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

Blood component adsorption material

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

[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 immunity before and after transplantation, and suppressing side effects of blood products such as fever and infection. Among these, technologies have been developed for adsorbing and removing leukocytes from blood by passing the blood through a column whose surface contains a material containing a ligand or resin that has affinity for leukocytes, or a material with a certain surface roughness that allows leukocytes to easily adsorb.

[0003] In particular, particulate blood component adsorption materials have a small specific surface area and are less likely to clog during filtration, making them suitable for blood processing, and a variety of particulate adsorption materials have been developed.

[0004] For example, Patent Document 1 discloses a carrier for adsorbing blood components, which comprises a water-insoluble carrier having a functional group on its surface covalently bonded to a sugar chain selected from the group consisting of sucrose, lactose, maltose, trehalose, and cellobiose, and the sugar chain is covalently bonded to an amino group of the functional group at the reducing end. The sugar chain is used to adsorb and remove both cytokines and leukocytes.

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

[0006] Patent Document 3 discloses a polymer system including at least one type of polymer, wherein the polymer contains residues of one or more types of aromatic monomers and one or more types of crosslinking agents, the polymer has an outer surface and a plurality of pores, and the polymer is functionalized with different functional groups on the outer surface and on the surfaces within 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 coats at least a portion of the surface of the hydrophobic porous polymer particles.

[0008] Patent Document 5 discloses a biocompatible polymer system including at least one type of polymer, wherein the polymer includes either a polyol or a zwitterionic functional group, and the polymer includes a solid support having a biocompatible hydrogel coating containing hydroxyl groups in the repeating units, and the polymer system is 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 leukocyte, specifically recognize and adhere to certain sugar chains.

[0010] Patent No. 5644149, Patent No. 3513155, Patent No. 5913368, JP 2021-7915, Patent No. 7033083

[0011] Largent et al., J. Biol. Chem., 1984, Vol. 259, pp. 1764-1769

[0012] However, conventional materials for adsorbing blood components such as particulate white blood cells have a problem in that they can only adsorb a subset of white blood cells, such as alveolar macrophages, which interact specifically with sugar chains, because they specifically remove blood components based on hydrogen bonds resulting from sugar-derived molecular structures, as disclosed in Non-Patent Document 1.

[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, so it is considered preferable to adsorb without distinguishing between monocytes and granulocytes.

[0014] Patent Documents 1 and 2 disclose materials that adsorb blood components based on binding via sugar-derived molecular structures. While Patent Document 1 discloses that the material can adsorb neutrophils and monocytes, which are types of granulocytes, it does not describe or suggest whether it can adsorb all monocytes and granulocytes. Furthermore, while Patent Document 1 introduces sugar chains for specific binding to white blood cells, it does not describe or suggest adsorption and removal based on van der Waals forces due to the physical structure of the material surface. Furthermore, Patent Document 2 does not specifically disclose the blood components that can be adsorbed.

[0015] Patent Document 3 describes a material that enables the adsorption and removal of proteins, toxins, and pathogens, but does not disclose any specific effects, and does not disclose or suggest anything about the adsorption and removal of cellular components such as white blood cells.

[0016] Patent Document 4 describes a separation material for chromatography, which is intended for use in the reversible adsorption of proteins, and cannot be directly applied to the irreversible adsorption and removal of blood components for the purpose of treating patients. Furthermore, there is no mention whatsoever of the adsorption and removal of cellular components such as white blood cells.

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

[0018] As described above, no material has been developed to date that can adsorb a wide range of blood components, such as leukocytes, without limiting the types of monocytes and granulocytes, by utilizing the van der Waals forces due to the physical structure of the material surface.

[0019] Therefore, an object of the present invention is to provide a blood component adsorption material that can control the van der Waals forces on the surface of the blood component adsorption material by immobilizing a polymer having hydroxyl groups at a specific content on the surface of porous particles made only of a polymer having aromatic hydrocarbon groups, thereby enabling the adsorption of various blood components such as leukocytes without limiting the types of monocytes and granulocytes.

[0020] The present inventors have conducted extensive research to solve the above problems, and as a result have found the following inventions (1) to (6): (1) A blood component adsorption material comprising porous particles consisting only of a first polymer having an aromatic hydrocarbon group in the repeating unit, and a second polymer having a hydroxyl group in the repeating unit immobilized on the surface of the porous particles, wherein the content of the second polymer on the surface of the blood component adsorption material is 3 to 30 mg / g. (2) The average content of the second polymer in the entire blood component adsorption material is 0.3 mg / g or less, and the pore volume per 1 g is 0.5 to 1.8 cm. ３ (3) The blood component adsorption 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 adsorption 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) The blood component adsorption material according to any one of (1) to (4), which is used for adsorption and removal of leukocytes. (6) A blood purification column comprising the blood component adsorption material according to any one of (1) to (5).

[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, by virtue of adsorption based on van der Waals forces due to the physical structure of the surface.

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

[0023] The blood component adsorption material of the present invention is characterized by comprising porous particles consisting only of a first polymer having an aromatic hydrocarbon group in the repeating unit, and a second polymer having a hydroxyl group in the repeating unit immobilized on the surface of the porous particles, wherein the content of the second polymer on the surface of the blood component adsorption material is 3 to 30 mg / g.

[0024] The "first polymer having an aromatic hydrocarbon group in the repeating unit" means a polymer having a hydrocarbon group containing an aromatic structure in the repeating unit. There are no particular limitations as long as the repeating unit contains an aromatic hydrocarbon group, and a plurality of repeating units may be contained. The aromatic hydrocarbon group is preferably a functional group in which a hydrocarbon structure is substituted on any one of a benzene ring, a naphthalene ring, and an acetylene ring, and more preferably contains a benzene ring.

[0025] The first polymer having an aromatic hydrocarbon group in a repeating unit may be a homopolymer consisting of a single repeating unit or a copolymer containing multiple types of repeating units. In either case, however, it is preferable that the first polymer contains divinylbenzene from the viewpoint of preventing dissolution of the particles and ensuring strength.

[0026] When the first polymer having an aromatic hydrocarbon group in the repeating unit is a homopolymer, for example, polystyrene, polyethylvinylbenzene, polymethylvinylbenzene, and polydivinylbenzene are preferred from the viewpoint of ease of handling and availability, and polydivinylbenzene is particularly preferred from the viewpoint of ensuring particle strength. Note that the substitution position of the substituent on each aromatic ring does not matter.

[0027] The composition of the first polymer having an aromatic hydrocarbon group in a repeating unit is not limited other than that it contains a repeating unit consisting of an aromatic hydrocarbon group, and it may be a copolymer containing multiple types of repeating units. For example, from the viewpoint of ensuring strength, poly(ethylvinylbenzene / divinylbenzene), poly(methylvinylbenzene / divinylbenzene) or poly(styrene / divinylbenzene) containing divinylbenzene is preferred, and poly(ethylvinylbenzene / divinylbenzene) is more preferred.

[0028] The number of repeating units or molecular weight of the chemical structure of the first polymer having an aromatic hydrocarbon group in the repeating unit is not particularly limited, but from the viewpoint of the physical properties and strength stability as a polymer, it is preferable that the first polymer be a polymer in which 100 or more repeating units are linked by covalent bonds.

[0029] It can be confirmed that the first polymer having an aromatic hydrocarbon group is a polymer in which 100 or more repeating units are covalently bonded, from the fact that it does not dissolve when immersed in isopropyl alcohol.

