JP2003268152A - Hydrophilic microporous film - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hydrophilic microporous film having an inhibitory effect sufficient to effectively remove a virus from a biologically active substance solution, and excellent in wettability by water, protein non-adsorbency and stain resistance. <P>SOLUTION: The hydrophilic microporous film is obtained by copolymerizing, by a graft polymerization method, a polymeric microporous film with a hydrophilic monomer having one vinyl group, and a crosslinking agent having two or more vinyl groups, in an amount of 20 to 1,000 mol% based on the hydrophilic monomer. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hydrophilic microporous membrane suitable for removing minute substances such as viruses.

[0002]

2. Description of the Related Art In recent years, when a preparation such as a plasma fractionation preparation or a biopharmaceutical product is administered to a human body, a sense of crisis about a virus that may be contained in the preparation and a pathogen such as a pathogenic protein has been highlighted. However, a method for removing them is needed. Membrane filtration is a method for physically removing pathogens such as viruses. The membrane filtration method is effective for all pathogens regardless of the type of pathogen and the chemical and thermal properties of the pathogen because the separation operation is performed according to the particle size.

Among pathogens, infection with an infectious virus represented by HIV virus or the like causes a serious disease, so that it is extremely necessary to remove contaminating viruses. The smallest type of virus is 18-24 nm in diameter
There are some parvoviruses and polioviruses with a diameter of about 25 to 30 nm.
There are HIV viruses of about 100 nm. In order to physically remove such a virus group by a membrane filtration method, a microporous membrane having a pore size of about 10 to 120 nm is required,
In recent years, in particular, there is an increasing need for removal of small viruses such as parvovirus.

On the other hand, a virus removal membrane used for purification of plasma fractionated preparations and biopharmaceuticals is required to have not only virus removal performance but also high permeability to physiologically active substances such as albumin and globulin. Therefore, an ultrafiltration membrane having a pore size of about several nm, a reverse osmosis membrane having a smaller pore size, etc. are not suitable as virus removal membranes. Since a preparation such as a plasma fractionation preparation or a biopharmaceutical is generally a highly viscous liquid, it is industrially preferable in productivity to increase the permeation rate by applying a high filtration pressure during filtration. Therefore, there is a need for a high-strength microporous membrane that does not break, burst, damage, or change in dimension under high filtration pressure. Particularly, as the pore size becomes smaller, the filtration pressure applied to the microporous membrane tends to become higher, and extremely high strength is required to withstand such a high filtration pressure.

Generally, a microporous membrane made of a hydrophilic resin is used as a microporous membrane used for purification of plasma fractionated preparations and biopharmaceuticals, but since it swells by hydration in water,
It has the drawback that it does not have the physical strength to withstand a high filtration pressure. On the other hand, a microporous membrane made of a hydrophobic resin having excellent physical strength is subjected to a moistening treatment with alcohol, a surfactant, etc. from a dried state when used, so that a microporous membrane made of a hydrophilic resin is used. It is more costly and cumbersome to handle than membranes.

Further, the microporous membrane made of a hydrophobic resin is apt to cause adsorption of proteins and the like, contamination of the membrane and clogging,
There is a drawback that it causes a rapid decrease in filtration rate. These drawbacks are largely due to the hydrophobicity of the membrane material, and attempts have been made to solve this drawback by imparting hydrophilicity to the hydrophobic separation membrane, and various methods such as the following have been proposed. Has been done. As a method for imparting hydrophilicity to a hydrophobic microporous membrane, a) a method of forming a membrane using a stock solution containing a hydrophilic resin and leaving the hydrophilic resin in the membrane (Japanese Patent Laid-Open No. 10-216488, etc.) ), B) after film formation, a method of impregnating the film with a solution of a hydrophilic resin to leave the hydrophilic resin in the film (Japanese Patent Laid-Open No. 5-310990, etc.), and c) physically or chemically for the film. The method is roughly classified into a method of activating the membrane by treatment and grafting a hydrophilic monomer on the membrane surface (Japanese Patent Laid-Open No. 62-179540).

However, the method a) has a drawback that the excellent physical strength of the hydrophobic resin is lowered because the entire membrane swells during use, and it cannot withstand a high filtration pressure. Further, the above method can only be formed into a film by using a hydrophilic resin having excellent compatibility with a hydrophobic resin as a hydrophilic resin, and cannot be applied to a hydrophilic resin having poor compatibility with a hydrophobic resin. There is also a problem.
Further, in the method b), it is difficult to impregnate a membrane having a small pore size with a hydrophilic resin, and therefore the membrane to be applied is limited to a membrane having a relatively large pore size. Therefore, it cannot be applied to a small-pore membrane for the purpose of removing minute viruses. Further, since it is difficult to control the pore size in the above method, it is difficult to stably manufacture the membrane, and it is not suitable for implementation on an industrial scale.

