JP2011092928A - Separation membrane and separation membrane module - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a separation membrane module of high water permeability and high performance, which hardly allows an organic substance, protein, platelet or the like to adhere to itself. <P>SOLUTION: This is a polysulfone-based separation membrane which includes a polysulfone-based polymer and a hydrophilic polymer and also includes in itself a component which is insoluble in N,N-dimethyl acetamide, wherein (a) the concentration of the polysulfone-based polymer in the insoluble component is at least 10 wt.% and at most 50 wt.%, (b) the water content of the insoluble component is at least 95 wt.%, and (c) a flexible layer, which is at least 7 nm in thickness, exists on the surface of the functional layer of the separation membrane of wet state. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a separation membrane and a separation membrane module, and is suitably used for applications that require blood compatibility, non-adhesion of proteins and organic substances, and require a small amount of eluate. For example, separation membranes for blood purification require blood compatibility and non-adhesion of proteins, while membranes for water purifiers, water purification membranes, sewage purification membranes, reverse osmosis membranes, membranes for biological component separation, etc. Non-adhesion is required. Therefore, the separation membrane and the separation membrane module of the present invention are preferably used in such fields. In particular, blood purification applications such as artificial kidneys are preferably used because they require less adhesion of blood components to the membrane and less eluate.

  Examples of the material of the separation membrane include cellulose, which is a natural material, and cellulose diacetate, cellulose triacetate, polyacrylonitrile, polymethyl methacrylate, and polysulfone-based polymers, which are derivatives thereof. Due to its high nature, it is particularly suitably used in water treatment membranes for water purifiers and medical separation membranes such as artificial kidneys used in dialysis treatment. As dialysis treatment, hemodiafiltration (HDF) and push-and-pull methods have been developed to improve dialysis efficiency and aggressive removal of low molecular weight proteins. Among membrane materials, polysulfone with high water permeability is used. Widely used as a dialysis technique.

  On the other hand, medical separation membranes that come into contact with body fluids or blood become serious problems when proteins, particularly coagulation proteins such as fibrinogen, adhere to the membrane, causing degradation of the performance of the separation membrane and 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, there is disclosed 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 to form the membrane (Patent Document 1). However, in these methods, in order to impart hydrophilicity to the surface, it is necessary to increase the amount of hydrophilic polymer in the film-forming stock solution. However, when the amount of the hydrophilic polymer is increased, elution of the hydrophilic polymer from the membrane becomes a problem. Therefore, a method in which a hydrophilic polymer is crosslinked and fixed in a polysulfone membrane by heat treatment or radiation treatment (Patent Document 2), or a hollow fiber membrane in which a hydrophilic polymer is crosslinked and exists in a polysulfone membrane structure in a hydrogel state (Patent Document 3). Is disclosed. However, simple crosslinking of the hydrophilic polymer does not completely solve the elution problem, and insolubilization of the hydrophilic polymer activates platelets and causes platelet adhesion to the material surface. It was.

  In order to solve the problem of achieving both the reduction of the elution of the hydrophilic polymer and the suppression of the adhesion of platelets, a membrane in which the crosslinking of the hydrophilic polymer is optimized is disclosed (Patent Documents 4 and 5). However, as a result of investigations by the present inventors, it has been found that even though adhesion of platelets and the like can be suppressed in these films, adhesion at the protein level cannot be suppressed.

That is, the present situation is that a membrane that suppresses the elution of the hydrophilic polymer and also suppresses the adsorption at the protein level has not yet been established.
Japanese Patent Publication No. 2-18695 Japanese Patent Publication No. 5-3331 Japanese Patent Laid-Open No. 4-300636 JP 9-323031 A JP 2003-201383 A

  The object of the present invention is to improve the drawbacks of the prior art, reduce the amount of eluate from the membrane, reduce the adhesion of proteins and the like for blood treatment applications, and remove organic substances such as sludge and humic substances for water treatment applications. The object is to provide a high-performance separation membrane module with little adhesion.

As a result of diligent studies to achieve the above-mentioned problems, the present inventors have found that a separation membrane module having a high water permeability is low in the amount of eluate from the membrane, excellent in blood compatibility, less attached to proteins and organic substances, and highly permeable. 1 to 7 are achieved.
1. A polysulfone separation membrane comprising a polysulfone polymer and a hydrophilic polymer, wherein the separation membrane contains a component insoluble in N, N-dimethylacetamide,
(B) The polysulfone polymer concentration in the insoluble component is 10% by weight or more and 50% by weight or less. (B) The water content of the insoluble component is 95% by weight or more. (C) Flexible on the functional layer surface of the separation membrane in a wet state. A polysulfone separation membrane having a layer and a thickness of 7 nm or more.
2. The hydrophilic polymer is composed of at least one hydrophilic homopolymer and at least one hydrophilic copolymer, and the hydrophilic homopolymer exists over the thickness direction of the separation membrane, while the hydrophilic copolymer is present. Is present only on the surface of the functional layer of the separation membrane.
3. The hydrophilic homopolymer contains at least one selected from polyvinyl pyrrolidone, polyalkylene glycol, polyvinyl acetate, and polyvinyl caprolactam, and the hydrophilic copolymer is a vinyl pyrrolidone / vinyl acetate copolymer, vinyl pyrrolidone. -Contains at least one selected from vinyl caprolactam copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, vinyl pyrrolidone / styrene copolymer, vinyl pyrrolidone / hydroxyethyl methacrylate copolymer, vinyl pyrrolidone / methyl methacrylate copolymer 3. The polysulfone-based separation membrane as described in 2 above, wherein
4). 4. The polysulfone according to any one of 1 to 3, wherein an ester group is present on the surface of the functional layer of the separation membrane, and the amount of carbon derived from the ester group is 0.3 (number of atoms) or more. System separation membrane.
5. 5. The polysulfone separation membrane according to any one of 2 to 4 above, wherein the hydrophilic copolymer is a vinylpyrrolidone / vinyl acetate copolymer, and the concentration of the functional layer surface is 10% by weight or more. .
6). 6. The separation membrane according to any one of 1 to 5 above, which is for blood purification.
7). A separation membrane module comprising the separation membrane according to any one of 1 to 6 above.

  The separation membrane and the separation membrane module in the present invention can be widely used for applications requiring a high-performance separation membrane with less eluate from the membrane and less adhesion of proteins, platelets and organic substances.

1 shows an embodiment of an artificial kidney used in the present invention. Relationship curve between force applied to cantilever and displacement of cantilever in force curve measurement using atomic force microscope beta ₂ - shows a circuit in microglobulin clearance measurement.

  In the present invention, it is an object of the separation membrane composed of a polysulfone-based polymer and a hydrophilic polymer to suppress high separation membrane performance and elution from the separation membrane while suppressing adhesion from platelets to proteins.

  In order to prevent the elution of the hydrophilic polymer, it is effective that the hydrophilic polymer has a gel structure. However, first of all, it is important that the hydrophilic polymer is crosslinked with the polysulfone-based polymer. did. Here, N, N-dimethylacetamide (hereinafter referred to as DMAc) is a solvent that dissolves both the polysulfone polymer and the hydrophilic polymer, but the hydrophilic polymer having a gel structure or the hydrophilic polymer and the polysulfone polymer are crosslinked. Those that take the structure are insoluble. Therefore, in the present invention, it is required that the polysulfone-based polymer is contained in a component insoluble in DMAc in an amount of 10% by weight or more, preferably 20% by weight or more. However, if the amount of the polysulfone polymer in the insoluble component is too large, protein adhesion occurs. Therefore, the amount of the polysulfone polymer in the insoluble component is 50% by weight or less, preferably 40% by weight or less. Further, the weight ratio of the components insoluble in DMAc is preferably 60% by weight or more, more preferably 70% by weight or more of the total hydrophilic polymer weight.

  The polysulfone polymer concentration in the insoluble component is determined as follows. The dried separation membrane is dissolved in DMAc to a concentration of 2.5% by weight, and the solution is filtered with a filter paper to obtain an insoluble component. Rinse well with DMAc to wash the attached polysulfone polymer. Then rinse with water to wash the DMAc. The insoluble component is taken out, and the polysulfone polymer concentration in the insoluble component can be calculated by elemental analysis.

  Next, in the present invention, in order to suppress not only adhesion of blood cell components such as platelets but also adhesion of proteins, particularly coagulation proteins, the water content and wetness in insoluble components containing 10% by weight or more of such polysulfone-based polymers. It was found that the “soft layer” on the functional layer surface of the separation membrane in the state is important. The wet state here refers to a state where the water content of the separation membrane (water weight / (dry separation membrane weight + water weight)) is 65% by weight or more.

  The reason why the water content of the insoluble component is important will be described below from the viewpoint of the activity characteristics of the protein. That is, the protein in the blood is water-soluble, and when it comes into contact with a hydrophobic polysulfone polymer, it causes adsorption or denaturation or causes activation. Here, since platelets are about 3 μm in size, they do not pass through the separation membrane or enter the membrane, whereas in the case of proteins, they do not pass through the separation membrane, depending on their size. A very small amount may enter the inside of the separation membrane. Even in a very small amount, proteins involved in coagulation and inflammation greatly affect blood activity. The component soluble in DMAc in the hollow fiber membrane has a high water content, so that there is little possibility of causing the above-described activation even when it comes into contact with the protein. However, since the water content of the insoluble component is generally low, there is a risk of blood activation when the protein comes into contact with the polysulfone polymer in the insoluble component. Therefore, it is important that the water content in the insoluble component is high, and it is preferably 95% by weight or more, more preferably 97% by weight or more. That is, when focusing on the adhesion of such proteins, not only the hydrophilic polymer on the surface of the separation membrane functional layer but also the pores of the membrane, so that the entire membrane is hydrophilic, There is a need to control all the states of the functional polymer. However, if the water content is too high, the number of cross-linking points with the polysulfone-based polymer decreases, so that it is preferably 99.5% by weight or less, more preferably 99% by weight or less.

