Blood component adsorbent material

Abstract

As a blood component adsorbent material capable of adsorbing various types of blood components such as leukocytes without limiting the types of monocytes and granulocytes, provided is a blood component adsorbent material that comprises porous particles formed exclusively of a first polymer, said first polymer having an aromatic hydrocarbon group in a repeating unit, and a second polymer immobilized on the surface of the porous particles and having a hydroxyl group in a repeating unit, wherein the content of the second polymer on the surface of the blood component adsorbent material is 3-30 mg / g.

Description

[Technical Field]

[0001] This invention relates to a blood component adsorption material. [Background technology]

[0002] In recent years, blood processing technologies, particularly materials for removing leukocytes from blood, have been developed for the purpose of treating inflammatory diseases, suppressing immunosuppression before and after transplantation, and suppressing side effects such as fever and infection from blood products. Among these, a technology has been developed that adsorbs and removes leukocytes from blood by passing blood through a column equipped with a material containing ligands or resins that have affinity for leukocytes on its surface, or a material with a certain surface roughness that facilitates the adsorption of leukocytes.

[0003] In particular, particulate blood component adsorbents have a small specific surface area and are less prone to clogging during filtration, making them suitable for blood processing, and various types of particulate adsorbents have been developed.

[0004] For example, Patent Document 1 discloses a blood component adsorption carrier for adsorbing and removing both cytokines and leukocytes, wherein a sugar chain selected from the group consisting of sucrose, lactose, maltose, trehalose, and cellobiose is covalently bonded to a functional group on the surface of a water-insoluble carrier, and the sugar chain is covalently bonded to the amino group of the functional group at its reducing end.

[0005] Furthermore, Patent Document 2 discloses a carrier for adsorbing blood components, characterized by comprising at least an outer layer made of a molded cellulose acetate and an inner layer made of polycarbonate formed inside the outer layer.

[0006] Patent Document 3 discloses a polymer system comprising at least one polymer, wherein the polymer comprises one or more aromatic monomer residues and one or more crosslinking agents, the polymer has an outer surface and a plurality of pores, and the polymer is functionalized by different functional groups on the outer surface and the surface inside the pores.

[0007] Patent Document 4 discloses coated particles comprising hydrophobic porous polymer particles and a coating layer made of a crosslinked hydroxyl group-containing polymer that covers at least a portion of the surface of the hydrophobic porous polymer particles.

[0008] Patent Document 5 discloses a biocompatible polymer system comprising at least one polymer, wherein the polymer comprises either a polyol or a zwitterionic functional group, the polymer comprises a solid support having a biocompatible hydrogel coating containing hydroxyl groups as repeating units, and the polymer system is also capable of adsorbing one or more of Gram-positive bacteria, Gram-positive bacterial fragments, and Gram-positive bacterial components.

[0009] Furthermore, Non-Patent Document 1 reports that alveolar macrophages, a type of white blood cell, specifically recognize and adhere to certain sugar chains. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] Patent No. 5644149 [Patent Document 2] Patent No. 3513155 [Patent Document 3] Patent No. 5913368 [Patent Document 4] Japanese Patent Publication No. 2021-7915 [Patent Document 5] Patent No. 7033083 [Non-patent literature]

[0011] [Non-Patent Document 1] Largent et al., J. Biol. Chem., 1984, Vol. 259, pp. 1764-1769. [Overview of the Initiative] [Problems that the invention aims to solve]

[0012] However, since conventional blood component adsorbing materials such as particulate white blood cells are specifically removed based on hydrogen bonds resulting from sugar-derived molecular structures, as disclosed in Non-Patent Document 1, there has been a problem that only some blood cells such as alveolar macrophages that specifically interact with sugar chains among white blood cells can be adsorbed.

[0013] White blood cells are classified into monocytes, granulocytes, and lymphocytes. In blood component adsorption, monocytes and granulocytes are involved as components that cause inflammation. Therefore, it is considered preferable to adsorb them without distinction, particularly between monocytes and granulocytes.

[0014] Patent Document 1 and Patent Document 2 disclose materials that adsorb blood components based on bonds formed by sugar-derived molecular structures. Although it is disclosed in the material of Patent Document 1 that neutrophils, which are a type of granulocyte, and monocytes can be adsorbed, there is no description or suggestion as to whether all monocytes and granulocytes can be adsorbed. Furthermore, although sugar chains for specific binding of white blood cells are introduced in Patent Document 1, there is no description or suggestion regarding adsorption removal based on van der Waals forces due to the physical structure of the material surface. Also, in Patent Document 2, the specific blood components that can be adsorbed are not shown.

[0015] Patent Document 3 describes materials that enable the adsorption and removal of proteins, toxins, and pathogens, but no specific effects are disclosed, and there is no disclosure or suggestion regarding the adsorption and removal of cellular components such as white blood cells.

[0016] Patent Document 4 is a separation material for chromatography and is assumed to be used for the purpose of reversible adsorption of proteins, and cannot be directly applied to the irreversible adsorption and removal of blood components for the purpose of treating patients. Also, there is no description regarding the adsorption and removal of cellular components such as white blood cells.

[0017] Patent Document 5 discloses a biocompatible polymer system in which a polyol functional group, such as a diol group, or a zwitterionic functional group is attached to a solid support in order to remove one type of bacterial component, and a hydrogel coating is further applied to prevent the adsorption of blood components to the surface of the solid support. However, there is no description or suggestion regarding the adsorption and removal of blood components based on van der Waals forces due to the physical structure. Furthermore, there is no description whatsoever regarding the adsorption and removal of cellular components such as leukocytes.

[0018] As described above, no material has been developed that can broadly adsorb blood components such as white blood cells, without being limited to specific types of monocytes and granulocytes, by utilizing van der Waals forces due to the physical structure of the material surface.

[0019] Therefore, the present invention aims to provide a blood component adsorbent that can adsorb various blood components such as leukocytes without limiting the types of monocytes and granulocytes, by controlling the van der Waals forces on the surface of the blood component adsorbent material by fixing a polymer having hydroxyl groups at a specific content on the surface of porous particles consisting only of polymers having aromatic hydrocarbon groups. [Means for solving the problem]

[0020] As a result of diligent research to solve the above problems, the inventors have discovered the following inventions (1) to (6). (1) A blood component adsorbent comprising porous particles consisting only of a first polymer having aromatic hydrocarbon groups in its repeating units, and a second polymer having hydroxyl groups in its repeating units, which is immobilized on the surface of the porous particles, wherein the content of the second polymer on the surface of the blood component adsorbent is 3 to 30 mg / g. (2) The content of the second polymer in the overall average of the blood component adsorbent material is 0.3 mg / g or less, and the pore volume per gram is 0.5 to 1.8 cm³. 3 (1) The blood component adsorbent material described above. (3) The blood component adsorbent material according to (1) or (2), wherein the first polymer is polystyrene, polyethylvinylbenzene, polydivinylbenzene, poly(ethylvinylbenzene / divinylbenzene) or poly(styrene / divinylbenzene). (4) The blood component adsorbent material according to any one of (1) to (3), wherein the second polymer is a polymer selected from the group consisting of polyhydroxyalkyl acrylate, polyhydroxyalkyl methacrylate, and polyvinyl alcohol. (5) A blood component adsorbent material according to any of (1) to (4) for the adsorption and removal of leukocytes. (6) A blood purification column comprising a blood component adsorbent material according to any of (1) to (5). [Effects of the Invention]

[0021] The blood component adsorption material of the present invention can adsorb various blood components, such as leukocytes, with high efficiency, without limiting the types of monocytes and granulocytes, based on adsorption based on van der Waals forces due to the physical structure of its surface. [Modes for carrying out the invention]

[0022] The present invention will be described in detail below.

[0023] The blood component adsorbent material of the present invention comprises porous particles consisting only of a first polymer having aromatic hydrocarbon groups in its repeating units, and a second polymer having hydroxyl groups in its repeating units, which is immobilized on the surface of the porous particles, characterized in that the content of the second polymer on the surface of the blood component adsorbent material is 3 to 30 mg / g.

[0024] "A first polymer having aromatic hydrocarbon groups in its repeating units" means a polymer having hydrocarbon groups containing aromatic structures in its repeating units. There are no particular limitations as long as the repeating units contain aromatic hydrocarbon groups, and multiple repeating units may be included. The aromatic hydrocarbon group is preferably a functional group in which a hydrocarbon structure is substituted on one of a benzene ring, a naphthalene ring, or an acetylene ring, and more preferably contains a benzene ring.

[0025] The first polymer having aromatic hydrocarbon groups in its repeating units may be a homopolymer consisting of a single repeating unit or a copolymer containing multiple types of repeating units. However, in either case, it is preferable that divinylbenzene is included to prevent particle dissolution and ensure strength.

[0026] When the first polymer having aromatic hydrocarbon groups in its repeating units is a homopolymer, polystyrene, polyethylvinylbenzene, polymethylvinylbenzene, and polydivinylbenzene are preferred for ease of handling and availability, and polydivinylbenzene is particularly preferred from the viewpoint of ensuring particle strength. The substitution positions of substituents on each aromatic ring are not relevant.

[0027] The composition of the first polymer having aromatic hydrocarbon groups in its repeating units is not limited to the repeating units consisting of aromatic hydrocarbon groups, and may be a copolymer containing multiple types of repeating units. For example, from the viewpoint of ensuring strength, poly(ethyl vinylbenzene / divinylbenzene), poly(methyl vinylbenzene / divinylbenzene), or poly(styrene / divinylbenzene) containing divinylbenzene are preferred, and poly(ethyl vinylbenzene / divinylbenzene) is more preferred.

[0028] There are no particular limitations on the number of repeating units or molecular weight of the chemical structure of the first polymer having aromatic hydrocarbon groups in its repeating units. However, from the viewpoint of polymer properties and strength stability, it is preferable that the polymer consists of 100 or more repeating units linked by covalent bonds.

