WO2015093160A1 - Membrane de séparation pour le traitement du sang et dispositif de traitement du sang qui en est équipé - Google Patents

Membrane de séparation pour le traitement du sang et dispositif de traitement du sang qui en est équipé Download PDF

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WO2015093160A1
WO2015093160A1 PCT/JP2014/079058 JP2014079058W WO2015093160A1 WO 2015093160 A1 WO2015093160 A1 WO 2015093160A1 JP 2014079058 W JP2014079058 W JP 2014079058W WO 2015093160 A1 WO2015093160 A1 WO 2015093160A1
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separation membrane
blood
water
mass
polymer
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PCT/JP2014/079058
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English (en)
Japanese (ja)
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智徳 小泉
真貴子 服部
貴浩 一
一樹 西澤
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旭化成メディカル株式会社
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Priority to CN201480065132.0A priority Critical patent/CN105992600B/zh
Priority to JP2015553416A priority patent/JP6149125B2/ja
Publication of WO2015093160A1 publication Critical patent/WO2015093160A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/14—Dynamic membranes
    • B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
    • B01D69/148—Organic/inorganic mixed matrix membranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0017—Filtration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0035—Gamma radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/007—Particle radiation, e.g. electron-beam, alpha or beta radiation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0079—Manufacture of membranes comprising organic and inorganic components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/08—Hollow fibre membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
    • B01D71/68—Polysulfones; Polyethersulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20—Targets to be treated
    • A61L2202/22—Blood or products thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/15—Use of additives
    • B01D2323/218—Additive materials
    • B01D2323/2182—Organic additives
    • B01D2323/21839—Polymeric additives
    • B01D2323/2187—Polyvinylpyrolidone
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/34—Use of radiation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/24—Dialysis ; Membrane extraction
    • B01D61/243—Dialysis

Definitions

  • the present invention relates to a separation membrane for blood processing and a blood processing device including the same.
  • a hollow fiber membrane blood treatment device using a selective separation membrane is widely used.
  • a hollow fiber membrane blood processor is used for oxygenation or plasma separation during blood opening surgery.
  • the hollow fiber membrane is excellent in mechanical strength and chemical stability, is easy to control the permeation performance, has less eluate, has less interaction with biological components, There is a need for products that are safe against sterility and that are guaranteed to be sterile.
  • hydrophilic polymers such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol, and polyethylene glycol in addition to hydrophobic polymers such as polysulfone resin.
  • PVP polyvinyl pyrrolidone
  • polyvinyl alcohol polyvinyl alcohol
  • polyethylene glycol in addition to hydrophobic polymers
  • hydrophilicity of the film is increased in the process of increasing the hydrophilicity of the film and improving blood compatibility, and the process of dry and wet film formation.
  • Film formation using a hollow internal liquid containing molecules and drying, and contact with a solution containing a hydrophilic polymer, and then drying the produced film to coat the hydrophilic polymer A method for imparting blood compatibility is known.
  • ethylene oxide gas, high-pressure steam, radiation, etc. are used.
  • ethylene oxide gas sterilization and high-pressure steam sterilization have problems such as allergies due to residual gas, treatment capacity of the sterilizer, and thermal deformation of materials.
  • radiation sterilization such as gamma rays and electron beams has become the mainstream.
  • the membrane module As a method for preventing such deterioration of the membrane material, if it is not a dry product, the membrane module is filled with an antioxidant solution and ⁇ -ray sterilized to prevent oxidative deterioration of the membrane (Patent Document 1). And the method (patent document 2) which suppresses the oxidation of a filling liquid by filling with a pH buffer solution and alkaline aqueous solution and sterilizing is disclosed.
  • Patent Document 3 a method of controlling the oxygen concentration during sterilization to 0.001% or more and 0.1% or less is disclosed.
  • Patent Document 3 a method of controlling the oxygen concentration during sterilization to 0.001% or more and 0.1% or less is disclosed.
  • Patent Document 3 it is necessary to sterilize by replacing the inside of the packaging bag with an inert gas, or to sterilize after a certain period of time by enclosing an oxygen scavenger in the packaging bag.
  • a technique for expressing sufficient blood compatibility by radiation sterilization in the atmosphere has not been established.
  • Non-Patent Document 1 when water is contained in a general polymer material, the water in the polymer is (1) “non-freezing water” that does not freeze even at ⁇ 100 ° C. due to strong interaction with the polymer. (2) Although it dissolves at 0 ° C., it is divided into “free water” having weak interaction with polymer or antifreeze water. In the polymer material having excellent biocompatibility, (3) “intermediate water that is frozen at a temperature lower than 0 ° C. during the temperature rising process and has an intermediate interaction with the polymer or antifreeze water. Is present. In general, “intermediate water” does not exist in polymer materials having poor biocompatibility.
  • Non-Patent Document 1 suggests that there is a close relationship between the presence of “intermediate water” in the water in the polymer material and the development of excellent biocompatibility of the polymer material. Results are disclosed.
  • free water is freely exchanged with bulk water, which is general water that does not interact with the polymer, it does not play the role of covering the surface of the polymer material. It exists to cover the surface of the polymer material by strong interaction.
  • antifreeze water destroys the structure of the hydration shell by interacting with the hydration shell itself of biological components such as proteins that are stabilized by forming a hydration shell in the blood. Due to the destruction of the hydration shell, the biological component is adsorbed on the surface of the polymer material. Therefore, when using a general polymer material that contains only "free water” and "antifreeze water", the biological component recognizes the surface of the polymer material as a foreign substance, which triggers an immune reaction. .
