JP5407713B2 - Polysulfone-based hollow fiber membrane module and manufacturing method - Google Patents

Description

  The present invention relates to a polysulfone-based hollow fiber membrane module, which has high separation performance and is suitably used for applications that require blood compatibility and non-adhesion of proteins and organic substances. For example, separation membranes for blood purification require blood compatibility and non-adhesion of proteins, while membranes for water purifiers, water purification membranes, sewage purification membranes, reverse osmosis membranes, membranes for biological component separation, etc. Since non-adhesion is required, it is preferably used.

  Medical hollow fiber membranes that come into contact with bodily fluids or blood cause serious problems when proteins or platelets adhere to them, causing degradation of the performance of the hollow fiber membranes or causing biological reactions. Moreover, also in water treatment membranes, such as a water purifier, adhesion of protein and organic substance causes the separation performance fall of a hollow fiber membrane. Various studies have been made to solve such problems by making the hollow fiber membranes hydrophilic. For example, a method of imparting hydrophilicity to a membrane and suppressing soiling by mixing polyvinyl pyrrolidone, which is a hydrophilic polymer, with polysulfone at the stage of the film-forming stock solution is disclosed (Patent Document 1). . However, in these methods, in order to impart hydrophilicity to the surface, it is necessary to increase the amount of the hydrophilic polymer in the film-forming stock solution, or a hydrophilic polymer that is compatible with the base polymer. And there are restrictions such as having to study the optimal stock solution composition according to the intended use of the material.

  Therefore, a method of introducing a hydrophilic component such as polyvinyl pyrrolidone that becomes water-insoluble by radiation or heat during the film forming process (Patent Document 2), or a polysulfone-based hollow fiber membrane with a hydrophilic polymer solution such as polyvinyl pyrrolidone. A method of forming a coating layer insolubilized by radiation crosslinking after being brought into contact with (Patent Document 3) is disclosed. However, an aqueous polymer such as polyvinylpyrrolidone and a polysulfone-based polymer have difficulty in forming a coating layer due to weak interaction between molecules.

  Therefore, a method in which a polyvinyl alcohol aqueous solution having a saponification degree within a certain range is brought into contact with a polysulfone separation membrane to efficiently form a coating layer on the membrane surface by the hydrophobic interaction between polysulfone and vinyl acetate (Patent Document 4). Is disclosed. However, as a result of investigations by the present inventors, when polyvinyl alcohol is coated on a separation membrane, the separation performance of the hollow fiber is markedly reduced, and furthermore, the adsorption of polyvinyl alcohol on polysulfone is too strong, resulting in a hollow fiber membrane module. It was found that when applied, the adsorption tends to be non-uniform in the longitudinal direction of the hollow fiber membrane. It is also known that the hydroxyl group of polyvinyl alcohol activates complement when it comes into contact with blood.

  Further, as a hollow fiber membrane with improved biocompatibility and water permeability, a method of forming a membrane from a mixed solution of a polysulfone polymer and polyglycols, vinylpyrrolidone and vinyl acetate copolymer is disclosed (Patent Document 5). . However, as biocompatibility, in addition to complement activity, it is necessary to suppress adhesion of platelets and the like, but this patent does not focus on adhesion of platelets and proteins. Furthermore, in recent years, sterilization methods for irradiating high energy rays such as γ rays and electron beams have become mainstream. However, this method has the problem that blood compatibility is lost due to such γ ray sterilization. It was. That is, in the film forming conditions in such a method, polyglycol, vinyl pyrrolidone, and vinyl acetate copolymer are only mixed at the time of film formation, and the surface amount and surface presence state of the ester group unit are completely taken into consideration. Absent. For this reason, as a result of investigations by the present inventors, it was found that even if an improvement in residual blood was observed, adhesion suppression of platelets and the like was insufficient. Moreover, it is considered that even the effect has been eliminated by γ-ray irradiation.

  There is also a method of making a membrane hydrophilic and improving water permeability by applying a mixed solution of polyvinyl acetal diethylaminoacetate and vinylpyrrolidone / vinyl acetate (6/4) copolymer to a polypropylene hollow fiber membrane (Patent Document 6). It is disclosed. However, this method is intended to improve water permeability and does not suppress adhesion of platelets. In the first place, in order to solve the problem of dissolving in water after hydrophilization treatment using only the vinylpyrrolidone / vinyl acetate (6/4) copolymer, the vinylpyrrolidone / vinyl acetate (6/4) copolymer is used. By covering the coalescence with water-insoluble polyvinyl acetal diethylaminoacetate, elution into water is suppressed. Therefore, the vinylpyrrolidone / vinyl acetate (6/4) concentration on the outermost surface is kept low. This cannot suppress the adhesion of platelets. Moreover, this method hydrophilizes the membrane only by physical adsorption. Therefore, even if there is no elution in about several hours, elution is a concern in long-term use. Furthermore, even if there is little elution of these polymers in contact with water, a solution having a greater elution force than water, such as blood, comes into contact with the membrane in medical applications. In such a case, there is a strong concern that the polymer that has only been physically adsorbed will be eluted into the blood.

  It is also said that even if the material surface is coated with a homopolymeric hydrophilic polymer such as polyvinylpyrrolidone or polyethylene glycol, the adhesion of proteins and the like can only be temporarily suppressed. That is, a separation membrane module satisfying blood compatibility with a high-performance separation membrane with less adhesion of blood components has not yet been established.

Japanese Patent Publication No. 2-18695 Japanese Patent Publication No.8-9668 JP-A-6-238139 JP 2006-198611 A JP-A-6-165926 JP-A-8-131791

  An object of the present invention is to provide a high-performance polysulfone-based separation membrane module that improves the disadvantages of the prior art and has less adhesion of proteins and organic substances.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have achieved a high-performance polysulfone-based separation membrane module having excellent blood compatibility and low adhesion of proteins and organic substances by the following configurations 1 to 10. Is done.
1. A module having a built-in polysulfone-based hollow fiber membrane, an infrared ray derived from an ester group C═O near 1730 cm ^{−1 on the} surface of the functional layer near the end face and near the center in the longitudinal direction of the polysulfone-based hollow fiber membrane The ratio (A _CO ) / (A _CC ) of the absorption peak intensity (A _CO ) to the infrared absorption peak intensity (A _CC ) derived from the benzene ring C═C of the polysulfone polymer in the vicinity of 1580 cm ⁻¹ is 0. A polysulfone-based hollow fiber membrane module, wherein the ratio of the measurement points of 005 or more and 0.001 or less is 10% or less.
2. 2. The polysulfone-based hollow fiber membrane module as described in 1 above, wherein (A _CO ) / (A _CC ) has an average value of 0.5 or less.
3. 3. The polysulfone-based hollow fiber membrane module as described in 1 or 2 above, wherein the ester group C═O is derived from a polymer.
4). 4. The polysulfone-based hollow fiber membrane module as described in 3 above, wherein the polymer from which the ester group C = O has has at least one unit selected from a carboxylic acid vinyl ester, an acrylic acid ester, and a methacrylic acid ester. .
5. 5. The polysulfone-based hollow fiber membrane module as described in 3 or 4 above, wherein the ratio of the ester group-containing unit in the polymer from which the ester group C = O is derived is 0.3 or more.
6). 6. The polysulfone-based hollow fiber membrane module according to any one of 3 to 5, wherein the ester group is derived from polyvinyl acetate and / or vinyl acetate and a vinylpyrrolidone copolymer.
7). Wherein in the functional layer surface, the infrared absorption peak intensity derived from the benzene ring C = C of polysulfone around 1580 cm ^-1 of the infrared absorption peak intensity derived from vinylpyrrolidone groups in the vicinity of _{^{1660cm -1 (A NCO) (A}} CC) The ratio (A _NCO ) / (A _CC ) with respect to the ratio of measuring points having an average value of 0.4 or more and 0.25 or less is 10% or less. Hollow fiber membrane module.
8). 8. The polysulfone hollow according to any one of 1 to 7 above, wherein the concentration of nitrogen atoms relative to all elements constituting the polysulfone hollow fiber membrane is 0.01 wt% or more and 0.1 wt% or less. Yarn membrane module.
9. 9. The polysulfone-based hollow fiber membrane module as described in any one of 1 to 8 above, which is for blood purification.
10. A state in which a hollow fiber membrane built in a polysulfone-based hollow fiber membrane module is wetted with a copolymer aqueous solution of vinyl pyrrolidone and vinyl acetate that is 0.2 to 6 times the dry weight of the hollow fiber membrane. A method for producing a polysulfone-based hollow fiber membrane module, characterized by performing radiation irradiation as follows.

  The present invention is a polysulfone-based hollow fiber membrane module characterized in that ester groups are localized on the surface of the hollow fiber membrane functional layer and are uniformly distributed on the surface, and have high water permeability and separation performance. In addition, it can be widely used for applications that require blood compatibility and the property of preventing adhesion of proteins and organic substances.

1 shows an embodiment of an artificial kidney used in the present invention. beta ₂ - shows a circuit in microglobulin clearance measurement.

  The present invention relates to a polysulfone-based hollow fiber membrane module characterized in that ester groups are localized on the surface of a hollow fiber membrane functional layer and are uniformly distributed on the surface.

  The functional layer as used in the field of this invention is a layer which contacts the liquid which a hollow fiber membrane module processes, and a functional layer surface means the surface in the layer. For example, in the case of an artificial kidney hollow fiber membrane in which the treatment liquid is blood, the functional layer surface is the inner surface of the hollow fiber membrane in contact with blood.

