JP4569315B2 - Modified hollow fiber membrane - Google Patents

Description

  The present invention relates to a modification with less eluate while imparting hydrophilicity, ionicity, hydrophobicity or physiological activity to a substrate. Biological component separation membrane, separation membrane for blood purification module, separation membrane for artificial kidney module, membrane for water purifier, separation membrane for water purification membrane, sewage purification membrane, RO membrane, porous beads, nonwoven fabric, knitted fabric Preferably used. In particular, it is suitably used for applications requiring blood compatibility, for example, separation membranes for blood purification modules.

  Many attempts have been made to impart hydrophilicity, ionicity, hydrophobicity or physiological activity to a substrate, particularly a separation membrane, to suppress deposits on the separation membrane or to remove a specific substance. For example, as an attempt to impart hydrophilicity to the polysulfone membrane, the polysulfone membrane is given hydrophilicity by adding an appropriate amount of a hydrophilic polymer, polyvinylpyrrolidone, to the polysulfone membrane, thereby fouling the membrane. Methods for suppressing this are disclosed in JP-A-61-1380, JP-B-2-18695, and JP-A-61-238834. Japanese Patent Application Laid-Open No. Sho 62-201603 discloses a method of imparting hydrophilicity to a polysulfone membrane by blending a graft or block copolymer comprising a hydrophilic polymer segment and a hydrophobic segment, thereby suppressing membrane contamination. This is disclosed in Japanese Utility Model Publication No. 63-77941. However, in these methods, the amount of polyvinyl pyrrolidone contained is limited in terms of spinnability and the like, and sufficient hydrophilicity cannot be imparted. Furthermore, a method is disclosed in which a hydrophilic polymer is added to an injection solution when a hollow fiber is spun (JP-A-10-118472). However, with this method, if the concentration of the hydrophilic polymer is too high, the injection solution viscosity increases and the spinnability deteriorates. Moreover, the introduction efficiency varies greatly depending on the type and molecular weight of the hydrophilic polymer.

As an attempt to introduce an ionic group, JP-A-2-2862 discloses that a polysulfone hollow fiber membrane is immersed in concentrated sulfuric acid to be sulfonated. However, there are problems that handling of concentrated sulfuric acid is not easy and that the polysulfone hollow fiber membrane is deteriorated by the concentrated sulfuric acid treatment. Furthermore, a method is also used in which an ionic group is introduced on the polymer surface by plasma irradiation or ion cluster beam, or a radical polymerizable monomer is allowed to act to form a graft polymerization layer on the surface. Although polymerization can be carried out on the surface, these methods also have problems that the introduction efficiency of ionic groups is low and unreacted monomers remain.
Japanese Patent Laid-Open No. 61-9380 Japanese Patent Publication No. 2-18695 Japanese Patent Laid-Open No. 61-238834 JP-A-62-201603 JP-A 63-77941 Japanese Patent Laid-Open No. 10-118472 JP-A-2-2862

  An object of the present invention is to provide a modified base material with less eluate while improving the disadvantages of the prior art and imparting hydrophilicity, ionicity, hydrophobicity or physiological activity to the base material.

In order to achieve the above object, the present invention has the following configuration.
(1) Modification obtained by filling at least one selected from a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group, and a physiologically active substance while filtering. Base material.
(2) After filling the substrate with at least one selected from a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group and a physiologically active substance, it is obtained by washing while filtering with a washing liquid. The modified substrate according to (1).
(3) The modified base material according to (1), which is obtained by washing without filtration with a washing liquid after filling with filtration.
(4) The modified substrate according to any one of (1) to (3), wherein the hydrophilic substance is a hydrophilic polymer.
(5) The modified substrate according to any one of (1) to (4), wherein the substance having an ionic group is a cationic polymer.
(6) The modified substrate according to any one of (1) to (5), wherein the substance having an ionic group is an anionic polymer.
(7) The modified substrate according to any one of (1) to (6), which is obtained by irradiating the substrate with radiation.
(8) The concentration in the eluate of a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group or a physiologically active substance from the substrate is 120 ppm or less (1) to ( The modified base material according to any one of 7).
(9) The modified substrate according to any one of (1) to (8), wherein the substrate is a separation membrane.
(10) The modified substrate according to (9), wherein the substrate is a biological component separation membrane.
(11) The modified base material according to any one of (9) and (10), wherein the base material is built in a blood purification module.
(12) The modified base material according to any one of (9) to (11), wherein the separation membrane is built in a module for an artificial kidney.
(13) The modified substrate according to any one of (9) to (12), wherein the separation membrane is a hollow fiber membrane.
(14) The modified substrate according to any one of (9) to (13), wherein the separation membrane is a polysulfone-based polymer.
(15) The modified substrate according to any one of (1) to (8), wherein the substrate is a porous bead.
(16) The modified substrate according to any one of (1) to (8), wherein the substrate is a nonwoven fabric.
(17) The modified substrate according to any one of (1) to (8), wherein the substrate is a knitted fabric.
(18) The modified substrate according to any one of (1) to (8), wherein the porous beads, nonwoven fabric, and knitted fabric are built in a column.
(19) The modified base material according to any one of (2) to (18), wherein a gas is used instead of the cleaning liquid.
(20) The modified group according to any one of (1) to (19), wherein a consumption amount of 0.01 N potassium permanganate solution with respect to the eluate from the substrate is 10 ml or less. Wood.
(21) The modified substrate according to any one of (1) to (20), wherein the platelet adhesion amount on the substrate surface is 20 / 1.0 × 10 ³ μm ² or less.
(22) The substrate is irradiated with radiation, and is selected from 10 mg or more of a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group and a physiologically active substance per 1 m ^{2 of the} substrate surface area. At least 1 sort is fix | immobilized, The modified base material in any one of (1)-(21) characterized by the above-mentioned.

