton may be substituted with another atom such as halogen or a substituent.
- a polysulfone type polymer may be used individually by 1 type, or may be used in mixture of 2 or more types.
- the hydrophilic polymer is not particularly limited as long as it is a polymer that exhibits hydrophilicity and is compatible with the polysulfone polymer, but a copolymer containing a vinylpyrrolidone unit is preferable.
- the copolymer containing a vinylpyrrolidone unit is preferably polyvinylpyrrolidone or a copolymer of vinylpyrrolidone and vinyl acetate from the viewpoint of compatibility with a polysulfone polymer.
- the copolymerization ratio of vinylpyrrolidone and vinyl acetate is preferably 6: 4 to 9: 1 from the viewpoint of protein adsorption on the membrane surface and interaction with the polysulfone polymer in the membrane.
- copolymer of vinyl pyrrolidone and vinyl acetate examples include LUVISKOL (trade name) VA64, VA73 and the like commercially available from BASF.
- LUVISKOL trade name
- VA64, VA73 and the like commercially available from BASF.
- One kind of hydrophilic polymer may be used alone, or two or more kinds of hydrophilic polymers may be mixed and used.
- the hollow fiber filtration membrane of this embodiment is a porous hollow fiber-like membrane having a large number of pores, and the average pore diameter of the pores increases from the outer surface portion to the inner surface portion of the hollow fiber filtration membrane. It has a type-asymmetric porous structure.
- the flux of the membrane is governed by the thickness of the region (dense layer) where the pore diameter is small in the membrane and the pore diameter. Therefore, when the dense layer is blocked, the flux decreases.
- the average pore diameter of the pores decreases from the upstream side of the filtration toward the downstream side of the filtration, large particles can be captured upstream of the filtration, the dense layer is not blocked by the large particles, and the decrease in flux can be suppressed.
- the inner surface portion refers to the film thickness from the inner surface of the membrane (the hollow portion side surface of the hollow fiber membrane) toward the outer surface (the membrane surface opposite to the hollow portion surface in the film thickness direction).
- part points out the range to 5 micrometers in a film thickness direction toward the inner surface from the outer surface of a film
- the hollow fiber filtration membrane has an inclined asymmetric porous structure in which the average pore diameter of the pores increases from the outer surface portion toward the inner surface portion, so that the hollow fiber cross-section is photographed with a scanning electron microscope (SEM).
- SEM scanning electron microscope
- the photographing magnification is set to 50,000 times, and the field of view is set horizontally with respect to the cross section in a cross section perpendicular to the length direction of the hollow fiber or a cross section parallel to the length direction and passing through the center of the hollow portion. .
- the photographing visual field is moved horizontally with respect to the film thickness direction, and the next visual field is photographed.
- This photographing operation is repeated to take a photograph of the film cross section without any gap from the outer surface to the inner surface, and a single film cross-sectional photograph is obtained by combining the obtained photographs.
- the average pore diameter in the range of (2 ⁇ m in the circumferential direction of the membrane) ⁇ (1 ⁇ m from the outer surface to the inner surface side) is calculated, and every 1 ⁇ m from the outer surface to the inner surface side
- the inclined structure of the film cross section is quantified. By such numerical conversion, it can be confirmed that the hollow fiber filtration membrane has an inclined porous structure in which the average pore diameter of the pores increases from the outer surface portion toward the inner surface portion.
- the average pore diameter is calculated by a method using image analysis. Specifically, binarization processing of the hole portion and the real portion is performed using Image-pro plus manufactured by Media Cybernetics. The hole part and the real part are identified based on the brightness, and the part or noise that cannot be identified is corrected with a freehand tool. The edge part which becomes the outline of a void
- holes that are interrupted at the edge of the field of view are also counted (that is, the diameter of a part of the missing holes is calculated as the area of one perfect circle).
- a range of 1 ⁇ m ⁇ 2 ⁇ m calculated as an average pore diameter of 50 nm or less is defined as a dense layer.
- the removal target is Viruses are also included, and the size of the smallest virus, parvovirus, is about 20 nm.
- the molecular size of a protein such as immunoglobulin, which is the main substance to be filtered, is about 10 nm.
- the dense layer is generally designed to capture 20 nm sized viruses and to penetrate 10 nm sized proteins.
- protein solutions such as immunoglobulins that are filtration solutions also contain contaminants such as aggregates of proteins (immunoglobulins and the like).
- This contaminant is contained in a larger amount than the virus, and its size is about 20 to 40 nm. Therefore, the pores of the dense layer may be blocked by this contaminant.
- the permeation rate of the solution, Flux is governed by the rate at which the solution permeates the dense layer, which is the region with the smallest pore diameter in the membrane. Therefore, when the pores are blocked in the dense layer, the flux over time during filtration decreases. To do. In fact, it is empirically known that when the amount of contaminants in the protein solution increases even slightly, the flux is significantly reduced. Thus, in the case of filtration of a protein solution, it is considered that the pores of the dense layer are blocked by impurities having a size of about 20 to 40 nm, which is the main cause of the decrease in flux over time. Moreover, blockage of the pores of the dense layer by the contaminants causes not only reduction in flux but also reduction in virus removal ability.
- the protein monomer which is a useful component, can be effectively removed by suppressing pore clogging in the dense layer during protein solution filtration, and suppressing the decrease in flux and the ability to remove viruses over time during filtration. It is preferable to collect in
- the present inventors have found that the trapping of contaminants on the upstream side of the filtration reduces the content of the hydrophilic polymer on the upstream side of the filtration of the hollow fiber filtration membrane, and the contaminants. It was found that this can be achieved by adsorbing at the upstream side of the filtration. Specifically, the ratio of the “content of hydrophilic polymer in the inner surface portion” and the “content of hydrophilic polymer in the membrane” of the hollow fiber filtration membrane (“content of hydrophilic polymer in the inner surface portion”) It was found that when “rate” / “content ratio of hydrophilic polymer in the membrane”) was 0.50 to 0.80, contaminants were adsorbed to the membrane on the upstream side of the filtration and trapped.
- the value of “content ratio of hydrophilic polymer in inner surface portion” / “content ratio of hydrophilic polymer in film” is more preferably 0.55 to 0.75, and further preferably 0.6 to 0.7. preferable.
- the pore surface in the dense layer is sufficiently hydrophilic. Accordingly, it is preferable that the content of the hydrophilic polymer in the outer surface portion where the dense layer exists is higher than the content of the hydrophilic polymer in the film. That is, the value of “content ratio of hydrophilic polymer in outer surface portion” / “content ratio of hydrophilic polymer in the film” is preferably more than 1.0.
- the “content ratio of the hydrophilic polymer” means the content of the hydrophilic polymer relative to the content of the polysulfone polymer, and specifically, Fourier transform infrared spectroscopy (FT-IR).
- FT-IR Fourier transform infrared spectroscopy
- the filtration upstream side of the hollow fiber filtration membrane that is, the content of hydrophilic polymer in the inner surface portion
- the filtration downstream side of the hollow fiber filtration membrane that is, the content of hydrophilic polymer in the outer surface portion, and in the membrane
- the content of the hydrophilic polymer can be measured by the following method.