  • intermediate water binds to a polymer material by interaction with “antifreeze water”, covers the surface of “antifreeze water”, and has a unique hydrogen bond that destroys the hydration shell of biological components. Since it does not have a structure, the biological component cannot recognize the foreign material on the surface of the polymer material. Therefore, it is speculated that the polymer material having “intermediate water” is excellent in blood compatibility.
  • JP-A-4-338223 Japanese Patent Laid-Open No. 7-194949 International Publication No. 2006/016575 JP-A-2-218374
  • the sterilization dose during radiation sterilization can be reduced, and the damage to the separation membrane due to radiation can be reduced, making it more blood compatible. It is possible to create a high separation membrane. Furthermore, a product with a low risk of bacterial growth can provide a safer product regardless of the storage environment.
  • Patent Document 4 there is a method in which an aqueous sodium chloride solution is passed through the module and sodium chloride is adhered to the separation membrane. This makes it possible to protect the separation membrane during the sterilization process.
  • the sodium chloride aqueous solution is passed through and dried, a large amount of salt is attached, and a large amount of priming solution is required to sufficiently wash away the salt. I need.
  • treatment is started without sufficient sodium chloride being washed away, not only is the effect of the high-concentration sodium chloride aqueous solution entering the patient's body, but in the early stage of blood introduction, the salt mass is lost to the blood flow in the hollow fiber. Can cause clot formation and residual blood.
  • the surface of the separation membrane contains water, it has good blood compatibility, but if an inorganic salt is added to give an antibacterial action to the surface of the separation membrane, the inorganic salt and the intermediate water on the surface of the separation membrane Because of the interaction, if the inorganic salt is not sufficiently washed away, the amount of intermediate water is reduced, and blood compatibility at the initial stage of blood contact is lowered. Even if the inorganic salt is finely divided, if the inorganic salt is present on the surface of the separation membrane having intermediate water, even if the inorganic salt is washed away after radiation sterilization, good blood compatibility may not be exhibited. This was a challenge.
  • the present invention provides a separation membrane for blood treatment that has excellent blood compatibility even when the amount of physiological saline used during priming is small and suppresses the growth of bacteria, and a blood treatment device incorporating the same. Objective.
  • the separation of the practical separation membrane on the surface of the separation functional membrane that comes into contact with the blood was separated as a result of water absorption from the dry state and the water content reaching saturation.
  • the ratio of the intermediate water in the functional membrane is 20% or more and the separation membrane contains 100 ⁇ g or more and 0.1 g or less of inorganic salt particles having a particle size of 3 ⁇ m or less, the amount of physiological saline used during priming is small. Found that the blood compatibility was excellent, and completed the present invention.
  • the amount of the inorganic salt contained in the central separation membrane is 1/5. Because it is the smallest compared to the / 5 part of the separation membrane, it minimizes the amount of inorganic salts adhering to the separation membrane, and exhibits remarkable antibacterial action on the blood inlet side and outlet side where bacteria are likely to be mixed. It becomes possible to do.
  • the inorganic salt By making the inorganic salt fine particles with a particle size of 3 ⁇ m or less, the inorganic salt instantly dissolves in the priming solution during priming before the start of treatment.
  • the particle size of the inorganic salt exceeds 3 ⁇ m, if treatment is started without sufficiently washing away the inorganic salt (for example, sodium chloride), not only the effects of the high concentration of aqueous inorganic salt solution entering the patient's body
  • the inorganic salt for example, sodium chloride
  • a lump of inorganic salt may obstruct blood flow in the hollow fiber, and may cause thrombus formation and residual blood.
  • coloring of inorganic salt particles after radiation sterilization may cause a problem in appearance.
  • the inorganic salt By making the inorganic salt into fine particles, the amount of the inorganic salt adhering to the separation membrane can be minimized, and the surface of the membrane can be washed with a smaller amount of priming solution. Further, by making fine particles and localizing them on the inner surface, the appearance problem is improved particularly when the inorganic salt particles are colored.
  • a blood treatment separation membrane having a blood inlet side end, a blood outlet side end, and a separation functional surface that contacts blood to be treated, Distilled water permeates the dry separation membrane, and when the water content reaches saturation, when the water present on the separation function surface is divided into antifreeze water, intermediate water and free water, the intermediate water The abundance ratio is 20% or more based on the total amount of the antifreeze water, the intermediate water and the free water,
  • the water content of the separation membrane is 10% by mass or less with respect to the total mass of the separation membrane
  • the separation membrane includes a separation membrane substrate and inorganic salt particles having a particle size of 3 ⁇ m or less attached to the surface of the separation membrane substrate, and the amount of the inorganic salt particles is from 100 ⁇ g to 0.1 g,
  • the 1/5 portions obtained by equally dividing the separation membrane into 5 portions between the blood inlet side end portion and the blood outlet side end portion it is included in the central 1/5 portion.
  • the separation membrane for blood treatment according to [1] wherein the separation membrane substrate contains an ethylene vinyl alcohol copolymer.
  • the separation membrane substrate contains a hydrophilic polymer and a polysulfone resin,
  • the hydrophilic polymer content A which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone-based resin in the entire separation membrane substrate, is 3% by mass or more and 10% by mass.
  • the abundance ratio B of the hydrophilic polymer which is a ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone-based resin on the separation function surface, is 35% by mass or more and 50% by mass or less.
  • the separation membrane for blood treatment of the present invention and the blood treatment device incorporating the membrane exhibit the effect of being excellent in blood compatibility and suppressing the growth of bacteria even if the amount of physiological saline used during priming is small.
