JP4882518B2 - Method for manufacturing medical separation membrane and medical separation membrane module - Google Patents

Description

  The production method of the present invention is suitably used for modifying the surface in order to achieve blood compatibility of the separation membrane and non-adhesion of proteins and organic substances. The modified separation membrane obtained by the present invention is, for example, a separation membrane for medical purification such as a separation membrane for blood purification, a separation membrane for biological components, a separation membrane for water purifier, a separation membrane for water purification, a separation membrane for purification of sewage Used for separation membrane for water treatment such as RO membrane. In particular, it is suitably used when manufacturing a module incorporating a blood purification separation membrane.

  Medical separation membranes that come into contact with bodily fluids or blood cause serious problems when proteins and platelets adhere, causing degradation of the separation membrane and causing biological reactions. In order to solve such a problem, various studies for modifying the separation membrane have been made.

  A method of introducing a hydrophilic component such as polyvinylpyrrolidone which is a water insolubilizing agent by radiation or heat in the process of film formation (Patent Document 1) or a polysulfone-based separation membrane having a high hydrophilicity such as polyvinylpyrrolidone. A method of forming a coating layer insolubilized by radiation crosslinking after contacting with a molecular solution (Patent Document 2) is disclosed.

However, as a result of intensive studies by the present inventors, the method of forming a coating layer of a modifying agent is effective for improving blood compatibility. Decrease sometimes occurred. Therefore, a modification method for improving blood compatibility while suppressing a decrease in the performance of the separation membrane is not yet known.
Japanese Patent Publication No.8-9668 JP-A-6-238139

  An object of the present invention is to provide a separation membrane in which a modifier is introduced while improving the drawbacks of the prior art and suppressing a decrease in the material separation ability of the separation membrane.

As a result of diligent investigations to achieve the above-mentioned problems, the inventors of the present invention have prepared a separation membrane manufacturing method required to introduce a modifier while suppressing a decrease in the material separation ability of the separation membrane. (1) to ( 6 ).
(1) In a method for producing a modified separation membrane in which a hydrophilic polymer solution is applied to the separation membrane, after the step of bringing the hydrophilic polymer into contact with the surface on one side of the separation membrane, the surface on the other side of the separation membrane medical from toward the surface contacting the solution of the hydrophilic polymer, the pressure (gauge pressure) performs the step of applying pressure at 500kPa or less gas than 50 kPa, and having a step of further irradiating the radiation Method for manufacturing a separation membrane.
(2) A method for producing a medical separation membrane, wherein the concentration of the hydrophilic polymer solution is 0.001 wt% or more and 30 wt% or less.
( 3 ) The method for producing a medical separation membrane according to 1 or 2 , wherein the separation membrane is a hollow fiber membrane.
(4) 1-3 method of manufacturing a medical separation membrane module, characterized in that a built-in medical separation membrane produced by the method according to the module in either.
(5) A method of manufacturing a medical separation membrane module according to 4, wherein the medical module being a module for blood purification.
(6) The method of producing the separation membrane module according to 4, wherein the medical module being a module for artificial kidney.

  By the method of the present invention, it is possible to introduce the modifier into the separation membrane while suppressing a decrease in the material separation ability of the separation membrane.

  In medical separation membranes such as blood purification separation membranes and biological component separation membranes, blood compatibility and non-adhesion of proteins are required. Moreover, in the separation membrane for water treatment, such as a water purifier membrane, a water purification membrane, a sewage purification membrane, and an RO membrane, non-adhesion of proteins and organic substances is required. For this reason, attempts have been made to impart blood compatibility and hydrophilicity by introducing a modifier into the surfaces of these separation membranes. Here, the modifier in the present invention means a compound or mixture used for improving performance in a broad sense including blood compatibility and hydrophilicity of the separation membrane. In the present invention, It is in a solid state at room temperature. However, when the modifier is brought into contact with the separation membrane surface, the performance of the separation membrane is often lowered. This is because the surface of the separation membrane is thickly coated with the modifier to block the pore openings of the separation membrane, and the modifier enters the pores, causing the pores to become smaller or clogged. It is thought that.

  Therefore, in the present invention, when introducing the modifier to the separation membrane, the step of bringing the modifier into contact with the surface on one side of the separation membrane, and the modifier from the surface on the other side of the separation membrane It has been found that the above problem can be solved by having a step of applying pressure with a liquid or gas toward the surface.

