Dialysis membrane, method for manufacturing same, and method for using same

Abstract

The purpose of the present invention is to provide a dialysis membrane capable of removing CPPs while suppressing a reduction in minerals and capable of being suitably used for blood processing including the adsorption of CPPs. The present invention pertains to a dialysis membrane comprising a hollow fiber membrane or a semipermeable membrane which is a flat membrane, wherein said dialysis membrane is used for blood processing including the adsorption of calciprotein particles which are complexes of calcium phosphate and proteins, and has a compound (A) in which a film-forming polymer constituting the semipermeable membrane has, in a portion other than terminals of a main chain, at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphoric acid group, a phosphono group, a phosphino group, and a thiol group, and / or has, separately from the semipermeable membrane, at least one electron-donating group selected from the group consisting of an amino group, a carboxy group, a phosphoric acid group, a phosphono group, a phosphino group, and a thiol group.

Description

Dialysis membrane, its manufacturing method, and its use

[0001] The present invention relates to a dialysis membrane used in blood treatment involving the adsorption of calciprotein particles, a method for producing the same, 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 blood 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 conventional 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] The adsorber using the adsorbent disclosed in Patent Document 1 is specialized for removing CPPs. Therefore, in order to perform normal dialysis, which optimizes the concentrations of calcium and magnesium in the blood as renal replacement therapy, while also removing CPPs, a dialyzer that artificially removes excess water and waste products from the blood is required, and in the case of Patent Document 1, a dialyzer must be used in addition to the adsorber.

[0007] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a dialysis membrane that can remove CPPs while suppressing the reduction of minerals such as calcium and magnesium, and that can be suitably used for blood treatment including CPP adsorption.

[0008] As a result of extensive research to solve the above-mentioned problems, the present inventors have found that a dialysis membrane composed of a semipermeable membrane, in which the membrane-forming polymer constituting the semipermeable membrane has a specific electron-donating group at a portion other than the end of the main chain, and / or the dialysis membrane has a compound having a specific electron-donating group separate from the semipermeable membrane, can remove CPPs from the liquid to be treated (preferably blood) while suppressing the reduction of minerals, and have completed the present invention.

[0009] The gist of the present invention is as follows: [1] A dialysis membrane used for blood treatment including adsorption of calcium protein particles, which are complexes of calcium phosphate and protein, comprising a semipermeable membrane that is a hollow fiber membrane or a flat membrane, wherein the membrane-forming polymer constituting the semipermeable membrane 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 in a portion other than the main chain terminal, and / or the dialysis membrane comprises, in addition to the semipermeable membrane, a compound (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 dialysis membrane according to [1] above, wherein the compound (A) is an electron-donating group-containing low-molecular-weight compound having a molecular weight of 1,000 or less, or an electron-donating polymer compound which is a reaction product of the electron-donating group-containing low-molecular-weight compound and a base polymer, and a coating layer is formed on the surface of the semipermeable membrane, and the coating layer is composed of a polymer mixture composed of the electron-donating low-molecular-weight compound and a coating polymer, or the electron-donating polymer compound. [3] The dialysis membrane according to [1] or [2] above, wherein the dialysis membrane has at least one phosphono group as an electron-donating group. [4] The dialysis membrane according to any one of [1] to [3] above, wherein the molar concentration of the electron-donating group in the dialysis membrane is 0.4 μmol or more per 1 g of dialysis membrane. [5] The dialysis membrane according to any one of [1] to [4] above, wherein the membrane-forming polymer constituting the semipermeable membrane is at least one selected from the group consisting of cellulose, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer. [6] A dialyzer comprising the dialysis membrane according to any one of [1] to [5] above, packed in a container having an inlet and an outlet for a liquid. [7] A dialysis system comprising the dialyzer according to [6] above and a pump for supplying a liquid to the dialyzer.[8] The method for producing a dialysis membrane according to [2], comprising a step of coating the surface of a semipermeable membrane, which is a hollow fiber membrane or a flat membrane, with a coating agent composed of the polymer mixture or the electron-donating polymer compound. [9] The method for producing a dialysis membrane according to [8], wherein the coating agent is soluble in both organic solvents and water.

[10] The method for producing a dialysis membrane according to [8] or [9], wherein the electron-donating low molecular weight compound further has at least one first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the base polymer has at least one second functional group selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamidoalkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group, and the electron-donating low molecular weight compound and the base polymer comprise a step of reacting the electron-donating low molecular weight compound with the base polymer to produce the electron-donating polymer compound.

