RU2797112C2 - Porous membrane - Google Patents

Abstract

FIELD: membranes.

SUBSTANCE: group of inventions relates to a porous membrane for removing viruses, a method for producing a porous membrane, and a method for reducing membrane adhesion. The porous membrane for removing viruses contains a hydrophobic polymer and a hydrophilic polymer, where the average value of T for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 to 7.0 when measuring the surface of the porous membranes using time-of-flight secondary ion mass spectrometry (TOFMS), wherein the ion derived from the hydrophobic polymer is C₆H₄O with m/z of 92, the ion derived from the hydrophilic polymer is C₄H₅O₂ with m/z of 85, the hydrophilic polymer is a methacrylate-based polymer, the hydrophobic polymer is a polysulfone-based polymer, and the hydrophilic polymer is coated on the base material membrane containing the hydrophobic polymer. Also described is a method for producing a porous membrane containing a hydrophobic polymer and a hydrophilic polymer, and a method for reducing the adhesion of the membrane after hydrophilization of the membrane from the base material containing the hydrophobic polymer.

EFFECT: provision of a porous membrane characterized by reduced membrane adhesion during production of the porous membrane, with the possibility of not only efficient production of the membrane module, but also preventing deterioration of the performance of the porous membrane.

12 cl, 1 tbl, 15 ex

Description

The field of technology to which the invention belongs

[0001]

The present invention relates to a porous membrane, a method for producing a porous membrane, and a method for reducing membrane adhesion.

State of the art

[0002]

In recent years, medical treatment options using fractionated plasma products and biopharmaceuticals as drugs have become widespread due to the low number of side effects and high treatment efficacy. However, fractionated plasma products are made from human blood, biopharmaceuticals are made from animal cells, and therefore there is a risk of contamination of medicines with pathogenic substances such as viruses.

[0003]

In order to prevent contamination of drugs with viruses, the removal or inactivation of viruses was certainly carried out. Examples of a method for removing or inactivating a virus include heat treatment, optical treatment, and chemical treatment. In relation to the problems of protein denaturation, the efficiency of virus inactivation and chemical contamination, attention has been drawn to the membrane filtration method, which is effective for all viruses, regardless of their thermal and chemical characteristics.

[0004]

Examples of virus that can be removed or inactivated include: a poliovirus having a diameter in the range between 25 and 30 nm; parvovirus, having a diameter in the range between 18 and 24 nm, as the smallest virus; and an HIV virus having a diameter in the range between 80 and 100 nm as a relatively large virus. In recent years, there has been a growing need in particular for the removal of small viruses such as parvovirus.

[0005]

The first performance requirement for a virus removal membrane is safety. Safety includes safety in avoiding contamination of fractionated plasma products and biopharmaceuticals with pathogenic substances such as viruses, and safety in avoiding contamination of fractionated plasma products and biopharmaceuticals with foreign materials such as eluate from a virus removal membrane.

In terms of safety, which is to avoid contamination by pathogenic substances such as viruses, sufficient removal of viruses becomes important when using a membrane to remove viruses. As stated in Non-Patent Literature 1, the clearance (LRV) achieved for small mouse virus or swine virus is 4.

In addition, within the safety framework of avoiding contamination by foreign materials such as eluate, it becomes important to prevent leakage of eluate from the virus removal membrane.

[0006]

The second performance requirement for a virus removal membrane is throughput. The term "throughput" refers to the efficient recovery of a protein such as 5 nm albumin and 10 nm globulin.

[0007]

Patent Literature 1 discloses a virus removal method using a porous membrane containing a hydrophobic polymer and a water-insoluble polymer.

Patent Literature 2 discloses a virus-removing membrane obtained by hydrophilizing a membrane surface using a graft polymerization method, whereby a film is formed using a thermally induced phase separation method and contains polyvinylidene difluoride (PVDF).

List of citations

Patent Literature Sources

[0008]

Patent Literature Source 1: International Publication No. WO 2016031834

Patent Literature Source 2: International Publication No. WO 2004035180

Source of non-patent literature

Non-Patent Literature Source 1: PDA Journal of GMP and Validation in Japan, vol. 7, no. 1, p. 44 (2005)

The essence of the invention

Technical problem

[0009]

The problem solved by the present invention is to provide a porous membrane characterized by a reduced degree of the phenomenon in which the membranes firmly adhere to each other during the manufacture of the porous membrane (herein referred to as "membrane adhesion"). Yet another problem is to provide a method for reducing membrane adhesion that occurs during the production of a porous membrane. Yet another problem of the present invention is to provide a porous hollow fiber membrane having reduced membrane adhesion that occurs during the manufacture of the porous hollow fiber membrane, (hereinafter, membrane adhesion in a porous hollow fiber membrane is sometimes referred to as "fiber adhesion"), and in providing a method for reducing membrane adhesion that occurs during the production of a porous hollow fiber membrane.

Solution of a problem

[0010]

As the inventor of the present invention has found, in the production of a porous membrane using the method disclosed in Patent Literature 1, there is a problem that membrane adhesion occurs in which the membranes adhere strongly to one another, especially after the porous membrane has been hydrophilized by coating. As first recognized by the inventor of the present invention, the occurrence of membrane adhesion in the production of a membrane module using a membrane involves the operations of peeling the membranes one from the other in such a way that not only the production efficiency of the membrane module is degraded, but there is also a risk of damage to the membrane as a result of the tearing operations. , resulting in poor performance of the membrane. As found by the inventor, in the presence of, in particular, a porous hollow fiber membrane, this problem becomes clearly apparent due to the occurrence of membrane adhesion, in which the porous hollow fiber membranes adhere firmly to each other after hydrophilization of the porous hollow fiber membrane as a result of coating, which is carried out when using porous hollow fiber membranes converted into a bundle. Thus, the inventors of the present invention have discovered a new problem in reducing the occurrence of membrane adhesion after hydrophilization, which was not previously known for porous membranes. As a result of painstaking research in order to solve this problem, the present inventors have completed the present invention by discovering the possibility of obtaining a porous membrane having reduced membrane adhesion and having a specific configuration as shown below.

[0011]

In other words, the present invention is as follows.

[1] A porous membrane containing a hydrophobic polymer and a hydrophilic polymer, where the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 or more when measuring the surface of the porous membrane when using time-of-flight secondary ion mass spectrometry (TOFMS).

[2] The porous membrane corresponding to [1], wherein the ion derived from the hydrophobic polymer is C ₆ H ₄ O (m/z=92).

[3] A porous membrane corresponding to [1] or [2], wherein the ion derived from the hydrophilic polymer is C ₄ H ₅ O ₂ (m/z=85).

[4] A porous membrane corresponding to any one of [1] to [3], wherein the hydrophilic polymer is a water-insoluble hydrophilic polymer.

[5] A porous membrane corresponding to any one of [1] to [4], wherein the hydrophilic polymer is electrically neutral.

[6] A porous membrane corresponding to any one of [1] to [5], wherein the hydrophilic polymer is a methacrylate-based polymer.

[7] The porous membrane corresponding to [6], wherein the methacrylate-based polymer is polyhydroxyethyl methacrylate.

[8] A porous membrane corresponding to any one of [1] to [7], wherein the hydrophobic polymer is a polysulfone-based polymer.

[9] A porous membrane corresponding to [8], wherein the polysulfone-based polymer is a polyethersulfone.

[10] A porous membrane corresponding to any one of [1] to [9] where the bubble point is between 1.4 and 2.0 MPa.

[11] A porous membrane corresponding to any one of [1] to [10], wherein the pure water permeability is between 150 and 500 l/(h⋅m ² ⋅bar).

[12] A porous membrane corresponding to any one of positions [1] to [11] for removing viruses.

[13] A porous membrane corresponding to any one of [1] to [12] wherein the logarithm of viral load reduction (LRV) is 4 or more.

[14] A porous membrane corresponding to any one of [1] to [13], wherein the base material membrane containing the hydrophobic polymer is coated with a hydrophilic polymer.

[15] A porous membrane corresponding to any one of [1] to [14], wherein the level of hydrophilic polymer content is in the range between 5 and 20% by weight. with respect to the hydrophobic polymer.

[16] A method for producing a porous membrane containing a hydrophobic polymer and a hydrophilic polymer, the method comprising:

a hydrophilization step comprising hydrophilizing a base material membrane containing a hydrophobic polymer with a hydrophilic polymer to obtain a hydrophilized porous membrane; And

a control step comprising treating the hydrophilized porous membrane such that the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 or more when measuring the surface of the porous membrane using time -flight mass spectrometry of secondary ions (FSMSVI).

[17] A method for reducing membrane adhesion after hydrophilizing a membrane of a base material containing a hydrophobic polymer, the method comprising:

a hydrophilization step comprising hydrophilizing a base material membrane containing a hydrophobic polymer with a hydrophilic polymer to obtain a hydrophilized porous membrane; And

a control step comprising treating the hydrophilized porous membrane such that the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 or more when the surface of the porous membrane is measured at using time-of-flight secondary ion mass spectrometry (TOFMS).

[18] The method according to [16] or [17], wherein the step of adjusting comprises washing and/or treating the hydrophilized porous membrane with high pressure hot water.

[19] A method according to any one of [16] to [18], wherein the hydrophilization step includes a process for converting the membrane from a base material into a bundle and subjecting it to a hydrophilization treatment.

[20] A porous membrane corresponding to any one of [1] to [15], wherein the porous membrane includes:

a dense layer at least in a downstream filtration portion of the membrane;

a gradient asymmetric structure where the average pore diameter for fine pores increases from a downstream filtration section to an upstream filtration section; And

gradient index for the average pore diameter in the transition from a dense layer to a coarse layer in the range between 0.5 and 12.0.

[21] The porous membrane corresponding to [20], wherein the degree of presence of pores corresponding to 10 nm or less in the dense layer is 8.0% or less.

[22] A porous membrane corresponding to [20] or [21], wherein the standard deviation value for the value of pore diameters/average pore diameter in the dense layer is 0.85 or less.

[23] A porous membrane corresponding to any one of [20] to [22], wherein the degree of presence of pores corresponding to a range between more than 10 nm and 20 nm or less in the dense layer is between 20.0% or more and 35.0% or less.

[24] A porous membrane corresponding to any one of [20] to [23], wherein the dense layer porosity is between 30.0% or more and 45.0% or less.

[25] A porous membrane corresponding to any one of [20] to [24] where the thickness of the dense layer is between 1 and 8 µm.

Beneficial effects of the invention

[0012]

The present invention provides a porous membrane characterized by reduced membrane adhesion during manufacture of the porous membrane. This makes it possible not only to efficiently produce the membrane module, but also to prevent degradation of the performance of the porous membrane.

Description of Embodiments

[0013]

Hereinafter, modes of carrying out the present invention (hereinafter sometimes referred to as "embodiments") will be described. The present invention is not limited by the following embodiments, and various modifications of the embodiments can be implemented within the scope of the gist of the present invention. The embodiments shown below are presented as examples of methods for implementing the technical idea of the present invention and the like, and the present invention is not limited by these examples.

