Coating agent for calciprotein particle adsorption and method for utilizing same

Abstract

The purpose of the present invention is to provide a novel CPP adsorbent capable of physically fixing an electron donating group interacting with CPP to the surface of a base material.　This coating agent for calciprotein particle adsorption, which is a complex of calcium phosphate and protein, is characterized by being a polymer (A) having at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphate group, a phosphono group, a phosphino group, and a thiol group.

Description

Coating agent for adsorbing calciprotein particles and its use

[0001] The present invention relates to a coating agent for the purpose of adsorbing and removing calciprotein particles and a method for using the same.

[0002] Phosphorus is a mineral essential to the human body. 85% of it exists in bones and teeth as calcium phosphate and magnesium phosphate. The remaining 15% is bound to proteins and lipids and exists in cells as a component of cell membranes and nucleic acids. It is also a component of ATP, which generates energy. It is also involved in various functions within the body, such as maintaining cellular pH balance and osmotic pressure. However, excess phosphate in the blood is known to form insoluble salts with calcium. In particular, calciprotein particles (CPPs), complexes of the serum protein Fetuin-A and calcium phosphate, aggregate, and it is believed that these aggregated CPPs promote arteriosclerosis and cause vascular calcification. Unfortunately, however, it is known that CPPs cannot be removed by dialysis (Non-Patent Documents 1-3).

[0003] Therefore, the present inventors have developed an adsorbent for removing CPPs from blood (Patent Document 1). This adsorbent has a structure in which electron-donating groups such as phosphono groups are directly and chemically bonded to the surface of a water-insoluble carrier via a hydrocarbon group by covalent bonding.

[0004] International Publication No. 2018 / 025809

[0005] Clin. Calcium, 2014(24), 1785-92Nephrol. Dial. Transplant. ,2018,1-7Scientific Reports,2018,8,1256

[0006] As a result of further investigations, the present inventors have come up with a new idea. Unlike the adsorbent of Patent Document 1, they have investigated whether it is possible to introduce electron-donating groups into a substrate by physically fixing electron-donating groups that interact with CPPs to the substrate surface. If an adsorbent capable of physically fixing electron-donating groups to the substrate surface is completed, it will be possible to impart CPP adsorption function to various substrates, and this is expected to lead to further diversification of CPP adsorbents.

[0007] That is, an object of the present invention is to provide a novel CPP adsorbent capable of physically fixing electron-donating groups that interact with CPPs to the surface of a substrate.

[0008] As a result of extensive research to solve the above problems, the present inventors have found that, if a polymer has a specific electron-donating group, the electron-donating group that interacts with CPP can be easily physically fixed to the surface of a substrate by a coating technique, and have thus completed the present invention.

[0009] The gist of the present invention is as follows: [1] A coating agent for adsorbing calcium protein particles, which are complexes of calcium phosphate and protein, characterized by being a polymer (A) having at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphate group, a phosphono group, a phosphino group, and a thiol group. [2] The coating agent according to [1], wherein the polymer (A) has at least one phosphono group as the electron-donating group. [3] The coating agent according to [1] or [2], wherein the polymer (A) is soluble in an organic solvent. [4] The coating agent according to [1] or [2], wherein the polymer (A) is an organic solvent-soluble polymer to which an adsorptive compound (C) having one phosphono group as the electron-donating group and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group is bonded. [5] The coating agent according to [1] or [2], wherein the polymer (A) is both organic solvent-soluble and water-soluble. [6] The coating agent according to [1] or [2], wherein the polymer (A) is an organic solvent-soluble and water-soluble polymer to which an adsorptive compound (C) having, as the electron-donating group, two or more phosphono groups and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group is bonded. [7] The coating agent according to any one of [1] to [6], wherein the content of constituent units derived from monomers containing an electron-donating group among all constituent units derived from monomers constituting the polymer (A) is 1 to 60 mol %. [8] The coating agent according to any one of [1] to [7], wherein the polymer (A) is a polymer in which a reactive polymer (B) having at least one second functional group selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamido alkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group, and an adsorptive compound (C) having a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the electron-donating group, are bonded together by a reaction between the first functional group and the second functional group. [9] A coating composition comprising the coating agent according to any one of [1] to [8].

[10] An adsorbent having a substrate surface coated with the coating agent according to any one of [1] to [8].

[11] The adsorbent according to

[10] , wherein the molar concentration of the electron-donating group in the adsorbent is 0.4 μmol or more per 1 g of adsorbent.

[12] The adsorbent according to

[10] or

[11] , wherein the substrate is in the form of beads, monoliths, fibers, or membranes.

[13] The adsorbent according to any one of

[10] to

[12] , wherein the substrate has pores that allow hemodialysis.

[14] A blood purifier comprising the adsorbent according to any one of

[10] to

[13] .

[15] A dialyzer comprising the adsorbent according to any one of

[10] to

[13] .

[16] A blood purification system comprising the blood purifier according to

[14] and a pump for supplying a liquid to the blood purifier.

[17] A dialysis system comprising the dialyzer according to

[15] and a pump for supplying a liquid to the dialyzer.

[18] A method for producing an adsorbent, comprising a step of contacting a substrate with a coating composition containing the coating agent according to any one of [1] to [8] at 0 to 50°C for 0.1 to 2 hours.

[0010]

[19] Use of a coating agent for adsorbing calciprotein particles, which are complexes of calcium phosphate and protein, wherein the coating agent is a polymer (A) having at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphate group, a phosphono group, a phosphino group, and a thiol group, and the coating agent is used so that the calciprotein particles are adsorbed by the electron-donating group.

[20] Use of the coating agent according to

[19] , wherein the polymer (A) has at least one phosphono group as the electron-donating group.

[21] Use of the coating agent according to

[19] or

[20] , wherein the polymer (A) is soluble in an organic solvent.

[22] Use of the coating agent according to

[19] or

[20] , wherein the polymer (A) is an organic solvent-soluble polymer to which an adsorptive compound (C) having one phosphono group as the electron-donating group and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group is bonded.

[23] Use of the coating agent according to

[19] or

[20] , wherein the polymer (A) is soluble in both organic solvents and water.

[24] Use of the coating agent according to

[19] or

[20] , wherein the polymer (A) is an organic solvent-soluble and water-soluble polymer to which an adsorptive compound (C) having, as the electron-donating group, two or more phosphono groups and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group is bonded.

[25] Use of the coating agent according to any one of

[19] to

[24] , wherein the content of constituent units derived from monomers containing electron-donating groups among all constituent units derived from monomers constituting the polymer (A) is 1 to 60 mol %.

[26] Use of the coating agent according to any one of

[19] to

[25] , wherein the polymer (A) is a polymer in which a reactive polymer (B) having at least one second functional group selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamido alkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group, and an adsorptive compound (C) having a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the electron-donating group, are bonded together by a reaction between the first functional group and the second functional group.

[0011]

[27] A method for adsorbing calciprotein particles, which are complexes of calcium phosphate and protein, comprising an adsorption step using a coating agent, wherein the coating agent is a polymer (A) having at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphate group, a phosphono group, a phosphino group, and a thiol group, and wherein the calciprotein particles are adsorbed by the electron-donating group.

[28] The method according to

[27] , wherein the polymer (A) has at least one phosphono group as the electron-donating group.

[29] The method according to

[27] or

[28] , wherein the polymer (A) is soluble in an organic solvent.

[30] The method according to

[27] or

[28] , wherein the polymer (A) is an organic solvent-soluble polymer to which an adsorptive compound (C) having one phosphono group as the electron-donating group and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group is bonded.

[31] The method according to

[27] or

[28] , wherein the polymer (A) is soluble in both organic solvents and water.

[32] The method according to

[27] or

[28] , wherein the polymer (A) is an organic solvent-soluble and water-soluble polymer to which an adsorptive compound (C) having, as the electron-donating group, two or more phosphono groups and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group is bonded.

[33] The method according to any one of

[27] to

[32] , wherein the content of constituent units derived from monomers containing an electron-donating group among all constituent units derived from monomers constituting the polymer (A) is 1 to 60 mol %.

[34] The method according to any one of

[27] to

[33] , wherein the polymer (A) is a polymer in which a reactive polymer (B) having at least one second functional group selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamido alkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group, and an adsorptive compound (C) having a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the electron-donating group, are bonded together by a reaction between the first functional group and the second functional group.

[0012] The coating agent of the present invention makes it possible to easily physically fix electron-donating groups that interact with CPPs to the surface of a substrate using a coating technique. Such a coating agent specialized for CPP adsorption is unprecedented, and is expected to advance CPP adsorption processing technology.

[0013] Figure 1 is a schematic diagram showing an example of a CPP adsorption system. Figure 2 is a schematic diagram showing an example of a dialysis system.

