Asymmetric cellulose-based filtration membrane for virus removal and method for producing the same

Abstract

In an asymmetric cellulose-based filtration membrane for virus removal and a method for manufacturing the same, the filtration membrane includes a main body. The surface on one side of the main body is the first outer surface, and the surface on the other side is the second outer surface. The average pore size of the second outer surface is 15 to 40 nm. The average pore size of the first outer surface is at least four times or more the average pore size of the second outer surface. The main body includes a pollutant capture layer and a virus collection layer for blocking viruses. One side of the pollutant capture layer is the first outer surface, and one side of the virus collection layer is the second outer surface. The average pore size of the pollutant capture layer is larger than the average pore size of the virus collection layer. And, the change gradient of the average pore size of the pollutant capture layer is larger than the change gradient of the average pore size of the virus collection layer. The method for manufacturing the filtration membrane includes preparing a membrane-forming solution, casting it on a support to form a liquid film, and immersing the liquid film in a coagulation bath for phase separation and curing.

Description

Technical Field

[0001] The present invention relates to the technical field of membrane materials, and more specifically, to an asymmetric cellulose-based filtration membrane for virus removal and a method for manufacturing the same.

Background Art

[0002] Membrane technology is a new technology in modern high-efficiency separation. Compared with conventional technologies such as distillation and rectification, it has advantages such as high separation efficiency, low energy consumption, and small occupied area. The core of membrane separation technology is the separation membrane. Among them, polymer filtration membranes are separation membranes manufactured by certain process technologies using organic polymer polymers as raw materials. Depending on the type of polymer polymer, polymer filtration membranes can be subdivided into cellulose-based polymer filtration membranes, polyamide-based polymer filtration membranes, sulfone-based polymer filtration membranes, polytetrafluoroethylene-based polymer filtration membranes, and the like. Also, depending on the pore size of the membrane, it can be divided into microfiltration membranes, ultrafiltration membranes, nanofiltration membranes, and reverse osmosis membranes.

[0003] In recent years, biopharmaceuticals (especially antibodies such as immunoglobulins) have been widely used because of their high therapeutic effects and few side effects. However, biopolymers such as antibodies are mainly produced from living organisms such as animal cells. Therefore, in order to be used as pharmaceuticals, it is necessary to separate and purify fluids containing biopolymers such as antibodies. In particular, it is necessary to ensure the safety of the corresponding biopharmaceuticals by removing various parvoviruses contained in the fluid (currently, the smallest mouse parvovirus has a particle size of about 20 nm). Currently, the most commonly used method for virus removal from fluids is membrane separation. This is because membrane separation technology has high separation efficiency, low energy consumption, can be carried out at room temperature, can efficiently block various viruses, and can efficiently recover various biopolymers without inactivating proteins.

[0004] For example, Patent Document 1 (application by EMD Millipore) discloses a multi-layer composite ultrafiltration membrane (Figs. 13 and 14). The composite ultrafiltration membrane includes at least one first porous membrane layer having a first side and a similar second side, and at least one second porous membrane layer having a similar first side and second side. The joint between the first layer and the second layer is integrated, and has a porosity transition band from the similar first side of the second layer to the similar second side of the first layer. At least one of the layers is an asymmetric ultrafiltration membrane. The membrane structure formed by such a composite has a strong inhibitory effect on parvovirus and can achieve a high protein yield, thus meeting the actual application needs, but there are the following problems. First, the filtration membrane is a composite membrane, and the pore size changes rapidly (becomes smaller) during the transition from one layer to another, so a wide range of particle sizes are likely to be retained at the interface of the layers generated by the co-casting method. When such particles are carried at the boundary of the layers, the service life of the filter is impaired. That is, the service life is significantly shortened. In addition, there is a risk of interlayer delamination / interlayer separation occurring while the composite membrane is wrinkled. In addition, the film-forming material used in the production of the composite membrane is mainly polyethersulfone. However, since both sides of the sulfone group of polyethersulfone are benzene rings, it is inferior in hydrophilicity, and the finally formed membrane has a certain adsorption effect on proteins. Therefore, the protein yield becomes general and the economic benefit decreases.

[0005] In addition, Patent Document 2 (application by Sartorius) also discloses a porous single-layer polymer membrane. At least one main surface of the polymer membrane has a surface porosity of at least 40%, and the total porosity of the polymer membrane is 0.8 to 1.4 times the surface porosity of at least 40% of the surface. Moreover, the polymer membrane has an asymmetry factor of 1.5 to 10. The polymer film is a single-layer filtration membrane and has excellent flux and a long service life. The polymer film is mainly used for the filtration of viruses, proteins or polymers. However, since the polymer membrane has a large average pore size, it can only block large particulate matter with a particle size of several hundred nanometers, and it is impossible to block parvovirus with a particle size of about 20 nm.

[0006] In order to further improve the protein yield, Patent Document 3 (Asahi Kasei application) also discloses a virus removal membrane that contains cellulose and is used to remove viruses from a solution containing protein. The virus removal membrane has a surface on the first side to which a solution containing protein is supplied and a surface on the second side through which the permeate that has passed through the virus removal membrane is discharged. The average pore size of the membrane is 13 to 21 nm. The membrane is made of a cellulose material and has very strong hydrophilicity. Therefore, it has a low protein adsorption rate while efficiently collecting viruses. Moreover, since the membrane is a single-layer membrane, there are no drawbacks such as a sudden change in pore size or easy separation between membrane layers. However, the filtration membrane also has certain drawbacks. First, the virus removal membrane is manufactured by the copper-ammonia complex method. That is, a film-forming substance is added to a copper-ammonia complex solution and various treatments are carried out. This manufacturing method not only pollutes the environment but also has extremely high risks and is very likely to cause great harm to the safety of the lives of researchers and developers. Second, since the thickness of the contaminant capture layer of the virus removal membrane (generally, the region in the membrane cross-section with an average pore size larger than 40 nm is referred to as the contaminant capture layer) is very small, the contaminant capture ability of the virus removal membrane is small. Therefore, foreign substances with large particles are likely to clog the flow path inside the membrane, shortening the service life of the virus removal membrane. In addition, since the manufactured virus removal membrane is a hollow fiber membrane, its pressure resistance is low and it is easily damaged. Therefore, the manufacturing process of the assembly and filter of the virus removal membrane becomes relatively complicated. Also, since the virus removal membrane has low pressure resistance, the pressure difference before and after the membrane is small. Therefore, the filtration rate is low and the economic benefit per unit time is extremely low.

[0007] That is, due to the existence of the above problems, the development of the virus removal membrane is restricted to a certain extent.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

[0009] In view of the defects existing in the prior art, an object of the present invention is to provide an asymmetric cellulose-based filtration membrane for virus removal and a method for manufacturing the same. The cellulose-based filtration membrane is integrally formed and does not require lamination, so the manufacturing process is relatively simple, green and environmentally friendly. In addition, the manufactured cellulose-based filtration membrane has a strong blocking effect on viruses and can achieve a high protein yield, thus meeting the actual application needs. [Means for Solving the Problems]

[0010] In order to achieve the above object, the present invention provides the following technical means.

[0011] An asymmetric cellulose-based filtration membrane for virus removal includes a main body, and a non-directional curved path is provided in the main body. One side surface of the main body is a first outer surface, and the other side surface of the main body is a second outer surface. The average pore size of the second outer surface is 15 to 40 nm. The average pore size of the first outer surface is at least 4 times or more the average pore size of the second outer surface.

[0012] The main body includes a pollutant capture layer and a virus collection layer for blocking viruses. One side of the pollutant capture layer is the first outer surface, and one side of the virus collection layer is the second outer surface. The other side of the pollutant capture layer and the other side of the virus collection layer are connected by continuous fibers.

[0013] The average pore diameter of the pollutant capture layer is larger than that of the virus capture layer. Moreover, the change gradient of the average pore diameter of the pollutant capture layer is larger than that of the virus capture layer.

[0014] The filtration membrane of the present invention is made of a cellulose-based material. Compared with other organic polymer film-forming materials such as PES (polyethersulfone), the filtration membrane made of a cellulose-based material has strong hydrophilicity, excellent biocompatibility, is non-toxic, and has a low adsorption amount for various proteins (generally, cellulose-based filtration membranes are considered to be the membrane materials that are least likely to adsorb proteins among organic filtration membranes). Therefore, it is particularly suitable for use as a virus removal membrane.

[0015] In the membrane body structure of the cellulose-based filtration membrane provided by the present invention, it is obvious that the pore size sizes on the two outer surfaces of the filtration membrane are different and have a certain difference. The pore size of the pores on one outer surface is large, and the pore size of the pores on the other outer surface is small. In the present invention, the outer surface of the filtration membrane with the smaller pore size is referred to as the second outer surface. That is, the second outer surface is the small pore surface of the filtration membrane (which also becomes the drainage surface). The average pore diameter of the second outer surface is 15 to 40 nm, and preferably, the average pore diameter of the second outer surface is 18 to 32 nm. Due to the interaction between the existence of the second outer surface (small pore surface) and the non-directional curved paths provided in the body (the non-directional curved paths refer to the groove structure with random orientation and / or the pore structure with discrete distribution. And each non-directional curved path penetrates each other), the filtration accuracy of the filtration membrane is improved. Also, it is ensured that the filtration membrane has a high blocking effect on parvovirus.

[0016] In the present invention, the other outer surface of the filtration membrane with the larger pore size is referred to as the first outer surface. That is, the first outer surface is the large pore surface of the filtration membrane (which also becomes the feed surface). The average pore diameter of the first outer surface is at least 4 times or more the average pore diameter of the first outer surface. The existence of the first outer surface (large pore surface) is advantageous for improving the membrane flux and accelerating the filtration speed of the entire membrane. As a result, the time for the fluid to pass through the filtration membrane is shortened, and the time cost is reduced.

[0017] The first outer surface and the second outer surface in the present invention have different average pore sizes and have a certain difference. This means that the cellulose-based filtration membrane is an asymmetric membrane. Thereby, while ensuring that the entire membrane has a high filtration rate, a large pollutant capture capacity, and a long service life, it is possible to ensure that the membrane has a strong capture capacity for parvovirus (especially parvovirus with a particle size of about 20 nm), thus meeting the actual application needs.

[0018] In addition, by observing the structure of the membrane body, it can be further found that a certain change occurs in the average pore size of the body from the region close to the first outer surface to the region close to the second outer surface. That is, the average pore size of the membrane body gradually changes with the thickness (however, within any small region, the pore size may hardly change), and does not change abruptly. This proves that the filtration membrane is integrally formed and has not undergone processes such as "composite".

[0019] The entire body of the filtration membrane in the present invention is mainly divided into two regions in the thickness direction. Among them, one region is a pollutant capture layer including the first outer surface, in which the pore diameter of the internal pores is relatively large (the average pore size of the pollutant capture layer is larger than the average pore size of the virus capture layer), and it is mainly used to block large-particle foreign substances in the fluid. The pollutant capture layer has a large pollutant capture capacity and a high flow rate, exerts a pre-filtration effect on the fluid, and exerts a protective effect on the virus capture layer to ensure that the entire membrane has high mechanical strength. The other region is a virus capture layer including the second outer surface, in which the pore diameter of the internal pores is relatively small, and it is mainly used to block small-particle foreign substances such as parvovirus in the fluid. Thereby, it exerts a separation effect to ensure that the filtration membrane has a high capture capacity for various viruses. Therefore, the filtration membrane is particularly suitable for use as a virus removal membrane. When actually used, the first outer surface (large pore surface) is used as the feed liquid surface, and the second outer surface (small pore surface) is used as the drain liquid surface.

