Fiber virus-removing membrane and its preparation process

Abstract

The application relates to a virus-removing membrane of fiber and a preparation process thereof. The virus-removing membrane of fiber comprises a porous body, the porous body has non-directional winding passages, the porous body comprises a supporting layer and a separation layer for intercepting viruses, the surface of one side of the supporting layer is a first surface, and the surface of one side of the separation layer is a second surface. The esterification coefficient Z1 of the first surface is 0.01-10.00, the PMI average pore diameter of the porous body is 15-45 nm, the protein yield of the virus-removing membrane is not less than 98%, the ester group exists in the first surface by controlling the esterification coefficient of the first surface, so that the pressure strength of the virus-removing membrane is not less than 20 psi. The application further discloses a preparation process of the virus-removing membrane. The virus-removing membrane of fiber is prepared by using a hydrolysis method, the preparation process is simple, environmental pollution caused by the copper ammonia method is avoided, the virus-removing membrane has high virus interception capacity, high protein yield and high pressure strength.

Description

Technical Field

[0001] This application relates to the field of membrane separation technology, and in particular to a cellulose virus removal membrane and its preparation process. Background Technology

[0002] Ensuring the viral safety of biopharmaceuticals is crucial during their production. Documents such as the 2020 edition of the Chinese Pharmacopoeia and ICH Q5A (Biotechnology Products – Viral Safety Evaluation) set clear and high requirements for the viral safety of biopharmaceuticals. Virus removal and / or inactivation steps must be performed during the production of all types of biopharmaceuticals to ensure their safety. Furthermore, a report on viral safety assessment test results must be attached to the drug application for review, and the content of this report directly affects the review outcome.

[0003] For the biopharmaceutical industry, the application of membrane separation technology, leveraging its advantages of high efficiency and ease of operation, plays a crucial role in ensuring effective separation and concentration during drug production, thus enhancing drug performance. Membrane separation technology is a physical method for removing viruses, depending solely on the size of the virus particles and independent of their chemical or thermal properties. Therefore, it offers advantages such as low risk of denaturation of active substances and mild separation conditions. Membrane separation technology has been widely applied in the biomedical field for the concentration and purification of biological agents, virus filtration, and other applications.

[0004] Membrane separation technology is an emerging technology that uses separation membranes as its core to achieve the separation, purification, and concentration of different components in a feed solution through the selective permeation of the membrane. Membrane separation technology is characterized by low energy consumption, no secondary pollution, simple operation, and high separation efficiency; therefore, it is widely used in the biopharmaceutical industry.

[0005] Chinese invention patent application CN113842792A (applied by Hangzhou Kebote Filter Material Co., Ltd.) discloses an asymmetric PES filter membrane for virus removal. This PES filter membrane comprises a main body, with one side surface being a first outer surface and the other side surface being a second outer surface. The average pore size of the first outer surface is 150-450 nm, and the average pore size of the second outer surface is 10-42 nm. The main body includes a pre-filtration layer and a separation layer for virus interception. One side of the pre-filtration layer is the first outer surface, and one side of the separation layer is the second outer surface. This PES filter membrane has a strong virus interception effect. However, PES material generally has low hydrophilicity and a high adsorption capacity for proteins. Although PES membranes can be hydrophilically modified, the hydrophilically modified PES filter membrane still exhibits a high protein adsorption rate.

[0006] Chinese invention patent application CN105980038A (application by Asahi Kasei Corporation) discloses a virus-removing membrane comprising cellulose for removing viruses from a protein-containing solution. This membrane has a suitable pore size distribution and, being made of cellulose material, exhibits strong hydrophilicity, achieving both high efficiency in retaining various small viruses and a high protein yield.

[0007] However, this virus-removing membrane also has certain drawbacks: First, it is prepared using the copper ammonia method, which not only pollutes the environment but is also extremely dangerous, posing a significant risk to the lives of researchers. Second, the membrane's pressure resistance is insufficient, only 15 psi (it can stably filter under 15 psi pressure), and it cannot withstand higher pressures (the membrane cannot efficiently retain viruses under pressures greater than 15 psi). This results in a small pressure difference between the membrane and its downstream side, leading to a lower filtration rate and consequently, a lower flux and lower economic efficiency per unit time. Furthermore, it increases the processing difficulty, requiring extra care during processing to avoid damaging the membrane.

[0008] In conclusion, the aforementioned problems have, to some extent, limited the development of antiviral membranes. Summary of the Invention

[0009] To address the shortcomings of existing technologies, the purpose of this application is to provide a cellulose virus-removing membrane and its preparation process. The preparation process of the cellulose virus-removing membrane is relatively simple and environmentally friendly. The obtained cellulose virus-removing membrane has a high virus retention capacity and high pressure resistance (greater than 20 psi). At the same time, it also has a high protein yield, which meets the needs of practical applications.

[0010] This application provides a cellulose virus-removing membrane and its preparation process, which adopts the following technical solution:

[0011] In a first aspect, this application provides a cellulose virus-removing membrane, employing the following technical solution:

[0012] A cellulose virus-removing membrane comprises a porous body with non-directional tortuous pathways within it. One side surface of the porous body is a first surface, and the other side surface is a second surface.

[0013] The porous body includes a support layer and a separation layer for trapping viruses, wherein the support layer and the separation layer are transitioned by continuous fibers, and one side surface of the support layer is the first surface;

[0014] The average aperture measured by SEM on the first surface is greater than the average aperture measured by SEM on the second surface.

[0015] The protein yield of the virus-removing membrane is not less than 98%;

[0016] The pressure resistance of the virus-removing membrane is not less than 20 psi;

[0017] The average pore size of the virus-removing membrane (PMI) is 15-45 nm.

[0018] The esterification coefficient Z1 of the first surface is 0.01-10.00;

[0019] The esterification coefficient Z is calculated using the following formula:

[0020] Esterification coefficient Z = X 1740 / X 1428 ;

[0021] X 1740 To determine the infrared absorption spectrum of the virus-free membrane using an FTIR Fourier transform infrared spectrometer with infrared attenuated total internal reflection, the 1740 cm⁻¹ infrared absorption spectrum was analyzed. -1 Nearby peak area;

[0022] X 1428 To determine the infrared absorption spectrum of the virus-free membrane using an FTIR Fourier transform infrared spectrometer with infrared attenuated total internal reflection, the 1428 cm⁻¹ infrared absorption spectrum was analyzed. -1 The area of ​​the nearby peak.

[0023] By adopting the above technical solution, the cellulose virus-removing membrane of the present invention has non-directional tortuous pathways in its main body. These non-directional tortuous pathways refer to randomly oriented groove structures and / or discretely distributed pore structures, and each non-directional tortuous pathway is interconnected. Furthermore, the fibers forming the porous structure of the membrane are continuous. It can be understood that "continuous" means that essentially all the fibers are interconnected as a whole, as if formed in one piece, without the need for additional adhesives or the like to connect them. Unless torn by external force, the network of fibers cannot be separated from each other.

[0024] The virus-removing membrane in this application exhibits an asymmetrical membrane structure, where the average pore size of the porous structure near the first surface is larger, while the average pore size near the second surface is smaller. The virus-removing membrane in this application has an average PMI pore size of 15-45 nm, ensuring good retention of small-sized viruses (20-40 nm).

[0025] In this invention application, the esterification coefficients of the first and second surfaces of the virus-removing membrane can be obtained in the following way: taking the esterification coefficient Z1 of the first surface of the flat sheet membrane as an example, the virus-removing membrane is unfolded and a 25cm section is taken. 2A 5cm x 5cm virus-removing membrane, the exact size depending on the actual situation, is used. Take 1cm from each of the upper left, lower left, upper right, lower right, and center areas of the virus-removing membrane. 2 A sample measuring 1 cm by 1 cm was taken. Taking the sample from the central region of the virus-free membrane as an example, the infrared absorption spectrum of the first surface was measured using an FTIR Fourier transform infrared spectrometer with infrared attenuated total reflectance. The esterification coefficient of the sample from the central region of the virus-free membrane was [value missing] at 1740 cm⁻¹ in the infrared absorption spectrum. -1 The peak area nearby is 1428 cm. -1 The ratio between peak areas in the vicinity, except for the esterification coefficients of the upper left, lower left, upper right, and lower right regions of the viral membrane, is similar. The esterification coefficient Z1 of the first surface of the viral membrane is taken as the average of the esterification coefficients of the five samples.

[0026] It is understandable that the 1740 cm⁻¹ in the infrared absorption spectrum... -1 The peak near the cellulose acetate peak refers to the carbonyl peak of cellulose acetate. Since cellulose acetate is a product of esterification of some hydroxyl groups in cellulose with acetic acid, and the ester group contains a carbonyl group, the carbonyl peak in the infrared absorption spectrum is used to characterize the ester group content on the surface of the virus-removing membrane. As cellulose acetate hydrolyzes, the ester groups on cellulose acetate are removed, and the peak area of ​​the carbonyl peak gradually decreases. The peak at 1428 cm⁻¹ in the infrared absorption spectrum... -1 The peak near the membrane refers to the vibration peak of the cellulose skeleton of cellulose acetate. After the hydrolysis of cellulose acetate, the vibration peak of the cellulose skeleton remains basically unchanged. Therefore, this peak is used as an internal standard peak. Thus, the esterification coefficient Z1 of the first surface can characterize the content of ester groups on the first surface to a certain extent. The content of ester groups is determined by the degree of hydrolysis of the membrane. The higher the degree of hydrolysis, the less ester group content and the lower the esterification coefficient. When the membrane is completely hydrolyzed, the esterification coefficient is 0 and there are no ester groups.

[0027] The inventors of this application unexpectedly discovered during the preparation of cellulose membranes using the hydrolysis method that when the esterification coefficient Z1 of the first surface of the virus-removing membrane is 0.01-10.00, the virus-removing membrane works stably under a pressure of not less than 20 psi, and the protein yield of the virus-removing membrane is still maintained at more than 98%. That is, by controlling the degree of hydrolysis of the cellulose membrane, the inventors of this application obtained a cellulose virus-removing membrane with good pressure resistance and high protein yield.

[0028] This may be because when the esterification coefficient Z1 of the first surface is 0.01-10.00, the porous matrix near the directly pressure-bearing first surface is not completely hydrolyzed (the esterification coefficient is not 0, indicating that there are still carbonyl peaks). The inventors of this application unexpectedly discovered that even with a low esterification coefficient of the first surface (e.g., close to 0.01), the virus-removing membrane of this application still exhibits significantly better pressure resistance (pressure resistance above 20 psi) compared to a membrane with an esterification coefficient of 0 on the first surface. This may be because the presence of carbonyl peaks on the first surface indicates that a small amount of cellulose acetate remains on the first surface of the virus-removing membrane. Compared to softer cellulose fibers, cellulose acetate fibers with better molecular chain rigidity have significantly better pressure resistance. The first surface of the virus-removing membrane directly bears the pressure of the liquid, while the small amount of uniformly dispersed cellulose acetate fibers with better pressure resistance significantly reinforces the porous matrix near the first surface, thereby greatly reducing the possibility of excessive deformation / structural collapse of the porous matrix near the first surface under high liquid pressure. When the porous matrix near the first surface can maintain a relatively stable state, the porous matrix, which is not directly under pressure and has a smaller pore structure and better self-supporting properties, is naturally less prone to excessive deformation, thus the virus removal membrane has better pressure resistance. That is, compared with a completely hydrolyzed membrane structure, even if the esterification coefficient Z1 of the first surface is only slightly increased, the pressure resistance of the virus removal membrane is still significantly improved.

