Blood purification material

Abstract

The purpose of the present invention is to provide a blood purification material that is capable of adsorbing and removing multiple inflammatory cytokines having different surface charges at high efficiency. The present invention provides a blood purification material having a water-insoluble base material, a ligand containing an acidic functional group, and a ligand containing a basic functional group. The ligand containing the acidic functional group and the ligand containing the basic functional group are bonded to the water-insoluble base material, and the value (MwA / MwB) obtained by dividing the molecular weight (MwA) of the ligand containing the acidic functional group by the molecular weight (MwB) of the ligand containing the basic functional group is less than 1.000.

Description

Blood purification materials

[0001] The present invention relates to a blood purification material.

[0002] In recent years, various blood purification materials and blood purification columns packed with such materials have been developed for the purpose of selectively separating and adsorbing blood components such as inflammatory cytokines from blood.

[0003] Commonly known methods for improving the adsorption performance of blood purification materials for blood components include using a material that has a strong interaction with the target substance (e.g., inflammatory cytokines) as the substrate, or attaching a ligand that has a strong interaction with the target substance to the substrate surface.

[0004] For example, Patent Document 1 discloses that a material containing dextran sulfate and tryptophan on the surface of cellulose beads suppresses the complement activation activity of blood-contacting materials and reduces the increase in C3a concentration in plasma.

[0005] Patent Document 2 discloses an adsorption material for blood components having a modified polymer in which a compound containing an acidic functional group is bound via an amide bond to the surface of a water-insoluble substrate, and discloses that cytokines can be adsorbed with high efficiency by specifying the water content of the modified polymer and the amount of acidic functional group introduced.

[0006] Patent Document 3 discloses that a hollow fiber membrane made of acrylonitrile and an anionic monomer surface-treated with a cationic polymer suppresses activation of the contact phase, which causes anaphylactoid reactions.

[0007] For example, it is known that patients with inflammatory diseases such as acute respiratory distress syndrome (ARDS) and sepsis experience a phenomenon known as cytokine storm, resulting in the excessive production of multiple inflammatory cytokines, such as interleukin-6 (IL-6) and interleukin-8 (IL-8). These inflammatory cytokines vary in molecular weight from 5 to 20 kDa and have different surface charges. However, in order to treat patients with inflammatory diseases, it is desirable to remove these multiple cytokines.

[0008] Japanese Patent No. 5374064 Japanese Patent Application Laid-Open No. 2023-121738 Japanese Patent No. 4579916

[0009] An object of the present invention is to provide a blood purification material that can efficiently adsorb and remove multiple inflammatory cytokines with different surface charges.

[0010] As a result of extensive research aimed at solving the above-mentioned problems, the inventors discovered that a blood purification material in which the mass-average molecular weight of a ligand containing an acidic functional group is smaller than the mass-average molecular weight of a ligand containing a basic functional group can highly efficiently adsorb multiple inflammatory cytokines with different surface charges, thereby completing the present invention.

[0011] That is, the present invention provides the following (1) to (7): (1) A blood purification material comprising a water-insoluble base material, a ligand containing an acidic functional group, and a ligand containing a basic functional group, wherein the ligand containing an acidic functional group and the ligand containing a basic functional group are bound to the water-insoluble base material, and the value obtained by dividing the mass average molecular weight (MwA) of the ligand containing an acidic functional group by the mass average molecular weight (MwB) of the ligand containing a basic functional group (MwA / MwB) is less than 1.000. (2) The blood purification material according to (1), wherein MwA / MwB is 0.001 to 0.430. (3) The MwA is 0.5×10 ２ ~90.0 x 10 ３ and the MwB is 1.0 × 10 ２ ~66.6 x 10 ３ (4) The blood purification material according to any one of (1) to (3), wherein the content of the acidic functional groups is 0.02 to 3.00 mmol per 1 g of dry weight, and the content of the basic functional groups is 0.50 to 2.00 mmol per 1 g of dry weight. (5) The blood purification material according to any one of (1) to (3), wherein the content of the acidic functional groups is 0.02 to 1.50 mmol per 1 g of dry weight, and the content of the basic functional groups is 0.70 to 1.50 mmol per 1 g of dry weight. (6) The blood purification material according to any one of (1) to (5), which is used for adsorbing inflammatory cytokines. (7) A blood purification column comprising the blood purification material according to any one of (1) to (6).

[0012] The blood purification material of the present invention can highly efficiently adsorb and remove a plurality of inflammatory cytokines with different surface charges.

[0013] The blood purification material of the present invention comprises a water-insoluble base material, a ligand containing an acidic functional group, and a ligand containing a basic functional group, wherein the ligand containing the acidic functional group and the ligand containing a basic functional group are bound to the surface of the water-insoluble base material, and the value obtained by dividing the mass average molecular weight (MwA) of the ligand containing the acidic functional group by the mass average molecular weight (MwB) of the ligand containing the basic functional group (MwA / MwB) is less than 1.000.

[0014] The term "blood purification material" refers to a material that adsorbs organic substances present in blood components, and includes at least a portion of the material as a water-insoluble base material. This includes both water-insoluble base materials alone and water-insoluble base materials to which an appropriate reinforcing material has been immobilized or mixed. The immobilization or mixing operation may be carried out before or after processing into the desired shape.

[0015] "Blood components" refer to components that make up blood, such as humoral factors in blood and cells in blood. There are no particular restrictions on the blood components that the blood purification material of the present invention is intended to adsorb, but humoral factors in blood are preferred as the blood components to be adsorbed.

[0016] "Humoral factors in blood" refers to organic substances dissolved in blood. Specific examples include urea, β2-microglobulin, inflammatory cytokines, proteins such as IgE or IgG, and polysaccharides such as lipopolysaccharide (hereinafter abbreviated as LPS). Of these, proteins such as urea and inflammatory cytokines, and polysaccharides such as LPS are preferred as the substance to be adsorbed, and when the blood purification material of the present invention is used for the purpose of treating inflammatory diseases, inflammatory cytokines are more preferred as the substance to be adsorbed.

[0017] "Inflammatory cytokines" refer to a group of proteins that are produced by various cells, including immunocompetent cells, in response to stimuli such as infection or trauma, and are released extracellularly to act, and examples thereof include interferon α, interferon β, interferon γ, interleukin 1 to interleukin 15, tumor necrosis factor α, tumor necrosis factor β, high mobility group box-1, erythropoietin, and monocyte chemotactic factors. Among these, inflammatory cytokines are classified into positively charged cytokines and negatively charged cytokines based on the difference in surface charge.