[0020] In the present invention, the change gradient of the average pore diameter refers to the change value of the average pore diameter per unit thickness. The larger this value is, the faster the change in the pore diameter with the thickness, and the smaller this value is, the smaller the change in the pore diameter with the membrane thickness. The calculation method of the change gradient of the average pore diameter is the difference between the maximum pore diameter and the minimum pore diameter in any region (unit: nm) / the thickness between the positions of both (the distance between the maximum pore diameter portion and the position of the minimum pore diameter in the region. Unit: μm). As a point of note, when there is a certain thickness at the position of the minimum pore diameter in the region, the thickness between the positions of both shall be the minimum thickness between the maximum pore diameter portion and the position of the minimum pore diameter. Further, the change gradient of the average pore diameter of the pollutant capture layer in the present invention is larger than that of the virus capture layer (that is, the change in the pore diameter with the thickness of the pollutant capture layer is slightly faster, and the change in the pore diameter with the thickness of the virus capture layer is slightly slower). This means that in the direction of the membrane body from the first outer surface to the second outer surface, the change in the pore diameter with the thickness basically decelerates. Also, the virus capture layer has a small average pore diameter and a small change gradient of the average pore diameter. That is, within the virus capture layer, the change in the pore diameter of the pores with the membrane thickness is small, or rather, it does not change with the membrane thickness. Therefore, the pore diameters of all the pores in the virus capture layer are small. Doing so is very advantageous for highly efficiently blocking various foreign substances such as parvovirus (about 20 nm) in proteins, and the purification efficiency becomes very high.

[0021] The cellulose-based filtration membrane of the present invention is integrally formed. Also, the average pore diameter of the membrane body gradually changes with the thickness and does not change abruptly. This means that the pore diameters of the pores in the vicinity of the virus collection layer in the pollutant capture layer are also small. On the other hand, in order to ensure that the entire membrane has a high flux, it is necessary to increase the overall average pore diameter in the pollutant capture layer. Therefore, the pollutant capture layer needs to have a relatively large average pore diameter change gradient. This ensures that the pore diameters of the pores in the virus collection layer are small, while the pollutant capture layer has a large pollutant capture capacity and the service life of the membrane is prolonged. Moreover, this ensures that the flux of the entire membrane is high, the attenuation of the flux is slow, and the economic benefit per unit is high.

[0022] In addition, the other side of the pollutant capture layer (the side separated from the first outer surface in the pollutant capture layer) and the other side of the virus collection layer (the side separated from the second outer surface in the virus collection layer) are connected by continuous fibers. As can be understood, "continuous" means that almost all the fibers are connected to each other as a whole without using an adhesive or the like to connect them separately, for example, they are integrally formed. In this case, the network-like fibers cannot be separated from each other unless torn by an external force. Also, the network-like continuous fibers are connected to the first outer surface and the second porous surface. Moreover, the material of each part of the cellulose-based filtration membrane in the present invention is uniform. That is, the entire membrane is made of a cellulose-based material and the material does not change.

[0023] In the present invention, the asymmetric membrane should be understood as follows. That is, both the contaminant capture layer and the virus collection layer are composed of the same type of material. These layers combine to form the overall structure and are directly formed during the membrane manufacturing process. Also, in the transition from the contaminant capture layer to the virus collection layer, only the membrane structure changes. In contrast, for example, a composite membrane has a multilayer structure. In the case of a composite membrane, in separate process steps, a dense layer as the virus collection layer is laminated on a porous (often microporous) support layer or support membrane. Also, in the case of a composite membrane, the materials constituting the support layer and the virus collection layer are often different.

[0024] As a method for measuring the average pore size on the membrane surface, after morphological characteristics evaluation of the membrane structure using a scanning electron microscope, it may be measured by computer software (such as Matlab, NIS-Elements, etc.) or manually, and appropriate calculations may be performed. During the membrane manufacturing process, in the direction perpendicular to the membrane thickness (when the membrane is in a flat membrane form, this direction is the planar direction; when the membrane is in a hollow fiber membrane form, this direction is perpendicular to the radial direction), various characteristics such as the pore size distribution become almost uniform and are basically maintained uniformly. Therefore, the overall average pore size of the corresponding plane can be reflected by the average pore size of a partial region of the corresponding plane. When actually measuring, first, the characteristics of the membrane surface may be evaluated with an electron microscope to obtain the corresponding SEM image. Next, since the pores on the membrane surface are almost uniform, for example, a certain area such as 1μm 2 (1μm×1μm) or 25μm 2 (5μm×5μm) may be selected. Note that the specific size of the area is determined according to the actual situation. Then, after measuring the pore sizes of all the pores in the area by the corresponding computer software or manually, the average pore size of the surface is obtained by calculation. Of course, those skilled in the art may also obtain the above parameters by other measuring means, and the above measuring means is only for reference.

[0025] As a further improvement of the present invention, the gradient of change in the average pore size of the pollutant capture layer is at least 3 nm / μm greater than the gradient of change in the average pore size of the virus capture layer.

[0026] The second outer surface is provided with a plurality of round-hole-shaped second pores, and the pore area ratio of the second pores on the second outer surface is 2 to 15%.

[0027] To further ensure that the pore diameter in the virus capture layer becomes smaller (having a high capture efficiency for various parvoviruses), and to further ensure that the flux of the entire membrane increases and the filtration speed becomes faster, the difference between the gradient of change in the average pore size of the pollutant capture layer and the gradient of change in the average pore size of the virus capture layer must not be too small. If the difference between the two is too small, the average pore size of the entire membrane will become too large, and the capture efficiency for various parvoviruses (particle size of about 20 nm) will become too low. However, if the average pore size of the entire membrane is too small, the flux of the entire membrane will become too low, the time cost will become too large, and the economic benefit per unit time will become excessively low. In contrast, the gradient of change in the average pore size of the pollutant capture layer in the present invention is at least 3 nm / μm greater than the gradient of change in the average pore size of the virus capture layer, having an appropriate difference. Thereby, it is further ensured that the pore diameter in the virus capture layer becomes smaller (contributing to high-efficiency blocking for various parvoviruses), and the flux of the entire membrane is further improved.

[0028] On the second outer surface of the membrane, there are a certain number of second pores with a certain pore diameter. The second pores on the second outer surface in the present invention have a round-hole-shaped structure, including circular second pores and elliptical second pores. Moreover, the pore area ratio of the second pores on the second outer surface (the ratio of the total area of the second pores to the membrane area) is 2 to 15%, and the pore area ratio is low. That is, the second outer surface is relatively dense. Through the interaction between the second pores with a certain pore diameter size and the second outer surface with a corresponding pore area ratio, it is further ensured that the filtration membrane has a high capture efficiency for various parvoviruses (particle size of about 20 nm).

[0029] As a method for testing the pore area ratio, after morphological characteristics evaluation of the membrane structure using a scanning electron microscope, measurement may be performed using computer software (e.g., Matlab, NIS-Elements, etc.) or manually, and appropriate calculations may be carried out. For example, 1 μm 2 (1 μm × 1 μm) or 25 μm 2 (5 μm × 5 μm) and other such fixed areas are selected. Note that the specific size of the area is determined according to the actual situation. Then, after measuring the pore areas of all the pores in the corresponding area using the corresponding computer software or manually, calculations are performed to obtain the total, and the pore area ratio of the surface is obtained by dividing by the corresponding area. Of course, those skilled in the art may also obtain the above parameters by other measurement means, and the above measurement means are only for reference. Also, among the features described later, the average diameter of the first fiber can also be obtained by a similar method (that is, the average value of the diameters of a plurality of first fibers in a fixed area).

[0030] As a further improvement of the present invention, the first outer surface includes a plurality of continuous linear first fibers, and circular holes-shaped first pores are formed surrounded between adjacent continuous first fibers. The average diameter of the first fiber is 100 to 250 nm. The average pore diameter of the first pore is 200 to 600 nm. The pore area ratio of the first pores on the first outer surface is 5 to 25%.

[0031] In the membrane body structure of the filtration membrane provided by the present invention, it is clear that a plurality of first fibers exist on the first outer surface of the membrane. The first fiber has an elongated structure, and the first pores on the first outer surface are surrounded by the first fiber. Also, the average diameter of the first fiber is 100 to 250 nm. According to the first fiber of such a thickness, the stability of the first pores is guaranteed, so it is convenient for exerting a certain pre-filtration effect on the fluid and blocking foreign particles of a certain particle size. Moreover, the mechanical strength of the membrane is guaranteed, and since the actual application needs are met, it is suitable for performing various processing treatments.

[0032] In addition, a certain number of first pores with a certain pore diameter exist on the first outer surface of the membrane. As is well known, factors such as the pore diameter size, number, and pore shape of the membrane all have a great influence on properties such as the filtration accuracy (collection efficiency) of the membrane and the flow rate of the membrane. The first pores on the first outer surface in the present invention have a round pore structure, including circular first pores and elliptical first pores. The average pore diameter of the first pores is 200 to 600 nm (preferably 250 to 550 nm), and the pore area ratio of the first pores on the first outer surface is 5 to 25% (the ratio of the total area of the first pores to the membrane area). Through the interaction between the first pores with a certain pore diameter size and the first outer surface with a corresponding pore area ratio, it is ensured that the filtration membrane has a large flow rate. This is convenient for the fluid to quickly pass through the porous membrane and shorten the filtration time. In addition, due to its high tensile strength, it meets the actual application needs.

[0033] As a further improvement of the present invention, the change gradient of the average pore diameter of the cellulose-based filtration membrane is 2 to 7 nm / 1 μm.

[0034] The ratio of the average pore diameter of the first outer surface to the average pore diameter of the second outer surface is 6 to 30.

[0035] The pore area ratio of the first outer surface is at least 3% larger than that of the second outer surface.

[0036] The filtration membrane of the present invention is integrally formed. Moreover, the pore size of the filtration membrane gradually changes with the thickness of the entire membrane (in some regions, the pore size may hardly change with the membrane thickness), and does not change abruptly. Therefore, the rate of change of the membrane pore size with thickness is reflected by the magnitude of the change gradient of the average pore size. The larger this value, the faster the change in pore size, and the smaller the value, the slower the change in pore size. The change gradient of the average pore size of the filtration membrane in the present invention is 2 - 7 nm / 1 μm, having an appropriate change gradient value of the pore size. This means that in the present invention, a certain change occurs in the membrane pore size with the thickness, and neither is the change in the membrane pore size too fast nor are there pores that are too large (if the pores in the contaminant capture layer are too large, the mechanical strength of the entire membrane becomes too low, resulting in no pressure resistance and being easily damaged by the action of pressure). In this case, the contaminant capture layer can exert a certain supporting effect on the virus collection layer, and since the entire membrane has excellent mechanical strength and pressure resistance, it is not easily damaged even under a large pressure. Also, the change gradient of the pore size should not be too small. If it is too small, the collection efficiency becomes excessively low or the flux becomes excessively low, making it impossible to meet the actual application needs. By having the above-described change gradient of the pore size throughout the membrane, it is possible to ensure the high-efficiency blocking property of the membrane against viruses, while the membrane has a large flux and also has a large contaminant capture capacity.

