Hollow fiber membranes made from polymer blends comprising aromatic sulfone polymers and polyoxazolines

Abstract

The present disclosure provides a hollow fiber membrane. The hollow fiber membrane is made from a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline wherein the polymer blend comprises from 27% to 30% by weight, based on the total weight of the polymer blend, of the aromatic sulfone polymer; wherein the hollow fiber membrane comprises an inner surface facing a lumen thereof, an outer surface facing an exterior, and an intermediate wall having a wall thickness; wherein the hollow fiber membrane is an unitary asymmetric permeable hollow fiber membrane.

Description

Technical Field

[0001] The present disclosure relates to porous membranes. In addition, the present disclosure relates to a method for producing such membranes. The present disclosure also relates to the use of such membranes for filtering and purifying liquid media. Background Art

[0002] Hollow fiber membranes are used for fine filtration in very wide range of different industrial, pharmaceutical or medical applications. In these applications, membrane separation methods are becoming more and more important because these methods provide the advantage that the material to be separated is not subject to thermal load or even undamaged. Ultrafiltration membranes can be used for the removal or separation of macromolecules. Many other applications of membrane separation methods are known from beverage industry, biotechnology, water treatment or sewage technology. Such membranes are usually classified according to their retention capacity (i.e., according to their ability to retain particles or molecules of a certain size) or about the size of the effective pores (i.e., the size of the pores that determine the separation behavior). Ultrafiltration membranes thus cover the size range of the pores that determine the separation behavior between about 0.01 μm and about 0.1 μm, so that particles or molecules in a range of greater than 20000 Dalton or greater than about 200000 Dalton can be retained. Better polymer membranes are needed. Summary of the invention

[0003] Therefore, in one aspect, the present disclosure provides a hollow fiber membrane; the hollow fiber membrane is made of a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline, wherein the polymer blend comprises 27 wt % to 30 wt % of the aromatic sulfone polymer based on the total weight of the polymer blend; wherein the hollow fiber membrane comprises an inner surface facing its lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness; wherein the hollow fiber membrane is an integral asymmetric permeable hollow fiber membrane.

[0004] In another aspect, the present disclosure provides use of the hollow fiber membrane of the present disclosure for filtering antibodies.

[0005] In another aspect, the present disclosure provides a method, comprising flowing a solution containing an antibody through the hollow fiber membrane according to any one of claims 1 ; and collecting the antibody.

[0006] Various aspects and advantages of the exemplary embodiments of the present disclosure have been summarized. The above overview is not intended to describe each illustrated embodiment or each specific implementation of the present disclosure. Additional features and advantages are disclosed in the following embodiments. The following drawings and detailed description more specifically illustrate certain embodiments using the principles disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 is a schematic perspective view of a partial cross-section of an exemplary hollow fiber membrane.

[0008] Figure 2 is a cross-sectional view of an exemplary hollow fiber membrane.

[0009] Figure 3A is a SEM photograph at 4,000x magnification of a cross section of a hollow fiber membrane according to the present disclosure.

[0010] Figure 3B yes Figure 3A SEM image of the cross section at 20,000x magnification. DETAILED DESCRIPTION

[0011] Before explaining any embodiment of the present disclosure in detail, it should be understood that the present invention is not limited in its application to the details of the use, construction and arrangement of the components set forth in the following description. The present invention can have other embodiments and can be practiced or performed in various ways that will become apparent to those of ordinary skill in the art after reading the present disclosure. In addition, it should be understood that the wording and terminology used herein are for descriptive purposes and should not be considered restrictive. The use of "including", "comprising" or "having" and its variations herein is meant to cover the items listed thereafter and their equivalents and additional items. It should be understood that other embodiments can be utilized and structural or logical changes can be made without departing from the scope of the present disclosure.

[0012] According to one embodiment of the present disclosure, the hollow fiber membrane Figure 1 Shown in. Figure 1 A perspective view of a partial cross-section of a portion of an exemplary hollow fiber membrane 12 is shown. The hollow fiber membrane 12 may have: a continuous hollow lumen 16 extending from one end of the fiber to the other end; an outer surface 18 facing outward, which forms the outside of the fiber; an inner surface 20 facing the hollow lumen 16, which defines the boundaries of the continuous hollow lumen 16; and an intermediate wall 22 having a wall thickness 26. The hollow fiber membrane 12 may be made of a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline. The hollow fiber membrane may be an integral asymmetric permeable hollow fiber membrane.

[0013] The wall thickness 26 measured between the outer surface 18 and the inner surface 20 of the hollow fiber membrane 12 may be in a range of 20 μm to 300 μm, 30 μm to 200 μm, or 40 μm to 80 μm.

[0014] Similarly, in order to achieve the desired flow through the lumen of the hollow fiber membrane according to the present disclosure, particularly a favorable pressure drop, it is preferred that the inner diameter of the hollow fiber membrane as described herein is in the range of 50 μm to 800 μm, 50 μm to 700 μm, 50 μm to 600 μm, 100 μm to 500 μm, 100 μm to 400 μm, or 100 μm to 300 μm. The wall thickness and diameter (i.e., inner diameter or lumen diameter, and outer diameter) of the membrane as described herein are also measured by conventional inspection methods, such as using scanning or transmission electron micrographs (SEM or TEM, respectively), for example, with a magnification of up to 20,000: 1. Scanning or transmission electron micrographs are measured. In some embodiments, the hollow fiber membrane may have a tortuous structure extending from the inner surface toward the outer surface. In some embodiments, the hollow fiber membrane may have a tortuous structure or path extending through the entire membrane wall. The invention relates to a kind of hollow fiber membrane.The hollow fiber membrane of the present invention can be used for the preparation ...These tortuous structures can for example help film to retain larger viral contaminants and allow smaller biopharmaceuticals (such as monoclonal antibodies (mAb)) to pass through film.These tortuous structures can increase the possibility of capturing viral contaminants while maintaining high mAb throughput.When hollow fiber membrane has tortuous structures, the hollow fiber membrane can have a small amount of structural defects, i.e. closed pores or large voids.The inner upstream side of the membrane is characterized by a porous surface, and the porous surface is constructed by an isotropic spherulitic structure.When the pore compartment is connected in the membrane and therefore has a tortuous morphology in place, the hollow fiber membrane can have a high transmembrane flow (TMF).

[0015] In some embodiments, the hollow fiber membrane may have two regions: a region with a minimum pore size and a region with a maximum pore size. In some embodiments, the region with the minimum pore size is adjacent to the inner surface. In some embodiments of those embodiments, the region with the maximum pore size is adjacent to the outer surface. In other embodiments, the region with the minimum pore size is adjacent to the outer surface. In some embodiments of these embodiments, the region with the maximum pore size is adjacent to the inner surface. "Adjacent" refers to a region with maximum or minimum pore size located at a distance from the surface in the range of 0 μm to 8 μm. In some embodiments, the size of the pores in the region with the smallest pore size can be in the range of 10nm to 100nm, 10nm to 90nm, 10nm to 80nm, 10nm to 70nm, 10nm to 60nm, 10nm to 50nm, 10nm to 40nm, 10nm to 30nm, 10nm to 20nm, 20nm to 80nm, 20nm to 70nm, 20nm to 60nm, 20nm to 50nm, 30nm to 70nm, 30nm to 60nm, 30nm to 50nm, 30nm to 40nm, 40nm to 90nm, 40nm to 80nm, 40nm to 70nm, 40nm to 60nm, or 40nm to 50nm. In some embodiments, the size of the pores in the region with the minimum pore size can be less than 100nm, 90nm, 80nm, 70nm, 60nm, 50nm, 40nm, 30nm, or 20nm. In some embodiments, the size of the pores in the region with the minimum pore size can be greater than 10nm, 15nm, 20nm, or 25nm. In some embodiments, the size of the pores in the region with the maximum pore size can be in the range of 0.05 μm to 10 μm. The average pore size of the region with the maximum pore size is greater than the average pore size of the region with the minimum pore size. The region with the minimum pore size can form a retaining layer. When the region with the minimum pore size is adjacent to the outer surface, the outer surface of the retaining layer adjacent to the membrane can form a more favorable membrane structure for filtering liquids (e.g., biopharmaceuticals). In some embodiments, at least some pores in the region with the minimum pore size or the region with the maximum pore size can be connected, such as connected by channels between the pores. The pores of these connections can form void spaces in the hollow fiber membrane so that these void spaces can help retain larger viral contaminants, allowing smaller biopharmaceuticals (e.g., mAbs) to pass through the membrane and facilitate collection of samples, such as mAbs after filtration. In some embodiments, the hollow fiber membrane includes a tortuous structure extending in the hollow fiber membrane, for example, extending from the inner surface toward the outer surface. In some embodiments, the hollow fiber membrane has a first pore region and a second pore region, wherein the first pore region is adjacent to the inner surface, and the second pore region is adjacent to the outer surface, and the density of the pores in the first region is greater than the density of the pores in the second region.In some embodiments, the hollow fiber membrane has a first pore region and a second pore region, wherein the first pore region is adjacent to the inner surface and the second pore region is adjacent to the outer surface, and the density of pores in the second region is greater than the density of pores in the first region. In some embodiments, the region with the smallest pore size has a lower flow rate than the region with the largest pore size.