C) In the hydrophilic microporous membrane obtained by graft-polymerizing a hydrophilic monomer, since the introduced hydrophilic layer has a weak structure in strength, sufficient filtration resistance against viruses and the like cannot be obtained, resulting in sufficient Virus removal performance cannot be obtained. There is an example in which a trace amount of a cross-linking agent is added to the polymerization liquid in order to prevent the pores from being blocked by the hydrophilic layer. However, even if the hydrophilic layer introduced by such a method has a low crosslink density, it has a weak structure in strength, and it is necessary to filter and separate substances of similar sizes such as virus and protein at high pressure. Is difficult. For example, JP-A-62-258711 discloses that a hydrophobic microporous membrane such as a polyolefin, an olefin and a halogenated olefin copolymer, polyvinylidene fluoride, or a polysulfone is irradiated with radiation, and a monomer containing a hydroxyl group, A method for copolymerizing a bifunctional monomer having two or more reactive groups is described. However, in the above-mentioned method, since the amount of the bifunctional monomer added is not sufficient, the hydrophilic layer introduced by grafting does not contribute to the particle blocking property, and there is a problem that sufficient particle blocking property cannot be obtained. Further, in the above method, since the hydrophilic layer introduced by grafting swells when wet, there is a defect that a membrane having a small pore size such as a virus removal membrane cannot obtain a sufficient filtration rate of a protein solution.

In addition, Japanese Patent Publication No. 7-505830 discloses a method of graft-polymerizing polyethylene glycol dimethacrylate as a cross-linking agent on a polypropylene film. However, only a cross-linking agent is used to introduce hydrophilicity by grafting. Since the layer is not sufficiently hydrophilic, it has a drawback that it causes protein adsorption and blockage, and a sufficient filtration rate of the protein solution cannot be obtained.

[0010]

DISCLOSURE OF THE INVENTION The present invention has sufficient inhibitory properties to effectively remove viruses and the like from a physiologically active substance solution, and is excellent in water wettability, protein non-adsorption property, stain resistance and the like. The purpose is to provide a hydrophilic microporous membrane.

[0011]

The present inventor has accomplished the present invention as a result of intensive studies to solve the above problems. That is, the present invention provides [1] a microporous polymer membrane, together with a hydrophilic monomer having one vinyl group,
A hydrophilic microporous membrane obtained by copolymerizing by a graft polymerization method using a crosslinking agent having two or more vinyl groups in a proportion of 20 mol% or more and 1000 mol% or less with respect to the hydrophilic monomer, [ 2] The hydrophilic microporous membrane according to [1], wherein the crosslinking agent has a number average molecular weight of 200 or more and 2000 or less, [3] the hydrophilic monomer according to [1] or [2], in which the hydrophilic monomer has a hydroxyl group. Microporous membrane,
[4] The hydrophilic microporous membrane according to [1], [2] or [3], wherein the material of the macromolecular microporous membrane is polyolefin or polyvinylidene fluoride, [5] maximum pore size determined by bubble point method Is 10 to 120 nm [1],
The hydrophilic microporous membrane according to [2], [3] or [4],
[6] A hydrophilic microporous membrane according to [1], [2], [3], [4] or [5], which is used for removing a virus in a liquid containing a physiologically active substance. Is.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The resin constituting the microporous polymer membrane of the present invention is a resin used for ordinary compression, extrusion, injection, inflation, blow molding, etc.
Polyethylene resin, polypropylene resin, polyolefin resin such as poly-4-methyl 1-pentene resin, polyethylene terephthalate resin, polybutylene terephthalate resin, polyethylene naphthalate resin, polybutylene naphthalate resin, polyester resin such as polycyclohexylene dimethylene terephthalate resin , Nylon 6, nylon 66, nylon 610, nylon 612, nylon 11, nylon 12, nylon 46, and other polyamide resins, polyvinylidene fluoride resin, ethylene / tetrafluoroethylene resin, polychlorotrifluoroethylene resin, and other fluorine-based resins, Polyphenylene ether resin, polysulfone resin, polyacetal resin and the like can be used. Of these, polyolefins and vinylidene resins are preferable, and polyethylene resins, polypropylene resins, and polyvinylidene fluoride resins are particularly preferable because they have good moldability and graft reactivity.