  • FIG. 5 is a diagram showing an outline of an IR measurement method for calculating the abundance ratio of intermediate water in water existing on the separation function surface when distilled water is infiltrated into a separation membrane from a dry state and the water content reaches saturation. is there.
  • An example of the experimental spectrum matrix A is shown.
  • the present embodiment a mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail below.
  • this invention is not limited to the following embodiment, In the range of the summary, various deformation
  • the separation membrane according to the present embodiment has an intermediate water content ratio (hereinafter simply referred to as an “intermediate water content ratio”) in the water existing on the surface of the separation function when the water content reaches saturation by infiltrating distilled water from the dry state. ] May be 20% or more.
  • the intermediate water abundance ratio is analyzed by measuring total reflection infrared absorption (ATR-IR) on the separation function surface of the separation membrane in the process of water permeating into the dry membrane. It is calculated by doing.
  • ATR-IR total reflection infrared absorption
  • the separation membrane according to the present embodiment has a blood inlet side end, a blood outlet side end, and a separation functional surface that contacts blood to be treated.
  • the “separation function surface” means a region corresponding to the film thickness of the blood contact surface detected by ATR-IR.
  • the separation functional surface is a detectable region when measured by ATR-IR, and is usually a region from the membrane surface to a depth of 1 ⁇ m or less.
  • “at the time when the distilled water has penetrated from the dry state and the water content has reached saturation” means that the water penetrates into the dry separation membrane as measured by ATR-IR. This means the point at which the increase in peak intensity derived from the hydroxyl group (3000 to 3700 cm ⁇ 1 ) is no longer observed.
  • the saturation of moisture can be determined by comparing the peak intensity derived from the hydroxyl group with the peak intensity of the benzene ring (near 1485 cm ⁇ 1 ) of the polysulfone resin.
  • the “dry state” means a state where the equilibrium moisture content has been reached, as exemplified in the examples.
  • the water content is saturated by infiltrating distilled water from the dry state.
  • the intermediate water may be retained so that the ratio of the intermediate water to the water existing on the separation function surface is 20% or more.
  • distilled water is infiltrated into the separation membrane in a dry state, and the existing ratio of intermediate water when the water content reaches saturation is preferably 20% or more, and more preferably 40% or more.
  • the separation membrane according to the present embodiment includes a separation membrane substrate that forms a membrane, and inorganic salt particles attached to the surface of the separation membrane substrate.
  • the separation membrane substrate includes, for example, a hydrophobic polymer and a hydrophilic polymer.
  • the hydrophobic polymer and the hydrophilic polymer may be the same polymer having a hydrophobic portion and a hydrophilic portion.
  • Examples of the hydrophobic polymer include a polysulfone resin.
  • the polysulfone resin is a sulfone (—SO 2 —) group-containing synthetic polymer, and examples thereof include polyphenylene sulfone, polysulfone, polyaryl ether sulfone, polyether sulfone, and copolymers thereof.
  • hydrophilic polymer examples include polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol.
  • examples of the same polymer having a hydrophobic portion and a hydrophilic portion include an ethylene vinyl alcohol copolymer.
  • the separation membrane substrate may include a polysulfone-based resin as a hydrophobic polymer and polyvinyl pyrrolidone as a hydrophilic polymer, or may be configured from a polysulfone-based resin and polyvinyl pyrrolidone. May be.
  • the separation membrane substrate may include an ethylene vinyl alcohol copolymer, or may include an ethylene vinyl alcohol copolymer.
  • the separation membrane substrate may contain a hydrophilic polymer such as polyvinylpyrrolidone and a polysulfone resin.
  • the hydrophilic polymer content A which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone resin in the entire separation membrane substrate, is 3% by mass or more and 10% by mass or less. It may be.
  • the hydrophilic polymer content A is preferably 3% by mass or more.
  • the content A of the hydrophilic polymer is preferably 4% by mass or more and 9% by mass or less, and more preferably 5% by mass or more and 8% by mass or less.
  • Examples of the method for measuring the content A of the hydrophilic polymer include a method using a measurement result by 1 H-NMR. That is, in the method using 1 H-NMR, the peak intensity derived from protons of a group unique to the polysulfone-based resin and the peak intensity derived from protons of a group unique to the hydrophilic polymer are determined from both compounds. The molar ratio is obtained, and the content of the hydrophilic polymer in the entire separation membrane substrate can be calculated based on the molar ratio.
  • the abundance ratio B of the hydrophilic polymer which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone resin on the separation function surface, is 35% by mass or more and 50% by mass or less.
  • the separation functional surface is a region corresponding to the film thickness of the blood contact surface detected by ATR-IR. For example, when the separation membrane is a hollow fiber, the separation functional surface is the outermost layer portion inside the hollow fiber membrane. That is, the surface where blood contacts the hollow fiber membrane. If the abundance ratio B of the hydrophilic polymer is 35% by mass or more, sufficient blood compatibility can be obtained. Moreover, the air remaining amount after priming can be reduced more as it is 50 mass% or less.
  • the abundance B of the hydrophilic polymer is preferably 39% by mass or more and 50% by mass or less, and more preferably 40% by mass or more and 50% by mass or less.
  • Examples of the method for measuring the abundance ratio B of the hydrophilic polymer include a method using a measurement result by an X-ray photoelectron spectrum (XPS). That is, the separation function surface is measured by XPS, and the ratio of the number of each atom on the surface is obtained from the peak intensity of atoms peculiar to the polysulfone resin and the hydrophilic polymer, and the mass ratio of both compounds obtained based on the ratio. From the above, the abundance ratio can be calculated.
