JP2003320229A - Modified hollow fiber membrane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a modified hollow fiber membrane which does not cause an increase in eluting material, etc., has a little interaction between the membrane surface of hollow fiber and biocomponents, does not adsorb protein and hardly causes deterioration, is excellent in biocompatibility, and can adsorb and trap foreign materials such as endotoxins reversely flowing from the outside of the hollow fiber by a film thickness part. <P>SOLUTION: The hollow fiber membrane mainly comprising a polysulfone polymer contains a copolymer of a vinyl polymerizable monomer having a zwitter-ion in the molecule, such as betaine, ammonium phosphate, and sulfobetaine, in the inner surface, and another vinyl polymerizable monomer. The copolymer is unevenly distributed in the hollow fiber membrane. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a hollow fiber membrane whose inner surface is modified. More specifically, by modifying the inner surface of the hollow fiber, the adsorption of protein components on the inner surface of the hollow fiber is suppressed, or the interaction of blood components on the inner surface of the hollow fiber is suppressed. The present invention relates to a medical membrane suitable for blood purification such as dialysis and blood filtration, or a selective separation membrane used in the pharmaceutical industry, food industry and the like.

[0002]

2. Description of the Related Art Hollow fiber membranes made of various materials are widely used as selective separation membranes in medical applications such as hemodialysis and blood filtration, pharmaceutical industry and food industry. In such applications, not only it has excellent mechanical strength and chemical stability, its permeability is easy to control, it has little eluate, little interaction with biological components, and it is safe for living organisms. However, a hollow fiber membrane that completely satisfies this has not yet been provided.

[0003] For example, when the material is a synthetic polymer, it is generally hydrophobic and the surface hydrophilicity is remarkably insufficient, so that interaction with blood components is caused and blood coagulation easily occurs. Permeability tends to deteriorate due to adsorption. Therefore, studies have been made to impart blood compatibility by incorporating a hydrophilic polymer into these synthetic polymer hollow fiber membranes. For example, a permselective separation membrane in which a hydrophilic polymer is contained in a polysulfone-based polymer and a method for producing the same have been proposed. However, also in this case, if the content of the hydrophilic polymer is low, the water wettability is deteriorated, blood compatibility is lowered and blood coagulation is easily caused, and conversely, if the content of the hydrophilic polymer is high, blood coagulation is reduced. However, there is a problem that the amount of hydrophilic polymer eluted from the membrane increases.

In JP-A-61-238306 and JP-A-63-97666, a polysulfone-based polymer, a hydrophilic polymer, and an additive serving as a nonsolvent or a swelling agent are added to the polysulfone-based polymer. Although a method for producing a polysulfone-based separation membrane using the system as a membrane-forming stock solution has been disclosed, there is a problem that the hydrophilic polymer is largely eluted.

Further, in JP-A-4-300636, a membrane in which polyvinylpyrrolidone, which is a hydrophilic polymer, is unevenly distributed on the inner surface side of a hollow fiber membrane is produced, and radiation treatment and / or
Alternatively, a method of insolubilizing the hydrophilic polymer and reducing elution of the hydrophilic polymer by performing heat treatment is disclosed. However, this method has a problem that blood compatibility is deteriorated, probably because the hydrophilic polymer is insolubilized by the crosslinking.

On the other hand, a vinyl-polymerizable monomer having a zwitterion in the molecule and another monomer having a structure similar to phospholipid which is a main component constituting a biological membrane and having excellent biocompatibility. A method of incorporating a copolymer with the body into a synthetic polymer hollow fiber membrane to impart blood compatibility has been studied. Japanese Unexamined Patent Publication No. 5-177119 discloses that zwitterions are 2
-A membrane in which a copolymer of methacryloyloxyethylphosphorylcholine and a methacrylic acid ester is coated on the pore surface of a porous membrane made of polyolefin or polyfluorinated polyolefin is disclosed. It is necessary to coat a large amount of 30% or more, preferably 50% or more, on the surface of the micropores in the porous membrane having a porosity of not less than%, and there is a fear of elution or desorption from the membrane.

[0007] As described above, up to now, the eluate and the like have not increased, the interaction between the membrane surface of the hollow fiber and the biological component is small, the protein is non-adsorptive, and the performance deterioration is unlikely to occur. No fully satisfactory hollow fiber membranes have been provided. Furthermore, in recent years, there has been a demand for higher performance of the membrane. For example, in the field of artificial dialysis, it has been pointed out that the backflow of endotoxin from the dialysate side has been pointed out as the performance of membranes has improved.To solve this problem, there is little interaction with blood components and adsorption of endotoxin. A highly functional film that can be removed is required.

[0008]

The object of the present invention is to provide a living body which does not increase the amount of eluate and the like, has little interaction between the membrane surface of the hollow fiber and biological components, is non-adsorbable to proteins, and is less likely to undergo performance deterioration. It is intended to provide a modified hollow fiber membrane having excellent compatibility. Another object of the present invention is to provide a modified hollow fiber membrane capable of adsorbing and trapping foreign matter such as endotoxin that flows back from the outside of the hollow fiber at the membrane thickness portion.

[0009]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a vinyl polymerizable monomer having a zwitterion in the molecule is formed on the inner surface of a hollow fiber membrane. In a hollow fiber membrane having a copolymer with another vinyl polymerizable monomer, it was found that the uneven distribution of the copolymer on the inner surface of the hollow fiber membrane can achieve the object of the present invention. Came to.