  That is, the decrease in the separation performance of the separation membrane is because the membrane pores are blocked or reduced in diameter by the modifier, so by applying pressure from the opposite side of the separation membrane surface in contact with the modifier, It is considered that the modifier could be prevented from entering the pores and covering the pore openings.

  Therefore, the step of bringing the modifier into contact with the surface on one side of the separation membrane and the step of applying pressure with a liquid or gas from the surface on the other side of the separation membrane to the surface in contact with the modifier are performed simultaneously. Alternatively, a step of applying pressure may be performed after the step of bringing the modifier into contact.

  When the step of bringing the modifier into contact and the step of applying pressure are performed simultaneously, it is considered that the modifier itself is prevented from entering the pores or covering the upper portions of the pores. In addition, when the pressure is applied after the step of bringing the modifier into contact, the modifier that enters the pores or covers the pore openings is considered to be blown away. .

  As described above, in the present invention, the step of contacting the modifier and the step of applying pressure are performed simultaneously or separately. Performing the two steps at the same time may start the step of contacting the modifier first, and after a certain time has elapsed, may start the step of applying pressure while continuing the step of contacting the modifier. Including. Or, conversely, the step of applying pressure may be started first, and after a certain time has elapsed, the step of contacting the modifier while continuing the step of applying pressure may be started. After performing the step of contacting the modifier and the step of applying pressure, only the step of contacting the modifier may be stopped and the step of applying pressure may be continued as it is. On the other hand, if the step of applying pressure is stopped first and the step of bringing the modifier into contact is continued, the modifier may enter the upper part of the pores or the inside thereof, which may cause a decrease in performance.

  In the method of the present invention, it is possible to prevent the modifier from entering the pores or covering the top of the pores by applying pressure from the other side toward the one side of the separation membrane in contact with the modifier. Therefore, the surplus amount is reduced among the modifiers introduced into the separation membrane. Even if pressure is applied from the same side of the separation membrane in contact with the modifier, such an effect cannot be obtained. Since the effect of the present invention is to modify only the blood contact surface of the separation membrane, the modifying agent present in the pores, in the upper part of the pores, or in the portion not in contact with the separation membrane is separated. Since it is not necessary to introduce it into the membrane, it becomes an excess amount. Furthermore, if the surplus amount is large, not only the performance is lowered but also the cost is disadvantageous, which is not preferable. Further, when the method of the present invention is used, the elution amount of the modifier into blood, body fluid or water treated with the separation membrane decreases. Since a medical device such as a medical module having a low elution is preferably used, the production method of the present invention is particularly preferably used.

  Examples of the shape of the separation membrane include a flat membrane and a hollow fiber membrane. Due to the size of the treatment area, a highly efficient hollow fiber membrane is often used.

  Here, bringing the modifier into contact with the surface of the separation membrane means passing the modifier solution through the surface of the separation membrane to be modified or immersing (only the surface of the separation membrane to be modified). It means to include a process. For example, in the case of a flat membrane, the object can be achieved by bringing the modifier solution into contact with one side and applying pressure from the other side. When the separation membrane is a hollow fiber membrane and it is desired to modify the inner surface of the hollow fiber, the modifier solution may be passed through the hollow fiber membrane, or the inner side of the hollow fiber membrane is filled with the modifier solution. Then, you may stand still for a fixed time. Furthermore, after filling with the modifier solution, the solution may be blown away and wetted by blowing the inside of the hollow fiber.

  Furthermore, when the separation membrane is built in the module, the object can be achieved by applying pressure from one side of the separation membrane while the modifier solution is in contact with the module or after contact. For example, if the separation membrane is a hollow fiber membrane, since the separation membrane is built in the module case, the purpose is achieved by filling the inside of the hollow fiber with the modifier solution and applying pressure from the outside of the hollow fiber. it can.

