WO2024087772A1 - 一种除病毒复合膜及其制备工艺 - Google Patents

一种除病毒复合膜及其制备工艺 Download PDF

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WO2024087772A1
WO2024087772A1 PCT/CN2023/110371 CN2023110371W WO2024087772A1 WO 2024087772 A1 WO2024087772 A1 WO 2024087772A1 CN 2023110371 W CN2023110371 W CN 2023110371W WO 2024087772 A1 WO2024087772 A1 WO 2024087772A1
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virus
composite membrane
porous substrate
layer
pore size
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PCT/CN2023/110371
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French (fr)
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贾建东
卢红星
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杭州科百特过滤器材有限公司
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  • the invention relates to the technical field of virus removal filtration, in particular to a virus removal composite membrane and a preparation process thereof.
  • Membrane technology is a new technology for efficient separation in the contemporary era. Compared with traditional distillation and rectification technologies, it has the advantages of high separation efficiency, low energy consumption, and small footprint.
  • the core of membrane separation technology is the separation membrane.
  • polymer filter membrane is a type of separation membrane made of organic high molecular polymers as raw materials and according to a certain process; with the development of the petroleum industry and science and technology, the application field of polymer filter membranes has been continuously expanded. At present, the fields of application include gas separation, seawater desalination, ultrapure water preparation, waste treatment, artificial organ manufacturing, medicine, food, agriculture, chemical industry and other aspects.
  • polymer filter membranes can be subdivided into cellulose polymer filter membranes, polyamide polymer filter membranes, sulfone polymer filter membranes, polytetrafluoroethylene polymer filter membranes, etc.; in addition, they can also be divided into microfiltration membranes, ultrafiltration membranes, nanofiltration membranes and reverse osmosis membranes according to the pore size of the membrane.
  • biopharmaceutical companies mainly use the fine pores of the ultrafiltration membrane cortex to filter and intercept viruses to ensure that the viruses in the biopharmaceuticals are cleared and improve the safety of the biopharmaceuticals.
  • common virus removal filter membranes include single-layer structures and double-layer structures.
  • the single-layer virus removal filter membrane typically has an asymmetric polyethersulfone filter membrane.
  • the surface of the polyethersulfone filter membrane has an ultrafiltration cortex structure that can intercept viruses;
  • the part below the ultrafiltration cortex can play a pre-filtration effect on the filtered fluid.
  • One layer of the double-layer virus removal filter membrane is a separation membrane layer with an ultrafiltration cortex, and the other layer is a support layer with a microporous structure. The support layer can improve the integrity of the separation layer on the virus removal filter membrane.
  • a Chinese patent with authorization announcement number CN1759924B applied by EMD Millipore Corporation discloses a multilayer composite ultrafiltration membrane (Figure 17), which includes at least one first porous membrane layer having a first face and an equivalent second face, and at least one second porous membrane layer having an equivalent first face and a second face, wherein the first layer and the second layer are connected and overlapped and have a porosity connection transition region from the equivalent first face of the second layer to the equivalent second face of the first layer, wherein at least one of the layers is an asymmetric ultrafiltration membrane; the composite membrane structure thus formed has a strong retention effect on parvoviruses, and at the same time can obtain a higher protein yield, meeting the needs of practical applications.
  • the microporous layer and ultrafiltration layer of the composite ultrafiltration membrane in the application are obtained by simultaneously co-casting two different LCST (lower critical solution temperature) or UCST (upper critical solution temperature) solutions, and controlling the temperature of the two layers of liquid to be between the two LCST or between the two UCST before the phase transformation process of the non-solvent, and then performing the non-solvent phase transformation process to obtain a composite ultrafiltration membrane containing a transition region.
  • the transition region in the composite ultrafiltration membrane has continuous holes, which can avoid the appearance of dense regions in the method of casting the ultrafiltration layer on the prefabricated microporous membrane, so that the composite ultrafiltration membrane blocks viral impurities in a diffusion manner, and the membrane flux is improved to a certain extent.
  • the transition zone of the composite ultrafiltration membrane requires strict control of the thickness of the first layer and the second layer, the relative viscosity of the solution, and the relative time of the formation layers, in order to achieve an ideal transition zone with better performance. Therefore, the preparation of a double-layer virus removal filtration membrane in this way is more complicated, the process is more cumbersome, and it is more difficult to adapt to various scenarios with different needs.
  • the double-layer PVDF membrane produced by Millipore Corporation of Billerica, Massachusetts, Viresolve @ membrane is made by casting an ultrafiltration layer on a prefabricated microporous membrane. It is used for virus removal filtration of biological products.
  • this type of double-layer or multi-layer membrane material obtained by casting an ultrafiltration layer on a prefabricated microporous membrane has an obvious dense layer structure at the interface of the two layers due to the undesired accumulation of solutes retained at the interface of the two layers before the cast ultrafiltration layer is formed. This dense structure will greatly reduce the membrane flux of the filtration flow and shorten the life of the membrane.
  • the purpose of the present invention is to provide a virus removal composite membrane and its preparation process.
  • a bonding area in the porous base layer that plays a supporting role in the virus removal composite membrane By forming a bonding area in the porous base layer that plays a supporting role in the virus removal composite membrane, the dense layer structure formed when the casting ultrafiltration layer is formed is eliminated, and the flux of the virus removal composite membrane is greatly improved while maintaining the various performances of the virus removal composite membrane without a significant degree of attenuation.
  • the present application provides a virus removal composite membrane, which adopts the following technical solution:
  • a virus removal composite membrane comprises a main body, one side outer surface of the main body is a liquid inlet surface, and the other side outer surface is a liquid outlet surface, and the main body comprises:
  • the porous substrate layer is a microporous membrane layer formed of a first polymer, the separation layer is formed of a second polymer, and the first polymer and the second polymer are different polymer materials;
  • the second polymer infiltrates from the surface of the porous substrate layer into the pore structure of the porous substrate layer to form a bonding region, and the holes formed by the second polymer in the bonding region are connected to the holes of the separation layer;
  • the PMI average pore size of the virus removal composite membrane is controlled to be 15-25 nm; the average pore size of the binding area measured by SEM is not less than 50 nm.
  • the average pore size of the filter membrane was tested by a PMI pore size tester, and the average PMI pore size of the filter membrane of the present invention was 15-25nm.
  • the tortuous path of the main structure and the certain thickness of the membrane ensured the removal of
  • the virus composite membrane has a good retention effect on small viral impurities (such as parvo virus of about 20nm), which can meet the actual virus removal application needs.
  • the virus removal composite membrane of the present application is prepared by casting a casting liquid used to form a separation layer onto a prefabricated porous substrate layer.
  • the prefabricated porous substrate layer can pre-filter the fluid so that impurities with larger particle sizes in the fluid can be retained in the porous substrate layer, and are not easy to enter the separation layer and cause the separation layer to be blocked prematurely, which can increase the load capacity of the virus removal filter membrane; the porous substrate layer can also play a supporting role, so that the integrity of the cast separation layer membrane is improved, and the strength of the virus removal composite membrane is also improved.
  • the thickness of the porous substrate layer can be adjusted according to actual needs, which makes the virus removal composite membrane more flexibly applicable to various separation scenarios.
  • the separation layer and porous substrate layer of the virus removal composite membrane in the present application are made of two different materials, and the material part for forming the separation layer is partially infiltrated into the porous substrate layer to form a binding area.
  • the porous substrate layer is prefabricated by the first polymer, and the separation membrane layer is cast by the second polymer.
  • Different materials can avoid the second polymer from being mutually dissolved or too much adhesion between the first polymer and the second polymer after penetrating into the porous substrate layer, ensuring that the second fiber formed by the second polymer in the binding area and the first fiber formed by the first polymer are basically discontinuous, thereby avoiding the local occurrence of crusting or agglomeration areas and causing the membrane flux of the virus removal composite membrane to be greatly reduced.
  • the porous substrate layer if it is mutually dissolved to a certain extent with the casting solution, will cause the interface between the porous substrate layer and the separation layer to become more uneven, and the separation layer will be transformed into the integrity of the membrane.
  • the second polymer in the bonding area is formed by infiltration along the interconnected pore structure of the porous substrate layer. Therefore, the bonding area achieves a good transition between the pore structure of the porous substrate layer and the pore structure of the separation layer, so that the second polymer does not accumulate undesirably on the surface of the porous substrate layer and the separation layer or in the porous substrate layer, thereby promoting the connectivity between the porous substrate layer and the separation layer, improving the membrane flux of the virus removal composite membrane, and also improving the bonding strength between the porous substrate layer and the separation layer.
  • the SEM average pore size of the holes in the binding area of the virus-removing composite membrane of the present application can be measured by using a scanning electron microscope to characterize the morphology of the membrane cross-sectional structure, and then using computer software (such as Matlab, NIS-Elements, etc.) or manually to measure and perform corresponding calculations; of course, technical personnel in this field can also obtain the above parameters through other measurement methods, and the above measurement methods are for reference only.
  • the average pore size of the SEM measurement of the bonding area should be no less than 50nm to ensure that the composite membrane can achieve a relatively large membrane flux and obtain a good pre-filtration effect and good bonding strength. If the average SEM pore size of the bonding area is less than 50nm, the possibility of forming a dense structure in the bonding area is greatly increased. Once a dense area is formed, the flux will be sharply reduced. Therefore, it is necessary to meet the requirement that the average SEM pore size of the bonding area is no less than 50nm after the composite membrane is formed.
  • the average pore size in the bonding area measured by SEM is 50-500 nm, and the thickness of the bonding area is not less than 10 ⁇ m.
  • the thickness of the bonding area can be calculated by characterizing the morphology of the membrane structure using a scanning electron microscope, and then measuring it using computer software (such as Matlab, NIS-Elements, etc.) or manually; of course, those skilled in the art can also obtain the above parameters by other measurement methods, and the above measurement methods are for reference only.
  • the binding area of the virus removal composite membrane in the present application is not less than 10 ⁇ m, the binding area can significantly improve the binding strength between the porous substrate layer and the separation layer.
  • the thickness of the binding area is less than 10 ⁇ m, the binding strength between the separation layer and the porous substrate layer will be significantly weakened, making it easy for the two membrane layers to separate in subsequent applications of the virus removal composite membrane.
  • the membrane flux and pre-filtration effect of the virus removal composite membrane can reach a high level. If the average pore size of the binding zone measured by SEM is less than 50nm, on the one hand, a dense area may appear in the binding zone, resulting in a significant reduction in the flux of the binding zone; On the other hand, if the pore size of the binding zone is too small, the adsorption of proteins in the fluid will increase, resulting in a decrease in the fluid protein yield. If the average pore size of the binding zone measured by SEM is too large, the bonding strength between the separation layer and the porous substrate layer will also be significantly reduced.
  • a large pore size indicates that the interaction between the second fiber formed by the second polymer infiltration in the binding zone and the first fiber is weak, and the bonding strength between the separation layer and the porous substrate layer is deteriorated.
  • the thickness of the bonding area accounts for 30-70% of the thickness of the porous substrate layer, and the thickness of the bonding area is 15-30 ⁇ m.