[11] The production method according to any one of the above-mentioned [8] to

[10] , wherein the semipermeable membrane is a hollow fiber membrane, and the inner surface of the hollow fiber membrane is coated by passing a coating composition containing the coating agent and water through the hollow fiber membrane.

[0010]

[12] Use of a dialysis membrane for adsorption of calciprotein particles, which are complexes of calcium phosphate and protein, wherein the dialysis membrane is composed of a semipermeable membrane that is a hollow fiber membrane or a flat membrane, and the dialysis membrane is such that the membrane-forming polymer constituting the semipermeable membrane 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 in a portion other than the main chain terminal, and / or the dialysis membrane contains a compound (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, separately from the semipermeable membrane, and the calciprotein particles are adsorbed by the electron-donating group.

[13] The use of the dialysis membrane according to

[12] above, wherein the compound (A) is an electron-donating group-containing low-molecular-weight compound having a molecular weight of 1,000 or less, or an electron-donating polymer compound which is a reaction product of the electron-donating group-containing low-molecular-weight compound and a base polymer, and a coating layer is formed on the surface of the semipermeable membrane, the coating layer being composed of a polymer mixture composed of the electron-donating low-molecular-weight compound and a coating polymer, or the electron-donating polymer compound.

[14] The use of the dialysis membrane according to

[12] or

[13] above, wherein the dialysis membrane has at least one phosphono group as the electron-donating group.

[15] The use of the dialysis membrane according to any one of

[12] to

[14] above, wherein the molar concentration of the electron-donating group in the dialysis membrane is 0.4 μmol or more per 1 g of dialysis membrane.

[16] Use of the dialysis membrane according to any one of the above-mentioned

[12] to

[15] , wherein the membrane-forming polymer constituting the semipermeable membrane is at least one selected from the group consisting of cellulose, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer.

[0011]

[17] A method for blood treatment including the adsorption of calciprotein particles, which are complexes of calcium phosphate and protein, comprising a step of treating blood with a dialysis membrane, wherein the dialysis membrane is composed of a semipermeable membrane that is a hollow fiber membrane or a flat membrane, and wherein the dialysis membrane is a membrane-forming polymer constituting the semipermeable membrane that 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 in a portion other than the main chain terminal, and / or the dialysis membrane contains a compound (A) separately from the semipermeable membrane that 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, and wherein the calciprotein particles are adsorbed by the electron-donating group.

[18] The method according to

[17] above, wherein the compound (A) is an electron-donating group-containing low molecular weight compound having a molecular weight of 1,000 or less, or an electron-donating polymer compound which is a reaction product of the electron-donating group-containing low molecular weight compound and a base polymer, and a coating layer is formed on the surface of the semipermeable membrane, and the coating layer is composed of a polymer mixture composed of the electron-donating low molecular weight compound and a coating polymer, or the electron-donating polymer compound.

[19] The method according to

[17] or

[18] above, wherein the dialysis membrane has at least one phosphono group as the electron-donating group.

[20] The method according to any one of

[17] to

[19] above, wherein the molar concentration of the electron-donating group in the dialysis membrane is 0.4 μmol or more per 1 g of dialysis membrane.

[21] The method according to any one of the above

[17] to

[20] , wherein the membrane-forming polymer constituting the semipermeable membrane is at least one selected from the group consisting of cellulose, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer.

[0012] The dialysis membrane of the present invention can remove CPPs from a liquid to be treated while suppressing the reduction of minerals. Furthermore, the use of the dialysis membrane of the present invention makes it possible to provide a dialysis system that includes CPP adsorption, which is easy to operate and easy to handle, without requiring the installation of a dialyzer and a CPP adsorber separately.

[0013] FIG. 1 is a schematic diagram showing an example of a dialysis system.

[0014] In the present disclosure, "calciprotein particle" refers to a complex of calcium phosphate and protein. More specifically, CPP refers to a complex of calcium phosphate (particularly Posner cluster; component is Ca9(PO4)6)) and protein such as Fetuin-A, and preferably refers to nanoparticles formed by 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 and the like (primary CPP), or a structure in which crystalline calcium phosphate is aggregated with Fetuin-A and the like, which is formed by subsequent phase transition (secondary CPP), with secondary CPP being preferred. CPPs also incorporate proteins present in body fluids other than Fetuin-A as complexes, 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. The 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 mutations in genes, etc. are also included.

[0015] The dialysis membrane according to the present invention, which will be described in detail below, is used for the adsorption of the above-mentioned CPPs and blood treatments that include CPP adsorption. Examples of blood treatments other than CPP adsorption using the dialysis membrane according to the present invention include hemodialysis, hemofiltration, and hemodiafiltration. 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 the dialysis membrane according to the present invention mainly adsorbs CPPs containing calcium phosphate crystals. Adsorbing CPPs, more specifically, means adsorbing CPPs present in blood. The dialysis membrane according to the present invention enables the removal of CPPs that cannot be separated by conventional dialysis or the like.

