CN112827478B - Bead for blood treatment - Google Patents

Bead for blood treatment Download PDF

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Publication number
CN112827478B
CN112827478B CN202110103157.7A CN202110103157A CN112827478B CN 112827478 B CN112827478 B CN 112827478B CN 202110103157 A CN202110103157 A CN 202110103157A CN 112827478 B CN112827478 B CN 112827478B
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China
Prior art keywords
beads
bead
blood treatment
blood
monomer
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CN202110103157.7A
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CN112827478A (en
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时水勇辅
井上觉
畑中美博
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Asahi Kasei Medical Co Ltd
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Asahi Kasei Medical Co Ltd
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Priority claimed from JP2019112280A external-priority patent/JP7309470B2/en
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    • 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
    • B01J20/28019—Spherical, ellipsoidal or cylindrical
    • 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
    • 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
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J20/28071—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being less than 0.5 ml/g
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
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  • Anesthesiology (AREA)
  • Hematology (AREA)
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  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • External Artificial Organs (AREA)
  • Materials For Medical Uses (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

Disclosed is a bead for blood treatment, which comprises a porous bead composed of at least one resin selected from the group consisting of an acrylic resin, a styrene resin and a cellulose resin, and a polymer supported on the surface of the porous bead, wherein the polymer contains a specific monomer as defined in the present specification as a monomer unit.

Description

Bead for blood treatment
The present application is a divisional application of the application having the application date of 2019, 6-27, and the application number of 201980043806.X, and the name of the application "beads for blood treatment".
Technical Field
The present invention relates to a bead for blood treatment.
Background
In the treatment of ischemic diseases represented by sepsis, various plasma exchange (apheresis) therapies are performed, which remove inflammatory mediators, such as cytokines and early warning substances (alarmin), which are considered to be causative substances, from the blood of a patient. In recent years, as one of the plasma exchange therapies, development of an adsorption type blood purifier for removing inflammatory mediators by adsorption is advanced.
As the adsorption type blood purifier on the market, for example, torayyxin (registered trademark) using an adsorbent in which a fiber having an endotoxin removal function is wound in a roll (Toray Medical co., ltd.); sepxisis (registered trademark) as an adsorption type blood purifier for continuous blood purification therapy (CRRT) using hollow fibers having an adsorption function of early warning hormone (HMGB 1) and cytokine (IL-6, etc.); and CytoSorb (registered trademark) (Cytosorbents Corporation agency) using porous polymer beads having a cytokine-removing function.
The blood purifier needs to have biocompatibility due to direct contact with the patient's blood. To impart biocompatibility to the blood purifier, the sorbent body may be coated with a biocompatible polymer, typically a hydrophilic polymer.
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 to perform a polymerization reaction. The antithrombotic coating material can be applied to artificial organs such as artificial blood vessels made of ePTFE and medical devices such as catheters, and can provide biocompatibility to the artificial blood vessels.
Patent document 2 describes a copolymer having 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 in the case of forming a homopolymer. By loading the copolymer on the filter, it is possible to provide a living body-derived liquid treatment filter capable of treating a living body-derived liquid containing red blood cells without adversely affecting the red blood cells.
Patent document 3 describes that a crosslinked polymer material having at least one of a plurality of zwitterionic moieties and oligomeric glycol moieties is coated on porous beads as an adsorbent.
Patent document 4 describes a biocompatible polymer obtained by copolymerizing N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB) with a biocompatible polymerizable monomer represented by an alkenyl compound having 1 double bond and an organic group.
Patent document 5 describes a biocompatible polymer obtained by copolymerizing 2-methoxyethyl acrylate (MEA) with N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB), wherein CMB is contained in an amount of 1 to 7 mol% based on the total monomer units.
Patent document 6 describes a biocompatible polymer obtained by copolymerizing 2-methoxyethyl acrylate (MEA) with [2- (methacryloyloxy) ethyl ] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB) or [3- (methacryloylamino) propyl ] dimethyl (3-sulfopropyl) ammonium hydroxide (SPBA), wherein SBAC contains 1 to 7 mol% of all monomer units.
Such an adsorption type blood purifier is expected to be effectively used in a scenario where excessive generation of inflammatory mediators such as cardiac surgery and organ transplantation surgery is a problem, in addition to treatment of ischemic diseases.
Prior art literature
Patent literature
Patent document 1: japanese patent laid-open No. 2017-025285
Patent document 2: japanese patent laid-open No. 2017-185037
Patent document 3: japanese patent application laid-open No. 2016-514568
Patent document 4: japanese patent application laid-open No. 2007-130194
Patent document 5: international publication No. 2015/098763
Patent document 6: international publication No. 2015/125890
Disclosure of Invention
Problems to be solved by the invention
The present invention aims to solve one or more problems in medical devices having conventional biocompatible polymers described in patent documents 1 to 6 and the like.
For example, when conventional biocompatible polymers as described in patent documents 1 to 3 and the like are applied (also referred to as "loading" in the present specification) to porous beads as adsorbents, the biocompatibility of the porous beads can be improved, but the surfaces of the porous beads are hydrophilized and the adsorptivity of inflammatory mediators as hydrophobic proteins is reduced. Therefore, it is considered that improvement of biocompatibility and improvement of adsorptivity are in a trade-off relationship.
In view of the above background, an object of the present invention is to provide, in a first embodiment, a bead for blood treatment having improved blood compatibility while maintaining the adsorptivity of a porous bead.
In addition, when a conventional biocompatible polymer as described in patent documents 2 to 4 or the like is applied to a medical material (also referred to as "loading" in the present specification), the biocompatibility of the medical material can be improved, but a polymer containing a zwitterion dissolves in blood when it comes into contact with water or blood because of its high water solubility. In the adsorption type blood purifier, it is considered that the amount of eluted substances is small, and as in patent documents 5 and 6, the polymer to be applied needs to sufficiently suppress the content of the monomer unit containing amphoteric ions.
In view of the above background, an object of the present invention is to provide a bead for blood treatment having high biocompatibility and reduced elution of a supported biocompatible polymer into blood in the second embodiment.
Solution for solving the problem
As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by supporting a polymer containing a monomer represented by the following general formula (1) as a monomer unit on a specific porous bead in the first embodiment, and completed the present invention. The following exemplifies the first embodiment of the present invention.
[1] A bead for blood treatment comprising a porous bead and a polymer supported on the surface of the porous bead,
the porous beads are composed of at least one resin selected from the group consisting of acrylic resins, styrene resins and cellulose resins,
the polymer contains a monomer represented by the following general formula (1) as a monomer unit,
Figure BDA0002916766810000041
{ in 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, and m is 0 to 17.}
[2] The bead for blood treatment according to item 1, wherein the ratio of nitrogen atoms on the surface of the bead for blood treatment is 0.2% to 0.7% by atomic percentage based on the total number of atoms ranging from atomic number No. 3 to atomic number No. 92.
[3] The bead for blood treatment according to item 1 or 2, wherein q is 1 or 2 and m is 0 to 11.
[4] The bead for blood treatment 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 all monomers constituting the polymer.
[5] The bead for blood treatment according to any one of items 1 to 4, wherein the polymer further contains a monomer having a charge as a monomer unit.
[6] The bead for blood treatment according to item 5, wherein the monomer having a charge is a monomer having at least one group selected from the group consisting of an amino group, a carboxyl group, a phosphate group, a sulfonate group and a zwitterionic group.
[7] The bead for blood treatment according to item 5, wherein the monomer having a charge is at least one selected from the group consisting of 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), 2- (methacryloyloxy) ethyl ] trimethylammonium, acrylic acid (AAc), methacrylic acid (MAc), N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB) and 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate (MPC).
[8] The bead for blood treatment according to any one of items 5 to 7, wherein the content of the monomer having a charge is 10 mol% or more and 60 mol% or less based on all monomers constituting the polymer.
[9] The bead for blood treatment according to any one of items 5 to 7, wherein the content of the monomer having a charge is 15 mol% or more and 40 mol% or less based on all monomers constituting the polymer.
[10] The bead for blood treatment according to any one of items 1 to 9, wherein the sum of the ratios of carbon atoms and oxygen atoms on the surface of the bead for blood treatment is 97.0% or more in terms of atomic percent, based on the total number of atoms from atomic number No. 3 to atomic number No. 92.
[11] The bead for blood treatment according to any one of items 1 to 10, wherein the amount of the polymer is 0.08mg or more and 114mg or less per 1g weight when the porous bead is dried.
[12] The bead for blood treatment according to any one of items 1 to 10, wherein the amount of the polymer is 2.0mg or more and 20mg or less per 1g weight when the porous bead is dried.
[13] The bead for blood treatment 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]The bead for blood treatment according to any one of items 1 to 13, wherein the porous bead has an integrated pore volume of 0.5cm and a pore diameter of 5nm to 100nm 3 The cumulative pore volume of the pore diameter of 100nm to 200nm is 0.2cm per gram 3 And/g or less.
[15] The bead for blood treatment according to any one of items 1 to 14, 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 lauryl methacrylate.
[16] The bead for blood treatment according to any one of items 1 to 15, which removes hydrophobic protein molecules exceeding 1000Da and less than 66000Da from blood.
[17] The bead for blood treatment according to any one of items 1 to 16, which removes cytokines and high mobility group box B1 (HMGB 1) from blood.
[18] A blood purifier having the blood treatment beads according to any one of items 1 to 17.
As a result of intensive studies to solve the above problems, the present inventors have found that, in the second embodiment, a polymer containing a specific amount of a zwitterionic monomer as a monomer unit is supported on the surface of a porous bead made of a specific resin as a medical material, whereby the elution amount of the polymer into water can be suppressed, and completed the present invention. The following exemplifies a second embodiment of the present invention.
[19] A bead for blood treatment comprising a porous bead and a polymer supported on the surface of the porous bead,
the porous beads are composed of at least one resin selected from the group consisting of acrylic resins, styrene resins and cellulose resins,
the above polymer contains a zwitterionic monomer as a monomer unit,
The zwitterionic monomer is 10 to 30 mol% based on the total monomers constituting the polymer.
[20] The bead for blood treatment according to item 19, wherein the ratio of nitrogen atoms on the surface of the bead for blood treatment is 0.2% to 0.9% by atomic percentage based on the total number of atoms ranging from atomic number No. 3 to atomic number No. 92.
[21] The bead for blood treatment according to item 19 or 20, wherein the zwitterionic monomer is at least one selected from the group consisting of a monomer represented by the following formula (2) and a monomer represented by the following formula (3).
Figure BDA0002916766810000071
{ in formula (2), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 And R is 4 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4,Z is-COO - Or SO 3 - 。}
Figure BDA0002916766810000072
{ in formula (3), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 、R 4 And R is 6 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4.}
[22] The bead for blood treatment according to any one of items 19 to 21, wherein the polymer further comprises a monomer represented by the following formula (4) as a monomer unit.
Figure BDA0002916766810000073
{ in formula (4), R 7 Is a hydrogen atom or 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 T is 0 to 3.}
[23] The bead for blood treatment according to item 22, wherein the polymer is composed of the zwitterionic monomer and the monomer of formula (4).
[24] The bead for blood treatment according to any one of items 19 to 23, wherein r is 1 to 3 and t is 0 or 1 in the formula (4).
[25]Any of items 19 to 24The bead for blood treatment of formula (2), wherein R 1 Is methyl, q is 1-3, R 3 And R is 4 Each independently is methyl or ethyl, and m is 0 or 1.
[26] The bead for blood treatment according to any one of items 19 to 25, wherein the zwitterionic monomer is at least one selected from the group consisting of N-methacryloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine, [2- (methacryloxyyl) ethyl ] dimethyl- (3-sulfopropyl) ammonium hydroxide, [3- (methacryloxyamino) propyl ] dimethyl (3-sulfopropyl) ammonium hydroxide, and 2- (methacryloxyyl) ethyl 2- (trimethylammoniumethyl) phosphate.
[27]The bead for blood treatment according to any one of items 19 to 26, wherein the porous bead has an integrated pore volume of 0.5cm and a pore diameter of 5nm to 100nm 3 The cumulative pore volume of the pore diameter of 100nm to 200nm is 0.2cm per gram 3 And/g or less.
[28] The bead for blood treatment according to any one of items 19 to 27, wherein the porous bead has a volume average particle diameter of 300 μm to 1000 μm.
[29] The bead for blood treatment according to any one of items 19 to 28, which removes hydrophobic protein molecules exceeding 1000Da and less than 66000Da from blood.
[30] The bead for blood treatment according to any one of items 19 to 29, which removes cytokines and high mobility group box B1 (HMGB 1) from blood.
[31] A blood purifier having the blood treatment beads according to any one of items 19 to 30.
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, one or more problems in medical devices having conventional biocompatible polymers can be solved. The above description should not be construed as disclosing all the embodiments of the present invention and all the advantages of the present invention. Further embodiments of the present invention and advantages thereof will be apparent by reference to the following description and drawings.
