JP6036882B2 - Separation membrane, separation membrane module, method for producing separation membrane, and method for producing separation membrane module - Google Patents

Description

The present invention comprises at least three components: (A) a polymer composed solely of hydrophobic units , (B) a polymer composed solely of hydrophilic units, and (C) a copolymer polymer composed of water-soluble units and hydrophilic units. The present invention relates to a separation membrane and a method for manufacturing the separation membrane module. The present invention is suitably used for applications that require blood compatibility, non-adhesion of proteins and organic substances, and non-elution of membrane components while maintaining high separation performance. For example, a separation membrane for blood purification requires blood compatibility, non-adhesion of proteins and platelets, and non-elution of membrane components while maintaining high protein separation performance. In addition, membranes for water purifiers, water purification membranes, sewage purification membranes, reverse osmosis membranes, membranes for biological component separation, etc., while maintaining high separation performance of organic substances, non-adhesion of proteins and organic substances, non-elution of membrane components Is required. Therefore, in this field, the separation membrane and the method for producing a separation membrane module of the present invention are preferably used.

In separation membranes for blood purification that come into contact with blood, the adhesion of proteins and platelets can cause serious degradation of the performance of the separation membrane and cause biological reactions. Moreover, also in water treatment membranes, such as a water purifier, adhesion of protein or organic substance causes the performance fall of a separation membrane. To solve this problem, attempts have been made to make the separation membrane hydrophilic, and various studies have been made.
For example, a method of suppressing contamination by imparting hydrophilicity to a membrane by mixing polyvinyl pyrrolidone, which is a homopolymer of a hydrophilic polymer, with a polysulfone polymer at the stage of forming a membrane solution (Patent Document 1). ) Is disclosed. However, this method is limited to a polymer that is compatible with the base polymer, and the hydrophilicity of the membrane surface is not sufficient. There are constraints such as the need to increase the amount and the need to study the optimal stock solution composition according to the intended use of the material.

On the other hand, a method of introducing a hydrophilic component such as polyvinylpyrrolidone that is insolubilized in water by radiation or heat during the film forming process (Patent Document 2), or a polyvinylsulfuridone for a separation membrane of a polysulfone polymer A method of forming a coating layer insolubilized by radiation crosslinking after contacting a hydrophilic polymer homopolymer solution (Patent Document 3) is disclosed. However, according to the above method, although the blood compatibility is better than mixing at the film-forming stock solution stage, the hydrophilic polymer homopolymer such as polyvinylpyrrolidone and the polysulfone polymer have weak intermolecular interaction. For this reason, it is difficult to form a coating layer, and the effluent from the separation membrane may increase.
Therefore, an aqueous solution of polyvinyl alcohol, which is a copolymer polymer composed of a hydrophilic unit and a hydrophobic unit, having a degree of saponification within a certain range is brought into contact with a polysulfone separation membrane, so that the polysulfone polymer and vinyl acetate of polyvinyl alcohol are contacted. A method of efficiently forming a coating layer on the surface of a membrane by hydrophobic interaction with the above (Patent Document 4) is disclosed. Although this method increases the protein and platelet adhesion inhibitory effect, it has been found that these separation membranes cause performance degradation. In this document, the protein adhesion suppressing effect of the separation membrane is only described as having a balance between hydrophilicity and hydrophobicity of the hydrophilic polymer, and details are not described.
Also disclosed is a method for producing a separation membrane by dissolving a polysulfone polymer and a graft copolymer or / and block copolymer made of polyvinylpyrrolidone and polystyrene in a membrane forming stock solution (Patent Document 5). However, these separation membranes are not preferable in terms of blood compatibility because the type of hydrophobic unit is not optimal.
In addition, hydrophilicity was imparted to the polysulfone polymer separation membrane by attaching polyvinyl acetal diethylaminoacetate, which is a copolymer comprising a hydrophilic unit and a hydrophobic unit, and one or more additional components. A method of manufacturing a separation membrane (Patent Document 6) is disclosed. Examples of the additive component disclosed in Patent Document 6 include polyvinylpyrrolidone which is a hydrophilic polymer, polyvinyl alcohol which is a copolymer polymer composed of a hydrophilic unit and a hydrophobic unit, and a vinylpyrrolidone-vinyl acetate copolymer. Is listed. Although the hydrophilicity of the separation membrane is improved by these methods, polyvinyl acetal diethylaminoacetate has a solubility in pure water at 20 ° C. of less than 1 g / 100 g, so the balance between hydrophilicity and hydrophobicity is not optimal and is not preferable. .

  That is, a separation membrane production method that achieves blood compatibility, suppression of protein and organic matter adhesion, and reduction of eluate from membrane components while maintaining high separation performance has not yet been established.

Japanese Patent Publication No. 2-18695 Japanese Patent Publication No.8-9668 JP-A-6-238139 JP 2006-198611 A Japanese Patent Publication No. 1997/13575 JP-A-8-131791

As a result of diligent investigations to achieve the above-mentioned problems, the present inventors have simultaneously achieved blood compatibility, suppression of protein and organic matter adhesion, and reduction of eluate from membrane components while maintaining high separation performance. The separation membrane and the separation membrane module . These are achieved by the following configurations 1 to 15 .
1. (A) a sex polymer composed only of hydrophobic units , (B) a polymer composed only of hydrophilic units, and (C) a copolymer polymer composed of hydrophilic units and hydrophobic units. ,
(A) has a solubility in pure water at 20 ° C. of less than 1 g / 100 g,
The glass transition point of (B) is 90 ° C. or higher, and the solubility in pure water at 20 ° C. is 10 g / 100 g or higher,
The glass transition point of (C) is 90 ° C. or higher, the solubility in pure water at 20 ° C. is 1 g / 100 g or higher , and the gelation concentration by γ-ray irradiation at an irradiation dose of 25 kGy is 2.0% by weight. And
The abundance ratio of (B) and (C) is 5% by weight or less,
Said (C) is a separation membrane which exists 5weight% or more in an upper surface or a lower surface.
2. When the amount of adsorption when the (C) is brought into contact with the film (A) in water is Aw and the amount of adsorption when the film is brought into contact with a 20 wt% acetonitrile mixed solution is Aa, Aa 2. The separation membrane as described in 1 above, wherein / Aw is 0.95 or less.
3 . The 600 wt%抱液of 10 wt% or more of the separation membrane below and water permeability 150mL / ^hr / m 2 / mmHg or more, the one or equal to or less than 900mL / ^hr / m 2 / mmHg 2. The separation membrane according to 2 .
4 . 4. The separation membrane according to any one of 1 to 3 , wherein (A) is a polysulfone polymer.
5 . 5. The separation membrane according to any one of 1 to 4 , wherein (B) is polyvinyl pyrrolidone and / or polyethylene glycol.
6 . Any one of 1 to 5 above, wherein the hydrophilic unit (C) is vinyl pyrrolidone and / or ethylene glycol, and the hydrophobic unit (C) is vinyl acetate and / or vinyl caprolactam. The separation membrane described.
7 . The separation membrane according to any one of 1 to 6 , wherein the separation membrane is used for blood purification.
8 . 8. A separation membrane module comprising the separation membrane according to any one of 1 to 7 above.
9 . (A) and a polymer composed only of hydrophobic units satisfies the following (a), (B) and a polymer composed only of hydrophilic units satisfies the following (b), the separation membrane composed of, (C) below (c copolymer polymer solution comprising a hydrophilic unit and a hydrophobic unit satisfying), after contacting the method for producing a separation membrane, which comprises irradiating the high energy beam.
(A) Solubility in pure water at 20 ° C. is less than 1 g / 100 g
(B) The glass transition point is 90 ° C. or higher and the solubility in pure water at 20 ° C. is 10 g / 100 g or higher.
(C) The glass transition point is 90 ° C. or higher, the solubility in pure water at 20 ° C. is 1 g / 100 g or more, and the gelation concentration by irradiation with γ rays at an irradiation dose of 25 kGy is 2.0 wt% or less
10 . 10. The method for producing a separation membrane according to 9, wherein the solution of (C) is contacted at 20 ° C. or more and 60 ° C. or less.
11 . (9) The method according to ( 9) or (10) above, further comprising the step of removing the solution of (C) after contacting the separation membrane until the liquid retention rate of the separation membrane is 10 wt% or more and 600 wt% or less. The manufacturing method of the separation membrane of description.
12 . The method for producing a separation membrane according to any one of 9 to 11 , wherein (A) is a polysulfone polymer.
13 . Said (B) is polyvinylpyrrolidone and / or polyethyleneglycol, The manufacturing method of the separation membrane in any one of said 9-12 characterized by the above-mentioned.
14 . Any of 9 to 13 above, wherein the hydrophilic unit (C) is vinyl pyrrolidone and / or ethylene glycol, and the hydrophobic unit (C) is vinyl acetate and / or vinyl caprolactam. The manufacturing method of the separation membrane of description.
15 . 15. A method for producing a separation membrane module comprising the separation membrane according to any one of 9 to 14 above.