  • the thickness of the bonding area in the porous substrate layer cannot be too large or too small. Because if the proportion of the bonding area is too small, on the one hand, the bonding strength between the separation layer and the porous substrate layer will become low, which is easy to cause peeling or damage in subsequent applications such as folding; on the other hand, the transition effect of the bonding area will become less obvious, and the phenomenon of undesirable accumulation of solutes cannot be alleviated, resulting in a significant reduction in the membrane flux of the virus removal composite membrane.
  • the proportion of the binding area is too large, the average pore size of the binding area is smaller than the original average pore size of the porous substrate layer, which can easily cause unavoidable membrane flux loss.
  • the area of the porous substrate layer used for pre-filtration is also reduced accordingly, and the performance of the membrane such as the loading capacity will also be greatly affected.
  • the thickness ratio of the bonding area to the porous substrate layer is controlled to be 30-70%, the thickness of the bonding area is 15-30 ⁇ m, which can ensure that the bonding area plays a good transition role between the separation layer and the porous substrate layer, thereby further improving the flux and mechanical strength of the composite membrane.
  • the ratio of the thickness of the bonding area to the thickness of the separation layer is 1:(0.5-2).
  • the thickness ratio of the bonding zone to the separation layer should not be too large or too small, because the separation layer is usually prepared by a casting liquid phase conversion method. Once the thickness ratio of the bonding zone to the separation layer is too small or too large, it is difficult to obtain a porosity-compared pore structure formed by the casting liquid phase separation in the bonding zone. For higher or better permeable pore structures, blockage may even occur, resulting in a significant decrease in membrane flux. Secondly, the thickness of the bonding area is too small relative to the thickness of the separation layer, which is equivalent to a thicker separation layer and a thinner bonding area. The bonding capacity of the bonding area is difficult to meet the requirement that the thicker separation layer can be well bonded to the porous substrate layer.
  • the standard deviation ⁇ of the thickness of the bonding area in the length direction and the width direction is no more than 3 ⁇ m.
  • the thickness standard deviation of the bonding area can be obtained by selecting a certain number of positions equidistantly along the length direction of the bonding area cross section in the cross-sectional electron microscope image in the length direction or width direction, and measuring the thickness at these positions using computer software (such as Matlab, NIS-Elements, etc.) or manually, and calculating the standard deviation.
  • computer software such as Matlab, NIS-Elements, etc.
  • those skilled in the art can also obtain the above parameters by other measurement methods, and the above measurement methods are for reference only.
  • the boundary between the bonding area and the porous substrate layer is relatively clear, the transition effect between the pore structure of the bonding area and the pore structure of the porous substrate layer is better, the resistance encountered by the fluid at different positions in the membrane during filtration is more uniform, the filtration process is more stable, and the attenuation of the membrane flux is lower.
  • the standard deviation of the thickness of the bonding area is too large, it means that the distribution of the bonding area on the side close to the porous base layer is not uniform.
  • the pressure at each location and the pressure resistance of each location are also quite different. This may cause the virus removal ability of some locations on the separation membrane to be affected, the virus retention effect to deteriorate, and the membrane flux may also decrease.
  • the bonding area includes first fibers formed by a first polymer and second fibers formed by a second polymer; the SEM average diameter of the first fibers in the bonding area is 0.1 ⁇ m to 2 ⁇ m, and the SEM average diameter of the second fibers in the bonding area is 0.05 ⁇ m to 1 ⁇ m.
  • the SEM average diameters of the first fibers and the second fibers in the bonding region can be determined by using a scanning electron microscope. After the microscope characterizes the morphology of the membrane cross-sectional structure, it is measured using computer software (such as Matlab, NIS-Elements, etc.) or manually, and the corresponding calculations are performed; of course, those skilled in the art can also obtain the above parameters by other measurement methods, and the above measurement methods are for reference only.
  • computer software such as Matlab, NIS-Elements, etc.
  • the average SEM diameter of the first fiber in the bonding area should not be less than 0.1 ⁇ m. If it is less than 0.1 ⁇ m, the first fiber cannot provide good support performance, the strength of the bonding area will be greatly reduced, and the bonding between the separation layer and the porous substrate layer will be significantly weakened. In addition, the average SEM diameter of the first fiber should not be too large. If it is greater than 2 ⁇ m, the flux in the bonding area will be significantly reduced.
  • the SEM average diameter of the second fiber in the binding area should not be greater than 1 ⁇ m. If it is greater than 1 ⁇ m, the second fiber may form a crust or agglomerate in the binding area, resulting in a significant reduction in the overall flux of the virus removal composite membrane.
  • the SEM average diameter of the second fiber in the binding area should not be too small. If it is less than 0.05 ⁇ m, the second fiber will greatly increase the original specific surface area in the pore structure of the porous substrate layer, so that when filtering the fluid, the protein in the fluid is more easily adsorbed, resulting in a decrease in protein yield and a decrease in the overall membrane load.
  • the ratio of the SEM average diameter of the first fibers in the bonding area to the SEM measured average pore size of the bonding area is 0.5 to 2.5
  • the ratio of the SEM average diameter of the second fibers in the bonding area to the SEM measured average pore size of the bonding area is 0.4 to 0.9
  • the SEM measured average pore size of the bonding area is 80nm to 200nm.
  • the holes in the binding zone are mainly formed by the first fiber and the second fiber
  • the SEM average pore size of the binding zone is 80-200nm and the ratio of the SEM average diameter of the first fiber to the SEM average pore size of the binding zone is 0.5-2.5, and the ratio of the SEM average diameter of the second fiber to the SEM average pore size of the binding zone is 0.4-0.9
  • the flux and binding strength of the virus removal composite membrane can be taken into account.
  • the diameter of the first fiber plays a major role in the strength of the binding area and the entire virus removal composite membrane. Therefore, the diameter of the first fiber should not be too small. However, under the premise of maintaining the pore size range of the bonding area, the diameter of the first fiber should not be too large. If the diameter of the first fiber is too large, it is very likely that the porosity of the porous substrate layer will be reduced, thereby seriously affecting the membrane flux of the composite membrane.
  • the second fiber is formed by the second polymer infiltrating into the pore structure of the porous substrate layer and then phase separation, so the second fiber will directly affect the bonding strength of the binding area and the connectivity of the binding area. If the diameter of the first fiber is too small, the first fiber is prone to unexpected accumulation within the limited pore size range of the binding area, resulting in the formation of a dense area and reducing the membrane flux. Moreover, the small diameter of the first fiber will also lead to a disguised increase in the specific surface area of the original macropores of the porous substrate layer, which will more easily cause adsorption of proteins during filtration, resulting in a decrease in protein yield. If the diameter of the first fiber is too large, the gap that the first fiber can form in the original pore structure of the porous substrate layer is too small or there are too few holes, resulting in a greater impact on the connectivity in the binding area.
  • the diameters of the first fiber and the second fiber also need to meet the above conditions at the same time to achieve better membrane flux, better binding strength and lower protein adsorption rate.
  • the ratio of the SEM average pore size of the bonding zone to the SEM average pore size of the porous substrate layer is 1:(3-20).
  • the ratio of the SEM average pore size of the binding area in the area near the separation layer to the original SEM average pore size of the porous substrate layer is 1: (3-20)
  • the porosity in the area of the binding area near the separation layer is higher, and the connectivity between the binding area and the separation layer is better, so the membrane flux of the virus removal composite membrane is further improved.
  • the bonding between the separation layer and the porous substrate layer is also enhanced.
  • the thickness of the separation layer is not less than 10 ⁇ m.
  • the thickness of the separation layer is less than 10 ⁇ m, the integrity of the separation layer obtained in the process of liquid phase conversion of the casting film will be significantly reduced.
  • the thickness of the separation layer is 10 to 40 ⁇ m, and the pore size of the separation layer decreases gradually toward the liquid outlet surface in the thickness direction; the separation layer includes a virus removal zone and a transition zone in the thickness direction, and the thickness ratio of the transition zone to the virus removal zone is 3 to 20.
  • the thickness of the separation layer is controlled to be 10-40 ⁇ m, the integrity of the separation membrane layer obtained by molding the casting liquid after the phase inversion process is good.
  • the pore size gradient of the separation layer in the thickness direction toward the liquid outlet surface becomes smaller, so that the separation layer can form a transition area for pre-filtration in the area close to the binding area, so that the separation layer can obtain a better pre-filtration effect.
  • the thickness ratio of the virus removal zone and the transition zone in the separation layer is controlled at 3 to 20, good integrity can be maintained while the pre-filtration effect of the separation layer is greatly improved.
  • the thickness ratio of the transition zone to the bonding zone is 0.2-4, the average pore size of the transition zone measured by SEM is 50-100 nm, and the average pore size of the bonding zone measured by SEM is 50-200 nm.
  • the transition zone refers to the area of the separation layer used for pre-filtration, and the bonding zone is also formed by the casting liquid of the separation layer infiltrating into the porous base layer.
  • the thickness ratio of the transition zone to the bonding zone is controlled between 0.2 and 4, and the SEM measured average pore size of the transition zone is 50 to 100 nm, and the SEM measured average pore size of the bonding zone is 50 to 200 nm, the bonding zone and the transition zone themselves have good continuity, the connectivity between the transition zone and the bonding zone is better, and the membrane flux of the virus removal composite membrane is better.
  • the thickness of the filtration zone is too small compared to the thickness of the binding zone, it means that the amount of casting liquid that has infiltrated the porous substrate layer is large, and the average diameter of the pores in the transition zone and the binding zone may be greatly different, and there may even be a large mutation in the pore size from the binding zone to the transition zone, resulting in a decrease in the overall membrane flux of the virus removal filter membrane.
  • the thickness of the transition zone is too small, the pre-filtration capacity of the separation layer will be weakened, and the porous It is difficult for the base layer or the bonding zone to achieve the pre-filtration effect close to that of the transition zone. If the thickness of the transition zone is too large compared to the thickness of the bonding zone, the bonding strength between the separation layer and the porous base layer will be weakened due to the thinning of the bonding zone.
  • the average pore size of the liquid outlet surface measured by SEM is 10-40 nm; and the hole area ratio of the liquid outlet surface is 2%-15%.
  • the average pore size measured by SEM at the liquid outlet has a key influence on the ability of the virus removal composite membrane to intercept viruses.
  • the liquid outlet structure is characterized by morphology using a scanning electron microscope, it is measured using computer software (such as Matlab, NIS-Elements, etc.) or manually, and corresponding calculations are performed; of course, those skilled in the art can also obtain the above parameters by other measurement methods, and the above measurement methods are for reference only.
  • the average pore size measured by SEM at the liquid outlet is between 10 and 40 nm, and the virus removal composite membrane can achieve a good ability to remove small viruses, and the pore area rate of the liquid outlet is 2 to 15%, which can ensure that the virus removal composite membrane has a good flux.
  • the average pore size of the porous substrate layer measured by SEM is ⁇ 80 nm, and the thickness of the porous substrate layer is 20-200 ⁇ m.
  • the average pore size of the porous substrate layer measured by SEM is greater than 80nm, which can prevent the permeation resistance from being too large due to the small pore size of the porous substrate layer itself, making it difficult for the casting liquid to penetrate into the porous substrate layer, and unable to form a bonding area with suitable thickness and good connectivity with the separation layer.