[0029] The fact that the first polymer, which has aromatic hydrocarbon groups, is a polymer in which 100 or more repeating units are covalently bonded together can be confirmed by the fact that it does not dissolve when impregnated in isopropyl alcohol.

[0030] The first polymer, having aromatic hydrocarbon groups in its repeating units, may have crosslinked structures or terminal structures derived from initiators for polymerization initiation and termination to maintain strength.

[0031] The presence of a cross-linked structure in the first polymer, which has aromatic hydrocarbon groups, can be confirmed by impregnating the first polymer in acetone and performing reflux operations in a Soxhlet extractor, which shows that it does not dissolve.

[0032] The term "second polymer having hydroxyl groups in the repeating units" refers to a polymer that contains hydroxyl groups as part of its chemical structure within the repeating units. There are no limitations on the molecular structure or molecular weight of the repeating units, but it is preferable that the molecular weight of the repeating units is 200 g / mol or less per hydroxyl group.

[0033] As the second polymer having hydroxyl groups in the repeating units, synthetic polymers such as polyvinyl alcohol, polyhydroxyalkyl acrylate and polyhydroxyacrylate, and polysaccharides such as dextran, dextran sulfate, alginic acid, hyaluronic acid, pectin, xyloglucan, xylan and heparin are preferred, and synthetic polymers are more preferred from the viewpoint of sterilization and stability, with polyvinyl alcohol, polyhydroxyalkyl acrylate and polyhydroxyacrylate being even more preferred.

[0034] From the viewpoint of ease of fixation to porous particles, the second polymer having hydroxyl groups in the repeating units may be a copolymer containing repeating units composed solely of hydrocarbons. Preferred repeating units composed solely of hydrocarbons include, for example, repeating units of polyethylene, polypropylene, polystyrene, polyethylvinylbenzene, polymethylvinylbenzene, and polydivinylbenzene. Preferred second polymers include, for example, poly(vinyl alcohol / ethylene), poly(vinyl alcohol / styrene), poly(vinyl alcohol / methylvinylbenzene), poly(vinyl alcohol / divinylbenzene), poly(hydroxyalkyl acrylate / ethylene), poly(hydroxyalkyl acrylate / styrene), poly(hydroxyalkyl acrylate / methylvinylbenzene), poly(hydroxyalkyl acrylate / divinylbenzene), poly(hydroxyacrylate / ethylene), poly(hydroxyacrylate / styrene), and poly(hydroxyacrylate / methylvinylbenzene), and poly(hydroxyacrylate / divinylbenzene).

[0035] There are no specific requirements for the proportion of repeating units containing hydroxyl groups in the repeating units of the second polymer. However, if the proportion is too low, the hydrophobicity increases, leading to an increase in platelet adhesion and subsequent clogging of the column. Therefore, it is preferable that the proportion be between 10% and 100%, more preferably between 40% and 100%, and particularly preferable between 95% and 100%.

[0036] There are no particular limitations on the number of repeats (hereinafter referred to as the degree of polymerization) or molecular weight of the second polymer having hydroxyl groups in its repeating units. However, from the viewpoint of surface interactions and modifiers, it is preferable that the polymer has a degree of polymerization of 10 to 10,000, with 10 to 10,000 repeating units linked by covalent bonds, and a polymer with a degree of polymerization of 30 to 10,000 is more preferable.

[0037] The degree of polymerization of the second polymer is determined by using the degree of polymerization specified for commercially available products, or, if the degree of polymerization is not specified, by dividing the weight-average molecular weight by the molecular weight of the repeating unit and rounding to the nearest tenth. For example, if the weight-average molecular weight is 10,000 and the molecular weight of the repeating unit is 250, the degree of polymerization is 40. If the second polymer is a copolymer consisting of two or more monomers, the molecular weight of the repeating unit is determined by multiplying the relative abundance of each repeating unit by the molecular weight of each repeating unit, adding up all the resulting values, and dividing by the total number of components to obtain a weighted average, which is considered to be the molecular weight of the repeating unit.

[0038] The second polymer, which has hydroxyl groups in its repeating units, may have crosslinked structures or terminal structures derived from initiators for polymerization initiation and termination to maintain strength.

[0039] "Porous particles" refers to particles having multiple pores, and in this invention, porous particles consist solely of the first polymer.

[0040] While there are no limitations on the pore volume of the blood component adsorbent material, to improve the strength of the blood component adsorbent material and stabilize the adsorption process, the pore volume per gram of blood component adsorbent material should be 0.5 cm³. 3 1.8cm or more 3 The following is preferable:

[0041] In blood component adsorption materials, the surface is defined by the infrared absorption spectrum (wavenumber 4500 cm) measured by total internal reflection (ATR) measurement. -1 ~500cm -1 This refers to the physical properties of the blood component adsorbent material up to a certain depth, as measured by ). The infrared absorption spectrum of the surface of the above blood component adsorbent material can be measured by the following method: Select the Advanced ATR mode of the Nicolet iS5 FT-IR (manufactured by Thermo Scientific; iD5 diamond ATR accessory included, detector: DTGS KBr, beam splitter: KBr) and set the parameters (number of scans: 16, data interval: 0.241 cm) -1, Automatic atmospheric correction: None). After setting, perform background measurement. After the background measurement is completed, spread 1 g of the blood component adsorbent material that has been dried in a hot air dryer at 60°C for 4 hours on the prism, press it against the prism until the pressure device locks, start the measurement within 20 minutes from the background measurement, and obtain the infrared absorption spectrum of the surface of the blood component adsorbent material. The measurement range is from a wavenumber of 4500 cm -1 to 500 cm -1 .

[0042] The overall average in the blood component adsorbent material means the physical properties of the blood component adsorbent material measured by the total reflection measurement (ATR) method in the infrared absorption spectrum (wavenumber 4500 cm -1 to 500 cm -1 ) after homogenizing the structure of the blood component adsorbent material. The overall average infrared absorption spectrum of the above blood component adsorbent material can be analyzed by the following method. Put 1 g of the blood component adsorbent material that has been dried in a hot air dryer at 60°C for 4 hours into a mortar (As One-made mortar, deep type, φ70×φ90×30 mm), apply at least the force that can break the blood component adsorbent material with a pestle and grind it 100 times, visually confirm that all the blood component adsorbent materials have been ground at least once and the structure of the blood component adsorbent material is homogenized, and obtain the overall average powder of the blood component adsorbent material. Perform the measurement in the same method as the measurement of the infrared absorption spectrum of the surface of the blood component adsorbent material except that the obtained powder is used instead of the blood component adsorbent material, and the overall average infrared absorption spectrum of the blood component adsorbent material can be obtained.

[0043] That the second polymer is immobilized on the surface of the porous particles means that the second polymer is physically or chemically fixed on the surface of the porous particles composed of the first polymer. There is no limitation on the mode of physical fixation, but fixation by aggregation on the surface of the porous particles or fixation by entanglement of the polymers is preferred. Also, there is no limitation on the mode of chemical fixation, but fixation by formation of a covalent bond or an ionic bond is preferred.

[0044] The second polymer can be immobilized on the surface of the porous particles by either physical or chemical means, but chemical immobilization is more preferable from the viewpoint of preventing leaching and ensuring stability during long-term storage.

[0045] There are no particular limitations on the method for chemically immobilizing the second polymer, but from the viewpoint of stability, immobilization by covalent bonding is preferred, and it is preferable that it is immobilized via a linker.

[0046] A "linker" is a chemical structure used to immobilize a first polymer and a second polymer by covalent bonds, and refers to a chemical structure formed by covalent bonds between the repeating units of the first polymer and the repeating units of the second polymer. For example, when a substituent is introduced to the aromatic ring of the first polymer and reacted with the hydroxyl group of the second polymer to form a bond, it refers to the structure from the carbon of the aromatic ring to the oxygen atom of the hydroxyl group after the reaction. There are no limitations on the chemical structures that can be included as a linker, but from the viewpoint of imparting it to an electrically neutral first polymer, electrically neutral chemical bonds such as amide bonds, alkylene groups, urea bonds, ether bonds, or ester bonds are preferred. Among these, from the viewpoint of suppressing clogging due to platelet adsorption, it is more preferable that the linker includes amide bonds, urea bonds, ether bonds, or ester bonds as bonds that are electrically neutral and can impart hydrophilicity, and from the viewpoint of bond stability, it is even more preferable that it includes amide bonds or ester bonds, with amide bonds being particularly preferred.

[0047] The amide bond in the linker may be a primary, secondary, or tertiary amide bond, but a secondary amide is preferred. Furthermore, there are no particular limitations on the position of the amide bond in the linker, but from the viewpoint of appropriately suppressing and imparting the hydrophobicity of the aromatic hydrocarbon group that platelets readily adsorb, it is preferable that it be covalently bonded to the aromatic ring of the first polymer via an alkylene group. The alkylene group is preferably methylene, ethylene, or propylene, with methylene being more preferred.

[0048] Furthermore, the linker may contain ionic functional groups to facilitate better control of the bonding of the second polymer. For example, amino groups or carboxylic acid groups are preferred, with amino groups being more preferred from the viewpoint of blood compatibility.

[0049] To achieve both fixation to the first polymer and fixation to the second polymer, the chemical structure in the linker may contain both electrically neutral chemical bonds and ionic functional groups. In this case, it is preferable that the chemical structure contains electrically neutral chemical bonds on the first polymer side and ionic functional groups on the surface side. For example, it is preferable that an amide bond is covalently bonded to the aromatic ring of the first polymer via an alkylene group, and that an amino group is further bonded to its tip.

[0050] There are no limitations on the method of immobilization by covalent bonding between the first polymer and the linker, but for example, a state in which the aromatic ring contained in the repeating unit of the first polymer and the linker are bonded by a carbon-carbon bond is preferred.