  According to the present invention, it is possible to provide a modified base material with less eluate while imparting hydrophilicity, ionicity, hydrophobicity or physiological activity to the base material.

  In the present invention, the substrate is efficiently filled with at least one selected from a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group, or a physiologically active substance while being filtered. Therefore, the elution of the introduced substance can be reduced. In the present invention, a generic term for a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group, or a physiologically active substance is called a functional substance.

  In addition, the hydrophilic substance in the present invention means a substance soluble in water having a hydrophilic group. 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. As the hydrophilic substance, a hydrophilic polymer is preferably used. Here, the polymer means a substance having a molecular weight of 500 or more, and the hydrophilic polymer means a substance that is a hydrophilic substance and is a polymer. Specific examples include polyalkylene glycols such as polyethylene glycol, polyvinyl pyrrolidone, and polyvinyl alcohol. By imparting hydrophilicity to the separation membrane, adhesion to proteins, blood cell components such as platelets, and fungi can be suppressed.

  The ionic group means a functional group having a charge, and examples thereof include an amino group, an aminosulfuric acid group, an imidazole group, a carboxyl group, a sulfonic acid group, and a phosphoric acid group.

  As the substance having an ionic group, a cationic polymer or an anionic polymer is preferably used.

  The cationic polymer means a polymer having a charge of 1 meq / g or more at pH 4.5. The weight average molecular weight of the cationic polymer is not particularly limited, but 500 or more, preferably 5000 or more, more preferably 10,000 or more is preferably used. Although not particularly limited, specifically, amino group-containing polymers such as polyalkyleneimine, polyvinylamine, polyallylamine, diethylaminoethyl dextran, polydiallyldimethylammonium chloride, vinyl imidazolium methochloride polymer and vinyl Imidazole polymers and the like, copolymers of these with other monomers, and derivatives such as grafts may also be used. Two or more kinds of cationic polymers may be used in combination. By imparting cationicity to the membrane, it exhibits a high effect on the adsorption of acidic substances such as oxidized low density lipoprotein.

  An anionic polymer means a polymer having a charge of 1 meq / g or more at pH 9.5. The weight average molecular weight of the anionic polymer is not particularly limited, but is preferably 500 or more, preferably 5000 or more, and more preferably 10,000 or more. Specific examples include, but are not limited to, polyacrylic acid, polyvinyl sulfate, polymethacrylic acid, polysulfonic acid, deoxyribonucleic acid, copolymers of these with other monomers, and derivatives such as grafts. Etc. By imparting anionic properties to the membrane, it is highly effective in adsorbing basic substances such as lysotium.

  Further, the hydrophobic group is a hydrocarbon having 6 to 50 carbon atoms, and may be any of linear, branched and cyclic. Moreover, you may have an unsaturated bond. Further, the entire functional substance may be hydrophilic. When a functional substance having a hydrophobic group is filtered and packed on a hydrophobic base material, in addition to the pressing effect of filtration, hydrophobic interaction works, so it can be introduced more efficiently and elution is reduced. Is a preferred choice. Furthermore, the hydrophobic group exhibits a high effect on the adsorption of fat and oil components such as lipoproteins and cytokines.

  Bioactive substances refer to proteins, peptides, and amino acids that affect biological functions, and molecular weights of 500 or more are preferably used. Specific examples include heparin and polymyxin B.

