WO2020009008A1 - Beads for blood processing - Google Patents

Beads for blood processing 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
Application number
PCT/JP2019/025744
Other languages
French (fr)
Japanese (ja)
Inventor
勇輔 時水
覚 井上
畑中　美博
Original Assignee
旭化成メディカル株式会社
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 JP2019112290A external-priority patent/JP7312030B2/en
Application filed by 旭化成メディカル株式会社 filed Critical 旭化成メディカル株式会社
Priority to EP20217448.8A priority Critical patent/EP3824921A1/en
Priority to US17/256,824 priority patent/US11850346B2/en
Priority to EP19829748.3A priority patent/EP3819000A4/en
Priority to CN202110103157.7A priority patent/CN112827478B/en
Priority to CN201980043806.XA priority patent/CN112351802B/en
Publication of WO2020009008A1 publication Critical patent/WO2020009008A1/en
Priority to US17/168,787 priority patent/US11850345B2/en

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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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    • 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
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    • B01J20/28076—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being more than 1.0 ml/g
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    • 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

Provided are beads for blood processing having porous beads and a polymer carried on the surface of the porous beads, wherein: the porous beads are configured from at least one resin selected from the group consisting of acrylic resins, styrene resins, and cellulose resins; and the polymer includes a specific monomer defined in the description as a monomer unit.

Description

血液処理用ビーズBlood processing beads
　本発明は、血液処理用ビーズに関する。 The present invention relates to beads for blood treatment.
　敗血症をはじめとする虚血性疾患の治療においては、その原因物質と考えられる炎症性メディエーター、例えばサイトカイン及びアラーミン等を患者の血液中から除去する、種々のアフェレシス療法が行われている。近年、アフェレシス療法の一つとして、炎症性メディエーターを吸着により除去する、吸着型血液浄化器の開発が進んでいる。 治療 In the treatment of ischemic diseases such as sepsis, various apheresis therapies for removing inflammatory mediators, such as cytokines and alarmin, which are considered causative substances, from the blood of patients are being performed. In recent years, as one of the apheresis therapies, an adsorption-type blood purifier that removes an inflammatory mediator by adsorption has been developed.
　上市されている吸着型血液浄化器としては、例えば、エンドトキシン除去機能を有する繊維をロール状に巻き付けた吸着体を用いた、トレミキシン（登録商標）（東レ・メディカル株式会社）；アラーミン（ＨＭＧＢ１）及びサイトカイン（ＩＬ－６等）吸着機能を有する中空糸を用いた、持続的血液浄化療法（ＣＲＲＴ）向け吸着型血液浄化器である、セプザイリス（登録商標）（バクスター株式会社）；並びにサイトカイン除去機能を有する多孔性ポリマービーズを用いた、ＣｙｔｏＳｏｒｂ（登録商標）（サイトソーベンツ社）等が挙げられる。 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.
　血液浄化器は患者の血液に直接触れるため、生体適合性を有することが必要である。血液浄化器に生体適合性を付与するため、吸着体は、生体適合性ポリマー、典型的には親水性ポリマーでコーティングされる。 Blood purifiers must be biocompatible because they come into direct contact with the patient's blood. To provide biocompatibility to the blood purifier, the adsorbent is coated with a biocompatible polymer, typically a hydrophilic polymer.
　例えば、特許文献１は、特定構造の単量体を含むメタノール溶液に特定のラジカル重合開始剤を加えて重合反応を行うことにより製造される、抗血栓性コーティング材を記載している。この抗血栓性コーティング材は、ｅＰＴＦＥ製人工血管等の人工器官、及びカテーテル等の医療機器に塗布され、それらに生体適合性を与えることができる。 For example, 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.
　特許文献２は、非イオン性基を有するモノマー単位と、塩基性含窒素官能基を有するモノマー単位と、ホモポリマーを形成した場合にＮ値が２以下となるモノマー単位とを含む、特定構造の共重合体を記載している。この共重合体をフィルター上に担持することにより、赤血球へ悪影響を与えずに赤血球を含む生体由来液を処理することが可能な、生体由来液処理フィルターを提供することができる。 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.
　特許文献３は、両性イオン部分およびオリゴエチレングリコール部分の少なくとも１つを複数有する架橋ポリマー材料を、吸着体としての多孔質ビーズ上にコーティングすることを記載している。 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.
　特許文献４は、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）と、二重結合１個及び有機基を有するアルケン化合物で表される生体適合性を有する重合性モノマーとを共重合させた、生体適合性ポリマーを記載している。 Patent Document 4 discloses biocompatibility represented by N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB) and an alkene compound having one double bond and an organic group. A biocompatible polymer obtained by copolymerizing a polymerizable monomer having a biocompatible polymer is described.
　特許文献５は、２－メトキシエチルアクリレート（ＭＥＡ）と、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）とを共重合させた生体適合性ポリマーであって、ＣＭＢが、全単量体単位中１～７モル％含まれる、生体適合性ポリマーを記載している。 Patent Document 5 discloses a biocompatible polymer obtained by copolymerizing 2-methoxyethyl acrylate (MEA) and N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB). Thus, a biocompatible polymer is described in which CMB is contained in an amount of 1 to 7 mol% in all monomer units.
　特許文献６は、２－メトキシエチルアクリレート（ＭＥＡ）と、［２－（メタクリロイルオキシ）エチル］ジメチル－（３－スルホプロピル）アンモニウムヒドロキシド（ＳＰＢ）、または［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホプロピル）アンモニウムヒドロキシド（ＳＰＢＡ）とを共重合させた生体適合性ポリマーであって、ＳＢＡＣが、全単量体単位中１～７モル％含まれる、生体適合性ポリマーを記載している。 Patent Document 6 discloses 2-methoxyethyl acrylate (MEA), [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB), or [3- (methacryloylamino) propyl] dimethyl. A biocompatible polymer obtained by copolymerizing (3-sulfopropyl) ammonium hydroxide (SPBA), wherein SBAC is contained in an amount of 1 to 7 mol% in all monomer units. ing.
　このような吸着型血液浄化器は、虚血性疾患の治療のほか、心臓手術及び臓器移植手術などの、炎症性メディエーターの過剰産生が問題となる場面での活用が期待されている。 吸着 In addition to treating ischemic diseases, 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.
特開２０１７－０２５２８５号公報JP 2017-025285 A 特開２０１７－１８５０３７号公報JP-A-2017-185037 特表２０１６－５１４５６８号公報JP-T-2016-514568 特表２００７－１３０１９４号公報Japanese Patent Publication No. 2007-130194 国際公開第２０１５／０９８７６３号WO 2015/098763 国際公開第２０１５／１２５８９０号WO 2015/125890
　本発明は、上記の特許文献１～６等に記載されている従来の生体適合性ポリマーを有する医療機器における一つ又は複数の課題を解決することを目的とする。 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.
　例えば、上記の特許文献１～３等に記載されているような従来の生体適合性ポリマーを、吸着体としての多孔質ビーズにコーティング（本願明細書において「担持」ともいう。）すると、多孔質ビーズの生体適合性を向上させることができるものの、多孔質ビーズの表面が親水化され、疎水性蛋白質である炎症性メディエーターの吸着性が低下する。そのため、生体適合性の向上と吸着性の向上とはトレードオフの関係にあると考えられている。 For example, when a conventional biocompatible polymer as described in Patent Documents 1 to 3 described above is coated on a porous bead as an adsorbent (also referred to as “support” in the specification of the present application), the porous bead becomes porous. Although the biocompatibility of the beads can be improved, the surface of the porous beads is hydrophilized, and the adsorptivity of the inflammatory mediator, which is a hydrophobic protein, is reduced. Therefore, it is considered that there is a trade-off between the improvement in biocompatibility and the improvement in adsorptivity.
　上記のような背景に鑑み、本発明は、第一の実施形態において、多孔質ビーズの吸着性を維持しつつ、改善された血液適合性を有する血液処理用ビーズを提供することを課題の一つとする。 In view of the above background, it is an object of the present invention to provide a blood processing bead having improved blood compatibility while maintaining the adsorptivity of porous beads in the first embodiment. One.
　また、特許文献２～４等に記載されているような従来の生体適合性ポリマーを、医療材料にコーティング（本願明細書において「担持」ともいう。）すると、医療材料の生体適合性を向上させることはできるものの、両性イオンを含むポリマーは水溶性が高いため、水や血液と接触したときに上記ポリマーが血液中に溶出してしまう。吸着型血液浄化器において、溶出物は少ないほうが良く、上記の特許文献５及び６のように、コーティングするポリマーは、両性イオンを含む単量体単位の含有率を十分に抑制することが必要であると考えられている。 In addition, when a conventional biocompatible polymer as described in Patent Documents 2 to 4 is coated on a medical material (also referred to as “support” in the specification of the present application), the biocompatibility of the medical material is improved. Although it is possible, the polymer containing amphoteric ions has high water solubility, so that the polymer elutes into blood when it comes into contact with water or blood. In an adsorption-type blood purifier, it is better that the amount of eluted matter is small. As described in Patent Documents 5 and 6, it is necessary for the polymer to be coated to sufficiently suppress the content of a monomer unit containing an amphoteric ion. It is believed that there is.
　上記のような背景に鑑み、本発明は、第二の実施形態において、生体適合性が高く、かつ担持された生体適合性ポリマーの血液中への溶出が少ない、血液処理用ビーズを提供することを課題の一つとする。 In view of the background 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.
　本願発明者らは、上記課題を解決するため鋭意検討を重ねた結果、第一の実施形態において、下記一般式（１）で表されるモノマーを単量体単位として含むポリマーを、特定の多孔質ビーズ上に担持することにより上記課題を解決できることを見いだし、本発明を完成するに至った。以下、本発明の第一の実施形態の例を列記する。
［１］
　多孔質ビーズ、及び上記多孔質ビーズの表面上に担持されたポリマーを有する、血液処理用ビーズであって、
　上記多孔質ビーズは、アクリル系樹脂、スチレン系樹脂、及びセルロース系樹脂からなる群から選択される少なくとも一つの樹脂から構成され、
　上記ポリマーは、下記一般式（１）：
Figure JPOXMLDOC01-appb-C000005
 ｛式（１）中、Ｒ１は、－ＣＨ３であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑＯＣＨ３又は－ＣＨ２ＣｍＨ２ｍ＋１であり、ｑは１～５であり、ｍは０～１７である。｝
で表されるモノマーを単量体単位として含む、血液処理用ビーズ。
［２］
　上記血液処理用ビーズの表面における窒素原子の割合が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で０．２％以上０．７％以下である、項目１に記載の血液処理用ビーズ。
［３］
　ｑは１又は２であり、ｍは０～１１である、項目１又は２に記載の多孔質吸着ビーズ。
［４］
　上記一般式（１）で表されるモノマーの含有量は、上記ポリマーを構成するモノマー全体を基準として４０モル％以上である、項目１～３のいずれか一項に記載の血液処理用ビーズ。
［５］
　上記ポリマーは、電荷を有するモノマーを単量体単位として更に含む、項目１～４のいずれか一項に記載の血液処理用ビーズ。
［６］
　上記電荷を有するモノマーは、アミノ基、カルボキシル基、リン酸基、スルホン酸基、及び両性イオン基からなる群から選択される少なくとも一つの基を有するモノマーである、項目５に記載の血液処理用ビーズ。
［７］
　上記電荷を有するモノマーは、２－アミノエチルメタクリレート（ＡＥＭＡ）、ジメチルアミノエチルメタクリレート（ＤＭＡＥＭＡ）、ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ）、［２－（メタクリロイルオキシ）エチル］トリメチルアンモニウム、アクリル酸（ＡＡｃ）、メタクリル酸（ＭＡｃ）、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）、及びリン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル（ＭＰＣ）からなる群から選択される少なくとも一つである、項目５に記載の血液処理用ビーズ。
［８］
　上記電荷を有するモノマーの含有量は、上記ポリマーを構成するモノマー全体を基準として１０モル％以上６０モル％以下である、項目５～７のいずれか一項に記載の血液処理用ビーズ。
［９］
　上記電荷を有するモノマーの含有量は、上記ポリマーを構成するモノマー全体を基準として１５モル％以上４０モル％以下である、項目５～７のいずれか一項に記載の血液処理用ビーズ。
［１０］
　上記血液処理用ビーズの表面における、炭素原子と酸素原子の割合の和が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で９７．０％以上である、項目１～９のいずれか一項に記載の血液処理用ビーズ。
［１１］
　上記ポリマーの量は、上記多孔質ビーズ乾燥時重量１ｇ当たり０．０８ｍｇ以上１１４ｍｇ以下である、項目１～１０のいずれか一項に記載の血液処理用ビーズ。
［１２］
　上記ポリマーの量は、上記多孔質ビーズ乾燥時重量１ｇ当たり２．０ｍｇ以上２０ｍｇ以下である、項目１～１０のいずれか一項に記載の血液処理用ビーズ。
［１３］
　上記多孔質ビーズの体積平均粒子径は、３００μｍ～１０００μｍである、項目１～１２のいずれか一項に記載の血液処理用ビーズ。
［１４］
　上記多孔質ビーズの細孔径５ｎｍ～１００ｎｍの積算細孔容量が０．５ｃｍ３／ｇ以上であり、細孔径１００ｎｍ～２００ｎｍの積算細孔容量が０．２ｃｍ３／ｇ以下である、項目１～１３のいずれか一項に記載の血液処理用ビーズ。
［１５］
　上記一般式（１）で表されるモノマーは、２－メトキシエチルメタクリレート、ｎ－ブチルメタクリレート、及びラウリル酸メタクリレートからなる群から選択される少なくとも一つである、項目１～１４のいずれか一項に記載の血液処理用ビーズ。
［１６］
　血液から１０００Ｄａ超～６６０００Ｄａ未満の疎水性蛋白質分子を除去する、項目１～１５のいずれか一項に記載の血液処理用ビーズ。
［１７］
　血液からサイトカイン及びハイモビリティグループボックス１（ＨＭＧＢ１）を除去する、項目１～１６のいずれか一項に記載の多孔質吸着ビーズ。
［１８］
　項目１～１７のいずれか一項に記載の血液処理用ビーズを有する、血液浄化器。 The inventors of the present application have conducted intensive studies to solve the above-mentioned problems. As a result, in the first embodiment, 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. Hereinafter, examples of the first embodiment of the present invention will be listed.
[1]
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):
Figure JPOXMLDOC01-appb-C000005
中 In the 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.
[2]
Item 1. 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. The porous adsorption bead according to item 1 or 2, wherein q is 1 or 2, and m is 0 to 11.
[4]
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.
[5]
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 blood treatment according to item 5, wherein the charged monomer is a monomer having at least one group selected from the group consisting of an amino group, a carboxyl group, a phosphate group, a sulfonic acid group, and a zwitterionic group. beads.
[7]
The charged monomer includes 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), [2- (methacryloyloxy) ethyl] trimethylammonium, acrylic acid (AAc), methacrylic acid. Acid (MAc), N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB), and 2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl (MPC) 6. 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 beads according to any one of Items 5 to 7, wherein the content of the charged monomer is 10 mol% or more and 60 mol% or less based on the entire monomers constituting the polymer.
[9]
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.
[10]
Items 1 to whose sum of the ratios of carbon atoms and oxygen atoms on the surface of the blood processing beads is 97.0% or more in atomic percentage based on the total number of atoms from atomic number 3 to atomic number 92. 10. The blood processing bead according to any one of items 9 to 9.
[11]
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.
[12]
11. 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 μm to 1000 μm.
[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.
[15]
15. 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. The blood processing bead according to any one of items 1 to 15, which removes a hydrophobic protein molecule of more than 1000 Da to less than 66000 Da from blood.
[17]
17. The porous adsorption beads according to any one of items 1 to 16, wherein cytokines and high mobility group box 1 (HMGB1) are removed from blood.
[18]
18. A blood purifier comprising the blood processing beads according to any one of items 1 to 17.
　本願発明者らは、上記課題を解決するため鋭意検討を重ねた結果、第二の実施形態において、医療用材料として特定の樹脂で構成される多孔質ビーズの表面上に、両性イオン型モノマーを単量体単位として特定量含むポリマーを担持することにより、該ポリマーの水への溶出量を抑制できることを見いだし、本発明を完成するに至った。以下、本発明の第二の実施形態の例を列記する。
［１９］
　多孔質ビーズ、及び上記多孔質ビーズの表面上に担持されたポリマーを有する、血液処理用ビーズであって、
　上記多孔質ビーズは、アクリル系樹脂、スチレン系樹脂、及びセルロース系樹脂からなる群から選択される少なくとも一つの樹脂から構成され、
　上記ポリマーは、両性イオン型モノマーを単量体単位として含み、
　上記両性イオン型モノマーは、上記ポリマーを構成するモノマー全体を基準として、１０モル％以上３０モル％以下である、血液処理用ビーズ。
［２０］
　上記血液処理用ビーズの表面における、窒素原子の割合が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で０．２％以上０．９％以下である、項目１９に記載の血液処理用ビーズ。
［２１］
　上記両性イオン型モノマーは、下記式（２）：
Figure JPOXMLDOC01-appb-C000006
 ｛式（２）中、Ｒ１は、水素原子又はメチル基であり、Ｙは、酸素原子又は－ＮＨ－であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑ－であり、ｑは１～５であり、Ｒ３およびＲ４は、それぞれ独立して、水素原子又は炭素原子数１～４のアルキル基であり、Ｒ５は、－ＣＨ２（ＣＨ２）ｍ－であり、ｍは０～４であり、Ｚは、－ＣＯＯ－又はＳＯ３ －である。｝
で表されるモノマー、及び
　下記式（３）：
Figure JPOXMLDOC01-appb-C000007
 ｛式（３）中、Ｒ１は、水素原子又はメチル基であり、Ｙは、酸素原子又は－ＮＨ－であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑ－であり、ｑは１～５であり、Ｒ３、Ｒ４、およびＲ6は、それぞれ独立して、水素原子又は炭素原子数１～４のアルキル基であり、Ｒ５は、－ＣＨ２（ＣＨ２）ｍ－であり、ｍは０～４である。｝
で表されるモノマーからなる群から選択される少なくとも一つである、項目１９又は２０に記載の血液処理用ビーズ。
［２２］
　上記ポリマーは、下記式（４）：
Figure JPOXMLDOC01-appb-C000008
 ｛式（４）中、Ｒ７は、水素原子又はメチル基であり、Ｒ８は、－ＣＨ２（ＣＨ２）ｒ－であり、ｒは１～５であり、Ｒ９は、－ＣＨ２ＣｔＨ２ｔ＋１であり、ｔは０～３である。｝
で表されるモノマーを単量体単位として更に含む、項目１９～２１のいずれか一項に記載の血液処理用ビーズ。
［２３］
　上記ポリマーは、上記両性イオン型モノマー、及び上記式（４）のモノマーから構成される、項目２２に記載の血液処理用ビーズ。
［２４］
　上記式（４）中、ｒは１～３であり、ｔは０又は１である、項目１９～２３のいずれか一項に記載の血液処理用ビーズ。
［２５］
　上記式（２）中、Ｒ１はメチル基であり、ｑは１～３であり、Ｒ３およびＲ４は、それぞれ独立して、メチル基又はエチル基であり、ｍは０又は１である、項目１９～２４のいずれか一項に記載の血液処理用ビーズ。
［２６］
　上記両性イオン型モノマーは、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン、［２－（メタクリロイルオキシ）エチル］ジメチル－（３－スルホプロピル）アンモニウムヒドロキシド、［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホプロピル）アンモニウムヒドロキシド、及びリン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチルからなる群から選択される少なくとも一つである、項目１９～２５のいずれか一項に記載の血液処理用ビーズ。
［２７］
　上記多孔質ビーズの細孔径５ｎｍ～１００ｎｍの積算細孔容量が０．５ｃｍ３／ｇ以上であり、細孔径１００ｎｍ～２００ｎｍの積算細孔容量が０．２ｃｍ３／ｇ以下である、項目１９～１６のいずれか一項に記載の血液処理用ビーズ。
［２８］
　上記多孔質ビーズの体積平均粒子径は、３００μｍ～１０００μｍである、項目１９～２７のいずれか一項に記載の血液処理用ビーズ。
［２９］
　血液から１０００Ｄａ超～６６０００Ｄａ未満の疎水性蛋白質分子を除去する、項目１９～１８のいずれか一項に記載の血液処理用ビーズ。
［３０］
　血液からサイトカイン及びハイモビリティグループボックス１（ＨＭＧＢ１）を除去する、項目１９～２９のいずれか一項に記載の多孔質吸着ビーズ。
［３１］
　項目１９～３０のいずれか一項に記載の血液処理用ビーズを有する、血液浄化器。 The inventors of the present application have made intensive studies to solve the above-described problems, and as a result, in the second embodiment, on the surface of porous beads composed of a specific resin as a medical material, a zwitterionic monomer was formed. By supporting a polymer containing a specific amount as a monomer unit, it has been found that the amount of the polymer eluted in water can be suppressed, and the present invention has been completed. Hereinafter, examples of the second embodiment of the present invention will be listed.
[19]
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 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.
[20]
Item 19, wherein 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 beads for blood treatment according to the above.
[21]
The amphoteric monomer is represented by the following formula (2):
Figure JPOXMLDOC01-appb-C000006
 ｛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 — . ｝
And a monomer represented by the following formula (3):
Figure JPOXMLDOC01-appb-C000007
 ｛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. ｝
21. The blood processing bead according to item 19 or 20, which is at least one selected from the group consisting of monomers represented by the formula:
[22]
The polymer has the following formula (4):
Figure JPOXMLDOC01-appb-C000008
 ｛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. ｝
22. The blood processing bead according to any one of items 19 to 21, further comprising a monomer represented by the following formula as a monomer unit.
[23]
23. The blood processing bead according to item 22, wherein the polymer is composed of the zwitterionic monomer and the monomer of the formula (4).
[24]
24. The blood processing bead according to any one of items 19 to 23, wherein in the formula (4), r is 1 to 3, and t is 0 or 1.
[25]
In the above formula (2), 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, and m is 0 or 1. 25. The blood processing bead according to any one of items 19 to 24.
[26]
The amphoteric monomers include N-methacryloyloxyethyl-N, N-dimethylammonium-α-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.
[27]
Item 19-wherein the 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. 17. The blood processing bead according to any one of items 16 to 16.
