A polyvinylidene fluoride hollow fiber membrane and its preparation method and application

Abstract

The invention provides a polyvinylidene fluoride hollow fiber membrane and a preparation method and application thereof, and relates to the technical field of hollow fiber membranes. The polyvinylidene fluoride hollow fiber membrane of the invention is provided with a through hollow cavity inside, and the cavity wall of the hollow cavity comprises an outer filter layer, an intermediate transition layer and an inner filter layer which are integrally arranged, the outer filter layer has a nanopore size, the inner filter layer has a micron pore size and a pore size range of 0.1-1 μm, the pore size of the cavity wall decreases from the inside to the outside, the thickness of the outer filter layer is 15-30% of the thickness of the cavity wall, and the thickness of the inner filter layer is 20-50% of the thickness of the cavity wall. The invention also provides a preparation method and application of the polyvinylidene fluoride hollow fiber membrane. Compared with the prior art, the invention solves the problems of poor hydrophilicity, low permeability, difficulty in extracting oil-soluble diluents and high residual toxicity risk in the existing general thermotropic phase preparation technology of polyvinylidene fluoride hollow fiber membranes for virus removal.

Description

Technical Field

[0001] The present invention relates to the technical field of hollow fiber membranes, and in particular to a polyvinylidene fluoride hollow fiber membrane and a preparation method and application thereof. Background Art

[0002] With the development of biotechnology, biomedical technology has become an innovative highland for the development of new drugs worldwide. Among them, in the production process of biomedicines such as vaccines and immune proteins, the removal of viruses is the key to ensuring the safety of drugs. Studies have shown that compared with traditional high-temperature, chemical and other sterilization methods, the method of removing viruses by membrane filtration not only has the advantages of high separation efficiency, wide separation spectrum, and high product yield, but also does not denature proteins during the membrane filtration process, which can maintain the high activity of the target drug.

[0003] At present, the membranes used for virus removal are mainly polyvinylidene fluoride hollow fiber membranes prepared by thermally induced phase separation technology and polyethersulfone flat membranes prepared by non-solvent induced phase separation technology. Among them, the hollow fiber membrane not only has higher integrated design, but also has higher separation accuracy and applicability to high-concentration raw material liquid. However, although there have been many research reports, hollow fiber membrane products for virus removal on the market are very rare. Patent CN111530304A discloses a large-flux virus-removing polyvinylidene fluoride hollow fiber microporous membrane and its preparation method, but it can only be used for the removal of larger-sized viruses (such as bacteriophages) and does not involve challenges to parvoviruses (such as porcine parvovirus, mouse parvovirus, etc.). Patent CN1265868C discloses a multilayer microporous membrane with good virus retention performance and is used for virus separation, but its membrane material is not hydrophilic and the permeability of active proteins needs to be considered. Patent CN1705505A discloses a hydrophilic microporous membrane, indicating that the improvement of hydrophilicity can significantly improve the yield of active protein in the separation process. Patent CN105980038B discloses a membrane for removing viruses, indicating that the asymmetric structure is conducive to the permeation of proteins, and explains the virus retention characteristics of the asymmetric region of the membrane. However, the thermotropic phase preparation technology of polyvinylidene fluoride hollow fiber membrane described in the above patent technology all uses oil-soluble diluents without exception, and there are generally complex processes, difficult diluent extraction, high production costs, poor production safety, heat source precipitation during application, and other problems that need to be further solved. Summary of the invention

[0004] In order to solve the above-mentioned technical problems, the present invention provides a polyvinylidene fluoride hollow fiber membrane with high separation accuracy, high hydrophilicity and high permeability for biomedical virus removal filtration and its green thermotropic phase preparation technology, which solves the common problems of the existing thermotropic phase preparation technology of polyvinylidene fluoride hollow fiber membrane for virus removal, such as poor hydrophilicity, low permeability, difficulty in extraction of oil-soluble diluents, and high risk of residual toxicity.

[0005] The present invention provides a polyvinylidene fluoride hollow fiber membrane, which is provided with a through hollow cavity inside. The cavity wall of the hollow cavity comprises an outer filter layer, an intermediate transition layer and an inner filter layer which are integrally arranged. The outer filter layer has a nanopore size, the inner filter layer has a micron pore size and a pore size range of 0.1-1 μm, the pore size of the cavity wall decreases from the inside to the outside, the thickness of the outer filter layer is 15-30% of the thickness of the cavity wall, and the thickness of the inner filter layer is 20-50% of the thickness of the cavity wall.

[0006] In some embodiments, the diameter of the hollow cavity is 200-500 μm, and the thickness of the cavity wall is 30-80 μm.

[0007] The polyvinylidene fluoride hollow fiber membrane of the present invention is a hydrophilic hollow fiber membrane, the contact angle of water on the outer surface of the polyvinylidene fluoride hollow fiber membrane is 50-70 degrees, and the water droplet infiltration disappearance time is ≤100 seconds, the contact angle of water on the inner surface of the polyvinylidene fluoride hollow fiber membrane is 10-50 degrees, and the water droplet infiltration disappearance time is ≤30 seconds.

[0008] The elongation at break of the polyvinylidene fluoride hollow fiber membrane of the present invention is greater than or equal to 200%, and the logarithmic removal rate of 20-30 nanometers of parvovirus is greater than 4.0, the permeability of active proteins below 15 nanometers is greater than 90%, and the recovery rate of active proteins below 15 nanometers is greater than 95%.