[0037] In the present invention, the pore size of the filtration membrane gradually changes with the thickness of the entire membrane (in some regions, the pore size may hardly change with the membrane thickness) and does not change abruptly. The change gradient of the average pore size can reflect the change situation of the membrane pore size with the thickness. In addition, the change situation of the membrane pore size with the thickness can be shown even better by the feature of the ratio of the average pore sizes of the two outer surfaces. The ratio of the average pore sizes of the two outer surfaces can be called the asymmetry factor. The smaller this value (the closer it is to 1), the stronger the symmetry of the two outer surfaces of the filtration membrane. Also, the larger this value, the greater the asymmetry of the two outer surfaces of the filtration membrane. As a result of measurement, the ratio of the average pore size of the first outer surface to the average pore size of the second outer surface is 6 to 30, and preferably, the ratio of the average pore sizes of both is 10 to 25. This means that the filtration membrane of the present invention has two asymmetric outer surfaces and has an appropriate degree of asymmetry. Such asymmetry not only ensures that the filtration membrane has a large flux and a long service life, but also ensures that the filtration membrane has a high collection efficiency for viruses, thus meeting the actual application needs.

[0038] As is well known, factors such as the pore size, number, and pore shape of the pores of the membrane all have a great influence on properties such as the filtration accuracy (collection efficiency) of the membrane and the flow rate of the membrane. In the present invention, the pore area ratio of the first outer surface is at least 3% larger than that of the second outer surface. That is, the pore area ratio of the first outer surface (large pore surface) is large, and the pore area ratio of the second outer surface (small pore surface) is small. With such a structure, the fluid can quickly pass through the first outer surface (large pore surface). The first outer surface exerts a pre-filtration effect on the fluid to ensure that the entire membrane has an excellent flux. Also, the second outer surface (small pore surface) is dense and can efficiently block various parvoviruses (especially mouse parvovirus with a particle size of about 20 nm). Thereby, it becomes difficult for parvoviruses to leak, and the actual application needs are met.

[0039] As a further improvement of the present invention, the PMI average pore size of the cellulose-based filtration membrane is 15 to 40 nm, the thickness of the cellulose-based filtration membrane is 70 to 120 μm, and the porosity is 25 to 55%.

[0040] When the average pore size of the filtration membrane was tested with a PMI pore size test device, the PMI average pore size of the filtration membrane in the present invention was 15 to 40 nm (preferably 18 to 30 nm). Also, due to the curved path of the main body structure and the certain thickness of the membrane, it is ensured that the filtration membrane has a strong blocking effect against nanoscale parvoviruses (even in the case of mouse parvovirus with a particle size of 20 nm), so it can meet the actual application needs and is suitable for use as a virus removal membrane.

[0041] Regarding the membrane thickness, after morphological characteristic evaluation of the membrane structure using a scanning electron microscope, it can be measured and calculated by using computer software (such as Matlab, NIS-Elements, etc.) or manually. Of course, those skilled in the art may also obtain the above parameters by other measurement means (for example, freeze-drying first and then measuring with a measurement tool), and the above measurement means are only for reference. When the membrane thickness is too small, the mechanical strength of the membrane decreases and the filtration time becomes excessively short, so effective filtration cannot be carried out. On the other hand, when the membrane thickness is too large, the filtration time becomes too long and the time cost becomes excessively large. In contrast, the thickness of the cellulose-based filtration membrane in the present invention is 70 to 120 μm. Therefore, it is guaranteed that the cellulose-based filtration membrane not only has high mechanical strength, but also can carry out effective filtration, has high filtration efficiency, shortens the filtration time, and reduces the time cost.

[0042] If the porosity of the membrane is too high, the tensile strength of the membrane will be excessively low and the mechanical performance will deteriorate, resulting in a decrease in industrial practical value and an inability to meet market needs. On the other hand, if the porosity of the membrane is too low, first, it will affect the flow rate of the membrane, the filtration speed of the membrane will be slow, the filtration time will be long, and the time cost will be high. Second, the pollutant capture ability of the membrane will be too low and the service life will be excessively short, so it is necessary to replace the membrane in a short period, resulting in a significant increase in economic cost. Therefore, the filtration membrane needs to have an appropriate porosity. The porosity is closely related to the material of the filtration membrane. Since the filtration membrane of the present invention is made of a cellulose-based material, based on this, the porosity of the filtration membrane is set to 25-55%. Due to the interaction between such porosity and the membrane material, the membrane not only has excellent tensile strength, but also has a fast filtration speed and a large flow rate. Furthermore, by having a high pollutant capture ability, it is possible to block many foreign particles, so the service life is extended and the economic cost is reduced.

[0043] As a further improvement of the present invention, the average pore diameter of the pollutant capture layer is 80-300 nm and the porosity is 35-70%. The thickness of the pollutant capture layer accounts for 70-90% of the membrane thickness.

[0044] The change gradient of the average pore diameter of the pollutant capture layer is 3-9 nm / μm.

[0045] In the present invention, generally, in the main body structure of the membrane, a region with a pore diameter larger than 40 nm is regarded as a contaminant capture layer, and a region with a pore diameter of 40 nm or less is regarded as a virus collection layer. Compared with the virus collection layer, the contaminant capture layer has larger pore diameters and higher porosity. As a result of testing, it was found that the average pore diameter of the contaminant capture layer is 80 to 300 nm (preferably 120 to 250 nm), and the porosity is 35 to 70% (preferably 40 to 65%). In this case, while ensuring that the filtration membrane has a high flow rate, it is also possible to exert a sufficient blocking effect on large-particle foreign matters (other foreign matters such as large-particle-size viruses) so as not to affect the subsequent blocking of parvoviruses. In addition, the thickness of the contaminant capture layer accounts for 70 to 90% of the total membrane thickness. This means that most of the region of the membrane is the contaminant capture layer. Moreover, due to the interaction of large pore diameters and high porosity, the entire membrane has a high flux, a fast filtration speed, a low time cost, a high contaminant capture ability, a long service life, and it is guaranteed that the attenuation of the flux is slow.

[0046] When the change gradient of the average pore size of the pollutant capture layer is too large, that is, when the change in the membrane pore size with thickness is too fast, the mechanical strength of the entire membrane is likely to decrease excessively, and the pollutant capture layer cannot provide a supporting effect on the virus capture layer, making it impossible to meet the actual application needs. On the other hand, when the change gradient of the average pore size of the pollutant capture layer is too small, that is, when the change in the membrane pore size with thickness is too slow, the capture efficiency of the filtration membrane for various parvoviruses becomes excessively low (the average pore size of the entire membrane becomes too large), or the overall flux of the filtration membrane becomes too small, resulting in an excessively long filtration time and an overly large time cost (the average pore size of the entire membrane becomes too small). In contrast, since the change gradient of the average pore size of the pollutant capture layer in the present invention is 3 - 9 nm / μm, it has an appropriate change gradient of the average pore size, and the change in the pore size size with thickness is relatively reasonable. Moreover, through the interaction with the large average pore size in the corresponding pollutant capture layer, it is ensured that the pollutant capture layer has a large pollutant capture capacity, the service life of the membrane is prolonged, the overall flux of the membrane is high, the attenuation of the flux is slow, and the economic benefit per unit is guaranteed to be high. Also, it is possible to ensure that reducing the pore size of the pores in the virus capture layer does not affect the high-efficiency blocking property of the entire filtration membrane against viruses.

[0047] Regarding parameters such as the average pore size, porosity, and thickness of the pollutant capture layer in the present invention, first, after disassembling the filtration membrane into the pollutant capture layer and the virus capture layer, corresponding parameter tests may be performed on the pollutant capture layer, or after morphological characteristic evaluation of the cross-sectional structure of the membrane using a scanning electron microscope, it may be measured and calculated by using computer software (such as Matlab, NIS-Elements, etc.) or manually. Of course, those skilled in the art may also obtain the above parameters by other measurement means, and the above measurement means are only for reference.

[0048] As a further improvement of the present invention, the average pore size of the region of the pollutant capture layer close to the first outer surface is larger than the average pore size of the region of the pollutant capture layer close to the second outer surface.

[0049] Moreover, the change gradient of the average pore diameter of the region on the side close to the first outer surface of the pollutant capture layer is larger than the change gradient of the average pore diameter of the region on the side close to the second outer surface of the pollutant capture layer.

[0050] Preferably, the pore size of the pores in the pollutant capture layer in the present invention changes so as to decelerate with the film thickness (in the direction from the first outer surface to the second outer surface). That is, in the region of the pollutant capture layer close to the first outer surface, the pore diameter of the pores is relatively large, and the change in the pore diameter with the thickness is fast (the change gradient value of the average pore diameter is large). On the other hand, in the region of the pollutant capture layer close to the second outer surface, the pore diameter of the pores is relatively small, and the change in the pore diameter with the thickness is slow (the change gradient value of the average pore diameter is small). Thereby, the transfer from the pollutant capture layer to the virus collection layer becomes sufficiently natural and there is no sudden change, so it is ensured that the whole film has high mechanical strength. And, compared with the film structure in which the pore diameter of the pores in the pollutant capture layer changes with a substantially constant gradient with the thickness, the filtration membrane in which the pore diameter of the pollutant capture layer changes so as to decelerate with the thickness has a larger pollutant capture capacity and a higher flux, and exhibits a good pre-filtration effect on the fluid.

[0051] As a further improvement of the present invention, the pollutant capture layer further includes a surface layer region, and one side of the surface layer region includes the first outer surface. The thickness of the surface layer region is 1 to 15 μm, and the porosity of the surface layer region is 10 to 55%. And, the average pore diameter of the region on the side close to the first outer surface of the surface layer region is smaller than the average pore diameter of the region on the side close to the virus collection layer of the surface layer region.

[0052] Among the filtration membranes manufactured by the present invention, in the pollutant capture layer of some filtration membranes, in the direction from the first outer surface (feed liquid surface) to the second outer surface (discharge liquid surface), the pore diameters of the pores of the membrane all decrease with the thickness (regardless of whether they decrease at a constant gradient or a decelerating gradient). In this case, the pores present on the first outer surface are the pores with the largest pore diameter in the overall structure of the membrane. However, in the pollutant capture layer of some filtration membranes, in the direction from the first outer surface (feed liquid surface) to the second outer surface (discharge liquid surface), the pore diameters of the pores of the membrane increase first and then decrease with the thickness. In this case, the region where the pores with the largest pore diameter appear in the overall structure of the membrane is a region close to the first outer surface, but not the first outer surface. In the main body structure of such a filtration membrane, in the present invention, the region where the pore diameter increases with the thickness in the pollutant capture layer is referred to as the surface layer region. When the pollutant capture layer of the filtration membrane includes the surface layer region, the side separated from the virus capture layer in the surface layer region becomes the first outer surface. The existence of the surface layer region contributes to the improvement of the tensile strength of the membrane. Moreover, further, by exerting a supporting and protecting effect on the virus capture layer, the whole membrane becomes more pressure-resistant, less likely to break, and the service life is further extended. In addition, as a result of measurement, it was found that the thickness of the surface layer region is 1 to 15 μm (preferably 3 to 10 μm), and the porosity is 10 to 55%. Since the surface layer region has an appropriate thickness and porosity, it can improve the supporting strength of the membrane while not affecting the filtration rate and pollutant capture ability of the whole membrane.