[0018] "Positively charged cytokines" are cytokines with an isoelectric point of 7.5 or higher, and examples thereof include interleukin 8 (hereinafter referred to as IL-8) and interferon β.

[0019] "Negatively charged cytokines" are cytokines with an isoelectric point of 6.5 or less, and examples thereof include interleukin-6 (hereinafter referred to as IL-6) and interleukin-12 (IL-12).

[0020] The blood purification material according to this embodiment is preferably for adsorbing proteins, more preferably for adsorbing cytokines. Among cytokines, IL-8 and IL-6 are major causative substances of inflammatory diseases, so the blood purification material is more preferably for adsorbing IL-8 and / or IL-6, and most preferably for adsorbing IL-8 and IL-6.

[0021] "Adsorption" refers to a state in which a substance adheres to a material and does not easily peel off, or an adsorption equilibrium state. There are no particular limitations on the principle of adsorption, but examples include intermolecular forces such as electrostatic interactions, hydrophobic interactions, hydrogen bonds, and van der Waals forces.

[0022] A "water-insoluble substrate" is a substrate that is insoluble in water. Here, "water-insoluble" means that the change in dry weight of the water-insoluble substrate before and after placing it in water is 1% or less. This change in dry weight is the ratio of the dry weight of the solids remaining after immersing the water-insoluble substrate in 37°C water in an amount 9 times the dry weight for 1 hour, then removing it with tweezers or the like, and vacuum-drying the remaining water at 50°C or less, to the dry weight of the water-insoluble substrate before immersion. If the substrate is not insoluble in water, there is a risk of excessive elution during use, which is undesirable from a safety standpoint.

[0023] "Dry weight" refers to the weight of a solid in a dry state. Here, a dry solid refers to a solid in which the amount of liquid component contained in the solid is 1% by weight or less, and a solid is considered to be in a dry state when the weight of the solid is measured and then dried by heating at 80°C at atmospheric pressure for 24 hours, and the weight loss of the remaining solid is 1% by weight or less of the weight before drying.

[0024] Examples of components constituting the water-insoluble substrate include polyethylene terephthalate, polybutylene terephthalate, polyaromatic vinyl compounds, polyester, polysulfone, polyether sulfone, polystyrene, and derivatives thereof (e.g., polycarbonate, polyether ketone, polyether ether ketone, polyphenylene sulfide, polyphenol, polyphenylene ether, polyphenylene ethynylene, polyamide imide, polystyrene sulfonic acid, poly(4-methylstyrene), poly(4-ethylstyrene), poly(4-isopropylstyrene), poly(2-chlorostyrene), poly(4- and compounds selected from the group consisting of poly(2,4-dimethylstyrene), poly(2,5-dichlorostyrene), poly(2,4,5-tribromostyrene), poly(2,3,4,5,6-pentafluorostyrene), sulfonated polysulfone, sulfonated polyethersulfone), polyvinyl alcohol, cellulose acetate, polyacrylonitrile, and homopolymers, copolymers, and mixtures thereof. When an acidic functional group or a basic functional group is to be fixed to the surface of a water-insoluble substrate, the component constituting the water-insoluble substrate has a large number of aromatic rings per unit weight, and is therefore easy to fix sulfate groups, sulfonic acid groups, or amino groups to, so it is preferable that the component be a compound selected from the group consisting of polystyrene, polystyrene derivatives, polysulfone, polysulfone derivatives, polyethersulfone, polyethersulfone derivatives, and mixtures thereof, more preferably a compound selected from the group consisting of polystyrene, polystyrene derivatives, polysulfone, polysulfone derivatives, and mixtures thereof, and even more preferably polystyrene.Examples of polystyrene derivatives include polystyrene sulfonic acid, poly(4-methylstyrene), poly(4-ethylstyrene), poly(4-isopropylstyrene), poly(2-chlorostyrene), poly(4-chlorostyrene), poly(3-hydroxystyrene), poly(4-methoxystyrene), poly(4-carboxystyrene), poly(4-nitrostyrene), poly(4-chloromethylstyrene), poly(2,4-dimethylstyrene), and poly(2,5-dichlorostyrene). Examples of polysulfone derivatives include sulfonated polysulfone, and examples of polyethersulfone derivatives include sulfonated polyethersulfone.

[0025] The water-insoluble substrate is preferably in the form of fibers or particles, which have a large specific surface area and are easy to handle.

[0026] When the water-insoluble substrate is in the form of a fiber, the form of the water-insoluble substrate is preferably a yarn bundle, a yarn, a net, a knitted fabric, a woven fabric, a felt, a net, etc., which are processed from fibers, and more preferably a yarn bundle, a knitted fabric, a woven fabric, a felt, and a net, which have a large specific surface area and a small flow resistance. Among these, the knitted fabric, the felt, and the net can be manufactured by a known method using fibers as a raw material. For example, the knitted fabric and the net can be manufactured by a plain weave method or a cylindrical knitting method. In particular, from the viewpoint of filling into a blood purifier, a knitted fabric manufactured by a cylindrical knitting method, which has a large filling weight per unit volume, is preferred.

[0027] The single fiber diameter (hereinafter also referred to as fiber diameter) of the fiber (for example, sea-island composite fiber) constituting the water-insoluble base material is not particularly limited, but from the viewpoint of increasing the contact area with the substance to be adsorbed and maintaining the strength of the material, it is preferably 3 to 200 μm, more preferably 5 to 50 μm, and even more preferably 10 to 40 μm. Any preferred lower limit value can be combined with any preferred upper limit value.

[0028] The "single fiber diameter" means the average value of the diameters of the fibers measured at 10 points on each photograph (100 points in total), obtained by randomly collecting 10 small fiber samples and photographing them at 1000 to 3000 magnifications using a scanning electron microscope.

[0029] When the water-insoluble base material is in the form of particles, the diameter of the particles is preferably 1 to 500 μm from the viewpoint of ensuring a sufficient specific surface area for adsorbing the target substance.

[0030] Since blood purification materials need to interact with substances to be adsorbed, they must have ligands bound to at least the surface that comes into contact with organic matter contained in blood or the like.

[0031] The "surface" refers to the surface of the water-insoluble substrate, and in the case of a shape having pores on the surface, the outermost layer portion along the irregularities of the pores is also included in the surface. Furthermore, in the case of a fiber having through-holes inside, not only the outermost layer portion of the water-insoluble substrate but also the outer layer of the through-holes inside the substrate is included in the surface.

