JP5338431B2 - Polysulfone separation membrane and method for producing polysulfone separation membrane module - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high performance polysulfone-based separation membrane module with less deposition of an organic substance, a protein and platelet. <P>SOLUTION: The polysulfone-based separation membrane module has a vinylpyrrolidone unit and a hydrophobic unit on the surface of the polysulfone-based separation membrane. A ratio of the hydrophobic unit amount existing on the membrane surface is made larger than a ratio of the hydrophobic unit amount at the inside of the membrane. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a method for producing a polysulfone-based separation membrane and a polysulfone-based separation membrane module. The present invention is suitably used for applications requiring blood compatibility and non-adhesion of proteins and organic substances. For example, separation membranes for blood purification require blood compatibility and non-adhesion of proteins, while membranes for water purifiers, water purification membranes, sewage purification membranes, reverse osmosis membranes, membranes for biological component separation, etc. Non-adhesion is required. Therefore, in such a field, the separation membrane module of the present invention and the manufacturing method thereof are preferably used.

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

  Therefore, in the process of film formation, a method of introducing a hydrophilic component such as polyvinylpyrrolidone into water insolubilized by radiation or heat to the formed film (Patent Document 2), or a polysulfone-based separation membrane is used for polyvinyl chloride. A method of forming a coating layer insolubilized by radiation crosslinking after contacting with a hydrophilic polymer solution such as pyrrolidone (Patent Document 3) is disclosed. However, an aqueous polymer such as polyvinylpyrrolidone and a polysulfone-based polymer have a problem that it is difficult to form a coating layer because the interaction between molecules is weak.

  Therefore, a method is disclosed in which a polyvinyl alcohol aqueous solution having a saponification degree within a certain range is brought into contact with a polysulfone separation membrane to efficiently form a coating layer on the membrane surface by the hydrophobic interaction between polysulfone and vinyl acetate. (Patent Document 4). However, as a result of investigations by the present inventors, it has been found that when polyvinyl alcohol is coated on a separation membrane, the performance of the separation membrane is significantly reduced. Furthermore, it is also known that hydroxyl groups such as polyvinyl alcohol tend to activate complement when in contact with blood.

  Further, a method is disclosed in which a vinyl pyrrolidone-styrene copolymer having a certain concentration is added to a polysulfone film forming stock solution so that a styrene unit is present inside the film and a vinyl pyrrolidone unit is present on the surface side (Patent Document 5). ). However, such a membrane structure is induced by the interaction between the styrene unit and polysulfone. Therefore, when the amount of vinylpyrrolidone-styrene is increased, the styrene unit and the polysulfone are spun when spinning from the membrane forming stock solution by phase separation. Due to this interaction, phase separation is difficult, and it is not easy to obtain high membrane performance.

Japanese Patent Publication No. 2-18695 Japanese Patent Publication No.8-9668 JP-A-6-238139 JP 2006-198611 A Japanese Patent Publication No. 9-13575

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

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that polysulfone-based separation membranes and polysulfone-based separation membrane modules having excellent blood compatibility and less protein and organic matter adhesion are the following 1-10. We have found that this can be achieved by configuration.
1. The polysulfone-based separation membrane surface has hydrophobic units other than vinylpyrrolidone units and polysulfone-based units, and the hydrophobic unit amount ratio existing on the membrane surface is 30% higher than the hydrophobic unit amount ratio existing inside the membrane. A polysulfone separation membrane characterized by being larger than the above.
2. 2. The polysulfone-based separation membrane according to 1 above, wherein the vinyl pyrrolidone unit and the hydrophobic unit constitute a copolymer.
3. 3. The polysulfone separation membrane according to 2 above, wherein the copolymer has at least one selected from a random copolymer, an alternating copolymer, and a block copolymer.
4). 4. The polysulfone-based separation membrane according to any one of 1 to 3, wherein the hydrophobic unit has at least one unit selected from vinyl acetate, vinyl caprolactam, and aliphatic hydrocarbon.
5. 5. The polysulfone separation membrane according to any one of 2 to 4 above, wherein the ratio of the hydrophobic unit in the copolymer is 10-80 mol%.
6). 6. The polysulfone separation membrane according to any one of 1 to 5, which is a separation membrane for blood purification.
7). 7. A polysulfone separation membrane module comprising the polysulfone separation membrane according to any one of 1 to 6 above.
8). A polysulfone-based separation membrane module comprising a copolymer solution composed of a vinylpyrrolidone unit and a hydrophobic unit other than a polysulfone-based unit, which is irradiated and / or heat-treated in contact with the polysulfone-based separation membrane. Production method.
9. 9. The polysulfone separation membrane module according to 8, wherein a pressure difference is provided between the inside and outside of the separation membrane when the copolymer solution of the vinyl pyrrolidone unit and the hydrophobic unit is brought into contact with the polysulfone separation membrane. Manufacturing method.
10. 10. The method for producing a polysulfone-based separation membrane module according to 8 or 9, wherein the hydrophobic unit is at least one unit selected from vinyl acetate, vinyl caprolactam, and aliphatic hydrocarbon.

  The polysulfone-based separation membrane and the polysulfone-based separation membrane module according to the present invention are separation membrane modules characterized in that they are present on the surface, and for applications that require blood compatibility and the property of preventing adhesion of proteins and organic substances. Can be used widely.

1 shows an embodiment of an artificial kidney used in the present invention. The circuit in (beta) _2- microglobulin clearance measurement implemented in Examples 1-10 and Comparative Examples 1-7 is shown.

  The present invention has a hydrophobic unit other than the vinylpyrrolidone unit and the polysulfone unit on the surface of the polysulfone separation membrane, and the hydrophobic unit amount ratio existing on the membrane surface is higher than the hydrophobic unit amount ratio existing inside the membrane. The separation membrane module is characterized by being large. Here, the unit amount ratio refers to the ratio of the abundance of hydrophobic units other than vinylpyrrolidone units or polysulfone units to the abundance of polysulfone units at any location in the membrane, and the measurement method will be described later. Street. In the following description, the term “hydrophobic unit” refers to a hydrophobic unit other than a polysulfone unit.