[0016] The average pore size or pore size of the pores can be determined, for example, by the method described in US2017 / 0304780 (Asahi et al.). The average pore size or pore size of the pores can be determined by photographing a cross section of the hollow fiber with a scanning electron microscope (SEM). For example, the shooting magnification is set to 50,000x, and the field of view is set horizontally with the cross section perpendicular to the length direction of the hollow fiber or parallel to the length direction and passing through the center of the hollow part. After shooting the set field of view, the shooting field of view is moved horizontally in the film thickness direction, and the next field of view is shot.

[0017] This photographing operation is repeated until a photograph of the cross section of the membrane crossing from the outer surface to the inner surface is taken without gaps, and the obtained photographs are merged to obtain a membrane cross-sectional photograph. In this cross-sectional photograph, the average pore size of the pores in each zone from the outer surface toward the inner surface side (2 μm in the membrane circumferential direction) × (1 μm from the outer surface toward the inner surface side) is calculated, and the gradient structure of the membrane cross section is quantified every 1 μm from the outer surface toward the inner surface side. Through this quantification, it can be determined whether the membrane has a gradient porous structure.

[0018] The average pore size or pore diameter can be calculated by using an image analysis method. The identification between the pore part and the solid part is based on their brightness, and the unrecognizable parts and noise are corrected by a freehand tool. After the binarization process, the diameter of the pore is calculated from the area value of the pore assuming that the pore is a perfect circle. All pores are calculated, and the average pore size is calculated for each area of ​​1μm×2μm. The pore parts located at the ends of the field of view and partially located in the field of view are also counted (that is, the area of ​​the pore part partially located in the field of view is assumed to be the area of ​​a complete perfect circle to calculate its diameter).

[0019] Another embodiment of the hollow fiber membrane according to the present disclosure is Figure 2 Shown in. Figure 2A cross-sectional view of an exemplary hollow fiber membrane 112 is shown. The hollow fiber membrane 112 may have: a continuous hollow lumen 116 extending from one end of the fiber to the other end; an outer surface 118 facing outward, the outer surface forming the outside of the fiber; an inner surface 120 facing the hollow lumen 116, the inner surface defining the boundaries of the continuous hollow lumen 116; and an intermediate wall 122 having a wall thickness 126. The hollow fiber membrane 112 may have a first cross-sectional area 128 that begins at the inner surface 120 and extends (in some embodiments, laterally) into the interior of the intermediate wall 122, terminating at an inner distance within the intermediate wall 122. In the first cross-sectional area 128, the pore size gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional area in the direction from the inner surface 120 to the outer surface 118 to an intermediate distance between the inner surface and the outer surface, the pore size being measured along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane).

[0020] The hollow fiber membrane 112 may have a second cross-sectional area 130 that begins at the location where the first cross-sectional area ends and extends (in some embodiments, laterally) to the outer surface 118 of the membrane. In the second cross-sectional area 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional area 130 in the direction from the start of the second cross-sectional area in the interior of the wall to the outer surface 118, and the pore size is measured along the vector defining the shortest cross-sectional distance from the start of the second cross-sectional area to the outer surface 118 of the membrane). In some embodiments, the pore size at the outer surface 118 may be smaller than the pore size at the inner surface 120.

[0021] The location in the interior of wall 122 where the first cross-sectional area 128 ends and the second cross-sectional area begins is defined as a transition location.

[0022] exist Figure 2In some embodiments of the hollow fiber membranes shown, the pore size in the first cross-sectional area 128 decreases gradually in the direction of the arrow (i.e., the pore size decreases gradually across the first cross-sectional area 128 in the direction from the inner surface 120 to the outer surface 118 to a distance of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% across the membrane wall, with the pore size measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional area 130, the pore size increases gradually in the direction of the arrow (i.e., the pore size increases gradually across the second cross-sectional area in the direction from the start of the second cross-sectional area in the interior of the wall to the outer surface 118, with the pore size measured along the vector defining the shortest cross-sectional distance from the start of the second cross-sectional area 130 to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be smaller than the pore size at the inner surface 112 .

[0023] exist Figure 2 In some embodiments of the hollow fiber membranes shown, the pore size of the first cross-sectional area 128 decreases gradually in the direction of the arrow (i.e., the pore size decreases gradually across the first cross-sectional area in the direction from the inner surface 120 to the outer surface 118 to a distance of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% across the membrane wall, with the pore size measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional area 130, the pore size increases gradually in the direction of the arrow (i.e., the pore size increases gradually across the second cross-sectional area in the direction from the start of the second cross-sectional area in the interior of the wall to the outer surface 118, with the pore size measured along the vector defining the shortest cross-sectional distance from the start of the second cross-sectional area to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be about 0.05 microns to 0.5 microns, and the pore size at the inner surface 112 may be about 0.05 microns to 5 microns.

[0024] exist Figure 2In some embodiments of the hollow fiber membranes shown, the pore size of the first cross-sectional area 128 decreases gradually in the direction of the arrow (i.e., the pore size decreases gradually across the first cross-sectional area in the direction from the inner surface 120 to the outer surface 118 to a distance of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% across the membrane wall, with the pore size measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional area 130, the pore size increases gradually in the direction of the arrow (i.e., the pore size increases gradually across the second cross-sectional area in the direction from the start of the second cross-sectional area in the interior of the wall to the outer membrane surface, with the pore size measured along the vector defining the shortest cross-sectional distance from the start of the second cross-sectional area to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be about 0.05 microns to 0.5 microns, the pore size at the inner surface 112 may be about 0.05 microns to 5 microns, and the pore size at the transition location may be about 0.015 microns to 0.035 microns.

[0025] exist Figure 2 In some embodiments of the hollow fiber membranes shown, the pore size in the first cross-sectional area 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional area in the direction from the inner surface 120 to the outer surface 118 to a distance of approximately 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-95% across the membrane wall, with the pore size measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane).

[0026] The aperture at the transition position (that is, the first cross-sectional area ends and is transformed to the position at the beginning of the second cross-sectional area) can form at least a portion of the retaining layer or retaining area in the hollow fiber membrane. The retaining layer or retaining area is the section of the hollow fiber membrane with the strongest (that is, the maximum) ability or performance of the small pollutant components of the liquid sample to be captured when the liquid sample is filtered by the membrane. Usually, the liquid sample to be filtered by the hollow fiber membrane contains the desired component preferably collected in the filtrate after filtration and the pollutant component preferably captured by the membrane. The retaining layer or retaining area are mainly based on the size difference of the pollutant and the desired component to filter pollutants from the liquid sample. One or more desired components in the liquid sample have the size that can pass through the retaining layer or retaining area and be collected in the filtrate, thereby producing the liquid sample of purification. For example, when the liquid sample containing both antibodies and viruses passes through the retaining layer or retaining area, in the liquid sample, large viruses (diameter is generally 15nm to 30nm) can be separated from smaller antibodies (diameter is generally 5nm to 10nm). The virus component of the liquid sample can be preferentially retained in the retaining layer or retaining area, while the antibody component of the liquid sample can pass through the retaining layer or retaining area and be collected in the filtrate. In some embodiments, the area with the smallest pore size (retaining layer) has a thickness of 5 μm to 100 μm, 10 μm to 90 μm, 20 μm to 80 μm, 30 μm to 70 μm, or 40 μm to 60 μm.

[0027] In some embodiments, the pore size at the transition location is less than 0.04 microns, less than 0.035 microns, or less than 0.03 microns.

[0028] In some embodiments, the pore size at the transition location is about 0.01 micron to 0.04 micron, 0.01 micron to 0.035 micron, 0.01 micron to 0.03 micron, 0.015 micron to 0.04 micron, 0.015 micron to 0.035 micron, or 0.015 micron to 0.03 micron.

[0029] exist Figure 2In some embodiments of the hollow fiber membrane shown, the pore size in the first cross-sectional area 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional area in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 microns to 50 microns from the outer surface, with the pore size measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional area 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional area in the direction from the start of the second cross-sectional area in the interior of the wall to the outer membrane surface 118, with the pore size measured along the vector defining the shortest cross-sectional distance from the start of the second cross-sectional area to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be smaller than the pore size at the inner surface 120.

[0030] exist Figure 2 In some embodiments of the hollow fiber membrane shown, the pore size in the first cross-sectional region 128 gradually decreases across the first cross-sectional region in a direction from the inner surface 120 to the outer surface 118 to a distance of 3 microns to 15 microns from the outer surface, and the pore size is measured along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane.

[0031] exist Figure 2 In some embodiments of the hollow fiber membrane shown, the pore size in the first cross-sectional region 128 gradually decreases across the first cross-sectional region in a direction from the inner surface 120 to the outer surface 118 to a distance of 3 to 8 microns from the outer surface, and the pore size is measured along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane.

[0032] exist Figure 2 In some embodiments of the hollow fiber membrane shown, the hollow fiber membrane wall thickness is 30 microns to 100 microns, 40 microns to 90 microns, or 50 microns to 65 microns, and the pore size of the membrane at the inner surface facing the lumen gradually decreases across the first cross-sectional area 128 in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 microns to 50 microns from the outer surface, and the pore size is measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane. In the second cross-sectional area 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional area in the direction from the start of the second cross-sectional area in the interior of the wall to the outer surface 118, and the pore size is measured along the vector defining the shortest cross-sectional distance from the start of the second cross-sectional area to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be smaller than the pore size at the inner surface 120.