That is, according to the present invention, [1] on the inner surface of a hollow fiber membrane containing a polysulfone-based polymer as a main component, there is a double molecule in the molecule represented by the following formula (1), (2) or (3). A hollow fiber having a copolymer of a vinyl polymerizable monomer having a cationic ion and another vinyl polymerizable monomer, wherein the copolymer is unevenly distributed on the inner surface of the hollow fiber membrane. film,

[Chemical 4] (In the formula, R is hydrogen or a methyl group, A, B, and C are alkylene groups in which a part of carbon-carbon bonds may be substituted with an ester bond or an amide bond, and X is a zwitterionic group. And Y represents a carboxylic acid group, a phosphoric acid group or a sulfonic acid group.) [2] The vinyl polymerizable monomer having a zwitterion in the molecule is betaine, ammonium phosphate or sulfobetaine [1]. [3] The hollow fiber membrane described in [3], wherein the sulfobetaine is a sulfobetaine compound represented by the following formula (4), formula (5) or formula (6):

[Chemical 5] [4] The hollow fiber membrane according to any one of [1] to [3], wherein the polysulfone-based polymer that is the main component of the hollow fiber membrane is polysulfone and / or polyether sulfone.
[5] The hollow fiber membrane contains polyvinylpyrrolidone and / or polyethylene glycol [1] to [4]
[6] The hollow fiber membrane according to any one of [1] to [5], wherein the contact angle of the film thickness portion of the hollow fiber membrane is 50 to 100 degrees. Containing a monomer unit derived from a vinyl polymerizable monomer having a zwitterion in the molecule in a copolymer of a vinyl polymerizable monomer having a zwitterion in the molecule and another vinyl polymerizable monomer The hollow fiber membrane according to any one of [1] to [6], wherein the ratio is 5 mol% or more and 95 mol% or less, [8] a vinyl polymerizable monomer having a zwitterion in the molecule, and another vinyl polymerization. The other vinyl polymerizable monomer in the copolymer with the polymerizable monomer is one or more vinyl polymerizable monomers selected from vinylpyrrolidone, styrene, and (meth) acrylic acid ester derivatives. The hollow fiber membrane according to any one of [1] to [7], [9] The (meth) acrylic acid ester derivative which is another vinyl-polymerizable monomer is a (meth) acrylic acid ester derivative represented by the following formula (7), formula (8) or formula (9) [8] Hollow fiber membrane described in

[Chemical 6] (In the formula, R ₁ and R ₃ are hydrogen or a methyl group, R ₂ , R ₄ ,
R ₈ represents hydrogen, an aliphatic hydrocarbon group having 1 to 20 carbon atoms, a polyalkylene oxide group or an aromatic hydrocarbon group, and A and R ₇ represent alkylene groups having 1 to 10 carbon atoms. [10] The surface concentration of the monomer unit derived from a vinyl polymerizable monomer having a zwitterion in the molecule on the surface of the hollow fiber membrane is 5 wt% or more, according to any one of [1] to [9]. Hollow fiber membrane, [11] Using a double spinneret, the inner hollow liquid was discharged from the inner side, and the polymer solution containing the polysulfone-based polymer, which is the material of the hollow fiber membrane, was discharged from the outer side at the same time. In a dry-wet spinning method of immersing in an installed coagulation bath and spinning, a copolymer of a vinyl-polymerizable monomer having a zwitterion in the molecule and another vinyl-polymerizable monomer is used in the hollow internal liquid. 0.001 wt% to 10 wt%
A method for producing a hollow fiber membrane, which comprises using a dissolved solution, [12] a copolymer of a vinyl polymerizable monomer having a zwitterion in a molecule and another vinyl polymerizable monomer A hollow characterized in that a solution in which 0.001 wt% to 10 wt% is dissolved is flown into the hollow portion of a hollow fiber membrane containing a polysulfone-based polymer as a main component to hold the copolymer on the inner surface of the hollow fiber membrane. Method for producing thread film, and [13] [11]
Alternatively, it is a hollow fiber membrane obtained by the method for producing a hollow fiber membrane according to [12].

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The hollow fiber membrane of the present invention, which will be described in detail below, contains a polysulfone-based polymer as a main component. In the present invention, the main component means that the polysulfone-based polymer is 50 wt% or more, preferably 50 wt% or more,
It means containing 99 wt% or less. Specific examples of the polysulfone-based polymer used in the present invention include polysulfone, polyether sulfone, polyaryl ether sulfone, and polyarylate-polyether sulfone, preferably polysulfone and polyether sulfone, and more preferably polysulfone. Is used.

Examples of components other than the polysulfone-based polymer forming the hollow fiber membrane include hydrophilic polymers such as polyvinylpyrrolidone and polyethylene glycol. The hydrophilic polymer is more than 0 wt%, 20 wt%
% Or less is preferable. More preferably 1 wt%
As described above, the content is 15 wt% or less. When the hydrophilic polymer is too low in molecular weight, there is a concern that it may fall off from the membrane, and when the molecular weight is too high, the viscosity of the polymer membrane-forming stock solution is too high when producing a hollow fiber.For example, in the case of polyvinylpyrrolidone, the molecular weight is Is preferably 1000 to 5,000,000, more preferably 2000 to 1,000,000, and the polyethylene glycol has a molecular weight of 1
It is preferably from 0 to 5,000,000, more preferably from 200 to 1,000,000.

In the hollow fiber membrane of the present invention, the contact angle of the membrane portion with water is preferably 50 to 100 degrees. More preferably, it is 55 to 95 degrees. The contact angle of the film thickness portion of the hollow fiber membrane in the present invention is measured by a commercially available dynamic contact angle measuring device (dataphy) as described in Examples below.
SCATS DCAT11) was used, and a hollow fiber whose end was fused was used as a sample. By the measurement,
The advancing contact angle and the receding contact angle of the outer surface of the hollow fiber can be determined. The contact angle measurement method that has been used conventionally,
That is, the synthetic polymer is molded into a flat surface, a water drop is placed on the surface, and the contact angle obtained by measuring the angle between the synthetic polymer flat surface and the water surface corresponds to the advancing contact angle. The advancing contact angle obtained by the above measuring method is taken as the contact angle. The lower the contact angle, the higher the hydrophilicity, and the higher the contact angle, the higher the hydrophobicity.

The hollow fiber membrane of the present invention is present on the outer surface side of the hollow fiber membrane by setting the contact angle of the membrane portion to preferably 50 to 100 degrees, and more preferably 55 to 95 degrees. Foreign substances such as endotoxins that try to permeate through the membrane can be efficiently adsorbed at the film thickness portion and can be prevented from permeating to the inner surface side. In the present invention, the film thickness portion refers to a portion excluding the inner surface of the hollow fiber membrane and its vicinity, and therefore, in the present invention, the contact angle of the film thickness portion is equal to the contact angle of the outer surface of the hollow fiber membrane. Therefore, in the present invention, the contact angle of the membrane part is measured by the contact angle on the outer surface of the hollow fiber membrane.