[0051] There is no limit to the number of carbon atoms in the linker, but in order to appropriately maintain the distance between the first polymer and the second polymer, and to make it easier to immobilize the second polymer by keeping the linker's mobility within a desirable range, the number of carbon atoms is preferably 2 to 30, more preferably 4 to 20, and even more preferably 6 to 15.

[0052] There are no particular limitations on the method for physically immobilizing the second polymer, but it is preferable to use a copolymer containing hydrophobic repeating units as the second polymer and agglomerate it with the first polymer through hydrophobic interactions of its structure, or to mix the second polymer during the formation of the first polymer and immobilize it by entanglement. From the viewpoint of expressing the performance of the blood component adsorbent material, the method of agglomerating it with the first polymer through hydrophobic interactions is preferred.

[0053] If the content of the second polymer on the surface of the blood component adsorbent is too low, interaction between the blood component adsorbent and blood cells will not occur, and the blood component adsorption performance will not be exhibited. If it is too high, the hydrophilicity will become too high, and the blood component adsorption performance will decrease. For this reason, the content of the second polymer on the surface of the blood component adsorbent is 3 mg / g to 30 mg / g, and more preferably 3 mg / g to 20 mg / g.

[0054] There are no restrictions on the content of the second polymer in the overall average of the blood component adsorbent material, but to improve the adsorption performance of humoral factors of blood components, it is preferable that the content of the second polymer in the overall average of the blood component adsorbent material be 0.3 mg / g or less.

[0055] There are no limitations on the particle size of the blood component adsorbent material, but in order to facilitate blood flow during adsorption of blood components, it is preferable that the particle size be between 10 μm and 10 mm, more preferably between 50 μm and 3 mm, and even more preferably between 100 μm and 1 mm.

[0056] The pore volume per gram of blood component adsorbent material refers to the volume of minute pores with a diameter of 200 nm or less, which can be determined by measuring the degree of freezing point depression due to capillary condensation of water within the pores using differential scanning calorimetry (DSC).

[0057] The pore volume per gram is calculated by first obtaining a thermal difference (DSC) curve in the hydrated state of the material using the DSC measurement method described below. Then, the melting point and amount of water are calculated from the obtained DSC curve, and the pore volume is further calculated. 1 g of the material is impregnated in 10 mL of pure water, and the container containing the solution is degassed for 10 minutes using an aspirator while being placed in an ultrasonic cleaner. Approximately 6 mg of the obtained hydrated material is taken out immediately before DSC measurement, and surface water is removed until no excessive water droplets are visible. Next, an aluminum sealed sample container is set in a DSC Q100 (manufactured by TA Instruments) that has been pre-calibrated for temperature and calorific value (melting point 0.0 °C, heat of fusion 79.7 cal / g) with pure water, and the blank weight is measured. Subsequently, approximately 6 mg of the material is sampled and sealed in an aluminum sealed sample container to be used as the measurement sample. The measurement sample is placed in the DSC Q100 and its weight is measured. The sample weight is obtained by subtracting the blank weight from the obtained weight. The sample is rapidly cooled to -55°C, then heated to 5°C at a rate of 0.3°C / min, and the differential scanning heat quantity is measured. The peak top temperature is taken as the melting point, and a DSC curve is obtained. Subsequently, the sample is removed and vacuum-dried at 110°C for 2 hours, and then placed back into the DSC Q100 to measure its weight. The amount of weight loss before and after vacuum drying is taken as the total moisture content. From the obtained DSC curve, total moisture content, and sample weight, the pore volume per gram of material is calculated according to the method of Ishikiriyama et al. (JOURNAL OF COLLOID AND INTERFACE SCIENCE, 1995, Vol. 171, pp. 103-111).

[0058] The porous particles consist only of the first polymer, and the porous particles are ground in a mortar and pestle so that they can be inserted into an NMR tube and solidified. 13 This can be confirmed by measuring the 1C NMR spectrum and observing a peak in the region originating from the aromatic ring (δ: 110-170 ppm).

[0059] The presence of a second polymer on the surface of the blood component adsorbent material indicates that the absorption wavelength of OH stretching (3340 cm) in the infrared absorption spectrum of the surface of the blood component adsorbent material is -1 This can be confirmed by the existence of ).

[0060] The content of the second polymer in the overall average of the blood component adsorbent material can be calculated by first measuring the dry weight of the blood component adsorbent material, then impregnating it overnight in tetrahydrofuran, hydrochloric acid, and sodium hydroxide aqueous solutions at 90°C or higher, repeatedly washing it with deionized water until it becomes neutral, drying it again, measuring the weight of the blood component adsorbent material after elution, and rounding the value obtained from Formula 1 below to two decimal places. The overall average content of the second polymer in the blood component adsorbent material (mg / g) = {dry weight (1000mg) - weight after elution (mg)} / 1g ... Equation 1

[0061] The peaks originating from CH stretching in the overall average infrared absorption spectrum of the blood component adsorbent material and the infrared absorption spectrum of the surface of the blood component adsorbent material are shown (2920 cm²). -1 The absorption intensity of the OH group, and the peaks (3340 cm²) of the overall average infrared absorption spectrum of the blood component adsorbent material and the infrared absorption spectrum of the surface of the blood component adsorbent material, respectively. -1 Based on the absorption intensity of ), the content of the second polymer on the surface of the blood component adsorbent material is calculated by rounding the obtained value to the first decimal place using Equation 2 below. Note that the value of "content of the second polymer in the overall average of 1 of the blood component adsorbent material" used in Equation 2 was calculated using the value obtained using Equation 1, before rounding to the second decimal place. The content of the second polymer on the surface of the blood component adsorbent material (mg / g) = the overall average content of the second polymer in the blood component adsorbent material (mg / g) × {peak absorption intensity derived from OH groups on the surface of the blood component adsorbent material / peak absorption intensity derived from CH stretching on the surface of the blood component adsorbent material} / {overall average peak absorption intensity derived from OH groups in the blood component adsorbent material / overall average peak absorption intensity derived from CH stretching in the blood component adsorbent material} ...Equation 2

[0062] The particle size of blood component adsorbent material refers to the average value of the diameter measured at 10 locations (100 locations in total) in each of 10 randomly selected particle samples, each photographed at 1000x to 3000x magnification using a scanning electron microscope.

[0063] "Blood component adsorbent material" refers to a material that has the ability to adsorb blood components.

[0064] "Blood components" refer to the components that make up blood, and are classified into humoral factors in the blood and cells in the blood. There are no particular restrictions on the blood components that the blood component adsorbent material of this embodiment can adsorb, but cells in the blood are preferred among blood components, and it is more preferable that the adsorbent can simultaneously adsorb cells in the blood and humoral factors in the blood.

[0065] "Cells in the blood" refers to cells contained in the blood, and examples include white blood cell components such as granulocytes, monocytes, and lymphocytes, as well as red blood cells and platelets. When the purpose is to treat inflammatory diseases, white blood cell components are preferred as the adsorption target, and among white blood cell components, the removal of monocytes and granulocytes is preferred, with activated granulocytes, activated monocytes, or activated granulocyte-activated platelet complexes and activated monocyte-activated platelet complexes being more preferred.

[0066] "Activated granulocytes" and "activated monocytes" refer to granulocytes and monocytes that release cytokines or reactive oxygen species in response to cytokines or LPS, etc. The degree of activation can be determined by measuring the amount of reactive oxygen species released by activated leukocytes or by measuring the expression of surface antigens using flow cytometry, etc.

[0067] "Activated platelets" refer to platelets that release cytokines or reactive oxygen species in response to cytokines or LPS, etc.

[0068] "Activated granulocyte-activated platelet complexes" and "activated monocyte-activated platelet complexes" refer to complexes formed when activated granulocytes or activated monocytes bind to activated platelets, exhibiting phagocytic activity towards the body's own tissues. In particular, in the treatment of patients with inflammatory diseases, it is considered necessary to remove activated granulocyte-activated platelet complexes that are thought to be directly involved in the pathogenesis.

[0069] The above granulocytes can be further classified into neutrophils, basophils, and eosinophils, but it is preferable that there is no selectivity for these and that components derived from monocytes and granulocytes are removed collectively.

[0070] "Humoral factors in the blood" refers to organic substances dissolved in the blood. Specifically, these include proteins such as urea, β2-microglobulin, cytokines, IgE, and IgG, and polysaccharides such as lipopolysaccharide (LPS). Among these, urea, proteins such as cytokines, and polysaccharides such as LPS are preferred as adsorption targets, and cytokines are even more preferred as adsorption targets when the purpose is to treat inflammatory diseases.

[0071] "Cytokines" refer to a group of proteins produced by various cells, including immune cells, in response to stimuli such as infection or trauma, and released extracellularly to exert their effects. Examples 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, or monocyte chemotactic factors. In particular, interleukin-8 (IL-8) is preferred as an adsorption target in the treatment of inflammatory diseases.

[0072] "Inflammatory diseases" refer to all diseases in which an inflammatory response is triggered in the body, such as 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., sepsis caused by gram-negative bacteria, sepsis caused by gram-positive bacteria, culture-negative sepsis, and fungal sepsis), influenza, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), pancreatitis, and idiopathic pulmonary pneumonia. Examples include fibrosis (IPF), inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), transfusion of blood products, organ transplantation, reperfusion injury after organ transplantation, cholecystitis, cholangitis, or neonatal blood type incompatibility.

[0073] Among inflammatory diseases, drug-induced hepatitis, alcoholic hepatitis, hepatitis A, B, C, D, or E, sepsis (e.g., sepsis from Gram-negative bacteria, sepsis from Gram-positive bacteria, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, pancreatitis, or idiopathic interstitial pneumonia are particularly favored as treatment targets because causative substances are released into the bloodstream and therapeutic effects through blood purification can be expected. The adsorption column of this embodiment is preferably used for the treatment of the above-mentioned inflammatory diseases, and more preferably for the treatment of sepsis (e.g., sepsis from Gram-negative bacteria, sepsis from Gram-positive bacteria, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, or idiopathic interstitial pneumonia, as these are diseases that are difficult to treat with drugs alone and are thought to involve both cytokines and activated leukocytes-activated platelets.

