Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
  • A61M1/3672—Means preventing coagulation
  • A61M1/3673—Anticoagulant coating, e.g. Heparin coating
• • 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
  • B01D67/0081—After-treatment of organic or inorganic membranes
  • B01D67/0088—Physical treatment with compounds, e.g. swelling, coating or impregnation
• • 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
  • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
• • 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
  • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
  • B01D71/401—Polymers based on the polymerisation of acrylic acid, e.g. polyacrylate
  • B01D71/4011—Polymethylmethacrylate
• • 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
  • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
  • B01D71/42—Polymers of nitriles, e.g. polyacrylonitrile
  • B01D71/421—Polyacrylonitrile
• • 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
  • B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
• • 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
• • 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
  • B01D2323/21826—Acids, e.g. acetic acid
• • 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
  • B01D2323/21827—Salts
• • 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
  • B01D2323/21834—Amines
• • 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
  • B01D2323/21834—Amines
  • B01D2323/21835—Cyclic amines comprising heterocyclic N-Ring, e.g. pyridine
• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D2325/00—Details relating to properties of membranes
  • B01D2325/06—Surface irregularities

Definitions

• the present invention relates to hollow fiber membranes and hollow fiber membrane modules.
• Hollow fiber membranes are cylindrical semipermeable membranes that are generally known to selectively allow substances to pass through the fine perforations on their surface. For this reason, hollow fiber membranes are used in a variety of liquid separation processes, including blood purification in hemodialysis (HD) and hemofiltration (HF). In hemodialysis, blood is passed through the inside of a hollow fiber membrane, and low molecular weight substances such as water and uremic toxins in the blood are removed to the outside of the hollow fiber membrane through diffusion and filtration.
• HD hemodialysis
• HF hemofiltration
• Patent Document 1 discloses a hollow fiber membrane made of a copolymer of acrylonitrile and sodium methallylsulfonate containing polyethyleneimine, the membrane surface of which is treated with an organic solvent, making it possible to adsorb both inflammatory cytokines and inflammatory cells.
• Patent Document 2 discloses a hollow fiber membrane that is made of a copolymer of acrylonitrile and sodium methallylsulfonate, and that is coated with polyethyleneimine on the surface, and then heparin is immobilized on the surface, thereby preventing blood coagulation on the membrane surface and allowing the membrane to adsorb inflammatory cytokines.
• Patent document 3 discloses a method for removing gram-negative bacteria, gram-positive bacteria, hepatitis viruses, and the like from whole blood using an adsorbent in which a polysaccharide containing heparin is covalently immobilized on polymer beads or hollow fibers with a cationized surface.
• Patent Document 1 does not mention anticoagulants, and there is a concern that blood may clot on the surface of the hollow fiber membrane when whole blood or blood with a low concentration of anticoagulant is passed through the membrane.
• the hollow fiber membrane in Patent Document 2 has an anticoagulant immobilized on the membrane surface, which inhibits blood coagulation on the membrane surface, but there is no description of the arithmetic mean roughness of the hollow fiber membrane surface, and it is thought that inflammatory cells cannot be adsorbed.
• the polymer beads or hollow fibers in Patent Document 3 have a cationized surface, and therefore may be capable of adsorbing inflammatory cytokines, but there is no description of the arithmetic mean roughness of the surface, and it is thought that they cannot adsorb inflammatory cells.
• Patent Document 4 The antithrombotic material in Patent Document 4 is not intended to adsorb inflammatory cytokines and inflammatory cells.
• the present invention aims to provide a hollow fiber membrane that combines inhibition of adhesion of blood coagulation components to the membrane surface with highly efficient adsorption and removal of inflammatory cells, inflammatory cytokines, etc.
• the present invention has the following configuration for solving the above problems.
• a hollow fiber membrane containing an anticoagulant the surface of which in contact with the liquid to be treated has an arithmetic mean roughness (Ra) in the radial direction of 0.10 to 0.80 ⁇ m.
• Ra arithmetic mean roughness
• the hollow fiber membrane according to (1) above, wherein the amount of the anticoagulant per 1 g of dry mass is 0.27 to 30.00 ⁇ mol.
• the hollow fiber membrane according to any one of (1) to (5) above which is used for blood purification.
• a hollow fiber membrane module comprising the hollow fiber membrane according to any one of (1) to (7) above.
• the hollow fiber membrane of the invention can highly efficiently adsorb and remove inflammatory cells and inflammatory cytokines while suppressing the adhesion of blood coagulation components.
• FIG. 2 is a diagram illustrating how to determine the arithmetic mean roughness.
• the hollow fiber membrane of the present invention contains an anticoagulant and is characterized in that the surface in contact with the treated liquid has an arithmetic mean roughness (Ra) in the radial direction of 0.10 to 0.80 ⁇ m.
• Anticoagulant refers to a compound that has the property of inhibiting blood coagulation, which progresses through activation of blood coagulation factors such as thrombin.
• anticoagulants examples include aspirin, apixaban, argatroban, ethyl icosapentate, sarpogrelate hydrochloride, ticlopidine hydrochloride, endoxaban, ozagrel sodium, citric acid, trisodium citrate, clopidogrel sulfate, dipyridamole, cilostazol, dabigatran, dalteparin sodium, dextran sulfate, trapidil, parnaparin sodium, beraprost sodium, prasugrel sulfate, heparin (e.g., heparin sodium, heparin potassium, heparin calcium, etc.), low molecular weight heparin, heparin derivatives such as acetylated heparin, polystyrene sulfonate, polyvinyl sulfonate, nafamostat mesilate, rivarox
• argatroban When filling a blood purification column or adding directly to blood, from the viewpoint of safety for the living body, argatroban, citric acid, trisodium citrate, dextran sulfate, heparin, heparin derivatives such as low molecular weight heparin or acetylated heparin, polystyrene sulfonic acid, polyvinyl sulfonic acid, or nafamostat mesilate are preferred. Among these, argatroban, trisodium citrate, heparin, low molecular weight heparin, or nafamostat mesilate, which have a long history of clinical use in extracorporeal circulation, are more preferred.
