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WO2020009008A1 - Billes pour le traitement du sang - Google Patents

Billes pour le traitement du sang Download PDF

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Publication number
WO2020009008A1
WO2020009008A1 PCT/JP2019/025744 JP2019025744W WO2020009008A1 WO 2020009008 A1 WO2020009008 A1 WO 2020009008A1 JP 2019025744 W JP2019025744 W JP 2019025744W WO 2020009008 A1 WO2020009008 A1 WO 2020009008A1
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WO
WIPO (PCT)
Prior art keywords
beads
blood
blood processing
monomer
polymer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2019/025744
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English (en)
Japanese (ja)
Inventor
勇輔 時水
覚 井上
畑中　美博
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asahi Kasei Medical Co Ltd
Original Assignee
Asahi Kasei Medical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2019112280A external-priority patent/JP7309470B2/ja
Application filed by Asahi Kasei Medical Co Ltd filed Critical Asahi Kasei Medical Co Ltd
Priority to EP20217448.8A priority Critical patent/EP3824921B1/fr
Priority to US17/256,824 priority patent/US11850346B2/en
Priority to EP19829748.3A priority patent/EP3819000B1/fr
Priority to CN201980043806.XA priority patent/CN112351802B/zh
Priority to CN202110103157.7A priority patent/CN112827478B/zh
Publication of WO2020009008A1 publication Critical patent/WO2020009008A1/fr
Anticipated expiration legal-status Critical
Priority to US17/168,787 priority patent/US11850345B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
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    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • B01J20/28019—Spherical, ellipsoidal or cylindrical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3687—Chemical treatment
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J20/28069—Pore volume, e.g. total pore volume, mesopore volume, micropore volume
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/28069—Pore volume, e.g. total pore volume, mesopore volume, micropore volume
    • B01J20/28071—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being less than 0.5 ml/g
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B01J20/28073—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being in the range 0.5-1.0 ml/g
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    • B01J20/28069—Pore volume, e.g. total pore volume, mesopore volume, micropore volume
    • B01J20/28076—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being more than 1.0 ml/g
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/28088—Pore-size distribution
    • B01J20/28092—Bimodal, polymodal, different types of pores or different pore size distributions in different parts of the sorbent
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B01J20/3206—Organic carriers, supports or substrates
    • B01J20/3208—Polymeric carriers, supports or substrates
    • B01J20/321—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions involving only carbon to carbon unsaturated bonds
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Definitions

  • the present invention relates to beads for blood treatment.
  • apheresis therapies for removing inflammatory mediators, such as cytokines and alarmin, which are considered causative substances, from the blood of patients are being performed.
  • apheresis therapies an adsorption-type blood purifier that removes an inflammatory mediator by adsorption has been developed.
  • Examples of commercially available adsorption-type blood purifiers include Toremixin (registered trademark) (Toray Medical Co., Ltd.) using an adsorbent obtained by winding fibers having a function of removing endotoxin into a roll; Alamine (HMGB1); Sepzairis (registered trademark) (Baxter Co., Ltd.), which is an adsorption-type blood purifier for continuous blood purification therapy (CRRT) using hollow fibers having a function of adsorbing cytokines (IL-6, etc.); CytoSorb (registered trademark) (CytoSorvents) using porous polymer beads having the same.
  • Blood purifiers must be biocompatible because they come into direct contact with the patient's blood.
  • the adsorbent is coated with a biocompatible polymer, typically a hydrophilic polymer.
  • Patent Document 1 describes an antithrombotic coating material produced by adding a specific radical polymerization initiator to a methanol solution containing a monomer having a specific structure and performing a polymerization reaction.
  • the antithrombotic coating material can be applied to a prosthetic device such as an artificial blood vessel made of ePTFE and a medical device such as a catheter to give them biocompatibility.
  • Patent Document 2 discloses a specific structure including a monomer unit having a nonionic group, a monomer unit having a basic nitrogen-containing functional group, and a monomer unit having an N value of 2 or less when a homopolymer is formed. A copolymer is described. By supporting the copolymer on a filter, it is possible to provide a biologically-derived liquid treatment filter capable of treating a biologically-derived liquid containing red blood cells without adversely affecting the red blood cells.
  • Patent Document 3 describes that a crosslinked polymer material having a plurality of at least one of a zwitterionic moiety and an oligoethylene glycol moiety is coated on porous beads as an adsorbent.
  • Patent Document 4 discloses biocompatibility represented by N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine (CMB) and an alkene compound having one double bond and an organic group.
  • CMB N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine
  • Patent Document 5 discloses a biocompatible polymer obtained by copolymerizing 2-methoxyethyl acrylate (MEA) and N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine (CMB).
  • MEA 2-methoxyethyl acrylate
  • CMB N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine
  • Patent Document 6 discloses 2-methoxyethyl acrylate (MEA), [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB), or [3- (methacryloylamino) propyl] dimethyl.
  • MEA 2-methoxyethyl acrylate
  • SPB 3-sulfopropyl ammonium hydroxide
  • SPBA 3-sulfoyl ammonium hydroxide
  • such an adsorption-type blood purifier is expected to be used in situations where overproduction of inflammatory mediators is a problem, such as in cardiac surgery and organ transplant surgery.
  • JP 2017-025285 A JP-A-2017-185037 JP-T-2016-514568 Japanese Patent Publication No. 2007-130194 WO 2015/098763 WO 2015/125890
  • An object of the present invention is to solve one or a plurality of problems in a medical device having a conventional biocompatible polymer described in Patent Documents 1 to 6 described above.
  • the present invention provides, in the second embodiment, blood processing beads having high biocompatibility and little elution of the supported biocompatible polymer into blood. Is one of the issues.
  • a polymer containing a monomer represented by the following general formula (1) as a monomer unit is converted into a specific porous material.
  • the present inventors have found that the above-mentioned problems can be solved by supporting them on porous beads, and have completed the present invention.
  • examples of the first embodiment of the present invention will be listed.
  • Porous beads and having a polymer supported on the surface of the porous beads, beads for blood treatment,
  • the porous beads are composed of at least one resin selected from the group consisting of an acrylic resin, a styrene resin, and a cellulose resin,
  • the polymer has the following general formula (1): ⁇
  • R 1 is —CH 3
  • R 2 is —CH 2 (CH 2 ) q OCH 3 or —CH 2 C m H 2m + 1
  • q is 1 to 5
  • m is 0-17.
  • a blood processing bead comprising a monomer represented by the formula (1) as a monomer unit.
  • the ratio of nitrogen atoms on the surface of the blood processing beads is 0.2% or more and 0.7% or less in atomic percentage based on the total number of atoms from atomic number 3 to atomic number 92.
  • Blood processing beads [3] 3.
  • Item 4 The blood processing beads according to any one of Items 1 to 3, wherein the content of the monomer represented by the general formula (1) is 40 mol% or more based on the entire monomers constituting the polymer.
  • Item 5 The blood processing bead according to any one of Items 1 to 4, wherein the polymer further includes a charged monomer as a monomer unit. [6] 6.
  • the charged monomer includes 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), [2- (methacryloyloxy) ethyl] trimethylammonium, acrylic acid (AAc), methacrylic acid.
  • the blood processing bead according to item 5 which is at least one selected from the group consisting of: [8] Item 8.
  • the blood processing bead according to any one of items 5 to 7, wherein the content of the charged monomer is 15 mol% or more and 40 mol% or less based on the entire monomers constituting the polymer.
  • the blood processing bead according to any one of items 9 to 9.
  • Item 11 The blood processing bead according to any one of items 1 to 10, wherein the amount of the polymer is 0.08 mg or more and 114 mg or less per 1 g of the dry weight of the porous beads.
  • the blood processing beads according to any one of items 1 to 10, wherein the amount of the polymer is 2.0 mg or more and 20 mg or less per 1 g of the dry weight of the porous beads. [13] 13 The blood processing bead according to any one of items 1 to 12, wherein the porous bead has a volume average particle diameter of 300 ⁇ m to 1000 ⁇ m. [14] Items 1 to whose cumulative pore volume of the porous beads having a pore diameter of 5 nm to 100 nm is 0.5 cm 3 / g or more and the cumulative pore volume of the porous beads having a pore diameter of 100 nm to 200 nm is 0.2 cm 3 / g or less. 14. The blood processing bead according to any one of items 13 to 13.
  • the monomer represented by the above general formula (1) is at least one selected from the group consisting of 2-methoxyethyl methacrylate, n-butyl methacrylate, and lauric methacrylate, any one of items 1 to 14.
  • the beads for blood treatment according to claim 1. [16] 16.
  • a blood purifier comprising the blood processing beads according to any one of items 1 to 17.
  • the porous beads are composed of at least one resin selected from the group consisting of an acrylic resin, a styrene resin, and a cellulose resin,
  • the polymer contains a zwitterionic monomer as a monomer unit,
  • the beads for blood treatment wherein the amphoteric monomer is 10 mol% or more and 30 mol% or less based on the whole monomers constituting the polymer.
  • the ratio of nitrogen atoms on the surface of the blood processing beads is 0.2% or more and 0.9% or less in atomic percentage based on the total number of atoms from atomic number 3 to atomic number 92.