[0016] The liquid to be treated by the dialysis membrane of the present invention can be blood. Blood includes whole blood, plasma, serum, etc. The semipermeable membrane constituting the dialysis membrane of the present invention can also be used for body fluids other than blood, such as cerebrospinal fluid, ascites, lymph, intra-articular fluid, bone marrow fluid, and liquid components derived from living organisms, including fractions obtained from these fluids.

[0017] <Dialysis Membrane> The dialysis membrane of the present invention is characterized in that it is composed of a semipermeable membrane that is a hollow fiber membrane or a flat membrane, and the polymer (also referred to as a membrane-forming polymer) constituting the semipermeable membrane has at least one electron-donating group selected from the group consisting of an amino group (—NH), a carboxy group (a carboxylic acid group, —COOH), a phosphate group (—O-P(═O)(OH)), a phosphono group (a phosphonic acid group, —P(═O)(OH)), a phosphino group (—PH), and a thiol group (—SH) at a site other than the main chain terminal, and / or the dialysis membrane contains, in addition to the semipermeable membrane, a compound (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 is used for CPP adsorption and blood treatment including CPP adsorption. The electron-donating group in the dialysis membrane is a site that interacts with CPP, and CPP can be adsorbed by the electron-donating group. In the present disclosure, the term "polymer" refers to a polymer having a repeating structure in which a large number of one or more types of monomers are linked together, and preferably refers to a polymer having a weight average molecular weight (Mw) of 1,000 to 4,000,000.

[0018] <<Semipermeable Membrane>> The shape, dimensions, and fractionation characteristics of the semipermeable membrane constituting the dialysis membrane can be appropriately selected in light of the intended use of the dialysis membrane.

[0019] Examples of semipermeable membranes include nanofiltration membranes (NF membranes), ultrafiltration membranes (UF membranes), and microfiltration membranes (MF membranes), with ultrafiltration membranes and microfiltration membranes being preferred. Nanofiltration membranes typically have a pore size of about 1 to 2 nm, ultrafiltration membranes typically have a pore size of 2 to 100 nm, and microfiltration membranes typically have a pore size of 0.1 μm or more. The pores in the semipermeable membrane are preferably pores of a size that allows hemodialysis; specifically, they preferably have a plurality of pores of an appropriate size that do not allow red blood cells, white blood cells, etc. to pass through but allow electrolytes, waste products, water, etc. to pass through, with the pore size being more preferably 1.0 nm to 50 nm. When the semipermeable membrane is a hollow fiber membrane, it may be a membrane in which the pore size is the same on the inner (hollow) surface and the outer surface (homogeneous membrane), or it may be a membrane with different pore sizes (asymmetric membrane).

[0020] The semipermeable membrane is preferably composed of a membrane-forming polymer. The membrane-forming polymer constituting the semipermeable membrane is preferably one that has excellent safety, such as blood compatibility, when used as a dialysis membrane. The membrane-forming polymer is preferably at least one selected from the group consisting of cellulose (regenerated cellulose), cellulose acetate, cellulose diacetate, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer, more preferably at least one selected from the group consisting of cellulose, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer, even more preferably at least one selected from the group consisting of cellulose, cellulose triacetate, polysulfone, and polyethersulfone, and even more preferably at least one selected from the group consisting of cellulose triacetate, polysulfone, and polyethersulfone. The semipermeable membrane may contain additives such as hydrophilizing agents (e.g., polyvinylpyrrolidone, etc.). The content of the membrane-forming polymer in the semipermeable membrane is preferably from 60 to 100% by mass, more preferably from 80 to 100% by mass, and even more preferably from 90 to 100% by mass.

[0021] The thickness of the semipermeable membrane 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 a suitable rigidity and is therefore easy to handle.

[0022] The shape of the semipermeable membrane is a hollow fiber shape (hollow fiber membrane) or a flat membrane shape (flat membrane), with the hollow fiber shape being preferred. Hollow fiber membranes have a larger treatment area per unit volume than flat membranes, making it easier to improve the adsorption efficiency of CPPs.

[0023] The inner diameter of the hollow fiber membrane is preferably 50 to 500 μm, more preferably 80 to 400 μm, and even more preferably 130 to 300 μm. The effective length of the hollow fiber membrane is preferably 5 to 40 cm, more preferably 10 to 30 cm. Within this range, the flow of the liquid (preferably a liquid containing CPP, more preferably blood) flowing through the hollow fiber membrane is smooth, and the area of ​​the treatment surface of the hollow fiber membrane is sufficient, thereby improving the treatment efficiency of the dialysis membrane, including adsorption of CPPs.