- the hollow fiber membrane is cut to a thickness of 10 ⁇ m so as to sandwich a plane perpendicular to the length direction or parallel to the length direction and passing through the center of the hollow portion.
- the cut hollow fiber membrane is sandwiched with a potassium bromide (KBr) plate, and 5 ⁇ 5 ⁇ m is made into one segment, and it is continuously infrared from the inner surface side to the outer surface side in the film thickness direction by microscopic FT-IR. Measure the absorption spectrum. From the measured spectrum, a peak derived from a polysulfone-based polymer (near 1580 cm ⁇ 1 ) and a peak derived from a hydrophilic polymer (for example, a hydrophilic polymer having a carbonyl bond has a vicinity of 1730 cm ⁇ 1 , for example, an ether bond.
- a polysulfone-based polymer near 1580 cm ⁇ 1
- a hydrophilic polymer for example, a hydrophilic polymer having a carbonyl bond has a vicinity of 1730 cm ⁇ 1 , for example, an ether bond.
- the vicinity of 1100 cm ⁇ 1 is detected, and the ratio of the hydrophilic polymer-derived peak / absorbance area ratio of the polysulfone-based polymer-derived peak to the content of the hydrophilic polymer in each divided segment Is calculated.
- the average value of the hydrophilic polymer content in all segments calculated as described above is defined as “the hydrophilic polymer content in the film”.
- the hydrophilic polymer content of the inner surface side (innermost) segment is defined as “the hydrophilic polymer content of the inner surface part” and the hydrophilic polymer content of the outer surface (outermost) segment.
- the content rate is defined as “the content rate of the hydrophilic polymer in the outer surface portion”.
- the content of hydrophilic polymer in the film is 6.0 to 10.0% by mass. It is preferably 6.5 to 9.5% by mass, and more preferably 7.0 to 9.0% by mass.
- the permeation rate of pure water is a measure of the flux of a filtration solution such as a protein solution.
- a filtration solution such as a protein solution.
- the pure water permeation rate of the hydrophilic hollow fiber filtration membrane of the present embodiment is preferably 80 to 240 L / (hr ⁇ m 2 ⁇ bar).
- the permeation rate of pure water is 80 L / (hr ⁇ m 2 ⁇ bar) or more, the filtration time is not too long and the protein can be recovered with high efficiency. Moreover, it is thought that the hole diameter has a size suitable for virus removal as it is 240 L / (hr ⁇ m 2 ⁇ bar) or less.
- the permeation rate of pure water is more preferably 180 to 230 L / (hr ⁇ m 2 ⁇ bar). The permeation rate of pure water can be measured by the method described in the examples.
- the virus removal mechanism in the porous hollow fiber filtration membrane as in this embodiment is considered as follows.
- this solution can be considered as if it permeates through a virus removal layer in which several layers of virus trapping surfaces perpendicular to the permeation direction overlap.
- There is always a distribution in the size of the pores in this plane and the virus is captured in the pores smaller than the size of the virus.
- the virus trapping rate on one side is low, but a high level of virus removal performance is realized by overlapping this layer. For example, even if the virus capture rate on one side is 20%, the entire layer has a virus capture rate of 99.999% by overlapping 50 layers of this plane.
- the dense layer (average pore diameter is 50 nm or less). It is preferable to increase the thickness. However, if the dense layer is too thick, the flux when the protein solution is filtered decreases, so the thickness of the dense layer is preferably 2 to 10 ⁇ m.
- a blood donated venoglobulin manufactured by Mitsubishi Tanabe Seiyaku Co., Ltd.
- IH 5% 2.5 g / 50 mL
- the filtration pressure is preferably 2.0 bar.
- the protein solution containing contaminants was filtered and the change in flux over time was evaluated. That's fine.
- the flux ratio immediately after the start of filtration and 60 minutes after the start of filtration may be considered.
- the Flux ratio, F 60 / F 20 , 20 minutes after the start of filtration (F 20 ) and 60 minutes after the start of filtration (F 60 ) is preferably 0.60 or more.
- the parvovirus clearance of the hollow fiber filtration membrane of the present embodiment is preferably 4.0 or more and more preferably 5.0 or more as a virus log removal rate (LRV).
- the parvovirus is preferably a porcine parvovirus (PPV) because it is close to a real liquid and easy to operate.
- the LRV of PPV can be measured by the method described in Examples.
- the method for producing the hollow fiber filtration membrane is not limited, but as an example, a polysulfone-based polymer, a hydrophilic polymer, and a solvent are mixed and dissolved, and a defoamed one is used as a membrane-forming stock solution. (Inner liquid), and simultaneously discharge from the annular part and the center part of the double pipe nozzle (spinner), respectively, lead to the coagulation liquid through the idle running part to form a hollow fiber, wind up after washing with water, hollow fiber
- the method include draining the internal liquid, heat treatment, and drying. Specifically, it is preferably manufactured by a manufacturing method having the following steps.
- Have The air travel time from when the hollow fiber membrane is pulled up from the coagulation bath to when it is introduced into the washing tank is 10 to 80 seconds.
- any solvent can be used as long as it is both a polysulfone-based polymer and a hydrophilic polymer used, and both are compatible.
- Specific examples include N-methyl-2-pyrrolidone (NMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), dimethyl sulfoxide, ⁇ -caprolactam, among others.
- Amide solvents such as NMP, DMF and DMAc are preferred, and NMP is more preferred.
- Non-solvent it is preferable to add a non-solvent to the film-forming stock solution.
- the non-solvent used include glycerin, water, and a diol compound, and among them, those having an ethylene glycol structure are preferable.
- the diol compound has a hydroxyl group at both ends of the molecule, and the one having an ethylene glycol structure is represented by the following formula 3 and has a repeating unit n of 1 or more.
- Specific examples of the diol compound include diethylene glycol (DEG), triethylene glycol (TriEG), tetraethylene glycol (TetraEG), polyethylene glycol, and the like. DEG, TriEG, and TetraEG are preferable, and TriEG is more preferable.
- the mass ratio of the solvent / non-solvent in the membrane forming stock solution is preferably about the same amount, but is preferably 35/65 to 65/35.
- the amount of the non-solvent of the compounds added to the film-forming stock solution other than the solvent and the solute (polysulfone polymer and hydrophilic polymer) described above
- the coagulation is moderately fast. Therefore, it is difficult to produce an excessively large pore diameter, and it is easy to obtain a filtration membrane having a preferred membrane structure as a filtration membrane for protein solution processing.
- the amount of the non-solvent is 35/65 or less because the progress of solidification is not too fast, so that an excessively small pore diameter is hardly generated and a macro void that becomes a structural defect is hardly generated.
- the concentration of the polysulfone polymer in the membrane forming stock solution is preferably 15 to 35% by mass, more preferably 20 to 30% by mass. Lowering the polysulfone-based polymer concentration in the membrane-forming stock solution increases the porosity, resulting in high permeation performance. However, if the polysulfone-based polymer concentration is too low, the membrane strength decreases and the pore size increases. May be incurred. On the other hand, a polysulfone polymer concentration of 35% by mass or less is preferable because the porosity is not too low, the permeation performance can be maintained, and the virus capture capacity of the membrane can be kept high.