[28]
28. The blood processing beads according to any one of items 19 to 27, wherein the porous beads have a volume average particle diameter of 300 μm to 1000 μm.
[29]
Item 19. The blood processing bead according to any one of items 19 to 18, which removes a hydrophobic protein molecule having a molecular weight of from more than 1000 Da to less than 66000 Da from blood.
[30]
30. The porous adsorptive beads according to any one of items 19 to 29, wherein cytokines and high mobility group box 1 (HMGB1) are removed from blood.
[31]
31. A blood purifier having the blood processing beads according to any one of items 19 to 30.
　本発明によれば、従来の生体適合性ポリマーを有する医療機器における一つ又は複数の課題を解決することができる。なお、上述の記載は、本発明の全ての実施形態及び本発明に関する全ての利点を開示したものとみなしてはならない。本発明の更なる実施形態及びその利点は、以下の記載及び図面を参照することにより明らかとなる。 According to the present invention, one or more problems in a medical device having a conventional biocompatible polymer can be solved. The above description should not be construed as disclosing all the embodiments of the present invention and all the advantages relating to the present invention. Further embodiments of the present invention and its advantages will become apparent with reference to the following description and drawings.
図１は、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎ（オルガノ社製、スチレン系ポリマービーズ）の、Ｌｏｇ微分細孔容積分布及び積算細孔容量を示すグラフである。FIG. 1 is a graph showing Log differential pore volume distribution and accumulated pore volume of Amberlite ™ XAD ™ 1180N (manufactured by Organo Corporation, styrene-based polymer beads). 図２は、ピュロソーブＴＭＰＡＤ９５０（ピュロライト社製、アクリル系ビーズ）の、Ｌｏｇ微分細孔容積分布及び積算細孔容量を示すグラフである。FIG. 2 is a graph showing Log differential pore volume distribution and accumulated pore volume of Purosorb TM PAD950 (Acrylic beads manufactured by Purolite). 図３は、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎ、及びピュロソーブＴＭＰＡＤ９５０の、累計体積粒度分布を示すグラフである。FIG. 3 is a graph showing the cumulative volume particle size distribution of Amberlite ™ XAD ™ 1180N and Purosorb ™ PAD950. 図４は、血小板付着性の評価方法を説明するための模式図である。FIG. 4 is a schematic diagram for explaining a method for evaluating platelet adhesion.
　以下、本発明の第一の及び第二の実施形態（総称して「本実施形態」という。）を例示する目的で詳細に説明するが、本発明は本実施形態に限定されるものではない。本願明細書において、各数値範囲の上限値及び下限値は任意に組み合わせることができる。 Hereinafter, 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. . In the present specification, the upper limit and the lower limit of each numerical range can be arbitrarily combined.
《血液処理用ビーズ》
〈生体適合性ポリマー〉
　第一の実施形態における血液処理用ビーズは、吸着体としての多孔質ビーズ上に担持されたポリマーを有する。ポリマーは、下記一般式（１）で表されるモノマーを単量体単位として含むポリマーである（「生体適合性ポリマー」ともいう。）。
Figure JPOXMLDOC01-appb-C000009
 　式（１）中、Ｒ１はメチル基（－ＣＨ３）である。Ｒ２は、末端にメトキシ基を有する直鎖アルキル基（－ＣＨ２（ＣＨ２）ｑＯＣＨ３）であるか、又はアルキル基（－ＣＨ２ＣｍＨ２ｍ＋１）である。Ｒ２において、ｑは１～５、好ましくは１～３、より好ましくは１又は２であり、ｍは０～１７、より好ましくは０～１１である。Ｒ２がアルキル基（－ＣＨ２ＣｍＨ２ｍ＋１）である場合、ＣｍＨ２ｍ＋１部分は、直鎖であってもよく、分岐鎖であってもよく、好ましくは直鎖である。 《Beads for blood treatment》
<Biocompatible polymer>
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”).
Figure JPOXMLDOC01-appb-C000009
 In the formula (1), 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 ). In 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. When 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.
　式（１）で表されるモノマーは、２－メトキシエチルメタクリレート（ＭＥＭＡ）、ｎ－ブチルメタクリレート（ＢＭＡ）、及びラウリル酸メタクリレート（ＬＭＡ）からなる群から選択される少なくとも一つであることがより好ましく、２－メトキシエチルメタクリレート（ＭＥＭＡ）であることが更に好ましい。式（１）で表されるモノマーが上記である場合、多孔質ビーズへの過度吸着性をより高く維持しつつ、血液適合性を向上させることができるため、好ましい。 More preferably, 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). 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.
　理論に限定されないが、第一の実施形態の血液処理用ビーズは、Ｒ１がメチル基（－ＣＨ３）であり、かつ特定のＲ２基を有するモノマーを単量体単位として含む生体適合性ポリマーを、特定の材料から構成される多孔質ビーズ上に担持することにより、多孔質ビーズの吸着性を維持しつつ、血液適合性を向上させることができる。そのメカニズムは、本願の出願時において未だ明らかではないが、発明者らは以下のように推察している。従来は、多孔質ビーズを生体適合性ポリマーで処理する際、十分な生体適合性を確保するために、より多くの生体適合性ポリマーを多孔質ビーズに含浸させることが好ましいと考えられてきた。そのため、多孔質ビーズに対して含浸性のよい生体適合性ポリマーが好ましく用いられてきた。そうすると、体適合性ポリマーの親水性によって多孔質ビーズ内部の細孔（吸着サイト）が過度に親水化され、疎水性である炎症性メディエーターの吸着を妨げる。また、多孔質ビーズ内部の吸着サイトが生体適合性ポリマーによって物理的に塞がれることにより、吸着性が低下すると考えられる。したがって、従来、多孔質ビーズの生体適合性の向上と吸着性の向上とはトレードオフの関係にある。 Although not limited to theory, 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. By supporting the polymer on porous beads made of a specific material, blood compatibility can be improved while maintaining the adsorptivity of the porous beads. The mechanism is not yet clear at the time of filing the present application, but the present inventors speculate as follows. Conventionally, when treating porous beads with a biocompatible polymer, it has been considered preferable to impregnate the porous beads with more biocompatible polymer in order to ensure sufficient biocompatibility. Therefore, a biocompatible polymer having good impregnation with the porous beads has been preferably used. Then, 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. In addition, it is considered that 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.
　これに対して、第一の実施形態の血液処理用ビーズは、上記特定の生体適合性ポリマーと、特定の材料から構成される多孔質ビーズとの組み合わせによって、多孔質ビーズの表面及び吸着サイトにおける親水性／疎水性のバランスが改善される。これに加えて、又は他の実施形態において、上記特定の生体適合性ポリマーと、特定の材料から構成される多孔質ビーズとの組み合わせによって、多孔質ビーズに対する含浸性が適度に調整される。その理由としては、Ｒ１が水素原子である生体適合性ポリマーは、多孔質ビーズに対して含浸性が高く、本願特定の材料から構成される多孔質ビーズの表面全体に対して、非選択的に、換言すればより均一に、コートされる傾向がある。一方で、Ｒ１がメチル基であるモノマーを単量体単位として含む第一の実施形態におけるポリマーは、多孔質ビーズに対する含浸性が適度に抑えられており、多孔質ビーズの表面のうち、生体適合性ポリマーが付着しにくい滑らかな表面よりも、付着しやすい荒い表面に優先的にコートされる傾向がある。その結果、多孔質ビーズの滑らかな表面は、生体適合性ポリマーが付着せずに残りやすい。この傾向は血小板にも当てはまり、血小板は、ビーズ表面の滑らかな表面よりも、荒い表面に付着しやすい。このとき、荒い表面には第一の実施形態におけるポリマーが優先的に付着しているので、血小板がビーズ表面に付着することを効果的に抑制することができる。さらに、生体適合性ポリマーが付着していない表面が存在することにより、多孔質ビーズに担持される生体適合性ポリマーの量を抑えつつ、吸着サイトの閉塞が低減される。その結果、第一の実施形態の血液処理用ビーズは、多孔質ビーズの吸着性を維持しつつ、血液適合性を向上させることができると考えられる。このように、第一の実施形態の血液処理用ビーズは、従来トレードオフの関係にあると考えられてきた生体適合性と吸着性とを、予想外にも両立させることができる。 On the other hand, 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. In addition, or in another embodiment, 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. The reason is that 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. On the other hand, 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. As a result, the smooth surface of the porous beads tends to remain without the biocompatible polymer attached. This tendency also applies to platelets, which tend to adhere to rough surfaces rather than the smooth surface of the bead surface. At this time, since 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. Furthermore, 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. As a result, it is considered that the blood processing beads of the first embodiment can improve blood compatibility while maintaining the adsorptivity of the porous beads. As described above, 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.
　式（１）で表されるモノマーの含有量は、生体適合性ポリマーを構成するモノマー全体を基準として、好ましくは４０モル％以上、より好ましくは６０モル％以上である。該モノマーの含有量の上限値は限定されず、生体適合性ポリマーを構成するモノマー全体を基準として、１００モル％であってもよく、又は８０モル％以下、若しくは６０モル％以下であってもよい。 含有 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.
　第一の実施形態において、生体適合性ポリマーは、式（１）で表されるモノマーと共重合可能な、電荷を有するモノマーを単量体単位として更に含むことが好ましい。本願明細書において、「電荷を有するモノマー」は、ｐＨ７．０の条件下で部分的もしくは完全に正電荷又は負電荷を帯びる官能基を有するモノマーである。生体適合性ポリマーが電荷を有するモノマーを単量体単位として更に含む場合、第一の実施形態における多孔質ビーズとの組み合わせにおいて、多孔質ビーズ上への生体適合性ポリマーの担持量が低減され、吸着性の低下を抑制できる。また、電荷を有するモノマーは高い親水性を有するため、生体適合性も向上する。その結果、より良好な吸着性及び血液適合性を有する血液処理用ビーズが得られる傾向にある。 In the first embodiment, the biocompatible polymer preferably further contains, as a monomer unit, a charged monomer copolymerizable with the monomer represented by the formula (1). In the specification of the present application, 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. When 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.
　第一の実施形態において、電荷を有するモノマーとしては、例えば、アミノ基（－ＮＨ２、－ＮＨＲ３、ＮＲ３Ｒ４）、カルボキシル基（－ＣＯＯＨ）、リン酸基（－ＯＰＯ３Ｈ２）、スルホン酸基（－ＳＯ３Ｈ）、及び両性イオン基からなる群から選択される少なくとも一つの基を有するモノマーが挙げられる。アミノ基において、Ｒ３及びＲ４は、それぞれ独立して、炭素数１～３のアルキル基であることが好ましく、炭素数１又は２のアルキル基であることがより好ましい。 In the first embodiment, 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. In the amino group, 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.
　これらの中でも、電荷を有するモノマーは、アミノ基、カルボキシル基、及び両性イオン基からなる群から選択される少なくとも一つの基を有するモノマーであることがより好ましい。電荷を有するモノマーは、アミノ基を有するカチオン性モノマー、カルボキシル基を有するアニオン性モノマー、アミノ基とカルボキシル基との両性イオン型モノマー、及びアミノ基とリン酸基との両性イオン型モノマーからなる群から選択される少なくとも一つであることが更に好ましい。電荷を有するモノマーがカルボキシル基を有する場合、多孔質ビーズがＣａ２＋を吸着し、血液凝固の亢進を抑制できる点で、更に好ましい。 Among these, 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.
　より具体的には、電荷を有するモノマーとしては、２－アミノエチルメタクリレート（ＡＥＭＡ）、ジメチルアミノエチルメタクリレート（ＤＭＡＥＭＡ）、ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ）、［２－（メタクリロイルオキシ）エチル］トリメチルアンモニウム、アクリル酸（ＡＡｃ）、メタクリル酸（ＭＡｃ）、リン酸２－（メタクリロイルオキシ）エチル、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）、［２－（メタクリロイルオキシ）エチル］ジメチル－（３－スルホプロピル）アンモニウムヒドロキシド（ＳＰＢ）、［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホプロピル）アンモニウムヒドロキシド（ＳＰＢＡ）、リン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル（ＭＰＣ）、及び［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホブチル）アンモニウムからなる群から選択される少なくとも一つであることがより好ましい。 More specifically, 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-α-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- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl (MPC) and [3- (methacryloylamino) propyl] dimethyl (3-sulfobutyl) ammonium Is more preferable.
　これらの中でも、電荷を有するモノマーは、メチルアミノエチルメタクリレート（ＤＭＡＥＭＡ）、ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ）、アクリル酸（ＡＡｃ）、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）、及びリン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル（ＭＰＣ）からなる群から選択される少なくとも一つであることがより好ましく、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）であることが更に好ましい。 Among these, the charged monomers are methylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), acrylic acid (AAc), N-methacryloyloxyethyl-N, N-dimethylammonium-α-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-α-N-methylcarboxybetaine (CMB).
　第一の実施形態において、電荷を有するモノマーの含有量は、生体適合性ポリマーを構成するモノマー全体を基準として、好ましくは１０モル％以上６０モル％以下、より好ましくは１５モル％以上４０モル％以下である。電荷を有するモノマーの含有量が上記範囲内である場合、多孔質ビーズへの含浸性及び親水性のバランスに優れ、より吸着性及び生体適合性に優れた血液処理用ビーズが得られる傾向にある。生体適合性ポリマーの組成及び構造の分析方法については、実施例の欄で詳述する。 In the first embodiment, 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.
　第一の実施形態において、生体適合性ポリマーの重量平均分子量（Ｍｗ）は、好ましくは５，０００以上５，０００，０００以下、より好ましくは１０，０００以上１，０００，０００以下、更に好ましくは１０，０００以上３００，０００以下である。生体適合性ポリマーの重量平均分子量が上記範囲内であると、多孔質ビーズへの適度な含浸性、血液中への溶出の防止、及び担持量の低減等の観点から好ましい。生体適合性ポリマーの重量平均分子量（Ｍｗ）の分析方法は、例えば、比較例に記載するように、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）などにより測定することができる。 In the first embodiment, 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.
　第一の実施形態において、多孔質ビーズ上に担持される生体適合性ポリマーの量（担持量）は、多孔質ビーズ乾燥時重量１ｇ当たり、好ましくは０．０８ｍｇ以上１１４ｍｇ以下、より好ましくは０．８ｍｇ以上５６ｍｇ以下、更に好ましくは２．０ｍｇ以上２０ｍｇ以下である。生体適合性ポリマーの担持量（コーティング量）の測定方法については、実施例の欄で詳述する。 In the first embodiment, 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.
　第一の実施形態における生体適合性ポリマーと特定の材料から構成される多孔質ビーズとの組み合わせによって、担持量が上記範囲に抑えられる。他の実施形態において、生体適合性ポリマーを多孔質ビーズに適用する条件を変更することによって、担持量を上記範囲に制御してもよい。担持量が上記範囲内であることにより、吸着サイトの閉塞が低減され、その結果、多孔質ビーズの吸着性をより高く維持しつつ、血液適合性を向上させることができると考えられる。 (4) 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. In another 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.
　生体適合性ポリマーが「多孔質ビーズの表面上に担持されている」とは、他の一つの表現では、生体適合性ポリマーが、多孔質ビーズの表面の少なくとも一部に存在する状態を指すものである。したがって、第一の実施形態において、生体適合性ポリマーは、多孔質ビーズの表面の全てに担持（コーティング）されている必要はない。また、本発明の課題を解決することができる限りにおいて、生体適合性ポリマーは、多孔質ビーズの細孔内に存在していてもよく、細孔をある程度閉塞していてもよい。 The phrase "the biocompatible polymer is supported on the surface of the porous bead" refers, in another expression, to a state in which the biocompatible polymer is present on at least a part of the surface of the porous bead. It is. Therefore, in the first embodiment, the biocompatible polymer does not need to be supported (coated) on all of the surfaces of the porous beads. In addition, as long as the object of the present invention can be solved, the biocompatible polymer may be present in the pores of the porous beads or may close the pores to some extent.
　第一の実施形態において、生体適合性ポリマーは、上記式（１）のモノマー、及び電荷を有する任意のモノマーに加えて、他のモノマーを単量体単位として更に含んでいてもよい。他のモノマーとしては、これらのモノマーと共重合可能であれば限定されない。 In the first embodiment, 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.
　第一の実施形態において、他のモノマーとしては、例えば、式（１）において、Ｒ１が水素（Ｈ）であるか、又は炭素数２以上のアルキル基であるモノマー；Ｒ２の－ＣＨ２（ＣＨ２）ｑＯＣＨ３において、末端がメトキシキ基ではなく、炭素数２以上のアルコキシ基、例えばエトキシ基、プロポキシ基、及びブトキシ基等であるモノマー；Ｒ２の－ＣＨ２（ＣＨ２）ｑＯＣＨ３において、ｑが０又は６以上であるモノマー；Ｒ２の－ＣＨ２ＣｍＨ２ｍ＋１において、ｍが１８以上であるモノマー；並びにこれらの組み合わせが挙げられる。 In a first embodiment, as the other monomer, for example, in the formula (1), or 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.
　第一の実施形態において、他のモノマーとしては、より具体的には、メチルアクリレート、エチルアクリレート、イソプロピルアクリレート、ブチルアクリレート、ヘキシルアクリレート、２－エチルヘキシルアクリレート、メチルメタクリレート、メトキシメチルアクリレート、メトキシエチルアクリレート、メトキシプロピルアクリレート、メトキシブチルアクリレート、エトキシメチルアクリレート、エトキシエチルアクリレート、エトキシプロピルアクリレート、エトキシブチルアクリレート、プロポキシメチルアクリレート、プロポキシエチルアクリレート、プロポキシプロピルアクリレート、プロポキシブチルアクリレート、ブトキシメチルアクリレート、ブトキシエチルアクリレート、ブトキシプロピルアクリレート、ブトキシブチルアクリレート、エトキシメチルメタクリレート、エトキシエチルメタクリレート、エトキシプロピルメタクリレート、エトキシブチルメタクリレート、プロポキシメチルメタクリレート、プロポキシエチルメタクリレート、プロポキシプロピルメタクリレート、プロポキシブチルメタクリレート、ブトキシメチルメタクリレート、ブトキシエチルメタクリレート、ブトキシプロピルメタクリレート、及びブトキシブチルメタクリレート等が挙げられる。 In the first embodiment, as the other monomer, more specifically, methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, methoxymethyl acrylate, methoxyethyl acrylate, Methoxypropyl acrylate, methoxybutyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, propoxyethyl acrylate, propoxypropyl acrylate, propoxybutyl acrylate, butoxymethyl acrylate, butoxyethyl acrylate, butoxypropyl Acrylate, Bute Cybutyl acrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, ethoxypropyl methacrylate, ethoxybutyl methacrylate, propoxymethyl methacrylate, propoxyethyl methacrylate, propoxypropyl methacrylate, propoxybutyl methacrylate, butoxymethyl methacrylate, butoxyethyl methacrylate, butoxypropyl methacrylate, and butoxy Butyl methacrylate and the like.
　第二の実施形態における血液処理用ビーズは、吸着体としての多孔質ビーズ上に担持されたポリマーを有する。ポリマーは、両性イオン型モノマーを単量体単位として含むポリマーである（「生体適合性ポリマー」ともいう。）。本願明細書において、「両性イオン型モノマー」は、ｐＨ７．０の条件下で、一分子内に、正電荷と負電荷の両方を有するモノマーである。生体適合性ポリマーが両性イオン型モノマーを単量体単位として含み、かつ、後述する特定の材料から構成される多孔質ビーズと組み合わせることによって、生体適合性が高く、かつ担持された生体適合性ポリマーの血液中への溶出が少ない血液処理用ビーズを提供することができる。その理由としては、理論に限定されないが、発明者らは以下のように推定している。すなわち、両性イオン型モノマーは高い親水性を有するため、生体適合性を向上させることができるが、しかしながら、水や血液に接した際に溶出しやすいという問題があった。特に、吸着型血液浄化器では、血液処理用ビーズは、数時間から長い時には１日以上、血液と接触し続ける。使用時に多孔質ビーズ上にコーティングしたポリマーが溶出すると、吸着型血液浄化器の生体適合性が長時間維持できなくなるとともに、そのポリマーが血液内に溶出する可能性が高まる。第二の実施形態では、ポリマーを担持させている多孔質ビーズが吸着体として機能し、溶出する生体適合性ポリマーをその細孔内に吸着することができる。その結果、より良好な血液適合性を有しつつ、生体適合性ポリマーの血液中への溶出が低減された、血液処理用ビーズを得ることができる。 血液 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”). In the present specification, 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. That is, since the zwitterionic monomer has high hydrophilicity, biocompatibility can be improved. However, there is a problem that it is easily eluted when it comes into contact with water or blood. In particular, in the case of an adsorption-type blood purifier, the beads for blood treatment keep in contact with blood for several hours to one day or more when they are long. When the polymer coated on the porous beads elutes during use, 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. In the second embodiment, 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.
　第二の実施形態において、両性イオン型モノマーとしては、アミノ基（－ＮＨ２、－ＮＨＲ３、ＮＲ３Ｒ４）とカルボキシル基（－ＣＯＯＨ）との両性イオン型モノマー、アミノ基とスルホン酸基（－ＳＯ３Ｈ）との両性イオン型モノマー、及びアミノ基とリン酸基（－ＯＰＯ３Ｈ２）との両性イオン型モノマーからなる群から選択される少なくとも一つであることが好ましく、アミノ基とカルボキシル基との両性イオン型モノマーである場合、多孔質ビーズがＣａ２＋を吸着し、血液凝固の亢進を抑制できる点で更に好ましい。 In the second embodiment, 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 ). When 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.
　第二の実施形態において、両性イオン型モノマーとしては、下記式（２）：
Figure JPOXMLDOC01-appb-C000010
 ｛式（２）中、Ｒ１は、水素原子又はメチル基であり、Ｙは、酸素原子又は－ＮＨ－であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑ－であり、ｑは１～５であり、Ｒ３およびＲ４は、それぞれ独立して、水素原子又は炭素原子数１～４のアルキル基であり、Ｒ５は、－ＣＨ２（ＣＨ２）ｍ－であり、ｍは０～４であり、Ｚは、－ＣＯＯ－又はＳＯ３ －である。｝
で表されるモノマーであることが好ましい。 In the second embodiment, the zwitterionic monomer includes the following formula (2):
Figure JPOXMLDOC01-appb-C000010
 ｛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
　上記式（２）中、Ｒ１はメチル基であり、ｑは１～３であり、Ｒ３およびＲ４は、それぞれ独立して、メチル基又はエチル基であり、ｍは０又は１であることが好ましい。 In the above formula (2), 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, and m is 0 or 1. Is preferred.