  • the amphoteric monomer is represented by the following formula (2): ⁇ In the formula (2), R 1 is a hydrogen atom or a methyl group, Y is an oxygen atom or —NH—, R 2 is —CH 2 (CH 2 ) q —, and q is 1 ⁇ is 5, R 3 and R 4 are each independently a hydrogen atom or an alkyl group carbon atoms 1 ⁇ 4, R 5 are, -CH 2 (CH 2) m - and is, m is 0 to 4, and Z is —COO 2 — or SO 3 — .
  • R 1 is a hydrogen atom or a methyl group
  • Y is an oxygen atom or —NH—
  • R 2 is —CH 2 (CH 2 ) q —
  • q is 1
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • R 5 is —CH 2 (CH 2 ) m —
  • m is from 0 to 4.
  • the polymer has the following formula (4): ⁇ In the formula (4), R 7 is a hydrogen atom or a methyl group, R 8 is —CH 2 (CH 2 ) r —, r is 1 to 5, and R 9 is —CH 2 C t H 2t + 1 , where t is 0-3.
  • R 1 is a methyl group
  • q is 1 to 3
  • R 3 and R 4 are each independently a methyl group or an ethyl group
  • m is 0 or 1. 25.
  • the amphoteric monomers include N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine, [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide, [ 3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide, and at least one selected from the group consisting of 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, Item 29.
  • the blood processing bead according to any one of items 19 to 25.
  • HMGB1 high mobility group box 1
  • FIG. 1 is a graph showing Log differential pore volume distribution and accumulated pore volume of Amberlite TM XAD TM 1180N (manufactured by Organo Corporation, styrene-based polymer beads).
  • FIG. 2 is a graph showing Log differential pore volume distribution and accumulated pore volume of Purosorb TM PAD950 (Acrylic beads manufactured by Purolite).
  • FIG. 3 is a graph showing the cumulative volume particle size distribution of Amberlite TM XAD TM 1180N and Purosorb TM PAD950.
  • FIG. 4 is a schematic diagram for explaining a method for evaluating platelet adhesion.
  • the present invention will be described in detail for the purpose of illustrating the first and second embodiments of the present invention (collectively, “the present embodiment”), but the present invention is not limited to the present embodiment. .
  • the upper limit and the lower limit of each numerical range can be arbitrarily combined.
  • the blood processing beads in the first embodiment have a polymer supported on porous beads as an adsorbent.
  • the polymer is a polymer containing a monomer represented by the following general formula (1) as a monomer unit (also referred to as “biocompatible polymer”).
  • R 1 is a methyl group (—CH 3 ).
  • R 2 is a linear alkyl group having a methoxy group at the terminal (—CH 2 (CH 2 ) q OCH 3 ) or an alkyl group (—CH 2 C m H 2m + 1 ).
  • R 2 q is 1 to 5, preferably 1 to 3, more preferably 1 or 2, and m is 0 to 17, more preferably 0 to 11.
  • R 2 is an alkyl group (—CH 2 C m H 2m + 1 )
  • the C m H 2m + 1 moiety may be linear or branched, and preferably linear.
  • the monomer represented by the formula (1) is at least one selected from the group consisting of 2-methoxyethyl methacrylate (MEMA), n-butyl methacrylate (BMA), and lauric methacrylate (LMA). More preferably, it is 2-methoxyethyl methacrylate (MEMA).
  • MEMA 2-methoxyethyl methacrylate
  • BMA n-butyl methacrylate
  • LMA lauric methacrylate
  • MEMA 2-methoxyethyl methacrylate
  • the case where the monomer represented by the formula (1) is as described above is preferable because the blood compatibility can be improved while maintaining the excessive adsorption property to the porous beads higher.
  • the blood processing beads of the first embodiment may be a biocompatible bead containing a monomer having R 1 as a methyl unit (—CH 3 ) and having a specific R 2 group as a monomer unit.
  • R 1 as a methyl unit (—CH 3 )
  • R 2 group as a monomer unit.
  • a biocompatible polymer having good impregnation with the porous beads has been preferably used.
  • the pores (adsorption sites) inside the porous beads are excessively hydrophilized due to the hydrophilicity of the biocompatible polymer, thereby preventing the adsorption of the hydrophobic inflammatory mediator.
  • the adsorptivity is reduced by physically blocking the adsorption site inside the porous beads with the biocompatible polymer. Therefore, conventionally, there is a trade-off between the improvement of the biocompatibility of the porous beads and the improvement of the adsorptivity.
  • the blood processing beads of the first embodiment the combination of the specific biocompatible polymer and porous beads made of a specific material, the surface of the porous beads and the adsorption site
  • the hydrophilic / hydrophobic balance is improved.
  • the combination of the specific biocompatible polymer and the porous beads composed of the specific material appropriately adjusts the impregnation property of the porous beads.
  • a biocompatible polymer in which R 1 is a hydrogen atom has a high impregnation property with respect to the porous beads, and is non-selective with respect to the entire surface of the porous beads composed of the specific material of the present invention. In other words, in other words, the coating tends to be more uniform.
  • the polymer according to the first embodiment which includes a monomer in which R 1 is a methyl group as a monomer unit, has a moderately low impregnation property with respect to the porous beads.
  • Rough surfaces that tend to adhere tend to be preferentially coated over smooth surfaces to which compatible polymers are less likely to adhere.
  • the smooth surface of the porous beads tends to remain without the biocompatible polymer attached.
  • platelets which tend to adhere to rough surfaces rather than the smooth surface of the bead surface.
  • the polymer according to the first embodiment is preferentially attached to the rough surface, it is possible to effectively suppress platelets from adhering to the bead surface.
  • the presence of the surface to which the biocompatible polymer is not attached reduces the amount of the biocompatible polymer supported on the porous beads and reduces the blocking of the adsorption site.
  • the blood processing beads of the first embodiment can improve blood compatibility while maintaining the adsorptivity of the porous beads.
  • the blood processing beads of the first embodiment can unexpectedly achieve both biocompatibility and adsorptivity, which have conventionally been considered to have a trade-off relationship.
  • the content of the monomer represented by the formula (1) is preferably at least 40 mol%, more preferably at least 60 mol%, based on the entire monomers constituting the biocompatible polymer.
  • the upper limit of the content of the monomer is not limited, and may be 100 mol%, or 80 mol% or less, or 60 mol% or less, based on the entire monomers constituting the biocompatible polymer. Good.
  • the biocompatible polymer preferably further contains, as a monomer unit, a charged monomer copolymerizable with the monomer represented by the formula (1).
  • the “charged monomer” is a monomer having a functional group that partially or completely has a positive or negative charge under the condition of pH 7.0.
  • the biocompatible polymer further includes a monomer having a charge as a monomer unit, in the combination with the porous beads in the first embodiment, the amount of the biocompatible polymer carried on the porous beads is reduced, A decrease in adsorptivity can be suppressed. Further, since the charged monomer has high hydrophilicity, biocompatibility is also improved. As a result, there is a tendency that blood treatment beads having better adsorption and blood compatibility are obtained.
  • examples of the charged monomer include an amino group (—NH 2 , —NHR 3 , NR 3 R 4 ), a carboxyl group (—COOH), and a phosphate group (—OPO 3 H 2 ). And a sulfonic acid group (—SO 3 H), and a monomer having at least one group selected from the group consisting of zwitterionic groups.
  • R 3 and R 4 are each independently preferably an alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms.
  • the charged monomer is more preferably a monomer having at least one group selected from the group consisting of an amino group, a carboxyl group, and a zwitterionic group.
  • the charged monomer is a group consisting of a cationic monomer having an amino group, an anionic monomer having a carboxyl group, a zwitterionic monomer having an amino group and a carboxyl group, and a zwitterionic monomer having an amino group and a phosphate group. More preferably, it is at least one selected from The case where the charged monomer has a carboxyl group is more preferable because the porous beads adsorb Ca 2+ and can suppress the enhancement of blood coagulation.
  • the charged monomer includes 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), [2- (methacryloyloxy) ethyl] trimethylammonium, acrylic Acid (AAc), methacrylic acid (MAc), 2- (methacryloyloxy) ethyl phosphate, N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine (CMB), [2- (methacryloyl) Oxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB), [3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide (SPBA), At least one selected from the group consisting of 2- (methacryloyl)
  • the charged monomers are methylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), acrylic acid (AAc), N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxy. More preferably, it is at least one selected from the group consisting of betaine (CMB) and 2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl (MPC), and N-methacryloyloxyethyl-N , N-dimethylammonium- ⁇ -N-methylcarboxybetaine (CMB).
  • CMB betaine
  • MPC trimethylammonio
  • the content of the charged monomer is preferably from 10 mol% to 60 mol%, more preferably from 15 mol% to 40 mol%, based on the total amount of the monomers constituting the biocompatible polymer. It is as follows. When the content of the charged monomer is within the above range, the beads for blood treatment have an excellent balance between impregnation and hydrophilicity of the porous beads, and more excellent adsorptivity and biocompatibility. . Methods for analyzing the composition and structure of the biocompatible polymer will be described in detail in Examples.
  • the weight-average molecular weight (Mw) of the biocompatible polymer is preferably from 5,000 to 5,000,000, more preferably from 10,000 to 1,000,000, and still more preferably. It is 10,000 or more and 300,000 or less. It is preferable that the weight-average molecular weight of the biocompatible polymer is within the above range from the viewpoints of appropriate impregnation into porous beads, prevention of elution into blood, and reduction of the amount of the carrier.