The porosity of the hydrophilic microporous membrane of the present invention is 20 to 90%, preferably 25 to 85%, and more preferably 30 to 70%. Porosity is 20
If it is less than%, the filtration rate is low, which is not preferable. 90%
If it exceeds, the reliability of removal of viruses and the like decreases, and the strength of the microporous membrane becomes insufficient, which is not preferable. The maximum pore size of the hydrophilic microporous membrane of the present invention varies depending on the use of the hydrophilic microporous membrane, and it is essential that the maximum pore size is 10 to 120 nm, preferably 15 to 100 nm for removing minute substances such as viruses. Most preferably 20
~ 70 nm. If the maximum pore size is less than 10 nm, the permeability and filtration rate of physiologically active substances such as globulin will decrease, and
If it exceeds 20 nm, the ability to remove viruses that cause serious infectious diseases deteriorates, which is not preferable. The maximum pore size referred to here is a value measured by the bubble point method based on ASTM F316-86.

The hydrophilic microporous membrane of the present invention may be in the form of flat membrane or hollow fiber. The flat film shape refers to a shape such as a sheet shape, a film shape, and a flat plate shape, and it is possible to add a pattern such as embossing or laminate a non-woven fabric or a woven fabric. The hollow fiber shape means a shape such as a pipe shape, a tube shape, a cylindrical shape, and a tubular shape. The thickness of the hydrophilic microporous membrane of the present invention is preferably 1 μm to 10 mm,
It is more preferably 5 μm to 5 mm, and most preferably 10 μm to 1 mm. If the film thickness is less than 1 μm, the reliability of virus removal is reduced, and the strength of the microporous membrane is not sufficient, and if it exceeds 10 mm, the permeation performance is reduced, which is not preferable.

A microporous membrane made of a hydrophobic resin having excellent physical strength can withstand a high filtration pressure, but on the other hand, adsorption of proteins and the like, contamination of the membrane and clogging of the membrane are likely to occur, resulting in a rapid decrease in filtration rate. cause. The hydrophilic microporous membrane of the present invention,
A cross-linking agent having two or more vinyl groups, together with a hydrophilic monomer having one vinyl group, is added to the polymer microporous membrane.
20 mol% or more, 10 with respect to the hydrophilic monomer
By using it in a proportion of not more than 00 mol% and copolymerizing it by a graft polymerization method, sufficient hydrophilization was achieved.

The hydrophilic monomer used in the present invention is not particularly limited as long as it is a hydrophilic monomer having one vinyl group. A monomer having two or more vinyl groups is not suitable because it has low protein permeability even if it is hydrophilic. The hydrophilic monomer in the present invention is a monomer that dissolves uniformly when mixed in pure water at 25 ° C. at 1% by volume under atmospheric pressure. For example, a vinyl monomer having a hydroxyl group such as hydroxypropyl acrylate or a functional group serving as a precursor thereof, a vinyl monomer having an anion exchange group such as triethylammonium ethyl methacrylate, and a cation exchange group such as sulfopropyl methacrylate may be used. And vinyl monomers having an amide bond such as vinylpyrrolidone. Among them, a vinyl monomer having one or more hydroxyl groups or a functional group serving as a precursor thereof is preferable because it has the highest permeability of the protein solution. Specifically, esters of acrylic acid or methacrylic acid such as hydroxypropyl acrylate and 2-hydroxyethyl methacrylate with polyhydric alcohols, alcohols having an unsaturated bond such as allyl alcohol, and vinyl acetate and vinyl propionate. Examples thereof include enol esters.

The cross-linking agent used in the present invention is a cross-linking agent having two or more vinyl groups which can be copolymerized with the hydrophilic monomer, and is introduced by bringing it into contact with the membrane simultaneously with the hydrophilic monomer. The crosslinking agent used in the present invention preferably has a number average molecular weight of 200 or more and 2000 or less, more preferably a number average molecular weight of 250 or more,
The number average molecular weight is 1,000 or less, most preferably 300 or more and 600 or less. The number average molecular weight of the cross-linking agent is 200
As described above, it is preferably 2000 or less because a high filtration rate of the protein solution can be obtained.