• the above anticoagulants may be purified or may form salts with sodium, potassium, etc., and are not particularly limited as long as they can inhibit blood coagulation reactions.
• Methods for impregnating the hollow fiber membrane with an anticoagulant include, for example, passing a solution containing an organic solvent in which the anticoagulant has been dissolved through a module filled with hollow fiber membranes, or immersing the hollow fiber membrane in a solution containing an organic solvent in which the anticoagulant has been dissolved.
• the hollow fiber membrane of the present invention preferably contains 0.07 to 50.00 ⁇ mol of anticoagulant per 1 g of dry mass.
• the amount of anticoagulant contained in the hollow fiber membrane per 1 g of dry mass is more preferably 0.17 to 45.00 ⁇ mol, even more preferably 0.21 to 40.00 ⁇ mol, particularly preferably 0.27 to 30.00 ⁇ mol, and most preferably 0.30 to 30.00 ⁇ mol. Any of the preferred lower limits can be arbitrarily combined with any of the preferred upper limits.
• the amount of anticoagulant contained in the hollow fiber membrane can be calculated by extracting the anticoagulant from the hollow fiber membrane and determining the concentration of the anticoagulant in the extract obtained.
• the amount of anticoagulant contained in the hollow fiber membrane per gram of dry mass can be controlled by the type of organic solvent in the solution containing the anticoagulant, the concentration of the anticoagulant, or the linear velocity, temperature, or time when the solution containing the anticoagulant is soaked in the hollow fiber membrane.
• the method for measuring the anticoagulant concentration in the extract may be selected appropriately depending on the type of anticoagulant.
• the anticoagulant is heparin or low molecular weight heparin, it can be measured using Testteam Heparin S (manufactured by Sekisui Medical Co., Ltd.).
• the anticoagulant concentration can be measured using liquid chromatography (HPLC). Specifically, it can be measured using the method described below in "Anticoagulant amount measurement.”
• Examples of the solvent for the solution containing the anticoagulant used when impregnating the hollow fiber membrane with the anticoagulant or the solvent for the extraction solution for extracting the anticoagulant include organic solvents, water, aqueous solutions containing salts (e.g., phosphate buffer, borate buffer, ammonium chloride buffer, aqueous sodium hydroxide solution, physiological saline, aqueous sodium carbonate solution, or aqueous sodium bicarbonate solution), or mixed solvents of these. Because hollow fiber membranes are insoluble or poorly soluble and anticoagulants are soluble or easily soluble, mixed solvents of organic solvents and water or aqueous solutions containing salts are preferred.
• salts e.g., phosphate buffer, borate buffer, ammonium chloride buffer, aqueous sodium hydroxide solution, physiological saline, aqueous sodium carbonate solution, or aqueous sodium bicarbonate solution
• organic solvents examples include N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran, acetonitrile, acetone, and dimethyl sulfoxide (hereinafter referred to as "DMSO").
• DMSO dimethyl sulfoxide
• Any of the organic solvents may be used alone, or two or more of them may be combined and used as a mixed solvent.
• the concentration of DMSO is preferably 10 to 50 mass%.
• the concentration of DMSO is preferably 10 to 50 mass%. The same applies when using a mixed solvent of another solvent and water or an aqueous solution containing a salt.
• the linear velocity is preferably 1.8 to 35.7 cm/min, and more preferably 5.3 to 26.7 cm/min.
• the temperature of the solution containing the anticoagulant when impregnating the hollow fiber membrane with the anticoagulant is preferably 10 to 80°C, more preferably 20 to 60°C, and the liquid passage time is preferably 5 minutes to 8 hours, more preferably 15 minutes to 6 hours.
• liquid to be treated refers to a solution in which the components to be removed are dissolved, dispersed, or suspended.
• the components to be removed include cells and humoral factors in the blood.
• Cells in blood refers to cells contained in blood. Examples include white blood cell components such as granulocytes, monocytes, neutrophils, and eosinophils, red blood cells, and platelets.
• Inflammatory cells refers to cells in the blood that have been activated by proteins such as inflammatory cytokines. Specific examples include activated leukocytes, activated platelets, and activated leukocyte-activated platelet complexes.
• activated leukocytes When the hollow fiber membrane of the present invention is used for the purpose of treating patients with inflammatory diseases or patients with renal disease complicated by inflammatory diseases, it is preferable to select activated leukocytes as the substance to be removed.
• Human factors in blood refers to organic substances dissolved in blood. Specific examples include urea, ⁇ 2-microglobulin, cytokines, proteins such as IgE or IgG, and polysaccharides such as lipopolysaccharide (hereinafter referred to as "LPS"). Of these, it is preferable to remove proteins such as cytokines or polysaccharides such as LPS when treating patients with inflammatory diseases, and urea or ⁇ 2-microglobulin when treating patients with renal diseases. Furthermore, it is even more preferable to remove inflammatory cytokines when treating patients with inflammatory diseases or patients with renal diseases complicated by inflammatory diseases.
• Intracellular cytokines refers to a group of proteins that are produced by various cells, including immune cells, in response to stimuli such as infection or trauma, and are released extracellularly to act. Examples include interferon ⁇ , interferon ⁇ , interferon ⁇ , interleukin 1 to interleukin 15, tumor necrosis factor ⁇ , tumor necrosis factor ⁇ , high mobility group box-1, erythropoietin, and monocyte chemotactic factor.