[0053] As a further improvement of the present invention, the average pore diameter of the virus capture layer is 20 to 40 nm, and the porosity is 10 to 45%. Also, the thickness of the virus capture layer is 5 to 25 μm, and the change gradient of the average pore diameter of the virus capture layer is 0 to 3 nm / 1 μm.

[0054] The virus capture layer is an area in the main structure of the filtration membrane for blocking parvovirus. Both the pore size and thickness of the virus capture layer have a significant impact on the virus capture efficiency. In the present invention, the average pore size of the virus capture layer is 20 - 40 nm. Since the pore sizes inside the virus capture layer are small, it is guaranteed that the filtration membrane has a high capture efficiency for foreign substances with small particle sizes (especially parvovirus with a particle size of 20 nm). Thereby, the actual application needs are met, so it is particularly suitable for application in the field of virus removal. On the other hand, in the prior art, for some filtration membranes, the thickness of the virus capture layer is extremely small (basically about 1 - 3 μm). Especially, this is the case for some filtration membranes with general hydrophilicity (for example, polyethersulfone filtration membranes). This is because the smaller the membrane pores, the stronger the adsorption ability. Therefore, if the thickness of the virus capture layer of a filtration membrane with general hydrophilicity is increased, it will be easier to adsorb proteins, resulting in an excessively low protein yield (the PES membrane has a certain adsorption effect on proteins. When the pore size is small, the adsorption effect becomes more prominent, so the thickness of the separation layer of the PES membrane needs to be relatively thin). However, even in this case, there are still certain problems. That is, there is a risk that the virus is likely to leak, and the high-efficiency blocking property of the filtration membrane cannot be maintained continuously.

[0055] In contrast, cellulose-based filtration membranes have strong hydrophilicity and basically have no adsorption effect on proteins. Therefore, in the present invention, by having a small pore region with a larger thickness (the thickness of the virus capture layer is 5 - 25 μm), while ensuring low protein adsorption, it can have a high capture efficiency, eliminating the risk of virus leakage. Moreover, since the thickness of the virus capture layer is not too large, it has almost no impact on the flux of the entire membrane. And the porosity of the virus capture layer is 10 - 45%. This means that the virus capture layer can exert a sufficient retention effect on parvovirus, has a high membrane capacity, and can further extend the service life of the membrane.

[0056] The change gradient of the average pore diameter of the virus capture layer is 0 to 3 nm / 1 μm, and the change gradient of the average pore diameter is small. This means that inside the virus capture layer, the change in the pore diameter with thickness is small, and thus there is no change. Due to the interaction between this point and the small average pore diameter of the virus capture layer, the high-efficiency blocking property of the filter membrane against viruses can be further improved. Therefore, even for a mouse parvovirus with a particle size of 20 nm, it can be blocked with high efficiency, there is no risk of leakage, and the service life is also extended.

[0057] Regarding parameters such as the average pore diameter, porosity, and thickness of the virus capture layer in the present invention, first, the filter membrane can be disassembled into a virus capture layer and a pollutant capture layer, and then corresponding parameter tests can be performed on the virus capture layer. Or, after morphological characteristic evaluation of the cross-sectional structure of the membrane using a scanning electron microscope, it can be measured and calculated by using computer software (such as Matlab, NIS-Elements, etc.) or manually. In addition, regarding the thickness of the virus capture layer, a blocking test can be performed using 20-nm gold colloids as foreign particles. The length of the region in the filter membrane that blocks the 20-nm gold colloids is the thickness of the virus capture layer. For the specific test method, reference may be made to the specification of Chinese Patent No. 105980037 (virus removal membrane). Of course, those skilled in the art may also obtain the above parameters by other measuring means, and the above measuring means are only for reference.

[0058] As a further improvement of the present invention, in the film thickness direction from the first outer surface to the second outer surface, the average pore diameter in the virus capture layer hardly changes with the thickness. Or, the average pore diameter in the virus capture layer continuously decreases with the thickness. Or, the average pore diameter in the virus capture layer decreases first and then increases with the thickness.

[0059] By controlling and adjusting the corresponding manufacturing parameters, it is possible to affect the main structure of the formed membrane and manufacture filtration membranes with different structures. When observing the main structure of the filtration membrane, it was found that in the virus capture layer of some filtration membranes, the average pore diameter of the pores hardly changed with the thickness (that is, the change gradient of the average pore diameter was 0).

[0060] On the other hand, in the virus capture layer of another filtration membrane, the average pore diameter of the pores continuously decreased with the thickness. In this case, in the virus capture layer, the position where the pore diameter of the pores is the smallest is the second outer surface. Such a structure of the virus capture layer contributes to ensuring the capture efficiency. Furthermore, in the virus capture layer of some filtration membranes, the average pore diameter of the pores decreased and then increased with the thickness. Such a structure of the virus capture layer is advantageous for improving the flux of the entire membrane on the premise of ensuring the capture efficiency. Due to the difference in the structure of the virus capture layer and the interaction with the thickness of the virus capture layer and the average pore diameter size of the virus capture layer, it is ensured that the filtration membrane has a high blocking rate against parvovirus and the entire filtration membrane has a high flux and mechanical strength.

[0061] As a further improvement of the present invention, the ratio of the average pore diameter of the pollutant capture layer to the average pore diameter of the virus capture layer is 2.5 to 9.5:1, and the thickness of the pollutant capture layer is at least 35 μm larger than the thickness of the virus capture layer.

[0062] In the present invention, the main body structure of the filtration membrane is mainly divided into two regions. Among them, the region with a relatively large pore diameter of the pores serves as the pollutant capture layer, and the region with a relatively small pore diameter of the pores serves as the virus collection layer. As a result of measurement, it was found that the ratio of the average pore diameter of the pollutant capture layer to the average pore diameter of the virus collection layer is 2.5 to 9.5:1 (preferably 4 to 9:1). This means, firstly, that the cellulose-based filtration membrane of the present invention is an asymmetric membrane, and the pore diameter of the pores changes with the thickness. Secondly, in the present invention, it also means that the change in the membrane pore diameter with the thickness is not too fast, there are no pores that are too large, and it has a reasonable membrane pore structure. By the reasonable change of the membrane pore diameter with the thickness, the high-efficiency blocking property of the filtration membrane against viruses is further guaranteed, and it is possible to ensure that the filtration membrane has a high flux and a large pollutant capture capacity.

[0063] On the premise of ensuring that the filtration membrane has a high collection efficiency, we desired to make the separation layer thinner (relatively smaller in thickness) and increase the difference between the thickness of the pollutant capture layer and the thickness of the virus collection layer. In this way, it is possible to give the filtration membrane a large flux. In the present invention, the thickness of the pollutant capture layer is at least 35 μm greater than the thickness of the virus collection layer. Such a main body structure of the membrane further means that most of the region of the filtration membrane is the pollutant capture layer and the separation layer is very thin. Thereby, it is further guaranteed that the whole filtration membrane has a large flux and the filtration speed is increased. Moreover, the filtration membrane further has a large pollutant capture capacity, a long service life, and a slow attenuation of the flux.

[0064] As a further improvement of the present invention, the pollutant capture layer includes pre-filtering fibers that form a porous structure. The pre-filtering fibers have a strip-like structure. Also, the virus collection layer includes separation fibers that form a porous structure. The separation fibers have a strip-like structure. The side of the pre-filtering fibers close to the virus collection layer and the side of the separation fibers close to the pollutant capture layer are continuous. The average diameter of the pre-filtering fibers is 40 to 100 nm, and the average diameter of the separation fibers is 20 to 90 nm.

[0065] In the membrane structure of the filtration membrane provided by the present invention, it is clear that the fiber structure does not change with the membrane thickness. Further, the pre-filter fibers in the pollutant capture layer have a strip structure, and the separation fibers in the virus collection layer also have a strip structure. This further indicates that the filtration membrane is integrally formed and there is no composite. Also, the pollutant capture layer and the virus collection layer formed by the strip-shaped pre-filter fibers and separation fibers have appropriate porosity and pore distribution, so that the whole membrane has a high flow rate and a high virus collection efficiency. Further, the average diameter of the pre-filter fibers is 40 to 100 nm, and the average diameter of the separation fibers is 20 to 90 nm. Such pre-filter fibers and separation fibers with such thicknesses can strengthen the stability of the pores inside the pollutant capture layer and the virus collection layer, so that collapse or shrinkage is less likely to occur, and the stability of the fluid flow rate is ensured. And finally, since it is guaranteed that the whole membrane has high mechanical strength and filtration stability, high-efficiency filtration over a long period of time becomes possible. Therefore, the filtration membrane is particularly suitable for application in the field of virus removal.

[0066] The degree of thickness of the fiber cross-section can be regarded as the diameter of the fiber. In the present invention, for the average diameter of the second fiber, after morphological characteristic evaluation of the cross-sectional structure of the filtration membrane using a scanning electron microscope, it may be measured by computer software (such as Matlab, NIS-Elements, etc.) or manually, and the average value may be calculated. Of course, as can be understood, those skilled in the art may also obtain the above parameters by other measuring means.

[0067] As a further improvement of the present invention, the film-forming material of the cellulose-based filtration membrane is a cellulose-based polymer with a mass percentage of acetyl group of 0 to 40%.

[0068] As a further improvement of the present invention, the film-forming material of the cellulose-based filtration membrane is at least one of nitrocellulose, cellulose acetate, and regenerated cellulose.

[0069] The film-forming material in the present invention is a cellulose-based polymer with an acetyl group mass percentage of 0 to 40% (that is, the mass fraction of the acetyl group in the cellulose-based polymer is 0 to 40%). Preferably, the cellulose-based polymer is at least one of nitrocellulose, cellulose acetate (including diacetate cellulose and triacetate cellulose), and regenerated cellulose (it may be one type of cellulose-based substance or multiple types of cellulose-based substances). These cellulose polymers are easily soluble in the corresponding organic solvents and have good film-forming and fiber-forming abilities. The produced film has strong hydrophilicity and is difficult to adsorb effective substances (mainly proteins) in the fluid. Therefore, the economic benefits are high and the service life is long. Moreover, since the cellulose-based polymer has a wide range of sources, it is easy to obtain and has a low cost.

[0070] As a further improvement of the present invention, the first water contact angle of the cellulose-based filtration membrane is 25 to 70°. The tensile strength of the cellulose-based filtration membrane is 6 to 15 MPa, and the elongation at break is 5 to 40%. The flux of the cellulose-based filtration membrane is greater than 300 L*h -1 *m -2 @30 psi. The cellulose-based filtration membrane has an LRV of 4 or more for virus foreign matters. The protein yield of the cellulose-based filtration membrane is 98% or more.

[0071] Under the action of a pressure of 30 psi, using a 0.4 g / L IVIG solution as the test solution, with the initial flux of the filtration membrane being 300 to 1000 L*h -1 *m -2 @30 psi, when the flux of the filtration membrane decays by 75% as the end point, the capacity of the filtration membrane is 300 L / m 2 or more.