　上記式（２）のモノマーとしては、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）、［２－（メタクリロイルオキシ）エチル］ジメチル－（３－スルホプロピル）アンモニウムヒドロキシド（ＳＰＢ）、［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホプロピル）アンモニウムヒドロキシド（ＳＰＢＡ）、及び［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホブチル）アンモニウムからなる群から選択される少なくとも一つであることがより好ましい。上記式（２）のモノマーとしては、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）である場合、多孔質ビーズがＣａ２＋を吸着し、血液凝固の亢進を抑制できる点でより好ましい。 Examples of the monomer of the above formula (2) include N-methacryloyloxyethyl-N, N-dimethylammonium-α-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. When the monomer of the above formula (2) is N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB), the porous beads adsorb Ca 2+ and cause blood coagulation. It is more preferable in that the increase can be suppressed.
　第二の実施形態において、両性イオン型モノマーとしては、下記式（３）：
Figure JPOXMLDOC01-appb-C000011
 ｛式（３）中、Ｒ１は、水素原子又はメチル基であり、Ｙは、酸素原子又は－ＮＨ－であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑ－であり、ｑは１～５であり、Ｒ３、Ｒ４、およびＲ6は、それぞれ独立して、水素原子又は炭素原子数１～４のアルキル基であり、Ｒ５は、－ＣＨ２（ＣＨ２）ｍ－であり、ｍは０～４である。｝
で表されるモノマーであることもまた好ましい。 In the second embodiment, the zwitterionic monomer includes the following formula (3):
Figure JPOXMLDOC01-appb-C000011
 ｛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.
　上記式（３）中、Ｒ１はメチル基であり、ｑは１～３であり、Ｒ３、Ｒ４およびＲ6は、それぞれ独立して、メチル基又はエチル基であり、ｍは１又は２であることが好ましい。 In the above formula (3), 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, and m is 1 or It is preferably 2.
　上記式（３）のモノマーとしては、リン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル（ＭＰＣ）が挙げられる。 モ ノ マ ー Examples of the monomer of the above formula (3) include 2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl (MPC).
　第二の実施形態において、両性イオン型モノマーとしては、上記式（２）及び（３）のモノマーからなる群から選択される少なくとも一つのモノマーであることが好ましい。 に お い て In the second embodiment, the zwitterionic monomer is preferably at least one monomer selected from the group consisting of the monomers of the above formulas (2) and (3).
　第二の実施形態において、両性イオン型モノマーの含有量は、生体適合性ポリマーを構成するモノマー全体を基準として、好ましくは１０モル％以上３０モル％以下、より好ましくは１２モル％以上３０モル％以下、さらに好ましくは１５モル％以上３０モル％以下である。両性イオン型モノマーの含有量が上記範囲内である場合、生体適合性ポリマーの水への溶出量を抑制しつつ、より高い生体適合性を有する血液処理用ビーズが得られる傾向にある。生体適合性ポリマーの組成及び構造の分析方法については、実施例の欄で詳述する。 In the second embodiment, 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. When the content of the zwitterionic monomer is within the above range, there is a tendency that beads for blood treatment having higher biocompatibility are obtained while suppressing the amount of biocompatible polymer eluted into water. Methods for analyzing the composition and structure of the biocompatible polymer will be described in detail in Examples.
　第二の実施形態において、ポリマーは、下記式（４）：
Figure JPOXMLDOC01-appb-C000012
 ｛式（４）中、Ｒ７は、水素原子又はメチル基であり、Ｒ８は、－ＣＨ２（ＣＨ２）ｒ－であり、ｒは１～５であり、Ｒ９は、－ＣＨ２ＣｔＨ２ｔ＋１であり、ｔは０～３である。｝
で表されるモノマーを単量体単位として更に含むことが、生体適合性ポリマーの水への溶出量を抑制しつつ、より高い生体適合性を有する血液処理用ビーズを得るうえで、好ましい。 In a second embodiment, the polymer has the following formula (4):
Figure JPOXMLDOC01-appb-C000012
 ｛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. ｝
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.
　式（４）中、Ｒ７は好ましくはメチル基であり、ｒは好ましくは１～３、より好ましくは１又は２であり、ｔは好ましくは０～２、より好ましくは０又は１である。 In the formula (4), 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.
　式（４）で表されるモノマーの含有量は、生体適合性ポリマーを構成するモノマー全体を基準として、好ましくは４０モル％以上、より好ましくは６０モル％以上である。該モノマーの含有量の上限値は限定されず、生体適合性ポリマーを構成するモノマー全体を基準として、好ましくは９０モル％以下、８０モル％以下、又は６０モル％以下であってもよい。 含有 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.
　第二の実施形態において、生体適合性ポリマーの重量平均分子量（Ｍｗ）は、好ましくは５，０００以上５，０００，０００以下、より好ましくは１０，０００以上１，０００，０００以下、更に好ましくは１０，０００以上３００，０００以下である。生体適合性ポリマーの重量平均分子量が上記範囲内であると、多孔質ビーズへの適度な含浸性、血液中への溶出の防止、及び担持量の低減等の観点から好ましい。生体適合性ポリマーの重量平均分子量（Ｍｗ）の分析方法は、例えば、比較例に記載するように、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）などにより測定することができる。 In the second embodiment, 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.
　生体適合性ポリマーが「多孔質ビーズの表面上に担持されている」とは、他の一つの表現では、生体適合性ポリマーが、多孔質ビーズの表面の少なくとも一部に存在する状態を指すものである。したがって、第二の実施形態において、生体適合性ポリマーは、多孔質ビーズの表面の全てに担持（コーティング）されている必要はない。また、本発明の課題を解決することができる限りにおいて、生体適合性ポリマーは、多孔質ビーズの細孔内に存在していてもよく、細孔をある程度閉塞していてもよい。 The phrase "the biocompatible polymer is supported on the surface of the porous bead" refers, in another expression, to a state in which the biocompatible polymer is present on at least a part of the surface of the porous bead. It is. Therefore, in the second embodiment, the biocompatible polymer does not need to be supported (coated) on all of the surfaces of the porous beads. In addition, as long as the object of the present invention can be solved, the biocompatible polymer may be present in the pores of the porous beads or may close the pores to some extent.
　第二の実施形態において、生体適合性ポリマーは、上記両性イオン型モノマー、及び上記式（４）のモノマーから構成されてもよい。しかしながら、生体適合性ポリマーは、上記両性イオン型モノマー、及び上記式（４）のモノマーに加えて、他のモノマーを単量体単位として更に含んでいてもよい。他のモノマーとしては、これらのモノマーと共重合可能であれば限定されない。 In the second embodiment, the biocompatible polymer may be composed of the zwitterionic monomer and the monomer of the formula (4). However, 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.
　第二の実施形態において、他のモノマーとしては、両性イオン型ではなく、かつ式（４）に該当しないモノマーである。他のモノマーとしては、例えば、ｐＨ７．０の条件下で部分的もしくは完全に正電荷を帯びる官能基、又は負電荷を帯びる官能基のいずれか一方を有する、カチオン性又はアニオン性モノマーが挙げられる。正電荷又は負電荷を帯びる官能基としては、例えば、アミノ基（－ＮＨ２、－ＮＨＲ３、ＮＲ３Ｒ４）、カルボキシル基（－ＣＯＯＨ）、リン酸基（－ＯＰＯ３Ｈ２）、及びスルホン酸基（－ＳＯ３Ｈ）が挙げられる。カチオン性又はアニオン性モノマーとしては、より具体的には、２－アミノエチルメタクリレート（ＡＥＭＡ）、ジメチルアミノエチルメタクリレート（ＤＭＡＥＭＡ）、ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ）、［２－（メタクリロイルオキシ）エチル］トリメチルアンモニウム、アクリル酸（ＡＡｃ）、メタクリル酸（ＭＡｃ）、及びリン酸２－（メタクリロイルオキシ）エチルが挙げられる。他のモノマーとしては、より具体的には、メチルアクリレート、エチルアクリレート、イソプロピルアクリレート、ブチルアクリレート、ヘキシルアクリレート、２－エチルヘキシルアクリレート、メチルメタクリレート、エチルメタクリレート、イソプロピルメタクリレート、ブチルメタクリレート、ヘキシルメタクリレート、２－エチルヘキシルメタクリレート、メトキシメチルアクリレート、エトキシメチルアクリレート、プロポキシメチルアクリレート、ブトキシメチルアクリレート、エトキシメチルメタクリレート、プロポキシメチルメタクリレート、ブトキシメチルメタクリレート、及び２－（２－エトキシエトキシ）エチルアクリレート（Ｅｔ２Ａ）等もまた挙げられる。これらの中でも、両性イオン型モノマー及び上記式（４）のモノマーと、カチオン性又はアニオン性モノマーとを組み合わせて使用することが好ましい。 In the second embodiment, the other monomer is not a zwitterionic type and does not correspond to the formula (4). Examples of 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. . Examples of 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). As the cationic or anionic monomer, more specifically, 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), [2- (methacryloyloxy) ethyl] trimethylammonium Acrylate (AAc), methacrylate (MAc), and 2- (methacryloyloxy) ethyl phosphate. As other monomers, more specifically, methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, isopropyl methacrylate, butyl methacrylate, hexyl methacrylate, 2-ethylhexyl Also included are methacrylate, methoxymethyl acrylate, ethoxymethyl acrylate, propoxymethyl acrylate, butoxymethyl acrylate, ethoxymethyl methacrylate, propoxymethyl methacrylate, butoxymethyl methacrylate, and 2- (2-ethoxyethoxy) ethyl acrylate (Et2A). Among these, it is preferable to use the zwitterionic monomer and the monomer of the above formula (4) in combination with a cationic or anionic monomer.
　第二の実施形態において、他のモノマーの量は、存在する場合、生体適合性ポリマーを構成するモノマー全体を基準として、１モル％以上、５モル％以上、又は１０モル％以上、３０モル％以下、２５モル％以下、又は２０モル％以下であってもよい。 In a second embodiment, 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. Hereinafter, it may be 25 mol% or less, or 20 mol% or less.
〈多孔質ビーズ〉
　本実施形態における血液処理用ビーズは、吸着体としての多孔質ビーズを有する。多孔質ビーズは、アクリル系樹脂、スチレン系樹脂、及びセルロース系樹脂からなる群から選択される少なくとも一つの樹脂から構成される。本願明細書において、本発明の課題を解決することができる限りにおいて、多孔質ビーズは、他の樹脂及び他の成分を含んでいてもよい。 <Porous beads>
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. In the present specification, the porous beads may include other resins and other components as long as the object of the present invention can be solved.
　多孔質ビーズとしては、市販の多孔質ビーズを使用することができる。アクリル系樹脂から構成される市販の多孔質ビーズとしては、例えば、アンバーライトＴＭＸＡＤＴＭ７ＨＰ（オルガノ社製）、ダイヤイオンＴＭＨＰ２ＭＧ（三菱ケミカル社製）、ピュロソーブＴＭＰＡＤ６１０（ピュロライト社製）、ピュロソーブＴＭＰＡＤ９５０（ピュロライト社製）及びＭｕｒｏｍａｃ（商標登録）ＰＡＰ－９２１０（室町ケミカル社製）等を挙げることができる。スチレン系樹脂から構成される市販の多孔質ビーズとしては、例えば、アンバーライトＴＭＸＡＤＴＭ４（オルガノ社製）、アンバーライトＴＭＸＡＤＴＭ２０００（オルガノ社製）、アンバーライトＴＭＦＰＸ６６（オルガノ社製）、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎ（オルガノ社製）、ダイヤイオンＴＭＨＰ２０（三菱ケミカル社製）、ダイヤイオンＴＭＨＰ２１（三菱ケミカル社製）、ダイヤイオンＴＭＳＰ７００（三菱ケミカル社製）、ピュロソーブＴＭＰＡＤ６００（ピュロライト社製）、ピュロソーブＴＭＰＡＤ９００（ピュロライト社製）、及びＭｕｒｏｍａｃ（商標登録）ＳＡＰ－９２１０（室町ケミカル社製）等を挙げることができる。セルロース系樹脂から構成される市販の多孔質ビーズとしては、例えば、ビスコパール（商標登録）ミニ（レンゴー株式会社社製）、及びＣ８３２９（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ社製）等を挙げることができる。 As the porous beads, commercially available porous beads can be used. Commercially available 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.). Commercially available porous beads composed of a styrene resin include, for example, Amberlite ™ XAD ™ 4 (manufactured by Organo), Amberlite ™ XAD ™ 2000 (manufactured by Organo), and Amberlite ™ 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).
　多孔質ビーズの体積平均粒子径は、好ましくは３００μｍ～１０００μｍ、より好ましくは４００μｍ～８００μｍ、更に好ましくは４２０μｍ～７００μｍである。体積平均粒子径が３００μｍ以上であることにより、血液をカラムに流した際の圧上昇を効果的に抑制することができ、体積平均粒子径が１０００μｍ以下であることにより、迅速な吸着性能を発揮することできる。本願において、多孔質ビーズの「体積平均粒子径」の測定方法については、実施例の欄で詳述する。 体積 The volume average particle diameter of the porous beads is preferably 300 μm to 1000 μm, more preferably 400 μm to 800 μm, and further preferably 420 μm to 700 μm. When the volume average particle diameter is 300 μm 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 μm or less, rapid adsorption performance is exhibited. You can do it. In the present application, a method for measuring the “volume average particle size” of the porous beads will be described in detail in the Examples section.
　多孔質ビーズの細孔径５ｎｍ～１００ｎｍの積算細孔容量が、０．５ｃｍ３／ｇ以上であることが好ましく、０．８ｃｍ３／ｇ以上であることがより好ましく、１．０ｃｍ３／ｇ以上であることが更に好ましい。該積算細孔容量の上限値は、好ましくは３．５ｃｍ３／ｇ以下、より好ましくは３．０ｃｍ３／ｇ以下、更に好ましくは２．５ｃｍ３／ｇ以下である。該積算細孔容量が上記範囲内である場合、ポリマーを担持させている多孔質ビーズの吸着性がより向上し、多孔質ビーズはより多くの疎水性蛋白質分子を除去することができるため好ましい。また該積算細孔容量が上記範囲内である場合、溶出する生体適合性ポリマーをその細孔内により効果的に吸着することができる。その結果、より良好な血液適合性を有しつつ、生体適合性ポリマーの血液中への溶出が低減された血液処理用ビーズを得ることができるため好ましい。 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. When the accumulated pore volume is within the above range, the adsorptivity of the porous beads carrying the polymer is further improved, and the porous beads can remove more hydrophobic protein molecules, which is preferable. When the cumulative pore volume is within the above range, the eluted biocompatible polymer can be more effectively adsorbed in the 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.
　積算細孔容量の特徴に加えて、又は他の実施形態において、多孔質ビーズの細孔径１００ｎｍ～２００ｎｍの積算細孔容量が、０．２ｃｍ３／ｇ以下であることが好ましく、０．１ｃｍ３／ｇ以下であることがより好ましく、０．０５ｃｍ３／ｇ以下であることが更に好ましい。該積算細孔容量が上記特徴を有する場合、多孔質ビーズは疎水性蛋白質分子の吸着に適したサイズの細孔を多く有し、その結果、より吸着性に優れた血液処理用ビーズを得ることができるため好ましい。多孔質ビーズの積算細孔容量の測定方法については、実施例の欄で詳述する。 In addition to the features of the cumulative pore volume, or in other embodiments, it is preferred that 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. When the cumulative pore volume has the above characteristics, 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.
〈血液処理用ビーズの元素割合及び原子割合〉
（元素分析に基づく元素割合）
　血液処理用ビーズ全体を構成する元素のうち、窒素元素の割合は、０質量％超１．０質量％以下であることが好ましく、０質量％超０．３質量％以下であることがより好ましい。窒素元素の割合が上記範囲内である場合、血液処理用ビーズは、疎水性蛋白質分子を吸着しつつ高い血液適合性を有するため好ましい。血液処理用ビーズ全体を構成する元素のうち、炭素元素、水素元素、及び酸素元素の総和は、９７．０質量％以上であることが好ましく、９９．０質量％以上であることがより好ましい。これらの元素の割合が上記範囲内である場合、血液処理用ビーズはより多くの疎水性蛋白質分子を除去することができるため好ましい。血液処理用ビーズ全体を構成する元素を基準とする元素割合は、元素分析で測定することができる。測定方法については、実施例の欄で詳述する。 <Element ratio and atomic ratio of blood processing beads>
(Element ratio based on elemental analysis)
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. . When the ratio of the nitrogen element is within the above range, the blood treatment beads are preferable because they have high blood compatibility while adsorbing hydrophobic protein molecules. Of the elements constituting the whole blood processing beads, 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. When the ratio of these elements is within the above range, 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.
（ＸＰＳに基づく原子割合）
　上記元素分析に基づく元素割合の特徴に加えて、又は他の実施形態において、血液処理用ビーズの表面に存在する窒素原子の割合は、血液処理用ビーズの表面に存在する原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数を基準として、原子百分率で０．２％以上０．９％以下であることが好ましく、０．２％以上０．７％以下であることがより好ましく、０．２％以上０．５％以下であることが更に好ましく、０．３％以上０．５％以下であることがより更に好ましい。血液処理用ビーズの表面に存在する窒素原子数の割合が上記範囲内である場合、血液処理用ビーズは、疎水性蛋白質分子を吸着しつつ高い血液適合性を有するため好ましい。なお、血液処理用ビーズの表面に存在する窒素原子の割合は、窒素を含有する生体適合性ポリマーを用いることにより調整することができる。例えば、第一の実施形態の場合、電荷を有するモノマーとして、窒素を含有するモノマーを用いてもよく、他のモノマーとして、窒素を含有する他のモノマーを用いてもよく、又はこれらの両方を用いてもよい（総称して、「窒素含有モノマー」ともいう。）。また、第二の実施形態の場合、両性イオン型モノマーとして、窒素を含有する両性イオン型モノマーを用いてもよく、他のモノマーとして、窒素を含有する他のモノマーを用いてもよく、又はこれらの両方を用いてもよい（総称して、「窒素含有モノマー」ともいう。）。より具体的には、（１）生体適合性ポリマーを構成する窒素含有モノマーの割合を調整することにより、及び／又は（２）多孔質ビーズ上の窒素を含有する生体適合性ポリマーの担持量を調整することにより、血液処理用ビーズの表面に存在する窒素原子の割合を調整することができる。血液処理用ビーズの表面に存在する炭素原子と酸素原子の割合の総和は、血液処理用ビーズの表面に存在する原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数を基準として、原子百分率で９７．０％以上であることが好ましい。血液処理用ビーズの表面に存在するリン原子の割合は、血液処理用ビーズの表面に存在する原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数を基準として、原子百分率で、好ましくは３％以下、より好ましくは１％以下である。血液処理用ビーズの表面に存在する特定の原子の割合は、X線光電分光法（ＸＰＳ）により測定することができる。測定方法については、実施例の欄で詳述する。 (Atomic ratio based on XPS)
In addition to the above-described characteristics of the elemental ratio based on the elemental analysis, or in another embodiment, 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. When the ratio of the number of nitrogen atoms present on the surface of the blood processing beads is within the above range, 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. For example, in the case of the first embodiment, as the charged monomer, 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”). In the case of the second embodiment, as the zwitterionic monomer, 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.
　血液処理用ビーズを粉砕して粉体にし、該粉体の表面をＸＰＳで測定することにより、血液処理用ビーズの全体を構成する特定原子の割合を、原子番号３番から９２番までの原子の総数を基準として測定することができる。このようにして測定した血液処理用ビーズの全体を構成する窒素原子の割合は、原子番号３番から９２番までの原子の総数を基準として、０％超０．１％以下であることが好ましい。血液処理用ビーズの全体を構成するリン原子の割合は、原子番号３番から９２番までの原子の総数を基準として、０．１％以下であることが好ましい。窒素原子及びリン原子の割合が、それぞれ上記範囲内である場合、血液処理用ビーズは、疎水性蛋白質分子を吸着しつつ高い血液適合性を有するため好ましい。 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. When the proportions of the nitrogen atom and the phosphorus atom are within the above ranges, the blood treatment beads are preferable because they have high blood compatibility while adsorbing hydrophobic protein molecules.
〈血液処理用ビーズの吸着性〉
　本実施形態における血液処理用ビーズは、例えば、血液から１０００Ｄａ超～６６０００Ｄａ未満の疎水性蛋白質分子を除去すると、ポリマーを担持させている多孔質ビーズの吸着性がより向上し、溶出する生体適合性ポリマーをその細孔内により効果的に吸着することができる。その結果、より良好な血液適合性を有しつつ、生体適合性ポリマーの血液中への溶出が低減された血液処理用ビーズを得ることができるため好ましい。本願明細書において、ある疎水性蛋白質分子を「除去することができる」とは、除去対象の疎水性蛋白質分子を含む血漿サンプル中を血液処理用ビーズに接触させて振とうさせたとき、該血液処理用ビーズへの該疎水性蛋白質の吸着率が３０％以上であることを意味する。血液処理用ビーズの吸着性の評価方法は、実施例の欄で詳述する。本実施形態における血液処理用ビーズは、より好ましくは８０００Ｄａ超～６６０００Ｄａ未満、更に好ましくは８０００Ｄａ超～５１０００Ｄａ未満の疎水性蛋白質分子を除去することができる。例えば、サイトカインは分子量約５～６０ｋＤａ（ＩＬ－１ｂ：約１７．５ｋＤａ、１Ｌ－６：約２４．５ｋＤａ、ＩＬ－８：約８ｋＤａ、ＩＬ－１０（二量体）：約３７．５ｋＤａ、ＴＮＦ－α（三量体）：約５１ｋＤａ）、アラーミンであるハイモビリティグループボックス１（ＨＭＧＢ１）は分子量約３０ｋＤａの疎水性蛋白質である。 <Adsorption of beads for blood treatment>
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. In the present specification, "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. For example, 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 -Α (trimer): about 51 kDa), an alarmin high mobility group box 1 (HMGB1) is a hydrophobic protein having a molecular weight of about 30 kDa.