• Adsorption refers to a state in which a substance adheres to a material and does not easily detach, or a state of adsorption equilibrium.
• Examples of the principle of adsorption include a state in which the substance adheres to a material through intermolecular forces such as electrostatic interactions, hydrophobic interactions, hydrogen bonds, or van der Waals forces, or a state in which the substance adheres physically through cell adhesion or phagocytosis by white blood cells.
• Ra Arimetic mean roughness
• the hollow fiber membrane surface can be calculated from an image obtained by observing the hollow fiber membrane surface at a magnification of 50x objective lens using a laser microscope (e.g., Ultra-Deep 3D Shape Measuring Microscope VK-9710, manufactured by Keyence Corporation) that is a laser confocal optical system, is capable of two-dimensional scanning, and has a line roughness analysis function (e.g., shape analysis application VK-H1A1/VK-H2A1, manufactured by Keyence Corporation).
• a laser microscope e.g., Ultra-Deep 3D Shape Measuring Microscope VK-9710, manufactured by Keyence Corporation
• the previously dried hollow fiber membrane When measuring the outer surface of the hollow fiber membrane, the previously dried hollow fiber membrane is placed directly on the sample stage and an image is captured, and when measuring the inner surface, the previously dried hollow fiber membrane is cut into a semi-cylindrical shape and an image is captured of the inner surface exposed. From the obtained image, 10 different positions are selected in random directions and locations and a reference length l is extracted in the radial direction of the hollow fiber membrane.
• Ra can be calculated from the extracted reference length l using the following formula (1).
• Figure 1 shows the extracted reference length l, the contour curve, and the average line
• Ra is the sum of the absolute values of the deviations from the average line of this extracted portion to the contour curve and the average value.
• f(x) is a function that represents the surface irregularity shape at an arbitrary position x in a laser microscope image.
• Ra is calculated with the reference length l set to 20 ⁇ m.
• the hollow fiber membrane When measuring Ra, the hollow fiber membrane must be vacuum-dried for at least 16 hours before measurement, since the shape of the membrane changes due to hydration of the membrane surface or the wetness of the hollow fiber membrane changes due to evaporation of water, resulting in variation in the measured value.
• Mean line means a line obtained by replacing the contour curve with a straight line using the least squares method, as specified in JIS B 0601:2001.
• Contour curve refers to the curve that traces the contour of the material surface when an image of the material surface to be measured is captured using a laser microscope, as shown in Figure 1, and is also called the measurement cross-sectional curve.
• the Ra of the hollow fiber membrane surface that comes into contact with the liquid to be treated is 0.10 to 0.80 ⁇ m, preferably 0.20 to 0.70 ⁇ m, and more preferably 0.30 to 0.60 ⁇ m, because forming sufficient unevenness on the surface makes it easier for cells in the blood to recognize the material, and because the membrane has a sufficient specific surface area to efficiently adsorb and remove humoral factors in the blood. Any of the preferred lower limit values can be combined with any of the preferred upper limit values.
• the "radial direction" of a hollow fiber membrane means the direction perpendicular to the longitudinal direction of the hollow fiber membrane, and is also called the circumferential direction.
• roughness can be imparted to the surface of the hollow fiber membrane by contacting the surface of the hollow fiber membrane with an organic solvent or an aqueous solution containing an organic solvent.
• Ra can also be controlled by the type, concentration, or temperature of the organic solvent used, or the time or flow rate of contact with the organic solvent.
• organic solvents used to impart roughness to the hollow fiber membrane surface include N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran, acetonitrile, acetone, DMSO or mixtures of these with water, diethyl ether, toluene, xylene, nitrobenzene, chloroform, dichloromethane, carbon tetrachloride, hexane, and heptane.
• N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran, acetonitrile, acetone, DMSO, or a mixed solvent of these with water is preferred, DMSO or a mixed solvent of DMSO and water is more preferred, and a mixed solvent of DMSO and water is even more preferred.
• Two or more organic solvents may be combined and used as a mixed solvent.
• the concentration of DMSO is preferably 10 to 50% by mass. The same applies when using a mixed solvent of other solvents and water.
• the temperature of the organic solvent is preferably 10 to 80°C, and more preferably 20 to 60°C.
• the time for contacting the hollow fiber membrane with the organic solvent is preferably 30 minutes to 5 hours, more preferably 1 to 4 hours, and even more preferably 1 to 3 hours.
• the linear velocity is preferably 1.8 to 35.7 cm/min, and more preferably 5.3 to 26.7 cm/min.
• the liquid passing time is preferably 30 minutes to 5 hours, more preferably 1 to 4 hours, and even more preferably 1 to 3 hours. The same applies when passing a solvent through the outside of the hollow fiber membrane.
• the temperature of the organic solvent is preferably 10 to 80°C, more preferably 20 to 60°C. The same applies when passing the organic solvent through the outside of the hollow fiber membrane.
• the hollow fiber membrane of the present invention preferably has amino groups on the surface that comes into contact with the liquid to be treated.
• the amino groups on the surface of the hollow fiber membrane that comes into contact with the liquid to be treated may originate from the material of the hollow fiber membrane, or may originate from a ligand containing an amino group that has been introduced onto the surface of the hollow fiber membrane.
• amino group includes, for example, amino groups derived from primary amines such as methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, and dodecylamine; amino groups derived from secondary amines such as methylhexylamine, diphenylmethylamine, and dimethylamine; amino groups derived from amines having unsaturated alkyl chains such as allylamine; amino groups derived from tertiary amines such as trimethylamine, triethylamine, dimethylethylamine, phenyldimethylamine, and dimethylhexylamine; 1-(3-aminopropyl)imidazole, pyridin-2-amine, and 3-sulfoaniline; or amino groups derived from compounds in which two or more amino groups are bonded to an alkyl chain, an aromatic compound, a heterocyclic compound, or
• amino groups derived from ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, hexaethyleneheptamine, heptaethyleneoctamine, octaethylenenonamine, dipropylenetriamine, polyethyleneimine, N-methyl-2,2'-diaminodiethylamine, N-acetylethylenediamine, or 1,2-bis(2-aminoethoxyethane) are preferred, as they are easily dissolved in a solvent, have a reactive site in the structure for introduction into the hollow fiber membrane, and have a high affinity for inflammatory cytokines, and ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, polyethyleneimine, or amino groups derived from polyethyleneimine are more preferred.