  As the modifier solution, the modifier may be dissolved in the solution, or a micelle or a colloid may be formed. As the modifier, for example, an amphiphilic polymer can be suitably used. Amphiphilic polymers include anionic surfactants such as sodium dodecyl sulfate bonded to cationic polymers such as polyethylenimine and polytrimethylaminoethyl acrylate chloride, dodecyltrimethylammonium bromide and dodecylpyridinium chloride. And those obtained by binding a cationic surfactant such as dextran sulfate, polyacrylic acid, and polystyrenesulfonic acid. Nonionic amphiphilic polymers also include Tween 20, 40 (registered trademark). Those obtained by binding these surfactants to nonionic polymers such as polyethylene glycol and polyvinylpyrrolidone are also known. The solvent is not particularly limited as long as the shape of the separation membrane does not deform, but water and alcohols are preferably used in consideration of handling properties. The alcohol here refers to a compound in which a hydrogen atom of a chain or alicyclic hydrocarbon is substituted with a hydroxyl group and a compound having a phenolic hydroxyl group. Alcohol includes, but is not limited to, methanol, ethanol, propanol, butanol, hexanol, ethanediol, propanediol, glycerin and the like. Further, since the surfaces of medical separation membranes, water treatment separation membranes and the like are often required to be hydrophilic, the modifier is preferably a hydrophilic substance. A hydrophilic substance means a substance soluble in water. The term “soluble in water” means that the solubility in water at 25 ° C. is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, and further preferably 0.1% by weight or more.

  Furthermore, when the modifying agent has a low molecular weight, since the intermolecular force is generally small, there is a concern that the modifying agent may elute when the modified separation membrane is used. The elution of the modifying agent not only lowers the effect obtained by the modification, but when used for medical purposes, it can be a problem for safety because it is eluted in blood or liquid. For this reason, a polymer is suitably used as the modifier. As described above, since the modifier is desirably a hydrophilic substance, the modifier most preferably used is a hydrophilic polymer. Here, the polymer means a substance having a molecular weight of 500 or more. Specific examples include, but are not limited to, polyvinyl pyrrolidone, polyalkylene glycols such as polyethylene glycol and polypropylene glycol, polyvinyl alcohol, dextran, pullulan, polyethyleneimine, polyallylamine, polyvinylamine, diethylaminoethyl dextran, polyacrylic. Examples thereof include acids, dextran sulfate, copolymers of these with other monomers, and grafts. These may be used alone or in combination of two or more.

  The amount of the modifier introduced into the separation membrane is determined by the reforming concentration and the reforming time. If the modifier concentration is increased and the reforming time is shortened, modification unevenness is likely to occur. Further, if the concentration is lowered and the reforming time is lengthened, the time required for the process is extended, which causes an increase in cost. Therefore, the concentration of the modifier solution is preferably 0.001% by weight to 30% by weight, and more preferably 0.001% by weight to 10% by weight.

  From the surface on the other side of the separation membrane to the surface where the modifier is brought into contact, the state where pressure is applied with liquid or gas refers to the state in which the modifier contacts the modifier from the opposite side of the separation membrane surface in contact with the modifier. A state in which liquid or gas is flowing toward the surface of the separation membrane. In other words, the pressure on the surface side with which the modifier is brought into contact may be lower than the pressure on the other surface side.

  Here, it is not necessary for the liquid or gas to be pressurized to pass through the separation membrane surface in contact with the modifying agent. If the pressure is too strong, the shape of the separation membrane may be damaged, or the modifier introduced into the separation membrane may be blown off excessively, so that the surface modification effect may be insufficient. On the other hand, if the pressure is too weak, it will not be possible to remove the modifier that has entered the pores of the separation membrane or the modifier that covers the top of the pores. There is a concern that the performance will decrease. Therefore, when applying pressure with gas, the strength of the gas pressure (gauge pressure) is preferably 1 kPa or more, more preferably 50 kPa or more. Moreover, 500 kPa or less is used suitably, and 200 kPa or less is used more suitably. When the pressure is applied with a liquid, the amount of the liquid flowing into the surface in contact with the modifier is preferably 1 mL / min or more, and more preferably 10 mL / min or more. Moreover, 1000 mL / min or less is used suitably and 500 mL / min is used more suitably. Here, the liquid is not particularly limited as long as the shape of the separation membrane is not deformed, but water and alcohols are preferably used in consideration of handleability and the like. The liquid may contain a modifier that does not cause a decrease in the performance of the separation membrane. Therefore, the concentration of the modifier contained in the liquid to which pressure is applied is 1/10 or less, preferably 1/100 or less, more preferably 1/1000 of the concentration of the modifier solution brought into contact with the surface to be modified. . However, as the time for applying the pressure becomes longer, as a matter of course, even if the concentration is low, the amount of the modifier entering the pores of the membrane increases, so that the performance of the separation membrane deteriorates.

