JP2012115743A - Hollow fiber membrane module - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polysulfone-based hollow fiber membrane module that has less deposition of an organic substance, a protein, platelet, etc., and less deterioration of membrane performance in use and that has excellent membrane performance stability with time.SOLUTION: The hollow fiber membrane module is characterized in that the peak area percentage of carbon originating from ester group by ESCA (Electron Spectroscopy for Chemical Analysis) in a built-in polysulfone-based hollow fiber membrane surface is ≥0.5 (number of atoms%) and ≤10 (number of atoms%), that the hydrophobic unit amount rate existing on the membrane surface is larger than the hydrophobic unit amount rate existing inside the membrane by ≥30%, and that the built-in hollow fiber membrane has a crimp structure with a wave height of 0.1-0.5 mm and a wavelength of 5.0-10.0 mm.

Description

  The present invention relates to a hollow fiber membrane module, and relates to a polysulfone-based hollow fiber membrane module having high separation performance and little membrane performance deterioration during use and excellent in membrane performance stability over time.

Medical separation membranes that come into contact with body fluids or blood cause serious problems when proteins or platelets adhere to them, causing degradation of the performance of the separation membrane or causing biological reactions. Moreover, also in water treatment membranes, such as a water purifier, adhesion of protein or organic substance causes the performance fall of a separation membrane.
To solve this problem, attempts have been made to make the separation membrane hydrophilic, and various studies have been made. 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 use an excessive amount of the hydrophilic high molecular weight in the film-forming stock solution, and hydrophilicity compatible with the base polymer. There are restrictions such as being limited to polymers and having to study the optimal stock solution composition according to the intended use of the material.

  Patent Document 2 discloses a method for hydrophilization by coating a film with polyvinyl acetal diethylaminoacetate and a hydrophilizing agent. In this method, there is a concern that polyvinyl acetal diethylaminoacetate covers the hydrophilizing agent, and the effect on non-adhesion is drastically reduced. In addition, since the membrane is immersed in each solution of polyvinyl acetal diethylaminoacetate and a hydrophilizing agent, there is a concern that the separation performance of the membrane may be lowered.

  A method (Patent Document 4) is disclosed in which a polysulfone-based separation membrane is brought into contact with a hydrophilic polymer solution such as polyvinylpyrrolidone and then a coating layer insolubilized by radiation crosslinking is formed (Patent Document 4). However, an aqueous polymer such as polyvinylpyrrolidone and a polysulfone-based polymer have a problem that it is difficult to form a coating layer because the interaction between molecules is weak.

A method is disclosed in which a polyvinyl alcohol aqueous solution having a saponification degree in a certain range is brought into contact with a polysulfone separation membrane, and a film layer on the membrane surface is efficiently formed by a hydrophobic interaction between polysulfone and vinyl acetate (patent) Reference 5). However, since this document is not a method relating to non-adhesiveness, as a result of studies by the present inventors, it has been found that when polyvinyl alcohol is simply coated on a separation membrane, the performance of the separation membrane is significantly reduced. Moreover, it is known that the hydroxyl group of polyvinyl alcohol tends to activate complement when it comes into contact with blood.
On the other hand, a hydrophilic method has been disclosed in which blood compatibility is improved by coating the surface of a hollow fiber membrane functional layer made of a hydrophobic polymer with an ester group-containing polymer (Patent Document 6). However, since the structure of the surface of the hollow fiber functional layer is changed by the polymer coating, it itself becomes a cause of performance degradation, and it is difficult to set optimum polymer conditions. Moreover, although suppression about platelet adhesion etc. to the surface of a functional layer is described, there is no description about the effect which suppresses the performance deterioration (membrane fouling) with time of the membrane module in use. Even if the optimum hydrophilization conditions for the surface of the hollow fiber functional layer are found, there is water around the protein and the surface of the material in which mobility is restricted by hydrogen bonding, so-called bound water. Only the hydrophilization by means of this cannot sufficiently suppress the attachment of protein hollow fibers due to the interaction between these bound waters. Furthermore, it is said that even if the material surface is covered with a hydrophilic polymer, adhesion of proteins and the like can only be temporarily suppressed (Non-patent Document 1).

  Therefore, there is no clear description about the stabilization of the membrane performance over time in use in the reports of these membrane hydrophilization technologies, and hollow fiber membrane modules that stabilize the membrane performance over time during use are not available. Not yet established.

Japanese Patent Publication No. 2-18695 JP-A-8-131791 Japanese Patent Publication No.8-9668 JP-A-6-238139 JP 2006-198611 A JP 2009-262147 A

Medical nanotechnology Kyorin books p115-116

An object of the present invention is to provide a polysulfone-based hollow fiber membrane module that improves the drawbacks of the prior art and has less adhesion of proteins and organic substances and has excellent membrane performance stability over time during use.

The object of the present invention is to improve the drawbacks of the prior art and to provide a polysulfone-based hollow fiber membrane module with less protein and organic matter adhesion and excellent membrane performance stability over time. Found to be achieved by.
1. The peak area percentage of the carbon derived from the ester group by X-ray electron spectroscopy (ESCA) on the surface of the incorporated polysulfone-based hollow fiber membrane is 0.5 (atomic%) or more and 10 (atomic%) or less, and The hydrophobic unit amount ratio existing on the membrane surface is 30% or more larger than the hydrophobic unit amount ratio existing inside the membrane, and the built-in hollow fiber membrane has a wave height of 0.1 to 0.5 mm and a wavelength of 5.0 to 10.0 mm. A hollow fiber membrane module characterized by having a crimp structure of
2. 2. The hollow fiber membrane module according to 1 above, wherein the peak area percentage of the carbon derived from the ester group by ESCA on the opposite surface of the functional layer is 10 (number of atoms) or less.
3. 3. The hollow fiber membrane module as described in 1 or 2 above, wherein the polymer containing an ester group is polyvinyl acetate or a copolymer of vinyl acetate and vinyl pyrrolidone.
4). The average sieving coefficient of albumin after 5 to 10 minutes when bovine blood at 37 ° C. with hematocrit 30%, total protein concentration 6 to 7 g / dl and sodium citrate was added at 200 ml / minute and filtration flow rate 16 ml / minute 4. The hollow fiber membrane module according to any one of 1 to 3, wherein the value [A] and the sieving coefficient [B] of albumin after 60 to 240 minutes satisfy the following relational expression.
[B] / [A] = 0.5-1.0
5. 3. The hollow fiber membrane module according to 2 above, wherein when the bovine blood is flowed under the conditions described in 4 above, the albumin sieving coefficient after 60 minutes from the beginning of the flow is 0.1 to 3.2%.
6). 6. The hollow fiber membrane module according to any one of 1 to 5 above, wherein the internal hollow fiber membrane has an inner diameter of 150 to 250 μm and a membrane area of 1.0 to 3.0 m ² .
7). The hollow fiber membrane module according to any one of 1 to 6 above, which is used as an artificial kidney.

  The hollow fiber membrane module in the present invention is characterized in that the ester group is localized on the surface of the hollow fiber membrane functional layer and has a built-in hollow fiber membrane having a specific crimp structure. It can be widely used in applications requiring little film adhesion and stability over time during use.

One aspect of the artificial kidney used in the present invention Circuits in Sc-Alb measurement carried out in Examples 1 to 5 and Comparative Examples 1 to 4 Hollow fiber crimp shape Machined crimp roll

  The hollow fiber membrane module of the present invention has a functional layer on one side surface of the encapsulated hollow fiber membrane, the ester group is localized on the surface of the hollow fiber membrane functional layer, and the encapsulated hollow fiber membrane is crimped. Has a shape.

  The presence of the ester group on the surface of the hollow fiber membrane functional layer suppresses the adhesion of proteins and platelets. It is said that the protein is attached to the material surface because the higher-order structure of the protein changes, the hydrophobic site inside is exposed, and a hydrophobic interaction occurs with the material surface. Therefore, it is considered that covering the hollow fiber membrane surface with a hydrophilic ester group suppresses performance deterioration due to protein adhesion via hydrophobic interaction. On the other hand, water whose mobility is constrained by hydrogen bonds, so-called bound water, is present around the protein and on the material surface. For this reason, the hydrophilicity of the hollow fiber membrane alone cannot sufficiently suppress the adhesion of proteins due to the interaction between these bound waters and the accompanying deterioration in membrane performance (fouling) over time. However, if the hollow fiber membrane is given a unique crimp structure that improves its performance as a module, the film thickness decreases as the membrane surface deposits flow outside the membrane, and at the same time, the attached protein itself dissociates. It is presumed that the deterioration of the hollow fiber membrane performance can be suppressed by the effect of increasing the speed.

  In the present invention, the peak area percentage of the carbon derived from the ester group by X-ray electron spectroscopy (hereinafter sometimes referred to as ESCA) on the surface of the functional layer of the hollow fiber is 0.5 (number of atoms%) or more, and 1 ( Atom%) or more is preferred. Further, if the amount of the ester group is too large, the performance of the hollow fiber membrane is likely to be lowered.