• the above polyamines may be linear, branched, or cyclic.
• the hydrogen atoms bonded to the basic nitrogen atoms contained in the polyamine may be substituted with a substituent such as an alkyl group having 1 to 10 carbon atoms, an unsaturated alkyl group such as a vinyl group or an allyl group, an aryl group such as a phenyl group, a naphthyl group or an anthracyl group, or a heteroaryl group such as an imidazolyl group, a pyridyl group or a piperidyl group, and there is no particular restriction on the number or substitution position of the substituents.
• a substituent such as an alkyl group having 1 to 10 carbon atoms, an unsaturated alkyl group such as a vinyl group or an allyl group, an aryl group such as a phenyl group, a naphthyl group or an anthracyl group, or a heteroaryl group such as an imidazolyl group, a pyridyl group or a
• Ligand means a compound that is bound to at least the surface of the hollow fiber membrane that comes into contact with the liquid to be treated. If the surface that comes into contact with the liquid to be treated is the inner surface of the hollow fiber membrane, the ligand is bound to the inner surface. If the surface that comes into contact with the liquid to be treated is the outer surface of the hollow fiber membrane, the ligand is bound to the outer surface. For surfaces that do not come into contact with the liquid to be treated, it does not matter whether they are modified with a ligand. It is preferable that the ligand is distributed over the entire surface that comes into contact with the liquid to be treated.
• Methods for binding the ligand to the surface of the hollow fiber membrane include, for example, a method in which the ligand is bound to the surface of the hollow fiber membrane by electrostatic interaction (for example, electrostatic interaction between an anionic functional group such as a sulfonic acid group and a cationic functional group such as a polyamine), a method in which a specific functional group present on the surface of the hollow fiber membrane is directly bound to the ligand by a covalent bond or hydrogen bond, or a method in which a specific functional group present on the surface of the hollow fiber membrane is bound to the ligand via a spacer.
• electrostatic interaction for example, electrostatic interaction between an anionic functional group such as a sulfonic acid group and a cationic functional group such as a polyamine
• a method in which a specific functional group present on the surface of the hollow fiber membrane is directly bound to the ligand by a covalent bond or hydrogen bond
• a specific functional group present on the surface of the hollow fiber membrane is bound to the
• the spacer structure can be, for example, a sulfonic acid group, an amide group, a carboxyl group, a sulfonamide group, a ureido group, or an ether group.
• an anionic functional group e.g., a sulfonic acid group
• a method of binding by electrostatic interaction is preferred because it allows ligands to be easily introduced to the surface.
• Methods for binding a ligand to the surface of a hollow fiber membrane include, for example, immersing the hollow fiber membrane in a solution in which a compound containing an amino group is dissolved, or passing a solution in which a compound containing an amino group is dissolved inside the hollow fiber membrane.
• Solvents for dissolving compounds containing amino groups include, for example, water, aqueous solutions containing salts (e.g., phosphate buffer, borate buffer, ammonium chloride buffer, aqueous sodium hydroxide solution, saline, aqueous sodium carbonate solution, or aqueous sodium bicarbonate solution), or mixtures of these, with water being preferred since it does not interfere with the introduction reaction into the hollow fiber membrane.
• salts e.g., phosphate buffer, borate buffer, ammonium chloride buffer, aqueous sodium hydroxide solution, saline, aqueous sodium carbonate solution, or aqueous sodium bicarbonate solution
• the pH of the solution in which the compound containing an amino group is dissolved is preferably 7 to 12, and the concentration of the compound containing an amino group in the solution is preferably 0.04 to 20 g/L.
• the solution temperature is preferably 10 to 80°C, more preferably 20 to 60°C, and the immersion time is preferably 30 minutes to 24 hours, more preferably 1 to 8 hours.
• the amount of amino groups on the surface of the hollow fiber membrane of the present invention that comes into contact with the liquid to be treated is preferably 0.05 to 1.00 mmol or less per 1 g of dry mass of the hollow fiber membrane, more preferably 0.10 to 0.50 mmol, and even more preferably 0.10 to 0.30 mmol. Any of the preferred lower limits can be arbitrarily combined with any of the preferred upper limits.
• the material of the hollow fiber membrane of the present invention may be, for example, a known material used in blood purification. If the hollow fiber membrane is made of only water-soluble components, the water in the blood may cause the hollow fiber membrane to swell and the fine pores to become blocked. In addition, because this makes it easy to introduce ligands, the material of the hollow fiber membrane is preferably a copolymer of a hydrophobic monomer and a hydrophilic monomer.
• Hydrophilic monomer means a monomer that can be polymerized to give a polymer that is insoluble in water.
• “Insoluble in water” means that the change in dry mass of the polymer before and after it is placed in water is 1% or less.
• the change in dry mass is the ratio of the dry mass of the solids remaining after immersing the polymer in 37°C water in an amount 9 times its dry mass for 1 hour, then removing it with tweezers, etc., and vacuum drying the remaining water at 50°C or less, to the dry mass of the polymer before immersion.
• Hydrophilic monomer means a monomer that gives a polymer that is soluble in water.