[0014] In the present disclosure, "calciprotein particles (hereinafter sometimes simply referred to as "CPP")" refers to a complex of calcium phosphate and protein. More specifically, CPP refers to a complex of calcium phosphate (particularly Posner clusters (component: Ca9(PO4)6)) and Fetuin-A, etc., and preferably refers to nanoparticles formed by the aggregation of calcium phosphate-containing Fetuin-A, etc. Examples of calcium phosphate include monetite (CaHPO4), brushite (CaHPO4.2H2O), amorphous calcium phosphate (Ca9PO4)6), and hydroxyapatite (Ca 10(PO4)6(OH)2), and the like, with amorphous calcium phosphate and hydroxyapatite being preferred. In the present disclosure, the CPP may be a structure in which amorphous calcium phosphate is aggregated with Fetuin-A or the like (primary CPP), or a structure in which crystalline calcium phosphate is aggregated with Fetuin-A or the like, which is formed by subsequent phase transition (secondary CPP), with secondary CPP being preferred. CPPs also incorporate proteins present in body fluids as complexes other than Fetuin-A, including, for example, albumin, fibrinogen, RANKL (Receptor activator of nuclear factor kappa-B ligand), BMP-2 (Bone morphogenetic protein 2), BMP-7 (Bone morphogenetic protein 7), and osteoprotegerin. Proteins incorporated as CPPs or complexes may be modified with a detection functional group such as a fluorescent label, or a reactive group for enhancing the ability to bind to other molecules, and this modification may be performed either in vivo or ex vivo. Abnormal forms produced by gene mutations, etc., are also included.

[0015] The coating agent of the present invention, described in detail below, is intended to adsorb the above-mentioned CPPs. CPPs include CPPs that are complexes of amorphous calcium phosphate and Fetuin-A, and CPPs in which at least a portion of amorphous calcium phosphate has undergone a phase transition from amorphous to crystalline. It is believed that CPPs containing calcium phosphate crystals are primarily adsorbed to the coating agent. More specifically, adsorbing CPPs means adsorbing CPPs present in body fluids. Such body fluids include cerebrospinal fluid, blood, plasma, serum, ascites, lymph, intra-articular fluid, bone marrow fluid, and liquid components derived from living organisms, including fractions obtained from these fluids. The coating agent of the present invention enables the removal of CPPs, which are typically difficult to separate by dialysis or other methods.

[0016] <Coating Agent> The coating agent according to the present invention is characterized by a polymer (A) having at least one electron-donating group selected from the group consisting of an amino group (-NH2), a carboxy group (carboxylic acid group, -COOH), a phosphate group (-O-P(=O)(OH)2), a phosphono group (phosphonic acid group, -P(=O)(OH)2), a phosphino group (-PH2), and a thiol group (-SH). The electron-donating group in the coating agent is a site that interacts with CPPs and can adsorb them. Furthermore, by using a polymer as the base material for the coating agent, an adsorbent with CPP adsorption capabilities can be easily produced simply by applying the coating agent to a substrate, thereby contributing to improved productivity. In this disclosure, the term "polymer" refers to a polymer having a repeating structure in which multiple units of one or more types of monomers are linked together, preferably having a weight-average molecular weight (Mw) of 1,000 to 4,000,000.

[0017] Examples of the electron-donating group include groups in which a hydrogen atom is bonded to a heteroatom such as N (nitrogen atom), S (sulfur atom), or P (phosphorus atom), such as an amino group (-NH), a thiol group (-SH), or a phosphino group (-PH); and groups having an acidic proton, such as groups derived from oxo acids, such as a carboxy group (carboxylic acid group, -COOH), a phosphate group (-O-P(=O)(OH)), or a phosphono group (phosphonic acid group, -P(=O)(OH)). These electron-donating groups may be used alone or in combination of two or more. Preferred electron-donating groups are groups having an acidic proton, and more preferably a phosphate group or a phosphono group. In particular, it is preferable that the polymer (A) has at least one phosphono group as the electron-donating group. Since a phosphono group is more easily adsorbed by CPPs than other electron-donating groups, improved CPP removal efficiency can be expected.

[0018] The group having an acidic proton may be partially in the form of a salt. Examples of counter cations that form such salts include alkali metal ions such as sodium ions and potassium ions; and Group 2 metal ions such as calcium ions and magnesium ions. The amino group serving as the electron-donating group may be substituted to the extent that it does not lose its nucleophilicity. Examples of such substituents include C1-6 alkyl group, and C 1-4 Alkyl groups are preferred, and C 1-2 Alkyl groups are more preferred, with methyl being even more preferred.

[0019] The electron-donating group is preferably bonded to the base polymer via a linker group. The linker group increases the positional freedom of the electron-donating group, making it easier for the electron-donating group to adsorb to the CPP and facilitating the bonding of the electron-donating group to the base polymer. The linker group is preferably covalently bonded to the electron-donating group.

[0020] Examples of the linker group include C 1-18 Examples thereof include a hydrocarbon group, —O—, —S—, —NH—, —C(═O)—, —C(═O)—S—, —O—C(═O)— (however, —C(═O)—O— is also included; the same applies hereinafter in the present disclosure), —NH—C(═O)— (however, —C(═O)—NH— is also included; the same applies hereinafter in the present disclosure), —NH—C(═O)—NH—, —NH—C(═S)—NH—, a polyalkylene glycol group, a polyvinyl alcohol group, or a group in which 2 to 5 of these groups are linked together, and a C group having —O—, —S—, —NH—, —C(═O)—, —C(═O)—S—, —O—C(═O)—, —NH—C(═O)—, —NH—C(═O)—NH— and / or —NH—C(═S)—NH— at at least one end 1-18 A hydrocarbon group is preferred, and a C group having —O—, —S—, —NH—, —C(═O)—, —O—C(═O)— and / or —NH—C(═O)— at one end on the base polymer side is preferred. 1-18 Hydrocarbon groups are more preferred.

[0021] C 1-18 Examples of the hydrocarbon group include C 1-18 Alkane-(n+1)yl groups (n indicates the number of electron-donating groups per linker group). 1-18 The number of carbon atoms in the hydrocarbon group is preferably 2 or more, and is preferably 16 or less or 14 or less (i.e., preferably 2 to 16, more preferably 2 to 14). 1-18 The hydrocarbon group may be straight-chain or branched, but is preferably straight-chain.

[0022] Because the linker group bonds the base polymer and the electron-donating group, when the number of electron-donating groups per linker group is n, the valency of the linker group is n + 1. For example, when the number of electron-donating groups per linker group is 2, the valency of the linker group is trivalent, bonding the base polymer and two electron-donating groups.

[0023] The linker group may have a substituent. Examples of the substituent include a hydroxy group, C 1-6 Examples of the substituents include one or more substituents selected from an alkoxy group and a halogeno group, with a hydroxy group being preferred. In particular, a hydroxy group is effective in improving the adsorptive power of CPP in cooperation with an electron-donating group. The number of substituents per linker group is not particularly limited as long as it is substitutable, but is, for example, 1 to 7, preferably 4 or less, more preferably 3 or less, and even more preferably 2 or less (i.e., preferably 1 to 7, more preferably 1 to 4, even more preferably 1 to 3, and particularly preferably 1 to 2). When the number of substituents per linker group is two or more, the multiple substituents may be the same or different from each other.

[0024] C 1-6 The alkoxy group refers to a linear or branched saturated aliphatic hydrocarbon oxy group having from 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, and n-hexoxy, and preferably C 1-4 is an alkoxy group, more preferably C 1-2 It is an alkoxy group, and even more preferably methoxy.

[0025] Examples of the halogeno group include fluoro, chloro, bromo and iodo, with chloro or bromo being preferred, and chloro being more preferred.

[0026] The number of electron-donating groups per linker group is preferably 1 or more, and more preferably 2 or more. In particular, the presence of two or more electron-donating groups per linker group increases adsorption to CPPs, allowing for greater adsorption of CPPs. On the other hand, since too many electron-donating groups per linker group may make production of the coating agent difficult, the number is preferably 5 or less, more preferably 4 or less, even more preferably 3 or less (i.e., preferably 1 to 5, more preferably 1 to 4, even more preferably 1 to 3), and even more preferably 1 or 2. Furthermore, when the number of electron-donating groups per linker group is 2 or more, it is preferable that at least one of the electron-donating groups is a group having an acidic proton (more preferably a phosphate group or a phosphono group, particularly preferably a phosphono group). Because groups having an acidic proton are easily adsorbed to CPPs, improved CPP removal efficiency can be expected.

[0027] The coating agent according to the present invention is preferably a polymer (A) in which a CPP adsorption ligand represented by formula (I) (hereinafter sometimes referred to as CPP adsorption ligand (I)) is bonded to a base polymer. In the case of a polymer in which the CPP adsorption ligand (I) is bonded, there is a certain distance between the electron-donating group and the main chain of the base polymer, so the base polymer is less likely to cause steric hindrance, and the electron-donating group is more likely to adsorb to the CPP.