[0032] "Bond" refers to a state in which a ligand is present on the surface of a water-insoluble substrate through chemical or physical interaction. Here, chemical interaction refers to a covalent bond, electrostatic interaction, or hydrogen bond, and physical interaction refers to van der Waals forces. Although not particularly limited, the bond between the water-insoluble substrate and the ligand is preferably a covalent bond, since this allows the ligand to stably exist on the surface when in contact with blood.

[0033] The term "ligand" refers to a compound bound to the surface of a water-insoluble substrate. Its chemical structure is not particularly limited as long as it contains at least one acidic or basic functional group. Examples of the ligand include ligands containing an acidic functional group and ligands containing a basic functional group. The functional group may be a combination of multiple identical or different functional groups. Furthermore, as long as the ligand has the acidic or basic functional group, it may further contain a neutral functional group. Examples of neutral functional groups include alkyl groups such as methyl or ethyl, and aryl groups such as phenyl, alkyl-substituted phenyl, or halogen-substituted phenyl. Examples of alkyl-substituted phenyl groups include para(p)-methylphenyl, meta(m)-methylphenyl, ortho(o)-methylphenyl, para(p)-ethylphenyl, meta(m)-ethylphenyl, ortho(o)-ethylphenyl. Examples of phenyl groups substituted with halogen atoms include para(p)-fluorophenyl groups, meta(m)-fluorophenyl groups, ortho(o)-fluorophenyl groups, para(p)-chlorophenyl groups, meta(m)-chlorophenyl groups, and ortho(o)-chlorophenyl groups. The neutral functional group and the acidic functional group or basic functional group may be bonded directly or via a spacer (the spacer involved in the bond is referred to as spacer 1). Examples of spacer 1 include a urea bond, an amide bond, and a urethane bond.

[0034] The water-insoluble base material and the ligand containing an acidic functional group or the ligand containing a basic functional group may be bonded directly or via a spacer derived from a reactive functional group (the spacer involved in this bond is referred to as spacer 2). Spacer 2 may be any spacer having an electrically neutral chemical bond such as a urea bond, an amide bond, an ether bond, an ester bond, or a urethane bond, and preferably has an amide bond or a urea bond. In the blood purification material of the present invention, spacer 2 is considered to be included in the ligand containing an acidic functional group or the ligand containing a basic functional group.

[0035] Examples of reactive functional groups that mediate the bond between a water-insoluble substrate and a ligand containing an acidic functional group and a ligand containing a basic functional group include active halogen groups such as haloalkyl groups (halomethyl groups, haloethyl groups, etc.), haloacyl groups (haloacetyl groups, halopropionyl groups, etc.), or haloacetamidoalkyl groups (haloacetamidomethyl groups, haloacetamidoethyl groups, etc.), epoxide groups, carboxyl groups, isocyanic acid groups, thioisocyanic acid groups, and acid anhydride groups. From the viewpoint of having appropriate reactivity, the reactive functional group is preferably an active halogen group, more preferably a haloacetamidoalkyl group, and even more preferably a haloacetamidomethyl group. Specific examples of water-insoluble substrates having reactive functional groups include polystyrene having chloroacetamidomethyl groups introduced on the surface and polysulfone having chloroacetamidomethyl groups introduced on the surface.

[0036] The reactive functional group can be bonded to the water-insoluble substrate by reacting the water-insoluble substrate with an appropriate reagent in advance. For example, if the component constituting the water-insoluble substrate is polystyrene and the reactive functional group is a chloroacetamidomethyl group, polystyrene having a chloroacetamidomethyl group bonded thereto can be obtained by reacting the polystyrene with N-hydroxymethyl-2-chloroacetamide. Polystyrene having a chloroacetamidomethyl group bonded thereto can be obtained by reacting, for example, tetraethylenepentamine having an amino group with polystyrene having a chloroacetamidomethyl group bonded thereto. In this case, the acetamidomethyl group corresponds to spacer 2, and tetraethylenepentamine corresponds to the ligand. The components constituting the water-insoluble substrate, the spacers (spacer 1 and spacer 2), and the ligand can be combined in any manner. Examples of the water-insoluble substrate to which a ligand is bonded include polystyrene to which a ligand containing a polyamine such as ethylenediamine, diethylenetriamine, triethylenetetramine, or tetraethylenepentamine is bonded via an acetamidomethyl group, and polysulfone to which a ligand containing a polyamine such as ethylenediamine, diethylenetriamine, triethylenetetramine, or tetraethylenepentamine is bonded via an acetamidomethyl group.

[0037] The term "ligand containing an acidic functional group" refers to a ligand having a sulfate group (-OSO) in a part of its chemical structure. ２ OH), sulfonic acid group (-SO ２ The term "a compound" refers to a compound containing at least one acidic functional group selected from the group consisting of a sulfonic acid group (-OH), a carboxylic acid group (-COOH), and salts thereof. There are no limitations on the chemical structure of the compound as long as it contains the acidic functional group. However, in this embodiment, when the water-insoluble base material is made of polystyrene, the acidic functional group is preferably a sulfonic acid group or a salt thereof, since it is easy to introduce the sulfonic acid group into the benzene ring.

[0038] The term "ligand containing a basic functional group" refers to a compound that contains, as part of its chemical structure, at least one basic functional group selected from the group consisting of an amino group and a salt thereof. There are no limitations on the chemical structure of the compound as long as it has an amino group. However, polyamines are preferred as ligands containing a basic functional group, from the viewpoints that they can be easily introduced into water-insoluble substrates via an amide bond, a urea bond, or the like, and that compounds with a large MwB can be used.

[0039] The term "polyamine" refers to a compound having two or more amino groups as part of its chemical structure. Examples include polyethyleneamines such as ethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, hexaethyleneheptamine, heptaethyleneoctamine, octaethylenenonamine, and polyethyleneimine. Tetraethylenepentamine is preferred as the polyamine. Furthermore, the amino groups in the polyamine structure are preferably derived from primary or secondary amines. The polyamine may be linear, branched, or cyclic. Furthermore, the polyamine may contain an unsaturated alkyl chain such as an alkyl group having 1 to 10 carbon atoms, a vinyl group, or an allyl group; an aromatic substituent such as a phenyl group, a naphthyl group, or an anthracyl group; or a heterocyclic substituent such as an imidazolyl group, a pyridyl group, or a piperidyl group.