  The adhesion of proteins and platelets is suppressed by the presence of ester groups on the surface of the hollow fiber membrane functional layer. This adhesion suppression function will be explained. First, protein adhesion to the material surface is caused by a change in the higher-order structure of the protein to expose the hydrophobic part inside, and the hydrophobic part is exposed to the hydrophobic interaction with the material surface. It is said to be the cause. On the other hand, if the hydrophilicity of the material surface is too strong, it is said that protein adhesion cannot be sufficiently suppressed. This is because water around the protein and the surface of the material has water whose mobility is constrained by hydrogen bonds, so-called bound water. When protein adheres to the surface of the material, the bound water present on both surfaces This is because the material having a strong surface hydrophilicity traps the bound water around the protein, where the action greatly affects. The mechanism of the adhesion suppression effect of the ester group is not fully understood, but considering the above, the ester group has moderate hydrophilicity, so it does not induce protein conformational changes. Since the degree of hydrophilicity is not too strong, it can be presumed that the protein material surface adhesion is prevented without trapping the bound water around the protein.

On the other hand, in the present invention, it was found that activated proteins and platelets also adhere to the surface on which the ester groups are present when the amount of ester groups is small compared to the amount of polysulfone, and the hollow fiber membrane functional layer It was concluded that the ester group on the surface of the hollow fiber membrane needs to be more than a certain amount uniformly at any part of the hollow fiber membrane. Therefore, the present inventors considered to represent the ratio of the amount of ester groups divided by the amount of polysulfone as an index indicating the amount of ester groups present, and as a result of various investigations, the results of polysulfone-based hollow fiber membranes Benzene ring C = C of polysulfone near 1580 cm ⁻¹ of infrared absorption peak intensity (A _CO ) derived from ester group C═O near 1730 cm ⁻¹ on the functional layer surface near the end face and the center in the longitudinal direction The ratio (A _CO ) / (A _CC ) to the infrared absorption peak intensity (A _CC ) of the origin is selected, and the average value is 0.005 or more, preferably 0.01 or more, more preferably 0.02 or more. It was found that the ratio of measurement points having the ratio of 0.001 or less is preferably 10% or less, and preferably 5% or less. In addition, since the average value of (A _CO ) / (A _CC ) may cause a decrease in the performance of the polysulfone hollow fiber membrane if it is too large, it is 0.5 or less, preferably 0.4 or less, and further 0.3 The following is preferred.

  Furthermore, it is preferable that the ester group is oriented on the outermost surface. The outermost surface can be measured with a thickness of about 10 nm by X-ray photoelectron spectroscopy (XPS). The peak of the carbon derived from the ester group (COO) can be obtained by dividing the peak appearing at +4.0 to 4.2 eV from the main peak derived from C1s CH or C—C. By calculating the ratio of the peak area to all elements (all the elements other than hydrogen atoms cannot be detected because hydrogen atoms cannot be detected), the carbon amount (number of atoms) derived from the ester group can be obtained. The peak area percentage of carbon derived from ester groups on the surface of the functional layer is 0.3 (number of atoms%) or more, preferably 0.5 (number of atoms%) or more, 7 (number of atoms%) or less, 5 (number of atoms%) The following is preferable.

  Further, the amount of carbon derived from the ester group on the surface opposite to the functional layer is preferably 2 (number of atoms%) or less, preferably 1 (number of atoms%) or less, and preferably not detected. This is because the water permeability of the membrane tends to decrease when the opposite surface also has ester groups.

In the longitudinal direction of the hollow fiber membrane, the vicinity of the end surface here refers to a portion within 5 cm from the end surface, and the vicinity of the central portion refers to a portion within ± 2.5 cm in the longitudinal direction from the center point of both end surfaces. The ratio of (A _CO ) / (A _CC ) is calculated as follows.

On the surface of the hollow fiber membrane functional layer, the measurement range is 3 μm × 3 μm, the number of integration is 30 times or more, and the infrared absorption spectrum is measured at 25 points by the absorption intensity. This 25-point measurement is performed on a total of three hollow fiber membranes per module at three different locations for one hollow fiber membrane. The obtained infrared absorption spectrum, drawing a base line with 1549～1620Cm ^-1, and the peak area of the portion surrounded by the positive portion of the reference line and the spectral and _{A CC,} likewise, 1711～1759Cm ^-1 Then, a reference line is drawn, and the ratio (A _CO ) / (A _CC ) between the two is calculated using the peak area as A _CO .

  The ester group can be introduced into the surface of the functional layer of the hollow fiber membrane by chemically modifying the surface of the functional layer with a reactive compound containing an ester group after forming the hollow fiber membrane. However, such a surface reaction may cause a decrease in the performance of the hollow fiber membrane, and there are various condition restrictions for actual application. Therefore, a polysulfone polymer having a chloroacetamidomethyl group that undergoes a crosslinking reaction even in an aqueous system is preferably used. In order to react with the functional group, it is preferable that the ester group-containing polymer also has an amino group.

  Therefore, when a polymer containing an ester group is used as the reactive compound, the ester group can be introduced into the functional layer surface relatively easily. Examples of the polymer containing an ester group include those having an ester group in the main chain such as polylactic acid and polyester, carboxylic acid vinyl esters such as vinyl acetate, acrylic acid esters such as methyl acrylate and methoxyethyl acrylate, and methyl methacrylate. And those contained in the side chain, such as methacrylic acid esters such as ethyl methacrylate and hydroxyethyl methacrylate. In particular, as the ester group-containing polymer, an aliphatic hydrocarbon polymer such as vinyl acetate or methacrylic acid ester is preferably used, and a polymer containing an aromatic ring such as polyethylene terephthalate has a degree of hydrophobicity. Since it becomes too strong, it is not preferably used in the present invention.

  In particular, those contained in side chains such as carboxylic acid vinyl esters, acrylic acid esters, and methacrylic acid esters are preferred from the viewpoint of inhibiting the adhesion of proteins and platelets. Among these, vinyl acetate, among the carboxylic acid vinyl esters, is excellent in suppressing the adhesion of proteins and platelets, and a copolymer of vinyl acetate and vinyl pyrrolidone is preferably used for the reasons described later. In addition, if the ratio (molar ratio) of ester group units to all units in the polymer is 0.3 or more, preferably 0.35 or more, the inhibitory effect of ester group proteins and platelet adhesion is exhibited.

  Moreover, as a copolymer, a block copolymer, an alternating copolymer, and a random copolymer are used suitably rather than a graft copolymer, and an alternating copolymer and a random copolymer are used more suitably. That is, the average number of repetitions of the same unit is preferably 5 or less.

  The reason for this is not clear, but it may be because when the ester group units are continuous, the interaction between the ester groups becomes strong and the ester groups are difficult to orient on the surface.

  As a method of introducing the ester group-containing polymer into the functional layer surface, a method of mixing the polymer with a stock solution for forming a hollow fiber membrane, a method of mixing with an injection solution for forming a hollow part during film formation, A method of coating the surface of the membrane with a polymer after forming the hollow fiber membrane is preferably used. Further, after coating, a method of insolubilization by radiation irradiation, heat treatment or the like, a method of immersing the hollow fiber membrane in a mixed solution of hydrophobic monomers, and causing a polymerization reaction on the surface of the hollow fiber membrane can be mentioned. In addition, when mixed with the membrane forming stock solution, a copolymer of vinyl acetate and vinylpyrrolidone is particularly suitable as the ester group-containing polymer from the viewpoint of compatibility with the polysulfone-based polymer.

  Among these, the method of coating the hollow fiber membrane surface is a preferable method because it can be carried out easily and in a small amount. For example, the ester group-containing polymer may be dissolved in a solvent and applied to the hollow fiber membrane and adsorbed, or the ester group-containing polymer may be fixed to the hollow fiber membrane material via a polymer or the like serving as a binder. good. Further, when the ester group-containing polymer is brought into contact with the hollow fiber membrane surface, a method of concentrating on the membrane surface using a pressure difference is efficient and is preferably used. The pressure difference may be either pressurization or reduced pressure. In addition, even if it does not take the method of giving a pressure difference using the ester group containing polymer solution itself and introducing it into the film surface, it may be pressurized with another solution such as gas or water after contacting the solution. The pressure difference is preferably 50 mmHg or more, more preferably 100 mmHg or more, at the inlet and outlet of the module.

  As the solvent for coating with the polymer solution as described above, water, alcohol or an aqueous alcohol solution is suitable. From the viewpoint of handleability, water or an aqueous alcohol solution is more preferably used. The alcohol concentration of the aqueous alcohol solution is preferably 70% by weight or less. If an organic solvent other than alcohol is used, there is a possibility that the film may be modified or the film performance may be changed. When such a solvent is used, a water-soluble polymer is preferably used as the ester group-containing polymer. Specifically, it is a copolymer of vinyl pyrrolidone and vinyl acetate, or a copolymer of vinyl alcohol and vinyl acetate. However, in the case of a copolymer of vinyl alcohol and vinyl acetate, the reason is unclear, but care must be taken because the membrane performance is significantly reduced. This is because vinyl alcohol has a strong intermolecular interaction of hydroxyl groups, so that water molecules are difficult to pass through the membrane, causing water permeability to decrease. On the other hand, a copolymer of vinyl pyrrolidone and vinyl acetate is preferably used because of its strong adsorptive power to polysulfone. Moreover, after coating other polymer, you may coat other polymer in the range which does not prevent the effect of ester group containing polymer, such as coating ester group containing polymer. Furthermore, the method of insolubilization by irradiation, heat treatment or the like after coating is a preferable method because it can reduce the elution of the polymer during blood treatment. In particular, in the case of coating with water or an alcohol solvent, the insolubilization treatment is important from the viewpoints of safety and environment.

The elution of the polymer into water per 1 m ^{2 of the} surface area of the hollow fiber membrane is 1 mg or less, preferably 0.5 mg or less. Elution into water is the amount eluted when the hollow fiber membrane module was washed with pure water at 1 L on the blood side and 2.5 L on the dialysate side, and then 4 L of 37 ° C. pure water was circulated at 200 mL / min for 4 hours. Ask.