  • the method of analyzing the weight average molecular weight (Mw) of the biocompatible polymer can be measured by, for example, gel permeation chromatography (GPC) as described in Comparative Examples.
  • the amount (support amount) of the biocompatible polymer supported on the porous beads is preferably 0.08 mg or more and 114 mg or less, more preferably 0.1 mg or less per 1 g of the dried weight of the porous beads. 8 mg or more and 56 mg or less, more preferably 2.0 mg or more and 20 mg or less.
  • the method of measuring the amount of the biocompatible polymer carried (the amount of coating) will be described in detail in Examples.
  • the amount of the carrier supported is suppressed to the above range by the combination of the biocompatible polymer and the porous beads made of a specific material in the first embodiment.
  • the loading may be controlled within the above range by changing the conditions for applying the biocompatible polymer to the porous beads. It is considered that when the loading amount is within the above range, the clogging of the adsorption site is reduced, and as a result, the blood compatibility can be improved while maintaining the adsorptivity of the porous beads higher.
  • the biocompatible polymer may be present in the pores of the porous beads or may close the pores to some extent.
  • the biocompatible polymer may further contain another monomer as a monomer unit in addition to the monomer of the above formula (1) and any charged monomer.
  • Other monomers are not limited as long as they can be copolymerized with these monomers.
  • R 1 is hydrogen (H), or monomers are alkyl group having 2 or more carbon atoms; the R 2 -CH 2 (CH 2 ) q A monomer in which OCH 3 is not a methoxy group but an alkoxy group having 2 or more carbon atoms, for example, an ethoxy group, a propoxy group, a butoxy group, etc .; —CH 2 (CH 2 ) q of R 2 In OCH 3 , a monomer in which q is 0 or 6 or more; a monomer in which m is 18 or more in —CH 2 C m H 2m + 1 of R 2 ; and a combination thereof.
  • the blood processing beads in the second embodiment have a polymer supported on porous beads as an adsorbent.
  • the polymer is a polymer containing a zwitterionic monomer as a monomer unit (also referred to as “biocompatible polymer”).
  • the “zwitterionic monomer” is a monomer having both a positive charge and a negative charge in one molecule under the condition of pH 7.0.
  • the biocompatible polymer contains amphoteric monomer as a monomer unit, and has high biocompatibility and is supported by being combined with porous beads composed of a specific material described later. Blood treatment beads with little elution of the compound into blood can be provided. The reason is not limited to the theory, but the inventors presume as follows.
  • the zwitterionic monomer has high hydrophilicity, biocompatibility can be improved.
  • biocompatibility can be improved.
  • the beads for blood treatment keep in contact with blood for several hours to one day or more when they are long.
  • the biocompatibility of the adsorptive blood purifier cannot be maintained for a long time, and the possibility that the polymer elutes into the blood increases.
  • the porous beads carrying the polymer function as an adsorbent, and the eluted biocompatible polymer can be adsorbed in the pores. As a result, it is possible to obtain blood processing beads having better blood compatibility and reduced elution of the biocompatible polymer into blood.
  • the zwitterionic monomer includes a zwitterionic monomer of an amino group (—NH 2 , —NHR 3 , NR 3 R 4 ) and a carboxyl group (—COOH), and an amino group and a sulfonic acid group. It is preferably at least one selected from the group consisting of a zwitterionic monomer with (—SO 3 H) and a zwitterionic monomer with an amino group and a phosphate group (—OPO 3 H 2 ).
  • the monomer is an amphoteric ionic monomer having a carboxyl group and a carboxyl group, it is more preferable that the porous beads can adsorb Ca 2+ and suppress the enhancement of blood coagulation.
  • the zwitterionic monomer includes the following formula (2): ⁇ In the formula (2), R 1 is a hydrogen atom or a methyl group, Y is an oxygen atom or —NH—, R 2 is —CH 2 (CH 2 ) q —, and q is 1 ⁇ is 5, R 3 and R 4 are each independently a hydrogen atom or an alkyl group carbon atoms 1 ⁇ 4, R 5 are, -CH 2 (CH 2) m - and is, m is 0 to 4, and Z is —COO 2 — or SO 3 — . ⁇ It is preferable that the monomer is represented by
  • R 1 is a methyl group
  • q is 1 to 3
  • R 3 and R 4 are each independently a methyl group or an ethyl group
  • m is 0 or 1. Is preferred.
  • Examples of the monomer of the above formula (2) include N-methacryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine (CMB) and [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl ) Consisting of ammonium hydroxide (SPB), [3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide (SPBA), and [3- (methacryloylamino) propyl] dimethyl (3-sulfobutyl) ammonium More preferably, it is at least one selected from the group.
  • SPB ammonium hydroxide
  • SPBA [3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide
  • SPBA [3- (methacryloylamino) propyl] dimethyl
  • the porous beads adsorb Ca 2+ and cause blood coagulation. It is more preferable in that the increase can be suppressed.
  • the zwitterionic monomer includes the following formula (3): ⁇ In the formula (3), R 1 is a hydrogen atom or a methyl group, Y is an oxygen atom or —NH—, R 2 is —CH 2 (CH 2 ) q —, and q is 1 , R 3 , R 4 , and R 6 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R 5 is —CH 2 (CH 2 ) m — And m is from 0 to 4. ⁇ Is also preferable.
  • R 1 is a methyl group
  • q is 1 to 3
  • R 3 , R 4 and R 6 are each independently a methyl group or an ethyl group
  • m is 1 or It is preferably 2.
  • Examples of the monomer of the above formula (3) include 2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl (MPC).
  • the zwitterionic monomer is preferably at least one monomer selected from the group consisting of the monomers of the above formulas (2) and (3).
  • the content of the zwitterionic monomer is preferably from 10 mol% to 30 mol%, more preferably from 12 mol% to 30 mol%, based on the entire monomers constituting the biocompatible polymer.
  • the content is more preferably 15 mol% or more and 30 mol% or less.
  • the polymer has the following formula (4): ⁇ In the formula (4), R 7 is a hydrogen atom or a methyl group, R 8 is —CH 2 (CH 2 ) r —, r is 1 to 5, and R 9 is —CH 2 C t H 2t + 1 , where t is 0-3.
  • R 7 is a hydrogen atom or a methyl group
  • R 8 is —CH 2 (CH 2 ) r —
  • r is 1 to 5
  • R 9 is —CH 2 C t H 2t + 1 , where t is 0-3.
  • ⁇ It is preferable to further include a monomer represented by the following formula as a monomer unit in order to obtain a blood processing bead having higher biocompatibility while suppressing the amount of the biocompatible polymer eluted into water.
  • R 7 is preferably a methyl group, r is preferably 1 to 3, more preferably 1 or 2, and t is preferably 0 to 2, more preferably 0 or 1.
  • the content of the monomer represented by the formula (4) is preferably at least 40 mol%, more preferably at least 60 mol%, based on the entire monomers constituting the biocompatible polymer.
  • the upper limit of the content of the monomer is not limited, and may be preferably 90 mol% or less, 80 mol% or less, or 60 mol% or less based on the entire monomers constituting the biocompatible polymer.
  • the weight-average molecular weight (Mw) of the biocompatible polymer is preferably from 5,000 to 5,000,000, more preferably from 10,000 to 1,000,000, even more preferably. It is 10,000 or more and 300,000 or less. It is preferable that the weight-average molecular weight of the biocompatible polymer is within the above range from the viewpoints of appropriate impregnation into porous beads, prevention of elution into blood, and reduction of the amount of the carrier.
  • the method of analyzing the weight average molecular weight (Mw) of the biocompatible polymer can be measured by, for example, gel permeation chromatography (GPC) as described in Comparative Examples.
  • the biocompatible polymer may be present in the pores of the porous beads or may close the pores to some extent.
  • the biocompatible polymer may be composed of the zwitterionic monomer and the monomer of the formula (4).
  • the biocompatible polymer may further include another monomer as a monomer unit in addition to the zwitterionic monomer and the monomer of the formula (4).
  • Other monomers are not limited as long as they can be copolymerized with these monomers.
  • the other monomer is not a zwitterionic type and does not correspond to the formula (4).
  • the other monomer include a cationic or anionic monomer having either a functional group that partially or completely takes a positive charge under a condition of pH 7.0 or a functional group carrying a negative charge.
  • the functional group having a positive charge or a negative charge include an amino group (—NH 2 , —NHR 3 , NR 3 R 4 ), a carboxyl group (—COOH), a phosphate group (—OPO 3 H 2 ), and And a sulfonic acid group (—SO 3 H).
  • AEMA 2-aminoethyl methacrylate
  • DMAEMA dimethylaminoethyl methacrylate
  • DEAEMA diethylaminoethyl methacrylate
  • Ac AAc
  • MAc methacrylate
  • the amount of the other monomer, if present, is at least 1 mol%, at least 5 mol%, or at least 10 mol%, at least 30 mol%, based on the total monomers making up the biocompatible polymer.
  • it may be 25 mol% or less, or 20 mol% or less.
  • the blood processing beads in the present embodiment have porous beads as an adsorbent.
  • the porous beads are composed of at least one resin selected from the group consisting of an acrylic resin, a styrene resin, and a cellulose resin.
  • the porous beads may include other resins and other components as long as the object of the present invention can be solved.
  • porous beads commercially available porous beads can be used.