  Moreover, although gas refers to air, oxygen, nitrogen, a carbon dioxide, argon, water vapor | steam, etc., it is not limited to these.

  As a method of applying pressure, while filling or passing the modifier solution inside the hollow fiber, pressure may be applied simultaneously from the outside of the hollow fiber, or after filling the modifier solution inside the hollow fiber, Pressure may be applied from the outside of the hollow fiber. For example, in the case of a hollow fiber membrane artificial kidney module, the blood inlet and outlet of the artificial kidney are vertically arranged so that they are either up or down, and modified from the blood inlet to the blood outlet. The solution is passed through the dialysis solution side inlet from the dialysate side inlet to the dialysate side outlet, and pressure is applied from the dialysate side of the hollow fiber membrane toward the blood side. The agent can be brought into contact with the inner surface of the hollow fiber membrane.

  Here, the separation membrane is a membrane that screens substances contained in blood or aqueous solution according to size. The separation membrane in the present invention is preferably made of a polymer material. Examples of the polymer material include polysulfone polymers such as polyvinyl chloride, polysulfone and polyethersulfone, polystyrene, polyurethane, polycarbonate, polyethylene, polypropylene, polymethyl methacrylate, polyamide, and cellulose polymer. It is not limited to.

  For the separation membrane made of a polymer material, the above polymers may be used alone or a mixture may be used. For example, in the case of a separation membrane made of a polysulfone-based polymer, polyvinyl pyrrolidone or the like is suitably used as a pore-forming agent or a hydrophilizing agent.

The method of the present invention is particularly preferably used when the affinity between the separation membrane and the modifier is high. Here, high affinity means that adsorption of 1 mg / m ² or more, more preferably 10 mg / m ² or more occurs when the modifier solution is brought into contact with the separation membrane. If the affinity between the separation membrane and the modifier is high, when the separation membrane is brought into contact with the modifier solution, the modifier is adsorbed to the surface of the separation membrane and even to the inside of the pores. It is thought that it is easy to get up. However, considering the use as a separation membrane for medical treatment or a separation membrane for water treatment, when the modifier has a high affinity with the separation membrane, it is adsorbed by a strong interaction, so it is modified into blood or liquid to be treated. It is preferable because elution of the quality agent is considered to be reduced. Moreover, since the density | concentration of the modifier solution to contact can also be reduced, it is preferable also from a cost surface. Therefore, a modifier having a high affinity for the separation membrane is often selected. For this reason, the method of the present invention is particularly suitably used for applications in which the separation membrane is treated with a modifier as described above, and further it is desired to suppress performance degradation.

  The affinity between the separation membrane and the modifier increases when a hydrophobic interaction, a hydrogen bond, an electrostatic interaction, or the like is formed between them. For example, in order to form a hydrophobic interaction, a hydrophobic separation membrane made of a polysulfone-based polymer, and polyvinyl alcohol as a modifier for the hydrophobic separation membrane are preferably used. Polyvinyl alcohol preferably has a saponification degree of 60% or more, more preferably 70% or more. Moreover, 99% or less is preferable and 98% or less is more preferable. This is because the separation membrane and the vinyl acetate unit of polyvinyl alcohol exhibit a hydrophobic interaction. As a result, the vinyl alcohol unit of polyvinyl alcohol is in a state facing the direction opposite to the direction with respect to the separation membrane, so that the surface of the separation membrane is covered with the vinyl alcohol unit and is made hydrophilic. The degree of saponification referred to here is a numerical value obtained by equation (3).

  Formula (1)

Formula (2)
(K) = (m) / ((n) + (m)) × 100 Formula (3)
Symbols in (Formula 3) are as follows.
(K): Degree of saponification (m): Number of monomer repeating units represented by formula (1) in polyvinyl alcohol (n): Number of monomer repeating units represented by formula (2) in polyvinyl alcohol Such amphiphilic polymers are also preferably used. For example, on a separation membrane made of a hydrophobic polymer, the hydrophobic portion of the amphiphilic polymer faces the direction of the separation membrane and exhibits a hydrophobic interaction with the separation membrane, and one hydrophilic portion is the separation membrane. The separation membrane is hydrophilized by covering the surface.

  Examples of hydrogen bonds include a polymethyl methacrylate polymer separation membrane and polyethylene glycol. Further examples of the formation of electrostatic interactions include a cationic separation membrane made of diethylaminoethylcellulose, an anionic modifier such as dextran sulfate, or a cationic separation membrane made of polyacrylonitrile and an anion such as polyethyleneimine. However, it is not limited to these.