[0040] The mass-average molecular weight (MwA) of a ligand containing an acidic functional group can be determined by preparing an extract by hydrolysis of the blood purification material with hydrochloric acid and performing gel permeation chromatography (hereinafter, GPC). An example of a specific measurement method is as follows. A blood purification material cut into a size of 2 cm x 2 cm is placed in a vial, 2 mL of 6 M hydrochloric acid is added, and the extract is prepared by heating at 110°C for 20 hours using a dry heat sterilizer. 0.5 mL of the obtained extract is taken, and 1 mL of water / methanol = 1 / 1 (with 0.1 N lithium nitrate added), and then a cation exchange resin is added and allowed to stand. The supernatant after standing is used as the measurement solution. The MwA can be determined by measuring the obtained measurement solution using a gel permeation chromatograph analyzer [e.g., Prominence GPC System (manufactured by Shimadzu Corporation)]. An example of the configuration of the GPC device and measurement conditions is as follows. Apparatus configuration Pump: LC-20AD Autosampler: SIL-20AHT Column oven: CTO-20A Detector: RID-10A Column: GMPWXL (inner diameter 7.8 mm x 30 cm, particle size 13 μm), manufactured by Tosoh Corporation Measurement conditions Measurement solvent: water / methanol = 1 / 1 (0.1 N lithium nitrate added) Flow rate: 0.5 mL / min Measurement time: 30 min Sample injection volume: 20 μL Standard material for calibration curve: PEG / PEO standard sample (0.1 kDa to 1258 kDa; manufactured by Agilent Corporation)

[0041] When the MwA is measured by GPC and no peak is observed on the resulting GPC chart, i.e., when the MwA is determined to be less than 1000, the MwA can be identified by performing gas chromatography mass spectrometry (hereinafter, GCMS) instead of GPC. The specific measurement method is as follows: A blood purification material cut into a size of 2 cm x 2 cm is placed in a vial, 2 mL of 6 M hydrochloric acid is added, and the mixture is heated at 110°C for 20 hours using a dry heat sterilizer to prepare an extract. 0.5 mL of the obtained extract is taken, and 1.5 mL of water is added to prepare a measurement solution. The obtained measurement solution can be measured using a gas chromatography mass spectrometer to identify the MwA. An example of the configuration of the GCMS device and measurement conditions is as follows: Equipment configuration Gas chromatograph: GC-2010 (Shimadzu Corporation) Detector: GCMS-QP2010 Plus (Shimadzu Corporation) Column: DB-WAX (Agilent) Measurement conditions Carrier gas: He 183 mL / min Oven temperature: 40°C (Hold 5 min) → 180°C (20°C / min, Hold 3 min) Vaporizer temperature: 200°C Ion source temperature: 200°C Interface temperature: 250°C Injection method: Split ratio 20:1

[0042] The mass average molecular weight (MwB) of a ligand containing a basic functional group can be determined by hydrolyzing the blood purification material with hydrochloric acid to prepare an extract using the same method as for measuring MwA, neutralizing the extract with a 6 M aqueous sodium hydroxide solution, and then performing GPC or GCMS using the same method as for measuring MwA.

[0043] If MwA is too large, the motility is inhibited by forming an ion complex with a ligand containing a basic functional group, and the interaction with blood components is reduced. If MwA is too small, when MwB is large, the ligand containing an acidic functional group is covered with the ligand containing a basic functional group, and the interaction with blood components is inhibited. For these reasons, MwA is set to 0.5 × 10 ２ ~90.0 x 10 ３ is preferable, and 0.5 × 10 ２ ~20.0 x 10 ３More preferably, 0.5 × 10 ２ ~1.3 × 10 ３ is more preferably 0.5 × 10 ２ ~1.0 x 10 ３ is even more preferable, and 0.7 × 10 ２ ~0.9 × 10 ３ The preferred lower limit value can be combined with any preferred upper limit value.

[0044] If MwB is too large, an ion complex is formed with a ligand containing an acidic functional group, inhibiting mobility and reducing interaction with blood components. If MwB is too small, when MwA is large, the ligand containing a basic functional group is covered with the ligand containing an acidic functional group, inhibiting interaction with blood components. For these reasons, MwB is set to 1.0 × 10 ２ ~66.0 x 10 ３ is preferred, and 1.0 × 10 ２ ~22.0 x 10 ３ More preferably, 1.0 × 10 ２ ~14.0 x 10 ３ is more preferably 1.0 × 10 ２ ~13.0 x 10 ３ is even more preferable, and 1.7 × 10 ２ ~13.0 x 10 ３ The preferred lower limit value can be combined with any preferred upper limit value.

[0045] The "value obtained by dividing MwA by MwB (MwA / MwB)" is calculated by dividing MwA by MwB. By making MwA / MwB less than 1.000, the adsorption rate of multiple inflammatory cytokines with different surface charges can be improved. This is thought to be because ligands containing acidic functional groups and ligands containing basic functional groups can each interact with blood components such as inflammatory cytokines without forming an ion complex. Furthermore, when MwA / MwB is 1.00 or greater, ligands containing acidic functional groups form hydrogen bonds with each other, preventing them from interacting with blood components such as inflammatory cytokines. Therefore, MwA / MwB is preferably less than 1.000, more preferably 0.001 or greater but less than 1.000, even more preferably 0.001 to 0.430, and most preferably 0.006 to 0.430. Any preferred lower limit can be combined with any preferred upper limit.

[0046] The content of acidic functional groups can be measured by acid-base back titration of the blood purification material. For example, the surface of the blood purification material, the dry weight of which has been measured in advance, is desalted with hydrochloric acid, and then repeatedly washed with ion-exchanged water until the pH of the washing solution becomes neutral. Subsequently, the material is dried by vacuum drying to remove water, and an aqueous sodium hydroxide solution of a known concentration is added to convert the acidic functional groups on the material surface into salts. The content of acidic functional groups can be determined by measuring the concentration of sodium hydroxide consumed during this process by titration.

[0047] If the content of acidic functional groups is too low, they will not be able to interact with blood components, and if it is too high, they will exhibit adsorption properties for anticoagulants, which may increase blood coagulation, so the content is preferably 0.02 to 3.00 mmol, more preferably 0.02 to 2.00 mmol, even more preferably 0.02 to 1.50 mmol, and most preferably 0.80 to 1.50 mmol per 1 g of dry weight of the blood purification material. Any preferred lower limit can be combined with any preferred upper limit.