  • porous beads composed of acrylic resin for example, (manufactured by Organo Corporation) Amberlite TM XAD TM 7HP, (manufactured by Mitsubishi Chemical Co.) Diaion TM HP2MG, Pyurosobu TM PAD610 (Purolite Co.), Pyurosobu TM PAD950 (manufactured by Purolite) and Muromac (registered trademark) PAP-9210 (manufactured by Muromachi Chemical Co., Ltd.).
  • porous beads composed of a styrene resin include, for example, Amberlite TM XAD TM 4 (manufactured by Organo), Amberlite TM XAD TM 2000 (manufactured by Organo), and Amberlite TM FPX66 (manufactured by Organo).
  • Amberlite TM XAD TM 1180N (manufactured by organo Co., Ltd.), (manufactured by Mitsubishi Chemical Co., Ltd.) Diaion TM HP20, (manufactured by Mitsubishi Chemical Co., Ltd.) Diaion TM HP21, Diaion TM SP700 (manufactured by Mitsubishi Chemical Co., Ltd.), Pyurosobu TM PAD600 ( Purolite TM PAD900 (Purolite), Muromac (registered trademark) SAP-9210 (Muromachi Chemical), and the like.
  • Examples of commercially available porous beads composed of a cellulosic resin include Biscopearl (registered trademark) mini (manufactured by Rengo Co., Ltd.) and C8329 (manufactured by Sigma-Aldrich).
  • the volume average particle diameter of the porous beads is preferably 300 ⁇ m to 1000 ⁇ m, more preferably 400 ⁇ m to 800 ⁇ m, and further preferably 420 ⁇ m to 700 ⁇ m.
  • the volume average particle diameter is 300 ⁇ m or more, it is possible to effectively suppress an increase in pressure when blood flows through the column, and when the volume average particle diameter is 1000 ⁇ m or less, rapid adsorption performance is exhibited. You can do it.
  • a method for measuring the “volume average particle size” of the porous beads will be described in detail in the Examples section.
  • the cumulative pore volume at a pore diameter of 5 nm to 100 nm of the porous beads is preferably 0.5 cm 3 / g or more, more preferably 0.8 cm 3 / g or more, and 1.0 cm 3 / g or more. Is more preferable.
  • the upper limit of the integrated pore volume is preferably 3.5 cm 3 / g or less, more preferably 3.0 cm 3 / g or less, and still more preferably 2.5 cm 3 / g or less.
  • the eluted biocompatible polymer can be more effectively adsorbed in the pores.
  • the cumulative pore volume of pore diameter 100 nm ⁇ 200 nm of the porous beads is not more than 0.2cm 3 / g, 0.1cm 3 / G or less, more preferably 0.05 cm 3 / g or less.
  • the porous beads have many pores of a size suitable for the adsorption of hydrophobic protein molecules, and as a result, obtain beads for blood treatment with more excellent adsorption. Is preferred because The method for measuring the integrated pore volume of the porous beads will be described in detail in the Examples section.
  • the ratio of the nitrogen element among the elements constituting the whole blood processing beads is preferably more than 0% by mass and 1.0% by mass or less, more preferably more than 0% by mass and 0.3% by mass or less.
  • the blood treatment beads are preferable because they have high blood compatibility while adsorbing hydrophobic protein molecules.
  • the total of the carbon element, the hydrogen element, and the oxygen element is preferably 97.0% by mass or more, more preferably 99.0% by mass or more.
  • the blood treatment beads are preferable because they can remove more hydrophobic protein molecules.
  • the element ratio based on the elements constituting the whole blood processing beads can be measured by elemental analysis. The measuring method will be described in detail in Examples.
  • the percentage of nitrogen atoms present on the surface of the blood processing bead is the same as the atomic number 3 lithium present on the surface of the blood processing bead.
  • the atomic percentage is preferably 0.2% or more and 0.9% or less, more preferably 0.2% or more and 0.7% or less, based on the total number of uranium atoms having the atomic number 92 from the atom. , 0.2% or more and 0.5% or less, more preferably 0.3% or more and 0.5% or less.
  • the blood processing beads are preferable because they have high blood compatibility while adsorbing hydrophobic protein molecules.
  • the ratio of the nitrogen atoms present on the surface of the blood processing beads can be adjusted by using a biocompatible polymer containing nitrogen.
  • a nitrogen-containing monomer may be used, as another monomer, another nitrogen-containing monomer may be used, or both of them may be used. They may be used (collectively referred to as “nitrogen-containing monomers”).
  • a nitrogen-containing zwitterionic monomer may be used, as another monomer, another nitrogen-containing monomer may be used, or (Also collectively referred to as “nitrogen-containing monomer”). More specifically, (1) adjusting the proportion of the nitrogen-containing monomer constituting the biocompatible polymer, and / or (2) reducing the loading amount of the nitrogen-containing biocompatible polymer on the porous beads. By adjusting the ratio, the ratio of nitrogen atoms present on the surface of the blood processing beads can be adjusted.
  • the sum of the proportions of carbon atoms and oxygen atoms present on the surface of the blood processing beads is based on the total number of uranium atoms having the atomic number 92 from the lithium atom having the atomic number 3 existing on the surface of the blood processing beads. It is preferably at least 97.0% in atomic percentage.
  • the ratio of phosphorus atoms present on the surface of the blood processing beads is preferably expressed in atomic percentage, based on the total number of uranium atoms having the atomic number 92 from the lithium atom having the atomic number 3 existing on the surface of the blood processing beads. Is 3% or less, more preferably 1% or less.
  • the ratio of a specific atom present on the surface of the blood processing beads can be measured by X-ray photoelectric spectroscopy (XPS). The measuring method will be described in detail in Examples.
  • the blood processing beads are pulverized into powder, and the surface of the powder is measured by XPS to determine the ratio of specific atoms constituting the entire blood processing beads to the atomic numbers 3 to 92. Can be measured on the basis of the total number.
  • the ratio of nitrogen atoms constituting the whole blood processing beads thus measured is preferably more than 0% and 0.1% or less based on the total number of atoms from atomic number 3 to atomic number 92. .
  • the ratio of phosphorus atoms constituting the whole blood processing beads is preferably 0.1% or less based on the total number of atoms from atomic number 3 to atomic number 92.
  • the blood treatment beads are preferable because they have high blood compatibility while adsorbing hydrophobic protein molecules.
  • the blood processing beads in the present embodiment are, for example, when the hydrophobic protein molecules of more than 1000 Da to less than 66000 Da are removed from blood, the adsorptivity of the porous beads supporting the polymer is further improved, and the biocompatible beads are eluted.
  • the polymer can be more effectively adsorbed in its pores. As a result, it is preferable because it is possible to obtain blood processing beads in which the biocompatible polymer has reduced elution into blood while having better blood compatibility.
  • can remove a certain hydrophobic protein molecule means that when a plasma sample containing a hydrophobic protein molecule to be removed is brought into contact with blood processing beads and shaken, It means that the adsorption rate of the hydrophobic protein to the beads for treatment is 30% or more.
  • the method for evaluating the adsorptivity of the blood processing beads will be described in detail in Examples.
  • the blood processing beads in the present embodiment can remove hydrophobic protein molecules more preferably from more than 8000 Da to less than 66000 Da, more preferably from more than 8000 Da to less than 51,000 Da.
  • cytokines have a molecular weight of about 5 to 60 kDa (IL-1b: about 17.5 kDa, 1L-6: about 24.5 kDa, IL-8: about 8 kDa, IL-10 (dimer): about 37.5 kDa, TNF - ⁇ (trimer): about 51 kDa), an alarmin high mobility group box 1 (HMGB1) is a hydrophobic protein having a molecular weight of about 30 kDa.
  • hydrophobic protein molecules to be removed examples include protein molecules considered to be the cause of sepsis, for example, PAMPs (pathogen-associated molecular patterns) which is an exogenous substance derived from a pathogenic microorganism; and various inflammatory mediators leading to an inflammatory reaction For example, alarmin, an endogenous substance released by tissue damage, and cytokines that cause an inflammatory response.
  • Hydrophobic protein molecules also include leukocytes.
  • PAMPs include, for example, endotoxin (LPS), peptidoglycan (PGN), lipoteichoic acid, double-stranded RNA (dsRNA), flagellin and the like.
  • Alamines include, for example, high mobility group box 1 (HMGB1), heat shock proteins (HSPs), histones, fibrinogen, neutrophil elastase, macrophage migration inhibitory factor (MIF) and the like.
  • HMGB1 high mobility group box 1
  • HSPs heat shock proteins
  • HSPs histones
  • fibrinogen neutrophil elastase
  • MIF macrophage migration inhibitory factor
  • the cytokine examples include interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-10 -11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, and IL-18), tumor necrosis factor (TNF- ⁇ , and TNF- ⁇ ), and the like.
  • the beads for blood treatment preferably remove alarmin and cytokines, and more preferably remove HMGB1 and cytokines.
  • the blood processing beads in the present embodiment are also excellent in biocompatibility while maintaining excellent adsorption as described above.
  • biocompatibility varies depending on the purpose and method of use of the blood purifier, but in the present specification, the amount of platelets adhered to the beads for blood treatment is used as an index of biocompatibility. The smaller the amount of platelets attached to the blood processing beads, the more excellent the blood processing beads are in biocompatibility. The method for evaluating the platelet adhesion of the blood processing beads will be described in detail in the Examples section.