  Since proteins easily adhere to a hydrophobic surface, it is considered important that the entire separation membrane surface is hydrophilic. However, on the other hand, even if the material surface is coated with a hydrophilic polymer such as polyvinylpyrrolidone or polyethylene glycol, it is said that the adhesion of proteins and the like can only be temporarily suppressed. In the present invention, the presence of both the vinylpyrrolidone unit and the hydrophobic unit on the surface of the separation membrane can effectively suppress protein and platelet adhesion. The reason for this is not clear, but it is thought that the presence of a good balance between the hydrophilicity and hydrophobicity of the surface is important for the suppression of protein and platelet adhesion. In particular, when a compound having a hydroxyl group is used, the hydrophilicity is too strong to maintain the above balance. However, it is considered that the vinylpyrrolidone group is not so hydrophilic as the hydroxyl group, and the hydrophobicity can be easily balanced.

  Therefore, the type of the hydrophobic unit and the ratio of the vinylpyrrolidone group on the surface to the hydrophobic unit are important. If the surface becomes too hydrophobic, it will cause protein and platelet adhesion. The amount of hydrophobic units on the surface is about 0.1% to 40% by weight, preferably 1% to 20% by weight. The amount of vinyl pyrrolidone unit on the surface is preferably 10% by weight or more, more preferably 15% by weight or more. Moreover, since the hydrophilic effect will become strong too much, 50 weight% or less is preferable, More preferably, it is 40 weight% or less. The amount of the vinyl pyrrolidone unit on the surface is a total value derived from the copolymer of the vinyl pyrrolidone unit and the hydrophobic unit and from the polyvinyl pyrrolidone when the separation membrane contains polyvinyl pyrrolidone. The amount of the vinyl pyrrolidone unit on the surface can be determined by ESCA or the like.

  The vinyl pyrrolidone unit and the hydrophobic unit on the surface preferably form a copolymer. Compared with the addition of each homopolymer, these units are copolymers, so that the adhesion suppressing effect is enhanced. There are many unclear points for this reason, but this may be due to the distribution of the surface of vinylpyrrolidone and the hydrophobic unit and the reasonably good balance between hydrophilicity and hydrophobicity within one molecule. It is done.

  Moreover, the surface here means the surface which has a separation function layer. For example, in the case of a hollow fiber membrane for artificial kidney, it refers to the inner surface of the hollow fiber membrane. Further, when referring to the surface in the present invention, a region of 50 nm or 10 nm may be used based on a region having a depth from the surface of up to 100 nm. Whether the hydrophobic unit quantity ratio existing on the film surface is larger than the hydrophobic unit quantity ratio inside the film is determined by, for example, combining X-ray photoelectron spectroscopy (ESCA) and total reflection infrared spectroscopy (ATR). Can know by. In this method, ESCA measures a composition having a depth of several nm to several tens of nm on the surface, and total reflection infrared spectroscopy (ATR) measures a composition having a depth of several μm. It depends. Therefore, if the value of the hydrophobic unit amount ratio obtained by ESCA is 30% or more larger than the value obtained by ATR, the hydrophobic unit amount ratio present on the membrane surface referred to in the present invention is It can be 30% or more larger than the hydrophobic unit amount ratio. In addition, the value of each measurement is an average value of three points. In addition, in the case of the hydrophobic functional group which cannot be detected by ESCA or ATR, it can also be known by acquiring a depth profile combining an analysis electron microscope, ion etching, time-of-flight secondary ion mass spectrometry, or the like.

  Further, as a result of studies by the present inventors, it has been found that when the amount of hydrophobic units in the separation membrane increases, the performance of the separation membrane decreases. This is because, if there is a certain degree of hydrophobicity on the surface of the membrane, the adhesion of proteins and the like is suppressed, but if the hydrophobicity of the membrane as a whole increases, it is not because water and water-soluble substances do not easily permeate. It is thought. That is, when considering the performance of the separation membrane, it is considered that hydrophilicity is preferable for the entire separation membrane.

From the above, the hydrophobic unit amount ratio existing on the membrane surface needs to be 30% or more larger than the hydrophobic unit amount ratio inside the membrane, but preferably 100% or more, and more preferably 300% or more. preferable. Here, the percentage of the hydrophobic unit quantity ratio (S) existing on the membrane surface is calculated by the following formula to indicate what percentage of the hydrophobic unit quantity ratio (I) inside the membrane.
((SI) / I) × 100 (%)
In the present invention, the hydrophobic unit refers to a unit in which a homopolymer composed of the hydrophobic unit is insoluble or hardly soluble in water. Here, insoluble or hardly soluble in water means that the solubility in 100 ml of pure water at 20 ° C. is 1 g or less, preferably 0.1 g or less. Specifically, methacrylic acid esters and acrylic acid esters such as methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, n-butyl methacrylate, and benzyl methacrylate, styrene monomers such as styrene, methyl styrene, and ethyl styrene, vinyl acetate, etc. Examples include a segment made of a polymer or copolymer of monomers such as carboxylic acid vinyl ester, aliphatic hydrocarbon, acrylonitrile, etc., especially vinyl acetate, vinyl caprolactam, aliphatic hydrocarbon, especially those having 2 to 2 carbon atoms. Since 18 linear saturated hydrocarbon groups have a high protein and platelet adhesion-suppressing function, they are preferably used. Here, when the hydrophobic unit has an aromatic functional group such as styrene or naphthalene, the effect of suppressing the adhesion of proteins or the like may be low due to excessive hydrophobicity.

  Moreover, as a preferable ratio of the hydrophobic unit in a copolymer, although it changes with hydrophobic units, it is generally 10 mol%-80 mol%. In particular, when the hydrophobic unit is made of vinyl acetate, 25 to 75 mol% is preferably used, and more preferably 35 to 65 mol%. However, when the vinyl acetate content is 60 mol% or more, it is difficult to dissolve in water. When it consists of vinylcaprolactam, 25-75 mol% is used suitably, More preferably, it is 45-55 mol%. In the case of a straight-chain saturated hydrocarbon having 4 carbon atoms, 1 to 50 mol% is preferably used, and more preferably 5 to 20 mol%.