[0030] The first polymer having an aromatic hydrocarbon group in the repeating unit may have a crosslinked structure for maintaining strength or a terminal structure derived from an initiator for initiating and terminating polymerization.

[0031] Whether the first polymer having an aromatic hydrocarbon group has a crosslinked structure can be confirmed by the fact that the first polymer does not dissolve when it is immersed in acetone and refluxed in a Soxhlet extractor.

[0032] The "second polymer having hydroxyl groups in the repeating unit" means a polymer containing hydroxyl groups in the repeating unit as a chemical structure. The molecular structure and molecular weight of the repeating unit are not limited, but it is preferable that the molecular weight of the repeating unit is 200 g / mol or less per hydroxyl group.

[0033] Preferred examples of the second polymer having a hydroxyl group in the repeating unit include 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, and from the standpoint of sterilization and stability, synthetic polymers are more preferred, with polyvinyl alcohol, polyhydroxyalkyl acrylate, and polyhydroxyacrylate being even more preferred.

[0034] From the viewpoint of ease of immobilization on porous particles, the second polymer having a hydroxyl group in the repeating unit may be a copolymer containing a repeating unit composed solely of hydrocarbons. Examples of repeating units composed solely of hydrocarbons include, for example, repeating units of polyethylene, polypropylene, polystyrene, polyethylvinylbenzene, polymethylvinylbenzene, and polydivinylbenzene. Examples of preferred second polymers include 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), poly(hydroxyacrylate / methylvinylbenzene), and poly(hydroxyacrylate / divinylbenzene).

[0035] There are no restrictions on the abundance ratio of the hydroxyl group-containing repeating units in the repeating units of the second polymer, but if the abundance ratio is too low, the hydrophobicity increases, leading to an increased platelet adhesion rate and clogging of the column. Therefore, the abundance ratio is preferably 10% or more and 100% or less, more preferably 40% or more and 100% or less, and particularly preferably 95% or more and 100% or less.

[0036] The number of repeating units (hereinafter referred to as the degree of polymerization) of the chemical structure of the second polymer having a hydroxyl group in the repeating unit or the molecular weight is not particularly limited, but from the viewpoint of surface interaction and modifying properties, the second polymer is preferably a polymer in which 10 or more and 10,000 or less repeating units are linked by covalent bonds, and has a degree of polymerization of 10 to 10,000, and more preferably a polymer with a degree of polymerization of 30 to 10,000.

[0037] When a commercially available product with a specified degree of polymerization is used as is, the degree of polymerization of the second polymer is adopted. When the degree of polymerization is not specified, the degree of polymerization is obtained by dividing the weight-average molecular weight by the molecular weight of the repeating unit and rounding off to the nearest whole number. For example, when the weight-average molecular weight is 10,000 and the molecular weight of the repeating unit is 250, the degree of polymerization is 40. When the second polymer is a copolymer composed of two or more types of monomers, the abundance ratio of each repeating unit is multiplied by the molecular weight of each repeating unit, and the weighted average obtained by adding up all the values ​​and dividing by the total number of components is regarded as the molecular weight of the repeating unit.

[0038] The second polymer having a hydroxyl group in the repeating unit may have a crosslinked structure for maintaining strength or a terminal structure derived from an initiator for initiating and terminating polymerization.

[0039] The term "porous particles" refers to particles having a plurality of pores, and the porous particles in the present invention are composed only of the first polymer.

[0040] There is no limitation on the pore volume of the pores contained in the blood component adsorption material. However, to improve the strength of the blood component adsorption material and make the adsorption process more stable, the pore volume per 1 g of the blood component adsorption material should be 0.5 cm. ３ Over 1.8cm ３ It is preferable that:

[0041] The surface of the blood component adsorption material is measured by the infrared absorption spectrum (wave number 4500 cm) using the attenuated total reflection (ATR) method. －１ ~500cm －１ The infrared absorption spectrum of the surface of the blood component adsorption material can be measured by the following method. The Advanced ATR mode of a Nicolet iS5 FT-IR (manufactured by Thermo Scientific; equipped with an iD5 Diamond ATR accessory, detector: DTGS KBr, beam splitter: KBr) is selected, and the parameters are set (number of scans: 16, data interval: 0.241 cm). －１(Automatic atmospheric correction: no). After setting, background measurement is carried out. After background measurement is completed, 1 g of blood component adsorption material, which has been dried in advance in a hot air dryer at 60°C for 4 hours, is spread on the prism and pressed against the prism until the pressure device locks. Measurement is started within 20 minutes of the background measurement, and the infrared absorption spectrum of the surface of the blood component adsorption material can be obtained. The measurement range is a wavenumber of 4500 cm. －１ ~500cm －１ Let's say.

[0042] The overall average of the blood component adsorption material is determined by measuring the infrared absorption spectrum (wave number 4500 cm) by the attenuated total reflectance (ATR) method after the structure of the blood component adsorption material is homogenized. －１ ~500cm －１ ) refers to the physical properties of the blood component adsorbent material measured by the infrared absorption spectrum (IR spectrum) method. The overall average infrared absorption spectrum of the blood component adsorbent material can be analyzed by the following method. 1 g of the blood component adsorbent material, which had previously been dried in a hot air dryer at 60°C for 4 hours, was placed in a mortar (a deep agate mortar manufactured by AS ONE, φ70 × φ90 × 30 mm), and ground 100 times with a pestle, applying a force sufficient to break the blood component adsorbent material. Visual inspection was performed to confirm that all of the blood component adsorbent material had been ground at least once and that the structure of the blood component adsorbent material was uniform, yielding an overall average powder of the blood component adsorbent material. The overall average infrared absorption spectrum of the blood component adsorbent material can be obtained by measuring the infrared absorption spectrum of the surface of the blood component adsorbent material using the same method as for measuring the infrared absorption spectrum of the blood component adsorbent material, except that the obtained powder was used instead of the blood component adsorbent material.

[0043] The immobilization of the second polymer on the surface of the porous particle means that the second polymer is physically or chemically immobilized on the surface of the porous particle made of the first polymer. There are no limitations on the physical immobilization method, but immobilization by aggregation or entanglement of the polymer on the surface of the porous particle is preferred. There are also no limitations on the chemical immobilization method, but immobilization by the formation of a covalent bond or an ionic bond is preferred.

[0044] The second polymer may be immobilized on the surface of the porous particle by either physical or chemical immobilization, but chemical immobilization is more preferred from the viewpoint of preventing elution and improving 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 immobilization via a linker is preferred.

[0046] The term "linker" refers to a chemical structure for covalently immobilizing a first polymer and a second polymer, and refers to a chemical structure formed by a covalent bond between the repeating unit of the first polymer and the repeating unit of the second polymer. For example, in the case where a substituent is introduced into an aromatic ring of the first polymer and reacted with a hydroxyl group of the second polymer to form a bond, the term "linker" refers to the structure between the carbon of the aromatic ring and the oxygen atom of the hydroxyl group after the reaction. There are no limitations on the chemical structure contained as the linker, but, for example, from the viewpoint of imparting a bond to the electrically neutral first polymer, electrically neutral chemical bonds such as amide bonds, alkylene groups, urea bonds, ether bonds, and ester bonds are preferred. Among these, from the viewpoint of suppressing clogging due to platelet adsorption, it is more preferred that the linker contains an amide bond, urea bond, ether bond, or ester bond, which are bonds that can impart electrically neutrality and hydrophilicity. From the viewpoint of bond stability, it is even more preferred that the linker contains an amide bond or ester bond, with an amide bond being particularly preferred.