[0014]

<Porous Membrane>

In one embodiment, the porous membrane comprises a hydrophobic polymer and a hydrophilic polymer, and the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 or more when measuring the surface of the porous membrane when using time-of-flight secondary ion mass spectrometry (TOFMS).

[0015]

In one embodiment, the porous membrane is not particularly limited as long as it is a porous membrane whose membrane adhesion is improved by setting the average T value of the porous membrane described above to an appropriate value, and examples of the porous membrane include planar membranes and hollow fiber membranes. From the point of view of the improvement degree of the adhesion of the membrane, hollow fiber membranes are preferable. The hollow fiber membrane has an inner surface and an outer surface as membrane surfaces, and the average T value with respect to the outer surface may be 1.0 or more. For a flat membrane, the average T value with respect to one of the two surfaces may be a value in the present invention, and it is preferable that both of the two surfaces exhibit a value in the present invention.

[0016]

With the porous membrane according to the present embodiments, the adhesion of the membrane during production is reduced. This makes it possible not only to efficiently produce the membrane module, but also to prevent degradation of the performance of the porous membrane. In one embodiment, the porous membrane suppresses the decrease in flux over time as a result of protein adsorption during filtration. In addition, in one embodiment, the porous membrane exhibits high virus removal performance.

[0017]

The porous membrane according to the present embodiments contains a hydrophobic polymer and a hydrophilic polymer. The porous membrane is not particularly limited as long as it is a porous membrane containing a hydrophobic polymer and a hydrophilic polymer. The hydrophobic polymer and the hydrophilic polymer may be subjected to the formation of a blended membrane, and the membrane resulting from the formation of the blended membrane (blended membrane) may be further coated with a hydrophilic resin. The porous membrane also includes membranes in which the base material membrane containing the hydrophobic polymer is hydrophilized with the hydrophilic polymer, for example by coating or grafting.

[0018]

As used herein, the term “hydrophobic polymer” refers to a polymer that forms a contact angle of more than 90 degrees when PBS buffer is added (a solution obtained by dissolving 9.6 g of Dulbecco's PBS (-) "Nissui" PBS buffer powder). , commercially available from Nissui Pharmaceutical Co., Ltd., in water in a total amount of 1 L) in contact with the polymer film.

[0019]

In one embodiment, the hydrophobic polymer is not particularly limited as long as it is a polymer having hydrophobicity, and examples thereof include polyolefins, polyamides, polyimides, polyesters, polyketones, polyvinylidene difluorides (PVDF), polymethyl methacrylates, polyacrylonitriles, and polysulfonic acid polymers. basis. From the point of view of high membrane-forming properties and controlled maintenance of the membrane structure, polysulfone-based polymers are preferred.

The hydrophobic polymers may be used alone or in mixtures of two or more of them.

[0020]

Examples of the polysulfone-based polymer include polysulfones (PSf) containing a repeating unit of Formula 1 below and polyethersulfones (PES) containing a repeating unit of Formula 2 below, and polyethersulfones are preferred from the point of view of membrane-forming properties. .

[0021]

Formula 1:

[0022]

Formula 2:

[0023]

Polysulfone-based polymers may contain a substituent such as a functional group or an alkyl group, or the hydrogen atom in the hydrocarbon backbones may be replaced by another atom such as a halogen atom or a substituent in the structures described by formula 1 and formula 2.

The polysulfone-based polymers may be used alone or in mixtures of two or more of them.

[0024]

In one embodiment, the porous membrane contains a hydrophilic polymer.

In one embodiment, in order to prevent a drastic decrease in filtration rate due to membrane plugging due to protein adsorption, the porous membrane can be hydrophilized by allowing the presence of a hydrophilic polymer on the surface of the pores of the membrane of the base material containing the hydrophobic polymer. The term "base material membrane" means a membrane that contains a hydrophobic polymer and is coated, grafted, or crosslinked. The base material membrane may contain a hydrophilic polymer. For example, the blended membrane may be a base material membrane.

Examples of the method for hydrophilizing a membrane from a base material include coating, a grafting reaction, and a crosslinking reaction after obtaining a membrane from a base material containing a hydrophobic polymer. The base material membrane can also be coated with a hydrophilic resin by coating, grafting reaction, crosslinking reaction, and the like after the hydrophobic polymer and the hydrophilic polymer are blended into the membrane.

[0025]

As used herein, the term "hydrophilic polymer" refers to a polymer that forms a contact angle of 90 degrees or less when PBS buffer (a solution obtained by dissolving 9.6 g of Dulbecco's PBS (-) "Nissui" PBS buffer powder) , commercially available from Nissui Pharmaceutical Co., Ltd., in water for a total amount of 1 L) in contact with the polymer film.

It is preferable to have a contact angle of 60 degrees or less, and more preferably 40 degrees or less. In the case of containing a hydrophilic polymer having a contact angle of 60 degrees or less, the porous membrane is easily wetted by water, and in the case of containing a hydrophilic polymer having a contact angle of 40 degrees or less, the tendency for the porous membrane to be easily wetted by water is still more obvious.

The term "contact angle" refers to the angle formed by a film with the surface of a water drop when a drop of water drops onto the surface of the film, and the contact angle is defined in JIS R3257.

[0026]

In one embodiment, examples of the hydrophilic polymer include water-insoluble hydrophilic polymers. The term "water-insoluble" denotes an elution rate of 0.1% or less for the case of using a membrane module manufactured to obtain an effective membrane area of 3 cm ² for dead-end filtration at a constant pressure of 2.0 bar using 100 ml of pure water at 25°C.

The degree of elution is calculated according to the following method.

Collect and concentrate the filtrate obtained by filtering 100 ml of pure water at 25°C. To calculate the degree of elution from the membrane, the amount of carbon was measured using the resulting concentrated liquid using a TOC-L total organic carbon meter (manufactured by Shimadzu Corporation).

[0027]

As used herein, the term "water-insoluble hydrophilic polymer" refers to a substance that satisfies the wetting angle and elution ratio described above. Water-insoluble hydrophilic polymers include not only hydrophilic polymers in which the substance itself is insoluble in water, but also hydrophilic polymers that are insolubilized in water during their manufacturing process, even though the hydrophilic polymers are originally water-soluble hydrophilic polymers. . In other words, even though the hydrophilic polymer is a water-soluble hydrophilic polymer, the hydrophilic polymer in the present embodiments is included in the water-insoluble hydrophilic polymers as long as the hydrophilic polymer is a substance that satisfies the above-described contact angle wetting, and also satisfies the above-described degree of elution in dead-end filtration at constant pressure after the manufacture of the filter as a result of insolubilization in water in the manufacturing process. The water-insoluble hydrophilic polymer obtained by insolubilizing the water-soluble hydrophilic polymer in the membrane manufacturing process may, for example, be a water-soluble hydrophilic polymer which is insolubilized in water such that the base material membrane is in the form of a hydrophobic polymer is coated with a water-soluble hydrophilic polymer obtained by copolymerization of a monomer containing an azido group in its side chain and a hydrophilic monomer such as 2-methacryloyloxyethylphosphorylcholine, and then the resulting membrane of the base material is subjected to heat treatment, covalently thereby binding the water-soluble hydrophilic polymer to the base material membrane. In addition, a hydrophilic monomer such as 2-hydroxyalkyl acrylate can also be grafted onto the membrane of the hydrophobic polymer backing material by graft polymerization.

[0028]

In view of preventing adsorption of the protein as a solute, the electrical neutrality of the hydrophilic polymer is preferred.

In the present embodiments, the term "electrically neutral" means "the absence of a charge in the molecule" or means the equality of the number of cations and the number of anions in the molecule.

[0029]

Examples of the hydrophilic polymer include vinyl-based polymers.

Examples of vinyl-based polymers include: homopolymers of hydroxyethyl methacrylate, hydroxypropyl methacrylate, dihydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, polyethylene glycol methacrylate, vinyl pyrrolidone, acrylamide, dimethylacrylamide, glucoxyoxyethyl methacrylate, 3-sulfopropylmethacryloxyethyldimethylammonium betaine, 2-methacryloyloxyethylphospho rilcholine, 1-carboxydimethylmethacryloyloxyethylmethaneammonium and the like; and random copolymers, graft type copolymers, and block type copolymers for a hydrophobic monomer such as styrene, ethylene, propylene, propyl methacrylate, butyl methacrylate, ethylhexyl methacrylate, octadecyl methacrylate, benzyl methacrylate or methoxyethyl methacrylate and a hydrophilic monomer such as hydroxyethyl methacrylate , hydroxypropyl methacrylate, dihydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, polyethylene glycol methacrylate, vinylpyrrolidone, acrylamide, dimethylacrylamide, glucoxyoxyethyl methacrylate, 3-sulfopropylmethacryloxyethyldimethylammoniumbetaine, 2-methacryloyloxyethylphosphorylcholine, or 1-carboxydimethylmethacryloyloxyethyl metaammonium. Preferred are methacrylate-based polymers, and more preferred is polyhydroxyethyl methacrylate.

In addition, examples of the vinyl-based polymer also include copolymers of a cationic monomer such as dimethylaminoethyl methacrylate or diethylaminoethyl methacrylate, an anionic monomer such as acrylic acid, methacrylic acid, vinylsulfonic acid, sulfopropyl methacrylate or phosphoxyethyl methacrylate, and the hydrophobic monomer described above, and a vinyl-based monomer also may be a polymer containing equal amounts of anionic monomers and cationic monomers so as to be electrically neutral.

[0030]

Examples of the hydrophilic polymer also include cellulose, which is a polysaccharide, and cellulose triacetate, which is a cellulose derivative. In addition, polysaccharides and their derivatives include materials obtained by subjecting to hydroxyalkyl cellulose and the like cross-linking treatment.

[0031]

The hydrophilic polymers may be polyethylene glycols and derivatives thereof, block copolymers of ethylene glycol and the hydrophobic monomer described above, random copolymers or block copolymers of ethylene glycol and propylene glycol, ethylbenzyl glycol, and the like. In addition, polyethylene glycols and the copolymers described above can be insolubilized in water by introducing a substituent at one end or both ends of them in the form of a hydrophobic group.

Examples of a compound obtained by introducing a hydrophobic group substituent at one or both ends of polyethylene glycols include α,ω-dibenzylpolyethylene glycols and α,ω-didodecylpolyethylene glycols, and the compound may be, for example, a copolymer of polyethylene glycol and a hydrophobic monomer such as as dichlorodiphenylsulfone containing a halogen group at both ends in its molecule.

[0032]

Examples of the hydrophilic polymer also include polyethylene terephthalates and polyether sulfones, which are obtained by polycondensation, and which are hydrophilized by replacing hydrogen atoms in the main chain of polyethylene terephthalates and polyether sulfones with hydrophilic groups. In hydrophilized polyethylene terephthalates, polyethersulfones, and the like, hydrogen atoms in the main chain may be replaced by anionic groups or cationic groups, or the number of anionic groups and the number of cationic groups may be equal.

[0033]

The hydrophilic polymer may be a polymer obtained by ring-opening an epoxy group in a bisphenol A type or novolac type epoxy resin, or by introducing a vinyl polymer, polyethylene glycol, and the like into an epoxy group.