[0048] The content of basic functional groups can be measured by acid-base back titration of the blood purification material. For example, the surface of the blood purification material, the dry weight of which has been measured in advance, is desalted with an aqueous sodium hydroxide solution, and then repeatedly washed with ion-exchanged water until the pH of the washing solution becomes neutral. The material is then dried by vacuum drying to remove water, and a known concentration of hydrochloric acid is added to convert the basic functional groups on the material surface into salts. The content of basic functional groups can be determined by measuring the concentration of hydrochloric acid consumed during this process by titration.

[0049] If the content of basic functional groups is too low, they will not be able to interact with blood components, and if it is too high, they may exhibit hemolytic toxicity to blood, raising concerns about reduced safety, so the content is preferably 0.50 to 2.00 mmol, more preferably 0.50 to 1.50 mmol, even more preferably 0.70 to 1.50 mmol, and most preferably 1.10 to 1.50 mmol per gram of dry weight of the blood purification material. Any of the preferred lower limits can be combined with any of the preferred upper limits.

[0050] The blood purification material according to this embodiment is preferably used as a material to be packed into a blood purification column, and is particularly suitable as a material for adsorbing and removing inflammatory cytokines when extracorporeal circulation is performed for the purpose of treating inflammatory diseases. When a blood purification column using the blood purification material is used for blood purification therapy, blood drawn outside the body may be passed directly through the column, or it may be used in combination with a plasma separation membrane or the like.

[0051] The term "inflammatory disease" refers to all diseases that induce an inflammatory response in the body, and includes, 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, hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome (ARDS; also referred to as acute respiratory distress syndrome or acute respiratory distress syndrome), acute lung injury (ALI), pancreatitis, idiopathic interstitial pneumonia (IDP), and the like. inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), reperfusion injury after organ transplantation, cholecystitis, cholangitis, or neonatal blood type incompatibility.

[0052] Among inflammatory diseases, the causative substances are released into the blood, and blood purification is particularly expected to be effective in treating these diseases. Therefore, preferred targets for treatment with a blood purification column are drug-induced hepatitis, alcoholic hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, and fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, pancreatitis, and idiopathic interstitial pneumonia. The blood purification column of this embodiment is preferably used, for example, to treat the above-mentioned inflammatory diseases. Among these, more preferred are sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, and fungal sepsis), which are difficult to treat with drugs alone and are considered to involve inflammatory cytokines.

[0053] Methods for evaluating the blood purification performance of blood purification materials include, for example, measuring the IL-6 adsorption rate and IL-8 adsorption rate. IL-6 and IL-8 are inflammatory cytokines contained in blood components, and are known to be significantly increased in the blood of patients with inflammatory diseases, making them suitable blood components for evaluating blood purification performance. The higher the IL-6 adsorption rate and IL-8 adsorption rate, the higher the blood purification performance of the blood purification material can be determined to be.

[0054] From the viewpoint of reducing the concentration of cytokines produced in the blood of patients with inflammatory diseases and enabling them to recover as quickly as possible from serious symptoms such as systemic shock and hypotension, the cytokine adsorption performance of the blood purification material preferably exhibits an IL-6 adsorption rate of 10% or more and an IL-8 adsorption rate of 20% or more. Furthermore, it is more preferable that the IL-6 adsorption rate is 10% or more and the IL-8 adsorption rate is 40% or more, or that the IL-6 adsorption rate is 20% or more and the IL-8 adsorption rate is 20% or more, and it is even more preferable that the IL-6 adsorption rate is 20% or more and the IL-8 adsorption rate is 40% or more.

[0055] The blood purification column of the present invention is characterized by comprising the above-mentioned blood purification material.

[0056] The term "blood purification column" refers to a column having at least a liquid inlet, a case, and a liquid outlet, with the case packed with a blood purification material. Examples of the column include radial flow columns.

[0057] The container shape of the blood purification column may be any shape as long as it has an inlet and outlet for a liquid containing blood components, etc. (hereinafter referred to as the liquid), and a case that allows the blood purification material to be filled into the case. One embodiment includes a container that can be filled with a blood purification material formed by wrapping a pipe around the blood purification material to form a cylinder (hereinafter referred to as the cylinder), in which the liquid enters from the outer periphery of the cylinder, flows to the inside of the cylinder, and then exits the container, or a container in which the liquid enters from the inside of the cylinder, flows to the outside of the cylinder, and then exits the container. From the viewpoint of production efficiency and preventing short-path flow of the treated liquid, a preferred container for a blood purification column has a structure in which blood purification material is wrapped around a pipe with holes on the side. Specifically, a radial flow-type container can be used, which includes: a central pipe with holes on its longitudinal side for allowing the supplied liquid to flow out; blood purification material packed around the central pipe and adsorbing target substances contained in the liquid; a plate connected to the upstream end of the central pipe so that the incoming liquid passes through the central pipe and is positioned to prevent the liquid from contacting the blood purification material without passing through the central pipe; and a plate sealing the downstream end of the central pipe and fixing the blood purification material in the space around the central pipe. The shape of the container can be, but is not limited to, a cylindrical shape or a prismatic shape such as a triangular, square, hexagonal, or octagonal prism. Another embodiment can be a container with a cylindrical space inside that can be filled with a circularly cut piece of blood purification material, and which has a liquid inlet and a liquid outlet. Specifically, an example is a container having a plate with a liquid inlet port for introducing a liquid and a plate with a liquid outlet port for discharging the introduced liquid, and an internal cylindrical case filled with a circularly cut-out blood purification material. Note that the shape of the blood purification material is not limited to circular, and can be modified as appropriate to suit the shape of the container of the blood purification column, such as oval, polygonal (e.g., triangular or rectangular), or trapezoidal.

[0058] Examples of containers for blood purification columns include glass, plastic / resin, and stainless steel containers, with plastic / resin containers being preferred in consideration of ease of handling and disposal in clinical settings and measurement locations. The size of the container is selected appropriately depending on the intended use, but in consideration of ease of handling and disposal in clinical settings and measurement locations, a size that is easy to hold in the hand is preferred, and it is preferred that the height of the entire blood purification column be 1 cm or more and 30 cm or less, the outer diameter be 1 cm or more and 10 cm or less, and the internal volume be 200 mL or less.

[0059] The blood purification material is preferably packed in a layered manner inside the blood purification column. Here, "layered" means that two or more sheets of the blood purification material are stacked in close contact with each other. Examples of methods for packing the blood purification column in a layered manner include stacking multiple sheets of blood purification material processed into a sheet form, as in an axial flow column, or wrapping the blood purification material processed into a sheet form around a pipe with holes, as in a radial flow column.