[0047] The amide bond contained in the linker may be any of primary amide, secondary amide, and tertiary amide bonds, with secondary amide being preferred. Furthermore, the bonding position of the amide bond contained in the linker is not particularly limited, but from the viewpoint of appropriately suppressing and imparting the hydrophobicity of the aromatic hydrocarbon group to which platelets are likely to adsorb, it is preferred that the linker be covalently bonded to the aromatic ring of the first polymer via an alkylene group. Examples of the alkylene group include methylene, ethylene, and propylene, with a methylene group being more preferred.

[0048] In addition, the linker may contain an ionic functional group to make it easier to control the binding of the second polymer. For example, an amino group or a carboxylic acid group is preferred, and an amino group is more preferred from the viewpoint of blood compatibility.

[0049] To achieve both immobilization to the first polymer and immobilization to the second polymer, the chemical structure in the linker may contain both an electrically neutral chemical bond and an ionic functional group. In this case, the chemical structure preferably contains an electrically neutral chemical bond on the first polymer side and an ionic functional group 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 an amino group is further bonded to the tip of the amide bond.

[0050] There is no limitation on the method of immobilizing the first polymer and the linker by covalent bonding, but for example, it is preferable that an aromatic ring contained in the repeating unit of the first polymer and the linker are bonded by a carbon-carbon bond.

[0051] There is no limitation on the number of carbon atoms in the linker; however, in order to make it easier to immobilize the second polymer by keeping the mobility of the linker within a preferred range while maintaining an appropriate distance between the first polymer and the second polymer, for example, the number of carbon atoms is preferably 2 or more and 30 or less, more preferably 4 or more and 20 or less, and even more preferably 6 or more and 15 or less.

[0052] There are no particular limitations on the method for physically immobilizing the second polymer, but preferred methods include using a copolymer containing a hydrophobic repeating unit as the second polymer and aggregating it onto the first polymer through the hydrophobic interaction of its structure, or mixing the second polymer into the first polymer during its formation and immobilizing it through entanglement.From the perspective of expressing the performance of the blood component adsorption material, the method of aggregating it onto the first polymer through hydrophobic interaction is preferred.

[0053] If the content of the second polymer on the surface of the blood component adsorption material is too low, no interaction occurs between the blood component adsorption material and blood cells, and blood component adsorption performance is not achieved, whereas if the content is too high, the blood component adsorption performance is reduced due to excessive hydrophilicity. Therefore, the content of the second polymer on the surface of the blood component adsorption material is 3 mg / g or more and 30 mg / g or less, and more preferably 3 mg / g or more and 20 mg / g or less.

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

[0055] There are no limitations on the particle size of the blood component adsorption material, but in order to allow blood to flow more easily when blood components are adsorbed, the particle size is preferably 10 μm or more and 10 mm or less, more preferably 50 μm or more and 3 mm or less, and even more preferably 100 μm or more and 1 mm or less.

[0056] The pore volume per 1 g of the blood component adsorption 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 caused by capillary coagulation of water in the pores by differential scanning calorimetry using a differential scanning calorimeter (hereinafter referred to as DSC).

[0057] The pore volume per 1 g is determined by obtaining a differential scanning calorimetry (DSC) curve of the target material in a water-containing state using the DSC measurement method described below, calculating the melting point and amount of water from the obtained DSC curve, and then calculating the pore volume. 1 g of the material is immersed 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 resulting water-containing material is removed immediately before DSC measurement, and excess surface water is removed to the extent that water droplets are no longer visible to the naked eye. Next, an aluminum sealed sample container is placed in a DSC Q100 (manufactured by TA Instruments) that has been previously calibrated for temperature and calorie (melting point 0.0 ° C, heat of fusion 79.7 cal / g) with pure water, and the blank weight is measured. Approximately 6 mg of the material is then sampled and sealed in an aluminum sealed sample container to serve as the measurement sample. The measurement sample is placed in the DSC Q100 and its weight is measured. The value obtained by subtracting the blank weight from the obtained weight is the sample weight. The measurement sample is rapidly cooled to -55 ° C, and the temperature is raised to 5 ° C at 0.3 ° C / min to measure the differential scanning calorimetry, and the peak top temperature is taken as the melting point to obtain a DSC curve. The sample is then removed and vacuum dried at 110 ° C for 2 hours, and the weight is measured again in the DSC Q100, and the amount lost 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 1 g 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 are made of only the first polymer by crushing the porous particles in a mortar to obtain a solid particle suitable for insertion into an NMR tube. １３ This can be confirmed by measuring CNMR and finding a peak in the region derived from aromatic rings (δ: 110 to 170 ppm).

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

[0060] The overall average content of the second polymer in the blood component adsorption material can be calculated by measuring the dry weight of the blood component adsorption material in advance, immersing the material overnight in tetrahydrofuran, hydrochloric acid, or an aqueous solution of sodium hydroxide at 90°C or higher, repeatedly washing with ion-exchanged water until the material becomes neutral, drying the material again, measuring the weight of the blood component adsorption material, and rounding off the value obtained from the following formula 1 to one decimal place as the weight of the blood component adsorption material after elution: Overall average content of the second polymer in the blood component adsorption material (mg / g) = {dry weight (1000 mg) - weight after elution (mg)} / 1 g ... formula 1

[0061] The peak due to CH stretching (2920 cm ) in the overall average infrared absorption spectrum of the blood component adsorption material and the infrared absorption spectrum of the surface of the blood component adsorption material －１ ) absorption intensity, and the peak (3340 cm) due to OH groups in the overall average infrared absorption spectrum of the blood component adsorption material and the infrared absorption spectrum of the surface of the blood component adsorption material. －１ ) is used to calculate the content of the second polymer on the surface of the blood component adsorption material by rounding off the obtained value to the nearest tenth place using the following formula 2. The value of "the overall average content of the second polymer in 1 of the blood component adsorption material" used in formula 2 was calculated using the value calculated using formula 1 before rounding off to the nearest tenth place. Content of the second polymer on the surface of the blood component adsorption material (mg / g) = Overall average content of the second polymer in the blood component adsorption material (mg / g) × {peak absorption intensity due to OH groups on the surface of the blood component adsorption material / peak absorption intensity due to CH stretching on the surface of the blood component adsorption material} / {overall average peak absorption intensity due to OH groups on the blood component adsorption material / overall average peak absorption intensity due to CH stretching on the blood component adsorption material} Formula 2

[0062] The particle diameter of the blood component adsorption material refers to the average value of diameter measurements taken at 10 locations per photograph (100 locations in total), obtained by randomly collecting 10 particle samples and photographing each sample at 1000x to 3000x magnifications using a scanning electron microscope.

[0063] The term "blood component adsorption material" refers to a material that has the ability to adsorb blood components.

[0064] The term "blood components" refers to components that make up blood, and is classified into humoral factors in blood and cells in blood. There are no particular restrictions on the blood components that the blood component adsorption material of this embodiment is intended to adsorb, but among blood components, cells in blood are preferred, and it is more preferred that the blood component adsorption material be able to simultaneously adsorb both cells in blood and humoral factors in blood.

[0065] "Cells in blood" means cells contained in blood, and examples thereof 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 an inflammatory disease, white blood cell components are preferably the target of adsorption, and among white blood cell components, monocytes and granulocytes are preferably removed, 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, 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 by flow cytometry, etc.