In addition, the hydrophilic polymer may be suitable polymers coupled using a silane.

The hydrophilic polymers may be used alone or in mixtures of two or more of them.

[0034]

As the hydrophilic polymer, homopolymers of hydroxyethyl methacrylate, hydroxypropyl methacrylate or dihydroxyethyl methacrylate are preferable from the viewpoint of ease of production; and random copolymers of a hydrophilic monomer such as 3-sulfopropylmethacryloxyethyldimethylammonium betaine, 2-methacryloyloxyethylphosphorylcholine, or 1-carboxydimethylmethacryloyloxyethylmethaneammonium and a hydrophobic monomer such as butyl methacrylate or ethylhexyl methacrylate; coating and workability when carrying out coating using a hydrophilic polymer, homopolymers of hydroxyethyl methacrylate or hydroxypropyl methacrylate are more preferred; and random copolymers of a hydrophilic monomer such as 3-sulfopropylmethacryloxyethyldimethylammonium betaine or 2-methacryloyloxyethylphosphorylcholine and a hydrophobic monomer such as butyl methacrylate or ethylhexyl methacrylate.

[0035]

The content level of the hydrophilic polymer is not particularly limited as long as there is no adhesion of the membrane during production of the porous membrane. In terms of water permeability performance or virus removal performance, examples of the lower limit value for the content level of hydrophilic polymer with respect to hydrophobic polymer are 5% by mass. or more, 6% of the mass. or more in another aspect, 7% of the mass. or more in another aspect, 8% of the mass. or more in yet another aspect, 9% of the mass. or more in yet another aspect and 10% of the mass. or more in yet another aspect. In addition, examples of the upper limit value for the level of content of the hydrophilic polymer in relation to the hydrophobic polymer is 20% of the mass. or less, 19% of the mass. or less in another aspect, 18% of the mass. or less in yet another aspect, 17% of the mass. or less in yet another aspect, 16% of the mass. or less in yet another aspect, 15% of the mass. or less in yet another aspect and 14% of the mass. or less in yet another aspect. The ratio between the hydrophilic polymer and the hydrophobic polymer (= weight of hydrophilic polymer/weight of hydrophobic polymer × 100) in the porous membrane hydrophilized by coating may be called the coating ratio. The “weight of hydrophilic polymer” in the expression for calculating the coating ratio is the weight of the hydrophilic polymer by which the base material membrane is coated, and does not include the weight of the hydrophilic polymer incorporated into the base material membrane at the time of preparing the blended membrane of the hydrophobic polymer and the hydrophilic polymer.

[0036]

The porous membrane according to the present embodiments or the base material membrane in the present embodiments may be a membrane obtained by intermixing a hydrophilic polymer and a hydrophobic polymer.

The hydrophilic polymer to be used in forming the blended membrane is not particularly limited as long as the hydrophilic polymer is compatible with a good solvent together with the hydrophobic polymer, but copolymers containing polyvinylpyrrolidone or vinylpyrrolidone are preferred as the hydrophilic polymer.

Specific examples of polyvinylpyrrolidone include LUVITEC (trade name) K 60, K 80, K 85 and K 90, all of which are commercially available from BASF SE, and LUVITEC (trade name) K 80, K 85 and K 90.

As the vinylpyrrolidone-containing copolymer, vinylpyrrolidone-vinyl acetate copolymers are preferred in view of compatibility with hydrophobic polymers and inhibition of interaction between the protein and the membrane surface.

From the point of view of protein adsorption on the membrane surface and interaction with polysulfone-based polymers in the membrane, a copolymerization ratio between vinylpyrrolidone and vinyl acetate in the range between 6:4 and 9:1 is preferred.

Specific examples of the vinylpyrrolidone-vinyl acetate copolymer include LUVISKOL (trade name) VA 64 and VA 73, all of which are commercially available from BASF SE.

The hydrophilic polymers may be used alone or in mixtures of two or more of them.

[0037]

In one embodiment, from the point of view of suppressing the elution of foreign material from the membrane during filtration, it is preferable to wash with hot water after the formation of the mixture membrane in the case of using a water-soluble hydrophilic polymer in the formation of the mixture membrane. As a result of washing, hydrophilic polymers that are not sufficiently entangled with hydrophobic polymers are removed from the membrane, and elution during filtration is suppressed.

As hot water washing, high pressure hot water treatment or hot water treatment after coating can be carried out.

[0038]

In one embodiment, the average value of T for the ratios between the number of ion counts derived from a hydrophilic polymer and the number of ion counts derived from a hydrophobic polymer in a porous membrane is, for example, 1.0 or more when measuring the membrane surface using time-of-flight mass spectrometry of secondary ions (SSMSVI).

[0039]

At an average T value of 1.0 or more, membrane adhesion is reduced. For example, in the presence of a hydrophobic polymer in the form of a polysulfone-based polymer and a hydrophilic polymer in the form of a methacrylate-based polymer, examples of a mechanism for reducing membrane adhesion include a mechanism in which, at an average T value of 1.0 or more, many hydroxyl groups in the polymer per methacrylate base are localized closer to the membrane surface as compared to the case of an average T value of less than 1.0, and water molecules in air bind to hydroxyl groups oriented towards the surface in such a way that a layer of water molecules is formed on the surface, which allows avoid strong membrane adhesion or polymer entanglement.

[0040]

The average value of T is measured in accordance with the method described in accordance with the section "Measurement of the ratio for the number of counts of ions" in the examples.

As the reference ion produced from the hydrophobic polymer, the ion which is the most representative of the hydrophobic polymer is selected and used as the detectable ion for the detection spectrum. As the detectable ion, for example, C ₆ H ₄ O (m/z=92) can be used in the case of a polyethersulfone, and C ₃ F (m/z=55) or C ₄ F (m/z= 67) in the case of PVDF. Examples of criteria for selecting ions to consider include selecting ions that are not identical to corresponding ions of other membrane-forming components and selecting ions that reflect the characteristics of the substance.

As the reference ion produced from the hydrophilic polymer, the ion which is the most representative of the hydrophilic polymer is selected and used as the detectable ion for the spectrum detection. As the detectable ion, for example, C ₄ H ₅ O ₂ (m/z=85) can be used in the case of polyhydroxyethyl methacrylate, C ₄ H ₆ NO (m/z=84) can be used in the case of polyvinylpyrrolidone, and can be used C ₂ H ₃ O ₂ (m/z=59) in the case of polyvinyl acetate.

[0041]

In one embodiment, the average value of T is not particularly limited as long as it is a value that allows the adhesion of the membrane to decrease during membrane manufacture. Examples of the upper limit value for the average T value are 7.0 or less, 6.0 or less, 5.0 or less, 4.0 or less, 3.0 or less, and 2.0 or less, and examples of the lower limit value for the average T value are 1.0 or more, 1.5 or more, 2.0 or more and 2.5 or more.

[0042]

In one embodiment, with a porous membrane, membrane adhesion during manufacture is reduced. In particular, the adhesion of the membrane is reduced after the hydrophilization treatment of the porous membrane. The degree of decrease in the adhesion of the membrane is not particularly limited. For example, the extent to which the adhesion of the membrane is reduced is not particularly limited as long as the adhesion of the membrane is reduced to the extent that tearing of the membranes is not necessary during the manufacture of the membrane module. For example, as can be determined, membrane adhesion is reduced when 4% of the membranes forming the bundle of membranes can be withdrawn without resistance from the hydrophilized bundle of membranes in the presence of membranes converted to the bundle.

[0043]

In one embodiment, the porous membrane has a gradient asymmetric structure. The gradient asymmetric structure is one in which the average pore diameter for fine pores increases from the downstream filtration portion of the membrane to the upstream filtration portion. A porous membrane may show a general trend towards an increase in the average pore diameter for fine pores from the downstream filtration section in the membrane to the upstream filtration section in the thickness direction, and the average pore diameter may locally and slightly reverse the trend. due to structural unevenness or measurement errors. The gradient index for the average pore diameter from a dense layer to a coarse layer is in the range between 0.5 and 12.0.

[0044]

In this document, when liquid is supplied towards the inner surface of a porous membrane, the interval that reaches 10% of the membrane thickness from the inner surface is the upstream filtration section, and the interval that reaches 10% of the membrane thickness from the outer surface, is a downstream filtration section.

[0045]

Herein, in a porous membrane, a field of view having an average pore diameter of 50 nm or less is defined as a dense layer, and a field of view having an average pore diameter of more than 50 nm is defined as a coarse layer.

[0046]

Herein, a dense layer and a coarse layer of a porous membrane are determined by imaging the cross-sectional surface of the membrane using a scanning electron microscope (SEM). For example, the observation field is set horizontally to the membrane thickness direction on an arbitrary section of the membrane cross-sectional surface at magnifications of 50,000. this get an image for the next field of view. By repeating the imaging operation, photographs of the cross-sectional surface of the membrane are obtained without any gap, and the photographs thus obtained are combined to obtain one photograph of the cross-sectional surface of the membrane. In this photograph of the cross-sectional surface, the average pore diameter in the range (2 µm in the perpendicular direction to the membrane thickness direction) × (1 µm from the downstream filtering surface to the upstream side of the filtering surface in the thickness direction membranes) is calculated on each micrometer from the downstream filter surface to the upstream side of the filter surface.

[0047]

Herein, the average pore diameter is calculated using a method using image analysis. Specifically, pore regions and solid regions are binarized using an Image-pro plus product manufactured by Media Cybernetics, Inc. A distinction is made between pore regions and solid regions based on brightness, sections that cannot be distinguished, or noise. adjusted manually using a software utility. The edge section which forms the contour of the pore region and the porous structure observed in the background of the pore region are isolated as the pore region. After binarization, the pore diameter is calculated based on the value of the area of one pore, assuming the presence of a pore profile in the form of a perfect circle. The calculation is carried out for each pore in order to calculate the average pore diameter for each interval of 1 μm×2 μm. As it should be noted, the counts also included continuous sections of pores at the ends of the observation fields.

[0048]

The gradient index for the mean pore diameter from the dense layer to the coarse layer is calculated from the first field of view, which is defined as the dense layer, and the second field of view, which is defined as the rough layer, with the second field of view adjacent to the first field of view . Its position is where the field of view changes from a field of view having an average pore diameter of 50 nm or less, which field of view is defined as a dense layer, to a field of view having an average pore diameter of more than 50 nm, while this field of observation is defined as a coarse layer. The gradient index is calculated using the adjacent fields of observation of the dense layer and the coarse layer. Specifically, the gradient index for the average pore diameter from a dense layer to a coarse layer can be calculated from the expression below.

Gradient index for average pore diameter from dense layer to coarse layer (nm/µm) = (average pore diameter for coarse layer (second observation field) (nm) - average pore diameter for dense layer (first observation layer) (nm) )/1 (µm)

[0049]

In one embodiment, the porous membrane includes a dense layer and a coarse layer. In one embodiment, the porous membrane includes a coarse layer on the upstream side of the filtration surface relative to the dense layer, and the dense layer and the coarse layer are adjacent to each other.