  • the thickness of the porous substrate layer is controlled between 20 and 200 ⁇ m, the integrity of the separation layer on the virus removal composite membrane and the mechanical strength of the virus removal composite membrane can be improved.
  • porous substrate layer is an asymmetric membrane layer structure.
  • the pore size gradient of the porous substrate layer increases from the liquid inlet surface to the binding area.
  • the average pore size variation gradient of the porous substrate layer is 1-6 nm/ ⁇ m.
  • the directional gradient of the radial bonding area of the porous substrate layer can be increased. Better control of the degree of penetration of the casting liquid on the porous substrate layer. Because the area on the side with a larger pore size contacts the casting liquid first, the casting liquid initially penetrates faster, and as the gradient of the pore size decreases, the resistance to the penetration of the casting liquid increases, and the penetration slows down. Therefore, the degree of penetration of the casting liquid can be controlled by controlling the gradient pore size structure of the porous substrate layer, which is more convenient to control.
  • porous substrate layer is a symmetrical membrane layer structure.
  • the tensile strength of the virus removal composite membrane is greater than 3MPa, and the elongation at break is 2-10%;
  • the flux of the virus removal composite membrane is greater than 600L*h -1 *m -2 @30psi;
  • the LRV of the virus removal composite membrane for viral impurities is not less than 2;
  • the protein yield of the virus-removing composite membrane is not less than 97%.
  • the important indicators for evaluating the mechanical strength of the filter membrane are the tensile strength and elongation at break of the filter membrane. Under certain conditions, the greater the tensile strength of the filter membrane, the better the mechanical strength of the filter membrane.
  • Tensile strength refers to the ability of the membrane to withstand parallel tensile forces. When tested under certain conditions, the membrane sample is subjected to a tensile load until it is destroyed. The tensile strength and elongation at break of the membrane can be calculated based on the maximum tensile load corresponding to the destruction of the membrane sample and the change in the size (length) of the membrane sample. Both tensile strength and elongation at break can be measured by a universal tensile testing machine.
  • the tensile strength test method is well known in the art. For example, the tensile strength test procedure is explained in detail in ASTM D790 or ISO178.
  • the tensile strength of the filter membrane of the present application is 3-15 MPa, and the elongation at break is 2-10%, which means that the filter membrane of the present application has greater tensile strength and elongation at break, better mechanical properties, and higher industrial practical value, which can fully meet market demand.
  • Permeation flux is also called permeation rate, or flux for short, which refers to the amount of material that passes through a unit membrane area per unit time under a certain working pressure during the separation process.
  • the size of the flux reflects the speed of filtration. The larger the flux, the faster the filtration speed of the membrane.
  • the flux of the virus removal composite membrane is large. At 600L*h -1 *m -2 @30psi, its flux is large, indicating that the filtration speed is fast. While ensuring the interception efficiency, the fluid can quickly pass through the filter membrane, with low time cost and high economic benefits.
  • the large flux of the virus removal composite membrane also shows that no obvious dense area is formed in the binding area of the virus removal composite membrane to hinder the fluid from passing through the virus removal composite membrane.
  • the viruses intercepted by the present invention are mainly various viruses with a particle size of 20nm or more (for example, mouse parvovirus, whose particle size is about 20nm).
  • the LRV of the virus removal composite membrane of the present invention for various viruses was not less than 2, indicating that the virus removal composite membrane has a very large virus interception rate, and has a sufficient retention effect on viral impurities to meet the needs of practical applications; the protein yield of the virus removal composite membrane is not less than 98%, indicating that the effective substance protein in the fluid is not easily adsorbed on the membrane.
  • the membrane pores will not be blocked, ensuring that the filter membrane still has a high service life, and on the other hand, the content of the effective substance protein in the fluid changes very little, the protein is basically not lost, and the economic benefit is guaranteed;
  • the testing method for viral impurities can refer to patents - CN105980037B-virus removal membrane, CN101816898B-ultrafiltration membrane and preparation method thereof, CN1759924B-ultrafiltration membrane and preparation method thereof, etc.
  • the LRV of the virus removal composite membrane for viral impurities is 2-4.
  • the membrane pores of the separation layer of the virus removal composite membrane are relatively large, so that the virus removal composite membrane has a very large flux; but at the same time, due to its large membrane pores, the virus removal composite membrane has a certain degree of retention efficiency for parvoviruses, especially for parvoviruses with a particle size of about 20nm, the LVR value cannot reach 4 (but its LRV value can also be greater than or equal to 2.5); in actual use, we will use double-layer stacking (the LRV values of the two stacked membranes are equal, for example, the LRV of the single-layer membrane is 3, then the LRV of the double-layer membrane is 6), then at this time, it can still efficiently and fully retain various parvoviruses of 20nm and above, and at the same time have a large flux; at the same time, due to the large membrane pores, the protein yield is still high.
  • solubility parameter difference between the first polymer and the second polymer is not less than 2.1.
  • the difference between the solubility parameters of the first polymer and the second polymer is less than 2.1, when the casting liquid formed by the second polymer penetrates into the porous substrate layer formed by the first polymer, the casting liquid is easy to be miscible with the solidified first polymer in the porous substrate layer, so that more fusion areas are generated in the binding area. These areas will block or reduce the porosity of the original binding area, resulting in a significant reduction in the membrane flux of the virus removal composite membrane.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • the viscosity of the casting solution is 3000-50000cps; the solid content is 15%-30%; the separation layer is prepared from the casting solution by a solvent phase separation method, wherein the casting solution includes 15-30 parts, 50-100 parts of an organic solvent, and 5-25 parts of a polar additive;
  • the surface energy of the casting solution is smaller than the surface energy of the porous substrate layer, and the difference between the surface energy of the porous substrate layer and the surface tension of the casting solution is greater than 20 dynes/cm.
  • the viscosity of the casting solution is 8000-20000 cps; solid content: 18%-26%.
  • the casting liquid is cast onto a prefabricated porous substrate layer, and a portion of the casting liquid penetrates into the porous substrate layer to form a bonding area, which enhances the connectivity between the porous substrate layer and the separation layer and the bonding strength between the porous substrate layer and the separation layer.
  • the viscosity of the casting solution has a great influence on the final membrane structure of the separation layer. On the other hand, the viscosity of the casting solution also has a great influence on the formation of the bonding zone.
  • the pore size of the porous substrate layer determines the degree of penetration of the casting solution and the effect of penetration (for example, the difference in penetration rate between the solute and the solvent).
  • the difference between the surface energy of the porous substrate layer and the surface energy of the casting liquid also affects the penetration of the casting liquid on the porous substrate layer.
  • the penetration process is a process of reducing the surface energy. Therefore, if the difference between the two is small, the penetration effect will be worse.
  • the thickness of the bonding area formed by the casting liquid penetrating into the porous substrate layer is more moderate, and the connectivity and bonding strength between the separation layer and the porous substrate layer are improved more significantly.
  • the membrane-forming material is selected from one of PES, PVDF, CA, and RC
  • the porous substrate layer includes a supporting membrane layer for bonding a separation layer made of one of nylon, PVDF, PTFE, PES, CA, and PE.
  • the porous substrate layer also includes a non-woven layer arranged on the side of the supporting membrane layer away from the separation layer.
  • the porous base layer is a supporting membrane layer made of non-woven fabric.
  • the organic solvent is at least one of butyl lactate, dimethyl sulfoxide, dimethylformamide, caprolactam, methyl acetate, ethyl acetate, N-ethylpyrrolidone, diethyl phthalate, dimethylacetamide, acetone and N-methylpyrrolidone; and the polar additive is at least one of acetamide, polyvinyl alcohol, polyethylene glycol and polyvinylpyrrolidone.
  • the curing liquid includes water and a penetrating additive, the content of the penetrating additive is 25-70%; the penetrating additive is at least one of isopropanol, ethanol and ethylene glycol.
  • the virus removal composite membrane of the present application can meet the application of biological material separation fields such as the virus removal field. Moreover, compared with other processes, the preparation process of the virus removal composite membrane is simpler and has higher economic benefits.
  • FIG1 is a scanning electron microscope (SEM) image of a cross section of a virus removal composite membrane prepared in Example 1 of the present invention, with a magnification of 300 ⁇ ;
  • FIG2 is a scanning electron microscope (SEM) image of a cross section of the virus removal composite membrane prepared in Example 1 of the present invention, with a magnification of 700 ⁇ ;
  • FIG3 is a scanning electron microscope (SEM) image of a cross section of the virus removal composite membrane binding area prepared in Example 1 of the present invention, with a magnification of 20K ⁇ ;
  • FIG4 is a scanning electron microscope (SEM) image of a cross section of the virus removal composite membrane binding area prepared in Example 1 of the present invention, with a magnification of 50K ⁇ ;
  • FIG5 is a scanning electron microscope (SEM) image of a cross section of the virus removal composite membrane prepared in Example 17 of the present invention, with a magnification of 700 ⁇ ;
  • FIG. 6 is a scanning electron microscope image of a cross section of the virus removal composite membrane binding region prepared in Example 17 of the present invention. (SEM) image, magnification 5K ⁇ ;
  • FIG7 is a scanning electron microscope (SEM) image of a cross section of the virus removal composite membrane prepared in Comparative Example 1 of the present invention, with a magnification of 5K ⁇ ;
  • FIG8 is a scanning electron microscope (SEM) image of the liquid outlet surface of the virus removal composite membrane prepared in Example 1 of the present invention, with a magnification of 20K ⁇ ;
  • Figure 9 is a schematic diagram of the virus removal composite membrane flux testing device of the present invention.
  • the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.
  • the structural morphology of the filter membrane is characterized by a scanning electron microscope of model S-5500 provided by Hitachi.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 20 parts of polyethersulfone, 75 parts of organic solvent butyl lactate, and 15 parts of polar additive polyvinyl alcohol; the casting solution has a viscosity of 11000 cps and a solid content of 20%;
  • phase separation and solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation and solidification treatment; the phase separation and solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 20 parts of polyethersulfone, 75 parts of organic solvent butyl lactate, and 15 parts of polar additive polyvinyl alcohol; the casting solution has a viscosity of 8000 cps and a solid content of 18%;
  • phase separation and solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation and solidification treatment; the phase separation and solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 26 parts of polyethersulfone, 90 parts of dimethyl sulfoxide as an organic solvent, and 20 parts of polyvinyl alcohol as a polar additive; the viscosity of the casting solution is 13000 cps, and the solid content is 21%;
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 17 parts of polyethersulfone, 62 parts of dimethylformamide as an organic solvent, and 10 parts of polyethylene glycol as a polar additive; the viscosity of the casting solution is 18000 cps, and the solid content is 20%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a solidification bath for phase separation solidification treatment, the solidification bath is an aqueous solution containing 29% isopropyl alcohol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 20 parts of polyethersulfone, 75 parts of organic solvent caprolactam, and 15 parts of polar additive polyvinyl alcohol; the viscosity of the casting solution is 14000 cps, and the solid content is 20%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 31% ethanol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 19 parts of polyethersulfone, 71 parts of organic solvent methyl acetate, and 13 parts of polar additive polyvinyl alcohol; the casting solution has a viscosity of 10000 cps and a solid content of 18%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 28% ethanol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 18 parts of polyethersulfone, 67 parts of organic solvent N-ethylpyrrolidone, and 11 parts of polar additive polyvinyl alcohol; the casting solution has a viscosity of 22000 cps and a solid content of 19%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 63% isopropyl alcohol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 20 parts of polyethersulfone, 75 parts of dimethylacetamide as an organic solvent, and 15 parts of polyethylene glycol as a polar additive; the viscosity of the casting solution is 15000 cps, and the solid content is 18%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 73% ethanol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 21 parts of polyethersulfone, 77 parts of organic solvent N-methylpyrrolidone, and 16 parts of polar additive polyvinylpyrrolidone; the viscosity of the casting solution is 24000cps, and the solid content is 20%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 46% ethylene glycol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 22 parts of polyethersulfone, 80 parts of an organic solvent N-methylpyrrolidone, and 17 parts of a polar additive polyvinylpyrrolidone; the casting solution has a viscosity of 31000 cps and a solid content of 21%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 50% ethanol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 28 parts of polyethersulfone, 95 parts of organic solvent N-ethylpyrrolidone, and 22 parts of polar additive polyethylene glycol; the viscosity of the casting solution is 17000cps, Solid content is 22%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 27% ethanol penetration additive; the phase separation solidification treatment time lasts for 20 seconds.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, the casting solution comprising the following materials in parts by weight: 19 parts of polyethersulfone, 71 parts of organic solvent methyl acetate, and 13 parts of polar additive polyethylene glycol; the casting solution has a viscosity of 11000 cps and a solid content of 18%;
  • phase separation solidification treatment immersing the porous substrate membrane after the cast film liquid into a coagulation bath water for phase separation solidification treatment, the coagulation bath is an aqueous solution containing 32% ethylene glycol penetration additive; the phase separation solidification treatment time lasts for 23 seconds.