  As described above, in the case of a medical separation membrane, radiation may be irradiated for sterilization. As the radiation, α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams and the like are used. In addition, medical devices such as artificial kidneys need to be sterilized, and in recent years, radiation sterilization methods are frequently used from the viewpoint of low residual toxicity and simplicity, and γ rays and electron beams are particularly preferably used. It has been.

  The contacted modifier may be cross-linked and gelled by radicals generated by radiation, and pore clogging may be further deteriorated. Such a problem can also be solved by the method of the present invention. That is, since only a small amount of the modifying agent is introduced, an excessive crosslinking reaction is unlikely to occur, so that the clogging of the separation membrane pores by the modifying agent can be suppressed. Therefore, it is considered that the performance of the separation membrane, that is, the permeability of proteins and the like is hardly impaired. That is, blood compatibility can be imparted and the performance degradation of the separation membrane can be suppressed.

  Further, in the case of a medical device to be sterilized by radiation, the modifying agent that has come into contact with the separation membrane by the radiation is immobilized by chemical bonding, so that the amount of eluate is reduced, which is preferable from the viewpoint of safety.

  Thus, since the method of the present invention can introduce blood compatibility to the surface while suppressing the performance degradation of the separation membrane, it is particularly suitably used as a medical separation membrane.

  The method of the present invention is suitably used in the production of medical separation membranes such as blood purification modules and artificial kidney modules.

  The blood purification module of the present invention refers to a module having a function of removing waste and harmful substances in blood by adsorption, filtration, and diffusion when circulating blood outside the body. There are adsorption columns.

  In addition, as an artificial kidney module, there are a coil type, a flat plate type, and a hollow fiber type, but from the viewpoint of processing efficiency, the hollow fiber type is currently widely used.

  The form of the separation membrane incorporated in the blood purification module is not particularly limited, and is used in the form of a flat membrane, a hollow fiber membrane or the like. However, the hollow fiber membrane type is preferable in consideration of the processing efficiency, that is, securing the surface area in contact with blood.

  An example about the manufacturing method of the hollow fiber membrane module used for an artificial kidney is shown.

  For example, when the hollow fiber membrane incorporated in the artificial kidney is made of polymethyl methacrylate, there are the following methods for producing the hollow fiber. Isotactic-polymethyl methacrylate (5 parts) and syndiotactic-polymethyl methacrylate (20 parts) are added to dimethyl sulfoxide (75 parts) and dissolved by heating to obtain a film-forming stock solution. This membrane-forming stock solution is discharged from an orifice-type double-cylinder die, allowed to pass through 300 mm in air, and then guided into a 100% water coagulation bath to obtain a hollow fiber separation membrane. At this time, dry nitrogen is used as the internal injection gas.

  Moreover, when a hollow fiber consists of a polysulfone type polymer, there exist the following methods in the manufacturing method of a hollow fiber. Polysulfone and polyvinylpyrrolidone (weight ratio 20: 1 to 1: 5 is preferable, 5: 1 to 1: 1 is more preferable) polysulfone good solvent (N, N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methyl) Pyrrolidone, dioxane, etc. are preferred) and a stock solution dissolved in a mixed solution of a poor solvent (concentration is preferably 10 to 30% by weight, more preferably 15 to 25% by weight), and the inside is discharged from the double annular die. The infusion solution is poured into the tube, and after running the dry section, it is guided 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.

  In order to use the method of the present invention, there is a method of applying pressure with a liquid or gas from the dialysate side after contacting a modifying agent on the blood side after modularization, or after that, applying gamma rays. Since sterilization can be performed simultaneously, it is preferable.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
1. Production of Hollow Fiber Membrane Module A hollow fiber membrane module used for an artificial kidney was produced by the following method.
(1) Production of hollow fiber membrane module 1 5 parts by weight of isotactic-polymethyl methacrylate and 20 parts by weight of syndiotactic-polymethyl methacrylate are added to 75 parts by weight of dimethyl sulfoxide and dissolved by heating to obtain a membrane-forming stock solution. Obtained. This membrane-forming stock solution was discharged from an orifice-type double cylindrical die, allowed to pass through 300 mm in air, and then led into a 100% water coagulation bath to obtain a hollow fiber membrane. At this time, dry nitrogen was used as the internal injection gas injected into the inner cylinder of the double cylinder. The resulting hollow fiber separation membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.