  About the water content of an insoluble component, it calculates | requires as follows. The dried separation membrane was dissolved in DMAc to a concentration of 2% by weight. The solution is filtered using filter paper to obtain insoluble components. After thoroughly washing the soluble component with DMAc, the insoluble component is replaced with water. Excess water is removed, and the weight (w) of the insoluble component in a water-containing state is measured. Then, the weight (d) of the insoluble component after sufficiently drying is measured. The water content is calculated by equation (1).

Water content (%) = (w−d) × 100 / w (1)
As a method for insolubilizing the hydrophilic polymer in the film, a crosslinking agent may be added or high energy such as radiation or heating may be applied to the hydrophilic polymer to cause a crosslinking reaction to cause gelation. In the method of adding a crosslinking agent, film physical properties are greatly affected by the type and amount of the crosslinking agent, and therefore, radiation crosslinking and thermal crosslinking that do not require the addition of a crosslinking agent are preferred. Therefore, as the hydrophilic polymer, a polymer that is easily cross-linked to radiation is preferably used. Furthermore, when a hydrophilic polymer is blended with a film forming stock solution with a polysulfone polymer, compatibility with the polysulfone polymer is also important.

  The hydrophilic polymer referred to in the present invention refers to a polymer containing a hydrophilic group, and refers to a polymer that is soluble in water or ethanol. This refers to those that dissolve 0.1 g or more with respect to water at 20 ° C. or 100 g of ethanol. The hydrophilic polymer can be further classified into a hydrophilic homopolymer and a hydrophilic copolymer.

  Examples of the hydrophilic homopolymer include polyvinyl pyrrolidone, polyalkylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinyl caprolactam, polyethyleneimine, and polyacrylic acid. The hydrophilic copolymer includes vinyl pyrrolidone / vinyl acetate copolymer, vinyl pyrrolidone / vinyl caprolactam copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, vinyl pyrrolidone / styrene copolymer, vinyl pyrrolidone / hydroxyethyl. Examples thereof include a methacrylate copolymer and a vinyl pyrrolidone / methyl methacrylate copolymer. Of these, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, and vinylpyrrolidone / vinylcaprolactam copolymer are preferably used from the viewpoint of compatibility with the polysulfone polymer.

Furthermore, the crosslinking reaction hardly occurs between the polysulfone-based polymers due to radiation. On the other hand, since a polysulfone polymer, a vinylpyrrolidone unit, and a polyalkylene glycol unit easily undergo radiation crosslinking, a hydrophilic homopolymer or hydrophilic copolymer containing these units is preferably used. Since the cross-linking reaction at this time is a radical reaction, a part of the cross-linking with the polysulfone-based polymer occurs, and the elution of the hydrophilic polymer can be greatly reduced by this cross-linking.
Next, the reason why the flexible layer is important on the surface of the functional layer of the separation membrane in a wet state can be estimated as follows. Large components such as platelets and blood cells do not enter the separation membrane and come into contact with the functional layer surface. For this reason, it is considered that the thicker the flexible layer, the more difficult the platelets and blood cells are to approach the polysulfone-based polymer, and no adhesion or activation occurs. On the other hand, if the flexible layer is too thick, proteins may be trapped in the flexible layer. From the above, the thickness of the flexible layer is 5 nm or more, preferably 7 nm or more. Moreover, 30 nm or less, Preferably it is 20 nm or less, Furthermore, 15 nm or less is preferable.

  The flexible layer on the surface of the separation membrane functional layer in the wet state is calculated from force curve measurement using an atomic force microscope. The force curve is represented by the amount of displacement of the cantilever on the horizontal axis when the vertical axis is the force applied to the cantilever. Until the short hand of the cantilever contacts the surface of the functional layer, the force curve changes parallel to the x-axis. If there is a flexible layer after the cantilever contacts the surface of the functional layer, a curved non-linear part appears. Thereafter, a linear linear correlation is obtained between the displacement of the cantilever and the force. The flexible layer consists of the intersection of the extension of the straight line after the short hand of the cantilever contacts the surface, the intersection of the extension of the line that has moved parallel to the x-axis before the short hand of the cantilever contacts the surface, and the cantilever The distance to the point where the short hand contacts the surface (FIG. 2).

  In order to control the weight ratio of insoluble components, polysulfone polymer concentration of insoluble components, moisture content of insoluble components, surface soft layer of functional layer, create separation membrane with uniform dispersion of hydrophilic polymer and polysulfone polymer It is necessary to. If the hydrophilic polymer is present non-uniformly, the crosslinking reaction proceeds with the agglomerated portion of the hydrophilic polymer as a nucleus, and the water content of the insoluble component decreases. Furthermore, the cross-linking reaction between the hydrophilic polymer and the polysulfone-based polymer hardly occurs. Details of conditions for creating a separation membrane in which the dispersion state of the hydrophilic polymer and the polysulfone-based polymer is uniform will be described later.

  Further, in order to increase the thickness of the flexible layer on the surface of the functional layer of the separation membrane, it is preferable to increase the amount of the hydrophilic polymer, but if it is excessively increased, the elution of the hydrophilic polymer will increase. For this reason, it is preferable that a large amount of the hydrophilic polymer is disposed on the surface of the functional layer and a small amount is disposed on the surface opposite to the functional layer. However, the hydrophilic polymer needs to exist over the thickness direction of the film. When the polysulfone-based polymer is exposed even in the thickness portion of the membrane, in addition to not being able to effectively suppress protein adsorption, the water permeability becomes low due to the increase in hydrophobicity. In such a membrane, the water content of insoluble components tends to be low. When comparing the amount of hydrophilic polymer on the functional layer surface and the opposite surface, it is appropriate to perform total reflection infrared absorbance measurement (ATR) that can detect a certain depth. The detection depth of ATR is said to be about 1-2 μm.

The water permeability of the separation membrane is preferably 200 mL / hr / m ² / mmHg or more, more preferably 300 mL / hr / m ² / mmHg or more, and further preferably 400 mL / hr / m ² / mmHg or more. If it is too high, internal filtration is likely to occur, and the solute removal performance is improved. However, in the case of blood treatment, since the stimulation given to the blood cells also increases, 2000 mL / hr / m ² / mmHg or less is preferable, and more preferable. Is preferably 1500 mL / hr / m ² / mmHg or less, more preferably 1000 mL / hr / m ² / mmHg or less. The water permeability (UFR) is calculated by the following formula.

UFR (mL / hr / m ² / mmHg) = Q _w / (P × T × A)
Here, Q _w : filtration amount (mL), T: outflow time (hr), P: pressure (mmHg), A: inner surface area of hollow fiber membrane (m ² )
Moreover, in the separation membrane module of the present invention, the difference between the measured value in the aqueous system of urea clearance of 1.6 m ² converted value and the measured value in the bovine plasma system is preferably within 5 mL / min, more preferably It is within 2 mL / min. This can be achieved by reducing the adhesion of the protein to the film up to the level defined in the present invention. A large difference between the solute removal performance of the aqueous system and the solute removal performance of the blood system means that the performance of the membrane over time is great when used in the blood system. Furthermore, the permeation resistance of the membrane is greatly different between the aqueous system and the blood system, and in the case of such a membrane, it is considered that the stimulation given to the blood cells is also large.

Here, in the above measurement, it is preferable to use a separation membrane module having a total membrane area of 1.6 m ^{2. When} it is difficult to produce a separation membrane module of 1.6 m ² , separation of membrane areas as close as possible is possible. It is also possible to measure the clearance with a membrane module and convert it to 1.6 m ² from the overall mass transfer coefficient. The total membrane area is the surface area of the separation membrane in contact with the treatment liquid, and corresponds to the surface area in the hollow fiber in the case of a hollow fiber membrane type artificial kidney.

  The method for measuring aqueous urea clearance is based on the dialyzer performance evaluation criteria edited by the Japanese Society for Artificial Organs published in September 1982. Among these, there are two measurement methods, but this experiment is based on TMP 0 mmHg.

The details of the measurement method for bovine plasma system urea clearance will be described later in Examples. In the case of an artificial kidney, the blood flow rate is 200 mL / min, the dialysate flow rate is 500 mL / min, and the filtration flow rate is 10 mL / min / m. Condition ² is assumed. The total protein concentration is 6.5 ± 0.5 g / dL, and the urea concentration is 1 g / L.

  From the viewpoint of removal performance, the value of the aqueous urea clearance is preferably 180 mL / min or more, more preferably 190 mL / min or more, and further preferably 195 mL / min or more.

Furthermore, in the separation membrane module of the present invention, with respect to β2-microglobulin (β ₂ -MG) clearance using bovine plasma converted to 1.6 m ² , the blood side flow rate is 400 mL / min and the blood side flow rate is 200 mL / min. It is preferably 1.05 times or more of the clearance of min, more preferably 1.1 times or more.

  In the field of hemodialysis treatment of chronic renal failure, Western patients are generally large in size and are often treated at a higher flow rate than the blood flow rate of 200 mL / min. Also in Japan, in recent years, there have been increasing cases where the blood flow rate is increased, so that a separation membrane module for hemodialysis suitable for high flow rates is desired. In general, when the blood flow rate increases, the clearance increases linearly and then gradually decreases, and then takes a constant value. This is because, as the blood flow rate increases, the solute removal capability of the separation membrane also increases, but the limit is reached where the amount of solute removal determined by the performance of the dialyzer is reached. In the present invention, it is possible to improve the solute removal ability of the separation membrane by performing the gel cross-linking structure in the separation membrane and the suppression of protein adhesion.