[0050]

In one embodiment, the porous membrane includes a coarse layer on the inner surface area and a dense layer on the outer surface area. In this case, the inner surface portion is the upstream filtration portion and the outer surface portion is the downstream filtration portion.

[0051]

In one embodiment, the dense layer is not particularly limited as long as it is present in at least the downstream filtration section. For example, there may be a dense bed start point at a downstream filtration area and a dense bed end point at a position above the downstream filtration area towards the upstream filtration surface.

[0052]

In one embodiment, the thickness of the dense layer is not particularly limited as long as it is a virus-removable thickness, and examples of dense layer thickness are between 1 and 10 µm, between 1 and 8 µm in yet another aspect, and between 2 and 8 µm in yet another aspect.

[0053]

In the porous membrane, in one embodiment, the degree of presence (%) of fine pores corresponding to 10 nm or less in the dense layer is 8.0% or less, and more preferably 5.0% or less.

The term "degree of presence (%) of small pores corresponding to 10 nm or less in a dense layer" refers to the average value of the values calculated using the expression below for all fields of observation determined as a dense layer based on image analysis. obtained using a SEM microscope.

(Cumulative number of fine pores having a pore diameter of 10 nm or less in one observation field defined as a dense layer/cumulative number of fine pores in the same observation field) × 100

[0054]

In the porous membrane, in one embodiment, the degree of presence (%) of fine pores corresponding to a range between more than 10 nm and 20 nm or less, in a dense layer in the range between 20.0% or more and 35.0% or less is preferable. .

The term "degree of presence (%) of fine pores corresponding to a range between more than 10 nm and 20 nm or less in a dense layer" refers to the average value for the values calculated using the expression below, for all fields of observation defined as a dense layer based on the analysis of images obtained using a SEM microscope.

(Cumulative number of fine pores characterized by a pore diameter in the range between more than 10 nm and 20 nm or less in one observation field defined as a dense layer/cumulative number of fine pores in the same observation field) × 100

[0055]

In a porous membrane, in one embodiment, a dense layer porosity (%) in the range between 30.0% or more and 45.0% or less is preferred.

The term "porosity (%) in the dense layer" refers to the average value of the values calculated using the expression below for all fields of observation, determined as a dense layer based on the analysis of images obtained using an SEM microscope.

(cumulative pore area in one field of view, defined as dense layer/area in the same field of view) × 100

[0056]

In order to achieve protein harvesting in a highly efficient manner while maintaining virus removal performance, a small standard deviation for the pore diameter/average pore size in the dense bed is also important. With a small standard deviation for the value of pore diameters/average pore diameter in the dense layer, the number of excessively large pores present and the number of excessively small pores present are small. According to studies by the present inventors, in order to suppress pore blocking due to protein monomers in a dense layer and collect protein in a highly efficient manner while maintaining virus trapping ability, it is preferable to have a standard deviation of pore diameter/average pore diameter in dense layer of 0.85 or less, and more preferably 0.70 or less.

[0057]

In one embodiment, a porous membrane can be used to filter a protein solution. Specifically, the filtration can remove, for example, the viruses contained in the protein solution. In this case, the pure water permeability is the standard for the flow representing the filtration rate of the protein solution. The filtration rate of the protein solution increases as the pure water permeability increases, despite the lower filtration rate of the protein solution than the pure water permeability due to the higher viscosity of the protein solution solution than that of pure water. Thus, in one embodiment, by increasing the pure water permeability, a protein processing membrane can be obtained that can harvest the protein in a more efficient manner.

[0058]

The virus removal mechanism of the virus removal membrane is discussed as follows. The virus-containing solution permeates the virus removal layer in which a plurality of virus trapping planes are stacked, each perpendicular to the direction of penetration. There is always a distribution of pore sizes in the planes for trapping viruses, and the virus is trapped in a pore having a size smaller than the virus. In this case, the degree of trapping of viruses on a single surface is small, but when a plurality of surfaces are stacked, high virus removal performance is achieved. For example, even though the virus trapping rate is 20% in one plane, when 50 layers of planes are stacked, the total virus trapping rate becomes 99.999%. Many viruses are trapped in the area where the average pore diameter is 50 nm or less.

[0059]

In one embodiment, the pure water permeability of the protein treatment membrane is preferably between 150 and 500 l/(h⋅m ² ⋅bar).

With a pure water permeability of 150 L/(h⋅m ² ⋅bar) or more, protein can be collected in a highly efficient manner. In addition, at a pure water permeability of 500 L/(h⋅m ² ⋅bar) or less, stable virus removal performance can be demonstrated.

[0060]

Herein, the pure water permeability is measured in accordance with the method described in accordance with the "Water permeability measurement" section in the examples.

[0061]

In one embodiment, using the method described above, a porous membrane formed from a hydrophobic polymer that is hydrophilized with a hydrophilic polymer can be realized.

[0062]

In the present embodiments, the term "bubble point (BP)" refers to the pressure at which a bubble forms on the downstream side of the filtration surface when air pressure is applied from the upstream filtration surface in a membrane immersed in hydrofluoroether. When air penetrates through a membrane immersed in a solvent, air penetrates through a pore at the greater applied pressure, the smaller the pore diameter. The maximum pore diameter of the membrane can be estimated as a result of estimating the pressure at the first infiltration of air.

The relationship between bubble point and maximum pore diameter is shown below.

_DBP =4γ⋅cosƟ/BP,

where D _BP is the maximum diameter, γ is the surface tension (n/m) for the solvent, cosƟ is the contact angle (-) between the solvent and the membrane, and BP is the bubble point (MPa).

[0063]

Preferred is a clearance of parvovirus for the porous membrane of 4 or more, and more preferably 5 or more, when expressed in terms of the LRV value in the case of using the porous membrane as a virus removal membrane. From the point of view of similarity to contaminating viruses in the actual purification process and ease of operation, porcine parvovirus (PSV) parvovirus is preferred.

The maximum pore diameter of the membrane refers to the LRV value, and the virus removal performance increases as the bubble point increases, but in order to be able to exhibit the virus removal performance while maintaining the permeability to the protein, which is a suitable component, or from the point From the point of view of controlled maintenance of pure water permeability, a bubble point in the range between 1.40 and 2.00 MPa is preferred, more preferably between 1.40 and 1.80 MPa, even more preferably between 1.50 and 1.80 MPa, and still more preferably between 1.60 and 1.80 MPa.

In the present embodiments, the bubble point is measured in accordance with the method described in accordance with the "Bubble point measurement" section in the examples.

[0064]

Parvovirus clearance is measured according to the method described in accordance with the "Measurement of porcine parvovirus clearance" section in the examples.

[0065]

<Method for producing a porous membrane and method for reducing the adhesion of the membrane>

One embodiment is a method for preparing a porous membrane containing a hydrophobic polymer and a hydrophilic polymer, the method comprising:

a hydrophilization step comprising hydrophilizing the base material membrane with a hydrophilic polymer to obtain a hydrophilized porous membrane, the base material membrane comprising a hydrophobic polymer; And

a control step comprising treating the hydrophilized porous membrane such that the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 or more when measuring the surface of the porous membrane using time -flight mass spectrometry of secondary ions (FSMSVI).

[0066]

One embodiment is a method of reducing membrane adhesion after hydrophilization of a membrane from a base material containing a hydrophobic polymer, the method comprising:

a hydrophilization step comprising hydrophilizing the base material membrane with a hydrophilic polymer to obtain a hydrophilized porous membrane, the base material membrane comprising a hydrophobic polymer; And

a control step comprising treating the hydrophilized porous membrane such that the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is 1.0 or more when measuring the surface of the porous membrane using time -flight mass spectrometry of secondary ions (FSMSVI).

[0067]

In one embodiment, the hydrophilization step is a process for coating a base material membrane as described below. In one embodiment, the control step is a rinsing process and/or a high pressure hot water process on a coated base material membrane in accordance with the following description of the invention. Only one process selected from the washing process and the high pressure hot water treatment process may be carried out, or both of these processes may be carried out.

[0068]

Hereinafter, specific examples of a method for producing a porous membrane and a method for reducing membrane adhesion will be described.

[0069]

In one embodiment, notwithstanding any particular limitation, for example, a porous membrane may be produced as follows. At the same time, the adhesion of the membrane can be reduced. Below in this document is a description of the invention, taking as an example the case of using a polysulfone-based polymer as a hydrophobic polymer.

[0070]

For example, in the case of a hollow fiber membrane, a solution obtained by mixing and dissolving a polysulfone-based polymer, a solvent and a non-solvent, and then degassing the resulting mixture is used as the membrane spinning solution. The membrane-forming spinning solution is ejected simultaneously with the liquid internal precipitant, respectively, from the annular section and the central section of the twin-tube nozzle (die) and is introduced into the coagulation bath through the air gap section to obtain a membrane. The resulting membrane is wound after washing with water, subjected to liquid removal in a hollow section, and then heat treated and dried. Following this, the resulting membrane is subjected to a hydrophilization treatment.

For the case of a flat membrane, as a membrane-forming spinning solution, for example, a solution obtained by mixing and dissolving a polysulfone-based polymer, a solvent and a non-solvent, and then degassing the resulting mixture is used. The membrane-forming dope is formed into a membrane using a typical process known in the art. In one exemplary process, a membrane dope is cast onto a support and the cast membrane is introduced into a non-solvent to induce phase separation. Thereafter, the membrane is introduced into a solvent that is a non-solvent for the polymer (for example, water, alcohol, or a mixture thereof), the solvent is removed, and the membrane is dried, whereby a porous membrane can be obtained. Following this, the resulting membrane is subjected to a hydrophilization treatment.

[0071]

As a solvent for use in the membrane dope, a wide range of solvents can be used as long as the solvent is a good solvent for polysulfone based polymers such as N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF ), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide or ε-caprolactam, but amide-based solvents such as NMP, DMF and DMAc are preferred, and NMP is more preferred.

[0072]

It is preferable to add a non-solvent to the membrane-forming dope. Examples of the non-solvent for use in the membrane dope include glycerol, water, and diol compounds, and diol compounds are preferred.

The term "diol compound" refers to a compound having a hydroxy group at both ends of the molecule, and as a diol compound, a compound which has the following formula 3 and which has an ethylene glycol structure having a repeating unit number n of 1 is preferable. or more.

Examples of the diol compound include diethylene glycol (DEG), triethylene glycol (TriEG), tetraethylene glycol (TetraEG), and polyethylene glycols (PEG) are preferred, and DEG, TriEG and TetraEG are preferred, and TriEG is more preferred.

[0073]

Formula 3:

[0074]

The detailed mechanism is unclear, but the addition of a non-solvent to the membrane dope increases the viscosity of the membrane dope, which suppresses the diffusion rate of the solvent and non-solvent in the coagulation liquid, thereby facilitating the controlled maintenance of coagulation and the preferred structure as a porous membrane, and is therefore suitable for use in obtaining the desired structure.

Preferred is a solvent/non-solvent ratio in the membrane spinning dope between 20/80 and 80/20 when expressed as a weight ratio.