  The functional substance can be efficiently filled with filtration to increase the surface density efficiently. Moreover, since it is strongly pressed against the substrate surface, elution can be reduced by an action such as physical entanglement in addition to the interaction of various forces. Further, if the substrate is a porous body such as a separation membrane or a porous bead, and the pore size is larger than the functional substance, the functional substance can be efficiently introduced into the pores by filtration and filling. Furthermore, since it is trapped inside the substrate, elution from the substrate can be kept low. The reason why a functional substance having a molecular weight of 500 or more is suitably used is that, in addition to the effect of filtration, a substance having a large molecular weight has a stronger intermolecular force, so that it can be efficiently introduced into the base material and less elution occurs. It is to become.

  In the present invention, the filtration means that when the substrate is a separation membrane, the functional substance solution and the cleaning liquid are filtered through the separation membrane. The filtered state refers to a state in which 1% or more, preferably 10% or more, more preferably 50% or more of the flow rate of the functional substance solution or the cleaning liquid comes out as a filtrate. When the separation membrane is a flat membrane and the filtrate flow rate is uneven depending on the location of the separation membrane, an average value of the entire separation membrane may be taken. When the separation membrane is used as a hollow fiber membrane for an artificial kidney, when filtration is performed from the blood side to the dialysate side, calculation may be made from the respective flow rates on the blood side and dialysate side. In addition, the direction of filtration is not particularly limited, and may be appropriately selected depending on the purpose and application. Although it is not particularly limited, in the case of an asymmetric membrane in which the inside of the hollow part is dense and the outside is sparse, such as a separation membrane comprising a blended hollow fiber membrane of polysulfone and polyvinylpyrrolidone for an artificial kidney, the outer side of the hollow fiber Since the clogging is likely to occur when the filter is applied from the inside, it is preferable to apply the filtration from the inside of the hollow fiber.

  In addition, the module containing the separation membrane is filled with the functional substance solution without filtration, and then filtered with a cleaning solution, so that the functional substance is substantially filled with filtration. You can also

  Further, the filtration in the case where the base material is porous beads, non-woven fabric, or knitted fabric is 10 mmHg or more at the inlet and outlet of the column when the functional material is packed after the base material is built in the column. , Preferably 20 mmHg or higher, more preferably 30 mmHg or higher, filling in a state where pressure is applied so as to produce a pressure difference. If the pressure difference is lower than 10 mmHg, the filtration effect, that is, the functional substance cannot be filled while being sufficiently pressed.

  The cleaning liquid as used in the present invention refers to a solution having a functional substance concentration of less than 0.001% by weight, preferably less than 0.0001% by weight. The direction in which the cleaning liquid is filtered must be the same as the direction in which the functional substance is filled by filtration. When the base material is a separation membrane and the functional substance is a high molecular weight substance, the functional substance is more strongly pressed against the membrane surface by filtration using a cleaning liquid, so that it is difficult to release from the separation membrane. . In the case of a low molecular weight substance, the functional quantity present on the membrane surface and pores is washed away together with the quantity of washing, so it is preferable to control the quantity of washing.

  By washing the washing liquid without filtering, the functional substance released from the separation membrane can be washed away. Also at this time, since the functional substances present on the membrane surface and the pores are washed away together with the washing amount, it is preferable to control the washing amount.

  Even when the substrate is a porous bead, a nonwoven fabric, or a knitted fabric, the functional substance may be washed away together with the amount of the cleaning solution, so that the cleaning amount is preferably controlled.

  Further, a gas may be used instead of the cleaning liquid. The gas is not particularly limited as long as the base material or the functional substance is not significantly modified at room temperature or does not react with the used gas, but an inert gas is preferable. Although it does not specifically limit, nitrogen, argon, etc. are used suitably.

  The term “filling” as used in the present invention is to introduce a functional substance into the base material. In this case, it is considered that the functional substance is immobilized on the base material by an action such as adsorption. Moreover, the functional substance may be chemically bonded to the base material. If the functional substance is immobilized by chemical bonding, there is little concern about elution, which is preferable. Depending on the functional substance or base material, there may be a case where a chemical bond is formed between the functional substance and the base material by heating or irradiation after the functional material is adsorbed to the base material. This is a preferred method because a chemical bond is formed on the surface. 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. For example, in order to sterilize a blood purification module with γ-rays, it is considered preferable to apply a dose of 20 kGy or more. Therefore, irradiation with radiation of 20 kGy or more is a preferable treatment because the functional substance can be immobilized and sterilized at the same time, and the eluate can be further reduced. An antioxidant may be added at the same time in order to prevent denaturation during irradiation. The term “antioxidant” as used herein refers to a molecule that has the property of easily giving electrons to other molecules. However, a base material, a hydrophilic substance, a substance having an ionic group, a substance having a hydrophobic group, or It has the property of suppressing the denaturation of physiologically active substances and nonionic hydrophilic polymers by radiation. For example, water-soluble vitamins such as vitamin C, polyphenols, alcohols such as methanol, ethanol, propanol, ethylene glycol and glycerin, sugars such as glucose, galactose, mannose and trehalose, sodium hydrosulfite, sodium pyrosulfite, Examples include, but are not limited to, inorganic salts such as sodium dithionate, uric acid, cysteine, glutathione, oxygen, and the like. 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 aqueous solution containing an antioxidant, since it changes with kinds, antioxidant dose, etc. of the contained antioxidant, what is necessary is just to use it by the optimal density | concentration suitably.