• soluble in water means that the polymer is immersed in 37°C water in an amount 9 times its dry mass for one hour, then removed with tweezers or the like, and the remaining water is vacuum-dried at 50°C or less. The change in the dry mass of the remaining solids is 50% or more of the dry mass of the polymer before immersion.
• Examples of materials for the hollow fiber membrane include polymers or copolymers of hydrophobic monomers selected from the group consisting of ethylene, propylene, acrylonitrile, acrylates such as methyl acrylate and ethyl acrylate, methacrylates such as methyl methacrylate and ethyl methacrylate, and styrene, polymers or copolymers of hydrophilic monomers selected from the group consisting of vinylpyrrolidone, ethylene glycol, propylene glycol, vinyl alcohol, methallylsulfonic acid, styrenesulfonic acid, and salts thereof, copolymers of the above hydrophobic monomers and the above hydrophilic monomers, aromatic polyethersulfones such as polysulfone or polyethersulfone, aromatic polyetherketones such as polyetherketone or polyetheretherketone, sulfonated aromatic polyethersulfones such as sulfonated polysulfone or sul
• the material of the hollow fiber membrane is preferably a copolymer of a hydrophobic monomer selected from the group consisting of acrylonitrile, methyl methacrylate, and styrene, and a hydrophilic monomer selected from the group consisting of methallylsulfonic acid, styrenesulfonic acid, and salts thereof, and more preferably a copolymer of acrylonitrile and methallylsulfonic acid or a salt thereof.
• it may be copolymerized with other monomers, and functional groups may be introduced into the side chains.
• a method for producing a hollow fiber membrane having an acrylonitrile/sodium methallylsulfonate copolymer as a constituent component will be described in detail, but the present invention is not limited to this.
• the yarn discharged at a nozzle temperature of 50°C is passed through 80 mm in air (room temperature), and then introduced into a coagulation bath consisting of water at 30°C to coagulate, and then washed in water at 35°C and wound up to obtain a hollow fiber membrane.
• the ratio of acrylonitrile when preparing the spinning dope is preferably 60 to 95 mol%.
• the ratio of sodium methallylsulfonate is preferably 5 to 40 mol%.
• the membrane thickness of the hollow fiber membrane can be determined appropriately according to the intended use.
• the membrane thickness of the hollow fiber membrane is preferably 20 to 80 ⁇ m, more preferably 30 to 70 ⁇ m, and even more preferably 40 to 60 ⁇ m.
• the inner diameter of the hollow fiber membrane can be determined appropriately according to the membrane thickness and outer diameter of the hollow fiber membrane.
• the inner diameter of the hollow fiber membrane is preferably 150 to 400 ⁇ m, and more preferably 200 to 300 ⁇ m.
• the pore size on the surface of the hollow fiber membrane When removing target substances by membrane separation, the pore size on the surface of the hollow fiber membrane must be larger than the size of the target substance. Therefore, although it depends on the size of the target substance, the pore size on the surface of the hollow fiber membrane is generally preferably 0.1 to 50 nm, and more preferably 1 to 30 nm.
• the surface of the hollow fiber membrane that comes into contact with the liquid to be treated may be either the inner or outer surface of the hollow fiber membrane.
• the surface that comes into contact with the liquid to be treated is the inner surface of the hollow fiber membrane, since this provides a more uniform flow path for the liquid to be treated and less dead space.
• the hollow fiber membrane of the present invention When the hollow fiber membrane of the present invention is packed into a module, the hollow fiber membrane may be a hollow fiber membrane bundle composed of multiple hollow fiber membranes.
• the hollow fiber membrane of the present invention is preferably used as a carrier for adsorbing and removing activated leukocytes and/or inflammatory cytokines.
• blood drawn outside the body may be passed directly through the module, or may be used in combination with a plasma separation membrane, etc.
• Inflammatory disease refers to all diseases that induce an inflammatory response in the body. For example, systemic lupus erythematosus, malignant rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, drug-induced hepatitis, alcoholic hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D or hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome (ARDS), and other conditions.
• ARDS acute respiratory distress syndrome
• ARDS acute respiratory distress syndrome or acute respiratory distress syndrome
• acute lung injury ALI
• pancreatitis idiopathic interstitial pneumonia (idiopathic pulmonary fibrosis; IPF)
• IPF idiopathic pulmonary fibrosis
• IPF inflammatory bowel disease
• transfusion of blood products organ transplantation, reperfusion injury after organ transplantation, cholecystitis, cholangitis, or neonatal blood type incompatibility.
• diseases in which causative substances are released into the blood and for which blood purification is particularly expected to have a therapeutic effect include drug-induced hepatitis, alcoholic hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, pancreatitis, and idiopathic interstitial pneumonia.
• sepsis e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis
• influenza e.g., acute respiratory distress syndrome, acute lung injury, pancreatitis, and idiopathic interstitial pneumonia.
• the number of hollow fiber membranes packed into the container is 100 to 200 or more, more activated leukocytes can be removed, and the increased membrane area increases the water permeability while increasing the amount of blood retained within the hollow fiber membrane.
• IL-8 is a type of inflammatory cytokine contained in blood components, and it is known that IL-8 is present at significantly high levels in blood components of patients with inflammatory diseases, particularly those with diseases caused by bronchiolitis or viral infections, making it an ideal blood component for evaluating blood purification performance. It can be determined that the higher the IL-8 adsorption rate, the higher the blood purification performance of the hollow fiber membrane.
• Another method for evaluating the blood purification performance of the hollow fiber membrane of the present invention is to evaluate the removal rate of activated leukocytes.
• a method for calculating the removal rate of activated leukocytes is, for example, to fill a container having an inlet and an outlet with hollow fiber membranes, pass a liquid containing activated leukocytes through the membrane, and calculate the removal rate from the change in concentration of activated leukocytes at the inlet and outlet.