[0075]

In view of membrane strength and penetration performance, a concentration of the polysulfone-based polymer in the membrane-forming dope in the range of between 15 and 35 wt %, and more preferably between 20 and 30 wt %, is preferred.

[0076]

The membrane-forming dope is obtained by dissolving a polysulfone-based polymer, a good solvent and a non-solvent with stirring at a constant temperature. Due to air oxidation of tertiary or lower nitrogen compounds (NMP, DMF, DMAc) and easy further oxidation by heating the compounds, a temperature of 80° C. or less is preferred at the time of dissolution of the compounds. In addition, it is preferable to obtain a membrane spinning solution in an inert gas atmosphere or in a vacuum. Examples of the inert gas include nitrogen and argon, and nitrogen is preferred from a production cost point of view.

[0077]

It is preferable to carry out defoaming for the membrane-forming spinning solution in view of suppressing the occurrence of defects after formation of the membrane and preventing fiber breakage during spinning in the case of a hollow fiber membrane.

The technological process of degassing can be carried out as follows. The pressure in the interior of the vessel containing the completely dissolved membrane dope is reduced to 2 kPa and the membrane dope is allowed to settle for 1 hour or more. The operation is repeated 7 times or more. The solution may be stirred during degassing in order to improve the efficiency of degassing.

[0078]

<Method of producing hollow fiber membrane)

When using the above-described membrane spinning dope, a hollow fiber membrane is obtained using the following processes.

[0079]

It is preferable to remove foreign material from the membrane dope prior to ejection from the spinneret. The removal of foreign material can prevent fiber breakage during spinning and allow controlled maintenance of the membrane structure. It is preferable to install a filter before ejecting the membrane-forming dope solution from the spinneret, also to prevent contamination by foreign material from the seal of the dope tank and the like. Filters having different pore diameters can be installed in a multi-stage configuration and are not particularly limited, for example, it is suitable to use a mesh filter having a pore diameter of 30 µm and a mesh filter having a pore diameter of 10 µm, in this order from the position closest to the membrane-forming dope tank.

[0080]

With regard to the composition of the liquid internal precipitant for use in membrane formation, it is preferable to use the same component as the component used in the good solvent for use in the membrane dope or coagulation liquid.

For example, when using NMP as the solvent for the membrane spinning solution and using the NMP/water system as the good solvent/non-solvent system for the coagulation liquid, it is preferable to form a liquid internal precipitant from NMP and water.

By increasing the amount of solvents in the liquid internal precipitator, the effect of slowing down the passage of coagulation is found, which allows the formation of the membrane structure to proceed slowly, and by increasing the amount of water, the effect of accelerating the passage of coagulation is found. In order to adequately facilitate coagulation in order to maintain the membrane structure in a controlled manner while obtaining a thus preferred membrane structure, a good solvent/water ratio in the liquid internal precipitant in the range between 60/40 and 80/20 expressed as a weight ratio is preferred for a porous membrane.

[0081]

In order to obtain proper pore diameters, a die temperature in the range between 25 and 50°C is preferred.

The membrane-forming spinning solution is introduced into the coagulation bath through the air gap section after ejection from the spinneret. A dwell time in the air gap region between 0.02 and 1.0 seconds is preferred. By setting the holding time to 0.02 seconds or more, coagulation is made sufficient before being introduced into the coagulation bath, and pore diameters can be made appropriate. By setting the holding time to 1.0 seconds or less, excessive passage of the membrane can be prevented, and precise controlled holding of the membrane structure in the coagulation bath can be achieved.

[0082]

In addition, it is preferable to seal the air gap portion. The detailed mechanism is not clear, but it is believed that by sealing the air gap portion in the air gap portion, an atmosphere of water vapor and a good solvent is formed, which allows the phase separation to proceed slowly before the membrane-forming dope is introduced into the coagulation bath, thereby suppressing the formation excessively small pores and decreasing the value of the coefficient of variation of pore diameters.

[0083]

The spinning speed is not particularly limited as long as the spinning speed satisfies the conditions under which a membrane without defect can be obtained, but in order to slow down the exchange of liquid between the membrane and the coagulation bath in the coagulation bath and to control the maintenance of the membrane structure, it is preferable if possible. lower spinning speed. Accordingly, in terms of productivity and solvent exchange, the spinning speed is preferably between 4 and 15 m/min.

[0084]

The term "draw ratio" refers to the ratio between the withdrawal rate and the linear rate of ejection of the membrane spinning dope from the spinneret. The term "high draw ratio" means a high draw ratio after ejection of the membrane spinning dope from the spinneret.

In general, for the case of producing a membrane using a wet phase separation process, the structure of the membrane is almost certain when the membrane-forming dope exits the coagulation bath through the air gap region. The internal space of the membrane is configured from continuous areas obtained as a result of the entanglement of polymer chains, and pore areas where the polymer is absent. The detailed mechanism is not clear, but when the membrane is overstretched to completion of coagulation, in other words, when the membrane is overstretched to polymer chain entanglement, the polymer chain entanglement breaks and the pore regions are connected, and as a result, excessively large pores are formed, or the pore regions are separated. , and excessively small pores are formed as a result. Excessively large pores cause viruses to leak out, and excessively small pores cause clogging.

In view of the controlled holding of the structure, it is preferable to reduce the draw ratio as much as possible, and the stretch ratio is preferably in the range between 1.1 and 6, and more preferably between 1.1 and 4.

[0085]

The membrane-forming spinning solution passes through the filter and spinneret, coagulates moderately in the air gap region, and is then introduced into the coagulation liquid. The detailed mechanism is not clear, but it is believed that by reducing the spinning speed, the fluid film obtained at the interface between the outer surface of the membrane and the coagulation liquid becomes thick, and the liquid exchange at this interface is slow, thereby allows the coagulation to proceed slowly compared to the coagulation for the case of high spinning speed, and therefore the transition roll for the average pore diameter from the dense layer to the coarse layer becomes smooth.

A good solvent exhibits an effect of slowing down coagulation, water exhibits an effect of accelerating coagulation, and therefore, in order to be able to proceed with coagulation at a proper speed to obtain an adequate thickness of a dense layer, thus obtaining a membrane having a preferred pore diameter, a good solvent/water ratio is preferred. in relation to the composition of the coagulation fluid in the range between 50/50 and 5/95 when expressed in terms of a mass ratio.

In view of the controlled maintenance of the pore diameter, a coagulation bath temperature between 10 and 40°C is preferred.

[0086]

The membrane pulled out of the coagulation bath is washed with warm water.

In the water washing process, it is preferable that the good solvents and non-solvents are necessarily removed. When the membrane is dried while containing a solvent, the solvent is concentrated in the membrane during drying and the polysulfone-based polymer dissolves or swells. As a result, it is possible to change the structure of the membrane.

In order to increase the diffusion rate of the solvents and non-solvents to be removed and to increase the water washing efficiency, a warm water temperature of 50° C. or more is preferable.

In order to sufficiently carry out the water wash, the residence time of the membrane in the water wash bath is preferably between 10 and 300 seconds.

[0087]

The membrane pulled out of the water washing bath is wound onto a bobbin using a winder. In this case, when winding the membrane in air, the membrane gradually becomes dried, and the membrane can only shrink slightly. In order to obtain identical membrane structures, it is preferable to wind the membranes in water in order to obtain homogeneous membranes.

[0088]

Both ends of the membrane wound on the bobbin are cut off and then the membrane is converted into a bundle and held by a support to prevent loosening of the arrangement. The membrane thus retained is flushed by the liquid supply in the particulate removal process.

On the hollow section of the membrane, wound on a bobbin, there remains a liquid that has become cloudy to white. Suspended in the liquid are polysulfone-based polymer particles ranging in size from nanometers to micrometers. When the membrane is dried without removing the liquid that has become cloudy, the particles can block the pores of the membrane, which degrades the performance of the membrane, and therefore it is preferable to remove the liquid in a hollow section in the particle removal process.

In the water immersion process, diffusion removes the good solvents and non-solvents contained in the membrane.

In the water immersion process, water temperatures in the range between 10 and 30° C. and immersion times in the range between 30 and 120 minutes are preferred.

It is preferable to carry out the dive water exchange several times.

[0089]

It is preferred that the wound membrane be treated with high pressure hot water. Specifically, it is preferable to place the membrane in the high-pressure steam sterilizer in a state of complete immersion of the membrane in water, and to carry out treatment for 2 to 6 hours at a temperature of 120° C. or more. The detailed mechanism is not clear, but using high pressure hot water treatment not only completely removes solvents and non-solvents slightly remaining in the membrane, but also optimizes entanglement and the state of being of polysulfone-based polymers in the dense layer region.

[0090]

The manufacture of the membrane from the base material containing the polysulfone-based polymer is completed by drying the membrane subjected to high pressure hot water treatment. The drying method such as air drying, reduced pressure drying, or hot air drying is not particularly limited, but it is preferable to dry the membrane in a state where both ends are fixed so that the membrane does not shrink during drying.

[0091]

In one embodiment, the base material membrane becomes a porous hollow fiber membrane through a coating process.

For example, in the case of hydrophilization treatment as a result of coating, the coating process includes: an immersion process of dipping a membrane of a base material into a coating liquid; a liquid de-liquid process of de-liquid in the form of excess liquid for coating the submerged membrane of the base material; and a drying process of drying the base material membrane free of liquid. In addition, a membrane washing process may be provided before and after the drying process.

In the immersion process, a base material membrane is immersed in a hydrophilic polymer solution in a beam-forming state. The solvent of the coating liquid is not particularly limited as long as the solvent is a good solvent for a hydrophilic polymer and also a poor solvent for polysulfone-based polymers, but alcohols are preferred.

From the point of view of suppressing the decrease in flow over time due to protein adsorption during filtration by sufficiently coating the pore surface of the membrane of the base material of the hydrophilic polymer coating, a lower limit value for the concentration of the hydrophilic polymer in the coating liquid of 0.5% is preferable. wt. or more. The upper limit value for the concentration is not particularly limited as long as the adhesion of the membrane is reduced, but from the point of view of preventing the decrease in flow due to an excessively small pore diameter as a result of coating the surface of the pores having a proper thickness, the upper limit value for concentration of 20.0% of the mass. or less, and preferably 10.0% of the mass. or less.

Preferred is the time of immersion of the membrane of the base material in the coating liquid, for example, in the range between 1 and 72 hours, and preferably between 1 and 24 hours.

[0092]

The base material membrane immersed in the coating liquid for a predetermined time is de-liquided in a de-liquid process in which liquid is released in the form of excess coating liquid adhering to the hollow portion and outer circumference of the membrane. The liquid-discharging method may be a liquid-discharging method such as a centrifugation method or a suction-liquid-discharging method, and in order to remove the remaining coating liquid, it is preferable to set the centrifugal force during the centrifugation operation to 10 G or more, and setting the time for the centrifugation operation to be 10 minutes or more, and in the case of methods other than centrifugation, it is preferable to use deliquid conditions in which a removal efficiency equivalent to the removal efficiency of the centrifugation method described above can be obtained.