[0029] Furthermore, as the esterification coefficient Z1 of the first surface gradually increases, the pressure resistance of the virus-free membrane initially improves rapidly, but the rate of improvement then gradually slows down. This may be because, for softer cellulose fibers, a small amount of cellulose acetate fiber, which has good pressure resistance, can provide good reinforcement. However, as the esterification coefficient Z1 of the first surface further increases, the reinforcing effect of cellulose acetate exhibits a diminishing marginal return. That is, as the esterification coefficient Z1 gradually increases, the porous matrix near the first surface already possesses good pressure resistance, with minimal deformation under pressure. Even if the pressure resistance of the porous matrix near the first surface is further improved, the reduction in deformation under pressure decreases, and the rate of improvement in pressure resistance slows down.

[0030] Furthermore, contrary to the common belief that incomplete hydrolysis of the virus-removing membrane leads to a decrease in protein yield, the incomplete hydrolysis of the first surface of the virus-removing membrane, while reducing hydrophilicity to some extent, resulted in a surprisingly high overall protein yield (not less than 98%). This is likely because, although the porous matrix near the first surface of the porous body is not completely hydrolyzed, it possesses a pore structure with a large pore size, orders of magnitude different from that of the protein. Both the adsorption effect of the pore walls and the retention effect of the pore structure on the protein are low. Therefore, even if the hydrolysis of the support layer is incomplete, its impact on the protein yield is minimal.

[0031] In summary, when the esterification coefficient Z1 of the first surface of the virus removal membrane is 0.01-10.00, the virus removal membrane has both high protein yield and high pressure resistance.

[0032] It is understandable that the PMI pore size of the non-viral membrane can be directly measured using a PMI membrane pore size analyzer.

[0033] A protein yield of no less than 98% for the virus-removing membrane means, according to PDA TR41, that after filtering a feed solution containing a certain concentration of protein using the virus-removing membrane, the ratio of protein in the filtrate to the feed solution is no less than 98%. A protein yield of no less than 98% indicates that the effective substance protein in the feed solution is not easily adsorbed onto the membrane. On the one hand, this prevents clogging of the filter pores, ensuring a longer service life for the virus-removing membrane; on the other hand, it ensures minimal change in the content of the effective substance protein in the feed solution, with minimal protein loss, thus guaranteeing economic benefits.

[0034] The pressure resistance of the virus-removing membrane is not less than 20 psi, which means that when using the virus-removing membrane of this application for virus removal filtration, the feed liquid is pressurized to not less than 20 psi using the dead-end filtration method; at this time, the virus-removing membrane of this application works normally and there are no obvious phenomena such as structural collapse or abnormal virus retention capacity.

[0035] Optionally, the esterification coefficient Z1 of the first surface is 0.10-9.50.

[0036] Optionally, the esterification coefficient Z1 of the first surface is 0.50-90.

[0037] Optionally, the pressure resistance of the virus-removing membrane is not less than 25 psi, and the esterification coefficient Z1 of the first surface is 1.00-8.00.

[0038] Optionally, the esterification coefficient Z1 of the first surface is 1.50-7.50.

[0039] Optionally, the esterification coefficient Z1 of the first surface is 2.00-7.50.

[0040] Optionally, the pressure resistance of the virus-removing membrane is not less than 30 psi, and the esterification coefficient Z1 of the first surface is 3.00-7.00.

[0041] By adopting the above technical solution, the inventors of this application discovered that, for the infrared spectral data of the first surface, there exists a preferred range for the esterification coefficient. Within this preferred range, the pressure resistance of the virus-removing membrane can be further improved and / or the protein yield of the virus-removing membrane can be further improved. As the first surface of the virus-removing membrane directly bears the pressure of the feed liquid, the esterification coefficient Z1 of the first surface has a very important influence on the pressure resistance of the virus-removing membrane. As the esterification coefficient Z1 of the first surface gradually increases, the pressure resistance of the virus-removing membrane continuously improves.

[0042] For example, when the esterification coefficient Z1 of the first surface is greater than 1.00, the virus-removing membrane can operate normally under a pressure of not less than 25 psi; when the esterification coefficient Z1 of the first surface is greater than 3.00, the virus-removing membrane can operate normally under a pressure of not less than 30 psi. This may be because, as the esterification coefficient Z1 of the first surface gradually increases, the degree of hydrolysis of the porous matrix near the first surface gradually decreases, and the content of cellulose acetate fibers in the porous matrix near the first surface gradually increases. The relatively large number, uniform dispersion, and better pressure resistance of cellulose acetate fibers form a better reinforcing effect on the porous matrix near the first surface, thereby significantly improving the pressure resistance of the virus-removing membrane. As another example, when the esterification coefficient Z1 of the first surface is less than 7, the protein yield of the virus-removing membrane is not less than 99%. This may be because, as the esterification coefficient Z1 of the first surface gradually decreases, the degree of hydrolysis of the porous matrix near the first surface gradually increases, the ester group content of the porous matrix near the first surface gradually decreases, and the protein adsorption rate of the porous matrix near the first surface decreases, thereby gradually increasing the protein yield of the virus-removing membrane.

[0043] It is understandable that the antiviral membrane with an esterification coefficient Z1 of 3-7 on the first surface is only a relatively preferred antiviral membrane, and does not mean that antiviral membranes with an esterification coefficient Z1 of 0.01-3 or 7-10 on the first surface are undesirable.

[0044] Optionally, the maximum value of the esterification coefficient Z of the first surface 1-max The difference between Z1 and Z1 is no greater than 2.5, and the minimum esterification coefficient Z of the first surface is... 1-min The absolute value of the difference between Z1 and Z2 is not greater than 2.5, and the maximum value of the esterification coefficient Z2 of the first surface is... 1-max The minimum esterification coefficient Z of the first surface 1-min The difference is no higher than 4.

[0045] By adopting the above technical solution, the maximum esterification coefficient Z of the first surface is achieved. 1-maxThis refers to the maximum value of the esterification coefficient among samples selected from the upper left, lower left, upper right, lower right, and middle regions of the first surface of the virus-removing membrane; the minimum value of the esterification coefficient Z on the first surface. 1-min This refers to the minimum esterification coefficient of the sample selected from the upper left, lower left, upper right, lower right, and middle regions of the first surface of the virus-removing membrane.

[0046] When the maximum value of the esterification coefficient of the first surface is Z 1-max The minimum value Z of the esterification coefficient of the first surface 1-min The relationship between the esterification coefficient Z1 of the first surface and the esterification coefficient Z1 satisfies a certain relationship (Z 1-max -Z1≤2.5;Z1-Z 1-min ≤2.5; Z 1-max -Z 1-min When the viral membrane density is ≤4), the probability of local high protein adsorption and / or local collapse is further reduced.

[0047] This may be because, except for the fact that the esterification coefficient Z1 of the first surface of the viral membrane is affected by the esterification coefficient of different regions, Z 1-max Z 1-min The smaller the differences between Z1 and Z2, the more uniform the overall hydrolysis degree of the first surface of the devirtual membrane. Since the hydrolysate enters from the second surface of the devirtual membrane and permeates towards the first surface during hydrolysis, a more uniform degree of hydrolysis on the first surface, viewed from the membrane thickness direction, indicates a relatively uniform overall degree of hydrolysis of the devirtual membrane. This reduces the probability of localized areas with relatively low or high degrees of hydrolysis. A relatively low degree of hydrolysis in a localized area may lead to excessively high local protein adsorption rates; a relatively high degree of hydrolysis in a localized area may result in relatively poor local pressure resistance.

[0048] It is understandable that the viral membrane (Z) has a more uniform esterification coefficient distribution on the first surface. 1-max -Z1≤2.5;Z1-Z 1-min ≤2.5; Z 1-max -Z 1-min ≤4) is only a relatively preferred antiviral membrane, and does not mean that antiviral membranes outside this range are undesirable.

[0049] Furthermore, the inventors of this application have discovered that when the esterification coefficient distribution on the first surface of the virus removal membrane is more uniform, the virus removal membrane can achieve the same good pressure resistance with a relatively low esterification coefficient.

[0050] This may be because the higher the uniformity of the esterification coefficient on the first surface of the deviral membrane, the higher the uniformity of hydrolysis in each region of the deviral membrane from the perspective of membrane thickness. This also indicates that the cellulose acetate fibers with better pressure resistance are more evenly distributed. The more evenly distributed cellulose acetate fibers have a more uniform reinforcement effect on the support layer. There are fewer breakthrough points for excessive deformation / structural collapse of the deviral membrane, that is, the membrane has better pressure resistance.

[0051] When the uniformity of the esterification coefficient on the first surface of the virus-removing membrane is relatively high, even if the esterification coefficient Z1 on the first surface of the virus-removing membrane is relatively low, the probability of localized areas with low pressure resistance is also lower because the hydrolysis uniformity of each region of the virus-removing membrane is relatively high. Therefore, the pressure resistance of the virus-removing membrane is also relatively high. Furthermore, when the above-mentioned virus-removing membrane (with a relatively low esterification coefficient Z1 on the first surface, but a relatively high uniformity of the esterification coefficient on the first surface) is applied, because the esterification coefficient Z1 on the first surface of the virus-removing membrane is relatively small, the degree of hydrolysis on the first surface of the virus-removing membrane is higher. From the perspective of membrane thickness, the overall degree of hydrolysis of the virus-removing membrane is relatively higher, and the protein yield of the virus-removing membrane is higher. The above-mentioned virus-removing membrane has both higher protein yield and higher pressure resistance.

[0052] Optionally, the average pore size of the virus removal membrane (PMI) is 15-25 nm.

[0053] By adopting the above technical solution, the average pore size of the virus removal membrane is 15-25nm, which can ensure that the virus removal membrane has a good retention effect on small-sized viruses, such as the small virus model virus PP7 bacteriophage and mouse parvovirus (about 20nm) specified in PDA TR41.

[0054] Optionally, the average pore size of the virus removal membrane (PMI) is 25-45 nm.