[0033] exist Figure 2In some embodiments of the hollow fiber membrane shown, the hollow fiber membrane wall thickness is 30 to 100 microns, 40 to 90 microns, or 50 to 65 microns, and the pore size of the membrane at the inner surface facing the lumen gradually decreases across the first cross-sectional area 128 in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 to 50 microns from the outer surface, and the pore size is measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface 118 of the membrane.

[0034] exist Figure 2 In some embodiments of the hollow fiber membrane shown, the hollow fiber membrane wall thickness is 30 microns to 100 microns, 40 microns to 90 microns, or 50 microns to 65 microns, and the pore size of the membrane at the inner surface facing the lumen gradually decreases across the first cross-sectional area 128 in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 microns to 15 microns from the outer surface, and the pore size is measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface 118 of the membrane.

[0035] exist Figure 2 In some embodiments of the hollow fiber membrane shown, the hollow fiber membrane wall thickness is 30 microns to 100 microns, 40 microns to 90 microns, or 50 microns to 65 microns, and the pore size of the membrane at the inner surface facing the tubular cavity gradually decreases across the first cross-sectional area 128 in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 microns to 8 microns from the outer surface, and the pore size is measured along the vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface 118 of the membrane.

[0036] In some embodiments, the pore size at the outer surface is about 0.05 microns to 2 microns, 0.05 microns to 1 micron, or 0.05 microns to 0.5 microns.

[0037] In some embodiments, the pore size at the inner surface is between about 0.05 microns and 5 microns.

[0038] In some embodiments, the pore size at the outer surface is between 0.05 microns and 0.5 microns, the pore size at the inner surface is between about 0.05 microns and 5 microns, and the pore size at the transition location is between about 0.015 microns and 0.04 microns.

[0039] In some embodiments, the pore size at the outer surface is between 0.05 microns and 0.5 microns, the pore size at the inner surface is between about 0.05 microns and 5 microns, and the pore size at the transition location is between about 0.015 microns and 0.035 microns.

[0040] In some embodiments, the pore size at the outer surface is about 0.05 microns to 0.5 microns, the pore size at the inner surface is about 0.05 microns to 5 microns, and the pore size at the transition location is about 0.015 microns to 0.03 microns.

[0041] In some embodiments, the hollow fiber membrane wall thickness is 30 microns to 100 microns, the pore size at the outer surface is about 0.05 microns to 2 microns, the pore size at the inner surface is about 0.05 microns to 5 microns, and the lowest or smallest pore size in the membrane is about 0.015 microns to 0.035 microns.

[0042] In some embodiments, the hollow fiber membrane wall thickness is 30 microns to 100 microns, the pore size at the outer surface is about 0.05 microns to 1 micron, the pore size at the inner surface is about 0.05 microns to 5 microns, and the lowest or smallest pore size in the membrane is about 0.015 microns to 0.035 microns.

[0043] In some embodiments, the hollow fiber membrane wall thickness is 30 microns to 100 microns, the pore size at the outer surface is about 0.05 microns to 0.5 microns, the pore size at the inner surface is about 0.05 microns to 5 microns, and the lowest or smallest pore size in the membrane is about 0.015 microns to 0.035 microns.

[0044] Aromatic sulfone polymers disclosed herein, such as polysulfone, polyethersulfone, polyphenylene sulfone, polyaryl ethersulfone or copolymers or modified products of these polymers or mixtures of these polymers can be used. In a preferred embodiment, the aromatic sulfone polymer can be a polysulfone or polyethersulfone having repeating molecular units as shown in the following formula (I) and formula (II):

[0045]

[0046] More preferably, polyethersulfone according to formula (II) is used as aromatic sulfone polymer, since such aromatic sulfone polymer has a lower hydrophobicity than, for example, polysulfone.Polysulfone may have a molecular weight of about 72 kg / mol.

[0047] In some embodiments, the aromatic sulfone polymer may be present at a concentration of 27 wt % to 30 wt %, 27 wt % to 29 wt %, 27 wt % to 28 wt %, 28 wt % to 30 wt %, or 28 wt % to 29 wt %, based on the total weight of the polymer blend. 27 wt % to 30 wt % of the aromatic sulfone polymer is important for membranes with pore sizes less than 30 nm intended to remove viruses / bacteriophages (20 nm to 30 nm) from monoclonal antibody (5 nm to 10 nm) solutions.

[0048] In some embodiments of the polymer blends, the polyoxazoline can be present in a concentration of 1 wt % to 35 wt %, 5 wt % to 35 wt %, 5 wt % to 30 wt %, 5 wt % to 25 wt %, 5 wt % to 20 wt %, 5 wt % to 15 wt %, 7 wt % to 15 wt %, 7 wt % to 12 wt %, or 8 wt % to 11 wt %, based on the total weight of the polymer blend.

[0049] In some embodiments of the polymer blends, the polyoxazoline may be present at a concentration of 8 wt % to 11 wt %, based on the total weight of the polymer blend.

[0050] In some embodiments, the polyoxazoline of the present disclosure can be poly(2-oxazoline). Poly(2-oxazoline) can be prepared by cationic ring-opening polymerization of various 2-oxazoline monomers. Polymerization of 2-alkyl substituted 2-oxazoline monomers provides poly(2-alkyl-2-oxazoline)

[0051] In some embodiments, the poly (2-oxazoline) of the present disclosure can be poly (2-ethyl-2-oxazoline) (PEtOx). Poly (2-oxazoline) has a high protein repelling potential. The residual groups of poly (2-oxazoline) can be changed to change the properties of the polymer, for example, to change from hydrophilic to hydrophobic. Poly (2-oxazoline) can have a molecular weight of about 25kg / mol to about 500kg / mol. Poly (2-oxazoline) can have a molecular weight of about 50kg / mol.

[0052] The poly(2-ethyl-2-oxazoline) may have a molecular weight of about 25 kg / mol to about 500 kg / mol. The poly(2-ethyl-2-oxazoline) may have a molecular weight of about 25 kg / mol to about 100 kg / mol. The poly(2-ethyl-2-oxazoline) may have a molecular weight of about 50 kg / mol.

[0053] Poly-(2-oxazoline) can exist with respect to the weight of film, and the concentration of 0.5 % by weight to 30 % by weight, 1 % by weight to 30 % by weight, 5 % by weight to 30 % by weight or 10 % by weight to 30 % by weight exists.Poly-(2-oxazoline) can exist with respect to the weight of film, and be greater than 0.5 % by weight, greater than 1 % by weight, greater than 2 % by weight, greater than 3 % by weight, greater than 4 % by weight, greater than 5 % by weight, greater than 6 % by weight, greater than 7 % by weight, greater than 8 % by weight, greater than 9 % by weight, greater than 10 % by weight, greater than 15 % by weight or greater than 20 % by weight exists.Poly-(2-oxazoline) can exist with respect to the weight of film, and be less than 30 % by weight, less than 28 % by weight, less than 25 % by weight, less than 23 % by weight, less than 20 % by weight, less than 15 % by weight or less than 10 % by weight exists. In some embodiments, the weight % ratio of aromatic sulfone polymer to poly(2-oxazoline) in the membrane can be 4:1 to 25:1, 4:1 to 10:1, 5:1 to 10:1, 10:1 to 15:1, 15:1 to 20:1, or 20:1 to 25:1.

[0054] The aromatic sulfone polymer and the poly(2-oxazoline) may be distributed throughout the membrane. The aromatic sulfone polymer and the poly(2-oxazoline) may be uniformly distributed throughout the membrane. The aromatic sulfone polymer and the poly(2-oxazoline) may be uniformly distributed throughout the membrane.

[0055] In some embodiments, poly (2-oxazoline) can be distributed throughout the film. Poly (2-oxazoline) can be distributed throughout the film. Poly (2-oxazoline) can be uniformly distributed throughout the film. In some embodiments, poly (2-oxazoline) can be uniformly distributed throughout the film. Poly (2-ethyl-2-oxazoline) can be distributed throughout the film. In some embodiments, poly (2-ethyl-2-oxazoline) can be uniformly distributed throughout the film. In some embodiments, poly (2-ethyl-2-oxazoline) can be uniformly distributed throughout the film. In some embodiments, poly (2-oxazoline) can be unevenly distributed throughout the film. In some embodiments, poly (2-ethyl-2-oxazoline) can be unevenly distributed throughout the film. For example, the concentration of poly (2-ethyl-2-oxazoline) at or adjacent to the outer surface can be greater than the concentration of poly (2-ethyl-2-oxazoline) at or adjacent to the inner surface.

[0056] In some embodiments, the polymer blend may further include additional hydrophilic polymers. Exemplary hydrophilic polymers may include polyvinyl pyrrolidone, polyethylene glycol, glycerol, polyvinyl alcohol, polyethylene glycol monoester, polysorbate, carboxymethyl cellulose, polyacrylic acid, polyacrylate or the modified substance or copolymer of these polymers. In some embodiments, the hydrophilic polymer may be polyethylene glycol. In some embodiments, the polymer blend does not include polyvinyl pyrrolidone.

[0057] In some embodiments, the hydrophilic polymer may be present in a concentration of 1 wt % to 75 wt % relative to the weight of the membrane. In some embodiments, the polymer blend may include greater than 7 wt %, greater than 10 wt %, greater than 20 wt %, greater than 30 wt %, greater than 40 wt %, greater than 50 wt %, or greater than 60 wt % polyvinylpyrrolidone. In some embodiments, the polymer blend may include less than 3 wt %, less than 2 wt %, or less than 1 wt % polyvinylpyrrolidone.