The vinyl polymerizable monomer having a zwitterion in the molecule (hereinafter referred to as "ZI") used in the present invention is represented by the following structural formula (1), (2) or (3). It is a compound having a polymerizable vinyl group.

[Chemical 7] (In the formula, R is hydrogen or a methyl group, A, B, and C are alkylene groups in which a part of carbon-carbon bonds may be substituted with an ester bond or an amide bond, and X is a zwitterionic group. And Y represents a carboxylic acid group, a phosphoric acid group or a sulfonic acid group.)

The zwitterion includes a cation group and an anion group in the same molecule, and combinations of groups having all kinds of charges can be used in the present invention.
Among these, ammonium zwitterions such as betaine, ammonium phosphate, and sulfobetaine represented by the following formula (10) are preferably used in terms of availability. Specific examples of the ammonium-based zwitterion include 2-methacryloyloxyethylphosphorylcholine and dimethyl (2-methacryloyloxyethyl)-(1
(2-sulfopropyl)) ammonium betaine, dimethyl (-2-methacrylamidopropyl-N- (3-sulfopropyl) -ammonium betaine, and the like.

[Chemical 8] (In the formula, R ₁₀ represents a functional group containing a vinyl polymerizable group,
R ₁₁ and R ₁₂ each represent an aliphatic hydrocarbon group having 1 to 10 carbon atoms or an aromatic hydrocarbon group. D is an alkylene group in which a part of the carbon-carbon bond may be replaced with an ester bond or an amide bond, and Z is a carboxylic acid group, a phosphoric acid group or a sulfonic acid group. Further, as the ammonium zwitterion, betaine, ammonium phosphate, and sulfobetaine in which an ammonium nitrogen atom constitutes a part of a heterocycle containing a vinyl polymerizable group are also preferably used. As a specific example, 1
Examples thereof include-(3-sulfopropyl) -2-vinyl-pyridinium betaine.

From the viewpoint of biocompatibility, it is desirable that the zwitterion has high polarization. From this point, sulfobetaine having a stronger negative charge is more preferred. Further, sulfobetaine can be easily and inexpensively obtained by adding a commercially available sultone such as propane sultone or butane sultone to a tertiary amine, which is advantageous for industrial use.
Among the sulfobetaines, particularly N, N-dimethyl-N-methacrylamidopropyl-N- (3-sulfopropyl) ammonium betaine represented by the following structural formula (4):
N, N-dimethyl-N-methacryloxyethyl-N- (3-sulfopropyl) ammonium betaine represented by the structural formula (5) or 1-represented by the structural formula (6)
(3-Sulfopropyl) -2-vinylpyridinium is commercially available, can be easily and inexpensively obtained, and is more advantageous for industrial use.

[Chemical 9]

In the present invention, the other vinyl polymerizable monomer used in the copolymer of ZI and another vinyl polymerizable monomer (hereinafter referred to as "ZI copolymer") is
Examples thereof include one or more vinyl polymerizable monomers selected from vinylpyrrolidone, styrene, and (meth) acrylic acid ester derivatives. Among them, vinylpyrrolidone and (meth) acrylic acid ester derivatives are preferably used, more preferably structural formula (7),
It is a (meth) acrylic acid ester derivative represented by (8) or (9), and is selected according to the required properties of the copolymer.

[Chemical 10] (In the formula, R ₁ and R ₃ are hydrogen or a methyl group, R ₂ , R ₄ ,
R ₈ represents hydrogen, an aliphatic hydrocarbon group having 1 to 20 carbon atoms, a polyalkylene oxide group or an aromatic hydrocarbon group. A and R ₇ represent an alkylene group having 1 to 10 carbon atoms. )

Specific examples thereof include butyl methacrylate, benzyl methacrylate, methacryloyloxyethyl phenylcarbamate, and phenyl methacryloyloxyethyl carbamate. As will be described later, when the ZI copolymer is used as a solution, it is aqueous / non-aqueous. Polyethylene glycol mono (meth) acrylate having a polyoxyethylene group is preferred in order to improve the solubility in both aqueous solvents. Here, the polyalkylene oxide group is a polyether composed of an alkylene group having 1 to 4 carbon atoms. More preferred is the following structural formula (11)
Is a (meth) acrylic acid ester derivative having polyethylene oxide. The number n of monomer units of polyethylene oxide is preferably 2 or more in order to improve the solubility, and more preferably 3 or more, but if the number of repetitions is too large, the polymerization reactivity is lowered, so 1000 or less is preferable, and more preferable. Is 500 or less.

[Chemical 11] (In the formula, n represents the number of repetitions.)

The content of the monomer unit derived from ZI is Am
and the monomer unit content derived from other vinyl polymerizable monomer is Bmol, the monomer unit content rate (mol%) of ZI in the copolymer (100 × Amo
When l / (Amol + Bmol)) is low, biocompatibility and hydrophilicity tend to be insufficient. On the other hand, if the content of the monomer unit is high, the solubility in water will be high and the solubility in organic solvent will be low, and the amount of elution from the membrane to water will increase, or the method of use will be limited. Come on. Therefore, in the present invention, the ZI monomer unit content is preferably in the range of 5 mol% to 95 mol%, more preferably in the range of 10 mol% to 50 mol%.

The ZI copolymer used in the present invention is used as a solution in the present invention. Therefore, it is preferable that the molecular weight of the ZI copolymer is as high as possible so long as the solubility in the solvent is not hindered. On the other hand, if the molecular weight is too low, elution or loss from the membrane is likely to occur, and the molecular weight is 5,000 or more,
It is preferably 0,000,000 or less, more preferably 10,000 or more and 5,000,000 or less.