The hollow fiber membrane module 1 was made by filling the case with a hollow fiber membrane so that the inner surface area was 1.6 m ² , potting, and opening both ends of the hollow fiber membrane. Both the inside and outside of the hollow fiber membrane were filled with pure water.
(2) Production of Hollow Fiber Membrane Module 2 Polysulfone (Amoco Udel-P3500) 16 parts by weight, polyvinylpyrrolidone (International Special Products Co .; hereinafter abbreviated as ISP) K30 3 parts by weight, polyvinylpyrrolidone (ISP K90) 3 parts by weight A part of the solution was dissolved in 77 parts by weight of dimethylacetamide and 1 part by weight of water to prepare a stock solution.

This stock solution is sent to a spinneret at a temperature of 50 ° C., and a solution comprising 63 parts by weight of dimethylacetamide and 37 parts by weight of water is discharged as a core liquid from a double slit tube having an inner diameter of 0.35 mm and an inner diameter of 0.25 mm. After forming a hollow fiber membrane, a solidification bath at a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water is linearly passed through a 350 mm dry zone atmosphere at a temperature of 30 ° C. and a dew point of 28 ° C. The hollow fiber membrane obtained by passing it through a water washing step at 60 to 75 ° C. for 90 seconds and a drying step at 130 ° C. for 2 minutes and passing through a crimping step at 160 ° C. was used as a wound bundle. The hollow fiber membrane module 2 was obtained by filling the case with a hollow fiber membrane so that the inner surface area was 1.6 m ² , potting, and opening both ends of the hollow fiber membrane module.
2. Measurement Method (1) Method for Testing Human Platelet Adhesion of Hollow Fiber As an index for measuring the blood compatibility of a base material, there is a method of counting the number of platelets attached to the base material. Specific experimental methods are shown below.

Double-sided tape was affixed to a circular plate made of polystyrene of 18 mmφ, and the hollow fibers cut out from the hollow fiber membrane modules 1 and 2 were fixed thereto. The pasted hollow fiber was cut into a semicylindrical shape with a single blade to expose the inner surface of the hollow fiber. 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 is attached to a Falcon (registered trademark) tube (18 mmφ, No. 2051) cut into a cylindrical shape so that the surface to which the hollow fiber is attached enters the inside of the cylinder, and is attached with Parafilm (registered trademark). Filled the gap. The cylindrical tube was washed with physiological saline and then filled with physiological saline. Immediately after collecting venous blood of healthy adults, heparin sodium injection solution (manufactured by Ajinomoto Co., Inc.) 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 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 was dried under reduced pressure at a room temperature of 0.5 Torr for 10 hours. This hollow fiber was attached to a sample stage of a scanning electron microscope with a double-sided tape. Thereafter, a thin film of platinum-palladium (Pt—Pd) was formed on the surface of the hollow fiber by sputtering to prepare a sample. The inner surface of the hollow fiber was observed with a field emission type scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times, and adhered in one field of view (4.3 × 10 ³ μm ² ). The platelet count was counted. In the vicinity of the center in the longitudinal direction of the hollow fiber, the average value of the number of adhering platelets in 20 different visual fields 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.

    In addition, in the platelet adhesion test, positive control and negative control are put into the standard for each experiment in order to confirm whether the test is properly performed. A positive control is a known sample known to have a low platelet count. A negative control is a known sample known to have a large number of platelet adhesion.

    As a positive control, hollow fiber membranes of artificial kidney PS-1.6UW manufactured by Kawasumi Chemical Co., Ltd. were used for evaluation of both hollow fiber membrane modules 1 and 2. As a negative control, a hollow fiber membrane of Toray's artificial kidney “Filtizer” (registered trademark) BG-1.6U was used for evaluation of the hollow fiber membrane module 1. The hollow fiber membrane module 2 was evaluated by subjecting the hollow fiber membrane module 2 wetted with pure water instead of polyvinyl alcohol to 27 kGy of γ-ray irradiation in the method of Example 3, and Toray Industries, Inc. An artificial kidney “Tresulfone” (registered trademark) TS-1.6UL hollow fiber membrane was used.