  As copolymers, block copolymers, alternating copolymers, and random copolymers have higher ability to suppress adhesion of proteins and platelets than graft copolymers, so random copolymers, alternating copolymers, and blocks A copolymer having at least one selected from copolymers is preferably used. This is presumably because, in the graft polymer, the unit part grafted to the main chain has many opportunities to come into contact with proteins and the like, and thus the characteristics of the graft chain part have a greater influence than the characteristics of the copolymer. Moreover, an alternating copolymer and a random copolymer are more preferable than a block copolymer. In the block copolymer, it is thought that the characteristics (hydrophilic part and hydrophobic part) of each unit are clearly separated. From the viewpoint of an appropriate balance between hydrophilicity and hydrophobicity in one molecule, a copolymer having at least one selected from a random copolymer and an alternating copolymer is most preferably used.

  Also, in order to make the hydrophobic unit quantity ratio existing on the membrane surface larger than the hydrophobic unit quantity ratio inside the membrane, the polymer containing the hydrophobic unit is mixed with the membrane forming stock solution of the separation membrane and molded. And a method in which a polymer containing a hydrophobic unit is contacted after forming a separation membrane, for example, a coating method. In the case where the separation membrane is a hollow fiber membrane, an injection solution is allowed to flow inside when discharging from the double annular die, and a polymer containing a hydrophobic unit may be added to the injection solution. Before the hollow fiber membrane is phase-separated and the membrane structure is determined, the polymer containing the hydrophobic unit in the injection solution diffuses toward the membrane-forming stock solution side, so that it can be localized on the inner surface of the membrane. At this time, it is preferable that the weight average molecular weight of the polysulfone-based polymer is small so that the polymer containing the hydrophobic unit easily diffuses into the membrane, and those having a molecular weight of 100,000 or less, and preferably 50,000 or less are suitably used. Further, after the above contact operation, a method of insolubilization by irradiation, heat treatment or both treatments, a method of causing a polymerization reaction to occur on the surface of the separation membrane by immersing the separation membrane in a mixed solution of vinylpyrrolidone monomer and hydrophobic monomer Etc. Also in these cases, a copolymer composed of a vinyl pyrrolidone unit and a hydrophobic unit is preferably used as the polymer containing the hydrophobic unit from the viewpoint of suppressing the adhesion of proteins and the like and handling properties.

  When wet film-forming is performed from a film-forming stock solution, high-molecular weight polymers gather on the surface to prevent entropy loss, and hydrophilic polymers tend to gather to prevent enthalpy loss. Thus, for example, in the case of a polysulfone membrane, a stock solution consisting of a three-component polymer of polysulfone, polyvinylpyrrolidone, and a polymer containing a hydrophobic unit is prepared, and the molecular weight of the polymer containing the hydrophobic unit is made higher than the molecular weight of polyvinylpyrrolidone. By enlarging, it can be concentrated on the surface. However, if the affinity of the polymer containing the hydrophobic unit with the polysulfone is high, the enthalpy effect is more dominant than the entropy effect, and the hydrophobic unit is concentrated not inside the surface but inside the separation membrane. In general, a copolymer with a vinyl pyrrolidone unit is used more favorably than a homopolymer of a hydrophobic unit because the affinity with polysulfone is weaker. In particular, aromatic hydrophobic units often have high affinity with polysulfone, and other hydrophobic units are preferably used.

  If the amount ratio of the hydrophobic unit inside the separation membrane increases, it is difficult to improve the performance of the separation membrane. Specifically, the polymer containing the hydrophobic unit is less than 1 part by weight, preferably less than 0.5 part by weight, and further less than 0.02 part by weight with respect to 100 parts by weight of the constituent components of the separation membrane. .

  The method of coating the polymer containing the hydrophobic unit after forming the separation membrane is preferably used because the hydrophobic unit can be easily present on the surface of the separation membrane. After coating, it may be insolubilized by irradiation, heat treatment or the like. Alternatively, the separation membrane may be immersed in a mixed solution of vinyl pyrrolidone monomer and hydrophobic monomer to cause the polymerization reaction on the surface of the separation membrane.

  Among these, the method of coating the surface of the separation membrane by bringing a copolymer solution of a vinylpyrrolidone unit and a hydrophobic unit into contact with the separation membrane is a preferable method because it can be carried out simply and in a small amount. For example, a copolymer of a vinyl pyrrolidone unit and a hydrophobic unit may be dissolved in water and then contacted, and the copolymer may be adsorbed on a separation membrane. A copolymer of a pyrrolidone unit and a hydrophobic unit may be immobilized. In addition, when the copolymer solution of the vinyl pyrrolidone unit and the hydrophobic unit is brought into contact with the separation membrane surface, the pressure difference between the inside and outside of the separation membrane is collected so that the copolymer that has entered the hollow fiber membrane is accumulated on the inner surface. And the method of concentrating on the membrane surface using the pressure difference is efficient and is preferably used. The pressure difference may be increased or reduced. Even if the copolymer solution of the vinyl pyrrolidone unit and the hydrophobic unit is not introduced to the membrane surface by applying a pressure difference, it may be pressurized with another solution such as gas or water after contacting the solution. The pressure difference between the inside and outside of the separation membrane is preferably 5 kPa or more, more preferably 10 kPa or more, and further preferably 20 kPa or more. In addition, when the pressure difference is high, the separation membrane may leak, so 100 kPa or less is preferable, more preferably 70 kPa or less, and even more preferably 50 kPa or less. The inner side of the separation membrane referred to here means the surface side of the separation membrane functional layer in contact with the treatment liquid, and the outer side means the opposite side. Taking a hollow fiber membrane for an artificial kidney as an example, the surface of the functional layer through which blood as the treatment liquid flows corresponds to the inside, and the opposite surface through which the dialysate flows corresponds to the outside.

  In addition to the copolymer of the vinyl pyrrolidone unit and the hydrophobic unit, the separation membrane contains a water-soluble polymer having a solubility in 100 g of water at 20 ° C. of 1 g or more, preferably 10 g or more. This is preferable from the viewpoint of suppression of platelet adhesion. Specifically, polyvinyl pyrrolidone, polyethylene glycol and the like are preferably used. This is thought to be because the appropriate balance between hydrophilicity and hydrophobicity on the surface is important for suppressing adhesion of proteins and platelets. The amount of the water-soluble polymer contained in the separation membrane is preferably 0.1% by weight or more, more preferably 1% by weight or more. Moreover, since there exists a tendency for film | membrane performance to become low when there is too much content, 30 weight% or less is preferable, More preferably, it is 10 weight% or less. The amount of the water-soluble polymer on the functional layer surface is preferably 10% by weight or more, more preferably 15% by weight or more. Moreover, since the hydrophilic effect will become strong too much, 50 weight% or less is preferable, More preferably, it is 40 weight% or less. The amount of the water-soluble polymer on the functional layer surface can be determined by ESCA or the like.