As a result of diligent investigations to achieve the above-mentioned problems, the present inventors have simultaneously achieved blood compatibility, suppression of protein and organic matter adhesion, and reduction of eluate from membrane components while maintaining high separation performance. The separation membrane and the separation membrane module are achieved by the following configurations 1 to 16.
1. (A) a hydrophobic polymer, (B) a polymer composed only of a hydrophilic unit, and (C) a copolymer polymer composed of a hydrophilic unit and a hydrophobic unit.
The glass transition point of (B) is 90 ° C. or higher, and the solubility in pure water at 20 ° C. is 10 g / 100 g or higher,
The glass transition point of (C) is 90 ° C. or higher, and the solubility in pure water at 20 ° C. is 1 g / 100 g or higher,
The abundance ratio of (B) and (C) is 5% by weight or less,
Said (C) is a separation membrane which exists 5weight% or more in an upper surface or a lower surface.
2. When the amount of adsorption when the (C) is brought into contact with the film (A) in water is Aw and the amount of adsorption when the film is brought into contact with a 20 wt% acetonitrile mixed solution is Aa, Aa 2. The separation membrane as described in 1 above, wherein / Aw is 0.95 or less.
3. (1) or (2), wherein (B) and (C) are 5% by weight or less of the entire separation membrane, and (C) is present at 5% by weight or more on any surface of the separation membrane. 2. The separation membrane according to 2.
4). The above-mentioned 1-3, wherein the separation membrane has a liquid retention of 10% by weight to 600% by weight and a water permeability of 150 mL / hr / m ² / mmHg or more and 900 mL / hr / m ² / mmHg or less. The separation membrane according to any one of the above.
5. 5. The separation membrane according to any one of 1 to 4, wherein (A) is a polysulfone polymer.
6). 6. The separation membrane according to any one of 1 to 5, wherein (B) is polyvinyl pyrrolidone and / or polyethylene glycol.
7). Any one of 1 to 6 above, wherein the hydrophilic unit (C) is vinyl pyrrolidone and / or ethylene glycol, and the hydrophobic unit (C) is vinyl acetate and / or vinyl caprolactam. The separation membrane described.
8). 8. The separation membrane according to any one of 1 to 7, wherein the separation membrane is used for blood purification.
9. A separation membrane module comprising the separation membrane according to any one of 1 to 8 above.
10. (C) A copolymer polymer solution consisting of a hydrophilic unit and a hydrophobic unit was brought into contact with a separation membrane consisting of (A) a hydrophobic polymer and (B) a polymer consisting only of a hydrophilic unit. Then, the manufacturing method of the separation membrane characterized by irradiating a high energy ray.
11. 11. The method for producing a separation membrane as described in 10 above, wherein the solution of (C) is contacted at 20 ° C. or more and 60 ° C. or less.
12 (10) The method according to (10) or (11) above, further comprising the step of removing the solution of (C) after contacting the separation membrane until the liquid retention rate of the separation membrane is 10 wt% or more and 600 wt% or less. The manufacturing method of the separation membrane of description.
13. Said (A) is polysulfone type polymer | macromolecule, The manufacturing method of the separation membrane in any one of said 10-12 characterized by the above-mentioned.
14 Said (B) is polyvinylpyrrolidone and / or polyethyleneglycol, The manufacturing method of the separation membrane in any one of said 10-13 characterized by the above-mentioned.
15. Any of 10 to 14 above, wherein the hydrophilic unit (C) is vinyl pyrrolidone and / or ethylene glycol, and the hydrophobic unit (C) is vinyl acetate and / or vinyl caprolactam. The manufacturing method of the separation membrane of description.
16. 16. A method for producing a separation membrane module, comprising the separation membrane according to any one of 10 to 15 above.

  The separation membrane according to the present invention and the separation membrane module in which the separation membrane is incorporated have good blood compatibility and are less likely to adhere to proteins and organic substances. Furthermore, since there are few effluents from a membrane component, it can be widely used for applications requiring blood compatibility, non-adhesion of proteins and organic substances, and non-elution of membrane components while maintaining high separation performance.

1 shows an embodiment of an artificial kidney used in the present invention.

Of the three components constituting the separation membrane in the present invention, (A) the polymer consisting only of the hydrophobic unit serves as a support for forming the separation membrane. In addition, it is considered that (B) a polymer composed only of a hydrophilic unit and (C) a copolymer polymer composed of a hydrophilic unit and a hydrophobic unit play a role of suppressing adhesion of proteins and organic substances. That is, as a result of intensive studies by the present inventors, it was found that a moderately hydrophilic region and a hydrophobic region are mixed on the surface of the separation membrane, which is effective for suppressing adhesion of proteins and organic substances. . In the present invention, (C), which is a copolymer polymer, is often more hydrophobic and generally less soluble in water than (B). Therefore, on the surface of the separation membrane, (B) the polymer consisting only of the hydrophilic unit mainly has a hydrophilic region, and (C) the hydrophobic part in the copolymer polymer consisting of the hydrophilic unit and the hydrophobic unit is mainly hydrophobic. It is presumed that it constitutes a sex region.

In the present invention, the hydrophobic unit is defined as a repeating unit that is hardly soluble or insoluble in water in a single polymer, and hardly soluble or insoluble in water means that the solubility in pure water at 20 ° C. is 1 g / 100 g. Less than. On the other hand, the hydrophilic unit is a repeating unit that is a single polymer and is easily soluble in water, and the solubility in pure water at 20 ° C. is defined as 10 g / 100 g or more.
In the hydrophobic region of the separation membrane surface, if the degree of hydrophobicity is too strong, protein denaturation will be caused. For example, protein adheres to the exposed polysulfone on the surface of the separation membrane made of (A) polysulfone, which is a polymer consisting only of hydrophobic units, and (B) polyvinylpyrrolidone, which is a polymer consisting only of hydrophilic units. In the hydrophilic region, when the degree of hydrophilicity of (B) is insufficient, the hydrophobicity of the separation membrane surface increases, so that proteins and organic substances may adhere, resulting in poor blood compatibility. . For this reason, as a result of intensive studies by the present inventors, it is important that the polymer consisting only of the hydrophilic unit (B) has a hydrophilicity of 10 g / 100 g or more in 20 ° C. pure water. I found. Further, it is preferably 20 g / 100 g or more. In addition, (C) a copolymer polymer composed of a hydrophilic unit and a hydrophobic unit is not as strong as (B), but (C) the degree of hydrophobicity is not too strong and has a certain degree of hydrophilicity. It is necessary to be. That is, the solubility in pure water at 20 ° C. is preferably 1 g / 100 g or more, and more preferably 5 g / 100 g or more.
Moreover, it is more preferable that the solubility in pure water at 20 ° C. is (B) ≧ (C) because the hydrophilic region and the hydrophobic region become clear and the effect of the present invention is enhanced.