[0055] By adopting the above technical solution, the average pore size (PMI) of the virus-removing membrane is 25-45 nm. Compared with virus-removing membranes with an average PMI of 15-25 nm, the membrane pores of the 25-45 nm membrane are larger, resulting in relatively weaker retention efficiency for viruses around 20 nm. However, it is more suitable for viruses of 30-50 nm, such as SV40 (approximately 45 nm). Furthermore, in practical use, the virus-removing membrane can be stacked in double layers, still achieving efficient and sufficient retention of various small viruses of 20 nm and above (retention rate for 20 nm viruses: LRV > 4 or even LRV > 6). Simultaneously, due to the larger pore size, the protein yield remains high. That is, the virus-removing membrane in this application is not limited to single-layer use. In practical use, a single-layer virus-removing membrane can be selected for use, or double or even more layers of virus-removing membranes can be stacked to achieve the desired virus filtration effect, depending on actual needs. In addition, stacking virus-removing membranes can further reduce the risk of virus leakage.

[0056] Optionally, the first surface includes a plurality of elongated and interlaced first fibers, the interlacing parts of each first fiber form nodes, and adjacent and interlaced first fibers surround each other to form pores. The average diameter of the first fiber measured by SEM is 50-180nm, the average pore size of the first surface measured by SEM is 300-4500nm, and the pore area ratio of the first surface is 10-50%.

[0057] By adopting the above technical solution, when observing the surface morphology of the virus-removing membrane through SEM images, it can be found that the first surface has a relatively obvious fibrous structure (i.e., the first fiber). These fibers are slender strip structures that intersect to form a node structure. Since these node structures have a larger radial dimension than the fiber structure, they can provide better support for the three-dimensional network structure near the first surface. The node structure, the diameter of the first fiber, the pore size of the first surface, the pore area ratio of the first surface, and the esterification coefficient of the first surface are all suitable, which can ensure that the porous body near the first surface of the virus-removing membrane has good pressure resistance.

[0058] If the diameter of the first fiber is too large (e.g., greater than 180 nm), although a thicker first fiber can make the first surface have stronger pressure resistance, a thicker first fiber will also create greater resistance to the liquid, which may lead to a decrease in the flux of the virus removal membrane. If the diameter of the first fiber is too small (e.g., less than 50 nm), the supporting effect on the pore structure of the first surface is weak, and the pressure resistance of the first surface that directly bears the pressure of the liquid is insufficient.

[0059] Understandably, the higher the esterification coefficient of the first fiber (closer to 10) and the thicker the first fiber (closer to 180nm), the higher the pressure resistance of the first surface. As the first fiber gradually hydrolyzes, its diameter gradually decreases, thus reducing the pressure resistance of the virus-removing membrane. Virus-removing membranes with different pressure resistance can be adapted to different application environments (different pressure environments). A suitable esterification coefficient for the first surface, i.e., a suitable esterification coefficient for the first fiber, and a reasonable size for the first fiber that matches its suitable esterification coefficient, maximizes the adaptability of the virus-removing membrane to various pressure environments, saving costs while minimizing the probability of membrane collapse.

[0060] The pores formed by the first fiber surrounding the solid part are used to guide the feed liquid into the interior of the filter membrane. Therefore, the first surface needs a large pore area ratio (e.g., not less than 10%) and a relatively high esterification coefficient Z1, that is, a relatively high content of cellulose acetate on the first surface. If the pore area ratio is too small, there will be more solid parts, and the feed liquid will come into too much contact with the solid parts of the first surface. This means that the probability of protein in the feed liquid coming into contact with esterified cellulose is higher, which may lead to a decrease in the protein yield of the virus removal membrane. The pore area ratio of the first surface should not be too large (e.g., greater than 50%). This is because the first surface is the part that directly bears the pressure of the feed liquid. An excessively high pore area ratio will lead to an excessive decrease in the pressure resistance of the first surface. The first surface may undergo excessive deformation under pressure, resulting in the collapse of the first surface.

[0061] The average pore size of a membrane surface can be measured by characterizing the membrane structure using a scanning electron microscope (SEM), followed by measurement using computer software (such as Matlab, NIS-Elements, etc.) or manually, and then performing corresponding calculations. During membrane fabrication, in the direction perpendicular to the membrane thickness (if the membrane is a flat sheet, this direction is planar; if the membrane is a hollow fiber membrane, this direction is perpendicular to the radius), its characteristics, such as pore size distribution, are roughly uniform and consistent. Therefore, the average pore size of a certain area on the corresponding plane can reflect the overall average pore size on that plane. In actual measurement, the membrane surface can be characterized using an electron microscope to obtain the corresponding SEM image. Since the pores on the membrane surface are roughly uniform, a certain area, such as 1 μm, can be selected. 2 (1μm x 1μm) or 25μm 2 (5μm by 5μm), the specific area size depends on the actual situation. Then, use appropriate computer software or manual measurement to determine the diameter of all holes on this area, and then calculate to obtain the average pore diameter of the surface. Of course, those skilled in the art can also obtain the above parameters through other measurement methods. The above measurement methods are for reference only.

[0062] Optionally, the thickness of the support layer is 5-30 μm, and the ratio of the thickness of the support layer to the esterification coefficient Z1 of the first surface is 2-8 μm.

[0063] Research has revealed a correlation between the thickness of the support layer of the virus-removing membrane and the esterification coefficient Z1 of the first surface of the membrane. For example, a thicker support layer results in a higher esterification coefficient Z1 on the first surface, making the membrane suitable for high-pressure (not less than 30 psi) environments. Conversely, a thinner support layer results in a lower esterification coefficient Z1 on the first surface, making the membrane suitable for high-pressure (20-30 psi) environments.

[0064] This may be because if the support layer of the virus-removing membrane is thicker, during hydrolysis, the hydrolysate enters from the second surface of the membrane and permeates towards the first surface. While the hydrolysate fully hydrolyzes the separation layer of the virus-removing membrane, if the support layer is thicker, the amount of hydrolysate hydrolyzing the first surface is relatively small, meaning the esterification coefficient Z1 of the first surface is relatively high. When the aforementioned virus-removing membrane is used in high-pressure (not less than 30 psi) environments, the higher esterification coefficient of the first surface and the relatively thicker support layer provide relatively higher pressure resistance, while the lower protein adsorption rate of the separation layer ensures a high protein yield, making this a highly preferred option.

[0065] If the thickness of the support layer of the virus removal membrane is relatively thin, a certain amount of hydrolysate can reach the vicinity of the first surface of the virus removal membrane relatively quickly and hydrolyze the first surface of the virus removal membrane. That is, the degree of hydrolysis of the first surface of the virus removal membrane is relatively high, that is, the first surface has a relatively low esterification coefficient.

[0066] If the ratio between the thickness of the support layer and the esterification coefficient Z1 of the first surface is too large, it indicates that the support layer is relatively thick and the esterification coefficient of the first surface is relatively small. That is, the degree of hydrolysis of the first surface is too high. Since the pore size and porosity of the porous body on the side close to the first surface are large, the side of the porous body close to the first surface cannot exhibit good pressure bearing capacity.

[0067] If the ratio between the thickness of the support layer and the esterification coefficient Z1 of the first surface is too small, it indicates that the thickness of the support layer is relatively small and the esterification coefficient of the first surface is relatively large. In this case, if we look at the overall degree of hydrolysis of the virus removal membrane from the direction of membrane thickness, the side of the separation layer near the support layer may not be fully hydrolyzed. The separation layer is a critical area affecting protein adsorption. If the separation layer is not fully hydrolyzed, it will reduce the overall protein yield of the virus removal membrane.

[0068] Optionally, the support layer includes several long strip-shaped and interlaced support fibers, with adjacent and interlaced support fibers surrounding each other to form pores, and the average diameter of the support fibers measured by SEM is 60-170 nm.

[0069] By adopting the above technical solution, the support layer is the part of the virus removal membrane structure directly subjected to the pressure of the feed liquid. Since the pore size of the support layer is larger than that of the separation layer, a relatively large-diameter fiber structure is needed to support the pore structure to ensure that the filter membrane is not prone to pore collapse under high feed liquid pressure. The fiber diameter of the support layer should not be too small (e.g., less than 60 nm). If the diameter of the support fiber is too small, it will not have sufficient self-supporting capacity. Conversely, the fiber diameter should not be too large (e.g., greater than 170 nm). Although the support layer can indeed achieve stronger self-supporting capacity, the hydrolysate will also experience greater resistance from the coarser fiber structure. Near areas where the support fibers are too large, the hydrolysate will experience greater resistance during permeation. From the perspective of membrane thickness, the first surface near this area may not be fully hydrolyzed, potentially leading to excessively high local esterification coefficients, thereby reducing the uniformity of the overall esterification coefficient of the first surface of the virus removal membrane.

[0070] Optionally, the SEM measured average pore size of the support layer is 200-700 nm, the porosity of the support layer is 40-75%, and the ratio between the SEM measured average diameter of the support fiber and the SEM measured average pore size of the support layer is 0.1-0.3.

[0071] By employing the above technical solution, the support layer, in addition to being directly subjected to the pressure of the feed liquid, also serves to filter large particles in the feed liquid. If the average pore size of the support layer measured by SEM is too large (e.g., greater than 700 nm), although the support layer with a larger pore structure generally has a greater dirt-holding capacity, its retention capacity for large particles is insufficient. Once large particles leak from the support layer, it is likely to cause rapid clogging of the separation layer and rapid decline in the filter membrane flux. Furthermore, an excessively large average pore size of the support layer also means a reduction in its pressure resistance. Once the support layer collapses under the pressure of the feed liquid, both the filter membrane flux and loading capacity will decrease. Therefore, although increasing the average pore size of the support layer measured by SEM within a certain range is beneficial for increasing the filter membrane loading capacity and reducing the rate of flux decline, the average pore size of the support layer should not be too large, otherwise it will lead to a decrease in the filter membrane loading capacity and an accelerated rate of flux decline. The average pore size of the support layer measured by SEM should not be too small (e.g., less than 200 nm). As a support layer that plays a role in pre-filtering large particles in the feed liquid, it needs to have a large space for holding large particles to avoid being quickly blocked by large particles and causing a rapid decline in flux.

[0072] The support layer has support fibers of appropriate diameter, allowing the hydrolysate to enter the separation layer under suitable resistance. At the same time, the support layer has filter pores with appropriate pore size and porosity, allowing the hydrolysate to enter the support layer more uniformly. In other words, the overall degree of hydrolysis in the support layer is more uniform, which reduces the probability of local areas of excessive or insufficient hydrolysis in the support layer.

[0073] Furthermore, there is a suitable relationship between the diameter of the supporting fiber and the pore size of the supporting layer. The larger the pore size of the supporting layer, the larger the supporting fiber needs to be.