  Furthermore, a method of insolubilization by irradiation with radiation, heat treatment or the like after coating is a preferable method because it can reduce elution of the copolymer. For example, irradiation or heat treatment may be performed in a state where the separation membrane is immersed in a copolymer solution of vinyl pyrrolidone units and hydrophobic units. Alternatively, the separation membrane may be immersed in a copolymer solution of a vinyl pyrrolidone unit and a hydrophobic unit, and then the solution may be taken out, followed by radiation irradiation or heat treatment. In the case of irradiation with radiation, if a certain amount of solvent is present, the copolymer of the vinyl pyrrolidone unit and the hydrophobic unit tends to be fixed and insolubilized on the separation membrane. This is due to the fact that the solvent becomes radicals upon irradiation with radiation, and this serves as a starting point to radicalize the copolymer and the separation membrane, and the copolymer is crosslinked and insolubilized into the membrane. Therefore, it is preferable that 0.2 weight times or more, further 1.0 weight times of the solvent remains with respect to the dry weight of the separation membrane. In addition, as a solvent, water is used suitably from a viewpoint of handleability. On the other hand, when the separation membrane module is not filled with water, it is preferable that only the separation membrane is wet from the viewpoint that the coated copolymer is less likely to elute during the time until irradiation. . Specifically, it is preferably 6.0 times or less, more preferably 4.0 times or less, with respect to the dry weight of the separation membrane. Alternatively, the separation membrane may be immersed in a copolymer solution of a vinylpyrrolidone unit and a hydrophobic unit, coated with the separation membrane, and then replaced with water or the like before irradiation or heat treatment. Furthermore, radiation or heat treatment may be performed after extracting the substituted water.

  When a copolymer solution of vinyl pyrrolidone units and hydrophobic units is used, the separation membrane cannot be coated sufficiently if the copolymer solution concentration is low. In addition, if the concentration is too high, the amount of eluate increases in many cases. The specific concentration varies depending on the type of copolymer, but is generally preferably 0.0001% by weight or more and 1% by weight or less, and more preferably 0.001% by weight or more and 0.1% by weight. The following is preferred.

  When the polymer that forms the separation membrane is dissolved in the good solvent, the solution contains insoluble components. When the water content of the insoluble components is 95% or more, preferably 97% or more, the separation membrane While suppressing elution of the polymer from the protein, protein adhesion can be more effectively suppressed. In order to suppress protein adhesion, a certain degree of hydrophilicity is required. However, when the separation membrane has a water-soluble polymer such as polyvinylpyrrolidone and no insoluble component is contained, the effect of suppressing adhesion may not be high depending on the type of protein. This is presumably because the protein is trapped in the diffuse layer of polyvinylpyrrolidone present on the membrane surface. If the diffuse layer is in a certain degree of cross-linking, it can be presumed that protein penetration can be suppressed.

About the water content of an insoluble component, it calculates | requires as follows. The dried separation membrane is dissolved with a good solvent to a concentration of 2% by weight. The solution is filtered using filter paper to obtain insoluble components. After thoroughly washing the soluble components with a good solvent, the good solvent 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 can be calculated by the following formula.
Moisture content (%) = (w−d) × 100 / w
For example, in the case of a separation membrane composed of a polysulfone polymer and polyvinylpyrrolidone or vinylpyrrolidone / vinyl acetate (6/4), dimethylacetamide is a good solvent.

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

  The dispersion state of the polymer in the hollow fiber membrane also affects the crosslinking reaction. That is, it is preferable that the crosslinkable polymer is finely dispersed in the hollow fiber membrane. Factors affecting the dispersion state of the polymer in the hollow fiber membrane include the composition ratio of the membrane forming stock solution, the stirring speed, the stirring time, the time to film formation after dissolution, and the copolymer of vinylpyrrolidone units and hydrophobic units. Is added to the injection solution, the injection solution composition, the injection solution temperature, and the coating method for coating the copolymer of the vinylpyrrolidone unit and the hydrophobic unit may be mentioned.

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

  Further, as a method for removing the soaked vinylpyrrolidone unit and hydrophobic unit copolymer solution, water, and the like, various methods such as reduced-pressure drying, high-temperature drying, low-temperature air drying, and blow drying can be used. In addition, it is known that when oxygen is present at the time of irradiation, oxygen radicals are generated and the polymer material of the separation membrane material is decomposed. Therefore, the oxygen concentration around the separation membrane when irradiated with radiation is desirably 10% or less. In the case of irradiating the separation membrane module with radiation, for example, the inside of the module is purged with nitrogen gas and then sealed, so that the oxygen concentration is lowered and the radiation is irradiated.

  In addition, as a procedure for incorporating the separation membrane into the module, the separation membrane may be coated with a copolymer of a vinylpyrrolidone unit and a hydrophobic unit and then incorporated into the module, and the separation membrane module incorporating the separation membrane may be incorporated in the module. Coating or the like may be performed by filling the polymer solution. After coating or the like, radiation irradiation or heat treatment may be performed as described above.

  A separation membrane coated with a copolymer of a vinyl pyrrolidone unit and a hydrophobic unit can exhibit high separation performance. For example, in the case of a copolymer in which vinyl pyrrolidone units are replaced with vinyl alcohol and vinyl acetate is used as a hydrophobic unit, the separation performance is significantly reduced by coating. This may be because the hydroxyl group of vinyl alcohol and water molecules or solute molecules are constrained by hydrogen bonds or the like and are difficult to pass through the membrane, but the detailed reason is unknown.

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

  When performing sterilization and modification of the substrate at the same time, an irradiation dose of 15 kGy or more is preferable. This is because 15 kGy or more is effective for sterilizing blood purification modules and the like with γ rays. However, when the irradiation dose is 100 kGy or more, blood compatibility is deteriorated because three-dimensional crosslinking or collapse of the copolymer of the vinyl pyrrolidone unit and the hydrophobic unit occurs.