  Furthermore, when the glass transition points of the above (B) and (C) are 90 ° C. or higher, preferably 100 ° C. or higher, it has been found that the effect of suppressing adhesion of proteins and the like is great. A polymer having a higher glass transition point has higher rigidity and less fluidity, so that the molecular mobility of the molecular chain is lowered. For this reason, it is speculated that the hydrophilic region and the hydrophobic region on the surface of the separation membrane may be further clarified. Moreover, although it is not certain about the reason, it has been found that if the glass transition points of (B) and (C) are 90 ° C. or higher, preferably 100 ° C. or higher, the separation performance is also affected.

In particular, it is preferable to crosslink (B) and (C) with high energy after forming the separation membrane, which is a preferable means for raising the glass transition point. For example, as a high energy source, a method of performing radiation irradiation, heat treatment, or both of them can be used. Among them, the crosslinking treatment by radiation irradiation is simple and can be preferably used in medical applications such as a blood purification membrane because it can be used for sterilization of products. There is an optimum range of irradiation doses for crosslinking these polymers and raising the glass transition point. That is, the irradiation dose is preferably 5 kGy, more preferably 10 kGy or more. In addition, if the irradiation dose is 100 kGy or more, excessive crosslinking or disintegration occurs, resulting in a decrease in blood compatibility.
When a polymer absorbs high energy such as irradiation, a cross-linking phenomenon occurs in the molecule and / or in the molecule depending on the environment around the polymer chain. When a polymer dissolved in a solution of a certain concentration or more is irradiated with radiation, intermolecular crosslinking proceeds preferentially, so that the polymer in the solution becomes insoluble. In the present invention, the gelation concentration is defined as the lower limit concentration of the solution. That is, as a result of intensive studies by the present inventors in order to increase the glass transition point by proceeding with the crosslinking of the polymer, as described above (B) and (C), gelation by irradiation with an irradiation dose of 25 kGy It has been found effective to use a material having a concentration of 2.0% by weight or less, and further 1.0% by weight or less. By using such a polymer, moderate hydrophilic regions and hydrophobic regions coexist on the surface of the separation membrane, thereby suppressing adhesion of proteins and organic substances.

Further, in the present invention, in order to simultaneously achieve blood compatibility, suppression of protein and organic matter adhesion, and reduction of eluate from membrane components while maintaining high separation performance, it becomes a support for the separation membrane (A It is preferred that there is a hydrophobic interaction between the polymer consisting only of hydrophobic units and the copolymer polymer of (C). Since (C) in the present invention is somewhat hydrophobic compared to (B) in the present invention, it is considered to be dominantly arranged around the hydrophobic polymer by hydrophobic interaction. Thereby, exposure of the hydrophobic polymer in the hydrophobic region on the surface of the separation membrane is eliminated, and protein adhesion is suppressed. In addition, the larger the hydrophobic interaction between the two, the stronger the (C) is adhered to the separation membrane, so that the effluent from the membrane components is reduced. Therefore, in the present invention, the strength of the hydrophobic interaction is expressed by the amount of the polymer polymer solution adsorbed to the target. That is, the adsorption amount when the copolymer polymer of (C) is contacted as an aqueous solution with the film made of (A) is Aw, and the adsorption amount when it is contacted as a 20 wt% acetonitrile mixed aqueous solution is Aa. In this case, Aa / Aw is preferably 0.95 or less, and more preferably 0.7 or less. In addition, (A) The adsorption amount to the film which consists of a polymer which consists only of a hydrophobic unit is calculated by measuring using a surface plasmon resonance apparatus (henceforth SPR). The SPR is a device that analyzes a change in mass of the film surface from a change in resonance angle of laser light irradiated at a constant angle.

The term “hydrophobic interaction” as used herein refers to the force that collects a compound when it is surrounded by a hydrophilic solvent such as water, avoiding it, and is the force that acts only in the presence of water. Point to. To use acetonitrile 20 wt% mixed aqueous solution, when this dissolved (C), is because the effect of the hydrophobic interaction that occurs between the hydrophobicity unit and a hydrophobic polymer is weakened, (C) Aw / Aw is 0.95 or less when Aw is the amount of adsorption when it is contacted in water and Aa is the amount of adsorption when it is contacted in a 20 wt% acetonitrile mixed aqueous solution. This is because it can be judged that the hydrophobic interaction is strong when it comes into contact with the surface.
Here, the reason why the “acetonitrile 20 wt% mixed aqueous solution” is used will be described in detail. In the selection of an aqueous solution with a reduced electrical polarity by adding a poor solvent compatible with water, in addition to acetonitrile, examples of the poor solvent include aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and dimethylacetamide, methanol, There are alcohol solvents such as ethanol, ether solvents such as diethyl ether and tetrahydrofuran, alkylamine solvents such as diethylamine and triethylamine, and aromatic solvents such as toluene and pyridine. Acetonitrile is used because it is highly compatible with water at an arbitrary ratio and can effectively reduce the polarity of an aqueous solution so that it can be used as a mixed solvent for chromatography. Moreover, there exists an optimal range in the ratio of water and acetonitrile in the mixed aqueous solution. If the ratio of water is too high, the change in polarity of the aqueous solution will be small, and it will be difficult to determine the change in the amount of adsorption. On the other hand, if the proportion of acetonitrile is too high, the solubility of the polymer will be different, and the measurement error will be high due to the mechanical properties of SPR. Specifically, 1 to 50% by weight acetonitrile mixed aqueous solution, preferably 5 to 30% by weight, and further 10 to 20% by weight is preferably used.

  In addition, as a result of studies by the present inventors, (B) and (C) are components having high solubility in water, and therefore, when the existing ratio of (B) and (C) is too high with respect to the entire separation membrane, It was found that the amount of elution from the separation membrane can be increased. In addition, there may be a problem with the formability of the film. That is, in the present invention, (B) and (C) are preferably 5% by weight or less, more preferably 3% by weight or less of the entire separation membrane. In order to maintain the moldability of the separation membrane and the balance between hydrophilicity and hydrophobicity, (B) and (C) are 0.5% by weight or more, more preferably 1% by weight or more with respect to the whole membrane. It is necessary to be. On the other hand, on the surface of the separation membrane, the above (C) is preferably present on any surface of the separation membrane in an amount of 5% by weight or more, more preferably 10% by weight or more in order to exert the effect of suppressing the adhesion of proteins and organic substances. I found it important to do. In addition, when the amount of (C) is too large, it may cause a decrease in blood compatibility due to an increase in hydrophobicity of the separation membrane and a decrease in performance due to clogging of the separation membrane. Preferably it is 40 weight% or less. The separation membrane surface here refers to a portion up to the measurement depth when the detector inclination of photoelectron spectroscopy (ESCA) is set to 90 °, and is measured by, for example, X-ray photoelectron spectroscopy (ESCA). be able to. In the case of polyvinylpyrrolidone or the like, the abundance ratio of the polymer in the entire separation membrane can be calculated by analyzing nitrogen using elemental analysis.