Drawings
FIG. 1 is a diagram showing AMBERLITE TM XAD TM 1180N (manufactured by Organo Corporation, styrene-based polymer beads) and cumulative pore volume.
FIG. 2 is a schematic representation of Purosorb TM Graph of Log differential pore volume distribution and cumulative pore volume for PAD950 (Purolite ltd. Manufactured by acrylic beads).
FIG. 3 is a diagram showing AMBERLITE TM XAD TM 1180N and Purosorb TM Graph of cumulative volumetric particle size distribution of PAD 950.
FIG. 4 is a schematic diagram for explaining a method of evaluating platelet adhesion.
Detailed Description
The first and second embodiments of the present invention (collectively referred to as "the present embodiment") will be described in detail below for the purpose of illustrating the present invention, but the present invention is not limited to the present embodiment. In the present specification, the upper limit value and the lower limit value of each numerical range may be arbitrarily combined.
Bead for blood treatment
Biocompatible polymers
The beads for blood treatment in the first embodiment have a polymer supported on porous beads as an adsorbent. The polymer is a polymer (also referred to as "biocompatible polymer") containing a monomer represented by the following general formula (1) as a monomer unit.
Figure BDA0002916766810000091
In the formula (1), R 1 Is methyl (-CH) 3 )。R 2 Is a straight-chain alkyl (-CH) with methoxy at the end 2 (CH 2 ) q OCH 3 ) Or alkyl (-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 is R 2 Is alkyl (-CH) 2 C m H 2m+1 ) In the case of C m H 2m+1 The moiety may be linear or branched, preferably linear.
The monomer represented by the formula (1) is more preferably at least one selected from the group consisting of 2-methoxyethyl methacrylate (MEMA), n-Butyl Methacrylate (BMA) and Lauryl Methacrylate (LMA), and further preferably 2-methoxyethyl methacrylate (MEMA). In the case where the monomer represented by the formula (1) is the above, it is preferable to improve the blood compatibility while maintaining higher excessive adsorptivity to the porous beads.
While not being bound by theory, the blood processing beads of the first embodiment are prepared by combining a bead containing R 1 Is methyl (-CH) 3 ) And has a specific R 2 The biocompatible polymer having the monomer as a monomer unit is supported on the porous beads made of a specific material, and can improve blood compatibility while maintaining the adsorptivity of the porous beads. The mechanism is still not clear at the time of application of the present application, but the inventors speculate as follows. Conventionally, when porous beads are treated with a biocompatible polymer, it is considered preferable to impregnate more biocompatible polymer into porous beads in order to ensure sufficient biocompatibility. Therefore, a biocompatible polymer having good impregnation properties with respect to the porous beads is preferably used. Thus, the pores (adsorption sites) inside the porous beads are excessively hydrophilized due to the hydrophilicity of the biocompatible polymer, and the adsorption as a hydrophobic inflammatory mediator is hindered. It is also believed that adsorption is reduced due to the adsorption sites within the porous beads being physically blocked by the biocompatible polymer. Therefore, the improvement of biocompatibility and the improvement of adsorptivity of the conventional porous beads are in a trade-off relationship.
In contrast, the beads for blood treatment according to the first embodiment have an improved balance between hydrophilicity and hydrophobicity of the surface and adsorption sites of the porous beads by combining the specific biocompatible polymer and the porous beads made of the specific material. In addition or in other embodiments, the impregnation properties for the porous beads may be appropriately adjusted by the combination of the above-described specific biocompatible polymer and the porous beads composed of a specific material. For this reason, the following tends to occur: r is R 1 Biocompatible polymers which are hydrogen atoms for porosityThe beads have high impregnation properties, and the entire surface of the porous beads made of a specific material is coated non-selectively, in other words, more uniformly. On the other hand, there is a tendency that: containing R 1 The polymer of the first embodiment, which is a monomer of methyl group as a monomer unit, can suitably suppress the impregnation property with respect to the porous beads, and among the surfaces of the porous beads, the surface of the porous beads is preferentially coated with a rough surface to which the biocompatible polymer is easily attached, compared with a smooth surface to which the biocompatible polymer is not easily attached. As a result, the smooth surface of the porous beads is not attached to the biocompatible polymer and is liable to remain. This tendency is also suitable for platelets, which tend to adhere to rough surfaces as compared to smooth surfaces on the bead surface. At this time, the polymer in the first embodiment preferentially adheres to the roughened surface, and therefore, adhesion of platelets to the bead surface can be effectively suppressed. Furthermore, the presence of the surface to which the biocompatible polymer is not attached suppresses the amount of the biocompatible polymer supported on the porous beads and reduces clogging of the adsorption site. As a result, the beads for blood treatment according to the first embodiment are considered to have improved blood compatibility while maintaining the adsorptivity of the porous beads. The blood treatment beads according to the first embodiment can achieve both biocompatibility and adsorptivity, which have been considered to be in a trade-off relationship in the past, unexpectedly.
The content of the monomer represented by the formula (1) is preferably 40 mol% or more, more preferably 60 mol% or more, based on the total monomers constituting the biocompatible polymer. The upper limit of the content of the monomer is not limited, and may be 100 mol%, 80 mol% or less, or 60 mol% or less based on the total monomers constituting the biocompatible polymer.
In the first embodiment, the biocompatible polymer preferably further contains a monomer having a charge copolymerizable with the monomer represented by formula (1) as a monomer unit. In the present specification, a "monomer having a charge" is a monomer having a functional group that is partially or completely positively or negatively charged at a pH of 7.0. In the case where the biocompatible polymer further contains a monomer having a charge as a monomer unit, in combination with the porous beads in the first embodiment, the amount of the biocompatible polymer supported on the porous beads is reduced, and the decrease in adsorptivity can be suppressed. In addition, the monomer having a charge has high hydrophilicity, and thus biocompatibility is improved. As a result, there is a tendency to obtain beads for blood treatment having better adsorptivity and blood compatibility.
In the first embodiment, examples of the monomer having a charge include monomers having a charge selected from the group consisting of amino groups (-NH) 2 、-NHR 3 、NR 3 R 4 ) Carboxyl (-COOH), phosphate (-OPO) 3 H 2 ) Sulfonic acid group (-SO) 3 H) And a zwitterionic group. In the amino group, R 3 And R is 4 Preferably each independently is an alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 or 2 carbon atoms.
Among them, the monomer having a charge 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 monomer having a charge is further preferably at least one selected from the group consisting of a cationic monomer having an amino group, an anionic monomer having a carboxyl group, a zwitterionic monomer of an amino group and a carboxyl group, and a zwitterionic monomer of an amino group and a phosphate group. Adsorption of Ca from porous beads 2+ In view of suppressing the blood coagulation acceleration, it is more preferable that the monomer having a charge has a carboxyl group.
More specifically, as the monomer having a charge, at least one selected from the group consisting of 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), 2- (methacryloyloxy) ethyl ] trimethylammonium phosphate, acrylic acid (AAc), methacrylic acid (MAc), 2- (methacryloyloxy) ethyl phosphate, N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB), 2- (methacryloyloxy) ethyl ] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB), 3- (methacryloylamino) propyl ] dimethyl (3-sulfopropyl) ammonium hydroxide (SPBA), 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate (MPC) and 3- (methacryloylamino) propyl ] dimethyl (3-sulfobutyl) ammonium phosphate is more preferable.
Among them, the monomer having a charge is more preferably at least one selected from the group consisting of dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), acrylic acid (AAc), N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB) and 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate (MPC), and further preferably N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB).
In the first embodiment, the content of the monomer having a charge is preferably 10 mol% or more and 60 mol% or less, more preferably 15 mol% or more and 40 mol% or less, based on the total monomers constituting the biocompatible polymer. When the content of the monomer having a charge is within the above range, there is a tendency that the balance between the impregnation property and the hydrophilicity of the porous beads is excellent, and the beads for blood treatment having more excellent adsorptivity and biocompatibility are obtained. The analytical methods for the composition and structure of biocompatible polymers are detailed in the columns of the examples.
In the first embodiment, the weight average molecular weight (Mw) of the biocompatible polymer is preferably 5000 or more and 5000000 or less, more preferably 10000 or more and 1000000 or less, still more preferably 10000 or more and 300000 or less. When the weight average molecular weight of the biocompatible polymer is within the above range, the porous beads are preferable from the viewpoints of proper impregnation into the porous beads, prevention of elution into blood, and reduction in the amount of the load. The analysis method of the weight average molecular weight (Mw) of the biocompatible polymer can be measured by Gel Permeation Chromatography (GPC) or the like, for example, as described in comparative examples.
In the first embodiment, the amount (load amount) of the biocompatible polymer supported on the porous beads is preferably 0.08mg or more and 114mg or less, more preferably 0.8mg or more and 56mg or less, still more preferably 2.0mg or more and 20mg or less per 1g weight of the porous beads when dried. The method for measuring the loading (coating amount) of the biocompatible polymer is described in detail in the columns of examples.
The loading is suppressed within the above range by the combination of the biocompatible polymer in the first embodiment and the porous beads composed of a specific material. In other embodiments, the loading may be controlled within the above range by changing the conditions under which the biocompatible polymer is applied to the porous beads. When the loading amount is within the above range, clogging of the adsorption site is reduced, and as a result, it is considered that the blood compatibility can be improved while maintaining higher adsorptivity of the porous beads.
The biocompatible polymer "supported on the surface of the porous bead" refers to a state in which the biocompatible polymer is present in at least a portion of the surface of the porous bead in one other manifestation. Thus, in the first embodiment, the biocompatible polymer is not necessarily supported (coated) on the entire surface of the porous beads. In addition, as long as the problems of the present invention can be solved, the biocompatible polymer may be present in the pores of the porous beads or may block the pores to some extent.
In the first embodiment, the biocompatible polymer may contain other monomers as monomer units in addition to the monomer of the above formula (1) and any monomer having a charge. The other monomer is not limited as long as it can be copolymerized with these monomers.
In the first embodiment, examples of the other monomer include R in the formula (1) 1 A monomer which is hydrogen (H) or an alkyl group having 2 or more carbon atoms; r is R 2 Of (C) CH 2 (CH 2 ) q OCH 3 In (3), a monomer having an alkoxy group having 2 or more carbon atoms such as an ethoxy group, a propoxy group, and a butoxy group, instead of a methoxy group, at the terminal; r is R 2 Of (C) CH 2 (CH 2 ) q OCH 3 Wherein q is a monomer of 0 or 6 or more; r is R 2 Of (C) CH 2 C m H 2m+1 Wherein m is a monomer of 18 or more; and combinations thereof.
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, butoxybutyl acrylate, ethoxymethyl methacrylate, ethoxypropyl methacrylate, ethoxybutyl methacrylate, propoxybutyl methacrylate, butoxymethyl methacrylate, and the like may be mentioned.
The beads for blood treatment in the second embodiment have a polymer supported on porous beads as an adsorbent. The polymer is a polymer (also referred to as a "biocompatible polymer") that contains zwitterionic monomers as monomer units. In the present specification, "zwitterionic monomer" refers to a monomer having both positive and negative charges in one molecule at pH 7.0. The biocompatible polymer contains a zwitterionic monomer as a monomer unit and is combined with a porous bead composed of a specific material described later, whereby a bead for blood treatment having high biocompatibility and reduced elution of the supported biocompatible polymer into blood can be provided. The inventors, although not limited by theory, speculate as to the reason for this, as follows. That is, the zwitterionic monomer has high hydrophilicity, and thus can improve biocompatibility, but has a problem of easy dissolution when in contact with water or blood. In particular, in the adsorption type blood purifier, the beads for blood treatment are in continuous contact with blood for a period of time ranging from several hours to 1 day or more. If the polymer coated on the porous beads dissolves out at the time of use, the possibility of the polymer dissolving out in blood increases while the biocompatibility of the adsorption type blood purifier cannot be maintained for a long period of time. In the second embodiment, the polymer-supported porous beads function as an adsorbent, and the eluted biocompatible polymer can be adsorbed in the pores thereof. As a result, can obtain better blood compatibility, and the biocompatible polymer to the blood dissolution reduced blood processing beads.
In the second embodiment, the zwitterionic monomer is preferably selected from amino groups (-NH) 2 、-NHR 3 、NR 3 R 4 ) And carboxyl (-COOH) zwitterionic monomers, amino groups and sulfonic acid groups (-SO) 3 H) Zwitterionic monomers of (C), and amino and phosphate groups (-OPO) 3 H 2 ) At least one of the group consisting of zwitterionic monomers, adsorbing Ca from porous beads 2+ Further, from the viewpoint of suppressing the blood coagulation acceleration, the zwitterionic monomer of amino group and carboxyl group is preferable.
In the second embodiment, the zwitterionic monomer is preferably a monomer represented by the following formula (2).
Figure BDA0002916766810000151
{ in formula (2), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 And R is 4 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4,Z is-COO - Or SO 3 - 。}
Preferably, in the above formula (2), R 1 Is methyl, q is 1-3, R 3 And R is 4 Each independently is methyl or ethyl, and m is 0 or 1.