  In order to perform the insolubilization, for example, radiation irradiation or heat treatment may be performed while the hollow fiber membrane is immersed in an ester group-containing polymer solution. Or after immersing a hollow fiber membrane in the copolymer solution of a vinylpyrrolidone unit and a hydrophobic unit, you may extract a solution, and may perform radiation irradiation and heat processing. In the case of irradiation with radiation, the ester group-containing polymer is more likely to be fixed and insolubilized in the hollow fiber membrane when a slight amount of solvent is present. This is considered to be caused by the fact that the solvent becomes a radical upon irradiation and this is the starting point, and the polymer and the material of the hollow fiber membrane are also radicalized, and the copolymer is crosslinked and insolubilized into the membrane. Therefore, it is more preferable that 0.2 weight times or more, further 1.0 weight times of the solvent remains with respect to the dry weight of the hollow fiber membrane when the radiation is irradiated. As the solvent, water or an aqueous solution is preferable. On the other hand, when the hollow fiber membrane module is not filled with water, there is less concern about elution in the time until radiation irradiation, so it is preferable that only the hollow fiber membrane is in a wet state. The specific water content is 6.0 times by weight or less, preferably 4.0 times by weight or less with respect to the dry weight of the hollow fiber membrane. In addition, after immersing the hollow fiber membrane in the ester group-containing polymer solution, it may be subjected to radiation irradiation or heat treatment after being replaced with water or the like. Furthermore, radiation or heat treatment may be performed after extracting the substituted water.

In addition, when the density | concentration of an ester group containing polymer solution is low, a hollow fiber membrane cannot fully be coated and the ratio of the location from which the value of ( _ACO ) / ( _ACC ) will be less than 0.001 will increase. If the concentration is too high, the amount of eluate from the polymer often increases. The specific concentration varies depending on the type of the polymer, but in general, it is preferably 0.0001% by weight or more and 1% by weight or less, and more preferably 0.0005% by weight or more and 0.5% by weight or less. Is preferred. For example, in a 7: 3 copolymer of vinyl pyrrolidone and vinyl acetate, 0.01% to 0.5% by weight is preferable. For a 6: 4 copolymer of vinylpyrrolidone and vinyl acetate, 0.0005% to 0.1% by weight is preferred. For a 5: 5 copolymer of vinylpyrrolidone and vinyl acetate, 0.0001% to 0.05% by weight is preferred.

  Moreover, as a method of extracting the immersed ester group-containing polymer solution, water, and the like from the module, various methods such as reduced-pressure drying, high-temperature drying, low-temperature air drying, and blow drying can be used. In addition, it is known that when oxygen is present at the time of irradiation, oxygen radicals are generated and the polymer material of the hollow fiber membrane material is decomposed. Therefore, the oxygen concentration around the hollow fiber membrane when irradiated with radiation is desirably 10% or less. When the hollow fiber membrane module is irradiated with radiation, for example, if the inside of the module is purged with an inert gas such as nitrogen gas or argon gas, the oxygen concentration decreases.

  The hollow fiber membrane may be coated with an ester group-containing polymer and then incorporated into the module, or may be coated by filling the hollow fiber membrane module with an ester group-containing polymer solution. After coating, radiation irradiation or heat treatment may be performed as described above.

  However, in order to introduce uniformly into the hollow fiber membrane, it is more efficient to coat the hollow fiber membrane module by filling it with an ester group-containing polymer solution. Furthermore, the higher the flow rate at which the polymer solution is passed through the hollow fiber membrane module, the more uniformly it can be coated, preferably 200 mL / min or more, more preferably 300 mL / min or more. On the other hand, if it is too fast, a sufficient amount cannot be coated, so it is 1000 mL / min or less, preferably 800 mL / min or less.

  Moreover, since the ratio of the part which is not polymer-coated increases when the density | concentration of a polymer solution is low, the density | concentration of a polymer solution is 1 ppm or more, Preferably it is 5 ppm or more, Furthermore, 10 ppm or more is preferable. Even if the concentration is too high, the amount of eluate increases, so the concentration of the polymer solution is preferably 1% by weight or less, more preferably 3000 ppm or less. A method in which the polymer solution is filtered from the surface of the functional layer of the hollow fiber membrane to the opposite side is preferably passed because the polymer can be accumulated on the surface of the functional layer. The filtration pressure at this time is preferably 50 mmHg or more, and more preferably 100 mmHg. In addition, after passing the polymer solution through filtration and blowing the gas from the direction opposite to the direction through which filtration was passed, or passing the liquid, the ester group on the opposite surface of the functional layer This is a suitable means for increasing the amount of the ester group-containing polymer on the surface of the functional layer while reducing the amount of the contained polymer. The gas flow rate at this time is preferably 70 NL / min or less, more preferably 50 NL / min or less, and the time is preferably 10 minutes or less. In the case of a liquid, it is preferably 1 L / min or less, more preferably 0.5 L / min or less, and the time is preferably 1 minute or less.

  If the molecular weight of the polymer is too large, the film surface cannot be covered uniformly. Therefore, the weight average molecular weight is preferably 100,000 or less, and more preferably 50,000 or less. On the other hand, if it is too small, the adsorptive power to the surface is reduced, so that the coating efficiency is deteriorated or the film is pulled out from the pores of the membrane, so that it is difficult to cover the surface. Therefore, the weight average molecular weight is preferably 1000 or more, more preferably 5000 or more.

  As the radiation in the present invention, α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams and the like are used. In addition, blood purification modules such as artificial kidneys need to be sterilized. In recent years, radiation sterilization methods using γ rays and electron beams have been frequently used from the viewpoint of low residual toxicity and simplicity. That is, when an ester group-containing polymer is coated on the hollow fiber membrane, insolubilization of the copolymer can be achieved simultaneously with sterilization.

  When performing sterilization and modification of the substrate at the same time, an irradiation dose of 15 kGy or more is preferable. This is because 15 kGy or more is effective for sterilizing blood purification modules and the like with γ rays. However, when the irradiation dose is 100 kGy or more, the ester group-containing polymer is deteriorated in blood compatibility because three-dimensional crosslinking or decomposition of the ester moiety occurs.

  Further, in the step of coating the hollow fiber membrane with an ester group-containing polymer and insolubilizing with radiation, components other than the polymer, for example, an antioxidant, may be contained in the solution. Further, after coating the hollow fiber membrane with an ester group-containing polymer solution, it may be contacted with an antioxidant solution.

  By adding an antioxidant, the amount of radicals generated can be adjusted. For example, in the blood purification module, when both insolubilization by radiation irradiation and sterilization are performed, if a hollow fiber membrane or the like deteriorates at either dose, an antioxidant may be used in combination. Antioxidants are molecules that have the property of easily giving electrons to other molecules. For example, water-soluble vitamins such as vitamin C, polyphenols, alcohols such as methanol, ethanol, propanol, ethylene glycol, propylene glycol and glycerin, sugars such as glucose, galactose, mannose and trehalose, sodium hydrosulfite, pyro Examples include, but are not limited to, inorganic salts such as sodium sulfite and sodium dithionate, uric acid, cysteine, and glutathione. These antioxidants may be used alone or in combination of two or more. When the method of the present invention is used for a medical device, it is necessary to consider its safety, and therefore, an antioxidant having low toxicity is preferably used.

  Note that dissolved oxygen in the aqueous solution and oxygen in the air promote oxidative decomposition. Therefore, the oxygen concentration in the aqueous solution is 10 mg / L or less, preferably 5 mg / L or less.

  About the density | concentration of the solution containing an antioxidant, it changes with the kind of antioxidant contained, the irradiation dose of a radiation, etc. If the concentration of the antioxidant is too low, the radicals generated from the solvent cannot be sufficiently erased, so that deterioration of the hollow fiber membrane or the like cannot be prevented. In addition, when a large amount of antioxidant is added, radicals are sufficiently eliminated, so that the amount of the copolymer immobilized on the hollow fiber membrane decreases, resulting in an increase in eluate and adhesion of proteins and platelets. The suppression effect is not sufficiently obtained. From the above, as the antioxidant, ethanol, n-propanol, 2-propanol, ethylene glycol, propylene glycol, and glycerin are preferably used, and the concentration range is 0.01 wt% or more and 90 wt% or less. Are preferably used. Particularly in the case of ethanol, n-propanol, and 2-propanol, 0.01% by weight or more and 10% by weight or less is preferably used, and more preferably 0.05% by weight or more and 1% by weight or less. In the case of propylene glycol and glycerin, the content is 0.1% by weight or more and 90% by weight, and more preferably 0.5% by weight or more and 70% by weight or less.

  Since the hollow fiber membrane which concerns on this invention has high adhesion inhibitory property, it can be used suitably as a hollow fiber membrane for water treatment, or a biological component separation membrane. It is particularly suitable for blood purification modules such as artificial kidneys. Here, the blood purification module refers to a module having a function of removing blood waste and harmful substances by circulating blood outside the body.

  The material to be the hollow fiber membrane of the present invention is a polysulfone polymer, such as polysulfone or polyethersulfone, which has an aromatic ring, a sulfonyl group, and an ether group in the main chain. For example, polysulfone represented by the following chemical formulas (1) and (2) is preferably used, but the present invention is not limited to these. N in the formula is an integer such as 50 to 80.

  Specific examples of polysulfone include Udel polysulfone P-1700, P-3500 (manufactured by Solvay), Ultrason S3010, S6010 (manufactured by BASF), Victrex (Sumitomo Chemical), Radel A (manufactured by Solvay), Ultra Polysulfone such as Son E (manufactured by BASF) is exemplified. In addition, the polysulfone used in the present invention is preferably a polymer composed only of the repeating unit represented by the above formula (1) and / or (2). However, it does not interfere with the effects of the present invention. It may be polymerized. Although it does not specifically limit, it is preferable that another copolymerization monomer is 10 weight% or less.

  Polyvinyl pyrrolidone, polyethylene glycol or the like may be added as a hydrophilizing agent or pore-forming agent to the membrane forming stock solution of the polysulfone-based hollow fiber membrane. . However, it is preferable to add polyvinylpyrrolidone from the viewpoint of suppressing platelet or protein adhesion.