[0028] [In formula (I), * represents a bond to the base polymer. 1 ~R 3 each independently represents an electron donating group, a hydrogen atom, a hydroxy group, or C 1-6 represents an alkoxy group or a halogeno group, R 1 ~R 3 At least one of L is an electron donating group. 1-17 represents a hydrocarbon group. Y represents —O—, —S—, —NH—, —C(═O)—, —C(═S)—, —O—C(═O)—, —NH—C(═O)—, —NH—C(═O)—NH—, —NH—C(═S)—NH—, a divalent polyalkylene glycol group, or a divalent polyvinyl alcohol group.]

[0029] Y is more preferably —O—, —S—, —NH—, —C(═O)—, —O—C(═O)— or —NH—C(═O)—, and particularly preferably —S— or —NH—.

[0030] The CPP adsorption ligand represented by formula (I) specifically includes a CPP adsorption ligand represented by formula (IA) (hereinafter, sometimes referred to as CPP adsorption ligand (IA)). In formula (IA), * represents a bond to the base polymer. 1A ~R 3A Two of them are electron-donating groups, and the rest are electron-donating groups, hydrogen atoms, hydroxy groups, and C 1-6 represents an alkoxy group or a halogeno group. A is a divalent C 1-17 represents a hydrocarbon group. A represents —O—, —S—, or —NH—.]

[0031] The CPP adsorption ligand represented by formula (I) also includes a CPP adsorption ligand represented by formula (IB) (hereinafter, sometimes referred to as CPP adsorption ligand (IB)).

[0032] In formula (IB), * represents a bond to the base polymer. 1B ~R 3B one of which is an electron-donating group, and the rest are each independently a hydrogen atom, a hydroxy group, or C 1-6 represents an alkoxy group or a halogeno group. B is a divalent C 1-17 represents a hydrocarbon group. B represents —O—, —S—, or —NH—.]

[0033] R 1 ~R 3 , R 1A ~R 3A and R 1B ~R 3B an electron-donating group represented by 1-6 The alkoxy group and the halogeno group are the same as those described above.

[0034] L, L A and L B Divalent C represented by1-17 The hydrocarbon group is preferably a divalent C 1-17 A linear saturated hydrocarbon group or a divalent C 1-17 A branched saturated hydrocarbon group, more preferably a divalent C 1-17 A CPP-adsorbing ligand having such a chain structure is unlikely to cause steric hindrance due to the structure corresponding to the linker group, so that the electron-donating group is easily adsorbed to the CPP.

[0035] C in L 1-17 The number of carbon atoms in the hydrocarbon group is preferably 1 to 15, more preferably 2 to 13, and even more preferably 3 to 11. Within this range, the electron-donating group is separated from the main chain of the base polymer, and the base polymer does not become a steric hindrance, so that the electron-donating group is easily adsorbed to the CPP. For the same reason, L A C in 1-17 The number of carbon atoms in the hydrocarbon group is preferably 1 to 12, more preferably 2 to 10, and even more preferably 3 to 8. B C in 1-17 The hydrocarbon group preferably has 6 to 16 carbon atoms, more preferably 7 to 15 carbon atoms, and even more preferably 8 to 14 carbon atoms.

[0036] The coating agent is not particularly limited in terms of the polymer structure as long as it is a polymer having a specific electron-donating group, but among these, polymer (A) is preferably a polymer in which a reactive polymer (B) having at least one second functional group selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamido alkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group is bonded to an adsorbent compound (C) having a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the electron-donating group, via a reaction between the first and second functional groups. By separating the component that constitutes the matrix (reactive polymer (B)) from the component that provides the electron-donating group (adsorbent compound (C)), the combination of the matrix skeleton and the electron-donating group can be freely selected, making it possible to provide a wide variety of coating agents. When polymer (A) is obtained by reacting reactive polymer (B) with adsorbent compound (C), the base polymer is usually derived from reactive polymer (B), and the electron-donating group possessed by polymer (A) is derived from adsorbent compound (C).

[0037] The second functional group of the reactive polymer (B) is preferably at least one selected from the group consisting of a halide methyl group, an epoxy group, and an acid anhydride group, which reacts well with the first functional group. Furthermore, the reactive polymer (B) is preferably a polymer that has the property of easily adhering to a substrate, such as a surface modifier, coating agent, adhesion promoter, paint, or film former. Preferred examples of the reactive polymer (B) include poly(methyl vinyl ether-alt-maleic anhydride), poly(ethylene-alt-maleic anhydride), poly(styrene / maleic anhydride), polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, poly(ethylene-co-methyl acrylate-co-glycidyl methacrylate), poly(vinylbenzyl chloride), poly(glycidyl methacrylate), poly[(isobutylene-alt-maleic acid, ammonium salt)-co-(isobutylene-alt-maleic anhydride)], poly(isobutylene-alt-maleic anhydride), poly(ethylene-graft-maleic anhydride), poly(propylene-graft-maleic anhydride), poly(isoprene-graft-maleic anhydride), and poly(ethylene-co-glycidyl methacrylate). Poly(methyl vinyl ether-alt-maleic anhydride), poly(ethylene-alt-maleic anhydride), polyethylene glycol diglycidyl ether, poly(styrene / maleic anhydride), poly(ethylene-co-methyl acrylate-co-glycidyl methacrylate), poly(vinylbenzyl chloride), and the like are soluble in organic solvents, as described below. Furthermore, poly(methyl vinyl ether-alt-maleic anhydride), poly(ethylene-alt-maleic anhydride), polyethylene glycol diglycidyl ether, and the like are soluble in water, as described below. These polymers may be inorganic salts, and may have functional groups at their terminals.

[0038] Examples of the adsorptive compound (C) include adsorptive compounds having an amino group such as pamidronic acid, alendronic acid, neridronic acid, etc.; adsorptive compounds having a thiol group such as 11-mercaptoundecylphosphonic acid, 12-mercaptododecylphosphonic acid, etc.; adsorptive compounds having a hydroxy group such as 2-hydroxyethylphosphonic acid, 2-hydroxyethylidenebisphosphonic acid, 6-hydroxyhexylphosphonic acid, etc. These compounds may form salts or hydrates.

[0039] The polymer (A) may have the property of being soluble in an organic solvent or water. Based on this property, the polymer (A) can also be characterized. The polymer (A) may or may not be soluble in an organic solvent. The polymer (A) may or may not be soluble in water.

[0040] In the present disclosure, "organic solvent-soluble" means that 0.1 wt % of the solute is completely dissolved in an organic solvent at 40 to 50°C. Specifically, "0.1 wt % of the solute is completely dissolved in an organic solvent at 40 to 50°C" means that after adding 0.1 wt % of the solute to an organic solvent adjusted to a temperature within the range of 40 to 50°C and stirring for 24 hours, the solid content of the solute remaining in the organic solvent is 0 to 0.001 wt %. The organic solvent may be any common organic solvent, regardless of polarity. Representative examples of organic solvents include hydrocarbon solvents such as benzene, toluene, xylene, and hexane; ether solvents such as tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether; alcohol solvents such as methanol, ethanol, and 2-propanol; and ketone solvents such as acetone and methyl ethyl ketone. If 0.1 wt % of the solute is completely dissolved in at least one of these organic solvents at 40 to 50°C, the solute is considered to be organic solvent-soluble. The organic solvent referred to here does not include a mixed solvent of an organic solvent and an aqueous solvent, which will be described later, but refers to a solvent consisting of 100 wt % organic solvent.

[0041] In this disclosure, "water-soluble" means that 0.1 wt% of the solute is completely dissolved in an aqueous solvent at 40-50°C. Specifically, "0.1 wt% of the solute is completely dissolved in an aqueous solvent at 40-50°C" means that after adding 0.1 wt% of the solute to an aqueous solvent adjusted to any temperature within the range of 40-50°C and stirring for 24 hours, the solid content of the solute remaining in the aqueous solvent is 0-0.001 wt%. Representative examples of aqueous solvents include water (including tap water, pure water, ultrapure water, etc.), physiological saline, buffer solutions, etc. If 0.1 wt% of the solute is completely dissolved in at least one of these aqueous solvents at 40-50°C, the solute is considered to be water-soluble. Note that the term "aqueous solvent" as used herein does not include mixed solvents of an aqueous solvent with the aforementioned organic solvents, but refers to a solvent consisting of 100 wt% aqueous solvent. Some solutes have solubility that changes depending on the pH, so when determining the water solubility of such solutes, it is advisable to use a buffer solution as the aqueous solvent.

[0042] The polymer (A) is preferably soluble in an organic solvent. When the polymer (A) has the property of being soluble in an organic solvent, the coating agent is less likely to be eluted during blood purification treatment.