[0074] In summary, the appropriate pore size and porosity of the support layer are used to ensure the overall hydrolysis uniformity of the support layer. The more uniform the degree of hydrolysis of the support layer, the fewer the breakthrough points of the support layer. Furthermore, if the support layer has an appropriate proportion and appropriate direct support fibers to support the filter pores of the support layer, even if the overall degree of hydrolysis of the support layer of the virus removal membrane is relatively high, that is, the esterification coefficient of the first surface is relatively small, the virus removal membrane can operate stably under relatively high pressure.

[0075] Optionally, the average pore size of the separation layer is 20-80 nm, the thickness of the separation layer is 5-45 μm, and the ratio of the thickness of the separation layer to the thickness of the porous body is 20-60%.

[0076] By adopting the above technical solution, the virus removal membrane must ensure a low risk of virus leakage, and the separation layer in the virus removal membrane is the area that plays a role in virus retention. In order to ensure that the virus removal membrane has a good virus retention effect, the average pore size of the separation layer measured by SEM should not be too large (e.g., greater than 45 nm) and the thickness should not be too small (e.g., less than 5 μm), so as to prevent the virus from leaking from the separation layer with a smaller thickness and / or a larger pore size.

[0077] Optionally, the average pore size of the separation layer is 20-45 nm.

[0078] By adopting the above technical solution, the average pore size of the separation layer is 20-45nm, which can ensure that the virus removal membrane has a good retention effect on small-sized viruses, such as the small virus model virus PP7 bacteriophage and mouse parvovirus (about 20nm) specified in PDATR41.

[0079] Optionally, the average pore size of the separation layer is 45-80 nm.

[0080] By adopting the above technical solution, the average pore size of the separation layer is 45-80 nm. Compared with the virus-removing membrane with an average pore size of 20-45 nm, the pores of the virus-removing membrane with an average pore size of 45-80 nm are larger, resulting in relatively weaker retention efficiency for viruses around 20 nm, but it is more suitable for viruses of 30-50 nm. Furthermore, in practical use, the virus-removing membrane can be stacked in double layers, still achieving efficient and sufficient retention of various small viruses of 20 nm and above. Simultaneously, due to the larger pore size, the protein yield remains high. That is, the virus-removing membrane in this application is not limited to single-layer use. In practical use, a single-layer virus-removing membrane can be selected for use, or double or even more layers of virus-removing membranes can be stacked to achieve the desired virus filtration effect, depending on actual needs. In addition, stacking virus-removing membranes can further reduce the risk of virus leakage.

[0081] Optionally, the porous body further includes a protective layer located on the side of the separation layer away from the support layer, the surface of the protective layer being the second surface, the thickness of the protective layer being 2-20 μm, and the ratio of the thickness of the protective layer to the thickness of the porous body being 5%-30%.

[0082] By adopting the above technical solution, the separation layer is located between the support layer and the protective layer, rather than being exposed on the surface of the virus removal membrane. Since the separation layer is located inside the protective layer, external mechanical damage often requires first destroying the protective layer before further damaging the separation layer structure. Because the separation layer is the area in the virus removal membrane that plays a role in virus interception, even if the protective layer structure is damaged, if the separation layer structure is not damaged, the risk of virus leakage from the filter membrane is still low. Therefore, placing the separation layer inside the protective layer greatly reduces the possibility of virus leakage due to external mechanical damage.

[0083] If the protective layer is thicker (e.g., thicker than 20 μm or thicker than 30% of the porous substrate thickness), it often provides better protection for the separation layer, but it also tends to have a greater impact on the filter membrane flux. If the protective layer is thinner (e.g., thinner than 2 μm or thinner than 5% of the porous substrate thickness), it has a smaller impact on the filter membrane flux, but it often means insufficient protection for the separation layer. Therefore, the thickness of the protective layer should be controlled within a certain range.

[0084] Optionally, the SEM measurement average pore size of the protective layer is 100-300 nm, and the porosity of the protective layer is 35-65%.

[0085] By adopting the above technical solution, since external mechanical forces often need to first damage the protective layer structure before further damaging the separation layer structure located inside the protective layer, the protective layer's resistance to mechanical damage has a significant impact on the protective effect of the separation layer. To ensure that the protective layer has a good protective effect on the separation layer while also considering the flux of the virus removal membrane, the average pore size and porosity of the protective layer measured by SEM need to be controlled within a certain range. This is because if the average pore size and / or porosity of the protective layer measured by SEM is too small (e.g., the average pore size measured by SEM is less than 100 nm and / or the porosity is less than 35%), it indicates that the protective layer has a relatively dense three-dimensional network structure, thus having stronger resistance to mechanical damage and therefore a better protective effect on the separation layer; however, an overly dense three-dimensional network structure also means greater resistance to hydrolysate, which may lead to insufficient hydrolysate penetration into the separation layer, resulting in a lower degree of hydrolysis within the separation layer. If the average pore size and / or porosity of the protective layer measured by SEM is too large (e.g., average pore size greater than 300 nm and / or porosity greater than 65%), it indicates that the three-dimensional network structure of the protective layer has low density. Although a low-density three-dimensional network structure offers less resistance to hydrolysate, it also means weak resistance to mechanical damage. Once the protective layer structure is damaged, the likelihood of damage to the exposed separation layer increases significantly, and the risk of virus leakage increases dramatically. Furthermore, during the hydrolysis of the virus removal membrane, the hydrolysate often enters the membrane from its second surface (the liquid outlet). If the average pore size and / or porosity of the protective layer measured by SEM is too small (e.g., average pore size less than 100 nm and / or porosity less than 35%), the overly dense three-dimensional network structure also means relatively high resistance to hydrolysate, potentially leading to a lower amount of hydrolysate penetrating into the support layer.

[0086] The protective layer possesses suitable thickness, average pore size, and porosity. While ensuring good protection of the separation layer, it minimizes resistance to the hydrolysate, allowing it to fully penetrate the separation layer and achieve the desired degree of hydrolysis. Simultaneously, the suitable pore size and porosity of the separation layer enable more uniform hydrolysate penetration, ensuring even hydrolysis of the entire layer and minimizing the probability of incomplete hydrolysis in localized areas leading to high protein adsorption rates. This guarantees and even improves the protein yield of the virus-removing membrane.

[0087] Optionally, the esterification coefficient Z2 of the second surface is 0-7.00, and the esterification coefficient Z2 of the second surface is lower than the esterification coefficient Z1 of the first surface.

[0088] By adopting the above technical solution, the porous body near the second surface is the key area affecting protein yield. This is because the separation layer is the region responsible for virus retention. The pore size of the separation layer is smaller, and the specific surface area of ​​the solid portion of the separation layer is larger. That is, the pore walls of the separation layer have a stronger adsorption effect on proteins compared to the pore walls of the support layer. Furthermore, due to the smaller pore size of the separation layer, it has a stronger protein retention effect compared to the support layer. However, in this application, during the hydrolysis of the virus-removing membrane, the hydrolysate enters the virus-removing membrane from the second surface and permeates from the smaller-pore separation layer to the larger-pore support layer. Compared to the hydrolysate content in the support layer, the hydrolysate content in the separation layer is relatively higher, meaning the degree of hydrolysis in the separation layer is relatively higher. Therefore, the protein adsorption rate of the separation layer is lower. In addition, since the separation layer is a relatively dense three-dimensional structure, it has high self-supporting performance. And because the separation layer does not directly bear pressure, even though the separation layer is basically made of soft pure cellulose, it still has sufficient pressure resistance.

[0089] It is generally believed that the separation layer should have a high degree of hydrolysis, or even approach complete hydrolysis, in order to give the separation layer sufficient hydrophilicity and enable the virus removal membrane to have a high protein yield.

[0090] The separation layer is nearly completely hydrolyzed, meaning the esterification coefficient Z2 of the second surface of the virus-removing membrane approaches 0. However, the inventors of this application have discovered that in certain application scenarios (e.g., pressurizing the feed solution to increase the overall filtration speed of the membrane, resulting in shorter fluid filtration time and lower time costs), the virus-removing membrane still collapses under higher pressure environments. In this case, even with a certain degree of esterification on the second surface (i.e., the separation layer is not completely hydrolyzed), the mechanical properties (pressure resistance) of the virus-removing membrane are further improved, while the protein yield remains high. That is, when the virus-removing membrane is applied to higher pressure environments, it can maintain a high protein yield even if the separation layer is not fully hydrolyzed, which is quite unexpected.

[0091] This may be because the second surface of the virus-removing membrane also has a certain esterification coefficient, that is, the second surface is not completely hydrolyzed, which means that there is a certain amount of cellulose acetate on the second surface. It can be understood that when the second surface also has a certain esterification coefficient, the esterification coefficient of the virus-removing membrane has a certain gradient change in the thickness direction of the virus-removing membrane, and the esterification coefficient Z1 of the first surface gradually decreases to the esterification coefficient Z2 of the second surface.

[0092] From the perspective of membrane thickness, when the second surface also has a certain esterification coefficient, the virus removal membrane as a whole contains a certain amount of cellulose acetate. A certain amount of cellulose acetate fibers that are present, uniformly dispersed, and have better pressure resistance form a significant reinforcing effect on the virus removal membrane as a whole, thereby greatly reducing the possibility of excessive deformation / structural collapse of the virus removal membrane as a whole when subjected to greater pressure from the liquid.

[0093] Meanwhile, under high-pressure operating conditions, the entire virus removal membrane is subjected to significant pressure from the feed liquid. The feed liquid passes through the entire virus removal membrane for a shorter period of time, resulting in a shorter contact time between the proteins in the feed liquid and the solid parts of the virus removal membrane, and thus a smaller amount of protein adsorbed by the virus removal membrane.

[0094] It is understandable that virus-removing membranes with a certain esterification coefficient on the second surface are mainly used for applications in certain high-pressure environments.

[0095] Optionally, the surface of the separation layer away from the support layer is the second surface, and the esterification coefficient Z2 of the second surface is 0-6.00, which is lower than the esterification coefficient Z1 of the first surface.

[0096] By adopting the above technical solution, the virus-removing membrane in this solution does not have a protective layer. That is, the virus-removing membrane in this solution has a two-layer structure, consisting only of a support layer and a separation layer. When the esterification coefficient Z2 of the second surface of the virus-removing membrane is close to 0, it indicates that the degree of hydrolysis of the porous matrix on the second surface of the virus-removing membrane is relatively high. For a two-layer virus-removing membrane, the porous matrix near the second surface is the separation layer, which is a key area affecting protein yield. The separation layer has a relatively higher degree of hydrolysis, yet still maintains a low protein adsorption rate. Furthermore, because the separation layer is a relatively dense three-dimensional structure, it has high self-supporting properties. Since the separation layer does not directly bear pressure, it also possesses sufficient pressure resistance. When the second surface of the virus-removing membrane also has a certain esterification coefficient, the virus-removing membrane can be applied to higher pressure environments.

[0097] Optionally, the thickness of the virus-removing membrane is 20-90 μm, the porosity of the virus-removing membrane is 10-60%, and the flux of the virus-removing membrane is greater than 60 L·h. -1 m -2 @30psi.