- the concentration of the hydrophilic polymer in the membrane forming stock solution is preferably 5 to 12% by mass.
- the hydrophilic polymer concentration is 5% by mass or more, the resulting film is sufficiently hydrophilic. For this reason, even when it is used for filtration of a physiologically active substance, it is preferable from the viewpoint that the physiologically active substance is hardly adsorbed on the membrane and the flux is hardly lowered.
- the hydrophilic polymer concentration by setting the hydrophilic polymer concentration to 12% by mass or less, the amount of the hydrophilic polymer on the pore surface in the obtained film falls within an appropriate range, and the pore diameter is excessively increased depending on the thickness of the hydrophilic polymer. Since it does not become small, it is preferable. Moreover, it is preferable also from a viewpoint of preventing the sticking with which hollow fibers adhere after drying.
- the membrane forming stock solution can be obtained, for example, by dissolving a polysulfone polymer, a hydrophilic polymer, a solvent, and a non-solvent at a constant temperature while stirring.
- the temperature at this time is preferably 30 to 60 ° C., which is higher than normal temperature.
- a compound containing nitrogen of 3rd grade or less (NMP, vinylpyrrolidone) is oxidized in the air, and the oxidation proceeds more easily when heated. Therefore, it is preferable to prepare the film forming stock solution in an inert gas atmosphere.
- the inert gas include nitrogen and argon, and nitrogen is preferable from the viewpoint of production cost.
- a defoaming process can be performed as follows, for example.
- the tank containing the film-forming stock solution in which the solute is completely dissolved is heated to 50 ° C., depressurized to 2 kPa, and left to stand for 1 hour or longer. This operation is preferably repeated 7 times or more.
- the solution may be stirred during the defoaming.
- the same components as those used for the film-forming stock solution and the coagulation liquid for the internal solution used at the time of film formation are preferable to use the same components as those used for the film-forming stock solution and the coagulation liquid for the internal solution used at the time of film formation.
- the internal solution is composed of NMP, TriEG and water. Is preferred.
- the amount of the solvent in the internal liquid increases, there is an effect of delaying the progress of coagulation and slowly progressing the formation of the film structure.
- the mass ratio of the solvent / non-solvent in the internal liquid is preferably 35/65 to 65/35, The amount may be approximately the same.
- the mass ratio of the organic component / water in the non-solvent is preferably 70/30 to 100/0.
- the spinneret temperature is preferably 40 to 60 ° C. in order to obtain an appropriate pore size.
- the residence time of the free running portion is preferably 0.01 to 0.75 seconds, more preferably 0.05 to 0.4 seconds, from the viewpoint of controlling the progress of solidification to obtain a preferable film structure.
- the draft ratio is preferably 1.1 to 6.0, and more preferably 1.1 to 4.0, in order to control stretching into the hollow fiber membrane in the spinning process.
- the draft ratio means the ratio between the take-up speed and the film-forming stock solution discharge linear speed from the spinning nozzle.
- a high draft ratio means a high stretch ratio after being discharged from the spinning nozzle.
- the coagulation liquid can be composed of organic solvent / non-solvent other than water, water, and hydrophilic polymer.
- the composition of the coagulation liquid has a mass ratio of solvent / non-solvent of 35/65 to 65/35.
- the mass ratio of organic component / water is preferably 70/30 to 10/90.
- the coagulation bath temperature is preferably 30 to 60 ° C. in order to obtain an appropriate pore size.
- the spinning speed is not particularly limited as long as a hollow fiber membrane having no defect is obtained, but it is preferably 5 to 15 m / min.
- the hollow fiber membrane pulled up from the coagulation bath travels in the air and is introduced into the washing tank.
- the traveling time in the air from when the hollow fiber membrane is pulled up from the coagulation bath to being introduced into the washing tank is usually about a few seconds, but according to the study by the present inventors, this traveling in the air It was found that when the time is increased, the content of the hydrophilic polymer in the inner surface portion of the hollow fiber membrane can be lowered. Although the mechanism is not clear, it is considered as follows. In the hollow part of the hollow fiber membrane pulled up from the coagulation bath, a good solvent of a polysulfone polymer and a hydrophilic polymer exists.
- the inner surface side comes into contact with a solution containing a good solvent for the polysulfone polymer and the hydrophilic polymer, and the outer surface side is in contact with air. It comes into contact.
- the inner surface side is in direct contact with the solution containing the good solvent, so that the entanglement between the polysulfone polymer and the hydrophilic polymer is weakened. It is considered that the hydrophilic polymer diffuses and moves to the solvent in the hollow part.
- the hydrophilic polymer does not easily move on the outer surface and other parts as occurs on the inner surface side. If the residence time in the air until the hollow fiber membrane pulled up from the coagulation bath is introduced into the washing tank is too long, the content of the hydrophilic polymer in the inner surface portion becomes too low, and conversely, this is shortened. If the amount is too much, the content of the hydrophilic polymer at the inner surface portion is not sufficiently lowered. Therefore, in order to make the content of the hydrophilic polymer at the inner surface portion within an appropriate range, the residence time in the air is set to 10-80. Seconds are preferable, and 15 to 80 seconds are more preferable. Further, by making this residence time not too long, the content of the hydrophilic polymer in the outer surface portion can be made higher than the content of the hydrophilic polymer in the film.
- the hollow fiber membrane that has traveled in the air is introduced into a water washing tank and washed with warm water.
- the hollow fiber membrane is dried while containing the solvent, the solvent is concentrated in the membrane during drying, and the polysulfone polymer may dissolve or swell, thereby changing the membrane structure and fixing to the membrane.
- the hydrophilic polymer that has not been converted remains, the pores may be blocked and the permeability of the membrane may be reduced.
- the temperature of hot water is preferably 50 ° C. or higher in order to increase the diffusion rate of the solvent / non-solvent to be removed and the hydrophilic polymer not immobilized on the membrane and increase the washing efficiency.
- the rinsing process preferably uses a Nelson roller. In order to perform sufficient washing with water, the residence time of the hollow fiber membrane in the washing bath is preferably 80 to 300 seconds.
- the hollow fiber membrane pulled up from the water washing bath is wound around a cassette by a winder.
- the hollow fiber membrane wound around the cassette is cut at both ends to be bundled and held by the support so as not to loosen.
- the gripped hollow fiber membrane is immersed and washed in hot water in the hot water treatment step.
- a cloudy liquid may remain in the hollow portion of the hollow fiber membrane in the state of being wound around the cassette. In this liquid, particles of a polysulfone polymer having a nanometer to micrometer size are suspended. If the hollow fiber membrane is dried without removing the white turbid liquid, the fine particles may block the pores of the hollow fiber membrane and the membrane performance may be lowered. Therefore, it is preferable to remove the liquid in the hollow portion.
- the hydrophilic polymer that has not been removed in the water washing step and not fixed to the membrane is efficiently removed.
- the temperature of hot water is preferably 50 to 100 ° C., and the washing time is preferably 30 to 120 minutes. The hot water is preferably changed several times during washing.
- the wound hollow fiber membrane is preferably further subjected to high-pressure hot water treatment.
- the hollow fiber membrane is preferably immersed in water and placed in a high-pressure steam sterilizer and treated at 120 ° C. or higher for 2 to 6 hours.