The separation membrane referred to in 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 a high protein and organic matter adhesion inhibitory property, 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.

  When the separation membrane is wet-formed from a stock solution, a polymer having a large molecular weight gathers to prevent entropy loss, and (B) and (C) gather on the surface to prevent enthalpy loss. In particular, (B) in the present invention is generally more hydrophilic than (C) and easily collects on the surface, so it may be added to the stock solution, or may be contacted and immobilized after forming the separation membrane. Further, (C) may be added to the stock solution, but there are restrictions such as the use of a high molecular weight substance or the use of a larger amount than (B). Therefore, separation with which the degree of hydrophobicity (A) is not exposed and blood compatibility, protein and organic matter adhesion suppression, and elution from membrane components are reduced while maintaining high separation performance. In order to form the membrane surface, it is preferable to adopt a method of immobilizing after contacting the (C) after forming the separation membrane. Such a method is suitably used because it can be carried out simply and in a small amount. Furthermore, in the wet membrane formation of a hollow fiber membrane type separation membrane, an injection solution is used in addition to the stock solution in order to form a hollow yarn. Therefore, (B) and (C) may be added to the injection solution to form a film.

  Moreover, in this invention, it discovered that the solution temperature when making (C) contact a separation membrane influences the elution amount. Regarding the amount of elution, when the separation membrane is a hollow fiber membrane, the solution obtained by perfusion with 4 L of ultrapure water heated to 37 ° C. for 4 hours is lyophilized and concentrated, and then liquid phase chromatography is used. (For example, it calculates by measuring by HPLC (AK-216-001) by Tosoh Corporation). When the amount of elution is high, membrane components flow into the blood during hemodialysis, which may cause dangerous side effects such as anaphylactic shock and complications. Therefore, in the present invention, the elution amount from the hollow fiber membrane is preferably 1.0 mg or less, more preferably 0.5 mg or less. Similarly, even when the separation membrane is a flat membrane, calculation is performed by liquid phase chromatography using a solution obtained by immersing in ultrapure water heated to 37 ° C. for 4 hours. In order to satisfy these conditions, the solution temperature is preferably 20 ° C. or higher, more preferably 30 ° C. or higher, and further preferably 40 ° C. or higher. This is presumably because the polymer solution is uniformly dissolved when contacted at a high temperature, so that the entire surface of the separation membrane is evenly coated and the high molecular weight that is not sufficiently immobilized is reduced. On the other hand, if the solution temperature is too high, depending on the type of polymer, the solution may be suspended due to the presence of a cloud point, so that it is not sufficiently coated and immobilized on the separation membrane surface. Therefore, for example, in the case of a vinylpyrrolidone / vinyl acetate copolymer, the temperature is preferably 60 ° C. or lower.

  The immobilization here includes that (B) and (C) form a coating layer on the surface of the separation membrane. For example, a method by physical adsorption in which a polymer solution is allowed to flow and contact the separation membrane, or a method in which high energy is irradiated after physical adsorption and insolubilization may be used. For example, as a high energy source, a method of performing radiation irradiation, heat treatment, or both of them can be used. In particular, the method in which a polymer solution is allowed to flow and contact the separation membrane, and then the polymer is insolubilized by irradiation, since the polymer is more strongly immobilized on the surface when the separation membrane is a blood purification separation membrane, It is effective because it has a high effect of reducing the amount of eluate to blood and the like.

Further, the irradiation and / or heat treatment may be performed in a state where the separation membrane is immersed in the polymer solution, or the irradiation and / or heat treatment may be performed after the separation membrane is immersed in the polymer solution and the solution is taken out. Etc. may be performed. However, when irradiation is performed after contacting the polymer, the polymer is more likely to be immobilized on the separation membrane if a certain amount of solvent is present. This is thought to be due to the radicals generated from the solvent upon irradiation being the starting point, and the contacted polymer and the hydrophobic polymer that is the support for the separation membrane are radicalized, crosslinked, and immobilized. . That is, even when the solution is drawn out as described above, the weight of the separation membrane is 0.1 times or more, more preferably 0.2 or more, and even 1.0 or more times the dry weight of the separation membrane. It is preferable that the solvent remains so that it becomes 10% by weight or more, 20% by weight or more, and further 100% by weight or more in terms of liquid ratio. In addition, as a solvent, water is used suitably from a viewpoint of handleability. On the other hand, even if the separation membrane module is not filled with water, only the separation membrane may be wet from the viewpoint that the adsorbed copolymer is less likely to elute during the time until irradiation. preferable. Specifically, the moisture content of the separation membrane is 6.0 wt. Times or less, further 4.0 wt. Times or less, 600 wt.% Or less, and further 400 wt. It is preferable to be wet with. The liquid retention rate here is a value calculated by the following (formula 1).
p = (w _w −w _d ) × c / w _d (Formula 1)
(P = liquid retention rate (% by weight) of separation membrane, w _w = weight of separation membrane (g), w _d = weight of separation membrane in dry state (g), c = water content in wetting liquid ( %))
Furthermore, in the present invention, when the water permeability of the separation membrane is low, the water distribution in the separation membrane becomes non-uniform in the step of removing water, so that radicals are efficiently generated from the water by radiation irradiation. As a result, the amount of eluate increases. That is, the water permeability is preferably 150 mL / hr / m ² / mmHg or more, more preferably 200 mL / hr / m ² / mmHg or more. On the other hand, if the water permeability is too high, the water in the separation membrane hardly remains and the liquid retention rate is not stable. It also causes a performance degradation. Specifically, the water permeability is preferably 900 mL / hr / m ² / mmHg or less, more preferably 800 mL / hr / m ² / mmHg or less. The water permeability here is a value calculated by the following (formula 2).
Water permeability (mL / hr / m ² / mmHg) = Q _w / (P × T × A) (Formula 2)
(Q _w : filtration amount (mL), T: outflow time (hr), P: pressure (mmHg), A: surface area of separation membrane (m ² ))
Further, after immersing the separation membrane in the polymer solution, it may be replaced with water and then subjected to radiation irradiation or heat treatment. Furthermore, after extracting the substituted water, radiation irradiation or heat treatment may be performed. In particular, when the above method is used for a blood purification separation membrane, a solvent such as water or alcohol is preferably used from the viewpoint of safety.
In the present invention, when heat treatment is performed after contacting the polymer, the separation membrane is heated by heating at a temperature at which thermal crosslinking of the polymer proceeds while the polymer is in contact with the separation membrane. It becomes easy to fix and insolubilize.
Moreover, as a method for removing the immersed polymer, water, and the like, various methods such as reduced pressure drying, high temperature drying, low temperature air drying, and blow drying can be used. In addition, it is known that when oxygen is present during irradiation, oxygen radicals are generated and the polymer material of the 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.

  For example, when the separation membrane is a blood purification hollow fiber membrane, the polymer solution may be brought into contact with both sides of the membrane. However, while maintaining high separation performance, blood compatibility, protein and organic matter adhesion suppression, and membrane It is also possible to contact only one of the surfaces of the separation membrane, in particular only the inner surface, in order to achieve a reduction of the eluate from the components at the same time. At that time, when a pressure difference generated from the surface to which the polymer is contacted toward the opposite side is used, the polymer is concentrated and is effectively adsorbed on the surface of the separation membrane. Note that, when the polymer is brought into contact, the solution itself may not be introduced to the membrane surface by applying a pressure difference, but after contacting the solution, the pressure may be applied using a solution such as gas or water.