Further, when the ester group-containing polymer is added to the film-forming stock solution, the weight average molecular weight of the polysulfone-based polymer is preferably 30,000 or more, and more preferably 50,000 or more. The weight average molecular weight of the ester group-containing polymer is 1.7 times or less, preferably 1.5 times or less, 0.5 times or more, preferably 1 time or more, relative to the weight average molecular weight of the polysulfone polymer. Is preferable from the viewpoint of suppression of platelet adhesion. This is because if the molecular weight of the ester group-containing polymer is too large relative to the polysulfone polymer, aggregation easily occurs in the ester group-containing polymer, and conversely, if it is too small, the polysulfone polymer cannot be entangled. This is probably because the ester group-containing polymer is easily detached in the process. The ester group-containing polymer concentration in the film-forming stock solution also depends on the amount of ester groups in the ester group-containing polymer, but the ratio (molar ratio) of ester group units to all units is about 0.3 to 0.7. Then, it is 0.15 times or more, further 0.2 times or more, preferably 0.3 times or more with respect to the polysulfone polymer concentration. Further, even if there are too many ester group-containing units, the membrane performance such as water permeability is lowered, so that it is 1 time or less, preferably 0.9 times or less. Moreover, you may add hydrophilic polymers, such as polyvinylpyrrolidone, as a 3rd component. The molecular weight of the hydrophilic polymer is preferably 10,000 or more, more preferably 50,000 or more. If the hydrophilic polymer concentration in the film-forming stock solution is too high, the platelet adhesion inhibitory effect of the ester group-containing polymer is reduced, so that the ester group-containing polymer concentration is 3 times or less, preferably 2 times or less, and further 1 time or less. preferable. The ester group-containing polymer is preferably a copolymer of vinyl pyrrolidone and vinyl acetate because of compatibility with the polysulfone polymer.

  Further, when the ester group-containing polymer is added to the hollow fiber membrane infusion solution, the concentration of the ester group-containing polymer in the infusion solution is 1% by weight or more, preferably 5% by weight or more, more preferably 10% by weight or more. Is preferred. Further, since the spinnability is lowered when the concentration is high, it is preferably 30% by weight or less, preferably 25% by weight or less, and more preferably 20% by weight or less.

The water permeability of the hollow fiber membrane is 200 mL / hr / m ² / mmHg or more, preferably 300 mL / hr / m ² / mmHg or more, more preferably 400 mL / hr / m ² / mmHg or more. Further, in the case of artificial kidney use, if water permeability is too high, a phenomenon such as residual blood may be observed. Therefore, it is preferably 2000 mL / hr / m ² / mmHg or less, more preferably 1500 mL / hr / m ² / mmHg or less. Is preferred.

Further, the presence of not only vinyl acetate groups but also vinyl pyrrolidone groups on the surface of the functional layer of the hollow fiber membrane is suitable for improving adhesion prevention of platelets and water permeability of the membrane. Since the, in the infrared absorption spectrum of the functional layer surface, red from the benzene ring C = C of polysulfone around 1580 cm ^-1 of the infrared absorption peak intensity derived from vinylpyrrolidone groups in the vicinity of 1660cm ^-1 _{(A NCO)} The ratio (A _NCO ) / (A _CC ) to the external absorption peak intensity (A _CC ) is preferably an average value of 0.4 or more, more preferably 0.6 or more, still more preferably 0.7 or more, and The ratio of measurement points of 0.25 or less is preferably 10% or less, more preferably 5% or less.

As a method for measuring the infrared absorption spectrum, as in the above-described method, the measurement range is 3 μm × 3 μm, the number of integration is 30 times or more, and the infrared absorption spectrum is measured at 25 absorption intensities. This 25-point measurement is performed on a total of three hollow fiber membranes per module at three different locations for one hollow fiber membrane. The obtained infrared absorption spectrum, drawing a base line with 1620～1711Cm ^-1, and the peak area of the portion surrounded by the positive portion of the reference line and the spectrum _{A NCO,} likewise, 1549～1620Cm ^-1 Then, a reference line is drawn, and the ratio (A _NCO ) / (A _CC ) between the two is calculated with the peak area as A _CC .

  In particular, introduction of an ester group into a hollow fiber membrane of a polysulfone-based polymer containing polyvinylpyrrolidone is a preferable method from the viewpoint of platelet adhesion inhibition and water permeability of the membrane. Since the vinyl pyrrolidone group contains a nitrogen atom, the concentration of the nitrogen atom with respect to all elements in the film is proportional to the vinyl pyrrolidone group. The concentration of nitrogen atoms can be determined by elemental analysis. When there are many vinylpyrrolidone groups in a film | membrane, since the whole film | membrane is hydrophilic, water permeability becomes high. On the other hand, if there are too many vinylpyrrolidone groups, problems such as an increase in eluate occur. Therefore, the concentration of nitrogen atoms relative to all elements is 0.15% by weight or more, preferably 0.25% by weight or more and 1% by weight or less, preferably 0.8% by weight or less.

Furthermore, if the amount of polyvinyl pyrrolidone or polyethylene glycol is too large on the surface of the functional layer, the ester group unit that suppresses platelet adhesion etc. is buried, so that sufficient effects cannot be exhibited, γ rays, electron beams, etc. When the radiation is irradiated, the vinylpyrrolidone unit or ethylene glycol unit may be cross-linked, which may reduce the platelet adhesion inhibitory effect by covering the ester group unit or reacting with the ester group. There is. Therefore, the average value of (A _NCO ) / (A _CC ) on the surface of the functional layer is 2 or less, preferably 1.5 or less, and more preferably 1.0 or less. The amount of vinylpyrrolidone unit is preferably 45% by weight or less, and more preferably 40% by weight or less. The amount of vinyl pyrrolidone unit on the surface of the functional layer can be determined by X-ray electron spectroscopy (XPS). Moreover, even if the molecular weight of polyvinyl pyrrolidone or polyethylene glycol is too large, the ester group unit may be buried. Therefore, the weight average molecular weight of the polyvinyl pyrrolidone and polyethylene glycol used at the time of film-forming stock solution or coating is preferably 2 million or less, and more preferably 1.5 million or less. The weight average molecular weight can be determined by gel permeation chromatography. A commercially available standard polyethylene oxide is used for the calibration curve of molecular weight.

  There are various methods for producing a hollow fiber membrane module depending on its application, but the rough steps can be divided into a hollow fiber membrane production step and a step of incorporating the hollow fiber membrane into the module.

  An example of a method for producing an artificial kidney as a blood purification module will be described. First, as a method for producing a hollow fiber membrane, polysulfone and polyvinylpyrrolidone (weight ratio of 20: 1 to 1: 5 is preferable, and 5: 1 to 1: 1 is more preferable) are used as a good solvent for polysulfone (N, N-dimethyl). Stock solution dissolved in a mixed solution of acetamide, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane, etc.) and a poor solvent (concentration is preferably 10 to 30% by weight, more preferably 15 to 25% by weight) Is discharged from the double annular die, the injection solution (core solution) is allowed to flow inside, and after running the dry part, it is guided to the coagulation bath. At this time, since the humidity of the dry part has an effect, the phase hollow fiber behavior in the vicinity of the outer surface is accelerated by replenishing moisture from the outer surface of the membrane during running of the dry part, and the pore diameter is enlarged. It is also possible to reduce transmission / diffusion resistance. However, when the relative humidity is too high, the solid solution coagulation on the outer surface becomes dominant, and the pore diameter becomes rather small, and as a result, there is a tendency to increase permeation / diffusion resistance during dialysis. Therefore, the relative humidity is preferably 60 to 90%. Moreover, it is preferable to use what consists of a composition based on the solvent used for the undiluted | stock solution as an injection | pouring liquid composition from process suitability. For example, when dimethylacetamide is used as an injection solution concentration, an aqueous solution of 45 to 80% by weight, more preferably 60 to 75% by weight, is preferably used. As the inner diameter of the hollow fiber membrane becomes smaller, the membrane mass transfer coefficient can be reduced, so that the substance removal performance of the hollow fiber membrane is improved, while blood components are more likely to adhere to the membrane or cause activation. Therefore, it is easy to cause phenomena such as residual blood. However, according to the method of the present invention, blood components can be prevented from adhering to the membrane, so that the inner diameter of the hollow fiber membrane can be reduced. From the above, the inner diameter of the hollow fiber membrane is 80 μm or more, preferably 100 μm or more, further 120 μm or more, 200 μm or less, preferably 180 μm or less, more preferably 160 μm or less.

  The method of incorporating the hollow fiber membrane in the module is not particularly limited, but an example is as follows. First, the hollow fiber membrane is cut to a required length, bundled in a necessary number, and then put into a cylindrical case. Then, a temporary cap is put on both ends, and a potting agent is put on both ends of the hollow fiber membrane. At this time, the method of adding the potting agent while rotating the module with a centrifuge is a preferable method because the potting agent is uniformly filled. After the potting agent is solidified, both ends are cut so that both ends of the hollow fiber membrane are open, and a hollow fiber membrane module is obtained.

  EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited by these examples. In any hollow fiber membrane produced below, the functional layer is the inner surface.
1. Production of hollow fiber membrane module (Outline of hollow fiber membrane module is as shown in Fig. 1)
(1) Polysulfone / polyvinylpyrrolidone mixed hollow fiber membrane 16 parts by weight of polysulfone (Amoco Udel-P3500), 2 parts by weight of polyvinylpyrrolidone (International Special Products, hereinafter referred to as ISP) K30, polyvinylpyrrolidone (ISP K90) 2 By weight, 79 parts of dimethylacetamide and 1 part of water were dissolved by heating to obtain a stock solution.
This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm of the annular slit portion. A solution composed of 60 parts by weight of N, N′-dimethylacetamide and 40 parts by weight of water was discharged from the inner tube as an injection solution. The discharged film forming solution passes through a dry zone atmosphere having a dry length of 350 mm, a temperature of 30 ° C., and a relative humidity of 78% RH, and is then introduced into a coagulation bath of 100% water and a temperature of 40 ° C. A hollow fiber membrane obtained through a second water washing step, a drying step at 130 ° C. for 2 minutes, and a crimping step at 160 ° C. was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm. The hollow fiber membrane is filled into the case so that the inner surface area of the hollow fiber membrane is 1.6 m ² , and both ends of the hollow fiber membrane are fixed to the case end by potting, and a part of the end of the potting material is The hollow fiber membrane module 1 was made by opening both sides of the hollow fiber membranes by cutting.
(2) Polysulfone Hollow Fiber Membrane 18 parts by weight of polysulfone (Amoco Udel-P3500) was heated and dissolved in 81 parts of dimethylacetamide and 1 part of water to prepare a membrane forming stock solution.