[0058] In some embodiments, the polymer blend may include a solvent and a non-solvent. Exemplary blends may include glycols, glycerol, butyrolactone, ε-caprolactam, N-methylpyrrolidone, water, or combinations thereof.

[0059] In some embodiments, based on the total weight of the polymer blend, the polymer blend can have 5 wt % to 18 wt % of poly (2-ethyl-2-oxazoline). In some embodiments, based on the total weight of the polymer blend, the polymer blend can have 5 wt % to 15 wt % of poly (2-ethyl-2-oxazoline). In some embodiments, based on the total weight of the polymer blend, the polymer blend can have 7 wt % to 12 wt % of poly (2-ethyl-2-oxazoline). In some embodiments, based on the total weight of the polymer blend, the polymer blend can have 8 wt % to 11 wt % of poly (2-ethyl-2-oxazoline).

[0060] In some embodiments, the polymer blend may have 25 to 60 wt % N-methylpyrrolidone, based on the total weight of the polymer blend. In some embodiments, the polymer blend may have 25 to 50 wt % N-methylpyrrolidone, based on the total weight of the polymer blend. In some embodiments, the polymer blend may have 25 to 40 wt % N-methylpyrrolidone, based on the total weight of the polymer blend.

[0061] In some embodiments, the polymer blend may have 27 to 30 weight percent polyethersulfone and 5 to 15 weight percent poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend. In some embodiments, the polymer blend may have 27 to 30 weight percent polyethersulfone and 7 to 12 weight percent poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend.

[0062] In some embodiments, the polymer blend may have 20 wt % to 40 wt % polyethylene glycol, based on the total weight of the polymer blend. In some embodiments, the polymer blend may have 25 wt % to 35 wt % polyethylene glycol, based on the total weight of the polymer blend.

[0063] In some embodiments, the polymer blend can have 27 to 30 weight percent polyethersulfone; 5 to 15 weight percent poly(2-ethyl-2-oxazoline); 30 to 40 weight percent N-methylpyrrolidone; and 5 to 40 weight percent polyethylene glycol, based on the total weight of the polymer blend.

[0064] In some embodiments, the polymer blend can have 27 to 30 weight percent polyethersulfone; 7 to 12 weight percent poly(2-ethyl-2-oxazoline); 30 to 35 weight percent N-methylpyrrolidone; and 25 to 35 weight percent polyethylene glycol, based on the total weight of the polymer blend.

[0065] It is also preferred that the wall thickness of the hollow fiber membrane as disclosed herein is in the range of 10 μm to 400 μm, 20 μm to 300 μm, 30 μm to 200 μm, or 40 μm to 80 μm. At a wall thickness of less than 20 μm, the mechanical properties of the hollow fiber membrane may drop below a certain desired level, and at a wall thickness of more than 400 μm, the transmembrane flow rate is reduced. Similarly, in order to achieve the desired flow through the lumen of the hollow fiber membrane according to the present disclosure, particularly a favorable pressure drop, it is preferred that the inner diameter of the hollow fiber membrane as described herein is in the range of 50 μm to 800 μm, 50 μm to 700 μm, 50 μm to 600 μm, 100 μm to 500 μm, 100 μm to 400 μm, or 100 μm to 300 μm.

[0066] The hollow fiber membrane according to the present invention preferably exhibits a flow rate of at least 0.01 mL / (cm 2 ·min·bar), preferably at least 0.1mL / (cm 2 ·min·bar), more preferably at least 0.15mL / (cm 2 ·min·bar), and even more preferably at least 0.2 mL / (cm 2 This ensures sufficient and stable filtration capacity in the application. It is further preferred that the hollow fiber membrane as disclosed herein exhibits a transmembrane flow rate of 0.01 mL / (cm 2 ·min·bar) to 10mL / (cm 2 ·min·bar), preferably 0.15mL / (cm 2·min·bar) to 5mL / (cm 2 ·min·bar), and more preferably 0.1 mL / (cm 2 ·min·bar) to 3mL / (cm 2 The transmembrane flow rate in water is in the range of 100 0.1% to 100 0.1% (min·bar). Transmembrane flow rates in these ranges allow sufficient and stable filtration capacity in suitable applications without deteriorating the retention capacity or compromising the mechanical stability. The transmembrane flow rate is preferably determined as described in the experimental section.

[0067] According to the hollow fiber membrane of the present disclosure, it is possible to prepare the hollow fiber membrane by the method disclosed in WO 2019 / 229667 A1 (Malek et al.), which is incorporated by reference in its entirety into the present disclosure. In the method for preparing the hollow fiber membrane, a polymer blend comprising an aromatic sulfone polymer and polyoxazoline can be selected as a spinning solution. The polymer blend selected as the spinning solution may also include one or more hydrophilic polymers, solvents and / or non-solvents. In some embodiments, the hollow fiber membrane may be made of a uniform spinning solution and a bore liquid of an aromatic sulfone polymer and poly (2-oxazoline). The bore liquid may include water, a solvent and a non-solvent. Therefore, the present disclosure further provides a method for producing hollow fiber membranes, the method comprising the following steps: providing a spinning solution comprising an aromatic sulfone polymer and polyoxazoline, and a core liquid comprising water, a solvent and a non-solvent; and spinning the aromatic sulfone polymer and poly(2-oxazoline) hollow fibers with an outer diameter of a spinning head in the range of 300 μm to 1000 μm, an outer diameter of a spinning head needle in the range of 200 μm to 1000 μm and an inner diameter of a spinning head needle in the range of 100 μm to 1000 μm.

[0068] In some embodiments, the spinning solution may further include a hydrophilic polymer. Long-chain polymers are advantageously used as at least one hydrophilic polymer, and the at least one hydrophilic polymer shows compatibility with a hydrophobic aromatic sulfone polymer. The aromatic sulfone polymer has repeated polymer units, and these polymer units themselves are hydrophilic. The hydrophilic polymer is preferably a modified substance or copolymer of polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyethylene glycol monoester, polysorbate such as polyoxyethylene sorbitan monooleate, carboxymethyl cellulose or these polymers. Polyvinyl pyrrolidone and polyethylene glycol are particularly preferred.

[0069] In some embodiments, the spinning solution comprises polyethylene glycol (PEG). In some embodiments, the polyethylene glycol in the spinning solution may have a molecular weight (MW) of about 100 g / mol to about 1,800 g / mol. In some embodiments, the polyethylene glycol in the spinning solution may have a molecular weight (MW) of about 200 g / mol, 400 g / mol, 500 g / mol, 600 g / mol, 1000 g / mol, 1200 g / mol, or 1,500 g / mol.

[0070] Within the context of the present disclosure, the at least one hydrophilic polymer may also comprise a mixture of different hydrophilic polymers. The hydrophilic polymer may for example be a mixture of chemically different hydrophilic polymers or a mixture of hydrophilic polymers with different molecular weights, for example a mixture of polymers with molecular weights that differ by a factor of 5 or more.

[0071] After preferably degassing and filtering to remove gas and undissolved particles, the uniform spinning solution is extruded together with the core liquid through the annular gap of a conventional hollow fiber die to produce a hollow fiber. The core liquid (i.e., as a coagulation medium for aromatic sulfone polymers and the internal filler of the tubular cavity of the stabilization hollow fiber at the same time) is extruded through the central nozzle opening coaxially arranged with the annular gap in the hollow fiber die. In the present disclosure, the terms "hollow fiber die" and "spinning head" are used interchangeably. The core liquid may include water and glycerol, but may also include additional ingredients and / or solvents, such as polyethylene glycol (PEG). Preferably, the core liquid further includes a non-solvent for film-forming polymers, such as water, low molecular weight polyethylene glycol or low molecular weight alcohol such as ethanol or isopropanol, and / or protic solvents such as ε-caprolactam, which have an average molecular weight less than 1000 daltons. Preferably, the core liquid includes water, N-methyl pyrrolidone and polyethylene glycol. The solvent may be present in 5% to 70% by weight relative to the weight of the solution.

[0072] The solvent system to be adopted must match the aromatic sulfone polymer and poly (2-oxazoline) adopted so that a uniform spinning solution can be produced. The solvent system preferably comprises a polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone or a mixture thereof, or a protic solvent such as ε-caprolactam. In addition, the solvent system may comprise up to 70% by weight of a latent solvent, whereby in the context of the present invention, the latent solvent is understood to be a solvent that dissolves the sulfone polymer poorly or only dissolves the sulfone polymer at an elevated temperature. In the case where ε-caprolactam is used as a solvent, for example, butyrolactone, propylene carbonate or polyalkylene glycol may also be used. In addition, the solvent system may contain a non-solvent for film-forming polymers, such as water, glycerol, a low molecular weight polyethylene glycol or a low molecular weight alcohol such as ethanol or isopropanol having a mean molecular weight less than 1000 daltons. Preferably, the solvent system contains N-methyl pyrrolidone.

[0073] In one embodiment, the spinning solution comprises aromatic sulfone polymer, poly-(2-oxazoline), polyethylene glycol, N-Methyl pyrrolidone and water. In another embodiment, the spinning solution comprises polyether sulfone, poly-(2-ethyl-2-oxazoline), polyethylene glycol, N-Methyl pyrrolidone and water. In yet another embodiment, the spinning solution comprises polyether sulfone, poly-(2-ethyl-2-oxazoline), PEG200 or PEG1500, N-Methyl pyrrolidone and water.