[0098] Secondly, this application provides a process for preparing a cellulose virus-removing membrane, which adopts the following technical solution:

[0099] S1. Preparation of casting solution, wherein the casting solution comprises the following raw materials in parts by weight: 15-40 parts of cellulose acetate, 30-80 parts of good solvent, and 20-50 parts of pore-forming agent.

[0100] S2. Extrusion film formation: The casting liquid is extruded from the die head;

[0101] S3. Phase separation and curing: The formed film is placed in a coagulation bath at 60-80°C for phase separation and curing to obtain a raw film. The coagulation bath is at least one of water or ethanol.

[0102] S4. Post-treatment: The raw membrane is immersed in a sodium hydroxide hydrolysis bath. During immersion, the second surface of the raw membrane is in contact with the sodium hydroxide hydrolysis bath. After immersion, the raw membrane is removed. The concentration of sodium hydroxide on the raw membrane is 0.15-0.80 g / g. The temperature of the hydrolysis bath during immersion is below 10℃. Subsequently, the raw membrane immersed in the hydrolysis bath is heated to 25-50℃ to hydrolyze and regenerate cellulose acetate into cellulose, thus obtaining the cellulose virus-removing membrane.

[0103] By adopting the above technical solution, this application uses a hydrolysis method to prepare a virus-removing membrane. Unlike the general hydrolysis method for preparing cellulose virus-removing membranes (such as the preparation method described in Chinese Patent No. CN1108853C, which involves immersing a cellulose acetate membrane in a sodium hydroxide hydrolysis solution at 20°C for 4 hours, at which point it can be considered that the cellulose acetate has been completely hydrolyzed into pure cellulose), this application first quantitatively impregnates the cellulose acetate membrane in a low-temperature sodium hydroxide hydrolysis bath, so that a certain amount of sodium hydroxide adheres to the cellulose acetate membrane (raw membrane), and then raises the temperature to hydrolyze the cellulose acetate membrane. The inventors of this application unexpectedly discovered that when the concentration of sodium hydroxide adhering to the cellulose acetate membrane is 0.15-0.80 g / g, the prepared cellulose virus-removing membrane has good pressure resistance and a high protein yield. Yes, it is understandable that the concentration of sodium hydroxide on the raw film is 0.15-0.80 g / g, which means that after the cellulose acetate membrane (raw film) is immersed in a hydrolysis bath, 0.15 g-0.80 g of sodium hydroxide is attached to each 1 g of cellulose acetate membrane.

[0104] This may be because when the cellulose acetate membrane is immersed at a temperature below 10°C, the number of ester groups hydrolyzed on the cellulose acetate membrane is relatively small. When the cellulose acetate membrane is removed from the hydrolysis bath, the mass difference (mass of the sodium hydroxide hydrolysis bath) before and after immersion can be relatively accurate.

[0105] When a cellulose acetate membrane is immersed in a sodium hydroxide hydrolysis bath, the second surface of the cellulose acetate membrane (raw membrane) comes into contact with the sodium hydroxide hydrolysis bath. Therefore, the sodium hydroxide hydrolysis bath permeates from the separation layer (with smaller pores) to the support layer (with larger pores). Compared to the content of hydrolysate in the support layer, the content of hydrolysate in the separation layer is relatively higher; that is, the degree of hydrolysis in the separation layer is relatively higher, while the degree of hydrolysis in the support layer is relatively lower. The concentration of sodium hydroxide adhering to the cellulose acetate membrane has a critical impact on the degree of hydrolysis. If the concentration of sodium hydroxide adhering to the cellulose acetate membrane is too low (e.g., less than 0.15 g / g), the low concentration may lead to a lower degree of hydrolysis in the separation layer, resulting in a reduced protein yield of the virus-removing membrane. If the concentration of sodium hydroxide adhering to the cellulose acetate membrane is too high (e.g., greater than 0.80 g / g), the degree of hydrolysis in the support layer may also be relatively high, resulting in a reduced pressure resistance of the virus-removing membrane. Therefore, the concentration of sodium hydroxide adhering to the cellulose acetate membrane needs to be strictly controlled. In addition, in order to control the concentration of sodium hydroxide adhering to the cellulose acetate membrane relatively precisely, the temperature of the hydrolysis bath needs to be strictly controlled when the cellulose acetate membrane is immersed in the hydrolysis bath, so as to minimize the hydrolysis during the cellulose acetate immersion process.

[0106] Furthermore, after the cellulose acetate membrane was impregnated with the hydrolysis bath, from the thickness direction of the membrane, the entire cellulose acetate membrane contained a certain amount of sodium hydroxide hydrolysis bath, with the content of sodium hydroxide hydrolysis bath being relatively higher on the side closer to the second surface and relatively lower on the side closer to the first surface. At this point, hydrolyzing the cellulose acetate membrane at 25-50℃ resulted in a relatively mild hydrolysis of the cellulose acetate membrane and a more uniform degree of hydrolysis of the virus-removing membrane.

[0107] In summary, the cellulose acetate membrane is impregnated to attach a certain amount of sodium hydroxide hydrolysis bath at a temperature below 10°C. Simultaneously, the cellulose acetate membrane is heated to a suitable temperature for hydrolysis. This results in a virus-removing membrane with a relatively fully hydrolyzed separation layer and a uniform and suitable esterification coefficient on the first surface.

[0108] Optionally, the virus-removing membrane is a flat sheet membrane, and step S2 includes: extruding the casting solution onto a carrier to form a liquid flat sheet membrane, wherein the second surface of the liquid flat sheet membrane is located on the carrier side and the first surface of the liquid flat sheet membrane is located on the air side; subsequently, immersing the liquid flat sheet membrane in a pretreatment solution to pre-separate the first surface of the liquid flat sheet membrane to obtain a molded membrane, wherein the pretreatment solution is an acetone aqueous solution with a concentration of 75-90 wt%, and the pre-separation time is 2-15 s.

[0109] By adopting the above technical solution, for flat sheet membranes, the main process involves pre-separation of the air side (first surface) of the liquid flat sheet membrane. A 75-90 wt% acetone aqueous solution is used to pretreat the first surface. The pretreatment solution has a high acetone content and a low water content. Acetone dilutes the first surface of the flat sheet membrane. Because the pretreatment solution (acetone aqueous solution) contains a certain amount of water, phase separation occurs on the first surface of the flat sheet membrane. Furthermore, the low water content in the pretreatment solution results in a slower phase separation rate on the first surface, ensuring sufficient time for the casting solution to form a large polymer-rich phase and a large solvent-rich phase. After the solvent-rich phase is removed, the required support layer structure with a large pore size can be formed.

[0110] When the concentration of the acetone aqueous solution is high and the thickness of the flat sheet membrane is thin (e.g., the concentration of the acetone aqueous solution is close to 90 wt%), the pore size of the support layer is large, making it easier for the coagulation bath to enter and quickly separate the phase to the carrier side, forming a two-layer flat sheet membrane, namely a support layer + separation layer. When the concentration of the acetone aqueous solution is low (e.g., the concentration of the acetone aqueous solution is close to 75 wt%) and the thickness of the flat sheet membrane is thick, the pore size of the support layer is small. In this case, the coagulation bath can enter relatively easily at first, and the phase separation can be achieved quickly to form the separation layer. Subsequently, due to the greater resistance of the separation layer, the coagulation bath penetration is hindered, the phase separation rate slows down, and a protective layer is formed on the carrier side, namely a three-layer membrane structure of support layer + separation layer + protective layer.

[0111] Optionally, the virus-removing membrane is a hollow fiber membrane, and step S2 includes: simultaneously ejecting casting solution and pretreatment solution from an annular spinneret to form a liquid hollow membrane, wherein the inner surface of the hollow membrane is the first surface, the outer surface of the hollow membrane is the second surface, and the pretreatment solution is located in the inner cavity of the casting solution, so that the first surface of the hollow membrane is pre-phase separated to obtain a shaped membrane, wherein the pretreatment solution is an acetone aqueous solution with a concentration of 75-90wt%, and the pre-phase separation time is 2-15s.

[0112] By adopting the above technical solution, for hollow fiber membranes, the pretreatment solution is located in the inner cavity of the casting solution. That is, the pretreatment solution pretreats the first surface of the hollow fiber membrane, and the acetone in the pretreatment solution dilutes the first surface of the flat membrane. Since the pretreatment solution contains water, phase separation occurs first on the inner surface (first surface) of the hollow fiber membrane. Because the water content in the pretreatment solution is low, the phase separation rate on the first surface is slow, thus ensuring that the casting solution has sufficient time to form a large polymer-rich phase and a large solvent-rich phase. After the solvent-rich phase is removed, the required support layer structure with a large pore size can be formed.

[0113] In this method, the outer surface (second surface) of the hollow fiber membrane is in direct contact with the coagulation bath. Since the coagulation bath is water or ethanol, the outer surface (second surface) of the hollow fiber membrane undergoes rapid phase separation, forming a relatively dense separation layer with smaller pore sizes. In other words, this method is used to prepare a two-layer hollow fiber membrane (support layer + separation layer).

[0114] Optionally, step S3 specifically includes the following process steps:

[0115] S31. Reprocessing: The second surface of the formed film is placed in a reprocessing solution for reprocessing. The reprocessing solution is an acetone aqueous solution with a concentration of 45-70 wt%, and the processing time is 0.5-10 s to obtain a reprocessed film.

[0116] S32. Curing: Place the reprocessed membrane in a coagulation bath until the reprocessed membrane is completely phase-separated and cured to obtain the raw membrane.

[0117] By adopting the above technical solution, not only is the inner surface (first surface) of the hollow fiber membrane pretreated, but the outer surface (second surface) is also retreated. During the retreatment of the second surface of the hollow fiber membrane, the acetone in the retreatment solution dilutes the second surface of the flat membrane. Since the retreatment solution contains water, phase separation also occurs on the outer surface (second surface) of the hollow fiber membrane. Because the water content in the retreatment solution is low, the phase separation rate on the second surface is slow, ensuring that the casting solution has sufficient time to form a large polymer-rich phase and a large solvent-rich phase. After the solvent-rich phase is removed, the desired protective layer structure with a large pore size can be formed.

[0118] Meanwhile, the retreatment solution is a 45-70 wt% acetone aqueous solution, and the pretreatment solution is a 75-90 wt% acetone aqueous solution. It can be seen that the water content in the pretreatment solution is less than that in the retreatment solution. This means that the phase separation rate on the inner surface (first surface) of the hollow fiber membrane is relatively slower than the phase separation rate on the outer surface (second surface) of the hollow fiber membrane, resulting in a larger pore size. Contacting the pretreated and retreated hollow fiber membranes with a coagulation bath forms a relatively dense separation layer with smaller pores. In other words, this scheme is used to form a three-layer hollow fiber membrane (support layer + separation layer + protective layer), with the support layer having a larger pore size than the protective layer.