[0074] "Adsorption" refers to a state in which a specific substance adheres to a material and does not easily detach. There are no particular restrictions on the principle of adsorption, but it can refer to states where substances adhere due to van der Waals forces such as ionic interactions like electrostatic interactions, hydrophobic interactions, and hydrogen bonds, or to states where substances adhere biologically, such as cell adhesion or phagocytosis by leukocytes. The blood component adsorption material in this embodiment is preferably capable of adsorption by van der Waals forces.

[0075] The blood component adsorption material of this embodiment can be manufactured, for example, by the following method, but is not limited to this method.

[0076] The production of porous particles consisting solely of the first polymer can be achieved by adding a monomer having an aromatic hydrocarbon group, a crosslinking agent, a dispersant, and an initiator during suspension polymerization. For example, the monomer can be a vinyl monomer having an aromatic ring, such as styrene, ethyl vinylbenzene, or divinylbenzene, and it is preferable that it contains at least divinylbenzene. The crosslinking agent can be divinylbenzene, the dispersant can be polyvinyl alcohol, and the initiator can be benzoyl peroxide.

[0077] Commercially available vinyl monomers can be used as is. Since commercially available divinylbenzene monomers are generally mixtures with ethyl vinylbenzene, the first polymer obtained by polymerization of divinylbenzene is a copolymer, poly(ethyl vinylbenzene / divinylbenzene).

[0078] The particle size of porous particles can be reduced by increasing the concentration of the dispersant.

[0079] The pore volume of porous particles can be increased by lowering the monomer concentration, increasing the initiator concentration, or lowering the crosslinking agent concentration (e.g., divinylbenzene concentration).

[0080] Methods for immobilizing the second polymer onto porous particles include, for example, dissolving the second polymer in an organic solvent and adding or coating the porous particles into the solution, or immobilizing an amine compound on the surface of the porous particles and reacting it with the terminal structure of the second polymer as a linker.

[0081] When the second polymer is dissolved in an organic solvent and porous particles are added or coated into the solution, the organic solvent is preferably N,N-dimethylformamide, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, toluene, xylene, hexane, or ethyl acetate, with N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, or ethyl acetate being particularly preferred.

[0082] The concentration of the second polymer in the organic solvent is preferably 1 to 10%, and more preferably 5%.

[0083] The second polymer can be a commercially available product.

[0084] When immobilizing an amine compound on the surface of porous particles and reacting it with the terminal structure of a second polymer as a linker, this can be achieved, for example, by immobilizing a hydroxyl group, carboxylic acid or epoxy group, urea group, or carboxylic anhydride group as the terminal structure of the second polymer and carrying out a condensation reaction with the amine or carboxylic acid of the amine compound.

[0085] The immobilization of amine compounds onto porous particles can be achieved by further immobilizing linker functional groups onto the aromatic rings contained in the first polymer. While there are no limitations on the linker functional groups, examples include alkyl halides, carboxylic acid groups, and epoxy groups.

[0086] The amine compounds to be immobilized are preferably ethylenediamine, diethylenetriamine, triethylenetetramine, polyethyleneimine, or glycine, with ethylenediamine or glycine being preferred. Commercially available compounds can be used.

[0087] As reaction solvents, for example, N,N-dimethylformamide, diethyl ether, dioxane, tetrahydrofuran, or dimethyl sulfoxide are preferred, with dimethyl sulfoxide being more preferred.

[0088] Examples of bases include organic bases such as triethylamine or 1,4-diazabicyclo[2.2.2]octane, or inorganic bases such as sodium hydroxide, but organic bases such as triethylamine are preferred.

[0089] The concentration of the amine compound in the reaction solution is preferably 50 mM to 1000 mM, and more preferably 50 mM to 100 mM.

[0090] The immobilization of alkyl halogens can be achieved, for example, by introducing hydroxyalkyl halogen compounds into porous particles in the presence of a catalyst.

[0091] The halogenated hydroxyalkyl compound is preferably, for example, N-hydroxymethyl-2-chloroacetamide, and commercially available products can be used.

[0092] Examples of reaction solvents include nitrobenzene, nitropropane, chlorobenzene, toluene, or xylene, but nitrobenzene or nitropropane are preferred.

[0093] Examples of catalysts include sulfuric acid, hydrochloric acid, nitric acid, or Lewis acids such as aluminum(III) halide (e.g., aluminum(III) chloride) or iron(III) halide (e.g., iron(III) chloride), with sulfuric acid being preferred.

[0094] The concentration of the catalyst in the reaction solution is preferably 5 wt% to 80 wt%, and more preferably 30 wt% to 70 wt%.

[0095] The reaction temperature is preferably 0°C to 90°C, and more preferably 5°C to 40°C.

[0096] The reaction time is preferably 1 minute to 120 hours, and more preferably 5 minutes to 24 hours.

[0097] The amount of the second polymer immobilized on the surface of the blood component adsorbent material and the overall average amount of the second polymer immobilized on the blood component adsorbent material can be controlled by increasing the concentration of the second polymer in the organic solvent, increasing the coating temperature, or decreasing the molecular weight of the second polymer when coating the material with the second polymer.

[0098] The amount of the second polymer immobilized on the surface of the blood component adsorbent and the average amount of the second polymer immobilized on the blood component adsorbent can be controlled by increasing the concentration of the second polymer during immobilization, increasing the temperature, or allowing the reaction to proceed for a longer period of time, when the second polymer is immobilized by a chemical reaction.

[0099] The above-mentioned blood component adsorption material is preferably used as a material to fill a container that forms the outer shape of the adsorption column.

[0100] The shape of the container that forms the outer shape of the adsorption column can be any container that can be filled with blood component adsorption material and has an inlet and outlet for blood. Examples include cylindrical containers or prismatic containers such as triangular, square, hexagonal, or octagonal prismatic containers.

[0101] Furthermore, the adsorption column equipped with the above-mentioned blood component adsorption material can be suitably used for extracorporeal circulation in the treatment of bacterial infections. When used for the treatment of bacterial infections, a preferred extracorporeal circulation method is to connect the adsorption column equipped with the above-mentioned blood component adsorption material to the patient with a blood circuit, pass the body fluid taken from the patient through the adsorption column, and return it to the patient. Regarding the processing time of body fluids, continuous processing is preferred from the viewpoint of suppressing further inflammation induction by blood components, more preferably 4 hours or more, and even more preferably 24 hours or more.

[0102] The adsorption column equipped with the above-mentioned adsorption material may be used in combination with other body fluid treatment methods or medical devices. Examples of other body fluid treatment methods or medical devices include plasma exchange, peritoneal dialysis, plasma separators, hemofilters, cardiopulmonary bypass, or ECMO.

[0103] One method for evaluating the adsorption performance of blood component adsorbents is to evaluate the adsorption rate of leukocytes. For example, one method for calculating the leukocyte adsorption rate is to fill a container with an inlet and outlet with the blood component adsorbent, pass a liquid containing leukocytes through it, and calculate the leukocyte adsorption rate from the changes in their concentrations at the inlet and outlet. Leukocyte concentration can be measured using a commercially available multi-parameter hematology analyzer, specifically using the following method.

[0104] A cylindrical column (1 cm inner diameter x 5.14 cm height) with blood inlets and outlets at the top and bottom is prepared by filling it with 3.1 mL of blood component adsorbent material. Human blood, kept warm at 37°C (ambient temperature), is passed through this column at a flow rate of 1.9 mL / min for 5 minutes. After 5 minutes, the blood at the column inlet and the blood components at the column outlet are analyzed to calculate the leukocyte adsorption rate of the blood component adsorbent material. The number of each blood component is measured using a multi-parameter automated hematology analyzer XT-1800i (manufactured by Sysmex Corporation). The leukocyte adsorption rate can be calculated using the following formula 3. The leukocyte adsorption rate (%) of the blood component adsorbent material = {(Total number of granulocytes and monocytes in the blood at the column inlet) - (Total number of granulocytes and monocytes in the blood at the column outlet)} / (Total number of granulocytes and monocytes in the blood at the column inlet) × 100 ... Equation 3

[0105] Since white blood cells are cells and their adsorption rates vary, a 20% or higher adsorption rate can be considered to indicate significant removal.

[0106] For the reasons stated above, leukocyte adsorption performance can be considered sufficiently expressed if the adsorption rate is 20% or higher, and an adsorption rate of 50% or higher is even more preferable.

[0107] Furthermore, since the blood component adsorption material of the present invention adsorbs leukocytes by van der Waals forces, it is considered that the difference in removal rates derived from leukocyte components is small. Therefore, if the leukocyte adsorption rate exceeds 20%, it is considered that 20% or more of each individual leukocyte component—monocytes, neutrophils, and granulocytes—have been removed, and even considering measurement variability, the removal is considered significant.