[0093]

In order to remove the coating liquid that was not removed in the de-liquid process, a washing process may be added after the de-liquid process. As a result of the washing process, the average T value can be adjusted, and specifically, the average T value can be increased.

[0094]

The washing liquid is not particularly limited as long as it is a poor solvent for polysulfone-based polymers, but an aqueous alcohol solution is preferred, and an aqueous methanol solution is more preferred. From the point of view of exfoliation of the hydrophilic polymer adhering to the membrane, the alcohol concentration in the aqueous solution is preferably between 0 and 25%.

The time for the washing process can be appropriately adjusted until the desired average T is reached. In addition, a plurality of washing processes can be carried out until the desired average T is reached.

[0095]

The flushed hollow fiber membrane is de-liquided in a de-liquid process in which liquid is released in the form of excess flush liquid adhering to the hollow portion and outer circumference of the membrane. The liquid discharge method may be a liquid discharge method such as a centrifugation method or a suction liquid discharge method, and in order to remove the remaining hydrophilic polymers, it is preferable to set the centrifugal force during the centrifugation operation to 10 G or more, and to set the time for a centrifugation operation of 10 minutes or more, and for the case of methods other than centrifugation, it is preferable to use deliquid conditions in which a removal efficiency equivalent to the removal efficiency of the centrifugation method described above can be obtained.

[0096]

By drying the liquid-free membrane, a porous hollow fiber membrane according to the present embodiments can be obtained. The drying method is not particularly limited, but vacuum drying is preferred because it is the most efficient.

The internal diameter of the porous hollow fiber membrane is preferably between 200 and 400 µm due to ease of processing into a membrane module. Examples of the upper limit value for the membrane thickness are 200 µm or less, 150 µm or less in another aspect, 100 µm or less in another aspect, and 80 µm or less in another aspect, and examples of the lower limit value for the membrane thickness are 20 µm or more, 30 µm or more in yet another aspect, 40 µm or more in yet another aspect, and 50 µm or more in yet another aspect.

[0097]

It is preferred that the dried hollow fiber membrane be subjected to a high pressure hot water treatment process. As a result of the high pressure hot water treatment process, the average T value can be adjusted, and specifically, the average T value can be increased.

[0098]

Process conditions for high pressure hot water treatment can be appropriately adjusted to achieve the desired average T value, but it is preferable, for example, to place the membrane in a high pressure steam sterilizer with the membrane completely immersed in water and to treat the membrane at a temperature component 120°C or more, for 1 hour or more. The present high-pressure hot water process is a high-pressure hot water process that is carried out after the base material membrane is coated, and which is clearly different from the high-pressure hot water process that is carried out at a temperature of 120°C. C or more, for 2 to 6 hours per step prior to coating the base material membrane. A variety of high pressure hot water processes can be carried out up to the desired average T value. The high pressure hot water process removes low molecular weight components in the hydrophilic polymer molecules supported on the membrane, so that the number of eluates can be reduced. from the membrane, and small pores in the membrane may also be opened.

[0099]

By drying the membrane subjected to high pressure hot water treatment, a porous hollow fiber membrane according to the present embodiments can be obtained. The drying method is not particularly limited, but vacuum drying is preferred due to its greatest efficiency.

[0100]

Only one process selected from the washing process and the high pressure hot water treatment process may be carried out, or both of these processes may be carried out.

[0101]

(Method of obtaining a flat membrane)

Using the above-described membrane-forming dope, a flat membrane is obtained using the following manufacturing processes.

The membrane-forming dope can be cast onto the support using any of the various casting machines known in the art. The support is not particularly limited as long as it is a material that does not create problems in making the membrane, and in one embodiment, examples of the support include nonwoven materials.

[0102]

The cast membrane is passed through a dry section of a predetermined length as needed, then sent to a coagulation bath and immersed and coagulated. One example of the temperature of the membrane spinning dope during casting is between 25° C. or more and 50° C. or less. One example of the thickness of the porous membrane is in the range between 20 µm or more and 100 µm or less.

[0103]

The membrane-forming dope cast on the support comes into contact with the coagulation liquid and coagulates to form a porous membrane. As the coagulation liquid, a non-solvent or a mixed solution containing a non-solvent and a solvent can be used. In this case, it is preferable to use water as the non-solvent and to use the solvent used during the preparation of the dope as the solvent. For example, when used as a solvent for the NMP membrane spinning solution and used as a good solvent/non-solvent for the coagulation liquid of the NMP/water system, a coagulation liquid formed from NMP and water is preferred. One example of the level of non-solvent in the coagulation liquid is in the range between 50% of the mass. or more and 95% of the mass. or less. One example of the temperature of the coagulation liquid is in the range between 10°C or more and 40°C or less.

[0104]

The shape in which the dope is brought into contact with the coagulation liquid is not particularly limited as long as the coagulation liquid and the membrane-forming dope cast on the support come into contact with each other sufficiently to enable coagulation. The shape may be the shape of a liquid bath in which the coagulation liquid is accumulated. In addition, in the liquid bath, if necessary, circulation or renewal of the liquid, the temperature and composition of which is controlled, can be ensured. The shape of the liquid bath is most suitable for use, but in some cases, the liquid may flow through the tube, or the coagulation liquid may be atomized using a spray gun or the like.

[0105]

The membrane, after being brought into contact with the coagulation liquid, is brought into contact with a liquid which is a non-solvent for the membrane materials, thereby removing the solvents. For the case of drying the membrane while containing solvents, it is possible for solvents to be concentrated in the membrane during drying in such a way that the polysulfone-based polymer dissolves or swells, resulting in a change in the structure of the membrane.

[0106]

Examples of the non-solvent used include water, alcohols, and mixtures thereof, and in order to improve washing efficiency, one example of the temperature of the non-solvent is 50° C. or more.

[0107]

For effective washing, one example of the residence time of the membrane in the bath for washing is in the range between 10 and 300 seconds.

[0108]

The washed membrane is dried to complete the manufacture of the membrane from the base material containing the polysulfone-based polymer. The drying method is air drying, vacuum drying, hot air drying, and the like, and is not particularly limited.

[0109]

In one embodiment, the base material membrane is tufted and contacted with a liquid in which a hydrophilic polymer is dissolved (sometimes referred to as "coating liquid"), thereby rendering the base material membrane hydrophilic. The form in which the base material membrane is brought into contact with the coating liquid is not particularly limited as long as the base material membrane is given the desired hydrophilicity. The shape may be the shape of a liquid bath in which the coating liquid is accumulated. In addition, in the liquid bath, if necessary, circulation or renewal of the liquid, the temperature and composition of which is controlled, can be ensured. The shape of the liquid bath is the most suitable for use, but in some cases the liquid may leak through the tubing.

[0110]

The membrane, after being brought into contact with the coating liquid, can be washed using a washing process. As a result of the washing process, the average T can be adjusted, and specifically, the average T can be increased.

[0111]

The washing liquid is not particularly limited as long as it is a poor solvent for polysulfone-based polymers, but an aqueous alcohol solution is preferred, and an aqueous methanol solution is more preferred. From the point of view of exfoliation of the hydrophilic polymer adhering to the membrane, the alcohol concentration in the aqueous solution is preferably between 0 and 25%.

[0112]

The wash process time can be appropriately adjusted until the desired average T is reached. In addition, a plurality of wash processes can be carried out until the desired average T is reached.

[0113]

The membrane after the washing process is dried by performing air drying, vacuum drying, hot air drying, and the like.

[0114]

Preferably, the membrane is subjected to a high pressure hot water treatment process after drying. As a result of the high pressure hot water treatment process, the average T value can be adjusted, and specifically, the average T value can be increased.

Process conditions for the high pressure hot water treatment can be appropriately adjusted to achieve the desired average T value, but it is preferable, for example, to place the membrane in a high pressure steam sterilizer with the membrane completely immersed in water and process at a temperature of 120°C or more for 1 hour or more. A variety of high pressure hot water processes can be carried out up to the desired average T value. The high pressure hot water process removes low molecular weight components in the hydrophilic polymer molecules supported on the membrane, so that the number of eluates can be reduced. from the membrane, and small pores in the membrane may also be opened.

[0115]

Only one process selected from the washing process and the high pressure hot water process may be carried out, or both of these processes may be carried out.

[0116]

The membrane treated with high pressure hot water is dried by a drying method such as air drying, vacuum drying or hot air drying, whereby a porous membrane according to the present embodiments can be obtained.

Examples

[0117]

Hereinafter, the present invention will be described in detail using examples, but the present invention is not limited by the following examples. The test methods shown in the examples are as follows.

[0118]

(1) Measuring the inner diameter and thickness of the membrane

The inner diameter and thickness of the membrane for the hollow fiber membrane are determined by taking an image of a vertically torn cross section of the porous hollow fiber membrane using a stereoscopic microscope. The thickness of the membrane is determined as (outer diameter - inner diameter)/2.

In addition, the area of the membrane is calculated from the internal diameter and the effective length of the membrane.

The membrane thickness for a planar membrane is determined by imaging a vertically torn cross section of a planar membrane using a stereoscopic microscope.

[0119]

(2) Ratio measurement for ion counts

The porous hollow fiber membrane is wrapped with powder paper and sandwiched between glass slides to flatten the membrane, and then, using a ULBAC-PHI INCORPORATED nano-TOF apparatus, the number of counts of ions produced from the hydrophobic polymer is measured on the outer surface of the porous hollow fiber membrane, wherein one outer surface of the flattened hollow fiber membrane is defined as the measurement surface. As a section to be analyzed in the hollow fiber membrane, the second part of the hollow fiber membrane obtained by converting the membrane into a bundle and dividing it into three equal parts is cut out about 1 cm in the lengthwise direction of the fiber and analyzed. Measurement conditions are given as primary ion: Bi ₃ ⁺⁺ , accelerating voltage: 30 kV, current: approximately 0.1 nA (as DC), analysis area: 600 μm×600 μm, and total time: 30 minutes and the spectrum was detected using a detector using the ion most representative of the hydrophobic polymer (C ₆ H ₄ O (m/z=92) in the following examples and comparative examples) as the detection ion. With regard to the characteristics of this measuring apparatus, the depth of measurement corresponds to an interval of 1 to 2 nm from the surface. The number of counts of ions produced from the hydrophilic polymer is measured under similar measurement conditions when detection is carried out using the ion most representative of the hydrophilic polymer (C ₄ H ₅ O ₂ (m/z=85) in the following examples and comparative examples) . The resolution for the area of analysis during measurement is defined as 256 × 256 pixels. The measured data is processed using the WincadenceN product, which is an embedded software. The resolution for the analysis area during data processing is defined as 256 × 256 pixels. The ratio between the number of counts of ions produced from the hydrophilic polymer (Ti) and the number of counts of ions produced from the hydrophobic polymer (To) (T ¹ =Ti/To) is determined, which is detected from a rectangular area of 1 image element in the circumferential direction. hollow fiber membrane and 400 µm in the fiber length direction of the hollow fiber membrane. Calculate the average value ( ^TA ) for the values of T ¹ from one end to the other end of the hollow fiber in the circumferential direction on the area of analysis in the method VPMSV. In addition, when using such a method, the average value (T ^B ) for T ¹ is also determined in relation to the other outer surface corresponding to the background of the one outer surface described above. In this case, a position at a distance in the range between approximately 1 and 2 cm from the measurement site on the above-described one outer surface in the direction along the length of the fiber can be used as the measurement site. As a result of obtaining the average value for T ^A and T ^B , T is determined. In this case, the end of the hollow fiber in the analysis area is determined as the area where the average intensity of the ions produced from the hydrophobic polymer on the outer surface of the hollow fiber is less than 80 % of the average for the intensities of hydrophobic polymer-derived ions on 50 pixels at the center of the outer surface of the hollow fiber.