[0119] Optionally, in step S4, the sodium hydroxide hydrolysis bath further includes a penetrant, the concentration of which is 1.5-3.5 wt%, and the penetrant is at least one of ethanol, 1-propanol, isopropanol, glycerol, hexafluoroisopropanol, or trifluoroethanol.

[0120] By adopting the above technical solution, the penetrant is used to reduce the surface tension of the sodium hydroxide hydrolysate, so that the sodium hydroxide hydrolysate can better penetrate into the small pores of the separation layer, thereby ensuring that the hydrolysate diffuses evenly in the small pore structure of the separation layer, and thus ensuring the degree of hydrolysis of the separation layer.

[0121] Optionally, the cellulose acetate is cellulose diacetate;

[0122] The good solvent is at least one selected from acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid;

[0123] The pore-forming agent is at least one of polyethylene glycol, polyvinylpyrrolidone, polyethyleneimine, and polyvinyl alcohol.

[0124] Optionally, the pore-forming agent is polyethylene glycol with a molecular weight of 20,000-150,000, and the water content of the polyethylene glycol is not higher than 0.5%.

[0125] By adopting the above technical solution, the molecular weight of the pore-forming agent is within a certain range, which is beneficial for adjusting the viscosity of the system, inhibiting the formation of macropores in the liquid membrane during phase separation, and effectively improving the stability of membrane flux; at the same time, it improves the membrane porosity and pore formation rate. The viscosity of the casting solution has a significant impact on the structure and performance of the final filter membrane, such as affecting the pore size, thickness, and flow rate of the filter membrane; this viscosity setting ensures that the final filter membrane has a suitable thickness and obtains an ideal pore size. Furthermore, by controlling the water content of the pore-forming agent, the uniformity of pore formation in the virus-removing membrane can be improved, ensuring that the pore size of the virus-removing membrane is within a suitable range, i.e., neither excessively small nor excessively large pores will appear. The virus-removing membrane has a suitable porosity, a suitable thickness, and a suitable pore size range, which can further improve the degree of hydrolysis of the subsequent virus-removing membrane, so that the degree of hydrolysis of the virus-removing membrane is within a suitable expected value, and the esterification coefficient Z1 of the first surface and the esterification coefficient Z2 of the second surface of the virus-removing membrane are within a more suitable expected value, thereby improving the pressure resistance of the virus-removing membrane and improving the protein yield of the virus-removing membrane.

[0126] In summary, this application includes at least one of the following beneficial technical effects:

[0127] 1. The virus-removing membrane of this application is prepared by hydrolysis, which is simple and avoids the environmental pollution caused by the copper ammonia method. In addition, the esterification coefficient of the first surface of the virus-removing membrane is 0.01-10.00, which significantly improves the pressure resistance of the virus-removing membrane (not less than 20 psi) while maintaining a high protein yield (not less than 98%).

[0128] 2. By limiting the uniformity of the esterification coefficient distribution on the first surface of the virus-removing membrane, when the first surface of the virus-removing membrane meets the uniformity index (Z... 1-max -Z1≤2.5、Z1-Z 1-min ≤2.5, Z 1-max -Z 1-min When the esterification coefficient Z1 of the first surface of the deviruation membrane is relatively low (≤4), the deviruation membrane can still achieve good pressure resistance and has a higher protein yield. Attached Figure Description

[0129] Figure 1 This is a typical cross-sectional SEM image of the virus-free membrane in this application. The image includes a three-layer structure (i.e., support layer + separation layer + protective layer), and the magnification of the image is 3k×.

[0130] Figure 2 This is a cross-sectional SEM image of the virus-removing membrane in Embodiment 1 of this application, and the magnification of the image is 5k×.

[0131] Figure 3 This is a SEM image of the first surface (inner surface) of the virus-removing membrane in Embodiment 1 of this application, and the magnification in the image is 5k×.

[0132] Figure 4 This is a SEM image of the second surface (outer surface) of the virus-free membrane in Embodiment 1 of this application, and the magnification of the image is 5k×.

[0133] Figure 5 This is a cross-sectional SEM image of the virus-removing membrane in Embodiment 7 of this application, and the magnification in the image is 4.5k×.

[0134] Figure 6 This is a cross-sectional SEM image of the virus-removing membrane near the first surface (inner surface) in Embodiment 7 of this application, and the magnification in the image is 20k×.

[0135] Figure 7 This is a cross-sectional SEM image of the virus-free membrane near the second surface (outer surface) in Embodiment 7 of this application, and the magnification in the image is 15k×.

[0136] Figure 8 This is a cross-sectional SEM image of the separation layer region of the virus-removing membrane in Embodiment 7 of this application, and the magnification of the image is 20k×.

[0137] Figure 9 This is a SEM image of the first surface (inner surface) of the virus-removing membrane in Embodiment 7 of this application, and the magnification of the image is 5k×.

[0138] Figure 10This is a SEM image of the second surface (outer surface) of the virus-free membrane in Embodiment 7 of this application, and the magnification in the image is 5k×.

[0139] Figure 11 This is the infrared absorption spectrum of the first surface of the virus-removing membrane in Embodiment 3 of this application.

[0140] Figure 12 This is the infrared absorption spectrum of the first surface of the virus-removing membrane in Embodiment 5 of this application.

[0141] Figure 13 This is the infrared absorption spectrum of the first surface of the virus-removing membrane in Comparative Example 1 of this application. Detailed Implementation

[0142] Example 1

[0143] This application discloses a process for preparing a cellulose virus-removing membrane, including the following process steps:

[0144] S1. Preparation of casting solution: The casting solution comprises the following raw materials in parts by weight: 25 parts cellulose diacetate, 45 parts good solvent, and 35 parts pore-forming agent. The good solvent is acetone, and the pore-forming agent is polyethylene glycol, which has a water content of 0.2% and a molecular weight of 80,000.

[0145] S2. Extrusion film formation: The casting solution is ejected from the annular spinneret, and at the same time, the pretreatment solution is ejected from the inner cavity to form a liquid hollow membrane. The inner surface of the hollow membrane is the first surface, and the outer surface of the hollow membrane is the second surface. The pretreatment solution is located in the inner cavity of the casting solution, which causes the first surface of the hollow membrane to pre-separate phases to obtain the formed membrane. The pretreatment solution is an acetone aqueous solution with a concentration of 85wt%.

[0146] S3, Phase Separation Curing, specifically includes:

[0147] S31. Reprocessing: The liquid hollow membrane first passes through the air section for 3 seconds. After passing through the air section, the hollow membrane enters the reprocessing solution for 5 seconds to obtain a reprocessed membrane. The reprocessing solution is an aqueous acetone solution with a concentration of 60 wt%.

[0148] S32. Curing: The retreated membrane, after pretreatment with the pretreatment solution for 8 seconds (3 seconds in the air section and 5 seconds in the retreatment section) and then further treated with the retreatment solution for 5 seconds, is placed in a coagulation bath until the retreated membrane is completely phase-separated and cured to obtain a green membrane. The coagulation bath is water.

[0149] S4. Post-treatment: The raw membrane is immersed in a sodium hydroxide hydrolysis bath at 5°C. During immersion, the sodium hydroxide hydrolysis bath penetrates from the second surface of the raw membrane towards the first surface. The raw membrane is then removed from the sodium hydroxide hydrolysis bath; the concentration of sodium hydroxide on the raw membrane is 0.59 g / g. Subsequently, the raw membrane immersed in the sodium hydroxide hydrolysis bath is heated to 40°C to hydrolyze the cellulose diacetate, yielding a cellulose virus-removing membrane. Glycerol at a mass percentage of 2.5% is added to the sodium hydroxide hydrolysis bath.

[0150] Examples 2-7

[0151] The main difference between Examples 2-7 and Example 1 is that the formulation of the casting solution and the various process parameters are different. In Example 4, the penetrant is ethanol; in Example 5, the penetrant is 1-propanol; in Example 7, the penetrant is isopropanol; the rest are detailed in Table 1.

[0152] Example 8

[0153] The main difference between Example 8 and Example 1 is that the S3 phase separation curing step does not include the S31 reprocessing step; other process parameters are detailed in Table 1.

[0154] Example 9

[0155] The main difference between Example 9 and Example 8 is that the formulation of the casting solution and the various process parameters are different, as detailed in Table 1.

[0156] Example 10

[0157] The main difference between Example 10 and Example 1 is that, in the step S2 extrusion film formation, the casting solution is extruded onto the carrier to form a liquid flat film, wherein the second surface of the liquid flat film is located on the carrier side and the first surface of the liquid flat film is located on the air side; then the liquid flat film is immersed in a pretreatment solution to pre-separate the first surface of the liquid flat film to obtain a formed film; the step S3 phase separation and curing does not include the step S31 reprocessing; other process parameters are detailed in Table 1.

[0158] Examples 11-12

[0159] The main difference between Examples 11-12 and Example 10 is that the formulation of the casting solution and the various process parameters are different, as detailed in Table 1.

[0160] Examples 13-15

[0161] The main difference between Examples 13-15 and Example 10 is that the formulation of the casting solution and the various process parameters are different, as detailed in Table 1.

[0162] Comparative Example 1

[0163] The main difference between Comparative Example 1 and Example 1 is that in step S4, the biofilm is placed in a sodium hydroxide hydrolysis bath at 40°C with a concentration of 0.5 mol / L, and soaked for 4 hours to hydrolyze the biofilm, yielding a cellulose virus-removing membrane. At this point, the infrared absorption spectrum of the first surface of this cellulose virus-removing membrane shows a value at 1740 cm⁻¹. -1 The peaks in the vicinity completely disappeared, indicating that the virus membrane was completely hydrolyzed; other process parameters are detailed in Table 1.

[0164] Comparative Example 2

[0165] The main difference between Comparative Example 1 and Example 1 is that it does not include step S4, that is, the biofilm is not hydrolyzed; other process parameters are detailed in Table 1.

[0166] Table 1: Casting solution formulations and process parameters for each embodiment and comparative example

[0167]

[0168] Notes: In Table 1, the contents of cellulose diacetate, acetone, and polyethylene glycol are all in parts by weight; the unit of water content of polyethylene glycol is %; the concentration of acetone aqueous solution in pretreatment and retreatment is wt%; the unit of pretreatment time and retreatment time is s; the unit of impregnation temperature and hydrolysis temperature in posttreatment is °C; the unit of sodium hydroxide concentration on the film is g / g.