The monomer of the above formula (2) is more preferably selected from the group consisting of N-methacryloyloxyethyl-N, N-dimethylammonium-. Alpha. -N-methylcarboxybetaine (CMB), [2- (methacryloyloxy) ethyl group]Dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB), [3- (methacryloylamino) propyl ] ]Dimethyl (3-sulfopropyl)Radical) ammonium hydroxide (SPBA) and [3- (methacryloylamino) propyl radical]At least one of the group consisting of dimethyl (3-sulfobutyl) ammonium. As the monomer of the above formula (2), ca is adsorbed from the porous beads 2+ From the viewpoint of suppressing the blood coagulation hyperactivity, N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB) is more preferable.
In the second embodiment, the zwitterionic monomer is also preferably a monomer represented by the following formula (3).
Figure BDA0002916766810000161
{ in formula (3), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 、R 4 And R is 6 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4.}
Preferably, in the above formula (3), R 1 Is methyl, q is 1-3, R 3 、R 4 And R is 6 Each independently is methyl or ethyl, m is 1 or 2.
The monomer of the above formula (3) is exemplified by 2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate (MPC).
In the second embodiment, the zwitterionic monomer is preferably at least one monomer selected from the group consisting of the monomers of the formulae (2) and (3).
In the second embodiment, the content of the zwitterionic monomer is preferably 10 mol% or more and 30 mol% or less, more preferably 12 mol% or more and 30 mol% or less, still more preferably 15 mol% or more and 30 mol% or less, based on the total monomers constituting the biocompatible polymer. When the content of the zwitterionic monomer is within the above range, there is a tendency to obtain a blood processing bead having higher biocompatibility while suppressing the elution amount of the biocompatible polymer to water. The analytical methods for the composition and structure of the biocompatible polymers are detailed in the columns of the examples.
In the second embodiment, from the viewpoint of obtaining a blood processing bead having higher biocompatibility while suppressing the elution amount of the biocompatible polymer to water, it is preferable that the polymer further contains a monomer represented by the following formula (4) as a monomer unit.
Figure BDA0002916766810000162
{ in formula (4), R 7 Is a hydrogen atom or 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 T is 0 to 3.}
In the formula (4), R 7 Preferably methyl, r is preferably 1 to 3, more preferably 1 or 2, t is preferably 0 to 2, more preferably 0 or 1.
The content of the monomer represented by the formula (4) is preferably 40 mol% or more, more preferably 60 mol% or more, based on the total monomers constituting the biocompatible polymer. The upper limit of the content of the monomer is not limited, but is preferably 90 mol% or less, or may be 80 mol% or less, or 60 mol% or less, based on the total monomers constituting the biocompatible polymer.
In the second embodiment, the weight average molecular weight (Mw) of the biocompatible polymer is preferably 5000 or more and 5000000 or less, more preferably 10000 or more and 1000000 or less, still more preferably 10000 or more and 300000 or less. When the weight average molecular weight of the biocompatible polymer is within the above range, it is preferable from the viewpoints of proper impregnation into the porous beads, prevention of elution into blood, reduction of the load, and the like. The analysis method of the weight average molecular weight (Mw) of the biocompatible polymer can be measured by Gel Permeation Chromatography (GPC) or the like, for example, as described in comparative examples.
The biocompatible polymer "supported on the surface of the porous bead" refers to a state in which the biocompatible polymer is present in at least a portion of the surface of the porous bead in one other manifestation. Thus, in the second embodiment, the biocompatible polymer is not necessarily supported (coated) on the entire surface of the porous beads. In addition, as long as the problems of the present invention can be solved, the biocompatible polymer may be present in the pores of the porous beads or may block the pores to some extent.
In the second embodiment, the biocompatible polymer may be composed of the above zwitterionic monomer and the monomer of formula (4). However, the biocompatible polymer may contain other monomers as monomer units in addition to the above zwitterionic monomer and the monomer of formula (4). The other monomer is not limited as long as it can be copolymerized with these monomers.
In the second embodiment, the other monomer is a monomer which is not zwitterionic and does not satisfy the formula (4). Examples of the other monomer include a cationic or anionic monomer having a functional group which is partially or completely positively charged or a functional group which is negatively charged at a pH of 7.0. Examples of the functional group having a positive or negative charge include an amino group (-NH) 2 、-NHR 3 、NR 3 R 4 ) Carboxyl (-COOH), phosphate (-OPO) 3 H 2 ) And a sulfonic acid group (-SO) 3 H) A. The invention relates to a method for producing a fibre-reinforced plastic composite More specifically, examples of the cationic or anionic monomer include 2-aminoethyl methacrylate (AEMA), dimethylaminoethyl methacrylate (DMAEMA), diethylaminoethyl methacrylate (DEAEMA), and [2- (methacryloyloxy) ethyl group]Trimethylammonium, acrylic acid (AAc), methacrylic acid (MAc) and 2- (methacryloyloxy) ethyl phosphate. More specifically, the other monomers include 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 methacrylate, methoxymethyl acrylate, ethoxymethyl acrylate, propoxymethyl acrylate, butoxymethyl acrylate, and methacrylic acidEthoxymethyl acid, propoxymethyl methacrylate, butoxymethyl methacrylate, and 2- (2-ethoxyethoxy) ethyl acrylate (Et 2A), and the like. Among them, a zwitterionic monomer and a monomer of the above formula (4) are preferably used in combination with a cationic or anionic monomer.
In the second embodiment, when other monomers are present, the amount of the other monomers may be 1 mol% or more, 5 mol% or more, or 10 mol% or more, 30 mol% or less, 25 mol% or less, or 20 mol% or less based on the total monomers constituting the biocompatible polymer.
Porous bead
The beads for blood treatment in this embodiment have porous beads as adsorbents. The porous beads are composed of at least one resin selected from the group consisting of acrylic resins, styrene resins, and cellulose resins. In the present specification, the porous beads may contain other resins and other components as long as the problems of the present invention can be solved.
As the porous beads, commercially available porous beads can be used. As commercially available porous beads composed of acrylic resins, for example, AMBERLITE may be mentioned TM XAD TM 7HP (Organo Corporation) Diaion) TM HP2MG (manufactured by Mitsubishi Chemical Corporation), purosorb TM PAD610 (manufactured by Purolite ltd.) PuroSorb TM PAD950 (manufactured by Purolite Ltd.) and Muromac (registered trademark) PAP-9210 (manufactured by MUROMACHI CHEMICALS INC.). As commercially available porous beads composed of a styrene-based resin, for example, AMBERLITE may be mentioned TM XAD TM 4 (Organo Corporation), AMBERLITE TM XAD TM 2000 (Organo Corporation), AMBERLITE TM FPX66 (Organo Corporation system), AMBERLITE TM XAD TM 1180N (Organo Corporation), diaion TM HP20 (Mitsubishi Chemical Corporation) Diaion TM HP21 (Mitsubishi Chemical Corporation) Diaion TM SP700 (manufactured by Mitsubishi Chemical Corporation), purosorb TM PAD600 (manufactured by Purolite ltd.) PuroSorb TM PAD900 (manufactured by Purolite ltd.) and Muromac (quotient)Label registration) SAP-9210 (manufactured by MUROMACHI CHEMICALS inc.) and the like. Examples of commercially available porous beads made of cellulose resin include viscus (trademark registered) mini (Rengo co., ltd.) and C8329 (Sigma-Aldrich).
The volume average particle diameter of the porous beads is preferably 300 μm to 1000. Mu.m, more preferably 400 μm to 800. Mu.m, still more preferably 420 μm to 700. Mu.m. The volume average particle diameter of 300 μm or more effectively suppresses the pressure increase when blood flows through the column, and the volume average particle diameter of 1000 μm or less enables rapid adsorption performance. In the present application, the method for measuring the "volume average particle diameter" of the porous beads is described in detail in the column of examples.
The cumulative pore volume of the porous beads having a pore diameter of 5nm to 100nm is preferably 0.5cm 3 Higher than/g, more preferably 0.8cm 3 Preferably 1.0cm or more, more preferably per gram 3 And/g. The upper limit of the cumulative pore volume is preferably 3.5cm 3 Less than/g, more preferably 3.0cm 3 Preferably less than/g, more preferably 2.5cm 3 And/g or less. When the cumulative pore volume falls 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, a bead for blood treatment having better blood compatibility and reduced elution of the biocompatible polymer into blood can be obtained, and is therefore preferable.
In addition to the characteristic of cumulative pore volume, or in other embodiments, it is also preferred that the porous beads have a cumulative pore volume of 0.2cm with a pore diameter of 100nm to 200nm 3 Less than/g, more preferably 0.1cm 3 Preferably less than/g, more preferably 0.05cm 3 And/g or less. In the case where the cumulative pore volume has the above-described characteristics, the porous beads have a large number of micropores having a size suitable for adsorption of hydrophobic protein molecules, and as a result, beads for blood treatment having more excellent adsorption can be obtained, which is preferable. Method for measuring cumulative pore volume of porous beads, in practice Details are given in the columns of the examples.
Element ratio and atomic ratio of beads for blood treatment
(element ratio based on element analysis)
The ratio of nitrogen element among the elements constituting the whole blood processing bead 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 nitrogen element is within the above range, the beads for blood treatment adsorb hydrophobic protein molecules and have high blood compatibility, so that it is preferable. Among the elements constituting the whole of the blood processing bead, the total of the carbon element, the hydrogen element, and the oxygen element is preferably 97.0 mass% or more, more preferably 99.0 mass% or more. When the ratio of these elements is within the above range, the beads for blood treatment are preferable because more hydrophobic protein molecules can be removed. The element ratio based on the elements constituting the whole of the blood processing bead can be measured by elemental analysis. The measurement method is described in detail in the columns of examples.
(atom ratio based on XPS)
In addition to the characteristic feature of the element ratio based on the above elemental analysis, or in other embodiments, the total number of the lithium atoms from atomic number 3 to uranium atoms from atomic number 92 on the surface of the blood processing bead is preferably 0.2% or more and 0.9% or less, more preferably 0.2% or more and 0.7% or less, still more preferably 0.2% or more and 0.5% or less, still more preferably 0.3% or more and 0.5% or less, based on the atomic percentage, with respect to the ratio of nitrogen atoms present on the surface of the blood processing bead. When the ratio of the number of nitrogen atoms present on the surface of the blood processing bead is within the above range, the blood processing bead preferably has high blood compatibility while adsorbing hydrophobic protein molecules. The ratio of nitrogen atoms present on the surface of the bead for blood treatment can be adjusted by using a biocompatible polymer containing nitrogen. For example, in the case of the first embodiment, as the monomer having a charge, a monomer containing nitrogen may be used, as the other monomer, another monomer containing nitrogen may be used, or both of them may also be used (also collectively referred to as "monomer containing nitrogen"). In the case of the second embodiment, as the zwitterionic monomer, a nitrogen-containing zwitterionic monomer may be used, as the other monomer, a nitrogen-containing other monomer may be used, or both of them may be used (also collectively referred to as "nitrogen-containing monomer"). More specifically, the ratio of nitrogen atoms present on the surface of the beads for blood treatment can be adjusted by (1) adjusting the ratio of the nitrogen-containing monomers constituting the biocompatible polymer and/or (2) adjusting the loading amount of the nitrogen-containing biocompatible polymer on the porous beads. The total ratio of carbon atoms to oxygen atoms present on the surface of the blood treatment bead is preferably 97.0% or more in terms of atomic percent based on the total number of lithium atoms from atomic number 3 to uranium atoms from atomic number 92 present on the surface of the blood treatment bead. The ratio of phosphorus atoms present on the surface of the blood treatment bead is preferably 3% or less, more preferably 1% or less in terms of atomic percentage, based on the total number of lithium atoms from atomic number 3 to uranium atoms from atomic number 92 present on the surface of the blood treatment bead. The ratio of the specific atoms present on the surface of the blood treatment beads can be measured by X-ray photoelectron spectroscopy (XPS). The measurement method is described in detail in the columns of examples.
The beads for blood treatment were pulverized to form a powder, and the surface of the powder was measured by XPS, whereby the ratio of specific atoms constituting the whole beads for blood treatment was measured based on the total number of atoms from atomic number No. 3 to atomic number No. 92. The ratio of nitrogen atoms constituting the whole blood treatment bead thus measured is preferably more than 0% and not more than 0.1% based on the total number of atoms from atomic number No. 3 to atomic number No. 92. The ratio of phosphorus atoms constituting the whole blood treatment bead is preferably 0.1% or less based on the total number of atoms from atomic number No. 3 to No. 92. When the ratio of the nitrogen atom and the phosphorus atom is within the above range, the beads for blood treatment adsorb hydrophobic protein molecules and have high blood compatibility, so that the beads are preferable.