[0120]

How the average T value is determined will be described in more detail. First, the ratio between the number of counts of ions produced from the hydrophilic polymer (Ti ⁿ ) and the number of counts of ions produced from the hydrophobic polymer (To ⁿ ) is determined (T ⁿ =Ti ⁿ / To ⁿ ), which is detected from a rectangular area of 1 pixel in the circumferential direction of the hollow fiber membrane and 400 µm in the lengthwise direction of the fiber of the hollow fiber membrane. In this case, n represents the number of rectangular regions, where in the area of analysis in the HMLMS method, one end of the hollow fiber membrane in a direction orthogonal to the direction of movement of the membrane during membrane formation is the first rectangular region, and the other end is the nth rectangular region. After determining all values from T ¹ to T ⁿ calculate the average value (T ^A ) for the values from T ¹ to T ⁿ . In addition, when using such a method, the average value (T ^B ) for the values from T ¹ to T ⁿ is also determined in relation to the other outer surface corresponding to the background of the one outer surface described above. In this case, a position at a distance in the range between approximately 1 and 2 cm from the measurement site on the above-described one outer surface in the direction along the length of the fiber can be used as the measurement site. As a result of obtaining the average value for T ^A and T ^B, T is determined.

[0121]

The length of one side of the analysis area may be appropriately set to a multiple of 1 or more or less than 1.5 with respect to the length between both ends of the flattened hollow fiber membrane in the circumferential direction, and is preferably, for example, 1.2 times the length between both ends of the flattened hollow fiber membrane in the circumferential direction. In addition, to determine T ^{n ,} the length of the rectangular region in the fiber length direction may be 2/3 or more of the analysis field of view, and is preferably 2/3 of the analysis field of view, for example.

[0122]

In addition, the number of counts of ions produced from the hydrophobic polymer on the surface of the flat membrane can be measured similarly to the case of a hollow fiber membrane, but the operation of wrapping the membrane with powder paper and flattening the membrane is not necessary. As the area analyzed on a flat membrane, choose any area of the resulting flat membrane. The measurement conditions, analysis area and total time are similar to those of the hollow fiber membrane. For the case of a flat membrane, the ratio between the number of ion counts produced from the hydrophilic polymer (Ti ⁿ ) and the number of ion counts produced from the hydrophobic polymer (To ⁿ ) (T ⁿ =Ti ⁿ /To ⁿ ) is determined, which is detected from a rectangular an area of 1 pixel in the direction orthogonal to the direction of movement of the membrane during membrane formation, and 400 μm in the direction of movement of the planar membrane during membrane formation. In this case, n represents the number of rectangular regions, where in the area of analysis in the PMLS method, one end of the flat membrane in a direction orthogonal to the direction of movement of the membrane during membrane formation is the first rectangular region, and the other end is the n-th rectangular region. For example, in the presence of a membrane over the entire analysis area, n is 256. After determining all values from T ¹ to T ⁿ , calculate the average value (T ^A ) for values from T ¹ to T ⁿ . In addition, when using such a method, the average value (T ^B ) for the values from T ¹ to T ⁿ with respect to the other surface is also determined. In this case, a position at a distance in the range between approximately 1 and 2 cm from the measurement site on the above-described one outer surface in the direction of movement during formation of the flat membrane can be used as the measurement site. As a result of obtaining the average value for T ^A and T ^B, T is determined.

[0123]

(3) Water permeability measurement

Using dead-end filtration at a constant pressure of 1.0 bar, the amount of filtered pure water at 25° C. was measured using a membrane module manufactured to give an effective membrane area of 3 cm ² , and the water permeability was calculated from the filtration time.

[0124]

(4) Bubble point measurement

The downstream side of the filtration surface of the membrane in a membrane module constructed to give an effective membrane area of 0.7 cm ² is filled with hydrofluoroether, after which the pressure is increased using compressed air from the upstream side of the filtration in a dead-end system and as the bubble point, determine the pressure when bubble formation is confirmed from the downstream filtering surface (when an air flow rate of 2.4 ml/min is reached).

[0125]

(5) Immunoglobulin filtration test

The membrane, made in such a way as to obtain an effective membrane area of 3 cm ² , is subjected to a sterilization treatment with high pressure steam at 122° C. for 60 minutes. Prepare a solution using the product Venoglobulin IH 5% IV (2.5 g/50 ml) available commercially from Mitsubishi Tanabe Pharma Corporation so as to obtain an immunoglobulin concentration of 15 g/l, a sodium chloride concentration of 0.1 mol /l and pH 4.5. The resulting solution is subjected to dead-end filtration at a constant pressure of 2.0 bar for 180 minutes.

Based on the amount of filtrate collected over 180 minutes, the concentration of immunoglobulin in the filtrate, and the area of the filter membrane, the integrated immunoglobulin permeability over 180 minutes is calculated.

[0126]

(6) Measurement of porcine parvovirus clearance

(6-1) Preparation of filter solution

Prepare a solution using the product Venoglobulin IH 5% I.V. (2.5 g/50 ml) available commercially from Mitsubishi Tanabe Pharma Corporation, so as to obtain an immunoglobulin concentration of 15 g/l, a sodium chloride concentration of 0.1 mol /l and pH 4.5. As a filter solution, a solution obtained by injecting a 0.5% (vol.) solution of porcine parvovirus (SPV) into the resulting solution is used.

(6-2) Membrane sterilization

The membrane, made in such a way as to obtain an effective membrane area of 3 cm ² , is subjected to a sterilization treatment with high pressure steam at 122° C. for 60 minutes.

(6-3) Filtering

The solution obtained in position (1) is subjected to dead-end filtration at a constant pressure of 2.0 bar for 180 minutes.

(6-4) Virus clearance

The titer (TCID ₅₀ value) of the filtrate obtained by filtering the filter solution is measured using a virological test. Virus clearance for PPV is calculated from the expression LRV=Log (TCID ₅₀ )/ml (filter solution) - Log (TCID ₅₀ )/ml (filtrate).

As it should be noted, a porous hollow fiber membrane according to one aspect of the present invention, which has a coverage ratio of approximately 10%, as demonstrated in Example 2 below, has been confirmed to show an LRV value of greater than 5.

[0127]

(Example 1)

As the membrane spinning solution, a solution obtained by mixing 24 mass parts of PES (ULTRASON (R) E 6020 P, manufactured by BASF SE), 31 mass parts of NMP (manufactured by Kishida Chemical Co., Ltd.) and 45 mass parts TriEG (manufactured by Kanto Chemical Co., Inc) under reduced pressure. The membrane-forming dope solution was ejected from the annular portion of the twin-tube nozzle, and a mixed liquid of 77 mass parts of NMP and 23 mass parts of water was ejected as liquid internal precipitator from the central portion. The ejected membrane-forming dope and liquid internal precipitant were introduced into a coagulation bath containing a coagulation liquid of 15 mass parts of NMP and 85 mass parts of water and having a temperature of 18.5° C. through the air gap sealed portion.

The membrane pulled from the coagulation bath was wound in water using a bobbin. The spinning speed was set to 5 m/min and the draw ratio was set to 1.79.

The wound membrane is cut off at both ends of the bobbin, converted into a bundle, and held at both ends by a support to prevent loosening of the assembly. The membrane was subjected to high-pressure hot water treatment at 128° C. for 6 hours, and then dried under reduced pressure to obtain a hollow fiber membrane from the base material.

The resulting hollow fiber membrane from the base material was formed into a bundle, immersed in a coating liquid containing 1.7 mass parts of polyhydroxyethyl methacrylate (manufactured using 2-hydroxyethyl methacrylate (manufactured by Kanto Chemical Co., Inc.), the same applies below in herein) having a weight average molecular weight of 120,000 and 98.3 parts by mass of methanol (manufactured by Wako Pure Chemical Industries, Ltd., the same applies hereinafter) for 20 hours, and then subjected to centrifugal evacuation of liquid at 537 G for 10 minutes. The fiber bundle, after being freed from liquid, was dried under reduced pressure for 20 hours. The vacuum dried fiber bundle was subjected to high pressure hot water treatment at 128°C for 60 minutes, and the treated fiber bundle was immersed in water at 20°C for 20 hours. The operation of high pressure hot water treatment and water immersion was carried out again, and the fiber bundle was dried under reduced pressure for 20 hours to obtain a fiber porous membrane.

As confirmed, four fibers were easily removed from the obtained fiber bundle, and membrane adhesion did not take place.

[0128]

(Example 2)

A hollow fiber porous membrane was obtained in the same manner as in Example 1, except that, after centrifugal emptying of the liquid, the fiber bundle was washed with a washing liquid containing 15 mass parts of methanol and 85 mass parts of water at a flow rate of 350 ml/min for 60 minutes. and the fiber bundle after washing was centrifugally de-liquided again at 537 G for 10 minutes.

[0129]

(Example 3)

A hollow fiber porous membrane was obtained in the same manner as in Example 2, except that the high pressure hot water treatment and the water immersion treatment were not carried out.

[0130]

(Example 4)

A hollow fiber porous membrane was prepared in the same manner as in Example 1, except for changing the composition of the coating liquid to 1.1 mass parts of polyhydroxyethyl methacrylate and 98.9 mass parts of methanol.

[0131]

(Example 5)

A hollow fiber porous membrane was obtained in the same manner as in Example 4, except that, after centrifugal emptying of the liquid, the fiber bundle was washed with a washing liquid containing 15 mass parts of methanol and 85 mass parts of water at a flow rate of 350 ml/min for 60 minutes. and the fiber bundle after washing was centrifugally de-liquided again at 537 G for 10 minutes.

[0132]

(Example 6)

A hollow fiber porous membrane was obtained in the same manner as in Example 1, except for changing the composition of the coating liquid to 2.3 mass parts of polyhydroxyethyl methacrylate and 97.7 mass parts of methanol.

[0133]

(Example 7)

A hollow fiber porous membrane was obtained in the same manner as in Example 6, except that, after centrifugal emptying of the liquid, the fiber bundle was washed with a washing liquid containing 15 mass parts of methanol and 85 mass parts of water at a flow rate of 350 ml/min for 60 minutes. and the fiber bundle after washing was centrifugally de-liquided again at 537 G for 10 minutes.