[0108] The adsorption performance of blood component adsorbents can be evaluated by following the steps 1) to 4) below, specifically for monocytes, neutrophils, basophils, and eosinophils. 1) Prepare a column by filling a cylindrical column (1 cm inner diameter x 5.14 cm height) with blood inlets and outlets at the top and bottom with 3.1 mL of blood component adsorbent material 4. 2) Pass human blood, kept warm at 37°C (ambient temperature), through the column at a flow rate of 1.9 mL / min for 5 minutes. 3) After 5 minutes, sample the blood from the column inlet and outlet, and obtain the values ​​for monocytes, neutrophils, basophils, and eosinophils using a multi-parameter automated hematology analyzer XT-1800i (manufactured by Sysmex Corporation). 4) Using formulas 4 to 7 below, the monocyte removal rate, neutrophil removal rate, basophil removal rate, and eosinophil removal rate of the blood component adsorbent are calculated by rounding the obtained values ​​to the first decimal place. Monocyte adsorption rate (%) of blood component adsorbent material = {(Number of monocytes in the blood at the column inlet) - (Number of monocytes in the blood at the column outlet)} / (Number of monocytes at the column inlet) × 100 ... Equation 4 Neutrophil adsorption rate (%) of blood component adsorbent material = {(Number of neutrophils in the blood at the column inlet) - (Number of neutrophils in the blood at the column outlet)} / (Number of neutrophils at the column inlet) × 100 ... Equation 5 Basophil adsorption rate (%) of blood component adsorbent material = {(Number of basophils in blood at column inlet) - (Number of basophils at column outlet)} / (Number of basophils in blood at column inlet) × 100 ... Equation 6 Eosinophil adsorption rate (%) of blood component adsorbent material = {(Number of eosinophils in the blood at the column inlet) - (Number of eosinophils at the column outlet)} / (Number of eosinophils in the blood at the column inlet) × 100 ... Equation 7

[0109] Another method involves impregnating fetal bovine serum (FBS) containing dissolved cytokines with a blood component adsorbent, evaluating the decrease in cytokine concentration in the FBS after impregnation, and calculating the cytokine adsorption rate. Since cytokines are substances that are desirable to remove from the blood for the improvement of the pathological condition of inflammatory diseases, a greater decrease in concentration due to impregnation indicates higher blood component adsorption performance. Examples of cytokines include interleukin-1β, interleukin-6, interleukin-8, high mobility group protein-1, and tumor necrosis factor-β, but interleukin-6 and interleukin-8 are more preferred because they are representative biomarkers in the treatment of inflammatory diseases.

[0110] Since the adsorption of cytokines onto the above-mentioned blood component adsorption material is thought to be an equilibrium reaction originating from intermolecular forces such as van der Waals forces, it is believed that adsorption equilibrium is reached after approximately 4 hours of adsorption treatment, regardless of the cytokine concentration.

[0111] For the reasons stated above, it is preferable that the cytokine adsorption rate be 100% after 4 hours. However, since it is time-dependent, an adsorption rate of 50% or more after 2 hours can be considered sufficient.

[0112] The performance degradation of blood component adsorbent materials due to sterilization can be evaluated by the following steps 1) to 5). 1) Measure the leukocyte adsorption rate of the blood component adsorbent material in advance. 2) Place 5 mL of blood component adsorbent material and 25 mL of distilled water into a 50 mL centrifuge tube and irradiate with gamma rays at an absorbed dose of 40 kGy to obtain sterilized blood component adsorbent material. 3) Prepare columns packed with the sterilized blood component adsorbent material and columns packed with the unsterilized blood component adsorbent material. 4) Human blood, kept warm at 37°C (ambient temperature), is passed through each column at a flow rate of 1.9 mL / min for 5 minutes. 5) After 5 minutes, sample the blood at the column inlet and column outlet, measure the leukocyte adsorption rate using a multi-parameter automated hematology analyzer XT-1800i (manufactured by Sysmex Corporation), and calculate the performance degradation rate of the blood component adsorbent material before and after sterilization by rounding the value obtained using the following formula 8 to the first decimal place. Performance degradation rate (%) of blood component adsorbent material before and after sterilization = 100 × {(leukocyte adsorption rate of blood component adsorbent material) - (leukocyte adsorption rate of blood component adsorbent material after sterilization)} / (leukocyte adsorption rate of blood component adsorbent material) ... Equation 8

[0113] While there are no limitations on the preferred range of performance degradation rates before and after sterilization of blood component adsorbent materials, it is preferable that the performance degradation rate be less than 50% in order to reduce the elution of degradation products from the blood component adsorbent material.

[0114] The platelet adsorption rate of blood component adsorbent materials can be evaluated by the following steps 1) to 4). 1) Prepare a column by filling a cylindrical column (1 cm inner diameter x 5.14 cm height) with blood inlets and outlets at the top and bottom with 3.1 mL of blood component adsorbent material. 2) Add nafamostat mesylate, an anticoagulant, to human blood kept warm at 37°C (ambient temperature) in the column to a concentration of 200 μg / mL, and immediately pass the column through at a flow rate of 0.7 mL / min for 5 minutes. 3) After 5 minutes, sample the blood from the column inlet and outlet, and obtain the platelet count using a multi-parameter automated hematology analyzer XT-1800i (manufactured by Sysmex Corporation). 4) Using the formula 9 below, round the obtained value to the first decimal place to calculate the platelet adsorption rate of the blood component adsorbent. Platelet adsorption rate (%) of blood component adsorbent material = 100 × {(Number of platelets in blood at column inlet) - (Number of platelets in blood at column outlet)} / (Number of platelets in blood at column inlet) ... Equation 9

[0115] While there are no limitations on the preferred range for platelet adsorption rate, it is preferable that the platelet adsorption rate be 50% or less, and more preferably 20% or less, in order to prevent the formation of aggregates in the blood circulation and to make clogging less likely. [Examples]

[0116] The blood component adsorbent material of the present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0117] In the examples, wt% means weight percent. M represents mol / L, and mM represents mmol / L. Unless otherwise specified, the weights of the blood component adsorbent, porous particles, first polymer, and second polymer are dry weights. Absorbance was measured at room temperature using a UV-Vis spectrophotometer (UV-1280; manufactured by Shimadzu Corporation). A blank measurement was performed before the absorbance measurement to subtract background peaks. Unless otherwise specified, infrared absorption spectra were measured using the following method.

[0118] Select the Advanced ATR mode on the Nicolet iS5 FT-IR (manufactured by Thermo Scientific; includes iD5 diamond ATR accessory, detector: DTGS KBr, beam splitter: KBr) and set the parameters (number of scans: 16, data interval: 0.241 cm). -1 (Automatic atmospheric correction: None) was applied, and after setting, background measurements were performed. Once the background measurement was complete, blood component adsorbent material, which had been pre-dried in a 60°C hot air dryer for 4 hours, was spread on the prism, pressed against the prism until the pressure device locked, and measurement was started within 20 minutes of the background measurement. The measurement range was wavenumber 4500 cm. -1 ~500cm -1 That's what I decided.

[0119] In the examples, the saponification rate of polyvinyl alcohol is synonymous with the percentage of hydroxyl groups in the repeating units, and the remaining unsaponified repeating units are polyvinyl acetate. For example, in polyvinyl alcohol with a saponification rate of 10%, 90 mol% of the repeats are polyvinyl acetate and 10 mol% are polyvinyl alcohol.

[0120] (Reactor settings) A 500 mL three-necked flask was equipped with a stirrer, a Liebig condenser, a thermocouple, and a whisk to create a reactor. The temperature was measured using the thermocouple and controlled with a mantle heater.

[0121] (Preparation of blood component adsorbent material 1) Manufacturing of porous particles: 115 mL of an aqueous PVA solution was prepared by dissolving 0.68 g of polyvinyl alcohol (PVA), and 115 mL of an aqueous phosphoric acid solution was prepared by dissolving 0.71 g of monosodium phosphate (MSP), 2.36 g of disodium phosphate (DSP), 0.01 g of trisodium phosphate (TSP), and 0.01 g of sodium nitrite. The entire PVA aqueous solution was added to a volumetric reactor and heated to 70°C, after which the entire phosphoric acid aqueous solution was added to form the aqueous phase. Furthermore, 106 g of divinylbenzene (DVB), 116 g of cyclohexanol, 11 g of polypropylene glycol (PPG), and 1.1 g of benzoyl peroxide (BPO) were mixed to form the organic phase. The organic phase was poured onto the aqueous phase of the reactor, and the stirrer was started and the mixture was stirred to confirm that the droplets were dispersed. The reaction was started when the temperature reached 80°C and continued for 16 hours.

[0122] The solvent was decanted from the reactor, and an equal volume of water was added to the removed solvent. The mixture was then stirred for 30 minutes, and the solvent was decanted again. The process from water addition onward was repeated a total of five times to wash the product. Next, the solvent was decanted, an equal volume of methanol was added, the mixture was stirred for 10 minutes, and the solvent was decanted again. The process from methanol addition onward was repeated a total of three times. Subsequently, the oligomer was extracted from the product in acetone using a Soxhlet extractor overnight, followed by vacuum drying for 8 hours. After impregnation with isopropyl alcohol, the product was added to purified water. Finally, the particles were sieved to standardize the particle size and dried in a hot air dryer at 100°C. The resulting porous particles were found to have a first polymer of poly(ethylbenzene / divinylbenzene) and no linker. This was designated as blood component adsorbent material 1.

[0123] The presence of the first polymer in blood component adsorbent material 1 was confirmed by measuring the infrared absorption spectrum of the surface of blood component adsorbent material 1, which revealed an out-of-plane bending vibration peak (800 cm²) originating from the disubstituted aromatic compound. -1 This was confirmed by the existence of ).

[0124] (Preparation of blood component adsorbent material 2) 2.4 g of N-methylol-α-chloroacetamide (hereinafter referred to as NMCA) was added to a mixed solution of 31 g of nitrobenzene and 31 g of concentrated sulfuric acid, and the mixture was stirred at 10°C until the NMCA dissolved to obtain an NMCA solution. Next, 0.2 g of paraformaldehyde (hereinafter referred to as PFA) was added to 2.0 g of nitrobenzene and 2.0 g of concentrated sulfuric acid, and the mixture was stirred at 20°C until the PFA dissolved to obtain a PFA solution. 4.2 g of the PFA solution was cooled to 5°C and mixed with the NMCA solution, stirred for 5 minutes, and 1 g of blood component adsorbent material 1 was added and impregnated for 2 hours. After impregnation, the blood component adsorbent material 1 was immersed in 200 mL of nitrobenzene at 0°C to stop the reaction, and the nitrobenzene adhering to the porous particles was washed off with methanol to obtain chlorous acid particles.

[0125] Ethylenediamine (EDA) was dissolved in a mixed solution of 0.2 g of triethylamine and 51 g of dimethyl sulfoxide (DMSO) to a concentration of 0.8 M. Chlorinated particles were added and impregnated at 40°C for 3 hours. The particles were filtered onto a glass filter and washed with 500 mL of DMSO. They were further washed with 60 mL of distilled water, and then washed with 3 L each of distilled water and physiological saline to obtain EDA-treated particles.