In the present invention, the biocompatibility of the surface of the hollow fiber membrane is basically influenced by the type of other vinyl-polymerizable monomer to be copolymerized with ZI and the content of the monomer unit derived from ZI. , ZI-derived monomer units are present on the membrane surface. The amount of such a ZI-derived monomer unit present can be determined by analyzing the surface of the hollow fiber membrane by X-ray photoelectron spectroscopy.
In X-ray photoelectron spectroscopy, the ratio of elements existing in the vicinity of the surface is obtained. Therefore, the ZI-derived monomer unit in the vicinity of the surface measured from the chemical formulas constituting the ZI copolymer and the film material The concentration (= weight of monomer unit derived from ZI / weight of monomer unit of membrane polymer) can be calculated. When an ammonium zwitterion is used as ZI, the quaternary nitrogen element contained in the molecule is not contained in the polysulfone polymer, so the concentration can be easily estimated by paying attention to the element. Since this concentration is a value near the film surface, in the present invention, this is adopted as the film surface concentration of the ZI-derived monomer unit.

In the present invention, it is preferable that the surface concentration of the ZI-derived monomer unit on the surface of the hollow fiber membrane thus measured is 5 wt% or more, since biocompatibility is exhibited, and more preferably 8 wt% or more. . If the surface concentration of the monomer unit is too high, elution may occur, so 50% by weight or less is preferred, and 47 is more preferred.
wt%.

In the present invention, the ZI copolymer is unevenly distributed on the inner surface of the hollow fiber membrane. Here, “unevenly distributed” means that the concentration of the copolymer on the inner surface is significantly higher than the concentration of the copolymer in the thickness part of the hollow fiber membrane, that is, the copolymer is It means that it exists unevenly on the inner surface. The ratio of the surface concentration to the bulk concentration of the ZI-derived monomer unit (surface concentration / bulk concentration) is preferably 10 or more, more preferably 20 or more. ZI
Peak bulk concentration of the monomer unit derived from the sample hollow fiber membrane was thoroughly washed with water, dried, which is dissolved in a suitable solvent such as heavy chloroform, the ^{1 H} NMR was measured, derived from a monomer unit derived from ZI It can be obtained by analyzing the integral ratio of peaks derived from and the polysulfone-based polymer. In the present invention, the inside of the hollow fiber membrane (thickness part)
It is preferable that the ZI copolymer is not present as much as possible in the pores, and is biased only on the inner surface of the hollow fiber membrane.

The uneven distribution of the ZI copolymer on the inner surface of the membrane is possible by adjusting the molecular weight of the ZI copolymer retained on the inner surface, or by adjusting the membrane structure itself such as the hollow fiber membrane pore size. However, when the hollow fiber membrane of the present invention is used for hemodialysis or hemofiltration, the membrane pore size is limited in order to prevent the amount of ultrafiltration and the loss of albumin. Therefore, the molecular weight of the ZI copolymer is practically limited. It becomes possible by adjusting.

In the present invention, since the ZI copolymer is unevenly distributed on the membrane surface, even if the concentration (bulk concentration) of the ZI-derived monomer unit per membrane weight is very low, the ZI-derived monomer on the hollow fiber membrane surface is Since the surface concentration of the unit can be sufficiently high, the bulk concentration is 0.001 ~
It may be in the range of 1.0 wt%, 0.05 to 0.5 w
A range of t% is preferred.

Next, the method for producing the hollow fiber membrane of the present invention will be described in detail. As a method for producing the hollow fiber membrane of the present invention, a generally known dry-wet spinning method can be used. That is, using a tube-in-orifice type double spinneret, the stock solution for film formation and the hollow inner solution are simultaneously extruded into the air from the spinneret, and after running in the idle section, the water mainly installed at the lower part of the spinneret is mainly used. It is immersed in a coagulation bath to
The wound hollow fiber membrane has excess additives and solvents removed by washing, and after adding glycerin as needed,
The hollow fiber membrane is formed by drying with a hot air dryer or the like. In this membrane production, in order to make the ZI copolymer unevenly distributed on the inner surface of the hollow fiber membrane, a solution in which the ZI copolymer is dissolved is used as the hollow inner solution.

The hollow fiber membrane obtained by this method has very little eluate. This is because the membrane-forming stock solution and the hollow internal solution in which the ZI copolymer is dissolved are contacted at the moment of being extruded from the spinneret, and the ZI copolymer is entangled with the molecular chains of the synthetic polymer forming the hollow fiber membrane. However, it is considered that the raw solution for film formation is solidified and is firmly fixed because the film forming stock solution is coagulated while being incorporated into the dense structure near the inner surface. It is also considered that the absence of extra ZI copolymer inside the film also contributes.

As the film-forming stock solution used in this method, a polymer solution in which additives such as polysulfone-based polymers and hydrophilic polymers, which are film materials, are uniformly dissolved in a solvent is used. The solvent is not particularly limited as long as it can dissolve these solutes uniformly, but generally N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylformamide, or a mixture thereof is used.

As described above, when the contact angle of the membrane portion of the hollow fiber membrane of the present invention is 50 to 100 degrees, foreign matter such as endotoxin which flows back from the outside of the hollow fiber is adsorbed and trapped in the membrane portion. can do. Therefore, the film thickness part is
It is preferable to have a porous structure with a well-developed network rather than a finger void structure with large independent voids. It is also possible to add polyethylene glycol, polyvinylpyrrolidone or the like as an additive to the stock solution for film formation in order to form a porous structure with a developed network. The additive is 0 wt% with respect to the polysulfone-based polymer
%, And 70 wt% or less is preferably added.
It is more preferable to add 1 wt% or more and 60 wt% or less.

As the hollow liquid, a non-solvent of polysulfone-based polymer or a mixed solvent of the non-solvent and a good solvent of polysulfone-based polymer is used. Generally, the performance of the hollow fiber membrane obtained by the ratio of the non-solvent and the good solvent of the hollow internal liquid,
For example, the ultrafiltration rate of pure water is controlled, and the ratio is determined according to the purpose. Generally, water or a lower alcohol is used as the non-solvent, and the same solvent as the film-forming stock solution is used as the good solvent to be mixed. A copolymer that dissolves in the hollow liquid is selected and used as a ZI copolymer.

The concentration of the ZI copolymer in the hollow liquid is 0.0
If it is from 01 wt% to 10 wt%, the amount necessary for exhibiting biocompatibility can be given to the film surface,
The range of wt% to 5 wt% is preferable.