However, if the pressure difference between the surface on which the polymer is contacted and the opposite side becomes too large, the performance of the separation membrane may be degraded. The reason for this is considered to be that when the pressure difference is high, the polymer is uniformly introduced into the separation membrane, but the membrane pores are clogged due to excessive adsorption. Therefore, when the hydrophobic polymer is a polysulfone polymer, the pressure difference is preferably within 60 kPa, and more preferably within 40 kPa. The lower limit of the pressure difference is not particularly limited in the present invention because the adsorption to the separation membrane proceeds even if there is no particular pressure difference, but is preferably 1 kPa or more, more preferably 15 kPa or more, Furthermore, 20 kPa or more is desirable.
Moreover, if the concentration of the polymer solution to be contacted is too high, the amount of polymer eluate may increase. The reason for this is considered to be that excessive crosslinking or collapse occurs. On the other hand, when the solution concentration is too low, the polymer is not effectively immobilized on the surface of the separation membrane, and the performance is low. Therefore, there is a certain range in the concentration of the polymer solution when contacting the polymer. The specific concentration varies depending on the type of polymer, but generally it is preferably 0.0001% by weight or more and 1% by weight or less, and more preferably 0.001% by weight or more and 0.1% by weight or less. preferable.

  In the step of bringing the polymer into contact with the separation membrane and insolubilizing the polymer by radiation, components other than the copolymer, for example, an antioxidant, may be contained in the polymer solution. Further, the separation membrane may be coated with a hydrophilic polymer solution and then contacted with an antioxidant solution.

  By adding an antioxidant, the amount of radicals generated can be adjusted. For example, in the manufacture of a blood purification module, it can be both insolubilized by radiation irradiation and sterilization, but when irradiated with a dose to achieve sterilization, the cross-linking of the contacted polymer progresses too much and the separation membrane May deteriorate. What is necessary is just to use an antioxidant together in order to prevent it. 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, glutathione, and oxygen. These antioxidants may be used alone or in combination of two or more. When the method of the present invention is used for a medical device, it is necessary to consider its safety, and therefore, an antioxidant having low toxicity is preferably used.

About the density | concentration of the solution containing an antioxidant, it changes with the kind of antioxidant contained, the irradiation dose of a radiation, etc. If the concentration of the antioxidant is too low, the radicals generated from the solvent cannot be sufficiently erased, so that deterioration of the 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, as the antioxidant, ethanol, n-propanol, 2-propanol, ethylene glycol, propylene glycol, and glycerin are preferably used, and the concentration range is 0.01 wt% or more and 90 wt% or less. Are preferably used. Particularly in the case of ethanol, n-propanol, and 2-propanol, 0.01% by weight or more and 10% by weight or less is preferably used, and more preferably 0.05% by weight or more and 1% by weight or less. In the case of propylene glycol and glycerin, the content is 0.1% by weight or more and 90% by weight, and more preferably 0.5% by weight or more and 70% by weight or less.
Specific examples of the polymer comprising only hydrophobic units in the present invention include polysulfone polymers. The polysulfone polymer has an aromatic ring, a sulfonyl group and an ether group in the main chain. For example, polysulfone represented by the chemical formulas of the following formulas (1) and (2) is preferably used. In the formula, n is an integer such as 50 to 80.

Specific examples of the polysulfone polymer include “Udel polysulfone” (registered trademark) P-1700, P-3500 (manufactured by Solvay), “Ultrason” (registered trademark) S3010, S6010 (manufactured by BASF), “ Examples include polysulfones such as Victrex (registered trademark) (Sumitomo Chemical), Radel A (registered trademark) (manufactured by Solvay), and Ultrason (registered trademark) E (manufactured by BASF). 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.

In addition, the polymer (B) composed of only hydrophilic units in the present invention refers to a polymer composed of only hydrophilic units, and examples thereof include polymers such as polyvinyl pyrrolidone and polyethylene glycol. However, since proteins easily adhere to hydrophobic surfaces, it is thought that the entire separation membrane surface is hydrophilic. However, with water-soluble polymers such as polyvinyl pyrrolidone and polyethylene glycol, the material surface cannot be It is said that even if it is coated, adhesion of proteins and the like can only be temporarily suppressed. That is, it is effective for suppressing adhesion of proteins, organic substances, etc. that the hydrophilicity and hydrophobicity are appropriately mixed on the surface of the separation membrane. Therefore, in the present invention, (B) the polymer consisting only of the hydrophilic unit mainly constitutes the hydrophilic region, while the copolymer polymer (C) mainly constitutes the relatively hydrophobic region. . On the other hand, instead of (C), when a polymer having a too high hydrophilicity and a glass transition point of less than 90 ° C. is used, such as polyvinyl alcohol having a hydroxyl group, the complement is activated when contacted with blood. It is known that
That is, in the copolymer polymer (C), the types and ratios of the hydrophilic unit and the hydrophobic unit to be constructed are important. For example, examples of hydrophilic units include vinyl pyrrolidone, alkylene glycol, alkylene imine, allylamine, vinylamine, acrylic acid, etc. Among them, vinylpyrrolidone groups are not as hydrophilic as hydroxyl groups, and are moderately hydrophilic and hydrophobic. It is easy to balance and is preferable.
In addition, as hydrophobic units, carboxylic acid vinyl esters such as vinyl acetate, methacrylic acid esters and acrylic acid esters such as methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, n-butyl methacrylate, and benzyl methacrylate, caprolactam, and methyl Examples thereof include alkyl vinyl ethers such as vinyl ether and ethyl vinyl ether, acrylonitrile and the like as repeating units.

In the present invention, in particular, when a polymer having vinyl acetate, vinyl caprolactam, or methyl vinyl ether is added to the polysulfone separation membrane as a copolymer repeating unit, the effect of suppressing the adhesion of proteins and platelets is high. Therefore, it is preferably used. The reason for this is considered to be that when (C) having the above repeating unit comes into contact with a separation membrane made of a polysulfone polymer, adsorption occurs due to high affinity due to hydrophobic interaction. In addition, as the copolymer polymer (C), a random copolymer or an alternating copolymer is preferably used. This is because in the case of a block copolymer or graft copolymer, the hydrophobic unit is often domained and the degree of hydrophobicity is often too strong.
Specifically, “KOLLIDON” (registered trademark) VA64 (manufactured by BASF), which is a copolymer of vinylpyrrolidone and vinyl acetate, and “LUVISKOL” (registered trademark), which is a copolymer of vinylpyrrolidone and vinylcaprolactam. ) VPC55 (manufactured by BASF) is preferably used, but is not particularly limited.
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 polymer is brought into contact with the separation membrane, the 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, three-dimensional crosslinking or collapse of the hydrophilic polymer occurs, and blood compatibility is lowered.
In the present invention, the separation membrane may be brought into contact with the polymer and fixed, and then incorporated into the module, or may be immobilized by bringing the polymer into contact with the separation membrane incorporated in the module. After contacting the polymer, irradiation or heat treatment may be performed as described above. 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 method of substrate (1) Production of hollow fiber membrane module 16 parts of polysulfone (Amoco Udel-P3500), 3 parts of polyvinylpyrrolidone (International Special Products Co .; hereinafter abbreviated as ISP K30), polyvinylpyrrolidone (ISP K90) 3 parts were heated and dissolved together with 77 parts of dimethylacetamide and 1 part of water to obtain a film forming stock solution.