  Further, in the step of coating the separation membrane with a copolymer of vinyl pyrrolidone unit and hydrophobic unit, and insolubilizing the copolymer by radiation, the copolymer in the copolymer solution of vinyl pyrrolidone unit and hydrophobic unit. Other components, for example, an antioxidant may be contained. Further, the separation membrane may be coated with a copolymer solution of vinyl pyrrolidone units and hydrophobic units, and then contacted with an antioxidant solution.

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

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

  In the present invention, the separation membrane 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, filtration, or diffusion.

  Since the separation membrane of the present invention has a high adhesion suppressing function, 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.

  The material to be the separation membrane of the present invention is not particularly limited, but a material used for medical use is preferable, for example, polyvinyl chloride, cellulosic polymer, polypropylene, polyacrylonitrile, polystyrene, polymethyl methacrylate, polycarbonate, Examples include polysulfone polymers such as polysulfone and polyethersulfone, and polyurethane. Among these, a polysulfone polymer is particularly preferably used because it is easy to mold and has excellent material permeation performance when formed into a membrane.

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

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

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

  An example of a method for producing an artificial kidney as a blood purification module will be described. First, as a method for producing a hollow fiber membrane as a separation membrane, polysulfone and polyvinylpyrrolidone (weight ratio of 20: 1 to 1: 5 is preferable, and 5: 1 to 1: 1 is more preferable) are used as a good solvent for polysulfone (N , N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane and the like) and a stock solution dissolved in a poor solvent (concentration is preferably 10 to 30% by weight, preferably 15 to 25% by weight) Is more preferable), when the injection solution is discharged from the double annular die, the injecting solution is flowed inward, 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. Therefore, the relative humidity is preferably 60 to 90%. Moreover, it is preferable to use what consists of a composition based on the solvent used for the undiluted | stock solution as an injection | pouring liquid composition from process suitability. For example, when dimethylacetamide is used as an injection solution concentration, an aqueous solution of 45 to 80% by weight, more preferably 60 to 75% by weight, is preferably used.

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

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

EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited by these examples.
1. Production of hollow fiber membrane module (1) Polysulfone / polyvinylpyrrolidone (PSf / PVP) mixed hollow fiber membrane 16 parts by weight of polysulfone (Amoco Udel-P3500), polyvinylpyrrolidone (International Special Products Co .; hereinafter abbreviated as ISP) K30 3 Part by weight and 3 parts by weight of polyvinylpyrrolidone (ISP K90) were dissolved by heating with 77 parts by weight of dimethylacetamide and 1 part by weight of water to obtain a film forming stock solution.

This 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 the annular slit part. After discharging and forming a hollow fiber membrane, it passes through a 350 mm dry zone atmosphere at a temperature of 30 ° C. and a dew point of 28 ° C., and then passed through a coagulation bath at a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water. A hollow fiber membrane obtained by passing through a water washing step at 60 to 75 ° C. for 90 seconds and a drying step at 130 ° C. for 2 minutes and a crimping step at 160 ° C. was used as a wound bundle. The case is filled so that the total membrane area of the hollow fiber membrane is 1.6 m ² , both ends of the hollow fiber membrane are fixed to the case end portion with a potting material, and a part of the end portion of the potting material is cut. Thus, the hollow fiber membranes at both ends were opened to obtain an artificial kidney module.

(2) Polysulfone (PSf) hollow fiber membrane 18 parts by weight of polysulfone (Amoco Udel-P3500) was dissolved by heating with 81 parts of dimethylacetamide and 1 part of water to obtain a membrane forming stock solution.

  This stock solution is sent to a spinneret at a temperature of 50 ° C., and a solution comprising 63 parts of dimethylacetamide and 37 parts of water is injected as an injection from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. After forming the hollow fiber membrane, after passing through a dry zone atmosphere with a dry length of 350 mm having a temperature of 30 ° C. and a dew point of 28 ° C., a coagulation bath having a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water Passing through a water washing step of 60 ° C./90 seconds, the hollow fiber membrane (hollow fiber membrane 2) was taken up as a wound bundle.

(3) Examination of addition of polymer to injection solution Polysulfone (Amoco Udel-P3500 (weight average molecular weight 47,000)) 18 parts by weight, polyvinylpyrrolidone (International Special Products, Inc .; hereinafter referred to as ISP) 9 parts by weight The solution was heated and dissolved in 72 parts by weight of dimethylacetamide and 1 part by weight of water to obtain a stock solution.

  10 parts by weight of a vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “Collidon VA64”) was dissolved in a solution of 63 parts by weight of dimethylacetamide and 37 parts by weight of water to prepare an injection solution.

  The membrane-forming stock solution is fed to a spinneret at a temperature of 50 ° C., and the injection solution is discharged from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm to form a hollow fiber membrane. Through a 350 mm dry zone atmosphere at 30 ° C. and 28 ° C. dew point, passed through a coagulation bath at a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water, and washed with water at 60 to 75 ° C. for 90 seconds, 130 A hollow fiber membrane (hollow fiber membrane 3) obtained by passing through a drying step at 2 ° C. for 2 minutes and undergoing a crimping step at 160 ° C. was used as a wound bundle.

Further, a hollow fiber membrane (hollow fiber membrane 4) was prepared in the same manner as described above, using a solution having a composition in which Kollidon VA64 was not added to the injection solution.
2. Measurement Method (1) Human Platelet Adhesion Test Method for 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% glutaraldehyde physiological saline, and washed with 20 ml of distilled water. The washed hollow fiber membrane was dried under reduced pressure at room temperature of 0.5 Torr for 10 hours. This hollow fiber membrane was attached to a sample stage of a scanning electron microscope with a double-sided tape. Thereafter, a thin film of Pt—Pd was formed on the surface of the hollow fiber membrane by sputtering to prepare a sample. The inner surface of the hollow fiber membrane was observed with a field emission type scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times. In one field of view (4.3 × 10 ³ μm ² ) The number of adherent platelets was counted. The average value of the number of adhering platelets in 10 different visual fields near the center in the longitudinal direction of the hollow fiber was defined as the number of adhering platelets (pieces / 4.3 × 10 ³ μm ² ). The end portion in the longitudinal direction of the hollow fiber was removed from the target of the number of adhesion because blood pools were easily formed.