Details of the method for measuring β ₂ -MG clearance will be described later. In the case of an artificial kidney, the blood flow rate is 200 mL / min, the dialysate flow rate is 500 mL / min, and the filtration flow rate is 10 mL / min / m ² . To do. The total protein concentration is 6.5 ± 0.5 g / dL, and the β ₂ -MG concentration is 1 mg / L.

From the viewpoint of removal performance, the β ₂ -MG clearance value is preferably 50 mL / min or more, more preferably 60 mL / min or more, and further preferably 70 mL / min or more at a blood flow rate of 200 mL / min.

  Furthermore, from the viewpoints of polysulfone polymer concentration of insoluble component, moisture content of insoluble component, water permeability of separation membrane, measured value of hydrophilic polymer concentration on the surface exposed by cutting any thickness direction of separation membrane Is preferably 1.5 times or more, more preferably 2 times or more higher than the measured value of the hydrophilic polymer concentration of the entire separation membrane. Usually, the hydrophilic polymer concentration on the surface exposed by cutting in the thickness direction of the separation membrane should practically show substantially the same value as the hydrophilic polymer of the entire separation membrane. However, when the separation membrane has a structure in which fine particles having polysulfone as a core are connected and the surface of the fine particles is uniformly covered with a hydrophilic polymer, that is, dispersion of the hydrophilic polymer and the polysulfone-based polymer. The above phenomenon occurs when the state uniformity is high. When cutting, it is considered that the weak part of the structure, that is, the part where the fine particles adhere to each other and the connecting part between the fine particles are peeled off. It is assumed that the measured value of the hydrophilic polymer concentration on the surface exposed by cutting an arbitrary thickness direction of the separation membrane is apparently higher than the measured value of the hydrophilic polymer concentration of the entire separation membrane. It is done.

  Here, since the hydrophilic polymer concentration on the cut surface is such that it covers fine particles, it is appropriate to perform X-ray electron spectroscopy measurement (hereinafter referred to as XPS) capable of detecting the extreme surface layer. In the case of XPS, the detection depth is said to be about 10 nm. Further, the value obtained by elemental analysis is used for the hydrophilic polymer concentration of the entire separation membrane. The hydrophilic polymer concentration on the surface of the functional layer obtained by XPS measurement is 20% by weight or more, preferably 25% by weight or more, and more preferably 30% by weight or more.

  As described above, as factors affecting the dispersion state of the polymer in the separation membrane and the separation membrane structure, the state of the membrane forming stock solution and the phase separation formation process are important. Specifically, the composition of the membrane forming stock solution, the chemical structural formula and molecular weight of the polysulfone polymer, the chemical structural formula and molecular weight of the hydrophilic polymer, the stirring speed and stirring time and the dissolution temperature of the membrane forming stock solution, and the film forming stock solution were dissolved. Thereafter, the time until film formation, the temperature and humidity of the discharge unit, and the like can be mentioned.

  For example, the concentration of the polysulfone-based polymer is 14 to 25% by weight, preferably 15 to 20% by weight, and the hydrophilic polymer is 2 to 10% by weight, preferably 3 to 9% by weight, as the membrane forming stock solution. The ratio of the hydrophilic polymer weight to the total polymer weight of the film-forming stock solution is 0.15 to 0.35 times, preferably 0.2 to 0.3 times. The polysulfone polymer molecular weight is preferably 30,000 or more, and the ratio of the hydrophilic polymer molecular weight to the polysulfone polymer molecular weight is 15 to 40 times, preferably 20 to 35 times. If the amount of the hydrophilic polymer or the molecular weight is lower than that of polysulfone, the proportion of the hydrophilic polymer remaining in the membrane decreases, so that the water content of the insoluble component after the crosslinking reaction decreases. On the other hand, if the amount of the hydrophilic polymer is too large or the molecular weight is too high, the polyvinyl pyrrolidone cannot be uniformly finely dispersed, so that the crosslinking reaction proceeds locally, and the water content also decreases. Furthermore, by using a hydrophilic polymer highly compatible with the polysulfone-based polymer, it can be uniformly dispersed. For example, polyvinyl pyrrolidone, polyalkylene glycol, polyvinyl acetate, polyvinyl caprolactam, vinyl pyrrolidone / vinyl acetate copolymer, vinyl pyrrolidone / vinyl caprolactam copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, vinyl pyrrolidone / styrene copolymer Vinylpyrrolidone / hydroxyethyl methacrylate copolymer, vinylpyrrolidone / methyl methacrylate copolymer, and the like. Of these, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, and vinylpyrrolidone / vinylcaprolactam copolymer are preferably used.

  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 may be a modified product in which a hydroxyl group, a chloroacetamidomethyl group or the like is introduced into an aromatic ring.

  Further, it is preferable that the stirring speed of the membrane forming stock solution is high because the dispersion state of the hydrophilic polymer and the polysulfone-based polymer can increase the separation membrane dispersion state, and the stirring blade speed is 30 rpm or more, preferably 50 rpm. That's it. As the melting temperature, when the temperature is low, uniform fine dispersion does not occur. If the dissolution temperature is too high, the polymer begins to decompose. For this reason, the melting temperature is preferably 60 ° C. or higher, more preferably 80 ° C. or higher, while 120 ° C. or lower is preferable, and 100 ° C. or lower is more preferable. Since the microphase separation starts to occur in the film-forming stock solution over time, the hydrophilic polymer is not uniformly finely dispersed. Therefore, spinning is preferably performed within 80 hours after dissolution. Furthermore, the storage temperature after dissolution is preferably 45 ° C. or higher, more preferably 60 ° C. or higher, while 90 ° C. or lower is preferable, and 80 ° C. or lower is more preferable.

  As spinning conditions, in order to make the hydrophilic polymer exist more on the surface of the functional layer than on the surface opposite to the membrane functional layer, the die temperature is 30 to 60 ° C., the temperature of the dry part is 20 to 50 ° C., and the relative humidity is 70 to 95. % RH is a suitable range. The temperature of the dry part is preferably lower than the die temperature, and preferably 10 ° C. or more. Further, the length of the dry part is preferably 10 to 100 cm. The die temperature is preferably not higher than the storage temperature of the film-forming stock solution. This is because when the temperature rises at the discharge section, the structure of the polymer is determined with its thermal history remaining, so that there is a possibility that strain remains in the polymer molecules after molding. In such a case, it is considered that the polysulfone polymer concentration of the insoluble component and the water content of the insoluble component are affected.

  Furthermore, since a larger amount of hydrophilic polymer is present on the surface of the functional layer than on the surface opposite to the membrane functional layer, the coagulation bath is preferably a mixed solution of a good solvent and a poor solvent of a polysulfone polymer. Examples of the good solvent include DMAc and N-methylpyrrolidone, and examples of the poor solvent include water and alcohol. The concentration of the good solvent is 10% by weight or more, preferably 15% by weight or more and 30% by weight or less, preferably 25% by weight or less.

  When the separation membrane is a hollow fiber membrane, the mouthpiece of the discharge part has a double annular structure, but it is preferable to flow the core liquid into the hollow inner space. In this case, the internal structure of the separation membrane is almost determined by the addition of the hydrophilic polymer to the core liquid and the post-treatment such as coating using the hydrophilic polymer after film formation. Thereafter, only the surface of the functional layer can be modified, and it is not particularly necessary to satisfy all of the various film forming conditions as described above.

  The hydrophilic polymer used at this time is preferably a polymer having a large rotation radius of molecular chains in water in order to give a flexible layer thickness on the surface of the functional layer. Specifically, the rotation radius of the molecular chain in water at a weight average molecular weight of 100,000 is 10 nm or more.

  As a result of intensive studies by the present inventors, as a general tendency, the radius of rotation of the molecular chain is larger in the hydrophilic copolymer having both the hydrophilic unit and the hydrophobic unit than in the hydrophilic homopolymer. I found out. This may be because, for example, in a homopolymer such as polyvinylpyrrolidone, the interaction between pyrrolidone rings is too strong, conversely, the binding between molecules is large and the radius of rotation of the molecular chain is small. .

  From this point of view, the preferred hydrophilic copolymer includes vinylpyrrolidone / vinyl acetate copolymer, vinylpyrrolidone / vinylcaprolactam copolymer, vinylpyrrolidone / vinyl alcohol copolymer, vinylpyrrolidone / styrene copolymer, Examples include vinyl pyrrolidone / hydroxyethyl methacrylate copolymer and vinyl pyrrolidone / methyl methacrylate copolymer. However, when the hydrophobic unit contains an aromatic ring, the degree of hydrophobicity is too strong, and it is often not preferable. As the copolymer, an alternating copolymer or a random copolymer is preferably used rather than a graft copolymer or a block copolymer. This is presumably because in the graft polymer and block copolymer, the properties of each unit are clearly separated, and the radius of rotation of the molecular chain is often not so large. Here, among the units constituting the copolymer, if the unit with the smaller constituent ratio is not continuous for five units on average, it is not regarded as a block polymer. Further, the ratio (molar ratio) between the hydrophilic unit and the hydrophobic unit unit depends on the chemical structure, but generally the ratio of the hydrophobic unit to all units is preferably 0.3 or more and 0.7 or less. In particular, in the case of a vinylpyrrolidone / vinyl acetate copolymer, the vinyl acetate ratio is preferably 0.35 or more and 0.7 or less.

  On the other hand, if a large amount of hydrophilic copolymer having both a hydrophilic unit and a hydrophobic unit is present in the thickness direction of the membrane, there arises a problem that the water permeability of the separation membrane is lowered due to a decrease in hydrophilicity. Therefore, it is preferable that the hydrophilic copolymer is present only on the functional layer surface of the membrane. The state in which only the surface of the functional layer is present in the present invention means that the presence of the hydrophilic copolymer can be confirmed on the surface of the functional layer, but the state is below the detection limit on the opposite surface of the functional layer. Point to.