Adsorption of beads for blood treatment
For example, when hydrophobic protein molecules of more than 1000Da and less than 66000Da are removed from blood, the adsorption of the polymer-supported porous beads is further improved, and the eluted biocompatible polymer can be more effectively adsorbed in the pores of the beads. As a result, a bead for blood treatment having better blood compatibility and reduced elution of the biocompatible polymer into blood can be obtained, and is therefore preferable. In the present specification, the term "removable" of a hydrophobic protein molecule means that the adsorption rate of the hydrophobic protein to the blood treatment beads is 30% or more when the hydrophobic protein molecule is contacted with the blood treatment beads and oscillated in a plasma sample containing the hydrophobic protein molecule to be removed. The method for evaluating the adsorptivity of the blood treatment beads is described in detail in the columns of examples. The beads for blood treatment in this embodiment can remove hydrophobic protein molecules more preferably exceeding 8000Da and less than 66000Da, still more preferably exceeding 8000Da and less than 51000 Da. For example, cytokine molecular weight of about 5-60 kDa (IL-1B: about 17.5kDa, IL-6: about 24.5kDa, IL-8: about 8kDa, IL-10 (dimer): about 37.5kDa, TNF-alpha (trimer): about 51 kDa), high mobility group protein B1 (HMGB 1) as a pre-alarm is a hydrophobic protein having a molecular weight of about 30 kDa.
Examples of the removed hydrophobic protein molecules include protein molecules considered to be a cause of sepsis, for example, pathogen-related molecular patterns (PAMPs, pathogen-associated molecular patterns) as exogenous substances derived from pathogenic microorganisms; and various inflammatory mediators that cause an inflammatory reaction, such as early warning agents that are endogenous substances released due to tissue damage, and cytokines that cause an inflammatory reaction. The hydrophobic protein molecule may be a leukocyte.
Examples of PAMPs include endotoxin (LPS), peptidoglycan (PGN), lipoteichoic acid, double-stranded RNA (dsRNA), and flagellin.
Examples of the early warning agent include high mobility group box protein B1 (HMGB 1), heat Shock Proteins (HSPs), histones, fibrinogen, neutrophil elastase, and macrophage Migration Inhibitory Factor (MIF).
Examples of cytokines include interleukins (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 and IL-18), tumor necrosis factors (TNF-. Alpha., and TNF-. Beta.), and the like.
Among them, the beads for blood treatment preferably remove forewarning substances and cytokines, more preferably remove HMGB1 and cytokines.
Biocompatibility of beads for blood treatment
The beads for blood treatment in this embodiment are excellent in biocompatibility while maintaining excellent adsorptivity as described above. The term "biocompatibility" varies depending on the purpose of the blood purifier and the method of use, but in the present specification, the amount of attached platelets to the blood processing beads is used as an index of biocompatibility. The more the amount of platelets attached to the blood processing beads is inhibited, the more excellent the biocompatibility of the blood processing beads is. The method for evaluating platelet adhesion of the blood treatment beads is described in detail in the columns of examples.
When the beads for blood treatment in the first embodiment are measured based on the method for evaluating the "platelet adhesion of beads for blood treatment" described in detail in the column of examples, the adsorption rate of platelets to porous beads is preferably 0.1% to 30%, more preferably 0.3% to 20%, and still more preferably 0.5% to 11%. For example, in the case of using porous beads made of an acrylic resin, the amount of the adhesive is preferably 0.1 to 22%, more preferably 0.3 to 13%, and even more preferably 0.5 to 9%. For example, in the case of using porous beads made of a styrene resin, the amount of the particles to be attached is preferably 0.5 to 30%, more preferably 1 to 22%, and still more preferably 3 to 11%.
When the blood treatment beads according to the second embodiment are measured by the method for evaluating the platelet adhesion of the blood treatment beads described in detail in the column of the examples, the platelet remaining ratio is preferably 81% to 100%, more preferably 83% to 95%, and even more preferably 85% to 95%.
Method for producing beads for blood treatment
The method for producing the blood processing beads according to the present embodiment is not limited. For example, the method for producing the blood processing bead of the present embodiment includes: the biocompatible polymer in the present embodiment is supported on the surface of porous beads composed of at least one resin selected from the group consisting of acrylic resins, styrene resins, and cellulose resins. The biocompatible polymer and the monomer in this embodiment are described in detail above, and thus description thereof is omitted here.
Method for producing biocompatible polymer
In the first embodiment, the method for producing the biocompatible polymer is not limited. For example, the method of manufacturing the biocompatible polymer includes: adjusting a monomer solution containing a monomer of formula (1) in an arbitrary solvent; adding an optional polymerization initiator to the monomer solution to adjust a polymerization solution; and polymerizing the above monomer.
In addition to the monomer of the formula (1), a monomer having a charge may be added to the monomer solution and/or the polymerization solution to be copolymerized with the monomer of the formula (1). The details of the monomers having charges are as described above, and thus, descriptions thereof are omitted here.
In the second embodiment, the method for producing the biocompatible polymer is not limited. For example, the method of manufacturing the biocompatible polymer includes: adjusting a monomer solution containing a zwitterionic monomer in an optional solvent; adding an optional polymerization initiator to the monomer solution to adjust a polymerization solution; and polymerizing the above monomer.
In addition to the zwitterionic monomer, the monomer of formula (4) may be added to the monomer solution and/or the polymerization solution to copolymerize with the zwitterionic monomer. The monomer of formula (4) is described in detail above, and thus, description thereof is omitted here.
In this embodiment, the polymerized biocompatible polymer may be purified by any purification method, for example, reprecipitation, dialysis, ultrafiltration, extraction, and the like. The purified biocompatible polymer may be dried by any drying method, such as reduced pressure drying, spray drying, freeze drying, heat drying, and the like.
Method for supporting biocompatible Polymer
As a method for supporting the biocompatible polymer on the surface of the porous beads, any supporting method, for example, a coating method, a spraying method, an impregnating method, and the like can be used.
For example, the impregnation method includes: the above biocompatible polymer is dissolved in an arbitrary solvent such as alcohol, chloroform, acetone, tetrahydrofuran, dimethylformamide, etc., to prepare a coating solution, and porous beads are immersed in the coating solution. After impregnation, the porous beads are removed from the coating solution and excess solution is removed, and then may be dried using any drying method. Examples of the drying method include air-drying in a drying gas, drying under reduced pressure at normal temperature in a reduced pressure atmosphere, and drying under reduced pressure while heating. From the viewpoint of reducing the amount of the porous beads per 1g of the polymer in the present embodiment, drying under reduced pressure is preferable.
Examples of the coating method and the spraying method include coating or spraying the porous beads with the coating solution and then drying the coated porous beads as described above.
Blood purifier
The blood purifier of the present embodiment includes the blood treatment beads of the present embodiment. The blood purifier generally includes a blood inlet, an interior space that can house blood processing beads, and a body vessel having a blood outlet. In the blood purification treatment, the blood before the treatment is usually introduced into the internal space through the blood inlet, and the blood treatment beads according to the present embodiment present in the internal space are contacted with each other, whereby the blood is treated, and the treated blood flows out through the blood outlet.
The shape of the main body container is not limited, and examples thereof include a cylindrical shape, typically a cylindrical column, and the like.
The material constituting the main container is not limited, and examples thereof include thermoplastic resins, such as polypropylene, polyethylene, polyester, polystyrene, polytetrafluoroethylene, polycarbonate, acrylonitrile Butadiene Styrene (ABS), and copolymers containing vinyl aromatic hydrocarbon and conjugated diene. In addition, thermosetting resins such as polyurethane and epoxy are sometimes used for sealing.
Examples
The present embodiment will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples and comparative examples.
Physical Property measurement 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), 2000 beads were measured, and the volume average thereof was calculated as the volume average particle diameter (. Mu.m).
Cumulative pore Capacity of porous beads
The porous beads swollen with ultrapure water were freeze-dried for 24 hours after freezing, and then the porous beads were dried, and then subjected to a degassing treatment (drying under reduced pressure) at 60℃for 15 hours using VacPrep061 (manufactured by Micromerics corporation, shimadzu corporation). Then, triStarII 3020 (manufactured by Micromerics Inc. of Shimadzu corporation) was used to utilize N 2 Gas adsorption method for accumulating pore volume (cm) 3 /g). In this case, desorption Cumulative Pore Volume by the BJH method is used as the cumulative pore volume.
Specific surface area of porous beads
The dried beads for blood treatment were subjected to degassing treatment (drying under reduced pressure) at 60℃for 15 hours using VacPrep061 (manufactured by Micromerics, shimadzu corporation). Then, triStarII 3020 (manufactured by Micromeritics Co., ltd.) was used to make use of N 2 Specific surface area (m) by gas adsorption method 2 /g). In this case, as the specific surface area, a value obtained by using a BET curve is used.
Physical Property measurement of coated beads
Determination of the amount of elution of coated beads
The 100mL conical beaker and the weighing flask were thoroughly washed with ultrapure water and dried completely. The weight of the dried weighing bottle was measured immediately before use (it was set as "weight of weighing bottle before treatment"). After adding 5.0mL (1.10 g at the time of drying) of the coated beads to a 100mL conical beaker, 50mL of ultrapure water was added (this solution was set as "sample solution"). In addition, only 50mL of ultrapure water (the solution was referred to as "Blank solution") was added to the other 100mL conical beaker. The upper part of these 2 beakers was then completely covered with aluminum foil, while autoclave sterilization treatment (LSX-500L, TOMY SEIKO co., ltd.) was performed at 121 ℃ for 20 minutes. After cooling the 2 beakers after autoclave sterilization treatment to room temperature, the solution in the beakers was filtered using filter paper (ADVANTEC, no.5 c) and transferred to a new 100mL conical beaker. The resulting 20mL of each of the 2 filtered solutions was added to the other weighing flask, and the water content of the solution in the weighing flask was evaporated on a hot plate. These weighing bottles were further dried in a hot air dryer (DN 4101, yamato Scientific co., ltd. System) at 105 ℃ for 1 hour, and the weight of the dried weighing bottles was measured (this was referred to as "weight of the treated weighing bottles").
The evaporation residue of the sample solution, the evaporation residue of the Blank solution, and the amount of the dissolved product of the beads after coating were calculated by the following formulas. Only when the calculated evaporation residue of the Blank solution was 0.3mg or less, the value of the amount of the dissolved product of the beads after coating was used. The amount of the eluted product of the beads after the application was measured and calculated 2 times, and when the average value thereof exceeded 1.0mg, it was judged that the elution was large, and when it was not more than 1.0mg, it was judged that the elution was small.
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 dissolution of coated beads (mg) =evaporation residue of sample solution (mg) -evaporation residue of Blank solution (mg)
1. Examples and comparative examples of the first embodiment
Examples 1 to 1
Synthesis of coated Polymer
Copolymers of 2-methoxyethyl methacrylate (MEMA, the compound of formula (i) of [ chemical formula 9 ]), N-diethylaminoethyl methacrylate (DEAEMA, the compound of formula (ii) of [ chemical formula 9 ]), and N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB, the compound of formula (iii) of [ chemical formula 9 ]) were synthesized by usual solution polymerization. The polymerization conditions were such that the concentration of each monomer was 1 mol/L in ethanol solution in the presence of Azobisisobutyronitrile (AIBN) 0.0025 mol/L as an initiator, and the polymerization was carried out at a reaction temperature of 60℃for 8 hours to obtain a polymer solution. The polymer thus obtained was dropwise added to diethyl ether, and the polymer thus precipitated was recovered. For the recovered polymer, a reprecipitation operation was performed using diethyl ether, whereby purification was performed. Then, the obtained polymer was dried under reduced pressure for 24 hours, thereby obtaining a coated polymer.
The moles of MEMA monomer units, DEAEMA monomer units, and CMB monomer units in the coating polymer were measured as follows. After the obtained coating polymer was dissolved in dimethyl sulfoxide, the reaction was carried out 1 The area ratio of 4.32ppm (derived from H atom unique to CMB) to 2.63ppm (derived from H atom unique to DEAEMA) to 0.65 to 2.15ppm (total H atom weight) in the graph calculated by the measurement by H-NMR was calculated by the following formula.
The molar ratio of DEAEMA monomer= ("area ratio of 2.63ppm region"/2)/("area ratio of 0.65 to 2.15ppm region"/5- "area ratio of 2.63ppm region" ×0.3) ×100)
Molar ratio of CMB monomer= ("area ratio of 4.32ppm region"/2)/("area ratio of 0.65-2.15ppm region"/5- "area ratio of 2.63ppm region" ×0.3) ×100)
Molar ratio of MEMA monomer = molar ratio of 100-DEAEMA monomer-molar ratio of CMB monomer
The molar ratio of MEMA monomer units, DEAEMA monomer units, and CMB monomer units in the coating polymer was calculated to be 80/10/10.
Coating liquid manufacture
After the above coating polymer was added to 70W/W% ethanol, the mixture was stirred for 12 hours, and a coating liquid having a coating polymer concentration of 0.1 wt% was prepared.