This stock solution is sent to a spinneret at a temperature of 50 ° C., and a solution comprising 63 parts of dimethylacetamide and 37 parts of water is injected as an injection from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. After forming the hollow fiber membrane, after passing through a dry zone atmosphere with a dry length of 350 mm having a temperature of 30 ° C. and a dew point of 28 ° C., a coagulation bath having a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water The hollow fiber membrane obtained by passing it through a water washing step at 60 to 75 ° C. for 90 seconds and a drying step at 130 ° C. for 2 minutes and passing through a crimping step at 160 ° C. was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm. The hollow fiber membrane is filled into the case so that the inner surface area of the hollow fiber membrane is 1.6 m ² , and both ends of the hollow fiber membrane are fixed to the case end by potting, and a part of the end of the potting material is The hollow fiber membrane module 2 was obtained by opening both sides of the hollow fiber membranes by cutting.
(3) Polyethersulfone / polyvinylpyrrolidone mixed hollow fiber membrane 19 parts by weight of polyethersulfone, 3 parts by weight of polyvinylpyrrolidone (manufactured by ISP) K90, 74 parts of dimethylacetamide, and 4 parts of water were dissolved by heating to obtain a membrane forming stock solution. .

This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm of the annular slit portion. A solution composed of 51 parts by weight of N, N′-dimethylacetamide and 49 parts by weight of water was discharged from the inner tube as an injection solution. The discharged film-forming solution passes through a dry zone atmosphere of 350 mm dry length, temperature 29 ° C., and relative humidity 95% RH, and is then introduced into a 100% water coagulation bath, followed by a water washing step of 90 seconds at 60 to 75 ° C. The hollow fiber membrane obtained by passing through a drying process at 130 ° C. for 2 minutes and undergoing a crimping process at 160 ° C. was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm. The hollow fiber membrane is filled into the case so that the inner surface area of the hollow fiber membrane is 1.6 m ² , and both ends of the hollow fiber membrane are fixed to the case end by potting, and a part of the end of the potting material is The hollow fiber membrane module 3 was made by opening both sides of the hollow fiber membrane at both ends by cutting.
(4) Examination of addition of ester group-containing polymer to injection solution Polysulfone (Amoco Udel-P3500) 18 parts by weight, polyvinylpyrrolidone (ISP) 9 parts by weight, 30 parts by weight of dimethylacetamide 72 parts by weight, water 1 part by weight, A film forming stock solution was obtained.

  10 parts by weight of a vinyl pyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “KOLLIDON” (registered trademark) VA64 (hereinafter referred to as VA64)) is dissolved in a solution of 63 parts by weight of dimethylacetamide and 37 parts by weight of water. To make an injection solution.

  The membrane-forming stock solution is fed to a spinneret at a temperature of 50 ° C., and the injection solution is discharged from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm to form a hollow fiber membrane. Passing through a 350 mm dry zone atmosphere at 30 ° C. and 28 ° C. dew point, passing through a coagulation bath at a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water, and washing with water at 60 to 75 ° C. for 90 seconds; A hollow fiber membrane (hollow fiber membrane 4) obtained by passing through a drying step of 2 ° C. for 2 minutes and undergoing a crimping step of 160 ° C. was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm.

A hollow fiber membrane (hollow fiber membrane 5) was prepared in the same manner as described above using a solution having a composition in which VA64 was not added to the injection solution.
(5) Hollow fiber membrane containing chloroacetamidomethylated polysulfone 175.3 g of a nitrobenzene solution of polysulfone (Amoco Udel-P3500) prepared to 7.13% by weight was cooled to 8 ° C., and separately at −5 ° C. for 30 minutes. 33 g of a sulfuric acid solution of 5.30% by weight of N-methylol-2-chloroacetamide prepared by stirring was added and the reaction was carried out at 8 ° C., and chloroacetamidomethylated polysulfone (chloroamide methyl group substitution degree 0.39) Got.

  Polysulfone (Amoco Udel-P3500) 18 parts by weight, chloroacetamidomethylated polysulfone 2 parts by weight, PVP (ISP) K30 10 parts by weight, together with 69 parts by weight of dimethylacetamide and 1 part by weight of water, were dissolved by heating to form a film. The stock solution was used.

This stock solution is sent to a spinneret at a temperature of 40 ° C., and a solution composed of 35 parts of dimethylacetamide and 65 parts of water is injected as an injection from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. After forming the hollow fiber membrane, after passing through a dry zone atmosphere with a dry length of 300 mm having a temperature of 27 ° C. and a dew point of 11 ° C., passing through a coagulation bath at a temperature of 40 ° C. consisting of 100% by weight of water and washing with water The hollow fiber membrane (hollow fiber membrane 6) was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm. The membrane was not dried until various evaluations were performed.
(6) Vinyl pyrrolidone / vinyl acetate copolymer-containing hollow fiber membrane (1)
18 parts by weight of polysulfone (Amoco Udel-P3500) and 9 parts by weight of vinylpyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) were dissolved with 72 parts by weight of dimethylacetamide and 1 part by weight of water. A film forming stock solution was obtained.

This stock solution is sent to a spinneret at a temperature of 50 ° C., and a solution consisting of 61 parts of dimethylacetamide and 39 parts of water is injected from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of the annular slit. After forming the hollow fiber membrane, after passing through a dry zone atmosphere having a dry length of 350 mm having a temperature of 29 ° C. and a dew point of 27 ° C., a coagulation bath having a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water After passing and washing with water, glycerin was applied so that the hollow fiber membrane was not dried, and then the hollow fiber membrane (hollow fiber membrane 7) was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm. In addition, as a result of measuring the weight average molecular weight of polysulfone (Amoco Udel-P3500) and VA64 by gel permeation chromatography, polysulfone was 35000 and VA64 was 52000. That is, the weight average molecular weight of VA64 is 1.5 times the weight average molecular weight of the polysulfone polymer.
(7) Vinyl pyrrolidone / vinyl acetate copolymer-containing hollow fiber membrane (2)
Polysulfone (Amoco Udel-P1700) 17 parts by weight, polyethylene glycol (molecular weight 600) vinylpyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) 1.7 weight was dissolved, did.

  0.5 parts by weight of a vinylpyrrolidone / vinyl acetate (6/4) copolymer (VASF, VA64) was dissolved in a solution of 61 parts by weight of dimethylacetamide and 39 parts by weight of water to prepare an injection solution.

This stock solution is sent to a spinneret portion at a temperature of 50 ° C., and the above-mentioned solution consisting of dimethylacetamide, water, and VA64 is discharged from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of the annular slit portion. After forming the hollow fiber membrane, after passing through a dry zone atmosphere having a dry length of 350 mm having a temperature of 29 ° C. and a dew point of 27 ° C., a coagulation bath having a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water After passing through and washing with water, glycerin was applied so that the hollow fiber membrane was not dried, and then the hollow fiber membrane (hollow fiber membrane 8) was used as a wound bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm. It was 29000 as a result of measuring the weight average molecular weight of polysulfone (Amoco Udel-P1700) by the gel permeation chromatography. That is, the weight average molecular weight of VA64 was 1.8 times the weight average molecular weight of the polysulfone polymer.
2. Measurement method (1) Measurement method of infrared absorption spectrum The hollow fiber membrane was cut into a semicylindrical shape with a single blade, rinsed with ultrapure water, and then dried at room temperature and 0.5 Torr for 10 hours. The inner surface of the dried hollow fiber membrane was measured by the microscopic ATR method of IRT-3000 manufactured by JASCO. The field of view (aperture) was set to 100 μm × 100 μm, the measurement range was 3 μm × 3 μm, the number of integration was 30 times, and the measurement was performed at a total of 25 points of 5 points in each direction. At a wavelength of 1549 to 1620 cm ⁻¹ of the obtained spectrum, a reference line is drawn, and the peak area of the part surrounded by the reference line and the positive part of the spectrum is the infrared absorption peak area ACC derived from the benzene ring C═C of polysulfone. It was. Similarly, a reference line was drawn at 1711 to 1759 cm ⁻¹ to obtain an infrared absorption peak area ACO derived from the ester group C═O. Furthermore, since a peak derived from the amide bond of the vinylpyrrolidone group appears in the vicinity of 1660 cm ^-1 in the obtained spectrum, a reference line is drawn at 1620 to 1711 cm ^-1 , and the infrared absorption peak area ANCO derived from the amide group NCO and did.

The above operation was performed on three different hollow fibers per module, and three different points were measured with the same hollow fiber. The average value of (A _CO ) / (A _CC ) and a ratio of 0.001 or less, (A The average value of _{NCO 3} ) / (A _CC ) and the ratio of 0.25 or less were calculated.
(2) Measurement of ester group amount on inner surface of hollow fiber membrane The amount of ester group on the inner surface of hollow fiber membrane was measured by X-ray photoelectron spectroscopy (XPS). Measurement equipment and conditions are as follows.