In the present invention, any cross-linking agent having two or more vinyl groups can be used,
Hydrophilic crosslinking agents are preferred. Here, the hydrophilic cross-linking agent is a cross-linking agent that dissolves uniformly when mixed with pure water at 25 ° C. at 1% by volume under atmospheric pressure. Specific examples of the cross-linking agent used in the present invention include divinylbenzene derivatives in an aromatic type, ethylene glycol dimethacrylate in an aliphatic type, a methacrylic acid type cross-linking agent such as polyethylene glycol dimethacrylate, an ethylene glycol diacrylate, Examples thereof include acrylic acid-based crosslinking agents such as polyethylene glycol diacrylate. Further, a cross-linking agent having three reactive groups such as trimethylolpropane trimethacrylate can also be used. Further, the cross-linking agent may be a mixture of two or more kinds. In the present invention, it is most preferable to use polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, or a mixture thereof from the viewpoint of protein permeability and particulate removal performance.

The graft polymerization method is a reaction in which radicals are generated in the microporous polymer membrane by means such as ionizing radiation or chemical reaction, and the radical is used as a starting point to graft-polymerize a monomer on the membrane. In the present invention, any means can be adopted to generate radicals in the microporous polymer film, but irradiation with ionizing radiation is preferable in order to generate uniform radicals in the entire film. As the type of ionizing radiation, γ rays, electron rays, β rays, neutron rays, etc. can be used, but electron beam or γ rays are used for implementation on an industrial scale.
Lines are most preferred. Ionizing radiation is obtained from radioisotopes such as cobalt 60, strontium 90, and cesium 137, or by an X-ray imaging device, an electron beam accelerator, an ultraviolet irradiation device, or the like.

The irradiation dose of ionizing radiation is preferably 1 kGy to 1000 kGy. If it is less than 1 kGy, radicals are not uniformly generated, and if it exceeds 1000 kGy, the film strength may be lowered. The graft polymerization method is generally classified into a pre-irradiation method in which radicals are generated in the film and then contacted with a reactive compound, and a simultaneous irradiation method in which radicals are generated in the film while the film is in contact with the reactive compound. To be done. In the present invention, any method can be applied, but the pre-irradiation method that produces less oligomer is most preferred.

The contact between the polymer microporous membrane that has generated radicals and the hydrophilic monomer and the cross-linking agent is achieved in the liquid phase even in the gas phase, but in the present invention, the graft reaction is performed in the liquid phase in which the reaction proceeds uniformly. The method of contacting is the preferred method.
In order to proceed the grafting reaction more uniformly, it is desirable that the hydrophilic monomer and the cross-linking agent are previously dissolved in a solvent and then contacted with the polymer microporous membrane. The solvent for dissolving the hydrophilic monomer and the crosslinking agent is not particularly limited as long as it can uniformly dissolve. As such a solvent, for example, ethanol or isopropanol,
Examples thereof include alcohols such as t-butyl alcohol, ethers such as diethyl ether and tetrahydrofuran, ketones such as acetone and 2-butanone, water, and a mixture thereof.

Graft polymerization is carried out using a reaction liquid of 0.3% by volume to 30% by volume as a combined concentration of a hydrophilic monomer and a crosslinking agent, and 10 × 10 ^-5 to 10 to 10 g per 1 g of the polymer microporous membrane.
It is desirable to carry out the reaction at a rate of 0 × 10 ⁻⁵ m ³ . If the graft polymerization is carried out within this range, the hydrophilic layer does not fill the pores and a film having excellent uniformity can be obtained. The reaction temperature during the graft polymerization is generally 20 ° C. to 80 ° C., but it is not particularly limited.

The hydrophilic microporous membrane of the present invention achieves high levels of protein permeability and fine particle inhibition by introducing a hydrophilic layer having a strong cross-linking structure into a hydrophobic polymer microporous membrane. ing. Therefore, in the present invention, the cross-linking agent is added to the hydrophilic monomer in an amount of 20 mol% or more and 1000
It is essential to use at a ratio of not more than mol% for copolymerization, and it is preferable to use a cross-linking agent for hydrophilic monomers at a ratio of 20 mol% or more and 500 mol% or less. Most preferably, it is used in a proportion of 30 mol% or more and 200 mol% or less.