  In addition, if there are many ester groups on the opposite surface of the functional layer, the performance of the hollow fiber membrane deteriorates. Therefore, the carbon peak derived from the ester group by X-ray electron spectroscopy (ESCA) on the opposite surface of the functional layer. The area percentage is preferably 10 (number of atoms%) or less, more preferably 5 (number of atoms%) or less, and further preferably 1 (number of atoms%) or less.

  Furthermore, since protein adhesion and the like are only required to be suppressed on the surface of the functional layer, the amount of carbon derived from the ester group on the surface of the functional layer is larger than that on the opposite surface of the functional layer. Localization on the surface of the layer is important for improving the separation performance of the membrane. For example, when the ester group-containing polymer is not localized on the surface and is also present in the film thickness direction, water molecules are constrained by the influence of hydrogen bonds and the like. It is conceivable that water molecules contained therein or waste products dissolved in the water molecules are difficult to pass through the membrane.

  From the above, in the present invention, the amount of the ester group-containing polymer present on the functional layer surface of the membrane is preferably 30% or more than the amount of the ester group-containing polymer inside the membrane, more preferably 100% or more, more preferably 300% or more.

  The amount of carbon derived from the ester group on the surface can be determined by X-ray electron spectroscopy (ESCA). A value measured at 90 ° is used as the measurement angle. When the measurement angle is 90 °, a region having a depth of about 10 nm from the surface is detected. Moreover, the average value of three places is used for a measurement place. 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 with respect to all elements, the carbon amount (number of atoms%) derived from the ester group can be obtained. 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 first decimal place. It can obtain | require by multiplying the peak area ratio of the component derived from COO from the carbon amount (atomic%) of C1s. As a result of peak splitting, if it was 0.4% or less, it was set below the detection limit.

  The surface of the functional layer referred to here is the surface on the side that comes into contact with the material to be treated, in the case of liquid treatment, the liquid to be treated. Taking the hollow fiber membrane for artificial kidneys as an example, the surface of the functional layer through which blood as the liquid to be treated flows corresponds to the inner surface, and the opposite surface through which the dialysate flows corresponds to the outer surface.

  If the functional layer surface is chemically modified with a reactive compound containing an ester group after forming the hollow fiber membrane, the ester group can be introduced into the functional layer surface.

  Here, such a surface reaction generally may cause a decrease in the performance of the hollow fiber membrane, and there are various condition restrictions for actual application. However, when a polymer containing an ester group is used, an ester group derived from the polymer can be introduced to the surface of the functional layer 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. In addition, a polymer using a monomer having an ester group in the side chain, such as methacrylic acid ester such as ethyl methacrylate and hydroxyethyl methacrylate, and vinyl acetate can be used. In addition, as an ester group-containing polymer, a polymer containing an aromatic ring such as polyethylene terephthalate is not preferable to be used in the present invention because the degree of hydrophobicity is too strong and does not contain an aromatic ring. Polymers are preferred. In order to improve the function of suppressing the adhesion of proteins and platelets, those containing an ester group in the side chain such as carboxylic acid vinyl ester, acrylic acid ester, and methacrylic acid ester are preferable. Among these, vinyl acetate is excellent in suppressing the adhesion of proteins and platelets.

  Whether the amount of the ester group-containing polymer existing on the film surface is larger than the amount of the ester group-containing polymer inside the film is determined by, for example, ESCA and total reflection infrared spectroscopy (hereinafter referred to as ATR). You can know by combining. This is because ESCA measures the depth of the surface up to about 10 nm, and ATR measures the composition up to several μm deep, although it is a surface measurement. Taking a polysulfone hollow fiber membrane as an example, if the ratio of the abundance of the ester group-containing polymer to the abundance of the polysulfone unit at an arbitrary location in the membrane is defined as a unit amount ratio, the value of the unit amount ratio obtained by ESCA is If the value obtained by ATR is 30% or more, the amount of ester group-containing polymer present on the film surface in the present invention can be 30% or more larger than the inside of the film. In addition, the value of each measurement is an average value of three points.

  In order to localize the ester group-containing polymer on the surface of the hollow fiber membrane functional layer, for example, the following method may be mentioned. When wet film-forming is performed from a film-forming stock solution, high-molecular weight polymers gather on the surface to prevent entropy loss, and hydrophilic polymers tend to gather to prevent enthalpy loss. Therefore, for example, in the case of a polysulfone membrane, by creating a stock solution consisting of a three-component polymer of polysulfone and polyvinylpyrrolidone and an ester group-containing polymer, the molecular weight of the ester group-containing polymer is equal to or higher than the molecular weight of polyvinylpyrrolidone, It can be concentrated on the surface. However, if the affinity of the ester group-containing polymer with polysulfone is high, the enthalpy effect is more dominant than the entropy effect, and the ester group is concentrated not inside the surface but inside the hollow fiber membrane. In general, copolymers with water-soluble units such as vinyl pyrrolidone units are more preferred than homopolymers containing only ester group units because of their lower affinity with polysulfone. . Also, in the spinning process of the hollow fiber membrane, an injection solution is allowed to flow inside when discharging from the double annular die. An ester group-containing polymer may be added to this injection solution. Before the hollow fiber membrane is phase-separated and the membrane structure is determined, the ester group-containing polymer in the injection solution diffuses to the membrane-forming stock solution side, so that it can be localized on the inner surface. Furthermore, a method of coating the surface of the functional layer of the separation membrane with an ester group-containing polymer after forming the hollow fiber membrane is simple and preferably used. Further, the ester group-containing polymer and the hollow fiber membrane may be immobilized by a chemical reaction. In addition, after coating, crosslinking to the separation membrane by radiation or heat treatment is a suitable means for suppressing elution of the ester group-containing polymer.

  A hydrophobic polymer is suitably used as the polymer that is the material of the separation membrane of the present invention. In the present invention, the hydrophobic polymer refers to a polymer having a solubility in 100 g of water at 20 ° C. of less than 0.001 g. Specific examples include polysulfone-based polymers, polystyrene, polyurethane, polyethylene, polypropylene, polycarbonate, polyvinylidene fluoride, and polyacrylonitrile, but are not limited thereto. Among these, a polysulfone-based polymer is preferably used because it can easily form a hollow fiber separation membrane and can be easily coated with an ester group-containing polymer. Here, the polysulfone-based polymer has an aromatic ring, a sulfonyl group and an ether group in the main chain, and examples thereof include polysulfone, polyethersulfone and polyallylethersulfone. 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 or modified. Although it does not specifically limit, it is preferable that another copolymerization monomer is 10 weight% or less.

On the other hand, polysulfone-based polymers are generally highly hydrophobic and adhere to many organic substances such as proteins. In particular, 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. Therefore, it is preferable that the ester group on the surface of the hollow fiber separation membrane functional layer is uniformly present in a certain amount or more at any site on the surface of the hollow fiber separation membrane functional layer. In the present invention, a ratio obtained by dividing the abundance of the ester group by the abundance of polysulfone can also be used as an index indicating the abundance of the ester group. At three different locations on the surface of the hollow fiber separation membrane functional layer, 1730 cm ^{− The} ratio (A _CO ) of the infrared absorption peak intensity (A _CO ) derived from the ester group C = O near ^{1 to} the infrared absorption peak intensity (A _CC ) derived from the benzene ring C = C of the polysulfone near 1580 cm ^−1. / (A _CC ) is selected, and the average value thereof is preferably 0.005 or more, more preferably 0.01 or more, still more preferably 0.02 or more, and the ratio is 0.001 or less. It has been found that the ratio is preferably 10% or less, more preferably 5% or less. The average value of (A _CO ) / (A _CC ) is preferably 1 or less, and more preferably 0.5 or less, because if the average value is too large, the performance of the hollow fiber separation membrane may be lowered.
The ratio of (A _CO ) / (A _CC ) is calculated as follows. On the functional layer surface, 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 measured at three different locations. 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 .

  As three different places, it is preferable to measure both end portions and the central portion of the hollow fiber membrane module. Furthermore, it is preferable to measure three or more hollow fibers.