  • Example 11 The difference from Example 11 is that the average pore size of the PMI of the porous base layer is 0.1 ⁇ m and the thickness is 100 ⁇ m.
  • Example 11 The difference from Example 11 is that the average pore size of the PMI of the porous substrate layer is 0.4 ⁇ m and the thickness is 130 ⁇ m.
  • Example 11 The difference from Example 11 is that the average pore size of the PMI of the porous base layer is 0.6 ⁇ m and the thickness is 150 ⁇ m.
  • Example 11 The difference from Example 11 is that the average pore size of the PMI of the porous base layer is 0.1 ⁇ m and the thickness is 200 ⁇ m.
  • Example 2 The difference from Example 1 is that the porous substrate layer adopts a PVDF microporous membrane.
  • Example 2 The difference from Example 1 is that the porous base layer adopts a microporous membrane made of CA material.
  • Example 2 The difference from Example 1 is that the porous base layer adopts a microporous membrane made of PTFE.
  • Example 2 The difference from Example 1 is that the porous base layer adopts a microporous membrane made of PE material.
  • Example 11 The difference from Example 11 is that the porous substrate layer adopts a microporous membrane with an average pore size gradient of 1 nm/ ⁇ m, the SEM average pore size of the macropore side surface is 0.6 ⁇ m, the SEM average pore size of the small pore side surface is 0.49 ⁇ m, and the separation layer is cast on the small pore side of the porous substrate layer.
  • Example 11 The difference from Example 11 is that the porous substrate layer adopts a microporous membrane with an average pore size gradient of 1 nm/ ⁇ m, the SEM average pore size of the macropore side surface is 0.6 ⁇ m, the SEM average pore size of the micropore side surface is 0.49 ⁇ m, and the separation layer is cast on the macropore side of the porous substrate layer.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • the casting solution comprises the following material compositions in parts by weight: 15 parts of cellulose diacetate, 1 part of polyvinyl pyrrolidone, 26 parts of acetamide, 29.4 parts of acetone and 28 parts of dimethylacetamide.
  • step S5 The membrane after phase separation in step S3 was hydrolyzed in a 0.02 mol/L 50°C sodium hydroxide aqueous solution for 6 hours. The carbonyl peak 1740 cm of cellulose acetate was verified to have completely disappeared by infrared spectroscopy.
  • Example 23 The difference from Example 23 is that the porous base layer adopts a microporous membrane made of PVDF material.
  • Example 23 The difference from Example 23 is that the porous base layer adopts a microporous membrane made of PTFE material.
  • Example 23 The difference from Example 23 is that the porous base layer adopts a microporous membrane made of PES material.
  • Example 23 The difference from Example 23 is that the porous base layer adopts a microporous membrane made of PE material.
  • a method for preparing a virus removal composite membrane comprises the following steps:
  • S2 preparing a casting solution, wherein the casting solution comprises the following material components in parts by weight: 25 parts of polyvinylidene fluoride and 75 parts of diethyl phthalate.
  • Example 28 The difference from Example 28 is that the porous base layer adopts a microporous membrane made of PTFE material.
  • Example 28 The difference from Example 28 is that the porous base layer adopts a microporous membrane made of PE material.
  • Example 28 The difference from Example 28 is that the porous base layer adopts a microporous membrane made of PES material.
  • Example 28 The difference from Example 28 is that the porous base layer adopts a microporous membrane made of CA material.
  • Example 2 The difference from Example 1 is that the porous base layer adopts a nylon microporous membrane composited with non-woven fabric.
  • Example 2 The difference from Example 1 is that the porous base membrane adopts a nylon microporous membrane with a PMI average pore size of 0.05 ⁇ m and a thickness of 110 ⁇ m.
  • Example 2 The difference from Example 1 is that the porous substrate membrane adopts a polyethersulfone microporous membrane with a PMI average pore size of 0.05 ⁇ m and a thickness of 110 ⁇ m.
  • the membrane structure of the nanoscale polymer filtration membrane obtained in each embodiment was characterized by scanning electron microscopy, and then the required data was obtained.
  • 1 shows the diameter of the first fiber in the binding area
  • 2 shows the diameter of the second fiber in the binding area
  • 3 and 4 show the holes measured in the binding area.
  • the surface tension difference represents: surface tension of porous substrate layer - surface tension of casting solution
  • the SEM average pore size at the interface refers to the average pore size measured by SEM in a region where the bonding region is close to one side of the separation layer and the distance from the separation layer is less than 20% of the thickness of the bonding region.
  • Ratio 1 represents the ratio of the average diameter of the first fibers measured by SEM to the average pore size of the bonding area measured by SEM.
  • Ratio 2 represents the ratio of the average diameter of the second fibers measured by SEM to the average pore size of the bonding region measured by SEM.
  • the virus removal composite membranes of Examples 1-11 and Comparative Examples 1-2 were subjected to tensile tests, membrane flux tests, virus retention tests, and protein yield tests.
  • the tensile test was carried out using a universal tensile testing machine.
  • the width of the sample was 10 mm
  • the sample gauge length was 50 mm
  • the tensile speed was 20 mm/min.
  • the membrane flux is calculated as follows:
  • the operating conditions used in the membrane flux measurement of the virus removal composite membrane in the present invention are: the inlet liquid is deionized water, the operating pressure is 30 psi, the operating temperature is 25° C., and the solution pH is 7; the flux test device is shown in FIG9 .
  • the virus retention test was performed according to the test method used in paragraph 114 of CN201010154974.7-Ultrafiltration membrane and its preparation method; the virus used was mouse parvovirus with a particle size of 20 nm.
  • test is performed according to the protein yield test method used in China CN201010154974.7-Superporous membrane and preparation method thereof, and other methods may also be used for testing.
  • the virus retention efficiency LRV in Examples 1 to 33 is greater than 2, indicating that the virus removal composite membrane prepared in the present application has a good virus retention efficiency. Secondly, in particular, the virus retention efficiency of Examples 4 and 10 can reach a level greater than 4. The possible reason is that the separation layer integrity in these two groups of examples is better, and the virus retention efficiency is higher. As for the virus removal composite membrane whose LRV is not greater than 4, we found that when the two layers are stacked and used for filtration, a retention effect of LRV greater than 4 can also be achieved.
  • Example 1 By comparing Example 1 with Comparative Examples 1 and 2, it can be clearly seen that the membrane flux drops sharply. In addition, from the electron microscope images of the two, it can be seen that an undesirable accumulation phenomenon is formed at the junction of the two membrane layers in Comparative Example 1, resulting in a significant impact on the membrane flux.
  • the virus removal composite membrane prepared by the present invention can take into account mechanical strength, membrane flux, virus retention efficiency and protein yield, and its test results are relatively good.
  • the thickness of the binding zone, the average pore size of the binding zone, the connectivity of the first fiber and the second fiber in the binding zone to the binding zone, and the separation layer When the above parameters of the binding zone meet the requirements of the present invention, it means that the morphology structure in the binding zone is more suitable for the composition of the virus removal composite membrane with good microvirus interception efficiency of the present application, so that the mechanical strength, membrane flux and protein yield of the virus removal composite membrane can reach a higher level.
  • the present application also coated a polyethersulfone casting solution with a surface tension difference of less than 20 dynes/cm and a nylon porous substrate layer with an average pore size of 0.2 ⁇ m on a PMI to prepare a virus removal composite membrane, and found that the binding area of the virus removal composite membrane only penetrated within the range of 2-5 ⁇ m, and the membrane flux of the prepared membrane layer tended to 0. This shows that when the surface tension difference is too small, the penetration of the casting solution is extremely difficult, and the binding area in the present application can basically not be formed.