[0009] The second object of the present invention is to provide a method for preparing a polyvinylidene fluoride hollow fiber membrane, the preparation method specifically comprising the following steps:

[0010] S1, polyvinylidene fluoride, a hydrophilic polymer, a structure inducer, a thermal stabilizer and a diluent are uniformly mixed to obtain a mixture, wherein the structure inducer is a low molecular weight polyol, and is selected from one or more of polyethylene glycol, diethylene glycol, and triethylene glycol having a molecular weight of not more than 1000, and the diluent is a water-soluble diluent, and is selected from one or more of caprolactone, caprolactam, butyrolactone, cyclopentane sulfone, and carbitol ester;

[0011] S2, the mixture obtained in step S1 is subjected to a blending and extrusion process through a twin-screw extruder to obtain a hollow fiber, and the temperature of the twin-screw is set at 140-190° C.;

[0012] S3, treating the hollow fiber in a gel bath at 10-40°C and in a hot water bath at 50-100°C in sequence, and then washing and drying to a fixed length to obtain a polyvinylidene fluoride hollow fiber membrane.

[0013] The technology of the present invention is based on a water-soluble diluent system to prepare a thermo-induced phase polyvinylidene fluoride hollow fiber membrane, avoiding the shortcomings of the traditional oil-soluble diluent system, such as the difficulty in extraction and the difficulty in regulating the membrane separation structure. Through the coordinated process regulation of the formula, process and post-treatment, a thermo-induced phase polyvinylidene fluoride hollow fiber membrane with high toughness is prepared. The prepared polyvinylidene fluoride hollow fiber membrane has extremely low residual precipitation and is not prone to the risk of biological heat source toxicity. The technology of the present invention is a controllable combination of the main temperature gradient phase separation technology and the surface non-solvent induced phase separation technology required for the thermo-induced phase forming and membrane separation structure formation of the hollow fiber membrane, that is, in the main phase separation process driven by the cooling of the high-temperature polyvinylidene fluoride homogeneous mixed liquid, the interface micro-region mass exchange between the water-soluble diluent and the aqueous gel bath is combined, and the green low-molecular-weight polyol is used as a pore channel structure inducer to construct a connected membrane protein transmission channel, and a membrane nanopore structure separation layer with high porosity, high separation accuracy and high permeability is constructed.

[0014] In some embodiments, the mixture is composed of the following components by mass percentage: 20-40% polyvinylidene fluoride, 1-8% hydrophilic polymer, 0.2-2% structure inducer, 0.05-1% thermal stabilizer, and the remainder is diluent.

[0015] In some embodiments, the hydrophilic polymer is selected from one or more of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol with a molecular weight of not less than 8000, and polyoxyethylene-polyoxypropylene copolymer.

[0016] In some embodiments, in step S2, a supporting core liquid is introduced into the hollow cavity during the co-extrusion process, and the supporting core liquid is selected from one or more of ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600, and the temperature of the supporting core liquid is 50-100°C.

[0017] In some embodiments, in the step S3, in the gel bath treatment, the gel bath is a mixed solution of water and a diluent, and the proportion of the diluent in the mixed solution is 5-30%.

[0018] In some embodiments, before the hollow fiber is subjected to the gel bath treatment, it is passed through an air gap, wherein the length of the air gap is ≤10 cm.

[0019] In some embodiments, in step S3, the hot water bath contains 0.1-2% by weight of an oxidative initiator, the oxidative initiator is a persulfate, and the pH value of the hot water bath is 1-5.

[0020] The third object of the present invention is to provide an application of a vinylidene fluoride hollow fiber membrane in biomedical virus removal filtration.

[0021] Compared with the prior art, the present invention has the following advantages: 1. Starting from the design of membrane-forming components and thermoinduced phase membrane control process, the present invention creates a polyvinylidene fluoride hollow fiber membrane with high separation accuracy, high hydrophilicity and high permeability for biomedical virus removal filtration through a water-soluble diluent system and a green thermoinduced phase preparation technology thereof, thereby avoiding the shortcomings of the current common thermoinduced phase membrane process using oil-soluble diluents, such as the difficulty in diluent extraction, production, and high toxicity risk in application.

[0022] 2. Different from the single membrane pore structure control process of the thermally induced phase separation process of the currently common oil-soluble diluent system, the technology of the present invention controllably combines the thermally induced phase separation technology controlled by the main temperature gradient and the precipitation phase separation technology controlled by the surface non-solvent induction. In the main process of controlling the thermally induced phase separation of the polyvinylidene fluoride casting liquid by temperature drop, the interface micro-region mass exchange between the water-soluble diluent and the aqueous gel bath, as well as the segregation effect of the diluent on the inner cavity side of the hollow fiber controlled by the core liquid are introduced to construct a polyvinylidene fluoride hollow fiber membrane characteristic skeleton structure composed of at least two differential structural layers, and to construct a polyvinylidene fluoride hollow fiber membrane with high strength, high permeability and high virus precision interception. At the same time, a green low molecular weight polyol is used as a pore channel structure inducer to construct a connected intramembrane protein transmission channel, and a membrane nanopore size structure separation layer with high porosity, high separation accuracy and high permeability is constructed.

[0023] 3. Different from the thermally induced phase separation process of the current common oil-soluble diluent system, its hydrophilic modification often requires subsequent treatment processes such as immersion adsorption and radiation cross-linking, and the amount of hydrophilic component grafting is usually low. The technology of the present invention introduces the hydrophilic component in situ. During the phase separation process, through the exchange of water-soluble diluents and aqueous gel baths, it induces the segregation and transfer of the hydrophilic component to the membrane pore interface, and constructs a polyvinylidene fluoride hollow fiber membrane with excellent hydrophilicity and anti-protein adhesion properties in one step, which can significantly reduce the adhesion of active proteins at the membrane pore interface, improve the permeability of proteins and the top wash recovery of some adsorbed proteins after filtration, thereby improving the yield of biopharmaceuticals.