Measuring device: ESCALAB220iXL
Excitation X-ray: monochromatic Al Kα1,2 line (1486.6 eV)
X-ray diameter: 0.15mm
Photoelectron escape angle: 90 ° (inclination of detector with respect to sample surface)
Since the peak appearing at +4.0 to 4.2 eV from the C1s CH or C—C main peak (around 285 eV) is a peak derived from the ester group (COO), all the elements (hydrogen Since atoms cannot be detected, the ratio of the peak area to all elements other than hydrogen atoms is calculated, and the amount of carbon derived from the ester group (number of atoms%) is calculated. More specifically, C1s mainly includes components derived from CHx, C—C, C═C, C—S, components derived mainly from C—O, C—N, and components derived from π-π * satellites. , C = O-derived component and COO-derived component. Therefore, peak splitting is performed with five components. The COO-derived component is a peak that appears at +4.0 to 4.2 eV from the main peak of CHx and C—C (near 285 eV). The peak area ratio of each component is calculated by rounding off the second digit of the decimal point. The amount of carbon derived from the ester group (number of atoms%) is obtained by multiplying the amount of carbon of C1s (number of atoms by%) by the peak area ratio of the component derived from COO. In addition, if it was 0.4% or less as a result of peak division, it was set as the detection limit or less.
(3) Measurement of amount of vinylpyrrolidone unit on inner surface of hollow fiber membrane The amount of vinylpyrrolidone unit on the inner surface of hollow fiber membrane was measured by XPS. ESCALAB220iXL was used as a measurement apparatus, a sample was set in the apparatus, and the measurement was performed at a detector angle of 90 degrees with respect to the incident angle of X-rays. The hollow fiber membrane was cut into a semicylindrical shape with a single blade, and the inner surface of the hollow fiber membrane was measured. The measurement sample was rinsed with ultrapure water, dried at room temperature and 0.5 Torr for 10 hours, and then subjected to measurement.

From the area intensities of the C1s, N1s, and S2p spectra obtained by XPS measurement, the surface quantity of nitrogen (a) and the surface quantity of sulfur (b) are obtained using the relative sensitivity coefficient attached to the device. The amount of polyvinyl pyrrolidone was calculated.
Surface vinylpyrrolidone unit amount (% by weight) = a × 100 / (a × 111 + b × 442)
(4) Human platelet adhesion test method of hollow fiber membrane A double-sided tape was affixed to an 18 mmφ polystyrene circular plate, and the hollow fiber membrane was fixed thereto. The attached hollow fiber membrane was cut into a semicylindrical shape with a single blade to expose the inner surface of the hollow fiber membrane. If dirt, scratches, folds, etc. are present on the inner surface of the hollow fiber, platelets will adhere to the part and may not be evaluated correctly. The circular plate was attached to a Falcon (registered trademark) tube (18 mmφ, No. 2051) cut into a cylindrical shape so that the surface on which the hollow fiber membrane was attached was inside the cylinder, and the gap was filled with parafilm. The cylindrical tube was washed with physiological saline and then filled with physiological saline. Immediately after collecting human venous blood, heparin was added to 50 U / ml. After discarding the physiological saline in the cylindrical tube, 1.0 ml of the blood was placed in the cylindrical tube and shaken at 37 ° C. for 1 hour within 10 minutes after blood collection. Thereafter, the hollow fiber membrane was washed with 10 ml of physiological saline, blood components were fixed with 2.5% volume glutaraldehyde physiological saline, and washed with 20 ml of distilled water. The washed hollow fiber membrane was dried under reduced pressure at room temperature of 0.5 Torr for 10 hours. This hollow fiber membrane was attached to a sample stage of a scanning electron microscope with a double-sided tape. Thereafter, a thin film of Pt—Pd was formed on the surface of the hollow fiber membrane by sputtering to prepare a sample. The inner surface of the hollow fiber membrane was observed with a field emission type scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times. In one field of view (4.3 × 10 ³ μm ² ) The number of adherent platelets was counted. The average value of the number of adhering platelets in 10 different visual fields near the center in the longitudinal direction of the hollow fiber was defined as the number of adhering platelets (pieces / 4.3 × 10 ³ μm ² ). The end portion in the longitudinal direction of the hollow fiber was removed from the target of the number of adhesion because blood pools were easily formed.

The smaller the number of platelets attached, the better the blood compatibility, and it is considered that 20 / 4.3 × 10 ³ μm ² or less is preferable. In addition, a polysulfone film was used as a control, and it was determined that the experiment had been established if the number of platelets adhered to the polysulfone film was 20 / 4.3 × 10 ³ μm ² or more.
(5) β ₂ -microglobulin clearance (β ₂ -MG CL) measurement As a performance evaluation of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured. β ₂ -microglobulin is a protein to be removed in dialysis treatment, and in recent years, the clearance is often used as a performance index of the membrane. .

  The bovine blood to which disodium ethylenediaminetetraacetate was added was adjusted so that the hematocrit was 30 ± 3% and the total protein amount was 6.5 ± 0.5 g / dL.

Next, the β ₂ -microglobulin concentration was added to 1 mg / l and stirred. The cow blood was divided into 2 L for circulation and 1.5 L for clearance measurement.

  The circuit was set as shown in FIG. As a dialysis machine, TR2000S manufactured by Toray Medical Co., Ltd. was used. TR2000S corresponds to the Bi pump, the F pump, and the dialysis apparatus in FIG.

  Dialysate (Kindaly AF No. 2 Fuso Yakuhin Kogyo Co., Ltd.) A solution and B solution were set in the dialyzer. RO water was allowed to flow from the dialysate side to the blood side. The dialysate concentration was 13 to 15 mS / cm, the temperature was 34 ° C. or higher, and the dialysate side flow rate was set to 500 ml / min.

The water removal rate of the water permeable device was set to 10 ml / (min · m ² ). Place the Bi circuit inlet into the beaker with 2L (37 ° C) of bovine blood adjusted as described above, start the Bi pump, discard the 90 seconds of liquid discharged from the Bo circuit outlet, and immediately The outlet part and the Do circuit outlet part were put in a circulation beaker to be in a circulation state.

  Subsequently, the F pump of the dialysis machine was moved and circulated for 1 hour, and then the Bi pump and the F pump were stopped.

  Next, the Bi circuit inlet was placed in the clearance-measured bovine blood prepared above, and the Bo circuit outlet was placed in a waste beaker. The liquid flowing out from the Do circuit outlet was discarded.

  The Di pump was started. In addition, the blood pump was started and the space between the trap and the Bi chamber was opened.

  After 2 minutes from the start, 10 ml of a sample was collected from bovine blood for clearance measurement (37 ° C.) and used as Bi solution. After 4 minutes and 30 seconds from the start, 10 ml of a sample was taken from the Bo circuit outlet and used as Bo solution. These samples were stored in a freezer at -20 ° C or lower.

The clearance was calculated from the concentration of β ₂ -microglobulin in each solution by the following equation (3). Since measured values may differ depending on the lot of bovine blood, all data used in the examples used bovine blood of the same lot.

Co (ml / min) = (CBi−CBo) × Q _B / CBi (3)
In the formula (3), C _O = β ₂ -microglobulin clearance (ml / min), CBi = β ₂ -microglobulin concentration in Bi solution, CB _o = β ₂ -microglobulin concentration in Bo solution, Q _B = Bi Pump flow rate (ml / min).
(6) Weight average molecular weight measurement The weight average molecular weight of the hydrophilic polymer was measured by gel permeation chromatography. A hydrophilic polymer aqueous solution of 0.1 wt% was filtered through a Mysori disk (water-based, manufactured by Tosoh Corporation) to remove dust and the like in the aqueous solution. The measurement conditions are as follows. Polyethylene glycol was used as a calibration curve for the weight average molecular weight.
Column: TSKgel GMPW _XL
Solvent: 0.1 mol / L lithium nitrate, water / methanol: 50 vol / 50 vol
Flow rate: 0.5 ml / min
Column temperature: 40 ° C
(7) Measurement of water permeation performance Filtration amount per unit time flowing out to the outside by applying a water pressure of 100 mmHg to the inside of the hollow fiber of the glass tube mini module (36 pieces: effective length 10 cm) sealed at both ends of the hollow fiber Was measured. The water permeability (UFR) was calculated by the following formula.

UFR (mL / hr / m ² / mmHg) = Q _w / (P × T × A)
Here, Q _w : filtration amount (mL), T: outflow time (hr), P: pressure (mmHg), A: surface area in hollow fiber membrane (m ² )
In Examples 1 to 8 and Comparative Examples 1 to 4, the hollow fiber membrane module 1 was used.
(8) Evaluation of residual blood property The residual blood thread means a hollow fiber in which blood remains after returning blood, and the residual blood property of the hollow fiber membrane module is evaluated by conducting the following model experiment. Can do.

  The hollow fiber membrane module was set up vertically so that Bi would be down, and 700 mL of physiological saline (flow rate: 200 mL / min) was washed from the bottom to the top on the module blood side.

  After the dialysate was flowed to the hollow fiber membrane module dialysis side at a flow rate of 500 mL / min, dialysis of bovine blood was started at 100 mL / min with bovine blood (30% hematocrit, total protein amount 6 g / dL). After the blood came out of Bo, the blood flow rate was changed to 200 mL / min, and Bi was changed upward. This was allowed to flow for 30 minutes. The water removal was 0. In the blood return operation, the dialysate was stopped and 300 mL of physiological saline was flowed from Bi at 100 mL / min.

The residual blood property was evaluated by counting the residual blood yarn present on the side surface of the hollow fiber membrane module after returning blood.
(9) Measurement of hydrophilic polymer elution amount After washing the hollow inner side of the hollow fiber membrane module with 700 ml of room-temperature ultrapure water and the outer side with 2500 ml of room-temperature ultrapure water, the inside is again washed with 300 ml of room-temperature ultrapure water. And the hydrophilic polymer adhering to the membrane was washed away. Thereafter, the blood side was perfused with 4000 ml of ultrapure water heated to 37 ° C. at a flow rate of 200 ml / min for 4 hours. Thereafter, the perfusate was concentrated 200 times and measured by GPC (gel permeation chromatography). From this value, the total amount of hydrophilic polymer eluted in the perfusate was calculated.