[0072] Generally, the stronger the hydrophilicity of the membrane, the less likely the membrane is to adsorb proteins in a fluid. That is, the protein yield increases. When contact angle tests were conducted on both the first outer surface and the second outer surface of the cellulose-based filtration membrane, as a result of the tests, it was found that the first water contact angle of the first outer surface and the second outer surface in the present invention was 25 to 70°. That is, the first water contact angle of the cellulose-based filtration membrane was 25 to 70° (the smaller the contact angle, the more hydrophilic). This means that the cellulose-based filtration membrane is overall very hydrophilic and has low adsorptivity to various proteins. Therefore, it is possible to have a high protein yield, and further economic benefits are guaranteed.

[0073] Important indicators for evaluating the mechanical strength of the filtration membrane are the tensile strength and elongation at break of the filtration membrane. Under certain conditions, the greater the tensile strength of the filtration membrane, the better the mechanical strength of the filtration membrane. Tensile strength refers to the ability of the membrane to withstand a parallel tensile action. When conducting tests under certain conditions, the membrane sample is subjected to the action of a tensile load until it breaks. Then, based on the maximum tensile load corresponding to the break point of the membrane sample and the change in the size (length) of the membrane sample, etc., the tensile strength and elongation at break of the membrane can be calculated. Both the tensile strength and elongation at break can be measured with a universal tensile testing machine. The test method for tensile strength is known in the art. For example, the procedures for tensile strength tests are described in detail in ASTM D790 or ISO178. The tensile strength of the filtration membrane in the present invention is 6 to 15 MPa, and the elongation at break is 5 to 40%. This means that the filtration membrane of the present invention has a large tensile strength and elongation at break and has good mechanical performance. Therefore, it has high industrial practical value and can fully meet market needs.

[0074] The permeate flux, also referred to as the permeation rate and abbreviated as flux, means the amount of substance permeating through a unit membrane area per unit time under a certain operating pressure in the separation process of the filtration membrane. The magnitude of the flux reflects the magnitude of the filtration rate, and the greater the flux, the faster the filtration rate of the membrane. The flux of the filtration membrane in the present invention is 300L*h -1 *m-2 Since it is greater than 30 psi, the flux is large. This means that the filtration rate of the filtration membrane is fast, so that while ensuring the collection efficiency, the fluid can pass through the filtration membrane quickly. Therefore, the time cost is low and the economic benefit is high.

[0075] The viruses blocked by the present invention mainly target various viruses with a particle size of 20 nm or more (for example, murine parvovirus with a particle size of about 20 nm). As a result of the blocking test, it was found that the LRV of the filtration membrane of the present invention for various viruses is all 4 or more. This means that the filtration membrane has a very high blocking rate for viruses and exerts a sufficient retention effect on virus foreign matters, thus meeting the actual application needs. In addition, the protein yield of the filtration membrane is 98% or more. This means that the protein, which is an effective substance in the fluid, is hardly adsorbed on the membrane. Therefore, firstly, it is guaranteed that the membrane pores will not be clogged and the filtration membrane has a long service life. Secondly, since it is guaranteed that the change in the content of the protein, which is an effective substance in the fluid, will be small, there is almost no loss in the protein, and the economic benefit is guaranteed. For the test method of virus foreign matters, reference may be made to the specification of Chinese Patent No. 105980037 (virus removal membrane), the specification of Chinese Patent No. 101816898 (ultrafiltration membrane and its manufacturing method), the specification of Chinese Patent No. 1759924 (ultrafiltration membrane and its manufacturing method), etc.

[0076] IVIG is an intravenous immunoglobulin preparation and serves as a protein model of an antibody. In the present invention, when an IVIG acetate buffer solution with a concentration of 0.4 g / L was used as a test solution (the test solution contained no other proteins except IVIG and no corresponding virus foreign matters), when the flux of the filtration membrane decreased to 25% of the initial flux (the flux decayed by 75%) under the action of a pressure of 30 psi, the volume of the passed test solution was 300 L / m 2 or more. That is, the capacity of the filtration membrane was 300 L / m 2 or more. This further means that the filtration membrane in the present invention has low non-specific adsorption and a long service life.

[0077] As a further improvement of the present invention, the flux of the cellulose-based filtration membrane is 45 to 150 L*h -1 *m -2 @ 30 psi. Further, the cellulose-based filtration membrane has an LRV of 5 or more with respect to virus foreign matters.

[0078] We noticed that among the cellulose-based filtration membranes produced by the present invention, some of the filtration membranes have relatively small membrane pores. Due to such a membrane structure, the filtration membrane can sufficiently capture parvovirus. In particular, since the LRV value for parvovirus with a particle size of about 20 nm can reach 5 or more, it is surely guaranteed that various viruses in the fluid do not easily leak. However, since the membrane pore diameters of these filtration membranes are relatively small, the flux decreases to some extent. Therefore, when measured, the flux was 45 to 150 L*h -1 *m -2 @ 30 psi (preferably 70 to 130 LMH). Since this flux is also relatively large, the fluid can still be rapidly purified within a short time. That is, these filtration membranes can efficiently block parvovirus with a particle size of 20 nm and above on the premise of having a large flux and a high protein yield. The LRV is at least greater than 5, and in some filtration membranes, the LRV value can be greater than 7.

[0079] The present invention further provides a method for manufacturing an asymmetric cellulose-based filtration membrane for virus removal. The manufacturing method includes the following steps.

[0080] S1: Prepare a membrane-forming solution and cast it on a support to form a liquid film. The membrane-forming solution is composed of, by weight, 10 to 30 parts of a film-forming polymer, 15 to 40 parts of a first organic solvent, and 30 to 75 parts of a pore-forming agent. The film-forming polymer is a cellulose-based polymer, and the first organic solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid.

[0081] The pore-forming agent is a non-solvent substance with a surface tension lower than 35 dyne / cm. Moreover, the substance is mutually soluble with the coagulation bath.

[0082] S2: Immerse the liquid film in the coagulation bath for phase separation and curing. The temperature of the coagulation bath is 15 to 45 °C, and the duration is 20 to 60 s to form a film. The coagulation bath is water or ethanol.

[0083] As a further improvement of the present invention, the temperature of the film-forming solution is 15 to 40 °C. The pore-forming agent is at least one of formamide, ethanol, 1-propanol, isopropanol, 1-butanol, 1-pentanol, 2-pentanol, and diethylamine.

[0084] As a further improvement of the present invention, before immersing the liquid film in the coagulation bath for phase separation and curing, immerse the liquid film in a preliminary phase separation solution for preliminary phase separation. The preliminary phase separation time is 2 to 10 s. The preliminary phase separation solution contains a second organic solvent and a non-solvent. The content of the non-solvent is 0 to 30%. The second organic solvent and the first organic solvent are mutually soluble. The second organic solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid. The non-solvent is water or ethanol.

[0085] As a further improvement of the present invention, place the formed film in a sodium hydroxide solution for hydrolysis. The hydrolysis temperature is 20 to 40 °C, the hydrolysis time is 15 to 45 min, and after hydrolysis, wash it to form a solid film.

[0086] When manufacturing the cellulose-based filtration membrane of the present invention, first, a film-forming solution is prepared. The film-forming solution contains a film-forming polymer, a first organic solvent, and a pore-forming agent. The film-forming polymer is a cellulose-based polymer having an acetyl group mass percentage of 0 to 40% (that is, the mass fraction of the acetyl group in the cellulose-based polymer is 0 to 40%). Preferably, the cellulose-based polymer is at least one of nitrocellulose, cellulose acetate (including diacetate cellulose and triacetate cellulose), and regenerated cellulose. These cellulose polymers are easily dissolved in the corresponding organic solvents and have good film-forming and fiber-forming abilities. The manufactured membrane has strong hydrophilicity and is difficult to adsorb effective substances (mainly proteins) in the fluid. In addition, the first organic solvent exists to sufficiently dissolve the corresponding cellulose-based polymer. During phase separation, the first organic solvent is dissolved in the coagulation bath, so that the cellulose-based polymer precipitates to form a filtration membrane with a certain pore size. In addition, a pore-forming agent is further added to the film-forming solution. The pore-forming agents added in the prior art are generally selected from substances with high specific surface tension such as polyvinylpyrrolidone (surface energy is about 60 - 65 dyne / cm). Since these substances are relatively easy to aggregate, pores are easily formed. During phase separation and curing, these pore-forming agents are relatively likely to aggregate on the air side of the liquid film. When the liquid film is immersed in a coagulation bath (for example, water, ethanol), it is the air-side liquid film that first contacts the coagulation bath. Therefore, the air-side liquid film rapidly phase-separates, and the pore-forming agent precipitates from the liquid film. As a result, a dense surface layer with small pore sizes is formed on the air side (the side away from the support). Although the pore size of the internal pores of the dense surface layer is also small, its thickness is too small, so the collection efficiency of the formed membrane is excessively low, and the pollutant capture ability is also low. Therefore, it has almost no substantial holding capacity (the service life is extremely short), and it is impossible to form a practically applicable virus removal membrane. On the other hand, in the case of non-solvents with low surface tension, these substances are difficult to aggregate and are generally inferior in the pore-forming effect, so they are generally not used as pore-forming agents. However, in accidental experiments, non-solvent substances with low surface tension (non-solvent substances with a surface tension lower than 35 dyne / cm.And when such a substance, which is miscible with the coagulation bath and is preferably at least one of formamide, ethanol, 1-propanol, isopropanol, 1-butanol, 1-pentanol, 2-pentanol, and diethylamine, was accidentally used as a pore-forming agent, unexpectedly, rapid mutual dissolution with the coagulation bath became possible by adding such a non-solvent substance with low surface tension. Due to the cooperation with the low surface tension substance, the coagulation bath could rapidly enter the support side in the liquid film. As a result, the region on the support side in the liquid film rapidly phase-separated, and the corresponding small pore region was formed as a virus trapping layer. On the other hand, the liquid film on the support separation side (air side) had a relatively slower phase separation rate, and the corresponding large pore region was formed as a contaminant trapping layer. Therefore, such a film-forming solution system can contribute to obtaining a filtration membrane with an ideal membrane pore size and membrane pore structure through interaction with appropriate phase separation and curing time (the temperature of the coagulation bath is 15 to 45 °C, the duration is 20 to 60 s, and the coagulation bath is water or ethanol). Also, such a film-forming solution system is only suitable for use in cellulose-based film formation and is not suitable for polyethersulfone. The inventor speculates that this is somewhat related to the structural shape of the film-forming material itself. That is, cellulose-based materials are more hydrophilic and thus suitable for this system and can form an ideal membrane structure.

[0087] A reasonable formulation of the film-forming solution has a great influence on the structure and performance of the finally formed filtration membrane. For example, it affects the pore size, thickness, flow rate, etc. of the filtration membrane. Through a reasonable formulation of the film-forming solution, it is ensured that the finally produced filtration membrane has an appropriate thickness and obtains an ideal pore size. In addition, the film-forming solution of the present invention may be manually cast (for example, manually poured, cast, or spread on the surface for casting), or may be automatically cast (for example, poured into a moving bed or cast separately), and many devices known in the art can be used for casting. The casting device includes, for example, a mechanical coater having a coating blade, a doctor blade, or a spray / pressurization system. Also, many casting speeds well-known in the art are applicable. For example, the casting speed can be about 2 to 6 feet per minute (fpm), etc. Note that the specific casting speed may be determined according to the situation.