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

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

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

1 mL of plasma was circulated at a flow rate of 0.5 mL / min for 2 hours. A hollow fiber was cut out from a mini module in an amount corresponding to 24 cm, cut into a length of about 1 mm, and placed in an Eppendorf tube. It was washed with a phosphate buffer (hereinafter abbreviated as PBS) (1 mL × 3 times, repeated if blood remained). Tween-20 (Katayama Chemical) was adjusted to 0.05 wt% with PBS (hereinafter abbreviated as PBS-T). Skimmed milk was dissolved in PBS-T so that it might become 0.1 weight%, and it wash | cleaned 3 times with this solution. The anti-human fibrinogen (HPR) antibody was diluted 10,000 times with a 0.1% by weight skim milk / PBS-T solution, added with 1 mL, and then rotated and stirred at room temperature for 2 hours with a rotator. After washing twice with 0.1 wt% skim milk / PBS-T solution, it was washed twice with 0.1 wt% skim milk / PBS solution. 1 mL of TMB one solution was added and stirred with a micromixer. The reaction was stopped by adding 200 μL of 6N hydrochloric acid in view of the color development (the reaction was controlled so that the absorbance of the control described later falls within the range of 1 to 1.5). Absorbance at 450 nm was measured. As a control, Toray's artificial kidney “Tresulfone” TS-1.6UL was used. From the absorbance (Ac) of the control and the absorbance (As) of the target sample, the relative adhesion amount of fibrinogen was determined by the following formula.
Fibrinogen relative adhesion rate (%) = As / Ac × 100.
(3) β ₂ -microglobulin (β ₂ -MG) clearance measurement For bovine blood to which disodium ethylenediaminetetraacetate was added, the hematocrit was 30 ± 3% and the total protein amount was 6.5 ± 0.5 g / dL. Adjusted as follows.

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

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

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

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

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

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

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

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

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

Co (ml / min) = (CBi−CBo) × Q _B / CBi
In the above formula, C _O = β ₂ -microglobulin clearance (ml / min), CBi = β ₂ -microglobulin concentration in Bi solution, CB _o = β ₂ -microglobulin concentration in Bo solution, Q _B = Bi pump Flow rate (ml / min).
(4) Measurement of the amount ratio of vinyl acetate units on the surface and inside of the separation membrane The amount ratio of vinyl acetate units on the surface and inside of the separation membrane was compared by the abundance ratio with respect to polysulfone. X-ray electron spectroscopy was used to measure the amount ratio of vinyl acetate units on the surface. ESCA LAB220iXL was used as a measuring apparatus, a sample was set in the apparatus, and the detector was measured at an angle of 90 degrees with respect to the incident angle of X-rays. At this angle, the measurement depth is about 10 nm.

  The hollow fiber membrane was thoroughly washed with ultrapure water and then dried at room temperature and 0.5 Torr for 10 hours. Thereafter, the hollow fiber membrane was cut into a semicylindrical shape with a single blade, and the amount ratio of vinyl acetate units on the inner surface of the hollow fiber membrane was measured. Furthermore, a part of the inner surface of the hollow fiber membrane was scraped with a single blade to expose the film thickness portion, and the vinyl acetate unit quantity ratio was measured. Measuring 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)
The amount ratio of vinyl acetate units on the surface can be obtained by dividing the peak because an ester group (COO) peak appears in the C1s peak. More specifically, C1s mainly includes components derived from CHx, C—C, C═C, C—S, components derived mainly from C—O, C—N, and components derived from π-π * satellites. , C = O-derived component, and ester group (COO) -derived component. Therefore, peak splitting is performed with five components. The COO-derived component is a peak appearing at +4.0 to 4.2 eV from the C1s CH or C—C main peak (near 285 eV). The peak area ratio of each component is calculated by rounding off the first decimal place. The ratio of the peak area to all elements (all atoms other than hydrogen atoms cannot be detected since hydrogen atoms cannot be detected) was calculated to determine the ester group amount (carbon amount of COO) (number of atoms%). Here, if it was 0.4% or less as a result of peak division, it was made below the detection limit. Further, the amount of polysulfone can be obtained by determining the amount of sulfur because one sulfur atom exists per repeating unit of polysulfone. Therefore, surface vinyl acetate unit amount ratio = ester group amount (number of atoms%) / sulfur amount (number of atoms%).

The amount of vinylpyrrolidone unit on the surface was 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 vinylpyrrolidone amount (% by weight) = (a × 111 / (a × 111 + b × 442)) × 100
The internal vinyl acetate unit amount ratio was determined by performing ATR measurement. The measurement conditions were a resolution of 4 and an integration count of 64. The intensity of the C═O peak derived from the ester group near 1730 cm ⁻¹ (A _CO ) and the intensity of the C═C absorption peak derived from the benzene ring of polysulfone near 1580 cm ⁻¹ (A _CC ) were determined. ATR is a measurement depth from the surface to about 2-3 μm.