As means for bringing the (A _CO ) / (A _CC ) within the above-mentioned range, when an ester group-containing polymer is added to the film-forming stock solution, the composition ratio of the film-forming stock solution, the die temperature during spinning, It is important to match various conditions such as temperature and humidity of the discharge part. These various conditions also differ depending on the type and molecular weight of the ester group-containing polymer. For example, when Kollidon VA64 (BASF), which is a copolymer of vinyl pyrrolidone and vinyl acetate (6/4), is used as the ester group-containing polymer, the amount of VA64 in the stock solution is 1 to 10% by weight, The base temperature is preferably 20 to 60 ° C., the dry part temperature is 10 to 60 ° C., and the relative humidity is preferably 70 to 95% RH. In addition, when an ester group-containing polymer is added to the injection solution, the composition ratio of the injection solution, the injection solution temperature, the composition of the film-forming stock solution, and the like have an effect. For example, in the case of VA64, the addition amount to the injection solution is 5 to 30% by weight, the injection solution temperature is 10 to 60 ° C., the polysulfone-based polymer concentration is 14 to 25% by weight as the composition of the film forming stock solution, and polyvinylpyrrolidone In the case of using 2 to 10% by weight is preferable. The weight average molecular weight of the polysulfone-based polymer is preferably small so that VA64 is easily diffused into the membrane, and 100,000 or less, further 50,000 or less is suitably used. Polysulfone polymers In the case of post-treatment such as coating, the concentration of the ester group-containing polymer in the coating solution, the contact time, and the temperature at the time of coating are affected. For example, when coating with a VA64 aqueous solution, the VA64 concentration is preferably 1 to 5000 ppm, the contact time is 10 seconds or more, and the temperature is 10 to 80 ° C. In addition, when coating is performed continuously rather than batchwise, the higher the flow rate of the VA64 aqueous solution, the more uniform coating is possible, but if it is too fast, a sufficient amount cannot be coated, so 200 to 1000 mL / min is preferable. It is a range.

  In addition to the ester group-containing polymer, the hollow fiber separation membrane contains a water-soluble polymer having a solubility in 100 g of water at 20 ° C. of 1 g or more, preferably 10 g or more. It is preferable from the viewpoint. It is thought that an appropriate balance between hydrophilicity and hydrophobicity on the surface is important for suppressing adhesion of proteins and platelets. In fact, in addition to the ester group-containing polymer, when there is a water-soluble polymer that is more hydrophilic than the ester group-containing polymer, the effect of inhibiting the adhesion of proteins and platelets is further improved. As the water-soluble polymer, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol and the like are suitable. The amount of the water-soluble polymer contained in the hollow fiber separation membrane is preferably 0.1% by weight or more, more preferably 1% by weight or more. Moreover, since there exists a tendency for film | membrane performance to become low when there is too much content, 30 weight% or less is preferable, More preferably, it is 10 weight% or less. The amount of the water-soluble polymer on the functional layer surface is preferably 10% by weight or more, more preferably 15% by weight or more. Moreover, since the hydrophilic effect will become strong too much, 50 weight% or less is preferable, More preferably, it is 40 weight% or less. The amount of the ester group-containing polymer in the hollow fiber separation membrane can be determined by elemental analysis or nuclear magnetic resonance (NMR) measurement. The amount of the water-soluble polymer on the functional layer surface can be determined by ESCA or the like.

  Furthermore, if the ester group-containing polymer is a copolymer having a water-soluble unit and an ester group unit, it is preferable because an appropriate balance between hydrophilicity and hydrophobicity can be achieved in one molecule. Therefore, as the copolymer, a block copolymer, an alternating copolymer, or a random copolymer is preferably used rather than a graft copolymer. This is presumably because, in the graft polymer, the unit part grafted to the main chain has many opportunities to come into contact with proteins and the like, and thus the characteristics of the graft chain part have a greater influence than the characteristics of the copolymer. Moreover, an alternating copolymer and a random copolymer are more preferable than a block copolymer. In the block copolymer, it is considered that the characteristics of each unit are clearly separated. From the viewpoint of balance between hydrophilicity and hydrophobicity in one molecule, a copolymer having at least one selected from a random copolymer and an alternating copolymer is preferably used. The molar ratio of ester group units in the ester group-containing polymer is preferably 0.3 or more and 0.7 or less. If the molar ratio of the ester group units is less than 0.3, the effect of suppressing the adhesion of ester groups is reduced. Moreover, when it exceeds 0.7, the effect of a water-soluble unit will reduce.

  The molar ratio of these units can be calculated by NMR or elemental analysis.

  Examples of the water-soluble unit include a vinyl pyrrolidone group, an ethylene glycol group, and a vinyl alcohol group. In particular, a vinylpyrrolidone-vinyl acetate copolymer has an appropriate balance between hydrophilicity and hydrophobicity and is preferably used. The balance between hydrophilicity and hydrophobicity of the entire surface is also important, and the amount of vinylpyrrolidone units on the surface is preferably 10% by weight or more, more preferably 15% by weight or more. Moreover, since the hydrophilic effect will become strong too much, 50 weight% or less is preferable, More preferably, it is 40 weight% or less. The amount of the vinyl pyrrolidone unit on the surface is, as described above, when polyvinyl pyrrolidone is contained in the hollow fiber separation membrane, the total of the vinyl pyrrolidone unit and the ester group unit derived from the copolymer and the polyvinyl pyrrolidone derived. Value. The amount of vinyl pyrrolidone unit on the surface can be determined by ESCA.

  In addition, when the water-soluble polymer has good compatibility with the hydrophobic polymer serving as a support for the hollow fiber separation membrane, it is preferable because it can be added to the hollow fiber separation membrane stock solution and used as a pore-forming agent. For example, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and polyethylene glycol (PEG) are preferably used for the polysulfone-based polymer.

  As a method of introducing a polymer containing an ester group to the surface of the functional layer, as described above, a method of forming the polymer by mixing it with the membrane forming stock solution of the hollow fiber separation membrane, a method of mixing with the injection solution, A method of coating after forming the hollow fiber separation 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 separation membrane in a mixed solution of hydrophobic monomers, and causing a polymerization reaction on the surface of the hollow fiber separation membrane are included.

  Among these, the method of coating the polymer containing the ester group on the surface of the hollow fiber separation membrane is a preferable method because it can be carried out simply and in a small amount. For example, a solution in which an ester group-containing polymer is dissolved in a solvent may be applied and adsorbed on a hollow fiber separation membrane, or an adhesive or the like, and the hollow fiber separation membrane material and the ester group-containing polymer are immobilized. May be. Further, when the ester group-containing polymer is brought into contact with the surface of the hollow fiber separation membrane, a pressure difference is generated between the front (functional layer) and the back of the hollow fiber separation membrane, and this is used to concentrate the membrane surface. The method is efficient and is preferably used. The pressure difference may be increased or reduced. In addition, there is a method in which the ester group-containing polymer solution itself causes a pressure difference to be introduced onto the film surface, but after contacting the solution, it may be pressurized with another solution such as gas or water.

In particular, when a polymer containing an ester group is surface-coated on a hollow fiber separation membrane, the higher the adsorption equilibrium constant of the hydrophobic polymer and the ester group-containing polymer used as the support of the hollow fiber separation membrane, the higher the hollow fiber separation membrane. It was found that the surface of can be uniformly covered. In addition, when the size of the ester group-containing polymer is smaller than the pore diameter of the hollow fiber separation membrane, the ester group-containing polymer passes through the membrane even if a pressure difference is generated inside and outside the hollow fiber separation membrane. The ester group-containing polymer cannot be localized efficiently on the functional layer surface. However, it has been found that if the adsorption equilibrium constant is high, the ester group-containing polymer can be efficiently localized on the surface regardless of the molecular weight. That is, the adsorption equilibrium constant is preferably 330 pg / (mm ² · ppm) or more, a more preferable range is 500 pg / (mm ² · ppm) or more, and a more preferable range is 550 pg / (mm ² · ppm) or more. It is. Further, it is particularly preferably 600 pg / (mm ² · ppm) or more. On the other hand, if a polymer having an adsorption binding constant with a hydrophobic polymer constituting the hollow fiber separation membrane exceeds 1100 pg / (mm ² · ppm), the polymer is excessively adsorbed when brought into contact with the hollow fiber separation membrane. In connection with this, the performance of the hollow fiber separation membrane deteriorates, for example, the protein removal efficiency deteriorates due to the decrease in the diameter of the membrane pore. Therefore, it is preferably 1100pg ^{/ (mm} 2 · ppm) or less, more preferably 1000pg ^{/ (mm} 2 · ppm) or less, more preferably ranges are 900pg ^{/ (mm} 2 · ppm) or less, particularly preferably The range is 850 pg / (mm ² · ppm) or less.

  When the adsorption equilibrium constant is high, the amount of adsorption to the membrane is large, and the performance often decreases. However, this can be dealt with by reducing the concentration of the coating solution or reducing the amount of the coating solution.

  The pressure difference between the inside and outside of the hollow fiber separation membrane is preferably 5 kPa or more, more preferably 10 kPa or more, and further preferably 20 kPa or more. In addition, when the pressure difference is high, the hollow fiber separation membrane may leak, so that it is preferably 100 kPa or less, more preferably 70 kPa or less, and even more preferably 50 kPa or less. In addition, the inside of the hollow fiber separation membrane said here says the surface side of the hollow fiber separation membrane functional layer which contacts a process liquid, and the outer side means the opposite side. Taking a hollow fiber membrane for an artificial kidney as an example, the surface of the functional layer through which blood as the treatment liquid flows corresponds to the inside, and the opposite surface through which the dialysate flows corresponds to the outside.