Under the above experimental conditions, the platelet adhesion number was 5 (pieces / 4.3 × 10 ³ μm ² ) or less for positive control and 40 (pieces / 4.3 × 10 ³ μm ² ) or more for negative control. When there is, the measured value is adopted. If the control platelet adhesion number is out of the above range, blood freshness may be lacking or excessive activation of blood may occur, so the test is repeated.

In this experiment, if the platelet adhesion number is 10 (pieces / 4.3 × 10 ³ μm ² ) or less, it is considered that the base material has good blood compatibility.
(2) β ₂ -microglobulin clearance measurement A plastic tube module having an effective length of 100 mm was prepared by passing 20 hollow fibers through a plastic tube and fixing both ends with an adhesive. The effective length is the length of the hollow fiber excluding the portion where the adhesive is attached at both ends, and is the length used for the substance exchange between the blood side and the dialysis side. The bovine serum used was filtered through a 0.45 μm filter. Β ₂ -microglobulin was added to bovine serum at 37 ° C. 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. The blood side and dialysate side were allowed to flow in a cross flow. 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. The clearance was calculated by the following formula.
<Calculation formula of clearance> Clearance (mL / min) = (blood side inlet concentration−blood side outlet concentration) / blood side inlet concentration × blood side flow rate The clearance converted to an inner surface area of 1.5 m ² was calculated.

Since there was a variation in the values for each experiment, a control was added for each experiment, and comparisons were made between experiments. For the evaluation of the hollow fiber membrane module 1, a hollow fiber membrane made of Toray's artificial kidney “Filtizer” (registered trademark) BG-1.6U was used for the control. For evaluation of the hollow fiber membrane module 2, 27 kGy of γ-ray irradiation was performed on the hollow fiber membrane module 2 wetted with pure water instead of polyvinyl alcohol in the method of Example 3. As a control, the same production lot was used. The relative removal rate (%) was obtained by comparing with the measurement result of the control as a percentage, and comparison was made between experiments using this value.
(Example 1) Using the hollow fiber membrane module 1 manufactured as described in 1 above, an aqueous solution of polyethylene glycol (manufactured by Nippon Oil & Fats Co., Ltd.) having a weight average molecular weight of 6000 (10000 ppm by weight) is shown in FIG. The hollow fiber membrane module was passed from the blood side inlet 3 to the blood side outlet 4, and simultaneously with the blood side, water was passed from the dialysate side outlet 9 and the dialysate side inlet 8 to the blood side. . Thereafter, it was washed with water in the same manner. The module was irradiated with gamma rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. As a negative control, an artificial kidney “Filtizer” (registered trademark) BG-1.6U (product lot: 91110412) manufactured by Toray Industries, Inc., an artificial kidney PS-1.6UW (product of Kawasumi Chemical Co., Ltd.) is used as a positive control. Using product lot: 1Y7335), it was confirmed that the platelet adhesion test was established. The following examples and comparative examples were also used in the same manner, and the confirmation of the platelet adhesion test was confirmed. The results are shown in Table 1. That is, it was found that the number of platelet adhesion was small and good blood compatibility was exhibited, and the clearance of β2-microglobulin was maintained at the same level as the control.
(Example 2) Using the hollow fiber membrane module 1 produced as described in 1 above, an aqueous solution of polyethylene glycol (manufactured by Nippon Oil & Fats Co., Ltd.) having a weight average molecular weight of 6000 (2000 ppm by weight) is shown in FIG. The hollow fiber membrane module was passed through the blood side inlet 3 to the blood side outlet 4, and simultaneously with the blood side, water was passed from the dialysate side outlet 9 to the dialysate side inlet 8. Thereafter, it was washed with water in the same manner. The module was irradiated with gamma rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 1. That is, it was found that the number of platelet adhesion was small and good blood compatibility was exhibited, and the clearance of β2-microglobulin was maintained at the same level as the control.
(Example 3) Using the hollow fiber membrane module 2 produced as described in 1 above, an aqueous solution of polyvinyl alcohol (manufactured by Aldrich Chemical Company, Inc., weight average molecular weight 10,000, saponification degree 80%) (1000 ppm by weight) 1) through the blood side inlet 3 of the hollow fiber membrane module as shown in FIG. 1 and then the blood side inlet 3 through the dialysate side outlet 9 in that order . Further, the filling solution was pushed from the dialysate side to the blood side with compressed air of 100 kPa (gauge pressure, the same applies hereinafter), and then the blood side filling solution was blown off. Furthermore, each of the dialysate side and the blood side was blown with nitrogen so that the liquid retention rate was 270% and the oxygen concentration was 3%. Thereafter, the module was irradiated with γ rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 1. That is, it was found that the number of platelet adhesion was small and good blood compatibility was exhibited, and the clearance of β2-microglobulin was maintained at the same level as the control.
(Comparative Example 1) Using the hollow fiber membrane module 1 produced as described in 1 above, an aqueous polyethylene glycol (Nippon Yushi Co., Ltd.) aqueous solution (2000 ppm by weight) having a weight average molecular weight of 6000 was used as shown in FIG. The hollow fiber membrane module was passed from the blood side inlet 3 to the blood side outlet 4. Thereafter, in the same manner, the module washed with water was irradiated with γ rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 1. That is, it was found that although the number of platelet adhesion was small and good blood compatibility was exhibited, the clearance of β2-microglobulin was lower than that of the control.
Comparative Example 2 Using the hollow fiber membrane module 1 manufactured as described above, pure water was passed from the blood side inlet 3 to the blood side outlet 4 of the hollow fiber membrane module as shown in FIG. Thereafter, the module was irradiated with γ rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 1. That is, the platelet adhesion number was large and the blood compatibility was poor, but the clearance of β2-microglobulin was comparable to the control.
(Comparative Example 3) Using the hollow fiber membrane module 2 produced as described in 1 above, an aqueous solution of polyvinyl alcohol (Aldrich Chemical Company, Inc., weight average molecular weight 10,000, saponification degree 80%) in water (1000 ppm by weight) 1) through the blood side inlet 3 of the hollow fiber membrane module as shown in FIG. 1 and then the blood side inlet 3 through the dialysate side outlet 9 in that order. Further, the filling solution on the blood side was blown off with compressed air of 100 kPa. Furthermore, each of the dialysate side and the blood side was blown with 100 kPa of nitrogen so that the liquid retention rate was 270% and the oxygen concentration was 3%. Thereafter, the module was irradiated with γ rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 1. That is, it was found that although the number of platelet adhesion was small and good blood compatibility was exhibited, the clearance of β2-microglobulin was lower than that of the control.
(Comparative Example 4) Using the hollow fiber membrane module 2 produced as described above 1, pure water was passed from the blood side inlet 3 to the blood side outlet 4 of the hollow fiber membrane module as shown in FIG. Next, the blood was charged in the order of passing from the blood side inlet 3 to the dialysate side outlet 9. Further, the filling solution on the blood side was blown off with compressed air of 100 kPa. Furthermore, each of the dialysate side and the blood side was blown with 100 kPa of nitrogen so that the liquid retention rate was 270% and the oxygen concentration was 3%. Thereafter, the module was irradiated with γ rays. The gamma irradiation dose was 27 kGy. The hollow fiber of the module was cut out and a platelet adhesion test was performed. The results are shown in Table 1. That is, the platelet adhesion number was large and the blood compatibility was poor, but the clearance of β2-microglobulin was comparable to the control.