  • XPS X-ray photoelectron spectrum
  • the separation membrane substrate contains polyvinylpyrrolidone
  • a polymer having a function of suppressing the radiation degradation of polyvinylpyrrolidone during radiation sterilization is used.
  • the polymer is coated with polyvinyl pyrrolidone present on the separation functional surface, so that direct contact between polyvinyl pyrrolidone and oxygen is avoided. It is presumed that the attack on polyvinylpyrrolidone from oxygen radicals during sterilization is prevented.
  • the separation membrane used for radiation sterilization is, for example, a method of drying using superheated steam when a separation membrane in a wet state (that is, a never dry separation membrane) is dried for the first time after spinning, or polyvinylpyrrolidone.
  • a separation membrane in a wet state that is, a never dry separation membrane
  • polyvinylpyrrolidone a polymer having an action of suppressing radiation degradation of the intermediate water.
  • the orientation and three-dimensional structure of polyvinylpyrrolidone are maintained in a state close to the water environment. It is considered that the intermediate water can be easily retained, and that the side chain decomposition due to radical transfer after radical generation is suppressed. As a result, the excessive decomposition reaction of polyvinyl pyrrolidone present on the surface of the separation function is suppressed, and the effect of imparting biocompatibility is not reduced, and protein adsorption to the separation membrane and activation by the membrane surface can be suppressed. It is considered that a separation membrane with high blood compatibility can be obtained.
  • the method of drying with superheated steam is to wind up the separation membrane in a wet state, wrap it in a bundle form in a film such as PE, and then put it in a drying chamber and introduce superheated steam to dry it.
  • it may be normal pressure or reduced pressure, but from the viewpoint of shortening the drying time and suppressing thermal decomposition, the temperature of the superheated steam is equal to or higher than the reverse temperature (the point at which the evaporation rate becomes equal regardless of humidity). 180 ° C. or less is preferable, and the drying time is preferably 30 seconds or less.
  • polymer having an action of suppressing deterioration of polyvinyl pyrrolidone due to irradiation
  • the surface of polyvinyl pyrrolidone is subjected to radiation sterilization.
  • the polymer is not particularly limited as long as it is a polymer that can be coated to suppress the decomposition and crosslinking of polyvinylpyrrolidone by radiation.
  • the polymer is soluble in the hollow inner liquid or the coating liquid, and the cause is unknown, but the polymer is required to have a hydroxyl group.
  • polystyrene resin examples include polyhydroxyalkyl methacrylates such as polyhydroxyethyl methacrylate, polyhydroxypropyl methacrylate, and polyhydroxybutyl methacrylate.
  • Polyhydroxyalkyl methacrylate is a synthetic polymer obtained by (co) polymerizing hydroxyalkyl methacrylate as a monomer unit, and is a compound having a hydroxyl group in a side chain. As a polymer, you may use by 1 type and may use 2 or more types of mixtures.
  • polymer in view of elution into the priming treatment solution, a polymer that is insoluble or hardly soluble in water is preferable, and polyhydroxyalkyl methacrylate is preferably used.
  • the weight average molecular weight of the polymer is preferably 10,000 or more, more preferably 100,000 or more, and further preferably 300,000 or more.
  • the solubility of such a polymer in 100 g of water at 20 ° C. is preferably less than 1 g, more preferably 0.8 g or less, and even more preferably 0.5 g or less.
  • the weight average molecular weight of the polymer can be measured by, for example, gel permeation chromatography (GPC).
  • the polymer is mixed and dissolved in a spinning stock solution at the time of membrane formation, and the polymer is turned into a hollow inner solution at the time of membrane formation.
  • a method of spinning by mixing and dissolving, a method of coating a separation membrane with a coating solution in which a polymer is dissolved, and the like are preferably used.
  • the method of mixing and dissolving in the hollow inner liquid at the time of membrane formation and spinning or coating is simple, and the amount of polymer used is small. it can.
  • a membrane-forming spinning stock solution containing a hollow inner liquid in which a polymer is dissolved, a polysulfone resin, polyvinylpyrrolidone and a solvent are used.
  • the polymer can be coated with polyvinylpyrrolidone present on the separation function surface.
  • the separation membrane is formed into a membrane, incorporated into a blood treatment device and molded, and then the polymer is dissolved on the separation functional surface.
  • a coating method can be adopted by passing the coating solution through and bringing it into contact.
  • a blood treatment separation membrane having excellent blood compatibility even after radiation sterilization in a dry state and a blood treatment device incorporating the membrane are provided.
  • the moisture content of the separation membrane according to this embodiment is 10% or less by mass based on the total mass of the separation membrane containing water.
  • the moisture content of the dry separation membrane may be 10% by mass or less.
  • condensation during storage can be further suppressed, which is more preferable in terms of appearance.
  • the mass does not increase, and it is easy to carry it together in a facility.
  • the moisture content can be reduced to 10% by mass or less by drying the separation membrane obtained by spinning using superheated steam.
  • the moisture content is 10% by mass or less by drying by a usual method using hot air or the like. can do.
  • the moisture content can be measured by the method described in the following examples.
  • the blood treatment device of the present embodiment is a blood treatment device incorporating the separation membrane of the present embodiment, such as hemodialysis, blood filtration, blood filtration dialysis, blood component fractionation, oxygenation, and plasma separation. Used for extracorporeal circulation blood purification therapy.