[0126] 0.5 g of the obtained EDA-treated particles were mixed with 10 mg of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride n-hydrate, 10 mg of immobilization PVA (saponification rate 10%), and 10 mL of water, and reacted for 24 hours. The resulting porous particles were removed onto filter paper and washed with 200 mL of methanol while suction filtration. Only the porous particles were peeled off the filter paper with a spatula and dried in a 50°C hot air dryer for 24 hours. The product removed from the hot air dryer was used as a linker to obtain blood component adsorbent material 2, which has a structure in which an amide bond is attached to the aromatic ring via a methylene group, an amino group is attached to the surface, and an amide bond is attached to the surface via an ethylene group.

[0127] The presence of a second polymer in blood component adsorbent material 2 was confirmed by infrared absorption spectroscopy of blood component adsorbent material 2, which revealed a peak originating from hydroxyl groups (3340 cm⁻¹). -1 This was confirmed by the existence of ).

[0128] (Preparation of blood component adsorbent material 3) Except for changing the saponification rate of the immobilization PVA (saponification rate 10%, degree of polymerization 500) from 10% to 35%, the manufacturing procedure was the same as for blood component adsorption material 2, and blood component adsorption material 3 was obtained.

[0129] (Preparation of blood component adsorbent material 4) Except for changing the saponification rate of the immobilization PVA (saponification rate 10%, degree of polymerization 500) from 10% to 95%, the manufacturing procedure was the same as for blood component adsorption material 2, and blood component adsorption material 4 was obtained.

[0130] (Preparation of blood component adsorbent material 5) Except for changing the amount of PVA added for immobilization from 10 mg to 3 mg, the manufacturing procedure was the same as for blood component 4, and blood component adsorbent material 5 was obtained.

[0131] (Preparation of blood component adsorbent material 6) Except for changing the amount of PVA added for immobilization from 10 mg to 20 mg, the manufacturing procedure was the same as for blood component 4, and blood component adsorbent material 6 was obtained.

[0132] (Preparation of blood component adsorbent material 7) Except for changing the amount of PVA added for immobilization from 10 mg to 25 mg, the manufacturing procedure was the same as for blood component 4, and blood component adsorbent material 7 was obtained.

[0133] (Preparation of blood component adsorbent material 8) Except for changing the amount of PVA added for immobilization from 10 mg to 5 mg, the manufacturing procedure was the same as for blood component 4, and blood component adsorbent material 5 was obtained.

[0134] (Preparation of blood component adsorbent material 9) 1 g of porous particles obtained by the same method as blood component adsorption material 1 and 1 g of poly(ethylene-vinyl alcohol) (polyethylene repeating unit content 40%, degree of polymerization 250) were added to 20 mL of toluene and stirred for 2 hours. The resulting porous particles were removed onto filter paper and washed by pouring 200 mL of methanol over the particles while suction filtration. Only the porous particles were peeled off the filter paper with a spatula and dried in a 50°C hot air dryer for 24 hours. Blood component adsorption material 9 was obtained in which poly(ethylene-vinyl alcohol) (polyethylene repeating unit content 40%) was immobilized by physical fixation without the presence of a linker.

[0135] (Preparation of blood component adsorbent material 10) 115 mL of PVA aqueous solution was prepared by dissolving 0.6 g of PVA, and 115 mL of phosphoric acid aqueous solution was prepared by dissolving 0.71 g of MSP, 2.4 g of DSP, 0.01 g of TSP, and 0.01 g of sodium nitrite. The entire PVA aqueous solution was added to the reactor and heated to 70°C, after which the entire phosphoric acid aqueous solution was added to form the aqueous phase. Furthermore, 106 g of DVB, 116 g of cyclohexanol, 6.0 g of PPG, 1.1 g of BPO, and 3.0 g of PVA (saponification rate 95%, degree of polymerization 500) were mixed to form the organic phase. The organic phase was poured onto the aqueous phase of the reactor, and the stirrer was started and the mixture was stirred to confirm that the droplets were dispersed. The reaction was started when the temperature reached 80°C and continued for 16 hours.

[0136] The solvent was decanted from the reactor, and an equal volume of water was added to the removed solvent. The mixture was then stirred for 30 minutes, and the solvent was decanted again. The process from the addition of water onward was repeated a total of five times to wash the product. Next, the solvent was decanted, an equal volume of methanol was added, and the mixture was stirred for 10 minutes, and the solvent was decanted again. The process from the addition of methanol onward was repeated a total of three times. Subsequently, the oligomer of the product was extracted from the product in acetone in a Soxhlet extractor overnight, and then vacuum-dried for 8 hours to obtain blood component adsorbent material 10 in which PVA was immobilized by physical fixation without the presence of a linker.

[0137] (Preparation of blood component adsorbent material 11) Chlorinated particles were prepared using the same procedure as for blood component adsorbent material 2. Furthermore, glycine (hereinafter referred to as GL) was dissolved in a mixed solution of 0.2 g of triethylamine and 51 g of DMSO to a concentration of 0.8 M, and the chlorinated particles were added and impregnated at 40°C for 3 hours. The particles were filtered onto a glass filter and washed with 500 mL of DMSO. After washing with DMSO, the particles were further washed with 60 mL of distilled water, and then washed with 3 L of distilled water and physiological saline to obtain GL-containing particles.

[0138] 0.5 g of the obtained GL-coated particles were mixed with 10 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 10 mg of poly(2-hydroxyethyl methacrylate) (hereinafter referred to as PHEMA, degree of polymerization 200), and 10 mL of water, and reacted for 24 hours. The resulting porous particles were removed onto filter paper and washed with 200 mL of methanol while suction filtration. Only the porous particles were collected from the filter paper with a spatula and dried in a 50°C hot air dryer for 24 hours to obtain a blood component adsorbent material 11 with immobilized PHEMA, having a structure in which an amide bond is attached to the aromatic ring via a methylene group as a linker, an amino group is attached to the surface side, and an ester group is attached to the surface side via an ethylene group.

[0139] (Preparation of blood component adsorbent material 12) Glycated particles were prepared using the same procedure as for blood component adsorbent material 11. Furthermore, 0.5 g of the GL-adsorbed particles were mixed with 10 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 10 mg of dextran sulfate (degree of polymerization 30), and 10 mL of water, and the mixture was reacted for 24 hours. The resulting porous particles were removed onto filter paper and washed with 200 mL of methanol while suction filtration. Only the porous particles were peeled off the filter paper with a spatula and dried in a 50°C hot air dryer for 24 hours. After removal from the hot air dryer, blood component adsorbent material 12 was obtained, in which dextran sulfate was immobilized and had a structure in which an amide bond was attached to the aromatic ring via a methylene group as a linker, an amino group was attached to the surface side, and an ester group was attached to the surface side via an ethylene group.

[0140] (Preparation of blood component adsorbent material 13) In the production of porous particles, the procedure was the same as for blood component adsorbent material 4, except that the organic phase was prepared by mixing 120g of DVB, 80g of toluene, 90g of isooctane, and 1.1g of BPO, to obtain blood component adsorbent material 13 with immobilized PVA.

[0141] (Preparation of blood component adsorbent material 14) In the production of porous particles, the procedure was the same as for blood component adsorbent material 4, except that the organic phase was prepared by mixing 130g of DVB, 116g of cyclohexanol, 11g of PPG, and 1.3g of benzoyl peroxide (BPO), to obtain blood component adsorbent material 14 with immobilized PVA.

[0142] (Preparation of blood component adsorbent material 15) In the production of porous particles, the procedure was the same as for blood component adsorbent material 4, except that the organic phase was prepared by mixing 83g of DVB, 116g of cyclohexanol, 38g of PPG, and 0.8g of BPO, to obtain blood component adsorbent material 15 with immobilized PVA.

[0143] (Preparation of blood component adsorbent material 16) Except for changing the immobilization PVA (saponification rate 10%) to immobilization PVA (saponification rate 100%, degree of polymerization 10000) and changing the solvent to which the EDA-treated particles are added from water to isopropanol, the blood component adsorbent 16 was manufactured using the same procedure as blood component adsorbent 2.

[0144] (Preparation of blood component adsorbent material 17) Except for changing poly(2-hydroxyethyl methacrylate) to poly(4-hydroxybutyl acrylate) (degree of polymerization 80), the blood component adsorbent 17 was manufactured using the same procedure as blood component adsorbent 11.

[0145] (Preparation of blood component adsorbent material 18) Except for replacing dextran sulfate with lactose, the blood component adsorbent 18 was manufactured using the same procedure as blood component adsorbent 12.

[0146] (Preparation of blood component adsorbent material 19) Except for changing dextran sulfate to dextran (degree of polymerization 250), the blood component adsorbent 19 was manufactured using the same procedure as blood component adsorbent 12.

[0147] (Preparation of blood component adsorbent material 20) Manufacturing of porous polystyrene particles: Except for changing the amount of DVB added from 106g to a mixture of 105g of styrene and 1g of DVB, changing the amount of PPG added from 11g to 14g, and changing the amount of BPO added from 1.1g to 0.7g, the same procedure as for blood component adsorbent material 1 was used to manufacture the material, and polystyrene porous particles were obtained in which the first polymer is poly(styrene / ethylvinylbenzene / divinylbenzene).

[0148] Except for changing the porous particles used to polystyrene porous particles, the blood component adsorbent material 20 was manufactured using the same procedure as blood component adsorbent material 4.