  Furthermore, it is preferable that the hydrophilic polymer existing over the thickness direction of the membrane is a hydrophilic homopolymer. As described above, the hydrophilic polymer may be confirmed on the surface exposed by cutting the arbitrary thickness direction of the separation membrane as described above. May be confirmed with an analytical electron microscope. Furthermore, polyvinylpyrrolidone and the like can be dyed by osmium staining. It may be confirmed by staining that the film exists in the thickness portion of the film with a transmission electron microscope of the cross section of the film. A preferred hydrophilic polymer concentration in the thickness portion of the membrane is 1% by weight or more, more preferably 3% by weight or more, and further preferably 5% by weight or more. However, if too much, problems such as elution occur, so 30% by weight or less is preferable, and more preferably 20% by weight or less.

  When a hydrophilic polymer is added to the core liquid, the composition ratio of the core liquid, the core liquid temperature, the composition of the film forming stock solution, and the like have an effect. For example, when a vinylpyrrolidone / vinyl acetate copolymer is added to a core solution to a film-forming stock solution composed of polysulfone and polyvinylpyrrolidone, the addition amount to the core solution is 5 to 30% by weight, and the core solution temperature is 10 to 10%. As the composition of the film forming stock solution at 60 ° C., the polysulfone concentration is preferably 14 to 25% by weight, and the polyvinyl pyrrolidone is preferably 2 to 10% by weight. The weight average molecular weight of polysulfone is preferably small so that a copolymer of vinylpyrrolidone / vinyl acetate is likely to remain on the membrane surface, and 100,000 or less, further 50,000 or less is suitably used.

  When post-treatment is performed on the hydrophilic polymer by coating or the like, the concentration of the hydrophilic polymer in the coating liquid, the contact time, and the temperature at the time of coating affect the thickness of the flexible layer. For example, when coating is performed using a vinylpyrrolidone / vinyl acetate copolymer aqueous solution, the aqueous solution concentration is preferably 1 to 5000 ppm, the contact time is 10 seconds or more, and the temperature is preferably 10 to 80 ° C. In addition, when coating is performed continuously rather than batchwise, it is possible to coat uniformly when the flow rate of the aqueous coating solution is high, 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 particular, when coating, the functional layer surface of the separation membrane can be uniformly covered when the adsorption equilibrium constant of the polysulfone polymer and the hydrophilic polymer in the coating liquid is higher. That is, the adsorption equilibrium constant is preferably 330 pg / (mm ² · ppm) or more, more preferably 500 pg / (mm ² · ppm) or more, and further preferably 550 pg / (mm ² · ppm) or more. On the other hand, if the adsorptive binding constant is too high, the effect of reducing the diameter of the separation membrane is increased. Therefore, it is preferably 1100 pg / (mm ² · ppm) or less, more preferably 1000 pg / (mm ² · ppm). Hereinafter, it is more preferably 900 pg / (mm ² · ppm) or less.

Furthermore, a method of causing a pressure difference between the inside and outside of the separation membrane to coat the hydrophilic polymer is suitable because it can be efficiently introduced onto the surface of the functional layer. This pressure difference is preferably 10 mmHg or more, more preferably 50 mmHg or more, on the inlet side (functional layer surface side) and outlet side (surface side opposite to the functional layer surface) of the coating liquid of the separation membrane module. Furthermore, after that, the flow of gas such as compressed air, water, and aqueous solution from the opposite direction of the hydrophilic polymer coating direction, that is, from the opposite side of the functional layer surface to the functional layer surface side, is performed only by the functional layer surface. This is a particularly suitable technique because it can be further coated. At this time, it is more preferable to use a hydrophilic copolymer having an adsorption equilibrium constant of 330 pg / (mm ² · ppm) or more as the hydrophilic polymer. Further, the flow rate of gas such as compressed air flowing from the opposite side of the functional layer surface toward the functional layer surface side is preferably 70 NL / min or less, more preferably 50 NL / min or less, and the time is preferably 10 minutes or less. In the case of water or an aqueous solution, it is preferably 1 L / min or less, more preferably 0.5 L / min or less, and the time is preferably 1 minute or less.

  The amount of the hydrophilic copolymer on the surface of the functional layer is preferably 5% by weight or more, more preferably 10% by weight or more, while 30% by weight or less is preferable and 25% by weight or less is more preferable. The amount of the hydrophilic copolymer on the surface can be determined by X-ray photoelectron spectroscopy (XPS) or the like. As the hydrophilic copolymer, a vinylpyrrolidone / vinyl acetate copolymer is preferable from the viewpoint of suppressing adhesion of platelets and the like.

  In this case, the peak area percentage of carbon derived from ester groups on the functional layer surface is preferably 0.3 (number of atoms%) or more, more preferably 0.5 (number of atoms) or more, while 7 (number of atoms). %) Or less, and more preferably 5 (number of atoms%) or less.

  The amount of carbon (number of atoms%) derived from the ester group on the surface can be determined by XPS. The peak of the carbon derived from the ester group (COO) can be obtained by dividing the peak appearing at +4.0 to 4.2 eV from the main peak derived from C1s CH or C—C. By calculating the ratio of the peak area to all elements (all the elements other than hydrogen atoms cannot be detected because hydrogen atoms cannot be detected), the carbon amount (number of atoms) derived from the ester group can be obtained. More specifically, C1s is mainly a component derived from CHx, C—C, C═C, C—S, a component mainly derived from C—O, C—N, a component derived from π-π * satellite, It is composed of five components: a component derived from C = O and a component derived from COO. Therefore, peak splitting is performed with five components. The COO-derived component is a peak that appears at +4.0 to 4.2 eV from the main peak of CHx and C—C (near 285 eV). The peak area ratio of each component is calculated by rounding off the second digit of the decimal point. The carbon amount derived from the ester group (number of atoms%) is determined by multiplying the carbon amount of C1s (number of atoms%) by the peak area ratio of the component derived from COO. If the peak division result is 0.4% or less, the value is below the detection limit. Further, the amount of hydrophilic copolymer on the surface can be determined from the amount of ester groups.

  The hydrophilic polymer insolubilization reaction is affected by the weight ratio of the insoluble component in the separation membrane, the polysulfone polymer concentration of the insoluble component, the water content of the insoluble component, and the surface flexible layer, all of which are affected by the crosslinking reaction of the hydrophilic polymer. This is an important process. The crosslinking reaction of the hydrophilic polymer is influenced not only by the radiation irradiation dose, the amount of radiation source, the irradiation time, the irradiation temperature, but also by the structure of the separation membrane and the dispersion state of the hydrophilic polymer and the polysulfone polymer. Although it cannot be generally stated, as the crosslinking reaction proceeds, the weight ratio of the insoluble component and the polysulfone polymer concentration in the insoluble component tend to increase, but the water content of the insoluble component and the surface flexible layer tend to decrease. Show.

  From the above, the radiation dose is 5 to 50 kGy, preferably 10 to 35 kGy, and the irradiation temperature is 10 to 60 ° C., preferably 20 to 50 ° C. As the radiation, α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams and the like are used. In particular, γ rays and electron beams are preferably used to obtain the crosslinked state of the present invention. In the case of γ rays, the amount of radiation source is 2.5 million to 10 million Ci or more, preferably 3 million to 7.5 million Ci.

  In addition, if the time from the film formation to the insolubilization reaction is long, the entanglement state between the hydrophilic polymer and the polysulfone polymer may change due to the molecular motion of the polymer. Therefore, it is preferable to perform the insolubilization treatment within 4 weeks after film formation, and further within 2 weeks.

  In order to promote the crosslinking reaction by radiation, it is preferable to add water or an aqueous hydrogen peroxide solution to the separation membrane. The amount of water contained in the separation membrane is 0.05 to 6 times, preferably 1 to 4 times the dry weight of the separation membrane. Further, the concentration of the aqueous hydrogen peroxide solution is 0.1 to 100 ppm, preferably 1 to 50 ppm.

  Further, it is preferable to use an antioxidant in order to suppress crosslinking. In particular, it is preferable to add an antioxidant in addition to water or an aqueous hydrogen peroxide solution. This is because when a substance that promotes crosslinking and a substance that inhibits coexist, the crosslinking reaction proceeds more gently, and it is easier to control the state of the insoluble component and the surface flexible layer. Here, the antioxidant means a molecule having a 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. Dissolved oxygen in the aqueous solution and oxygen in the air promote oxidative decomposition. Therefore, the oxygen concentration in the aqueous solution is 10 mg / L or less, preferably 5 mg / L or less. Further, the oxygen concentration in the gas in contact with the separation membrane is 5% or less, preferably 3% or less.

  As the antioxidant, monohydric alcohols such as ethanol, propanol, butanol, pentanol, and hexanol are preferably used.

  About the density | concentration of the solution containing an antioxidant, it changes with the kind of antioxidant contained, radiation irradiation conditions, etc. If the concentration of the antioxidant is too low, the generated radicals cannot be sufficiently erased. In addition, when a large amount of an antioxidant is added, radicals are sufficiently erased. For this reason, the concentration range is preferably 0.01% by weight or more and 90% by weight or less. 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, it 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 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 separation membrane of the present invention has high adhesion inhibiting 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.

  There are various methods for producing a separation membrane module depending on its use. For example, the steps can be divided into a separation membrane production step and a step of incorporating the separation membrane into the module.