[0024] 4. The polyvinylidene fluoride hollow fiber membrane prepared by the present invention has excellent mechanical properties, and its elongation at break can reach more than 200%, and is particularly suitable for application in the separation fields such as medicine and biology that have high requirements on membrane strength, membrane separation accuracy and membrane separation scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a panoramic electron micrograph of a cross section of a polyvinylidene fluoride hollow fiber membrane of Comparative Example 1 in a specific embodiment of the present invention;

[0026] Figure 2This is an enlarged electron micrograph of a cross section of a polyvinylidene fluoride hollow fiber membrane of Comparative Example 1 in a specific embodiment of the present invention;

[0027] Figure 3 This is a panoramic electron micrograph of a cross section of a polyvinylidene fluoride hollow fiber membrane of Example 1 in a specific embodiment of the present invention;

[0028] Figure 4 This is an enlarged electron micrograph of a cross section of a polyvinylidene fluoride hollow fiber membrane of Example 1 in a specific embodiment of the present invention;

[0029] Figure 5 This is an enlarged electron micrograph of a cross section of a polyvinylidene fluoride hollow fiber membrane of Example 3 in a specific embodiment of the present invention;

[0030] Figure 6 This is an enlarged electron micrograph of the cross section of the polyvinylidene fluoride hollow fiber membrane of Example 5 in a specific implementation manner of the present invention. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned purposes, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below. It should be noted that the following embodiments are only used to illustrate the implementation method and typical parameters of the present invention, and are not used to limit the parameter range described in the present invention. Reasonable changes derived therefrom are still within the scope of protection of the claims of the present invention.

[0032] It should be noted that the endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed in this article.

[0033] Unless otherwise defined, all terms, symbols and other scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. In some cases, terms with conventionally understood meanings are defined herein for the purpose of clarification or ease of reference, and such definitions herein should not be construed as indicating significant differences from conventional understandings in the art. The technical methods described or cited herein are generally well understood by those skilled in the art and are adopted by conventional methods. Unless otherwise stated, the use of commercially available kits, reagents and instruments is carried out in accordance with the protocols and parameters given by the manufacturer.

[0034] A specific embodiment of the present invention provides a polyvinylidene fluoride hollow fiber membrane, which is provided with a through hollow cavity inside. The cavity wall of the hollow cavity includes an outer filter layer, an intermediate transition layer and an inner filter layer which are integrally arranged. The outer filter layer has a nanopore size, and the inner filter layer has a micron pore size with a pore size range of 0.1-1μm. The pore size of the cavity wall decreases from the inside to the outside and the average pore size is 15-40nm. The thickness of the outer filter layer is 15-30% of the thickness of the cavity wall, and the thickness of the inner filter layer is 20-50% of the thickness of the cavity wall.

[0035] The pore size distribution of the micron pore structure layer of the polyvinylidene fluoride hollow fiber membrane of the present invention is 0.1-1 micron, so as to reduce the flow field resistance required for the feed liquid to enter the membrane channel, which is beneficial to improve the permeability of the membrane. At the same time, studies have shown that the micron pore structure layer can be used as a pre-filtration layer for the feed liquid, which can achieve a short-term destruction of the strong attraction between protein molecules during the separation process, and inhibit the formation of active protein antibody aggregates during the filtration process. Further, the micron pore structure layer with a relatively high proportion is a defect-free double continuous membrane pore connection structure, and the coarser polyvinylidene fluoride membrane pore skeleton formed by it is beneficial to provide excellent membrane mechanical properties. At the same time, the proportion of the nanopore structure layer of the present invention to the total thickness of the membrane layer is relatively low, combined with the narrow pore size distribution characteristics, while ensuring efficient and accurate interception of microviruses, it can ensure that the membrane has high active protein permeability.

[0036] In some embodiments, the diameter of the hollow cavity is 200-500 μm, and the thickness of the cavity wall is 30-80 μm.

[0037] The polyvinylidene fluoride hollow fiber membrane of the present invention is a hydrophilic hollow fiber membrane, the contact angle of water on the outer surface of the polyvinylidene fluoride hollow fiber membrane is 50-70 degrees, and the water droplet infiltration disappearance time is ≤100 seconds, the contact angle of water on the inner surface of the polyvinylidene fluoride hollow fiber membrane is 10-50 degrees, and the water droplet infiltration disappearance time is ≤30 seconds.

[0038] It can be seen from the above data that the polyvinylidene fluoride hollow fiber membrane of the present invention has excellent membrane hydrophilicity, can reduce the adhesion of active proteins on the membrane channel interface, improve the permeability of proteins and subsequent top wash recovery, thereby improving the yield of biopharmaceuticals.

[0039] The elongation at break of the polyvinylidene fluoride hollow fiber membrane of the present invention is greater than or equal to 200%, and the logarithmic removal rate of 20-30 nanometers of parvovirus is greater than 4.0, the permeability of active proteins below 15 nanometers is greater than 90%, and the recovery rate of active proteins below 15 nanometers is greater than 95%.

[0040] The second object of the present invention is to provide a method for preparing a polyvinylidene fluoride hollow fiber membrane, the preparation method specifically comprising the following steps:

[0041] S1, polyvinylidene fluoride, a hydrophilic polymer, a structure inducer, a thermal stabilizer and a diluent are uniformly mixed to obtain a mixture, wherein the structure inducer is a low molecular weight polyol, and is selected from one or more of polyethylene glycol, diethylene glycol, and triethylene glycol having a molecular weight of not more than 1000, and the diluent is a water-soluble diluent, and is selected from one or more of caprolactone, caprolactam, butyrolactone, cyclopentane sulfone, and carbitol ester;

[0042] S2, the mixture obtained in step S1 is subjected to a blending and extrusion process through a twin-screw extruder to obtain a hollow fiber, and the temperature of the twin-screw is set at 140-190° C.;

[0043] S3, treating the hollow fiber in a gel bath at 10-40°C and in a hot water bath at 50-100°C in sequence, and then washing and drying to a fixed length to obtain a polyvinylidene fluoride hollow fiber membrane.