[0074] The width of the annular gap and the inner diameter of the central nozzle opening are selected according to the desired properties of the hollow fiber membrane according to the present disclosure. That is, the spinning head exhibits a spinning head outer diameter for spinning dope in the range of 300 μm to 1000 μm, a spinning head needle outer diameter in the range of 200 μm to 1000 μm, and a spinning head needle inner diameter in the range of 100 μm to 1000 μm.

[0075] After leaving the hollow fiber die (i.e., spinning head) and before entering the coagulation medium, the hollow fiber can pass through a climate-controlled area with defined climatic conditions. The climate-controlled area can thus take the form of, for example, a packaging chamber. For technical reasons, it may be necessary to have an air gap between the hollow fiber die and the climate-controlled area. However, this gap should advantageously be as small as possible; the climate-controlled area is preferably directly after the hollow fiber die.

[0076] In this respect, it is preferred that the retention time of the hollow fibers in the climate-controlled area is 0.5 seconds to 10 seconds, whereby the climate-controlled area contains air with a relative humidity of 20% to 95% and a temperature of 25° C. to 75° C. Preferably, the retention time of the hollow fibers in the climate-controlled area is 0.5 seconds to 5 seconds. In order to establish stable conditions in the climate-controlled area, the air preferably flows through the climate-controlled area at a speed of less than 0.5 m / s and particularly preferably at a speed in the range of 0.15 m / s to 0.35 m / s.

[0077] In one embodiment, the climate controlled area contains air having a relative humidity of 20% to 95% and a temperature of 25° C. to 75° C. In one embodiment, the climate controlled area contains air having a relative humidity of 60% to 75% and a temperature of 30° C. to 50° C. In one embodiment, the climate controlled area contains air having a relative humidity of 75% to 90% and a temperature of 30° C. to 50° C. In one embodiment, the climate controlled area contains air having a relative humidity of 60% to 75% and a temperature of 50° C. to 70° C. In one embodiment, the climate controlled area contains air having a relative humidity of 75% to 90% and a temperature of 50° C. to 70° C.

[0078] When the hollow fiber is guided through a climate-controlled area, before the hollow fiber solidifies, the pre-solidification of the hollow fiber is induced by absorbing water vapor acting as a non-solvent on the outside of the hollow fiber. At the same time, the retention time should be set within a preferred range in the method according to the present disclosure. These measures affect the formation of the outer layer of the hollow fiber membrane according to the present invention, so that in some embodiments, the outer layer can obtain a substantially isotropic structure.

[0079] After passing through the climate-controlled area, the pre-coagulated hollow fibers are guided through an aqueous coagulation medium preferably adjusted to 20° C. to 90° C. to complete the formation of the membrane structure. The coagulation medium is preferably adjusted to a temperature in the range of 20° C. to 90° C. Preferably, the coagulation medium, such as a precipitation bath, is water or a water bath.

[0080] In the coagulation medium, the membrane structure is first precipitated to a degree that it has sufficient stability, and can be turned in the coagulation medium via, for example, a deflection roller or similar device. During the further process of the method, coagulation is completed and the membrane structure is stabilized. The extraction of solvent system and soluble substances is carried out simultaneously here. Usually, most of the hydrophilic polymers are extracted from the membrane structure so that the coagulation bath is used as a washing or extraction bath at the same time. In the coagulation or washing bath, water is preferably used as the coagulation or washing medium. In some embodiments, the extraction of solvent system and soluble substances can be carried out at different steps. The hollow fiber bundle can be placed in a box and rinsed with hot water. In this step, most of the hydrophilic polymers can be extracted from the membrane structure.

[0081] The hollow fiber membrane according to the present disclosure can be textured (if necessary) to improve the exchange properties of the hollow fiber membrane in the bundle. The membrane can then be collected. The hollow fiber membrane can be dried. The dried membrane can then be wound. Finally, the hollow fiber membrane can be processed using conventional methods, such as being wound on a coil or directly formed into a bundle with a suitable fiber count and length. Before producing the bundle, a supplementary line in the form of, for example, a multifilament yarn can be added to the hollow fiber membrane to ensure better flow around the spacing of the hollow fiber membranes relative to each other and the individual hollow fiber membranes in the bundle.

[0082] According to the present disclosure, the concentration of the sulfone polymer in the spinning solution is preferably in the range of 27% by weight to 30% by weight. When the concentration is lower than 27% by weight, disadvantages may be produced regarding virus retention. The sulfone polymer may also contain additives, such as antioxidants, nucleating agents, UV absorbers, etc., to selectively change the properties of the film. The concentration of poly (2-oxazoline) in the spinning solution may be in the range of 5% by weight to 30% by weight.

[0083] In some embodiments, the spinning solution may have 27 wt % to 30 wt % of the aromatic sulfone polymer, relative to the weight of the solution; 7 wt % to 15 wt % of the poly(2-oxazoline), relative to the weight of the solution; 30 wt % to 40 wt % of the solvent, relative to the weight of the solution; and 25 wt % to 50 wt % of the hydrophilic polymer, relative to the weight of the solution.

[0084] In some embodiments, the spinning solution may have 27 wt % to 30 wt % polyethersulfone, relative to the weight of the solution; 10 wt % to 30 wt % poly(2-ethyl-2-oxazoline), relative to the weight of the solution; and 50 wt % to 63 wt % N-methylpyrrolidone, relative to the weight of the solution.

[0085] In some embodiments, the spinning solution may have 27 to 30 weight percent polyethersulfone, relative to the weight of the solution; 5 to 20 weight percent poly(2-ethyl-2-oxazoline), relative to the weight of the solution; 20 to 68 weight percent N-methylpyrrolidone, relative to the weight of the solution; and 5 to 40 weight percent polyethylene glycol, relative to the weight of the solution.

[0086] In some embodiments, the spinning solution may have 27 wt % to 30 wt % polyethersulfone; 5 wt % to 15 wt % poly(2-ethyl-2-oxazoline); 30 wt % to 40 wt % N-methylpyrrolidone; and 5 wt % to 40 wt % polyethylene glycol, based on the total weight of the solution.

[0087] In some embodiments, the spinning solution may have 27 wt % to 30 wt % polyethersulfone; 7 wt % to 12 wt % poly(2-ethyl-2-oxazoline); 30 wt % to 35 wt % N-methylpyrrolidone; and 25 wt % to 35 wt % polyethylene glycol, based on the total weight of the solution.

[0088] In some embodiments, based on the total weight of solution, the spinning solution can have 5 wt % to 18 wt % of poly-(2-ethyl-2-oxazoline). In some embodiments, based on the total weight of solution, the spinning solution can have 5 wt % to 15 wt % of poly-(2-ethyl-2-oxazoline). In some embodiments, based on the total weight of solution, the spinning solution can have 7 wt % to 12 wt % of poly-(2-ethyl-2-oxazoline). In some embodiments, based on the total weight of solution, the spinning solution can have 8 wt % to 11 wt % of poly-(2-ethyl-2-oxazoline).

[0089] In some embodiments, the spinning solution may have 25 to 60 wt% N-methylpyrrolidone based on the total weight of the solution. In some embodiments, the spinning solution may have 25 to 50 wt% N-methylpyrrolidone based on the total weight of the solution.

[0090] In some embodiments, the spinning solution may have 25 to 40 wt% N-methylpyrrolidone, based on the total weight of the solution. In some embodiments, the spinning solution may have 27 to 30 wt% polyethersulfone, based on the total weight of the solution; and 5 to 15 wt% poly(2-ethyl-2-oxazoline).

[0091] In some embodiments, the spinning solution can have 27 wt % to 30 wt % polyethersulfone; and 7 wt % to 12 wt % poly(2-ethyl-2-oxazoline), based on the total weight of the solution.

[0092] In some embodiments, the spinning solution can have 27 wt % to 30 wt % polyethersulfone; and 8 wt % to 11 wt % poly(2-ethyl-2-oxazoline), based on the total weight of the solution.

[0093] In some embodiments, the spinning solution can have 20 wt% to 40 wt% polyethylene glycol based on the total weight of the solution. In some embodiments, the spinning solution can have 25 wt% to 35 wt% polyethylene glycol based on the total weight of the solution.

[0094] In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution may have a molecular weight of 200 g / mol (PEG200), 400 g / mol (PEG400), 600 g / mol (PEG600), 1000 g / mol (PEG1000), 1200 g / mol (PEG1200), or 1500 g / mol (PEG1500).

[0095] In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution may have a molecular weight of 200 g / mol to 600 g / mol. In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution may have a molecular weight of 500 g / mol to 1000 g / mol. In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution may have a molecular weight of 1000 g / mol to 1500 g / mol.

[0096] The present invention provides polymer membranes with excellent protein rejection properties. As a result, these membranes block more slowly, showing higher throughput behavior and thus longer life. These membranes further exhibit an asymmetric structure that is promising for the preparation of highly selective membranes. The protein rejection properties of the membranes can provide better filtration properties, which results in higher throughput due to less fouling.