  • the area of the separation membrane to be incorporated is not particularly limited, but may be, for example, 0.3 to 3.0 m 2 .
  • a blood treatment device it is preferably used in hemodialyzers, blood filter devices, blood filter dialyzers, etc., and these are continuous applications, continuous hemodialyzers, continuous blood filter devices, continuous blood filter dialyzer devices It is more preferable to use as. Depending on each application, detailed specifications such as separation membrane dimensions and fractionation are determined.
  • the method for producing a separation membrane for blood treatment includes a step of forming the separation membrane described above, and a step of drying a never dry separation membrane to a moisture content of 10% or less using superheated steam. And sterilizing the separation membrane with radiation.
  • the manufacturing method of the separation membrane for blood processing of this embodiment suppresses the radiation degradation of the process which forms the separation membrane mentioned above, the process which dries the moisture content of a separation membrane to 10 mass% or less, and polyvinylpyrrolidone And a step of radiation sterilizing a separation membrane having at least a separation functional surface having a polymer having the function of:
  • the shape of the separation membrane incorporated in the blood treatment device preferably has a hollow shape.
  • the separation membrane may be a hollow fiber.
  • the crimp is provided from the viewpoint of permeation performance.
  • the separation membrane according to this embodiment contains 100 ⁇ g or more and 0.1 g or less of inorganic salt particles having a particle size of 3 ⁇ m or less attached to the surface of the separation membrane substrate.
  • the amount of inorganic salt particles having a particle size of 3 ⁇ m or less may be 100 ⁇ g or more and 0.1 g or less per 2.5 m 2 of the separation functional surface area of the separation membrane substrate (or separation membrane).
  • Substantially all of the inorganic salt particles adhering to the surface of the separation membrane substrate may have a particle size of 3 ⁇ m or less.
  • the inorganic salt By making the inorganic salt fine particles with a particle size of 3 ⁇ m or less, the inorganic salt instantly dissolves in the priming solution during priming before the start of treatment.
  • the particle diameter of the inorganic salt particles is preferably 2 ⁇ m or less, and more preferably 1 ⁇ m or less.
  • the particle diameter of the inorganic salt particles can be measured, for example, by the method described in the following examples.
  • the amount of inorganic salt particles adhering to the surface of the separation membrane substrate is preferably 100 ⁇ g or more from the viewpoint of suppressing the growth ability of bacteria.
  • the amount of the inorganic salt in the separation membrane is preferably 0.1 g or less in order to be washed away with a small amount of priming solution.
  • coloring of inorganic salt particles after radiation sterilization may cause a problem in appearance.
  • the inorganic salt By making the inorganic salt into fine particles, it is possible to minimize the amount of the inorganic salt adhering to the separation membrane, and it is possible to wash the salt on the membrane surface with a smaller amount of priming solution. Further, by making fine particles and localizing them on the inner surface, the appearance problem is improved particularly when the inorganic salt particles are colored.
  • the inorganic contained in the central 1/5 portion is the smallest. This makes it possible to exert a remarkable antibacterial action on the blood inlet side and outlet side where bacteria are likely to be mixed while minimizing the amount of inorganic salt adhering to the separation membrane.
  • the inorganic salt in the present embodiment is not particularly limited, and inorganic salts such as sodium chloride, calcium chloride, sodium carbonate, sodium acetate, magnesium chloride, potassium sulfate, ammonium chloride, and sodium nitrate can be used.
  • inorganic salts such as sodium chloride, calcium chloride, sodium carbonate, sodium acetate, magnesium chloride, potassium sulfate, ammonium chloride, and sodium nitrate can be used.
  • sodium chloride is preferable from the viewpoint of safety to the human body.
  • the method for generating the inorganic salt particles is not particularly limited, but a method of crushing and dispersing an inorganic salt aqueous solution with an atomizer (atomizer) with pressurized air, drying the generated mist, and forming an aerosol (Japanese Industrial Standard JIS B9928: 1998 Annex 3 Method 1) or a method of bubbling an aqueous solution of inorganic salt particles with pressurized air and drying fine droplets formed when the generated bubbles burst (Japanese Industrial Standard JIS) B9928: 1998 Annex 3 method 2).
  • Aerosol containing inorganic salt particles is blown into the blood inlet side and outlet side of the blood purifier by piping, and the outer surface side of the separation membrane is decompressed, so that it is contained in the central 1/5 separation membrane. It is possible to make the amount of the inorganic salt particles to be the smallest as compared with the amount of the inorganic salt particles contained in the separation membrane of the other 1/5 portion.
  • the measurement method used in this example is as follows. [Calculation of the ratio of intermediate water to water existing on the surface of the separation function when distilled water penetrates the dry separation membrane and the water content reaches saturation] The intermediate water abundance ratio was calculated by (1) IR measurement, (2) determination of when the water content reached saturation, and (3) data analysis by chemometrics.
  • FIG. 1 is a schematic diagram showing a measurement method.
  • the sampling procedure was as follows. Priming was performed by washing the inner surface (separation function surface) of the hollow fiber separation membrane with 100 mL / min distilled water per 1.5 m 2 for 5 minutes. The blood processor after priming is disassembled and a hollow fiber separation membrane as a sample is sampled, lyophilized in advance, and left in a constant temperature and humidity chamber at a temperature of 23 ° C. and a humidity of 50% for 24 hours or more. Those that reached the rate (referred to as “dry state”) were subjected to measurement. 1) KIRIYAMA filter paper (No.