[0044] In some embodiments, the mixture is composed of the following components by mass percentage: 20-40% polyvinylidene fluoride, 1-8% hydrophilic polymer, 0.2-2% structure inducer, 0.05-1% thermal stabilizer, and the remainder is diluent.

[0045] The function of the heat stabilizer is to improve the thermal stability of the melt during melt extrusion, which can improve the stability of the hollow fiber membrane spinning process and the uniformity of the membrane fibers. The present invention is based on the application of the polyvinylidene fluoride hollow fiber membrane in the field of biomedical virus removal filtration, and the dissolution and toxicity safety of the membrane fibers during the application process should also be considered. The mass fraction of the heat stabilizer is preferably 0.05-1%.

[0046] In some embodiments, the hydrophilic polymer is selected from one or more of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol with a molecular weight of not less than 8000, and polyoxyethylene-polyoxypropylene copolymer.

[0047] In some embodiments, in step S2, a supporting core liquid is introduced into the hollow cavity during the co-extrusion process, and the supporting core liquid is selected from one or more of ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600, and the temperature of the supporting core liquid is 50-100°C.

[0048] Compared with the prior art, the temperature drop on the inner cavity side of the hollow fiber is regulated by the supporting core liquid, and the segregation effect of the supporting core liquid on the diluent is used to form a polyvinylidene fluoride hollow fiber membrane having at least two differential structural layers, and the differential structural layers are linked to form an integrated membrane pore structure distribution that decreases from large to small from the inner cavity surface side to the outer surface side, and a nanopore retention layer with high separation accuracy is formed on the outer surface side of the hollow fiber membrane to ensure efficient retention of tiny viruses.

[0049] In some embodiments, in the gel bath treatment in step S3, the gel bath is a mixed solution of water and a diluent, the proportion of the diluent in the mixed solution is 5-30%. The diluent is a water-soluble diluent, and is selected from one or more of caprolactone, caprolactam, butyrolactone, sulfolane, and carbitol esters.

[0050] In some embodiments, before the hollow fiber is subjected to the gel bath treatment, it is passed through an air gap, wherein the length of the air gap is ≤10 cm.

[0051] In some embodiments, in step S3, the hot water bath contains 0.1-2% by weight of an oxidative initiator, the oxidative initiator is a persulfate, and the pH value of the hot water bath is 1-5.

[0052] The specific embodiment of the present invention also provides an application of a vinylidene fluoride hollow fiber membrane in biomedical virus removal filtration. In the process of biomedical virus removal filtration, the membrane material is not only required to have excellent virus removal ability, but also to have high permeability to active protein substances. During the implementation of this patent, researchers found through a large number of studies that nanofiltration membranes and reverse osmosis membranes with pore sizes of several nanometers or less are not suitable for biomedical virus removal processes, ultrafiltration membranes with very thick retention layers are not suitable for biomedical virus removal processes, and thin ultrafiltration membranes with poor hydrophilicity are also not suitable for biomedical virus removal processes.

[0053] The technical effects of the present invention are described below in conjunction with specific embodiments.

[0054] It is worth mentioning that the pore size distribution of the micron-pore structure layer of the above-mentioned polyvinylidene fluoride hollow fiber membrane is obtained by obtaining a microscopic morphology photograph of the membrane cross section under a scanning electron microscope, and digitally calibrating and statistically calculating the pore structure of the micron-pore structure layer area in the morphology photograph.

[0055] The maximum pore size of the hollow fiber membrane of the present invention measured by the bubble point method does not exceed 50 nanometers, the average pore size is 10-50 nanometers, and the preferred average pore size is 15-40 nanometers.

[0056] The fixed-length drying is to fix the length of the hollow fiber membrane with a fixed-length bracket during the drying process of the hollow fiber membrane, so as to prevent the hollow fiber membrane from being deformed due to curling or the like during the drying process.

[0057] The test method of the water contact angle of the above-mentioned polyvinylidene fluoride hollow fiber membrane refers to the national standard "GB-T 30693-2014", and the initial contact angle of the membrane surface is measured by a contact angle measuring instrument. It can be understood that for those skilled in the art, even if different test instruments are used, there is not much difference in the test results, and those skilled in the art can choose by themselves. The time required for the water droplet to disappear is the change of the contact angle of the test water droplet on the membrane surface over time, which is jointly affected by the chemical properties of the membrane material and the modified material used, the pore structure of the hydrophilic hollow fiber membrane, the chemical properties of the pore interface, and other membrane microstructure characteristics.

[0058] In the evaluation of the microvirus interception and removal of the polyvinylidene fluoride hollow fiber membrane of the present invention, two methods are preferably used: nano-colloidal particle removal replacement evaluation and virus removal evaluation:

[0059] (1) Nano-colloidal particle removal alternative evaluation method: Gold colloid solution with a particle size of 15-35 nanometers is preferred.

[0060] Gold colloid removal evaluation value = logarithmic removal rate of colloidal gold LRV / 1.7 = log 10 (C o / C f ) / 1.7

[0061] Among them, C o is the absorbance value of the gold colloid solution before filtration, C f is the absorbance value of the filtered filtrate (the absorbance values ​​are all measured at the maximum absorbance wavelength of colloidal gold). The evaluation value of the polyvinylidene fluoride hollow fiber membrane for gold colloid removal is greater than 1.00, and preferably greater than 1.05.

[0062] (2) Virus removal evaluation method:

[0063] Virus titer logarithmic reduction value LRV = log 10 (C o / C f )

[0064] Among them, C o is the virus infection titer in the original solution before filtration, C f The virus infection titer of the filtrate after filtration. The polyvinylidene fluoride hollow fiber membrane of the present invention has a logarithmic removal rate LRV of virus titer greater than 4.00, wherein LRV greater than 4.00 is generally considered to meet the regulatory requirements for virus removal.