　除去される疎水性蛋白質分子としては、敗血症の原因と考えられる蛋白質分子、例えば、病原微生物に由来する外因性物質であるＰＡＭＰｓ(pathogen-associated molecular patterns)；並びに炎症反応に繋がる種々の炎症性メディエーター、例えば、組織障害により放出される内因性物質であるアラーミン、及び炎症反応を引き起こすサイトカインが挙げられる。疎水性蛋白質分子としては、白血球もまた挙げられる。 Examples of the hydrophobic protein molecules to be removed 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としては、例えば、エンドトキシン（ＬＰＳ）、ペプチドグリカン（ＰＧＮ）、リポテイコ酸、二本鎖ＲＮＡ（ｄｓＲＮＡ）、及びフラジェリン等が挙げられる。 PAMPs include, for example, endotoxin (LPS), peptidoglycan (PGN), lipoteichoic acid, double-stranded RNA (dsRNA), flagellin and the like.
　アラーミンとしては、例えば、ハイモビリティグループボックス１（ＨＭＧＢ１）、熱ショックタンパク（ＨＳＰｓ）、ヒストン、フィブリノーゲン、好中球エラスターゼ、及びマクロファージ遊走阻止因子（ＭＩＦ）等が挙げられる。 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.
　サイトカインとしては、例えば、インターロイキン（ＩＬ－１、ＩＬ－２、ＩＬ－３、ＩＬ－４、ＩＬ－５、ＩＬ－６、ＩＬ－７、ＩＬ－８、ＩＬ－９、ＩＬ－１０、ＩＬ－１１、ＩＬ－１２、ＩＬ－１３、ＩＬ－１４、ＩＬ－１５、ＩＬ－１６、ＩＬ－１７、及びＩＬ－１８）、並びに腫瘍壊死因子（ＴＮＦ－α、及びＴＮＦ－β）等が挙げられる。
　これらの中でも、血液処理用ビーズは、アラーミン及びサイトカインを除去することが好ましく、ＨＭＧＢ１及びサイトカインを除去することがより好ましい。 Examples of the cytokine 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-α, and TNF-β), and the like. Can be
Among these, the beads for blood treatment preferably remove alarmin and cytokines, and more preferably remove HMGB1 and cytokines.
〈血液処理用ビーズの生体適合性〉
　本実施形態における血液処理用ビーズは、上記のように優れた吸着性を維持しながら、生体適合性にも優れている。用語「生体適合性」とは、血液浄化器の目的や使用方法によって異なるが、本願明細書においては、血液処理用ビーズへの血小板の付着量を生体適合性の指標として用いる。血液処理用ビーズへの血小板の付着量が抑制されるほど、血液処理用ビーズは生体適合性に優れている。血液処理用ビーズの血小板付着性の評価方法は、実施例の欄で詳述する。 <Biocompatibility of blood processing beads>
The blood processing beads in the present embodiment are also excellent in biocompatibility while maintaining excellent adsorption as described above. The term "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.
　第一の実施形態における血液処理用ビーズは、実施例の欄で詳述する「血液処理用ビーズの血小板付着性」の評価方法に基づいて測定した場合に、多孔質ビーズへの血小板吸着率は、好ましくは０．１％～３０％、より好ましくは０．３％～２０％、更に好ましくは０．５％～１１％である。例えば、アクリル系樹脂から構成される多孔質ビーズを用いた場合、該付着量は、好ましくは０．１％～２２％、より好ましくは０．３％～１３％、更に好ましくは０．５％～９％である。例えば、スチレン系樹脂から構成される多孔質ビーズを用いた場合、該付着量は、好ましくは０．５％～３０％、より好ましくは１％～２２％、更に好ましくは３％～１１％である。 The blood processing beads in the first embodiment, when measured based on the evaluation method of "platelet adhesion of blood processing beads" 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%. For example, when porous beads composed of an acrylic resin are used, the amount of adhesion is preferably 0.1% to 22%, more preferably 0.3% to 13%, and still more preferably 0.5%. ９9%. For example, when porous beads composed of a styrene-based resin are used, the attached amount is preferably 0.5% to 30%, more preferably 1% to 22%, and still more preferably 3% to 11%. is there.
　第二の実施形態における血液処理用ビーズは、実施例の欄で詳述する「血液処理用ビーズの血小板付着性」の評価方法に基づいて測定した場合に、血小板残存率は、好ましくは８１％～１００％、より好ましくは８３％～９５％、更に好ましくは８５％～９５％である。 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%.
《血液処理用ビーズの製造方法》
　本実施形態の血液処理用ビーズの製造方法は限定されない。例えば、本実施形態の血液処理用ビーズの製造方法は、アクリル系樹脂、スチレン系樹脂、及びセルロース系樹脂からなる群から選択される少なくとも一つの樹脂から構成される多孔質ビーズの表面上に、本実施形態における生体適合性ポリマーを担持することを含む。本実施形態における生体適合性ポリマー及びモノマーについての詳細は上述したので、ここでは記載を省略する。 << Method of manufacturing beads for blood treatment >>
The method for producing the blood processing beads of the present embodiment is not limited. For example, 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.
〈生体適合性ポリマーの製造方法〉
　第一の実施形態において、生体適合性ポリマーの製造方法は限定されない。例えば、生体適合性ポリマーの製造方法は、任意の溶媒中に式（１）のモノマーを含有するモノマー溶液を調整することと、上記モノマー溶液に任意の重合開始剤を添加して重合溶液を調整することと、上記モノマーを重合させることとを含む。 <Method for producing biocompatible polymer>
In the first embodiment, the method for producing the biocompatible polymer is not limited. For example, 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.
　式（１）のモノマーに加えて、電荷を有するモノマーを、上記モノマー溶液中及び／又は上記重合溶液中に更に添加して、式（１）のモノマーと共重合させてもよい。電荷を有するモノマーについての詳細は上述したので、ここでは記載を省略する。 加 え In addition to the monomer of the formula (1), 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.
　第二の実施形態において、生体適合性ポリマーの製造方法は限定されない。例えば、生体適合性ポリマーの製造方法は、任意の溶媒中に両性イオン型モノマーを含有するモノマー溶液を調整することと、上記モノマー溶液に任意の重合開始剤を添加して重合溶液を調整することと、上記モノマーを重合させることとを含む。 に お い て In the second embodiment, the method for producing the biocompatible polymer is not limited. For example, 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.
　両性イオン型モノマーに加えて、上記式（４）のモノマーを、上記モノマー溶液中及び／又は上記重合溶液中に更に添加して、両性イオン型モノマーと共重合させてもよい。上記式（４）のモノマーについての詳細は上述したので、ここでは記載を省略する。 モ ノ マ ー In addition to the zwitterionic 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.
　本実施形態において、重合された生体適合性ポリマーは、任意の精製方法、例えば、再沈澱法、透析法、限外濾過法、及び抽出法等によって精製することができる。精製された生体適合性ポリマーは、任意の乾燥方法、例えば、減圧乾燥、噴霧乾燥、凍結乾燥、及び加熱乾燥等によって乾燥させることができる。 In the present embodiment, 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.
〈生体適合性ポリマーの担持方法〉
　生体適合性ポリマーを多孔質ビーズの表面上に担持する方法としては、任意の担持方法、例えば塗布法、スプレー法、及びディップ法等を用いることができる。 <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.
　例えば、ディップ法は、任意の溶媒、例えばアルコール、クロロホルム、アセトン、テトラヒドロフラン、及びジメチルホルムアミド等に上記生体適合性ポリマーを溶解したコーティング溶液を調整し、コーティング溶液に多孔質ビーズを浸漬することを含む。含浸後、コーティング溶液から多孔質ビーズを取り出して余分な溶液を取り除き、次いで任意の乾燥方法により乾燥させることができる。乾燥方法としては、乾燥気体中での風乾、減圧雰囲気中で常温又は加熱しながら乾燥を行う減圧乾燥等が挙げられる。減圧乾燥は、本実施形態における多孔質ビーズ１ｇ当たりのポリマーの量を少なくする観点から好ましい。 For example, 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. . After impregnation, the porous beads can be removed from the coating solution to remove excess solution and then dried by any drying method. Examples of 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.
　塗布法及びスプレー法では、例えば、上記コーティング溶液を多孔質ビーズに塗布又はスプレーした後、上記のように乾燥させることを含む。 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.
《血液浄化器》
　本実施形態の血液浄化器は、本実施形態の血液処理用ビーズを有する。血液浄化器は、一般に、血液入口、内部空間、及び血液出口を有する本体容器を有し、内部空間は血液処理用ビーズを収容することができる。血液浄化処理の際には、一般に、処理前の血液が血液入口を通って内部空間へと導入され、内部空間内に存在する本実施形態の血液処理用ビーズと接触することによって処理され、処理済み血液は血液出口を通って流出することができる。 《Blood purifier》
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. In the blood purification treatment, generally, 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.
　本体容器の形状としては、限定されないが、例えば、筒状、典型的には円筒状のカラム等を挙げることができる。 形状 The shape of the main container is not limited, and examples thereof include a cylindrical column, typically a cylindrical column.
　本体容器を構成する材料としては、限定されないが、熱可塑性樹脂、例えばポリプロピレン、ポリエチレン、ポリエステル、ポリスチレン、ポリ四フッ化エチレン、ポリカーボネート、アクリロニトリルブタジエンスチレン（ＡＢＳ）、及びビニル芳香族炭化水素と共役ジエンとからなる共重合体等が挙げられる。また、封止のために熱硬化性樹脂、例えばポリウレタン、及びエポキシ等が用いられることもある。 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.
　以下、実施例及び比較例により本実施形態を具体的に説明するが、本発明はこれらの実施例及び比較例に限定されるものではない。 Hereinafter, the present embodiment will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples and Comparative Examples.
《多孔質ビーズの物性測定》
〈多孔質ビーズの体積平均粒子径〉
　超純水にて膨潤された多孔質ビーズの大きさをデジタルマイクロスコープＶＨＸ―９００（キーエンス社製）を用いて２０００ビーズ測定し、それらの体積平均を体積平均粒子径（μｍ）として算出した。 《Measurement of physical properties of porous beads》
<Volume average particle diameter of porous beads>
The size of the porous beads swollen with ultrapure water was measured using a digital microscope VHX-900 (manufactured by Keyence Corporation) at 2,000 beads, and the volume average thereof was calculated as a volume average particle diameter (μm).
〈多孔質ビーズの積算細孔容量〉
　超純水にて膨潤された多孔質ビーズを凍結後２４時間凍結乾燥し、多孔質ビーズを乾燥させた後、ＶａｃＰｒｅｐ０６１（島津製作所－マイクロメリティックス社製）を用いて６０℃で１５時間の脱ガス処理（減圧乾燥）を行った。その後、ＴｒｉＳｔａｒII　３０２０（島津製作所－マイクロメリティックス社製）を用いてＮ２ガス吸着法にて積算細孔容量（ｃｍ３／ｇ）の測定を行った。この際、積算細孔容量としてはＢＪＨ法によるDesorption Cumulative Pore Volumeを採用した。 <Integrated pore volume of porous beads>
The porous beads swollen with ultrapure water are freeze-dried for 24 hours after freezing, and the porous beads are dried. Degassing treatment (drying under reduced pressure) was performed. Thereafter, TriStarII 3020 - was measured accumulated in using (Shimadzu Micromeritics Ltd. ticks, Inc.) N 2 gas adsorption method pore volume (cm 3 / g). At this time, a Desorption Cumulative Pore Volume by the BJH method was adopted as the integrated pore volume.
〈多孔質ビーズの比表面積〉
　上記の乾燥後の血液処理用ビーズを、ＶａｃＰｒｅｐ０６１（島津製作所－マイクロメリティックス社製）を用いて６０℃で１５時間の脱ガス処理（減圧乾燥）を行った。その後、ＴｒｉＳｔａｒII　３０２０（島津製作所－マイクロメリティックス社製）を用いてＮ２ガス吸着法にて比表面積（ｍ２／ｇ）の測定を行った。この際、比表面積としてはＢＥＴプロットによる値を採用した。 <Specific surface area of porous beads>
The dried beads for blood treatment were subjected to a degassing treatment (drying under reduced pressure) at 60 ° C. for 15 hours using VacPrep061 (manufactured by Shimadzu Corporation-Micromeritics). Thereafter, TriStarII 3020 - was measured with a specific surface area of at using (Shimadzu Micromeritics Ltd. ticks, Inc.) N 2 gas adsorption method (m 2 / g). At this time, a value based on a BET plot was adopted as the specific surface area.
《コート後ビーズの物性測定》
〈コート後ビーズの溶出量測定〉
　１００ｍＬコニカルビーカーと秤量瓶を超純水で十分に洗浄し、完全に乾燥させた。乾燥させた秤量瓶の重量を、使用直前に測定した（これを「処理前の秤量瓶の重量」とする）。１００ｍＬコニカルビーカーに、コート後ビーズ５．０ｍＬ（乾燥時１．１０ｇ）を加えた後、超純水を５０ｍＬ加えた（この溶液を「サンプル溶液」とする）。また、別の１００ｍＬコニカルビーカーに超純水５０ｍＬのみを加えた（この溶液を「Ｂｌａｎｋ溶液」とする）。次に、この２種類のビーカーの上部をアルミホイルで完全に覆い、同時に、１２１℃で２０分間オートクレーブ滅菌処理（ＬＳＸ－５００Ｌ、トミー精工社製）を行った。オートクレーブ滅菌処理後の２種類のビーカーを室温まで冷却後、ビーカー内の溶液を、濾紙（ＡＤＶＡＮＴＥＣ、Ｎｏ．５Ｃ）を用いて濾過し、新しい１００ｍＬコニカルビーカーに移し替えた。得られた２種類の濾過後溶液を、それぞれ２０ｍＬずつ別の秤量瓶に入れ、ホットプレート上で秤量瓶内の溶液の水分を蒸発させた。その後、それらの秤量瓶を、熱風乾燥機（ＤＮ４１０１、ヤマト社製）内で、１０５℃で１時間さらに乾燥し、乾燥後の秤量瓶の重量を測定した（これを「処理後の秤量瓶の重量」とする）。 《Measurement of physical properties of coated beads》
<Measurement of elution amount of beads after coating>
The 100 mL conical beaker and the weighing bottle were sufficiently washed with ultrapure water and completely dried. The weight of the dried weighing bottle was measured immediately before use (this is referred to as “weight of the weighing bottle before treatment”). After coating, 5.0 mL of beads (1.10 g when dried) were added to a 100 mL conical beaker, and then 50 mL of ultrapure water was added (this solution is referred to as a “sample solution”). Further, only 50 mL of ultrapure water was added to another 100 mL conical beaker (this solution is referred to as “Blank solution”). Next, the upper portions of the two types of beakers were completely covered with aluminum foil, and at the same time, autoclave sterilization (LSX-500L, manufactured by Tommy Seiko) was performed at 121 ° C. for 20 minutes. After the two types of beakers after the autoclave sterilization treatment were cooled to room temperature, the solution in the beakers was filtered using filter paper (ADVANTEC, No. 5C), and transferred to a new 100 mL conical beaker. Each of the obtained two types of filtered solutions was placed in another weighing bottle of 20 mL each, and the water content of the solution in the weighing bottle was evaporated on a hot plate. Thereafter, the weighing bottles were further dried at 105 ° C. for 1 hour in a hot air dryer (DN4101, manufactured by Yamato Co., Ltd.), and the weight of the weighing bottles after drying was measured (this was referred to as “the weighing bottle after treatment”. Weight)).
　サンプル溶液の蒸発残存物、Ｂｌａｎｋ溶液の蒸発残存物、およびコート後ビーズの溶出物量を以下の式により算出した。算出されたＢｌａｎｋ溶液の蒸発残存物が０．３ｍｇ以下になった場合にのみ、コート後ビーズの溶出物量の値として採用した。コート後ビーズの溶出物量の値は、２度測定及び算出し、その平均値が１．０ｍｇを超えた場合に溶出が多いと判断し、１．０ｍｇ以下の時に溶出が少ないと判断した。
　サンプル溶液の蒸発残存物（ｍｇ）＝処理後の秤量瓶の重量（ｍｇ）－処理前の秤量瓶の重量（ｍｇ）
　Ｂｌａｎｋ溶液の蒸発残存物（ｍｇ）＝処理後の秤量瓶の重量（ｍｇ）－処理前の秤量瓶の重量（ｍｇ）
　コート後ビーズの溶出物量（ｍｇ）＝サンプル溶液の蒸発残存物（ｍｇ）－Ｂｌａｎｋ溶液の蒸発残存物（ｍｇ） 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.
Evaporation residue of sample solution (mg) = weight of weighing bottle after treatment (mg)-weight of weighing bottle before treatment (mg)
Evaporation residue of Blank solution (mg) = Weight of weighing bottle after treatment (mg)-Weight of weighing bottle before treatment (mg)
Amount of eluate of beads after coating (mg) = evaporation residue of sample solution (mg)-evaporation residue of Blank solution (mg)
１．第一の実施形態の実施例及び比較例
《実施例１－１》
〈コーティングポリマーの合成〉
　２－メトキシエチルメタクリレート（ＭＥＭＡ、［化９］の構造式（ｉ）の化合物）と、Ｎ，Ｎ－ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ、［化９］の構造式（ｉｉ）の化合物）と、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ、［化９］の構造式（ｉｉｉ）の化合物）との共重合体を通常の溶液重合によって合成した。重合条件は、エタノール溶液中、開始剤としてアゾイソブチロニトリル（ＡＩＢＮ）０．００２５モル／Ｌ存在下、各モノマー濃度を１モル／Ｌとし、反応温度６０℃にて８時間重合反応を行い、ポリマー重合液を得た。得られたポリマー重合液をジエチルエーテルに滴下し、析出したポリマーを回収した。回収したポリマーを、ジエチルエーテルを用いて再沈殿操作を行うことで精製した。その後、得られたポリマーを減圧条件下で２４時間乾燥してコーティングポリマーを得た。 1. Example of First Embodiment and Comparative Example << Example 1-1 >>
<Synthesis of coating polymer>
2-methoxyethyl methacrylate (MEMA, a compound of the structural formula (i) of [Formula 9]), N, N-diethylaminoethyl methacrylate (DEAEMA, a compound of the structural formula (ii) of [Formula 9]), and N- A copolymer with methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB, compound of structural formula (iii) of Chemical Formula 9) was synthesized by ordinary solution polymerization. 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.
　コーティングポリマー中のＭＥＭＡモノマー単位と、ＤＥＡＥＭＡモノマー単位と、ＣＭＢモノマー単位とのモル比は以下のように測定した。得られたコーティングポリマーをジメチルスルホキシドへ溶解した後、１Ｈ－ＮＭＲ測定を行うことにより算出したチャートにおける４．３２ｐｐｍ（ＣＭＢに固有のＨ原子由来）のピーク及び２．６３ｐｐｍ（ＤＥＡＥＭＡに固有のＨ原子由来）のピークと、０．６５－２．１５ｐｐｍ（全体のＨ原子量）の面積比から次の式により算出した。
　ＤＥＡＥＭＡモノマーのモル比＝（“２．６３ｐｐｍ領域の面積比”／２）／（“０．６５－２．１５ｐｐｍ領域の面積比”／５－“２．６３ｐｐｍ領域の面積比”×０．３）×１００
　ＣＭＢモノマーのモル比＝（“４．３２ｐｐｍ領域の面積比”／２）／（“０．６５－２．１５ｐｐｍ領域の面積比”／５－“２．６３ｐｐｍ領域の面積比”×０．３）×１００
　ＭＥＭＡモノマーのモル比＝１００－ＤＥＡＥＭＡモノマーのモル比－ＣＭＢモノマーのモル比
　コーティングポリマーにおけるＭＥＭＡモノマー単位と、ＤＥＡＥＭＡモノマー単位と、ＣＭＢモノマー単位とのモル比は、８０／１０／１０と算出された。 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).
Molar ratio of DEAEMA monomer = (“area ratio of 2.63 ppm region” / 2) / (“area ratio of 0.65-2.15 ppm region” / 5− “area ratio of 2.63 ppm region” × 0.3 ) × 100
Molar ratio of CMB monomer = (“area ratio of 4.32 ppm region” / 2) / (“area ratio of 0.65-2.15 ppm region” / 5− “area ratio of 2.63 ppm region” × 0.3 ) × 100
Molar ratio of MEMA monomer = 100−molar ratio of DEAEMA monomer−molar ratio of CMB monomer The molar ratio of MEMA monomer unit, DEAEMA monomer unit, and CMB monomer unit in the coating polymer was calculated to be 80/10/10. .
〈コーティング液の調製〉
　上記コーティングポリマーを７０Ｗ／Ｗ％のエチルアルコールへ添加した後、１２時間撹拌し、コーティングポリマー濃度が０．１重量％のコーティング液を調整した。 <Preparation of coating liquid>
After the above coating polymer was added to 70 W / W% ethyl alcohol, the mixture was stirred for 12 hours to prepare a coating solution having a coating polymer concentration of 0.1% by weight.
〈ビーズの調製〉
　多孔質ビーズとしてアンバーライトＴＭＸＡＤＴＭ１１８０Ｎ（オルガノ社製、スチレン系ポリマービーズ、体積平均粒子径６０９μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量１．４７２ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．０２０ｃｍ３／ｇ）を用いた。アンバーライトＴＭＸＡＤＴＭ１１８０ＮのＬｏｇ微分細孔容積分布及び積算細孔容量のグラフを図１に、累計体積粒度分布のグラフを図３に示す。超純水で膨潤されたビーズ２ｍＬ（乾燥時０．４４ｇ）をポリプロピレン（ＰＰ）製の１５ｍＬコニカルチューブに入れた後、７０Ｗ／Ｗ％のエチルアルコール１０ｍＬを加えた。振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、４０ｒ／ｍｉｎで１２時間振とう後、振とう後の溶液をセルストレーナー（ミニセルストレーナーII、ナイロンメッシュ７０μｍ、フナコシ社製）にて濾過した。濾過後の溶液の２２０ｎｍにおける吸光度を島津紫外可視分光光度計ＵＶ－２６００（島津製作所社製）にて測定後、濾過にて得られたビーズを再度１５ｍＬコニカルチューブに加えた。このコニカルチューブへの７０Ｗ／Ｗ％のエチルアルコールの添加、振とう機による１２時間の振とう、セルストレーナーによる溶液除去の一連の作業を、濾過後溶液の２２０ｎｍにおける吸光度が０．０３以下になるまで繰り返し行った。 <Preparation of beads>
As porous beads, Amberlite ™ XAD ™ 1180N (manufactured by Organo Co., Ltd., styrene-based polymer beads, volume average particle diameter 609 μm, cumulative pore volume of 1.472 cm 3 / g with pore diameter of 5 nm to 100 nm, cumulative of pore diameter of 100 nm to 200 nm) A pore volume of 0.020 cm 3 / g) was used. FIG. 1 shows a graph of the log differential pore volume distribution and the cumulative pore volume of Amberlite ™ XAD ™ 1180N, and FIG. 3 shows a graph of the cumulative volume particle size distribution. After 2 mL of beads swollen with ultrapure water (0.44 g when dried) was placed in a 15 mL conical tube made of polypropylene (PP), 10 mL of 70 W / W% ethyl alcohol was added. After shaking using a shaking machine (Invitro shaker WAVE-S1, manufactured by TAITEC) at a shaking angle of 10 degrees and 40 r / min for 12 hours, the solution after shaking was washed with a cell strainer (Mini Cell Strainer II, nylon mesh 70 μm, (Funakoshi). After measuring the absorbance at 220 nm of the solution after filtration with a Shimadzu UV-visible spectrophotometer UV-2600 (manufactured by Shimadzu Corporation), 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.