[0097] In some embodiments, the hollow fiber membrane of the present disclosure may be suitable for applications in the field of filtration, such as for filtering antibodies including monoclonal antibodies (mAb). Due to the unique combination of the characteristics of the hollow fiber membrane as described herein (preferably obtained from the method as described herein), the present disclosure further provides the use of the membrane as described herein for filtering liquid (e.g., microfiltration or ultrafiltration). "Microfiltration" and "ultrafiltration" have common meanings in the art. Preferably, the use as described herein includes clarifying and / or purifying liquid media, particularly aqueous liquids. In some embodiments, the liquid that can be filtered by the hollow fiber membrane of the present disclosure may include a biological product selected from a capsid, a virus, a virus-like particle or a solution containing an antibody. The hollow fiber membrane can remove 15nm or larger contaminating phages or viruses greater than 3, 4, 5, 6 or 7 logarithmic reduction values ​​(LRV). The hollow fiber membrane can be operated using a constant flow rate or a constant pressure. These membrane properties enable faster processing time and greater flexibility to be achieved in the processing equipment for performing filtration, as well as the ability to operate under a variety of conditions.

[0098] In some embodiments, the present disclosure provides a method. The method may include passing a solution containing an antibody through a hollow fiber membrane of the present disclosure; and collecting the antibody. Viruses or bacteriophages of 15 nm or greater may be at least partially removed from the solution containing the antibody. In some embodiments, the solution containing the antibody may be a concentrated antibody solution having a concentration greater than 50 mg / ml.

[0099] Exemplary embodiments

[0100] Embodiment 1 is a hollow fiber membrane; the hollow fiber membrane is made of a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline, wherein the polymer blend comprises 27 wt % to 30 wt % of the aromatic sulfone polymer based on the total weight of the polymer blend; wherein the hollow fiber membrane comprises an inner surface facing its lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness; wherein the hollow fiber membrane is an integral asymmetric permeable hollow fiber membrane.

[0101] Embodiment 2 is the hollow fiber membrane according to embodiment 1, wherein the aromatic sulfone polymer comprises polysulfone or polyethersulfone.

[0102] Embodiment 3 is the hollow fiber membrane according to any one of embodiments 1 to 2, wherein the polyoxazoline is poly(2-ethyl-2-oxazoline) (PEtOx).

[0103] Embodiment 4 is the hollow fiber membrane according to any one of embodiments 1 to 3, wherein the region with the smallest pore size is adjacent to the inner surface.

[0104] Embodiment 5 is a hollow fiber membrane according to embodiment 4, wherein the region having the largest pore size is adjacent to the outer surface.

[0105] Embodiment 6 is the hollow fiber membrane according to any one of embodiments 1 to 3, wherein the region having the smallest pore size is adjacent to the outer surface.

[0106] Embodiment 7 is a hollow fiber membrane according to embodiment 6, wherein the region having the largest pore size is adjacent to the inner surface.

[0107] Embodiment 8 is the hollow fiber membrane according to any one of embodiments 4 to 7, wherein the size of the pores in the region having the smallest pore size is in the range of 10 nm to 20 nm.

[0108] Embodiment 9 is the hollow fiber membrane according to any one of embodiments 4 to 8, wherein at least some of the pores of the region with the smallest pore size or the region with the largest pore size are connected.

[0109] Embodiment 10 is a hollow fiber membrane according to embodiment 9, wherein at least some of the pores of the region with the smallest pore size or the region with the largest pore size are connected by channels between the pores.

[0110] Embodiment 11 is the hollow fiber membrane according to any one of embodiments 1 to 10, wherein the hollow fiber membrane includes a tortuous structure extending in the hollow fiber membrane.

[0111] Embodiment 12 is a hollow fiber membrane according to embodiment 11, wherein at least some of the tortuous structures extend from the inner surface toward the outer surface.

[0112] Embodiment 13 is a hollow fiber membrane according to any one of embodiments 1 to 12, wherein the polymer blend comprises greater than 7 wt% or less than 3 wt% polyvinylpyrrolidone.

[0113] Embodiment 14 is the hollow fiber membrane according to any one of embodiments 1 to 13, wherein the polymer blend does not contain polyvinyl pyrrolidone.

[0114] Embodiment 15 is the hollow fiber membrane according to any one of embodiments 4 to 10, wherein the region with the smallest pore size has a lower flow rate than the region with the largest pore size.

[0115] Embodiment 16 is the hollow fiber membrane according to any one of embodiments 4 to 10, wherein the region having the smallest pore size (retaining layer) has a thickness of 5 μm to 100 μm.

[0116] Embodiment 17 is the hollow fiber membrane according to any one of embodiments 1 to 16, wherein the hollow fiber membrane has greater than 3 log reduction values ​​(LRV) against viruses or bacteriophages of 15 nm or larger.

[0117] Embodiment 18 is the hollow fiber membrane according to any one of embodiments 1 to 17, wherein the hollow fiber membrane is capable of removing viruses or bacteriophages of 15 nm or larger.

[0118] Embodiment 19 is use of the hollow fiber membrane according to any one of embodiments 1 to 18 for filtering antibodies.

[0119] Embodiment 20 is a method comprising passing a solution containing an antibody through the hollow fiber membrane according to any one of embodiments 1 to 18; and collecting the antibody.

[0120] Embodiment 21 is a method according to embodiment 20, wherein viruses or bacteriophages of 15 nm or larger are removed from the antibody-containing solution.

[0121] Embodiment 22 is a method according to any one of embodiments 20 to 21, wherein the antibody-containing solution is a concentrated antibody solution.

[0122] Embodiment 23 is a porous hollow fiber membrane, which comprises: an aromatic sulfone polymer and a polyoxazoline; an inner surface facing the lumen of the hollow fiber membrane, an outer surface facing the outside, and an intermediate wall having a wall thickness; wherein a first cross-sectional area starts at the inner surface and extends laterally into the interior of the intermediate wall, terminates at an internal distance within the intermediate wall, and the pore size gradually decreases across the first cross-sectional area in the direction from the inner surface to the outer surface; wherein the hollow fiber membrane has a second cross-sectional area, which starts at the end of the first cross-sectional area and extends laterally to the outer surface of the membrane

[0123] And the pore diameter gradually increases across the second cross-sectional area in a direction from the starting point of the second cross-sectional area to the outer surface.

[0124] Embodiment 24 is a porous hollow fiber membrane according to embodiment 23, wherein the pore size at the outer surface is smaller than the pore size at the inner surface.

[0125] Embodiment 25 is a porous hollow fiber membrane according to any one of embodiments 23 to 24, wherein the pores located where the first cross-sectional area ends and the second cross-sectional area begins form at least a portion of the retention area.

[0126] Embodiment 26 is a porous hollow fiber membrane according to any one of embodiments 23 to 25, wherein the pores located where the first cross-sectional area ends and the second cross-sectional area begins have a pore size of less than 0.035 microns.

[0127] Embodiment 27 is a porous hollow fiber membrane according to any one of embodiments 23 to 26, wherein the pores located where the first cross-sectional area ends and the second cross-sectional area begins have a pore size of less than 0.03 microns.

[0128] Embodiment 28 is a porous hollow fiber membrane according to any one of embodiments 23 to 27, wherein the pores located where the first cross-sectional area ends and the second cross-sectional area begins have a pore size of about 0.01 microns to 0.035 microns.

[0129] Embodiment 29 is a porous hollow fiber membrane according to any one of embodiments 23 to 28, wherein the pores located where the first cross-sectional area ends and the second cross-sectional area begins have a pore size of about 0.01 microns to 0.03 microns.

[0130] Embodiment 30 is a method comprising: allowing a liquid containing antibodies and viruses to flow through a porous hollow fiber membrane; wherein the hollow fiber membrane comprises an aromatic sulfone polymer and a polyoxazoline; wherein the hollow fiber membrane comprises an inner surface facing the hollow fiber membrane lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness; wherein a first cross-sectional area begins at the inner surface and extends laterally to the interior of the intermediate wall, terminating at an internal distance within the intermediate wall; wherein the pore size gradually decreases across the first cross-sectional area in a direction from the inner surface to the outer surface; wherein the hollow fiber membrane has a second cross-sectional area, the second cross-sectional area starting from where the first cross-sectional area ends and extending laterally to the outer surface of the membrane; wherein the pore size gradually increases across the second cross-sectional area in a direction from the starting point of the second cross-sectional area to the outer surface; and collecting the liquid.

[0131] Embodiment 31 is a method comprising: allowing a liquid containing antibodies and viruses to flow through a porous hollow fiber membrane; wherein the hollow fiber membrane comprises an aromatic sulfone polymer and a polyoxazoline; wherein the hollow fiber membrane comprises an inner surface facing the hollow fiber membrane lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness; wherein a first cross-sectional area begins at the inner surface and extends laterally to the interior of the intermediate wall, terminating at an internal distance within the intermediate wall; wherein the pore size gradually decreases across the first cross-sectional area in a direction from the inner surface to the outer surface; wherein the hollow fiber membrane has a second cross-sectional area, the second cross-sectional area starting from the end point of the first cross-sectional area and extending laterally to the outer surface of the membrane; wherein the pore size gradually increases across the second cross-sectional area in a direction from the starting point of the second cross-sectional area to the outer surface; retaining at least a portion of the virus in the membrane; and collecting the liquid from the membrane.

[0132] Embodiment 32 is a method according to any one of embodiments 30 to 31, wherein the pore size at the outer surface is smaller than the pore size at the inner surface.

[0133] Embodiment 33 is a method according to any one of embodiments 30 to 32, wherein viruses are removed from the liquid.