Abstract

一种除病毒复合膜及其制备方法，该除病毒复合膜包括主体，主体包含：包括进液面的多孔基底层和包括出液面的分离层；多孔基底层为由第一聚合物形成微孔膜层，分离层由第二聚合物形成，第一聚合物和第二聚合物为不同的聚合物材料；多孔基底层靠近分离层的一侧区域内，第二聚合物从多孔基底层的表面渗入多孔基底层的孔结构中形成结合区，结合区内的第二聚合物形成的孔洞与分离层的孔洞相连通。该除病毒复合膜不仅对于细小病毒具有较好的截留效率，还具有较好的流通性、机械强度以及较高的蛋白收率，特别适合应用于生物制品除病毒以及医药领域。

Description

一种除病毒复合膜及其制备工艺 技术领域
本发明涉及除病毒过滤的技术领域，特别是一种除病毒复合膜及其制备工艺。
背景技术
膜技术是当代高效分离的新技术，与传统的蒸馏、精馏等技术相比，它具有分离效率高，能耗低，占地面积小等优点，膜分离技术的核心就是分离膜。其中聚合物滤膜是一类以有机高分子聚合物为原材料，根据一定工艺制成的分离膜；随着石油工业和科技的发展，聚合物滤膜的应用领域不断扩大，目前已应用的领域有气体分离、海水淡化、超纯水制备、污废处理、人工脏器的制造、医药、食品、农业、化工等各方面。
根据高分子聚合物种类的不同，聚合物滤膜可以细分为纤维素类聚合物滤膜、聚酰胺类聚合物滤膜、砜类聚合物滤膜、聚四氟乙烯类聚合物滤膜等；此外，也可以根据膜的孔径大小可以分为微滤膜、超滤膜、纳滤膜及反渗透膜。
近年来，由于来源于细胞系的生物技术产品可能存在被病毒污染的风险，因此在对生物制剂的生产过程中，对病毒的去除或灭活作用一直是研究的关键，可以极大地降低病原性病毒医源性传播，降低风险，这对于产品的安全性至关重要。在生物制品进入临床试验和上市之前，必须证明其生产过程具有清除已知和假定病毒的能力。
目前，生物制品企业主要是利用超滤膜皮层的细小孔径进行过滤截留病毒以保障生物制品中的病毒得到清楚，提高生物制品的安全性。目前常见的除病毒滤膜包括有单层结构和双层结构。单层结构的除病毒滤膜典型的有不对称的聚醚砜滤膜，聚醚砜滤膜的表面具有超滤皮层结构，可以对病毒起到拦截作用； 超滤皮层以下部分可以对过滤的流体起到预过滤的效果。双层结构的除病毒滤膜的其中一层为带有超滤皮层的分离膜层，另一层为具有微孔结构的支撑层，支撑层可以提高除病毒滤膜上分离层的完整性。
EMD密理博公司申请的一件授权公告号为CN1759924B的中国专利中公开了一种多层复合超滤膜(附图17)，该复合超滤膜包括至少一层具有第一面和等价的第二面的第一多孔膜层，以及至少一层具有等价的第一面和第二面的第二多孔膜层，该第一层与第二层的连接相叠加并具有从所述第二层的等价的第一面至所述第一层的等价的第二面的孔隙率连接过渡区域，其中所述层中的至少一层是非对称超滤膜；这样复合形成的膜结构对细小病毒就有较强的截留作用，同时能够得到较高的蛋白质收率，满足了实际应用的需求。
该申请中的复合超滤膜的微孔层和超滤层是通过同时共浇铸两种不同的LCST(下临界溶解温度)或UCST(上临界溶解温度)的溶液，并在非溶剂的相转化过程前，控制两层液体的温度处于两个LCST之间或两个UCST之间，随后再进行非溶剂相转化过程，得到含有过渡区域的复合超滤膜。该复合超滤膜中的过渡区域具有连续的孔洞，可以避免预制微孔膜上浇铸超滤层的方式中致密区域的出现，使得复合超滤膜以扩散的方式阻挡病毒杂质，膜通量有一定程度的提高。
但是该复合超滤膜的过渡区域需要通过严格控制第一层和第二层的厚度、溶液的相对粘度以及形成层的相对时间等，才可达到理想的性能较好的过渡区域，因此采用该方式制备双层的除病毒过滤膜较为复杂，工艺更繁琐，也更难适应各类不同需求的场景。
Millipore Corporation of Billerica，Massachusetts生产的双层PVDF双层膜——Viresolve@膜，是通过在预制的微孔膜上浇铸超滤层而制得的，主要 用于生物制品的除病毒过滤。但是经研究发现这类在预制的微孔膜上浇铸超滤层得到的双层或多层膜材料，由于浇铸的超滤层在成型前，在两层的界面处所保留的溶质发生非期望的堆积，使得两层的界面处产生了明显的致密层结构，该层致密结构会极大地降低过滤流的膜通量，降低了膜的寿命。
发明内容
本发明所要达到的目的是提供一种除病毒复合膜及其制备工艺，通过在除病毒复合膜中起支撑作用的多孔基底层内形成结合区，使得浇铸超滤层成型时形成的致密层结构得到消除，并在维持除病毒复合膜各项性能不发生较大程度衰减的前提下，使得除病毒复合膜的通量得到极大地提高。
第一方面，本申请提供一种除病毒复合膜，采用如下技术方案：
一种除病毒复合膜,包括主体，所述主体的一侧外表面为进液面，另一侧外表面为出液面，所述主体包含：
包括进液面的多孔基底层和包括出液面的分离层；所述多孔基底层的平均孔径大于所述分离层的平均孔径；
所述多孔基底层为由第一聚合物形成微孔膜层，所述分离层由第二聚合物形成，所述第一聚合物和第二聚合物为不同的聚合物材料；
所述多孔基底层靠近分离层的一侧区域内，所述第二聚合物从多孔基底层的表面渗入多孔基底层的孔结构中形成结合区，所述结合区内的所述第二聚合物形成的孔洞与分离层的孔洞相连通；
所述除病毒复合膜的PMI平均孔径控制为15-25nm；所述结合区的SEM测量平均孔径不小于50nm。
通过PMI孔径测试仪对滤膜的平均孔径进行测试，得到本发明滤膜的PMI平均孔径为15-25nm，再通过主体结构的曲折通路以及膜一定的厚度，保证了除 病毒复合膜对于细小病毒杂质(如20nm左右的parvo病毒)具有较好的截留效果，可以满足实际的除病毒应用需求。
本申请的除病毒复合膜是将用于形成分离层的铸膜液浇铸到预制的多孔基底层上制备得到。预制的多孔基底层可以对流体进行预过滤，使得流体中颗粒尺寸较大的杂质可以被截留在多孔基底层内，不易进入分离层中而使得分离层过早出现堵塞的情况，可以提高除病毒滤膜的载量；多孔基底层还可以起到支撑的作用，使得浇铸的分离层膜完整性得到提高，除病毒复合膜的强度也得到提高。其次，多孔基底层的厚度是可根据实际需要进行调整的，这使得除病毒复合膜可以更加灵活地适用于各类分离场景。
本申请中的除病毒复合膜的分离层和多孔基底层是采用两种不同材料，而且用于形成分离层的材料部分渗入多孔基底层内形成了结合区。其中，多孔基底层由第一聚合物预制得到，分离膜层由第二聚合物浇铸制得。不同的材料可以避免第二聚合物在渗透到多孔基底层中后，第一聚合物和第二聚合物发生互溶或者粘连过多的情况发生，确保结合区内由第二聚合物形成的第二纤维和由第一聚合物形成的第一纤维基本是不连续的，从而避免局部出现结皮或结块的区域而导致除病毒复合膜的膜通量大幅度降低。同时，因为多孔基底层如果与铸膜液发生一定程度的互溶，会导致多孔基底层与分离层的分界面变得更加不平整，会分离层相转化成膜的完整性。
其次，结合区内的第二聚合物是沿着多孔基底层的相互连通的孔结构渗透形成，因此结合区既对多孔基底层的孔结构与分离层的孔结构之间达成了良好的过渡，使得第二聚合物并未在多孔基底层与分离层的表面或者多孔基底层内发生非期望的堆积，促进了多孔基底层与分离层之间的连通性，提高了除病毒复合膜的膜通量，也使得多孔基底层与分离层之间的结合强度得到提高。
此外，本申请的除病毒复合膜中的结合区内孔洞的SEM平均孔径的测量方式可以通过使用扫描电子显微镜对膜截面结构进行形貌表征后，再利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量，并进行相应计算；当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。
经测量发现结合区的SEM测量平均孔径应不小于50nm，以保证复合膜能达到比较大的膜通量，并获得较好的预过滤效果和较好的结合强度。如果结合区的SEM平均孔径小于50nm，可能在结合区内形成致密结构的可能性大大增加，一旦形成了致密区域，就会导致通量急剧降低。因此，必须满足复合膜成型后，结合区的SEM平均孔径不小于50nm。
进一步的，所述结合区内的SEM测量平均孔径为50～500nm，且所述结合区的厚度不小于10μm。
结合区的厚度可以通过使用扫描电子显微镜对膜结构进行形貌表征后，再利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量后计算测得；当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。
本申请中除病毒复合膜的结合区的厚度不小于10μm时，结合区可以明显提高多孔基底层和分离层之间的结合强度。而当结合区的厚度小于10μm时，分离层和多孔基底层之间的结合强度会明显减弱，使得除病毒复合膜的后续应用容易出现两层膜层脱离等问题。
其次，结合区的SEM测量平均孔径为50～500nm时，除病毒复合膜的膜通量和预过滤效果都可以达到较高的水平。如果结合区的SEM测量平均孔径小于50nm时，一方面结合区内可能出现致密区域，导致结合区的通量大幅度降低； 另一方面，结合区的孔径过小会导致对流体中蛋白的吸附量变大，从而导致流体蛋白收率降低。如果结合区的SEM测量平均孔径过大，则分离层和多孔基底层之间的结合强度也会出现明显降低。因为结合区的孔径是由第二聚合物渗入第一聚合物已成型的孔结构后得到的，孔径过大说明结合区内第二聚合物渗透形成的第二纤维与第一纤维之间的相互作用较弱，分离层与多孔基底层之间的结合强度变差。
进一步的，所述结合区的厚度占多孔基底层厚度的30～70％，所述结合区的厚度为15～30μm。
通过采用上述技术方案，结合区占多孔基底层的厚度不能过大也不能过小，因为如果结合区的占比过小，一方面分离层和多孔基底层之间的结合强度会变低，容易在后续的应用比如折叠等过程中发产生剥离或损伤等问题；另一方面也会使得结合区的过渡作用变得不明显，无法缓解溶质非期望堆积的现象，导致除病毒复合膜的膜通量也会明显降低。
其次，如果结合区的占比过大，结合区的平均孔径小于多孔基底层原本的平均孔径，因此容易造成无法避免的膜通量损失。而且多孔基底层的孔洞用于预过滤的区域也相应地减少，则膜载量等性能也会受到较大的影响。
此外，在控制结合区占多孔基底层的厚度比为30～70％时，结合区的厚度为15～30μm，可以保证结合区对分离层和多孔基底层之间起到较好的过渡作用，从而进一步提高复合膜的通量以及机械强度。
进一步的，所述结合区的厚度与分离层的厚度比为1∶(0.5～2)。
通过采用上述技术方案，结合区的厚度与分离层的厚度比不宜过大或过小，因为分离层的制备通常是采用铸膜液相转化法制备得到，一旦结合区和分离层的厚度比过小或过大，结合区内由铸膜液分相形成的孔结构较难获得孔隙率相 对较高或者贯通性较好的孔结构，甚至可能形成堵塞的情况而导致膜通量大幅度下降。其次，结合区厚度相对于分离层的厚度比过小，相当于分离层较厚而结合区较薄，则结合区的结合能力很难满足较厚的分离层可以较好地结合在多孔基底层上。
进一步的，所述结合区的厚度在长度方向和宽度方向上的标准差σ均不大于3μm。
结合区的厚度标准差可以通过在长度方向或宽度方向的截面电镜图中沿结合区截面上的长度方向等距选取一定数量的位置，并利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量这些位置处的厚度大小，并计算其标准差。当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。
结合区长度方向和宽度方向上的厚度的标准差不大于3μm时，结合区与多孔基底层之间的界限较为分明，结合区的孔结构与多孔基底层的孔结构之间过渡效果较好，过滤时流体在膜内不同位置受到的阻力更为均匀，过滤过程更为稳定，膜通量的衰减更低。
如果结合区的厚度标准差过大，说明结合区靠近多孔基底层的一侧区域内分布并不均匀，那么在过滤流体的过程中，各处受到的压力以及各处本身的耐压情况也有较大的不同，则很可能导致分离膜上部分位置的除病毒能力受到影响，病毒截留效果变差，以及膜通量也可能变小。
进一步的，所述结合区包括由第一聚合物形成的第一纤维、以及由第二聚合物形成的第二纤维；所述结合区内的第一纤维的SEM平均直径为0.1μm～2μm，所述结合区内的第二纤维的SEM平均直径为0.05μm～1μm。
结合区内的第一纤维和第二纤维的SEM平均直径可以通过使用扫描电子显 微镜对膜截面结构进行形貌表征后，再利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量，并进行相应计算；当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。