[0043] When the polymer (A) is soluble in an organic solvent, the polymer (A) may be either water-soluble or not, but it is also preferable that the polymer (A) is both water-soluble and organic solvent-soluble. If the polymer (A) is water-soluble, for example, when producing a coating agent, an adsorptive compound (C) having two or more electron-donating groups (preferably phosphono groups) exhibiting the same water solubility can be used as a raw material together with the water-soluble reactive polymer (B).

[0044] When the polymer (A) is both organic solvent-soluble and water-soluble, the coating agent is preferably an organic solvent-soluble and water-soluble polymer to which an adsorptive compound (C) having two or more phosphono groups as electron-donating groups and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group is bonded. For example, when the polymer (A) is both organic solvent-soluble and water-soluble, any of the CPP adsorptive ligands (IA) to (IB) may be bonded to the polymer (A), but it is preferable that the CPP adsorptive ligand (IA) be bonded. Such coating agents possess both organic solvent-soluble and water-soluble properties. Therefore, they are compatible with a variety of hydrophilic and hydrophobic substrates, enabling more stable application. Furthermore, adsorptive compounds (C) having two phosphono groups include those used as existing pharmaceuticals, and are therefore desirable from the standpoint of safety.

[0045] Examples of the adsorbent compound (C) having two or more phosphono groups as electron-donating groups and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group include pamidronic acid, alendronic acid, neridronic acid, and 2-hydroxyethylidenebisphosphonic acid. Among these, pamidronic acid, alendronic acid, and neridronic acid are preferred due to their good CPP adsorption performance, and alendronic acid is more preferred. In this case, the reactive polymer (B) may be a combination of an organic solvent-soluble and water-soluble polymer, and examples include poly(methyl vinyl ether-alt-maleic anhydride), poly(ethylene-alt-maleic anhydride), and polyethylene glycol diglycidyl ether. Among these, poly(methyl vinyl ether-alt-maleic anhydride) is particularly preferred due to its good CPP adsorption performance.

[0046] When the polymer (A) is soluble in an organic solvent (preferably when it is soluble in an organic solvent but not in water), production is easy, and therefore, as a coating agent, an organic solvent-soluble polymer to which an adsorptive compound (C) having one phosphono group as an electron-donating group and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group is bonded is preferred. For example, when the polymer (A) is soluble in an organic solvent, any of the CPP adsorptive ligands (IA) to (IB) may be bonded to the polymer (A), but it is preferred that the CPP adsorptive ligand (IB) be bonded to the polymer (A).

[0047] Examples of the adsorbent compound (C) having one phosphono group as the electron-donating group and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group include 11-mercaptoundecylphosphonic acid, 12-mercaptododecylphosphonic acid, 2-hydroxyethylphosphonic acid, and 6-hydroxyhexylphosphonic acid, with 11-mercaptoundecylphosphonic acid and 12-mercaptododecylphosphonic acid being preferred. In this case, it is preferable to combine the reactive polymer (B) with one that is soluble in organic solvents but not in water, and preferred examples include poly(vinylbenzyl chloride), poly(styrene / maleic anhydride), and poly(ethylene-co-methyl acrylate-co-glycidyl methacrylate).

[0048] Furthermore, the inventors have conducted research and found that the organic solvent solubility of polymer (A) correlates with the organic solvent solubility of the raw material reactive polymer (B), and similarly, the water solubility of polymer (A) correlates with the water solubility of the raw material reactive polymer (B). In other words, if the raw material reactive polymer (B) is organic solvent soluble, the coating agent tends to be organic solvent soluble, and if the raw material reactive polymer (B) is water soluble, the coating agent tends to be water soluble. Therefore, if the characteristics of the raw material reactive polymer (B) are known, the characteristics of the coating agent can also be understood to a certain extent. The method for determining the organic solvent solubility or water solubility of the raw material reactive polymer (B) is the same as that for the polymer (A) described above.

[0049] Furthermore, as the amount of structural units having a highly hydrophilic functional group (for example, a -C(=O)-O-C(=O)- group formed by dehydration condensation of two oxo acid molecules) in the reactive polymer (B) increases (for example, when the amount of such structural units is 40 mol% or more of all the structural units in the reactive polymer (B)), the reactive polymer (B) tends to be both organic solvent-soluble and water-soluble. On the other hand, as the amount of structural units having a highly hydrophilic functional group decreases (for example, when the amount of such structural units is less than 40 mol% of all the structural units in the reactive polymer (B)), the reactive polymer (B) tends to be organic solvent-soluble but not water-soluble.

[0050] Of all the monomer-derived structural units constituting the polymer (A), the content of structural units derived from monomers containing electron-donating groups is preferably 1 to 60 mol%, more preferably 20 to 55 mol%, and even more preferably 35 to 50 mol%. The content of structural units derived from monomers containing electron-donating groups can be measured by organic composition analysis, infrared spectroscopic analysis, mass spectrometry, nuclear magnetic resonance (NMR), gas chromatography, high-performance liquid chromatography, evolved gas analysis, elemental analysis, or the like. For example, NMR measurement can be performed, and the reactivity of the reactive polymer (B) with the adsorptive compound (C) can be calculated from the peak area of ​​the electron-donating group contained in the polymer (A) detected, thereby determining the content of structural units derived from monomers containing electron-donating groups in the polymer (A).

[0051] The coating agent can be produced, for example, by reacting a reactive polymer (B) having a second functional group with an adsorptive compound (C) having a first functional group. The reaction conditions can be appropriately set depending on the types of the first and second functional groups. In the reaction between the reactive polymer (B) and the adsorptive compound (C), the adsorptive compound (C) is used in an amount, by mass, of preferably 0.01 to 25 times, more preferably 0.1 to 15 times, and even more preferably 0.5 to 10 times the amount of the reactive polymer (B). Within the above range, a coating agent with sufficient CPP adsorption performance can be produced.

[0052] The reaction of the reactive polymer (B) with the adsorptive compound (C) can also be carried out in the presence of a solvent, and examples of the solvent include aqueous solvents such as water (including tap water, pure water, ultrapure water, etc.), physiological saline, buffer solutions, etc., hydrocarbon solvents such as benzene, toluene, xylene, hexane, etc., ether solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, etc., alcohol solvents such as methanol, ethanol, 2-propanol, etc., and ketone solvents such as acetone, methyl ethyl ketone, etc., which may be used alone or in combination of two or more. For example, when the reactive polymer (B) is soluble in an organic solvent, preferred reaction solvents are hydrocarbon solvents (preferably hexane, toluene), ether solvents (preferably tetrahydrofuran), alcohol solvents (preferably 2-propanol), and ketone solvents (preferably acetone). When the reactive polymer (B) is soluble in both organic solvents and water, the reaction solvent is preferably an aqueous solvent (preferably water), a hydrocarbon solvent (preferably toluene), an ether solvent (preferably tetrahydrofuran), or an alcohol solvent (preferably 2-propanol). By selecting a preferred solvent depending on the properties of the reactive polymer (B), the production of the coating agent can be stabilized.

[0053] The reaction temperature of the reactive polymer (B) and the adsorbent compound (C) is preferably 0 to 80° C., more preferably 10 to 70° C., and even more preferably 20 to 60° C. Within this range, the reaction between the reactive polymer (B) and the adsorbent compound (C) proceeds stably.

[0054] The reaction time of the reactive polymer (B) and the adsorbent compound (C) is preferably 0.1 to 24 hours, more preferably 1 to 12 hours, and even more preferably 2 to 8 hours. Within this range, the reaction between the reactive polymer (B) and the adsorbent compound (C) proceeds sufficiently.

[0055] <Coating Composition> The present disclosure further includes a coating composition containing the coating agent. By forming the coating composition, it becomes easy to process a substrate with the coating agent.

[0056] The coating composition may further contain a solvent. The inclusion of a solvent in the coating composition facilitates coating of the coating composition on a substrate, allowing the coating agent to be uniformly fixed to the substrate surface. The solvent used in the coating composition is not particularly limited, and examples thereof include aqueous solvents such as water (including tap water, pure water, ultrapure water, etc.), physiological saline, and buffer solutions; hydrocarbon solvents such as benzene, toluene, xylene, and hexane; ether solvents such as tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether; alcohol solvents such as methanol, ethanol, and 2-propanol; and ketone solvents such as acetone and methyl ethyl ketone. These solvents may be used alone or in combination of two or more. Among these, at least one solvent selected from the group consisting of aqueous solvents, toluene, hexane, tetrahydrofuran, 2-propanol, and acetone is preferred. These solvents allow the coating agent to be fixed to the substrate surface by the simple process of coating without impairing the properties of the coating agent.