Bead manufacture
As porous beads, AMBERLITE was used TM XAD TM 1180N (manufactured by Organo Corporation, styrene-based polymer beads, volume average particle diameter 609 μm, cumulative pore volume of 5nm to 100nm, 1.472 cm) 3 Per g, cumulative pore volume of 0.020cm with pore diameter of 100nm to 200nm 3 /g)。AMBERLITE TM XAD TM 1180N of Log differential pore volume distribution and cumulative pore volume is shown in FIG. 1 and cumulative volume particle size distribution is shown in FIG. 3. 2mL (0.44 g when dried) of beads swollen with ultrapure water was added to a 15mL conical tube made of polypropylene (PP), and 10mL of 70W/W% ethanol was added thereto. After the solution was oscillated at an oscillation angle of 10℃and 40 r/min for 12 hours using an oscillator (In Vitro Shaker WAVE-S1, manufactured by TAITEC Co., ltd.), the oscillated solution was filtered using a cell filter (Mini Cell StrainerII, nylon mesh 70 μm, funakoshi Co., ltd.). The absorbance at 220nm of the filtered solution was measured by using an Shimadzu ultraviolet-visible spectrophotometer UV-2600 (manufactured by Shimadzu corporation), and the beads obtained by filtration were again added to a 15mL conical tube. This series of operations of adding 70W/W% ethanol to the conical tube, shaking the tube with a shaker for 12 hours, and removing the solution with a cell filter was repeated until the absorbance at 220nm of the filtered solution was 0.03 or less.
Coating method
10mL of the coating solution was placed in a 15mL conical tube containing 2mL of the beads obtained by the above treatment, and the mixture was oscillated at an oscillation angle of 10℃and 40 r/min for 3 hours using an oscillator (In Vitro Shaker WAVE-S1, manufactured by TAITEC Co.). The post-coating solution was then filtered through a cell filter (Mini Cell StrainerII, nylon mesh 70 μm, funakoshi co., ltd.) to obtain coated beads. The absorbance at 220nm of the post-filtration coating solution was measured by means of an Shimadzu ultraviolet-visible spectrophotometer UV-2600, and the post-filtration coated beads were again introduced into a 15mL conical tube. The coating amount (mg/bead dry g) of the beads was calculated by the following formula, and the coating amount of the coating polymer was 6 mg/bead dry g.
Weight of coating polymer in solution after treatment (mg) =weight of coating polymer in solution before treatment (mg) ×absorbance at 220nm of solution after treatment/absorbance at 220nm of solution before treatment
Coating amount (mg/bead dry g) = (weight of coating polymer in solution before treatment-weight of coating polymer in solution after treatment)/dry g using bead
Next, after drying in vacuo at 50℃for 15 hours (absolute pressure of 0.003MPa or less) in a 15mL conical tube containing the coated beads, 12mL of 20W/W% ethanol was added to the conical tube. After shaking at an shaking angle of 10℃and 40 r/min for 12 hours using a shaker (In Vitro Shaker WAVE-S1, manufactured by TAITEC Co.), the solution of the infiltrated beads was removed by using a cell strainer (Mini Cell StrainerII, nylon gauze 70 μm, funakoshi Co., ltd.), and the resultant beads were again added to a 15mL conical tube. Then, a series of operations of adding 12mL of ultrapure water to a 15mL conical tube, shaking for 3 hours by a shaker, and removing the solution by a cell filter was repeated 5 times in total. Finally, 12mL of physiological saline (injection of Otsuka physiological saline, manufactured by Otsuka pharmaceutical industry Co., ltd.) was filled into the conical tube, and sterilization was performed by gamma irradiation to obtain beads for blood treatment.
Elemental analysis of blood processing bead entity
The solution contained in 1mL of the above beads for blood treatment was removed by a cell strainer, and the resulting beads were added to a 15mL conical tube. Then, 12mL of ultrapure water was added to the 15mL conical tube, whereby the bead solution was replaced with ultrapure water. The beads for blood treatment replaced with ultrapure water were dried under vacuum at 50℃for 15 hours (absolute pressure of 0.003MPa or less). The dried beads for blood treatment were subjected to elemental analysis using an elemental analyzer (EMGA-930, manufactured by horiba, inc.). The test was analyzed by 3 samples and the average value was used. As a result, the nitrogen element ratio was 0.3 mass% or less.
XPS measurement of bead surface for blood treatment
50 beads were randomly selected from the dried beads for blood treatment, and the surface state of 1 bead was measured by XPS using K-alpha+ (manufactured by Thermo Fisher Scientific Co.) for 1 bead. The measurement conditions were irradiation of X-rays: single crystal spectroscopic AI kα, X-ray spot diameter: 150 μm, neutralizing electron gun: and (3) using. The value of the nitrogen atom existence rate relative to the total number of the uranium atoms from the lithium atom of atomic number No. 3 to the uranium atom of atomic number No. 92, which was present on the surface of these 50 beads for blood treatment, was averaged, and calculated as the nitrogen atom existence rate (%). The results are shown in Table 3.
XPS measurement of bead entirety for blood treatment
The dried beads for blood treatment were pulverized with a polishing rod to prepare a powder of the beads for blood treatment. The surface state of the powder was measured by XPS using K-alpha+ (manufactured by Thermo Fisher Scientific Co.). The measurement conditions were irradiation of X-rays: single crystal spectroscopic AI kα, X-ray spot diameter: 150 μm, neutralizing electron gun: and (3) using. The measurement was performed on 10 samples, and the value obtained by averaging the values of the nitrogen atom existence rates with respect to the total number of the lithium atoms in atomic number 3 to the uranium atoms in atomic number 92 was calculated as the nitrogen atom existence rate (%) of the whole blood treatment bead. The results are shown in Table 3.
Adsorption of beads for blood treatment
Heparin sodium (5 ten thousand units of heparin sodium injection solution/50 mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers so as to have a concentration of 2000IU/mL, and Escherichia coli O111 was added so as to have a concentration of 0.1 μg/mL: lipopolysaccharide (LPS) derived from B4 (manufactured by Sigma-Aldrich Co., ltd.) was oscillated at an oscillation angle of 10℃at 10 r/min for 24 hours using an oscillator (In Vitro Shaker WAVE-S1 manufactured by TAITEC Co.). Then, the mixture was centrifuged at 2000g for 20 minutes at room temperature using a centrifuge (hybrid high-speed cooling centrifuge 6200, manufactured by Kagaku Co., ltd.) to obtain a supernatant as a plasma sample. The obtained plasma sample (3.6 mL) and the blood treatment beads (0.45 mL, 0.10g when dried) were mixed in a 5mL tube made of polypropylene (PP), and the mixture was shaken at an oscillation angle of 10℃and 10 r/min for 2 hours at 37℃using an oscillator (the mixture was taken as a sample in contact with the beads). At this time, a sample in which beads were not added to 3.6mL of the obtained plasma sample was also prepared, and the same treatment as that performed in the presence of the sample in contact with the beads was performed (this was set as a sample in which no contact with the beads was performed). Using a centrifuge, the shaken PP-tube was centrifuged at 2000g for 1 min at room temperature to obtain a supernatant of the sample with and without contact with the beads. Using the obtained supernatant, a Bio-Plex system (Bio-Plex Pro human cytokine GI27-Plex panel, manufactured by Bio-Rad Co., ltd.) was used for each cytokine concentration, and the measurement was performed according to the accompanying processing instructions. In addition, the HMGB-1 concentration was measured using HMGB1ELISAK Kit II (manufactured by Shino-Test Corporation) according to the accompanying treatment instructions. The cytokine and HMGB-1 adsorption rate of the beads were calculated by the following formula. The results are shown in Table 1.
Various cytokine adsorption rates (%) = ("cytokine concentration of sample without contact with bead" - "cytokine concentration of sample with contact with bead present")/"cytokine concentration of sample without contact with bead" ×100)
HMGB-1 adsorption rate (%) = ("HMGB-1 concentration of sample without contact with bead" - "HMGB-1 concentration of sample with contact with bead present")/"HMGB-1 concentration of sample without contact with bead" ×100)
The concentration of cytokine not in contact with the beads and the concentration of HMGB-1 not in contact with the beads in this experiment were: IL-1b:3658pg/mL, IL-6:5540pg/mL, IL-8:6144pg/mL, IL-10:846pg/mL, TNF-. Alpha: 8085pg/mL, HMGB-1:27ng/mL.
Platelet adhesion of beads for blood treatment
Heparin sodium (5 ten thousand units per 50mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers so as to have a concentration of 1200IU/mL (heparin sodium injection solution was set as pre-treatment blood). For 4.4mL of pre-treatment blood, 0.65mL (0.15 g when dried) of the above beads for blood treatment was mixed in a 5mL tube made of polypropylene (PP). The tube was radially attached to a disk-shaped rotor having a diameter of 20cm, manufactured by titter RT-5 (titech co., ltd.) so as to extend along the radial direction of the rotor. The disk-shaped rotating body was attached so that the angle of the rotation surface became 22 degrees from horizontal, and stirred at a speed of 4rpm for 3 hours at 37 ℃. The blood after contact with the beads was filtered using a cell filter (Mini Cell StrainerII, nylon mesh 70 μm, funakoshi co., ltd.) to remove the beads (this was defined as post-treatment blood). Platelet concentration of the treated blood was measured by a micro cell counter XT-1800i (manufactured by Sysmex Co.). The results of calculating the adhesion rate of the platelets to the beads from the following formula are shown in Table 1.
Platelet adsorption ratio (%) = (platelet count of blood before treatment-platelet count of blood after treatment)/(platelet count of blood before treatment) ×100
The pre-treatment blood used in this experiment was white blood cell concentration: 4920/μl, red blood cell concentration: 430X 10 ^ 4/μl, platelet concentration: 240X 10 ^ 3/μl, hematocrit value: 38.8%. In addition, the activated clotting time of the pre-treatment blood, as measured by Hemochrom Jr. Signal+ (manufactured by International Technidyne Corporation Co., ltd., hemochron Test Cartridge JACT-LR), was 304 seconds.