As GPC measurement conditions, GMPW _XL manufactured by Tosoh Corporation was used as the column, the flow rate was 0.5 ml / min, and the solvent was a mixed solvent of methanol: water = 1: 1 (volume ratio) to which 0.1 N lithium nitrate was added. The column temperature was 40 ° C. As a calibration curve for the amount of hydrophilic polymer, K90 polyvinyl pyrrolidone manufactured by BASF Corporation was used to obtain a concentration in terms of polyvinyl pyrrolidone. When the polyvinyl pyrrolidone concentration was less than 10 ppm, the detection limit was not exceeded (the detection limit for the amount of hydrophilic polymer eluted in 4 L was 0.4 mg).
Example 1
500 mL of 0.1% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (7/3) copolymer (BASF, VA73) from the blood side inlet (Bi) to the blood side outlet (Bo) of the hollow fiber membrane module 1 The solution was passed for 1 minute at / min. Next, VA73 was accumulated on the inner surface of the hollow fiber membrane by passing the solution from the blood side inlet (Bi) to the dialysate side inlet (Di) at 500 mL / min for 1 minute. At this time, in order to accumulate the VA 73 entering the hollow fiber membrane on the inner surface, the filling solution was pushed out from the dialysate side to the blood side with 100 kPa compressed air. Thereafter, the filling solution on the blood side was blown to maintain the aqueous solution only in the hollow fiber membrane. Further, each of the dialysis solution side and the blood side was blown with nitrogen for 1 minute each, and the inside of the module was replaced with nitrogen, and then the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 0.6%.

With respect to the hollow fiber membrane module, the amount of hydrophilic polymer eluted was measured, and was below the detection limit (0.25 mg / m ² ). In addition, the elution amount of the hydrophilic polymer when not irradiated with γ rays was 1.8 mg / m ² . Furthermore, as a result of evaluating the residual blood property, the residual blood thread was as few as seven. When XPS measurement was performed on the inner surface and the outer surface of the hollow fiber membrane, the carbon amount derived from the ester group was 2.4 (number of atoms%) on the inner surface and 1.2 (number of atoms%) on the outer surface. The results of other various tests are shown in Table 1.
(Example 2)
A vinylpyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64, 0.1% by weight aqueous solution of 500 mL / ml from the blood side inlet (Bi) of the hollow fiber membrane module 1 to the blood side outlet (Bo) The liquid was passed for 1 minute at min. Next, VA64 was accumulated on the inner surface of the hollow fiber membrane by passing the solution from the blood side inlet (Bi) to the dialysate side inlet (Di) at 500 mL / min for 1 minute. At this time, in order to accumulate VA64 that had entered the hollow fiber membrane on the inner surface, the filling solution was pushed from the dialysate side to the blood side with 100 kPa compressed air. Thereafter, the filling solution on the blood side was blown to maintain the aqueous solution only in the hollow fiber membrane. Further, each of the dialysis solution side and the blood side was blown with nitrogen for 1 minute each, and the inside of the module was replaced with nitrogen, and then the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 0.7%.
(Example 3)
The same operation as in Example 2 was performed except that a 0.01% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) was used. The oxygen concentration in the module was 0.8%.

With respect to the hollow fiber membrane module, the amount of hydrophilic polymer eluted was measured, and was below the detection limit (0.25 mg / m ² ). In addition, the elution amount of the hydrophilic polymer when not irradiated with γ rays was 1.7 mg / m ² . Furthermore, as a result of evaluation of residual blood properties, there were few residual blood threads. When XPS measurement was performed on the inner surface and the outer surface of the hollow fiber membrane, the carbon amount derived from the ester group was 1.6 (atomic%) on the inner surface and 0.6 (atomic%) on the outer surface. The results of other various tests are shown in Table 1.
Example 4
A vinyl pyrrolidone / vinyl acetate (6/4) copolymer (VASF, VA64) was used in the same manner as in Example 2 except that a mixed aqueous solution of 0.001% by weight and ethanol 0.1% by weight was used. It was. The oxygen concentration in the module was 0.7%.

With respect to the hollow fiber membrane module, the amount of hydrophilic polymer eluted was measured, and was below the detection limit (0.25 mg / m ² ). Furthermore, as a result of evaluation of residual blood properties, the residual blood thread was as few as one. When XPS measurement was performed on the inner surface and the outer surface of the hollow fiber membrane, the carbon content derived from the ester group was 0.9 on the inner surface and the outer surface was not detected. The results of other various tests are shown in Table 1. That is, by coexisting with ethanol as an antioxidant, it was shown that high water permeability and β ₂ -microglobulin removal performance can be achieved while achieving platelet adhesion suppression even when the VA64 concentration is reduced.
(Example 5)
The same operation as in Example 2 was performed except that a mixed aqueous solution of 0.001% by weight of vinylpyrrolidone / vinyl acetate (6/4) copolymer (VA64, VA64) and 0.1% by weight of hexanol was used. It was. The oxygen concentration in the module was 0.7%. The results are shown in Table 1. That is, it was shown that by coexisting with the antioxidant hexanol, high water permeability and β ₂ -microglobulin removal performance can be achieved while achieving platelet adhesion inhibition even when the VA64 concentration is reduced.
(Example 6)
A vinyl pyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) was used in the same manner as in Example 2 except that a mixed aqueous solution of 0.0005% by weight and ethanol 0.1% by weight was used. It was. The oxygen concentration in the module was 0.7%. The results are shown in Table 1.
(Example 7)
The same operation as in Example 2 was performed except that a 0.01% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (5/5) copolymer (manufactured by BASF) was used. The oxygen concentration in the module was 0.7%. When XPS measurement was performed on the inner surface and the outer surface of the hollow fiber membrane, the amount of carbon derived from the ester group was 5.2 (number of atoms%) on the inner surface and 2.2 (number of atoms%) on the outer surface. The other results are shown in Table 1. While achieving high water permeability and β ₂ -microglobulin removal performance while achieving platelet adhesion inhibition, 2.2 (number of atoms%) of ester groups were detected on the outer surface. Compared to 4, the water permeability was slightly lower.
(Example 8)
A 60 vol% methanol aqueous solution of 0.008% by weight polyvinyl acetate was passed from the blood side inlet (Bi) of the hollow fiber membrane module 1 to the blood side outlet (Bo) at 500 mL / min for 1 minute. Next, after passing through the blood side inlet (Bi) through the dialysate side inlet (Di) at 500 mL / min for 1 minute, pure water was passed in the same manner as above to replace methanol. Next, the filling liquid was pushed out from the dialysate side to the blood side with compressed air of 100 kPa. Thereafter, the filling solution on the blood side was blown to maintain the aqueous solution only in the hollow fiber membrane. Further, each of the dialysis solution side and the blood side was blown with nitrogen for 1 minute each, and the inside of the module was replaced with nitrogen, and then the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 0.6%. The hollow fiber of the module was cut out and a platelet adhesion test was performed . Due to the presence of a large amount of polyvinyl acetate on the inner surface of the hollow fiber membrane, the water permeability of the hollow fiber membrane was slightly low, but exhibited high platelet adhesion inhibitory properties.
(Comparative Example 1)
The same operation as in Example 2 was performed except that water was used. The oxygen concentration in the module was 0.7%. In addition, although the ester group unit is not included, the value of A _CO / A _CC is slightly output because noise is picked up. As a result of evaluating the residual blood performance of the module, there were as many as 35 residual blood threads. When XPS measurement was performed on the inner surface and the outer surface of the hollow fiber membrane, the amount of carbon derived from the ester group was not detected on both the inner surface and the outer surface. The results of other various tests are shown in Table 1. That is, it was a membrane to which platelets adhered.
(Comparative Example 2)
A mixed aqueous solution of 0.001% by weight of vinylpyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) and 0.1% by weight of ethanol was used. The same operation as Example 2 was performed except nitrogen substitution. The oxygen concentration in the module was 19%.

With respect to the hollow fiber membrane module, the elution amount of the hydrophilic polymer was measured and found to be 2.5 mg / m ² . Furthermore, as a result of evaluation of residual blood properties, there were as many as 30 residual blood threads. The results of other various tests are shown in Table 1. It is assumed that the decomposition of the vinyl acetate unit progressed due to the presence of oxygen.
(Comparative Example 3)
A vinyl pyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) was used in the same manner as in Example 2 except that a mixed aqueous solution of 0.0003 wt% and ethanol 0.1 wt% was used. It was. The oxygen concentration in the module was 0.9%. The results are shown in Table 1.
(Comparative Example 4)
The same operation as in Example 2 was performed except that a mixed aqueous solution of 0.1% by weight of polyvinylpyrrolidone (manufactured by BASF) K90 and 0.1% by weight of ethanol was used. The oxygen concentration in the module was 0.9%. As a result of evaluating residual blood properties of the module, there were as many as 37 residual blood threads. The other results are shown in Table 1. That is, platelet adhesion could not be suppressed only by increasing the amount of the hydrophilic homopolymer on the inner surface of the hollow fiber membrane.
(Comparative Examples 5 and 6)
The same operation as in Example 2 was carried out except that a polyvinyl acetate (PVAc) 0.01 wt% aqueous solution and a polyvinyl alcohol (saponification degree 98%, molecular weight 10,000) 0.001 wt% aqueous solution were used. The oxygen concentration in the module was 0.9%. The results are shown in Table 1.
(Comparative Example 7)
The same operation as in Example 2 was performed except that a 0.01% by weight aqueous solution of vinylpyrrolidone / styrene (9/1) copolymer (ISP) was used. The oxygen concentration in the module was 0.9%. The results are shown in Table 1. That is, it was found that platelet adhesion could not be suppressed only by using a copolymer of hydrophilic vinylpyrrolidone and hydrophobic styrene, and ester groups were important.