  • the intensity of the peak derived from the polysulfone resin-derived benzene ring was 0.1 or more.
  • the point at which the peak of the hydroxyl group is saturated is the point at which an increase in the peak intensity derived from the hydroxyl group (3000 to 3700 cm ⁇ 1 ) is no longer observed with respect to the peak intensity of the benzene ring (near 1485 cm ⁇ 1 ) of the polysulfone resin. .
  • the spectrum matrix A is divided into three types of antifreeze water (in the present embodiment, the hydrogen bond region is detected spectroscopically, so described as “bound water” below), intermediate water, and free water.
  • Decomposition was performed into four components (pure spectrum matrix K) composed of chemical components and difference spectra, and a concentration matrix C corresponding to each (Equation (1)). At that time, the matrix was limited so that the decomposition could be achieved uniquely.
  • spectral decomposition was performed by subjecting a non-negative condition that a pure spectrum and a concentration matrix had absolutely no negative elements. This is based on the basis that the absorption spectrum and concentration cannot be negative.
  • the first measurement spectrum A 1, the second measurement spectrum A 2, the spectrum of the time t from ... measurement start represents a A t, bound water, intermediate water, K 1 free water and the difference spectrum, K 2 , K 3 , K 4 are set (it is unknown which component is K 1 , K 2 , K 3 , K 4 at this point), and the concentration ratio of the four components at the time t from the start of measurement is If C 1t , C 2t , C 3t , and C 4t are set, equation (1) can be expressed as equation (2) below.
  • Spectra K 1 , K 2 , K 3 , and K 4 were obtained by generating random numbers in the matrix C of Equation (2) and substituting the negative values with 0 for the non-negative condition that the concentration should not be negative. .
  • a component having a negative value in the spectrum K is replaced with 0, and C is obtained.
  • K was determined from this C under non-negative conditions. This operation was repeated until all the components of K and C became 0 or more, and a solution was obtained.
  • the difference spectrum is the one whose concentration is almost zero, and among the other three spectra, it has a large peak at 1550 to 1800 cm ⁇ 1 and 3100 to 3500 cm ⁇ . binding those have little peak at 1 water, 3400 cm -1 intermediate water one having a peak near, were assigned free water broad peak with a peak at 3200,3400cm -1.
  • the blood treatment device was disassembled without pretreatment such as priming, and the taken out hollow fiber separation membrane for blood treatment was equally divided into five in the length direction from the blood inlet side end to the outlet side end.
  • About 1 g of a hollow fiber separation membrane (sample) sampled from each fragment after division was accurately weighed.
  • Distilled water for high-performance liquid chromatographs 046-16971; Wako Pure Chemical Industries, Ltd.
  • the sodium ions were quantified by ion chromatography. What performed the same operation without a sample was made into the blank.
  • the value obtained by subtracting the sodium concentration of the blank from the sodium concentration of the extract is multiplied by the volume of distilled water, divided by the sampled hollow fiber separation membrane mass to obtain the amount of sodium per 1 g of hollow fiber, and further the chloride per 1 g of hollow fiber.
  • the amount of sodium was calculated.
  • the amount of sodium chloride per gram of hollow fiber in each sample divided equally into 5 was calculated.
  • the amount of sodium chloride of the whole hollow fiber separation membrane was computed by multiplying each 1/5 mass of the whole hollow fiber separation membrane, and totaling.
  • Priming was performed by washing the blood treatment device with physiological saline (Otsuka raw food injection, Otsuka Pharmaceutical Co., Ltd.).
  • the separation membrane collected by disassembling the blood processor after priming was processed with silicon so that the effective length was 15 cm and the area of the inner surface of the membrane was 5 ⁇ 10 ⁇ 3 m 2 to prepare a minimodule.
  • the mini-module was washed by flowing 10 mL of physiological saline inside the hollow fiber. Thereafter, 15 mL of heparin-added blood (heparin 1000 IU / L) was circulated at 37 ° C. for 4 hours through the mini-module prepared above at a flow rate of 1.3 mL / min.
  • the inside of the mini module was washed with 10 mL and the outside with 10 mL with physiological saline.
  • Half of the entire hollow fiber membrane having a length of 7 cm was collected from the washed mini-module, and then cut into a Spitz tube for LDH measurement as a measurement sample.
  • Triton X-100 / PBS solution obtained by dissolving Triton X-100 (Nacalai Tesque) in phosphate buffer solution (PBS) (Wako Pure Chemical Industries, Ltd.) was used for LDH measurement.
  • PBS phosphate buffer solution
  • sonication was performed for 60 minutes to destroy cells (mainly platelets) adhering to the separation membrane, and LDH in the cells was extracted.
  • 0.05 mL of this extract was collected, and further reacted with 2.7 mL of 0.6 mM sodium pyruvate solution and 0.3 mL of 1.277 mg / mL nicotinamide adenine dinucleotide (NADH) solution.
  • NADH nicotinamide adenine dinucleotide
  • ⁇ 340 nm (absorbance immediately after sample reaction ⁇ absorbance after 60 minutes of sample) ⁇ (absorbance immediately after reaction of blank ⁇ absorbance after 60 minutes of blank)
  • the separation membrane having excellent blood compatibility those having an LDH activity of 40 or less are preferable.
  • Pseudomonas arginosa was injected into the blood treatment device after radiation sterilization from the blood inlet side.
  • the concentration of the bacteria was 1 ⁇ 10 7 cells / mL, and 88 mL of the bacterial solution was injected.
  • a physiological saline containing a surfactant was injected, and 500 mL of a discharge liquid was collected.