  As an example of a blood purification module, an outline of a method for producing an artificial kidney incorporating a hollow fiber membrane made of polysulfone and polyvinylpyrrolidone will be described. First, as a method for producing a hollow fiber membrane as a separation membrane, polysulfone and polyvinylpyrrolidone are used as a good solvent for polysulfone (N, N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane, etc. are preferable) and poor. When the stock solution dissolved in the solvent mixed solution is discharged from the double annular die, the core solution is caused to flow inside, and the dry part is run and then led 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. Moreover, as a core liquid composition, it is preferable to use what consists of a composition based on the solvent used for the undiluted | stock solution from process suitability. As the core liquid concentration, for example, when dimethylacetamide is used, an aqueous solution of 45 to 80% by weight, and further 60 to 75% by weight is preferably used.

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

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

(1) Measurement of polysulfone content in insoluble component The dried separation membrane is dissolved in DMAc at a concentration of 2.5% by weight, and the solution is filtered with a filter paper to obtain an insoluble component. Rinse well with DMAc to wash the attached polysulfone polymer. Then rinse with water to wash the DMAc. Remove insoluble components and perform elemental analysis. Polysulfone polymer has one sulfur atom per repeating unit, polyvinylpyrrolidone, polyalkylene glycol, polyvinyl acetate, polyvinylcaprolactam, vinylpyrrolidone / vinyl acetate copolymer, vinylpyrrolidone / vinylcaprolactam copolymer, vinylpyrrolidone / Since hydrophilic polymers such as vinyl alcohol copolymer and vinyl pyrrolidone / styrene copolymer do not have sulfur atoms, the concentration of polysulfone polymers contained in insoluble components can be determined by determining the concentration of sulfur atoms relative to the total number of atoms. Can be calculated.
(2) Moisture content of insoluble components The dried hollow fiber membrane was stirred and dissolved in DMAc 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.
(3) Measurement of flexible layer on inner surface of hollow fiber The hollow fiber membrane was cut into a semicylindrical shape with a single blade, and the inner surface was measured with an atomic force microscope (AFM). The measurement sample was rinsed with ultrapure water, dried at room temperature and 0.5 Torr for 10 hours, and then subjected to measurement.

  After affixing the hollow fiber to the sample stage, a water drop was dropped to wet the membrane, and the moisture content was 65% by weight or more. In that state, force curve measurement was performed in contact mode. Note that the sample surface was not dried during the measurement. If the cantilever is approached to the sample and there is a soft layer on the surface, a bend is observed. The distance of this curved part was made into the flexible layer. The measurement was performed at 20 locations and the average value was adopted. The average value was rounded off to the first decimal place.

Scanning probe microscope SPM 9500-J3 (SHIMADZU, Kyoto, Japan) as an AFM observation condition, observation mode is contact mode, probe is NP-S (120 mm, wide) (Nihon VEECO KK, Tokyo, Japan), scan The range was 5 μm × 5 μm, and the scan speed was 1 Hz.
(4) Measurement of molecular chain rotation radius in water of hydrophilic polymer Incorporate a multi-angle laser light scattering photometer (MALLS) and a differential refractometer into a molecular chain solution that has been subjected to size separation by gel permeation chromatography (GPC). Thus, the absolute molecular weight distribution and molecular chain rotation radius of the polymer substance can be obtained. The measurement conditions are as follows.
a) GPC
Apparatus: Gel permeation chromatography (manufactured by WATERS)
Detector: differential refractive index detector RI410, sensitivity 8 × (50%) (manufactured by WATERS)
Column: Two TSKgel GMPW _XL (manufactured by Tosoh Corporation) are connected. Solvent: 0.1 M NH ₄ Cl (pH 9.5)
Flow rate: 0.716 mL / min
Temperature: 23 ° C
b) MALLS
Device: DAWN-DSP type multi-low angle laser light scattering photometer (manufactured by Wyatt Technology)
Wavelength: 632.8 nm (He-Ne)
Temperature: 23 ° C
(5) Adsorption equilibrium constant measurement of hydrophilic polymer to polysulfone After fixing an Au sensor chip manufactured by GE Healthcare Bioscience Co., Ltd. to a spin coater, 0.1 wt% chlorobenzene of polysulfone (Amoco Udel-P3500) One or two drops of the solution was dropped with a Pasteur pipette. Immediately thereafter, an Au sensor chip having a polysulfone-based polymer thinned on the surface was produced by spin-drying at 3000 rpm for 1 minute. This sensor chip was inserted into BIACORE 3000 manufactured by GE Healthcare Bioscience Co., Ltd., and the sensor chip was washed with water for 2000 seconds, and then the following operation was repeated with a hydrophilic polymer aqueous solution having a concentration of 5 to 1000 ppm.
1. 750 μL of a hydrophilic polymer aqueous solution was flowed and adsorbed on the polysulfone surface.
2. Washed with water for 2000 seconds.
3. The adsorbed hydrophilic polymer was peeled off by flowing 750 μL of 0.025 wt% Triton.
4. Washed with water for 2000 seconds.

The amount adsorbed on the surface of the polysulfone polymer was set to 0 after washing with water for 2000 seconds immediately after insertion of the sensor chip. It was set as the value of the difference at the time when was completed. Operation 4. When the value is higher than the value after washing with water immediately after insertion of the sensor chip, it is considered that the hydrophilic polymer was not completely peeled off by 0.025% by weight of triton, and the increment is regarded as the amount of adsorption. Added. The above operation was repeated at 5 to 1000 ppm. From the adsorption isotherm obtained as described above (the horizontal axis is the concentration of the hydrophilic polymer and the vertical axis is the adsorption amount), a general solution adsorption model (Freund's) on the polymer and its adsorption surface is 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 binding constant, n: Freundlich constant)
(6) X-ray photoelectron spectroscopy (XPS) measurement The hollow fiber membrane was cut into a semicylindrical shape with a single blade, and the inner surface and the outer surface of the hollow fiber membrane were measured at three points by the following method. 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)
When the hollow fiber membrane is composed only of polysulfone and polyvinylpyrrolidone, the amount of surface polyvinyl pororidone can be calculated from the following equation by calculating the amount of nitrogen (a (number of atoms)) and the amount of sulfur (b (number of atoms)). .
Surface polyvinylpyrrolidone amount (% by weight) = (a × 111 / (a × 111 + b × 442)) × 100
When a vinylpyrrolidone / vinyl acetate copolymer is used as the hydrophilic copolymer, the carbon amount derived from the ester group is +4.0 to 4 from the C1s CH or C—C main peak (around 285 eV). The peak appearing at 2 eV is divided into peaks, the ratio of the peak area to all elements is calculated, and the amount of carbon derived from the ester group (number of atoms) is calculated to calculate the amount of hydrophilic copolymer on the surface. Can do.
(7) Human platelet adhesion test method of hollow fiber membrane A double-sided tape was affixed to an 18 mmφ polystyrene circular plate, and the hollow fiber membrane was fixed thereto. The attached hollow fiber membrane was cut into a semicylindrical shape with a single blade to expose the inner surface of the hollow fiber membrane. If dirt, scratches, folds, etc. are present on the inner surface of the hollow fiber, platelets will adhere to the part and may not be evaluated correctly. The circular plate was attached to a Falcon (registered trademark) tube (18 mmφ, No. 2051) cut into a cylindrical shape so that the surface on which the hollow fiber membrane was attached was inside the cylinder, and the gap was filled with parafilm. The cylindrical tube was washed with physiological saline and then filled with physiological saline. Immediately after collecting human venous blood, heparin was added to 50 U / ml. After discarding the physiological saline in the cylindrical tube, 1.0 ml of the blood was placed in the cylindrical tube and shaken at 37 ° C. for 1 hour within 10 minutes after blood collection. Thereafter, the hollow fiber membrane was washed with 10 ml of physiological saline, blood components were fixed with 2.5% by volume glutaraldehyde physiological saline, and washed with 20 ml of distilled water. The washed hollow fiber membrane was dried under reduced pressure at room temperature of 0.5 Torr for 10 hours. This hollow fiber membrane was attached to a sample stage of a scanning electron microscope with a double-sided tape. Thereafter, a thin film of Pt—Pd was formed on the surface of the hollow fiber membrane by sputtering to prepare a sample. The inner surface of the hollow fiber membrane was observed with a field emission type scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times. In one field of view (4.3 × 10 ³ μm ² ) The number of adherent platelets was counted. The average value of the number of adhering platelets in 10 different visual fields near the center in the longitudinal direction of the hollow fiber was defined as the number of adhering platelets (number / 4.3 × 10 ³ μm ² ). When it exceeded 100 pieces / 4.3 × 10 ³ μm ² in one visual field, it was counted as 100. 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. In addition, it is preferable that the number of platelet adhesion is 20 / 4.3 × 10 ³ μm ² or less.
(8) Measurement of relative adhesion rate of fibrinogen As the adhesion of protein 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, the hollow fiber membrane of Comparative Example 5 was used. From the absorbance (Ac) of the control and the absorbance (As) of the target sample, the relative adhesion rate (Fib adhesion rate) of fibrinogen was determined by the following formula.
Fibrinogen relative adhesion rate (%) = As / Ac × 100
(9) Measurement of dissolution property of hydrophilic polymer When the separation membrane was incorporated in the hollow fiber membrane module, the measurement was performed as follows. The hollow inside of the hollow fiber membrane module is washed with 700 ml of room-temperature ultrapure water and the outside is washed with 2500 ml of room-temperature ultrapure water, and then the inside is washed again with 300 ml of room-temperature ultrapure water and adhered to the membrane. The hydrophilic polymer was washed away. Thereafter, the blood side was perfused with 4000 ml of ultrapure water heated to 37 ° C. at a flow rate of 200 ml / min for 4 hours. Thereafter, the perfusate was concentrated 200 times and measured by GPC (gel permeation chromatography). From this value, the total amount of hydrophilic polymer eluted in the perfusate was calculated.