[0088] As a further improvement of the present invention, before immersing the liquid film in a coagulation bath for phase separation and curing, the liquid film is immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time is 2 to 10 s. The pre-phase separation solution contains a second organic solvent and a non-solvent. The content of the non-solvent is 0 to 30%. The second organic solvent and the first organic solvent are mutually soluble. The second organic solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid. The non-solvent is water or ethanol.

[0089] On the premise of ensuring the capture efficiency, in the market, it is required to make the flux of the filtration membrane as large as possible. This enables more fluid to be filtered in a short time, and the economic benefit per unit time becomes even higher. However, in order to increase the flux of the filtration membrane, the porosity of the entire filtration membrane must be increased. In order to further improve the flux of the entire cellulose-based filtration membrane, it is required that the filtration membrane has a high porosity. Therefore, in the present invention, a pretreatment is performed when the liquid membrane is phase-separated and cured so that the filtration membrane has a more ideal porosity. That is, first, preliminary phase separation is carried out. That is, the liquid membrane is put into a solution for preliminary phase separation. The solution for preliminary phase separation is a mixture of a second organic solvent and a non-solvent. The second organic solvent is mutually soluble with the first organic solvent. Also, the second organic solvent may be the same as or different from the first organic solvent. The non-solvent is water or ethanol. The presence of the non-solvent enables the phase separation of the liquid membrane on the air side to be assisted. The content of the non-solvent is 0 to 30%, and since the content of the non-solvent is extremely low, the liquid membrane phase-separates slowly. As a result, pores with a large pore diameter are formed near the air side. Depending on the difference in the solution for preliminary phase separation and the difference in the preliminary phase separation time, the portion of the final filtration membrane where the pore diameter is the largest is the first outer surface or a portion close to the first outer surface. Due to the preliminary phase separation, a part of the pores with a large pore diameter is formed, so that the coagulation bath penetrates more easily into the liquid membrane on the support side, and the phase separation becomes more sufficient. As a result, the finally formed filtration membrane has a higher porosity and a higher flux.

[0090] As a further improvement of the present invention, the formed membrane is placed in a sodium hydroxide solution and hydrolyzed. The hydrolysis temperature is 20 to 40 °C, the hydrolysis time is 15 to 45 min, and after hydrolysis, it is washed to form a solid membrane.

[0091] The manufactured cellulose-based filtration membrane is added to an aqueous sodium hydroxide solution with a concentration of 0.005 to 0.03 mol / L for hydrolysis, and after hydrolysis, it is washed with deionized water to form a solid membrane. The solid membrane after hydrolysis has better hydrophilicity and lower non-specific adsorption to proteins, so the protein yield is further improved and the economic benefit is increased.

Advantages of the Invention

[0092] The beneficial effects of the present invention are as follows. That is, the asymmetric cellulose-based filtration membrane for virus removal provided by the present invention includes a main body. One surface of the main body is the first outer surface, and the first outer surface is a macroporous surface. Also, the second outer surface is a microporous surface with an average pore diameter of 15 to 40 nm. The first outer surface is a macroporous surface, and the average pore diameter of the first outer surface is at least four times or more the average pore diameter of the second outer surface. The main body includes a pollutant capture layer and a virus collection layer for blocking viruses. The main body includes a pollutant capture layer and a virus collection layer for blocking viruses. One side of the pollutant capture layer is the first outer surface, and one side of the virus collection layer is the second outer surface. The other side of the pollutant capture layer and the other side of the virus collection layer are connected by continuous fibers. This means that the filtration membrane is integrally manufactured and formed only with one type of membrane-forming solution without the need for lamination. Therefore, the manufacturing process is relatively simple. Also, the average pore diameter of the pollutant capture layer is larger than that of the virus collection layer. And the change gradient of the average pore diameter of the pollutant capture layer is larger than that of the virus collection layer, and the pore diameter changes in a decelerating manner with the thickness. Thereby, while ensuring that the filtration membrane has a strong blocking effect on parvovirus, a high protein yield can be obtained. And it has a large flux, a fast filtration speed, a large capacity, and a long service life. Therefore, it meets the actual application needs and is particularly suitable for the field of virus removal. In addition, the present invention further provides a manufacturing method of the filtration membrane. The manufacturing method is convenient, fast, effective, easy to operate, green and environmentally friendly, so it is suitable for large-scale popularization.

Brief Description of the Drawings

[0093]

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Figure 14

Mode for Carrying Out the Invention

[0094] In order to describe the overall concept of the present application in more detail and clearly, the following will be described in detail in the form of examples. Unless otherwise specified, all raw materials and equipment used in the production of the filtration membrane in the following examples are commercially available through business routes. In addition, the structural form of the filtration membrane was evaluated using a scanning electron microscope of model number S-5500 manufactured by Hitachi.

[0095] Example 1

[0096] The method for manufacturing an asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0097] S1: A film-forming solution was prepared and cast on a carrier to form a liquid film. The film-forming solution was composed of 12 parts by weight of a film-forming polymer, 17 parts of a first organic solvent, and 58 parts of a pore-forming agent.

[0098] The film-forming polymer was cellulose diacetate, the first organic solvent was acetone, and the pore-forming agent was ethanol. Also, the temperature of the film-forming solution was 34°C.

[0099] S2: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 24°C and the duration being 32 s. Also, the coagulation bath was water.

[0100] The filtration membrane included a pollutant capture layer and a virus collection layer. The gradient of the pore size change in the pollutant capture layer was larger than that in the virus collection layer. The average pore size of the region closer to the first outer surface in the pollutant capture layer was larger than the average pore size of the region closer to the second outer surface in the pollutant capture layer. Also, the gradient of the change in the average pore size of the region closer to the first outer surface in the pollutant capture layer was larger than the gradient of the change in the average pore size of the region closer to the second outer surface in the pollutant capture layer. The average pore size within the virus collection layer decreased in a continuous gradient with the thickness.

[0101] Example 2

[0102] The method for manufacturing an asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0103] S1: A membrane-forming solution was prepared and cast on a support to form a liquid film. The membrane-forming solution was composed of, by weight parts, 24 parts of a film-forming polymer, 34 parts of a first organic solvent, and 34 parts of a pore-forming agent. The film-forming polymer was cellulose triacetate, the first organic solvent was dioxane, and the pore-forming agent was formamide. Also, the temperature of the membrane-forming solution was 18°C.

[0104] S2: The liquid film was immersed in a coagulation bath for phase separation and curing. The membrane was formed with the temperature of the coagulation bath being 18°C and the duration being 48 s. Also, the coagulation bath was water.

[0105] The filtration membrane included a pollutant capture layer and a virus collection layer. The gradient of the pore size change in the pollutant capture layer was larger than that in the virus collection layer. The average pore size of the region closer to the first outer surface in the pollutant capture layer was larger than the average pore size of the region closer to the second outer surface in the pollutant capture layer. Also, the gradient of the change in the average pore size of the region closer to the first outer surface in the pollutant capture layer was larger than the gradient of the change in the average pore size of the region closer to the second outer surface in the pollutant capture layer. The average pore size within the virus collection layer hardly changed with the thickness.

[0106] Example 3

[0107] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0108] S1: A film-forming solution was prepared and cast onto a support to form a liquid film. The film-forming solution was composed of, by weight, 20 parts of a film-forming polymer, 28 parts of a first organic solvent, and 42 parts of a pore-forming agent. The film-forming polymer included 10 parts of cellulose diacetate and 10 parts of cellulose triacetate. The first organic solvent was dimethylacetamide, and the pore-forming agent was 2-pentanol. Also, the temperature of the film-forming solution was 28°C.

[0109] S2: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 34°C and the duration being 40 s. Also, the coagulation bath was water.

[0110] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. Also, the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface was almost the same as the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The average pore size in the virus collection layer became smaller with the thickness and then became larger.

[0111] Example 4

[0112] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0113] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 14 parts of a film-forming polymer, 20 parts of a first organic solvent, and 50 parts of a pore-forming agent. The film-forming polymer was cellulose diacetate, the first organic solvent was N-methylpyrrolidone, and the pore-forming agent was ethanol. Also, the temperature of the film-forming solution was 32°C.

[0114] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 7.5 s. The pre-phase separation solution contained a second organic solvent and a non-solvent. The content of the non-solvent was 5%. The second organic solvent was N-methylpyrrolidone and the non-solvent was water.

[0115] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath at 30°C and the duration at 24 s. Also, the coagulation bath was water.

[0116] The filter membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. Also, the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The average pore size within the virus collection layer decreased in a continuous gradient with the thickness.

[0117] Example 5

[0118] The manufacturing method of an asymmetric cellulose-based filter membrane for virus removal included the following steps.

[0119] S1: A film-forming solution was prepared and cast onto a support to form a liquid film. The film-forming solution was composed of, by weight, 16 parts of a film-forming polymer, 23 parts of a first organic solvent, and 62 parts of a pore-forming agent. The film-forming polymer was cellulose diacetate, the first organic solvent was acetone, and the pore-forming agent was diethylamine. Also, the temperature of the film-forming solution was 36°C.

[0120] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 5 s. The pre-phase separation solution contained a second organic solvent and a non-solvent. The content of the non-solvent was 20%. The second organic solvent was acetone and the non-solvent was water.

[0121] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 25°C and the duration being 28 s. Also, the coagulation bath was water.

[0122] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The pollutant capture layer included a surface layer region, and the surface layer region included a first outer surface. In the pollutant capture layer (in the direction from the first outer surface to the second outer surface), the pore size of the membrane pores increased first and then decreased with the thickness. Also, the average pore size in the virus collection layer decreased with a continuous gradient with the thickness.

[0123] Example 6

[0124] The method for manufacturing an asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0125] S1: A film-forming solution was prepared and cast onto a support to form a liquid film. The film-forming solution was composed of, by weight, 21 parts of a film-forming polymer, 30 parts of a first organic solvent, and 66 parts of a pore-forming agent. The film-forming polymer was nitrocellulose, the first organic solvent was dioxane, and the pore-forming agent was isopropanol. Also, the temperature of the film-forming solution was 24°C.

[0126] S2: The liquid film was immersed in the solution for preliminary phase separation to perform preliminary phase separation. The preliminary phase separation time was set to 7 s. The solution for preliminary phase separation contained a second organic solvent and a non-solvent. The content of the non-solvent was 15%. The second organic solvent was dioxane, and the non-solvent was ethanol.

[0127] S3: The liquid film was immersed in the coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 32 °C and the duration being 44 s. Also, the coagulation bath was ethanol.

[0128] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. Also, the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The average pore size in the virus collection layer decreased first and then increased with the thickness.

[0129] Example 7

[0130] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0131] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 26 parts of a film-forming polymer, 36 parts of a first organic solvent, and 36 parts of a pore-forming agent. The film-forming polymer was cellulose triacetate, the first organic solvent was acetic acid, and the pore-forming agent was 1-pentanol. Also, the temperature of the film-forming solution was 26 °C.

[0132] S2: Before immersing the liquid film in the coagulation bath for phase separation and curing, the liquid film was immersed in the solution for preliminary phase separation to perform preliminary phase separation. The preliminary phase separation time was set to 9 s. The solution for preliminary phase separation was a second organic solvent, and the second organic solvent was butyric acid.

[0133] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 36°C and the duration being 52 s. Also, the coagulation bath was water.