[0057] The solvent used in the coating composition can also be selected depending on the properties of the polymer (A). When the polymer (A) is soluble in an organic solvent, the solvent used in the coating composition is preferably a hydrocarbon solvent (preferably hexane or toluene), an ether solvent (preferably tetrahydrofuran), an alcohol solvent (preferably 2-propanol), or a ketone solvent (preferably acetone). When the polymer (A) is soluble in both an organic solvent and water, the solvent used in the coating composition is preferably an aqueous solvent (preferably water), a hydrocarbon solvent (preferably toluene), an ether solvent (preferably tetrahydrofuran), or an alcohol solvent (preferably 2-propanol). By selecting a preferred solvent depending on the properties of the polymer (A), the coating agent can be fixed to the surface of a substrate by the simple procedure of coating while taking advantage of the properties of the coating agent.

[0058] The solvent used in the coating composition can also be selected depending on the properties of the substrate to be coated. For example, when the substrate is in the form of beads, the solvent used in the coating composition is preferably an aqueous solvent (preferably water), a hydrocarbon solvent (preferably hexane or toluene), an ether solvent (preferably tetrahydrofuran), an alcohol solvent (preferably 2-propanol), or a ketone solvent (preferably acetone). For example, when the substrate is in the form of a membrane (preferably a hollow fiber membrane), the solvent used in the coating composition is preferably an aqueous solvent (preferably water) or a hydrocarbon solvent (preferably hexane or toluene). By selecting a preferred solvent depending on the properties of the substrate, the coating agent can be fixed to the surface of the substrate by the simple operation of coating without impairing the properties of the substrate.

[0059] The coating composition may further contain additives, such as pore size retaining agents such as glycerin, blood compatible polymers such as poly-2-methacryloyloxyethyl phosphorylcholine, and hydrophilic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol.

[0060] The concentration of the coating agent in the coating composition is preferably 0.01 to 40% by mass, more preferably 0.05 to 30% by mass, and even more preferably 0.1 to 15% by mass. Within this range, the coating agent can be uniformly coated on the substrate, and CPP adsorption performance can be fully exhibited.

[0061] The coating composition is produced by mixing a coating agent, a solvent, and additives as needed. Alternatively, the coating composition can be produced by using the coating agent-containing liquid after reaction as a raw material for the coating composition. In the former case, the components can be appropriately mixed so that the coating agent has a desired concentration. In the latter case, the concentration of the coating agent in the coating composition can be adjusted by adjusting the amount of reaction solvent before producing the coating agent or by adding solvent after producing the coating agent.

[0062] <Adsorbent> The present disclosure further encompasses an adsorbent in which the surface of a substrate is coated with the coating agent. By coating the substrate surface with the coating agent, a substrate having CPP adsorption performance can be easily obtained. In the adsorbent, the coating agent is preferably physically fixed to the substrate surface, and more preferably fixed to the substrate surface by a mechanism other than a chemical bond (particularly a covalent bond). In the adsorbent, it is desirable that the coating agent be uniformly coated on the substrate surface.

[0063] The molar concentration of the electron donating group in the adsorbent is sufficient for CPP adsorption if it is 0.40 μmol or more per 1 g of adsorbent, but is preferably 15 μmol or more, more preferably 50 μmol or more. The upper limit is not particularly limited, but 1000 μmol or less is practical, and it may be 400 μmol or less (i.e., preferably 0.40 to 1000 μmol, more preferably 15 to 1000 μmol, and even more preferably 50 to 400 μmol). Here, the molar concentration of the electron donating group in the adsorbent can be measured by inductively coupled plasma (ICP) atomic emission spectroscopy (ICP-AES), ICP mass spectrometry, atomic absorption spectrometry, X-ray fluorescence analysis, etc. For example, the electron donating group in the adsorbent can be quantified from the intensity of the wavelength detected by ICP-AES.

[0064] The substrate is preferably water-insoluble. Specifically, "water-insoluble" means that when 1 g of the substrate is placed in water and vigorously shaken for 30 seconds every 5 minutes at 20±5°C, the amount of water required to dissolve the substrate within 30 minutes is 1,000 mL or more, preferably 10,000 mL or more. More specifically, when 1 g of the substrate is placed in water and vigorously shaken for 30 seconds every 5 minutes at 20±5°C, not all of the substrate placed in the water dissolves. Furthermore, the substrate is preferably solid at room temperature and normal pressure.

[0065] The substrate preferably has pores that allow hemodialysis. Specifically, "pores that allow hemodialysis" means that the substrate has a large number of pores of an appropriate size that do not allow red blood cells, white blood cells, proteins, etc. to pass through, but allow electrolytes, waste products, water, etc. to pass through. The pore size is generally 1.0 nm to 50 nm.

[0066] The substrate is preferably hydrophilic. Specifically, it is preferable that hydrophilic groups such as hydroxyl groups, ether groups, and amino groups are exposed on the surface. In addition, it is preferable that the substrate exhibits little nonspecific adsorption to components in body fluids and has excellent safety, such as blood compatibility.

[0067] The substrate may be in the form of beads, monoliths, fibers, membranes (including hollow fiber membranes, semipermeable membranes, and flat membranes), etc., and an appropriate substrate may be selected depending on the intended use. Because of their wide range of applicable uses, beads or membranes are preferred as substrates.

[0068] The beaded substrate may have an exclusion limit molecular weight that allows the substance to be adsorbed (i.e., CPP) to enter the pores. The exclusion limit molecular weight here generally refers to the molecular weight of the smallest molecule that cannot enter the pores in gel permeation chromatography, as described in textbooks (e.g., Hiroyuki Hatano and Toshihiko Hanai, Experimental High Performance Liquid Chromatography, Kagaku Dojin, etc.), and is generally measured using globular proteins. The exclusion limit molecular weight of the beaded substrate is, for example, 10,000 or more, preferably 100,000 or more, and more preferably 1,000,000 or more. There is no particular upper limit, but if the exclusion limit molecular weight is too large, the density of the beaded substrate decreases, affecting the strength, i.e., the pressure resistance, of the beaded substrate. From this perspective, the exclusion limit molecular weight is, for example, 100 million or less, preferably 50 million or less, and more preferably 10 million or less (i.e., preferably 10,000 to 100 million, more preferably 100,000 to 50 million, and even more preferably 1,000,000 to 10 million).

[0069] The number-based average particle size of the bead-like substrate is, for example, 10 μm or more, preferably 100 μm or more, more preferably 200 μm or more, and for example, 5 mm or less, preferably 1 mm or less, more preferably 0.8 mm or less (i.e., preferably 10 μm to 5 mm, more preferably 100 μm to 1 mm, and even more preferably 200 μm to 0.8 mm). The average particle size of the bead-like substrate can be determined on a number basis by measuring the diameter of each bead-like substrate individually from an enlarged photograph of the bead-like substrate taken with a stereomicroscope or the like.

[0070] Examples of bead-shaped substrates include inorganic materials, organic materials, and composite materials obtained by combining these, such as organic-organic materials and organic-inorganic materials. Examples of inorganic materials include glass beads and silica gel. Examples of organic materials include synthetic polymers such as cross-linked polyvinyl alcohol, cross-linked polyacrylate, cross-linked polyacrylamide, and cross-linked polystyrene; and polysaccharides such as crystalline cellulose, cross-linked cellulose, cross-linked agarose, and cross-linked dextran.

[0071] The bead-shaped substrates include GCL2000, a porous cellulose gel, and Sephacryl, a polymer in which allyl dextran and methylenebisacrylamide are covalently crosslinked. (R) S-1000, Toyopearl, an acrylate-based carrier (R) , Sepharose, an agarose-based cross-linked carrier (R) CL4B and Cellufine, a cellulose-based cross-linked carrier (R) Examples of commercially available products include:

[0072] The film-like substrate is preferably formed from a polymer, and the polymer is more preferably at least one selected from the group consisting of cellulose, cellulose diacetate, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer.

[0073] The membrane thickness of the membrane substrate is preferably 1 to 100 μm, more preferably 5 to 80 μm, and even more preferably 10 to 60 μm. Within this range, the membrane has appropriate rigidity and is easy to handle. The membrane is preferably in the form of a hollow fiber membrane. The inner diameter of the hollow fiber contained in the hollow fiber membrane is preferably 50 to 500 μm, more preferably 80 to 400 μm, and even more preferably 130 to 300 μm. Furthermore, in the case of a hollow fiber membrane, the effective length is preferably 5 to 40 cm, and more preferably 10 to 30 cm. Within this range, the flow of the CPP-containing liquid (hereinafter sometimes referred to as "CPP-containing liquid") flowing inside the hollow fiber becomes smooth, and the surface area of ​​the substrate becomes sufficient, allowing for an increased amount of CPP coating agent to come into contact with the CPP-containing liquid.