- this high-pressure hydrothermal treatment not only completely removes the solvent / non-solvent that remains in the hollow fiber membrane and the hydrophilic polymer not fixed to the membrane, but also polysulfone.
- the existence state of the base polymer and the hydrophilic polymer is optimized (specifically, the hydrophilic polymer covers the surface of the pores so that the pore diameter is not excessively reduced), and it is considered that the structure is preferable as a virus removal membrane. It is done.
- the processing time may be longer than the above, this optimization is completed within a processing time of 6 hours or less, so that it is preferable to set it to 6 hours or less from the viewpoint of production efficiency.
- the hollow fiber filtration membrane of the present embodiment is not particularly limited, such as air drying, reduced pressure drying, hot air drying, etc., but should be dried with both ends of the hollow fiber membrane fixed so that the membrane does not shrink during drying. Is preferred.
- Inner Diameter Measurement, Film Thickness Measurement The inner diameter and outer diameter of the hollow fiber membrane were determined by photographing a vertical split section of the membrane with a stereomicroscope. The film thickness was defined as (outer diameter ⁇ inner diameter) / 2. The membrane area was calculated from the inner diameter and the hollow fiber length.
- the average pore diameter in the range of (2 ⁇ m in the circumferential direction of the membrane) ⁇ (1 ⁇ m from the outer surface to the inner surface side) is calculated, and the membrane cross section is taken every 1 ⁇ m from the outer surface to the inner surface side.
- the slant structure was quantified.
- the average pore diameter was calculated as follows. Using Image-pro plus made by Media Cybetics, the hole part and the real part are identified based on the brightness, and the edge part that becomes the outline of the hole part is corrected by the free hand tool for the part and noise that could not be identified. In addition, the porous structure observed in the back of the hole part was identified as the hole part, and the binarization process of the hole part and the real part was performed.
- the hole diameter was calculated on the assumption that the area value of holes / piece was a perfect circle.
- the pores that were interrupted at the edge of the field of view were also counted and implemented for every hole, and the average pore diameter was calculated for each range of 2 ⁇ m ⁇ 1 ⁇ m.
- a range having an average pore diameter of 50 nm or less was defined as a dense layer, and a range having an average pore diameter of more than 50 nm was defined as a coarse layer.
- Thickness of dense layer The thickness of the dense layer was set to the number in the range showing the average pore diameter of 50 nm or less in (6) ⁇ 1 ( ⁇ m).
- the content of the hydrophilic polymer of the segment present on the innermost side is expressed as “content of hydrophilic polymer in the inner surface part” Rate ”, the content of hydrophilic polymer in the outer surface side (outermost) segment, the content of hydrophilic polymer in the outer surface region, and the average value of the content of hydrophilic polymer in all segments The content of the hydrophilic polymer in the medium ”.
- Example 1 Polyethersulfone (PES) 27 parts by mass (BASF Ultrason (trade name) E6020P), vinylpyrrolidone and vinyl acetate copolymer (BASF Luviskol (registered trademark) VA64, hereinafter referred to as “VA”) 9 After mixing 50 parts by mass, 30.4 parts by mass of N-methyl-2-pyrrolidone (NMP) (manufactured by Kishida Chemical Co., Ltd.) and 33.6 parts by mass of triethylene glycol (TriEG) (manufactured by Kanto Chemical Co., Ltd.) A solution obtained by repeating vacuum degassing 7 times was used as a film forming stock solution. The spinneret temperature is set to 50 ° C.
- NMP N-methyl-2-pyrrolidone
- TriEG triethylene glycol
- the membrane forming stock solution is discharged, and a mixed liquid of NMP 45.1 parts by mass, TriEG 49.9 parts by mass and water 5 parts by mass is contained from the center.
- the liquid was discharged.
- the discharged film forming solution and the internal solution pass through the idle running part, and then run in a coagulation bath filled with a coagulating liquid consisting of 30 ° C., NMP 28.5 parts by mass, TriEG 31.5 parts by mass and water 40 parts by mass. I let you.
- the hollow fiber membrane pulled out from the coagulation bath was allowed to run in the air for 15 seconds, then was run in a water washing tank set at 55 ° C., and was finally wound up in water.
- the spinning speed was 8 m / min and the draft ratio was 2.
- the wound hollow fiber membrane was cut at both ends, bundled, held by a support so as not to loosen, immersed in hot water at 80 ° C., and washed for 60 minutes.
- the washed hollow fiber membrane was subjected to high-pressure hot water treatment at 128 ° C. for 6 hours and then vacuum-dried to obtain a porous hollow fiber filtration membrane.
- Example 2 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the air travel time after leaving the hollow fiber membrane coagulation bath was changed to 30 seconds.
- Example 3 A hollow fiber membrane was obtained in the same manner as in Example 1, except that the air travel time after leaving the hollow fiber membrane coagulation bath was changed to 70 seconds.
- Example 4 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the coagulating liquid composition was changed to 19 parts by mass of NMP, 21 parts by mass of TriEG, and 60 parts by mass of water.
- Example 5 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the coagulating liquid composition was changed to 9.5 parts by mass of NMP and 10.5 parts by mass of TriEG.
- Example 6 Example 5 except that the composition of the film forming solution was changed to 26 parts by mass of PES, 10 parts by mass of VA, 32 parts by mass of NMP, 32 parts by mass of TriEG, and the composition of the inner solution was changed to 42.8 parts by mass of NMP, 52.2 parts by mass of TriEG, and 5 parts by mass of water. In the same manner, a hollow fiber membrane was obtained.
- Example 7 The composition of the film forming solution is 24 parts by mass of PES, 12 parts by mass of VA, 30.4 parts by mass of NMP, 33.6 parts by mass of TriEG, the composition of the inner solution is 52.8 parts by mass of NMP, 42.2 parts by mass of TriEG, 5 parts by mass of water, A hollow fiber membrane was obtained in the same manner as in Example 1 except that the composition was changed to 38.9 parts by mass of NMP, 31.1 parts by mass of TriEG, and 30 parts by mass of water.
- Example 8 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the composition of the membrane forming solution was changed to 27 parts by mass of PES, 8 parts by mass of VA, 30.9 parts by mass of NMP, and 34.1 parts by mass of TriEG.
- Example 9 The composition of the film-forming solution is 26 parts by mass of PES, 10 parts by mass of VA, 30.4 parts by mass of NMP, 33.6 parts by mass of TriEG, and the composition of the coagulation bath is 38.3 parts by mass of NMP, 46.7 parts by mass of TriEG, 15 parts by mass of water, A hollow fiber membrane was obtained in the same manner as in Example 6 except that the temperature was changed to 20 ° C. and the spinning speed was changed to 5 m / min.
- Table 1 shows the measurement results of (1) to (8) for the hollow fiber membranes obtained in Examples 1 to 9. All of the hollow fiber membranes obtained in Examples 1 to 9 suppressed protein adsorption to the pore surface during filtration and were excellent in protein permeability. In addition, even in the presence of impurities, the decrease in flux over time during protein solution filtration was suppressed, and the performance of the useful components was excellent.
- Example 1 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the air travel time after leaving the hollow fiber membrane coagulation bath was changed to 3 seconds.