[0134] The filtration membrane included a pollutant capture layer and a virus capture layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus capture layer. The average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. Also, the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface was approximately the same as the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The average pore size within the virus capture layer hardly changed with the thickness.

[0135] Example 8

[0136] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0137] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 18 parts of a film-forming polymer, 26 parts of a first organic solvent, and 70 parts of a pore-forming agent. The film-forming polymer included 10 parts of cellulose diacetate and 8 parts of cellulose triacetate. The first organic solvent was valeric acid, and the pore-forming agent was 1-propanol. Also, the temperature of the film-forming solution was 38°C.

[0138] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 8 s. The pre-phase separation solution was a second organic solvent, and the second organic solvent was propionic acid.

[0139] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 27°C and the duration being 36 s. Also, the coagulation bath was water.

[0140] S4: The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.01 mol / L for hydrolysis. The hydrolysis temperature was 25 °C and the hydrolysis time was 20 min. After hydrolysis, it was washed to form a solid film.

[0141] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region near the first outer surface in the pollutant capture layer was larger than the average pore size of the region near the second outer surface in the pollutant capture layer. Also, the change gradient of the average pore size of the region near the first outer surface in the pollutant capture layer was approximately the same as the change gradient of the average pore size of the region near the second outer surface in the pollutant capture layer. The average pore size in the virus collection layer decreased in a continuous gradient with the thickness.

[0142] Example 9

[0143] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0144] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 28 parts of a film-forming polymer, 38 parts of a first organic solvent, and 38 parts of a pore-forming agent. The film-forming polymer was cellulose triacetate, the first organic solvent was dimethylacetamide, and the pore-forming agent was 1-butanol. Also, the temperature of the film-forming solution was 20 °C.

[0145] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 4 s. The pre-phase separation solution included a second organic solvent and a non-solvent. The content of the non-solvent was 25%. The second organic solvent was dimethylacetamide and the non-solvent was water.

[0146] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The temperature of the coagulation bath was 21 °C and the duration was 56 s to form a film. Also, the coagulation bath was water.

[0147] S4: The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.025 mol / L and hydrolyzed. The hydrolysis temperature was 35 °C, the hydrolysis time was 40 min, and after hydrolysis, it was washed to form a solid film.

[0148] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore diameter of the pollutant capture layer was larger than that of the virus collection layer. The pollutant capture layer included a surface layer region, and the surface layer region included a first outer surface. In the pollutant capture layer (in the direction from the first outer surface to the second outer surface), the pore diameter of the membrane pores increased first and then decreased with the thickness. Also, the average pore diameter in the virus collection layer hardly changed with the thickness.

[0149] Example 10

[0150] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0151] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 22 parts of a film-forming polymer, 32 parts of a first organic solvent, and 46 parts of a pore-forming agent. The film-forming polymer included 10 parts of cellulose diacetate and 12 parts of cellulose triacetate. The first organic solvent was N-methylpyrrolidone, and the pore-forming agent was isopropanol. Also, the temperature of the film-forming solution was 30 °C.

[0152] S2: Before immersing the liquid film in a coagulation bath for phase separation and curing, the liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 6.5 s. The pre-phase separation solution included a second organic solvent and a non-solvent. The content of the non-solvent was 10%. The second organic solvent was N-methylpyrrolidone, and the non-solvent was water.

[0153] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The temperature of the coagulation bath was 38 °C, and the duration was 42 s to form a film. Also, the coagulation bath was water.

[0154] S4: The formed membrane was placed in an aqueous sodium hydroxide solution with a concentration of 0.02 mol / L for hydrolysis. The hydrolysis temperature was 30 °C, the hydrolysis time was 30 min, and after hydrolysis, it was washed to form a solid membrane.

[0155] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The pollutant capture layer included a surface layer region, and the surface layer region included a first outer surface. In the pollutant capture layer (in the direction from the first outer surface to the second outer surface), the pore size of the membrane pores increased first and then decreased with the thickness. Also, the average pore size in the virus collection layer decreased first and then increased with the thickness.

[0156] Comparative Example 1

[0157] The pore-forming agent in Example 1 was replaced from ethanol with polyvinylpyrrolidone, and it was manufactured without changing the remaining conditions. When inspected, it was found that the membrane had a dense surface layer and the pore size was also very small, about 20 - 30 nm. However, the thickness of the dense surface layer was very small, about 1 μm, and it had no capacity, so it was impossible to form a practically applicable virus removal membrane.

[0158] Example 11

[0159] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0160] S1: A membrane-forming solution was prepared and cast on a support to form a liquid film. The membrane-forming solution was composed of, by weight, 26 parts of a film-forming polymer, 20 parts of a first organic solvent, and 50 parts of a pore-forming agent. The film-forming polymer was cellulose diacetate, the first organic solvent was N-methylpyrrolidone, and the pore-forming agent was ethanol. Also, the temperature of the membrane-forming solution was 30 °C.

[0161] S2: The liquid film was immersed in a coagulation bath for phase separation and curing. The coagulation bath was at a temperature of 25°C and the duration was 28 s to form a film. Also, the coagulation bath was water.

[0162] S3: The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.02 mol / L for hydrolysis. The hydrolysis temperature was 30°C and the hydrolysis time was 30 min. After hydrolysis, it was washed to form a solid film.

[0163] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. Also, the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The average pore size within the virus collection layer decreased in a continuous gradient with the thickness.

[0164] Example 12

[0165] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0166] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 28 parts of a film-forming polymer, 24 parts of a first organic solvent, and 40 parts of a pore-forming agent. The film-forming polymer was cellulose triacetate, the first organic solvent was butyric acid, and the pore-forming agent was isopropanol. Also, the temperature of the film-forming solution was 25°C.

[0167] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 4 s. The pre-phase separation solution included a second organic solvent and a non-solvent. The content of the non-solvent was 10%. The second organic solvent was propionic acid and the non-solvent was water.

[0168] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The coagulation bath was at a temperature of 20 °C and the duration was 24 s to form a film. Also, the coagulation bath was water.

[0169] S4: The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.015 mol / L for hydrolysis. The hydrolysis temperature was 30 °C and the hydrolysis time was 40 min. After hydrolysis, it was washed to form a solid film.

[0170] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. Also, the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface was larger than the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The average pore size within the virus collection layer decreased in a continuous gradient with the thickness.

[0171] Example 13

[0172] The method for manufacturing an asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0173] S1: A film-forming solution was prepared and cast onto a support to form a liquid film. The film-forming solution was composed of, by weight, 30 parts of a film-forming polymer, 22 parts of a first organic solvent, and 45 parts of a pore-forming agent. The film-forming polymer included 15 parts of cellulose diacetate and 15 parts of cellulose triacetate. The first organic solvent was dioxane and the pore-forming agent was 1-butanol. Also, the temperature of the film-forming solution was 30 °C.

[0174] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 2 s. The pre-phase separation solution included a second organic solvent and a non-solvent. The content of the non-solvent was 25%. The second organic solvent was propionic acid and the non-solvent was water.

[0175] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 20°C and the duration being 22 s. Also, the coagulation bath was water.

[0176] S4: The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.01 mol / L for hydrolysis. The hydrolysis temperature was 40°C and the hydrolysis time was 45 min. After hydrolysis, it was washed to form a solid film.

[0177] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The pollutant capture layer included a surface layer region, and the surface layer region included a first outer surface. In the pollutant capture layer (in the direction from the first outer surface to the second outer surface), the pore size of the membrane pores increased first and then decreased with the thickness. Also, the average pore size in the virus collection layer decreased in a continuous gradient with the thickness.

[0178] Example 14

[0179] The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal included the following steps.

[0180] S1: A film-forming solution was prepared and cast on a support to form a liquid film. The film-forming solution was composed of, by weight, 27 parts of a film-forming polymer, 18 parts of a first organic solvent, and 35 parts of a pore-forming agent. The film-forming polymer included 18 parts of cellulose diacetate and 9 parts of cellulose triacetate. The first organic solvent was acetone, and the pore-forming agent was 1-pentanol. Also, the temperature of the film-forming solution was 35°C.

[0181] S2: The liquid film was immersed in a pre-phase separation solution for pre-phase separation. The pre-phase separation time was 6 s. The pre-phase separation solution included a second organic solvent and a non-solvent. The content of the non-solvent was 10%. The second organic solvent was dimethylacetamide, and the non-solvent was ethanol.

[0182] S3: The liquid film was immersed in a coagulation bath for phase separation and curing. The film was formed with the temperature of the coagulation bath being 23°C and the duration being 23 s. Also, the coagulation bath was water.

[0183] S4: The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.008 mol / L for hydrolysis. The hydrolysis temperature was 35°C and the hydrolysis time was 35 min. After hydrolysis, it was washed to form a solid film.

[0184] The filtration membrane included a pollutant capture layer and a virus collection layer. The change gradient of the pore size of the pollutant capture layer was larger than that of the virus collection layer. The average pore size of the region near the first outer surface in the pollutant capture layer was larger than the average pore size of the region near the second outer surface in the pollutant capture layer. Also, the change gradient of the average pore size of the region near the first outer surface in the pollutant capture layer was larger than the change gradient of the average pore size of the region near the second outer surface in the pollutant capture layer. The average pore size in the virus collection layer decreased in a continuous gradient with the thickness.

[0185] 1: Structural property evaluation

[0186] After morphological property evaluation of the membrane structure of the nanoscale polymer filtration membrane obtained in each example by a scanning electron microscope, the necessary data were acquired. The specific results are as shown in the following table.

[0187]

Table 1

[0188]

Table 2

[0189]

Table 3

[0190]

Table 4

[0191] Note: As is clear from Table 4, the change gradients of the average pore diameters in the virus capture layers of the filtration membranes produced in Example 2, Example 7, and Example 9 were all smaller than 0.5 nm / μm. In this case, we regarded that the pore diameters hardly changed with the film thickness.

[0192] As is clear from Tables 1 to 4, all of the filtration membranes produced in Examples 1 to 10 of the present invention had an ideal membrane structure. These filtration membranes were integrally formed, and since a composite process was unnecessary, the processes and manufacturing were simple. Moreover, these filtration membranes were asymmetric membranes and had a reasonable membrane structure. While ensuring high-efficiency blocking performance against viruses, these filtration membranes had a high flux and capacity, a long service life, and low protein adsorption properties, and thus were suitable for applications in the field of virus removal.

[0193] Performance characteristics

[0194] The membrane flux is calculated by the following formula.

[0195] Calculation formula for membrane flux (J): J = V / (T × A) J--Membrane flux Unit: L*h -1 *m -2 V--Sampling volume (L), T--Sampling time (h), A--Effective membrane area (m2)

[0196] The operating conditions adopted for measuring the separation performance of the filtration membrane in the present invention were that the feed liquid was deionized water, the operating pressure was 30 psi, the operating temperature was 25 °C, and the pH of the solution was 7. Also, the flux test device was the one shown in Fig. 11.

[0197]

Table 5

[0198] As is clear from the above table, the filtration membranes produced in Examples 1 to 10 had excellent hydrophilicity, and all had a small first contact angle. Moreover, they had a high flux and a high capacity, with a fast filtration rate and a long service life. Furthermore, they had good tensile strength and elongation at break, and had high practicality in processing. In addition, when comparing Example 1 and Example 4, it was found that the filtration membrane produced in Example 4 had a higher porosity and a higher flux. This means that it is preferable to perform preliminary phase separation in advance during production. That is, before immersing the liquid membrane in the coagulation bath for phase separation and curing, it is preferable to immerse the liquid membrane in a solution for preliminary phase separation to perform preliminary phase separation.