[0067] The term "activated platelets" refers to platelets that release cytokines, active oxygen, etc. in response to cytokines, LPS, etc.

[0068] The terms "activated granulocyte-activated platelet complex" and "activated monocyte-activated platelet complex" refer to activated granulocytes or activated monocytes bound to activated platelets, which have the ability to phagocytose autologous tissue. In particular, in the treatment of patients with inflammatory diseases, it is considered necessary to remove activated granulocyte-activated platelet complexes, which are thought to be directly involved in the pathology.

[0069] The granulocytes are further classified into neutrophils, basophils, and eosinophils, but it is preferable that components derived from monocytes and granulocytes are removed together without any selectivity among them.

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

[0071] The term "cytokine" refers to a group of proteins that are produced by various cells, including immunocompetent cells, in response to stimuli such as infection or trauma, and are released extracellularly to act. Examples of cytokines include interferon α, interferon β, interferon γ, interleukin 1 to interleukin 15, tumor necrosis factor α, tumor necrosis factor β, high mobility group box-1, erythropoietin, and monocyte chemotactic factor, and in the treatment of inflammatory diseases, interleukin 8 (IL-8) is particularly preferred as the target for adsorption.

[0072] The term "inflammatory disease" refers to all diseases that induce an inflammatory response in the body, and includes, for example, systemic lupus erythematosus, malignant rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, drug-induced hepatitis, alcoholic hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, and fungal sepsis), influenza, acute respiratory distress syndrome (ARDS, also referred to as acute respiratory distress syndrome or acute respiratory distress syndrome), acute lung injury (ALI), pancreatitis, idiopathic interstitial pneumonia (IDP), and the like. 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, hepatitis B, hepatitis C, hepatitis D, or hepatitis E, sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, pancreatitis, or idiopathic interstitial pneumonia are preferred as treatment targets, since causative substances are released into the blood and blood purification is particularly expected to have a therapeutic effect. The adsorption column of this embodiment is preferably used, for example, in the treatment of the above-mentioned inflammatory diseases, and more preferably in the treatment of sepsis (e.g., gram-negative bacterial sepsis, gram-positive bacterial sepsis, culture-negative sepsis, fungal sepsis), influenza, acute respiratory distress syndrome, acute lung injury, or idiopathic interstitial pneumonia, which are difficult to treat with drugs alone and are considered 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 peel off. There are no particular limitations on the principle of adsorption, but it refers to a state in which the substance adheres due to van der Waals forces, such as ionic interactions such as electrostatic interactions, hydrophobic interactions, and hydrogen bonds, or a state in which the substance adheres due to biological factors such as cell adhesion or leukocyte phagocytosis. The blood component adsorption material of this embodiment is preferably capable of adsorption due to van der Waals forces.

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

[0076] The production of porous particles consisting only of the first polymer can be achieved by adding a monomer having an aromatic hydrocarbon group, a crosslinking agent, a dispersing agent, and an initiator during suspension polymerization. For example, the monomer may be a vinyl monomer having an aromatic ring, such as styrene, ethylvinylbenzene, or divinylbenzene, and preferably contains at least divinylbenzene. The crosslinking agent may be divinylbenzene, the dispersing agent may be polyvinyl alcohol, and the initiator may be benzoyl peroxide.

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

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

[0079] The pore volume of the porous particles can be increased by decreasing the monomer concentration, increasing the initiator concentration, or decreasing the crosslinker concentration (eg, divinylbenzene concentration).

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

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

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

[0083] The second polymer may be commercially available.

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

[0085] The immobilization of the amine compound on the porous particle can be achieved by further immobilizing a functional group acting as a linker to the aromatic ring contained in the first polymer. The functional group acting as the linker is not limited, but examples thereof include a halogenated alkyl group, a carboxylic acid group, and an epoxy group.

[0086] The amine compound to be immobilized is preferably, for example, ethylenediamine, diethylenetriamine, triethylenetetramine, polyethyleneimine, glycine, etc., and more preferably ethylenediamine or glycine. These may be commercially available products.

[0087] The reaction solvent is preferably, for example, N,N-dimethylformamide, diethyl ether, dioxane, tetrahydrofuran or dimethyl sulfoxide, and more preferably dimethyl sulfoxide.

[0088] Examples of the base include organic bases such as triethylamine or 1,4-diazabicyclo[2.2.2]octane, and inorganic bases such as sodium hydroxide, with organic bases such as triethylamine being preferred.

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

[0090] The immobilization of halogenated alkyl groups can be carried out, for example, by introducing a halogenated hydroxyalkyl compound 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 the reaction solvent include nitrobenzene, nitropropane, chlorobenzene, toluene, and xylene, with nitrobenzene or nitropropane being preferred.

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

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

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

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

[0097] The amount of the second polymer immobilized on the surface of the blood component adsorption material and the average amount of the second polymer immobilized on the entire blood component adsorption 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 the second polymer is coated.

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

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

[0100] The shape of the container that forms the exterior of the adsorption column may be any container that can be filled with a blood component adsorption material and has an inlet and outlet for blood, and examples thereof include cylindrical containers and prismatic containers such as triangular, quadrangular, hexagonal, or octagonal prisms.

[0101] Furthermore, an adsorption column comprising the 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 involves connecting an adsorption column comprising the blood component adsorption material to a patient via a blood circuit, passing body fluids extracted from the patient through the adsorption column, and returning the body fluids to the patient. From the viewpoint of suppressing further inflammation induced by blood components, continuous treatment is preferred, more preferably 4 hours or more, and even more preferably 24 hours or more.

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

[0103] Methods for evaluating the adsorption performance of blood component adsorption materials include methods for evaluating the leukocyte adsorption rate. Methods for calculating the leukocyte adsorption rate include, for example, filling a container having an inlet and an outlet with the blood component adsorption material, passing a liquid containing leukocytes through the material, and calculating the leukocyte adsorption rate from the changes in leukocyte concentration at the inlet and outlet. The leukocyte concentration can be measured using a commercially available multi-parameter hematology analyzer, and specifically, can be measured by the following method.

[0104] A cylindrical column (inner diameter 1 cm × height 5.14 cm) with an upper and lower blood inlet and outlet was packed with 3.1 mL of blood component adsorption material to prepare a column. Human blood kept at 37°C (external temperature) was passed through this column at a flow rate of 1.9 mL / min for 5 minutes, and the blood components at the column inlet and outlet after 5 minutes were analyzed to calculate the leukocyte adsorption rate of the blood component adsorption material. The number of each blood component was measured using a multi-parameter automated hematology analyzer XT-1800i (manufactured by Sysmex Corporation). The leukocyte adsorption rate can be calculated using the following equation 3: Leukocyte adsorption rate of blood component adsorption material (%) = {(total number of granulocytes and monocytes in blood at the column inlet) - (total number of granulocytes and monocytes in blood at the column outlet)} / (total number of granulocytes and monocytes in blood at the column inlet) × 100 ...Equation 3

[0105] Since white blood cells are cells and there is variability in the measurement of the adsorption rate, an adsorption rate of 20% or more can be determined to be significantly removed.

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

[0107] Furthermore, because the blood component adsorption material of the present invention adsorbs leukocytes by van der Waals forces, it is believed that differences in removal rates resulting from leukocyte components are small. Therefore, if the leukocyte adsorption rate exceeds 20%, it is believed that 20% or more of the individual leukocyte components, monocytes, neutrophils, and granulocytes, have all been removed, and significant removal has been achieved even when measurement variability is taken into account.