[0024] <<Electron-donating group>> The dialysis membrane has an electron-donating group in the following manner (i) and / or (ii): Aspect (i): The membrane-forming polymer constituting the semipermeable membrane has an electron-donating group at a site other than the main chain terminal; Aspect (ii): The semipermeable membrane has a compound (A) having an electron-donating group separate from the semipermeable membrane. When the dialysis membrane has an electron-donating group in at least the above manner (i) or (ii), it is capable of adsorbing CPPs.

[0025] 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 oxoacids, 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 dialysis membrane has at least one phosphono group as the electron-donating group. Because phosphono groups are more easily adsorbed by CPPs than other electron-donating groups, the presence of a phosphono group as the electron-donating group is expected to improve the CPP removal efficiency of the dialysis membrane.

[0026] 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 C 1-6 alkyl group, and C 1-4 Alkyl groups are preferred, and C 1-2 An alkyl group is more preferred, and a methyl group is even more preferred.

[0027] The molar concentration of the electron-donating group in the dialysis membrane is 0.4 μmol or more per gram of dialysis membrane to efficiently adsorb CPPs, but can be, for example, 15 μmol or more, 50 μmol or more, 100 μmol or more, 300 μmol or more, or 800 μmol or more. There is no particular upper limit, but a practical upper limit is 1000 μmol or less. That is, the molar concentration of the electron-donating group in the dialysis membrane is preferably 0.4 to 1000 μmol per gram of dialysis membrane, and may be 15 to 1000 μmol, 50 to 1000 μmol, 100 to 1000 μmol, 300 to 1000 μmol, or 800 to 1000 μmol. When the dialysis membrane has multiple types of electron-donating groups, the total molar concentration of these groups is preferably within the above range. The molar concentration of the electron-donating group in the dialysis membrane can be measured by ICP atomic emission spectrometry (ICP-AES), ICP mass spectrometry, atomic absorption spectrometry, X-ray fluorescence spectrometry, etc. For example, the inorganic elements contained in the electron-donating group in the dialysis membrane can be quantified by ICP-AES (Inductively Coupled Plasma-Atomic Emission Spectrometry), and the molar concentration can be calculated based on the quantitative value.

[0028] In the case of aspect (i), the electron donating group may be present in any part of the film-forming polymer other than the main chain terminal, and may be present not only in the main chain but also in the side chain (including the side chain terminal), preferably in the main chain. When the electron donating group is present in the main chain, the electron donating group may be bonded to the main chain via a linker group, or may be bonded to the main chain as a pendant group. In the case of aspect (i), the electron donating group is preferably bonded to the main chain or side chain via a linker group (R1). The presence of the linker group (R1) increases the positional freedom of the electron donating group, making it easier for the electron donating group to adsorb to the CPP.

[0029] Examples of the linker group (R1) include C 1-18Examples 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 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 having —O—, —S—, —NH—, —C(═O)—, —O—C(═O)—, and / or —NH—C(═O)— at one end on the film-forming polymer side is preferred. 1-18 Hydrocarbon groups are more preferred.

[0030] 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 (R1)). 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.

[0031] Since the linker group (R1) mediates the bond between the film-forming polymer and the electron-donating group, when the number of electron-donating groups per linker group (R1) is n, the valence of the linker group (R1) is n + 1. For example, when the number of electron-donating groups per linker group (R1) is 2, the valence of the linker group (R1) is trivalent, bonding the film-forming polymer and two electron-donating groups.

[0032] The linker group (R1) may have a substituent. Examples of the substituent include a hydroxy group, a C 1-6Examples 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 (R1) 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 4, more preferably 1 to 3, and even more preferably 1 to 2). When the number of substituents per linker group (R1) is 2 or more, the multiple substituents may be the same or different from each other.

[0033] 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. 1-4 An alkoxy group is preferred, and C 1-2 An alkoxy group is more preferred, and a methoxy group is even more preferred.

[0034] Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group. A chloro group or a bromo group is preferred, and a chloro group is more preferred.