- Table 1 shows the measurement results of (1) to (8) for the hollow fiber membrane obtained in Comparative Example 1. Since the hollow fiber membrane obtained in Comparative Example 1 had a short air travel time after leaving the coagulation bath, the content of the hydrophilic polymer on the inner surface side was not sufficiently low, and in the presence of impurities. The decrease in flux over time during protein solution filtration could not be suppressed.
- Example 2 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the air travel time after leaving the hollow fiber membrane coagulation bath was changed to 110 seconds.
- Table 1 shows the measurement results of (1) to (8) for the hollow fiber membrane obtained in Comparative Example 2.
- the hollow fiber membrane obtained in Comparative Example 2 had too long a running time in the air after leaving the coagulation bath, so that the content of the hydrophilic polymer on the inner surface side was too low. As a result, not only contaminants but also monomers were adsorbed upstream of the filtration and clogging occurred, resulting in a decrease in flux over time.
- Example 3 A hollow fiber membrane was obtained in the same manner as in Example 6 except that the composition of the membrane forming solution was changed to 26 parts by mass of PES, 12 parts by mass of VA, 29.5 parts by mass of NMP, and 32.5 parts by mass of TriEG.
- Table 1 shows the measurement results of (1) to (8) for the hollow fiber membrane obtained in Comparative Example 3.
- the hollow fiber membrane obtained in Comparative Example 3 has an excessively high content of hydrophilic polymer in the membrane, so that it is possible to suppress the decrease in flux over time during protein solution filtration in the presence of impurities. There wasn't.
- Example 4 A hollow fiber membrane was obtained in the same manner as in Example 1 except that the composition of the membrane forming solution was changed to 27 parts by mass of PES, 7 parts by mass of VA, 31.4 parts by mass of NMP, and 34.6 parts by mass of TriEG. Table 1 shows the measurement results of (1) to (8) for the hollow fiber membrane obtained in Comparative Example 4. In the hollow fiber membrane obtained in Comparative Example 4, the content of the hydrophilic polymer in the membrane was too low, and the flux decreased with time.
- the filtration membrane of this embodiment can be widely used for general filtration.
- it can be suitably used to remove impurities (for example, pathogenic substances such as viruses) from physiologically active substance solutions such as pharmaceuticals and their raw materials and plasma fractionated preparations.
- impurities for example, pathogenic substances such as viruses
- physiologically active substance solutions such as pharmaceuticals and their raw materials and plasma fractionated preparations.
- it can be preferably used when removing impurities from a protein solution containing contaminants such as protein aggregates.
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Abstract
Description
特許文献2には、熱誘起相分離法により製膜されたポリフッ化ビニリデン(PVDF)からなる中空糸膜にグラフト重合法により表面が親水化されたウイルス除去膜が開示されている。
特許文献2に記載のPVDF膜は熱誘起相分離法により製膜されている。熱誘起相分離法は、膜厚方向で細孔の孔径が変化する傾斜型非対称構造を作製し難く、一般的に均質構造膜となる。従って、傾斜型非対称構造を有する膜に比べ、高いFluxを得ることができない。
[1]ポリスルホン系高分子と親水性高分子を含み、多数の細孔を有する中空糸濾過膜であって、
該細孔の平均孔径が、膜の外表面部位から内表面部位に向かって大きくなる傾斜型非対称多孔質構造を有し、
膜中の親水性高分子の含有率が6.0~10.0質量%であり、
内表面部位の親水性高分子の含有率と膜中の親水性高分子の含有率の比が0.50~0.80である
中空糸濾過膜。
[2]外表面部位の親水性高分子の含有率が膜中の親水性高分子の含有率よりも高い、[1]に記載の中空糸濾過膜。
[3]純水の透過速度が80~240L/(hr・m2・bar)である、[1]又は[2]に記載の中空糸濾過膜。
[4]厚みが2~10μmの緻密層を有する、[1]~[3]のいずれか1項に記載の中空糸濾過膜。
[5]前記ポリスルホン系高分子は、ポリエーテルスルホンである、[1]~[4]のいずれか1項に記載の中空糸濾過膜。