[0169] Performance testing and data

[0170] The detection methods are as follows:

[0171] Esterification coefficient: Using the virus-removing membranes prepared in each example and comparative example as samples, taking the virus-removing membrane (flat sheet membrane) of Example 10 as an example, the virus-removing membrane was unfolded and a 25cm section was taken. 2 A 5cm x 5cm virus-removing membrane, the exact size depending on the actual situation, is used. Take 1cm from each of the upper left, lower left, upper right, lower right, and center areas of the virus-removing membrane. 2 A sample measuring 1 cm x 1 cm (the specific area depends on the actual situation) was used. The infrared absorption spectra of five samples were measured using an FTIR Fourier transform infrared spectrometer with infrared attenuated total reflectance. Taking the first surface of the sample in the middle region of the virus-free membrane as an example, the esterification coefficient of the first surface of this sample was 1740 cm⁻¹ in the infrared absorption spectrum. -1 The peak area near the carbonyl peak is 1428 cm⁻¹ -1The ratio between the peak areas (vibrational peaks of the cellulose skeleton) in the vicinity. The esterification coefficient Z1 of the first surface of the virus-free membrane is the average of the esterification coefficients of the first surface of the sample in the upper left, lower left, upper right, lower right, and middle regions of the first surface of the virus-free membrane. Z 1-max Z represents the maximum esterification coefficient of the first surface of the sample in the upper left, lower left, upper right, lower right, and middle regions of the first surface of the virus membrane; 1-min Z2 is the minimum esterification coefficient of the first surface of the sample in the upper left, lower left, upper right, lower right, and middle regions of the first surface of the virus-free membrane. Z2 is the average esterification coefficient of the second surface of the sample in the upper left, lower left, upper right, lower right, and middle regions of the second surface of the virus-free membrane.

[0172] PMI average pore size test: The virus-removing membranes prepared in each example and comparative example were used as samples, and the average PMI pore size of each sample was tested using a CFP-1J00AEX PMI pore size tester.

[0173] Pressure resistance test: The virus-removing membranes prepared in each example or comparative example were used as samples for pressure resistance testing. The testing method followed the guidance document TR41 issued by PDA. During the test, PP7 bacteriophage was used to retain the virus, the feed stream was immunoglobulin IVIG, and the buffer system was PBS. During the virus challenge test, the pressure of the feed solution was adjusted, and the critical pressure at which the virus-removing membrane showed obvious structural collapse (significant change in flux) was measured. This critical pressure is the pressure resistance of the virus-removing membrane. For example, if the pressure resistance of the virus-removing membrane is 30 psi, it means that when the virus-removing membrane uses dead-end filtration for virus filtration, if the pressure of the feed solution is below 30 psi, the virus-removing membrane is working normally and there is no obvious structural collapse or abnormal virus retention capacity.

[0174] Protein yield test and LRV: The virus-removing membranes prepared in each example or comparative example were used as samples for virus challenge testing. The detection method referred to the guidance document TR41 issued by PDA. During the test, PP7 phage was used as the intercepted virus, the material flow was immunoglobulin IVIG, and the buffer system was PBS. The pressure of the material solution was adjusted adaptively. If the critical point pressure of the virus-removing membrane was less than 30 psi or higher than 35 psi, the material solution was pressurized to the critical point pressure of the virus-removing membrane during the virus challenge test; if the critical point pressure of the virus-removing membrane was between 30 psi and 35 psi, the material solution was pressurized to 30 psi during the virus challenge test. The LRV was calculated by detecting the titer of PP7 phage in the challenge solution and filtrate. The protein yield was calculated by detecting the protein concentration in the challenge solution and filtrate.

[0175] The esterification coefficient, pressure resistance, protein yield, and other parameters of the virus-removing membranes prepared in each embodiment and comparative example are detailed in Table 2.

[0176] Table 2: Esterification coefficient, compressive strength, protein yield, and LRV of the virus-removing membranes prepared in each example and comparative example.

[0177]

[0178] Note: In Table 2, Z1 is the esterification coefficient of the first surface of the virus membrane; Z 1-max Z represents the maximum value of the esterification coefficient of the first surface. 1-min This is the minimum value of the esterification coefficient of the first surface;

[0179] If the esterification coefficient of the first surface of the viral membrane satisfies: Z 1-max -Z1≤2.5、Z1-Z 1-min ≤2.5, Z 1-max -Z 1-min If the value is ≤4, then the virus removal membrane meets the uniformity index; otherwise, it does not meet the uniformity index.

[0180] Z2 is the esterification coefficient of the second surface excluding the viral membrane;

[0181] The unit of pressure resistance of the virus removal membrane is psi. The pressure resistance of the virus removal membrane in Example 1 is 33 psi. This means that when the virus removal membrane in Example 1 is used for virus removal filtration and dead-end filtration is adopted, the virus removal membrane works normally when the feed liquid is pressurized to 33 psi, and there are no obvious structural collapses or abnormal virus retention capacity.

[0182] Protein yield of the virus-free membrane is expressed in %; average pore size of the virus-free membrane PMI is expressed in nm.

[0183] The morphological parameters of the virus-removing membranes prepared in each embodiment and comparative example are detailed in Table 3.

[0184] Table 3: Morphological parameters of the virus-removing membranes prepared in each example and comparative example

[0185]

[0186]

[0187] Note: In Table 3, Examples 1-7 are hollow fiber membranes with a three-layer structure (support layer + separation layer + protective layer); Examples 8-9 are hollow fiber membranes with a two-layer structure (support layer + separation layer); Examples 10-11 are flat sheet membranes with a three-layer structure; and Example 12 is a flat sheet membrane with a two-layer structure.

[0188] In the first surface, the average diameter is the average diameter measured by SEM of the first surface of the virus-free membrane, in nm; the average pore size is the average pore size measured by SEM of the first surface of the virus-free membrane, in nm; and the pore area ratio is the pore area ratio of the first surface of the virus-free membrane, in %.

[0189] In the support layer, the thickness of the support layer is in μm, the average diameter is the average diameter of the support fibers measured by SEM, and the average pore size is the average pore size measured by SEM, and the porosity of the support layer is in %.

[0190] The ratio is the ratio between the thickness of the support layer of the virus-removing membrane and the esterification coefficient Z1 of the first surface of the virus-removing membrane, in μm;

[0191] In the separation layer, the thickness of the separation layer is in μm, and the average pore size is the average pore size measured by SEM of the separation layer, in nm.

[0192] In the protective layer, the thickness is in μm, the average pore size is the average pore size measured by SEM and is in nm; the porosity of the protective layer is in %.

[0193] For the virus removal membrane as a whole, the thickness of the virus removal membrane is measured in μm.

[0194] in conclusion:

[0195] By comparing the technical solutions and performance parameters of Example 2 and Comparative Example 1, it is easy to see that even though the esterification coefficient of the first surface is low (the esterification coefficient Z1 of the first surface is 0.48), compared with the membrane with an esterification coefficient of 0 on the first surface (the completely hydrolyzed virus-removing membrane), the pressure resistance of the virus-removing membrane is significantly improved (pressure resistance increases from 15 psi to 23 psi). Contrary to the common belief that incomplete hydrolysis of the virus-removing membrane will lead to a decrease in protein yield, the overall protein yield of the virus-removing membrane remains high despite incomplete hydrolysis of the first surface. This may be because the first surface of the virus-removing membrane still contains a small amount of cellulose acetate fibers with better molecular chain rigidity. The small amount of uniformly dispersed cellulose acetate fibers with better pressure resistance form a significant reinforcing effect on the virus-removing membrane, resulting in a significant improvement in the pressure resistance of the virus-removing membrane. Furthermore, since the first surface and support layer of the deviruviral membrane have large pore structures, their size is orders of magnitude different from that of proteins. Therefore, both the adsorption effect of the pore walls and the retention effect of the pore structure on proteins are low, resulting in a relatively high overall protein yield of the deviruviral membrane.

[0196] By comparing the technical solutions and performance parameters of Examples 1-2 and Examples 4-6, it is easy to see that as the esterification coefficient Z1 of the first surface of the virus-removing membrane gradually increases, the pressure resistance of the virus-removing membrane gradually increases, from 23 psi to over 33 psi, and the protein yield of the virus-removing membrane is not less than 99%. The virus-removing membrane possesses both high pressure resistance and high protein yield. Furthermore, in practical applications, a virus-removing membrane with suitable pressure resistance can be selected according to requirements.

[0197] By comparing the technical solutions and performance parameters of Example 3 and Comparative Example 2, it is easy to see that although the esterification coefficient Z1 of the first surface of the virus-removing membranes of Example 3 and Comparative Example 2 is similar, the protein yield of the virus-removing membrane of Example 3 is much higher than that of the virus-removing membrane of Comparative Example 2. This may be because the degree of hydrolysis of the separation layer is relatively high. Although the esterification coefficient Z1 of the first surface of the virus-removing membranes of Example 3 and Comparative Example 2 is similar, the degree of hydrolysis of the separation layer of the virus-removing membrane of Example 3 is higher than that of the separation layer of the virus-removing membrane of Comparative Example 2. Therefore, the protein yield of the virus-removing membrane of Example 3 is much higher than that of the virus-removing membrane of Comparative Example 2.

[0198] By comparing Examples 1 and 4, and Examples 10 and 11, it is easy to see that even though the esterification coefficient Z1 of the first surface of the virus-removing membrane is relatively low, the distribution of the esterification coefficient of the first surface of the virus-removing membrane meets the uniformity index (Z). 1-max -Z1≤2.5、Z1-Z 1-min ≤2.5, Z 1-max -Z 1-min When the esterification coefficient is ≤4), the virus-removing membrane can achieve relatively good pressure resistance with a relatively low esterification coefficient. For example, the esterification coefficient Z1 of the first surface of the virus-removing membrane in Example 1 is 6.42, and the esterification coefficient Z1 of the first surface of the virus-removing membrane in Example 4 is 7.31. Although the esterification coefficient Z1 of the first surface of the virus-removing membrane in Example 4 is higher than that of the virus-removing membrane in Example 1, the pressure resistance of Examples 1 and 3 is similar. However, since the degree of hydrolysis of the virus-removing membrane in Example 1 is relatively high, that is, the protein yield of the virus-removing membrane in Example 1 is higher.

[0199] Furthermore, for virus-removing membranes such as those in Examples 13-14, which have a relatively low initial LRV but are higher than 2.5, two layers of virus-removing membranes can be stacked and used in series to achieve an LRV > 5, making them suitable for materials with higher filtration requirements. That is, the virus-removing membranes in this application are not limited to single-layer use. In actual use, a single-layer virus-removing membrane can be selected for use, or two or more layers of virus-removing membranes can be stacked to achieve the desired virus filtration effect, depending on actual needs.