In the present invention, a hydrophilic layer is introduced into the hydrophobic microporous membrane to realize high protein permeability. Therefore, the graft ratio of the hydrophobic microporous membrane is preferably 3% or more and 50% or less, more preferably 4% or more,
It is 30% or less, most preferably 5% or more and 20% or less. If the graft ratio is less than 3%, the hydrophilicity of the membrane will be insufficient, causing a rapid decrease in filtration rate due to protein adsorption. If it exceeds 50%, relatively small pores are filled with the hydrophilic layer, and a sufficient filtration rate cannot be obtained. The graft ratio here is a value defined by the following formula. Graft ratio (%) = (membrane weight after grafting−membrane weight before grafting) / membrane weight before grafting × 100

The hydrophilic microporous membrane of the present invention having a maximum pore size determined by the bubble point method of 10 to 120 nm exhibits excellent performance in removing viruses from a liquid containing a physiologically active substance. As a method for confirming virus removal performance, the filtering method using alternative particles typified by gold colloid has a good correlation with virus removal performance because its principle is measurement by filtration as in virus removal. Is preferred because it has Examples of virus substitute model substances that can be used for such purposes include gold colloid particles and polystyrene / latex fine particles. Gold particles with a particle size close to that of viruses and a narrow particle size distribution are used. Colloidal particles are preferred.

The hydrophilic microporous membrane of the present invention exhibits excellent performance in removing viruses from a liquid containing a physiologically active substance. In addition, removal of protein preparations and bacteria in water,
A medical separation membrane that can be used for concentration or media, an industrial process filter that removes fine particles from chemicals, treated water, etc.,
Separation membranes for oil / water separation and liquid / gas separation, separation membranes for purifying sewage and sewage, separators such as lithium-ion batteries,
And a wide range of applications such as solid electrolyte supports for polymer batteries.

The present invention will be described in detail below with reference to examples. The test methods shown in the examples are as follows. (1) Thickness of Hollow Fiber The outer diameter and the inner diameter of a hollow fiber-shaped microporous membrane were determined by photographing a vertical cross section of the membrane with a stereomicroscope. The film thickness was calculated as 1/2 of the difference between the outer diameter and the inner diameter of the hollow fiber.

(2) Porosity The volume and weight of the microporous membrane were measured, and the porosity was calculated from the obtained results using the following formula. Porosity (%) = 100 × (1-weight ÷ (density of resin × volume)) (3) Permeability of water The permeation rate of pure water at a temperature of 25 ° C. by constant pressure dead end filtration was measured to determine the film thickness, the membrane area, Filtration pressure (0.1 MPa),
And the filtration time were calculated according to the following formula to obtain the water permeability. Permeability (m ³ / m ² / sec / Pa / 25 μm) = filtration amount ÷ (membrane area × differential pressure × filtration time × (25 μm / membrane thickness))

(4) Maximum Pore Size The bubble point (N / m ² ) determined by the bubble point method based on ASTM F316-86 is the maximum pore size (n
It was converted as m). (5) Graft ratio From the weight change before and after grafting, the graft ratio was calculated according to the following formula. Graft ratio (%) = {(membrane weight after grafting−membrane weight before grafting) / membrane weight before graph} ×
100

(6) Gold colloid rejection rate 100 ppm gold colloid having an average particle size of 20 nm
A water dispersion containing water, filtration pressure 0.3 MPa, filtration temperature 25
Constant-pressure dead end filtration was performed under the condition of ° C. The filtrate was fractionated every 0.005 (m ³ / m ² ) of the integrated filtration amount, the absorbance at the wavelength of 524 nm of the second fraction was measured, and the gold colloid removal rate was calculated from the following equation. Gold colloid removal rate (%) = (absorbance of unfiltered solution-absorbance of filtrate) / absorbance of unfiltered solution x 100

(7) Filtration Test of 3% Bovine Immunoglobulin Solution Bovine immunoglobulin was 5% manufactured by Invitrogen Corporation.
A wt% bovine immunoglobulin solution was diluted to 3 wt% with a physiological saline solution (Japan Pharmacopoeia) manufactured by Otsuka Pharmaceutical Co., Ltd., and a virus removal membrane (PLANOVA manufactured by Asahi Kasei Co., Ltd.) was added.
35 N (trade name)) was prefiltered to remove impurities and used as a stock solution for filtration. The filtration stock solution is filtered at a filtration pressure of 0.3M.
Constant-pressure dead-end filtration was performed under conditions of Pa and a filtration temperature of 25 ° C. for 1 hour, and the permeation amount of a 3% bovine immunoglobulin solution was calculated from the following formula. Permeation rate of 3% bovine immunoglobulin solution (m ³ / m ² / hour) =
Filtration amount ÷ (membrane area)

[0032]