[6]前記親水性高分子は、ビニルピロリドン単位を含む共重合体である、[1]~[5]のいずれか1項に記載の中空糸濾過膜。
従って、血漿分画製剤やバイオ医薬品の精製工程において、タンパク質溶液からウイルス等の病原性物質を除去するための膜として好適である。
ポリスルホン系高分子とは、スルホン基(-SO2-)をその構造内に有する高分子であり、具体例としては、例えば、下記の式1で示される繰り返し単位を有するポリアリールエーテルスルホンや、下記式2で示される繰り返し単位を有するポリエーテルスルホンが挙げられ、特に、式2で示される繰り返し単位を有するポリエーテルスルホンが好ましい。
ポリスルホン系高分子は、1種類を単独で使用されても、2種以上混合して使用されてもよい。
親水性高分子は、1種類を単独で使用されても、2種以上を混合して使用されてもよい。
膜のFluxは、膜内で孔径が小さくなっている領域(緻密層)の厚さ、およびその孔径に支配される。従って、緻密層が閉塞されるとFluxが低下する。濾過上流側から濾過下流側に向けて、細孔の平均孔径が小さくなると、濾過上流において大きな粒子を捕捉でき、大きな粒子による緻密層の閉塞が少なく、Fluxの低下を抑制することができる。
本実施形態において、内表面部位とは、膜の内表面(中空糸膜の中空部側表面)から外表面(中空部表面とは膜厚方向に反対側の膜表面)に向かって、膜厚方向に5μmまでの範囲を指す。また、外表面部位とは、膜の外表面から内表面に向かって、膜厚方向に5μmまでの範囲を指す。
この撮影操作を繰り返し、外表面から内表面まで隙間なく膜断面の写真を撮影し、得られた写真を結合することで一枚の膜断面写真を得る。この断面写真において、(膜の円周方向に2μm)×(外表面から内表面側に向かって1μm)の範囲における細孔の平均孔径を算出し、外表面から内表面側に向かって1μm毎に膜断面の傾斜構造を数値化する。
かかる数値化により、中空糸濾過膜が、細孔の平均孔径が外表面部位から内表面部位に向かって大きくなる傾斜型多孔質構造を有することを確認することができる。
本実施形態においては、平均孔径が50nm以下であると算出された1μm×2μmの範囲を緻密層と定義する。
しかし、濾過溶液である免疫グロブリン等のタンパク質溶液中には、タンパク質(免疫グロブリン等)の会合体等の夾雑物も含まれている。この夾雑物はウイルスよりも大量に含まれており、その大きさは約20~40nmである。そのため、この夾雑物により緻密層の孔が閉塞されることがある。
また、夾雑物による緻密層の孔の閉塞は、Flux低下だけではなく、ウイルス除去能の低下も招く。夾雑物により緻密層の孔が閉塞されると、ウイルスを捕捉できる孔が減少し、緻密層におけるウイルス捕捉容量が減少するためである。
したがって、タンパク質溶液濾過中の緻密層での孔の閉塞を抑制し、濾過中の経時的なFluxの低下とウイルス除去能の低下を抑制することで、有用成分であるタンパク質単量体を効率的に回収することが好ましい。
具体的には、中空糸濾過膜の「内表面部位の親水性高分子の含有率」と「膜中の親水性高分子の含有率」の比(「内表面部位の親水性高分子の含有率」/「膜中の親水性高分子の含有率」)が、0.50~0.80であると、夾雑物が濾過上流側で膜に吸着し、捕捉されることが分かった。
この詳細な機構は不明であるが、主な夾雑物であるタンパク質の会合体は、単量体間が疎水性相互作用や静電相互作用により会合し、単量体よりも不安定な構造を有しているため、親水化度が不十分な孔の表面に接触すると、単量体と比較して孔の表面により吸着しやすくなるためと考えられる。
「内表面部位の親水性高分子の含有率」/「膜中の親水性高分子の含有率」の値は、0.55~0.75がより好ましく、0.6~0.7がさらに好ましい。
そして、中空糸濾過膜の濾過上流側、つまり内表面部位の親水性高分子の含有率、中空糸濾過膜の濾過下流側、つまり外表面部位の親水性高分子の含有率、及び、膜中の親水性高分子の含有率は、以下の方法により測定できる。
中空糸膜を、その長さ方向に垂直に、或いは、長さ方向に平行で中空部の中心を通る面を間に挟むように厚さ10μmに切断する。切断した中空糸膜を臭化カリウム(KBr)板ではさみ、5×5μmを1セグメントとし、顕微FT-IRにより透過法で、膜厚方向に内表面側から外表面側まで連続的に赤外吸収スペクトルを測定する。測定したスペクトルよりポリスルホン系高分子由来のピーク(1580cm-1付近)と親水性高分子由来のピーク(例えば、カルボニル結合を有する親水性高分子ならば、1730cm-1付近、例えば、エーテル結合を有する親水性高分子ならば、1100cm-1付近)を検出し、親水性高分子由来ピークの吸光度面積/ポリスルホン系高分子由来ピークの吸光度面積比より、各分割したセグメントの親水性高分子の含有率を算出する。
以上のようにして算出した全セグメントの親水性高分子の含有率の平均値を「膜中の親水性高分子の含有率」とする。
そして、内表面側(最も内側)のセグメントの親水性高分子の含有率を、「内表面部位の親水性高分子の含有率」、外表面側(最も外側)のセグメントの親水性高分子の含有率を、「外表面部位の親水性高分子の含有率」とする。
本実施形態の親水性中空糸濾過膜の純水の透過速度は80~240L/(hr・m2・bar)であることが好ましい。純水の透過速度が80L/(hr・m2・bar)以上であると、濾過時間が長過ぎず、高効率にタンパク質を回収可能である。また、240L/(hr・m2・bar)以下であると、孔径がウイルス除去に適したサイズを有していると考えられる。純水の透過速度は、180~230L/(hr・m2・bar)であることがより好ましい。
なお、純水の透過速度は実施例に記載の方法により測定することができる。
ウイルスを含んだ溶液が多孔質膜を透過する際、この溶液は、あたかも透過方向に対して垂直なウイルス捕捉面が何層も重なったウイルス除去層を透過するかのように考えることができる。この面の中の孔の大きさには必ず分布が存在し、ウイルスのサイズよりも小さな孔の部分でウイルスが捕捉される。この時、一つの面でのウイルス捕捉率は低いが、この面が何層も重なることにより、高いウイルス除去性能が実現される。例えば、一つの面でのウイルス捕捉率が20%であっても、この面が50層重なることにより、全体としてのウイルス捕捉率は99.999%となる。
また、濾過するときの免疫グロブリンの濃度を考えた場合、近年、生産効率を向上させる目的で免疫グロブリン濃度は高くなる傾向にあるので、1.5質量%の濃度とするのが好ましく、溶液中に約5%の二量体以上の会合体が含まれる献血ヴェノグロブリン(田辺三菱製薬社製)IH 5%静注(2.5g/50mL)を希釈して使用するのが好ましい。また、濾過圧力を考えた場合、高圧で濾過すればFluxが高くなり免疫グロブリンの回収効率が向上するが、圧力が高すぎるとフィルターと配管の接続部の密閉性の保持が困難となるため、濾過圧力は2.0barとするのが好ましい。
本実施形態において、中空糸濾過膜の製造方法に限定はないが、一例としては、ポリスルホン系高分子、親水性高分子、溶媒を混合溶解し、脱泡したものを製膜原液とし、芯液(内液)とともに、二重管ノズル(紡口)の環状部、中心部からそれぞれ同時に吐出し、空走部を経て凝固液中に導いて中空糸を形成し、水洗後巻取り、中空糸内液抜き、熱処理、乾燥させる方法が挙げられる。
具体的には、以下のような工程を有する製造方法で製造されることが好ましい。
スルホン系高分子、親水性高分子及び溶媒を含む製膜原液と内液を、それぞれ、二重管ノズルの環状部と中心部から同時に吐出する工程、
前記工程で吐出された吐出物を凝固液中に導いて中空糸膜を形成する工程、及び、
前記中空糸膜を凝固液から引き上げ、空中を走行させた後、水洗槽に導入する工程、
を有し、
前記中空糸膜を凝固浴から引き上げてから水洗槽に導入するまでの空中走行時間が10~80秒である、
中空糸濾過膜の製造方法。
ジオール化合物とは、分子の両末端に水酸基を有するものであり、エチレングリコール構造を有するものとは、下記式3で表され、繰り返し単位nが1以上のものである。
ジオール化合物の具体例としては、ジエチレングリコール(DEG)、トリエチレングリコール(TriEG)、テトラエチレングリコール(TetraEG)、ポリエチレングリコール等が挙げられ、DEG、TriEG、TetraEGが好ましく、TriEGがより好ましい。