[0060] The blood purification column may be filled with the blood purification material alone or in combination with other water-insoluble substrates and / or various spacers, such as knitted fabrics, woven fabrics, nonwoven fabrics, sheet-shaped fibers, membranes, beads, and hydrogels.

[0061] The blood purification material of the present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0062] Example 1 Polystyrene was used as the sea component and polypropylene as the island component, and they were melt-metered separately and fed into a spin pack equipped with a sea-island composite spinneret having 700 distribution holes for the island components per nozzle to form a sea-island composite stream, which was then melt-discharged. The island ratio was controlled to 50 wt %, and the distance from the surface of the sea-island composite fiber to the outermost island component was adjusted to 2 μm, to obtain sea-island composite fibers with a single fineness of 3.0 dtex (fiber diameter 20 μm).

[0063] The sea-island composite fiber was used to adjust the density adjustment scale of a cylindrical knitting machine (model name: circular knitting machine MR-1, Maruzen Sangyo Co., Ltd.) to obtain a fabric with a basis weight of 60 g / m２ A knitted fabric A having a bulk density of 0.20 g / mL was produced.

[0064] 8 g of N-hydroxymethyl-2-chloroacetamide (hereinafter referred to as NMCA) was added to a mixed solution of 62 mL of nitrobenzene and 41 mL of 98 wt% sulfuric acid, and the mixture was stirred at 5°C until the NMCA was dissolved, to prepare an NMCA solution. Next, 0.5 g of paraformaldehyde (hereinafter referred to as PFA) was added to a mixed solution of 5 mL of nitrobenzene and 3 mL of 98 wt% sulfuric acid, and the mixture was stirred at 50°C until the PFA was dissolved, to prepare a PFA solution. 8 mL of the PFA solution was cooled to 5°C, then mixed with 111 mL of the NMCA solution, and stirred for 5 minutes. 5 g of knitted fabric A was immersed in the mixed solution of the PFA solution and NMCA solution for 2 hours.

[0065] Next, knitted fabric A that had been immersed in the mixed solution of the PFA solution and the NMCA solution was immersed in a mixed solution of 62 mL of nitrobenzene and 41 mL of 98 wt % sulfuric acid for 4 hours at 50° C. Knitted fabric A was immersed in 100 mL of nitrobenzene at 0° C. to stop the reaction, and then filtered using a glass filter and washed with 1,000 mL of methanol.

[0066] Knitted fabric A, which had been washed with methanol, was immersed in a mixed solution of 1.3 mL of tetraethylenepentamine (TEPA; manufactured by Sigma-Aldrich; product number: 30-0850-05), 2 mL of triethylamine, and 93 mL of dimethyl sulfoxide (DMSO) at 40°C for 3 hours. Knitted fabric A was filtered using a glass filter and washed with 1000 mL of DMSO. The DMSO adhering to the knitted fabric was washed with 1000 mL of methanol and 2000 mL of ion-exchanged water, yielding blood purification material 1.

[0067] Example 2 Blood purification material 2 was obtained by performing the same operations as in Example 1 (method of producing blood purification material 1), except that knitted fabric A was not immersed in a mixed solution of nitrobenzene and 98% by weight sulfuric acid and the amount of TEPA added was changed from 1.3 mL to 0.7 mL.

[0068] Example 3 Blood purification material 3 was obtained by performing the same operations as in Example 1 (method of producing blood purification material 1), except that 1.3 mL of TEPA was replaced with 5 g of polyethyleneimine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 166-17825; average molecular weight: approximately 10,000 (catalog value)).

[0069] Example 4 Blood purification material 4 was obtained by performing the same operations as in Example 1 (method of producing blood purification material 1), except that 1.3 mL of TEPA was replaced with 5 g of 30% polyethyleneimine P-70 solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 169-11955; average molecular weight: approximately 70,000 (catalog value)).

[0070] (Comparative Example 1) Knitted fabric A was produced in the same manner as in Example 1. Next, an NMCA solution was prepared in the same manner as in Example 1, and 5 g of knitted fabric A was immersed in the solution for 2 hours. Knitted fabric A was immersed in 100 mL of nitrobenzene at 0°C to stop the reaction, and then filtered using a glass filter and washed with 1,000 mL of methanol.

[0071] Knitted fabric A, which had been washed with methanol, was immersed in a mixed solution of 0.5 mL of ethylenediamine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and 199 mL of DMSO at 40°C for 3 hours. Knitted fabric A was filtered using a glass filter and washed with 200 mL of DMSO. DMSO adhering to knitted fabric A was washed with 1000 mL of methanol.

[0072] Knitted fabric A was added directly to a 1.0 mass% polyacrylic acid 25000 solution prepared by dissolving polyacrylic acid 25000 (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 162-18581; average molecular weight: approximately 25000 (catalog value)) in 180 mL of methanol to a concentration of 1.0 mass%, and 0.9 g of DMT-MM (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was then added, followed by immersion for 2 hours at 40° C. Knitted fabric A was filtered using a glass filter and washed with 1000 mL of methanol.

[0073] After washing with methanol, knitted fabric A was immersed in a mixed solution of 1.5 mL of TEPA and 93 mL of methanol for 3 hours at 40° C. Knitted fabric A was filtered using a glass filter and washed with 1000 mL of methanol and 2000 mL of ion-exchanged water, thereby obtaining blood purification material 5.

[0074] Comparative Example 2 Blood purification material 6 was obtained by performing the same operations as in Comparative Example 1 (method of producing blood purification material 1), except that 1.5 mL of TEPA was replaced with 5 g of polyethyleneimine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 166-17825; average molecular weight: approximately 10,000 (catalog value)).

[0075] (Example 5) Blood purification material 7 was obtained by performing the same operations as in Example 1 (method of producing blood purification material 1), except that knitted fabric A was not immersed in a mixed solution of nitrobenzene and 98 wt% sulfuric acid and the amount of NMCA added was changed from 8 g to 6 g.

[0076] Comparative Example 3 Blood purification material 8 was obtained by performing the same operations as in Comparative Example 1 (method for producing blood purification material 5), except that 1.5 mL of TEPA was replaced with 5 g of polyethyleneimine (branched) (manufactured by Sigma-Aldrich; product number: 408727; mass average molecular weight: up to 25,000 (catalog value)) and polyacrylic acid 25,000 was replaced with polyacrylic acid solution (approximately 25%) 8,000 to 12,000 (manufactured by Fujifilm Wako Pure Chemical Industries; product number: 168-07375; molecular weight: approximately 150,000).