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

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

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

For the following Examples 1 to 9 and Comparative Examples 1 to 5, a polysulfone / polyvinylpyrrolidone (PSf / PVP) mixed hollow fiber membrane (hollow fiber membrane 1) was used.
Example 1
500 mL of a 0.1% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “Collidon VA64”) was passed from the blood side inlet to the blood side outlet of the hollow fiber membrane module. Next, VA64 was accumulated on the inner surface of the hollow fiber membrane by passing 500 mL from the blood side inlet to the dialysate side inlet. In order to accumulate VA64 that has entered the hollow fiber membrane on the inner surface, the filling solution was pushed out from the dialysate side to the blood side with 100 kPa compressed air. Thereafter, the filling solution on the blood side was blown to maintain the aqueous solution only in the hollow fiber membrane. Further, each of the dialysate side and the blood side was blown with nitrogen, and then the module was irradiated with γ rays. The module was subjected to platelet adhesion test, β ₂ -microglobulin clearance measurement, and measurement of the amount of vinyl acetate units in the membrane surface and inside. The results are shown in Table 1. That is, VA64 could be uniformly and locally localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high.
(Example 2)
The same operation as in Example 1 was performed, except that “Colidon VA64” 0.01 wt% aqueous solution was used. The results are shown in Table 1. That is, VA64 could be uniformly and locally localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high. The reason why β ₂ -microglobulin removal performance is higher than that of Comparative Example 1 is that the VA64 covers the functional layer surface and the effect of suppressing adhesion of proteins and the like is higher than the effect of narrowing the pore diameter. This is probably because there was little performance degradation due to clogging. The water content of the insoluble component was 95.2%, and the relative adsorption rate of fibrinogen was 65%.
(Example 3)
The same operation as in Example 1 was carried out except that “Kollidon VA64” 0.001 wt% aqueous solution was used. The results are shown in Table 1. That is, a large amount of VA64 could be localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high. The reason why the platelet adhesion inhibitory ability is slightly reduced as compared with Examples 1 and 2 is considered to be because the amount of VA64 on the surface of the functional layer is small as compared with Examples 1 and 2.
Example 4
The same operation as in Example 1 was performed except that a mixed aqueous solution of “Kollidon VA64” 0.001 wt% and ethanol 0.1 wt% was used. The results are shown in Table 1. That is, VA64 could be uniformly and locally localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high. Despite the same treatment concentration as VA64, the reason why the platelet adhesion inhibitory activity is higher than that in Example 3 is considered to be that γ-rays were protected against VA64 by ethanol. The water content of the insoluble component was 97.3%, and the relative adsorption rate of fibrinogen was 28%. Compared to Example 1, even though the platelet adhesion number was the same, fibrinogen adhesion was suppressed to less than half.
(Example 5)
“Collidon VA64” 0.01 wt% aqueous solution was filled in the same operation as in Example 1, but no blow with compressed air was performed. The results are shown in Table 1. That is, even when γ-ray irradiation is performed with the membrane immersed in a VA64 solution, a large amount of VA64 can be uniformly localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance is high. It was.
(Example 6)
The same operation as in Example 1 was performed except that a 0.1% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (7/3) copolymer (manufactured by BASF, “Lubicol VA73”) was used. The results are as shown in Table 1, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high. That is, a large amount of VA73 could be localized on the functional layer surface. Platelet adhesion was suppressed as compared with Comparative Example 1, but was slightly higher than that of Example 1. This is presumably because VA73 has few ester groups which are hydrophobic units in the molecule, and the balance between hydrophilicity and hydrophobicity is worse than VA64, and therefore it is inferior in adhesion suppression.
(Example 7)
Vinyl pyrrolidone / vinyl acetate (3/7) copolymer (manufactured by BASF, “Lubicol VA37”) 0.1 wt% methanol solution was passed from the blood side inlet of the hollow fiber membrane module to the blood side outlet, Next, filling was performed in the order of passing from the blood side inlet to the dialysate side outlet. Further, water was passed in the same manner, and then blown, purged with nitrogen and irradiated with γ rays in the same manner as in Example 1. The results are as shown in Table 1. Even when water-insoluble vinylpyrrolidone / vinyl acetate (3/7) copolymer was introduced into the separation membrane with an alcohol aqueous solution and replaced with water, γ-rays were irradiated. It was possible to achieve both high separation membrane performance and platelet adhesion inhibition. That is, VA37 could be uniformly and locally localized on the surface of the functional layer, and platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high.
(Reference Example 1)
A vinyl pyrrolidone / vinyl caprolactam (5/5) copolymer (manufactured by BASF, “Rubitec” VPC55K65W) was used in the same manner as in Example 1 except that a 0.1 wt% aqueous solution was used. Accumulated. The results are shown in Table 1. The results are shown in Table 1. That is, a large amount of VPC55K65W could be localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high.
(Reference Example 2)
The same operation as in Example 1 was carried out except that a 0.1% by weight aqueous solution of vinylpyrrolidone / 1-butene (90/10) copolymer (manufactured by ISP, “Ganex” P-904LC) was used. P-904LC was accumulated in The results are shown in Table 1. The results are shown in Table 1. That is, a large amount of Ganex P-904LC could be localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high.
(Comparative Example 1)
The same operation as in Example 1 was performed except that water was used instead of the vinylpyrrolidone / vinyl acetate (6/4) copolymer. The results are shown in Table 1. Although β ₂ -microglobulin removal performance was high, it was a surface to which many platelets adhered. The water content of the insoluble component was 94.7%, and the relative adsorption rate of fibrinogen was 110%.
(Comparative Example 2)
The same operation as in Example 1 was performed except that a 0.01% by weight aqueous solution of polyvinylpyrrolidone (manufactured by BASF, K90) was used. The results are shown in Table 1. In other words, even when a hydrophilic vinylpyrrolidone homopolymer was used, it was a surface to which platelets adhere well.
(Comparative Example 3)
The same operation as in Example 1 was performed except that a 0.01% by weight aqueous solution of polyethylene glycol (molecular weight 50,000) was used. The results are shown in Table 1. Polyethylene glycol is a hydrophilic polymer that dissolves well in water, but has a surface on which many platelets adhere.
(Comparative Example 4)
The purpose of filling “Coridon VA64” from the surface to the inside of the hollow fiber membrane is to pass 0.1% by weight aqueous solution of “Coridon VA64” from the blood side inlet to the blood side outlet of the hollow fiber membrane module. Filling was performed in the order of passing from the dialysate side inlet to the dialysate side outlet. The module was irradiated with γ rays while being filled with the aqueous solution. The results are shown in Table 1. That is, since the amount of VA64 is too large on the surface and inside of the functional layer, the platelet adhesion is suppressed, but the β ₂ -microglobulin removal performance is remarkably low.

(Comparative Example 5)
A vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “Collidon VA64”) is the same as in Example 1 except that a mixed aqueous solution of 0.0001% by weight and ethanol 0.1% by weight was used. The operation was performed. The results are shown in Table 1. That is, since VA64 cannot be localized on the surface of the functional layer, the platelet adhesion inhibitory property was hardly recognized. The water content of the insoluble component was 97.1%, and the relative adsorption rate of fibrinogen was 105%. Compared to Example 4, the water content of the insoluble component is about the same, but the amount of ester groups on the inner surface of the hollow fiber membrane is small, so it is considered that fibrinogen adhesion could not be suppressed.
(Comparative Example 6)
The same operation as in Example 1 was performed except that a 0.1% by weight aqueous solution of polyvinyl alcohol (PVA) (molecular weight 10,000, saponification degree 80%) was used. The results are shown in Table 1. That is, although a large amount of PVA could be localized on the functional layer surface, the β ₂ -microglobulin removal performance was a low value.