  • the platelet adsorption rate to the porous beads Preferably 0.1% to 30%, more preferably 0.3% to 20%, and still more preferably 0.5% to 11%.
  • the amount of adhesion is preferably 0.1% to 22%, more preferably 0.3% to 13%, and still more preferably 0.5%.
  • the attached amount is preferably 0.5% to 30%, more preferably 1% to 22%, and still more preferably 3% to 11%. is there.
  • the blood processing beads in the second embodiment have a platelet residual ratio of preferably 81% when measured based on the evaluation method of “platelet adhesion of blood processing beads” described in detail in the Examples section. -100%, more preferably 83% -95%, even more preferably 85% -95%.
  • the method for producing the blood processing beads of the present embodiment is not limited.
  • the method for producing blood processing beads of the present embodiment the acrylic resin, styrene resin, and on the surface of the porous beads composed of at least one resin selected from the group consisting of cellulose resin, Supporting the biocompatible polymer in the present embodiment is included. Since the details of the biocompatible polymer and the monomer in the present embodiment have been described above, the description is omitted here.
  • a method for producing a biocompatible polymer includes adjusting a monomer solution containing a monomer of the formula (1) in an arbitrary solvent, and adjusting a polymerization solution by adding an arbitrary polymerization initiator to the monomer solution. And polymerizing the monomer.
  • a charged monomer may be further added to the monomer solution and / or the polymerization solution to copolymerize with the monomer of the formula (1). Since the details of the charged monomer have been described above, the description is omitted here.
  • a method for producing a biocompatible polymer includes adjusting a monomer solution containing a zwitterionic monomer in an arbitrary solvent, and adjusting a polymerization solution by adding an arbitrary polymerization initiator to the monomer solution. And polymerizing the monomer.
  • the monomer of formula (4) may be further added to the monomer solution and / or the polymerization solution to copolymerize with the zwitterionic monomer. Since the details of the monomer of the above formula (4) have been described above, the description is omitted here.
  • the polymerized biocompatible polymer can be purified by any purification method, for example, a reprecipitation method, a dialysis method, an ultrafiltration method, an extraction method, or the like.
  • the purified biocompatible polymer can be dried by any drying method, for example, drying under reduced pressure, spray drying, freeze drying, and heat drying.
  • Biocompatible polymer loading method As a method for supporting the biocompatible polymer on the surface of the porous beads, any supporting method, for example, an application method, a spray method, a dip method, or the like can be used.
  • the dip method includes preparing a coating solution in which the biocompatible polymer is dissolved in any solvent such as alcohol, chloroform, acetone, tetrahydrofuran, and dimethylformamide, and immersing the porous beads in the coating solution. .
  • the porous beads can be removed from the coating solution to remove excess solution and then dried by any drying method.
  • the drying method include air drying in a dry gas, and vacuum drying in which drying is performed at room temperature or while heating in a reduced pressure atmosphere. Drying under reduced pressure is preferred from the viewpoint of reducing the amount of polymer per 1 g of the porous beads in the present embodiment.
  • the coating method and the spraying method include, for example, coating or spraying the coating solution on the porous beads and then drying as described above.
  • the blood purifier of the present embodiment has the blood processing beads of the present embodiment.
  • a blood purifier generally has a main body container having a blood inlet, an internal space, and a blood outlet, and the internal space can accommodate blood processing beads.
  • the blood before the treatment is introduced into the internal space through the blood inlet, and is treated by contacting the blood processing beads of the present embodiment present in the internal space. Spent blood can flow out through the blood outlet.
  • the shape of the main container is not limited, and examples thereof include a cylindrical column, typically a cylindrical column.
  • the material constituting the main container is not limited, but may be a thermoplastic resin such as polypropylene, polyethylene, polyester, polystyrene, polytetrafluoroethylene, polycarbonate, acrylonitrile butadiene styrene (ABS), and vinyl aromatic hydrocarbon and conjugated diene. And the like. Further, a thermosetting resin such as polyurethane and epoxy may be used for sealing.
  • the evaporation residue of the sample solution, the evaporation residue of the Blank solution, and the amount of eluted beads after coating were calculated by the following formulas. Only when the calculated evaporation residue of the Blank solution was 0.3 mg or less, it was adopted as the value of the amount of eluate of beads after coating. The value of the eluate amount of the coated beads was measured and calculated twice, and it was judged that the elution was large when the average value exceeded 1.0 mg, and it was judged that the elution was small when the average value was 1.0 mg or less.
  • MEMA 2-methoxyethyl methacrylate
  • DEAEMA N-diethylaminoethyl methacrylate
  • CMB compound of structural formula (iii) of Chemical Formula 9
  • the polymerization conditions were as follows: In an ethanol solution, in the presence of 0.0025 mol / L of azoisobutyronitrile (AIBN) as an initiator, each monomer concentration was set to 1 mol / L, and the polymerization reaction was carried out at a reaction temperature of 60 ° C. for 8 hours. Thus, a polymer polymerization solution was obtained. The obtained polymer polymerization solution was dropped into diethyl ether, and the precipitated polymer was recovered. The recovered polymer was purified by performing a reprecipitation operation using diethyl ether. Thereafter, the obtained polymer was dried under reduced pressure for 24 hours to obtain a coating polymer.
  • AIBN azoisobutyronitrile
  • the molar ratio of MEMA monomer units, DEAEMA monomer units, and CMB monomer units in the coating polymer was measured as follows. After dissolving the obtained coating polymer in dimethyl sulfoxide, a peak calculated at 4.32 ppm (derived from an H atom unique to CMB) and 2.63 ppm (H specific to DEAEMA) in a chart calculated by performing 1 H-NMR measurement. It was calculated by the following formula from the area ratio of 0.65 to 2.15 ppm (total H atom weight) and the peak of (atomic origin).
  • FIG. 1 shows a graph of the log differential pore volume distribution and the cumulative pore volume of Amberlite TM XAD TM 1180N
  • FIG. 3 shows a graph of the cumulative volume particle size distribution.
  • the beads obtained by filtration were added again to a 15 mL conical tube. After a series of operations of adding 70 W / W% ethyl alcohol to the conical tube, shaking for 12 hours with a shaker, and removing the solution with a cell strainer, the absorbance at 220 nm of the solution after filtration becomes 0.03 or less. It was repeated until.
  • ⁇ Coating method 10 mL of the above coating solution is added to a 15 mL conical tube containing 2 mL of beads obtained by the above treatment, and the mixture is shaken at a shaking angle of 10 degrees and 40 r / min using a shaker (Invitro Shaker WAVE-S1, manufactured by TAITEC). Shake for 3 hours. Thereafter, the solution after the coating treatment was filtered through a cell strainer (Mini Cell Strainer II, nylon mesh 70 ⁇ m, manufactured by Funakoshi) to obtain beads after coating.
  • the absorbance at 220 nm of the solution after the coating treatment after filtration was measured with a Shimadzu UV-visible spectrophotometer UV-2600, and the coated beads obtained by filtration were added again to a 15 mL conical tube.
  • the amount of coating on the beads was calculated by the following formula, and as a result, the coating amount of the coating polymer was 6 mg / g dry beads.
  • ⁇ XPS measurement of blood treatment bead surface Fifty beads were randomly selected from the dried blood processing beads, and the surface condition of each bead was measured by XPS using K-Alpha + (manufactured by Thermo Fisher Scientific). The measurement conditions were irradiation X-ray: single crystal spectroscopy AI K ⁇ , X-ray spot diameter: 150 ⁇ m, and neutralizing electron gun: used. The value of the nitrogen atom abundance ratio with respect to the total number of uranium atoms of atomic number 92 to the number of uranium atoms of atomic number 92 present on the surface of the 50 beads for blood processing is averaged, Was calculated as the nitrogen atom abundance (%). Table 3 shows the results.
  • ⁇ XPS measurement of whole blood processing beads The dried blood processing beads were pulverized with a pestle to produce a powder of blood processing beads. The surface condition of the powder was measured by XPS using K-Alpha + (manufactured by Thermo Fisher Scientific). The measurement conditions were irradiation X-ray: single crystal spectroscopy AI K ⁇ , X-ray spot diameter: 150 ⁇ m, and neutralizing electron gun: used. The measurement was performed on 10 samples, and the value of the nitrogen atom abundance ratio with respect to the total number of the uranium atoms of the atomic number 92 from the lithium atom of the atomic number 3 was averaged. ). Table 3 shows the results.
  • the mixture was centrifuged at 2,000 g for 20 minutes at room temperature using a centrifuge (hybrid high-speed cooling centrifuge 6200, manufactured by Kubota Corporation), and the supernatant was obtained as a plasma sample.
  • 3.6 mL of the obtained plasma sample and 0.45 mL (0.10 g when dried) of the blood processing beads described above were mixed in a 5 mL polypropylene (PP) tube, and the mixture was shaken at a shaking angle of 10 ° using a shaker.
  • the sample was shaken at 10 r / min for 2 hours at 37 ° C. (this is referred to as a sample with beads contact).
  • a sample to which no beads were added was also prepared for 3.6 mL of the obtained plasma sample, and the same treatment as the sample with beads contact was performed (this is referred to as a sample without beads contact).
  • the PP tube that had been shaken was centrifuged at 2,000 g for 1 minute at room temperature using a centrifuge to obtain a supernatant with and without sample contact with beads.