〈コーティング方法〉
　上記処理により得られたビーズ２ｍＬを含有した１５ｍＬコニカルチューブに、上記コーティング液１０ｍＬを加え、振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、４０ｒ／ｍｉｎで３時間振とうさせた。その後、コート処理後溶液をセルストレーナー（ミニセルストレーナーII、ナイロンメッシュ７０μｍ、フナコシ社製）にて濾過し、コート後ビーズを得た。濾過後のコート処理後溶液の２２０ｎｍにおける吸光度を島津紫外可視分光光度計ＵＶ－２６００にて測定後、濾過にて得られたコート後ビーズを再度１５ｍＬコニカルチューブに加えた。ここでビーズへのコーティング量（ｍｇ／ビーズ乾燥ｇ）を下記式により算出した結果、コーティングポリマーのコーティング量は６ｍｇ／ビーズ乾燥ｇであった。
　処理後溶液内コーティングポリマー重量（ｍｇ）＝処理前溶液内コーティングポリマー重量（ｍｇ）×処理後溶液の２２０ｎｍの吸光度／処理前溶液内の２２０ｎｍの吸光度
　コーティング量（ｍｇ／ビーズ乾燥ｇ）＝（処理前溶液内コーティングポリマー重量－処理後溶液内コーティングポリマー重量）／使用ビーズ乾燥ｇ <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 μm, 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. Here, the amount of coating on the beads (mg / g dry beads) was calculated by the following formula, and as a result, the coating amount of the coating polymer was 6 mg / g dry beads.
Weight of coating polymer in solution after treatment (mg) = weight of coating polymer in solution before treatment (mg) × absorbance at 220 nm of solution after treatment / absorbance at 220 nm in solution before treatment Coating amount (mg / g of dried beads) = (treatment Weight of coated polymer in solution before treatment-Weight of coated polymer in solution after treatment) / Dried beads used
　続いて、上記のコート後ビーズを含有した１５ｍＬコニカルチューブを、５０℃で１５時間真空乾燥（絶対圧力０．００３ＭＰａ以下）を行った後、コニカルチューブ内に２０Ｗ／Ｗ％のエチルアルコールを１２ｍＬ加えた。振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、４０ｒ／ｍｉｎで１２時間振とう後、ビーズが浸潤した溶液をセルストレーナー（ミニセルストレーナーII、ナイロンメッシュ７０μｍ、フナコシ社製）にて除去し、得られたビーズを再度１５ｍＬコニカルチューブに加えた。その後、１５ｍＬコニカルチューブへの超純水１２ｍＬの添加、振とう機による３時間の振とう、セルストレーナーによる溶液除去の一連の作業を計５度繰り返し行った。最後にコニカルチューブに生理食塩水（大塚生食注、大塚製薬工場社製）を１２ｍＬ充填し、γ線照射により滅菌作業を行い、血液処理用ビーズを得た。 Subsequently, after vacuum-drying (absolute pressure 0.003 MPa or less) the 50 mL conical tube containing the coated beads and containing the beads at 50 ° C. for 15 hours, 12 mL of 20 W / W% ethyl alcohol was added into the conical tube. Was. After shaking using a shaker (Invitro Shaker WAVE-S1, manufactured by TAITEC) at a shaking angle of 10 degrees and 40 r / min for 12 hours, the solution in which the beads were infiltrated was subjected to a cell strainer (Mini Cell Strainer II, nylon mesh 70 μm, The resulting beads were again added to a 15 mL conical tube. Thereafter, a series of operations of adding 12 mL of ultrapure water to a 15 mL conical tube, shaking for 3 hours with a shaker, and removing the solution with a cell strainer was repeated a total of 5 times. Finally, the conical tube was filled with 12 mL of physiological saline (Otsuka Raw Food Injection, manufactured by Otsuka Pharmaceutical Factory) and sterilized by γ-irradiation to obtain blood processing beads.
〈血液処理用ビーズ全体の元素分析〉
　上記の血液処理用ビーズ１ｍＬに含まれる溶液をセルストレーナーにて除去し、得られたビーズを１５ｍＬコニカルチューブに加えた。その後、１５ｍＬコニカルチューブへ超純水１２ｍＬを添加することで、ビーズ溶液を超純水にて置換した。超純水にて置換された血液処理用ビーズを５０℃で１５時間真空乾燥（絶対圧力０．００３ＭＰａ以下）を行った。乾燥後の血液処理用ビーズを、元素分析装置（株式会社堀場製作所製、酸素・窒素・水素分析装置ＥＭＧＡ－９３０）を用いて元素分析を行った。試験は３検体で分析し、その平均値を採用した。その結果、窒素元素の割合は０．３質量％以下であった。 <Elemental analysis of whole blood processing beads>
The solution contained in 1 mL of the blood treatment beads was removed with a cell strainer, and the obtained beads were added to a 15 mL conical tube. Then, the bead solution was replaced with ultrapure water by adding 12 ml of ultrapure water to a 15 ml conical tube. The blood treatment beads replaced with ultrapure water were vacuum dried (absolute pressure: 0.003 MPa or less) at 50 ° C. for 15 hours. The dried beads for blood treatment were subjected to elemental analysis using an elemental analyzer (oxygen / nitrogen / hydrogen analyzer EMGA-930, manufactured by Horiba, Ltd.). In the test, three samples were analyzed, and the average value was adopted. As a result, the ratio of the nitrogen element was 0.3% by mass or less.
〈血液処理用ビーズ表面のＸＰＳ測定〉
　上記の乾燥後の血液処理用ビーズから無作為に５０粒選択し、そのビーズ１粒１粒の表面状態を、Ｋ－Ａｌｐｈａ＋（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ　社製）を用いて、ＸＰＳにて測定した。測定条件は、照射Ｘ線：単結晶分光ＡＩ　Ｋα、Ｘ線スポット径：１５０μｍ、中和電子銃：使用、であった。それらの５０粒の血液処理用ビーズ表面に存在する、原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数に対する窒素原子存在率の値を平均化したものを、血液処理用ビーズ表面の窒素原子存在率（％）として算出した。その結果を表３に記す。 <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 Kα, X-ray spot diameter: 150 μm, 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.
〈血液処理用ビーズ全体のＸＰＳ測定〉
　上記の乾燥後の血液処理用ビーズをすりこぎ棒により粉砕し、血液処理用ビーズの粉体を作製した。その粉体の表面状態を、Ｋ－Ａｌｐｈａ＋（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ　社製）を用いて、ＸＰＳにて測定した。測定条件は、照射Ｘ線：単結晶分光ＡＩ　Ｋα、Ｘ線スポット径：１５０μｍ、中和電子銃：使用、であった。測定は１０検体について行い、原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数に対する窒素原子存在率の値を平均化したものを、血液処理用ビーズ全体の窒素原子存在率（％）として算出した。その結果を表３に記す。 <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 Kα, X-ray spot diameter: 150 μm, 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.
〈血液処理用ビーズの吸着性〉
　健常ボランティアから採血した血液にヘパリンナトリウム（ヘパリンナトリウム注５万単位／５０ｍＬ、ニプロ社製）を２０００　ＩＵ／ｍＬ濃度になるように添加後、Ｅｓｃｈｅｒｉｃｈｉａ　ｃｏｌｉ　Ｏ１１１：Ｂ４由来のリポポリサッカライド（ＬＰＳ）（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ社製）を０．１μｇ／ｍＬ濃度になるように添加し、振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、１０ｒ／ｍｉｎで２４時間、３７℃で振とうさせた。その後、遠心機（ハイブリッド高速冷却遠心機　６２００、久保田商事社製）を用いて、室温で２０００ｇで２０分間遠心し、上清を血漿サンプルとして取得した。取得した血漿サンプル３．６ｍＬと上記の血液処理用ビーズ０．４５ｍＬ（乾燥時０．１０ｇ）をポリプロピレン（ＰＰ）製の５ｍＬチューブ内で混合し、振とう機を用いて振とう角度１０度、１０ｒ／ｍｉｎで２時間、３７℃で振とうさせた（これをビーズ接触有サンプルとする）。この時、取得した血漿サンプル３．６ｍＬにビーズを添加しないサンプルも準備し、ビーズ接触有サンプルと同じ処理を行った（これをビーズ接触無サンプルとする）。振とうさせた後のＰＰ製チューブを、遠心機を用いて、室温で２０００ｇで１分間遠心し、ビーズ接触有及び無サンプルの上清を取得した。取得した上清を用いて、各種サイトカイン濃度をＢｉｏ－Ｐｌｅｘシステム（Ｂｉｏ－Ｒａｄ社製　Ｂｉｏ－Ｐｌｅｘ　Ｐｒｏ　ヒト　サイトカイン　ＧＩ２７－ｐｌｅｘ　パネル）を用いて、添付の取扱説明書に従い測定した。またＨＭＧＢ－１濃度はＨＭＧＢ１　ＥＬＩＳＡＫ　Ｋｉｔ　ＩＩ（株式会社　シノテスト製）を用いて、添付の取扱説明書に従い測定した。ここで、ビーズのサイトカイン、ＨＭＧＢ－１吸着率は下記式にて算出した。その結果を表１に記す。
　各種サイトカイン吸着率（％）＝（“ビーズ接触無サンプルのサイトカイン濃度”－“ビーズ接触有サンプルのサイトカイン濃度”）／“ビーズ接触無サンプルのサイトカイン濃度”×１００
　ＨＭＧＢ－１吸着率（％）＝（“ビーズ接触無サンプルのＨＭＧＢ－１濃度”－“ビーズ接触有サンプルのＨＭＧＢ－１濃度”）／“ビーズ接触無サンプルのＨＭＧＢ－１濃度”×１００
　尚、今回の実験におけるビーズ接触無サイトカイン濃度、ビーズ接触無ＨＭＧＢ－１濃度はＩＬ－１ｂ：３６５８ｐｇ／ｍＬ、ＩＬ－６：５５４０ｐｇ／ｍＬ、ＩＬ－８：６１４４ｐｇ／ｍＬ、ＩＬ－１０：８４６ｐｇ／ｍＬ、ＴＮＦ－α：８０８５ｐｇ／ｍＬ、ＨＭＧＢ－１：２７ｎｇ／ｍＬであった。 <Adsorption of beads for blood treatment>
Heparin sodium (50,000 heparin injection / 50 mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers to a concentration of 2000 IU / mL, and then lipopolysaccharide (LPS) derived from Escherichia coli O111: B4 (LPS) ( Sigma-Aldrich) was added to a concentration of 0.1 μg / mL, and the mixture was shaken at a shaking angle of 10 °, 10 r / min for 24 hours using a shaker (Invitro Shaker WAVE-S1, manufactured by TAITEC). Shake at 37 ° C. Thereafter, 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). At this time, 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. Using the obtained supernatant, the 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. The HMGB-1 concentration was measured using HMGB1 ELISA Kit II (manufactured by Shino Test Co., Ltd.) according to the attached instruction manual. Here, the cytokine and HMGB-1 adsorption rates of the beads were calculated by the following equation. Table 1 shows the results.
Various cytokine adsorption rates (%) = (“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
In this experiment, 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. mL, TNF-α: 8085 pg / mL, and HMGB-1: 27 ng / mL.
〈血液処理用ビーズの血小板付着性〉
　健常ボランティアから採血した血液にヘパリンナトリウム（ヘパリンナトリウム注５万単位／５０ｍＬ、ニプロ社製）を１２００　ＩＵ／ｍＬ濃度になるように添加した（これを処理前血液とする）。処理前血液４．４ｍＬに対し上記の血液処理用ビーズ０．６５ｍＬ（乾燥時０．１５ｇ）をポリプロピレン（ＰＰ）製の５ｍＬチューブ内で混合した。ＲＯＴＡＴＯＲ　ＲＴ－５（タイテック社製）の直径２０ｃｍの円板状回転体上に、チューブを回転体の半径方向に沿うよう放射状に取り付けた。円板状回転体の回転面の角度が水平から２２度になるようにセットして、４ｒｐｍの速度で３時間、３７℃で回転攪拌した。ビーズ接触後の血液をセルストレーナー（ミニセルストレーナーII、ナイロンメッシュ７０μｍ、フナコシ社製）にて濾過し、ビーズを除去した（これを処理後血液とする）。処理後血液の血小板濃度を、ミクロセルカウンター　ＸＴ－１８００ｉ（Ｓｙｓｍｅｘ社製）にて測定した。下記式からビーズへの血小板付着率を算出した結果を表１に示す。
　血小板吸着率（％）＝（処理前血液の血小板数－処理後血液の血小板数）／（処理前血液の血小板数）×１００
　尚、今回の実験で使用した処理前血液は、白血球濃度：４９２０個／μＬ、赤血球濃度：４３０×１０＾４個／μＬ、血小板濃度：２４０×１０＾３個／μＬ、ヘマトクリット値：３８．８％であった。またヘモクロンＪｒ．シグニチャー＋（インターナショナルテクニダイン社製、ヘモクロン　テストカ－トリッジ　ＪＡＣＴ－ＬＲ）にて測定した、処理前血液の活性化凝固時間は３０４秒であった。 <Platelet adhesion of blood processing beads>
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 μm, manufactured by Funakoshi) to remove beads (this is referred to as blood after treatment). After the 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 / μL, erythrocyte concentration: 430 × 10 4 cells / μL, platelet concentration: 240 × 10 3 cells / μL, 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.).
《実施例１－２》
　コーティングポリマーの組成がＭＥＭＡ／ＤＥＡＥＭＡ／ＣＭＢ＝６０／２０／２０（モル比）であること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-2 >>
Blood processing beads were prepared in the same manner as in Example 1-1, except that the composition of the coating polymer was MEMA / DEAEMA / CMB = 60/20/20 (molar ratio). 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.
《実施例１－３》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝７５／２５（モル比）であること、及びコーティングポリマーのコーティング量が８ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-3 >>
Blood processing beads as in Example 1-1, except that the composition of the coating polymer was MEMA / CMB = 75/25 (molar ratio) and the coating amount of the coating polymer was 8 mg / g of 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 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.
《実施例１－４》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝７５／２５（モル比）であること、使用コーティング液のコーティングポリマー濃度が０．５重量％であること、及びコーティングポリマーのコーティング量が３１ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-4 >>
When the composition of the coating polymer is MEMA / CMB = 75/25 (molar ratio), the coating polymer concentration of the used coating solution is 0.5% by weight, and the coating amount of the coating polymer is 31 mg / g of dry beads. Except for this, 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 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.
《実施例１－５》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝７５／２５（モル比）であること、使用コーティング液のコーティングポリマー濃度が０．０３３重量％であること、及びコーティングポリマーのコーティング量が２．４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-5 >>
The composition of the coating polymer is MEMA / CMB = 75/25 (molar ratio), the coating polymer concentration of the used coating solution is 0.033% by weight, and the coating amount of the coating polymer is 2.4 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 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.
《実施例１－６》
　コーティングポリマーの組成がＭＥＭＡ／ＤＥＡＥＭＡ＝８０／２０（モル比）であること、及びコーティングポリマーのコーティング量が１０ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-6 >>
Blood processing beads as in Example 1-1, except that the composition of the coating polymer was MEMA / DEAEMA = 80/20 (molar ratio) and the coating amount of the coating polymer was 10 mg / g of 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 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.
《実施例１－７》
　コーティングポリマーの組成がＭＥＭＡ／ＤＥＡＥＭＡ／ＡＡｃ（アクリル酸、［化９］の構造式（ｉｖ）の化合物）＝６０／２８／１２（モル比）であること、及びコーティングポリマーのコーティング量が８ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-7 >>
The composition of the coating polymer is MEMA / DEAEMA / AAc (acrylic acid, the compound of the structural formula (iv) of Chemical Formula 9) = 60/28/12 (molar ratio), and the coating amount of the coating polymer is 8 mg / Blood processing beads were prepared in the same manner as in Example 1-1 except that the beads were dried 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.
《実施例１－８》
　コーティングポリマーの組成がＭＥＭＡ／ＤＥＡＥＭＡ／ＡＡｃ＝７１／１５／１４（モル比）であること、及びコーティングポリマーのコーティング量が５ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-8 >>
As in Example 1-1, except that the composition of the coating polymer was MEMA / DEAEMA / AAc = 71/15/14 (molar ratio), and that the coating amount of the coating polymer was 5 mg / g dry beads. Blood processing beads were 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 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.
《実施例１－９》
　コーティングポリマーの組成がＭＥＭＡ／ＤＥＡＥＭＡ／ＭＡｃ（メタアクリル酸、［化９］の構造式（ｖ）の化合物）＝６２／１５／２３（モル比）であること、及びコーティングポリマーのコーティング量が４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。 << Example 1-9 >>
The composition of the coating polymer is MEMA / DEAEMA / MAc (methacrylic acid, the compound of the structural formula (v) of Chemical Formula 9) = 62/15/23 (molar ratio), and the coating amount of the coating polymer is 4 mg. / 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.
《実施例１－１０》
　コーティングポリマーの組成がＭＥＭＡ＝１００（モル比）であること、及びコーティングポリマーのコーティング量が１１ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。 << Example 1-10 >>
Blood processing beads were prepared in the same manner as in Example 1-1, except that the composition of the coating polymer was MEMA = 100 (molar ratio) and the coating amount of the coating polymer was 11 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.
《実施例１－１１》
　コーティングポリマーの組成がＢＭＡ（ｎ‐ブチルメタクリレート、［化９］の構造式（ｖｉ）の化合物）／ＤＥＡＥＭＡ／ＣＭＢ＝８０／１０／１０（モル比）であること、コーティングポリマーの溶液として７０Ｗ／Ｗ％のエチルアルコールの代わりに１００Ｗ／Ｗ％のエチルアルコールを用いたこと、及びコーティングポリマーのコーティング量が４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-11 >>
The composition of the coating polymer is BMA (n-butyl methacrylate, a compound of the structural formula (vi) of [Formula 9]) / DEAEMA / CMB = 80/10/10 (molar ratio), and 70 W / Blood processing beads in the same manner as in Example 1-1, except that 100 W / W% ethyl alcohol was used instead of W% ethyl alcohol, and that the coating amount of the coating polymer was 4 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 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
《実施例１－１２》
　コーティングポリマーの組成がＢＭＡ／ＣＭＢ＝７０／３０（モル比）であること、及びコーティングポリマーのコーティング量が６ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-12 >>
Blood processing beads in the same manner as in Example 1-1, except that the composition of the coating polymer was BMA / CMB = 70/30 (molar ratio) and the coating amount of the coating polymer was 6 mg / g of 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 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.
《実施例１－１３》
　コーティングポリマーの組成がＬＭＡ（ラウリル酸メタクリレート、［化９］の構造式（ｖｉｉ）の化合物）／ＤＥＡＥＭＡ／ＣＭＢ＝８０／１０／１０（モル比）であること、コーティングポリマーの溶液として７０Ｗ／Ｗ％のエチルアルコールの代わりに１００Ｗ／Ｗ％のｎ－ブチルアルコールを用いたこと、及びコーティングポリマーのコーティング量が４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-13 >>
The composition of the coating polymer is LMA (lauryl methacrylate, a compound of the structural formula (vii) of Chemical Formula 9) / DEAEMA / CMB = 80/10/10 (molar ratio), and 70 W / W as a coating polymer solution % Blood alcohol was used instead of 100% ethyl alcohol, and the coating amount of the coating polymer was 4 mg / g dry beads, in the same manner as in Example 1-1. Beads were made. 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.
《実施例１－１４》
　コーティングポリマーの組成がＬＭＡ／ＤＥＡＥＭＡ／ＣＭＢ＝６０／２０／２０（モル比）であること、コーティングポリマーの溶液として７０Ｗ／Ｗ％のエチルアルコールの代わりに１００Ｗ／Ｗ％のｎ－ブチルアルコールを用いたこと、及びコーティングポリマーのコーティング量が４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-14 >>
The composition of the coating polymer is LMA / DEAEMA / CMB = 60/20/20 (molar ratio), and 100 W / W% n-butyl alcohol is used as the coating polymer solution instead of 70 W / W% ethyl alcohol. 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.
《実施例１－１５》
　コーティングポリマーの組成がＬＭＡ／ＤＥＡＥＭＡ／ＣＭＢ＝４０／３０／３０（モル比）であること、及びコーティングポリマーの溶液として７０Ｗ／Ｗ％のエチルアルコールの代わりに１００Ｗ／Ｗ％のエチルアルコールを用いたこと以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-15 >>
The composition of the coating polymer was LMA / DEAEMA / CMB = 40/30/30 (molar ratio), and 100 W / W% ethyl alcohol was used as the coating polymer solution instead of 70 W / W% ethyl alcohol. Except for this, 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. 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.
《実施例１－１６》
　コーティングポリマーの組成がＬＭＡ／ＣＭＢ＝７０／３０（モル比）であること、コーティングポリマーの溶液として７０Ｗ／Ｗ％のエチルアルコールの代わりに１００Ｗ／Ｗ％のエチルアルコールを用いたこと、及びコーティングポリマーのコーティング量が５ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-16 >>
That the composition of the coating polymer is LMA / CMB = 70/30 (molar ratio), that 100 W / W% ethyl alcohol is used as the coating polymer solution instead of 70 W / W% ethyl alcohol, Blood processing beads were prepared in the same manner as in Example 1-1, except that the coating amount of was 5 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.