内液中の溶媒の量が多くなると、凝固の進行を遅らせ、膜構造形成をゆっくりと進行させる効果がある。非溶媒量が多くなると、一般的には増粘効果により、溶液の拡散を遅らし、凝固の進行を遅らせ、膜構造形成をゆっくりと進行させる効果がある。また、水が多くなると、凝固の進行を早める効果がある。凝固の進行を適切に進行させ、膜構造を制御して好ましい膜構造を得るためには、内液中の溶媒/非溶媒の質量比は、35/65~65/35であることが好ましく、ほぼ同量程度であってもよい。非溶媒中の有機成分/水の質量比は、70/30~100/0にすることが好ましい。
紡糸速度は、欠陥のない中空糸膜が得られる条件であれば特に制限されないが、好ましくは5~15m/minである。
その機構は明らかではないが、以下のように考えられる。
凝固浴から引き上げられた中空糸膜の中空部には、ポリスルホン系高分子と親水性高分子の良溶媒が存在する。従って、凝固浴から引き上げられた中空糸膜が空中を走行している間、内表面側はポリスルホン系高分子と親水性高分子に対する良溶媒を含んだ溶液に接触し、外表面側は空気と接触した状態となる。
このように、中空糸膜が空中を走行している間、その内表面側は良溶媒を含んだ溶液に直接、接触しているため、ポリスルホン系高分子と親水性高分子の絡まり合いが弱まり、親水性高分子が中空部の溶媒に拡散移動すると考えられる。一方、この間、外表面側は空気と接触しているため、外表面やその他の部位では、内表面側で起きているような親水性高分子の移動が起こりにくいと考えられる。
凝固浴から引き上げられた中空糸膜の水洗槽に導入されるまでの空中の滞留時間を長くしすぎると、内表面部位の親水性高分子の含有率が低くなりすぎ、反対に、これを短くしすぎると内表面部位の親水性高分子の含有率が十分低くならないため、内表面部位の親水性高分子の含有率を適切な範囲にするためには、この空中の滞留時間を10~80秒とすることが好ましく、15~80秒とすることがより好ましい。
また、この滞留時間を長くし過ぎないことによって、外表面部位の親水性高分子の含有率を膜中の親水性高分子の含有率より高くすることができる。
中空糸膜の内径及び外径は、膜の垂直割断面を実体顕微鏡で撮影することにより求めた。(外径-内径)/2を膜厚とした。また、膜面積はこの内径と中空糸長さより算出した。
1.0barの定圧デッドエンド濾過による25℃の純水の濾過量(L)を測定し、濾過時間(hr)と膜面積(m2)で除して透過速度(L/hr・m2・bar)を測定した。
中空糸本数が4本、中空糸膜の有効長が8cmになるように組み立てられたフィルターを122℃で60分高圧滅菌処理をした。献血ヴェノグロブリン(田辺三菱製薬社製)IH5%静注(2.5g/50mL)を用いて、溶液の免疫グロブリン濃度が15g/L、塩化ナトリウム濃度が0.1M、pHが4.5になるように溶液を調製した。調製した溶液をデッドエンドで、2.0barの一定圧力で60分濾過を行った。10分間隔で濾液を回収し、10分から20分の濾液回収量(mL)と50分から60分の濾液回収量(mL)の比をF60/F20としてFlux比を測定した。
生物工学会誌 第84巻10号(P392-394)に従い同様の条件で、(3)で調製した溶液のSize Exclusion Chromatography測定を行い、得られたクロマトグラムの各面積値より、免疫グロブリンの濾過試験に用いた濾過溶液中の夾雑物含有量を測定した。
免疫グロブリン濾過試験で用いられた溶液中の免疫グロブリンの単量体/会合体の存在比は94.8/5.2であった。
(3)免疫グロブリンの濾過試験において調製した溶液に0.5容量%のブタパルボウイルス(PPV)溶液をspikeした溶液を濾過溶液とした。(3)免疫グロブリンの濾過試験と同様にして濾過試験を行った。濾液のTiter(TCID50値)をウイルスアッセイにて測定した。PPVのウイルスクリアランス(ウイルス対数除去率(LRV))は、
LRV=Log(TCID50/mL(濾過溶液))―Log(TCID50/mL(濾液))
により算出した。
中空糸膜断面を走査型電子顕微鏡(SEM)により、撮影倍率を50,000倍、中空糸断面の膜厚方向に対して水平に視野を設定して撮影した。設定した一視野での撮影後、膜厚方向に対して水平に撮影視野を移動し、次の視野を撮影した。この撮影操作を繰り返し、膜の外表面から内表面まで隙間なく膜断面の写真を撮影し、得られた写真を結合して一枚の膜断面写真を得た。この断面写真において、(膜の円周方向に2μm)×(外表面から内表面側に向かって1μm)の範囲における平均孔径を算出し、外表面から内表面側に向かって1μm毎に膜断面の傾斜構造を数値化した。
平均孔径は、以下のようにして算出した。Media Cybemetics社製Image―pro plusを用いて、明度を基準に空孔部と実部を識別し、識別できなかった部分やノイズをフリーハンドツールで補正し、空孔部の輪郭となるエッジ部分や、空孔部の奥に観察される多孔構造は空孔部として識別して、空孔部と実部の二値化処理を行った。二値化処理の後、空孔/1個の面積値を真円と仮定し、空孔の直径を算出した。視野の端部で途切れた空孔部についてもカウントして、全ての孔毎に実施し、2μm×1μmの範囲毎に平均孔径を算出した。
平均孔径が50nm以下の範囲を緻密層と定義し、平均孔径が50nm超の範囲を粗大層と定義した。
緻密層の厚みは、(6)において平均孔径50nm以下を示した範囲の数×1(μm)とした。
中空糸膜を厚さ10μm程度に薄膜切片として切り出したものを2枚のKBr板で挟み、プレス機を用いて錠剤を成型した。錠剤としたものをFT-IRの顕微透過法を用いて、5μm×5μmを1セグメントとし、膜厚方向に内表面側から外表面側まで連続的にセグメント毎の赤外吸収スペクトルを測定した。測定したスペクトルよりポリスルホン系高分子由来のピーク(1580cm-1付近)と親水性高分子由来のピーク(1730cm-1付近)を検出し、親水性高分子由来ピークの吸光度面積/ポリスルホン系高分子由来ピークの吸光度面積比より、各分割したセグメントの親水性高分子の含有率を算出した。
上記のようにして算出したセグメントの親水性高分子の含有率のうち、もっとも内側(中空部側)に存在するセグメントの親水性高分子の含有率を「内表面部位の親水性高分子の含有率」、外表面側(最も外側)のセグメントの親水性高分子の含有率を外表面部位の親水性高分子の含有率、全てのセグメントの親水性高分子の含有率の平均値を「膜中の親水性高分子の含有率」とした。 そして、これらの値を用いて、「内表面部位の親水性高分子の含有率」と「膜中の親水性高分子の含有率」、「外表面部位の親水性高分子の含有率」と「膜中の親水性高分子の含有率」の比を算出した。
ポリエーテルスルホン(PES)27質量部(BASF社製Ultrason(商品名)E6020P)、ビニルピロリドンと酢酸ビニルの共重合体(BASF社製Luviskol(登録商標)VA64、以下「VA」と記載する)9質量部、N-メチル-2-ピロリドン(NMP)(キシダ化学社製)30.4質量部、トリエチレングリコール(TriEG)(関東化学社製)33.6質量部を50℃で混合した後、減圧脱泡を7回繰り返した溶液を製膜原液とした。
二重管ノズルの環状部から紡口温度は50℃に設定して、製膜原液を吐出し、中心部からNMP45.1質量部、TriEG49.9質量部及び水5質量部の混合液を内液として吐出した。吐出された製膜原液と内液は、空走部を経てた後、30℃、NMP28.5質量部、TriEG31.5質量部及び水40質量部からなる凝固液を満たした凝固浴中を走行させた。
凝固浴から引き出された中空糸膜は、15秒間空中走行させた後、55℃に設定された水洗槽を走行させ、最後に水中で巻き取った。紡糸速度は8m/minとし、ドラフト比は2とした。
巻き取られた中空糸膜は両端を切断し、束にし、弛まないように支持体に把持させ、80℃の熱水に浸漬し、60分間洗浄した。洗浄された中空糸膜を128℃、6時間の条件で、高圧熱水処理した後、真空乾燥して、多孔質中空糸濾過膜を得た。
中空糸膜の凝固浴を出た後の空中走行時間を30秒間に変更した以外は、実施例1と同様にして中空糸膜を得た。
中空糸膜の凝固浴を出た後の空中走行時間を70秒間に変更した以外は、実施例1と同様にして中空糸膜を得た。
凝固液組成をNMP19質量部、TriEG21質量部、水60質量部に変更した以外は実施例1と同様にして中空糸膜を得た。
凝固液組成をNMP9.5質量部、TriEG10.5質量部に変更した以外は実施例1と同様にして中空糸膜を得た。