• the removal rate of activated leukocytes is preferably 80% or less.
• the removal rate of activated leukocytes is preferably 2.5% or more and 30% or less.
• Water permeability refers to the amount of water passing through the through holes present on the surface of the hollow fiber membrane. The larger the hole diameter or the more holes there are, the more water flow paths there are, and therefore the higher the water permeability of the hollow fiber membrane.
• the water permeability is preferably 0.5 to 5.0 L/h/m 2 /mmHg, more preferably 1.0 to 3.0 L/h/m 2 /mmHg, and even more preferably 1.0 to 1.5 L/h/m 2 /mmHg.
• the water permeability is preferably 0.016 to 0.100 L/h/m 2 /mmHg, more preferably 0.022 to 0.050 L/h/m 2 /mmHg, and even more preferably 0.025 to 0.030 L/h/m 2 /mmHg. Any preferred lower limit may be combined with any preferred upper limit in any desired combination.
• the diameter or number of the through holes present on the surface of the hollow fiber membrane that contribute to water permeability can be controlled by the composition of the spinning solution or the spinning conditions during membrane production.
• the "permeability maintenance rate" is determined by calculating the rate of change in permeability before and after contacting the surface of the hollow fiber membrane with the liquid to be treated. If there is no change in the permeability of the hollow fiber membrane even after contacting with the liquid to be treated, the permeability maintenance rate will be a high value. On the other hand, if the permeability decreases due to contact with the liquid to be treated, the permeability maintenance rate will be a low value.
• the permeability maintenance rate is preferably 20% or more, more preferably 30% or more, even more preferably 50% or more, and most preferably 60% or more.
• the water permeability maintenance rate decreases when blood clotting components adhere to the surface of the hollow fiber membrane when blood is passed through it.
• the amount of anticoagulant contained in the hollow fiber membrane to an appropriate amount, it is possible to suppress blood clotting components adhering to the hollow fiber membrane surface and maintain water permeability.
• the hollow fiber membrane module of the present invention is characterized in that the hollow fiber membrane of the present invention is filled in a container, i.e., it is equipped with the hollow fiber membrane of the present invention.
• the hollow fiber membrane module of the present invention can be used in blood purification applications for purifying or removing a target blood component from a liquid containing blood components, etc., and can be used, for example, for separating specific blood components.
• blood components it is preferably used for adsorbing and removing cells in blood and humoral factors in blood, and is particularly preferably used as a hollow fiber membrane module for adsorbing and removing activated leukocytes and/or inflammatory cytokines.
• the shape of the container for the hollow fiber membrane module may be any shape that has an inlet and outlet for a liquid containing blood components, an inlet and outlet for a dialysis fluid, and a case, and that allows the hollow fiber membrane to be filled in the case.
• the hollow fiber membrane is cut to the required length, bundled together in the required number, and then placed in a cylindrical case. Then, temporary caps are placed on both ends, and potting material is placed on both ends of the hollow fiber membrane. After the potting material has solidified, both ends of the hollow fiber membrane are cut so that both ends are open. Headers are attached to both ends of the case, and the headers and nozzles of the case are plugged to obtain a hollow fiber membrane module.
• the filling rate of the hollow fiber membrane (the total longitudinal cross-sectional area of the filled hollow fiber membrane relative to the longitudinal cross-sectional area of the case) is preferably 20 to 80%, and more preferably 30 to 70%.
• the hollow fiber membrane module may be filled with hollow fiber membranes alone, or with other hollow fiber membranes or various other fillers.
• fillers include fibers in the form of sheets such as knitted fabrics, woven fabrics, and nonwoven fabrics, membranes, particles, and hydrogels.
• the hollow fiber membrane of the present invention will be specifically explained below using examples, but the present invention is not limited to these examples.
• the hollow fiber membrane was cut into a length of 5 cm, further cut into a semi-cylindrical shape to expose the inner surface, and vacuum dried at 25 ° C. for 16 hours.
• the inner surface of the dried hollow fiber membrane was photographed with a laser microscope (Keyence Corporation; Ultra-Deep 3D Shape Measuring Microscope VK-9710) at a magnification of 50 times the objective lens.
• the reference length 1 was set to 20 ⁇ m, and 10 points were extracted at random positions, and the radial Ra of the inner surface was measured by analyzing it in line roughness mode using the analysis software installed in the VK-9710 (JIS B 0601: 2001 compliant).
• the above operation was performed on three different images, and the average value of the values obtained in a total of 30 points in each image was obtained, and the radial Ra of the inner surface of the hollow fiber membrane was calculated. The value rounded off to the third decimal place was used.
• the extracts obtained from hollow fiber membranes 1 to 3, hollow fiber membranes 13 to 17, and hollow fiber membranes 27 to 28 described below were reacted according to the operating procedure described in the attached document of Test Team Heparin S (Sekisui Medical Co., Ltd.), and the absorbance at 405 nm was measured using a microplate reader (Molecular Devices Japan Co., Ltd.; model: SpectraMax M5) to determine the heparin concentration in the extract.
• the extracts obtained from hollow fiber membranes 4 to 11 and hollow fiber membranes 18 to 26 described below were measured using a liquid chromatograph (HPLC) under the following conditions to determine the anticoagulant concentration in the extract.
• the amount of anticoagulant per gram of dry mass of hollow fiber membrane was calculated from the following formula (2) for hollow fiber membranes 1-3, 13-17, and 27-28, and from the following formula (3) for hollow fiber membranes 4-11 and 18-26.
• Amount of anticoagulant per 1 g of dry mass of hollow fiber membrane (Heparin concentration in extract (IU/mL) x volume of extract (mL) x 8 ( ⁇ g/IU) / molecular weight of heparin (g/mol)) / mass of hollow fiber membrane (g) ... formula (2)
• the mass per unit of heparin sodium was 8 ⁇ g/IU, and the molecular weight of heparin was 12,000 g/mol.