Further, after filtering and filling the functional material on the base material and further irradiating with radiation, if at least 10 mg or more of the functional material is immobilized per 1 m ^{2 of the} surface area of the base material, the functional material The effect of can be demonstrated. The immobilization of the functional substance here may be adsorption or chemical bonding of the base material and the functional substance as described above. When the functional substance is originally contained in the base material, the immobilization amount here refers to the total of the filtered amount and the original amount.

  Moreover, in this invention, it is preferable that the density | concentration in the elution liquid of the functional substance from a base material is 120 ppm or less, More preferably, it is 100 ppm, Furthermore, it is 80 ppm or less.

    Here, the concentration of the functional substance in the eluate refers to the concentration of the functional substance in the aqueous solution when the substrate is built in the module or column and immersed in the aqueous solution. When a base material is a medical use, the density | concentration of the aqueous solution immersed in the part which the blood or a blood component contacts is pointed out. For example, if the base material is a wet type artificial kidney hollow fiber membrane, the elution concentration of the aqueous solution existing inside the hollow fiber membrane may be measured. As a method of taking out, natural fall may be sufficient. Further, when the substrate is porous beads and is built in the column together with the aqueous solution, the elution concentration of the supernatant may be measured by centrifuging and sedimenting the porous beads. When the substrate is in a wet state or a dry state, the module or column is filled with pure water, and the amount of the functional substance eluted after being immersed at room temperature for one week may be measured. Moreover, when the functional substance is originally contained in the base material, it is not necessary to distinguish the elution of the functional substance filled later from the elution of the functional substance originally contained in the base material. Here, the functional substance elution concentration is the sum of both. A detailed measurement method will be described later. When the amount of elution exceeds 120 ppm, there is a possibility that the functional substance is eluted in the blood in the case of the base material in contact with blood. Since high molecular weight substances are difficult to be metabolized or may accumulate in the body, the elution of high molecular weight substances into blood requires particular attention. Further, when a biological material is separated and then the separated liquid is used for analysis, such as a biological component separation membrane, there is a concern that the eluted functional substance may be an inhibitory factor for the analysis.

  Furthermore, although the details of the measurement method will be described later, the consumption of 0.01 N potassium permanganate solution is preferably 10 ml or less, more preferably 8 ml or less, and further 5 ml for the same aqueous solution as described above. It is as follows. Potassium permanganate is an oxidizing agent and reacts with organic substances and reducing inorganic substances. The measurement method is a simple method for measuring water pollution. Therefore, since the amount of the eluate other than the functional substance can also be measured, when considering together with the elution concentration of the functional substance, it is possible to comprehensively judge the eluate.

When the substrate comes into contact with blood, high blood compatibility is required. As a means for evaluating blood compatibility, there is a method of checking adhesion of platelets. If the number of platelets attached to the substrate surface is small, it can be said that the blood compatibility is high. Specifically, 20 pieces / 1.0 × 10 ³ μm ² or less, preferably 15 pieces / 1.0 × 10 ³ μm ² or less, and more preferably 10 pieces / 1.0 × 10 ³ μm ² or less. The number of platelet adhesion is the number of platelets adhering to the surface of the modified substrate when the modified substrate and blood are brought into contact with each other for 1 hour per surface area of the modified substrate of 1.0 × 10 ³ μm ² . The value obtained as a number. A detailed measurement method will be described later. If the amount of platelet adhesion exceeds 20 / 1.0 × 10 ³ μm ² , blood compatibility becomes insufficient and the effect of suppressing adhesion of organic substances such as proteins and biological components becomes insufficient. When the blood compatibility of the base material is insufficient, the base material can be efficiently modified by filling with a physiologically active substance such as a hydrophilic substance or heparin by filtration. When the purpose of modifying the base material is to introduce an ionic group and also requires blood compatibility, both the ionic group and the hydrophilic substance may be filtered and packed.

  The separation membrane referred to in the present invention has a function of sieving the size of a substance according to the porous pore diameter in the membrane. Examples of the porous beads include cellulose beads. The bead particle size may be appropriately selected in consideration of the application to be used. Regarding the nonwoven fabric and the knitted fabric, the material and the like are not particularly limited, and may be appropriately selected in consideration of the intended use.