  For Example 10 and Comparative Example 7 below, a polysulfone (PSf) hollow fiber membrane (hollow fiber membrane 2) was used.

(Example 8)
A plastic tube mini-module having an effective length of 100 mm, in which 36 polysulfone (PSf) hollow fiber membranes (hollow fiber membrane 2) were passed through the plastic tube and both ends were fixed with an adhesive, was prepared and thoroughly washed with pure water. Next, 3 mL of a 0.01% by weight aqueous solution of vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “Collidon VA64”) was passed through the inside of the hollow fiber membrane, and then the inside of the hollow fiber membrane. 3 mL was allowed to flow outward from. Thereafter, the inner and outer solutions were blown out and then irradiated with 25 kGy of γ rays. After the γ-ray irradiation, various tests were performed after thoroughly washing with pure water.

As the performance of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured by the following method. That is, β ₂ -microglobulin was added to 37 ° C. bovine serum so that the concentration was 5 mg / L. This was flowed to the blood side of the minimodule at 1 mL / min, and 37 ° C. physiological saline was flowed to the dialysate side at 20 mL / min. After circulating for 2 hours, the bovine serum on the blood side and the physiological saline on the dialysate side were collected in full volume and requested to SRL for analysis, and the concentration of β ₂ -microglobulin was measured. From the measurement result, the clearance converted to an effective membrane area of 1.8 m ² was calculated.

Moreover, since the clearance measurement of (beta) _2- microglobulin in a minimodule has the dispersion | variation in the numerical value for every experiment, control was added for every experiment and the comparison between experiments was performed. For control, a hollow fiber membrane made of Toray's artificial kidney “Tresulfone” TS-1.6UL was used. TS-1.6UL used for control was the same production lot. The relative removal rate (%) was obtained by comparing with the measurement result of TS-1.6UL as a percentage, and comparison between experiments was performed using this value.

The results are shown in Table 2. That is, VA64 could be uniformly and locally localized on the surface of the functional layer, and the platelet adhesion inhibitory and β ₂ -microglobulin removal performance was high. Moreover, it is thought that the inhibitory effect of platelet adhesion was slightly inferior to Example 2 because of the hollow fiber membrane having a single composition of polysulfone and the absence of PVP which is a water-soluble polymer.

(Comparative Example 7)
The same operation as in Example 8 was performed except that water was used instead of VA64. The results are shown in Table 2. That is, it was a surface to which platelets adhered well.

  The following Example 9 and Comparative Example 8 were compared using membranes (hollow fiber membranes 3 and 4) in which vinyl pyrrolidone units and copolymers of hydrophobic units were added to the injection solution.

Example 9
A plastic tube mini module having an effective length of 100 mm, in which 36 hollow fiber membranes 3 were passed through a plastic tube and both ends were fixed with an adhesive, was thoroughly washed with pure water. The water inside and outside the hollow fiber membrane was extracted by compressed air blow, and then irradiated with 25 kGy of γ rays. After the γ-ray irradiation, various tests were performed after thoroughly washing with pure water. As the performance of the hollow fiber membrane, the clearance of β ₂ -microglobulin was measured in the same manner as in Example 8. The results are shown in Table 3. That is, platelet adhesion was suppressed and β ₂ -microglobulin removal performance was high. Compared to Comparative Example 8, the reason why β ₂ -microglobulin removal performance is high is that VA64 covers the surface of the functional layer and the adhesion suppressing effect of proteins and the like is high, so that the performance degradation due to clogging of the membrane due to proteins was small. it is conceivable that.

(Comparative Example 8)
36 hollow fiber membranes 4 were passed through a plastic tube, the same operation as in Example 9 was performed, and the same evaluation was performed on the obtained hollow fiber membranes. The results are shown in Table 3. That is, it was a surface to which a large amount of platelets adhered, and the β ₂ -microglobulin removal performance was lower than that of Example 9.

1 Hollow fiber membrane 2 Case 3 Potting agent 4 Blood side inlet (Bi)
5 Blood side outlet 1 (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 (8)

A polysulfone-based separation membrane surface vinylpyrrolidone unit and a hydrophobic unit other than polysulfone units, said hydrophobic units of methacrylic acid esters, acrylic acid esters, styrene monomers, vinyl carboxylate, aliphatic hydrocarbons and acrylonitrile Is a segment composed of a polymer or copolymer of a monomer selected from the above, and the hydrophobic unit amount ratio present on the surface of the membrane having the separation functional layer is more than the hydrophobic unit amount ratio present in the membrane The separation membrane contains a component that is larger than 30% and is insoluble in a solution in which the separation membrane having the polysulfone-based polymer, the vinylpyrrolidone unit and the hydrophobic unit is dissolved in a good solvent at a concentration of 2% by weight, The water content of the insoluble component is 95% or more Polysulfone-based separation membrane, characterized in that. 2. The polysulfone separation membrane according to claim 1, wherein the vinyl pyrrolidone unit and the hydrophobic unit constitute a copolymer. The polysulfone separation membrane according to claim 1 or 2, wherein the copolymer has at least one selected from a random copolymer, an alternating copolymer, and a block copolymer. The polysulfone separation membrane according to any one of claims 1 to 3 , wherein a ratio of the hydrophobic unit in the copolymer is 10 to 80 mol%. The polysulfone-based separation membrane according to any one of claims 1 to 4 , which is a separation membrane for blood purification. A polysulfone-based separation membrane module comprising the polysulfone-based separation membrane according to any one of claims 1 to 5 . A copolymer solution composed of a vinylpyrrolidone unit and a hydrophobic unit other than a polysulfone unit , wherein the hydrophobic unit is a methacrylic acid ester, an acrylic acid ester, a styrene monomer, a carboxylic acid vinyl ester, an aliphatic hydrocarbon. And a polysulfone-based separation membrane module, wherein the copolymer solution , which is at least one unit selected from acrylonitrile, is irradiated and / or heat-treated in contact with the surface having the separation functional layer in the polysulfone-based separation membrane Manufacturing method. The polysulfone separation membrane according to claim 7 , wherein a pressure difference is provided between the inside and outside of the separation membrane when the copolymer solution of the vinyl pyrrolidone unit and the hydrophobic unit is brought into contact with the polysulfone separation membrane. Module manufacturing method.

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