Examples 1 to 2
A blood treatment bead was produced 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 nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 3
Blood treatment beads were produced in the same manner 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/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 4
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/cmb=75/25 (molar ratio), the concentration of the coating polymer using the coating liquid was 0.5 wt%, and the coating amount of the coating polymer was 31 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 5
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/cmb=75/25 (molar ratio), the concentration of the coating polymer using the coating liquid was 0.033 wt%, and the coating amount of the coating polymer was 2.4 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 6
Blood treatment beads were produced in the same manner 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/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 7
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/DEAEMA/AAc (acrylic acid, [ compound of formula (iv) of chemical formula 9 ]) =60/28/12 (molar ratio), and the coating amount of the coating polymer was 8 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 8
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/DEAEMA/aac=71/15/14 (molar ratio), and the coating amount of the coating polymer was 5 mg/dry g of the beads. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 9
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/DEAEMA/MAc (methacrylic acid, [ compound of formula (v) of chemical formula 9 ]) =62/15/23 (molar ratio), and the coating amount of the coating polymer was 4 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 10
Blood treatment beads were produced 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/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 11
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was BMA (n-butyl methacrylate, [ compound of formula (vi) of chemical formula 9 ])/DEAEMA/cmb=80/10/10 (molar ratio), 100W/W% ethanol was used as a solution of the coating polymer instead of 70W/W% ethanol, and the coating amount of the coating polymer was 4 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 12
A blood treatment bead was produced 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/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 13
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was LMA (lauryl methacrylate, [ compound of formula 9] of structural formula (vii)/DEAEMA/cmb=80/10/10 (molar ratio), 100W/W% of n-butanol was used as a solution of the coating polymer instead of 70W/W% of ethanol, and the coating amount of the coating polymer was 4 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 14
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was LMA/DEAEMA/cmb=60/20/20 (molar ratio), 100W/W% of n-butanol was used as a solution of the coating polymer instead of 70W/W% of ethanol, and the coating amount of the coating polymer was 4 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 15
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was LMA/DEAEMA/cmb=40/30/30 (molar ratio), and that 100W/W% ethanol was used as a solution of the coating polymer instead of 70W/W% ethanol. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 16
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was LMA/cmb=70/30 (molar ratio), 100W/W% ethanol was used as a solution of the coating polymer instead of 70W/W% ethanol, and the coating amount of the coating polymer was 5 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 17
Blood treatment beads were produced in the same manner 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/dry g of the beads. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 18
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/MPC (2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, [ compound of formula (viii) of chemical formula 9 ])=85/15 (molar ratio), and the coating amount of the coating polymer was 7 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 19
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEMA/DMAEMA (dimethylaminoethyl methacrylate, [ compound of formula 9] having the structural formula (ix)) =80/20 (molar ratio), and the coating amount of the coating polymer was 9 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Examples 1 to 20
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 (manufactured by Purolite Ltd., acrylic polymer beads, volume average particle diameter 621 μm, cumulative pore volume of 5nm to 100nm, 0.823 cm) 3 Per g, cumulative pore volume of 0.038cm with pore diameter of 100nm to 200nm 3 Per g), and the coating amount of coating polymer was 14mg per bead dry g, exceptA bead for blood treatment was prepared in the same manner as in example 1-1. Purosorb TM A plot of Log differential pore volume distribution and cumulative pore volume of PAD950 is shown in fig. 2, and a plot of cumulative volume particle size distribution is shown in fig. 3. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 21
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in examples 1-2, except that PAD950 and the coating amount of the coating polymer were 13 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Examples 1 to 22
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in examples 1 to 3, except that PAD950 and the coating amount of the coating polymer were 6 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Examples 1 to 23
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in examples 1 to 4, except that PAD950 and the coating amount of the coating polymer were 19 mg/bead dry g. Elemental separation was carried out in the same manner as in example 1-1 As a result of the analysis, the nitrogen element content was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Examples 1 to 24
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in examples 1 to 6, except that PAD950 and the coating amount of the coating polymer were 16 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Examples 1 to 25
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in examples 1 to 7, except that PAD950 and the coating amount of the coating polymer were changed to 13 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Examples 1 to 26
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in examples 1 to 10, except that PAD950 and the coating amount of the coating polymer were 15 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 1
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEA (2-methoxyethyl acrylate, [ compound of formula (x) of chemical formula 9 ])/DEAEMA/cmb=80/10/10 (molar ratio), the concentration of the coating polymer using the coating liquid was 0.3 wt%, and the coating amount of the coating polymer was 55 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Comparative examples 1 to 2
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was MEA/DEAEMA/cmb=80/10/10 (molar ratio), the concentration of the coating polymer using the coating liquid was 0.5 wt%, and the coating amount of the coating polymer was 94 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 3
A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was BA (butyl acrylate, [ compound of formula 9] of structural formula (xi) =100 (molar ratio), and the coating amount of the coating polymer was 16 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 4
Blood treatment beads were produced in the same manner as in example 1-1, except that the composition of the coating polymer was BA/DEAEMA/cmb=60/20/20 (molar ratio), and the coating amount of the coating polymer was 12 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 5
(Synthesis of coating Polymer)
Into a 3-neck eggplant-shaped flask was charged 7.50g (MC 3A, [ chemical formula 9 ] of 3-methoxypropyl acrylate]A compound of formula (xii), 30.2g of 1, 4-dioxane and 7.5mg of Azobisisobutyronitrile (AIBN). The reaction system was purged with nitrogen gas by stirring for 30 minutes while flowing dry nitrogen gas into the reaction solution. The mixture was immersed in an oil bath at a temperature of 75℃in the lower portion of a 3-necked eggplant-shaped flask, and stirred under a nitrogen flow for 6 hours, thereby conducting polymerization. The polymerization reaction proceeds by 1 H NMR confirmed that the reaction was stopped by naturally cooling the polymerization system to room temperature after confirming a sufficiently high reaction conversion (about 90%). 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 recovered. After dissolution in tetrahydrofuran, the reprecipitation with hexane was repeated 2 times to purify the precipitate, and the obtained precipitate was stirred in water for 24 hours. The water was removed by decantation, and the precipitate was dissolved in tetrahydrofuran and recovered. The solvent was distilled off under reduced pressure and then dried with a vacuum dryer to obtain a polymer. The molecular weight was measured using a part of the obtained polymer, and as a result, the number average molecular weight (Mn) was 31000 and the molecular weight distribution (Mw/Mn) was 2.5.
Using the above-mentioned coating polymer, coating of beads was carried out in the same manner as in example 1-1, and 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 nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 6
Blood treatment beads were produced in the same manner as in comparative examples 1 to 5, except that the concentration of the coating polymer using the coating liquid was 0.5% by weight, and the coating amount of the coating polymer was 91 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 7
(Synthesis of coating Polymer)
Synthesis was carried out by the same procedure as in comparative examples 1 to 5 except that 15g of 2-methoxyethyl acrylate (MEA), 60g of 1, 4-dioxane and 15mg of azobisisobutyronitrile were used as initiators and polymerized at 75℃for 10 hours. As a result of molecular weight analysis by GPC, the number average molecular weight (Mn) was 20000 and the molecular weight distribution (Mw/Mn) was 2.4.
Using the above-mentioned coating polymer, coating of beads was carried out in the same manner as in example 1-1, and 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 nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Comparative examples 1 to 8
Blood treatment beads were produced in the same manner as in comparative examples 1 to 7, except that the concentration of the coating polymer using the coating liquid was 0.3% by weight, and the coating amount of the coating polymer was 56 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 9
Blood treatment beads were produced in the same manner as in comparative examples 1 to 7, except that the concentration of the coating polymer using the coating liquid was 0.5% by weight, and the coating amount of the coating polymer was 97 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Comparative examples 1 to 10
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM A blood treatment bead was produced in the same manner as in example 1-1, except that the composition of the coating polymer was PAD950, MEA/DEAEMA/cmb=80/10/10 (molar ratio), and the coating amount of the coating polymer was 20 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 11
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 2 except that PAD950 and the coating amount of the coating polymer were 63 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 12
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 5, except that PAD950 and the coating amount of the coating polymer were 24 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 13
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 6, except that PAD950 and the coating amount of the coating polymer were 114 mg/bead dry g. Elemental analysis was performed by the same method as in example 1-1, resulting in a nitrogen element ratioIs 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 14
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 7, except that PAD950 and the coating amount of the coating polymer were 23 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 15
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 8, except that PAD950 and the coating amount of the coating polymer were 70 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 16
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 9, except that PAD950 and the coating amount of the coating polymer were 107 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Comparative examples 1 to 17
A blood treatment bead was produced in the same manner as in example 1-1, except that PVP (manufactured by polyvinylpyrrolidone K90, FUJIFILM Wako Pure Chemical Corporation) was used as the coating polymer, the concentration of the coating polymer using the coating liquid was 0.5 wt%, and the coating amount of the coating polymer was 35 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1.
Comparative examples 1 to 18
A blood treatment bead was produced in the same manner as in example 1-1, except that the concentration of the coating polymer using the coating liquid was 0% by weight, and the coating amount of the coating polymer was 0 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 1. The results obtained by XPS measurement of the bead surface and XPS measurement of the whole bead were shown in Table 3, in the same manner as in example 1-1.
Comparative examples 1 to 19
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM Blood treatment beads were produced in the same manner as in comparative examples 1 to 17, except that PAD950 and the coating amount of the coating polymer were 34 mg/bead dry g. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2.
Comparative examples 1 to 20
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 blood treatment beads were produced in the same manner as in comparative examples 1 to 18. Elemental analysis was performed in the same manner as in example 1-1, and as a result, the nitrogen element ratio was 0.3 mass% or less. The results of the cytokine adsorption performance evaluation and the platelet adhesion evaluation performed by the same method as in example 1-1 are shown in Table 2. Benefit (benefit) XPS measurement of the bead surface and XPS measurement of the bead as a whole were performed in the same manner as in example 1-1, and the results obtained are shown in Table 3.
The composition of the biocompatible polymer (coating agent), the type of porous beads, the loading amount (coating amount) of the biocompatible polymer, the biocompatibility (platelet adhesion amount) of the beads for blood treatment, and the cytokine adsorptivity of the beads for blood treatment in the examples and comparative examples of the first embodiment are shown in tables 1 and 2 below. The atomic ratios of the surface and the whole of the beads for blood treatment in examples and comparative examples, based on XPS measurement, are shown in table 3 below.
The ratio of nitrogen element based on elemental analysis of the beads for blood treatment used in the examples and comparative examples of the first embodiment is 0.3 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 is 99.0 mass% or more based on the elemental analysis of the beads for blood treatment.
TABLE 1
Figure BDA0002916766810000461
TABLE 2
Figure BDA0002916766810000471
TABLE 3
Figure BDA0002916766810000481
[ chemical formula 9]
Figure BDA0002916766810000491
Referring to tables 1 and 2, it is understood that the beads for blood treatment of examples have a smaller amount of biocompatible polymer than the beads for blood treatment of comparative examples, and have improved blood compatibility while maintaining high adsorptivity of porous beads.
The biocompatible polymers of examples 1-1 to 1-19 of Table 1 had platelet adhesion rates of all 14% or less even when the coating amount was 11mg or less. In contrast, when the coating amount of the biocompatible polymers of comparative examples 1-1 to 1-5 and 1-7 and 1-18 was 21mg or less, the platelet adhesion rate was 15% or more. When the coating amount was 50mg or more as in comparative examples 1 to 6, 1 to 8 and 1 to 9, the platelet adhesion rate was 14% or less, but the cytokine adsorption amount was significantly reduced. Similarly, the polymers of examples 1-20 to 1-26 of Table 2 had platelet adhesion rates of 8% or less in all cases even when the coating amount was 20mg or less. In contrast, the polymers of comparative examples 1-10 to 1-16 and 1-20 had platelet adhesion rates of all 10% or more even when the coating amount was 20mg or more.
Referring to tables 1 to 3, it is understood that the beads for blood treatment of examples 1-1, 1-3 to 1-6, 1-8, 1-12, 1-15, 1-18, 1-20 and 1-22 have a smaller loading of the biocompatible polymer, have higher adsorptivity of porous beads and have improved blood compatibility than the beads for blood treatment of comparative example, by setting the total number of atoms from atomic number 3 to 92 as a reference, and the ratio of nitrogen atoms present on the surface of the beads for blood treatment to be 0.2% or more and 0.7% or less by atomic percentage.
2. Examples and comparative examples of the second embodiment
Examples 2 to 1
Synthesis of coated Polymer
Copolymers of 2-methoxyethyl methacrylate (MEMA, the compound of formula (i) of [ chemical formula 10 ]), N-diethylaminoethyl methacrylate (DEAEMA, the compound of formula (ii) of [ chemical formula 10 ]), and N-methacryloyloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine (CMB, the compound of formula (iii) of [ chemical formula 10 ]) were synthesized by usual solution polymerization. The polymerization conditions were such that the concentration of each monomer was 1 mol/L in ethanol solution in the presence of Azobisisobutyronitrile (AIBN) 0.0025 mol/L as an initiator, and the polymerization was carried out at a reaction temperature of 60℃for 8 hours to obtain a polymer solution. The polymer thus obtained was dropwise added to diethyl ether, and the polymer thus precipitated was recovered. For the recovered polymer, a reprecipitation operation was performed using diethyl ether, whereby purification was performed. Then, the obtained polymer was dried under reduced pressure for 24 hours, thereby obtaining a coated polymer.
The moles of MEMA monomer units, DEAEMA monomer units, and CMB monomer units in the coating polymer were measured as follows. After the obtained coating polymer was dissolved in dimethyl sulfoxide, the reaction was carried out 1 The area ratio of 4.32ppm (derived from H atom unique to CMB) to 2.63ppm (derived from H atom unique to DEAEMA) to 0.65 to 2.15ppm (total H atom weight) in the graph calculated by the measurement by H-NMR was calculated by the following formula.
The molar ratio of DEAEMA monomer= ("area ratio of 2.63ppm region"/2)/("area ratio of 0.65 to 2.15ppm region"/5- "area ratio of 2.63ppm region" ×0.3) ×100)
Molar ratio of CMB monomer= ("area ratio of 4.32ppm region"/2)/("area ratio of 0.65-2.15ppm region"/5- "area ratio of 2.63ppm region" ×0.3) ×100)
Molar ratio of MEMA monomer = molar ratio of 100-DEAEMA monomer-molar ratio of CMB monomer
The molar ratio of MEMA monomer units, DEAEMA monomer units, and CMB monomer units in the coating polymer was calculated to be 80/10/10.
Coating liquid manufacture
After the above coating polymer was added to 57W/W% ethanol, the mixture was stirred for 12 hours, and a coating liquid having a coating polymer concentration of 0.2 wt% was prepared.
Bead manufacture
As porous beads, AMBERLITE was used TM XAD TM 1180N (manufactured by Organo Corporation, styrene-based polymer beads, volume average particle diameter 609 μm, cumulative pore volume of 5nm to 100nm, 1.472 cm) 3 Per g, cumulative pore volume of 0.020cm with pore diameter of 100nm to 200nm 3 /g)。AMBERLITE TM XAD TM 1180N Log differential pore volume distribution and cumulative pore volume are shown in FIG. 1A graph of the cumulative volume particle size distribution is shown in FIG. 3. 8mL of beads swollen with ultrapure water (1.76 g when dried) was added to a 50mL conical tube made of polypropylene (PP), and 40mL of 57W/W% ethanol was added. After shaking at an shaking angle of 10℃and 40 r/min for 12 hours using a shaker (In Vitro Shaker WAVE-S1, manufactured by TAITEC Co.), the shaking solution was filtered using a Cell filter (Cell filter, nylon mesh 70 μm, funakoshi Co., ltd.). The absorbance at 220nm of the filtered solution was measured by using an Shimadzu ultraviolet-visible spectrophotometer UV-2600 (manufactured by Shimadzu corporation), and the beads obtained by filtration were again added to a 50mL conical tube. This series of operations of adding 57W/W% ethanol to the conical tube, shaking the tube with a shaker for 12 hours, and removing the solution with a cell filter was repeated until the absorbance at 220nm of the filtered solution was 0.03 or less.