[0065] In the evaluation of the permeability of the polyvinylidene fluoride hollow fiber membrane to active protein of the present invention, two evaluation methods, active protein permeability and active protein recovery rate, are preferably used:

[0066] Active protein permeability = C f / C o *100%

[0067] Among them, C o is the concentration of active protein solution before filtration, C f is the active protein concentration of the filtrate.

[0068] Active protein recovery rate = m f / m o *100%

[0069] Among them, m o is the weight of active protein in the total volume filtered, m f is the weight of the active protein obtained by filtration (the weight of the active protein obtained by filtering the filtrate + the weight of the active protein recovered by top washing after filtration, PBS buffer is preferably used for top washing, which is determined based on the process requirements).

[0070] Example 1

[0071] This embodiment provides a polyvinylidene fluoride hollow fiber membrane, which is prepared by the following method:

[0072] S1. Add 25% by mass of polyvinylidene fluoride, 71.4% by mass of caprolactam, 3% by mass of polyoxyethylene-polyoxypropylene copolymer, 0.3% by mass of triethylene glycol and 0.3% by mass of calcium stearate into a high-speed mixer and blend uniformly to obtain a mixture;

[0073] S2, setting the temperature of each section of the twin-screw extruder to 155-170°C and the twin-screw speed to 280 rpm, passing the mixture mixed in step S1 through the twin-screw extruder, and extruding it through a hollow fiber die to form a hollow fiber, and introducing triethylene glycol at a temperature of 70°C into the interior of the hollow fiber;

[0074] S3, introducing the hollow fiber obtained in step S2 into a gel bath for curing after passing through an air gap, the air gap is 2 cm, the gel bath is a 12% by mass caprolactam aqueous solution, and the temperature is 10°C;

[0075] S4, transferring the hollow fiber cured in step S3 to water at 25°C for soaking and cleaning;

[0076] S5, preparing a persulfate solution with a mass fraction of 0.4% and a pH value of 3, soaking the hollow fiber after the cleaning treatment in S4 in the persulfate solution, setting the water bath temperature to 80° C., and soaking for 15 hours;

[0077] S6, transferring the hollow fiber treated in S5 into deionized water, soaking and cleaning; then fixing the hollow fiber on a support and drying it to obtain the polyvinylidene fluoride hollow fiber membrane.

[0078] The polyvinylidene fluoride hollow fiber membrane prepared in this embodiment is subjected to component packaging, sterilization and other treatments to obtain a polyvinylidene fluoride hollow fiber membrane separation device used for biomedical virus removal filtration.

[0079] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for pure water flux test. The result showed that the pure water flux of the hollow fiber membrane separation device was about 330 L / m 2 ·h·3bar.

[0080] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for evaluation of 20 nm gold colloid removal, and the evaluation value was >1.1.

[0081] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for PPV virus removal evaluation, and the result was LRV>5.0.

[0082] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for active protein recovery evaluation, and the results showed that the permeability of 150KDa active protein was ≥93%, and the recovery rate of 150KDa active protein was ≥97%.

[0083] like Figure 3 As shown in FIG. 1 , a cross-sectional panoramic electron micrograph of the polyvinylidene fluoride hollow fiber membrane is shown. The inner cavity diameter is measured to be approximately 330 microns. Figure 4 As shown, it is an enlarged electron micrograph of the cross section of the polyvinylidene fluoride hollow fiber membrane. According to measurement, the membrane layer thickness is about 50 microns, the thickness of its micron pore structure layer accounts for about 35% of the membrane layer thickness, the average pore size is about 0.63 microns, the thickness of its nanopore structure layer accounts for about 22% of the membrane layer thickness, and the rest is the intermediate transition layer.

[0084] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a tensile test, and the results showed that its elongation at break was approximately 275%.

[0085] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a bubble point method pore size test, and the results showed that its average pore size was about 23 nanometers.

[0086] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a water contact angle test. The results showed that the contact angle of water on the outer surface of the membrane was about 60 degrees, and the time required for the water droplet to infiltrate and disappear was about 71 seconds; the contact angle of water on the inner surface of the membrane was about 30 degrees, and the time required for the water droplet to infiltrate and disappear was about 18 seconds.

[0087] Example 2

[0088] This embodiment provides a polyvinylidene fluoride hollow fiber membrane, which is prepared by the following method:

[0089] S1. Add 20% by mass of polyvinylidene fluoride, 76.5% by mass of caprolactone, 3% by mass of polyvinyl pyrrolidone, 0.4% by mass of polyethylene glycol 300 and 0.1% by mass of calcium ricinoleate into a high-speed mixer and blend evenly;

[0090] S2, setting the temperature of each section of the twin-screw extruder to 150-165° C. and the twin-screw speed to 200 rpm, passing the mixture uniformly mixed in step S1 through the twin-screw extruder, and extruding through a hollow fiber die to form a hollow fiber, and introducing diethylene glycol at a temperature of 60° C. into the hollow fiber;

[0091] S3, introducing the hollow fiber obtained in step S2 into a gel bath for solidification after passing through an air gap, the air gap is 1 cm, the gel bath is a 10% by mass caprolactone aqueous solution, and the temperature is 30°C;

[0092] S4, transferring the hollow fiber cured in step S3 to water at 25°C for soaking and cleaning;

[0093] S5, preparing a persulfate solution with a mass fraction of 0.3% and a pH value of 1, soaking the hollow fiber after the cleaning treatment in S4 in the persulfate solution, setting the water bath temperature to 80° C., and soaking for 6 hours;

[0094] S6, transferring the hollow fiber treated in S5 to deionized water, soaking and washing; then fixing the hollow fiber on a support and drying it to obtain the polyvinylidene fluoride hollow fiber membrane;

[0095] S7. The hollow fiber membrane is subjected to component packaging, sterilization and other treatments to obtain a polyvinylidene fluoride hollow fiber membrane separation device for use in biomedical virus removal filtration.