[0074] The method for producing an adsorbent preferably includes a step of contacting a substrate with a coating composition containing a coating agent at 0 to 50°C for 0.1 to 2 hours. The contacting step allows the coating agent to be applied to the substrate. The contacting method is not particularly limited, but examples include adding the substrate to the coating composition and mixing; or flowing the coating composition through the substrate. If the substrate is housed in a container, the shape of the container can be utilized during contact between the coating composition and the substrate. In the case of a membrane-like substrate, for example, the structure of a dialyzer can be utilized to coat the surface of the membrane-like substrate (the inner surface of the hollow fiber membrane) by flowing the coating composition through the blood inlet of the dialyzer. The contact temperature between the coating composition and the substrate is preferably 5 to 40°C, more preferably 10 to 35°C. The contact time between the coating composition and the substrate is preferably 0.2 to 1.5 hours, more preferably 0.3 to 1 hour. When the contact temperature and contact time are within the above ranges, an adsorbent with sufficient CPP adsorption performance can be produced without impairing the properties of the substrate.

[0075] The method for producing the adsorbent may further include a step of removing excess coating composition after the contacting step, for example by applying compressed air to the substrate or by carrying out a separation step such as filtration.

[0076] The method for producing the adsorbent may further include a step of drying the substrate to which the coating composition has been applied after the contacting step.

[0077] It is preferable that the original function of the substrate is not significantly impaired even after coating. For example, in the case of a membrane-type adsorbent, the membrane area is 1.5 m 2 The clearance value of urea per unit volume is preferably 125 ml / min or more, more preferably 140 ml / min or more. Although there is no particular upper limit, the clearance value is, for example, 250 ml / min or less (i.e., preferably 125 to 250 ml / min, more preferably 140 to 250 ml / min).

[0078] <Applications> Because the coating agent according to the present invention has CPP adsorption properties, it can be used to treat (adsorb) various liquids containing CPPs, including water, buffer solutions, and other liquids that may contain CPPs. For example, the coating agent can selectively remove CPPs from body fluids that contain CPPs.

[0079] When removing CPP from a CPP-containing liquid, it is preferable to use the adsorbent because it simplifies the removal procedure. Specifically, it is preferable to contact the adsorbent with the CPP-containing liquid. This allows at least a portion or all of the CPP in the CPP-containing liquid to be adsorbed onto the coating agent, resulting in a CPP-containing liquid with a reduced CPP content. Furthermore, after contacting the adsorbent with the CPP-containing liquid, a separation step may be carried out, if necessary, to separate the CPP-containing liquid from the adsorbent.

[0080] Methods for removing CPP from a CPP-containing liquid include, for example, a method in which an adsorbent and a CPP-containing liquid are added to a container, and the two are brought into sufficient contact by standing or shaking, and then solid-liquid separation such as decanting or filtration is performed to obtain a CPP-containing liquid with a reduced CPP content; a method in which an adsorbent is filled into a container having an inlet and outlet for the CPP-containing liquid, and the CPP-containing liquid is allowed to flow from the inlet toward the outlet to bring the adsorbent and the CPP-containing liquid into sufficient contact, and a CPP-containing liquid with a reduced CPP content is obtained from the outlet; and the like.

[0081] 1) Blood Purifier and Blood Purifier System The present disclosure further encompasses a blood purifier including the adsorbent. It is known that some calcium ions in blood exist as CPPs, which can be causative agents of vascular calcification, chronic inflammation, and the like. It has also been reported that in patients with chronic kidney disease, the amount of CPPs in the blood increases with declining renal function and cannot be removed by conventional dialysis. Removing CPPs from the blood is meaningful in solving various problems caused by these CPPs. In a blood purifier, the adsorbent is preferably packed in a container having an inlet and an outlet. The blood purifier may be packed with one type of adsorbent, or two or more different types of adsorbents.

[0082] Specific examples of blood purifiers include CPP adsorption devices that mainly remove CPPs from blood; dialyzers (for example, dialyzers); plasma separators; and blood filters.

[0083] The present disclosure further includes a blood purification system having the blood purifier and a pump for supplying a liquid to the blood purifier. By providing the blood purification system with a pump, the CPP-containing liquid can be efficiently supplied to the blood purifier. The blood purification system may include one or more blood purifiers. When a single blood purification system includes two or more blood purifiers, the adsorbents filled in the blood purifiers may be the same or different from each other. Furthermore, when a single blood purification system includes two or more blood purifiers, the two or more blood purifiers may be installed in series or in parallel.

[0084] In a blood purification system, CPPs can be removed from blood by passing blood drawn from a patient through a blood purifier. The blood drawing rate (blood flow rate Qb) can be adjusted as needed, and in the case of humans, for example, it can be adjusted to 50 mL / min or more and 550 mL / min or less. The blood treatment frequency can be adjusted as needed depending on the patient's symptoms, severity, age, sex, etc., and can be, for example, from once to five times per week, and from one hour to eight hours or less per treatment. These blood flow rates and treatment frequencies are similar to those of the CPP adsorption system and dialysis system described below.

[0085] By adsorbing CPPs in the blood in this way, blood phosphorus concentration can be effectively reduced, and as a result, it becomes possible to treat diseases whose symptoms are alleviated or treated by reducing blood phosphorus concentration. Examples of diseases whose symptoms are alleviated or treated by reducing blood phosphorus concentration include cerebral infarction, angina pectoris, myocardial infarction, heart failure, cerebrovascular disease, pneumonia, digestive diseases, cardiac hypertrophy, sarcopenia, emphysema, thymic atrophy, adipose tissue atrophy, dementia, frailty, growth disorders, skin pruritus, valvular heart disease, secondary hyperparathyroidism, bone metabolism disorders such as osteoporosis, and calciphylaxis.

[0086] 2) CPP Adsorber and CPP Adsorption System The present disclosure further encompasses a CPP adsorber comprising the adsorbent. Because a CPP adsorber is a device primarily used to remove CPPs from blood, the CPP adsorber is suitable for applications targeting CPPs in blood for removal. In the CPP adsorber, the adsorbent is preferably packed in a container having an inlet and an outlet. The CPP adsorber may be packed with one type of adsorbent, or two or more different types of adsorbents. For CPP adsorber applications, it is particularly preferable to use a bead-shaped substrate.

[0087] The present disclosure further includes a CPP adsorption system having the CPP adsorber and a pump for supplying a liquid to the CPP adsorber. By including the pump in the CPP adsorption system, the CPP-containing liquid can be efficiently supplied to the CPP adsorber.

[0088] Here, a CPP adsorption system will be described with reference to FIG. 1 . The CPP adsorption system is not limited to the illustrated example, and appropriate modifications can be made within the scope of the above and below-described concepts, all of which are within the technical scope of the present invention. FIG. 1 is a schematic diagram showing an example of a CPP adsorption system. The CPP adsorption system preferably includes a CPP adsorber 1 and a pump 10. The same figure shows an enlarged cross-sectional view of a main portion of the CPP adsorber 1. As shown in this enlarged cross-sectional view, the CPP adsorber 1 preferably comprises a column 22 packed with a plurality of bead-shaped adsorbents 21. The coating agent according to the present invention is fixed to the surface of each bead-shaped substrate. In FIG. 1 , filters 23 are attached to both ends of the column 22 to prevent the bead-shaped adsorbents 21 from leaking while allowing blood to flow through the bead-shaped adsorbents 21. 1, covers 24a and 24b that can be fixed liquid-tightly to the column 22 with screws or the like are attached to the surface of the column 22 where the filter 23 is attached, and blood can be supplied to the beaded adsorbent 21 in the column 22 through a blood inlet 25a and a blood outlet 25b formed in the covers 24a and 24b. Note that a blood line I indicates the flow path of blood containing CPPs from the time it is withdrawn from a patient until it is returned to the patient.

[0089] In the CPP adsorption system, a blood purifier such as a dialyzer or a plasma separator (excluding the CPP adsorber) may be connected upstream or downstream of the CPP adsorber. By providing a blood purifier other than the CPP adsorption device in the CPP adsorption system, CPP removal and blood purification such as hemodialysis, plasma separation, and filtration can be performed simultaneously. For example, in FIG. 1 , the CPP adsorber 1 is connected downstream to the dialyzer 2, allowing CPP removal and hemodialysis to be performed simultaneously. The dialysate is supplied from the dialysate supply device 3 to the dialyzer 2 through the dialysis line II-A, passes through the dialyzer 2 from downstream to upstream, and then returns to the dialysate supply device 3 through the dialysis line II-B and is treated as waste liquid.

[0090] The CPP adsorption system may further include an arterial pressure monitor 11 and a venous pressure monitor 12. By including these, the blood purification process can be performed more safely. The CPP adsorption system preferably includes the arterial pressure monitor 11 upstream of the CPP adsorber 1. The CPP adsorption system preferably includes the venous pressure monitor 12 downstream of the CPP adsorber 1 (or, if a blood purifier other than the CPP adsorber 1 is included, the blood purifier other than the CPP adsorber 1).

[0091] The CPP adsorption system may include one or more CPP adsorbers. When a CPP adsorption system includes two or more CPP adsorbers, the adsorbents packed in the CPP adsorbers may be the same or different from one another. When a CPP adsorption system includes two or more CPP adsorbers, the two or more CPP adsorbers may be installed in series or in parallel.