[Production Example] A composition comprising 40% by weight of polyvinylidene fluoride resin (SOLFEY, SOLEF1012, crystal melting point: 173 ° C) and 60% by weight of triphenyl phosphate was stirred and mixed at 70 ° C using a Henschel mixer, and then cooled. Then, the powdered material is put in from the hopper, and 35 m
The mixture was melt-mixed at 210 ° C. using an m twin-screw extruder. Subsequently, while spinning tri (2-ethylhexyl) phosphate heated to 120 ° C. inside the hollow at a rate of 7 ml / min, a spinneret composed of an annular orifice having an inner diameter of 0.8 mm and an outer diameter of 1.2 mm. It was further extruded into a hollow fiber shape, cooled and solidified in a water bath whose temperature was adjusted to 40 ° C., and wound on a cassette. After that, triphenyl phosphate and tri (2-ethylhexyl phosphate) were extracted and removed with ethanol, and the adhering ethanol was dried and removed, and then heat-treated at 130 ° C. for 1 hour in a fixed length fixed state to form hollow fibers. A microporous film of The obtained microporous membrane had a thickness of 44 μm, a maximum pore size of about 36 nm, a porosity of about 59%, and a water permeability of 8.98 × 10.
^-10 (m ³ / m ² / sec / Pa).

[0033]

Example 1 For 3 g of the microporous membrane obtained by the method of Production Example,
Hydrophilization treatment was carried out by the graft polymerization method. Nitrogen atmosphere
Underneath, use cobalt-60 as a radiation source at a temperature of -60 ° C.
After γ-irradiation with a dose of 100 kGy, fill the reaction vessel
It was After filling, the inside of the reaction vessel is 13.33P with an oil rotary pump.
Vacuum was applied until the temperature was a or less, and the temperature was kept at room temperature for 15 minutes. Hydrophilic
About 50 mol% of monomer and hydrophilic monomer
The cross-linking agent and the solvent were mixed to prepare a graft reaction solution. Ingredient
Physically, 0.65% by volume of hydroxypropyl acryl
Rate (Tokyo Kasei Co., Ltd., special grade reagent), 2.17 volume
% Polyethylene glycol dimethacrylate (Al
made by drich, number average molecular weight 875), 25% by volume
t-butyl alcohol (manufactured by Junsei Chemical Co., Ltd., reagent
And a monomer containing 72.18% by volume of distilled water
Bubble nitrogen through the solution to remove dissolved oxygen from the monomer solution.
I removed it. Then, this graft reaction solution 2 × 10 ^-Five
m³Is sucked into the degassed reaction vessel, and the reaction temperature is 40 ° C.
And reacted for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. Grafting rate is 9.0%, 3% bovine immunoglobulin solution permeation amount is 14.
4 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 9
It was 9.2%.

[0035]

Example 2 3 g of the same hydrophobic microporous membrane obtained in the method of Production Example as in Example 1 was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, cobalt-60 as a radiation source, -6
After γ-irradiation with a dose of 100 kGy at a temperature of 0 ° C.,
The reaction vessel was filled. After the filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less by an oil rotary pump and kept at room temperature for 15 minutes.

A hydrophilic monomer, a cross-linking agent of about 23 mol% with respect to the hydrophilic monomer, and a solvent were mixed to prepare a graft reaction solution. Specifically, 1.10% by volume of hydroxypropyl acrylate (Tokyo Kasei Co., Ltd., reagent grade), 1.72% by volume of polyethylene glycol dimethacrylate (Aldrich, number average molecular weight 87).
5), 25% by volume of t-butyl alcohol (manufactured by Junsei Chemical Co., Ltd., special grade reagent), and 72.18% by volume of distilled water were bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. The graft ratio is 7.5%, and the permeation amount of a 3% bovine immunoglobulin solution is 17.
5 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 8
It was 7.4%.

[0038]

Example 3 3 g of the same hydrophobic microporous membrane obtained in the method of Production Example as in Example 1 was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, using cobalt 60 as a radiation source,
After irradiation with γ-rays at a temperature of −60 ° C. and a dose of 100 kGy, the reaction vessel was filled. After filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less with an oil rotary pump, and the reaction vessel was kept at room temperature for 1 hour.
Hold for 5 minutes.