[0199] Note: When there is a certain difference in the first water contact angle between the two outer surfaces of the membrane, the first water contact angle of the membrane in the present invention was taken as the average value of the first water contact angles of the two outer surfaces.

[0200] In addition, based on the test method used in Paragraph 114 of the specification of Chinese Patent Application No. 201010154974.7 (Ultrafiltration Membrane and Its Manufacturing Method), a virus retention test was made possible.

[0201] The virus used was murine parvovirus with a particle size of 20 nm.

[0202] As a result of the test, it was found that the filtration membranes produced in Examples 1 to 10 had an LRV of 4 or more with respect to virus foreign matters having a particle size of 20 nm. From this, it was shown that the filtration membrane of the present invention has a sufficient retention effect on viruses of 20 nm and above. In addition, the protein yield of the filtration membrane was 98% or more. Therefore, the filtration membrane is particularly suitable for application in the field of virus removal.

[0203] The filtration membrane produced in Example 11 had a LRV of 5.9 against virus foreign matter with a particle size of 20 nm. The filtration membrane produced in Example 12 had a LRV of 6.4 against virus foreign matter with a particle size of 20 nm. The filtration membrane produced in Example 13 had a LRV of 7.1 against virus foreign matter with a particle size of 20 nm. The filtration membrane produced in Example 14 had a LRV of 6.7 against virus foreign matter with a particle size of 20 nm. From this, it was further shown that the filtration membrane of the present invention has a very sufficient blocking effect against viruses of 20 nm and above.

[0204] Filtration accuracy test: A collection efficiency test was conducted on the filtration membranes obtained in each example. The particles to be blocked were gold colloids with a particle size of 20 nm. The experimental equipment was a particle counter KB-3 manufactured by Tianjin Luogen Co., Ltd.

[0205] Experimental preparation: Assemble the experimental apparatus according to Figure 12 and clean the apparatus. The apparatus was washed with ultrapure water. A filtration membrane with a diameter of 47 mm was taken and attached to the butterfly filter. Also, ensure that the assembled filter has good airtightness.

[0206] Experimental procedure:

[0207] Pour the test solution into the tank and pressurize it to 10 kPa while paying attention to the exhaust of the butterfly filter. Then, collect the filtrate downstream of the butterfly filter in a clean bottle.

[0208] Count the number of particles in the filtrate and the stock solution with a particle counter.

[0209] Collection efficiency:

[0210]

Equation

[0211] η ─── Collection efficiency (%) n0 ─── Number of particles in the stock solution. Average value counted in 5 groups (particles) n1 ─── Number of particles in the filtrate. Average value counted in 5 groups (particles)

[0212] As a result of the tests, it was found that the collection efficiencies of Examples 1 to 10 for 20-nm gold colloids were 99.99% or more, and the collection efficiencies of Examples 11 to 14 for 20-nm gold colloids were all 99.999% or more.

[0213] The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above examples. Any technical means belonging to the concept of the present invention belongs to the protection scope of the present invention. It should be pointed out that those skilled in the art can make some improvements and supplements on the premise of not departing from the principle of the present invention, and these improvements and supplements should also be regarded as within the protection scope of the present invention.

Claims

1. A virus-removing asymmetric cellulose-based filtration membrane comprising a main body, having an omnidirectional curved path therein, with one side surface of the main body being a first outer surface and the other side surface of the main body being a second outer surface, wherein the average pore size of the second outer surface is 15 to 40 nm, the average pore size of the first outer surface is at least four times or more the average pore size of the second outer surface, the main body includes a pollutant capture layer and a virus collection layer for blocking viruses, one side of the pollutant capture layer being the first outer surface, one side of the virus collection layer being the second outer surface, and the other side of the pollutant capture layer and the other side of the virus collection layer are continuous and migrated by fibers, the average pore size of the pollutant capture layer is larger than the average pore size of the virus collection layer, and the gradient of change in the average pore size of the pollutant capture layer is larger than the gradient of change in the average pore size of the virus collection layer. An asymmetric cellulose-based filtration membrane for virus removal, characterized in that

2. the gradient of change in the average pore size of the pollutant capture layer is at least 3 nm / μm larger than the gradient of change in the average pore size of the virus collection layer, the second outer surface is provided with a plurality of circular second pores, and the pore area ratio of the second pores on the second outer surface is 2 to 15%. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that

3. the first outer surface includes a plurality of continuous linear first fibers, and circular first pores are formed by being surrounded between adjacent continuous first fibers. The average diameter of the first fibers is 100 to 250 nm, the average pore size of the first outer surface is 200 to 600 nm, and the pore area ratio of the first pores on the first outer surface is 5 to 25%. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that

4. the gradient of change in the average pore size of the cellulose-based filtration membrane is 2 to 7 nm / 1μm, the ratio of the average pore size of the first outer surface to the average pore size of the second outer surface is 6 to 30, the pore area ratio of the first outer surface is at least 3% larger than the pore area ratio of the second outer surface. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that

5. The PMI average pore size of the cellulose-based filtration membrane is 15 to 40 nm, the thickness of the cellulose-based filtration membrane is 70 to 120 μm, and the porosity is 25 to 55%. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that.

6. The average pore size of the pollutant capture layer is 80 to 300 nm, and the porosity is 35 to 70%. The thickness of the pollutant capture layer occupies 70 to 90% of the membrane thickness, and the change gradient of the average pore size of the pollutant capture layer is 3 to 9 nm / μm. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that.

7. The average pore size of the region of the pollutant capture layer close to the first outer surface is larger than the average pore size of the region of the pollutant capture layer close to the second outer surface. And the change gradient of the average pore size of the region of the pollutant capture layer close to the first outer surface is larger than the change gradient of the average pore size of the region of the pollutant capture layer close to the second outer surface. The asymmetric cellulose-based filtration membrane for virus removal according to claim 6, characterized in that.

8. The pollutant capture layer further includes a surface layer region, and one side of the surface layer region includes a first outer surface. The thickness of the surface layer region is 1 to 15 μm, and the porosity of the surface layer region is 10 to 55%. And the average pore size of the region of the surface layer region close to the first outer surface is smaller than the average pore size of the region of the surface layer region close to the virus capture layer. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1 or 6, characterized in that.

9. The average pore size of the virus capture layer is 20 to 40 nm, the porosity is 10 to 45%, the thickness of the virus capture layer is 5 to 25 μm, and the change gradient of the average pore size of the virus capture layer is 0 to 3 nm / 1μm. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that.

10. In the film thickness direction from the first outer surface to the second outer surface, the average pore size in the virus capture layer hardly changes with the thickness. Or, the average pore size in the virus capture layer decreases with a continuous gradient with the thickness. Or, the average pore size in the virus capture layer decreases first and then increases with the thickness. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1 or 9, characterized in that.

11. The ratio of the average pore diameter of the pollutant capture layer to the average pore diameter of the virus collection layer is 2.5 to 9.5:1, The thickness of the pollutant capture layer is at least 35 μm greater than the thickness of the virus collection layer, and the asymmetric cellulose-based filtration membrane for virus removal according to claim 1 is characterized in that.

12. The pollutant capture layer includes pre-filter fibers that form a porous structure, the pre-filter fibers have a strip structure, the virus collection layer includes separation fibers that form a porous structure, the separation fibers have a strip structure, the side of the pre-filter fibers close to the virus collection layer and the side of the separation fibers close to the pollutant capture layer are continuous, the average diameter of the pre-filter fibers is 40 to 100 nm, and the average diameter of the separation fibers is 20 to 90 nm. The asymmetric cellulose-based filtration membrane for virus removal according to claim 1 is characterized in that.

13. The film-forming material of the cellulose-based filtration membrane is a cellulose-based polymer with a mass percentage of acetyl groups of 0 to 40%, and the asymmetric cellulose-based filtration membrane for virus removal according to claim 1 is characterized in that.

14. The film-forming material of the cellulose-based filtration membrane is at least one of nitrocellulose, cellulose acetate, and regenerated cellulose, and the asymmetric cellulose-based filtration membrane for virus removal according to claim 1 or 13 is characterized in that.

15. The first water contact angle of the cellulose-based filtration membrane is 25 to 70°, the tensile strength of the cellulose-based filtration membrane is 6 to 15 MPa, and the elongation at break is 5 to 40%, The flux of the cellulose-based filtration membrane is 300 L*h －１ *m －２ greater than 30 psi, the cellulose-based filtration membrane has an LRV of 4 or more with respect to virus foreign substances, and the protein yield of the cellulose-based filtration membrane is 98% or more, Under the action of a pressure of 30 psi, with a 0.4 g / L IVIG solution as the test solution, the initial flux of the filtration membrane is 300 to 1000 L*h －１ *m －２ @ 30 psi, and when the flux of the filtration membrane decays by 75% as the end point, the capacity of the filtration membrane is 300 L / m ２ The asymmetric cellulose-based filtration membrane for virus removal according to claim 1, characterized in that it is 300 L / m or more

16. The flux of the cellulose-based filtration membrane is 45 to 150 L*h －１ *m －２ @ 30 psi, and The cellulose-based filtration membrane has an LRV of 5 or more with respect to virus foreign matters, and the asymmetric cellulose-based filtration membrane for virus removal according to claim 1 is characterized in that.

17. A method for manufacturing an asymmetric cellulose-based filtration membrane for virus removal according to any one of claims 1 to 16, S1: Prepare a film-forming solution and cast it on a support to form a liquid film. The film-forming solution is composed of 10 to 30 parts by weight of a film-forming polymer, 15 to 40 parts by weight of a first organic solvent, and 30 to 75 parts by weight of a pore-forming agent. The film-forming polymer is a cellulose-based polymer, The first organic solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid, The pore-forming agent is a non-solvent substance with a surface tension lower than 35 dynes / cm, and the substance is mutually soluble with the coagulation bath; S2: Immerse the liquid film in the coagulation bath for phase separation and curing, with the temperature of the coagulation bath being 15 - 45°C and the duration being 20 - 60 s to form a film, and the coagulation bath being water or ethanol; A manufacturing method characterized by including the above.

18. The temperature of the film-forming solution is 15 - 40°C; The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal according to claim 17, wherein the pore-forming agent is any one of formamide, ethanol, 1-propanol, isopropanol, 1-butanol, 1-pentanol, 2-pentanol, and diethylamine.

19. Before immersing the liquid film in the coagulation bath for phase separation and curing, immerse the liquid film in a pre-phase separation solution for pre-phase separation, with the pre-phase separation time being 2 - 10 s. The pre-phase separation solution contains a second organic solvent and a non-solvent, and the content of the non-solvent is 0 - 30%; The manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal according to claim 17, wherein the second organic solvent and the first organic solvent are mutually soluble, the second organic solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid, and the non-solvent is water or ethanol.

20. A manufacturing method of the asymmetric cellulose-based filtration membrane for virus removal according to claim 17, characterized in that the formed membrane is placed in a sodium hydroxide solution for hydrolysis, with the hydrolysis temperature being 20 - 40°C and the hydrolysis time being 15 - 45 min, and after hydrolysis, it is washed to form a solid membrane.

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