[0108] Among the adsorption performances of the blood component adsorption material, the adsorption rates of monocytes, neutrophils, basophils, and eosinophils can be evaluated by the following procedures 1) to 4). 1) A cylindrical column (inner diameter 1 cm x height 5.14 cm) with upper and lower blood inlets and outlets is prepared by packing 3.1 mL of blood component adsorption material 4. 2) Human blood maintained at 37°C (external temperature) is passed through the column at a flow rate of 1.9 mL / min for 5 minutes. 3) After 5 minutes, blood samples are taken from the column inlet and outlet, and the monocyte count, neutrophil count, basophil count, and eosinophil count are obtained using an XT-1800i automated hematology analyzer (Sysmex Corporation). 4) The monocyte removal rate, neutrophil removal rate, basophil removal rate, and eosinophil removal rate of the blood component adsorption material are calculated using the following formulas 4) to 7, rounding each obtained value to one decimal place. Equation 4: Monocyte adsorption rate (%) of blood component adsorption material = {(number of monocytes in blood at the column inlet) - (number of monocytes in blood at the column outlet)} / (number of monocytes at the column inlet) x 100 Equation 4: Neutrophil adsorption rate (%) of blood component adsorption material = {(number of neutrophils in blood at the column inlet) - (number of neutrophils in blood at the column outlet)} / (number of neutrophils at the column inlet) x 100 Equation 5: Basophil adsorption rate (%) of blood component adsorption material = {(number of basophils in blood at the column inlet) - (number of basophils at the column outlet)} / (number of basophils in blood at the column inlet) x 100 Equation 6: Eosinophil adsorption rate (%) of blood component adsorption material = {(number of eosinophils in blood at the column inlet) - (number of eosinophils at the column outlet)} / (number of eosinophils in blood at the column inlet) x 100 Equation 7:

[0109] Another method involves impregnating a blood component adsorption material with fetal bovine serum (hereinafter, FBS) in which cytokines have been dissolved, evaluating the amount of cytokine concentration reduction in the FBS after impregnation, and calculating the cytokine adsorption rate. Because cytokines are substances that are preferably removed from the blood to improve the pathology of inflammatory diseases, the greater the amount of concentration reduction due to impregnation, the higher the blood component adsorption performance can be determined. 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 used in the treatment of inflammatory diseases.

[0110] The adsorption of cytokines to the blood component adsorption material is thought to be an equilibrium reaction resulting from intermolecular forces such as van der Waals forces. Therefore, it is thought that adsorption equilibrium will be reached if the adsorption treatment is carried out for about 4 hours, regardless of the cytokine concentration.

[0111] For the reasons stated above, it is preferable that the cytokine adsorption rate is 100% for all cytokines within 4 hours, and since it is time-dependent, if it is 50% or higher within 2 hours, it can be considered that sufficient adsorption performance is being exhibited.

[0112] The performance degradation of the blood component adsorption material due to sterilization can be evaluated by the following steps 1) to 5). 1) The leukocyte adsorption rate of the blood component adsorption material is measured in advance. 2) 5 mL of the blood component adsorption material and 25 mL of distilled water are placed in a 50 mL centrifuge tube and irradiated with gamma rays at an absorbed dose of 40 kGy to obtain a sterilized blood component adsorption material. 3) A column filled with the obtained sterilized blood component adsorption material and a column filled with the blood component adsorption material before sterilization are prepared. 4) Human blood kept at 37°C (external temperature) is passed through each column at a flow rate of 1.9 mL / min for 5 minutes. 5) After 5 minutes, blood is sampled from the column inlet and outlet, and the leukocyte adsorption rate is measured using an XT-1800i automated hematology analyzer (Sysmex Corporation). The value obtained is rounded to one decimal place using the following formula 8 to calculate the performance degradation rate of the blood component adsorption material before and after sterilization. Performance decrease 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] There is no limitation on the preferred range of the rate of performance reduction of the blood component adsorption material before and after sterilization, but it is preferable that the rate of performance reduction be less than 50%, as this can reduce the elution of decomposition products from the blood component adsorption material.

[0114] The platelet adsorption rate of the blood component adsorption material can be evaluated by the following steps 1) to 4). 1) A cylindrical column (inner diameter 1 cm x height 5.14 cm) with upper and lower blood inlets and outlets is prepared by packing 3.1 mL of the blood component adsorption material. 2) Human blood kept at 37°C (external temperature) is added to the column with the anticoagulant nafamostat mesilate to a concentration of 200 μg / mL, and the blood is immediately passed through the column at a flow rate of 0.7 mL / min for 5 minutes. 3) After 5 minutes, blood samples are taken from the column inlet and outlet, and the platelet count is obtained using an XT-1800i automated hematology analyzer (Sysmex Corporation). 4) The platelet adsorption rate of the blood component adsorption material is calculated using the following formula 9, rounding the obtained value to one decimal place. Platelet adsorption rate (%) of blood component adsorption 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] There is no limitation on the preferred range of the platelet adsorption rate, but in order to prevent the formation of aggregates during blood circulation and to make clogging less likely to occur, the platelet adsorption rate is preferably 50% or less, and more preferably 20% or less.

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

[0117] In the examples, wt% means % by weight. M stands for mol / L, and mM stands for mmol / L. Unless otherwise specified, the weights of the blood component adsorption material, porous particles, first polymer, and second polymer represent dry weights. Absorbance was measured at room temperature using an ultraviolet-visible spectrophotometer (UV-1280; manufactured by Shimadzu Corporation). A blank measurement was performed before absorbance measurement, and the background peak was subtracted. Unless otherwise specified, infrared absorption spectra were measured using the following method.

[0118] The Advanced ATR mode of the Nicolet iS5 FT-IR (manufactured by Thermo Scientific; iD5 Diamond ATR accessory attached, detector: DTGS KBr, beam splitter: KBr) was selected, and the parameters were set (number of scans: 16, data interval: 0.241 cm). －１ After the background measurement was completed, the blood component adsorption material, which had been dried in a hot air dryer at 60°C for 4 hours, was spread over the prism and pressed against the prism until the pressure device locked. Measurement was started within 20 minutes of the background measurement. The measurement range was a wavenumber of 4500 cm. －１ ~500cm －１ It was decided.

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

[0120] (Setting of reactor) A 500 mL three-neck flask was equipped with a stirrer, a Dimroth condenser, a thermocouple and a whisk to form a reactor, and the temperature was controlled by a mantle heater while measuring the temperature with the thermocouple.

[0121] (Preparation of Blood Component Adsorption Material 1) Preparation of Porous Particles: 115 mL of a PVA aqueous solution containing 0.68 g of polyvinyl alcohol (PVA) was prepared, and 115 mL of a phosphoric acid aqueous solution containing 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 was prepared. The entire PVA aqueous solution was added to a reactor and heated to 70°C, after which the entire phosphoric acid aqueous solution was added to form an 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 an organic phase. The organic phase was poured onto the aqueous phase in the reactor, and the agitator was started to stir, confirming that the droplets were dispersed. The reaction was started when the temperature reached 80°C and continued for 16 hours.