[0096] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for pure water flux test. The result showed that the pure water flux of the hollow fiber membrane separation device was about 350 L / m 2 ·h·3bar.

[0097] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for evaluation of 25 nm gold colloid removal, and the results showed an average value of >1.05.

[0098] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for evaluation of bovine viral diarrhea virus removal, and the result was LRV>5.5.

[0099] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for active protein recovery evaluation, and the results showed that the permeability of 150KDa active protein was ≥95%, and the recovery rate of 150KDa active protein was ≥99%.

[0100] The prepared polyvinylidene fluoride hollow fiber membrane was observed and measured by electron microscopy, and the results showed that the membrane layer thickness was about 65 microns, the inner cavity diameter was about 310 microns, the thickness of the inner micron-pore structure layer accounted for about 41% of the membrane layer thickness, the average pore diameter was about 0.48 microns, the thickness of the nanopore structure layer accounted for about 25% of the membrane layer thickness, and the rest was the intermediate transition layer.

[0101] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a tensile test, and the results showed that its elongation at break was approximately 250%.

[0102] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a bubble point method pore size test, and the results showed that its average pore size was about 35 nanometers.

[0103] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a water contact angle test. The results showed that the contact angle of water on the outer surface of the membrane was about 60 degrees, and the time required for the water droplet to disappear was about 71 seconds; the contact angle of water on the inner surface of the membrane was about 40 degrees, and the time required for the water droplet to disappear was about 18 seconds.

[0104] Example 3

[0105] This embodiment provides a polyvinylidene fluoride hollow fiber membrane, which is prepared by the following method:

[0106] S1. Add 40% by mass of polyvinylidene fluoride, 52.8% by mass of butyrolactone, 5% by mass of polyoxyethylene, 1.0% by mass of diethylene glycol, 0.6% by mass of polyethylene glycol 400 and 0.6% by mass of calcium stearate into a high-speed mixer and blend evenly.

[0107] S2, set the temperature of each section of the twin-screw extruder to 170-180°C, the twin-screw speed to 210 rpm, pass the mixture mixed in step S1 through the twin-screw extruder, and extrude it through the hollow fiber die to form a hollow fiber. Polyethylene glycol 200 at a temperature of 90°C is introduced into the hollow fiber;

[0108] S3, introducing the hollow fiber obtained in step S2 into a gel bath for curing after passing through an air gap, the air gap is 6 cm, the gel bath is a 20% by mass aqueous solution of butyrolactone, and the temperature is 10°C;

[0109] S4, transferring the hollow fiber cured in step S3 to water at 25°C for soaking and cleaning;

[0110] S5, prepare a persulfate solution with a mass fraction of 2% and a pH value of 5. Soak the hollow fiber after the cleaning treatment in S4 in the persulfate solution, set the water bath temperature to 70°C, and soak for 20 hours;

[0111] S6, transferring the hollow fiber treated in S5 to deionized water, soaking and washing; then fixing the hollow fiber on a support and drying it to obtain the polyvinylidene fluoride hollow fiber membrane;

[0112] S7. The hollow fiber membrane is subjected to component packaging, sterilization and other treatments to obtain a polyvinylidene fluoride hollow fiber membrane separation device for use in biomedical virus removal filtration.

[0113] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for pure water flux test. The result showed that the pure water flux of the hollow fiber membrane separation device was about 260 L / m 2 ·h·3bar.

[0114] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for evaluation of 20 nm gold colloid removal, and the results showed an average value of >1.3.

[0115] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for MMV virus removal evaluation, and the result was LRV>5.5.

[0116] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for active protein recovery evaluation, and the results showed that the permeability of 150KDa active protein was ≥90%, and the recovery rate of 150KDa active protein was ≥95%.

[0117] like Figure 5 As shown, it is an enlarged electron micrograph of the cross section of the polyvinylidene fluoride hollow fiber membrane. The thickness of the membrane layer is measured to be about 35 microns. The diameter of the inner cavity is measured to be about 380 microns. The thickness of the micropore structure layer of the hollow fiber membrane accounts for about 33% of the membrane thickness, the average pore size is about 0.25 microns, the thickness of the nanopore structure layer accounts for about 16% of the membrane thickness, and the rest is the intermediate transition layer.

[0118] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a tensile test, and the results showed that its elongation at break was approximately 310%.

[0119] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a bubble point method pore size test, and the results showed that its average pore size was about 18 nanometers.

[0120] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a water contact angle test. The results showed that the contact angle of water on the outer surface of the membrane was about 65 degrees, and the time required for the water droplet to disappear was about 83 seconds; the contact angle of water on the inner surface of the membrane was about 25 degrees, and the time required for the water droplet to disappear was about 20 seconds.

[0121] Example 4

[0122] This embodiment provides a polyvinylidene fluoride hollow fiber membrane, which is prepared by the following method:

[0123] S1. Add 30% by mass of polyvinylidene fluoride, 65% by mass of carbitol ester, 2% by mass of polyvinyl pyrrolidone, 2% by mass of polyethylene glycol 20000, 0.7% by mass of polyethylene glycol 200 and 0.3% by mass of calcium ricinoleate into a high-speed mixer and blend evenly.

[0124] S2, set the temperature of each section of the twin-screw extruder to 160-175°C, the twin-screw speed to 230 rpm, pass the mixture mixed in step S1 through the twin-screw extruder, and extrude it through the hollow fiber die to form a hollow fiber. A mixture of ethylene glycol and polyethylene glycol 600 in equal proportions at a temperature of 80°C is introduced into the hollow fiber;

[0125] S3, introducing the hollow fiber obtained in step S2 into a gel bath for curing after passing through an air gap, the air gap is 3 cm, the gel bath is a 12% by mass carbitol ester aqueous solution, and the temperature is 25°C;

[0126] S4, transferring the hollow fiber cured in step S3 to water at 25°C for soaking and cleaning;

[0127] S5, prepare a persulfate solution with a mass fraction of 0.8% and a pH value of 4. Soak the hollow fiber after the cleaning treatment in S4 in the persulfate solution, set the water bath temperature to 85°C, and soak for 6 hours;

[0128] S6, transferring the hollow fiber treated in S5 to deionized water, soaking and washing; then fixing the hollow fiber on a support and drying it to obtain the polyvinylidene fluoride hollow fiber membrane;

[0129] S7. The hollow fiber membrane is subjected to component packaging, sterilization and other treatments to obtain a polyvinylidene fluoride hollow fiber membrane separation device for use in biomedical virus removal filtration.