A hydrophilic monomer, a cross-linking agent of about 50 mol% with respect to the hydrophilic monomer, and a solvent were mixed to prepare a graft reaction solution. Specifically, 0.91% by volume of hydroxypropyl acrylate (Tokyo Kasei Co., Ltd., special grade reagent), 1.91% by volume of polyethylene glycol dimethacrylate (Aldrich, number average molecular weight 55).
0), 25% by volume of t-butyl alcohol (manufactured by Junsei Kagaku Co., Ltd., reagent grade), and 72.18% by volume of distilled water were bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. Grafting rate is 9.0%, 3% bovine immunoglobulin solution permeation amount is 22.
0 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 9
It was 8.0%.

[0041]

Example 4 3 g of the same hydrophobic microporous membrane as in Example 1 obtained by the method of Production Example was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, using cobalt 60 as a radiation source,
After irradiation with γ-rays at a temperature of −60 ° C. and a dose of 100 kGy, the reaction vessel was filled. After filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less with an oil rotary pump, and the reaction vessel was kept at room temperature for 1 hour.
Hold for 5 minutes.

A hydrophilic monomer, a crosslinking agent of about 100 mol% with respect to the hydrophilic monomer, and a solvent were mixed to prepare a graft reaction solution. Specifically, 0.64% by volume of hydroxypropyl acrylate (Tokyo Kasei Co., Ltd., special grade reagent), 2.18% by volume of polyethylene glycol dimethacrylate (Aldrich, number average molecular weight 44).
0), 25% by volume of t-butyl alcohol (manufactured by Junsei Kagaku Co., Ltd., reagent grade), and 72.18% by volume of distilled water were bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. The graft rate was 9.6%, and the permeation amount of a 3% bovine immunoglobulin solution was 13.
2 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 9
It was 7.7%.

[0044]

Example 5 3 g of the same hydrophobic microporous membrane obtained in the method of Production Example as in Example 1 was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, using cobalt 60 as a radiation source,
After irradiation with γ-rays at a temperature of −60 ° C. and a dose of 100 kGy, the reaction vessel was filled. After filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less with an oil rotary pump, and the reaction vessel was kept at room temperature for 1 hour.
Hold for 5 minutes.

A hydrophilic monomer, a cross-linking agent of about 50 mol% with respect to the hydrophilic monomer, and a solvent were mixed to prepare a graft reaction solution. Specifically, 1.24% by volume of hydroxypropyl acrylate (Tokyo Kasei Co., Ltd., reagent special grade), 1.58% by volume of polyethylene glycol dimethacrylate (Aldrich, number average molecular weight 33).
0), 25% by volume of t-butyl alcohol (manufactured by Junsei Kagaku Co., Ltd., reagent grade), and 72.18% by volume of distilled water were bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. Graft ratio is 1
0.7%, 3% bovine immunoglobulin solution permeation amount is 12.
4 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 8
It was 7.9%.

[0047]

Comparative Example 1 3 g of the same hydrophobic microporous membrane as in Example 1 obtained by the method of Production Example was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, using cobalt 60 as a radiation source,
After irradiation with γ-rays at a temperature of −60 ° C. and a dose of 100 kGy, the reaction vessel was filled. After filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less with an oil rotary pump, and the reaction vessel was kept at room temperature for 1 hour.
Hold for 5 minutes.

A hydrophilic monomer, a cross-linking agent of about 6 mol% with respect to the hydrophilic monomer, and a solvent were mixed to prepare a graft reaction solution. Specifically, 1.98% by volume of hydroxypropyl acrylate (Tokyo Kasei Co., Ltd., special grade reagent), 0.84% by volume of polyethylene glycol dimethacrylate (Aldrich, number average molecular weight 87).
5), 25% by volume of t-butyl alcohol (manufactured by Junsei Chemical Co., Ltd., special grade reagent), and 72.18% by volume of distilled water were bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. Grafting rate is 8.1%, 3% bovine immunoglobulin solution permeation amount is 12.
6 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 7
It was 4.9%.

[0050]

Comparative Example 2 3 g of the same hydrophobic microporous membrane obtained in the method of Production Example as in Example 1 was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, using cobalt 60 as a radiation source,
After irradiation with γ-rays at a temperature of −60 ° C. and a dose of 100 kGy, the reaction vessel was filled. After filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less with an oil rotary pump, and the reaction vessel was kept at room temperature for 1 hour.
Hold for 5 minutes.