通过采用上述技术方案，结合区内第一纤维的SEM平均直径不应小于0.1μm，如果小于0.1μm，则第一纤维无法起到较好的支撑性能，结合区的强度会大幅度降低，分离层与多孔基底层之间的结合会明显变弱。而且第一纤维的SEM平均直径不应过大，如果大于2μm，结合区内的通量会发生明显的降低。
其次，结合区内的第二纤维的SEM平均直径不应大于1μm，如果大于1μm，第二纤维可能会在结合区内形成结皮或结块，从而导致除病毒复合膜整体的通量大幅度降低。结合区内第二纤维的SEM平均直径不应过小，如果小于0.05μm，则第二纤维在多孔基底层的孔结构内较大程度地增大了原本的比表面积，从而使得在过滤流体时，流体中的蛋白容易更多地被吸附，导致蛋白收率降低，膜整体载量也降低。
进一步的，所述结合区内的第一纤维SEM平均直径与所述结合区的SEM测量平均孔径比值为0.5～2.5，所述结合区内的第二纤维的SEM平均直径与所述结合区的SEM测量平均孔径比值为0.4～0.9，所述结合区的SEM测量平均孔径为80nm～200nm。
通过采用上述技术方案，由于结合区的孔洞主要是由第一纤维和第二纤维共同形成的，当结合区的SEM测量平均孔径为80～200nm且第一纤维SEM平均直径与结合区的SEM测量平均孔径比值为0.5～2.5，的第二纤维的SEM平均直径与结合区的SEM测量平均孔径比值为0.4～0.9时，可以兼顾除病毒复合膜的通量和结合强度。
因为第一纤维的直径对结合区以及整张除病毒复合膜的强度起到主要的影 响，因此第一纤维的直径不宜过小。但是维持结合区孔径大小范围的前提下，第一纤维的直径也不宜过大，如果第一纤维的直径过大，那么很有可能会使得多孔基底层的孔隙率降低，从而较为严重地影响复合膜的膜通量。
第二纤维是由第二聚合物渗透入多孔基底层的孔结构中后再分相形成的，因此第二纤维会直接影响到结合区的结合强度以及结合区的连通性。如果第一纤维的直径过小，则第一纤维容易在限定的结合区孔径范围下发生非期望的堆积，导致致密区域的形成而降低了膜通量。而且第一纤维的直径过小也会导致变相地增大了多孔基底层原有大孔的孔比表面积，那么在过滤时更容易造成对蛋白的吸附作用，导致蛋白收率降低。如果第一纤维的直径过大，则第一纤维在多孔基底层原有的孔结构中能形成的间隙过小或者孔洞过少，导致结合区内的连通性受到较大的影响。
因此，在保证结合区的SEM平均孔径满足80～200nm时，第一纤维和第二纤维的直径还需要同时满足上述条件才可达到较优的膜通量、较好的结合强度和较低的蛋白吸附率。
进一步的，所述结合区靠近分离层一侧且距离分离层的距离小于20％的结合区厚度的区域内，结合区的SEM平均孔径与所述多孔基底层的SEM平均孔径之比为1∶(3～20)。
通过采用上述技术方案，结合区的SEM平均孔径在靠近分离层的一侧区域内与多孔基底层的原本的SEM平均孔径之比为1∶(3～20)时，结合区靠近分离层的区域内孔隙率较高，结合区与分离层之间的连通性较好，因此除病毒复合膜的膜通量进一步得到提高。其次，分离层与多孔基底层之间的结合性也得到了增强。
进一步的，所述分离层的厚度不小于10μm。
通过采用上述技术方案，分离层的厚度若小于10μm，则铸膜液相转化的过程得到分离层膜层的完整性会有明显降低。
进一步的，所述分离层的厚度为10～40μm，所述分离层在厚度方向上向出液面方向孔径呈梯度变小；所述分离层在厚度方向上包括除病毒区和过渡区，所述过渡区与除病毒区的厚度比为3～20。
通过采用上述技术方案，分离层的厚度控制在10～40μm时，铸膜液在相转化过程后成型得到的分离膜层的完整性较好。分离层在厚度方向上向出液面的方向孔径梯度变小，使得分离层可以在靠近结合区的区域内形成用于预过滤的过渡区域，使得分离层可以获得较好的预过滤效果。
分离层中除病毒区和过渡区的厚度比控制在3～20时可以保持较好的完整性的同时，分离层的预过滤效果也得到较大的提升。
进一步的，所述过渡区与结合区的厚度比为0.2～4，所述过渡区的SEM测量平均孔径为50～100nm，所述结合区的SEM测量平均孔径为50～200nm。
通过采用上述技术方案，过渡区是指用于进行预过滤的分离层的区域，而结合区也是由分离层的铸膜液渗入多孔基底层而形成的，当过渡区与结合区的厚度比控制在0.2～4之间、且所述过渡区的SEM测量平均孔径为50～100nm，所述结合区的SEM测量平均孔径为50～200nm时，结合区与过渡区之间本身就具有较好的连续性，过渡区与结合区之间的连通性更好，除病毒复合膜的膜通量更好。
其次，过滤区的厚度与结合区的厚度比若是过小，说明铸膜液渗入多孔基底层中的量较多，过渡区与结合区的孔洞相比，平均直径可能相差会变得较大，甚至可能从结合区到过渡区时孔径发生大幅度的突变，从而导致除病毒过滤膜整体的膜通量降低。而且过渡区的厚度过小会减弱分离层的预过滤能力而多孔 基底层或者结合区均很难起到接近过渡区的预过滤效果。过渡区的厚度与结合区的厚度比若过大，则结合区由于厚度变薄会使得分离层与多孔基底层之间的结合强度变弱。
进一步的，所述出液面的SEM测量平均孔径为10～40nm；所述出液面的孔洞面积率为2％～15％。
通过采用上述技术方案，出液面的SEM测量平均孔径对于除病毒复合膜的截留病毒的能力具有关键的影响。通过使用扫描电子显微镜对出液面结构进行形貌表征后，再利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量，并进行相应计算；当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。出液面的SEM测量平均孔径为10～40nm之间，除病毒复合膜可以达到较好的去除细小病毒的能力，而且出液面的孔洞面积率为2～15％，可以保证除病毒复合膜具有较好的通量。
进一步的，所述多孔基底层的SEM测量平均孔径≥80nm，所述多孔基底层的厚度20～200μm。
通过采用上述技术方案，多孔基底层的SEM测量平均孔径大于80nm可以防止因为多孔基底层本身的孔径过小而产生的渗透阻力过大，以致铸膜液渗入多孔基底层困难，无法形成厚度合适且与分离层连通性较好的结合区。其次，多孔基底层的厚度控制在20～200μm之间时，可以使得除病毒复合膜上分离层的完整性以及除病毒复合膜的机械强度都能得到提高。
进一步的，所述多孔基底层为非对称膜层结构。
进一步的，所述多孔基底层自进液面向结合区的方向上孔径梯度增大。
进一步的，所述多孔基底层的平均孔径变化梯度为1-6nm/μm。
通过采用上述技术方案，多孔基底层的孔径向结合区的方向梯度增大可以 更好地控制铸膜液在多孔基底层上渗透程度。因为孔径大的一侧区域先与铸膜液接触，铸膜液开始的渗透速度较快，而随着孔径的梯度减小，铸膜液渗透的阻力变大，渗透减慢，所以可以通过控制多孔基底层的梯度变化的孔径结构以控制铸膜液的渗透程度，控制更加方便。
进一步的，所述多孔基底层为对称膜层结构。
进一步的，所述除病毒复合膜的拉伸强度为大于3MPa，断裂伸长率为2～10％；
所述除病毒复合膜的通量大于600L*h-1*m-2@30psi；
所述除病毒复合膜对于病毒杂质的LRV不低于2；
所述除病毒复合膜的蛋白质收率不低于97％。
评价滤膜机械强度大小的重要指标就是滤膜的拉伸强度和断裂伸长率；在一定条件下，滤膜的拉伸强度越大，也就说明了该滤膜的机械强度越好；拉伸强度是指膜所能承受平行拉伸作用的能力；在一定条件下测试时，膜样品受到拉伸载荷作用直至破坏，根据膜样品破坏时对应的最大拉伸载荷和膜样品尺寸(长度)的变化等，就可以计算出膜的拉伸强度和断裂伸长率；拉伸强度，断裂伸长率均可以通过万能拉力试验机测得，拉伸强度的测试方法在本领域中是公知的，例如在ASTM D790或ISO178就详细解释了拉伸强度测试的程序；本申请滤膜的拉伸强度为3～15MPa，断裂伸长率为2～10％，说明了本申请中滤膜具有较大的拉伸强度和断裂伸长率，其机械性能较好，工业实用价值较高，完全能够满足市场需求。
渗透通量也称渗透速率，简称通量，指滤膜在分离过程中一定工作压力下单位时间内通过单位膜面积上的物质透过量；通量的大小，就反映着过滤速度的快慢；通量越大，说明膜的过滤速度越快；本申请中除病毒复合膜的通量大 于600L*h-1*m-2@30psi，其通量较大，说明过滤速度较快，在保证截留效率的同时，流体能够快速通过滤膜，时间成本较低，经济效益较高。此外，除病毒复合膜的通量较大也说明了除病毒复合膜的结合区中未形成明显的致密区域而阻碍流体通过除病毒复合膜。
本发明所截留的病毒主要针对的是粒径为20nm及其以上的各种病毒(例如鼠细小病毒，其粒径就为20nm左右)，经过截留测试后发现，本发明除病毒复合膜对各种病毒的LRV均不低于2，说明了该除病毒复合膜对病毒具有非常大的截留率，对病毒杂质起到足够的保留作用，满足实际应用的需求；除病毒复合膜的蛋白质收率不低于98％，说明了流体中的有效物质蛋白质不容易吸附在膜上，一方面不会将膜孔堵住，保证滤膜依然具有较高的使用寿命，另一方面保证流体中的有效物质蛋白质的含量变化很小，蛋白质基本不会损失，经济效益有保证；病毒杂质的测试方法可以参考专利-CN105980037B-去除病毒的膜，CN101816898B-超滤膜及其制备方法，CN1759924B-超滤膜及其制备方法等。
进一步的，所述除病毒复合膜对于病毒杂质的LRV为2～4。
在本申请制得的除病毒复合膜中，除病毒复合膜分离层的膜孔相对较大，从而使得该除病毒复合膜具有非常大的通量；但同时由于其膜孔较大，从而一定程度上降低了除病毒复合膜对细小病毒的截留效率，特别是对粒径为20nm左右的细小病毒，其LVR值无法达到4(但其LRV值也能大于等于2.5)；在实际使用时，我们会进行双层堆叠使用(堆叠的两层膜其LRV值相等，例如单层膜LRV为3，那么双层膜LRV即为6)，那么此时依然能够对20nm及以上的各种细小病毒进行高效充分截留，同时还具有较大的通量；同时由于膜孔较大，蛋白质收率依然较高。
进一步的，所述第一聚合物和所述第二聚合物的溶度参数相差不小于2.1。
通过采用上述技术方案，第一聚合物与第二聚合物的溶度参数如果相差小于2.1，那么第二聚合物形成的铸膜液在渗透入由第一聚合物形成的多孔基底层中时，铸膜液容易与多孔基底层中的已经固化的第一聚合物形成互溶，使得结合区内产生较多的交融区域。这些区域会堵塞或者降低原本结合区的孔隙率，导致除病毒复合膜的膜通量明显的降低。
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制的多孔基底膜；多孔基底层的PMI平均孔径为≥0.08μm；
S2：制备铸膜液，并将其流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
其中所述铸膜液的粘度为3000-50000cps；固含量：15％-30％；所述分离层由铸膜液通过溶剂分相法制备得到，其中铸膜液包括15-30份、有机溶剂50-100份、极性添加剂5-25份；
S3：使用固化液进行固化处理；将液膜与多孔基底层一同浸入固化液内至少持续10秒；
进一步的，所述铸膜液的表面能小于多孔基底层的表面能，且所述多孔基底层的表面能与铸膜液的表面张力之差大于20达因/厘米。
进一步的，所述铸膜液的粘度为8000-20000cps；固含量：18％-26％。
本申请中铸膜液浇铸到预制的多孔基底层上，铸膜液部分渗入多孔基底层内形成结合区，结合区增强了多孔基底层与分离层之间的连通性以及多孔基底层与分离层之间的结合强度。
铸膜液的粘度一方面对分离层最终形成的膜层结构有较大的影响，另一方面铸膜液的粘度对于结合区的形成也有较大的影响。其次，多孔基底层的孔径决定了铸膜液渗透的程度以及渗透的效果(比如溶质和溶剂之间的渗透速度差 异、渗透形成的结合区的厚度均匀程度)。再者，多孔基底层的表面能与铸膜液的表面能之差也对铸膜液在多孔基底层上的渗透有影响，渗透过程是降低表面能的一个过程，因此两者的差值如果较小，渗透效果会变差。
因此，本申请通过控制铸膜液的粘度、多孔基底层的平均孔径以及多孔基底层的表面能与铸膜液的表面能之差大于20达因/厘米时，铸膜液渗透到多孔基底层中形成的结合区厚度更加适中，而且对于分离层与多孔基底层之间的连通性和结合强度的提高更为显著。
进一步的，所述成膜材料选自PES、PVDF、CA、RC中的一种，所述多孔基底层包括由尼龙、PVDF、PTFE、PES、CA、PE中的一种制得的用于结合分离层的支撑膜层。