  • concentrations of various cytokines were measured using a Bio-Plex system (Bio-Plex Pro human cytokine GI27-plex panel manufactured by Bio-Rad) according to the attached instruction manual.
  • HMGB-1 concentration was measured using HMGB1 ELISA Kit II (manufactured by Shino Test Co., Ltd.) according to the attached instruction manual.
  • cytokine and HMGB-1 adsorption rates of the beads were calculated by the following equation. Table 1 shows the results.
  • cytokine concentration of sample without bead contact ⁇ “cytokine concentration of sample with bead contact”
  • cytokine concentration of sample without bead contact ⁇ 100
  • HMGB-1 adsorption rate (“HMGB-1 concentration of sample without bead contact” ⁇ “HMGB-1 concentration of sample with bead contact”) / “HMGB-1 concentration of sample without bead contact” ⁇ 100
  • the concentration of cytokine without beads and the concentration of HMGB-1 without beads were 3658 pg / mL for IL-1b, 5540 pg / mL for IL-6, 6144 pg / mL for IL-8, and 846 pg / IL for IL-10.
  • TNF- ⁇ 8085 pg / mL
  • HMGB-1 27 ng / mL.
  • Heparin sodium (50,000 heparin injection / 50 mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers to a concentration of 1200 IU / mL (this is referred to as pre-treatment blood).
  • the blood processing beads (0.65 mL, 0.15 g when dried) were mixed in a polypropylene (PP) 5 mL tube with 4.4 mL of blood before treatment.
  • the tube was radially mounted on a disk-shaped rotating body of ROTATOR RT-5 (manufactured by Taitec) having a diameter of 20 cm along the radial direction of the rotating body.
  • the rotating surface of the disk-shaped rotator was set so that the angle of rotation was 22 degrees from the horizontal, and rotationally stirred at 37 ° C. for 3 hours at a speed of 4 rpm.
  • the blood after contacting the beads was filtered with a cell strainer (Mini Cell Strainer II, nylon mesh 70 ⁇ m, manufactured by Funakoshi) to remove beads (this is referred to as blood after treatment).
  • the platelet concentration of the blood was measured using a microcell counter XT-1800i (manufactured by Sysmex). Table 1 shows the result of calculating the platelet adhesion rate to the beads from the following equation.
  • Platelet adsorption rate (%) (platelet count of blood before treatment ⁇ platelet count of blood after treatment) / (platelet count of blood before treatment) ⁇ 100
  • the blood before treatment used in this experiment was as follows: leukocyte concentration: 4920 cells / ⁇ L, erythrocyte concentration: 430 ⁇ 10 4 cells / ⁇ L, platelet concentration: 240 ⁇ 10 3 cells / ⁇ L, hematocrit value: 38. 8%. Hemocron Jr.
  • the activated coagulation time of the blood before treatment was 304 seconds as measured by Signature + (Hemocron Test Cartridge JACT-LR, manufactured by International Technidyne Co., Ltd.).
  • Example 1-1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Example 1-1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • / Beads for blood treatment were prepared in the same manner as in Example 1-1 except that the ratio was / g dry beads. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Example 1-1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Blood processing beads were prepared in the same manner as in Example 1-1, except that the coating amount of the coating polymer was 4 mg / g of dry beads. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the
  • Blood processing beads were prepared in the same manner as in Example 1-1, except that the coating amount of the coating polymer was 7 mg / g of dry beads. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Example 1-20 As beads, Purosorb TM PAD950 (manufactured by Purolite, acrylic polymer beads, volume average particle diameter 621 ⁇ m, cumulative pore volume of pore diameter 5 nm to 100 nm 0.823 cm 3 / g, pore diameter instead of Amberlite TM XAD TM 1180N) Blood processing beads as in Example 1-1, except that the integrated pore volume of 0.038 cm 3 / g) of 100 nm to 200 nm was selected, and that the coating amount of the coating polymer was 14 mg / g of dry beads. Was prepared.
  • FIG. 2 shows a graph of the Log differential pore volume distribution and the accumulated pore volume of Purosorb TM PAD950, and FIG.
  • Example 3 shows a graph of the cumulative volume particle size distribution. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Example 1-21 Blood processing beads in the same manner as in Example 1-2, except that Purosorb TM PAD950 was selected as the beads instead of Amberlite TM XAD TM 1180N, and that the coating amount of the coating polymer was 13 mg / g of dry beads.
  • Example 1-1 Blood processing beads in the same manner as in Example 1-2, except that Purosorb TM PAD950 was selected as the beads instead of Amberlite TM XAD TM 1180N, and that the coating amount of the coating polymer was 13 mg / g of dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Example 1-22 Blood processing beads in the same manner as in Example 1-3, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 6 mg / g dry beads.
  • Example 1-1 Blood processing beads in the same manner as in Example 1-3, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 6 mg / g dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Example 1-23 Blood processing beads in the same manner as in Example 1-4, except that Purosorb TM PAD950 was selected as the beads instead of Amberlite TM XAD TM 1180N, and that the coating amount of the coating polymer was 19 mg / g dry beads.
  • Example 1-1 Blood processing beads in the same manner as in Example 1-4, except that Purosorb TM PAD950 was selected as the beads instead of Amberlite TM XAD TM 1180N, and that the coating amount of the coating polymer was 19 mg / g dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Example 1-24 Blood processing beads in the same manner as in Example 1-6, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as the beads, and that the coating amount of the coating polymer was 16 mg / g dry beads.
  • Example 1-1 Blood processing beads in the same manner as in Example 1-6, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as the beads, and that the coating amount of the coating polymer was 16 mg / g dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Example 1-25 Blood processing beads in the same manner as in Example 1-7, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 13 mg / g dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Example 1-26 Blood processing beads in the same manner as in Example 1-10, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 15 mg / g dry beads.
  • Example 1-1 Blood processing beads in the same manner as in Example 1-10, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 15 mg / g dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • BA butyl acrylate
  • the compound of the structural formula (xi) of [Formula 9]) 100 (molar ratio)
  • the coating amount of the coating polymer is 16 mg / g dry beads.
  • blood processing beads were produced. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • the progress of the polymerization reaction was confirmed by 1 H NMR, and after confirming that the reaction conversion was sufficiently high (around 90%), the reaction was stopped by allowing the polymerization system to cool to room temperature.
  • the polymer was precipitated by dropping the polymerization solution into hexane, the supernatant was removed by decantation, and the precipitate was dissolved in tetrahydrofuran and collected. After dissolving in tetrahydrofuran, the operation of reprecipitating with hexane was repeated twice to purify, and the resulting precipitate was further stirred in water for 24 hours. The water was removed by decanting, and the precipitate was dissolved in tetrahydrofuran and collected.
  • Example 1-1 Using the above coating polymer, beads were coated in the same manner as in Example 1-1. As a result, the coating amount was calculated to be 19 mg / bead dry g. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Comparative Example 1-6 Blood processing beads were prepared in the same manner as in Comparative Example 1-5, except that the coating polymer concentration of the coating solution used was 0.5% by weight, and the coating amount of the coating polymer was 91 mg / g of dry beads. . Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Comparative Example 1-7 (Synthesis of coating polymer) A method similar to that of Comparative Example 1-5 was used except that polymerization was carried out at 75 ° C. for 10 hours using 15 g of 2-methoxyethyl acrylate (MEA), 60 g of 1,4-dioxane, and 15 mg of azobisisobutyronitrile as initiators. Synthesis was performed. From the result of GPC molecular weight analysis, the number average molecular weight (Mn) was 20,000 and the molecular weight distribution (Mw / Mn) was 2.4.
  • Mn 2-methoxyethyl acrylate
  • Mw / Mn molecular weight distribution
  • Example 1-1 Using the above coating polymer, beads were coated in the same manner as in Example 1-1. As a result, the coating amount was calculated to be 21 mg / bead dry g. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Comparative Example 1-8 Blood processing beads were prepared in the same manner as in Comparative Example 1-7, except that the coating polymer concentration of the used coating solution was 0.3% by weight, and the coating amount of the coating polymer was 56 mg / g of dry beads. . Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Comparative Example 1-9 Blood processing beads were prepared in the same manner as in Comparative Example 1-7, except that the coating polymer concentration of the used coating solution was 0.5% by weight and the coating amount of the coating polymer was 97 mg / g of dry beads. . Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1. Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Comparative Example 1-11 Blood processing beads as in Comparative Example 1-2, except that Purosorb TM PAD950 was selected as the beads instead of Amberlite TM XAD TM 1180N, and that the coating amount of the coating polymer was 63 mg / g dry beads.
  • Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Comparative Example 1-12 Blood processing beads as in Comparative Example 1-5, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 24 mg / g dry beads. Was prepared. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Comparative Example 1-13 Blood processing beads in the same manner as in Comparative Example 1-6, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as the beads, and that the coating amount of the coating polymer was 114 mg / g dry beads. Was prepared. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Comparative Example 1-14 Blood processing beads in the same manner as in Comparative Example 1-7, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 23 mg / g dry beads. Was prepared. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Comparative Example 1-15 Blood processing beads in the same manner as in Comparative Example 1-8, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as the beads, and that the coating amount of the coating polymer was 70 mg / g dry beads. Was prepared. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Comparative Example 1-16 Blood processing beads in the same manner as in Comparative Example 1-9, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as the beads, and that the coating amount of the coating polymer was 107 mg / g dry beads. Was prepared. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Comparative Example 1-17 >> PVP (polyvinyl pyrrolidone K90, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the coating polymer, the coating polymer concentration of the coating solution used was 0.5% by weight, and the coating amount of the coating polymer was 35 mg / bead dry. Except for g, blood processing beads were prepared in the same manner as in Example 1-1. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • PVP polyvinyl pyrrolidone K90, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
  • Example 1-18 Blood processing beads were prepared in the same manner as in Example 1-1, except that the coating polymer concentration of the used coating solution was 0% by weight and the coating amount of the coating polymer was 0 mg / g of dry beads. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 1 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • Comparative Example 1-19 Blood processing beads were used in the same manner as in Comparative Example 1-17, except that Purosorb TM PAD950 was selected in place of Amberlite TM XAD TM 1180N as beads, and that the coating amount of the coating polymer was 34 mg / g of dry beads. Produced. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less. Table 2 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
  • Comparative Example 1-20 Blood processing beads were produced in the same manner as in Comparative Example 1-18, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads. Elemental analysis was performed in the same manner as in Example 1-1, and as a result, the ratio of nitrogen element was 0.3% by mass or less.
  • Table 2 shows the results of evaluation of cytokine adsorption performance and evaluation of platelet adhesion in the same manner as in Example 1-1.
  • Table 3 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 1-1.
  • the composition of the biocompatible polymer (coating agent), the type of porous beads, the amount of the biocompatible polymer carried (the coating amount), Compatibility (platelet adhesion) and cytokine adsorption of the blood treatment beads are shown in Tables 1 and 2 below.
  • Table 3 below shows the atomic ratio based on XPS measurement of the surface of the blood processing beads and the whole in the examples and comparative examples.
  • the ratio of nitrogen element based on the elemental analysis of the blood processing beads used in the examples and comparative examples of the first embodiment was 0.3% by mass or less in all the blood processing beads.
  • the total of the ratios of the carbon element, the hydrogen element, and the oxygen element based on the elemental analysis of the blood processing beads was 99.0% by mass or more in all the blood processing beads.
  • the blood processing beads of the examples have a smaller amount of the biocompatible polymer carried than the blood processing beads of the comparative example, while maintaining high adsorption of the porous beads. It can be seen that the blood compatibility is improved.
  • biocompatible polymers of Examples 1-1 to 1-19 in Table 1 had a platelet adhesion rate of 14% or less even when the coating amount was 11 mg or less.
  • the biocompatible polymers of Comparative Examples 1-1 to 1-5 and 1-7 and 1-18 had a platelet adhesion rate of 15% or more when the coating amount was 21 mg or less.
  • the coating amount is 50 mg or more as in Comparative Examples 1-6, 1-8 and 1-9, the platelet adhesion rate becomes 14% or less, but the cytokine adsorption amount is significantly reduced.
  • all of the polymers of Examples 1-20 to 1-26 in Table 2 had a platelet adhesion rate of 8% or less even when the coating amount was 20 mg or less.
  • the polymers of Comparative Examples 1-10 to 1-16 and 1-20 all had a platelet adhesion rate of 10% or more even when the coating amount was 20 mg or more.
  • the blood processing beads of Examples 1-1, 1-3 to 1-6, 1-8, 1-12, 1-15, 1-18, 1-20 and 1-22 Is based on the fact that the percentage of nitrogen atoms present on the surface of the blood processing beads is 0.2% or more and 0.7% or less in atomic percentage based on the total number of atoms from atomic number 3 to atomic number 92. It can be seen that the amount of the biocompatible polymer carried is smaller, the adsorptivity of the porous beads is higher, and the blood compatibility is improved as compared with the blood processing beads of the comparative example.
  • MEMA 2-methoxyethyl methacrylate
  • DEAEMA N-diethylaminoethyl methacrylate
  • CMB N-dimethylammonium- ⁇ -N-methylcarboxybetaine
  • the polymerization conditions were as follows: In an ethanol solution, in the presence of 0.0025 mol / L of azoisobutyronitrile (AIBN) as an initiator, each monomer concentration was set to 1 mol / L, and the polymerization reaction was carried out at a reaction temperature of 60 ° C. for 8 hours. Thus, a polymer polymerization solution was obtained. The obtained polymer polymerization solution was dropped into diethyl ether, and the precipitated polymer was recovered. The recovered polymer was purified by performing a reprecipitation operation using diethyl ether. Thereafter, the obtained polymer was dried under reduced pressure for 24 hours to obtain a coating polymer.
  • AIBN azoisobutyronitrile
  • the molar ratio of MEMA monomer units, DEAEMA monomer units, and CMB monomer units in the coating polymer was measured as follows. After dissolving the obtained coating polymer in dimethyl sulfoxide, a peak calculated at 4.32 ppm (derived from an H atom unique to CMB) and 2.63 ppm (H specific to DEAEMA) in a chart calculated by performing 1 H-NMR measurement. It was calculated by the following formula from the area ratio of 0.65 to 2.15 ppm (total H atom weight) and the peak of (atomic origin).
  • FIG. 1 shows a graph of the log differential pore volume distribution and the cumulative pore volume of Amberlite TM XAD TM 1180N
  • FIG. 3 shows a graph of the cumulative volume particle size distribution.
  • the beads obtained by filtration were added again to a 50 mL conical tube. After a series of operations of adding 57 W / W% ethyl alcohol to the conical tube, shaking for 12 hours with a shaker, and removing the solution with a cell strainer, the absorbance at 220 nm of the solution after filtration becomes 0.03 or less. It was repeated until.
  • a shaking machine Invitro Shaker WAVE-S1, manufactured by TAITEC
  • ⁇ XPS measurement of blood treatment bead surface Fifty beads were randomly selected from the dried blood processing beads, and the surface condition of each bead was measured by XPS using K-Alpha + (manufactured by Thermo Fisher Scientific). The measurement conditions were irradiation X-ray: single crystal spectroscopy AI K ⁇ , X-ray spot diameter: 150 ⁇ m, and neutralizing electron gun: used. The value of the nitrogen atom abundance ratio with respect to the total number of uranium atoms of atomic number 92 to the number of uranium atoms of atomic number 92 present on the surface of the 50 beads for blood processing is averaged, Was calculated as the nitrogen atom abundance (%). Table 6 shows the results.
  • ⁇ XPS measurement of whole blood processing beads The dried blood processing beads were pulverized with a pestle to produce a powder of blood processing beads. The surface condition of the powder was measured by XPS using K-Alpha + (manufactured by Thermo Fisher Scientific). The measurement conditions were irradiation X-ray: single crystal spectroscopy AI K ⁇ , X-ray spot diameter: 150 ⁇ m, and neutralizing electron gun: used. The measurement was performed on 10 samples, and the value of the nitrogen atom abundance ratio with respect to the total number of the uranium atoms of the atomic number 92 from the lithium atom of the atomic number 3 was averaged. ). Table 6 shows the results.
  • FIG. 4 is a schematic diagram for explaining a method for evaluating platelet adhesion.
  • Blood treatment beads (1.5 mL, 0.33 g when dried) were swollen with physiological saline (Otsuka Raw Food Injection, Otsuka Pharmaceutical Factory).
  • the swollen blood processing beads (11) were packed in a 2.5 mL syringe while taking care not to allow air to enter.
  • the upper and lower blood processing beads were sandwiched between a mesh (12) and an O-ring (13) to prevent the beads from leaking.
  • a mini column (10) packed with 1.5 mL of blood processing beads was prepared.
  • Heparin sodium (50,000 heparin unit / 50 mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers to a concentration of 1000 IU / mL (this is referred to as “blood before treatment (21)”).
  • a physiological saline solution (Otsuka Raw Food Infusion, manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) was charged into a mini-column (10) filled with blood processing beads by a syringe pump (20) (TE- (351, manufactured by Terumo Corporation) at a flow rate of 1 mL / min for 10 minutes.
  • the blood before treatment (21) was passed at a flow rate of 1 mL / min using a syringe pump (20) (TE-351, manufactured by Terumo Corporation).
  • a syringe pump (20) TE-351, manufactured by Terumo Corporation.
  • the blood after treatment (31) became 9 mL.
  • the blood flow was terminated.
  • the platelet concentrations of the post-treatment blood and the pre-treatment blood were measured with a microcell counter XT-1800i (manufactured by Sysmex), and the percentage of platelets remaining in the beads was calculated from the following formula, and was 85%.
  • Platelet residual ratio (%) platelet count of blood after treatment / platelet count of blood before treatment ⁇ 100
  • the blood before treatment used in this experiment was: leukocyte concentration: 5310 cells / ⁇ L, erythrocyte concentration: 505 ⁇ 10 4 cells / ⁇ L, platelet concentration: 196 ⁇ 10 3 / ⁇ L, hematocrit value: 41. 0%. Hemocron Jr.
  • the activated coagulation time of the pre-treatment blood was 319 seconds as measured by Signature + (Hemocron Test Cartridge JACT-LR, manufactured by International Technidyne Co., Ltd.).
  • the mixture was centrifuged at 2,000 g for 20 minutes at room temperature using a centrifuge (hybrid high-speed cooling centrifuge 6200, manufactured by Kubota Corporation), and the supernatant was obtained as a plasma sample.
  • 3.6 mL of the obtained plasma sample and 0.45 mL (0.10 g when dried) of the blood processing beads described above were mixed in a 5 mL polypropylene (PP) tube, and the mixture was shaken at a shaking angle of 10 ° using a shaker.