  The separation membrane as the modified base material of the present invention is preferably used as a biological component separation membrane. The biological component separation membrane refers to a membrane that separates a biological substance by filtration or dialysis and collects a part thereof. In the biological component separation membrane, adsorption of biological components inside the membrane cannot be suppressed only by making the surface of the membrane hydrophilic. Therefore, in the biological component separation membrane, it is a preferable form to perform the hydrophilic treatment to the inside of the membrane pores. Although there is no particular limitation, the membrane is finely packed by filtering the separation membrane with a hydrophilic polymer such as polyvinyl pyrrolidone, polyalkylene glycol, or polyvinyl alcohol having a weight average molecular weight of 50,000 or less. A modified separation membrane that has been hydrophilized to the inside of the pores can be obtained.

  The separation membrane of the present invention is preferably used for a blood purification module. A blood purification module is a module that has the function of removing waste and harmful substances in the blood by adsorption, filtration, and diffusion when circulating blood outside the body, such as artificial kidneys and exotoxin adsorption columns. There is.

  The separation membrane is preferably used as an artificial kidney module. As a module for an artificial kidney, 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.

  Although the material used as the separation membrane of the present invention is not particularly limited, materials used for medical use are preferable, for example, polyvinyl chloride, cellulose polymer, polystyrene, polymethyl methacrylate, polycarbonate, polysulfone, polyethersulfone, etc. And polysulfone-based polymers, polyurethane and the like. Of these, polysulfone is particularly suitable because it is easy to mold and has excellent material permeation performance when formed into a membrane.

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

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

  There are various methods for producing a blood purification module according to the present invention, depending on its use. As a rough process, a process for producing a separation membrane for blood purification and incorporating the separation membrane into the module is described. Can be divided into processes. The step of filling while filtering and the step of washing may be used before the step of incorporating the separation membrane into the module or after the separation membrane is incorporated into the module, but may be performed after modularization. desirable. If γ-ray irradiation is performed after modularization, sterilization can be performed at the same time, which is preferable.

  There are various methods for manufacturing a blood purification module depending on its application, but the rough process is divided into a process for manufacturing a separation membrane for blood purification and a step of incorporating the separation membrane into the module. Can do.

  An example about the manufacturing method of the hollow fiber membrane module used for an artificial kidney is shown. As a method for producing a hollow fiber membrane incorporated in an artificial kidney, there are the following methods. That is, a solution obtained by dissolving polysulfone and polyvinylpyrrolidone in a good solvent or a mixed solvent containing a good solvent is used as a stock solution. The polymer concentration is preferably 10 to 30% by weight, and more preferably 15 to 25% by weight. The weight ratio of polysulfone and polyvinylpyrrolidone is preferably 20: 1 to 1: 5, and more preferably 5: 1 to 1: 1. As the good solvent, N, N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane and the like are preferable. The undiluted solution is discharged from the outer pipe of the double annular die, and after running through the dry section, it is led to the coagulation bath. An injection solution or a gas for forming a hollow portion is discharged from a tube inside the double annular base. 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. It is also possible to reduce the diffusion resistance. However, when the relative humidity is too high, the solid solution coagulation on the outer surface becomes dominant, and the pore diameter is rather reduced, and as a result, the permeation / diffusion resistance during dialysis tends to increase. Therefore, the relative humidity is preferably 60 to 90%. Moreover, as an injection liquid composition, it is preferable to use what consists of a composition based on the solvent used for the undiluted | stock solution from process aptitude. 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. Thereafter, 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.

  An example of the basic structure of an artificial kidney using the hollow fiber membrane module obtained as described above is shown in FIG. A bundle of hollow fiber membranes 5 is inserted into a cylindrical plastic case 7, and both ends of the hollow fiber are sealed with a resin 10. The case 7 is provided with an inlet 8 and an outlet 9 for dialysate, and dialysate, saline, filtered water and the like flow outside the hollow fiber membrane 5. An inlet port portion 1 and an outlet port portion 2 are provided at the ends of the case 7, respectively. The blood 6 is introduced from the blood introduction port 3 provided in the inlet side port portion 1 and is guided into the hollow fiber membrane 5 by the funnel-shaped port portion 1. The blood 6 filtered by the hollow fiber membrane 5 is collected by the outlet side port portion 2 and discharged from the blood outlet 4. A blood circuit 11 is connected to the blood inlet 3 and the blood outlet 4.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
1. Method for producing hollow fiber membrane module 18 parts by weight of polysulfone (Udelpolysulfone (registered trademark) P-3500 manufactured by Solvay) and 9 parts by weight of polyvinylpyrrolidone (K30 manufactured by BASF) were added to 72 parts by weight of N, N′-dimethylacetamide and In addition to a mixed solvent of 1 part by weight of water, the mixture was dissolved by heating at 90 ° C. for 14 hours to obtain a film forming stock solution. This film-forming stock solution was discharged from an outer tube of an orifice type double cylindrical die having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. A solution consisting of 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water was discharged from the inner tube as the core liquid. The discharged film-forming stock solution passed through a dry length of 350 mm, and was then introduced into a 100% water coagulation bath to obtain a hollow fiber.