The ZI copolymer solution remains in the hollow interior even after the hollow fiber membrane is coagulated until it is finally washed. Therefore, if the molecular weight of the ZI copolymer is too low, the ZI copolymer will diffuse through the membrane. , The ZI copolymer is added to the entire film,
The feature of the present invention that the hydrophilic polymer is unevenly distributed on the inner surface of the membrane cannot be achieved. Therefore, the molecular weight of the ZI copolymer is preferably 5,000 or more and 10,000,000 or less, more preferably 10,000 or more and 5,000,000 or less.

The coagulation bath is mainly composed of water and may be mixed with a solvent extracted from the membrane-forming stock solution, but if the concentration of the solvent is too high, the coagulated hollow fiber membrane may re-swell and dissolve. Therefore, it is necessary to constantly replenish water so that the concentration of the solvent does not exceed 70 wt% to reduce the concentration of the solvent.

Further, the hollow fiber membrane of the present invention can be produced by using a hollow fiber membrane which has been formed in advance. In the method,
The hollow fiber membrane can be formed in advance by using various known hollow fiber membrane forming methods. An adsorption treatment solution is prepared by dissolving the ZI copolymer in a suitable solvent that dissolves the ZI copolymer such as methanol, ethanol and isopropanol but does not dissolve the polysulfone polymer, and prepares an adsorption treatment solution in the hollow portion of the hollow fiber membrane. By passing this adsorption treatment solution or enclosing the adsorption treatment solution in the hollow portion of the hollow fiber membrane, the ZI copolymer is brought into contact with the inner surface of the hollow fiber membrane, and the ZI copolymer is contacted with the ZI copolymer.
Adsorb the I-copolymer. After that, wash the excess Z
The I-copolymer and the solvent are removed, and drying is performed if necessary.
These treatments can be performed either at the module stage in which the hollow fiber is molded or at the stage of the hollow fiber itself before molding.

If the concentration of the ZI copolymer in the adsorption treatment solution is 0.001 wt% to 10 wt%, the amount necessary for exhibiting biocompatibility can be imparted to the membrane surface,
The range of 0.01 wt% to 5 wt% is preferable.

In the production of the hollow fiber membrane of the present invention, the ZI copolymer is used as a solution as described above. Z
The solution of the I copolymer comes into contact with the membrane material from the inner surface side of the hollow fiber membrane. If the molecular weight of the ZI copolymer is too low, it will diffuse in the film, and the ZI copolymer will be imparted to the entire film, resulting in uneven distribution of the hydrophilic polymer on the inner surface of the film. Will not be achieved. Therefore, the molecular weight of the ZI copolymer is preferably 5,000 or more and 10,000,000 or less, and more preferably 10,000 or more and 5,000,000 or less.
The following is more preferable.

As described above, the hollow fiber membrane of the present invention can be produced by a method of adsorbing the ZI copolymer on the inner surface of the hollow fiber membrane which has been formed in advance, or from the spinneret. And a solution containing a ZI copolymer are simultaneously extruded into the air, run in an idle section, and then are immersed in a coagulation bath mainly composed of water installed at the lower part of the spinneret for coagulation. It can also be produced by a method in which the copolymer is unevenly distributed on the inner surface of the hollow fiber membrane.

[0039]

EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. (Measurement of amount of eluate) 1.5 g of hollow fiber membrane was added to 150 ml of distilled water.
And heated at 70 ° C. for 1 hour to prepare an extract. This extract was measured for ultraviolet absorbance at a wavelength of 220 to 350 nm using distilled water that had been boiled and cooled without a hollow fiber membrane as a control. The amount of eluate was represented by the highest absorbance value in the wavelength range of 220 to 350 nm.

(Measurement of molecular weight) GPC column KD-8
06M, KD-803, KD-802 (all Sho
Wdex) connected measuring device System-21
(Manufactured by Shodex) and used as a developing solution in dimethylacetamide (manufactured by Kishida Chemical 000-24543).
Hereinafter, DMAc), column temperature 50 ° C., 1 ml / min
The flow rate was measured. Polystyrene standard sample (TSK
The reduced molecular weight was calculated using STANDARD POLYSTYRENE manufactured by Tosoh Corporation. In the present invention, the weight average molecular weight is defined as the molecular weight.

(Measurement of Surface Concentration of ZI Copolymer) A hollow fiber membrane was cut open to expose the inside, and several tubes were lined up so as to be in the measurement visual field, which were then XPS (Physical Electro).
Nis, Inc. PHI-5400) apparatus was measured under the following conditions. Excitation source MgKα (15 kV / 26.
7 mA), analysis area 3.5 mm x 1 mm, capture area is S
urvey Scan (for qualitative analysis) 1100-0e
V, NarrowScan (for quantitative analysis and chemical analysis) Cl
s, Ols, S2p, N1s, Pass Energy
Is Survey Scan: 178.9 eV, Narr
ow Scan: 35.75 eV. The obtained Narro
The quaternary nitrogen element concentration was obtained from the area intensity of the w Scan spectrum and quantitatively calculated using the library relative sensitivity coefficient of the device. The relative sensitivity coefficient used was Cls: 0.296,
Ols: 0.711, S2p: 0.666, N1s:
It is 0.477.

(Measurement of bulk concentration of ZI monomer unit per membrane weight) 100 mg of hollow fiber membrane was dissolved in 1 ml of heavy chloroform (Aldrich 22,578-9),
¹ H with an NMR apparatus (Bruker DPX-400)
NMR was measured. The bulk concentration of the ZI monomer unit was calculated from the ratio of the integrated value of the ammonium adjacent methyl group peak of the obtained NMR spectrum and the integrated value of the aromatic peak derived from the polysulfone polymer.

(Measurement of Contact Angle) One end of a hollow fiber having a length of 2 cm is fused with a cutter knife heated by a burner, and the other end is fixed to a sample stage with a double-sided tape.
Immerse in pure water at 5 ° C for 10 minutes, then contact angle meter (dat
aphysics, manufactured by DCAT11), immersion speed 0.1 mm / sec, immersion length 5.0 mm, measurement temperature 2
It was measured under the condition of 5 ° C. The advancing contact angle, the receding contact angle and the average value are obtained as the measurement results, and the advancing contact angle is defined as the contact angle.