This stock solution is sent to a spinneret at a temperature of 50 ° C., and a solution consisting of 63 parts of dimethylacetamide and 37 parts of water is discharged 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. After forming the hollow fiber membrane, it is passed through a coagulation bath at a temperature of 40 ° C. consisting of 20% by weight of dimethylacetamide and 80% by weight of water through a dry zone atmosphere having a length of 350 mm at a temperature of 30 ° C. and a dew point of 28 ° C. After passing through a water washing step at 60 to 75 ° C. for 90 seconds, 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 a case so that the effective membrane area (total surface area of the portion excluding the potted portion in the module) is 1.6 m ² , both ends are potted with resin, The part was opened on both sides to form an artificial kidney module.
(2) Preparation of flat membrane 16 parts of polysulfone (Amoco Udel-P3500), 3 parts of polyvinyl pyrrolidone (ISP K30) and 3 parts of polyvinyl pyrrolidone (ISP K90) were heated and dissolved together with 77 parts of dimethylacetamide and 1 part of water. A film forming stock solution was obtained.

On the glass plate heated so that the surface temperature might be set to 100 degreeC with a hotplate, the said film forming undiluted | stock solution was cast so that the thickness of a flat film might be 203 micrometers. After casting, the glass plate was immediately immersed in a solidified water bath at a temperature of 40 ° C., and then cut into a size of 20 cm × 20 cm to obtain a flat film.
2. Measurement method (1) Method of calculating the amount of adsorption by surface plasmon resonance (SPR) measurement After fixing an Au sensor chip manufactured by GE Healthcare Bioscience Co., Ltd. to a spin coater, polysulfone (Amoco Udel-P3500) 0. One or two drops of a 1 wt% chlorobenzene solution was dropped with a Pasteur pipette. Immediately after that, it was rotated and dried at 3000 rpm for 1 minute to prepare an Au sensor chip in which the polysulfone polymer was thinned on the surface. This sensor chip was inserted into BIACORE 3000 manufactured by GE Healthcare Bioscience Co., Ltd., and cleaned by flowing 0.025 wt% triton aqueous solution at 20 μL / min for 5 minutes and pure water for 20 minutes on the surface of the sensor chip for 300 seconds. Thereafter, the following operation was performed.
1. An aqueous solution in which a polymer sample was dissolved was allowed to flow at 20 μL / min for 3 minutes so that the polymer was adsorbed on the polysulfone surface so as to be 0.1% by weight.
2. It was washed by flowing pure water for 20 minutes.
3. A 0.025 wt% Triton aqueous solution was allowed to flow at 20 μL / min for 15 minutes to separate the adsorbed polymer.
4). It was washed by flowing pure water for 20 minutes.
5. The polymer was adsorbed on the surface of the polysulfone by flowing a 20 wt% acetonitrile mixed solution in which the polymer sample was dissolved at 20 μL / min for 3 minutes so as to be 0.1 wt%.
6). It was washed by flowing pure water for 20 minutes.
7. A 0.025 wt% triton aqueous solution was flowed at 20 μL / min for 15 minutes to separate the adsorbed polymer.
8). It was washed by flowing pure water for 20 minutes.
The adsorption amount of the polymer sample dissolved in water on the polysulfone polymer surface is the value at the time when the operation 2 is completed, with the value after washing the triton aqueous solution and water immediately after insertion of the sensor chip being 0. did. The adsorption amount of the polymer sample dissolved in the 20% by weight acetonitrile mixed solution was 0 when the operation 4 was completed and 0 when the operation 6 was completed.
(2) Measurement of polymer abundance (% by weight) on the surface of the separation membrane and the whole membrane X-ray electron spectroscopy was used for measurement of the polymer abundance (% by weight) on the surface of the separation membrane. The equipment and conditions are as follows.

Device: ESCA LAB220iXL
Excitation X-ray: monochromatic Al Kα1,2 line (1486.6 eV)
X-ray diameter: 0.15mm
Photoelectron escape angle: 90 ° (inclination of detector relative to sample surface)
Measurement depth: about 10nm
The separation membrane was thoroughly washed with ultrapure water and then dried at room temperature and 0.5 Torr for 10 hours. Thereafter, when the separation membrane was a hollow fiber membrane, it was cut into a semicylindrical shape with a single blade, and the inner surface of the hollow fiber membrane was subjected to measurement.
For example, the amount (% by weight) of vinylpyrrolidone-vinyl acetate copolymer in a separation membrane in which polysulfone, polyvinylpyrrolidone, and vinylpyrrolidone-vinyl acetate copolymer are mixed can be calculated as follows. By X-ray electron spectroscopy, the elemental composition (atomic%) on the surface of the separation membrane and the division result (%) of the C1s peak are obtained. From these values, the peak composition (atomic%) derived from the ester group (COO) is determined, and the abundance (% by weight) of vinyl acetate units in the vinylpyrrolidone-vinyl acetate copolymer is obtained. From the result and the existing amount (% by weight) between known vinylpyrrolidone-vinyl acetate copolymer units, the existing amount (% by weight) of the vinylpyrrolidone-vinyl acetate copolymer on the inner surface of the hollow fiber membrane can be obtained. .
Similarly, the abundance (% by weight) of polyvinylpyrrolidone can be calculated from the division result (%) of the C1s peak derived from the vinylpyrrolidone group (C═O).

  The high molecular weight abundance (% by weight) of the entire separation membrane was calculated by performing elemental analysis using decomposition to reduced pressure chemiluminescence. The equipment and conditions are as follows.