[0149] (Preparation of blood component adsorbent material 21) Manufacturing of hydroxyl group-containing porous particles: Except for changing the added 106g of DVB to a mixture of 90g of DVB and 16g of glycidyl ether that does not contain aromatic hydrocarbon groups, the blood component adsorbent material 21 was prepared using the same procedure as for blood component adsorbent material 1. 1g of the epoxy group-containing porous particles was added to 50mL of a 6 N aqueous sodium hydroxide solution and heated at 60°C for 24 hours to open the epoxy group and convert it into a diol group-containing porous particle consisting of two hydroxyl groups. Only the particles were removed from the solution and repeatedly washed with water until the washing solution was no longer colored by phenolphthalein. After washing, the diol group-containing porous particles that did not contain the linker or the second polymer, in which the first polymer was poly(ethylvinylbenzene / divinylbenzene / glycidyl ether ring-opened product) and in which repeating units that do not contain aromatic hydrocarbon groups existed in the first polymer were used as blood component adsorbent material 21.

[0150] (Preparation of blood component adsorbent 22) Manufacturing of chloromethyl group-containing porous particles: The blood component adsorbent material was manufactured using the same procedure as for material 1, except that the 106g of added DVB was replaced with a mixture of 36g of chloromethylstyrene and 70g of DBV, to obtain chloromethyl group-containing porous particles in which the first polymer is poly(ethylvinylbenzene / divinylbenzene / chloromethylstyrene).

[0151] Except for changing the chloroformed particles to chloromethylated particles and the poly(2-hydroxyethyl methacrylate) to polyvinyl alcohol (saponification rate 95%, degree of polymerization 500), the blood component adsorbent material 22 was manufactured using the same procedure as blood component adsorbent material 11, and a blood component adsorbent material 22 was obtained in which an amino group was attached via a methylene group as a linker, and an ester group was further attached to the surface side via a methylene group.

[0152] Measurement of pore volume of blood component adsorbent material 1: 1 g of blood component adsorbent material 1 was impregnated into 10 mL of pure water, and the container containing the solution was degassed for 10 minutes using an aspirator while being placed in an ultrasonic cleaner. The resulting hydrated blood component adsorbent material 1 was removed immediately before DSC measurement, and surface water was removed until no water droplets were visible. Next, an aluminum sealed sample container was set in a DSC Q100 (manufactured by TA Instruments) that had been pre-calibrated in temperature and calorific value (melting point 0.0 °C, heat of fusion 79.7 cal / g) with pure water, and the blank weight was measured. Subsequently, approximately 6 mg of blood component adsorbent material 1 was sampled and sealed in the aluminum sealed sample container to be used as the measurement sample. The measurement sample was placed in the DSC Q100, and its weight was measured. The value obtained by subtracting the blank weight from the obtained weight was taken as the sample weight. Subsequently, the measurement sample was rapidly cooled to -55 °C, and the temperature was raised to 5 °C at 0.3 °C / min, and the differential scanning calorific value was measured to obtain a DSC curve. Subsequently, the sample was removed and vacuum-dried at 110°C for 2 hours. It was then placed back into a DSC Q100 and its weight was measured. The amount of moisture loss before and after vacuum drying was defined as the total moisture content. From the obtained DSC curve, total moisture content, and sample weight, the pore volume per gram of blood component adsorbent material 1 was calculated according to the method of Ishikiriyama et al. (JOURNAL OF COLLOID AND INTERFACE SCIENCE, 1995, Vol. 171, pp. 103-111). The results are shown in Table 1.

[0153] (Pore volume measurement of blood component adsorbent materials 2-15) The pore volume per gram of blood component adsorbent materials 2-15 was measured using the same method as for measuring the pore volume per gram of blood component adsorbent material 1. The results are shown in Table 1.

[0154] (Pore volume measurement of blood component adsorbent materials 16-22) The pore volume per gram of blood component adsorbent materials 16-22 was measured using the same method as for measuring the pore volume per gram of blood component adsorbent material 1. The results are shown in Table 2.

[0155] (Measurement of the content of the second polymer in the overall average of blood component adsorbent material 1) Blood component adsorbent material 1 was dried in a hot air dryer at 60°C for 4 hours. The weight of the dried blood component adsorbent material 1 was taken as the dry weight of blood component adsorbent material 1, and 1 g was weighed and set aside. Subsequently, it was impregnated overnight in tetrahydrofuran at 90°C or higher, 6 N hydrochloric acid, and 6 N sodium hydroxide aqueous solution, respectively, then washed five times with deionized water, dried in a vacuum dryer for 12 hours, and weighed again. The obtained value was taken as the weight of blood component adsorbent material 1 after elution, and the value obtained from Equation 10 was rounded to the second decimal place to calculate the content of the second polymer in the overall average of blood component adsorbent material 1. The results are shown in Table 1. The overall average content of the second polymer in blood component adsorbent material 1 (mg / g) = {dry weight (1000mg) - weight after elution (mg)} / 1g ... Equation 10

[0156] (Measurement of the content of the second polymer on the surface of blood component adsorbent material 1): The Advanced ATR mode was selected for the Nicolet iS5 FT-IR (manufactured by Thermo Scientific; iD5 diamond ATR accessory included, detector: DTGS KBr, beam splitter: KBr), and the parameters were set (number of scans: 16, data interval: 0.241 cm-1, automatic atmospheric correction: none). After setting, background measurements were performed. After the background measurements were completed, blood component adsorption material 1, which had been pre-dried in a 60°C hot air dryer for 4 hours, was spread on the prism, pressed against the prism until the pressure device locked, and measurements were started within 20 minutes of the background measurements to obtain the infrared absorption spectrum of the surface of blood component adsorption material 1.

[0157] Furthermore, 1 g of blood component adsorbent material 1, which had been pre-dried in a 60°C hot air dryer for 4 hours, was taken and placed in a mortar (AS ONE agate mortar, deep type, φ70 × φ90 × 30 mm). It was then ground 100 times with a pestle, applying enough force to break at least the porous particles, and it was visually confirmed that all porous particles had been ground at least once. The measurement was performed using the same method as for measuring the infrared absorption spectrum of the surface of porous particles, except that the obtained powder was used in place of the porous particles, and the overall average infrared absorption spectrum of blood component adsorbent material 1 was obtained. Each peak originating from CH stretching (2920 cm) -1 ) Absorption intensity and peak (3340 cm) originating from the OH group -1 Based on the absorption intensity of ), the content of the second polymer on the surface of blood component adsorbent material 1 was calculated by rounding the obtained value to the second decimal place using the following formula 11. The value of "content of the second polymer in the overall average of blood component adsorbent material 1" used in formula 11 was calculated using the value before rounding to the second decimal place, calculated using formula 10. The results are shown in Table 1. The content of the second polymer on the surface of blood component adsorbent material 1 (mg / g) = the overall average content of the second polymer in blood component adsorbent material 1 (mg / g) × {peak absorption intensity derived from OH groups on the surface of blood component adsorbent material 1 / peak absorption intensity derived from CH stretching on the surface of blood component adsorbent material 1} / {overall average peak absorption intensity derived from OH groups in blood component adsorbent material 1 / overall average peak absorption intensity derived from CH stretching in blood component adsorbent material 1} ... Equation 11

[0158] (Measurement of the content of the second polymer in the overall average of blood component adsorbent materials 2-15) The content of the second polymer in the overall average of blood component adsorbent materials 2 to 15 was measured using the same method as for measuring the content of the second polymer in the overall average of blood component adsorbent material 1. The results are shown in Table 1.

[0159] (Measurement of the content of the second polymer on the surface of blood component adsorbent materials 2-15) The content of the second polymer on the surfaces of blood component adsorbent materials 2-15 was measured using the same method as for measuring the content of the second polymer on the surface of blood component adsorbent material 1. The results are shown in Table 1.

[0160] (Measurement of the content of the second polymer in the overall average of blood component adsorbent materials 16-22) The content of the second polymer in the overall average of blood component adsorbent materials 16-22 was measured using the same method as for measuring the content of the second polymer in the overall average of blood component adsorbent material 1. The results are shown in Table 2.

[0161] (Measurement of the content of the second polymer on the surface of blood component adsorbent materials 16-22) The content of the second polymer on the surfaces of blood component adsorbent materials 16-22 was measured using the same method as for measuring the content of the second polymer on the surface of blood component adsorbent material 1. The results are shown in Table 2.

[0162] [Table 1]

[0163] [Table 2]

[0164] In Tables 1 and 2, "first polymer" refers to the name of the first polymer contained in the blood component adsorbent material, and "second polymer" refers to the name of the second polymer contained in the blood component adsorbent material.

[0165] (Example 1) To confirm the adsorption performance of blood component adsorption material 2, blood was passed through a column packed with blood component adsorption material 2 for a predetermined time, and the amount of leukocyte reduction in the solution before and after passing the blood through was measured to calculate the leukocyte adsorption rate. The method for measuring and calculating the leukocyte adsorption rate is shown below.

[0166] A cylindrical column (1 cm inner diameter x 5.14 cm height) with blood inlets and outlets at the top and bottom was prepared by filling it with 3.1 mL of blood component adsorbent material 2. Human blood, kept warm at 37°C (ambient temperature), was passed through this column at a flow rate of 1.9 mL / min for 5 minutes. After 5 minutes, the blood at the column inlet and the blood components at the column outlet were analyzed, and the leukocyte adsorption rate of blood component adsorbent material 2 was calculated. The results are shown in Table 1. The number of each blood component was measured using a multi-parameter automated hematology analyzer XT-1800i (Sysmex Corporation). The adsorption rate of each blood component was calculated using the following formula 12. The results are shown in Table 3. Leukocyte adsorption rate (%) of blood component adsorbent material 2 = {(Total number of granulocytes and monocytes in the blood at the column inlet) - (Total number of granulocytes and monocytes in the blood at the column outlet)} / (Total number of granulocytes and monocytes in the blood at the column inlet) × 100 ... Equation 12

[0167] (Measurement of IL-8 adsorption rate of blood component adsorbent material 2) To confirm the IL-8 adsorption performance of blood component adsorbent material 2, the blood component adsorbent material 2 was impregnated in a liquid containing IL-8 for a predetermined time, then removed, and the IL-8 adsorption rate was measured from the difference in the amount of IL-8 in the liquid before and after impregnation. The measurement method is shown below.