《実施例１－１７》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝８５／１５（モル比）であること、及びコーティングポリマーのコーティング量が９ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-17 >>
Blood processing beads as in Example 1-1, except that the composition of the coating polymer was MEMA / CMB = 85/15 (molar ratio) and the coating amount of the coating polymer was 9 mg / g of 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 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
《実施例１－１８》
　コーティングポリマーの組成がＭＥＭＡ／ＭＰＣ（リン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル、［化９］の構造式（ｖｉｉｉ）の化合物）＝８５／１５（モル比）であること、及びコーティングポリマーのコーティング量が７ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-18 >>
The composition of the coating polymer is MEMA / MPC (2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl phosphate, a compound of the structural formula (viii) of Chemical Formula 9) = 85/15 (molar ratio). 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.
《実施例１－１９》
　コーティングポリマーの組成がＭＥＭＡ／ＤＭＡＥＭＡ（ジメチルアミノエチルメタクリレート、［化９］の構造式（ｉｘ）の化合物）＝８０／２０（モル比）であること、及びコーティングポリマーのコーティング量が９ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Example 1-19 >>
The composition of the coating polymer is MEMA / DMAEMA (dimethylaminoethyl methacrylate, a compound of the structural formula (ix) of Chemical Formula 9) = 80/20 (molar ratio), and the coating amount of the coating polymer is 9 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.
《実施例１－２０》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０（ピュロライト社製、アクリル系ポリマービーズ、体積平均粒子径６２１μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量０．８２３ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．０３８ｃｍ３／ｇ）を選択したこと、及びコーティングポリマーのコーティング量が１４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。ピュロソーブＴＭＰＡＤ９５０のＬｏｇ微分細孔容積分布及び積算細孔容量のグラフを図２に、累計体積粒度分布のグラフを図３に示す。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-20 >>
As beads, Purosorb TM PAD950 (manufactured by Purolite, acrylic polymer beads, volume average particle diameter 621 μm, cumulative pore volume of pore diameter 5 nm to 100 nm 0.823 cm 3 / g, pore diameter instead of Amberlite ™ XAD ™ 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. 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.
《実施例１－２１》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１３ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－２と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Example 1-21 >>
Blood processing beads in the same manner as in Example 1-2, except that Purosorb ™ PAD950 was selected as the beads instead of Amberlite ™ XAD ™ 1180N, and that the coating amount of the coating polymer was 13 mg / g of 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.
《実施例１－２２》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が６ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－３と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Example 1-22 >>
Blood processing beads in the same manner as in Example 1-3, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 1180N as beads, and that the coating amount of the coating polymer was 6 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.
《実施例１－２３》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１９ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－４と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。 << Example 1-23 >>
Blood processing beads in the same manner as in Example 1-4, except that Purosorb ™ PAD950 was selected as the beads instead of Amberlite ™ XAD ™ 1180N, and that the coating amount of the coating polymer was 19 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.
《実施例１－２４》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１６ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－６と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Example 1-24 >>
Blood processing beads in the same manner as in Example 1-6, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 1180N as the beads, and that the coating amount of the coating polymer was 16 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.
《実施例１－２５》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１３ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－７と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Example 1-25 >>
Blood processing beads in the same manner as in Example 1-7, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 1180N as beads, and that the coating amount of the coating polymer was 13 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.
《実施例１－２６》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１５ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１０と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Example 1-26 >>
Blood processing beads in the same manner as in Example 1-10, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 1180N as beads, and that the coating amount of the coating polymer was 15 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.
《比較例１－１》
　コーティングポリマーの組成がＭＥＡ（２－メトキシエチルアクリレート、［化９］の構造式（ｘ）の化合物）／ＤＥＡＥＭＡ／ＣＭＢ＝８０／１０／１０（モル比）であること、使用コーティング液のコーティングポリマー濃度が０．３重量％であること、及びコーティングポリマーのコーティング量が５５ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法でサイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Comparative Example 1-1 >>
The composition of the coating polymer is MEA (2-methoxyethyl acrylate, a compound of the structural formula (x) of Chemical Formula 9) / DEAEMA / CMB = 80/10/10 (molar ratio), and the coating polymer of the coating solution used Blood processing beads were prepared in the same manner as in Example 1-1, except that the concentration was 0.3% by weight and the coating amount of the coating polymer was 55 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.
《比較例１－２》
　コーティングポリマーの組成がＭＥＡ／ＤＥＡＥＭＡ／ＣＭＢ＝８０／１０／１０（モル比）であること、使用コーティング液のコーティングポリマー濃度が０．５重量％であること、及びコーティングポリマーのコーティング量が９４ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。 << Comparative Example 1-2 >>
The composition of the coating polymer is MEA / DEAEMA / CMB = 80/10/10 (molar ratio), the coating polymer concentration of the used coating solution is 0.5% by weight, and the coating amount of the coating polymer is 94 mg / Blood processing beads were prepared in the same manner as in Example 1-1 except that the beads were dried 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.
《比較例１－３》
　コーティングポリマーの組成がＢＡ（ブチルアクリレート、［化９］の構造式（ｘｉ）の化合物）＝１００（モル比）であること、及びコーティングポリマーのコーティング量が１６ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Comparative Example 1-3 >>
Except that the composition of the coating polymer is BA (butyl acrylate, the compound of the structural formula (xi) of [Formula 9]) = 100 (molar ratio), and that the coating amount of the coating polymer is 16 mg / g dry beads. In the same manner as in Example 1-1, 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.
《比較例１－４》
　コーティングポリマーの組成がＢＡ／ＤＥＡＥＭＡ／ＣＭＢ＝６０／２０／２０（モル比）であること、及びコーティングポリマーのコーティング量が１２ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << Comparative Example 1-4 >>
As in Example 1-1, except that the composition of the coating polymer was BA / DEAEMA / CMB = 60/20/20 (molar ratio), and that the coating amount of the coating polymer was 12 mg / g dry beads. Blood processing beads were 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 1 shows the results of platelet adhesion evaluation performed in the same manner as in Example 1-1.
《比較例１－５》
（コーティングポリマーの合成）
　３口ナスフラスコに３－メトキシプロピルアクリレート７．５０ｇ（ＭＣ３Ａ、［化９］の構造式（ｘｉｉ）の化合物）、１，４－ジオキサン３０．２ｇ、及びアゾビスイソブチロニトリル（ＡＩＢＮ）７．５ｍｇを加えた。乾燥窒素ガスを反応溶液中に通しながら３０分間攪拌し、反応系を窒素置換した。３口ナスフラスコの下部温度を７５℃に設定したオイルバスに浸漬し、窒素気流下、６時間攪拌することで重合を行った。重合反応の進行を１Ｈ　ＮＭＲによって確認し、十分に高い反応転化率（９０％前後）であることを確認した後、重合系を室温まで放冷することで反応を停止した。重合溶液をヘキサンに滴下することでポリマーを沈殿させ、デカントによって上澄みを除き、沈殿物をテトラヒドロフランに溶解させて回収した。テトラヒドロフランに溶解した後、ヘキサンで再沈殿させる作業を２回繰り返して精製を行い、得られた沈殿物を更に水中で２４時間攪拌した。デカントによって水を取り除き、沈殿物をテトラヒドロフランに溶解させて回収した。溶媒を減圧留去した後、真空乾燥機で乾燥し、重合体を得た。得られた重合体の一部を用いて、分子量を測定したところ、数平均分子量（Ｍｎ）３１０００及び分子量分布（Ｍｗ／Ｍｎ）２．５であった。 << Comparative Example 1-5 >>
(Synthesis of coating polymer)
7.50 g of 3-methoxypropyl acrylate (MC3A, compound of the structural formula (xii) of Chemical Formula 9), 30.2 g of 1,4-dioxane, and azobisisobutyronitrile (AIBN) 7 0.5 mg was added. The mixture was stirred for 30 minutes while passing dry nitrogen gas through the reaction solution, and the reaction system was replaced with nitrogen. The polymerization was carried out by immersing the lower temperature of the three-necked eggplant flask in an oil bath set at 75 ° C. and stirring the mixture in a nitrogen stream for 6 hours. 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. After the solvent was distilled off under reduced pressure, the residue was dried with a vacuum drier to obtain a polymer. When the molecular weight was measured using a part of the obtained polymer, the number average molecular weight (Mn) was 31,000 and the molecular weight distribution (Mw / Mn) was 2.5.
　上記コーティングポリマーを用いて、実施例１－１と同様の方法でビーズのコーティングを行った結果、コーティング量は１９ｍｇ／ビーズ乾燥ｇと算出された。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 ビ ー ズ 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.
《比較例１－６》
　使用コーティング液のコーティングポリマー濃度が０．５重量％であること、及びコーティングポリマーのコーティング量が９１ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－５と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。 << 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.
《比較例１－７》
（コーティングポリマーの合成）
　２－メトキシエチルアクリレート（ＭＥＡ）１５ｇ、１，４－ジオキサン６０ｇ、アゾビスイソブチロニトリル１５ｍｇを開始剤として７５℃で１０時間重合を行った以外は、比較例１－５と同等の手法で合成を行った。ＧＰＣの分子量分析の結果から、その数平均分子量（Ｍｎ）は２０，０００であり、分子量分布（Ｍｗ／Ｍｎ）は２．４であった。 << 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.
　上記コーティングポリマーを用いて、実施例１－１と同様の方法でビーズのコーティングを行った結果、コーティング量は２１ｍｇ／ビーズ乾燥ｇと算出された。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 ビ ー ズ 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.
《比較例１－８》
　使用コーティング液のコーティングポリマー濃度が０．３重量％であること、及びコーティングポリマーのコーティング量が５６ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－７と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。 << 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.
《比較例１－９》
　使用コーティング液のコーティングポリマー濃度が０．５重量％であること、及びコーティングポリマーのコーティング量が９７ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－７と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << 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.
《比較例１－１０》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、コーティングポリマーの組成がＭＥＡ／ＤＥＡＥＭＡ／ＣＭＢ＝８０／１０／１０（モル比）であること、及びコーティングポリマーのコーティング量が２０ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-10 >>
Purosorb ™ PAD950 was selected as the beads instead of Amberlite ™ XAD ™ 1180N, the composition of the coating polymer was MEA / DEAEMA / CMB = 80/10/10 (molar ratio), and the coating amount of the coating polymer Blood processing beads were prepared in the same manner as in Example 1-1, except that was 20 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.
《比較例１－１１》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が６３ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－２と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-11 >>
Blood processing beads as in Comparative Example 1-2, except that Purosorb ™ PAD950 was selected as the beads instead of Amberlite ™ XAD ™ 1180N, and that the coating amount of the coating polymer was 63 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.
《比較例１－１２》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が２４ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－５と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-12 >>
Blood processing beads as in Comparative Example 1-5, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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.
《比較例１－１３》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１１４ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－６と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-13 >>
Blood processing beads in the same manner as in Comparative Example 1-6, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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.
《比較例１－１４》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が２３ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－７と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-14 >>
Blood processing beads in the same manner as in Comparative Example 1-7, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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.
《比較例１－１５》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が７０ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－８と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-15 >>
Blood processing beads in the same manner as in Comparative Example 1-8, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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.
《比較例１－１６》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が１０７ｍｇ／ビーズ乾燥ｇであること以外は、比較例１－９と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Comparative Example 1-16 >>
Blood processing beads in the same manner as in Comparative Example 1-9, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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.
《比較例１－１７》
　コーティングポリマーとしてＰＶＰ（ポリビニルピロリドンＫ９０、富士フイルム和光純薬社製）を用いたこと、使用コーティング液のコーティングポリマー濃度が０．５重量％であること、及びコーティングポリマーのコーティング量が３５ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で血小板付着性評価を実施した結果を表１に示す。 << 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.
《比較例１－１８》
　使用コーティング液のコーティングポリマー濃度が０重量％であること、及びコーティングポリマーのコーティング量が０ｍｇ／ビーズ乾燥ｇであること以外は、実施例１－１と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表１に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Comparative 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.
《比較例１－１９》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、及びコーティングポリマーのコーティング量が３４ｍｇ／ビーズ乾燥ｇであること以外は比較例１－１７と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、血小板付着性評価を実施した結果を表２に示す。 << Comparative Example 1-19 >>
Blood processing beads were used in the same manner as in Comparative Example 1-17, except that Purosorb ™ PAD950 was selected in place of Amberlite ™ XAD ™ 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.
《比較例１－２０》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は比較例１－１８と同様に血液処理用ビーズを作製した。実施例１－１と同様の方法で元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例１－１と同様の方法で、サイトカイン吸着性能評価、血小板付着性評価を実施した結果を表２に示す。実施例１－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表３に示す。 << Comparative Example 1-20 >>
Blood processing beads were produced in the same manner as in Comparative Example 1-18, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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.
　以上、第一の実施形態の実施例及び比較例における、生体適合性ポリマー（コート剤）の組成、多孔質ビーズの種類、生体適合性ポリマーの担持量（コート量）、血液処理用ビーズの生体適合性（血小板付着量）、血液処理用ビーズのサイトカイン吸着性を下記表１及び２に記載する。また、実施例及び比較例における、血液処理用ビーズの表面及び全体のＸＰＳ測定に基づく原子割合を、下表３に記載する。 As described above, 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.
　第一の実施形態の実施例および比較例で使用した血液処理用ビーズの元素分析に基づく窒素元素の割合は、すべての血液処理用ビーズにおいて０．３質量％以下であった。また、血液処理用ビーズの元素分析に基づく、炭素元素と水素元素と酸素元素の割合の総和は、すべての血液処理用ビーズにおいて９９．０質量％以上であった。 割 合 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. In addition, 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.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　表１～２を参照すると、実施例の血液処理用ビーズは、比較例の血液処理用ビーズに比べて、生体適合性ポリマーの担持量がより少なく、多孔質ビーズの吸着性を高く維持しつつ、血液適合性を向上させることが分かる。 Referring to Tables 1 and 2, 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.
　表１の実施例１－１～１－１９の生体適合性ポリマーは、コート量が１１ｍｇ以下でも血小板付着率がすべて１４％以下であった。これに対して、比較例１－１～１－５及び１－７、１－１８の生体適合性ポリマーはコート量が２１ｍｇ以下のとき血小板付着率が１５％以上であった。比較例１－６、１－８及び１－９のようにコート量を５０ｍｇ以上にすれば、血小板付着率は１４％以下となるが、サイトカイン吸着量が顕著に減少してしまう。同様に表２の実施例１－２０～１－２６のポリマーは、コート量が２０ｍｇ以下でも血小板付着率がすべて８％以下であった。これに対して、比較例１－１０～１－１６及び１－２０のポリマーは、コート量を２０ｍｇ以上にしても血小板付着率がすべて１０％以上であった。 All the 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. On the other hand, 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. When 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. Similarly, 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. On the other hand, 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.
　表１～３を参照すると、実施例１－１、１－３～１－６、１－８、１－１２、１－１５、１－１８、１－２０及び１－２２の血液処理用ビーズは、血液処理用ビーズの表面に存在する窒素原子の割合が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で０．２％以上０．７％以下であることにより、比較例の血液処理用ビーズに比べて、生体適合性ポリマーの担持量がより少なく、多孔質ビーズの吸着性が高く、また、改善された血液適合性を有することが分かる。 Referring to Tables 1 to 3, 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.
２．第二の実施形態の実施例及び比較例
《実施例２－１》
〈コーティングポリマーの合成〉
　２－メトキシエチルメタクリレート（ＭＥＭＡ、［化１０］の構造式（ｉ）の化合物）と、Ｎ，Ｎ－ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ、［化１０］の構造式（ｉｉ）の化合物）と、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ、［化１０］の構造式（ｉｉｉ）の化合物）との共重合体を通常の溶液重合によって合成した。重合条件は、エタノール溶液中、開始剤としてアゾイソブチロニトリル（ＡＩＢＮ）０．００２５モル／Ｌ存在下、各モノマー濃度を１モル／Ｌとし、反応温度６０℃にて８時間重合反応を行い、ポリマー重合液を得た。得られたポリマー重合液をジエチルエーテルに滴下し、析出したポリマーを回収した。回収したポリマーを、ジエチルエーテルを用いて再沈殿操作を行うことで精製した。その後、得られたポリマーを減圧条件下で２４時間乾燥してコーティングポリマーを得た。 2. Example of Second Embodiment and Comparative Example << Example 2-1 >>
<Synthesis of coating polymer>
2-methoxyethyl methacrylate (MEMA, a compound of structural formula (i) of [Formula 10]), N, N-diethylaminoethyl methacrylate (DEAEMA, a compound of structural formula (ii) of [Formula 10]), and N- A copolymer with methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB, a compound of structural formula (iii) of Chemical Formula 10) was synthesized by ordinary solution polymerization. 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.
　コーティングポリマー中のＭＥＭＡモノマー単位と、ＤＥＡＥＭＡモノマー単位と、ＣＭＢモノマー単位とのモル比は以下のように測定した。得られたコーティングポリマーをジメチルスルホキシドへ溶解した後、１Ｈ－ＮＭＲ測定を行うことにより算出したチャートにおける４．３２ｐｐｍ（ＣＭＢに固有のＨ原子由来）のピーク及び２．６３ｐｐｍ（ＤＥＡＥＭＡに固有のＨ原子由来）のピークと、０．６５－２．１５ｐｐｍ（全体のＨ原子量）の面積比から次の式により算出した。
　ＤＥＡＥＭＡモノマーのモル比＝（“２．６３ｐｐｍ領域の面積比”／２）／（“０．６５－２．１５ｐｐｍ領域の面積比”／５－“２．６３ｐｐｍ領域の面積比”×０．３）×１００
　ＣＭＢモノマーのモル比＝（“４．３２ｐｐｍ領域の面積比”／２）／（“０．６５－２．１５ｐｐｍ領域の面積比”／５－“２．６３ｐｐｍ領域の面積比”×０．３）×１００
　ＭＥＭＡモノマーのモル比＝１００－ＤＥＡＥＭＡモノマーのモル比－ＣＭＢモノマーのモル比
　コーティングポリマーにおけるＭＥＭＡモノマー単位と、ＤＥＡＥＭＡモノマー単位と、ＣＭＢモノマー単位とのモル比は、８０／１０／１０と算出された。 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).
Molar ratio of DEAEMA monomer = (“area ratio of 2.63 ppm region” / 2) / (“area ratio of 0.65-2.15 ppm region” / 5− “area ratio of 2.63 ppm region” × 0.3 ) × 100
Molar ratio of CMB monomer = (“area ratio of 4.32 ppm region” / 2) / (“area ratio of 0.65-2.15 ppm region” / 5− “area ratio of 2.63 ppm region” × 0.3 ) × 100
Molar ratio of MEMA monomer = 100−molar ratio of DEAEMA monomer−molar ratio of CMB monomer The molar ratio of MEMA monomer unit, DEAEMA monomer unit, and CMB monomer unit in the coating polymer was calculated to be 80/10/10. .
〈コーティング液の調製〉
　上記コーティングポリマーを５７Ｗ／Ｗ％のエチルアルコールへ添加した後、１２時間撹拌し、コーティングポリマー濃度が０．２重量％のコーティング液を調整した。 <Preparation of coating liquid>
After the above coating polymer was added to 57 W / W% ethyl alcohol, the mixture was stirred for 12 hours to prepare a coating liquid having a coating polymer concentration of 0.2% by weight.
〈ビーズの調製〉
　多孔質ビーズとしてアンバーライトＴＭＸＡＤＴＭ１１８０Ｎ（オルガノ社製、スチレン系ポリマービーズ、体積平均粒子径６０９μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量１．４７２ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．０２０ｃｍ３／ｇ）を用いた。アンバーライトＴＭＸＡＤＴＭ１１８０ＮのＬｏｇ微分細孔容積分布及び積算細孔容量のグラフを図１に、累計体積粒度分布のグラフを図３に示す。超純水で膨潤されたビーズ８ｍＬ（乾燥時１．７６ｇ）をポリプロピレン（ＰＰ）製の５０ｍＬコニカルチューブに入れた後、５７Ｗ／Ｗ％のエチルアルコール４０ｍＬを加えた。振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、４０ｒ／ｍｉｎで１２時間振とう後、振とう後の溶液をセルストレーナー（セルストレーナー、ナイロンメッシュ７０μｍ、フナコシ社製）にて濾過した。濾過後の溶液の２２０ｎｍにおける吸光度を島津紫外可視分光光度計ＵＶ－２６００（島津製作所社製）にて測定後、濾過にて得られたビーズを再度５０ｍＬコニカルチューブに加えた。このコニカルチューブへの５７Ｗ／Ｗ％のエチルアルコールの添加、振とう機による１２時間の振とう、セルストレーナーによる溶液除去の一連の作業を、濾過後溶液の２２０ｎｍにおける吸光度が０．０３以下になるまで繰り返し行った。 <Preparation of beads>
As porous beads, Amberlite ™ XAD ™ 1180N (manufactured by Organo Co., Ltd., styrene-based polymer beads, volume average particle diameter 609 μm, cumulative pore volume of 1.472 cm 3 / g with pore diameter of 5 nm to 100 nm, cumulative of pore diameter of 100 nm to 200 nm) A pore volume of 0.020 cm 3 / g) was used. FIG. 1 shows a graph of the log differential pore volume distribution and the cumulative pore volume of Amberlite ™ XAD ™ 1180N, and FIG. 3 shows a graph of the cumulative volume particle size distribution. 8 mL of beads (1.76 g at the time of drying) swollen with ultrapure water were put into a 50 mL conical tube made of polypropylene (PP), and then 40 mL of 57 W / W% ethyl alcohol was added. After shaking using a shaking machine (Invitro Shaker WAVE-S1, manufactured by TAITEC) at a shaking angle of 10 degrees and 40 r / min for 12 hours, the solution after shaking is subjected to a cell strainer (cell strainer, nylon mesh 70 μm, Funakoshi). (Trade name). After measuring the absorbance at 220 nm of the solution after filtration with a Shimadzu UV-visible spectrophotometer UV-2600 (manufactured by Shimadzu Corporation), 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.