As GPC measurement conditions, a mixed solvent of methanol: water = 1: 1 (volume ratio) using GMPW _XL manufactured by Tosoh Corporation as a column, adding a flow rate of 0.5 ml / min, and adding 0.1 N lithium nitrate as a solvent. Was carried out at a column temperature of 40 ° C. As a calibration curve for the amount of hydrophilic polymer, K90 polyvinyl pyrrolidone manufactured by BASF Corporation was used to obtain a concentration in terms of polyvinyl pyrrolidone. When the polyvinyl pyrrolidone concentration was less than 10 ppm, the detection limit was not exceeded (the detection limit of the amount of hydrophilic polymer eluted in 4 L was 0.4 mg).
(10) Measurement of water permeation performance Filtration volume per unit time flowing out to the outside by applying a water pressure of 100 mmHg to the inside of the hollow fiber of the glass tube mini module (36 pieces: effective length 10 cm) sealed at both ends of the hollow fiber Was measured. The water permeability (UFR) was calculated by the following formula.

UFR (mL / hr / m ² / mmHg) = Q _w / (P × T × A)
Here, Q _w : filtration amount (mL), T: outflow time (hr), P: pressure (mmHg), A: inner surface area of hollow fiber membrane (m ² )
(11) Aqueous urea clearance measurement The experiment was performed based on the dialyzer performance evaluation criteria published in September 1982 and edited by the Japanese Society for Artificial Organs. Among these, there are two types of measurement methods, but this experiment was based on TMP 0 mmHg. The clearance was calculated using the following formula. For those with different membrane areas, the overall mass transfer coefficient can be calculated from the clearance and the area converted from there.
Clearance _{C L (ml / min) =} {(CBi-CBo) / CBi} × Q B
Where CBi: urea module inlet side concentration, CBo: urea module outlet side concentration, Q _B : module supply liquid amount (ml / min)
(12) Measurement of bovine plasma urea clearance 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, urea was added to 1 g / 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 11 Bi pump, 12 F pump, and 9 dialyzer in FIG.

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

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

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

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

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

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

  The clearance was calculated from the concentration of each solution by the following equation (3).

Co (ml / min) = (CBi−CBo) × Q _B / CBi (3)
In the equation (3), C _O = urea clearance (ml / min), CBi = urea concentration in Bi solution, CB _o = urea concentration in Bo solution, and Q _B = Bi pump flow rate (ml / min).
(13) β ₂ -MG Clearance Measurement With the same method as bovine plasma urea clearance measurement, bovine blood added with disodium ethylenediaminetetraacetate was added and stirred so that the β ₂ -MG concentration was 1 mg / L. The measurement may be performed simultaneously with the measurement of urea clearance. The clearance measurement at a blood flow rate of 400 mL / min was performed in the same manner after the sampling for the clearance measurement at a blood flow rate of 200 mL / min was completed. The clearance calculation formula can be obtained by changing urea in (3) to β ₂ -MG.
Example 1
20 parts by weight of polysulfone (Amoco Udel-P3500), 5 parts by weight of polyvinylpyrrolidone (International Special Products Co .; hereinafter referred to as ISP) K90 were stirred at 50 rpm with a stirring blade together with 74 parts by weight of dimethylacetamide and 1 part by weight of water. Then, it was dissolved by heating at 90 ° C. for 10 hours to obtain a film forming stock solution. The stock solution was stored at 50 ° C. for 48 hours and then spun. Since the weight average molecular weight of polysulfone P3500 is 35,000 and the weight average molecular weight of polyvinylpyrrolidone K90 is 1,200,000, the molecular weight ratio of polysulfone to polyvinylpyrrolidone is 34 times.

A film-forming stock solution is fed to a spinneret part at a temperature of 50 ° C., and a solution comprising 67 parts by weight of dimethylacetamide and 33 parts by weight of water as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of an annular slit part After forming a hollow fiber membrane, a coagulation bath having a temperature of 40 ° C. consisting of 12% by weight of dimethylacetamide and 88% by weight of water is passed through a dry zone atmosphere at a temperature of 30 ° C., a relative humidity of 95% RH and 350 mm. A hollow fiber membrane obtained by passing through a water washing step at 75 ° C. for 40 seconds, a water washing step at 65 ° C. for 20 seconds, then a drying step at 130 ° C. for 2 minutes, and a crimping step at 160 ° C. Was taken up as a bundle. The hollow fiber membrane is filled into the case so that the total membrane area is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end with a potting material, and a part of the end of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain the module shown in FIG.

  An ethanol 1 wt% aqueous solution was passed from the blood side inlet (Bi) of the hollow fiber membrane module to the blood side outlet (Bo) at 500 mL / min for 1 minute. Next, the solution was passed from the blood side inlet (Bi) to the dialysate side inlet (Di) at 500 mL / min for 1 minute. At this time, an aqueous solution from which dissolved oxygen was degassed was used. The filling solution was pushed out from the dialysate side to the blood side with 100 kPa pressurized air, and no ethanol aqueous solution remained in the module case, and only the hollow fiber membrane was wet. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  Thereafter, each of the dialysate side and the blood side was blown with nitrogen at a flow rate of 10 L / min for 1 minute each, and the inside of the module was replaced with nitrogen, and then the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. When the amount of polyvinyl pyrrolidone on the inner surface of the hollow fiber membrane was measured by XPS, it was 34% by weight. When the inner surface was cut with a single blade and the exposed surface was measured by XPS, the amount of polyvinylpyrrolidone was 15% by weight. The polyvinyl pyrrolidone in the film was measured by elemental analysis and found to be 5% by weight. ATR measurement was performed on the inner surface and the outer surface of the hollow fiber membrane. Ratio of peak intensity (A _PVP ) near 1650 cm ⁻¹ derived from the amide group of polyvinylpyrrolidone and peak intensity (A _PSf ) near 1580 cm ^−1, which is a peak derived from the benzene ring of polysulfone (A _PVP / A _PSf ) The inner surface showed a value 3.0 times higher than the outer surface, and the inner surface had a larger amount of polyvinylpyrrolidone.

The other results are shown in Table 1. By using ethanol as an antioxidant and controlling the cross-linking of polyvinylpyrrolidone by γ-ray irradiation, it is possible to achieve low elution and high water permeability of polyvinylpyrrolidone while greatly suppressing platelet adhesion and fibrinogen adhesion. It was.
(Example 2)
The same operation as in Example 1 was performed except that a 1% by weight aqueous solution of hexanol was used instead of the 1% by weight aqueous solution of ethanol as the solution to be wetted. The amount of water contained in the hollow fiber membrane was 2.7 times the dry weight of the hollow fiber membrane.

Various tests were performed on the module. The results are shown in Table 1.
(Example 3)
Polysulfone (Amoco Udel-P3500) 18 parts by weight, Polyvinylpyrrolidone (ISP) K90 4 parts by weight with dimethylacetamide 77 parts by weight, water 1 part by weight at 90 ° C. for 10 hours while stirring at 50 rpm with a stirring blade It melt | dissolved and was used as the film forming stock solution. The stock solution was stored at 60 ° C. for 48 hours and then spun.

A film-forming stock solution is fed to a spinneret part at a temperature of 50 ° C., and a solution comprising 65 parts by weight of dimethylacetamide and 35 parts by weight of water as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of the annular slit part. After forming a hollow fiber membrane, a solidification bath at a temperature of 40 ° C. consisting of 14% by weight of dimethylacetamide and 86% by weight of water is passed through a dry zone atmosphere at a temperature of 30 ° C., a relative humidity of 75% RH and 350 mm. The hollow fiber membrane obtained after passing through the 85 ° C. water washing step for 120 seconds, passing through the 130 ° C. drying step for 2 minutes, and passing through the 160 ° C. crimping step was used as a wound bundle. The hollow fiber membrane is filled into the case so that the total membrane area is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end with a potting material, and a part of the end of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain the module shown in FIG.

  In the same manner as in Example 1, the hollow fiber membrane was wetted with a 1% by weight aqueous ethanol solution. The amount of water contained in the hollow fiber membrane was 2.7 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. By using ethanol as an antioxidant and controlling the cross-linking of polyvinylpyrrolidone by γ-ray irradiation, it is possible to achieve low elution and high water permeability of polyvinylpyrrolidone while greatly suppressing platelet adhesion and fibrinogen adhesion. It was.
Example 4
Using the hollow fiber membrane module obtained by the same method as in Example 3, the hollow fiber membrane was wetted using pure water instead of the ethanol aqueous solution as the solution to be wetted. In addition, the pure water which deaerated dissolved oxygen was used. Thereafter, compressed air was flowed to each of the blood side and the dialysate side, and the amount of water contained in the hollow fiber membrane was dried to be 0.1 times the dry weight of the hollow fiber membrane. After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 15 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. Realize low elution and high water permeability of polyvinylpyrrolidone while greatly suppressing platelet adhesion and fibrinogen adhesion by controlling the crosslinking of polyvinylpyrrolidone by γ-ray irradiation by reducing the amount of water that promotes the crosslinking reaction I was able to.
(Comparative Example 1)
A hollow fiber membrane module obtained by the same method as in Example 3 was used. As in Example 4, pure water was used as the solution to be wetted, but the operation of extracting the filling liquid with compressed air was not performed. The module was filled with pure water and irradiated with 25 kGy of γ rays.

Various tests were performed on the module. The results are shown in Table 1. Polyvinylpyrrolidone elution was small because the amount of water that promotes the crosslinking reaction was large and the crosslinking of polyvinylpyrrolidone by γ-ray irradiation was too advanced, but platelet adhesion and fibrinogen adhesion could not be suppressed.
(Comparative Example 2)
A hollow fiber membrane module obtained by the same method as in Example 3 was used. A 15 kGy γ-ray was irradiated in the same manner as in Comparative Example 1 except that a 0.5% by weight aqueous solution of sodium pyrosulfite was used instead of pure water as the solution to be wetted.