The resulting hollow fibers are inserted into a cylindrical plastic case having a dialysate inlet and a dialysate outlet as shown in FIG. 1 and sealed at both ends with a resin, and then filled with water. A hollow fiber membrane module for artificial kidneys having a thread inner surface area of 1.6 m ² was prepared.
2. Filling the hollow fiber membrane module Polyvinylpyrrolidone or glycerin was used as a hydrophilic substance. In addition, the platelet adhesion of a film | membrane can be suppressed by giving hydrophilicity to a film | membrane. As the cleaning liquid, water or an aqueous glycerin solution was used. Both the polyvinyl pyrrolidone aqueous solution and the cleaning liquid were passed through the module at a flow rate of 500 ml / min to replace the water in the hollow fiber membrane module. The filling was performed at room temperature, and both the polyvinylpyrrolidone aqueous solution and the cleaning liquid were performed at a liquid temperature of 20 ± 5 ° C.
3. Measurement method (1) Rabbit platelet adhesion test method for hollow fiber membranes 30 hollow fiber separation membranes are bundled, and both ends are fixed to a glass tube module case with an epoxy potting agent so as not to block the hollow portion of the hollow fiber. It was created. The mini module had a diameter of about 7 mm and a length of about 10 cm. The blood inlet and the dialysate outlet of the minimodule were connected by a silicone tube, and 100 ml of distilled water was allowed to flow from the blood outlet at a flow rate of 10 ml / min to wash the hollow fiber and the inside of the module. Thereafter, physiological saline was filled, and the dialysate inlet and outlet were capped. Next, physiological saline priming was performed at a flow rate of 0.59 ml / min from the blood inlet for 2 hours, and then 3.2% trisodium citrate dihydrate aqueous solution and rabbit fresh blood were added 1: 9 (volume ratio). ) Was perfused for 1 hour at a flow rate of 0.59 ml / min. Then, it was washed with physiological saline with a 10 ml syringe, filled with 3% aqueous glutaraldehyde solution both inside the hollow fiber and on the dialysate side, and placed overnight or longer to fix glutaraldehyde. Thereafter, glutaraldehyde was washed with distilled water, a hollow fiber membrane was cut out from the minimodule and dried under reduced pressure for 5 hours or more. The hollow fiber membrane was attached to a sample stage of a scanning electron microscope with a double-sided tape, and then sliced in the longitudinal direction to expose the inner surface. Thereafter, a thin film of Pt—Pd was formed on the sample by sputtering. The inner surface of the sample was observed with a scanning electron microscope (S800 manufactured by Hitachi, Ltd.) at a magnification of 3000 times, and the number of adhering platelets in one visual field (1.12 × 10 ³ μm ² ) was counted. A value obtained by dividing the average value of the number of adhering platelets in 10 different visual fields by 1.12 was defined as the number of adhering platelets (number / 1.0 × 10 ³ μm ² ).

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 high platelet adhesion. A negative control is a known sample known to have low platelet adhesion. The positive control is a hollow fiber membrane of Toray's artificial kidney “Filtizer” BG-1.6U, and the negative control is a hollow fiber membrane of Kawasumi Chemical's artificial kidney PS-1.6UW. In the platelet adhesion test, a sample having a platelet adhesion number of 30 (pieces / 1.0 × 10 ³ μm ² ) or more under the above experimental conditions is used as a positive control. Similarly, a sample having a platelet adhesion number of 5 (pieces / 1.0 × 10 ³ μm ² ) or less is used as a negative control. After the test, the measured value is adopted when the platelet adhesion number of the positive control is not less than the above value and the platelet adhesion number of the negative control is not more than the above value. 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.
(2) Measurement of eluate (a) Polyvinylpyrrolidone (PVP) concentration measurement Since polyvinylpyrrolidone (PVP) is filled as a functional substance, the concentration of the substance was measured by HPLC under the conditions shown below.

Since the eluate is a wet type artificial kidney hollow fiber membrane, an aqueous solution immersed in a portion in contact with blood, that is, a liquid filled inside the hollow fiber membrane is spontaneously dropped from the blood outlet 4. Extracted. In addition, after filling with PVP, after irradiating γ rays within 2 days, the elution concentration was measured for the module left at room temperature for 1 week.
Equipment: Waters, GPC-244
Column: TSKgel GMPWXL 1 solvent: mixed solvent of methanol: water = 1: 1 (volume ratio) added with 0.1 N LiNO ₃ Flow rate: 0.5 ml / min
Temperature: 40 ° C
(B) Measurement of glycerin concentration Since glycerin was filled as a functional substance, the concentration of the substance was measured by gas chromatography (GC) under the following conditions.