〈コート後ビーズの作成〉
　上記処理により得られたビーズを含有した５０ｍＬコニカルチューブに、上記コーティング液４０ｍＬを加え、振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、４０ｒ／ｍｉｎで１２時間振とうさせた。その後、コート処理後溶液をセルストレーナー（セルストレーナー、ナイロンメッシュ７０μｍ、フナコシ社製）にて濾過し、コート後ビーズを得た。濾過後のコート処理後溶液の２２０ｎｍにおける吸光度を島津紫外可視分光光度計ＵＶ－２６００にて測定後、濾過にて得られたコート後ビーズを再度５０ｍＬコニカルチューブに加えた。 <Preparation of beads after coating>
40 mL of the above coating solution is added to a 50 mL conical tube containing the beads obtained by the above treatment, and a shaking machine (Invitro Shaker WAVE-S1, manufactured by TAITEC) is used at a shaking angle of 10 degrees and 40 r / min for 12 minutes. Shake for hours. Thereafter, the solution after the coating treatment was filtered through a cell strainer (cell strainer, nylon mesh 70 μm, manufactured by Funakoshi) to obtain beads after coating. After the absorbance at 220 nm of the solution after the coating treatment after filtration was measured with a Shimadzu UV-visible spectrophotometer UV-2600, the coated beads obtained by filtration were added again to a 50 mL conical tube.
　続いて、上記のコート後ビーズを含有した５０ｍＬコニカルチューブを、５０℃で１５時間真空乾燥（絶対圧力０．００３ＭＰａ以下）を行った後、コニカルチューブ内に２０Ｗ／Ｗ％のエチルアルコールを４０ｍＬ加えた。振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、４０ｒ／ｍｉｎで１２時間振とう後、ビーズが浸潤した溶液をセルストレーナー（セルストレーナー、ナイロンメッシュ７０μｍ、フナコシ社製）にて除去し、得られたビーズを再度５０ｍＬコニカルチューブに加えた。その後、５０ｍＬコニカルチューブへの超純水４０ｍＬの添加、振とう機による３時間の振とう、セルストレーナーによる溶液除去の一連の作業を計３度繰り返し行い、コート後ビーズを得た。得られたコート後ビーズの溶出物量を測定したところ、１．０ｍｇ以下であり、溶出物は少なかった。 Subsequently, after vacuum-drying (absolute pressure 0.003 MPa or less) the 50 mL conical tube containing the coated beads at 50 ° C. for 15 hours, 40 mL of 20 W / W% ethyl alcohol was added into the conical tube. Was. After shaking using a shaker (Invitro shaker WAVE-S1, manufactured by TAITEC) at a shaking angle of 10 degrees and 40 r / min for 12 hours, the solution in which the beads were infiltrated was subjected to a cell strainer (cell strainer, nylon mesh 70 μm, Funakoshi). And the resulting beads were again added to a 50 mL conical tube. Thereafter, a series of operations of adding 40 mL of ultrapure water to a 50 mL conical tube, shaking for 3 hours with a shaker, and removing the solution with a cell strainer was repeated a total of three times to obtain coated beads. When the amount of eluate of the obtained coated beads was measured, it was 1.0 mg or less, and the amount of eluate was small.
〈血液処理用ビーズの作成〉
　上記のコート後ビーズ３ｍＬを１５ｍＬコニカルチューブに加えた。その後、１５ｍＬコニカルチューブへの超純水１２ｍＬの添加、振とう機による３時間の振とう、セルストレーナーによる溶液除去の一連の作業を計２度繰り返し行った。最後にコニカルチューブに生理食塩水（大塚生食注、大塚製薬工場社製）を１２ｍＬ充填し、γ線照射により滅菌作業を行い、血液処理用ビーズを得た。 <Preparation of blood processing beads>
After the above coating, 3 mL of beads were added to a 15 mL conical tube. Thereafter, a series of operations of adding 12 mL of ultrapure water to a 15 mL conical tube, shaking for 3 hours with a shaker, and removing the solution with a cell strainer was repeated twice in total. Finally, the conical tube was filled with 12 mL of physiological saline (Otsuka Ishoku Injection, manufactured by Otsuka Pharmaceutical Factory Co., Ltd.), and sterilized by γ-irradiation to obtain beads for blood treatment.
《血液処理用ビーズの物性測定》
〈血液処理用ビーズ全体の元素分析〉
　上記の血液処理用ビーズ１ｍＬに含まれる溶液をセルストレーナーにて除去し、得られたビーズを１５ｍＬコニカルチューブに加えた。その後、１５ｍＬコニカルチューブへ超純水１２ｍＬを添加することで、ビーズ溶液を超純水にて置換した。超純水にて置換された血液処理用ビーズを５０℃で１５時間真空乾燥（絶対圧力０．００３ＭＰａ以下）を行った。乾燥後の血液処理用ビーズを、元素分析装置（株式会社堀場製作所製、酸素・窒素・水素分析装置ＥＭＧＡ－９３０）を用いて元素分析を行った。試験は３検体で分析し、その平均値を採用した。その結果、窒素元素の割合は０．３質量％以下であった。 《Measurement of physical properties of blood processing beads》
<Elemental analysis of whole blood processing beads>
The solution contained in 1 mL of the blood treatment beads was removed with a cell strainer, and the obtained beads were added to a 15 mL conical tube. Then, the bead solution was replaced with ultrapure water by adding 12 ml of ultrapure water to a 15 ml conical tube. The blood treatment beads replaced with ultrapure water were vacuum dried (absolute pressure: 0.003 MPa or less) at 50 ° C. for 15 hours. The dried beads for blood treatment were subjected to elemental analysis using an elemental analyzer (oxygen / nitrogen / hydrogen analyzer EMGA-930, manufactured by Horiba, Ltd.). In the test, three samples were analyzed, and the average value was adopted. As a result, the ratio of the nitrogen element was 0.3% by mass or less.
〈血液処理用ビーズ表面のＸＰＳ測定〉
　上記の乾燥後の血液処理用ビーズから無作為に５０粒選択し、そのビーズ１粒１粒の表面状態を、Ｋ－Ａｌｐｈａ＋（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ　社製）を用いて、ＸＰＳにて測定した。測定条件は、照射Ｘ線：単結晶分光ＡＩ　Ｋα、Ｘ線スポット径：１５０μｍ、中和電子銃：使用、であった。それらの５０粒の血液処理用ビーズ表面に存在する、原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数に対する窒素原子存在率の値を平均化したものを、血液処理用ビーズ表面の窒素原子存在率（％）として算出した。その結果を表６に記す。 <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 Kα, X-ray spot diameter: 150 μm, 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.
〈血液処理用ビーズ全体のＸＰＳ測定〉
　上記の乾燥後の血液処理用ビーズをすりこぎ棒により粉砕し、血液処理用ビーズの粉体を作製した。その粉体の表面状態を、Ｋ－Ａｌｐｈａ＋（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ　社製）を用いて、ＸＰＳにて測定した。測定条件は、照射Ｘ線：単結晶分光ＡＩ　Ｋα、Ｘ線スポット径：１５０μｍ、中和電子銃：使用、であった。測定は１０検体について行い、原子番号３番のリチウム原子から原子番号９２番のウラン原子の総数に対する窒素原子存在率の値を平均化したものを、血液処理用ビーズ全体の窒素原子存在率（％）として算出した。その結果を表６に記す。 <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 Kα, X-ray spot diameter: 150 μm, 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.
〈血液処理用ビーズのフロー評価法による血小板付着性〉
　図４は、血小板付着性の評価方法を説明するための模式図である。血液処理用ビーズ１．５ｍＬ（乾燥時０．３３ｇ）を、生理食塩水（大塚生食注、大塚製薬工場社製）にて膨潤させた。上記膨潤した血液処理用ビーズ（１１）を、空気が入らないように注意しながら、２．５ｍＬシリンジに詰めた。このとき、ビーズが漏れないよう、図４に示すように、血液処理用ビーズの上下を、メッシュ（１２）及びＯ－リング（１３）で挟んだ。血液処理用ビーズ１．５ｍＬが詰まったミニカラム（１０）を作製した。 <Adhesion of blood platelets to platelets by flow evaluation method>
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. At this time, as shown in FIG. 4, 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.
　健常ボランティアから採血した血液にヘパリンナトリウム（ヘパリンナトリウム注５万単位／５０ｍＬ、ニプロ社製）を１０００ＩＵ／ｍＬ濃度になるように添加した（これを「処理前血液（２１）」とする）。次に、図４に示すように実験回路を組み立て、血液処理用ビーズを詰めたミニカラム（１０）に、生理食塩水（大塚生食注、大塚製薬工場社製）をシリンジポンプ（２０）（ＴＥ－３５１、テルモ社製）を用いて、流速１ｍＬ／ｍｉｎで１０分間通液させた。続いて、上記の処理前血液（２１）を流速１ｍＬ／ｍｉｎで、シリンジポンプ（２０）（ＴＥ－３５１、テルモ社製）を用いて通液した。処理前血液の通液開始２分後から、ミニカラム通液後の血液を１５ｍＬコニカルチューブ（３０）に採取し、採取した血液（これを「処理後血液（３１）」とする）が９ｍＬになった時点で血液の通液を終了した。処理後血液と処理前血液の血小板濃度を、ミクロセルカウンター　ＸＴ－１８００ｉ（Ｓｙｓｍｅｘ社製）にて測定し、下記式からビーズへの血小板残存率を算出したところ、８５％であった。上記の方法により、血小板残存率が８０％以下である場合、血液処理用ビーズの血小板付着量は多いと判断し、血小板残存率が８０％より高い場合、血液処理用ビーズの血小板付着量は少ないと判断した。
　血小板残存率（％）＝処理後血液の血小板数／処理前血液の血小板数×１００
　尚、今回の実験で使用した処理前血液は、白血球濃度：５３１０個／μＬ、赤血球濃度：５０５×１０＾４個／μＬ、血小板濃度：１９６×１０＾３個／μＬ、ヘマトクリット値：４１．０％であった。ヘモクロンJr．シグニチャー＋（インターナショナルテクニダイン社製、ヘモクロン　テストカ－トリッジ　ＪＡＣＴ－ＬＲ）にて測定した、処理前血液の活性化凝固時間は３１９秒であった。 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)”). Next, as shown in FIG. 4, an experimental circuit was assembled, and 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. Subsequently, 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). Two minutes after the start of the passage of the blood before the treatment, the blood after the passage through the mini-column was collected in a 15 mL conical tube (30), and the collected blood (hereinafter referred to as “blood after treatment (31)”) became 9 mL. At that point, 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%. According to the above method, when the residual platelet ratio is 80% or less, it is determined that the blood processing beads have a large platelet adhesion amount, and when the platelet residual ratio is higher than 80%, the blood processing beads has a small platelet adhesion amount. Was determined.
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 / μL, erythrocyte concentration: 505 × 10 4 cells / μL, platelet concentration: 196 × 10 3 / μL, 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.).
《実施例２－２》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝９０／１０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物量を測定したところ、１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８３％であり、血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << Example 2-2 >>
Except that the composition of the coating polymer was MEMA / CMB = 90/10 (molar ratio), the same coated beads and blood processing beads as in Example 2-1 were produced. The amount of eluted beads after coating was measured in the same manner as in Example 2-1 and found to be 1.0 mg or less, and the amount of eluted was small. 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 83%, 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.
〈血液処理用ビーズの吸着性〉
　健常ボランティアから採血した血液にヘパリンナトリウム（ヘパリンナトリウム注５万単位／５０ｍＬ、ニプロ社製）を２０００　ＩＵ／ｍＬ濃度になるように添加後、Ｅｓｃｈｅｒｉｃｈｉａ　ｃｏｌｉ　Ｏ１１１：Ｂ４由来のリポポリサッカライド（ＬＰＳ）（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ社製）を０．１μｇ／ｍＬ濃度になるように添加し、振とう機（インビトロシェイカーＷＡＶＥ－Ｓ１、ＴＡＩＴＥＣ社製）を用いて振とう角度１０度、１０ｒ／ｍｉｎで２４時間、３７℃で振とうさせた。その後、遠心機（ハイブリッド高速冷却遠心機　６２００、久保田商事社製）を用いて、室温で２０００ｇで２０分間遠心し、上清を血漿サンプルとして取得した。取得した血漿サンプル３．６ｍＬと上記の血液処理用ビーズ０．４５ｍＬ（乾燥時０．１０ｇ）をポリプロピレン（ＰＰ）製の５ｍＬチューブ内で混合し、振とう機を用いて振とう角度１０度、１０ｒ／ｍｉｎで２時間、３７℃で振とうさせた（これをビーズ接触有サンプルとする）。この時、取得した血漿サンプル３．６ｍＬにビーズを添加しないサンプルも準備し、ビーズ接触有サンプルと同じ処理を行った（これをビーズ接触無サンプルとする）。振とうさせた後のＰＰ製チューブを、遠心機を用いて、室温で２０００ｇで１分間遠心し、ビーズ接触有及び無サンプルの上清を取得した。取得した上清を用いて、各種サイトカイン濃度をＢｉｏ－Ｐｌｅｘシステム（Ｂｉｏ－Ｒａｄ社製　Ｂｉｏ－Ｐｌｅｘ　Ｐｒｏ　ヒト　サイトカイン　ＧＩ２７－ｐｌｅｘ　パネル）を用いて、添付の取扱説明書に従い測定した。またＨＭＧＢ－１濃度はＨＭＧＢ１　ＥＬＩＳＡＫ　Ｋｉｔ　ＩＩ（株式会社　シノテスト製）を用いて、添付の取扱説明書に従い測定した。ここで、ビーズのサイトカイン、ＨＭＧＢ－１吸着率は下記式にて算出した。その結果を表５に示す。
　各種サイトカイン吸着率（％）＝（“ビーズ接触無サンプルのサイトカイン濃度”－“ビーズ接触有サンプルのサイトカイン濃度”）／“ビーズ接触無サンプルのサイトカイン濃度”×１００
　ＨＭＧＢ－１吸着率（％）＝（“ビーズ接触無サンプルのＨＭＧＢ－１濃度”－“ビーズ接触有サンプルのＨＭＧＢ－１濃度”）／“ビーズ接触無サンプルのＨＭＧＢ－１濃度”×１００
　尚、今回の実験におけるビーズ接触無サイトカイン濃度、ビーズ接触無ＨＭＧＢ－１濃度はＩＬ－１ｂ：３６５８ｐｇ／ｍＬ、ＩＬ－６：５５４０ｐｇ／ｍＬ、ＩＬ－８：６１４４ｐｇ／ｍＬ、ＩＬ－１０：８４６ｐｇ／ｍＬ、ＴＮＦ－α：８０８５ｐｇ／ｍＬ、ＨＭＧＢ－１：２７ｎｇ／ｍＬであった。 <Adsorption of beads for blood treatment>
Heparin sodium (50,000 heparin injection / 50 mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers to a concentration of 2000 IU / mL, and then lipopolysaccharide (LPS) derived from Escherichia coli O111: B4 (LPS) ( Sigma-Aldrich) was added to a concentration of 0.1 μg / mL, and the mixture was shaken at a shaking angle of 10 °, 10 r / min for 24 hours using a shaker (Invitro Shaker WAVE-S1, manufactured by TAITEC). Shake at 37 ° C. Thereafter, 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). At this time, 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. Using the obtained supernatant, the 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. The HMGB-1 concentration was measured using HMGB1 ELISA Kit II (manufactured by Shino Test Co., Ltd.) according to the attached instruction manual. Here, the cytokine and HMGB-1 adsorption rates of the beads were calculated by the following equation. Table 5 shows the results.
Various cytokine adsorption rates (%) = (“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
In this experiment, 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. mL, TNF-α: 8085 pg / mL, and HMGB-1: 27 ng / mL.
《実施例２－３》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝８０／２０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８９％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。実施例２－２と同様の方法で、サイトカイン吸着性能評価を実施した結果を表５に示す。 << Example 2-3 >>
Except that the composition of the coating polymer was MEMA / CMB = 80/20 (molar ratio), 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 platelet remaining rate was 89%, and the amount of platelet adhesion 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. Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
《実施例２－４》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝７０／３０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８９％であり血小板付着量は少なかった。 << Example 2-4 >>
Except that the composition of the coating polymer was MEMA / CMB = 70/30 (molar ratio), 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 platelet remaining rate was 89%, and the amount of platelet adhesion was small.
《実施例２－５》
　コーティングポリマーの組成がＭＥＭＡ／ＭＰＣ（リン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル、［化１０］の構造式（ｉｖ）の化合物）＝８５／１５（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８３％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << Example 2-5 >>
The composition of the coating polymer is MEMA / MPC (2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl phosphate, compound of structural formula (iv) of Chemical Formula 10) = 85/15 (molar ratio). Except for this, 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 platelet remaining rate was 83%, and the amount of platelet adhesion 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.
《実施例２－６》
　コーティングポリマーの組成がＭＥＭＡ／ＳＰＢ（２－（メタクリロイルオキシ）エチル］ジメチル－（３－スルホプロピル）アンモニウムヒドロキシド、［化１０］の構造式（ｖ）の化合物）＝８８／１２（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８４％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << Example 2-6 >>
The composition of the coating polymer is MEMA / SPB (2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide, the compound of the structural formula (v) of [formula 10] = 88/12 (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. 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.
《実施例２－７》
　コーティングポリマーの組成がＭＥＭＡ／ＳＰＢ＝７０／３０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８７％であり血小板付着量は少なかった。 << Example 2-7 >>
Except that the composition of the coating polymer was MEMA / SPB = 70/30 (molar ratio), 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 87%, and the amount of adhered platelets was small.
《実施例２－８》
　コーティングポリマーの組成がＭＥＭＡ／ＳＰＢＡ（［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホプロピル）アンモニウムヒドロキシド、［化１０］の構造式（ｖｉ）の化合物））＝８８／１２（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８３％であり血小板付着量は少なかった。 << Example 2-8 >>
The composition of the coating polymer is MEMA / SPBA ([3- (methacryloylamino) propyl] dimethyl (3-sulfopropyl) ammonium hydroxide, the compound of the structural formula (vi) of [Formula 10]) = 88/12 (molar ratio) ) Other than the above, 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. 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 83%, and the amount of platelet adhesion was small.
《実施例２－９》
　コーティングポリマーの組成がＭＥＡ（２－メトキシエチルアクリレート、［化１０］の構造式（ｖｉｉ）の化合物）／ＣＭＢ＝７０／３０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８５％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。実施例２－２と同様の方法で、サイトカイン吸着性能評価を実施した結果を表５に示す。 << Example 2-9 >>
The same as Example 2-1 except that the composition of the coating polymer was MEA (2-methoxyethyl acrylate, the compound of the structural formula (vii) of Chemical Formula 10) / CMB = 70/30 (molar ratio). Beads after certain 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 85%, 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. Table 5 shows the results of evaluating the cytokine adsorption performance in the same manner as in Example 2-2.
《実施例２－１０》
　コーティングポリマーの組成がＭＣ３Ａ（３－メトキシプロピルアクリレート、［化１０］の構造式（ｖｉｉｉ）の化合物）／ＣＭＢ＝７０／３０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８７％であり血小板付着量は少なかった。 << Example 2-10 >>
The same as Example 2-1 except that the composition of the coating polymer was MC3A (3-methoxypropyl acrylate, a compound of the structural formula (viii) of Chemical Formula 10) / CMB = 70/30 (molar ratio). 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.
《実施例２－１１》
　コーティングポリマーの組成がＥｔ２Ａ（２－（２－エトキシエトキシ）エチルアクリレート、［化１０］の構造式（ｉｘ）の化合物）／ＣＭＢ＝７０／３０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８６％であり血小板付着量は少なかった。 << Example 2-11 >>
Example 2 except that the composition of the coating polymer was Et2A (2- (2-ethoxyethoxy) ethyl acrylate, a compound of the structural formula (ix) of Chemical Formula 10) / CMB = 70/30 (molar ratio). 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.
《実施例２－１２》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０（ピュロライト社製、アクリル系ポリマービーズ、体積平均粒子径６２１μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量０．８２３ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．０３８ｃｍ３／ｇ）を選択したこと以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。ピュロソーブＴＭＰＡＤ９５０のＬｏｇ微分細孔容積分布及び積算細孔容量のグラフを図２に、累計体積粒度分布のグラフを図３に示す。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は９１％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << Example 2-12 >>
As beads, Purosorb TM PAD950 (manufactured by Purolite, acrylic polymer beads, volume average particle diameter 621 μm, cumulative pore volume of pore diameter 5 nm to 100 nm 0.823 cm 3 / g, pore diameter instead of Amberlite ™ XAD ™ 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, and FIG. 3 shows a graph of the cumulative volume particle size distribution. 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.
《実施例２－１３》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと、コーティングポリマーの組成がＭＥＭＡ／ＤＥＡＥＭＡ／ＣＭＢ＝６０／２０／２０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８６％であり血小板付着量は少なかった。 << Example 2-13 >>
As beads, it was chosen Pyurosobu TM PAD950 instead of Amberlite TM XAD TM 1180N, except that the composition of the coating polymer is MEMA / DEAEMA / CMB = 60/ 20/20 ( molar ratio), Example 2 The same coated beads and blood processing beads as in Example 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.
《実施例２－１４》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は、実施例２－３と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８７％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << 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.
《実施例２－１５》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は、実施例２－７と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８５％であり血小板付着量は少なかった。 << 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.
《実施例２－１６》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は、実施例２－９と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８５％であり血小板付着量は少なかった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。実施例２－２と同様の方法で、サイトカイン吸着性能評価を実施した結果を表５に示す。 << Example 2-16 >>
Coated beads and blood treatment beads were prepared in the same manner as in Example 2-9, except that Purosorb ™ PAD950 was selected instead of Amberlite ™ XAD ™ 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. 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.
《実施例２－１７》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は、実施例２－１０と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８８％であり血小板付着量は少なかった。 << 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.
《比較例２－１》
　使用コーティング液のコーティングポリマー濃度が０重量％である（コーティングポリマーを溶解させなかった）こと以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は７４％であり血小板付着量は多かった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。実施例２－２と同様の方法で、サイトカイン吸着性能評価を実施した結果を表５に示す。 << 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.
《比較例２－２》
　コーティングポリマーの組成がＭＥＭＡ＝１００（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は７９％であり血小板付着量は多かった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。実施例２－２と同様の方法で、サイトカイン吸着性能評価を実施した結果を表５に示す。 << Comparative Example 2-2 >>
Except that the composition of the coating polymer was MEMA = 100 (molar ratio), 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 79%, 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.
《比較例２－３》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝９５／５（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は７９％であり血小板付着量は多かった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << Comparative Example 2-3 >>
Except that the composition of the coating polymer was MEMA / CMB = 95/5 (molar ratio), beads after coating and beads for blood treatment were produced in the same manner as in 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 79%, 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.