Production of coated beads
40mL of the coating solution was placed in a 50mL conical tube containing the beads obtained by the above treatment, and the tube was oscillated at an oscillation angle of 10℃and 40 r/min for 12 hours using an oscillator (In Vitro Shaker WAVE-S1, manufactured by TAITEC Co.). The post-coating solution was then filtered using a Cell filter (Cell filter, nylon mesh 70 μm, funakoshi co., ltd.) to obtain coated beads. The absorbance at 220nm of the post-filtration coating solution was measured by means of an Shimadzu ultraviolet-visible spectrophotometer UV-2600, and the coated beads obtained by filtration were again introduced into a 50mL conical tube.
Then, after drying the 50mL conical tube containing the coated beads in vacuo at 50℃for 15 hours (absolute pressure of 0.003MPa or less), 40mL of 20W/W% ethanol was added to the conical tube. After shaking at an oscillation angle of 10℃and 40 r/min for 12 hours using a shaker (In Vitro Shaker WAVE-S1, manufactured by TAITEC Co.), the solution impregnated with the beads was removed by a Cell Strainer (Cell Strainer, nylon mesh 70 μm, manufactured by Funakoshi Co., ltd.), and the resultant beads were again added to a 50mL conical tube. Then, a series of operations of adding 40mL of ultrapure water to a 50mL conical tube, shaking for 3 hours by a shaker, and removing the solution by a cell filter was repeated 3 times in total to obtain coated beads. The amount of the eluted product of the coated beads was 1.0mg or less, and the amount of the eluted product was small.
Bead for blood treatment
The 3mL of the coated beads described above were added to a 15mL conical tube. Then, a series of operations of adding 12mL of ultrapure water to a 15mL conical tube, shaking for 3 hours by a shaker, and removing the solution by a cell filter was repeated 2 times in total. Finally, 12mL of physiological saline (a physiological saline injection solution of Otsuka, manufactured by Otsuka pharmaceutical industry Co., ltd.) was filled into the conical tube, and sterilization was performed by gamma ray irradiation to obtain beads for blood treatment.
Physical Property measurement of beads for blood treatment
Elemental analysis of blood processing bead entity
The solution contained in 1mL of the above beads for blood treatment was removed by a cell strainer, and the resulting beads were added to a 15mL conical tube. Then, 12mL of ultrapure water was added to the 15mL conical tube, whereby the bead solution was replaced with ultrapure water. The beads for blood treatment replaced with ultrapure water were dried under vacuum at 50℃for 15 hours (absolute pressure of 0.003MPa or less). The dried beads for blood treatment were subjected to elemental analysis using an elemental analyzer (EMGA-930, manufactured by horiba, inc.). The test was analyzed by 3 samples and the average value was used. As a result, the nitrogen element ratio was 0.3 mass% or less.
XPS measurement of bead surface for blood treatment
50 beads were randomly selected from the dried beads for blood treatment, and the surface state of 1 bead was measured by XPS using K-alpha+ (manufactured by Thermo Fisher Scientific Co.) for 1 bead. The measurement conditions were irradiation of X-rays: single crystal spectroscopic AI kα, X-ray spot diameter: 150 μm, neutralizing electron gun: and (3) using. The value of the nitrogen atom existence rate relative to the total number of the uranium atoms from the lithium atom of atomic number No. 3 to the uranium atom of atomic number No. 92, which was present on the surface of these 50 beads for blood treatment, was averaged, and calculated as the nitrogen atom existence rate (%). The results are shown in Table 6.
XPS measurement of bead entirety for blood treatment
The dried beads for blood treatment were pulverized with a polishing rod to prepare a powder of the beads for blood treatment. The surface state of the powder was measured by XPS using K-alpha+ (manufactured by Thermo Fisher Scientific Co.). The measurement conditions were irradiation of X-rays: single crystal spectroscopic AI kα, X-ray spot diameter: 150 μm, neutralizing electron gun: and (3) using. The measurement was performed on 10 samples, and the value obtained by averaging the values of the nitrogen atom existence rates with respect to the total number of the lithium atoms in atomic number 3 to the uranium atoms in atomic number 92 was calculated as the nitrogen atom existence rate (%) of the whole blood treatment bead. The results are shown in Table 6.
Platelet adhesion by flow-through evaluation method for blood treatment beads
FIG. 4 is a schematic diagram for explaining a method of evaluating platelet adhesion. 1.5mL (0.33 g when dried) of the beads for blood treatment was swelled with physiological saline (an injection of Otsuka physiological saline, manufactured by Otsuka pharmaceutical Co., ltd.), and the swelled beads (11) for blood treatment was filled into a 2.5mL syringe without introducing air. At this time, the upper and lower sides of the beads for blood treatment are sandwiched between the net (12) and the O-ring (13) as shown in FIG. 4 so that the beads do not leak. A mini column (10) containing 1.5mL of beads for blood treatment was prepared.
Heparin sodium (5 ten thousand units per 50mL, manufactured by Nipro Corporation) was added to blood collected from healthy volunteers so as to have a concentration of 1000IU/mL (this was referred to as "blood before treatment (21)"). Then, as shown in FIG. 4, an experimental circuit was assembled, and physiological saline (an injection solution of Otsuka physiological saline, manufactured by Otsuka pharmaceutical manufacturing Co., ltd.) was circulated at a flow rate of 1 mL/min for 10 minutes using a syringe pump (20) (manufactured by TE-351, TERUMO CORPORATION) in a mini column (10) in which beads for blood treatment were incorporated. The pre-treatment blood (21) was then circulated at a flow rate of 1 mL/min by using a syringe pump (20) (TE-351, TERUMO CORPORATION). After 2 minutes from the start of the flow of the blood before the treatment, the blood after the flow of the mini column was collected in a 15mL conical tube (30), and the flow of the blood was terminated at the point when the collected blood (this was designated as "blood after treatment (31)") was 9 mL. Platelet concentrations of the post-treatment blood and the pre-treatment blood were measured by a micro cell counter XT-1800i (manufactured by Sysmex Co.). The residual ratio of the platelets to the beads was calculated from the following formula, and found to be 85%. By the above method, when the platelet remaining ratio is 80% or less, it is determined that the platelet adhering amount of the blood processing beads is large, and when the platelet remaining ratio is higher than 80%, it is determined that the platelet adhering amount of the blood processing beads is small.
Platelet residual ratio (%) =platelet count of post-treatment blood/platelet count of pre-treatment blood×100
The pre-treatment blood used in this experiment was white blood cell concentration: 5310/μl, red blood cell concentration: 505×10 ^ 4/μl, platelet concentration: 196X 10 ^ 3/μl, hematocrit value: 41.0%. The activated clotting time of the pre-treatment blood, as measured by Hemochromon Jr.Signature+ (manufactured by International Technidyne Corporation Co., ltd., hemochron Test Cartridge JACT-LR), was 319 seconds
Examples 2 to 2
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/cmb=90/10 (molar ratio). As a result of measuring the amount of eluted beads after coating in the same manner as in example 2-1, the amount of eluted beads was 1.0mg or less, and the amount of eluted beads was small. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 83% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Adsorption of beads for blood treatment
After heparin sodium (5 ten thousand units of heparin sodium injection solution/50 mL, nipro Corporation) was added to blood collected from healthy volunteers so as to have a concentration of 2000IU/mL, escherichia coli O111 was added so as to have a concentration of 0.1 μg/mL: lipopolysaccharide (LPS) derived from B4 (manufactured by Sigma-Aldrich Co., ltd.) was oscillated at an oscillation angle of 10℃at 10 r/min for 24 hours using an oscillator (In Vitro Shaker WAVE-S1 manufactured by TAITEC Co.). Then, the mixture was centrifuged at 2000g for 20 minutes at room temperature using a centrifuge (hybrid high-speed cooling centrifuge 6200, manufactured by Kagaku Co., ltd.) to obtain a supernatant as a plasma sample. The obtained plasma sample (3.6 mL) and the blood treatment beads (0.45 mL, 0.10g when dried) were mixed in a 5mL tube made of polypropylene (PP), and the mixture was shaken at an oscillation angle of 10℃and 10 r/min for 2 hours at 37℃using an oscillator (the mixture was taken as a sample in contact with the beads). At this time, a sample in which beads were not added to 3.6mL of the obtained plasma sample was also prepared, and the same treatment as that performed in the presence of the sample in contact with the beads was performed (this was set as a sample in which no contact with the beads was performed). For the PP tube after shaking, centrifugation was performed at 2000g for 1 minute at room temperature using a centrifuge to obtain a supernatant of the sample in which the contact with the beads was present and the contact with the beads was not present. Using the obtained supernatant, a Bio-Plex system (Bio-Plex Pro human cytokine GI27-Plex panel, manufactured by Bio-Rad Co., ltd.) was used for each cytokine concentration, and the measurement was performed according to the accompanying processing instructions. In addition, the HMGB-1 concentration was measured using HMGB1 ELISAK Kit II (manufactured by Shino-Test Corporation) according to the accompanying treatment instructions. The cytokine and HMGB-1 adsorption rate of the beads were calculated by the following formula. The results are shown in Table 5.
Various cytokine adsorption rates (%) = ("cytokine concentration of sample without contact with bead" - "cytokine concentration of sample with contact with bead present")/"cytokine concentration of sample without contact with bead" ×100)
HMGB-1 adsorption rate (%) = ("HMGB-1 concentration of sample without contact with bead" - "HMGB-1 concentration of sample with contact with bead present")/"HMGB-1 concentration of sample without contact with bead" ×100)
The concentration of cytokine not in contact with the beads and the concentration of HMGB-1 not in contact with the beads in this experiment were: IL-1b:3658pg/mL, IL-6:5540pg/mL, IL-8:6144pg/mL, IL-10:846pg/mL, TNF-. Alpha: 8085pg/mL, HMGB-1:27ng/mL.
Examples 2 to 3
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/cmb=80/20 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 89%, and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6. The results of the cytokine adsorption performance evaluation performed by the same method as in example 2-2 are shown in Table 5.
Examples 2 to 4
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/cmb=70/30 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 89%, and the platelet adhesion amount was small.
Examples 2 to 5
The coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/MPC (2- (methacryloyloxy) ethyl 2- (trimethylammonio) ethyl phosphate, [ compound of formula (iv) of chemical formula 10 ])=85/15 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 83% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Examples 2 to 6
The coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/SPB ([ 2- (methacryloyloxy) ethyl ] dimethyl- (3-sulfopropyl) ammonium hydroxide [ compound of formula (v) of chemical formula 10) ]=88/12 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 84% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Examples 2 to 7
The same coated beads and blood treatment beads as in example 2-1 were produced except that the composition of the coating polymer was MEMA/spb=70/30 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 87% and the platelet adhesion amount was small.
Examples 2 to 8
The coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/SPBA ([ 3- (methacryloylamino) propyl ] dimethyl (3-sulfopropyl) ammonium hydroxide, [ compound of formula (vi) of chemical formula 10) ]=88/12 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 83% and the platelet adhesion amount was small.
Examples 2 to 9
Coated beads and beads for blood treatment were prepared in the same manner as in example 2-1, except that the composition of the coating polymer was MEA (2-methoxyethyl acrylate, [ compound of formula 10] of structural formula (vii))/cmb=70/30 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 85% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6. The results of the cytokine adsorption performance evaluation performed by the same method as in example 2-2 are shown in Table 5.
Examples 2 to 10
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MC3A (3-methoxypropyl acrylate, [ compound of formula 10] of structural formula (viii)/cmb=70/30 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 87% and the platelet adhesion amount was small.
Examples 2 to 11
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was Et2A (2-ethoxyethoxy) ethyl acrylate, [ compound of formula (ix) of chemical formula 10 ])/cmb=70/30 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the rate of remaining platelets was 86%, and the amount of platelets adhered was small.
Examples 2 to 12
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 (manufactured by Purolite Ltd., acrylic polymer beads, volume average particle diameter 621 μm, cumulative pore volume of 5nm to 100nm, 0.823 cm) 3 Per g, cumulative pore volume of 0.038cm with pore diameter of 100nm to 200nm 3 Per g), the same coated beads and beads for blood treatment as in example 2-1 were prepared. Purosorb TM A plot of Log differential pore volume distribution and cumulative pore volume of PAD950 is shown in fig. 2, and a plot of cumulative volume particle size distribution is shown in fig. 3. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 91% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Examples 2 to 13
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950, coated beads and beads for blood treatment were prepared in the same manner as in example 2-1 except that the composition of the coating polymer was MEMA/DEAEMA/CMB=60/20/20 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of performing elemental analysis of the beads for blood treatment by the same method as in example 2-1, the ratio of nitrogen element was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the rate of remaining platelets was 86%, and the amount of platelets adhered was small.