  In the present invention, the adsorption equilibrium constant is a value calculated by measurement using a surface plasmon resonance apparatus (hereinafter abbreviated as SPR). SPR is a device that analyzes the change in mass on the surface of a thin film from the change in the resonance angle of laser light irradiated at a certain angle. The hydrophobic polymer contained in the hollow fiber separation membrane is spin-coated onto a gold chip for SPR. Then, a thin film is formed, and each adsorption amount when each ester group-containing polymer aqueous solution having a concentration arbitrarily selected in the range of 5 to 1000 ppm is flowed is obtained, and the adsorption isotherm created from the value is adsorbed. Derive the equilibrium constant.

  In the case of coating, since it is necessary to use a solvent that does not deform the hollow fiber separation membrane, water or an aqueous alcohol solution is preferably used. However, many ester group-containing polymers are hardly soluble in water or alcohol. Therefore, compared with the polymer which consists only of said vinyl acetate etc., the copolymer which made these copolymerize a water-soluble unit is used suitably also from such a viewpoint.

  In this case, as described above, the ratio of the ester unit in the copolymer is preferably 0.3 or more and 0.7 or less, more preferably 0.35 or more, 0, from the suppression effect and solubility of protein and platelet adhesion. .55 or less is preferable. In particular, when the water-soluble unit is made of vinylpyrrolidone, it is preferably used because the performance of the hollow fiber separation membrane by coating hardly deteriorates. In particular, a copolymer of vinyl acetate and vinyl pyrrolidone is preferable. A copolymer of vinyl alcohol and vinyl acetate may have low membrane performance, possibly because water molecules are constrained by the influence of a hydrogen bond due to a hydroxyl group and the solute hardly passes through the membrane. Furthermore, when the polysulfone-based hollow fiber separation membrane is coated, the performance deterioration may be larger than that of a copolymer of vinyl acetate and vinyl pyrrolidone because the adsorption equilibrium constant is high.

  Furthermore, a method of insolubilization by irradiation, heat treatment, or the like after coating is a preferable method because elution of the ester group-containing polymer can be reduced. For example, radiation irradiation or heat treatment may be performed in a state where the hollow fiber separation membrane is immersed in an ester group-containing polymer solution. Alternatively, the hollow fiber separation membrane may be immersed in a copolymer solution of a vinyl pyrrolidone unit and a hydrophobic unit, and then the solution may be extracted, followed by radiation irradiation or heat treatment. At this time, by extracting the solution, an air lock may be formed in the hollow portion of the hollow fiber membrane like gas-liquid-gas-liquid-gas, which may cause performance degradation due to blockage of the hollow fiber. The method of discharging the liquid forming the air lock is not particularly limited, but a method of performing gas blowing from the one end to the other end of the hollow portion of the hollow fiber membrane module is preferred, and gas blowing is preferably performed at a high pressure. -It is preferable to carry out alternately at low pressure periodically. In the case of irradiation with radiation, the ester group-containing polymer is more likely to be fixed and insolubilized in the hollow fiber separation membrane when a certain amount of solvent is present. This is presumably because the solvent becomes radicals upon irradiation, and the polymer and the material of the hollow fiber separation membrane are radicalized, and the copolymer is crosslinked and insolubilized in the membrane. Therefore, it is 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 separation membrane. In addition, as a solvent, water is used suitably from a viewpoint of handleability. On the other hand, when the hollow fiber separation membrane module is not filled with water, there is less concern about elution in the time until radiation irradiation, and therefore it is preferable that only the hollow fiber separation membrane is in a wet state. Specifically, it is preferably 6.0 times or less, more preferably 4.0 times or less, with respect to the dry weight of the hollow fiber separation membrane. In addition, after immersing the hollow fiber separation membrane in the ester group-containing polymer solution, it may be replaced with water or the like before irradiation or heat treatment. Furthermore, radiation or heat treatment may be performed after extracting the substituted water. The extraction operation is preferably performed by gas blowing in the direction from one end to the other end of the hollow portion of the hollow fiber membrane module, and more preferably by high-pressure-low-pressure alternating periodic gas blowing.

  Moreover, when the peak area percentage of the carbon derived from the ester group of the hollow fiber separation membrane functional layer is 0.1 (number of atoms%) or more and is dissolved in a good solvent for the polymer forming the hollow fiber separation membrane, When an insoluble component is contained and the water content of the insoluble component is 95% or more, preferably 97% or more, protein adhesion is suppressed more effectively while suppressing elution of the polymer from the hollow fiber separation membrane. can do. In order to suppress protein adhesion, a certain degree of hydrophilicity is required. However, when the hollow fiber separation membrane has a water-soluble polymer such as polyvinylpyrrolidone and no insoluble component is contained, the effect of suppressing adhesion may not be high depending on the type of protein. This is presumably because the protein is trapped in the diffuse layer of polyvinylpyrrolidone present on the membrane surface. If the diffuse layer is in a certain degree of cross-linking, it can be presumed that protein penetration can be suppressed.

About the water content of an insoluble component, it calculates | requires as follows. The dried hollow fiber separation membrane is dissolved with a good solvent to a concentration of 2% by weight. The solution was filtered using a filter paper to obtain an insoluble component. After sufficiently washing the soluble component with a good solvent, the insoluble component is replaced with water. Excess water was removed, and the weight (w) of the insoluble component in the water-containing state was measured. Then, the weight (d) of the insoluble component after sufficiently drying was measured. The water content can be calculated by the following formula.
Moisture content (%) = (w−d) × 100 / w
For example, in the case of a hollow fiber separation membrane composed of a polysulfone polymer and polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate (6/4), dimethylacetamide is a good solvent.

  In order to form an insoluble component, it is preferable to cause a crosslinking reaction between molecules or within a molecule by subjecting the hollow fiber separation membrane to radiation or heat treatment. In addition, the moisture content can be 95% or more by controlling the radiation dose, heating temperature, and time. In general, the radiation dose is preferably 5 to 50 kGy, and the heating condition is preferably 120 to 300 ° C., although it varies depending on the polymer. Moreover, it is also possible to control a crosslinking reaction by using an antioxidant when irradiating radiation. Details of the antioxidant will be described later.

  Further, the dispersion state of the polymer in the hollow fiber membrane also affects the crosslinking reaction. That is, the crosslinkable polymer is preferably finely dispersed in the hollow fiber membrane. Factors affecting the dispersion state of the polymer in the hollow fiber membrane include the composition ratio of the stock solution, the stirring speed, the stirring time, the time to film formation after dissolution, and the case where an ester group-containing polymer is added to the injection solution. In the case of coating an injection solution composition, an injection solution temperature, and an ester group-containing polymer, a coating method and the like can be mentioned.

  For example, when a vinyl pyrrolidone / vinyl acetate (6/4) copolymer is coated on a hollow fiber membrane made of polysulfone and polyvinyl pyrrolidone, the ratio of polyvinyl pyrrolidone in the membrane forming stock solution is 15 to 35 with respect to the total polymer weight. % By weight is preferred. When the amount of polyvinyl pyrrolidone is small, the hydrophilic ratio decreases, so that the water content decreases even after the crosslinking reaction. If the amount is too large, the polyvinyl pyrrolidone cannot be finely dispersed, so that the crosslinking reaction proceeds and the water content decreases. Moreover, when the stirring speed is 30 rpm or more, preferably 50 rpm or more, the dispersion state of polyvinylpyrrolidone can be increased, which is preferable. Furthermore, since the microphase separation starts to occur in the film-forming stock solution after a lapse of time after dissolution, the polyvinyl pyrrolidone is not finely dispersed. Therefore, it is preferable to spin within 1 week after dissolution. Further, when coating the ester group-containing polymer, it is effective to generate a pressure difference inside and outside the hollow fiber separation membrane.

  Even if the adsorption equilibrium constant is high, the hollow fiber separation membrane may not be sufficiently coated if the concentration of the ester group-containing polymer solution is low. On the other hand, if the concentration is too high, the amount of eluate increases and the performance of the hollow fiber separation membrane is often lowered. 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 0.001% by weight or more and 0.1% by weight or less. Is preferred.

  For example, in the case of a vinylpyrrolidone / vinyl acetate (7/3) copolymer, it is preferably 0.05% by weight or more and 1% by weight or less. In the case of vinyl pyrrolidone / vinyl acetate (6/4) copolymer and vinyl pyrrolidone / vinyl acetate (5/5) copolymer, 0.001% by weight or more and 1% by weight or less are preferable. Furthermore, 0.005 wt% or more and 0.1 wt% or less is preferable. In the case of vinylpyrrolidone / vinyl acetate (3/7) copolymer and polyvinyl acetate, 0.001% by weight or more and 0.5% by weight or less are preferable. Moreover, although mentioned later for details, by making an antioxidant coexist, even if it lowers the lower limit of the said density | concentration further, the adhesion inhibitory effect of protein, platelets, etc. can be expressed.