《比較例２－４》
　コーティングポリマーの組成がＭＥＭＡ／ＣＭＢ＝６０／４０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．２ｍｇであり、溶出物は多かった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。 << Comparative Example 2-4 >>
Except that the composition of the coating polymer was MEMA / CMB = 60/40 (molar ratio), 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 to find that it was 1.2 mg, and the eluate was large. 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.
《比較例２－５》
　コーティングポリマーの組成がＭＥＡ／ＤＥＡＥＭＡ／ＣＭＢ＝４０／２０／４０（モル比）であること以外は、実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．４ｍｇであり、溶出物は多かった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << Comparative Example 2-5 >>
Except that the composition of the coating polymer was MEA / DEAEMA / CMB = 40/20/40 (molar ratio), beads after coating and beads for blood treatment were produced in the same manner as in Example 2-1. 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 1.4 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.
《比較例２－６》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は、比較例２－１と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で血小板付着性評価を実施した結果、血小板残存率は８０％であり血小板付着量は多かった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。実施例２－２と同様の方法で、サイトカイン吸着性能評価を実施した結果を表５に示す。 << 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 ™ XAD ™ 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.
《比較例２－７》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりにピュロソーブＴＭＰＡＤ９５０を選択したこと以外は、比較例２－５と同様であるコート後ビーズ、血液処理用ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．４ｍｇであり、溶出物は多かった。実施例２－１と同様の方法で血液処理用ビーズの元素分析を行った結果、窒素元素の割合は０．３質量％以下であった。実施例２－１と同様の方法で、ビーズ表面のＸＰＳ測定、ビーズ全体のＸＰＳ測定を行った結果を表６に示す。 << 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.
《比較例２－８》
（ビーズの合成）
　酢酸ビニル１００ｇ、トリアリルイソシアヌレート６４．３ｇ、酢酸エチル１００ｇ、ヘプタン１００ｇ、ポリ酢酸ビニル（重合度５００）７．５ｇおよびアゾイソブチロニトリル（ＡＩＢＮ）３．８ｇよりなる均一混合液と、ポリビニルアルコール（ケン化率８７－８９％）１重量％、リン酸二水素ナトリウム二水和物０．０５重量％およびリン酸水素二ナトリウム十二水和物１．５重量％を溶解した超純水４００ｍＬとをフラスコに入れ、十分に撹拌しながら６５℃で１８時間、さらに７５℃で５時間加熱撹拌して懸濁重合を行なった。溶液を濾過して得られた粒状共重合体を、超純水により洗浄した後、アセトン抽出により洗浄した。最後に、洗浄後の粒状共重合体を、苛性ソーダ４６．５ｇおよびメタノール２Ｌよりなる溶液中で４０℃で１８時間攪拌することで、ＰＶＡ系ポリマービーズ（体積平均粒子径１１０μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量０．２７０ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．００５ｃｍ３／ｇ以下）を得た。 << Comparative Example 2-8 >>
(Synthesis of beads)
A homogeneous mixture comprising 100 g of vinyl acetate, 64.3 g of triallyl isocyanurate, 100 g of ethyl acetate, 100 g of heptane, 7.5 g of polyvinyl acetate (polymerization degree 500) and 3.8 g of azoisobutyronitrile (AIBN); Ultrapure water in which 1% by weight of alcohol (87-89% of saponification), 0.05% by weight of sodium dihydrogen phosphate dihydrate and 1.5% by weight of disodium hydrogen phosphate dodecahydrate are dissolved 400 mL was placed in a flask, and heated and stirred at 65 ° C. for 18 hours and further at 75 ° C. for 5 hours while sufficiently stirring to carry out suspension polymerization. The granular copolymer obtained by filtering the solution was washed with ultrapure water and then washed with acetone. Finally, the granular copolymer after washing is stirred at 40 ° C. for 18 hours in a solution composed of 46.5 g of caustic soda and 2 L of methanol to obtain PVA-based polymer beads (volume average particle diameter 110 μm, pore diameter 5 nm to 100 nm). Of 0.270 cm 3 / g, and an integrated pore volume of 0.005 cm 3 / g or less with a pore diameter of 100 nm to 200 nm).
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、比較例２－１と同様であるコート後ビーズを作製した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は１．０ｍｇ以下で低かった。 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 ™ XAD ™ 1180N as beads. When the elution of beads was determined in the same manner as in Example 2-1, the elution amount was as low as 1.0 mg or less.
《比較例２－９》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－１と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は１．８ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１０》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－３と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は２．０ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１１》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－４と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は２．３ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１２》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－６と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は１．９ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１３》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－７と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は２．２ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１４》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－８と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は２．１ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１５》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－９と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は１．３ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１６》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、上記で得られたＰＶＡ系ポリマービーズを選択したこと以外は、実施例２－１０と同様であるコート後ビーズを使用した。実施例２－１と同様の方法でビーズの溶出を判定したところ、溶出量は１．２ｍｇであり、溶出物は多かった。 << 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 ™ XAD ™ 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.
《比較例２－１７》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、活性炭ビーズ（クレハ社製、平均粒子径５７６μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量０．１３４ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．００５ｃｍ３／ｇ以下）を選択したこと以外は、比較例２－１と同様であるコート後ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．０ｍｇ以下であり、溶出物は少なかった。 << Comparative Example 2-17 >>
As beads, instead of Amberlite ™ XAD ™ 1180N, activated carbon beads (manufactured by Kureha Co., Ltd., average particle diameter 576 μm, 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.
《比較例２－１８》
　ビーズとして、アンバーライトＴＭＸＡＤＴＭ１１８０Ｎの代わりに、活性炭ビーズ（クレハ社製、平均粒子径５７６μｍ、細孔径５ｎｍ～１００ｎｍの積算細孔容量０．１３４ｃｍ３／ｇ、細孔径１００ｎｍ～２００ｎｍの積算細孔容量０．００５ｃｍ３／ｇ以下）を選択したこと以外は、実施例２－４と同様であるコート後ビーズを作製した。実施例２－１と同様の方法でコート後ビーズの溶出物測定を行ったところ１．２ｍｇであり、溶出物は多かった。 << Comparative Example 2-18 >>
As beads, instead of Amberlite ™ XAD ™ 1180N, activated carbon beads (manufactured by Kureha Co., Ltd., average particle diameter 576 μm, 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) Except for selecting a pore volume of 0.005 cm 3 / g or less), coated beads were produced in the same manner as in Example 2-4. The eluate of the beads after coating was measured in the same manner as in Example 2-1 to find that it was 1.2 mg, and the eluate was large.
　以上、第二の実施形態の実施例及び比較例における、生体適合性ポリマー（コート剤）の組成、多孔質ビーズの種類、コート後ビーズの溶出物測定結果、血液処理用ビーズの生体適合性（血小板付着量）を下記表４及び５に記載する。また、実施例及び比較例における、血液処理用ビーズの表面及び全体のＸＰＳ測定に基づく原子割合を、下表６に記載する。 As described above, the composition of the biocompatible polymer (coating agent), the type of the porous beads, the measurement results of the eluate of the coated beads, and the biocompatibility of the blood processing beads (Examples and Comparative Examples) in Examples and Comparative Examples of the second embodiment. 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.
　第二の実施形態の実施例および比較例で使用した血液処理用ビーズの元素分析に基づく窒素元素の割合は、すべての血液処理用ビーズにおいて０．３質量％以下であった。また、血液処理用ビーズの元素分析に基づく、炭素元素と水素元素と酸素元素の割合の総和は、すべての血液処理用ビーズにおいて９９．０質量％以上であった。 割 合 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. In addition, 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.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　本発明の血液処理用ビーズは、例えば、敗血症をはじめとする虚血性疾患の治療に使用することができる。また、本発明の血液処理用ビーズは、虚血性疾患の治療のほか、心臓手術及び臓器移植手術などの炎症性メディエーターの過剰産生が問題となる場面での活用も期待される。 ビ ー ズ 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.
　１０　　ミニカラム
　１１　　血液処理用ビーズ
　１２　　メッシュ
　１３　　Ｏ－リング
　２０　　シリンジポンプ
　２１　　処理前血液
　３０　　コニカルチューブ
　３１　　処理後血液 DESCRIPTION OF SYMBOLS 10 Mini column 11 Beads for blood processing 12 Mesh 13 O-ring 20 Syringe pump 21 Blood before processing 30 Conical tube 31 Blood after processing

Claims (31)

  1. 　多孔質ビーズ、及び前記多孔質ビーズの表面上に担持されたポリマーを有する、血液処理用ビーズであって、
    　前記多孔質ビーズは、アクリル系樹脂、スチレン系樹脂、及びセルロース系樹脂からなる群から選択される少なくとも一つの樹脂から構成され、
    　前記ポリマーは、下記一般式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ｛式（１）中、Ｒ１は、－ＣＨ３であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑＯＣＨ３又は－ＣＨ２ＣｍＨ２ｍ＋１であり、ｑは１～５であり、ｍは０～１７である。｝
    で表されるモノマーを単量体単位として含む、血液処理用ビーズ。     Porous beads, and having a polymer carried 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):
    Figure JPOXMLDOC01-appb-C000001
    中 In the 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.
  2. 　前記血液処理用ビーズの表面における、窒素原子の割合が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で０．２％以上０．７％以下である、請求項１に記載の血液処理用ビーズ。 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. The beads for blood treatment according to claim 1.
  3. 　ｑは１又は２であり、ｍは０～１１である、請求項１又は２に記載の多孔質吸着ビーズ。 The porous adsorptive beads according to claim 1, wherein q is 1 or 2, and m is 0 to 11.
  4. 　前記一般式（１）で表されるモノマーの含有量は、前記ポリマーを構成するモノマー全体を基準として４０モル％以上である、請求項１～３のいずれか一項に記載の血液処理用ビーズ。 The blood processing bead according to any one of claims 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. .
  5. 　前記ポリマーは、電荷を有するモノマーを単量体単位として更に含む、請求項１～４のいずれか一項に記載の血液処理用ビーズ。 The blood processing beads according to any one of claims 1 to 4, wherein the polymer further includes a charged monomer as a monomer unit.
  6. 　前記電荷を有するモノマーは、アミノ基、カルボキシル基、リン酸基、スルホン酸基、及び両性イオン基からなる群から選択される少なくとも一つの基を有するモノマーである、請求項５に記載の血液処理用ビーズ。 The blood treatment according to claim 5, wherein the charged monomer is a monomer having at least one group selected from the group consisting of an amino group, a carboxyl group, a phosphate group, a sulfonic acid group, and a zwitterionic group. For beads.
  7. 　前記電荷を有するモノマーは、２－アミノエチルメタクリレート（ＡＥＭＡ）、ジメチルアミノエチルメタクリレート（ＤＭＡＥＭＡ）、ジエチルアミノエチルメタクリレート（ＤＥＡＥＭＡ）、［２－（メタクリロイルオキシ）エチル］トリメチルアンモニウム、アクリル酸（ＡＡｃ）、メタクリル酸（ＭＡｃ）、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン（ＣＭＢ）、及びリン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチル（ＭＰＣ）からなる群から選択される少なくとも一つである、請求項５に記載の血液処理用ビーズ。 The charged monomer is 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), [2- (methacryloyloxy) ethyl] trimethylammonium, acrylic acid (AAc), methacrylic acid. Acid (MAc), N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB), and 2- (methacryloyloxy) ethyl phosphate 2- (trimethylammonio) ethyl (MPC) The blood processing bead according to claim 5, which is at least one selected from the group consisting of:
  8. 　前記電荷を有するモノマーの含有量は、前記ポリマーを構成するモノマー全体を基準として１０モル％以上６０モル％以下である、請求項５～７のいずれか一項に記載の血液処理用ビーズ。 The blood processing beads according to any one of claims 5 to 7, wherein the content of the charged monomer is 10 mol% or more and 60 mol% or less based on the entire monomers constituting the polymer.
  9. 　前記電荷を有するモノマーの含有量は、前記ポリマーを構成するモノマー全体を基準として１５モル％以上４０モル％以下である、請求項５～７のいずれか一項に記載の血液処理用ビーズ。 The blood processing beads according to any one of claims 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.
  10. 　前記血液処理用ビーズの表面における、炭素原子と酸素原子の割合の和が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で９７．０％以上である、請求項１～９のいずれか一項に記載の血液処理用ビーズ。 2. The sum of the proportions of carbon atoms and oxygen atoms on the surface of the blood processing beads is 97.0% or more in atomic percentage based on the total number of atoms from atomic number 3 to atomic number 92. 10. The blood processing bead according to any one of items 9 to 9.
  11. 　前記ポリマーの量は、前記多孔質ビーズ乾燥時重量１ｇ当たり０．０８ｍｇ以上１１４ｍｇ以下である、請求項１～１０のいずれか一項に記載の血液処理用ビーズ。 The blood processing beads according to any one of claims 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.
  12. 　前記ポリマーの量は、前記多孔質ビーズ乾燥時重量１ｇ当たり２．０ｍｇ以上２０ｍｇ以下である、請求項１～１０のいずれか一項に記載の血液処理用ビーズ。 The blood processing beads according to any one of claims 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. 　前記多孔質ビーズの体積平均粒子径は、３００μｍ～１０００μｍである、請求項１～１２のいずれか一項に記載の血液処理用ビーズ。 The blood processing beads according to any one of claims 1 to 12, wherein the volume average particle diameter of the porous beads is 300 μm to 1000 μm.
  14. 　前記多孔質ビーズの細孔径５ｎｍ～１００ｎｍの積算細孔容量が０．５ｃｍ３／ｇ以上であり、細孔径１００ｎｍ～１０００ｎｍの積算細孔容量が０．２ｃｍ３／ｇ以下である、請求項１～１３のいずれか一項に記載の血液処理用ビーズ。 2. The porous bead according to claim 1, wherein the cumulative pore volume at a pore size of 5 nm to 100 nm is 0.5 cm 3 / g or more, and the cumulative pore volume at a pore size of 100 nm to 1000 nm is 0.2 cm 3 / g or less. 14. The blood processing bead according to any one of items 13 to 13.
  15. 　前記一般式（１）で表されるモノマーは、２－メトキシエチルメタクリレート、ｎ－ブチルメタクリレート、及びラウリル酸メタクリレートからなる群から選択される少なくとも一つである、請求項１～１４のいずれか一項に記載の血液処理用ビーズ。 15. The monomer according to claim 1, wherein the monomer represented by the general formula (1) is at least one selected from the group consisting of 2-methoxyethyl methacrylate, n-butyl methacrylate, and lauric methacrylate. Item 14. The blood processing beads according to Item.
  16. 　血液から１０００Ｄａ超～６６０００Ｄａ未満の疎水性蛋白質分子を除去する、請求項１～１５のいずれか一項に記載の血液処理用ビーズ。 The bead for blood treatment according to any one of claims 1 to 15, which removes a hydrophobic protein molecule of more than 1000 Da and less than 66000 Da from blood.
  17. 　血液からサイトカイン及びハイモビリティグループボックス１（ＨＭＧＢ１）を除去する、請求項１～１６のいずれか一項に記載の多孔質吸着ビーズ。 多孔 The porous adsorptive beads according to any one of claims 1 to 16, wherein cytokines and high mobility group box 1 (HMGB1) are removed from blood.
  18. 　請求項１～１７のいずれか一項に記載の血液処理用ビーズを有する、血液浄化器。 A blood purifier comprising the blood processing beads according to any one of claims 1 to 17.
  19. 　多孔質ビーズ、及び前記多孔質ビーズの表面上に担持されたポリマーを有する、血液処理用ビーズであって、
    　前記多孔質ビーズは、アクリル系樹脂、スチレン系樹脂、及びセルロース系樹脂からなる群から選択される少なくとも一つの樹脂から構成され、
    　前記ポリマーは、両性イオン型モノマーを単量体単位として含み、
    　前記両性イオン型モノマーは、前記ポリマーを構成するモノマー全体を基準として、１０モル％以上３０モル％以下である、血液処理用ビーズ。     Porous beads, and having a polymer carried 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 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 entire monomers constituting the polymer.
  20. 　前記血液処理用ビーズの表面における、窒素原子の割合が、原子番号３番から９２番までの原子の総数を基準として、原子百分率で０．２％以上０．９％以下である、請求項１９に記載の血液処理用ビーズ。 20. 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 beads for blood treatment according to claim 1.
  21. 　前記両性イオン型モノマーは、下記式（２）：
    Figure JPOXMLDOC01-appb-C000002
     ｛式（２）中、Ｒ１は、水素原子又はメチル基であり、Ｙは、酸素原子又は－ＮＨ－であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑ－であり、ｑは１～５であり、Ｒ３およびＲ４は、それぞれ独立して、水素原子又は炭素原子数１～４のアルキル基であり、Ｒ５は、－ＣＨ２（ＣＨ２）ｍ－であり、ｍは０～４であり、Ｚは、－ＣＯＯ－又はＳＯ３ －である。｝
    で表されるモノマー、及び
    　下記式（３）：
    Figure JPOXMLDOC01-appb-C000003
     ｛式（３）中、Ｒ１は、水素原子又はメチル基であり、Ｙは、酸素原子又は－ＮＨ－であり、Ｒ２は、－ＣＨ２（ＣＨ２）ｑ－であり、ｑは１～５であり、Ｒ３、Ｒ４、およびＲ6は、それぞれ独立して、水素原子又は炭素原子数１～４のアルキル基であり、Ｒ５は、－ＣＨ２（ＣＨ２）ｍ－であり、ｍは０～４である。｝
    で表されるモノマーからなる群から選択される少なくとも一つである、請求項１９又は２０に記載の血液処理用ビーズ。     The zwitterionic monomer has the following formula (2):
    Figure JPOXMLDOC01-appb-C000002
     ｛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 — . ｝
    And a monomer represented by the following formula (3):
    Figure JPOXMLDOC01-appb-C000003
     ｛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. ｝
    The blood processing bead according to claim 19 or 20, which is at least one selected from the group consisting of monomers represented by the following formulae.
  22. 　前記ポリマーは、下記式（４）：
    Figure JPOXMLDOC01-appb-C000004
     ｛式（４）中、Ｒ７は、水素原子又はメチル基であり、Ｒ８は、－ＣＨ２（ＣＨ２）ｒ－であり、ｒは１～５であり、Ｒ９は、－ＣＨ２ＣｔＨ２ｔ＋１であり、ｔは０～３である。｝
    で表されるモノマーを単量体単位として更に含む、請求項１９～２１のいずれか一項に記載の血液処理用ビーズ。     The polymer has the following formula (4):
    Figure JPOXMLDOC01-appb-C000004
     ｛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. ｝
    22. The blood processing bead according to claim 19, further comprising a monomer represented by the following formula as a monomer unit.
  23. 　前記ポリマーは、前記両性イオン型モノマー、及び前記式（４）のモノマーから構成される、請求項２２に記載の血液処理用ビーズ。 23. The blood processing bead according to claim 22, wherein the polymer is composed of the zwitterionic monomer and the monomer of the formula (4).
  24. 　前記式（４）中、ｒは１～３であり、ｔは０又は１である、請求項１９～２３のいずれか一項に記載の血液処理用ビーズ。 血液 The blood processing bead according to any one of claims 19 to 23, wherein in the formula (4), r is 1 to 3, and t is 0 or 1.
  25. 　前記式（２）中、Ｒ１はメチル基であり、ｑは１～３であり、Ｒ３およびＲ４は、それぞれ独立して、メチル基又はエチル基であり、ｍは０又は１である、請求項１９～２４のいずれか一項に記載の血液処理用ビーズ。 In the formula (2), 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, and m is 0 or 1. The blood processing beads according to any one of claims 19 to 24.
  26. 　前記両性イオン型モノマーは、Ｎ－メタクリロイルオキシエチル－Ｎ，Ｎ－ジメチルアンモニウム－α－Ｎ－メチルカルボキシベタイン、［２－（メタクリロイルオキシ）エチル］ジメチル－（３－スルホプロピル）アンモニウムヒドロキシド、［３－（メタクリロイルアミノ）プロピル］ジメチル（３－スルホプロピル）アンモニウムヒドロキシド、及びリン酸２－（メタクリロイルオキシ）エチル２－（トリメチルアンモニオ）エチルからなる群から選択される少なくとも一つである、請求項１９～２５のいずれか一項に記載の血液処理用ビーズ。 The zwitterionic monomer includes N-methacryloyloxyethyl-N, N-dimethylammonium-α-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, The blood processing bead according to any one of claims 19 to 25.
  27. 　前記多孔質ビーズの細孔径５ｎｍ～１００ｎｍの積算細孔容量が０．５ｃｍ３／ｇ以上であり、細孔径１００ｎｍ～２００ｎｍの積算細孔容量が０．２ｃｍ３／ｇ以下である、請求項１９～２６のいずれか一項に記載の血液処理用ビーズ。 20. The porous beads have a cumulative pore volume of 0.5 cm 3 / g or more for pore diameters of 5 nm to 100 nm, and a cumulative pore volume of 100 nm to 200 nm for pore diameters of 0.2 cm 3 / g or less. 27. The blood processing beads according to any one of to 26.
  28. 　前記多孔質ビーズの体積平均粒子径は、３００μｍ～１０００μｍである、請求項１９～２７のいずれか一項に記載の血液処理用ビーズ。 ビ ー ズ The blood processing beads according to any one of claims 19 to 27, wherein the porous beads have a volume average particle diameter of 300 μm to 1000 μm.
  29. 　血液から１０００Ｄａ超～６６０００Ｄａ未満の疎水性蛋白質分子を除去する、請求項１９～２８のいずれか一項に記載の血液処理用ビーズ。 ビ ー ズ The blood processing bead according to any one of claims 19 to 28, which removes a hydrophobic protein molecule of more than 1000 Da and less than 66000 Da from blood.
  30. 　血液からサイトカイン及びハイモビリティグループボックス１（ＨＭＧＢ１）を除去する、請求項１９～２９のいずれか一項に記載の多孔質吸着ビーズ。 多孔 The porous adsorption beads according to any one of claims 19 to 29, which removes cytokines and high mobility group box 1 (HMGB1) from blood.
  31. 　請求項１９～３０のいずれか一項に記載の血液処理用ビーズを有する、血液浄化器。 A blood purifier comprising the blood processing beads according to any one of claims 19 to 30.
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