Examples 2 to 14
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 was prepared as a coated bead and a bead for blood treatment in the same manner as in examples 2 to 3. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 87% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Examples 2 to 15
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 was prepared as coated beads and beads for blood treatment in the same manner as in examples 2 to 7. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 85% and the platelet adhesion amount was small.
Examples 2 to 16
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 was prepared as coated beads and beads for blood treatment in the same manner as in examples 2 to 9. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. Benefit (benefit)As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 85% and the platelet adhesion amount was small. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6. The results of the cytokine adsorption performance evaluation performed by the same method as in example 2-2 are shown in Table 5.
Examples 2 to 17
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 was prepared as coated beads and beads for blood treatment in the same manner as in examples 2 to 10. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 88%, and the platelet adhesion amount was small.
Comparative examples 2 to 1
A coated bead and a blood treatment bead were produced in the same manner as in example 2-1, except that the concentration of the coating polymer using the coating liquid was 0% by weight (the coating polymer was not dissolved). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 74% and the platelet adhesion amount was large. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6. The results of the cytokine adsorption performance evaluation performed by the same method as in example 2-2 are shown in Table 5.
Comparative examples 2 to 2
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was mema=100 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 79%, and the platelet adhesion amount was large. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6. The results of the cytokine adsorption performance evaluation performed by the same method as in example 2-2 are shown in Table 5.
Comparative examples 2 to 3
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/cmb=95/5 (molar ratio). As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the platelet residual rate was 79%, and the platelet adhesion amount was large. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Comparative examples 2 to 4
Coated beads and blood treatment beads were produced in the same manner as in example 2-1, except that the composition of the coating polymer was MEMA/cmb=60/40 (molar ratio). As a result of measurement of the eluted fraction of the beads after coating in the same manner as in example 2-1, 1.2mg of the eluted fraction was found to be excessive. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less.
Comparative examples 2 to 5
Coated beads and blood treatment beads were produced in the same manner as in example 2-1 except that the composition of the coating polymer was MEA/DEAEMA/CMB=40/20/40 (molar ratio). As a result of measurement of the eluted fraction of the beads after coating in the same manner as in example 2-1, 1.4mg of the eluted fraction was found to be more. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Comparative examples 2 to 6
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 was prepared as a coated bead and a bead for blood treatment in the same manner as in comparative example 2-1. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. As a result of evaluation of platelet adhesion by the same method as in example 2-1, the rate of remaining platelets was 80%, and the amount of platelets adhered was large. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6. The results of the cytokine adsorption performance evaluation performed by the same method as in example 2-2 are shown in Table 5.
Comparative examples 2 to 7
As beads, replacing AMBERLITE TM XAD TM 1180N, selected from Purosorb TM PAD950 was prepared as coated beads and beads for blood treatment in the same manner as in comparative examples 2 to 5. As a result of measurement of the eluted fraction of the beads after coating in the same manner as in example 2-1, 1.4mg of the eluted fraction was found to be more. As a result of the elemental analysis of the beads for blood treatment performed in the same manner as in example 2-1, the nitrogen element ratio was 0.3 mass% or less. The results of XPS measurement of the bead surface and XPS measurement of the whole bead were obtained by the same method as in example 2-1 and are shown in Table 6.
Comparative examples 2 to 8
(Synthesis of beads)
Comprises 100g of vinyl acetate, 64.3g of triallyl isocyanurate, 100g of ethyl acetate, 100g of heptane, 7.5g of polyvinyl acetate (polymerization degree 500) and azobisisobutyronitrileA homogeneous mixture of 3.8g of nitrile (AIBN), and 400mL of ultrapure water in which 1% by weight of polyvinyl alcohol (saponification rate 87-89%), 0.05% by weight of sodium dihydrogen phosphate dihydrate and 1.5% by weight of disodium hydrogen phosphate dodecahydrate were dissolved were added to a flask, and the mixture was stirred well while heating at 65℃for 18 hours and then at 75℃for 5 hours, to thereby carry out suspension polymerization. The granular copolymer obtained by filtering the solution was washed with ultrapure water, and then washed with acetone extraction. Finally, the washed particulate copolymer was stirred in a solution containing 46.5g of caustic soda and 2L of methanol at 40℃for 18 hours to thereby obtain PVA based polymer beads (volume average particle diameter 110 μm, cumulative pore volume of 5nm to 100nm, 0.270 cm) 3 Per g, cumulative pore volume of 0.005cm with pore diameter of 100nm to 200nm 3 /g or less).
As beads, replacing AMBERLITE TM XAD TM 1180N, the same coated beads as in comparative example 2-1 were produced, except that the PVA based polymer beads obtained above were selected. The elution of beads was determined by the same method as in example 2-1, and as a result, the elution amount was low and was 1.0mg or less.
Comparative examples 2 to 9
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in example 2-1, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 1.8mg, and the amount of eluted was large.
Comparative examples 2 to 10
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 3, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 2.0mg, and the amount of eluted was large.
Comparative examples 2 to 11
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 4, except that the PVA based polymer beads obtained above were selected. The elution of the beads was judged by the same method as in example 2-1,as a result, the amount of eluted was 2.3mg, and the amount of eluted was large.
Comparative examples 2 to 12
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 6, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 1.9mg, and the amount of eluted was large.
Comparative examples 2 to 13
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 7, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 2.2mg, and the amount of eluted was large.
Comparative examples 2 to 14
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 8, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 2.1mg, and the amount of eluted was large.
Comparative examples 2 to 15
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 9, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 1.3mg, and the amount of eluted was large.
Comparative examples 2 to 16
Use as beads instead of AMBERLITE TM XAD TM 1180N, coated beads were prepared in the same manner as in examples 2 to 10, except that the PVA based polymer beads obtained above were selected. The elution of beads was judged by the same method as in example 2-1, and as a result, the elution amount was 1.2mg, and the amount of eluted was large.
Comparative examples 2 to 17
As beads, replacing AMBERLITE TM XAD TM 1180N, selecting activated carbon beads (KUREHA CORPORATION cumulative pores with average particle diameter of 576 μm and pore diameter of 5 nm-100 nm)Capacity of 0.134cm 3 Per g, cumulative pore volume of 0.005cm with pore diameter of 100nm to 200nm 3 Per g or less), the coated beads were produced in the same manner as in comparative example 2-1. As a result of measurement of the elution product of the beads after coating in the same manner as in example 2-1, the amount of the elution product was 1.0mg or less.
Comparative examples 2 to 18
As beads, replacing AMBERLITE TM XAD TM 1180N, activated carbon beads (KUREHA CORPORATION, average particle size 576 μm, cumulative pore volume of 5 nm-100 nm, 0.134 cm) 3 Per g, cumulative pore volume of 0.005cm with pore diameter of 100nm to 200nm 3 Per g or less), the coated beads were produced in the same manner as in examples 2 to 4. As a result of measurement of the eluted fraction of the beads after coating in the same manner as in example 2-1, 1.2mg of the eluted fraction was found to be excessive.
The composition of the biocompatible polymer (coating agent), the type of porous beads, the measurement result of the elution product of the coated beads, and the biocompatibility (platelet adhesion amount) of the beads for blood treatment in the examples and comparative examples of the second embodiment are shown in tables 4 and 5 below. The atomic ratios of the surface and the whole of the beads for blood treatment in examples and comparative examples, based on XPS measurement, are shown in table 6 below.
The ratio of nitrogen element based on elemental analysis of the beads for blood treatment used in the examples and comparative examples of the second embodiment is 0.3 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 is 99.0 mass% or more based on the elemental analysis of the beads for blood treatment.
TABLE 4
Figure BDA0002916766810000661
TABLE 5
Figure BDA0002916766810000671
TABLE 6
Figure BDA0002916766810000681
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Figure BDA0002916766810000691
Industrial applicability
The beads for blood treatment of the present invention can be used for treating ischemic diseases typified by sepsis, for example. In addition, the blood processing beads of the present invention are expected to be effectively used in a scenario where excessive production of inflammatory mediators such as cardiac surgery and organ transplantation surgery is a problem, in addition to treatment of ischemic diseases.
Description of the reference numerals
10. Mini column
11. Bead for blood treatment
12. Net
13 O-ring
20. Injection pump
21. Pretreatment blood
30. Conical tube
31. Post-treatment blood

Claims (16)

1. A bead for blood treatment having a porous bead and a polymer coated on the surface of the porous bead,
the porous beads are composed of at least one resin selected from the group consisting of acrylic resins, styrene resins, and cellulose resins,
The polymer contains a zwitterionic monomer as a monomer unit,
the zwitterionic monomer is 10 mol% or more and 30 mol% or less based on the total monomers constituting the polymer,
the ratio of nitrogen atoms on the surface of the blood treatment bead is 0.2% to 0.9% by atomic percentage based on the total number of atoms from atomic number No. 3 to atomic number 92.
2. The bead for blood treatment according to claim 1, wherein the porous bead has a cumulative pore volume of 0.5cm and a pore diameter of 5nm to 100nm 3 The cumulative pore volume of the pore diameter of 100nm to 200nm is 0.2cm per gram 3 And/g or less.
3. The bead for blood treatment according to claim 1, wherein the porous bead has a volume average particle diameter of 300 μm to 1000 μm.
4. The blood processing bead of claim 1 that removes hydrophobic protein molecules from blood that exceed 1000Da and are less than 66000 Da.
5. The bead for blood treatment according to claim 4, which removes cytokines and high mobility group box B1 (HMGB 1) from blood.
6. The bead for blood treatment according to claim 1, wherein the porous bead has a cumulative pore volume of 0.5cm and a pore diameter of 5nm to 100nm 3 The cumulative pore volume of the pore diameter of 100nm to 200nm is 0.2cm per gram 3 And/g or less, wherein the porous beads have a volume average particle diameter of 300-1000 [ mu ] m, and the blood processing beads remove cytokines and high mobility group box B1 (HMGB 1) from blood.
7. The bead for blood treatment according to any one of claims 1 to 6, wherein the zwitterionic monomer is at least one selected from the group consisting of a monomer represented by the following formula (2) and a monomer represented by the following formula (3),
Figure FDA0004220855220000021
in the formula (2), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 And R is 4 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4,Z is-COO - Or SO 3 - ，
Figure FDA0004220855220000022
In the formula (3), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 、R 4 And R is 6 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4.
8. The bead for blood treatment according to claim 7, wherein in the formula (2), R 1 Is methyl, q is 1-3, R 3 And R is 4 Each independently is methyl or ethyl, and m is 0 or 1.
9. The bead for blood treatment according to claim 7, wherein the zwitterionic monomer is at least one selected from the group consisting of N-methacryloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine, [2- (methacryloxyyl) ethyl ] dimethyl- (3-sulfopropyl) ammonium hydroxide, [3- (methacryloylamino) propyl ] dimethyl (3-sulfopropyl) ammonium hydroxide, and 2- (methacryloxyyl) ethyl 2- (trimethylammoniumethyl) phosphate.
10. The bead for blood treatment according to any one of claims 1 to 6, wherein the polymer further comprises a monomer represented by the following formula (4) as a monomer unit,
Figure FDA0004220855220000023
in the formula (4), R 7 Is a hydrogen atom or 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 T is 0 to 3.
11. The blood processing bead of claim 10, wherein the polymer is comprised of the zwitterionic monomer and the monomer of formula (4).
12. The bead for blood treatment according to claim 10, wherein r is 1 to 3 and t is 0 or 1 in the formula (4).
13. The bead for blood treatment according to claim 12, wherein the zwitterionic monomer is at least one selected from the group consisting of a monomer represented by the following formula (2) and a monomer represented by the following formula (3),
Figure FDA0004220855220000031
in the formula (2), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 And R is 4 Each independently is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4,Z is-COO - Or SO 3 - ，
Figure FDA0004220855220000032
In the formula (3), R 1 Is a hydrogen atom or methyl group, Y is an oxygen atom or-NH-, R 2 is-CH 2 (CH 2 ) q -, q is 1 to 5, R 3 、R 4 And R is 6 Each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms，R 5 is-CH 2 (CH 2 ) m -, m is 0 to 4.
14. The bead for blood treatment according to claim 13, wherein in the formula (2), R 1 Is methyl, q is 1-3, R 3 And R is 4 Each independently is methyl or ethyl, and m is 0 or 1.
15. The bead for blood treatment according to claim 14, wherein the zwitterionic monomer is at least one selected from the group consisting of N-methacryloxyethyl-N, N-dimethylammonium- α -N-methylcarboxybetaine, [2- (methacryloxyyl) ethyl ] dimethyl- (3-sulfopropyl) ammonium hydroxide, [3- (methacryloylamino) propyl ] dimethyl (3-sulfopropyl) ammonium hydroxide, and 2- (methacryloxyyl) ethyl 2- (trimethylammoniumethyl) phosphate.
16. A blood purifier having the blood treatment bead of any one of claims 1 to 15.
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