  Moreover, as a method of extracting the immersed ester group-containing polymer solution, water, and the like, 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 during irradiation, oxygen radicals are generated and the polymer material of the hollow fiber separation membrane material is decomposed. Therefore, the oxygen concentration around the hollow fiber separation membrane when irradiated with radiation is desirably 10% or less. When irradiating the hollow fiber separation membrane module with radiation, for example, the inside of the module is purged with nitrogen gas and then sealed, so that the oxygen concentration is lowered and the radiation is irradiated.

  In addition, as a step of coating, the hollow fiber separation membrane may be coated with an ester group-containing polymer and then incorporated into the module, or the hollow fiber separation membrane module may be coated with an ester group-containing polymer solution. Also good. After coating, radiation irradiation or heat treatment may be performed as described above.

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 separation 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 separation 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. Furthermore, after coating the hollow fiber separation 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, when a blood purification module serves both as insolubilization by radiation irradiation and sterilization, if a hollow fiber separation membrane or the like deteriorates at either dose, an antioxidant may be used in combination. In addition, when the hollow fiber separation membrane is coated with the ester group-containing polymer solution, the addition amount of the ester group-containing polymer can be reduced by adding an antioxidant. For example, when an antioxidant such as ethanol is used in combination with a vinylpyrrolidone / vinyl acetate (6/4) copolymer and a vinylpyrrolidone / vinyl acetate (5/5) copolymer, the copolymer is described above. The lower limit value of the preferred range can be reduced to 1/10 or less. This is presumably because the antioxidant suppresses the decomposition reaction of the ester group due to radiation. The term “antioxidant” as used herein refers to a molecule that has 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.

  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 separation membrane or the like cannot be prevented. In addition, when a large amount of antioxidant is added, radicals are sufficiently erased, and the amount of the copolymer immobilized on the hollow fiber separation membrane decreases. Adhesion suppression effect cannot be obtained sufficiently. 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.

  The hollow fiber separation membrane of the present invention is a membrane that selectively removes a specific substance contained in a liquid to be treated, such as blood or an aqueous solution, by adsorption or the size of the substance.

    Since the hollow fiber membrane module of the present invention has high adhesion inhibition properties, it can be suitably used as a separation 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 circulating blood outside the body to remove waste and harmful substances in the blood, such as an artificial kidney and an exotoxin adsorption column. The artificial kidney module includes a coil type, a flat plate type, and a hollow fiber membrane type, and the hollow fiber membrane type is preferable from the viewpoint of processing efficiency.

  As for the shape of the hollow fiber separation membrane of the present invention, it is desirable to provide a specific crimp structure in order to secure a gap between the hollow fiber membranes, prevent a drift of fluid flowing through the gap, and prevent membrane deterioration.

  Here, the crimp is a wave-like shape imparted to the hollow fiber membrane or a similar shape, and the one that retains the wave-like shape to the extent that the hollow fiber membrane is hung vertically is called a crimp. Yes. The characteristic value is evaluated by the crimp wavelength (repeating unit in the length direction of the hollow fiber membrane) and the wave height (size in which the hollow fiber membrane swings perpendicularly to the length direction).

  A module made of a hollow fiber membrane having a relatively large wavelength is likely to cause channeling of the external perfusate because the contact between the hollow fiber membranes increases. Therefore, the wavelength is 10 mm or less.

  On the other hand, a module made of a hollow fiber membrane having a relatively small wavelength is preferable from the viewpoint of improving module performance because the flow of dialysate or buffer solution in the module is improved even if the crimp wave height applied to the hollow fiber membrane is small. Since the hollow fiber membrane is subjected to a physical load of imparting crimps with a short period in the crimping process during film formation, the yarn tends to be crushed and often lacks the stability of the crimp. Therefore, the wavelength is 5 mm or more.

  In the case of a module comprising a hollow fiber membrane having a relatively large wave height, the effect of reducing the contact between the hollow fiber membranes is increased. However, when the hollow fiber bundle is inserted into the module case, the diameter of the hollow fiber membrane bundle is increased. The insertability of is worsened. Moreover, since a physical load is imparted to the hollow fiber membrane by applying a large wave height in the crimping process during film formation, yarn collapse tends to occur, and the stability of the crimp is often lacking. Therefore, the wave height is 0.5 mm or less, and preferably 0.3 mm or less.

  On the other hand, a module comprising a hollow fiber membrane having a relatively small wave height has a good insertion property when the hollow fiber bundle is inserted into the module case because the diameter of the hollow fiber membrane bundle is small. It is difficult to reduce the contact between the hollow fiber membranes. Therefore, the wave height is 0.1 mm or more.

  There are various methods for producing a hollow fiber membrane module depending on its use. For example, the steps include a hollow fiber separation membrane production step, a crimp application step, and the hollow fiber separation membrane incorporated into the module. Can be divided into processes.

  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 which is a hollow fiber separation membrane, polysulfone and polyvinylpyrrolidone (weight ratio of 20: 1 to 1: 5 is preferable, and 5: 1 to 1: 1 is more preferable) are good solvents for polysulfone. (N, N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane, etc. are preferred) and a stock solution dissolved in a poor solvent (concentration is preferably 10 to 30% by weight, preferably 15 to 25%) Injecting the injection solution to the inside when discharging from the double annular die, and after running the dry part, lead to the coagulation bath. At this time, the humidity of the dry part has an effect, so that the phase separation behavior near the outer surface is accelerated by replenishing moisture from the outer surface of the membrane while the dry part is running.・ Diffusion resistance can be reduced. 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 100% RH. 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, further 60 to 75% by weight, particularly preferably 63 to 65% by weight is suitably used.

Next, the hollow fiber after being spun and passed through the coagulation bath is passed through a water-washing bath, whereby the residual solvent and further the excess hydrophilic polymer are washed. Thereafter, a crimp is imparted to the hollow fiber membrane through a step of drying the hollow fiber membrane online with a dryer. As a method of continuously crimping the spun hollow fiber membrane, (1) a method in which the hollow fiber membrane is passed between two gears having meshing teeth and continuously rotating, (2) a timing pulley and timing Examples include a method of passing between belts, (3) a method of passing between concave and convex belts, and (4) running between a pair of rotating crimp rolls. In the embodiment of the present invention, the method (4) is preferably used in terms of operability, but is not particularly limited.

  The crimp roll as a crimping device referred to in the present invention is a cylindrical body made of stainless steel having a diameter of φ1 or more and φ10 or less, or a stainless steel rod plated, more preferably having a diameter of φ2 or more and φ5 or less. Is a roll in which the longitudinal direction is aligned in parallel around the cylindrical body serving as the central axis and arranged at equal intervals. However, the material of the cylindrical body is not limited to the materials listed above. In the case of a cylindrical body having a diameter of less than φ1, “deflection” occurs due to insufficient strength of the cylindrical body itself, and it is difficult to uniformly apply a crimp of the same period to the hollow fiber membrane when the crimp is applied. There is no need to separate and assemble the rod and the cylindrical body of the central shaft, and there is no problem even if it is a blade-type integral similar to this as shown in FIG. It is preferable in that the body itself can minimize the occurrence of “deflection” due to insufficient strength. If it exceeds φ10, it is considered that the device becomes complicated and large, and the cost is increased, which is not suitable for cost reduction.

In the crimp provision method of this invention, it is preferable that the shortest distance at the time of the closest approach between a pair of crimp rolls is constant at the time of roll operation. As a result, for example, generation of flat yarns, deformed yarns, and crushing yarns due to play between the crimp roll and the drive portion can be suppressed, and the repetition of the crimp wave height and wavelength described above can be achieved, and further, Stable crimping can be applied without thread breakage or yarn disturbance during the process.

  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.

The present invention can be preferably applied to a hollow fiber membrane module having a built-in hollow fiber membrane having an inner diameter of 150 to 250 μm and a membrane area of 1.0 to 3.0 m ² , and can be particularly preferably used for an artificial kidney.

  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.
1. Measurement method (1) X-ray photoelectron spectroscopy (ESCA) measurement
The hollow fiber membrane was cut into a semi-cylindrical shape with a single blade, and the inner surface and the outer surface of the hollow fiber membrane were each measured at three points. The measurement sample was rinsed with ultrapure water, dried at room temperature and 0.5 Torr for 10 hours, and then subjected to measurement. 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)
As the amount of carbon derived from the ester group, the peak appearing at +4.0 to 4.2 eV from the C1s CH or C—C main peak (near 285 eV) is a peak derived from the ester group (COO), so that the peak splitting Then, the ratio of the peak area with respect to all elements (all elements other than hydrogen atoms cannot be detected since hydrogen atoms cannot be detected) was calculated, and the carbon amount (number of atoms%) derived from the ester group was determined.