[0134] Embodiment 34 is a method according to any one of embodiments 30 to 33, wherein at least 3 log reduction values ​​(LRV) of viruses are removed from the liquid.

[0135] Embodiment 35 is a method according to any one of embodiments 30 to 34, wherein at least 4 log reduction values ​​(LRV) of viruses are removed from the liquid.

[0136] Embodiment 36 is a method according to any one of embodiments 30 to 35, wherein the liquid is water.

[0137] Embodiment 37 is a method according to any one of embodiments 30 to 36, wherein the virus has a diameter of 15 nm or greater.

[0138] Embodiment 38 is a method according to any one of embodiments 30 to 37, wherein the virus has a diameter of 15 nm to 30 nm.

[0139] Embodiment 39 is a method according to any one of embodiments 30 to 38, wherein the antibody has a diameter of 5 nm to 10 nm.

[0140] Embodiment 40 is a method according to any one of embodiments 30 to 39, wherein the aperture located where the first cross-sectional area ends and the second cross-sectional area begins forms at least a portion of the retention area.

[0141] Embodiment 41 is a method according to any one of the eighth to eighteenth embodiments, wherein the virus is retained in the holding area.

[0142] Embodiment 41 is an article comprising the porous hollow fiber membrane according to any one of Embodiments 1 to 18 and 23 to 29.

[0143] The following working examples are intended to illustrate the present disclosure but not to limit it.

[0144] Example

[0145] Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.

[0146] The following abbreviations are used herein: mL = milliliter, L = liter, kg = kilogram, g = gram, mg = milligram, m = meter, cm = centimeter, mm = millimeter, nm = nanometer, s = second, min = minute, hr = hour, psi = pounds per square inch, and wt. % = weight percent.

[0147] Scanning electron microscopy (SEM) images were obtained using a FEI 250 scanning electron microscope (Thermo Fisher Scientific, Waltham, MA) with xT Microscope Control operating software or a Coxem EM-30AX scanning electron microscope (Coxem Company, Daejeon, Korea) with NanoStation operating software.

[0148] Table 1. Materials list

[0149]

[0150] Method A. Method for Determining Transmembrane Flux (TMF)

[0151] Hollow fiber membrane test module is prepared by placing ten hollow fiber membranes (10cm length) in a straight cylindrical polycarbonate tube (internal diameter 8mm and length 60mm). The tube has a side-positioned outlet around the middle between the two ends of the cylinder. The hollow fiber membrane is embedded in the tube using hot melt adhesive at the two ends of the tube. After curing, the protruding ends and unnecessary glue of the hollow fiber membrane are removed using a razor blade. Visual inspection of the opening of the membrane, and only use modules in which all hollow fiber membranes have an open and unobstructed lumen portion. The polycarbonate tube is capped with a cover for attaching to a port of flexible tubing at each end. The completed test module is attached to the support, placed in a vertical orientation, filled with 18 megohms of water, and connected to a measurement system.

[0152] The measurement system includes: a pressure tank filled with 18 megohm water, the pressure tank connected to one end of the test module with flexible tubing; two pressure gauges (a first pressure gauge is located between the pressure tank and the test module, and a second pressure gauge is located downstream of the opposite end of the module); and a flush valve, which is located downstream of the module and the second pressure gauge. The measurement system also includes a heater located between the pressure tank and the first pressure gauge, through which the water passes. The heater warms the water to 25°C.

[0153] A pressure of 5.8 psi was applied to the pressure tank. At the beginning of the test, the air in the system was displaced by closing the side outlet and opening the flush valve. The flush valve was then closed and the side outlet was opened to operate the module in a dead-end filtration configuration. Water flowed from the pressure tank through the lumen of the membrane for four minutes, filtered through the membrane wall, and left the module through the side outlet into the first collection container. The first collection container was then replaced with a tared second collection container. The filtered water was collected in the second collection container for 60 seconds. The amount of water collected in the second container was determined using a digital balance. The differential pressure was determined by reading the difference between the two pressure gauges.

[0154] The transmembrane flux (TMF) was calculated according to Equation 1 based on the membrane dimensions, pressure difference and the weight of water.

[0155] Equation 1 .

[0156]

[0157] in:

[0158] m W = the amount of water (in grams) that passes through the membrane sample during the measurement period

[0159] ρ w = Density of water at 25°C

[0160] Δt=Measurement time (minutes)

[0161] A M = Total inner surface area of ​​the hollow membranes in the test module

[0162] Δp = pressure difference along the length of the test module (bar)

[0163] Method B. Method for determining the viscosity of spinning solutions (polymer blends)

[0164] The rheometer was used with a HAAKE RheoStress1 rheometer (Thermo Fisher Scientific, Waltham, MA) with a Z20DIN sensor device (Thermo Fisher Scientific) at 60°C and 10 s -1 The viscosity of the casting solution was measured at a shear rate of .

[0165] Method C. Phi-X174 phage culture preparation

[0166] Phi-X174 phage (ATCC 13706-B1) was obtained from ATCC (Manassas, VA). A phage culture was generated by growing 1 L of E. coli (ATCC 13706) culture in CRITERION nutrient broth (Hardy Diagnostics, Santa Maria, CA) plus 5% sodium chloride at 37°C with mixing at 210 revolutions per minute (rpm) to an OD of 0.45. The culture was inoculated with approximately 1,000 plaque forming units (pfu) of Phi-X174 phage. The inoculated culture was grown for an additional 4 hours at 37°C with mixing at 210 rpm. The inoculated Phi-X174 culture was then purified using anion exchange chromatography. The purified Phi-X174 was passed through a 0.2

[0167] Sterile filter through a micron syringe filter. Determine phage concentration according to Method D and store at 4°C.

[0168] Method D. Determination of Phi-X174 phage concentration

[0169] The following procedures were used to determine the phage concentration of the filtrate sample, feed solution, and Phi-X174 culture preparation. The solution of interest was serially diluted (10 times). Top agar (CRITERION nutrient broth (Hardy Diagnostics) with 0.9% agar, 2.5 mL) was mixed with 50 microliters of Escherichia coli (ATCC 13706) culture (grown overnight at 37°C under 210rpm shaking in CRITERION nutrient broth plus 5% sodium chloride) and 100 microliters of diluted Phi-X174 phage. The mixture was poured on the top of a standard nutrient agar plate (CRITERION nutrient broth with 1.5% agar) and incubated at 37°C for 3 to 4 hours. After incubation, plaque forming units (pfu) were counted. The number of pfu is related to the number of phage particles. The phage particle concentration (particles / mL) was calculated based on the pfu count adjusted for dilution. The log reduction value (LRV) was determined by the difference in the number of plaques present in the feed solution and the number of plaques present in the filtrate (see Equation 2). The LRV reported with the designation “>” indicates that no pfu were observed for any serial dilution sample of the filtrate.

[0170] Equation 2 .

[0171]

[0172] Method E. Preparation of porcine circovirus (PCV2d)

[0173] Porcine circovirus (1000 mL of PCV2d USA / NC24897 / 2016P14 variant, 5.62×10 6 TCID50 / mL) was centrifuged at 4,200g for 15 minutes to remove cell debris. The supernatant was collected and centrifuged at 35,000rpm for 2 hours using a 45TI rotor and an Optima XPN-100 ultracentrifuge (Beckman Coulter, Indianapolis, IN). The viral pellet was resuspended in 5.7mL of phosphate buffered saline (25mM, 4mS / cm). After resuspension, the solution was centrifuged at 1000g for 10 minutes to remove any undissolved particles. A total of 5.5mL of suspended virus was collected. A 20-microliter aliquot of the suspension was diluted into 180 microliters of phosphate buffered saline (PBS, 1X) for viral TCID50 titration in PK-15 cells. The concentration of the suspended virus was determined to be 4.64×10 7TCID50 / mL. PCV2d virus was diluted into a total of 20 mL of PBS (1X) and filtered through a BC1EMPHAZE AEX hybrid purifier (3M Company, Maplewood, MN). The PCV2d concentration after filtration was 3.16×10 6 TCID50 / mL. Store the stock solution frozen.

[0174] Example 1 .

[0175] The spinning solution was prepared by vigorously mixing 27 wt% polyethersulfone, 9 wt% poly(2-ethyl-2-oxazoline), 32.4 wt% N-methylpyrrolidone, 29.6 wt% poly(ethylene glycol) 200 (PEG200) and 2 wt% ultrapure deionized water at a temperature of about 55°C. The resulting spinning solution was cooled to about 50°C, filtered and degassed. A temperature-controlled spinning head (35°C) with an outer diameter of 0.41 mm for the spinning solution, an outer diameter of 0.3 mm for the needle and an inner diameter of 0.15 mm for the spinning head needle was used. The spinning head was fixed at a distance of 25 cm above the precipitation bath.

[0176] A mixture of the above spinning solution and NMP: polyethylene glycol (PEG200): water (50:45:5) is used as the core liquid in the spinning needle of the spinning head to produce hollow fibers. The hollow fibers are transferred to an aqueous precipitation bath heated to about 35°C. After this solidification and fixing step, the wet hollow fiber membrane is immediately wound on a wheel and then assembled into a hollow fiber membrane bundle having a length of about 30cm and including about 1200 individual hollow fiber membranes. The hollow fiber membrane is extracted with hot water (about 90°C) for about one hour and then dried with air at about 90°C for about one hour. The obtained hollow fiber membrane has a physical inner diameter of about 200 microns and a wall thickness of about 60 microns.