[0168] A 0.1 mL polypropylene container was placed in the container with blood component adsorbent material 2. Fetal bovine serum (FBS), prepared to have an IL-8 concentration of 2000 pg / mL, was added to this container in a 1 cm³ container. 3 30 mL of the blood component adsorbent material 2 was added, and after inverting and mixing in a 37°C incubator for 2 hours, the IL-8 concentration in the FBS was measured by enzyme-linked immunosorbent assay (ELISA). The IL-8 adsorption rate was calculated from the IL-8 concentration before inverting and mixing using the following formula 13. The results are shown in Table 3. IL-8 adsorption rate (%) of blood component adsorbent material 2 = {IL-8 concentration before inversion and mixing (pg / mL) - IL-8 concentration after inversion and mixing (pg / mL)} / IL-8 concentration before inversion and mixing (pg / mL) × 100 ... Equation 13

[0169] (Example 2) Using blood component adsorbent materials 3-6 and 8-15, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 3.

[0170] (Comparative Example 1) Using blood component adsorbent materials 1 and 7, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 3.

[0171] [Table 3]

[0172] In Table 3, "leukocyte adsorption rate" refers to the leukocyte adsorption rate of the blood component adsorbent, and "IL-8 adsorption rate" refers to the IL-8 adsorption rate of the blood component adsorbent.

[0173] The results in Table 3 demonstrate that the blood component adsorbent material of this embodiment adsorbs blood components such as white blood cells with high efficiency.

[0174] (Example 3) Using blood component adsorption material 16, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0175] (Example 4) Using blood component adsorption material 17, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0176] (Example 5) Using blood component adsorption material 19, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0177] (Example 6) Using blood component adsorption material 20, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0178] (Example 7) Using blood component adsorbent material 22, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0179] (Example 8) A cylindrical column (1 cm inner diameter x 5.14 cm height) with blood inlets and outlets at the top and bottom was prepared by filling it with 3.1 mL of blood component adsorbent material 4. Human blood, kept warm at 37°C (ambient temperature), was passed through this column at a flow rate of 1.9 mL / min for 5 minutes. After 5 minutes, blood samples were taken from the column inlet and outlet, and the monocyte count, neutrophil count, basophil count, and eosinophil count were obtained using a multi-parameter automated hematology analyzer XT-1800i (Sysmex Corporation). The values ​​obtained using equations 4-7 were rounded to the first decimal place to calculate the monocyte removal rate, neutrophil removal rate, basophil removal rate, and eosinophil removal rate of blood component adsorbent material 4. The results are shown in Table 6.

[0180] (Example 9) 5 mL of blood component adsorbent material 4 and 25 mL of distilled water were placed in a 50 mL centrifuge tube. Sterilized blood component adsorbent material 4 was obtained by gamma irradiation at an absorbed dose of 40 kGy. The measurement procedure was the same as in Example 1, except that blood component adsorption material 2 was replaced with sterilized blood component adsorption material 4. The obtained leukocyte adsorption rate was taken as the leukocyte adsorption rate after sterilization. Using the leukocyte adsorption rate of blood component adsorption material 4 obtained in Example 2 and the leukocyte adsorption rate after sterilization, the value obtained using Equation 8 was rounded to the first decimal place to calculate the performance degradation rate of blood component adsorption material 4 before and after sterilization. The results are shown in Table 4.

[0181] (Example 10) The measurement procedure was the same as in Example 9, except that blood component adsorption material 4 was replaced with blood component adsorption material 12, and the leukocyte adsorption rate after sterilization was obtained. Furthermore, using the leukocyte adsorption rate of blood component adsorption material 12 in Example 2 and the leukocyte adsorption rate after sterilization, the performance degradation rate of blood component adsorption material 12 before and after sterilization was calculated by rounding the value obtained from Equation 8 to the first decimal place. The results are shown in Table 4.

[0182] (Example 11) The measurement procedure was the same as in Example 9, except that blood component adsorption material 4 was replaced with blood component adsorption material 17, and the leukocyte adsorption rate after sterilization was obtained. Furthermore, using the leukocyte adsorption rate of blood component adsorption material 17 in Example 4 and the leukocyte adsorption rate after sterilization, the performance degradation rate of blood component adsorption material 17 before and after sterilization was calculated by rounding the value obtained from Equation 8 to the first decimal place. The results are shown in Table 4.

[0183] (Example 12) The measurement procedure was the same as in Example 9, except that blood component adsorption material 4 was replaced with blood component adsorption material 19, and the leukocyte adsorption rate after sterilization was obtained. Furthermore, using the leukocyte adsorption rate of blood component adsorption material 19 in Example 5 and the leukocyte adsorption rate after sterilization, the performance degradation rate of blood component adsorption material 19 before and after sterilization was calculated by rounding the value obtained from Equation 8 to the first decimal place. The results are shown in Table 4.

[0184] [Table 4]

[0185] In Table 4, "Leukocyte adsorption rate after sterilization" refers to the leukocyte adsorption rate of the blood component adsorbent material after sterilization, and "Performance degradation rate before and after sterilization" refers to the performance degradation rate of the blood component adsorbent material before and after sterilization.

[0186] The results in Table 4 show that the blood component adsorbent material of this embodiment, which contains the synthetic polymers polyvinyl alcohol and poly(4-hydroxybutyl acrylate) as a second polymer, exhibits a smaller rate of performance degradation before and after sterilization than the blood component adsorbent material of this embodiment, which contains the natural polymers dextran sulfate and dextran as a second polymer.

[0187] (Example 13) A cylindrical column (1 cm inner diameter x 5.14 cm height) with blood inlets and outlets at the top and bottom was prepared by packing 3.1 mL of blood component adsorbent material 4 into it. Human blood, kept warm at 37°C (ambient temperature), was added to this column with nafamostat mesylate, an anticoagulant, at a concentration of 200 μg / mL, and the column was immediately passed through at a flow rate of 0.7 mL / min for 5 minutes. After 5 minutes, blood samples were taken from the column inlet and outlet, and platelet counts were obtained using a multi-parameter automated hematology analyzer XT-1800i (Sysmex Corporation). The platelet adsorption rate of blood component adsorbent material 4 was calculated by rounding the value obtained using Equation 9 to the first decimal place. The results are shown in Table 7.

[0188] (Example 14) The measurement was performed using the same procedure as in Example 13, except that blood component adsorption material 4 was replaced with blood component adsorption material 25, and the platelet adsorption rate of blood component adsorption material 25 was calculated. The results are shown in Table 7.

[0189] (Comparative Example 2) Using blood component adsorption material 18, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0190] (Comparative Example 3) Using blood component adsorption material 21, the leukocyte adsorption rate and IL-8 adsorption rate were measured in the same manner as in Example 1. The results are shown in Table 5.

[0191] [Table 5]

[0192] (Comparative Example 4) Except for replacing blood component adsorbent material 4 with blood component adsorbent material 18, the same procedure as in Example 8 was used for measurement and calculation, and the monocyte removal rate, neutrophil removal rate, basophil removal rate, and eosinophil count removal rate of blood component adsorbent material 18 were calculated. The results are shown in Table 6.

[0193] [Table 6]

[0194] In Table 6, "monocyte adsorption rate" refers to the monocyte adsorption rate of the blood component adsorption material, "neutrophil adsorption rate" refers to the neutrophil adsorption rate of the blood component adsorption material, "basophil adsorption rate" refers to the basophil adsorption rate of the blood component adsorption material, and "eosinophil adsorption rate" refers to the eosinophil adsorption rate of the blood component adsorption material.

[0195] The results in Table 6 show that the van der Waals force-based blood component adsorption material of this embodiment adsorbs blood components with higher efficiency than blood component adsorption materials that rely on specific recognition of sugar chains, regardless of the components of the leukocyte.

[0196] (Comparative Example 5) The measurement was performed using the same procedure as in Example 13, except that blood component adsorption material 4 was replaced with blood component adsorption material 1, and the platelet adsorption rate of blood component adsorption material 1 was calculated. The results are shown in Table 7.

[0197] [Table 7]

[0198] In Table 7, the platelet adhesion rate refers to the platelet adhesion rate of the blood component adsorbent material.

[0199] The results in Table 7 show that the blood component adsorbent material of this embodiment can suppress platelet adsorption, and in particular, the blood component adsorbent material containing an amide bond as a linker has a particularly suppressed platelet adsorption rate. [Industrial applicability]

[0200] The blood component adsorption material of the present invention can adsorb white blood cells and the like with high efficiency, and can therefore be used as an adsorption carrier for columns used for the treatment of inflammatory diseases, immunosuppression before transplantation, and suppression of side effects such as fever and infection from blood products.

Claims

1. A blood component adsorbent comprising porous particles consisting only of a first polymer having aromatic hydrocarbon groups in its repeating units, and a second polymer having hydroxyl groups in its repeating units, immobilized on the surface of the porous particles, wherein the content of the second polymer on the surface of the blood component adsorbent is 3 to 30 mg / g.

2. The content of the second polymer in the overall average of the blood component adsorbent material is 0.3 mg / g or less, and the pore volume per gram is 0.5 to 1.8 cm². ３ The blood component adsorbent material according to claim 1.

3. The blood component adsorbent material according to claim 1 or 2, wherein the first polymer is polystyrene, polyethylvinylbenzene, polydivinylbenzene, poly(ethylvinylbenzene / divinylbenzene), or poly(styrene / divinylbenzene).

4. The blood component adsorbent material according to claim 1 or 2, wherein the second polymer is a polymer selected from the group consisting of polyhydroxyalkyl acrylate, polyhydroxyalkyl methacrylate, and polyvinyl alcohol.

5. A blood component adsorbent material according to claim 1 or 2, for the purpose of adsorbing and removing leukocytes.

6. A blood purification column comprising the blood component adsorption material according to claim 1 or 2.

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