  • the collected discharged liquid was subjected to suction filtration with a membrane filter, and the number of viable bacteria of the bacteria collected on the filter was measured by the same method as in JIS L1902.
  • the membrane spinning solution is 79 parts by mass of dimethylacetamide (manufactured by Kishida Chemical Co., Ltd., reagent grade), 17 parts by mass of polysulfone (manufactured by Solvay, P-1700) and 4 parts by mass of polyvinylpyrrolidone (manufactured by BASF, K-90). The part was dissolved.
  • As the hollow inner liquid a 60% by mass aqueous solution of dimethylacetamide was used. From the tube-in-orifice type spinneret, the membrane-spun stock solution and the hollow inner solution were discharged. The temperature of the film-forming spinning solution at the time of discharge was 40 ° C.
  • the discharged film-forming spinning solution was immersed in a 60 ° C. coagulation bath made of water through a dropping part covered with a hood and coagulated.
  • the spinning speed was 30 m / min. After solidification, it is washed with water, bundled so that the effective membrane area when assembled in a module is 1.5 m 2 , packed in PE film, put into a drying room, introduced 180 ° C superheated steam, dried To obtain a hollow separation membrane.
  • the washing temperature was 90 ° C. and the washing time was 180 seconds.
  • the discharge amounts of the film-forming spinning solution and the hollow inner solution were adjusted so that the film thickness after drying was 35 ⁇ m and the inner diameter was 185 ⁇ m.
  • the method for generating inorganic salt fine particles is a method of bubbling with pressurized air using a 5% by weight aqueous sodium chloride solution and drying fine droplets formed when the generated bubbles burst to form an aerosol (Japan).
  • the industry standard JIS B9928: 1998 Annex 3 method 2) was used.
  • the aerosol was introduced into the blood inlet side and outlet side at 100 L / min for 4 seconds each, and at the same time, the inlet and outlet ports of the dialysate were depressurized with a vacuum pump via piping.
  • gamma ray sterilization was performed at 25 kGy in an atmosphere with an oxygen concentration of 0.5% to obtain a blood treatment device.
  • the sodium chloride particle size in the separation membrane was 3 ⁇ g or less, and the amount of adhesion was 103 ⁇ g in total for each 1/5 portion.
  • the amount of inorganic salt contained in the separation membrane of the central 1/5 portion is 2.2% by mass, which is the smallest compared to the other 1/5 portion of the separation membrane.
  • the number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 3.7 ⁇ 10 7 .
  • the presence ratio of the intermediate water was 48%, the water content was 0.8% by mass, and the LDH activity was 6.5 [ ⁇ abs / hr / m 2 ].
  • Example 2 The hollow inner solution is 0.03% by mass of 60% by mass aqueous solution of dimethylacetamide and polyhydroxyethyl methacrylate (pHEMA, Scientific Polymer Products, Inc., weight average molecular weight 350,000, solubility less than 0.1 g).
  • a hollow fiber separation membrane was obtained in the same manner as in Example 1 except that the membrane was dissolved in After assembling a module having an effective membrane area of 2.5 m 2 from the obtained separation membrane, fine particles of sodium chloride were introduced into the surface of the separation membrane. The same method as in Example 1 was used as the method for generating the inorganic salt fine particles.
  • the aerosol was introduced at 100 L / min to the blood inlet side and the outlet side for 100 seconds, respectively, and at the same time, the inlet and outlet ports of the dialysate were decompressed with a vacuum pump via piping. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
  • the sodium chloride particle size in the separation membrane was 3 ⁇ m or less, and the adhesion amount was 2700 ⁇ g in total for each 1/5 portion.
  • the amount of inorganic salt contained in the separation membrane of the central 1/5 portion is It was 2.4% by mass, which was the smallest compared with the other 1/5 portion of the separation membrane.
  • the number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 3.5 ⁇ 10 7 .
  • the intermediate water content was 60%, the water content was 1% by mass, and the LDH activity was 5.5 [ ⁇ abs / hr / m 2 ], which was a good result.
  • Example 1 In the same manner as in Example 2, a hollow fiber separation membrane was obtained. After assembling a module having an effective membrane area of 2.5 m 2 from the obtained separation membrane, 0.45 mass% sodium chloride aqueous solution was passed from the blood inlet side to the outlet side, and the sodium chloride aqueous solution was infiltrated into the module. After that, compressed air was aerated and dried until there was no weight change. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device. The sodium chloride particle diameter in the separation membrane was 3 ⁇ m or more, and the adhesion amount was 0.3 g (1.6% by mass with respect to the mass of the hollow fiber separation membrane).
  • the particles have a size of about several millimeters that can be visually confirmed, and coloring due to gamma sterilization is seen, which is not preferable in appearance.
  • Met The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 2.0 ⁇ 10 7 .
  • the water content was 1% by mass.
  • As for the abundance ratio of the intermediate water a slight peak change was observed with the constrained water, but accurate quantification was impossible due to the influence of excessive sodium chloride adhesion.
  • Example 2 In the same manner as in Example 2, a hollow fiber separation membrane was obtained. After assembling a module having an effective membrane area of 2.5 m 2 from the obtained separation membrane, 6.0 mass% sodium chloride aqueous solution was passed from the blood inlet side to the outlet side, and the sodium chloride aqueous solution was infiltrated into the module. After that, compressed air was aerated and dried until there was no weight change. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device. The sodium chloride particle size in the separation membrane was 3 ⁇ m or more, and the adhesion amount was 7.2 g (35.8 mass% with respect to the weight of the hollow fiber separation membrane).