As the eluate, the same blood side filling solution as described above was used.
apparatus
GC: 5890 Series II (manufactured by Hewlett Packard)
Integrator: EZ Chrom Elite (Scientific Software Inc.)
Injection port: Split / Splitless injection port (manufactured by Hewlett Packard)
Detection: Flame ion detection (manufactured by Hewlett Packard)
Column: DB-WAX (J & W) Serial number (SN): US1302123H
Phase: Polyethylene glycol 30m long, 0.25mm ID, 0.25μm film thickness
Measurement conditions Injection
Injection temperature: 250 ℃
Column head pressure: 15psi
Carrier gas: He
Injection mode: Split (Line flow 50ml / min.)
Septum purge: He 3.0ml / min.
Injection volume: 1.0 μl
Detection unit
Detector temperature: 250 ° C
Gas: H2 40ml / min., Air 400ml / min., Aux (N2) 40ml / min.
Oven Column oven temperature, initial 50 ℃ (holding 3.0min)
Final 250 ℃ (holding 5.0min)
Rate 20 ° C / min. Linear gradient (c) Potassium permanganate (KMnO ₄ ) consumption measurement method Take 10 ml of the same blood-side filling solution as above in a stoppered Erlenmeyer flask, and add 0.01 N potassium permanganate solution 20 ml. Then, 1.0 ml of 10 vol% dilute sulfuric acid was added, boiled for 3 minutes, and after cooling, 1.0 ml of 10 wt% potassium iodide solution was added thereto, sealed tightly, shaken well, and allowed to stand for 10 minutes. This was titrated with 0.01N sodium thiosulfate aqueous solution. At this time, 5 drops (about 0.15 ml) of the starch solution was added as an indicator with a dropper.

    The starch solution was prepared as follows. 1 g of starch was placed in a beaker, 20 ml of water was added and stirred, and added to 60 ml of boiling hot water in a separate beaker while stirring. After the addition was completed, boiling continued for another minute, and then 20 g of sodium chloride was dissolved and added. The total amount was adjusted to 100 ml and allowed to cool.

    In addition, when there are many eluates in a filling liquid and it cannot measure in the said procedure, after diluting and measuring suitably, the value which multiplied the dilution rate to potassium permanganate consumption may be used.

Reference example 1
A 0.1% by weight aqueous solution of PVP (BASF K12) was introduced through the blood outlet 4 of the hollow fiber membrane module and out of the dialysate outlet 9, and PVP was introduced into the hollow fiber membrane by filtration. The flow rate was 1 L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. Thereafter, the elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a positive control, Toray's artificial kidney “Filtizer” BG-1.6U (product lot: 91110412) and as a negative control, Kawasumi Chemical Co., Ltd. artificial kidney PS-1.6UW (product lot: 1Y7335) ) Was used to confirm 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. As a result, as shown in Table 1, it was possible to obtain a membrane with less elution and less platelet adhesion.

Comparative Example 1
1 L of a PVP (BASF K90) 0.002 wt% aqueous solution was filtered in the same manner as in Reference Example 1. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, as shown in Table 1, a film with less elution and less platelet adhesion could be obtained.

Example 1
1 L of a PVP (BASF K90) 0.002 wt% aqueous solution was filtered in the same manner as in Reference Example 1. Thereafter, it was washed by filtering with water in the same manner as described above. The flow rate was 2L. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, it was as shown in Table 1. The average molecular weight of PVP (K90) is 1.2 million, which is larger than the pore diameter of the membrane. For this reason, even if it wash | cleans by further filtering with water, the added PVP is hardly washed away to the dialysate outlet, the effect of pressing on the membrane surface is higher, and the elution is less than that of Reference Example 1, and platelets. It is considered that a film with little adhesion could be obtained.

Comparative Example 2
A 0.1 wt% aqueous solution of polyvinylpyrrolidone (BASF K90) was filtered in the same manner as in Reference Example 1 to introduce 1 L. Thereafter, water was introduced from the blood outlet 4 and discharged to the blood inlet 3 for washing. The flow rate was 0.5L. At this time, the inlet 8 for dialysate and the outlet 9 for dialysate were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, it was as shown in Table 1. Even after washing with water, only the PVP pressed against the membrane surface remained, so it is considered that a membrane with little elution and less platelet adhesion could be obtained.