(List of Reagents) The following reagents were used unpurified for the synthesis of ZI copolymers and the formation of hollow fibers. SPP: N, N-dimethyl-N-methacrylamidopropyl-N- (3-sulfopropyl) ammonium betaine CAS No. 5205-95-8; RAS-414, SPE: N, N-dimethyl-N-methacryloxyethyl-N- (3-sulfopropyl) ammonium betaine CAS No. 5205-95-8; 3537-26-1; Rashi RAS-413-SPV: 1- (3-sulfopropyl) -2-vinylpyridinium betaine CAS No. 6613-64-
5; Rashi's RAS-415-PE-350: polyethylene glycol monomethacrylate; NOF CORPORATION Blemmer PE-350-ammonium peroxodisulfate; Wako Pure Chemical 018-
03282 • Methanol; Kishida chemistry 000-48663 • DMAc: N, N-dimethylacetamide; Kishida chemistry 000-24543 • PSf: polysulfone; BASF Ultrason S3010 • TEG: tetraethylene glycol; Wako Pure Chemical 02
3-08135 * PVP: polyvinylpyrrolidone; ISP company Plasdon K90 * 20HD: lauryl hydroxy sulfobetaine; Kao Amphitol 20HDCAS No. 13197-7
6-7

[0045]

Example 1 SPP (5.0
g), PE-350 (17.5 g), ammonium peroxodisulfate (0.26 g), methanol (200 m)
1) was weighed, degassed with nitrogen gas for 30 minutes, and heated at 60 ° C. for 6 hours using an oil bath. 22.9 g of a starch syrup-like product was obtained by evaporating methanol (ZI monomer unit content = 30 mol%, molecular weight = 31200). PSf (18 parts by mass), DMAc
(57 parts by mass) and TEG (25 parts by mass) were added to the mixture, and the mixture was stirred and dissolved at 60 ° C. for 6 hours to obtain a stock solution for film formation. Using a spinneret having an annular orifice, while discharging a DMAc aqueous solution having a concentration of 40 wt% containing 1 wt% of the ZI copolymer obtained above as a hollow internal liquid,
This film-forming stock solution was simultaneously discharged while being kept at 45 ° C. (film-forming stock solution / hollow inner solution = 1.2 / 1.0 (volume ratio)). The stock solution was placed 55 cm below the discharge part.
It was passed through a water bath at ℃ and wound up. Further, it was washed with hot water at 90 ° C. for 90 minutes under running water to remove excess copolymer and solvent. The water permeability of the obtained hollow fiber membrane is 299 ml.
/ M ² · mmHg · hr, the surface concentration of the ZI copolymer on the inner surface is 13 wt%, the bulk concentration is 0.2 wt%
Met. In addition, the absorbance of the extract from this hollow fiber membrane was 0.022 according to the method of measuring the amount of eluate. The contact angle of this hollow fiber was 86 °.

[0046]

Example 2 PSf (18 parts by mass) was added to DMAc (79 parts).
(Part by mass) and PVP (3 parts by mass) were added to the mixture, and the mixture was stirred and dissolved at 60 ° C. for 6 hours to obtain a stock solution for film formation. Using a spinneret having an annular orifice, 1 wt% of the ZI copolymer obtained by the same method as in Example 1 as a hollow internal liquid
While the added DMAc aqueous solution having a concentration of 40 wt% was discharged, the film forming stock solution was simultaneously discharged while being kept at 45 ° C. (film forming stock solution / hollow inner solution = 1.2 / 1.0 (volume ratio)). ). The stock solution was placed 36 cm below the discharge part.
It was passed through a water bath at 5 ° C. and wound up. Furthermore, 90 ℃
Was washed with hot water for 90 minutes to remove excess copolymer and solvent. The water permeability of the obtained hollow fiber membrane is 302 ml /
m is ² · mmHg · hr, the surface concentration of the ZI copolymer of the inner surface is 16 wt%, the bulk density was 0.3 wt%. In addition, the absorbance of the extract from this hollow fiber membrane was 0.025 according to the method of measuring the amount of eluate. The contact angle of this hollow fiber was 70 °.

[0047]

Example 3 SPE (5.0
g), PE-350 (11.77 g), ammonium peroxodisulfate (0.25 g), methanol (200 m)
1) was weighed, degassed with nitrogen gas for 30 minutes, and heated at 60 ° C. for 6 hours using an oil bath. 22.9 g of a starch syrup-like product was obtained by evaporating methanol (ZI monomer unit content = 40 mol%, molecular weight = 122000). A hollow fiber membrane was obtained in the same manner as in Example 1 except that the DMAc aqueous solution having a concentration of 40 wt% containing 1 wt% of the ZI copolymer obtained above was used as the hollow internal liquid. The water permeability of the obtained hollow fiber membrane is 297 ml / m ^2.
-MmHg-hr, and the surface concentration of the ZI copolymer on the inner surface was 19 wt% and the bulk concentration was 0.2 wt%. In addition, the absorbance of the extract from this hollow fiber membrane was 0.015 according to the eluate amount measurement method. The contact angle of this hollow fiber was 85 °.

[0048]

Example 4 SPV (5.0
g), PE-350 (11.77 g), ammonium peroxodisulfate (0.25 g), methanol (200 m)
1) was weighed, degassed with nitrogen gas for 30 minutes, and heated at 60 ° C. for 6 hours using an oil bath. 22.9 g of a starch syrup-like product was obtained by evaporating methanol (ZI monomer unit content = 28 mol%, molecular weight = 16000). A hollow fiber membrane was obtained in the same manner as in Example 1 except that the DMAc aqueous solution having a concentration of 40 wt% containing 1 wt% of the ZI copolymer obtained above was used as the hollow internal liquid. The water permeability of the obtained hollow fiber membrane is 330 ml / m ^2.
-MmHg-hr, the surface concentration of the ZI copolymer on the inner surface was 16 wt%, and the bulk concentration was 0.3 wt%. In addition, the absorbance of the extract from this hollow fiber membrane was 0.028 according to the method of measuring the amount of eluate. The contact angle of this hollow fiber was 86 °.