[0122] The solvent alone was decanted from the reactor, and an equal amount of water to the removed solvent was added. The mixture was then stirred for 30 minutes, and the solvent was decanted. The process from the addition of water onward was repeated a total of five times to wash the product. The solvent was then decanted, and an equal amount of methanol was added, followed by stirring for 10 minutes and decantation of the solvent. The process from the addition of methanol onward was repeated a total of three times. The product was then placed in a Soxhlet extractor overnight in acetone to extract the oligomers, after which it was vacuum-dried for 8 hours, impregnated with isopropyl alcohol, and added to purified water. Finally, the particles were sieved to a uniform particle size and dried in a hot air dryer at 100°C. The resulting porous particles were designated as blood component adsorption material 1, in which the first polymer was poly(ethylbenzene / divinylbenzene) and did not contain a linker.

[0123] The presence of the first polymer in the blood component adsorption material 1 can be confirmed by measuring the infrared absorption spectrum of the surface of the blood component adsorption material 1 and detecting a C—H out-of-plane bending vibration peak (800 cm ) derived from a disubstituted aromatic compound. －１ ) was confirmed by the presence of

[0124] (Preparation of Blood Component Adsorbing Material 2) 2.4 g of N-methylol-α-chloroacetamide (hereinafter, 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 was dissolved to prepare an NMCA solution. Next, 0.2 g of paraformaldehyde (hereinafter, 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 was dissolved to prepare a PFA solution. 4.2 g of the PFA solution was cooled to 5°C, mixed with the NMCA solution, and stirred for 5 minutes. 1 g of blood component adsorbing material 1 was added, and the mixture was impregnated for 2 hours. After the impregnation, the blood component adsorbing 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 with methanol to obtain chlorinated 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, and the chlorinated particles were added and soaked at 40°C for 3 hours. The particles were filtered on a glass filter and washed with 500 mL of DMSO. The particles were further washed with 60 mL of distilled water, and then with 3 L each of distilled water and physiological saline to obtain EDA-modified particles.

[0126] 0.5 g of the resulting EDA-modified particles were mixed with 10 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate, 10 mg of immobilization PVA (saponification rate 10%), and 10 mL of water, and the mixture was allowed to react for 24 hours. The resulting porous particles were placed on filter paper, and 200 mL of methanol was poured over the particles while suction filtering. The porous particles were then peeled off from the filter paper with a spatula and dried in a hot air dryer at 50°C for 24 hours. The product removed from the hot air dryer was used as a linker to obtain blood component adsorption material 2, which had a structure in which an amide bond was attached to the aromatic ring via a methylene group, an amino group was attached to the surface side, and an amide bond was attached to the surface side via an ethylene group.

[0127] The fact that the blood component adsorption material 2 contains the second polymer can be confirmed by measuring the infrared absorption spectrum of the blood component adsorption material 2 and finding that a peak (3340 cm) derived from a hydroxyl group is present. －１) was confirmed by the presence of

[0128] (Preparation of blood component adsorption material 3) Blood component adsorption material 3 was obtained by the same manufacturing procedure as blood component adsorption material 2, except that the saponification rate of the immobilization PVA (saponification rate 10%, polymerization degree 500) was changed from 10% to 35%.

[0129] (Preparation of Blood Component Adsorption Material 4) Blood component adsorption material 4 was obtained by the same manufacturing procedure as blood component adsorption material 2, except that the saponification rate of the immobilization PVA (saponification rate 10%, polymerization degree 500) was changed from 10% to 95%.

[0130] (Preparation of Blood Component Adsorption Material 5) Blood component adsorption material 5 was obtained by the same production procedure as for blood component 4, except that the amount of immobilizing PVA added was changed from 10 mg to 3 mg.

[0131] (Preparation of Blood Component Adsorption Material 6) Blood component adsorption material 6 was obtained by the same production procedure as for blood component 4, except that the amount of immobilizing PVA added was changed from 10 mg to 20 mg.

[0132] (Preparation of Blood Component Adsorption Material 7) Blood component adsorption material 7 was obtained by the same production procedure as for blood component 4, except that the amount of immobilizing PVA added was changed from 10 mg to 25 mg.

[0133] (Preparation of Blood Component Adsorption Material 8) Blood component adsorption material 5 was obtained by the same production procedure as for blood component 4, except that the amount of immobilizing PVA added was changed from 10 mg to 5 mg.

[0134] (Preparation of Blood Component Adsorption Material 9) 1 g of porous particles obtained by the same method as for Blood Component Adsorption Material 1 and 1 g of poly(ethylene-vinyl alcohol) (polyethylene repeat unit content 40%, degree of polymerization 250) were added to 20 mL of toluene and stirred for 2 hours. The obtained porous particles were placed on filter paper and washed by pouring 200 mL of methanol onto the particles while suction filtering. The porous particles alone were peeled off from the filter paper with a spatula and dried in a hot air dryer at 50°C for 24 hours. Blood component adsorption material 9 was obtained, in which poly(ethylene-vinyl alcohol) (polyethylene repeat unit content 40%) was immobilized by physical immobilization without containing a linker.

[0135] (Preparation of Blood Component Adsorption Material 10) 115 mL of a PVA aqueous solution containing 0.6 g of PVA dissolved therein and 115 mL of a phosphoric acid aqueous solution containing 0.71 g of MSP, 2.4 g of DSP, 0.01 g of TSP, and 0.01 g of sodium nitrite were prepared. The entire PVA aqueous solution was added to a reactor and heated to 70 °C, after which the entire phosphoric acid aqueous solution was added to form an 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 an organic phase. The organic phase was poured onto the aqueous phase in the reactor, and the agitator was started to stir, confirming that the droplets were dispersed. The reaction started when the temperature reached 80 °C and continued for 16 hours.

[0136] The solvent alone was decanted from the reactor, and an amount of water equal to the amount of the removed solvent was added. The mixture was then stirred for 30 minutes, and the solvent was decanted. The operations from the addition of water onwards were repeated a total of five times to wash the product. Next, the solvent was decanted, and an equal amount of methanol was added, followed by stirring for 10 minutes and decantation of the solvent. The operations from the addition of methanol onwards were repeated a total of three times. The product was then placed in a Soxhlet extractor in acetone overnight to extract the oligomer, and then vacuum dried for 8 hours to obtain a blood component adsorption material 10 in which PVA was immobilized by physical immobilization without containing a linker.

[0137] (Preparation of Blood Component Adsorption Material 11) Chlorinated particles were prepared using the same procedure as for Blood Component Adsorption Material 2. Glycine (hereinafter, 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 allowed to soak 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 each of distilled water and physiological saline to obtain GL-modified particles.

[0138] 0.5 g of the resulting GL 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 the mixture was allowed to react for 24 hours. The resulting porous particles were placed on filter paper, and 200 mL of methanol was poured over the particles while suction filtering. The porous particles alone were collected from the filter paper with a spatula and dried in a hot air dryer at 50°C for 24 hours to obtain a blood component adsorption material 11 with immobilized PHEMA, which had a structure in which an amide bond was attached to an 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.

[0139] (Preparation of Blood Component Adsorption Material 12) GL particles were prepared using the same procedure as for blood component adsorption material 11. Furthermore, 0.5 g of GL 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 allowed to react for 24 hours. The resulting porous particles were placed on filter paper, and washed with 200 mL of methanol while suction filtering. The porous particles were then removed from the filter paper with a spatula and dried in a hot air dryer at 50°C for 24 hours. The material was removed from the hot air dryer, yielding blood component adsorption material 12 with immobilized dextran sulfate. The material had a structure in which an amide bond was attached to an 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 adsorption material 13) In the production of porous particles, the same procedure as for blood component adsorption material 4 was used, except that the organic phase was prepared by mixing 120 g of DVB, 80 g of toluene, 90 g of isooctane, and 1.1 g of BPO, to obtain blood component adsorption material 13 with immobilized PVA.