[0177] The membrane wall cross section was examined using SEM (8,000 to 20,000x magnification). Scanning electron microscope (SEM) images of cross sections of hollow fiber membranes are shown in Figure 3A and Figure 3B For the prepared membrane, the pore size at the inner surface facing the lumen is about 0.06 microns to 3 microns. The pore size gradually decreases in the direction from the inner membrane surface to the outer membrane surface up to a distance of about 57 microns (95%) across the membrane wall (the pore size is measured along the vector defining the shortest cross-sectional distance from the inner membrane surface to the outer surface of the membrane). The pore size then turns to gradually increase in size (along the same vector direction) toward the outer surface, with the pore size at the outer surface of the membrane being about 0.05 microns to 0.2 microns. The pore size at the location in the membrane wall where the pore size changes from continuously decreasing to continuously increasing is less than 0.03 microns.

[0178] Transmembrane flux (TMF) values ​​were measured according to Method A and the results are reported in Table 1.

[0179] Example 2. Filtration of mAb Solution

[0180] A solution of 5 mg / mL of mAb in Tris-HCl buffer (pH 7 and conductivity 5 mS / cm) was prepared from Chinese hamster ovary (CHO) suspension cell cultures expressing a biosimilar IgG1 mAb (pI of about 7.9). The mAb solution was filtered using a 3M Polisher ST BC4 capsule (3M Company) followed by a 0.2 micron PES membrane filter. The mAb solution was stored at 4°C until use. The concentration of the mAb was determined by measuring the absorbance of the solution at 280 nm and comparing the result with a previously prepared standard concentration curve.

[0181] Hollow fiber membrane test module was prepared and tested according to the following process. A polycarbonate tube with a length of 30mm and an inner diameter of 4mm was used. A single hole was drilled in the side of each tube. An open hole connector was attached to the hole using an adhesive cured by ultraviolet (uv) / visible light to form a side port. A cover was attached to the side port. About 25 to 30 hollow fibers prepared according to Example 1 were placed in each tube. The inserted hollow fibers were cut with a razor blade to provide a hollow fiber overhang of about 15mm at each end of the tube. The overhanging hollow fibers were sealed with wax and then encapsulated in the tube using polyurethane resin. After curing for 24 hours, the protruding ends were removed using a razor blade. The opening of the membrane was examined using a microscope, and only tubes in which all hollow fiber membranes had an open and unobstructed lumen portion were used. A cover with an open port for attaching to a flexible tubing was fastened to each end of the polycarbonate tube with glue. The total internal hollow fiber surface area (i.e., total lumen surface area) was about 5cm 2 The test modules were sterilized using gamma irradiation (25 kGy to 45 kGy) prior to use.

[0182] The completed test module is attached to the support and placed in a vertical orientation. The open port of the cover at the bottom of the module is connected to the three-way valve at the bottom of the vertically mounted pressure tank using flexible tubing. The pressure tank is initially filled with ultrapure water (obtained from MILLI-Q water purification system, EMD Millipore, Billerica, MA). The three-way valve between the pressure tank and the test module is opened, so as to allow water to flow into the lumen of the hollow fiber and flow out of the opposite end of the module. When the lumen of the hollow fiber is full of water, the open port at the upper end of the test module is capped. Pressure is gradually increased to 30psi. The cover on the side port of the test module is removed, so as to allow filtrate to leave the module and enter the first collecting container. Water is filtered by the hollow fiber module for a minimum of 10 minutes at 30psi. Then the three-way valve at the bottom of the pressure tank is closed, and any retained water in the pressure tank is removed.

[0183] The pressure tank was decompressed and filled with a 5mg / mL mAb solution. The pressure tank was then sealed, pressurized to 30psi, and a three-way valve was opened. The filtrate was collected in a second tare collection container placed on a digital balance, and the filtrate weight was recorded every 10 seconds. The filtration was performed for 150 minutes. The flux (380LMH) of the mAb solution was maintained constant throughout the filtration period. The ratio of the flux at 150 minutes to the flux at 60 minutes was 1.0. The ratio of the flux at 60 minutes to the flux at 20 minutes was 1.0. The total mAb filtered for 150 minutes was calculated to be 5.0kg / m 2 .

[0184] Example 3. Filtration of mAb solution spiked with Phi-X174 phage

[0185] The same method as described in Example 2 was followed, except that the 5 mg / mL mAb solution was spiked with 10 7 pfu / mL of Phi-X174 phage.

[0186] The filtrate was collected in a tared second collection container placed on a digital balance and the filtrate weight was recorded every 10 seconds. The filtration was performed for 60 minutes. The flux of the spiked mAb solution (380 LMH) remained essentially constant throughout the filtration period. The ratio of the flux at 60 minutes after the start of filtration to the flux at 20 minutes was 0.97. The total mAb filtered in 60 minutes was calculated to be 1.9 kg / m 2 The LRVs of Phi-X174 phages filtered through the membrane are reported in Table 1.

[0187] Example 4. Filtration of PCV2d

[0188] 6 mL of PCV2d sample (as described above, 3.16 × 10 6TCID50 / mL) was diluted with 143 g of PBS (1X). The same procedure as described in Example 2 was followed, except that the total internal hollow fiber surface area (i.e., total lumen surface area) was approximately 1 cm 2 , and 4.5mL or 10mL of PCV2d solution was filtered through the test module.

[0189] The concentration of PCV2d in the feed solution was compared with that in the filtrate (TCID50 / mL was determined using PK-15 cells) and the LRV of the virus was calculated. The results are reported in Table 1.

[0190] Table 1. Test results of hollow fiber membranes of Example 1

[0191]

[0192] All references and publications cited herein are expressly incorporated into the present disclosure in their entirety by reference. Illustrative embodiments of the present invention have been discussed, and reference has been made to possible variations within the scope of the present invention. For example, features described in conjunction with an illustrative embodiment may be used in conjunction with other embodiments of the present invention. These and other variations and modifications in the present invention will be apparent to those skilled in the art without departing from the scope of the present invention, and it should be understood that the present invention is not limited to the illustrative embodiments set forth herein. Therefore, the present invention is limited only by the claims provided below and their equivalents.

Claims

1. A hollow fiber membrane, The hollow fiber membrane is made of a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline, wherein the polymer blend comprises 27 wt % to 30 wt % of the aromatic sulfone polymer based on the total weight of the polymer blend; wherein the hollow fiber membrane comprises an inner surface facing its lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness; The hollow fiber membrane is an integral asymmetric permeable hollow fiber membrane. 2 . The hollow fiber membrane of claim 1 , wherein the aromatic sulfone polymer comprises polysulfone or polyethersulfone. 3 . The hollow fiber membrane according to claim 1 , wherein the polyoxazoline is poly(2-ethyl-2-oxazoline) (PEtOx).

4. The hollow fiber membrane according to any one of claims 1 to 3, wherein the region with the smallest pore size is adjacent to the inner surface.

5. The hollow fiber membrane of claim 4, wherein the region having the largest pore size is adjacent to the outer surface.

6. The hollow fiber membrane according to any one of claims 1 to 3, wherein a region having a smallest pore size is adjacent to the outer surface.

7. The hollow fiber membrane of claim 6, wherein the region having the largest pore size is adjacent to the inner surface. 8 . The hollow fiber membrane according to claim 4 , wherein the size of the pores in the region having the smallest pore diameter is in the range of 10 nm to 20 nm. 9 . The hollow fiber membrane according to claim 4 , wherein at least some of the pores of the region with the smallest pore size or the region with the largest pore size are connected. 10 . The hollow fiber membrane according to claim 9 , wherein at least some of the pores of the region having the smallest pore size or the region having the largest pore size are connected by channels between the pores.

11. The hollow fiber membrane according to any one of claims 1 to 10, wherein the hollow fiber membrane comprises a tortuous structure extending in the hollow fiber membrane.

12. The hollow fiber membrane of claim 11, wherein at least some of the meandering structures extend from the inner surface toward the outer surface.

13. The hollow fiber membrane according to any one of claims 1 to 12, wherein the polymer blend comprises more than 7 wt% or less than 3 wt% polyvinylpyrrolidone.

14. The hollow fiber membrane according to any one of claims 1 to 13, wherein the polymer blend does not contain polyvinyl pyrrolidone. 15 . The hollow fiber membrane according to claim 4 , wherein the region having the smallest pore size has a lower flow rate than the region having the largest pore size. 16 . The hollow fiber membrane according to claim 4 , wherein the region having the smallest pore size (retaining layer) has a thickness of 5 μm to 100 μm.

17. The hollow fiber membrane of any one of claims 1 to 16, wherein the hollow fiber membrane has greater than 3 log reduction values ​​(LRV) against viruses or bacteriophages of 15 nm or larger.

18. The hollow fiber membrane according to any one of claims 1 to 17, wherein the hollow fiber membrane is capable of removing viruses or bacteriophages of 15 nm or more.

19. Use of the hollow fiber membrane according to any one of claims 1 to 18 for filtering antibodies.

20. A method comprising allowing a solution containing an antibody to flow through the hollow fiber membrane according to any one of claims 1 to 18; and The antibodies are collected.

21. The method of claim 20, wherein viruses or bacteriophages of 15 nm or larger are removed from the antibody-containing solution.

22. The method of any one of claims 20 to 21, wherein the antibody-containing solution is a concentrated antibody solution.

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