[0200] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A cellulose virus-removing membrane comprising a porous body having non-directional tortuous pathways within the porous body, one side surface of the porous body being a first surface, and the other side surface of the porous body being a second surface, characterized in that: The porous body includes a support layer and a separation layer for trapping viruses, wherein the support layer and the separation layer are transitioned by continuous fibers, and one side surface of the support layer is the first surface; The average aperture measured by SEM on the first surface is greater than the average aperture measured by SEM on the second surface. The protein yield after removing the virus membrane is not less than 98%; The pressure resistance of the virus-removing membrane is not less than 20 psi; The average pore size of the porous matrix is ​​15-45 nm. The esterification coefficient Z1 of the first surface is 0.01-10.00; The esterification coefficient Z is calculated using the following formula: Esterification coefficient Z = X 1740 / X 1428 ; X 1740 For the FTIR Fourier transform infrared spectrometer, the infrared absorption spectrum of the virus membrane was determined by infrared attenuated total reflection, and the peak area near 1740 cm -1 in the infrared spectrum. X 1428 For the FTIR Fourier transform infrared spectrometer, the infrared absorption spectrum of the virus membrane was determined by infrared attenuated total reflection, and the peak area near 1428 cm -1 in the infrared spectrum. The esterification coefficient Z2 of the second surface is lower than the esterification coefficient Z1 of the first surface. In the thickness direction of the virus-free membrane, the esterification coefficient Z1 of the first surface gradually decreases to the esterification coefficient Z2 of the second surface.

2. The cellulose virus-removing membrane according to claim 1, characterized in that: The virus-removing membrane has a pressure resistance of not less than 25 psi, and the esterification coefficient Z1 of the first surface is 1.00-8.

00.

3. The cellulose virus-removing membrane according to claim 1, characterized in that: The maximum value of the esterification coefficient Z on the first surface 1-max The difference between Z1 and Z1 is no greater than 2.5, and the minimum esterification coefficient Z of the first surface is... 1-min The absolute value of the difference between Z1 and Z2 is not greater than 2.5, and the maximum value of the esterification coefficient Z2 of the first surface is... 1-max The minimum esterification coefficient Z of the first surface 1-min The difference is no higher than 4.

4. The cellulose virus-removing membrane according to claim 1, characterized in that: The first surface includes a plurality of long strip-shaped and interlaced first fibers, the interlacing parts of each first fiber form nodes, and adjacent and interlaced first fibers surround each other to form pores. The average diameter of the first fiber measured by SEM is 50~180nm, the average pore size of the first surface measured by SEM is 300~4500nm, and the pore area ratio of the first surface is 10~50%.

5. The cellulose virus-removing membrane according to claim 2, characterized in that: The thickness of the support layer is 5-30 μm, and the ratio of the thickness of the support layer to the esterification coefficient Z1 of the first surface is 2-8 μm.

6. The cellulose virus-removing membrane according to claim 1, characterized in that: The support layer comprises several long strips of interlaced support fibers, with adjacent and interlaced support fibers surrounding each other to form pores. The average diameter of the support fibers measured by SEM is 60~170nm.

7. The cellulose virus-removing membrane according to claim 6, characterized in that: The average pore size of the support layer measured by SEM is 200~700nm, the porosity of the support layer is 40~75%, and the ratio between the average diameter of the support fiber measured by SEM and the average pore size of the support layer measured by SEM is 0.1-0.

3.

8. The cellulose virus-removing membrane according to claim 1, characterized in that: The average pore size of the separation layer is 20~80nm, the thickness of the separation layer is 5~45μm, and the ratio of the thickness of the separation layer to the thickness of the porous body is 20~60%.

9. The cellulose virus-removing membrane according to claim 1, characterized in that: The surface of the separation layer away from the support layer is the second surface, and the esterification coefficient Z2 of the second surface is 0-6.

00. The esterification coefficient Z2 of the second surface is lower than the esterification coefficient Z1 of the first surface.

10. The cellulose virus-removing membrane according to claim 1, characterized in that: The virus-removing membrane has a thickness of 20-90 μm, a porosity of 10-60%, and a flux greater than 60 L·h. -1 m -2 @30psi.

11. The cellulose virus-removing membrane according to claim 1, characterized in that: The porous body further includes a protective layer located on the side of the separation layer away from the support layer. The surface of the protective layer is the second surface. The thickness of the protective layer is 2~20μm, and the ratio of the thickness of the protective layer to the thickness of the porous body is 5%-30%.

12. The cellulose virus-removing membrane according to claim 11, characterized in that: The average pore size of the protective layer, as measured by SEM, is 100-300 nm, and the porosity of the protective layer is 35-65%.

13. The cellulose virus-removing membrane according to claim 11, characterized in that: The esterification coefficient Z2 of the second surface is 0-7.00, and the esterification coefficient Z2 of the second surface is lower than the esterification coefficient Z1 of the first surface.

14. The preparation process of a cellulose virus-removing membrane according to any one of claims 1-10, characterized in that: The process includes the following steps: S1. Preparation of casting solution, wherein the casting solution comprises the following raw materials in parts by weight: 15-40 parts of cellulose acetate, 30-80 parts of good solvent, and 20-50 parts of pore-forming agent; S2. Extrusion film formation: The casting liquid is extruded from the die head; S3. Phase separation curing: The formed film is placed in a coagulation bath at 60-80℃ for phase separation curing to obtain a green film. The coagulation bath is at least one of water or ethanol. S4. Post-treatment: The raw membrane is immersed in a sodium hydroxide hydrolysis bath. During immersion, the second surface of the raw membrane is in contact with the sodium hydroxide hydrolysis bath. After immersion, the raw membrane is removed. The concentration of sodium hydroxide on the raw membrane is 0.15-0.80 g / g. The temperature of the hydrolysis bath during immersion is below 10℃. Subsequently, the raw membrane immersed in the hydrolysis bath is heated to 25-50℃ to hydrolyze and regenerate cellulose acetate into cellulose, thus obtaining the cellulose virus-removing membrane.

15. The preparation process of a cellulose virus-removing membrane according to any one of claims 11-13, characterized in that: The process includes the following steps: S1. Preparation of casting solution, wherein the casting solution comprises the following raw materials in parts by weight: 15-40 parts of cellulose acetate, 30-80 parts of good solvent, and 20-50 parts of pore-forming agent; S2. Extrusion film formation: The casting liquid is extruded from the die head; S3. Phase separation curing: The formed film is placed in a coagulation bath at 60-80℃ for phase separation curing to obtain a green film. The coagulation bath is at least one of water or ethanol. S4. Post-treatment: The raw membrane is immersed in a sodium hydroxide hydrolysis bath. During immersion, the second surface of the raw membrane is in contact with the sodium hydroxide hydrolysis bath. After immersion, the raw membrane is removed. The concentration of sodium hydroxide on the raw membrane is 0.15-0.80 g / g. The temperature of the hydrolysis bath during immersion is below 10℃. Subsequently, the raw membrane immersed in the hydrolysis bath is heated to 25-50℃ to hydrolyze and regenerate cellulose acetate into cellulose, thus obtaining the cellulose virus-removing membrane. The virus-removing membrane is a flat sheet membrane; step S2 includes: extruding the casting solution onto a carrier to form a liquid flat sheet membrane, wherein the second surface of the liquid flat sheet membrane is located on the carrier side and the first surface of the liquid flat sheet membrane is located on the air side; then immersing the liquid flat sheet membrane in a pretreatment solution to pre-separate the first surface of the liquid flat sheet membrane to obtain a molded membrane, wherein the pretreatment solution is an acetone aqueous solution with a concentration of 75~90wt%, and the pre-separation time is 2~15s.

16. The preparation process of a cellulose virus-removing membrane according to claim 14, characterized in that: The virus-removing membrane is a hollow fiber membrane; step S2 includes: simultaneously ejecting casting solution and pretreatment solution from an annular spinneret to form a liquid hollow membrane, wherein the inner surface of the hollow membrane is the first surface, the outer surface of the hollow membrane is the second surface, and the pretreatment solution is located in the inner cavity of the casting solution, so that the first surface of the hollow membrane is pre-phase separated to obtain a shaped membrane, wherein the pretreatment solution is an acetone aqueous solution with a concentration of 75~90wt%, and the pre-phase separation time is 2~15s.

17. The preparation process of a cellulose virus-removing membrane according to any one of claims 11-13, characterized in that: The process includes the following steps: S1. Preparation of casting solution, wherein the casting solution comprises the following raw materials in parts by weight: 15-40 parts of cellulose acetate, 30-80 parts of good solvent, and 20-50 parts of pore-forming agent; S2. Extrusion film formation: The casting liquid is extruded from the die head; S3. Phase separation curing: The formed film is placed in a coagulation bath at 60-80℃ for phase separation curing to obtain a green film. The coagulation bath is at least one of water or ethanol. S4. Post-treatment: The raw membrane is immersed in a sodium hydroxide hydrolysis bath. During immersion, the second surface of the raw membrane is in contact with the sodium hydroxide hydrolysis bath. After immersion, the raw membrane is removed. The concentration of sodium hydroxide on the raw membrane is 0.15-0.80 g / g. The temperature of the hydrolysis bath during immersion is below 10℃. Subsequently, the raw membrane immersed in the hydrolysis bath is heated to 25-50℃ to hydrolyze and regenerate cellulose acetate into cellulose, thus obtaining the cellulose virus-removing membrane. The virus-removing membrane is a hollow fiber membrane; step S2 includes: simultaneously ejecting casting solution and pretreatment solution from an annular spinneret to form a liquid hollow membrane, wherein the inner surface of the hollow membrane is the first surface, the outer surface of the hollow membrane is the second surface, and the pretreatment solution is located in the inner cavity of the casting solution, so that the first surface of the hollow membrane is pre-phase separated to obtain a shaped membrane, wherein the pretreatment solution is an acetone aqueous solution with a concentration of 75~90wt%, and the pre-phase separation time is 2~15s; Step S3 specifically includes the following process steps: S31. Reprocessing: The second surface of the formed film is placed in a reprocessing solution for reprocessing. The reprocessing solution is an acetone aqueous solution with a concentration of 45-70 wt%, and the processing time is 0.5-10 s to obtain a reprocessed film. S32. Curing: Place the reprocessed membrane in a coagulation bath until the reprocessed membrane is completely phase-separated and cured to obtain the raw membrane.

18. The preparation process of a cellulose virus-removing membrane according to claim 14, characterized in that: In step S4, the sodium hydroxide hydrolysis bath further includes a penetrant with a concentration of 1.5-3.5 wt%, and the penetrant is at least one of ethanol, 1-propanol, isopropanol, glycerol, hexafluoroisopropanol, or trifluoroethanol.

19. The preparation process of a cellulose virus-removing membrane according to claim 14, characterized in that: The cellulose acetate is cellulose diacetate; The good solvent is at least one selected from acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid; The pore-forming agent is at least one of polyethylene glycol, polyvinylpyrrolidone, polyethyleneimine, and polyvinyl alcohol.

20. The preparation process of a cellulose virus-removing membrane according to claim 19, characterized in that: The pore-forming agent is polyethylene glycol with a molecular weight of 20,000-150,000, and the water content of the polyethylene glycol is not higher than 0.5%.

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