[0077] Comparative Example 4 Blood purification material 9 was obtained by performing the same operations as in Comparative Example 1 (method for producing blood purification material 5), except that the 1.0 mass% polyacrylic acid 25000 solution was changed to a polyacrylic acid sodium salt-containing solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 192023; mass average molecular weight: 2000) to which 10 mL of 1 N hydrochloric acid had been added.

[0078] Comparative Example 5 Using Comparative Example 1 (method for producing blood purification material 5) as a reference, blood purification material 10 was obtained by performing the same operations as in Comparative Example 1, except that 1.5 mL of TEPA was replaced with 5 g of polyethyleneimine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 167-17811; average molecular weight: approximately 1,800), and the 1.0 mass % polyacrylic acid 25,000 solution was replaced with a polyacrylic acid sodium salt-containing solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; product number: 192023; mass average molecular weight: approximately 2,000) prepared by adding 10 mL of 1 N hydrochloric acid.

[0079] <Measurement of MwA of blood purification material by GPC> A blood purification material cut into a size of 2 cm x 2 cm was placed in a vial, 2 mL of 6 M hydrochloric acid was added, and the mixture was heated at 110°C for 20 hours using a dry heat sterilizer to prepare an extract. 0.5 mL of the obtained extract was taken, and 1.5 mL of water / methanol = 1 / 1 (with 0.1 N lithium nitrate added) was added. A cation exchange resin (manufactured by Organo; product number: IR120B H) was then added and allowed to stand for 1 hour. The supernatant after standing was used as the measurement solution. The obtained measurement solution was measured using a gel permeation chromatograph analyzer (Prominence GPC system; manufactured by Shimadzu Corporation) to identify the MwA. The configuration of the GPC device and measurement conditions are as follows. Apparatus configuration Pump: LC-20AD Autosampler: SIL-20AHT Column oven: CTO-20A Detector: RID-10A Column: GMPWXL (inner diameter 7.8 mm x 30 cm, particle size 13 μm), manufactured by Tosoh Corporation Measurement conditions Measurement solvent: water / methanol = 1 / 1 (0.1 N lithium nitrate added) Flow rate: 0.5 mL / min Measurement time: 30 min Sample injection volume: 20 μL Standard material for calibration curve: PEG / PEO standard sample (0.1 kDa to 1258 kDa; manufactured by Agilent Corporation)

[0080] <Measurement of MwA of Blood Purification Material by GCMS> When the MwA of the blood purification material was measured by GPC and no peak was observed on the obtained GPC chart, the MwA was measured by GCMS using the following method. A 2 cm x 2 cm piece of blood purification material was cut into a vial, 2 mL of 6 M hydrochloric acid was added, and the mixture was heated at 110°C for 20 hours using a dry heat sterilizer to prepare an extract. 0.5 mL of the obtained extract was sampled and 1.5 mL of water was added to prepare a measurement solution. The obtained measurement solution was measured using a gas chromatograph mass spectrometer to identify the MwA. The GCMS device configuration and measurement conditions are as follows. Equipment configuration Gas chromatograph: GC-2010 (Shimadzu Corporation) Detector: GCMS-QP2010 (Shimadzu Corporation) Column: DB-WAX (Agilent) Measurement conditions Carrier gas: He 183 mL / min Oven temperature: 40°C (Hold 5 min) → 180°C (20°C / min, Hold 3 min) Vaporizer temperature: 200°C Ion source temperature: 200°C Interface temperature: 250°C Injection method: Split ratio 20:1

[0081] <Measurement of MwB of blood purification material by GPC> The blood purification material cut into a size of 2 cm x 2 cm was placed in a vial, 2 mL of 6 M hydrochloric acid was added, and the mixture was heated at 110 ° C. for 20 hours using a dry heat sterilizer to prepare an extract. 0.5 mL of the obtained extract was collected and neutralized with 0.5 mL of 6 M aqueous sodium hydroxide solution, followed by the addition of 1 mL of water / methanol = 1 / 1 (with 0.1 N lithium nitrate added). An anion exchange resin (manufactured by Organo; product number: HPR4780 Cl) was then added and allowed to stand for 1 hour. The supernatant after standing was used as the measurement solution. The MwB of the obtained measurement solution was identified by measuring it using a gel permeation chromatograph analyzer using the same procedure as for the GPC measurement of MwA.

[0082] <Measurement of MwB of blood purification material by GCMS> When the MwB of the blood purification material was measured by GPC and no peak was observed on the obtained GPC chart, the MwB was measured by GCMS using the following method. A blood purification material cut into a size of 2 cm x 2 cm was placed in a vial, 2 mL of 6 M hydrochloric acid was added, and the mixture was heated at 110°C for 20 hours using a dry heat sterilizer to prepare an extract. 0.5 mL of the obtained extract was sampled and neutralized with 0.5 mL of 6 M aqueous sodium hydroxide solution, and then 1 mL of water was added to prepare a measurement solution. The obtained measurement solution was measured using a gas chromatograph mass spectrometer using the same procedure as for measuring MwA by GCMS, and the MwB was identified.

[0083] <Measurement of the content of acidic functional groups per gram of dry weight of blood purification material> 0.5 g of blood purification material was placed in a 50 mL polypropylene centrifuge tube, and 40 mL of 6 M hydrochloric acid was added. The mixture was then mixed by inversion at room temperature for 30 minutes. After mixing, the solution alone was decanted, and 20 mL of ion-exchanged water was added and mixed by inversion for 5 minutes. This procedure was repeated 10 times. The pH of the final decanted solution was confirmed to be 6 or higher using litmus paper. The washed blood purification material was placed in a vacuum dryer heated to 40°C and vacuum-dried for 24 hours. The dried blood purification material was placed in a 50 mL polypropylene centrifuge tube, and 40 mL of 0.1 M aqueous sodium hydroxide solution was added. The mixture was then mixed by inversion for 30 minutes. 5 mL of the supernatant solution was removed from the centrifuge tube and placed in another 15 mL polypropylene centrifuge tube. 5 mL of 0.1 M hydrochloric acid was added, followed by 0.02 mL each of methyl red aqueous solution and phenolphthalein aqueous solution. Using a burette, 0.02 mL of 0.05 M sodium hydroxide aqueous solution was added dropwise to the centrifuge tube, and the solution was inverted 10 times to mix. The color of the solution was confirmed. The amount of sodium hydroxide added when the solution first changed color from reddish-orange to yellow was recorded as the titer. The obtained value was rounded to two decimal places using the following formula (1) to calculate the content of acidic functional groups per gram of dry weight of the blood purification material. Acidic functional group content (mmol / g) per 1 g dry weight of blood purification material = {volume of 0.1 M sodium hydroxide aqueous solution added (40 mL) / volume of sodium hydroxide aqueous solution removed (5 mL)} × titer per 1 g (mL / g) × concentration of sodium hydroxide aqueous solution (0.05 mol / L) Equation 1