Example 2
A polyvinyl pyrrolidone (BASF K90) 0.002% by weight aqueous solution was introduced from the blood outlet 4 of the hollow fiber membrane module and exited to the blood inlet 3 to introduce polyvinyl pyrrolidone into the hollow fiber membrane without filtration. At this time, the inlet 8 for dialysate and the outlet 9 for dialysate were plugged. The flow rate was 1 L. Thereafter, water was introduced from the blood outlet 4 and out of the dialysate outlet 9 and was washed by filtration. The flow rate was 2L. At this time, the blood inlet 3 and the dialysate inlet 8 were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, it was as shown in Table 1.

Comparative Example 3
2 L of glycerin (manufactured by Wako Pure Chemical Industries, Ltd.) 0.1% by weight was filtered in the same manner as in Reference Example 1 and introduced. Thereafter, water was introduced from the blood outlet 4 and discharged to the blood inlet 3 for washing. The flow rate was 0.5L. At this time, the inlet 8 for dialysate and the outlet 9 for dialysate were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, it was as shown in Table 1.

Example 3
1 L of a PVP (BASF K90) 0.002 wt% aqueous solution was filtered in the same manner as in Reference Example 1. Thereafter, in the same manner as described above, 1 L of glycerin (manufactured by Wako Pure Chemical Industries, Ltd.) was filtered and then introduced with 1 L. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, as shown in Table 1, a film with less elution and less platelet adhesion could be obtained.

Comparative Example 4
1 L of water was introduced by filtration in the same manner as in Reference Example 1. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The PVP concentration, glycerin concentration, and potassium permanganate consumption in the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, as shown in Table 1, although the amount of eluate was small, it was a membrane to which platelets adhered.

Comparative Example 5
A 0.1% by weight aqueous solution of PVP (BASF K90) was introduced from the blood outlet 4 of the hollow fiber membrane module and discharged to the blood inlet 3. The flow rate was 1 L. At this time, the inlet 8 for dialysate and the outlet 9 for dialysate were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, as shown in Table 1, although there was little platelet adhesion, it was a membrane with much elution because it was not filtered.

Comparative Example 6
A 0.1% by weight aqueous solution of PVP (BASF K90) was introduced from the blood outlet 4 of the hollow fiber membrane module and discharged to the blood inlet 3. The flow rate was 1 L. Thereafter, water was introduced from the blood outlet 4 and discharged to the blood inlet 3 for washing. The flow rate was 0.5L. In each of the above steps, the dialysate inlet 8 and dialysate outlet 9 were plugged. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, as shown in Table 1, although elution was small, platelet adhesion was also large. Since PVP is not filtered and filled, unlike Example 4, PVP is considered washed away.

Comparative Example 7
2 L of glycerin was introduced by filtration in the same manner as in Reference Example 1 of 0.1% by weight. Thereafter, the module was irradiated with γ rays. The absorbed dose of γ rays was 27 kGy. The elution PVP concentration, glycerin concentration, and potassium permanganate consumption of the blood side filling solution of the module were measured. Furthermore, the hollow fiber of this module was cut out and the platelet adhesion number was evaluated. As a result, as shown in Table 1, it was a membrane with little platelet adhesion but much elution. Naturally, if the amount of introduction at the time of filtration is too large, the amount of eluate increases, so the amount of introduction needs to be controlled.

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

Claims (8)

Outer solution of hydrophilic substance with respect to the hollow fiber membrane, while applying a pressure to produce a pressure difference over 30mmHg at the inlet and outlet of the module from the inside of the hollow fiber membrane having a polysulfone-based polymer and polyvinyl pyrrolidone A method comprising a step of washing the hollow fiber membrane while applying filtration in a state in which the same pressure difference as that of the filtration is generated in the same direction as the filtration and filling in the same direction as the filtration and filling, while being filtered while being filtered. The concentration of any of the substances obtained in the above eluate is 120 ppm or less, and the platelet adhesion amount on the inner surface of the hollow fiber membrane is 20 / 1.0 × 10 ³ μm ² or less. Hollow fiber membrane.   The modified hollow fiber membrane according to claim 1, wherein the hydrophilic substance is a hydrophilic polymer. The modified hollow fiber membrane according to claim 1 or 2 , which is obtained by irradiation with radiation. The modified hollow fiber membrane according to any one of claims 1 to 3 , wherein the modified hollow fiber membrane is incorporated in a blood purification module. The modified hollow fiber membrane according to any one of claims 1 to 4 , wherein the modified hollow fiber membrane is incorporated in a module for an artificial kidney. Modified substrate according to any one of claims 1 to 5, wherein the use of gas in the step of performing the cleaning. The modified hollow fiber membrane according to any one of claims 1 to 6 , wherein a consumption amount of 0.01 N potassium permanganate solution with respect to an eluate from the base material is 10 ml or less. Be those wherein the hollow fiber membrane is irradiated, 10 mg or more hydrophilic substance per substrate surface area 1 m ² is according to any one of claims 1 to 7, characterized in that it is immobilized Modified hollow fiber membrane.

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