[0092] 3) Dialyzer and Dialysis System The present disclosure further encompasses a dialyzer comprising the adsorbent. By using an adsorbent having CPP adsorption performance as a dialysis substrate, CPP removal and hemodialysis can be performed simultaneously. In the dialyzer, the adsorbent is preferably packed in a container having an inlet and an outlet. The dialyzer may be packed with one type of adsorbent, or two or more different types of adsorbents. Examples of dialyzers include hemodialysis devices and hemodiafiltration devices. These dialyzers may be hollow fiber type or laminated type (keel type). For dialyzer applications, it is particularly preferable to use a membrane-shaped substrate (more preferably a hollow fiber membrane). Note that membrane-shaped substrates also include dialysis membranes with large pores, known as high-performance membranes.

[0093] The present disclosure further includes a dialysis system having the dialyzer and a pump for supplying a liquid to the dialyzer. By including the pump in the dialysis system, the CPP-containing liquid can be efficiently supplied to the dialyzer. As the dialysis treatment, a general hemodialysis treatment can be performed.

[0094] A dialysis system will now be described with reference to FIG. 2. The dialysis system is not limited to the illustrated example, and appropriate modifications can be made within the scope of the above and below-described concepts, all of which are within the technical scope of the present invention. FIG. 2 is a schematic diagram showing an example of a dialysis system. The dialysis system preferably includes a dialyzer 2 and a pump 10. The dialyzer 2 is filled with a membrane-like adsorbent whose surface is coated with the coating agent of the present invention. Other than the adsorbent, the configuration is similar to that of a typical dialyzer (specifically, a dialyzer). The adsorbent is provided on a support and housed in a main body case having a blood inlet, a blood outlet, a dialysate inlet, and a dialysate outlet. The membrane-like adsorbent in FIG. 2 is composed of hollow fibers, and a coating agent is fixed to the inner surface of the hollow fibers. Blood line I indicates the flow path of blood containing CPPs from the time it is withdrawn from a patient to the time it is returned to the patient.

[0095] A dialysate supply device 3 is connected to the dialyzer 2. The dialysate is supplied from the dialysate supply device 3 to the dialyzer 2 through a dialysis line II-A, passes through the dialyzer 2 from the downstream side to the upstream side, and then returns to the dialysate supply device 3 through a dialysis line II-B and is treated as waste liquid.

[0096] The dialysis system may further include an arterial pressure monitor 11 and a venous pressure monitor 12. By including these, blood purification treatment can be performed more safely. The dialysis system preferably includes the arterial pressure monitor 11 upstream of the dialyzer 2. The dialysis system preferably includes the venous pressure monitor 12 downstream of the dialyzer 2.

[0097] A dialysis system may include one or more dialyzers. When a dialysis system includes two or more dialyzers, the adsorbents filled in the dialyzers may be the same or different from each other. When a dialysis system includes two or more dialyzers, the two or more dialyzers may be installed in series or in parallel.

[0098] This application claims the benefit of priority based on Japanese Patent Application No. 2024-056274, filed on March 29, 2024. The entire contents of the specification of Japanese Patent Application No. 2024-056274, filed on March 29, 2024, are incorporated herein by reference.

[0099] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples, and can of course be practiced with appropriate modifications within the scope of the above and below-described aims, all of which are included within the technical scope of the present invention. In the following, unless otherwise specified, "parts" means "parts by mass" and "%" means "% by mass."

[0100] <1. Solubility in Organic Solvent> Solubility in organic solvents was evaluated by adding 0.1 wt % of the solute to an organic solvent adjusted to a temperature within the range of 40 to 50°C, stirring for 24 hours, and then checking for the presence or absence of solid solute remaining in the organic solvent. If any solid solute remained, the weight of the solid was measured. If the solid solute remaining in the organic solvent was 0 to 0.001 wt %, the solute was considered to be soluble in the organic solvent. In the table, the solubility evaluation is indicated by "◯" meaning soluble in the organic solvent and "×" meaning insoluble in the organic solvent.

[0101] <2. Water Solubility> Solubility in aqueous solvents was evaluated by adding 0.1 wt % of the solute to an aqueous solvent adjusted to a temperature within the range of 40 to 50°C, stirring for 24 hours, and then checking for the presence or absence of solid solute remaining in the aqueous solvent. If any solid solute remained, the weight of the solid was measured. If the solid solute remaining in the aqueous solvent was 0 to 0.001 wt %, the solute was considered to be water-soluble. In the table, the solubility evaluation is indicated by "〇" meaning soluble in water and "×" meaning insoluble in water.

[0102] <3. Evaluation of Adsorption Performance> The adsorption performance of the adsorbent was evaluated by the following method. 1) Circulation Method When the substrate was a hollow fiber membrane (dialyzer), first, bovine serum albumin (Sigma-Aldrich) was dissolved in phosphorus-free DMEM (Thermo Fisher Scientific) and calcium-free DMEM (Thermo Fisher Scientific) to a concentration of 40 mg / mL, and bovine-derived Fetuin-A (Sigma-Aldrich) was dissolved in the latter to a concentration of 0.5 mg / mL, respectively, and then the resulting mixture was mixed and stirred at 37°C for 2 hours to prepare a CPP-containing solution. The amount of CPP in the CPP-containing solution before adsorption treatment was determined by adding a near-infrared fluorescent probe (Osteosense (registered trademark), IVISense Osteo 680 Fluorescent Probe) to the CPP-containing solution to bind to the CPP, followed by fractionation using a gel filtration spin column (Micro Biospin 30 column), and quantifying the fluorescence of the high molecular weight fraction containing CPP using a near-infrared scanner (Odyssey CLx Imaging System). Adsorption treatment was performed by circulating the CPP-containing solution through a hollow fiber membrane adsorbent (flow rate 200 mL / min, 37°C, 60 minutes). The CPP-containing solution used was in an amount such that the ratio of the volume of the hollow fiber membrane adsorbent to the volume of the CPP-containing solution was 1:1.0 to 1:1.5. The amount of CPP in the CPP-containing solution after adsorption treatment was quantified in the same manner as above, and the CPP adsorption rate was calculated based on formula (1). The calculated CPP adsorption rate was evaluated according to the following criteria: CPP adsorption rate (%) = (Q Ａ -Q Ｂ ) / Q Ａ ×100...(1) (In formula (1), Q Ａ : Amount of CPP in the CPP-containing solution before adsorption treatment, Q Ｂ (C: amount of CPP in CPP-containing solution after adsorption treatment) <Criteria> S: CPP adsorption rate is 30% or more, A: CPP adsorption rate is 10% or more and less than 30%, B: CPP adsorption rate is more than 0% and less than 10%, C: CPP adsorption rate is 0%

[0103] 2) Batch Method When the substrate was beads, a CPP-containing solution was prepared in the same manner as above, and the amount of CPP in the CPP-containing solution was quantified in the same manner as above. 3.2 mL of the CPP-containing solution was added to 0.2 mL of the obtained bead-shaped adsorbent, and the mixture was shaken at 37°C for 3 hours to perform an adsorption treatment. The CPP adsorption rate was calculated based on formula (1), and the CPP adsorption was evaluated based on the criteria shown in "1) Circulation Method."

[0104] <4. Dialysis Performance Evaluation (Clearance)> The clearance of the hollow fiber membrane adsorbent was measured in accordance with the aqueous performance evaluation in the "Performance Evaluation Method for Blood Purifiers 2012" established by the Japanese Society for Dialysis Therapy. The flow rate conditions were QB: 200 mL, QD: 500 mL. Furthermore, if the performance standard value for urea clearance of a type I hemodialyzer, 125 mL / min or more, as set forth in the "Function Classification of Blood Purifiers (Hollow Fiber Type) 2013" established by the Japanese Society for Dialysis Therapy, was met, it was determined that the clearance performance was maintained (indicated as "○" in the table).

[0105] <5. Content of Monomer Having Electron-Donating Group> ３１ The reaction rate between the adsorptive compound (C) and the reactive polymer (B) was obtained from the area of ​​the peak derived from the reacted ligand contained in the coating composition by PNMR analysis. Using the obtained reaction rate, the proportion of monomers containing an electron-donating group among the monomers constituting the polymer (A) was calculated.

[0106] 6. Molar concentration of electron-donating groups in the adsorbent Approximately 1 g of the adsorbent was weighed out into a conical beaker, and sulfuric acid and nitric acid were added to the adsorbent, followed by wet decomposition on a hot plate. The decomposition solution was adjusted to a constant volume of 50 mL, and the P content was measured by ICP-AES.