• the amount of anticoagulant per gram of dry mass of the hollow fiber membrane was rounded to two decimal places.
• IL-8 adsorption rate measurement A polypropylene container was filled with 38 hollow fiber membranes measuring 4 cm each. Fetal bovine serum (hereinafter referred to as "FBS") prepared to have an IL-8 concentration of 2000 pg/mL was added to the container so that the volume was 88 mL per 1 cm3 of hollow fiber membrane. After mixing by inversion in an incubator at 37°C for 1 hour, the IL-8 concentration in the FBS was measured using Quantikine ELISA Human IL-8/CXCL8 (R&D SYSTEMS, CataLog No. D8000C). The IL-8 adsorption rate was calculated from the IL-8 concentrations before and after mixing by inversion according to the following formula (4).
• FBS Fetal bovine serum
• the IL-8 adsorption rate was calculated by rounding off the first decimal place.
• ⁇ Measurement of activated leukocyte removal rate according to the first condition Healthy human volunteer blood to which LPS had been added to a concentration of 70 EU/mL was activated by shaking at 65 rpm at 37°C for 30 minutes.
• the activated blood was passed through a hollow fiber membrane module at a flow rate of 0.63 mL/min, and blood samples were collected at the inlet and outlet of the hollow fiber membrane module.
• the sample at the outlet of the hollow fiber membrane module was taken after passing blood for 6.5 minutes, starting from the time when blood flowed into the hollow fiber membrane module at 0 minutes.
• the collected samples were measured using a multi-item automated blood cell analyzer, and the activated leukocyte removal rate of the hollow fiber membrane under the first condition was measured using the following formula (5).
• Activated leukocyte removal rate (%) under first condition (activated leukocyte concentration in blood at the outlet of the hollow fiber membrane module (cells/ ⁇ L))/(activated leukocyte concentration in blood at the inlet of the hollow fiber membrane module (cells/ ⁇ L)) (5)
• the activated leukocyte removal rate was calculated by rounding off the first decimal place.
• ⁇ Measurement of water permeability under the first condition The inside of the hollow fiber membrane of the hollow fiber membrane module was filled with water, and a water pressure of 100 mmHg was applied to the inside of the hollow fiber membrane for 15 minutes. The amount of filtration flowing out to the outside of the hollow fiber membrane per unit time was measured, and the water permeability under the first condition was calculated using the following formula (6).
• ⁇ Measurement of water permeability after fresh bovine blood flow and calculation of water permeability maintenance rate under the first condition Using the hollow fiber membrane module used in the above-mentioned "Measurement of water permeability under the first condition", a blood flow test was carried out using fresh bovine blood (hematocrit 30%, total protein concentration 6.0 g/dL). A circuit was connected to the inlet and outlet of the hollow fiber membrane module, and fresh bovine blood kept warm in a water bath at 37°C was passed through at 100 mL/min for 2 hours. After the flow was stopped, physiological saline was passed through at 100 mL/min for 5 minutes to wash the inside of the hollow fiber membrane module.
• Water permeability maintenance rate (%) under first condition water permeability after fresh bovine blood is passed (L/h/m 2 /mmHg)/water permeability under first condition (L/h/m 2 /mmHg) ⁇ 100 (Equation (7))
• the water permeability maintenance rate under the first condition was calculated by rounding off the first decimal place.
• Example 1 "SepXiris” (registered trademark: manufactured by Baxter Co., Ltd.), a hollow fiber membrane composed of a copolymer of acrylonitrile/sodium methallylsulfonate and having polyethyleneimine on the surface, was disassembled with a pipe cutter. 124 of the hollow fiber membranes were bundled and packed into a housing with a diameter of about 5 mm and a length of 10 cm, and both ends were fixed to the housing with an epoxy resin-based chemical reaction adhesive "Quickmender” (registered trademark: manufactured by Konishi Co., Ltd.). After the adhesive hardened, the end faces were cut to open, and a hollow fiber membrane module was produced.
• a 50% by mass DMSO aqueous solution at 30° C. was passed through the inside of the hollow fiber membrane of the module at a flow rate of 0.6 mL/min for 1.5 hours, a 50% by mass DMSO saline solution in which heparin sodium (manufactured by AY Pharmaceuticals) was dissolved to a concentration of 0.1 mg/mL at a flow rate of 0.6 mL/min for 30 minutes, a saline solution in which heparin sodium was dissolved to a concentration of 0.1 mg/mL at a flow rate of 0.6 mL/min for 30 minutes, and a saline solution at a flow rate of 0.6 mL/min for 5 minutes, thereby obtaining a hollow fiber membrane module 1 and a hollow fiber membrane 1.
• Example 2 A hollow fiber membrane module 2 and a hollow fiber membrane 2 were obtained in the same manner as in Example 1, except that the concentration of the 50% by mass DMSO saline solution in which heparin was dissolved and the heparin sodium concentration of the saline solution were changed to 0.5 mg/mL.
• Example 3 A hollow fiber membrane module 3 and a hollow fiber membrane 3 were obtained in the same manner as in Example 1, except that the concentration of the 50% by mass DMSO saline solution in which heparin was dissolved and the heparin sodium concentration of the saline solution were changed to 0.04 mg/mL.
• Example 4 The same operations as in Example 1 were performed, except that 50 mass% DMSO saline and saline in which nafamostat mesilate (manufactured by Nichi-Iko Pharmaceutical) was dissolved to a concentration of 10 mg/mL were used instead of sodium heparin, to obtain a hollow fiber membrane module 4 and a hollow fiber membrane 4.