[0084] <Measurement of the amount of basic functional groups introduced per gram of dry mass of blood purification material> 0.5 g of blood purification material was placed in a 50 mL polypropylene centrifuge tube, and 20 mL of 6 M aqueous sodium hydroxide solution was added. The mixture was then mixed by inversion at room temperature for 30 minutes. After mixing, the solution alone was decanted, and 20 mL of ion-exchanged water was added and mixed by inversion for 5 minutes. This process of decanting the solution alone, adding 20 mL of ion-exchanged water, and mixing by inversion for 5 minutes was repeated 10 times. Finally, the pH of the decanted solution was confirmed to be 8 or less using litmus paper. The washed blood purification material was placed in a vacuum dryer heated to 40°C and vacuum-dried for 24 hours. The dried blood purification material was placed in a 50 mL polypropylene centrifuge tube, and 40 mL of 0.1 M hydrochloric acid was added. The mixture was then mixed by inversion for 30 minutes. 5 mL of the supernatant solution was removed from the centrifuge tube and placed in another 15 mL polypropylene centrifuge tube, followed by the addition of 0.02 mL each of methyl red aqueous solution and phenolphthalein aqueous solution. Using a burette, 0.02 mL of 0.05 M sodium hydroxide aqueous solution was added dropwise to the centrifuge tube, and the solution was inverted 10 times to mix. The color of the solution was then confirmed. The amount of sodium hydroxide added when the solution first changed color from reddish-orange to yellow was defined as the titer per gram. The obtained value was rounded to two decimal places using the following formula 2 to calculate the content (mmol / g) of basic functional groups per gram of dry weight of the blood purification material. Basic functional group content (mmol / g) per 1 g dry weight of blood purification material = {volume of 0.1 M hydrochloric acid added (40 mL) / volume of hydrochloric acid removed (5 mL)} × titer per 1 g (mL / g) × concentration of aqueous sodium hydroxide solution (0.05 mol / L) Equation 2

[0085] <Measurement of IL-6 adsorption rate of blood purification material> Six blood purification material cut into disks with a diameter of 8 mm were placed in a polypropylene assist tube. Fetal bovine serum (FBS) adjusted to an IL-6 concentration of 2000 pg / mL was added to the assist tube in a volume of 1 cm. ３ Converted to 24 mL for the blood purification material (solid-liquid ratio: 0.04 cm３ / mL) was added to the FBS, and the mixture was mixed by inversion in an incubator at 37°C for 1 hour, after which the IL-6 concentration in the FBS was measured by enzyme-linked immunosorbent assay (ELISA). The IL-6 adsorption rate was calculated from the IL-6 concentrations before and after mixing by inversion using the following formula 3. The IL-6 adsorption rate was calculated by rounding off to one decimal place. IL-6 adsorption rate (%) = {IL-6 concentration before mixing by inversion (pg / mL) - IL-6 concentration after mixing by inversion (pg / mL)} / IL-6 concentration before mixing by inversion (pg / mL) × 100 ... formula 3

[0086] <Measurement of IL-8 adsorption rate of blood purification material> Four 6 mm diameter disks of blood purification material were cut into a polypropylene assist tube. FBS prepared to have an IL-8 concentration of 2000 pg / mL was added to the assist tube by 1 cm ３ Converted to 286 mL for the blood purification material (solid-liquid ratio: 0.004 cm ３ / mL) was added to the cells, and the cells were mixed by inversion in an incubator at 37°C for 1 hour, after which the IL-8 concentration in the FBS was measured by ELISA. The IL-8 adsorption rate was calculated from the IL-8 concentrations before and after mixing by inversion using the following formula 4. The IL-8 adsorption rate was calculated by rounding off to one decimal place. IL-8 adsorption rate (%) = {IL-8 concentration before mixing by inversion (pg / mL) - IL-8 concentration after mixing by inversion (pg / mL)} / IL-8 concentration before mixing by inversion (pg / mL) × 100 ... formula 4

[0087] The MwA, MwB, content of acidic functional groups, content of basic functional groups, IL-6 adsorption rate, and IL-8 adsorption rate of blood purification materials 1 to 9 were measured, and the results are shown in Table 1.

[0088]

[0089] The results in Table 1 clearly show that blood purification materials 1 to 4 and 7, which have an MwA / MwB ratio of less than 1.000, i.e., blood purification materials in which MwA is smaller than MwB, have high adsorption rates for multiple cytokines (IL-6 and IL-8) with different surface charges. In contrast, blood purification materials 5, 6, 8, and 9, which have an MwA larger than MwB, have low adsorption rates for multiple cytokines with different surface charges.

[0090] The blood purification material of the present invention can adsorb inflammatory cytokines with high efficiency, and can therefore be used as an adsorption material for extracorporeal circulation.

Claims

1. A blood purification material comprising a water-insoluble base material, a ligand containing an acidic functional group, and a ligand containing a basic functional group, wherein the ligand containing the acidic functional group and the ligand containing a basic functional group are bonded to the water-insoluble base material, and the molecular weight (MwA) of the ligand containing the acidic functional group divided by the molecular weight (MwB) of the ligand containing the basic functional group (MwA / MwB) is less than 1.

000.

2. The blood purification material according to claim 1, wherein the MwA / MwB is 0.001 to 0.

430.

3. The MwA is 0.5 x 10 ２ ~90.0 x 10 ３ and the MwB is 1.0×10 ２ ~66.0 x 10 ３ The blood purification material according to claim 1 or 2.

4. A blood purification material according to any one of claims 1 to 3, wherein the content of the acidic functional groups is 0.02 to 3.00 mmol per 1 g of dry weight, and the content of the basic functional groups is 0.50 to 2.00 mmol per 1 g of dry weight.

5. A blood purification material according to any one of claims 1 to 3, wherein the content of the acidic functional groups is 0.02 to 1.50 mmol per 1 g of dry weight, and the content of the basic functional groups is 0.70 to 1.50 mmol per 1 g of dry weight.

6. The blood purification material according to any one of claims 1 to 5, which is for adsorbing inflammatory cytokines.

7. A blood purification column comprising the blood purification material according to any one of claims 1 to 6.

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