When the hollow fiber separation membrane support is polysulfone, the molecular weight of the vinyl pyrrolidone unit is 111 and the molecular weight of the polysulfone unit is 442. Therefore, the amount of vinyl pyrrolidone unit on the surface is the amount of nitrogen (a (number of atoms)). It calculated from the following formula from the value of the amount of sulfur (b (number of atoms%)).
Surface vinylpyrrolidone amount (% by weight) = (a × 111 / (a × 111 + b × 442)) × 100
When the hollow fiber separation membrane support is polyacrylonitrile, the acrylic unit has 3 carbon atoms, the nitrogen number is 1, the vinyl pyrrolidone has 6 carbon atoms, the oxygen number is 1 and the nitrogen number is 1. It can be calculated from the ratio.

(2) Measurement of the amount ratio of vinyl acetate units inside and inside the hollow fiber separation membrane The amount of ester group-containing polymer on the surface of the hollow fiber separation membrane can be calculated by using ESCA as shown in (1). ESCA was used to measure the amount ratio of vinyl acetate units on the surface. The measuring apparatus and conditions were the same as (1).

  The amount ratio of vinyl acetate units on the surface is that the ester group (COO) peak appears on the C1s peak derived from the ester group-derived carbon amount (atomic%) obtained in the same manner as in (1). can get. Further, the amount of polysulfone can be obtained by determining the amount of sulfur because one sulfur atom exists per repeating unit of polysulfone. Therefore, surface vinyl acetate unit amount ratio = ester group amount (number of atoms%) / sulfur amount (number of atoms%).

The internal vinyl acetate unit amount ratio was determined by performing ATR measurement. The measurement conditions were a resolution of 4 and an integration count of 64. The intensity of the C═O peak derived from the ester group near 1730 cm ⁻¹ (A _CO ) and the intensity of the C═C absorption peak derived from the benzene ring of polysulfone near 1580 cm ⁻¹ (A _CC ) were determined. ATR is a measurement depth from the surface to about 2-3 μm.

  Various concentrations of polysulfone and polyvinyl acetate were dissolved in N, N-dimethylacetamide. Solutions of various concentrations were dropped onto a glass plate heated to 110 ° C. with a hot plate and cast to a thickness of 203 μm. After casting, it was left on a hot plate for 5 minutes to evaporate the solvent, and then immersed in a water bath together with the glass plate to obtain a transparent film (being immersed in the water bath is for easy removal of the film from the glass plate. ).

This film was subjected to ATR measurement, and a calibration curve of the intensity ratio of (A _CO ) and (A _CC ) to the vinyl acetate unit quantity ratio was obtained.

The ATR measurement was performed on the inner surface of the hollow fiber membrane, and the internal vinyl acetate unit amount ratio was obtained from the intensity ratio of (A _CO ) and (A _CC ) using the above calibration curve.

In the case of polyacrylonitrile, a calibration curve was prepared with a film in the same manner as above for the ratio of the C≡N peak intensity (A _CN ) derived from the nitrile group near 2200 cm ⁻¹ and A _CO , The vinyl unit quantity ratio was determined.

(3) Measuring method of ester group distribution by 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 measurement was carried out with a visual field area (aperture) of 100 μm × 100 μm, the number of integrations being 30 times per point, and the aperture being moved by 3 μm, and a total of 25 points, 5 points each in length and width. 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 A derived from the benzene ring C═C of polysulfone. _CC . Similarly, a reference line was drawn at 1711 to 1759 cm ⁻¹ to obtain an infrared absorption peak area A _CO derived from the ester group C═O.

The above operation was performed on three different hollow fibers per module, and three different points were measured with the same hollow fiber, and the average value of (A _CO ) / (A _CC ) and a ratio of 0.001 or less were calculated. .

(4) Calculation of adsorption equilibrium constant The adsorption equilibrium constant was determined by surface plasmon resonance measurement. After fixing an Au sensor chip manufactured by GE Healthcare Bioscience Co., Ltd. to a spin coater, a 0.1 wt% chlorobenzene solution of polysulfone (Amoco Udel-P3500) or a 0.1 wt% dimethylsulfoxide solution of polyacrylonitrile Was dropped with a Pasteur pipette. Immediately after that, the Au sensor chip having a thin layer of polysulfone or polyacrylonitrile was prepared by spin drying at 3000 rpm for 1 minute. After inserting this sensor chip into BIACORE 3000 manufactured by GE Healthcare Biosciences, and washing the sensor chip with water for 2000 seconds, the following operations were carried out with various polymer aqueous solutions having respective concentrations of 5, 10, 50, 100, 500, and 1000 ppm. Repeated.
1. Various polymer aqueous solutions were flowed at 750 μL at 20 μL / min and adsorbed on the polysulfone surface or polyacrylonitrile.
2. Washed with water for 2000 seconds.
3. 750 μL of 0.025 wt% Triton was flowed at 20 μL / min, and the adsorbed various polymers were peeled off.
4. Washed with water for 2000 seconds.

The amount adsorbed on the surface of polysulfone or polyacrylonitrile was set to 0 after washing with water for 2000 seconds immediately after the insertion of the sensor chip, and the difference at the time when each operation 2 was completed. In addition, when it becomes higher than the value after performing water washing immediately after the insertion of the sensor chip at the time when the operation 4 is completed, it is considered that various polymers are not completely peeled off by 0.025 wt% triton, and the increment is It added to the amount of adsorption. The above operation was repeated at 5 to 1000 ppm. From the adsorption isotherm obtained as described above (the horizontal axis represents the concentration of various polymers and the vertical axis represents the adsorption amount), a general solution adsorption model (Freund's) on the polymer and its adsorption surface was obtained. The adsorption equilibrium constant was calculated by applying the least square method using (Rich equation approximation) (Equation 1).
Q = KC ⁿ (Formula 1)
(Q: adsorption amount per unit area, K: adsorption equilibrium constant, n: Freundlich constant).

(5) Measurement of water content of insoluble component The dried hollow fiber membrane was stirred and dissolved in dimethylacetamide for 5 hours or more so as to be 2 g / vol%. The insoluble component was filtered with a filter paper (“Advantech” (registered trademark) No. 7 manufactured by Toyo Filter Paper Co., Ltd.), and then the soluble component was sufficiently washed with dimethylacetamide. The insoluble component (gel-like material) was collected in the centrifuge tube, and after further stirring with dimethylacetamide, the gel was sedimented by centrifugation and the supernatant was removed three times or more. Thereafter, after removing the supernatant, pure water was added, and after sufficiently stirring, the gel was settled by centrifugation, and the supernatant was removed five times to replace dimethylacetamide with pure water. Excess water was taken out and the weight (w) containing water was measured. The obtained hydrogel was freeze-dried for 24 hours or more, and after complete drying, the weight (d) was measured. The water content was calculated by the following formula.
Water content (%) = (w−d) × 100 / w.

(6) 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 inside of this 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 solution 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 wt% 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.

As a material having good antithrombogenicity, the platelet adhesion number is 40 (pieces / 4.3 × 10 ³ μm ² ) or less, further 20 (pieces / 4.3 × 10 ³ μm ² ) or less, preferably 10 ( Pieces / 4.3 × 10 ³ μm ² ) or less.

(7) Measurement of relative adhesion rate of fibrinogen As protein adhesion to the hollow fiber membrane, the relative adsorption rate of fibrinogen, which is one of coagulation proteins, was measured.

  A plastic tube mini-module having an effective length of 100 mm, in which 36 hollow fiber membranes were passed through a plastic tube and both ends were fixed with an adhesive, was thoroughly washed with pure water.

  Next, after collecting human venous blood, citric acid was added to 10% by volume immediately. The blood was centrifuged at 3000 rpm for 15 minutes at 4 ° C. to obtain plasma.

1 mL of plasma was circulated at a flow rate of 0.5 mL / min for 2 hours. A hollow fiber was cut out from a mini module in an amount corresponding to 24 cm, cut into a length of about 1 mm, and placed in an Eppendorf tube. It was washed with a phosphate buffer (hereinafter abbreviated as PBS) (1 mL × 3 times, repeated if blood remained). Tween-20 (Katayama Chemical) was adjusted to 0.05 wt% with PBS (hereinafter abbreviated as PBS-T). Skimmed milk was dissolved in PBS-T so that it might become 0.1 weight%, and it wash | cleaned 3 times with this solution. The anti-human fibrinogen (HPR) antibody was diluted 10,000 times with a 0.1% by weight skim milk / PBS-T solution, added with 1 mL, and then rotated and stirred at room temperature for 2 hours with a rotator. After washing twice with 0.1 wt% skim milk / PBS-T solution, it was washed twice with 0.1 wt% skim milk / PBS solution. 1 mL of TMB one solution was added and stirred with a micromixer. The reaction was stopped by adding 200 μL of 6N hydrochloric acid in view of the color development (the reaction was controlled so that the absorbance of the control described later falls within the range of 1 to 1.5). Absorbance at 450 nm was measured. As a control, Toray's artificial kidney “Tresulfone” TS-1.6UL was used. From the absorbance (Ac) of the control and the absorbance (As) of the target sample, the relative adhesion amount of fibrinogen was determined by the following formula.
Fibrinogen relative adhesion rate (%) = As / Ac × 100.