[0049]

[Example 5] DM having a concentration of 40 wt% was used as the hollow internal liquid.
A hollow fiber membrane was obtained in the same manner as in Example 1 except that the Ac aqueous solution was used. A small module was prepared by bundling 400 hollow fiber membranes each having a length of 20 cm. 100 ml of an aqueous 40 wt% ethanol solution containing 1 wt% of the ZI copolymer of Example 1 was passed through this small module for 60 minutes to adsorb the ZI copolymer. Then, the hollow fiber membrane was washed with hot water at 90 ° C to remove excess copolymer and ethanol. The water permeability of the obtained hollow fiber membrane is 350 ml.
/ M ² · mmHg · hr, the surface concentration of the ZI copolymer on the inner surface is 12 wt%, the bulk concentration is 0.2 wt%
Met. In addition, the absorbance of the extract from this hollow fiber membrane was 0.089 as measured by the method of measuring the amount of eluate. The contact angle of this hollow fiber was 87 °.

[0050]

Comparative Example 1 DMA having a concentration of 40 wt% as a hollow internal liquid
Hollow in the same manner as in Example 1 except that the aqueous solution c was used.
A thread film was obtained. The water permeability of the obtained hollow fiber membrane is 957 ml.
/ M ^Two-MmHg-hr, ZI copolymer on the inner surface
Both the surface concentration and the bulk concentration were 0 wt%. Also,
The extraction liquid from this hollow fiber membrane was absorbed by the method of measuring the amount of eluate.
The luminous intensity was 0.013. Also, the contact angle of this hollow fiber
Was 86 °.

[0051]

Comparative Example 2 A hollow fiber membrane was obtained in the same manner as in Example 1 except that a 40 wt% concentration DMAc aqueous solution containing 1 wt% of 20HD was used as the hollow internal liquid. The water permeability of the obtained hollow fiber membrane is 297 ml / m ² · mmHg · hr.
And the surface concentration of 20HD on the inner surface is 14 wt%,
The bulk concentration was 2.2 wt%. In addition, the absorbance of the extract from this hollow fiber membrane by the method of measuring the amount of eluate is 0.
It was as high as 115. The contact angle of this hollow fiber is 19 °
Met. This means that 20HD is a low molecule and has penetrated from the inner surface to the outer surface through the film thickness portion.

[0052]

[Comparative Example 3] DM as a hollow liquid having a concentration of 40 wt%
A hollow fiber membrane was obtained in the same manner as in Example 1 except that the Ac aqueous solution was used. The obtained hollow fiber membrane was immersed in an aqueous ethanol solution having a concentration of 40 wt% to which 1 wt% of the ZI copolymer of Example 1 was added, and the ZI copolymer was adsorbed on the entire hollow fiber membrane. Then, the hollow fiber membrane was washed with hot water at 90 ° C. to remove excess copolymer and ethanol. The water permeability of the obtained hollow fiber membrane is 330 ml / m ² · mmHg · hr, and the surface concentration of the ZI copolymer on the inner surface is 12 wt%.
The bulk concentration was 2.4 wt%. Moreover, the absorbance of the extract from this hollow fiber membrane was as high as 0.102 by the eluate amount measurement method. The contact angle of this hollow fiber is 4
It was 4 °.

[0053]

[Evaluation Example 1] Using the hollow fiber membranes obtained in Examples 1-5 and Comparative Examples 1-3, the ultrafiltration rate (UFR) of bovine plasma was evaluated.
Was measured. That is, a hollow fiber membrane with a length of 15 cm
A small module was made by bundling 0 pieces. Heparin-added bovine plasma heated to 37 ° C. (heparin 5000 IU / l, protein concentration 6.5 g / dl) was passed through this small module at a linear velocity of 0.4 cm / sec, and the transmembrane pressure difference was 333.0.
Ultrafiltration was performed for 120 minutes under the condition of 5 Pa. Fifteen, three
The filtrate was collected at 0, 60, and 120 minutes, and the weight was measured to calculate UFR. The results are shown in Table 1. In the hollow fiber membrane in which the ZI copolymer is present on the inner surface, no deterioration in UFR performance was observed.

[0054]

[Table 1]

[0055]

Evaluation Example 2 Using the hollow fiber membranes obtained in Examples 1 to 5 and Comparative Examples 1 to 3, the endotoxin permeability was measured. That is, the test liquid having an endotoxin concentration of 100 ng / ml was bundled with 200 hollow fiber membranes of 9.5 cm to evaluate Example 1
After performing total filtration at 5 ml / min for 10 minutes from the dialysate side to the blood side of the module prepared by the same method as described above, the filtrate is collected at the blood side outlet, and the LAL reagent for endotoxin detection (Wako Pure Chemical Industries: horseshoe crab hemocyte) The endotoxin was detected using the extract HS-J). The results are shown in Examples 1 to 4.
No endotoxin was detected in the filtrate in the hollow fiber membrane obtained in Comparative Example 1 and 12 ng / ml in the filtrate in the hollow fiber membrane obtained in Comparative Example 2, which was obtained in Comparative Example 3. In the obtained hollow fiber membrane, 9 ng / ml endotoxin was detected in the filtrate.

[0056]

Test Example 3 Adhesion of platelets was evaluated for the hollow fiber membranes obtained in Examples 1 to 5 and Comparative Example 1. That is,
A small module was made by bundling 28 hollow fiber membranes 14 cm in length, and heparin-added human fresh blood was added to the module.
cc is allowed to pass for 5 minutes, followed by saline 10c
Blood was drained by flushing c. Next, the hollow fiber is chopped into 2 to 3 mm, put into a Spitz tube, and put into a phosphate buffer solution (PB
S) (manufactured by Wako Pure Chemical Industries, Ltd.) in Triton X-10
0.5 volume T obtained by dissolving 0 (manufactured by Nacalai Tesque)
0.5 ml of the rithon X-100 / PBS solution was added, and ultrasonic waves were extracted for 60 minutes. 0.1m of extract
3 ml of LDH reaction reagent (LDH monotest: Boehringer Mannham) is reacted with this extract, and 0.5 ml is immediately collected to measure the absorbance at 340 nm. The residual liquid was reacted at 37 ° C. for 1 hour and then the absorbance at 340 nm was measured to measure the decrease in the absorbance. Similarly, the absorbance of the membrane that was not reacted with blood was also measured to obtain Δ340
nm = (absorbance immediately after sample reaction−absorbance after 60 minutes of sample) − (absorbance immediately after blank reaction−absorbance after 60 minutes of blank). Therefore, the higher the reduction rate, the higher the LDH activity of the film. LDH is an enzyme in the cell membrane, and most of the cells adhering to the membrane surface are platelets as observed by electron microscopy.
The amount of platelets adhered to the membrane surface was relatively evaluated from the quantitative value of. The results are shown in Table 2. In the hollow fiber membrane in which the ZI copolymer is unevenly distributed on the inner surface, the amount of platelets adhered to the membrane surface is small.