In the following Comparative Examples 8 to 10 , the hollow fiber membrane module 2 was used.
( Comparative Example 8 )
A vinyl pyrrolidone / vinyl acetate (6/4) copolymer (BASF, VA64) 0.01 wt% aqueous solution of 500 mL / min from the blood side inlet (Bi) to the blood side outlet (Bo) of the hollow fiber membrane module 2 For 1 minute. Next, VA64 was accumulated on the inner surface of the hollow fiber membrane by passing the solution from the blood side inlet (Bi) to the dialysate side inlet (Di) at 500 mL / min for 1 minute. At this time, in order to accumulate the VA64 that had entered the hollow fiber membrane on the inner surface, the filling solution was pushed from the dialysate side to the blood side with 100 kPa compressed air. Thereafter, the filling solution on the blood side was blown to maintain the aqueous solution only in the hollow fiber membrane. Further, each of the dialysis solution side and the blood side was blown with nitrogen for 1 minute each, and the inside of the module was replaced with nitrogen, and then the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 0.8%. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 2. The reason why the water permeability is improved as compared with Comparative Example 10 to be described later is considered to be because hydrophilicity is imparted by VA64 to the highly hydrophobic membrane made of only polysulfone.
( Comparative Example 9 )
A vinyl pyrrolidone / vinyl acetate (6/4) copolymer (VASF, VA64) was operated in the same manner as in Comparative Example 8 except that a 0.001% by weight aqueous solution and ethanol 0.1% by weight mixed aqueous solution were used. went. The oxygen concentration in the module was 0.9%. The results are shown in Table 2.
(Comparative Example 10 )
The same operation as in Comparative Example 8 was performed except that water was used. The oxygen concentration in the module was 0.8%. The results are shown in Table 2.

In the following Example 9 and Comparative Examples 11 and 12 , the hollow fiber membrane module 3 was used.
(Example 9 )
The same operation as in Example 2 was performed, except that a 0.001 wt% aqueous solution of vinylpyrrolidone / vinyl acetate (5/5) copolymer (VA55, VA55) was used. The oxygen concentration in the module was 0.9%. The results are shown in Table 3.
(Comparative Example 11 )
The same operation as in Example 2 was performed except that a 0.01% by weight aqueous solution of polyethylene glycol (molecular weight: 50,000) was used. The oxygen concentration in the module was 0.9%. The results are shown in Table 3.
(Comparative Example 12 )
The same operation as in Example 2 was performed except that water was used. The oxygen concentration in the module was 0.8%. The results are shown in Table 3.

For Example 10 and Comparative Example 13 below, the comparison of the addition of the ester group-containing polymer to the injection solution (hollow fiber membranes 4 and 5) was performed.
(Example 10 )
A plastic tube mini-module having an effective length of 100 mm, in which 36 hollow fiber membranes 4 were passed through a plastic tube and both ends were fixed with an adhesive, was thoroughly washed with pure water. The water inside and outside the hollow fiber membrane was extracted by compressed air blow, and then irradiated with 25 kGy of γ rays. After the γ-ray irradiation, various tests were performed after thoroughly washing with pure water. As the performance of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured by the following method. That is, β ₂ -microglobulin was added to 37 ° C. bovine serum so that the concentration was 5 mg / L. This was flowed to the blood side of the minimodule at 1 mL / min, and 37 ° C. physiological saline was flowed to the dialysate side at 20 mL / min. After circulating for 2 hours, the bovine serum on the blood side and the physiological saline on the dialysate side were collected in full volume and requested to SRL for analysis, and the concentration of β ₂ -microglobulin was measured. The clearance converted to 1.8 m ² was calculated from the measurement result. Since the clearance of β ₂ -microglobulin in the mini-module has a variation in numerical values for each experiment, the number of experiments was set to 3 times and an average value was adopted. The numerical value was calculated by rounding off the first decimal place. The other results are shown in Table 4.
(Comparative Example 13 )
36 hollow fiber membranes 5 were passed through a plastic tube, the same operation as in Example 10 was performed, and the obtained hollow fiber membranes were also evaluated in the same manner. The results are shown in Table 4. That is, it was a surface to which platelets adhered well, and the β ₂ -microglobulin removal performance was also lower than that of Example 12.

In Example 11 and Comparative Example 14 below, a hollow fiber membrane (hollow fiber membrane 6) containing chloroacetamidomethylated polysulfone (CAMPS) was used.
(Example 11 )
47 g of allylamine hydrochloride was dissolved in 110 g of methanol, and 103 g of vinyl acetate was added. Furthermore, after adding 41 g of azobisisobutyronitrile as a polymerization initiator, the mixture was heated to 60 ° C. and reacted for 24 hours, and then 41 g of azobisisobutyronitrile was added, and further at 60 ° C. for 24 hours. Reacted. At the end of the polymerization reaction, the residual monomer and homopolymer were removed to obtain an allylamine hydrochloride-vinyl acetate copolymer. By elemental analysis, the allylamine content in the copolymer was calculated to be 28 mol%.

  A 36 mm hollow fiber membrane (hollow fiber membrane 6) containing chloroacetamidomethylated polysulfone (CAMPS) was passed through a plastic tube, and a plastic tube mini-module with an effective length of 100 mm was fixed with both ends fixed with adhesive. Washed. Next, since the reaction between the chloroacetamidomethyl group and the amino group easily proceeds, the allylamine / vinyl acetate copolymer obtained above was mainly immobilized on the inner surface of the hollow fiber membrane. That is, after the water filled inside and outside the hollow fiber membrane was extracted, a 60% by weight isopropanol aqueous solution of 5% by weight of allylamine / vinyl acetate copolymer (adjusted to pH 9.0) was added to the inside of the hollow fiber membrane module. And allowed to react at room temperature for 1 hour. After the reaction, the unreacted allylamine / vinyl acetate copolymer was washed with a 60% by weight aqueous isopropanol solution, and then washed and replaced with pure water. Various tests were performed on the hollow fiber membrane.

As the performance of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured in the same manner as in Example 10 . The results are shown in Table 5.
(Comparative Example 14 )
A plastic tube module having an effective length of 100 mm was prepared by passing 36 CAMPS-containing hollow fiber membranes (hollow fiber membranes 6) through a plastic tube and fixed at both ends with an adhesive, and thoroughly washed with pure water. Next, a 60 wt% aqueous isopropanol solution (adjusted to pH 9.0) was passed through only the inside of the hollow fiber membrane module and allowed to stand at room temperature for 1 hour. Thereafter, it was washed and replaced with pure water. Various tests were performed on the hollow fiber membrane.

As the performance of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured in the same manner as in Example 10 . The results are shown in Table 5.

In the following Example 12 , the hollow fiber membrane 7 was used, and in the Comparative Example 15 , the hollow fiber membrane 8 was used.
(Example 12 )
A plastic tube mini-module with an effective length of 100 mm, in which 36 hollow fiber membranes 7 were passed through a plastic tube and both ends were fixed with an adhesive, was thoroughly washed with pure water to remove glycerin. The water inside and outside the hollow fiber membrane was extracted by compressed air blow, and then irradiated with 25 kGy of γ rays. After the γ-ray irradiation, various tests were performed after thoroughly washing with pure water.

As the performance of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured in the same manner as in Example 9 . The results are shown in Table 6.
(Comparative Example 15 )
36 hollow fiber membranes 8 were passed through a plastic tube, and the same operation as in Example 12 was performed. The obtained hollow fiber membranes were also evaluated in the same manner. The results are shown in Table 6. That is, it was a surface to which platelets adhered well, and the β ₂ -microglobulin removal performance was lower than in Example 12 . This is because the distribution of the presence of VA64 on the inner surface of the film varies and the platelet adhesion cannot be effectively suppressed. On the other hand, a large amount of VA64 is present in the film thickness portion, resulting in low water permeability. it is conceivable that. As for the hollow fiber membrane, _A CO _{/ A CC} when not irradiated with γ-rays _{0.01, A} CO _/ A _CC proportion of 0.001 or less was 15%. The number of platelet adhesion was 60 (pieces / 4.3 × 10 ³ μm), and platelet adhesion could not be sufficiently suppressed.

Claims (7)

A module in which a polysulfone-based hollow fiber membrane is incorporated, and an ester group C═O in a vinyl acetate unit near 1730 cm ⁻¹ on the functional layer surface in the vicinity of the end face and in the vicinity of the center in the longitudinal direction of the polysulfone-based hollow fiber membrane The ratio (A _CO ) / (A _CC ) of the infrared absorption peak intensity (A _CO ) derived from the polysulfone polymer near 1580 cm ^{−1 to} the infrared absorption peak intensity (A _CC ) derived from the benzene ring C═C average 0.005 to 0.5, and 0.001 Ri following der proportion than 10% of the measurement points, and the infrared absorption peak intensity _{(a NCO)} from vinylpyrrolidone groups in the vicinity of 1660 cm ^-1 Of polysulfone near 1580 cm ^{−1 to} the infrared absorption peak intensity (A _CC ) derived from the benzene ring C═C (A _NCO ) / (A _CC ) Has an average value of 0.4 or more, and polysulfone-based hollow fiber membrane module ratio of 0.25 or less of measurement points, characterized in der Rukoto 10% or less. The polysulfone-based hollow fiber membrane module according to claim 1, wherein the ester group C = O in the vinyl acetate unit is derived from a polymer. The polysulfone-based hollow fiber membrane module according to claim 2 , wherein a ratio of the ester group-containing unit in the polymer from which the ester group C = O is derived is 0.3 or more. The polysulfone type according to any one of claims 1 to 3 , wherein the concentration of nitrogen atoms with respect to all elements constituting the polysulfone type hollow fiber membrane is 0.01 wt% or more and 0.1 wt% or less. Hollow fiber membrane module. The polysulfone-based hollow fiber membrane module according to any one of claims 1 to 4 , which is used for blood purification. The hollow fiber membranes embedded in the polysulfone type hollow fiber membrane module, the hollow fiber membrane by dry weight relative to 0.2 times by weight or more, of 6 times by weight or less, a copolymer aqueous solution of vinylpyrrolidone and vinyl acetate, A method for producing a polysulfone-based hollow fiber membrane module, characterized in that irradiation with radiation is carried out in a wet state in an aqueous solution having an aqueous solution concentration of 0.0005 wt% or more and 0.5 wt% or less . The method for producing a polysulfone-based hollow fiber membrane module according to claim 6, wherein the hollow fiber membrane contains polyvinyl pyrrolidone.

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