(8) Measurement of time-dependent change in albumin sieving coefficient (Sc-Alb) The time-dependent change in albumin sieving coefficient (Sc-Alb) was measured as an indicator of the stability of the membrane performance over time when the hollow fiber membrane was used. Albumin is one of the proteins useful for the living body, and in recent hollow fiber membrane modules, excessive penetration of albumin with the increase in the pore size of the membrane to remove uremic protein (also called low molecular weight protein). Alternatively, a fractionation property that allows a low molecular weight protein having a smaller molecular weight to permeate while suppressing loss is required, and the sieving coefficient of albumin is a representative index for measuring the separation performance of a membrane. That is, by measuring the change over time in the albumin sieving coefficient, the stability over time of the performance of the hollow fiber membrane module can be known.

  The change with time of the albumin sieving coefficient was carried out as follows. The bovine blood to which sodium citrate was added was adjusted to a hematocrit of 30%, a total protein concentration of 6.5 g / dl, and 37 ° C., and set in a circuit 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. 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 16 ml / (min · m ² ). The Bi circuit inlet is put into the beaker for circulating 2L (37 ° C) of the bovine blood prepared as described above, the Bi pump is started, the liquid discharged from the Bo circuit outlet is discarded for 90 seconds, and then immediately Bo The circuit outlet part and the Do circuit outlet part were put in a circulation beaker to be in a circulation state.

Subsequently, the Di pump of the dialyzer was started at 500 (ml), and sampling was performed from Bi, Bo, and Do over time.
The albumin concentration for each elapsed time was measured, and the albumin sieving coefficient for each elapsed time was calculated by the following formula. 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.

Sc-Alb (%) = CDo / (CBi + CBo)
In the above formula, CDo = albumin concentration at the outlet of the Do circuit (g / ml), CBo = albumin concentration at the outlet of the Bo circuit (g / ml), CBi = albumin concentration at the inlet of the Bi circuit (g / ml)
(9) Method of measuring crimp wave height and wavelength A hollow fiber membrane was taken out from a hollow fiber membrane bundle of 200 mm or more incorporated in a module case so as not to apply a tension that would change the crimp shape during extraction. Take 10 pieces randomly from the hollow fiber membranes taken out, place any part 18cm on the black paper so that the wave height is the largest, and take care not to apply tension. (Within 0.5 cm from the top) with tape, as shown in Fig. 5, connect one line at any position from the top to the top of the next peak with a line, measure the length, and measure the wavelength. It was.
The wave height was defined as a distance between two adjacent valleys at an arbitrary position by a straight line and a peak between the peaks between the two valleys and a straight line drawn from the peaks.
This measurement was performed on the ten hollow fiber membranes taken out, and an average value was taken. The average value is expressed in millimeters, and the second decimal place of the average value is rounded off, and the values up to the first decimal place are the wave height and wavelength, respectively.
(10) β ₂ -microglobulin (β ₂ -MG) clearance 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 by the following formula from the concentration of β ₂ -microglobulin in each solution. 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
In the above formula, 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).
2. Production of hollow fiber membrane (1) Polysulfone / polyvinylpyrrolidone (PSf / PVP) mixed hollow fiber membrane 16 parts by weight of polysulfone (Amoco Udel-P3500), polyvinylpyrrolidone (International Special Products, hereinafter referred to as ISP) K30 3 weight 3 parts by weight of polyvinylpyrrolidone (ISP K90) was dissolved in 77 parts by weight of dimethylacetamide and 1 part by weight of water to prepare a stock solution.

  This stock solution is sent to a spinneret part at a temperature of 50 ° C., and 63 to 65 parts by weight of dimethylacetamide and 35 to 37 parts by weight of water are injected from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. The amount of the spinning solution and the hollow fiber internal coagulating solution was adjusted so that the hollow fiber membrane after drying had an outer diameter of 263 μm and an inner diameter of 185 μm. Then, after passing through a 350 mm dry zone atmosphere at a temperature of 30 ° C. and a dew point of 28 ° C., it is passed through a coagulation bath at a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water, and washed with water at 60 to 75 ° C. for 90 seconds. The hollow fiber membrane (hollow fiber membrane 1) was obtained by passing the process and the drying process at 130 ° C. for 2 minutes.

  The inner surface of the hollow fiber membrane, that is, the amount of the functional layer polyvinyl pyrrolidone was 23% by weight, and the amount of polyvinyl pyrrolidone in the membrane was calculated by elemental analysis and found to be 3.1% by weight.

(2) Polysulfone (PSf) hollow fiber membrane 18 parts by weight of polysulfone (Amoco Udel-P3500) was heated and dissolved in 80 to 81 parts of dimethylacetamide and 1-2 parts 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 It was allowed to pass through and passed through a water washing step of 60 ° C./90 seconds to obtain a hollow fiber membrane (hollow fiber membrane 2).

(3) Chloroacetamidomethylated polysulfone-containing hollow fiber membrane 17.5.3 g of a nitrobenzene solution of polysulfone (Amoco Udel-P3500) prepared to 7.13 wt% was cooled to 8 ° C. and separately stirred at −5 ° C. for 30 minutes. Then, 33 g of a 5.30 wt% sulfuric acid solution of N-methylol-2-chloroacetamide prepared was added and the reaction was carried out at 8 ° C. to obtain chloroacetamidomethylated polysulfone (chloroamide methyl group substitution degree 0.39). It was.

  Polysulfone (Amoco Udel-P3500) 18 parts by weight, chloroacetamidomethylated polysulfone 2 parts by weight, PVP (ISP) K30 10 parts by weight, dimethylacetamide 67 to 69 parts by weight, water 1 to 3 parts by weight were dissolved. A film forming stock solution was obtained.

  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 having a dry length of 300 mm having a temperature of 27 ° C. and a dew point of 11 ° C., the hollow fiber membrane is passed through a coagulation bath made of 100% by weight of water at a temperature of 40 ° C. (Hollow fiber membrane 3) was obtained.

(4) Examination of polymer addition to injection solution Polysulfone (Amoco Corporation Udel-P3500 (weight average molecular weight 47,000)) 18 parts by weight, polyvinylpyrrolidone (International Special Products, Inc .; hereinafter abbreviated as ISP), K30 9 weights in dimethyl 72 parts by weight of acetamide and 1 part by weight of water were dissolved by heating to obtain a stock solution.

  A solution of 63 to 65 parts by weight of dimethylacetamide and 35 to 37 parts by weight of water dissolves 10 parts by weight of a vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “Collidon VA64”) did.

  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. Through a 350 mm dry zone atmosphere at 30 ° C. and 28 ° C. dew point, passed through a coagulation bath at a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water, and washed with water at 60 to 75 ° C. for 90 seconds, 130 A hollow fiber membrane (hollow fiber membrane 4) was obtained after passing through a drying step at 2 ° C. for 2 minutes and a crimping step at 160 ° C.

Further, a hollow fiber membrane (hollow fiber membrane 5) was obtained in the same manner as described above using a solution having a composition in which Kollidon VA64 was not added to the injection solution.
3. Examination of Crimping Method As a method of crimping, A. A method of passing a hollow fiber membrane between two continuously rotating gears having meshing teeth; C. passing between the timing pulley and the timing belt; A method of passing between the uneven belts; Crimping was performed by running between a pair of rotating crimp rolls, and Crimp A, Crimp B, Crimp C, and Crimp D were obtained.
4). Creation of a hollow fiber membrane module A crimp is applied to the hollow fiber membranes 1 to 5, the case is filled with a hollow fiber membrane area of 1.6 m ² , and both ends of the hollow fiber membrane are end-cased by a potting material. The hollow fiber membrane module was made by opening the hollow fiber membranes at both ends by cutting a part of the end of the potting material.
5. Preparation of allylamine / vinyl acetate copolymer 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%.