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

Explanation of symbols

1. 1. Arterial header 2. Venous header 3. Blood side inlet 4. Blood side outlet Hollow fiber membrane6. Blood 7. Module case 8. Dialysate side inlet 9. Dialysate side outlet 10. Potting unit 11. Blood circuit

Claims (6)

The method of manufacturing a modified separation membrane for imparting a hydrophilic polymer in the separation membrane, after the process of the one surface of the separation membrane is contacted with a solution of a hydrophilic polymer, said hydrophilic the other side of the surface of the separation membrane toward the surface contacting the solution of the sex polymer, the pressure (gauge pressure) performs the step of applying pressure at 500kPa or less gas than 50 kPa, medical further comprising a step of further irradiating the radiation A method for producing a separation membrane. The method for producing a medical separation membrane according to claim 1, wherein the concentration of the hydrophilic polymer solution is 0.001 wt% or more and 30 wt% or less. The method for producing a medical separation membrane according to claim 1 or 2 , wherein the separation membrane is a hollow fiber membrane. Method for producing a medical separation membrane module, characterized in that a built-in manufactured medical separation membrane module according to the method of any of claims 1-3. The method for manufacturing a separation membrane module according to claim 4 , wherein the medical module is a blood purification module. The method for manufacturing a separation membrane module according to claim 4 , wherein the medical module is a module for an artificial kidney.

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