  • the sample was shaken at 10 r / min for 2 hours at 37 ° C. (this is referred to as a sample with beads contact).
  • a sample to which no beads were added was also prepared for 3.6 mL of the obtained plasma sample, and the same treatment as the sample with beads contact was performed (this is referred to as a sample without beads contact).
  • the PP tube that had been shaken was centrifuged at 2,000 g for 1 minute at room temperature using a centrifuge to obtain a supernatant with and without sample contact with beads.
  • concentrations of various cytokines were measured using a Bio-Plex system (Bio-Plex Pro human cytokine GI27-plex panel manufactured by Bio-Rad) according to the attached instruction manual.
  • HMGB-1 concentration was measured using HMGB1 ELISA Kit II (manufactured by Shino Test Co., Ltd.) according to the attached instruction manual.
  • cytokine and HMGB-1 adsorption rates of the beads were calculated by the following equation. Table 5 shows the results.
  • cytokine concentration of sample without bead contact ⁇ “cytokine concentration of sample with bead contact”
  • cytokine concentration of sample without bead contact ⁇ 100
  • HMGB-1 adsorption rate (“HMGB-1 concentration of sample without bead contact” ⁇ “HMGB-1 concentration of sample with bead contact”) / “HMGB-1 concentration of sample without bead contact” ⁇ 100
  • the concentration of cytokine without beads and the concentration of HMGB-1 without beads were 3658 pg / mL for IL-1b, 5540 pg / mL for IL-6, 6144 pg / mL for IL-8, and 846 pg / IL for IL-10.
  • TNF- ⁇ 8085 pg / mL
  • HMGB-1 27 ng / mL.
  • MEMA / CMB 80/20 (molar ratio
  • Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
  • MEMA / CMB 70/30 (molar ratio)
  • a coated bead and a blood processing bead were prepared in the same manner as in Example 2-1 except that The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less.
  • Example 2-1 The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 84%, and the amount of adhered platelets was small. Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • MEMA / SPB 70/30 (molar ratio)
  • the same coated beads and blood processing beads as in Example 2-1 were prepared.
  • the eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1.
  • the ratio of the nitrogen element was 0.3% by mass or less.
  • the platelet adhesion was evaluated in the same manner as
  • Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
  • Beads after blood coating and beads for blood treatment were produced. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less.
  • the platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 87%, and the amount of adhered platelets was small.
  • a coated bead and a blood treatment bead similar to -1 were prepared. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less.
  • the platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the platelet remaining rate was 86%, and the amount of platelet adhesion was small.
  • Example 2-12 As beads, Purosorb TM PAD950 (manufactured by Purolite, acrylic polymer beads, volume average particle diameter 621 ⁇ m, cumulative pore volume of pore diameter 5 nm to 100 nm 0.823 cm 3 / g, pore diameter instead of Amberlite TM XAD TM 1180N) Coated beads and beads for blood treatment were prepared in the same manner as in Example 2-1 except that the integrated pore volume of 100 nm to 200 nm (0.038 cm 3 / g) was selected.
  • FIG. 2 shows a graph of the Log differential pore volume distribution and the accumulated pore volume of Purosorb TM PAD950
  • FIG. 3 shows a graph of the cumulative volume particle size distribution.
  • Example 2-1 The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 91%, and the amount of adhered platelets was small. Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Example 2-14 Except that Purosorb TM PAD 950 was selected instead of Amberlite TM XAD TM 1180N as beads, coated beads and blood treatment beads were produced in the same manner as in Example 2-3. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 87%, and the amount of adhered platelets was small. Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Example 2-15 Coated beads and blood treatment beads were prepared in the same manner as in Example 2-7 except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads.
  • the eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less.
  • the platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 85%, and the amount of adhered platelets was small.
  • Example 2-16 Coated beads and blood treatment beads were prepared in the same manner as in Example 2-9, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 85%, and the amount of adhered platelets was small.
  • Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads.
  • the eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio
  • Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
  • Example 2-17 Coated beads and beads for blood treatment were prepared in the same manner as in Example 2-10, except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the platelet remaining rate was 88%, and the amount of platelet adhesion was small.
  • Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads.
  • the eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the
  • Comparative Example 2-1 Except that the coating polymer concentration of the used coating solution was 0% by weight (the coating polymer was not dissolved), the same coated beads and blood processing beads as in Example 2-1 were produced. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 74%, and the amount of adhered platelets was large.
  • Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
  • MEMA 100 (molar ratio)
  • Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
  • Comparative Example 2-6 Coated beads and beads for blood treatment were prepared in the same manner as in Comparative Example 2-1 except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. The platelet adhesion was evaluated in the same manner as in Example 2-1. As a result, the residual ratio of platelets was 80%, and the amount of adhered platelets was large.
  • Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
  • Comparative Example 2-7 Coated beads and blood treatment beads were prepared in the same manner as in Comparative Example 2-5 except that Purosorb TM PAD950 was selected instead of Amberlite TM XAD TM 1180N as beads. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.4 mg. Elemental analysis of the beads for blood treatment was performed in the same manner as in Example 2-1. As a result, the ratio of the nitrogen element was 0.3% by mass or less. Table 6 shows the results of XPS measurement of the bead surface and XPS measurement of the whole bead in the same manner as in Example 2-1.
  • Coated beads were prepared in the same manner as Comparative Example 2-1 except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N as beads.
  • the elution amount was as low as 1.0 mg or less.
  • Comparative Example 2-9 As the beads, coated beads similar to those in Example 2-1 were used, except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 1.8 mg, and the amount of eluted was large.
  • Comparative Example 2-10 As the beads, coated beads similar to those in Example 2-3 were used except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of beads was determined in the same manner as in Example 2-1, the elution amount was 2.0 mg, and the amount of eluted was large.
  • Comparative Example 2-11 As coated beads, the same beads as in Example 2-4 were used except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 2.3 mg, and the eluate was large.
  • Comparative Example 2-12 As the beads, coated beads similar to those in Example 2-6 were used except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 1.9 mg, and the amount of eluted was large.
  • Comparative Example 2-13 As the beads, coated beads similar to those in Example 2-7 were used, except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 2.2 mg, and the amount of eluted was large.
  • Comparative Example 2-14 As the beads, coated beads similar to those in Example 2-8 were used, except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 2.1 mg, and the amount of eluted was large.
  • Comparative Example 2-15 As coated beads, the same beads as in Example 2-9 were used, except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 1.3 mg, and the amount of eluted was large.
  • Comparative Example 2-16 As the beads, coated beads similar to those in Example 2-10 were used, except that the PVA-based polymer beads obtained above were selected instead of Amberlite TM XAD TM 1180N. When the elution of the beads was determined in the same manner as in Example 2-1, the elution amount was 1.2 mg, and there were many eluted substances.
  • Comparative Example 2-17 As beads, instead of Amberlite TM XAD TM 1180N, activated carbon beads (manufactured by Kureha Co., Ltd., average particle diameter 576 ⁇ m, cumulative pore volume 0.134 cm 3 / g with pore diameter 5 nm to 100 nm, cumulative fine pore with pore diameter 100 nm to 200 nm) A coated bead was produced in the same manner as in Comparative Example 2-1 except that a pore volume of 0.005 cm 3 / g or less was selected. The eluate of the beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less.
  • Platelet adhesion are shown in Tables 4 and 5 below.
  • Table 6 below shows the atomic ratio based on XPS measurement of the surface of the blood processing beads and the whole in the examples and comparative examples.
  • the ratio of nitrogen element based on the elemental analysis of the beads for blood treatment used in Examples and Comparative Examples of the second embodiment was 0.3% by mass or less in all the beads for blood treatment.
  • the total of the ratios of the carbon element, the hydrogen element, and the oxygen element based on the elemental analysis of the blood processing beads was 99.0% by mass or more in all the blood processing beads.
  • the blood processing beads of the present invention can be used, for example, for treating ischemic diseases such as sepsis.
  • the blood processing beads of the present invention are also expected to be used in cases where overproduction of inflammatory mediators becomes a problem, such as in cardiac surgery and organ transplant surgery, in addition to treatment of ischemic diseases.

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Abstract

L'invention concerne des billes pour le traitement du sang comprenant des billes poreuses et un polymère porté sur la surface des billes poreuses. Les billes poreuses sont conçues à partir d'au moins une résine choisie dans le groupe constitué par des résines acryliques, des résines de styrène et des résines de cellulose ; et le polymère comprend un monomère spécifique défini dans la description en tant que motif monomère.
PCT/JP2019/025744 2018-07-02 2019-06-27 Billes pour le traitement du sang Ceased WO2020009008A1 (fr)

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EP20217448.8A EP3824921B1 (fr) 2018-07-02 2019-06-27 Billes pour le traitement du sang
US17/256,824 US11850346B2 (en) 2018-07-02 2019-06-27 Beads for blood processing
EP19829748.3A EP3819000B1 (fr) 2018-07-02 2019-06-27 Billes pour le traitement du sang
CN201980043806.XA CN112351802B (zh) 2018-07-02 2019-06-27 血液处理用珠
CN202110103157.7A CN112827478B (zh) 2018-07-02 2019-06-27 血液处理用珠
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EP4245860A4 (fr) * 2020-10-12 2024-07-10 Taag Genetics Corp Dispositif pour l'extraction et la purification d'acides nucléiques
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