• Example 5 The same operations as in Example 4 were performed, except that the concentration of 50 mass% DMSO saline solution in which nafamostat mesylate was dissolved and the saline solution in which nafamostat mesylate was dissolved were changed to 50 mg/mL, and a hollow fiber membrane module 5 and a hollow fiber membrane 5 were obtained.
• Example 6 The same operations as in Example 4 were performed to obtain a hollow fiber membrane module 6 and a hollow fiber membrane 6, except that the concentration of 50 mass% DMSO saline solution in which nafamostat mesylate was dissolved and the saline solution in which nafamostat mesylate was dissolved were changed to 5 mg/mL.
• Example 7 The same operations as in Example 1 were carried out, except that 50 mass% DMSO saline and saline in which argatroban (manufactured by Nichi-Iko Pharmaceuticals) was dissolved to a concentration of 50 mg/mL were used instead of heparin sodium, to obtain a hollow fiber membrane module 7 and a hollow fiber membrane 7.
• argatroban manufactured by Nichi-Iko Pharmaceuticals
• Example 8 A hollow fiber membrane module 8 and a hollow fiber membrane 8 were obtained in the same manner as in Example 7, except that the 50% by mass DMSO saline solution in which argatroban was dissolved and the argatroban concentration of the saline solution were changed to 100 mg/mL.
• Example 9 The same operations as in Example 1 were carried out, except that 50 mass% DMSO saline and saline in which trisodium citrate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was dissolved to a concentration of 0.04 mg/mL were used instead of sodium heparin, to obtain a hollow fiber membrane module 9 and a hollow fiber membrane 9.
• Example 10 The same operations as in Example 9 were performed to obtain a hollow fiber membrane module 10 and a hollow fiber membrane 10, except that the concentration of trisodium citrate in the 50 mass% DMSO saline solution and the saline solution was changed to 0.1 mg/mL.
• Example 11 The hollow fiber membrane module 11 and the hollow fiber membrane 11 were obtained in the same manner as in Example 9, except that the citric acid concentration of the 50 mass % DMSO saline solution in which citric acid was dissolved and the saline solution was changed to 0.01 mg/mL.
• Example 1 The same operations as in Example 1 were carried out, except that a 50% by mass DMSO aqueous solution, a 50% by mass DMSO saline solution in which heparin sodium was dissolved to a concentration of 0.1 mg/mL, a saline solution in which heparin sodium was dissolved to a concentration of 0.1 mg/mL, and a saline solution were not passed through the hollow fiber membrane module, to obtain a hollow fiber membrane module 12 and a hollow fiber membrane 12.
• Example 2 The same operation as in Example 3 was carried out, except that the 50% by mass DMSO aqueous solution and the 50% by mass DMSO saline solution in which heparin sodium was dissolved to a concentration of 0.1 mg/mL were not passed through, to obtain a hollow fiber membrane module 13 and a hollow fiber membrane 13.
• Comparative Example 3 The same operations as in Comparative Example 2 were carried out except that the heparin sodium concentration of the physiological saline was changed to 1.0 mg/mL, to obtain a hollow fiber membrane module 14 and a hollow fiber membrane 14.
• Activated leukocyte removal rate (%) under the second condition (Activated leukocyte concentration in blood at the outlet of the hollow fiber membrane module (cells/ ⁇ L)) / (Activated leukocyte concentration in blood at the inlet of the hollow fiber membrane module (cells/ ⁇ L)) ... formula (8)
• Water permeability maintenance rate (%) under second condition water permeability after measurement of activated leukocyte removal rate (L/h/m 2 /mmHg)/water permeability under second condition (L/h/m 2 /mmHg) ⁇ 100 (Equation (10))
• the permeability maintenance rate of the second condition was rounded off to the first decimal place.
• Example 12 A hollow fiber membrane module 15 and a hollow fiber membrane 15 were obtained by carrying out the same operations as in Example 1, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 13 A hollow fiber membrane module 16 and hollow fiber membranes 16 were obtained by the same operation as in Example 2, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 14 A hollow fiber membrane module 17 and a hollow fiber membrane 17 were obtained in the same manner as in Example 3, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 15 A hollow fiber membrane module 18 and a hollow fiber membrane 18 were obtained by carrying out the same operations as in Example 4, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 16 A hollow fiber membrane module 19 and a hollow fiber membrane 19 were obtained in the same manner as in Example 5, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 17 A hollow fiber membrane module 20 and hollow fiber membranes 20 were obtained by carrying out the same operations as in Example 6, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 18 A hollow fiber membrane module 21 and a hollow fiber membrane 21 were obtained by the same operation as in Example 7, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 19 A hollow fiber membrane module 22 and a hollow fiber membrane 22 were obtained by the same operation as in Example 8, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 20 A hollow fiber membrane module 23 and a hollow fiber membrane 23 were obtained by the same operation as in Example 9, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 21 A hollow fiber membrane module 24 and hollow fiber membranes 24 were obtained by the same operation as in Example 10, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Example 22 A hollow fiber membrane module 25 and a hollow fiber membrane 25 were obtained by the same operation as in Example 11, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.
• Comparative Example 4 The same operation as in Comparative Example 1 was carried out, except that the number of hollow fiber membranes packed in the housing was changed to 40, and the length was changed to 12 cm, to obtain a hollow fiber membrane module 26 and a hollow fiber membrane 26.
• Comparative Example 5 The same operation as in Comparative Example 2 was carried out, except that the number of hollow fiber membranes packed in the housing was changed to 40, and the length was changed to 12 cm, to obtain a hollow fiber membrane module 27 and a hollow fiber membrane 27.
• Comparative Example 6 A hollow fiber membrane module 28 and a hollow fiber membrane 28 were obtained in the same manner as in Comparative Example 3, except that the number of hollow fiber membranes packed in the housing was changed to 40 and the length was changed to 12 cm.

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