製膜原液組成をPES26質量部、VA10質量部、NMP32質量部、TriEG32質量部に、内液組成をNMP42.8質量部、TriEG52.2質量部、水5質量部に変更した以外は実施例5と同様にして中空糸膜を得た。
製膜原液組成をPES24質量部、VA12質量部、NMP30.4質量部、TriEG33.6質量部に、内液組成をNMP52.8質量部、TriEG42.2質量部、水5質量部に、凝固液組成をNMP38.9質量部、TriEG31.1質量部、水30質量部に変更した以外は実施例1と同様にして中空糸膜を得た。
製膜原液組成をPES27質量部、VA8質量部、NMP30.9質量部、TriEG34.1質量部に変更した以外は実施例1と同様にして中空糸膜を得た。
製膜原液組成をPES26質量部、VA10質量部、NMP30.4質量部、TriEG33.6質量部に、凝固浴組成をNMP38.3質量部、TriEG46.7質量部、水15質量部に、凝固浴温度を20℃に、紡糸速度を5m/minに変更した以外は、実施例6と同様にして中空糸膜を得た。
実施例1~9で得られた中空糸膜はいずれも、濾過中の孔表面へのタンパク質の吸着を抑制し、タンパク質の透過性に優れていた。また、夾雑物存在下においても、タンパク質溶液濾過中の経時的なFlux低下を抑制し、有用成分の透過性に優れた性能であった。
中空糸膜の凝固浴を出た後の空中走行時間を3秒間に変更した以外は、実施例1と同様に中空糸膜を得た。
比較例1で得られた中空糸膜について、(1)~(8)について測定した結果を表1に示す。
比較例1で得られた中空糸膜は、凝固浴を出た後の空中走行時間が短かったため、内表面側の親水性高分子の含有率が十分に低くならず、夾雑物存在下でのタンパク質溶液濾過中の経時的なFlux低下を抑制することができなかった。
中空糸膜の凝固浴を出た後の空中走行時間を110秒間に変更した以外は、実施例1と同様に中空糸膜を得た。
比較例2で得られた中空糸膜について、(1)~(8)について測定した結果を表1に示す。
比較例2で得られた中空糸膜は、凝固浴を出た後の空中走行時間が長すぎたため、内表面側の親水性高分子の含有率が低下しすぎた。その結果、濾過上流において、夾雑物だけでなく単量体までもが吸着し、目詰まりが発生したため、経時的なFlux低下が生じた。
製膜原液組成をPES26質量部、VA12質量部、NMP29.5質量部、TriEG32.5質量部に変更した以外は、実施例6と同様に中空糸膜を得た。
比較例3で得られた中空糸膜について、(1)~(8)について測定した結果を表1に示す。
比較例3で得られた中空糸膜は、膜中の親水性高分子の含有率が高くなり過ぎたため、夾雑物存在下でのタンパク質溶液濾過中の経時的なFlux低下を抑制することができなかった。
製膜原液組成をPES27質量部、VA7質量部、NMP31.4質量部、TriEG34.6質量部に変更した以外は、実施例1と同様に中空糸膜を得た。
比較例4で得られた中空糸膜について、(1)~(8)について測定した結果を表1に示す。
比較例4で得られた中空糸膜は、膜中の親水性高分子の含有率が低くなり過ぎたため、経時的なFlux低下が生じた。
特に、医薬品やその原料などの生理活性物質溶液や血漿分画製剤から不純物(例えば、ウイルス等の病原物質)を除去する際に好適に用いることができる。
とりわけ、タンパク質の会合体等の夾雑物を含むタンパク質溶液から不純物を除去する際に好ましく用いることができる。
Claims (6)
- ポリスルホン系高分子と親水性高分子を含み、多数の細孔を有する中空糸濾過膜であって、
該細孔の平均孔径が、膜の外表面部位から内表面部位に向かって大きくなる傾斜型非対称多孔質構造を有し、
膜中の親水性高分子の含有率が6.0~10.0質量%であり、
内表面部位の親水性高分子の含有率と膜中の親水性高分子の含有率の比が0.50~0.80である、
中空糸濾過膜。 - 外表面部位の親水性高分子の含有率が膜中の親水性高分子の含有率よりも高い、
請求項1に記載の中空糸濾過膜。 - 純水の透過速度が80~240L/(hr・m2・bar)である、請求項1又は2に記載の中空糸濾過膜。
- 厚みが2~10μmの緻密層を有する、請求項1~3のいずれか1項に記載の中空糸濾過膜。
- 前記ポリスルホン系高分子は、ポリエーテルスルホンである、請求項1~4のいずれか1項に記載の中空糸濾過膜。
- 前記親水性高分子は、ビニルピロリドン単位を含む共重合体である、請求項1~5のいずれか1項に記載の中空糸濾過膜。
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JP2016557771A JP6522001B2 (ja) | 2014-11-04 | 2015-11-04 | 中空糸濾過膜 |
EP15856904.6A EP3216515B1 (en) | 2014-11-04 | 2015-11-04 | Hollow fiber filtration membrane |
ES15856904T ES2786179T3 (es) | 2014-11-04 | 2015-11-04 | Membrana de filtración de fibras huecas |
US15/523,513 US20170304780A1 (en) | 2014-11-04 | 2015-11-04 | Hollow fiber filtration membrane |
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WO2020203716A1 (ja) * | 2019-03-29 | 2020-10-08 | 旭化成メディカル株式会社 | 多孔質膜 |
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EP3246085A4 (en) * | 2015-01-16 | 2018-01-03 | Asahi Kasei Medical Co., Ltd. | Porous hollow fiber membrane |
US11389765B2 (en) * | 2019-01-09 | 2022-07-19 | Lawrence Livermore National Security, Llc | Hierarchical triply periodic minimal surface structures as heat exchangers and reactors |
US11885568B2 (en) | 2019-01-09 | 2024-01-30 | Lawrence Livermore National Security, Llc | Systems and methods for periodic nodal surface based reactors, distributors, contactors and heat exchangers |
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WO2022208201A1 (en) | 2021-03-30 | 2022-10-06 | 3M Innovative Properties Company | Hollow-fiber membrane comprising polysulfone and polyoxazoline and method making thereof |
CN114570213B (zh) * | 2022-01-17 | 2022-09-30 | 纳美盾新材料有限公司 | 一种改性中空纤维纳滤膜及其制备方法 |
CN115090134B (zh) * | 2022-06-29 | 2023-11-03 | 天津鼎芯膜科技有限公司 | 一种具有梯度孔结构的膜材料及其制备方法和应用 |
WO2024042431A1 (en) | 2022-08-24 | 2024-02-29 | Solventum Intellectual Properties Company | Hollow-fiber membrane made from a polymeric blend comprising an aromatic sulfone polymer and polyoxazoline |
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