[0035] The number of electron-donating groups per linker group (R1) is preferably 1 or more, more preferably 2 or more. In particular, by having two or more electron-donating groups per linker group (R1), adsorption to CPPs is enhanced, allowing for greater CPP adsorption. On the other hand, if the number of electron-donating groups per linker group (R1) is too large, it may be difficult to introduce them into the membrane-forming polymer, so the number is preferably 5 or less, more preferably 4 or less, even more preferably 3 or less, and even more preferably 1 or 2 (i.e., preferably 1 to 5, more preferably 1 to 4, even more preferably 1 to 3, and even more preferably 1 to 2). Furthermore, when the number of electron-donating groups per linker group (R1) 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). Since groups having an acidic proton are easily adsorbed to CPPs, an improvement in the CPP removal efficiency of the dialysis membrane can be expected.

[0036] In the case of embodiment (ii), a compound (A) having an electron-donating group is contained in addition to the semipermeable membrane. The compound (A) may be a low-molecular-weight compound having an electron-donating group, or a polymer having an electron-donating group. Preferred examples of the compound (A) include the following compounds (A-1) and (A-2). Compound (A-1): A low-molecular-weight compound containing an electron-donating group and having a molecular weight of 1,000 or less Compound (A-2): An electron-donating polymer compound which is a reaction product of compound (A-1) and a base polymer

[0037] Compound (A-1) is not particularly limited as long as it is a compound having an electron-donating group and a molecular weight of not more than 1000. The molecular weight of compound (A-1) is preferably 50 to 1000, more preferably 100 or more, and more preferably 800 or less, and even more preferably 600 or less (i.e., preferably 50 to 1000, more preferably 100 to 1000, even more preferably 100 to 800, and still more preferably 100 to 600).

[0038] In addition to the electron-donating group, the compound (A-1) may further have a functional group (hereinafter also referred to as a first functional group) such as an amino group, an amide group, a carboxylic acid group (including activated carboxylic acid groups such as a carbonyl halide group, a carboxylic anhydride group, and a carboxylic ester group), a sulfonic acid group (including activated sulfonic acid groups such as a sulfonyl halide), an epoxy group, a thiol group, or a hydroxy group, and preferably has at least one first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group. Examples of the compound (A-1) include C 1-18 A compound in which an electron-donating group is bonded to a hydrocarbon is preferred, and C 1-18 A compound in which an electron-donating group and a first functional group are bonded to a hydrocarbon is more preferred.

[0039] Said C 1-18 Examples of hydrocarbons include aliphatic hydrocarbons having 1 to 18 carbon atoms, alicyclic hydrocarbons having 1 to 18 carbon atoms, and aromatic hydrocarbons having 6 to 18 carbon atoms, with aliphatic hydrocarbons having 1 to 18 carbon atoms being preferred, linear aliphatic hydrocarbons having 1 to 18 carbon atoms being more preferred, and linear saturated aliphatic hydrocarbons having 1 to 18 carbon atoms being even more preferred. 1-18 The number of carbon atoms in the hydrocarbon is preferably 2 or more, and is preferably 16 or less or 14 or less (that is, preferably 2 to 16, more preferably 2 to 14).

[0040] C 1-18 The hydrocarbon may have a substituent, and examples of the substituent include the same as those of the above-mentioned linker group (R1), and preferred embodiments thereof are also the same.

[0041] The compound (A-1) (particularly the compound (A-1) which gives the compound (A-2)) is a C 1-18 Hydrocarbons are preferred, and straight-chain saturated aliphatic hydrocarbons having 1 to 18 carbon atoms and having an electron-donating group and a first functional group bonded to both ends thereof are more preferred.

[0042] Examples of compound (A-1) include compounds having an amino group as a first functional group, such as pamidronic acid, alendronic acid, and neridronic acid; compounds having a thiol group as a first functional group, such as 11-mercaptoundecylphosphonic acid and 12-mercaptododecylphosphonic acid; and compounds having a hydroxy group as a first functional group, such as 2-hydroxyethylphosphonic acid, 2-hydroxyethylidenebisphosphonic acid and 6-hydroxyhexylphosphonic acid. These compounds may form salts or hydrates.

[0043] The base polymer from which compound (A-2) is derived is preferably a polymer having at least one functional group (hereinafter also referred to as a second functional group) selected from the group consisting of a halogenated alkyl group, a halogenated acetyl group, a halogenated acetamidoalkyl group, an epoxy group, a carboxy group, an isocyano group, a thioisocyano group, and an acid anhydride group.

[0044] The second functional group of the base polymer 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. The base polymer is also preferably a polymer that easily adheres to substrates, such as those used in surface modifiers, coating agents, adhesion promoters, paints, and film formers. Preferred examples of the base polymer 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.