Various tests were performed on the module. The results are shown in Table 1. Since the amount of sodium pyrosulfite used as an antioxidant was large, polyvinylpyrrolidone was hardly cross-linked and platelet adhesion and fibrinogen adhesion could be suppressed, but polyvinylpyrrolidone was eluted frequently.
(Comparative Example 3)
Polysulfone (Amoco Udel-P1700) 18 parts by weight, Polyvinylpyrrolidone (ISP) K90 4 parts by weight with dimethylacetamide 77 parts by weight and water 1 part by stirring at 10 ° C. with a stirring blade at 50 ° C. for 10 hours It melt | dissolved and it was set as the film forming stock solution. This stock solution was stored at 40 ° C. for 96 hours and then spun. In addition, since the weight average molecular weight of polysulfone P1700 is 29,000 and the weight average molecular weight of polyvinylpyrrolidone K90 is 1,200,000, the molecular weight ratio of polysulfone to polyvinylpyrrolidone is 41 times.

A film-forming stock solution is sent to a spinneret part at a temperature of 50 ° C., and a solution comprising 63 parts by weight of dimethylacetamide and 37 parts by weight of water as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of an annular slit part After forming a hollow fiber membrane, a solidification bath at a temperature of 40 ° C. composed of 7% by weight of dimethylacetamide and 93% by weight of water is passed through a dry zone atmosphere at a temperature of 30 ° C., a relative humidity of 98% RH and 350 mm. Then, a water washing step at 85 ° C. was passed for 120 seconds, then a drying step at 130 ° C. was passed for 2 minutes, and the hollow fiber membrane obtained through a crimping step at 160 ° C. was used as a wound bundle. The hollow fiber membrane is filled into the case so that the total membrane area is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end with a potting material, and a part of the end of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain the module shown in FIG.

  In the same manner as in Example 1, the hollow fiber membrane was wetted with a 1% by weight aqueous ethanol solution. The amount of water contained in the hollow fiber membrane was 2.7 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. In the same manner as in Example 3, ethanol was used as an antioxidant and the crosslinking of polyvinylpyrrolidone by γ-ray irradiation was controlled. However, in the case where the original hollow fiber membrane was a functional layer, a large amount of polyvinylpyrrolidone was present. The inner surface flexible layer was thin and platelets adhered.
(Comparative Example 4)
16 parts by weight of polysulfone (Amoco Udel-P3500), 4 parts by weight of polyvinylpyrrolidone (ISP) K30, 2 parts by weight of polyvinylpyrrolidone (ISP) K90 together with 77 parts by weight of dimethylacetamide and 1 part by weight of water at 50 rpm with a stirring blade While stirring, the mixture was heated and dissolved at 80 ° C. for 10 hours to obtain a film-forming stock solution. The stock solution was stored at 60 ° C. for 48 hours and then spun.
In addition, since the weight average molecular weight of polyvinylpyrrolidone K30 is 62,000, the molecular weight ratio of polysulfone to polyvinylpyrrolidone is 7.

A film-forming stock solution is sent to a spinneret part at a temperature of 50 ° C., and a solution comprising 63 parts by weight of dimethylacetamide and 37 parts by weight of water as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of an annular slit part After forming a hollow fiber membrane, a solidification bath at a temperature of 40 ° C. consisting of 14% by weight of dimethylacetamide and 86% by weight of water is passed through a dry zone atmosphere at a temperature of 30 ° C., a relative humidity of 77% RH and 350 mm. Then, a 90 ° C. water washing step was allowed to pass for 150 seconds, then a 130 ° C. drying step was passed for 2 minutes, and a hollow fiber membrane obtained through a 160 ° C. crimping step was used as a wound bundle. The hollow fiber membrane is filled into the case so that the total membrane area is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end with a potting material, and a part of the end of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain the module shown in FIG.

  In the same manner as in Example 1, the hollow fiber membrane was wetted with a 10% by weight aqueous ethanol solution. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 20 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. Although ethanol was used as an antioxidant to control the crosslinking of polyvinylpyrrolidone by γ-ray irradiation, the inner surface, which is the functional layer of the original hollow fiber membrane, did not contain much polyvinylpyrrolidone. The layer thickness was thin and platelets adhered. In addition, since γ rays were irradiated, insoluble components were present in the membrane, but the polysulfone concentration of the insoluble components was low, so that the hydrophilic polymer (polyvinylpyrrolidone) was often eluted.
(Comparative Example 5)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used. Further, the hollow fiber membrane was wetted in the same manner as in Comparative Example 4 except that a 1 wt% ethanol aqueous solution was used as the solution to be wetted. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. Although ethanol was used as an antioxidant to control the crosslinking of polyvinylpyrrolidone by γ-ray irradiation, the inner surface, which is the functional layer of the original hollow fiber membrane, did not contain much polyvinylpyrrolidone. The layer thickness was thin and platelets adhered.
(Comparative Example 6)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used. Further, the hollow fiber membrane was wetted in the same manner as in Comparative Example 4 except that pure water was used instead of the ethanol 1 wt% aqueous solution. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

  Various tests were performed on the module. The results are shown in Table 1.

Further, the aqueous urea clearance was 197 mL / min, and the urea clearance in the bovine plasma system was 190 mL / min, which was a difference of 7 mL / min. The β ₂ -MG clearance was 71 mL / min at a blood flow rate of 200 mL / min, and 72 mL / min at a blood flow rate of 400 mL / min, which was 1.01 times.
(Example 5)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used. In addition, instead of an aqueous solution of 1% by weight of ethanol as a solution to be moistened, vinylpyrrolidone / vinyl acetate (6: 4) copolymer (BASF, “KOLLIDON” (registered trademark) VA64, hereinafter referred to as VA64) 100 ppm and ethanol 0 The hollow fiber membrane was wetted in the same manner as in Comparative Example 4 except that the module was filled with a 1% by weight mixed aqueous solution. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

In addition, when GPC-MALLS measurement was performed about VA64 aqueous solution, the rotation radius of the molecular chain in the weight average molecular weight 100,000 was 12 nm. Furthermore, the adsorption equilibrium constant of VA64 on polysulfone was 676 pg / (mm ² · ppm).

Various tests were performed on the module. When the XPS measurement was performed on the inner surface of the hollow fiber membrane, the amount of polyvinylpyrrolidone on the inner surface was 19% by weight, and the amount of VA64 was 16% by weight. On the other hand, when the outer surface was subjected to XPS measurement, a peak derived from an ester group was not detected, and VA64 was not present on the outer surface. Furthermore, when the inner surface was cut with a single blade and the exposed surface was measured by XPS, the amount of polyvinylpyrrolidone was 10% by weight, and no peak derived from an ester group was detected. The polyvinyl pyrrolidone in the film was measured by elemental analysis and found to be 3% by weight. ATR measurement was performed on the inner surface and the outer surface of the hollow fiber membrane. Ratio of peak intensity (A _PVP ) near 1650 cm ⁻¹ derived from the amide group of polyvinylpyrrolidone and peak intensity (A _PSf ) near 1580 cm ^−1, which is a peak derived from the benzene ring of polysulfone (A _PVP / A _PSf ) Was 3.5 times higher on the inner surface than on the outer surface. That is, it was found that polyvinyl pyrrolidone, which is a hydrophilic homopolymer, is also present in the film thickness portion, but VA64, which is a hydrophilic copolymer, is present only on the inner surface. The other results are shown in Table 1. When the inner surface flexible layer thickness swelled to 15 nm by introduction of VA64, low elution and high water permeability of the hydrophilic polymer could be realized while significantly suppressing platelet adhesion and fibrinogen adhesion.

Furthermore, the aqueous urea clearance was 196 mL / min, and the urea clearance in the bovine plasma system was 194 mL / min, a difference of 2 mL / min. Further, β ₂ -MG clearance was 71 mL / min at a blood flow rate of 200 mL / min, and 79 mL / min at a blood flow rate of 400 mL / min, which was 1.11 times.
(Example 6)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used. In addition, a mixed aqueous solution of 100 ppm of vinylpyrrolidone / vinyl acetate (5: 5) copolymer (hereinafter referred to as VA55) and 0.1% by weight of ethanol was used in place of the 1% by weight aqueous solution of ethanol. The hollow fiber membrane was wetted in the same manner as in Comparative Example 4. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

  Various tests were performed on the module. The results are as shown in Table 1. By swelling the inner surface flexible layer thickness to 15 nm with VA55, the adhesion of platelets and fibrinogen is greatly suppressed, and low elution of hydrophilic polymer and high water permeability are realized. We were able to.

Further, the aqueous urea clearance was 195 mL / min, and the urea clearance in the bovine plasma system was 194 mL / min, which was a difference of 1 mL / min. Further, the β ₂ -MG clearance was 68 mL / min at a blood flow rate of 200 mL / min, 75 mL / min at a blood flow rate of 400 mL / min, and was 1.10 times.
(Example 7)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used. In addition, a mixed aqueous solution of 100 ppm of vinylpyrrolidone / vinylcaprolactam (5: 5) copolymer (hereinafter referred to as VPC55) and 0.1% by weight of ethanol was used instead of the 1% by weight aqueous solution of ethanol. In the same manner as in Comparative Example 4, the hollow fiber membrane was wetted. The amount of water contained in the hollow fiber membrane was 2.7 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

  Various tests were performed on the module. The results are shown in Table 1. By supplementing the inner surface flexible layer thickness with VPC55, it was possible to achieve low elution and high water permeability of the hydrophilic polymer while largely suppressing platelet adhesion and fibrinogen adhesion.