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

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

[0143] (Preparation of blood component adsorption material 16) Blood component adsorption material 16 was obtained by following the same procedures as blood component adsorption material 2, except that the immobilization PVA (saponification rate 10%) was changed to immobilization PVA (saponification rate 100%, polymerization degree 10,000) and the solvent to which the EDA particles were added was changed from water to isopropanol.

[0144] (Preparation of Blood Component Adsorbing Material 17) Blood component adsorbing material 17 was obtained by the same production procedure as blood component adsorbing material 11, except that poly(2-hydroxyethyl methacrylate) was replaced with poly(4-hydroxybutyl acrylate) (degree of polymerization 80).

[0145] (Preparation of Blood Component Adsorbing Material 18) Blood component adsorbing material 18 was obtained by the same production procedure as blood component adsorbing material 12, except that dextran sulfate was replaced with lactose.

[0146] (Preparation of Blood Component Adsorbing Material 19) Blood component adsorbing material 19 was obtained by the same production procedure as blood component adsorbing material 12, except that dextran sulfate was replaced with dextran (degree of polymerization 250).

[0147] (Preparation of blood component adsorption material 20) Production of polystyrene porous particles: The same procedure as for blood component adsorption material 1 was used to produce polystyrene porous particles, with the first polymer being poly(styrene / ethylvinylbenzene / divinylbenzene), except that the added DVB was replaced with a mixture of 105 g of styrene and 1 g of DVB, the amount of PPG added was changed from 11 g to 14 g, and the amount of BPO added was changed from 1.1 g to 0.7 g.

[0148] Blood component adsorption material 20 was obtained by the same production procedure as blood component adsorption material 4, except that the porous particles used were changed to polystyrene porous particles.

[0149] (Preparation of Blood Component Adsorption Material 21) Production of Hydroxyl Group-Containing Porous Particles: Epoxy group-containing porous particles were obtained by the same procedure as for blood component adsorption material 1, except that the 106 g of DVB was replaced with a mixture of 90 g of DVB and 16 g of glycidyl ether containing no aromatic hydrocarbon groups. 1 g of the epoxy group-containing porous particles was added to 50 mL of a 6N aqueous sodium hydroxide solution and heated at 60°C for 24 hours to open the epoxy groups and convert them into diol group-containing porous particles consisting of two hydroxyl groups. The particles were removed from the solution and repeatedly washed with water until the washing solution was no longer colored with phenolphthalein. After washing, the diol group-containing porous particles contained no linker or second polymer, a first polymer that was poly(ethylvinylbenzene / divinylbenzene / glycidyl ether ring-opened product), and a repeating unit containing no aromatic hydrocarbon groups. This was designated blood component adsorption material 21.

[0150] (Preparation of blood component adsorbent 22) Production of chloromethyl group-containing porous particles: Production was carried out in the same manner as for blood component adsorbent material 1, except that the 106 g of DVB added was changed to a mixture of 36 g of chloromethylstyrene and 70 g of DBV, and chloromethyl group-containing porous particles in which the first polymer was poly(ethylvinylbenzene / divinylbenzene / chloromethylstyrene) were obtained.

[0151] The blood component adsorption material 22 was produced using the same procedure as blood component adsorption material 11, except that the chlorinated particles were replaced with chloromethylated particles and the poly(2-hydroxyethyl methacrylate) was replaced with polyvinyl alcohol (saponification rate 95%, polymerization degree 500). This resulted in blood component adsorption material 22 having an amino group attached via a methylene group as a linker and an ester group attached via a methylene group on the surface side.

[0152] Measurement of pore volume of blood component adsorption material 1: 1 g of blood component adsorption material 1 was impregnated in 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 adsorption material 1 was removed immediately before DSC measurement, and surface water was removed to the extent that water droplets were no longer visible. Next, an aluminum sealed sample container was placed in a DSC Q100 (manufactured by TA Instruments) that had previously been temperature and calorific calibrated with pure water (melting point 0.0 ° C, heat of fusion 79.7 cal / g), and the blank weight was measured. Subsequently, approximately 6 mg of blood component adsorption material 1 was sampled and sealed in an aluminum sealed sample container to prepare a 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 used as the sample weight. The measurement sample was then rapidly cooled to -55°C and heated to 5°C at a rate of 0.3°C / min to measure differential scanning calorimetry, and a DSC curve was obtained. The sample was then removed and vacuum-dried at 110°C for 2 hours, and then placed again in the DSC Q100 to measure its weight. The amount of water lost before and after vacuum drying was recorded as the total moisture content. From the obtained DSC curve, total moisture content, and sample weight, the pore volume per gram of blood component adsorption 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] (Measurement of Pore Volume of Blood Component Adsorption Materials 2 to 15) The pore volumes per 1 g of blood component adsorption materials 2 to 15 were measured in the same manner as in the measurement of the pore volume per 1 g of blood component adsorption material 1. The results are shown in Table 1.

[0154] (Measurement of Pore Volume of Blood Component Adsorption Materials 16 to 22) The pore volumes per 1 g of blood component adsorption materials 16 to 22 were measured in the same manner as in the measurement of the pore volume per 1 g of blood component adsorption material 1. The results are shown in Table 2.

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

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

[0157] Furthermore, 1 g of blood component adsorption material 1, which had been dried in advance in a hot air dryer at 60°C for 4 hours, was taken and placed in a mortar (a deep agate mortar manufactured by AS ONE, φ70 × φ90 × 30 mm), and ground 100 times with a pestle, applying a force sufficient to break the porous particles at least enough to break them. It was visually confirmed that all of the porous particles had been ground at least once. Measurement was performed in the same manner as for measuring the infrared absorption spectrum of the surface of the porous particles, except that the obtained powder was used instead of the porous particles, and an overall average infrared absorption spectrum of blood component adsorption material 1 was obtained. The peaks due to the CH stretching (2920 cm) were measured. －１ ) and the peak due to OH groups (3340 cm －１ ) was used to calculate the content of the second polymer on the surface of the blood component adsorption material 1 from the following formula 11, by rounding the obtained value to one decimal place. The value of "the overall average content of the second polymer in the blood component adsorption material 1" used in formula 11 was calculated using the value calculated using formula 10 before rounding to one decimal place. The results are shown in Table 1. Content of the second polymer on the surface of the blood component adsorption material 1 (mg / g) = Overall average content of the second polymer in the blood component adsorption material 1 (mg / g) × {peak absorption intensity due to OH groups on the surface of the blood component adsorption material 1 / peak absorption intensity due to CH stretching on the surface of the blood component adsorption material 1} / {overall average peak absorption intensity due to OH groups on the surface of the blood component adsorption material 1 / overall average peak absorption intensity due to CH stretching on the surface of the blood component adsorption material 1} Formula 11

[0158] (Measurement of Overall Average Content of Second Polymer of Blood Component Adsorbing Materials 2 to 15) The overall average content of the second polymer of blood component adsorbing materials 2 to 15 was measured in the same manner as in measuring the overall average content of the second polymer of blood component adsorbing material 1. The results are shown in Table 1.