For the following Examples 1 to 5 and Comparative Examples 1 to 4, a polysulfone / polyvinylpyrrolidone (PSf / PVP) mixed hollow fiber membrane (hollow fiber membrane 1) was used. The crimp was D.
Example 1
The obtained hollow fiber membrane was crimped using a crimp roll shown in FIG. In FIG. 4, a hollow fiber membrane was passed through a cylindrical crimping device having a diameter of 10 mm at room temperature to crimp the wave height to 0.3 mm and a wavelength of 8.0 mm, and then wound with a winder. In addition, in order to suppress yarn disturbance at the time of crimping, an electrostatic removing device (TCFB-OR-2000 manufactured by Kasuga Electric) was installed before and after the crimp roll. The obtained hollow fiber membrane yarn bundle of 200 mm or more is cut into a predetermined length and then put into a module case, both ends of the hollow fiber membrane yarn bundle are fixed with polyurethane resin, the end portion of the polyurethane resin is cut, and the inner surface area is cut. A 1.6 m ² hollow fiber membrane module was prepared (excluding the portion sealed with polyurethane resin). For the module, a 0.1% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “Collidon VA64”) from the blood side inlet (Bi) of the hollow fiber membrane module prepared above. 500 mL was passed through the blood side outlet (Bo). Next, by passing 500 mL from the blood side inlet (Bi) to the dialysate side inlet (Di), VA64 was accumulated on the inner surface of the hollow fiber membrane. The liquid temperature at this time was 30 degreeC, and the flow rate was 500 mL / min. In order to accumulate VA64 that has entered the hollow fiber membrane on the inner surface, the filling solution was pushed from the dialysate side to the blood side with 200 kPa compressed air. Thereafter, 200 kPa of compressed air is blown from one end of the blood side to the other end for 15 sec at a flow rate of 38 L / min to discharge the blood-side filling liquid, and further air is supplied at a maximum pressure of 200 kPa, a minimum pressure of 100 kPa, and a flow rate of 20 L / min. Was blown for 5 sec at a cycle of 1 time / sec, so that the aqueous solution was held only in the hollow fiber membrane. Further, each of the dialysate 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 entire module was irradiated with 25 kGy of γ rays to be immobilized on the membrane. Thereafter, the module was subjected to a Sc-Alb aging test. For other tests, the hollow fiber in the module was cut out and tested. The ester group-derived carbon amount was measured twice under the same conditions. The results are shown in Table 1. In other words, Sc-Alb was stable over time by being able to localize VA64 uniformly and in a large amount on the surface of the functional layer and improving the flow in the module by crimping. In addition, the adsorption equilibrium constant has shown the result of the polysulfone film and Kollidon VA64.
When the crimp shape of the hollow fiber membrane taken out from the hollow fiber membrane module was measured, the wave height was 0.3 mm and the wavelength was 8.0 mm.
(Example 2)
The same operation as in Example 1 was performed except that crimping was performed so that the wave height was 0.3 mm and the wavelength was 10.0 mm through a crimping device. The results are shown in Table 1. That is, the VA64 can be uniformly and many localized on the surface of the functional layer, and by improving the flow in the module by crimping, the stability of Sc-Alb with time was high. In addition, the adsorption equilibrium constant has shown the result of the polysulfone film and Kollidon VA64. In other words, Sc-Alb was stable over time by being able to localize VA64 uniformly and in a large amount on the surface of the functional layer and improving the flow in the module by crimping. In addition, the adsorption equilibrium constant has shown the result of the polysulfone film and Kollidon VA64.
(Example 3)
The same operation as in Example 1 was performed except that crimping was performed so that the wave height was 0.3 mm and the wavelength was 5.0 mm through a crimping device. The results are shown in Table 1. That is, the VA64 can be uniformly and many localized on the surface of the functional layer, and by improving the flow in the module by crimping, the stability of Sc-Alb with time was high. In addition, the adsorption equilibrium constant has shown the result of the polysulfone film and Kollidon VA64.
Example 4
The same operation as in Example 1 was performed except that crimping was performed so that the wave height was 0.5 mm and the wavelength was 8.0 mm through a crimping device. The results are shown in Table 1. That is, the VA64 can be uniformly and many localized on the surface of the functional layer, and by improving the flow in the module by crimping, the stability of Sc-Alb with time was high. In addition, the adsorption equilibrium constant has shown the result of the polysulfone film and Kollidon VA64.
(Example 5)
The same operation as in Example 1 was performed, except that crimping was performed so that the wave height was 0.1 mm and the wavelength was 8.0 mm through a crimping device. The results are shown in Table 1. That is, the VA64 can be uniformly and many localized on the surface of the functional layer, and by improving the flow in the module by crimping, the stability of Sc-Alb with time was high. In addition, the adsorption equilibrium constant has shown the result of the polysulfone film and Kollidon VA64.
(Comparative Example 1)
The same operation as in Example 1 was performed except that crimping was performed so that the wave height was 8.0 mm and the wavelength was 32.0 mm through a crimping device. The same operation as in Example 1 was performed. In addition, about the measurement of ester group origin carbon content, it performed twice on the same conditions. The results are shown in Table 1. That is, Sc-Alb 5 to 10 minutes after the start of blood introduction was 1.50%, and 0.51% after 60 to 240 minutes, and the Sc-Alb was a hollow fiber membrane module with low stability over time. .
(Comparative Example 2)
The same operation as in Example 1 was performed except that water was used. In addition, about the measurement of ester group origin carbon content, it performed twice on the same conditions. The results are shown in Table 1. It is a surface to which platelets and fibrinogen adhere well, and Sc-Alb is 1.53% 5 to 10 minutes after the start of blood transduction, and 0.48% after 60 to 240 minutes. It was a hollow fiber membrane module with low stability.
(Comparative Example 3)
As in Example 1, a 0.1% by weight aqueous solution of PVA (molecular weight 10,000, saponification degree 80%) was added to the hollow fiber membrane module crimped to the blood side outlet from the blood side inlet (Bi) of the hollow fiber membrane module. (Bo), and then passed through the dialysate side inlet (Di) from the dialysate side outlet (Do) in one pass at a flow rate of 200 mL / min for 30 minutes. Thereafter, in the same manner as in Example 1, blowing, nitrogen substitution, and γ-ray irradiation were performed. The results are shown in Table 1. That is, Sc-Alb was 0.1% or less because a large amount of PVA was present including the pores of the film thickness by allowing the liquid to flow uniformly inside and outside the hollow fiber membrane.
(Comparative Example 4)
In the same manner as in Example 1, crimped hollow fiber membrane module was charged with 0.1% by weight of polyvinyl acetate 60% by weight methanol aqueous solution from the dialysate side outlet (Do) of the hollow fiber membrane module to the blood side outlet (Bo). 500 mL was passed through. Next, 500 mL was passed from the blood side inlet (Bi) to the blood side outlet (Bo). Then, after replacing methanol with water by the same operation as above using pure water, blow, nitrogen substitution, and γ-ray irradiation were performed in the same manner as in Example 1. The results are shown in Table 1. That is, since a large amount of polyvinyl acetate is also present on the opposite side of the functional layer, Sc-Alb was 0.1% or less.

1 Hollow fiber membrane 2 Case 3 Potting agent 4 Blood side inlet (Bi)
5 Blood side outlet (Bo)
6 Dialysate side inlet (Di)
7 Dialysate side outlet (Do)
8 Reference line 9 Dialysis device 10 Hollow fiber membrane module 11 Bi pump 12 F pump 13 Disposal container 14 Blood for circulation 15 Blood for clearance measurement 16 Bi circuit 17 Bo circuit 18 Di circuit 19 Do circuit 20 Hot water tank 21. 21. Hollow fiber to which crimp is applied Crimp wavelength 23. Crimp wave height

Claims (7)

The peak area percentage of the carbon derived from the ester group by X-ray electron spectroscopy (ESCA) on the surface of the incorporated polysulfone-based hollow fiber membrane is 0.5 (atomic%) or more and 10 (atomic%) or less, and The hydrophobic unit amount ratio existing on the membrane surface is 30% or more larger than the hydrophobic unit amount ratio existing inside the membrane, and the built-in hollow fiber membrane has a wave height of 0.1 to 0.5 mm and a wavelength of 5.0 to 10.0 mm. A hollow fiber membrane module characterized by having a crimp structure of 2. The hollow fiber membrane module according to claim 1, wherein the peak area percentage of carbon derived from ester groups by ESCA on the opposite surface of the functional layer is 10 (number of atoms) or less. The hollow fiber membrane module according to claim 1 or 2, wherein the polymer containing an ester group is polyvinyl acetate or a copolymer of vinyl acetate and vinyl pyrrolidone. The average sieving coefficient of albumin after 5 to 10 minutes when bovine blood at 37 ° C. with hematocrit 30%, total protein concentration 6 to 7 g / dl and sodium citrate was added at 200 ml / minute and filtration flow rate 16 ml / minute The hollow fiber membrane module according to any one of claims 1 to 3, wherein the value [A] and the sieving coefficient [B] of albumin after 60 to 240 minutes satisfy the following relational expression.
[B] / [A] = 0.5-1.0 The hollow fiber membrane module according to claim 2, wherein when the bovine blood is flowed under the condition according to claim 4, an albumin sieving coefficient after 60 minutes from the beginning of the flow is 0.1 to 3.2%. The hollow fiber membrane module according to claim 1, the inner diameter of the built-in hollow fiber membrane 150～250Um, membrane area is characterized by a 1.0~3.0m ^2. The hollow fiber membrane module according to any one of claims 1 to 6, which is used as an artificial kidney.

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