Apparatus: Trace nitrogen analyzer ND-100 type (Mitsubishi Chemical Corporation)
Electric furnace temperature: Pyrolysis part (800 ° C), catalyst part (900 ° C)
Main oxygen flow rate: 200mL / min
Oxygen flow rate: 200 mL / min
Argon flow rate: 400 mL / min
The separation membrane was introduced into the analyzer, pyrolyzed and oxidized, and the produced nitric oxide was measured by a chemiluminescence method. Subsequently, it quantified with the analytical curve previously created with the pyridine standard solution.
(3) Measurement of Gelation Concentration The aqueous solution of the polymer used was adjusted every 1000 ppm with the lower limit of the concentration being 1000 ppm and the upper limit being 30000 ppm, and each sample was irradiated with γ-rays at 25 kGy. The lower limit of the concentration at which precipitation occurred in the sample after irradiation was taken as the gelation concentration. However, the presence or absence of precipitation was determined by whether or not precipitation was obtained when filtration was performed with a 0.2 μm filter.
(4) Human platelet adhesion test method of hollow fiber membrane A double-sided tape was attached to an 18 mmφ polystyrene circular plate, and a hollow fiber membrane irradiated with γ rays at 25 kGy 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 (pieces / 4.3 × 10 ³ μm ² ). The end portion in the longitudinal direction of the hollow fiber was removed from the target of the number of adhesion because blood pools were easily formed. The platelet adhesion number is preferably 50 / 4.3 × 10 ³ μm ² or less, more preferably 20 / 4.3 × 10 ³ μm ² or less.
(5) Measurement of elution amount (in the case of hollow fiber membrane module) The hollow fiber membrane irradiated with γ rays at 25 kGy was subjected to priming washing and then perfused with ultrapure water. The priming method is as follows. First, it was connected to the blood circuit with the blood side inlet down. Ultrapure water was allowed to flow from the blood inlet side to the blood outlet side at a flow rate of 100 mL / min for 7 minutes. Then, it connected to the blood circuit with the dialysate inlet down. Ultrapure water was flowed from the dialysate inlet side to the dialysate outlet side at a flow rate of 500 mL / min for 5 minutes. Thereafter, again with the blood side inlet down, ultrapure water was allowed to flow from the blood inlet side to the blood outlet side at a flow rate of 100 mL / min for 3 minutes. Thereafter, 4 L of ultrapure water heated to 37 ° C. was used for perfusion for 4 hours from the blood inlet side to the blood outlet side at a flow rate of 200 mL / min with the blood side inlet facing up.
The perfusate for 4 hours was concentrated 100 times by lyophilization, and the solution was measured by HPLC (AK-216-001) manufactured by Tosoh Corporation. The elution amount of the high molecular weight substance was calculated using polyvinyl pyrrolidone (ISP K90) as a calibration curve. The amount of elution is preferably 1.0 mg or less, more preferably 0.5 mg or less.
(In the case of flat film) The flat film irradiated with γ rays at 25 kGy was washed with ultrapure water for 5 minutes. Then, after immersing in 1 L of ultrapure water heated to 37 ° C. for 4 hours, the obtained solution was concentrated 100 times by freeze-drying, and the solution was subjected to HPLC (AK- 216-001).
(6) β ₂ -microglobulin clearance measurement A plastic tube module having an effective length of 12.5 mm in which 36 hollow fibers are passed through a plastic tube and both ends are fixed with an adhesive, and the concentration is 5 mg / L. β ₂ -microglobulin was added to 37 ° C. bovine serum. 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 circulation for 2 hours, the bovine serum on the blood side and the physiological saline on the dialysate side were collected in total and requested to SRL for analysis, and the concentration of β ₂ -microglobulin was measured. From the measurement results, the clearance converted into a separation membrane module having an effective membrane area of 1.8 m ² was calculated. The value of β ₂ -microglobulin clearance is preferably 60 mL / min or more, and more preferably 65 mL / min or more.
(7) Measurement of water permeability A glass tube mini-module (36 pieces: effective length: 10 cm) in which both ends of the hollow fiber membrane are sealed is prepared, and a water pressure of 100 mmHg is applied to the inside of the hollow fiber membrane to flow outward. The amount of filtration per unit time was measured. The water permeability was calculated by the following (Formula 3).

UFRS = Q _w / (P × T × A) (Formula 3)
(UFRS: water permeability (mL / hr / m ² / mmHg), Q _w : filtration amount (mL), T: outflow time (hr), P: pressure (mmHg), A: inner surface area of hollow fiber membrane (m ² )
Example 1
A 1000 ppm aqueous solution of vinylpyrrolidone / vinyl acetate (7/3) copolymer (manufactured by BASF, "LUVISKOL" (registered trademark) VA73W) and a mixed aqueous solution of 1000 ppm of acetonitrile by 20% by weight are adsorbed by the above SPR measurement method. Was calculated. Moreover, the gelation concentration was calculated | required by (3). Subsequently, “LUVISKOL” (registered trademark) VA73W 100 ppm aqueous solution is passed at 25 ° C. from the blood side inlet to the blood side outlet of the hollow fiber membrane module, and then 500 mL is passed from the blood side inlet to the dialysate side inlet. As a result, “LUVISKOL” (registered trademark) VA73W was accumulated on the inner surface of the hollow fiber membrane. Thereafter, the filling solution was pushed out from the dialysate side to the blood side with 100 kPa compressed air, and then the filling solution on the blood side After blowing the dialysate side and the blood side with nitrogen, the module was irradiated with γ-rays at 25 kGy. Weight%), separation membrane surface abundance (wt%), platelet adhesion test, elution amount, and β ₂ -microglobulin clearance measurement. The results were as shown in Table 1. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7.
(Example 2)
The same operation as in Example 1 was performed except that a vinylpyrrolidone / vinyl acetate (6/4) copolymer (manufactured by BASF, “KOLLIDON” (registered trademark) VA64) was used. These results were as shown in Table 1. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7. Moreover, the water permeability was measured.
Example 3
The same operation as in Example 1 was performed, except that a vinylpyrrolidone / vinyl acetate (5/5) copolymer ("LUVISKOL" (registered trademark) VA55I, manufactured by BASF Corporation) was used. These results were as shown in Table 1. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7.
Example 4
The same operation as in Example 1 was performed, except that a vinylpyrrolidone / vinylcaprolactam (5/5) copolymer ("LUVISKOL" (registered trademark) VPC55, manufactured by BASF Corporation) was used. These results were as shown in Table 1. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7.
(Example 5)
Using “KOLLIDON” (registered trademark) VA64, the same operation as in Example 1 was performed except that the concentration of the aqueous solution passed through the hollow fiber membrane module was 10 ppm. These results were as shown in Table 1. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7.
(Example 6)
Using “KOLLIDON” (registered trademark) VA64, the same operation as in Example 1 was performed except that the concentration of the aqueous solution passed through the hollow fiber membrane module was 10 ppm and the temperature of the aqueous solution was 30 ° C. These results were as shown in Table 1. That is, it was found that the number of platelet adhesion was small, and β ₂ -microglobulin clearance was maintained at the same level as the control shown in Comparative Example 7. However, since the temperature of the aqueous solution was 30 ° C., the amount of elution was further smaller than that in Example 5.
(Example 7)
Using “KOLLIDON” (registered trademark) VA64, the same operation as in Example 1 was performed except that the concentration of the aqueous solution passed through the hollow fiber membrane module was 10 ppm and the temperature of the aqueous solution was 45 ° C. These results were as shown in Table 1. That is, it was found that the number of platelet adhesion was small, and β ₂ -microglobulin clearance was maintained at the same level as the control shown in Comparative Example 7. However, since the temperature of the aqueous solution was 45 ° C., the amount of elution was further smaller than in Examples 5 and 6.
(Example 8)
Using “KOLLIDON” (registered trademark) VA64, the same operation as in Example 1 was performed except that the concentration of the aqueous solution passed through the hollow fiber membrane module was 5 ppm. These results were as shown in Table 1. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7. However, since the amount of the inner surface of (C) was small, the platelet adhesion number was larger than Example 5 using 10 ppm and Example 1 using 100 ppm.
(Comparative Example 1)
The same operation as in Example 1 was performed except that polyvinyl alcohol (Aldrich, saponification degree 80%, molecular weight 10,000) was used. These results were as shown in Table 1. That is, the platelet adhesion number was small and the eluate was maintained in the same level as the control shown in Comparative Example 7, but the β ₂ -microglobulin clearance was low. This is considered because the glass transition point of the used polyvinyl alcohol is low and the balance between the hydrophilic region and the hydrophobic region on the surface of the separation membrane is poor.
(Comparative Example 2)
The same operation as in Example 1 was performed except that a vinylpyrrolidone / vinyl acetate (3/7) copolymer (BASF Corporation, “LUVISKOL” (registered trademark) VA37E) was used. These results were as shown in Table 1. That is, the platelet adhesion number was small and the eluate was maintained in the same level as the control shown in Comparative Example 7, but the β ₂ -microglobulin clearance was low. This is considered to be because “LUVISKOL” (registered trademark) VA37E used has a low glass transition point and low solubility, and the balance between the hydrophilic region and the hydrophobic region on the surface of the separation membrane is poor.
(Comparative Example 3)
The same operation as in Example 1 was performed except that polyvinyl acetate (manufactured by Aldrich, molecular weight: 113,000) was used. These results were as shown in Table 1. That is, the platelet adhesion number was small and the eluate was maintained in the same level as the control shown in Comparative Example 7, but the β ₂ -microglobulin clearance was low. This is probably because the polyvinyl acetate used has a low glass transition point and low solubility, and the balance between the hydrophilic region and the hydrophobic region on the surface of the separation membrane is poor.
(Comparative Example 4)
The same operation as in Example 1 was performed except that a polyvinylpyrrolidone / polystyrene (5/5) graft copolymer (manufactured by Nippon Shokubai Co., Ltd.) was used. These results were as shown in Table 1. That is, although the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7, the platelet adhesion number was large. This is presumably because the polyvinyl pyrrolidone / polystyrene (5/5) graft copolymer used has low solubility and the balance between the hydrophilic region and the hydrophobic region on the surface of the separation membrane is poor.
(Comparative Example 5)
The same operation as in Example 1 was performed except that polyvinylpyrrolidone K90 was used. These results were as shown in Table 1. That is, the β ₂ -microglobulin clearance was maintained at the same level as the control shown in Comparative Example 7, but the platelet adhesion number and elution amount were large. This is because the used polyvinylpyrrolidone K90 is not a copolymer polymer consisting of a hydrophilic unit and a hydrophobic unit, the value of Aa / Aw is 1 or more, and the balance between the hydrophilic region and the hydrophobic region on the surface of the separation membrane is It is thought to be bad.
(Comparative Example 6)
The same procedure as in Example 1 was performed, except that the membrane-forming stock solution was 18 parts of polysulfone, 81 parts of dimethylacetamide, and 1 part of water to prepare a hollow fiber membrane module. These results were as shown in Table 1. That is, although the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7, the platelet adhesion number was large.
(Comparative Example 7)
The same operation as in Example 1 was performed except that water was used as the liquid that passed through the hollow fiber membrane module. These results were as shown in Table 1. That is, the platelet adhesion number was large.
Example 9
The flat membrane was immersed in a 100 ppm aqueous solution of “KOLLIDON” (registered trademark) VA64. After the moisture was cut off, the flat membrane was placed in a gas-tight container and filled with nitrogen, and then irradiated with γ rays at 25 kGy. The elution amount of the flat membrane after γ-ray irradiation was measured. The results are shown in Table 2. That is, it was found that the elution amount was maintained at the same level as the control shown in Comparative Example 9.
(Example 10)
The same operation as in Example 9 was carried out except that 14 parts of polysulfone, 5 parts of polyvinylpyrrolidone K30 and 5 parts of polyvinylpyrrolidone K90 were dissolved in 77 parts of dimethylacetamide and 1 part of water to prepare a film-forming stock solution. The results are shown in Table 2. That is, the amount of elution increased.
(Comparative Example 8)
The same operation as in Example 9 was performed except that polysulfone was heated and dissolved in 77 parts of dimethylacetamide and 1 part of water to obtain a film-forming stock solution. The results are shown in Table 2.
(Example 11)
“KOLLIDON” (registered trademark) VA64 was used, and the same operation as in Example 1 was performed except that the liquid retention rate was 5% and the water permeability was 200 mL / hr / m ² / mmHg. The results are shown in Table 3. That is, it was found that the number of platelet adhesion was small, and β ₂ -microglobulin clearance was maintained at the same level as the control shown in Comparative Example 7. However, the elution amount was larger than that in Example 2.
(Example 12)
Using “KOLLIDON” (registered trademark) VA64, the concentration of the aqueous solution passed through the hollow fiber membrane module was 1000 ppm, except that the liquid permeability was 300% and the water permeability was 140 mL / hr / m ² / mmHg. The same operation as in Example 1 was performed. The results are shown in Table 3. That is, it was found that the number of adhered platelets was small, and the elution amount and β ₂ -microglobulin clearance were maintained at the same level as the control shown in Comparative Example 7. However, β ₂ -microglobulin clearance was lower than that in Example 2.