[0130] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for pure water flux test. The result showed that the pure water flux of the hollow fiber membrane separation device was about 290 L / m 2 ·h·3bar.

[0131] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for evaluation of 20 nm gold colloid removal, and the result was LRV>1.15.

[0132] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for PPV virus removal evaluation, and the result was LRV>5.0.

[0133] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for active protein recovery evaluation, and the results showed that the permeability of 150KDa active protein was ≥92%, and the recovery rate of 150KDa active protein was ≥96%.

[0134] The prepared polyvinylidene fluoride hollow fiber membrane was observed and measured by electron microscopy, and the results showed that the membrane layer thickness was about 45 microns, the inner cavity diameter was about 340 microns, the thickness of the inner micron-pore structure layer accounted for about 37% of the membrane layer thickness, the average pore diameter was about 0.39 microns, the thickness of the nanopore structure layer accounted for about 25% of the membrane layer thickness, and the rest was the intermediate transition layer.

[0135] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a tensile test, and the results showed that its elongation at break was approximately 300%.

[0136] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a bubble point method pore size test, and the results showed that its average pore size was about 25 nanometers.

[0137] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a water contact angle test. The results showed that the contact angle of water on the outer surface of the membrane was about 61 degrees, and the time required for the water droplet to infiltrate and disappear was about 83 seconds; the contact angle of water on the inner surface of the membrane was about 47 degrees, and the time required for the water droplet to infiltrate and disappear was about 21 seconds.

[0138] Example 5

[0139] This embodiment provides a polyvinylidene fluoride hollow fiber membrane, which is prepared by the following method:

[0140] S1. Add 35% by mass of polyvinylidene fluoride, 30% by mass of sulfolane, 31.6% by mass of caprolactone, 3% by mass of polyoxyethylene, 1.5% by mass of polyvinyl pyrrolidone, and 0.4% by mass of calcium stearate into a high-speed mixer and blend evenly;

[0141] S2, set the temperature of each section of the twin-screw extruder to 165-180°C, the twin-screw speed to 280 rpm, pass the mixture mixed in step S1 through the twin-screw extruder, and extrude it through the hollow fiber die to form a hollow fiber. A mixture of ethylene glycol and polyethylene glycol 600 in equal proportions at a temperature of 80°C is introduced into the hollow fiber;

[0142] S3, introducing the hollow fiber obtained in step S2 into a gel bath for curing after passing through an air gap, the air gap is 3 cm, the gel bath is a 12% by mass carbitol ester aqueous solution, and the temperature is 25°C;

[0143] S4, transferring the hollow fiber cured in step S3 to water at 25°C for soaking and cleaning;

[0144] S5, prepare a persulfate solution with a mass fraction of 0.8% and a pH value of 4. Soak the hollow fiber after the cleaning treatment in S4 in the persulfate solution, set the water bath temperature to 85°C, and soak for 6 hours;

[0145] S6, transferring the hollow fiber treated in S5 to deionized water, soaking and washing; then fixing the hollow fiber on a support and drying it to obtain the polyvinylidene fluoride hollow fiber membrane;

[0146] S7. The hollow fiber membrane is subjected to component packaging, sterilization and other treatments to obtain a polyvinylidene fluoride hollow fiber membrane separation device for use in biomedical virus removal filtration.

[0147] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for pure water flux test. The result showed that the pure water flux of the hollow fiber membrane separation device was about 285 L / m 2 ·h·2bar.

[0148] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for the removal evaluation of 20 nm gold colloid, and the result was LRV>1.2.

[0149] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for PPV virus removal evaluation, and the result was LRV>5.0.

[0150] The prepared polyvinylidene fluoride hollow fiber membrane separation device was used for active protein recovery evaluation, and the results showed that the permeability of 150KDa active protein was ≥92%, and the recovery rate of 150KDa active protein was ≥97%.

[0151] The prepared polyvinylidene fluoride hollow fiber membrane was observed and measured by electron microscopy, and the results showed that the membrane layer thickness was about 36 microns, the inner cavity diameter was about 340 microns, the thickness of the inner micron-pore structure layer accounted for about 50% of the membrane layer thickness, the average pore diameter was about 0.39 microns, the thickness of the nanopore structure layer accounted for about 30% of the membrane layer thickness, and the rest was the intermediate transition layer.

[0152] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a tensile test, and the results showed that its elongation at break was approximately 300%.

[0153] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a bubble point method pore size test, and the results showed that its average pore size was about 25 nanometers.

[0154] The prepared polyvinylidene fluoride hollow fiber membrane was subjected to a water contact angle test. The results showed that the contact angle of water on the outer surface of the membrane was about 61 degrees, and the time required for the water droplet to infiltrate and disappear was about 83 seconds; the contact angle of water on the inner surface of the membrane was about 47 degrees, and the time required for the water droplet to infiltrate and disappear was about 21 seconds.