A hydrophilic monomer, a cross-linking agent of about 6 mol% with respect to the hydrophilic monomer, and a solvent were mixed to prepare a graft reaction solution. Specifically, 2.43% by volume of hydroxypropyl acrylate (Tokyo Kasei Co., Ltd., special grade reagent), 0.39% by volume of polyethylene glycol dimethacrylate (Aldrich, number average molecular weight 33).
0), 25% by volume of t-butyl alcohol (manufactured by Junsei Kagaku Co., Ltd., reagent grade), and 72.18% by volume of distilled water were bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. Grafting rate is 7.2%, 3% bovine immunoglobulin solution permeation amount is 16.
6 × 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 4
It was 9.9%.

[0053]

Comparative Example 3 3 g of the same hydrophobic microporous membrane obtained in the method of Production Example as in Example 1 was subjected to a hydrophilization treatment by a graft method. In a nitrogen atmosphere, using cobalt 60 as a radiation source,
After irradiation with γ-rays at a temperature of −60 ° C. and a dose of 100 kGy, the reaction vessel was filled. After filling, the inside of the reaction vessel was evacuated to 13.33 Pa or less with an oil rotary pump, and the reaction vessel was kept at room temperature for 1 hour.
Hold for 5 minutes.

A cross-linking agent and a solvent were mixed to prepare a graft reaction solution. Specifically, 2.82% by volume of polyethylene glycol dimethacrylate (manufactured by Aldrich,
Number average molecular weight of 330), 25% by volume of t-butyl alcohol (manufactured by Junsei Chemical Co., Ltd., special grade reagent), and 72.
A monomer solution containing 18% by volume of distilled water was bubbled with nitrogen to remove dissolved oxygen from the monomer solution. Then, 2 × 10 ⁻⁵ m ³ of this graft reaction solution was introduced into the degassed reaction vessel by suction and reacted at a reaction temperature of 40 ° C. for 2 hours.

After the reaction, the membrane was taken out from the reaction vessel, washed repeatedly with ethanol, and then dried at 60 ° C. for 10 hours. The performance of the obtained film is shown in Table 1. Grafting rate is 9.2%, 3% bovine immunoglobulin solution permeation rate is 5.2
× 10 ⁻³ m ³ / m ² / hour, gold colloid rejection rate is 9
It was 9.1%.

[0056]

[Table 1]

[0057]

EFFECTS OF THE INVENTION The hydrophilic microporous membrane of the present invention exhibits high gold colloid removal performance as well as high protein solution permeation performance. It is possible to provide a separation membrane capable of achieving both a permeation performance of a physiologically active substance and a virus removal performance at a practical level in filtration of an active substance solution.

[Brief description of drawings]

FIG. 1 is a correlation diagram showing a relationship between a gold colloid inhibition rate and a 3% bovine immunoglobulin solution permeation amount in Examples and Comparative Examples of the membrane of the present invention.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C08F 255/00 C08F 255/00 259/08 259/08 // C08L 101: 00 C08L 101: 00 F term ( Reference) 4D006 GA07 KA12 MA01 MA03 MA22 MB09 MB16 MC22 MC23 MC28 MC29X MC48 MC54 MC82 NA23 NA42 NA44 NA59 NA62 PA01 PB55 PC41 4F074 AA15 AA16 AA20 AA38 AA44 AA46 AA55 AA64 A56 A26 A18 A13 A16 A18 A13 A16 A18 A13 A11 A17 A55 A11 A11 A17 A55 A11 AB22 AB28 AB40 AC36 BA28 BA29 BA40 DB36 FA09 GA08

Claims (6)

[Claims] 1. A macromolecular microporous membrane comprising a hydrophilic monomer having one vinyl group and a cross-linking agent having two or more vinyl groups in an amount of 20 mo with respect to the hydrophilic monomer.
A hydrophilic microporous membrane obtained by copolymerization by a graft polymerization method using a proportion of 1% or more and 1000 mol% or less. 2. The number average molecular weight of 200 or more, 2
The hydrophilic microporous membrane according to claim 1, which is 000 or less. 3. The hydrophilic microporous membrane according to claim 1, wherein the hydrophilic monomer has a hydroxyl group. 4. The hydrophilic microporous membrane according to claim 1, 2 or 3, wherein the material of the polymer microporous membrane is polyolefin or polyvinylidene fluoride. 5. The maximum pore size determined by the bubble point method is 1
The hydrophilic microporous membrane according to claim 1, 2, 3 or 4, which has a thickness of 0 to 120 nm. 6. The method for removing a virus in a liquid containing a physiologically active substance, 1, 2, 3, 4 or 5.
The hydrophilic microporous membrane described.