Further, the aqueous urea clearance was 194 mL / min, and the urea clearance in the bovine plasma system was 194 mL / min, which was a difference of 0 mL / min. The β ₂ -MG clearance was 70 mL / min at a blood flow rate of 200 mL / min, and 76 mL / min at a blood flow rate of 400 mL / min, which was 1.09 times.
(Example 8)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used. A mixed aqueous solution of VA64 100 ppm and ethanol 0.1% by weight from the blood side inlet (Bi) of the hollow fiber membrane module through the blood side outlet (Bo), from the dialysate outlet (Do) to the dialysate side inlet (Di), One-pass liquid was passed at 500 mL / min for 5 minutes. Thereafter, the filling liquid was not extracted by compressed air. The module was filled with the above mixed aqueous solution and irradiated with 25 kGy of γ rays.

Various tests were performed on the module. When the inner surface of the hollow fiber membrane was measured by XPS, the amount of polyvinylpyrrolidone on the inner surface was 20% by weight and the amount of VA64 was 19% by weight. On the other hand, when the XPS measurement was performed on the outer surface, the amount of VA64 was 14% by weight. Furthermore, when the inner surface was cut with a single blade and the exposed surface was measured by XPS, the amount of polyvinylpyrrolidone was 10% by weight and the amount of VA64 was 7% by weight. The polyvinyl pyrrolidone in the film was measured by elemental analysis and found to be 3% by weight. ATR measurement was performed on the inner surface and the outer surface of the hollow fiber membrane. Ratio of peak intensity (A _PVP ) near 1650 cm ⁻¹ derived from the amide group of polyvinylpyrrolidone and peak intensity (A _PSf ) near 1580 cm ^−1, which is a peak derived from the benzene ring of polysulfone (A _PVP / A _PSf ) Was 3.2 times higher on the inner surface than on the outer surface. That is, it was found that both the polyvinyl pyrrolidone that is a hydrophilic homopolymer and the VA64 that is a hydrophilic copolymer are also present in the film thickness portion.

The other results are shown in Table 1. It was possible to achieve low elution and high water permeability of the hydrophilic polymer while significantly suppressing platelet adhesion and fibrinogen adhesion. However, since VA64 is also present in the film thickness portion, it is considered that the water permeability is slightly low.
(Comparative Example 7)
Using the hollow fiber membrane module obtained by the same method as in Comparative Example 4, the hollow fiber membrane was wetted in the same manner as in Comparative Example 4 except that a VA64 100 ppm aqueous solution was used. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. Platelet adhesion could be suppressed by swelling the inner surface flexible layer with VA64 to 13 nm. However, since ethanol as an antioxidant was not added to the filling liquid, cross-linking with γ-rays progressed, and fibrinogen Adhesion could not be suppressed.
(Comparative Example 8)
A hollow fiber membrane module obtained by the same method as in Comparative Example 4 was used, and a mixed aqueous solution of 100 ppm of polyvinylpyrrolidone (ISP) K30 and 0.1% by weight of ethanol was used as in Comparative Example 4. The hollow fiber membrane was wetted. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

In addition, when GPC-MALLS measurement was performed on the polyvinylpyrrolidone K30 aqueous solution, the rotation radius of the molecular chain at a weight average molecular weight of 100,000 was 9 nm. Furthermore, the adsorption equilibrium constant of polyvinylpyrrolidone K30 on polysulfone was 310 pg / (mm ² · ppm).

Various tests were performed on the module. The results are shown in Table 1. Polyvinylpyrrolidone added after the hollow fiber membrane was not able to swell the inner surface flexible layer thickness, and therefore could not suppress platelet adhesion. This is probably because the flexible layer thickness could not be sufficiently compensated because the rotation radius of the molecular chain of polyvinylpyrrolidone was small and the adsorption equilibrium constant on polysulfone was small.
(Comparative Example 9)
18 parts by weight of polysulfone (Amoco Udel-P3500) was heated and dissolved together with 81 parts of dimethylacetamide and 1 part of water, and heated and dissolved at 80 ° C. for 10 hours while stirring at 50 rpm with a stirring blade to obtain a film forming stock solution. The stock solution was stored at 60 ° C. for 48 hours and then spun.

A film-forming stock solution is fed to a spinneret part at a temperature of 50 ° C., and a solution comprising 20 parts by weight of dimethylacetamide and 80 parts by weight of water as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of an annular slit part. After forming a hollow fiber membrane, a solidification bath at a temperature of 40 ° C. consisting of 14% by weight of dimethylacetamide and 86% by weight of water is passed through a dry zone atmosphere at a temperature of 30 ° C., a relative humidity of 95% RH and 350 mm. Then, a water washing step at 80 ° C. was allowed to pass for 120 seconds, then a drying step at 130 ° C. was passed for 2 minutes, and a hollow fiber membrane obtained through a crimping step at 160 ° C. was used as a wound bundle. The hollow fiber membrane is filled into the case so that the total membrane area is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end with a potting material, and a part of the end of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain the module shown in FIG.

  The hollow fiber membrane was wetted using a mixed aqueous solution of VA64 100 ppm and ethanol 0.1 wt% in the same manner as in Example 5. The amount of water contained in the hollow fiber membrane was 1.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

Various tests were performed on the module. The results are shown in Table 1. The inner surface flexible layer thickness was 10 nm by swelling with VA64, and platelet adhesion could be suppressed. However, since there is almost no hydrophilic polymer in the film thickness part, it is considered that insoluble components were not obtained and fibrinogen adhesion could not be suppressed. Furthermore, the water permeability was low.
Example 9
Polysulfone (Amoco Udel-P3500) 18 parts by weight Polyvinylpyrrolidone (International Special Products, Inc .; hereinafter abbreviated as ISP) 9 parts by weight K30 72 parts by weight dimethylacetamide and 1 part by weight water were dissolved by heating and stirred with a stirring blade at 50 rpm. While stirring, the film was dissolved by heating at 80 ° C. for 10 hours to obtain a film-forming stock solution. The stock solution was stored at 60 ° C. for 48 hours and then spun.

The film-forming stock solution is sent to a spinneret part at a temperature of 50 ° C., and a solution of 63 parts by weight of dimethylacetamide and 37 parts by weight of water is used as a core solution from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. A solution in which 10 parts by weight of VA64 was dissolved was discharged. After forming the hollow fiber membrane, it was passed through a coagulation bath at a temperature of 40 ° C. composed of 14% by weight of dimethylacetamide and 86% by weight of water through a dry zone atmosphere at a temperature of 28 ° C., a relative humidity of 95% RH, and 350 mm. A water washing step at 80 ° C. was allowed to pass for 120 seconds, then a drying step at 130 ° C. was allowed to pass for 2 minutes, and a hollow fiber membrane obtained through a crimping step at 160 ° C. was used as a wound bundle. The hollow fiber membrane is filled into the case so that the total membrane area is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end with a potting material, and a part of the end of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain the module shown in FIG.

  In the same manner as in Example 1, the hollow fiber membrane was wetted with a 1% by weight aqueous ethanol solution. The amount of water contained in the hollow fiber membrane was 2.8 times the dry weight of the hollow fiber membrane.

  After that, after the inside of the module was replaced with nitrogen in the same manner as in Example 1, the module was irradiated with 25 kGy of γ rays. The oxygen concentration in the module was 1%.

  Various tests were performed on the module. The results are shown in Table 1. It was possible to achieve low elution and high water permeability of the hydrophilic polymer while significantly suppressing platelet adhesion and fibrinogen adhesion.

1 Hollow fiber membrane 2 Case 3 Potting agent 4 Blood side inlet (Bi)
5 Blood side outlet (Do)
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

Claims (9)

A polysulfone separation membrane comprising a polysulfone polymer and a hydrophilic polymer, wherein the separation membrane contains a component insoluble in N, N-dimethylacetamide,
(B) The polysulfone polymer concentration in the insoluble component is 10% by weight or more and 50% by weight or less. (B) The water content of the insoluble component is 95% by weight or more. (C) Flexible on the functional layer surface of the separation membrane in a wet state. A polysulfone separation membrane having a layer and a thickness of 7 nm or more. The hydrophilic polymer is composed of at least one hydrophilic homopolymer and at least one hydrophilic copolymer, and the hydrophilic homopolymer exists over the thickness direction of the separation membrane, while the hydrophilic copolymer is present. Is present only on the surface of the functional layer of the separation membrane. The hydrophilic homopolymer contains at least one selected from polyvinyl pyrrolidone, polyalkylene glycol, polyvinyl acetate, and polyvinyl caprolactam, and the hydrophilic copolymer is a vinyl pyrrolidone / vinyl acetate copolymer, vinyl pyrrolidone. -Contains at least one selected from vinyl caprolactam copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, vinyl pyrrolidone / styrene copolymer, vinyl pyrrolidone / hydroxyethyl methacrylate copolymer, vinyl pyrrolidone / methyl methacrylate copolymer The polysulfone separation membrane according to claim 2, wherein The ester group is present on the surface of the functional layer of the separation membrane, and the amount of carbon derived from the ester group is 0.3 (number of atoms) or more. Polysulfone separation membrane. 5. The polysulfone-based separation according to claim 2, wherein the hydrophilic copolymer is a vinylpyrrolidone / vinyl acetate copolymer, and the concentration of the functional layer surface is 10% by weight or more. film. The separation membrane according to any one of claims 1 to 5, wherein the separation membrane is for blood purification. A separation membrane module comprising the separation membrane according to claim 1. 8. The separation membrane according to claim 7, wherein the difference between the measured value in the aqueous system and the measured value in the bovine plasma system is within 5 mL / min for the urea clearance of 1.6 m ² converted value of the separation membrane module. module. For β ₂ -microglobulin clearance using bovine plasma in 1.6 m ² equivalent of the separation membrane module, the clearance at a blood flow rate of 400 mL / min is 1.05 times or more of the clearance at a blood flow rate of 200 mL / min The separation membrane module according to claim 7 or 8, wherein