[0155] Comparative Example 1

[0156] This comparative example provides an analysis of a commercially available Planova bioEX brand virus removal hollow fiber membrane module. Figure 1 As shown in FIG. 1 , a cross-sectional panoramic electron micrograph of the polyvinylidene fluoride hollow fiber membrane in the Planova bioEX module is shown. The inner diameter of the hollow fiber membrane is measured to be approximately 330 μm. Figure 2 The figure shows an enlarged electron micrograph of the cross section of the polyvinylidene fluoride hollow fiber membrane. The membrane thickness is measured to be about 43 microns. The thickness of the micropore structure layer accounts for about 13% of the membrane thickness, and the thickness of the nanopore structure layer accounts for about 70% of the membrane thickness, which is consistent with the description of the patent group (CN105980037B, CN105980038B, CN108602026B, etc.). Combined with the manufacturer's data review and test analysis, the pure water flux of the Planova bioEX module is about 150 L / m 2 ·h·3bar; the removal evaluation value of 20nm gold colloid is ≥1.2; the logarithmic reduction value LRV of porcine parvovirus (PPV) titer is >5.0, and the logarithmic reduction value LRV of mouse parvovirus (MMV) titer is >4.5; the permeability of 150KDa active protein is ≥88%, and the recovery rate of 150KDa active protein is ≥93%.

[0157] It can be seen from the results of Comparative Example 1 and Examples 1-5 that the present invention starts with the design of film-forming components and thermoinduced phase membrane control process, and through a water-soluble diluent system combined with an aqueous gel bath, creates a polyvinylidene fluoride hollow fiber membrane with high separation accuracy, high hydrophilicity and high permeability for biomedical virus removal filtration and its green thermoinduced phase preparation technology, which avoids the shortcomings of the current common thermoinduced phase membrane process using oil-soluble diluents, such as the difficulty in diluent extraction and high risk of toxicity in production and application.

[0158] Although the disclosure is disclosed as above, the protection scope of the disclosure is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the disclosure, and these changes and modifications will fall within the protection scope of the present invention.

Claims

1. A polyvinylidene fluoride hollow fiber membrane, characterized in that: A through hollow cavity is arranged inside the hollow cavity, and the cavity wall of the hollow cavity includes an outer filter layer, an intermediate transition layer and an inner filter layer which are arranged integrally, the outer filter layer has a nanopore size, the inner filter layer has a micron pore size and a pore size range of 0.1-1 μm, the pore size of the cavity wall decreases from the inside to the outside, the thickness of the outer filter layer is 15-30% of the thickness of the cavity wall, and the thickness of the inner filter layer is 20-50% of the thickness of the cavity wall; the elongation at break of the polyvinylidene fluoride hollow fiber membrane is greater than or equal to 200%, and the logarithmic removal rate of 20-30 nanometers of small viruses is greater than 4.0, the permeability of active proteins below 15 nanometers is greater than 90%, and the recovery rate of active proteins below 15 nanometers is greater than 95%; The preparation method of the polyvinylidene fluoride hollow fiber membrane specifically comprises the following steps: S1, uniformly mixing polyvinylidene fluoride, a hydrophilic polymer, a structural inducer, a thermal stabilizer and a diluent to obtain a mixture, wherein the mixture is composed of the following by mass percentage: polyvinylidene fluoride 20-40%, hydrophilic polymer 1-8%, structural inducer 0.2-2%, thermal stabilizer 0.05-1%, and the remainder is diluent; the structural inducer is a low molecular weight polyol, and is selected from polyethylene glycol, diethylene glycol, One or more of triethylene glycol, the diluent is a water-soluble diluent, and is selected from one or more of caprolactone, caprolactam, butyrolactone, cyclopentane sulfone, and carbitol acetate; S2, the mixture obtained in step S1 is subjected to a blending and extrusion process through a twin-screw extruder to obtain a hollow fiber, and the twin-screw is set at a temperature of 140-190°C; S3, the hollow fiber is sequentially subjected to a gel bath treatment at 10-40°C and a hot water bath treatment at 50-100°C, and then washed with water and dried to a fixed length to obtain a polyvinylidene fluoride hollow fiber membrane.

2. The polyvinylidene fluoride hollow fiber membrane according to claim 1, characterized in that: The diameter of the hollow cavity is 200-500 μm, and the thickness of the cavity wall is 30-80 μm.

3. The polyvinylidene fluoride hollow fiber membrane according to claim 1, characterized in that: The polyvinylidene fluoride hollow fiber membrane is a hydrophilic hollow fiber membrane, the contact angle of water on the outer surface of the polyvinylidene fluoride hollow fiber membrane is 50-70°, and the water droplet wetting and disappearing time is ≤100s, the contact angle of water on the inner surface of the polyvinylidene fluoride hollow fiber membrane is 10-50°, and the water droplet wetting and disappearing time is ≤30s.

4. The polyvinylidene fluoride hollow fiber membrane according to claim 1, characterized in that: The hydrophilic polymer is selected from one or more of polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol with a molecular weight of not less than 8000, and polyoxyethylene-polyoxypropylene copolymer.

5. The method for preparing a polyvinylidene fluoride hollow fiber membrane according to claim 1, characterized in that: In the step S2, a supporting core liquid is introduced into the hollow cavity during the co-extrusion process. The supporting core liquid is selected from one or more of ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600. The temperature of the supporting core liquid is 50-100°C.

6. The method for preparing a polyvinylidene fluoride hollow fiber membrane according to claim 1, characterized in that: In step S3, in the gel bath treatment, the gel bath is a mixed solution of water and a diluent, and the ratio of the diluent in the mixed solution is 5-30%; and / or, before the hollow fiber is subjected to the gel bath treatment, it is passed through an air gap, and the length of the air gap is ≤10 cm.

7. The method for preparing a polyvinylidene fluoride hollow fiber membrane according to claim 1, characterized in that: In step S3, the hot water bath contains 0.1-2% by weight of an oxidative initiator, the oxidative initiator is persulfate, and the pH value of the hot water bath is 1-5.

8. Use of the polyvinylidene fluoride hollow fiber membrane as claimed in any one of claims 1 to 7 in biomedical virus removal filtration.

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