[0045] Compound (A-2) may be any polymer compound obtained by reacting compound (A-1) with a base polymer, and is preferably, for example, a compound obtained by reacting a first functional group of compound (A-1) with a second functional group of the base polymer to form a bond, or a compound obtained by reacting a first functional group of compound (A-1) with a second functional group of the base polymer to form a bond via a linker group (R1-1), and more preferably, a compound obtained by reacting a first functional group of compound (A-1) with a second functional group of the base polymer to form a bond. Examples of the linker group (R1-1) include the same examples as those of the linker group (R1) above.

[0046] The compound (A-2) is preferably, for example, a polymer to which a CPP-adsorption ligand represented by the following formula (I) (hereinafter also referred to as CPP-adsorption ligand (I)) is bonded. Note that Y in formula (I) may be a group containing a group derived from the first functional group possessed by the compound (A-1), or a group containing a linker group (R1-1), or may be a group containing a group derived from the first functional group and a linker group (R1-1). Y is preferably a group containing at least a group derived from the first functional group. When the compound (A-2) is a polymer to 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 there is a high degree of freedom in the position of the electron-donating group, and the electron-donating group is more likely to be adsorbed to CPP.

[0047] [In formula (I), * represents a bond to the portion derived from 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(═O)—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.]

[0048] Y is preferably —O—, —S—, —NH—, —C(═O)—, —O—C(═O)—, or —NH—C(═O)—, more preferably —O—, —S—, or —NH—, and particularly preferably —S— or —NH—.

[0049] Specifically, the CPP adsorption ligand (I) includes a CPP adsorption ligand represented by formula (IA) (hereinafter also referred to as CPP adsorption ligand (IA)). The CPP adsorption ligand (IA) has a structure in which two or more electron-donating groups are close to each other, and therefore can more effectively adsorb CPP.

[0050] In formula (IA), * represents a bond to the portion derived from 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—.]

[0051] The CPP adsorption ligand (I) also includes a CPP adsorption ligand represented by formula (IB) (hereinafter also referred to as CPP adsorption ligand (IB)).

[0052] In formula (IB), * represents a bond to the portion derived from 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—.]

[0053] R 1 ~R 3 , R 1A ~R 3A , and R 1B ~R 3BThe electron-donating group represented by the formula (I) is the same as the one exemplified in the above section on electron-donating groups, and preferred embodiments thereof are also the same. 1-6 The alkoxy group and the halogeno group are the same as those exemplified in the linker group (R1) above, and the preferred embodiments thereof are also the same.

[0054] L, L A , and L B Divalent C represented by 1-17 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 It is a linear saturated hydrocarbon group. In this way, if the electron donating group is separated from the main chain of the base polymer and the structure has reduced steric hindrance, the electron donating group can easily adsorb CPP. 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. 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.

[0055] In compound (A-2), the content of structural units derived from monomers containing an electron-donating group among all structural units derived from structural monomers is preferably 1 to 60 mol %, more preferably 20 to 55 mol %, and even more preferably 35 to 50 mol %.

[0056] Here, the content of the structural unit derived from the monomer containing an electron-donating group 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, etc. For example, NMR measurement is performed, and the reactivity of compound (A-1) with the base polymer is calculated from the peak area of ​​the electron-donating group contained in compound (A-2) detected, thereby determining the content of the structural unit derived from the monomer containing an electron-donating group in compound (A-2).

[0057] <<Coating Layer>> The semipermeable membrane may be surface-treated as necessary, and may have a coating layer on its surface. When the dialysis membrane has electron-donating groups in the above-mentioned embodiment (ii), it is preferable that a coating layer composed of compound (A) is formed on the surface of the semipermeable membrane. The coating layer is preferably physically fixed to the surface of the semipermeable membrane, and more preferably, the coating layer is fixed to the surface of the semipermeable membrane by a mechanism other than chemical bonding (particularly covalent bonding). Since the coating layer having electron-donating groups is physically fixed to the surface of the semipermeable membrane, a dialysis membrane having electron-donating groups can be obtained more easily than a dialysis membrane in which electron-donating groups are introduced into the membrane-forming polymer constituting the semipermeable membrane. Furthermore, a dialysis membrane having electron-donating groups can be obtained in which deterioration of the semipermeable membrane (e.g., membrane thickness reduction and embrittlement) is suppressed compared to a dialysis membrane in which electron-donating groups are bonded to a semipermeable membrane formed using a membrane-forming polymer by chemical modification such as covalent bonding.

[0058] When compound (A) is compound (A-1), the coating layer is preferably composed of a polymer mixture (AI) composed of compound (A-1) and a coating polymer. When compound (A) is compound (A-2), the coating layer is preferably composed of compound (A-2). A coating layer composed of compound (A-2) makes it even more difficult for electron-donating groups to escape from the dialysis membrane than a coating layer composed of polymer mixture (AI), making it possible to obtain a dialysis membrane having electron-donating groups with high stability.