[0057]

[Table 2]

[0058]

INDUSTRIAL APPLICABILITY The hollow fiber membrane of the present invention can achieve modification of the membrane surface without causing an increase in eluate. That is, the amount of eluate is small, and deterioration of membrane performance and activation of platelets are slight, endotoxin is not detected in the filtrate, medical applications such as hemodialysis and hemofiltration, and as a selective separation membrane in the pharmaceutical industry, food industry, etc. A useful film was obtained.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) B01D 71/40 B01D 71/40 71/44 71/44 71/82 500 71/82 500 C08F 212/14 C08F 212/14 220/10 220/10 220/54 220/54 226/06 226/06 D01F 6/76 D01F 6/76 D (72) Inventor Shunji Maniwa 6-4100 Asahi-cho, Nobeoka-shi, Miyazaki Asahi Kasei Corporation Inner F-term (reference) 4C077 AA05 AA11 BB01 BB02 CC06 KK30 LL05 MM03 NN02 NN03 NN14 PP09 PP15 4D006 GA06 GA13 KE02Q MA01 MA06 MB14 MB18 MC24 MC24X MC37 MC37X MC40 MC40X MC62 MC62X MC74 MC74X41QQ47 NA04 NA02 NA01 NA10 NA01 NA02 NA02 AB07P AL08P AL08Q AM21P AQ08Q AQ11P BA32P BA34Q BA38Q BA56P CA04 DA01 JA11 4L035 BB04 CC20 DD03 EE20 MF01

Claims (13)

[Claims] 1. The following formula (1), (2) or (3) is formed on the inner surface of a hollow fiber membrane containing a polysulfone-based polymer as a main component.
, A vinyl polymerizable monomer having a zwitterion in the molecule, and a copolymer of another vinyl polymerizable monomer, and the copolymer is on the inner surface of the hollow fiber membrane A hollow fiber membrane characterized by being unevenly distributed. [Chemical 1] (In the formula, R is hydrogen or a methyl group, A, B, and C are alkylene groups in which a part of carbon-carbon bonds may be substituted with an ester bond or an amide bond, and X is a zwitterionic group. And Y represents a carboxylic acid group, a phosphoric acid group or a sulfonic acid group.) 2. The hollow fiber membrane according to claim 1, wherein the vinyl polymerizable monomer having a zwitterion in the molecule is betaine, ammonium phosphate or sulfobetaine. 3. Sulfobetaine is represented by the following formula (4):
The hollow fiber membrane according to claim 2, which is a sulfobetaine compound represented by (5) or (6). [Chemical 2] 4. The hollow fiber membrane according to claim 1, wherein the polysulfone-based polymer which is the main component of the hollow fiber membrane is polysulfone and / or polyether sulfone. 5. The hollow fiber membrane according to claim 1, wherein the hollow fiber membrane contains polyvinylpyrrolidone and / or polyethylene glycol. 6. The contact angle of the membrane portion of the hollow fiber membrane is 50 to 1
The hollow fiber membrane according to any one of claims 1 to 5, which is 00 degrees. 7. A copolymer of a vinyl-polymerizable monomer having a zwitterion in a molecule and another vinyl-polymerizable monomer,
The content of the monomer unit derived from the vinyl polymerizable monomer having a zwitterion in the molecule is 5 mol% or more and 95 mol or more.
% Or less, The hollow fiber membrane according to any one of claims 1 to 6. 8. A copolymer of a vinyl polymerizable monomer having a zwitterion in the molecule and another vinyl polymerizable monomer,
The other vinyl-polymerizable monomer is one or two or more vinyl-polymerizable monomers selected from vinylpyrrolidone, styrene, and (meth) acrylic acid ester derivatives. Hollow fiber membrane. 9. Another vinyl-polymerizable monomer (meth)
The hollow fiber membrane according to claim 8, wherein the acrylic acid ester derivative is a (meth) acrylic acid ester derivative represented by the following formula (7), formula (8) or formula (9). [Chemical 3] (In the formula, R ₁ and R ₃ are hydrogen or a methyl group, R ₂ , R ₄ ,
R ₈ represents hydrogen, an aliphatic hydrocarbon group having 1 to 20 carbon atoms, a polyalkylene oxide group or an aromatic hydrocarbon group, and A and R ₇ represent alkylene groups having 1 to 10 carbon atoms. ) 10. The surface concentration of the monomer unit derived from a vinyl polymerizable monomer having a zwitterion in the molecule on the surface of the hollow fiber membrane is 5 wt% or more.
The hollow fiber membrane according to any one of 1. 11. A double spinneret is used to simultaneously discharge a hollow inner liquid from the inside and a polymer solution containing a polysulfone-based polymer, which is a hollow fiber membrane material, from the outer side, and then set at the bottom of the spinneret. In the dry-wet spinning method of immersing in a coagulation bath and spinning, 0.001 wt% of a copolymer of a vinyl polymerizable monomer having a zwitterion in the molecule and another vinyl polymerizable monomer in the hollow internal liquid % To 10 wt% dissolved solution is used. 12. A solution prepared by dissolving 0.001 wt% to 10 wt% of a copolymer of a vinyl-polymerizable monomer having a zwitterion in the molecule and another vinyl-polymerizable monomer is used as a polysulfone-based solution. A method for producing a hollow fiber membrane, characterized in that the copolymer is retained on the inner surface of the hollow fiber membrane by allowing it to flow into the hollow portion of the hollow fiber membrane containing a molecule as a main component. 13. A hollow fiber membrane obtained by the method for producing a hollow fiber membrane according to claim 11 or 12.