[0159] (Measurement of the content of the second polymer on the surface of blood component adsorption materials 2 to 15) The content of the second polymer on the surface of blood component adsorption materials 2 to 15 was measured in the same manner as in measuring the content of the second polymer on the surface of blood component adsorption material 1. The results are shown in Table 1.

[0160] (Measurement of Overall Average Content of Second Polymer of Blood Component Adsorbing Materials 16 to 22) The overall average content of the second polymer of blood component adsorbing materials 16 to 22 was measured in the same manner as in measuring the overall average content of the second polymer of blood component adsorbing material 1. The results are shown in Table 2.

[0161] (Measurement of the content of the second polymer on the surface of the blood component adsorption materials 16 to 22) The content of the second polymer on the surface of the blood component adsorption materials 16 to 22 was measured in the same manner as in the measurement of the content of the second polymer on the surface of the blood component adsorption material 1. The results are shown in Table 2.

[0162]

[0163]

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

[0165] Example 1 To confirm the adsorption performance of the blood component adsorption material 2, blood was passed through a column packed with the blood component adsorption material 2 for a predetermined period of time, the amount of leukocyte reduction in the solution before and after passing the blood was measured, and the leukocyte adsorption rate was calculated. The methods for measuring and calculating the leukocyte adsorption rate are described below.

[0166] A cylindrical column (inner diameter 1 cm × height 5.14 cm) with an upper and lower blood inlet and outlet was packed with 3.1 mL of blood component adsorption material 2 to prepare a column. Human blood maintained at 37°C (external temperature) was passed through the column at a flow rate of 1.9 mL / min for 5 minutes. After 5 minutes, the blood components at the column inlet and outlet were analyzed, and the leukocyte adsorption rate of blood component adsorption material 2 was calculated. The results are shown in Table 1. Measurement of the number of each blood component was performed using a multi-parameter automated hematology analyzer XT-1800i (manufactured by 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 adsorption material 2 (%) = {(total number of granulocytes and monocytes in blood at the column inlet) - (total number of granulocytes and monocytes in blood at the column outlet)} / (total number of granulocytes and monocytes in blood at the column inlet) × 100 (Formula 12)

[0167] (Measurement of IL-8 adsorption rate of blood component adsorption material 2) To confirm the IL-8 adsorption performance of the blood component adsorption material 2, the blood component adsorption material 2 was immersed in a liquid containing IL-8 for a predetermined period of 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 described below.

[0168] The blood component adsorption material 2 was placed in a 0.1 mL polypropylene container. Fetal bovine serum (hereinafter referred to as FBS) prepared to have an IL-8 concentration of 2000 pg / mL was poured into the container to a depth of 1 cm. ３ The blood component adsorption material 2 was added to make a total volume of 30 mL, and the mixture was mixed by inversion in an incubator at 37°C for 2 hours, after which 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 mixing by inversion using the following formula 13. The results are shown in Table 3. IL-8 adsorption rate of blood component adsorption material 2 (%) = {IL-8 concentration before mixing by inversion (pg / mL) - IL-8 concentration after mixing by inversion (pg / mL)} / IL-8 concentration before mixing by inversion (pg / mL) × 100 ... formula 13

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

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

[0171]

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

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

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

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

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

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

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

[0179] Example 8 A cylindrical column (inner diameter 1 cm × height 5.14 cm) with upper and lower blood inlets and outlets was packed with 3.1 mL of blood component adsorption material 4. Human blood maintained at 37°C (external 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 an XT-1800i multiparameter automated hematology analyzer (Sysmex Corporation). The values ​​obtained using Equations 4 to 7 were rounded to one decimal place to calculate the monocyte removal rate, neutrophil removal rate, basophil removal rate, and eosinophil removal rate of the blood component adsorption material 4. The results are shown in Table 6.

[0180] Example 9 5 mL of blood component adsorption material 4 and 25 mL of distilled water were placed in a 50 mL centrifuge tube. Sterilized blood component adsorption material 4 was obtained by gamma ray irradiation at an absorbed dose of 40 kGy. Measurements were performed using the same procedures as in Example 1, except that blood component adsorption material 2 was replaced with sterilized blood component adsorption material 4, and the resulting leukocyte adsorption rate was taken as the leukocyte adsorption rate after sterilization. The performance degradation rate of blood component adsorption material 4 before and after sterilization was calculated by rounding the value obtained using Equation 8 from the leukocyte adsorption rate of blood component adsorption material 4 obtained in Example 2 and the leukocyte adsorption rate after sterilization. The results are shown in Table 4.

[0181] Example 10 Measurements were performed in the same manner 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 of Example 2 and the leukocyte adsorption rate after sterilization, the value obtained from Equation 8 was rounded to one decimal place to calculate the performance degradation rate of blood component adsorption material 12 before and after sterilization. The results are shown in Table 4.

[0182] Example 11 Measurements were performed in the same manner 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 of Example 4 and the leukocyte adsorption rate after sterilization, the value obtained from Equation 8 was rounded to one decimal place to calculate the performance degradation rate of blood component adsorbent 17 before and after sterilization. The results are shown in Table 4.

[0183] Example 12 The leukocyte adsorption rate after sterilization was determined by performing measurements in the same manner as in Example 9, except that blood component adsorption material 4 was replaced with blood component adsorption material 19. Furthermore, using the leukocyte adsorption rate of blood component adsorption material 19 in Example 5 and the leukocyte adsorption rate after sterilization, the value obtained from Equation 8 was rounded to one decimal place to calculate the rate of performance decline of blood component adsorption material 19 before and after sterilization. The results are shown in Table 4.

[0184]

[0185] In Table 4, "leukocyte adsorption rate after sterilization" means the leukocyte adsorption rate of the blood component adsorption material after sterilization, and "performance reduction rate before and after sterilization" means the performance reduction rate of the blood component adsorption material before and after sterilization.

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

[0187] Example 13 A cylindrical column (inner diameter 1 cm × height 5.14 cm) with upper and lower blood inlets and outlets was packed with 3.1 mL of blood component adsorption material 4. Human blood kept at 37°C (external temperature) was added to this column with the anticoagulant nafamostat mesilate to 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 the platelet count was obtained using an XT-1800i automated hematology analyzer (Sysmex Corporation). The value obtained using Equation 9 was rounded to one decimal place to calculate the platelet adsorption rate of blood component adsorption material 4. The results are shown in Table 7.

[0188] Example 14 Measurements were carried out in the same manner 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 The leukocyte adsorption rate and IL-8 adsorption rate were measured using blood component adsorption material 18 in the same manner as in Example 1. The results are shown in Table 5.

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

[0191]

[0192] Comparative Example 4 Measurements and calculations were performed in the same manner as in Example 8, except that blood component adsorption material 4 was replaced with blood component adsorption material 18, and the monocyte removal rate, neutrophil removal rate, basophil removal rate, and eosinophil removal rate of blood component adsorption material 18 were calculated. The results are shown in Table 6.

[0193]

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

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

[0196] Comparative Example 5 Measurements were carried out in the same manner 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]

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

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

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

Claims

1. It has porous particles composed only of a first polymer having an aromatic hydrocarbon group in the repeating unit, and a second polymer having a hydroxyl group in the repeating unit immobilized on the surface of the porous particles, and the content of the second polymer on the surface of the blood component adsorbing material is 3 to 30 mg / g. A blood component adsorbing material.

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

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

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

5. It is for leukocyte adsorption and removal. The blood component adsorbing material according to claim 1 or 2.

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