[0059] The coating polymer constituting the polymer mixture (AI) is not particularly limited, and may be any polymer that can form a coating layer on the surface of the semipermeable membrane and that can fix the compound (A-1) to the surface of the semipermeable membrane by the coating layer.

[0060] The coating polymer is preferably a polymer that has the property of easily adhering to a substrate, such as a polymer that is used in applications such as a surface modifier, coating agent, adhesion promoter, paint, film former, etc. Preferred coating polymers include polyvinylpyrrolidone, polyalkylene glycol, polyvinyl alcohol, polyethyleneimine, polyacrylic acid, carboxymethyl cellulose, hydroxypropyl cellulose, poly-2-methacryloyloxyethyl phosphorylcholine, poly(ethylene-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly(isobutylene-alt-maleic anhydride), poly(styrene / maleic anhydride), poly(ethylene-alt-maleic anhydride), poly(methyl vinyl ether ...methyl vinyl ether-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly(methyl vinyl ether-alt-maleic anhydride), poly( Examples of suitable polymers include poly(propylene-graft-maleic anhydride), poly(isoprene-graft-maleic anhydride), poly(ethylene-graft-maleic anhydride), poly(propylene glycol) diglycidyl ether, poly(glycidyl methacrylate), poly(ethylene-co-glycidyl methacrylate), poly(ethylene-co-methyl acrylate-co-glycidyl methacrylate), and poly(vinylbenzyl chloride), and these may be used alone or in combination of two or more. These polymers may be inorganic salts and may have functional groups at their terminals.

[0061] The coating polymer constituting the polymer mixture (AI) and / or the base polymer from which the compound (A-2) is derived may have the property of being soluble in organic solvents or water. Based on this property, the coating polymer and / or the base polymer can also be characterized. The coating polymer and / or the base polymer may or may not be soluble in organic solvents. The coating polymer and / or the base polymer may or may not be soluble in water.

[0062] 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.

[0063] 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.

[0064] The coating polymer and base polymer can be soluble in both organic solvents and water.

[0065] If the coating polymer and base polymer are soluble in organic solvents, the coating agent is less likely to be eluted during blood purification treatment. If the coating polymer and base polymer are water-soluble, a compound (A-1) having two or more electron-donating groups (preferably phosphono groups) exhibiting the same water solubility can be used. Compound (A-1) having two or more electron-donating groups has excellent adsorption properties for CPPs, which is desirable from the perspective of efficient removal of CPPs.

[0066] When the coating polymer or base polymer is soluble in an organic solvent (preferably soluble in an organic solvent but not soluble in water), the compound (A-1) is preferably a compound 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 hydroxy group, because it is easy to produce. For example, when the coating polymer or base polymer is soluble in an organic solvent, the compound (A-1) is preferably a compound 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. 1-18 A compound having one phosphono group bonded to one end of a linear alkane and one first functional group bonded to the other end is preferred. Compound (A-2) obtained from compound (A-1) may be a polymer having any of the above CPP adsorption ligands (IA) to (IB) bonded thereto, but a polymer having CPP adsorption ligand (IB) bonded thereto is preferred.

[0067] Examples of compounds 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 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 advisable to combine the coating polymer and base polymer with those that are 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).

[0068] When the coating polymer or base polymer is water-soluble (preferably water-soluble and organic solvent-soluble), the compound (A-1) is preferably a compound 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. For example, when the coating polymer or base polymer is water-soluble and organic solvent-soluble, the compound (A-1) is preferably a compound having C 1-18 A compound having two or three phosphono groups bonded to one end of a straight-chain alkane and one first functional group bonded to the other end is preferred. Compound (A-2) obtained from compound (A-1) may be a polymer having any of the above CPP adsorption ligands (IA) to (IB) bonded thereto, but a polymer having the above CPP adsorption ligand (IA) bonded thereto is preferred.

[0069] If the coating polymer and base polymer have both organic solvent solubility and water solubility, they will have good compatibility with various semipermeable membranes with hydrophilic or hydrophobic properties. In addition, the compound (A-1) having two phosphono groups includes compounds that are used as existing pharmaceuticals, and is therefore desirable from the viewpoint of safety.

[0070] Examples of compounds 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 coating polymer and base polymer may be combined with a polymer that is water-soluble and organic solvent-soluble, 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) and poly(ethylene-alt-maleic anhydride) are preferred due to their good CPP adsorption performance, and poly(methyl vinyl ether-alt-maleic anhydride) is more preferred.