Claims (15)

(A) a polymer composed only of hydrophobic units, (B) a polymer composed solely of hydrophilic units, and (C) a copolymer polymer composed of hydrophilic units and hydrophobic units. ,
(A) has a solubility in pure water at 20 ° C. of less than 1 g / 100 g,
(B) has a glass transition point of 90 ° C. or higher and a solubility in pure water of 20 ° C. of 10 g / 100 g or higher.
(C) has a glass transition point of 90 ° C. or higher, a solubility in pure water of 20 ° C. of 1 g / 100 g or higher, and a gelation concentration by γ-ray irradiation with an irradiation dose of 25 kGy of 2.0% by weight or lower. ,
The abundance ratio of (B) and (C) is 5% by weight or less,
Said (C) is a separation membrane which exists 5weight% or more in an upper surface or a lower surface. When the amount of adsorption when the (C) is brought into contact with the film (A) in water is Aw and the amount of adsorption when the film is brought into contact with a 20 wt% acetonitrile mixed solution is Aa, Aa The separation membrane according to claim 1, wherein / Aw is 0.95 or less. The抱液rate of the separation membrane is 10 wt% to 600 wt% or less, and claims water permeability 150mL / ^hr / m 2 / mmHg or more, equal to or less than 900mL / ^hr / m 2 / mmHg 3. The separation membrane according to 1 or 2. The separation membrane according to any one of claims 1 to 3, wherein (A) is a polysulfone polymer. The separation membrane according to any one of claims 1 to 4, wherein (B) is polyvinylpyrrolidone and / or polyethylene glycol. The hydrophilic unit (C) is vinyl pyrrolidone and / or ethylene glycol, and the hydrophobic unit (C) is vinyl acetate and / or vinyl caprolactam. The separation membrane according to 1. The separation membrane according to any one of claims 1 to 6, wherein the separation membrane is used for blood purification. A separation membrane module comprising the separation membrane according to claim 1. A separation membrane comprising (A) a polymer consisting only of a hydrophobic unit satisfying the following (a) and (B) a polymer consisting only of a hydrophilic unit satisfying the following (b):
(C) A method for producing a separation membrane in which a copolymer polymer solution composed of a hydrophilic unit and a hydrophobic unit satisfying the following (c) is contacted and then irradiated with high energy rays.
(A) Solubility in pure water at 20 ° C. is less than 1 g / 100 g (b) Glass transition point is 90 ° C. or higher and solubility in pure water at 20 ° C. is 10 g / 100 g or higher (c) Glass transition point is 90 ° C. or higher The gelation concentration by γ-ray irradiation with a solubility in pure water at 20 ° C. of 1 g / 100 g or more and an irradiation dose of 25 kGy is 2.0% by weight or less. The method for producing a separation membrane according to claim 9, wherein the solution of (C) is contacted at 20 ° C. or more and 60 ° C. or less. The step of contacting the solution of (C) with the surface of the molded separation membrane, and then removing the solution until the liquid retention rate of the separation membrane is 10 wt% or more and 600 wt% or less. The method for producing a separation membrane according to claim 9 or 10. The method for producing a separation membrane according to any one of claims 9 to 11, wherein (A) is a polysulfone polymer. The method for producing a separation membrane according to any one of claims 9 to 12, wherein (B) is polyvinylpyrrolidone and / or polyethylene glycol. The hydrophilic unit (C) is vinyl pyrrolidone and / or ethylene glycol, and the hydrophobic unit (C) is vinyl acetate and / or vinyl caprolactam. The manufacturing method of the separation membrane as described in 2. A method for producing a separation membrane module, comprising a separation membrane obtained by the method for producing a separation membrane according to claim 9.

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