[0134]

(Example 8)

A hollow fiber porous membrane was obtained in the same manner as in Example 1, except for changing the composition of the coating liquid to 5.0 mass parts of polyhydroxyethyl methacrylate and 95.0 mass parts of methanol, after centrifugally emptying the fiber bundle from the liquid, washing the fiber bundle with washing liquid, containing 15 mass parts of methanol and 85 mass parts of water, at a flow rate of 350 ml/min for 60 minutes and the fiber bundle after washing was subjected to centrifugal release from the liquid again at 537 G for 10 minutes.

[0135]

(Example 9)

A hollow fiber porous membrane was obtained in the same manner as in Example 8, except for changing the composition of the coating liquid to 10.0 mass parts of polyhydroxyethyl methacrylate and 90.0 mass parts of methanol.

[0136]

(Example 10)

A hollow fiber porous membrane was prepared in the same manner as in Example 8, except for changing the composition of the coating liquid to 15.0 mass parts of polyhydroxyethyl methacrylate and 85.0 mass parts of methanol.

[0137]

(Example 11)

A hollow fiber porous membrane was obtained in the same manner as in Example 2, except for carrying out the liquid-draining operation using a vacuum ejector, where the compressed air supply pressure to the vacuum ejector was set to 0.4 MPa and the liquid-drained time was set to 10 minutes, and carrying out the operation of release from the liquid in the form of a washing liquid when using a vacuum ejector, where the pressure of compressed air supply to the vacuum ejector was set to 0.4 MPa and the release time from the liquid was set to 10 minutes.

(Example 12)

The membrane spinning dope described in Example 1 was applied to a nonwoven fabric made from polyester, and the membrane spinning dope was coagulated by introducing the nonwoven fabric into a coagulation bath at 18.5° C. containing a coagulation liquid formed from 15 parts by weight of NMP and 85 mass parts of water, and then continuously subjected to continuous drying with hot air to obtain a membrane from the base material. The flat membrane, after drying with hot air, was formed into a bundle and put into a liquid bath containing a coating liquid containing 1.7 mass parts of polyhydroxyethyl methacrylate (manufactured using 2-hydroxyethyl methacrylate (manufactured by Kanto Chemical Co., Inc.), the same the same applies hereinafter) having a weight average molecular weight of 120,000, and 98.3 mass parts of methanol (manufactured by Wako Pure Chemical Industries, Ltd., the same applies hereinafter). The flat membrane drawn from the liquid bath was dried under reduced pressure, the membrane bundle after vacuum drying was subjected to high-pressure hot water treatment under conditions of 128° C. for 60 minutes, and the membrane bundle after high-pressure hot water treatment was dried under reduced pressure to obtain flat surface.

[0138]

(Comparative example 1)

A hollow fiber porous membrane was obtained in the same manner as in Example 1, except that the high-pressure hot water treatment was not carried out and immersed in water after being freed from liquid as a coating liquid. This is a porous membrane corresponding to Example 1 in Patent Literature 1.

[0139]

Fiber adhesion occurred in the fiber bundle after vacuum drying, and there was an operation requiring careful precautions so that the fibers would break off without damaging the fibers during the operation of removing the fibers from the fiber bundle during the production of the membrane module. Therefore, the operational efficiency deteriorated significantly.

[0140]

(Comparative example 2)

A hollow fiber porous membrane was obtained in the same manner as in Example 4, except that the high-pressure hot water treatment was not carried out and immersed in water after being freed from liquid as a coating liquid.

[0141]

Fiber adhesion occurred in the fiber bundle after vacuum drying, and there was an operation requiring careful precautions so that the fibers would break off without damaging the fibers during the operation of removing the fibers from the fiber bundle during the production of the membrane module. Therefore, the operational efficiency deteriorated significantly.

[0142]

(Comparative example 3)

A hollow fiber porous membrane was obtained in the same manner as in Example 6, except that the high-pressure hot water treatment was not carried out and immersed in water after being freed from liquid as a coating liquid.

[0143]

Fiber adhesion occurred in the fiber bundle after vacuum drying, and there was an operation requiring careful precautions so that the fibers would break off without damaging the fibers during the operation of removing the fibers from the fiber bundle during the production of the membrane module. Therefore, the operational efficiency deteriorated significantly.

[0144]

The measurement results of (1) to (5) for the porous hollow fiber membranes obtained in Examples 1 to 11 and Comparative Examples 1 to 3 are shown in Table 1. "-" in Table 1 indicates unmeasured items.

[0145]

[Table 1]

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Comparative Example 1 Comparative Example 2 Comparative Example 3 Hydrophilizing agent concentration (wt. %) 1.7 1.7 1.7 1.1 1.1 2.3 2.3 5 10 15 1.7 1.7 1.1 2.3 Solvent concentration 98.3 98.3 98.3 98.9 98.9 97.7 97.7 95 90 85 98.3 98.3 98.9 97.7 Liquid Release as Coating Liquid Way Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Fluid release due to suction Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Time (min) 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Washing treatment With or without washing treatment No wash treatment With washing treatment With washing treatment No wash treatment With washing treatment No wash treatment With washing treatment With washing treatment With washing treatment With washing treatment With washing treatment No wash treatment No wash treatment No wash treatment Solvent concentration (% mass) - 15 15 - 15 - 15 15 15 15 15 - - - Washing time (min) - 60 60 - 60 - 60 60 60 60 60 - - - Release from liquid in the form of flushing liquid Way - Centrifugal liquid release Centrifugal liquid release - Centrifugal liquid release - Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Centrifugal liquid release Fluid release due to suction - - - Time (min) - 10 10 - 10 - 10 10 10 10 10 - - - Autoclaving With or without autoclaving With autoclaving With autoclaving Without autoclaving With autoclaving With autoclaving With autoclaving With autoclaving With autoclaving With autoclaving With autoclaving With autoclaving Without autoclaving Without autoclaving Without autoclaving Temperature (°C) 128 128 - 128 128 128 128 128 128 128 128 - - - Time (min) 60 60 - 60 60 60 60 60 60 60 60 - - - Membrane adhesion Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Absent Present Present Present Inner Diameter (µm) 273.7 273.7 273.7 274.7 274.7 272.3 272.3 275.6 275.6 275.6 274.5 273.7 274.7 272.3 Membrane thickness (µm) 39.2 39.2 39.2 39.8 39.8 40.3 40.3 40.0 40.0 40.0 40 39.2 39.8 40.3 Ratio for the number of ion counts (T) 1.6 1.55 1.65 1.35 1.15 1.6 1.65 2.3 6.95 6.25 1.4 0.35 0.2 0.25 Water permeability (l/m ² /h) 278 302 288 310 316 285 288 224 101 15 288 273 298 265 Bubble point (MPa) 1.72 1.74 1.74 1.72 1.74 1.68 1.76 1.72 1.78 ˃ 1.8 1.75 1.71 1.69 1.74 Immunoglobulin permeability (kg/m2/3 hours at 2 bar) 7.1 8.3 7.3 5.9 5.6 8.6 8.5 - - - 9.1 7.95 7.35 8.4 Coverage ratio (%) 9.5 10 10 8.5 8.6 10.2 10.5 13.3 18.2 22.2 9.1 9.5 8.5 10.2

Applicability in industry

[0146]

The porous membrane according to the present invention can be used in the purification of fractionated plasma products, biopharmaceuticals and the like, as appropriate, and therefore shows industrial applicability.

Claims (32)

1. A porous membrane for removing viruses containing a hydrophobic polymer and a hydrophilic polymer, where the average value of T for the ratios between the number of counts of ions produced from a hydrophilic polymer and the number of counts of ions produced from a hydrophobic polymer is from 1.0 to 7.0 when measuring the surface of a porous membrane using time-of-flight mass spectrometry of secondary ions ( VPMSVI), and the ion produced from the hydrophobic polymer is C ₆ H ₄ O with m/z equal to 92, the ion derived from the hydrophilic polymer is C ₄ H ₅ O ₂ with m/z being 85, the hydrophilic polymer is a methacrylate-based polymer, the hydrophobic polymer is a polysulfone-based polymer, and the hydrophilic polymer coating is applied to the base material membrane containing the hydrophobic polymer. 2. The membrane of claim. 1, where the hydrophilic polymer is a water-insoluble hydrophilic polymer. 3. The membrane according to claim 1 or 2, wherein the hydrophilic polymer is electrically neutral. 4. The membrane according to any one of paragraphs. 1-3, where the methacrylate-based polymer is polyhydroxyethyl methacrylate. 5. The membrane according to any one of paragraphs. 1-4, where the polysulfone-based polymer is a polyethersulfone. 6. The membrane according to any one of paragraphs. 1-5 where the bubble point is between 1.4 and 2.0 MPa. 7. The membrane according to any one of paragraphs. 1-6, where the pure water permeability is in the range between 150 and 500 l/(h⋅m ² ⋅bar). 8. The membrane according to any one of paragraphs. 1-7, where the logarithm of the magnitude of the reduction in viral load (LRV) is 4 or more. 9. The membrane according to any one of paragraphs. 1-8, where the content of the hydrophilic polymer is in the range between 5 and 20% of the mass. with respect to the hydrophobic polymer. 10. A method for producing a porous membrane containing a hydrophobic polymer and a hydrophilic polymer, the method comprising: a hydrophilizing step comprising hydrophilizing the base material membrane containing the hydrophobic polymer by coating the base material membrane with the hydrophilic polymer to obtain a hydrophilized porous membrane; And a control step comprising treating the hydrophilized porous membrane so that the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is from 1.0 to 7.0 when measuring the surface of the porous membrane when using time-of-flight secondary ion mass spectrometry (TSMSS), and the ion produced from the hydrophobic polymer is C ₆ H ₄ O with m/z equal to 92, the ion derived from the hydrophilic polymer is C ₄ H ₅ O ₂ with m/z being 85, the hydrophilic polymer is a methacrylate-based polymer, the hydrophobic polymer is a polysulfone-based polymer, and the adjustment step includes washing and/or treating the hydrophilized porous membrane with high pressure hot water at a temperature of 120° C. or more for 1 hour or more. 11. A method for reducing membrane adhesion after hydrophilization of a membrane from a base material containing a hydrophobic polymer, the method comprising: a hydrophilizing step comprising hydrophilizing the base material membrane containing the hydrophobic polymer by coating the base material membrane with the hydrophilic polymer to obtain a hydrophilized porous membrane; And a control step comprising treating the hydrophilized porous membrane so that the average T value for the ratios between the number of ion counts produced from the hydrophilic polymer and the number of ion counts produced from the hydrophobic polymer is from 1.0 to 7.0 when measuring the surface of the porous membrane when using time-of-flight secondary ion mass spectrometry (TSMSS), and the ion produced from the hydrophobic polymer is C ₆ H ₄ O with m/z equal to 92, the ion derived from the hydrophilic polymer is C ₄ H ₅ O ₂ with m/z being 85, the hydrophilic polymer is a methacrylate-based polymer, the hydrophobic polymer is a polysulfone-based polymer, and the adjustment step includes washing and/or treating the hydrophilized porous membrane with high pressure hot water at a temperature of 120° C. or more for 1 hour or more. 12. The method according to any one of claims 10 or 11, wherein the step of hydrophilization comprises converting the membrane from the base material into a bundle and subjecting the hydrophilization treatment.