  • the particles have a size of about several mm that can be visually confirmed, and coloring due to gamma ray sterilization is seen, which is not preferable in appearance.
  • Met The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 2.0 ⁇ 10 7 .
  • the water content was 1% by mass.
  • As for the abundance ratio of the intermediate water a slight peak change was observed with the constrained water, but accurate quantification was impossible due to the influence of excessive sodium chloride adhesion.
  • Example 3 In the same manner as in Example 2, a hollow fiber separation membrane was obtained. After assembling a module having an effective membrane area of 2.5 m 2 from the obtained separation membrane, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device. The number of viable bacteria in the measurement of the growth ability of the bacteria was 7.0 ⁇ 10 7 , and the growth of the bacteria was not suppressed. The presence ratio of the intermediate water was 60%, the water content was 1.0% by mass, and the LDH activity was 5.5 [ ⁇ abs / hr / m 2 ].
  • Example 4 A hollow fiber separation membrane was obtained in the same manner as in Example 1 except that the drying step using superheated steam was not performed. After assembling a module having an effective membrane area of 2.5 m 2 from the obtained separation membrane, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device. The number of viable bacteria in the measurement of the growth ability of the bacteria was 5.5 ⁇ 10 7 , and the growth of the bacteria was not suppressed. The presence ratio of the intermediate water was 12%, the water content was 0.7% by mass, and the LDH activity was 395 [ ⁇ abs / hr / m 2 ].
  • Example 5 A hollow fiber separation membrane was obtained in the same manner as in Example 1 except that the drying step using superheated steam was not performed. After assembling a module having an effective membrane area of 2.5 m 2 from the obtained separation membrane, fine particles of sodium chloride were introduced into the surface of the separation membrane. The same method as in Example 1 was used as the method for generating the inorganic salt fine particles. The aerosol was introduced into the blood inlet side and outlet side at 100 L / min for 4 seconds each, and at the same time, the inlet and outlet ports of the dialysate were depressurized with a vacuum pump via piping. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
  • the sodium chloride particle size in the separation membrane was 3 ⁇ m or less, and the adhesion amount was 103 ⁇ g. Further, when the length from the blood inlet side end portion to the outlet side end portion of the blood treatment separation membrane is divided into five, the amount of inorganic salt contained in the separation membrane of the central 1/5 portion is 2.2% by mass, which is the smallest compared to the other 1/5 portion of the separation membrane. The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 3.0 ⁇ 10 7 . The presence ratio of the intermediate water was 12%, the water content was 0.7% by mass, and the LDH activity was 390 [ ⁇ abs / hr / m 2 ].
  • the separation membrane for blood treatment according to the present invention and the blood treatment device incorporating the membrane are excellent in blood compatibility even if the amount of physiological saline used during priming is small, and suppresses the growth of bacteria. It can be suitably used in extracorporeal circulation therapies such as filtration, hemofiltration dialysis, blood component fractionation, oxygenation, and plasma separation.

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Abstract

L'invention concerne une membrane de séparation pour le traitement du sang qui comprend une partie d'extrémité côté entrée du sang, une partie d'extrémité côté sortie du sang et une surface à fonction de séparation qui entre en contact avec le sang à traiter. Lorsque de l'eau distillée est infiltrée dans la membrane de séparation à l'état sec jusqu'à ce que la teneur en eau atteigne le niveau de saturation et qu'ensuite l'eau présente sur la surface à fonction de séparation est divisée en eau non congelable, eau intermédiaire et eau libre, le rapport de teneur de l'eau intermédiaire est de 20 % ou plus par rapport à la somme de l'eau non congelable, l'eau intermédiaire et l'eau libre. La teneur en eau de la membrane de séparation est inférieure ou égale à 10 % en masse par rapport à la masse totale de la membrane de séparation. La membrane de séparation comprend un matériau de base de membrane de séparation et des grains de sel inorganique avec une taille de grain inférieure ou égale à 3 µm, lesdits grains de sel inorganique adhérant à la surface de la membrane de séparation et la quantité desdits grains de sel inorganique étant comprise entre 100 µg et 0,1 g inclus. Lorsque la membrane de séparation est également divisée en cinq zones entre la partie d'extrémité côté entrée de sang et la partie d'extrémité côté sortie de sang, le cinquième de zone centrale contient la plus petite quantité de grains de sel inorganique parmi les cinq cinquièmes de zone ainsi obtenues.
PCT/JP2014/079058 2013-12-18 2014-10-31 Membrane de séparation pour le traitement du sang et dispositif de traitement du sang qui en est équipé WO2015093160A1 (fr)

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EP3950118A4 (fr) * 2019-03-29 2022-05-18 Asahi Kasei Medical Co., Ltd. Purificateur de sang

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CN111918682B (zh) * 2018-03-30 2023-06-23 旭化成医疗株式会社 血液净化器及其制法
WO2020203926A1 (fr) * 2019-03-29 2020-10-08 旭化成メディカル株式会社 Dispositif de purification du sang et son procédé de fabrication

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JP2004161954A (ja) * 2002-11-15 2004-06-10 Terumo Corp 血液適合性高分子およびそれを用いた医療用器具
JP2012105579A (ja) * 2010-11-17 2012-06-07 Yamagata Univ 溶液から細胞を分離する細胞分離方法、および、細胞分取用水和性組成物

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EP3950118A4 (fr) * 2019-03-29 2022-05-18 Asahi Kasei Medical Co., Ltd. Purificateur de sang

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