[0107] Example 1-1: Preparation of coating agent and coating composition Alendronate sodium trihydrate (Tokyo Chemical Industry Co., Ltd., CAS No.: 121268-17-5) was added to 1 M NaOH and stirred, and water was added to prepare a 0.16 g / mL solution. To 150 mL of this solution, 3.0 g of poly(methyl vinyl ether-alt-maleic anhydride) (Sigma-Aldrich, CAS No.: 9011-16-9) was added, and water was added so that the total amount became 300 g. The mixture was stirred at 45°C for 6 hours to obtain a coating composition.

[0108] Examples 1-2 to 1-8 Coating compositions were obtained in the same manner as in Example 1-1, except that the reactive polymer (B) and adsorptive compound (C) shown in Table 1 were used and the amounts of each were adjusted as shown in the table. The compounds in the table are as follows: Poly(ethylene-alt-maleic anhydride) (Sigma-Aldrich, CAS number: 9006-26-2) Polyethylene glycol diglycidyl ether (Tokyo Chemical Industry Co., Ltd., CAS number: 26403-72-5) Poly[(isobutylene-alt-maleic acid, ammonium salt)-co-(isobutylene-alt-maleic anhydride)] (Sigma-Aldrich, CAS number: 55893-87-3)

[0109] Examples 1-9 to 1-10 In Example 1-9, water was added to 0.1 g of neridronic acid (manufactured by Biosynth, CAS No. 79778-41-9) and 0.1 g of poly(methyl vinyl ether-alt-maleic anhydride) (manufactured by Sigma-Aldrich, CAS No. 9011-16-9) so that the total amount was 10 g, and the mixture was stirred at 45°C for 6 hours to obtain a coating composition. In Example 1-10, a coating composition was obtained in the same manner as in Example 1-9, except that neridronic acid was changed to disodium pamidronate (manufactured by Tokyo Chemical Industry Co., Ltd., CAS No. 57248-88-1).

[0110] Comparative Example 1 Water was added to 1.0 g of polyvinylpyrrolidone (manufactured by Thermo Scientific Chemicals, CAS No. 9003-39-8) so that the total amount became 100 g, and the mixture was stirred at 45° C. for 2 hours to obtain a colorless and transparent coating composition.

[0111]

[0112] Example 2-1: Production of coating agent and coating composition Tetrahydrofuran was added to 2.0 g of 12-mercaptododecylphosphonic acid (Sigma-Aldrich, CAS No.: 159239-33-5) and 1.0 g of poly(vinylbenzyl chloride) (Sigma-Aldrich, CAS No.: 121961-20-4) so ​​that the total amount was 100 g, and the mixture was stirred at 45°C for 5 hours to obtain a colorless and transparent coating composition.

[0113] Examples 2-2 to 2-4 Coating compositions were obtained in the same manner as in Example 2-1, except that the reactive polymer (B) and adsorptive compound (C) shown in Table 2 were used and the amounts thereof were adjusted as shown in the table. The compounds in the table are as follows. 11-mercaptoundecylphosphonic acid (Sigma-Aldrich, CAS No.: 156125-36-9) Poly(styrene-co-maleic anhydride) (partially isooctyl ester, cumene terminated, Sigma-Aldrich, CAS No.: 160611-46-1) Poly(styrene / maleic anhydride) (Polyscience, CAS No.: 9011-13-6) Poly(ethylene-co-methyl acrylate-co-glycidyl methacrylate) (Sigma-Aldrich, CAS No.: 51541-08-3)

[0114]

[0115] Example 3-1: Production of hollow fiber membrane adsorbent Water was passed through the blood inlet of a dialyzer (manufactured by Nipro Corporation, FB-150Uβeco, cellulose triacetate (CTA), inner diameter: 200 μm, membrane thickness: 15 μm) to pre-clean the inner surface. Next, 300 g of the coating composition produced in Example 1-1 was passed through the blood inlet at a flow rate of 50 mL / min for 30 minutes, and then compressed air was fed in to discharge the coating composition remaining inside the dialyzer. The dialyzer was then dried at 37°C for 24 hours to obtain a hollow fiber membrane adsorbent.

[0116] Examples 3-2 to 3-3 A hollow fiber membrane adsorbent was obtained in the same manner as in Example 3-1, except for using the following dialyzers: Example 3-2: Dialyzer (manufactured by Nipro Corporation, PES-15Sgαeco, polyethersulfone (PES), inner diameter: 200 μm, membrane thickness: 40 μm) Example 3-3: Dialyzer (manufactured by Fresenius Medical Care Japan, FX-S 140, polysulfone (PS), inner diameter: 185 μm, membrane thickness: 35 μm)

[0117] Examples 3-4 to 3-7 Hollow fiber membrane adsorbents were obtained in the same manner as in Example 3-1, except that the coating compositions shown in Table 3 were used.

[0118]

[0119] As shown in Table 3, the CPP adsorption rate was ranked B to S, confirming that the obtained adsorbent was capable of adsorbing CPP. It was also confirmed that, even after the coating agent was applied, the obtained adsorbent exhibited the inherent dialysis performance of the adsorbent itself, regardless of the substrate material. Furthermore, Table 3 confirmed that sufficient CPP adsorption performance was exhibited when the electron-donating group was 0.4 μmol or more per gram of adsorbent.

[0120] Example 4-1: Production of bead-shaped adsorbent To 100 g of the coating composition produced in Example 1-1, 25 mL of porous cellulose beads (exclusion limit molecular weight: 5,000,000, particle size: 400 to 500 μm) was added, stirred at room temperature for 30 minutes, and then filtered. The filtered porous cellulose beads were vacuum-dried overnight at 70° C. to obtain a bead-shaped adsorbent.

[0121] Examples 4-2 to 4-10, Comparative Example 2 Beaded adsorbents were obtained in the same manner as in Example 4-1, except that the coating compositions shown in Table 4 were used.

[0122]

[0123] As shown in Table 4, the CPP adsorption rate was ranked B to S, confirming that the obtained adsorbent was capable of adsorbing CPP.

[0124] As described above, all of the obtained adsorbents exhibited good CPP adsorption performance. Furthermore, even after processing with the coating agent, the substrate did not lose its inherent functionality. These findings demonstrate that the coating agent of the present invention can impart CPP adsorption functionality to various substrates.

[0125] 1: CPP adsorbent 2: Dialyzer 3: Dialysis fluid supply device 10: Pump 11: Arterial pressure monitor 12: Venous pressure monitor 21: Beaded adsorbent 22: Column 23: Filter 24a, 24b: Lid 25a: Blood inlet 25b: Blood outlet I: Blood line II-A, II-B: Dialysis fluid line

Claims

1. A coating agent for adsorbing calcium protein particles, which are complexes of calcium phosphate and protein, characterized in that the polymer (A) has at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphate group, a phosphono group, a phosphino group, and a thiol group.

2. The coating agent according to claim 1, wherein the polymer (A) has at least one phosphono group as the electron-donating group.

3. The coating agent according to claim 1, wherein the polymer (A) is soluble in an organic solvent.

4. The coating agent according to claim 1, wherein the polymer (A) is an organic solvent-soluble polymer to which an adsorptive compound (C) having one phosphono group as the electron-donating group and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group is bonded.

5. The coating agent according to claim 1, wherein the polymer (A) is soluble in both organic solvents and water.

6. The coating agent according to claim 1, wherein the polymer (A) is an organic solvent-soluble and water-soluble polymer to which an adsorptive compound (C) is bonded, the adsorptive compound (C) having two or more phosphono groups as the electron-donating groups and a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxyl group.

7. The coating agent according to claim 1, wherein the content of structural units derived from monomers containing electron-donating groups in the polymer (A) is 1 to 60 mol % of all structural units derived from monomers constituting the polymer (A).

8. The coating agent according to claim 1, wherein the polymer (A) is a polymer formed by bonding a reactive polymer (B) having at least one second functional group selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamido alkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group, and an adsorptive compound (C) having a first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the electron-donating group, through a reaction between the first functional group and the second functional group.

9. A coating composition comprising the coating agent according to any one of claims 1 to 8.

10. An adsorbent material having a substrate surface coated with the coating agent according to any one of claims 1 to 8.

11. The adsorbent according to claim 10, wherein the molar concentration of the electron-donating groups contained in the adsorbent is 0.4 μmol or more per gram of the adsorbent.

12. The adsorbent material according to claim 10, wherein the substrate is in the form of beads, monoliths, fibers or membranes.

13. The adsorbent material of claim 10, wherein the substrate has pores that allow hemodialysis.

14. A blood purifier comprising the adsorbent material according to claim 10.

15. A dialyzer comprising the adsorbent material of claim 10.

16. A blood purification system comprising: the blood purifier according to claim 14; and a pump for supplying a liquid to the blood purifier.

17. A dialysis system comprising: a dialyzer according to claim 15; and a pump for supplying a liquid to said dialyzer.

18. A method for producing an adsorbent, comprising the step of contacting a substrate with a coating composition containing the coating agent according to any one of claims 1 to 8 at 0 to 50°C for 0.1 to 2 hours.

Images