进一步的，所述多孔基底层还包括有设于支撑膜层背离分离层一侧的非织造层。
进一步的，所述多孔基底层采用无纺布制成的支撑膜层。
进一步的，所述有机溶剂为乳酸丁酯、二甲亚砜、二甲基甲酰胺、己内酰胺、乙酸甲酯、乙酸乙酯、N-乙基吡咯烷酮、邻苯二甲酸二乙酯、二甲基乙酰胺、丙酮和N-甲基吡咯烷酮中的至少一种；所述极性添加剂为乙酰胺、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮中的至少一种。
进一步的，所述固化液包括水和渗透添加剂，所述渗透添加剂的含量为25-70％；渗透添加剂为异丙醇、乙醇和乙二醇中的至少一种。
通过在固化液中加入渗透添加剂，使得铸膜液在相转化形成膜层的过程中，当分离层表面的孔径较小的皮层形成后，防止其对固化液的阻碍作用过强，而导致分离层的过渡区以及多孔基底层中的结合区中的铸膜液的相转化效果变差。在过渡区可能形成较大的孔洞而使得分离层的孔径梯度变化过大，预过滤 效果变差。在结合区也可能形成较粗的纤维，使得结合区的通量明显降低。
因此，通过在固化液中加入渗透添加剂以获得梯度变化更小的分离层以及连通性更好的结合区。
综上所述，本发明的有益效果为：
在预制的多孔基底层上浇铸铸膜液以形成用于分离病毒的分离层，同时在多孔基底层靠近分离层的区域内形成厚度适中、形态良好、连通性优越的结合区，使得除病毒复合膜在能起到较好的除病毒能力以及预过滤能力的前提下，除病毒复合膜的膜通量以及分离层的结合强度均得到提高。本申请的除病毒复合膜可以满足除病毒领域等生物材料分离领域的应用。而且，除病毒复合膜的制备工艺相较于其他工艺而言，制备工艺更为简单，经济效益更高。
附图说明
下面结合附图对本发明作进一步说明：
图1为本发明实施例1制备获得的除病毒复合膜截面的扫描电镜(SEM)图,放大倍率为300×；
图2为本发明实施例1制备获得的除病毒复合膜截面的扫描电镜(SEM)图,放大倍率为700×；
图3为为本发明实施例1制备获得的除病毒复合膜结合区截面的扫描电镜(SEM)图,放大倍率为20K×；；
图4为为本发明实施例1制备获得的除病毒复合膜结合区截面的扫描电镜(SEM)图,放大倍率为50K×；；
图5为为本发明实施例17制备获得的除病毒复合膜截面的扫描电镜(SEM)图,放大倍率为700×；
图6为为本发明实施例17制备获得的除病毒复合膜结合区截面的扫描电镜 (SEM)图,放大倍率为5K×；
图7为为本发明对比例1制备获得的除病毒复合膜截面的扫描电镜(SEM)图,放大倍率为5K×；
图8为为本发明实施例1制备获得的除病毒复合膜出液面的扫描电镜(SEM)图,放大倍率为20K×；
图9为为本发明除病毒复合膜通量测试装置的示意图；。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点，下面结合附图和具体实施方式对本发明进行进一步的详细描述。需要说明的是，在不冲突的情况下，本申请的实施例及实施例中的特征可以相互组合。其中，采用日立公司提供的型号为S-5500的扫描电镜对滤膜的结构形貌进行表征。
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是，本发明还可以采用其他不同于在此描述的其他方式来实施，因此，本发明的保护范围并不受下面公开的具体实施例的限制。
实施例1
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为90μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜20份、有机溶剂乳酸丁酯75份、极性添加剂聚乙烯醇15份；铸膜液的粘度为11000cps，固含量为20％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理；分相固化处理时间持续20秒。
实施例2
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜20份、有机溶剂乳酸丁酯75份、极性添加剂聚乙烯醇15份；铸膜液的粘度为8000cps，固含量为18％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理；分相固化处理时间持续20秒。
实施例3
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜26份、有机溶剂二甲亚砜90份、极性添加剂聚乙烯醇20份；铸膜液的粘度为13000cps，固含量为21％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴中进行分相固化 处理，凝固浴为含有25％乙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例4
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜17份、有机溶剂二甲基甲酰胺62份、极性添加剂聚乙二醇10份；铸膜液的粘度为18000cps，固含量为20％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴中进行分相固化处理，凝固浴为含有29％异丙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例5
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜20份、有机溶剂己内酰胺75份、极性添加剂聚乙烯醇15份；铸膜液的粘度为14000cps，固含量为20％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有31％乙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例6
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜19份、有机溶剂乙酸甲酯71份、极性添加剂聚乙烯醇13份；铸膜液的粘度为10000cps，固含量为18％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有28％乙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例7
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜18份、有机溶剂N-乙基吡咯烷酮67份、极性添加剂聚乙烯醇11份；铸膜液的粘度为22000cps，固含量为19％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多 孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有63％异丙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例8
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜20份、有机溶剂二甲基乙酰胺75份、极性添加剂聚乙二醇15份；铸膜液的粘度为15000cps，固含量为18％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有73％乙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例9
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜21份、有机溶剂N-甲基吡咯烷酮77份、极性添加剂聚乙烯吡咯烷酮16份；铸膜液的粘度为24000cps，固含量为20％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有46％乙二醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例10
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜22份、有机溶剂N-甲基吡咯烷酮80份、极性添加剂聚乙烯吡咯烷酮17份；铸膜液的粘度为31000cps，固含量为21％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有50％乙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例11
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜28份、有机溶剂N-乙基吡咯烷酮95份、极性添加剂聚乙二醇22份；铸膜液的粘度为17000cps， 固含量为22％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有27％乙醇渗透添加剂的水溶液；分相固化处理时间持续20秒。
实施例12
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚醚砜19份、有机溶剂乙酸甲酯71份、极性添加剂聚乙二醇13份；铸膜液的粘度为11000cps，固含量为18％；
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理，凝固浴为含有32％乙二醇渗透添加剂的水溶液；分相固化处理时间持续23秒。
实施例13
与实施例11的区别在于，多孔基底层的PMI平均孔径为0.1μm，厚度为100μm。
实施例14
与实施例11的区别在于，多孔基底层的PMI平均孔径为0.4μm，厚度为 130μm。
实施例15
与实施例11的区别在于，多孔基底层的PMI平均孔径为0.6μm，厚度为150μm。
实施例16
与实施例11的区别在于，多孔基底层的PMI平均孔径为0.1μm，厚度为200μm。
实施例17
与实施例1的区别在于，多孔基底层采用PVDF微孔膜。
实施例18
与实施例1的区别在于，多孔基底层采用CA材质的微孔膜。
实施例19
与实施例1的区别在于，多孔基底层采用PTFE材质的微孔膜。
实施例20
与实施例1的区别在于，多孔基底层采用PE材质的微孔膜。
实施例21
与实施例11的区别在于，多孔基底层采用平均孔径变化梯度为1nm/μm。材质的微孔膜，其大孔侧表面的SEM平均孔径为0.6μm，其小孔侧表面的SEM平均孔径为0.49μm，且分离层浇铸于多孔基底层的小孔侧。
实施例22
与实施例11的区别在于，多孔基底层采用平均孔径变化梯度为1nm/μm。材质的微孔膜，其大孔侧表面的SEM平均孔径为0.6μm，其小孔侧表面的SEM平均孔径为0.49μm，且分离层浇铸于多孔基底层的大孔侧。
实施例23
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：15份的二醋酸纤维素，1份聚乙烯吡咯烷酮、26份乙酰胺、29.4份丙酮28份的二甲基乙酰胺。
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理。
S5：将步骤S3分相后的膜在0.02mol/L和50℃的氢氧化钠水溶液中水解6小时，通过红外进行验证，醋酸纤维素的羰基峰1740cm完全消失。
实施例24
与实施例23的区别在于，多孔基底层采用PVDF材质的微孔膜。
实施例25
与实施例23的区别在于，多孔基底层采用PTFE材质的微孔膜。
实施例26
与实施例23的区别在于，多孔基底层采用PES材质的微孔膜。
实施例27
与实施例23的区别在于，多孔基底层采用PE材质的微孔膜。
实施例28
一种除病毒复合膜的制备方法，包括以下步骤：
S1：准备预制多孔基底膜；多孔基底为尼龙微孔膜；多孔基底层的PMI平 均孔径为0.22μm，厚度为110μm；
S2：制备铸膜液，铸膜液包括以下重量份物质组成：聚偏氟乙烯25份、邻苯二甲酸二乙酯75份。
S3：流延铸膜液，将铸膜液流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
S4：固化分相，将流延铸膜液后的多孔基底膜浸入凝固浴水中进行分相固化处理。
实施例29
与实施例28的区别在于，多孔基底层采用PTFE材质的微孔膜。
实施例30
与实施例28的区别在于，多孔基底层采用PE材质的微孔膜。
实施例31
与实施例28的区别在于，多孔基底层采用PES材质的微孔膜。
实施例32
与实施例28的区别在于，多孔基底层采用CA材质的微孔膜。
实施例33
与实施例1的区别在于，多孔基底层采用无纺布复合的尼龙微孔膜。
对比例1
与实施例1的区别在于，多孔基底膜采用PMI平均孔径为0.05μm的尼龙微孔膜，厚度为110μm。
对比例2
与实施例1的区别在于，多孔基底膜采用PMI平均孔径为0.05μm的聚醚砜微孔膜，厚度为110μm。
一、结构表征
用扫描电镜对各实施例所获得的纳米级聚合物过滤膜的膜结构进行形貌表征，然后获得所需数据。在图3中，1示意结合区内第一纤维的直径，2示意结合区内第二纤维的直径，3和4示意结合区内所测量的孔洞。
表面张力测试方法：从铸膜液中取样并采用毛细管法测试铸膜液的表面张力；预制的多孔基底膜的表面张力为其临界表面张力值，可通过测量已知表面张力的液体与多孔基底膜之间的接触角制成接触角余弦值-液体克分子体积图，图中外推至于余弦值为1的位置即可得到临界表面张力。
具体结果如下表：
表1
上表中，表面张力差值表示：多孔基底层的表面张力-铸膜液的表面张力
交界处SEM平均孔径表示：结合区靠近分离层一侧且距离分离层的距离小于20％的结合区厚度的区域内的SEM测量平均孔径。
表2

比例1表示：第一纤维的SEM测量平均直径与结合区的SEM测量平均孔径之比。
比例2表示：第二纤维的SEM测量平均直径与结合区的SEM测量平均孔径之比。
表3
对实施例1-11以及对比例1-2的除病毒复合膜进行拉伸测试、膜通量测试、病毒截留测试以及蛋白收率测试。
膜拉伸测试方法
拉伸测试采用万能拉力试验机进行测试，试样的宽度为10mm，试样标距为50mm，拉伸速度为20mm/min。
膜通量测试方法
膜通量计算如下式：
膜通量(J)的计算公式为：J＝V/(T×A)式中:
J--膜通量单位：L*h-1*m-2
V--取样体积(L)；T--取样时间(h)；A--膜有效面积(m2)
本发明中除病毒复合膜的膜通量测定采用的操作条件为：进液为去离子水，操作压力为30psi，操作温度为25℃，溶液pH为7；通量测试装置为图9。
病毒截留测试方法
根据CN201010154974.7-超滤膜及其制备方法中第114段所使用的测试方法进行病毒截留测试；所使用的病毒为粒径为20nm的鼠细小病毒。
蛋白收率测试方法
根据中国CN201010154974.7-超多孔膜及其制备方法中所使用的蛋白质收率测试方法进行测试，也可以用其他方法进行测试。
表4

实施例1～实施例33中病毒截留效率LRV均大于2，说明本申请制备得到的除病毒复合膜具有较好的病毒截留效率。其次，特别的，实施例4和实施例10的病毒截留效率可以达到大于4的程度，可能的原因是这两组实施例中的分离层完整性更好，对于病毒的截留效率更高。而对于LRV未大于4的除病毒复合膜而言，我们发现当其两层进行层叠使用过滤时也可以达到LRV大于4的截留效果。
结论：本发明根据实施例1与对比例1和2进行对比可以明显看出膜通量急剧下降，而且从两者的电镜图中可以看出对比例1中的两层膜交界处形成了非期望的堆积现象，导致膜通量受到了较大的影响。
其次，通过本发明的实施例1～实施例12的结构表征参数中可以看出，符合本发明中公开的结合区参数范围下，本发明制备得到的除病毒复合膜在机械强度、膜通量、病毒截留效率以及蛋白收率上都能兼顾，其测试结果都较优。具体的，在复合膜结合区的结构参数中可以看到，结合区的厚度、结合区的平均孔径、结合区内的第一纤维以及第二纤维对于结合区的连通性以及对分离层 和多孔基底层之间的结合强度具有较为明显的影响。当结合区的上述参数满足本发明的要求时，说明结合区内的形貌结构更适合本申请的对微小病毒截留效率好的除病毒复合膜的构成，使得除病毒复合膜的机械强度、膜通量以及蛋白收率均能达到较高的水平。
本申请还对表面张力之差小于20达因/厘米的聚醚砜铸膜液和PMI平均孔径为0.2μm尼龙多孔基底层进行涂覆制备除病毒复合膜，发现除病毒复合膜的结合区仅在2-5μm的范围内渗透，而且制得的膜层膜通量趋向于0。说明当表面张力相差过小时，铸膜液的渗透极为困难，基本不能形成本申请中的结合区。
以上已详细描述了本发明的较佳实施例，但应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改。这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (28)

  1. 一种除病毒复合膜,包括主体，所述主体的一侧外表面为进液面，另一侧外表面为出液面，其特征在于，所述主体包含：
    包括进液面的多孔基底层和包括出液面的分离层；所述多孔基底层的平均孔径大于所述分离层的平均孔径；
    所述多孔基底层为由第一聚合物形成微孔膜层，所述分离层由第二聚合物形成，所述第一聚合物和第二聚合物为不同的聚合物材料；
    所述多孔基底层靠近分离层的一侧区域内，所述第二聚合物从多孔基底层的表面渗入多孔基底层的孔结构中形成结合区，所述结合区内的所述第二聚合物形成的孔洞与分离层的孔洞相连通；
    所述除病毒复合膜的PMI平均孔径控制为15-25nm；所述结合区的SEM测量平均孔径不小于50nm。
  2. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述结合区内的SEM测量平均孔径为50～500nm，且所述结合区的厚度不小于10μm。
  3. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述结合区的厚度占多孔基底层厚度的30～70％，所述结合区的厚度为15～30μm。
  4. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述结合区的厚度与分离层的厚度比为1∶(0.5～2)。
  5. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述结合区的厚度在长度方向和/或宽度方向上的标准差σ均不大于3μm。
  6. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述结合区包括由第一聚合物形成的第一纤维、以及由第二聚合物形成的第二纤维；所述结合区内的第一纤维的SEM平均直径为0.1μm～2μm，所述结合区内的第二纤维的SEM平均直径为0.05μm～1μm。
  7. 根据权利要求6所述的一种除病毒复合膜，其特征在于，所述结合区内的第一纤维SEM平均直径与所述结合区的SEM测量平均孔径比值为0.5～2.5，所述结合区内的第二纤维的SEM平均直径与所述结合区的SEM测量平均孔径比值为0.4～0.9，所述结合区的SEM测量平均孔径为80nm～200nm。
  8. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述结合区靠近分离层一侧且距离分离层的距离小于20％的结合区厚度的区域内，结合区的SEM平均孔径与所述多孔基底层的SEM平均孔径之比为1∶(3～20)。
  9. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述分离层的厚度不小于10μm。
  10. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述分离层的厚度为10～40μm，所述分离层在厚度方向上向出液面方向孔径呈梯度变小；所述分离层在厚度方向上包括除病毒区和过渡 区，所述过渡区与除病毒区的厚度的厚度比为3～20。
  11. 根据权利要求10所述的一种除病毒复合膜，其特征在于，所述过渡区与结合区的厚度比为0.2～4，所述过渡区的SEM测量平均孔径为50～100nm，所述结合区的SEM测量平均孔径为50～200nm。
  12. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述出液面的SEM测量平均孔径为15～40nm；所述出液面的孔洞面积率为2％～15％。
  13. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述多孔基底层的SEM测量平均孔径≥80nm，所述多孔基底层的厚度20～200μm。
  14. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述多孔基底层为非对称膜层结构。
  15. 根据权利要求14所述的一种除病毒复合膜，其特征在于，所述多孔基底层自进液面向结合区的方向上孔径梯度增大。
  16. 根据权利要求15所述的一种除病毒复合膜，其特征在于，所述多孔基底层的平均孔径变化梯度为1-6nm/μm。
  17. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述多孔基底层为对称膜层结构。
  18. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述除病毒复合膜的拉伸强度为大于3MPa，断裂伸长率为2～10％；
    所述除病毒复合膜的通量大于600L*h-1*m-2@30psi；
    所述除病毒复合膜对于病毒杂质的LRV不低于2；
    所述除病毒复合膜的蛋白质收率不低于97％。
  19. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述除病毒复合膜对于病毒杂质的LRV为2～4。
  20. 根据权利要求1所述的一种除病毒复合膜，其特征在于，所述第一聚合物和所述第二聚合物的溶度参数相差不小于2.1。
  21. 一种除病毒复合膜的制备方法，其特征在于，包括以下步骤：
    S1：准备预制的多孔基底膜；多孔基底层的PMI平均孔径为≥0.08μm；
    S2：制备铸膜液，并将其流延到多孔基底层上，部分铸膜液渗透侵入多孔基底膜中形成结合区区域，另一部分未渗透的铸膜液形成液膜；
    其中所述铸膜液的粘度为3000-50000cps；固含量：15％-30％；所述分离层由铸膜液通过非溶剂分相法制备得到，其中铸膜液包括成膜材料15-30份、有机溶剂50-100份、极性添加剂5-25份；
    S3：使用固化液进行固化处理；将液膜与多孔基底层一同浸入固化液内至少持续10秒。
  22. 根据权利要求21所述的一种除病毒复合膜的制备方法，其特征在于，所述铸膜液的表面张力小于多孔基底层的表面张力，且所述多孔基底层的表面能与铸膜液的表面张力之差大于20达因/厘米。
  23. 根据权利要求21所述的一种除病毒复合膜的制备方法，其特征在于，所述铸膜液的粘度为8000-20000cps；固含量：18％-26％。
  24. 根据权利要求21所述的一种除病毒复合膜的制备方法，其特征在于，所述成膜材料选自PES、PVDF、CA、RC中的一种，所述多孔基底层包括由尼龙、PVDF、PTFE、PES、CA、PE中的一种制得的用于结合分离层的支撑膜层。
  25. 根据权利要求24所述的一种除病毒复合膜的制备方法，其特征在于，所述多孔基底层还包括有设于支撑膜层背离分离层一侧的非织造层。
  26. 根据权利要求21所述的一种除病毒复合膜的制备方法，其特征在于，所述多孔基底层采用无纺布制成的支撑膜层。
  27. 根据权利要求21所述的一种除病毒复合膜的制备方法，其特征在于，所述有机溶剂为乳酸丁酯、二甲亚砜、二甲基甲酰胺、己内酰胺、乙酸甲酯、乙酸乙酯、N-乙基吡咯烷酮、、邻苯二甲酸二乙酯、二甲基乙酰胺、丙酮和N-甲基吡咯烷酮中的至少一种；所述极性添加剂为乙酰胺、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮中的至少一种。
  28. 根据权利要求21所述的一种除病毒复合膜的制备方法，其特征在于，所述固化液包括水和渗透添加剂，所述渗透添加剂的含量为25-70％；渗透添加剂为异丙醇、乙醇和乙二醇中的至少一种。
PCT/CN2023/110371 2022-10-27 2023-07-31 一种除病毒复合膜及其制备工艺 WO2024087772A1 (zh)

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