[0071] The inventors have found that the organic solvent solubility and water solubility of the coating layer are correlated with the organic solvent solubility and water solubility of the polymer (coating polymer and / or base polymer) constituting the coating layer. In other words, if the polymer constituting the coating layer is soluble in an organic solvent, the coating layer tends to be soluble in an organic solvent, and if the polymer constituting the coating layer is soluble in water, the coating layer tends to be soluble in water. Therefore, if the properties of the polymer constituting the coating layer are known, the properties of the coating layer can also be understood to a certain extent.

[0072] Furthermore, the more 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) are contained in the polymer constituting the coating layer (for example, when this structural unit accounts for 40 mol% or more of all structural units in the polymer constituting the coating layer), the more likely the polymer constituting the coating layer will be soluble in both organic solvents and water. On the other hand, when the number of structural units having a highly hydrophilic functional group is reduced (for example, when this structural unit accounts for less than 40 mol% of all structural units in the polymer constituting the coating layer), the polymer constituting the coating layer will tend to be soluble in organic solvents but not in water.

[0073] When the dialysis membrane has a coating layer on the semipermeable membrane, the content of the coating layer in the dialysis membrane is preferably 0.1 to 98 parts by mass, more preferably 0.5 to 95 parts by mass, and even more preferably 1.0 to 93 parts by mass, per 100 parts by mass of the semipermeable membrane, from the viewpoints of CPP adsorption efficiency, solute permeability, and water permeability. Furthermore, the content of the coating layer in the dialysis membrane is preferably 0.5 to 95 g / m 2 of the surface of the semipermeable membrane, from the viewpoints of CPP adsorption efficiency, solute permeability, and water permeability. 2 The amount is preferably 1.0 to 90 g / m 2 More preferably, 2.0 to 85 g / m 2 is more preferable.

[0074] <Method for producing dialysis membrane> When the dialysis membrane has an electron-donating group in the above-mentioned aspect (i), first, a membrane-forming polymer having an electron-donating group at a site other than the main chain end is produced by including a monomer having an electron-donating group as a polymerization component of the membrane-forming polymer constituting the dialysis membrane, or by introducing an electron-donating group into the membrane-forming polymer.Then, a semipermeable membrane is formed using the membrane-forming polymer by a known method, thereby producing a dialysis membrane having an electron-donating group in the above-mentioned aspect (i).In addition, after forming a semipermeable membrane using the membrane-forming polymer by a known method, an electron-donating group can also be introduced into the membrane-forming polymer to produce a dialysis membrane having an electron-donating group in the above-mentioned aspect (i).

[0075] Examples of the monomer having an electron-donating group include a monomer having at least one electron-donating group and at least one carbon-carbon unsaturated bond. Examples include a monomer in which the electron-donating group and the carbon-carbon unsaturated bond are directly bonded, and a monomer in which the electron-donating group and the carbon-carbon unsaturated bond are bonded via a linker group (R2). From the viewpoint of CPP adsorption efficiency, a monomer in which the electron-donating group and the carbon-carbon unsaturated bond are bonded via a linker group (R2) is preferred. Examples of the linker group (R2) possessed by the monomer include the same examples as those for the linker group (R1), and preferred embodiments thereof are also the same. Examples of the carbon-carbon unsaturated bond include a vinyl group, a methacryloyl group, an acryloyl group, and the like.

[0076] An example of a method for introducing an electron-donating group into a film-forming polymer is to react a functional group possessed by the film-forming polymer with a compound (B) having an electron-donating group and a functional group reactive with the functional group. Examples of the compound (B) include the compounds exemplified as compound (A-1) that yields compound (A-2). The film-forming polymer may be provided with a functional group by incorporating a monomer having a functional group (e.g., a carboxylic acid anhydride such as maleic anhydride or itaconic anhydride) as a polymerization component.

[0077] The amount of electron-donating groups introduced into the membrane-forming polymer may be appropriately determined so that the molar concentration of the electron-donating groups in the dialysis membrane falls within the above range.

[0078] When the dialysis membrane has an electron-donating group in the above embodiment (ii) and the compound (A) is the compound (A-1), the compound (A-1) can be immobilized (preferably physically immobilized) by contacting the semipermeable membrane with the compound (A-1) using a known method. From the viewpoint of ease of production of the dialysis membrane, it is preferred to use a polymer mixture (AI) prepared by mixing the compound (A-1) with a coating polymer as the coating agent (C1) and immobilize the compound (A-1) on the semipermeable membrane by coating.

[0079] The coating agent (C1) may be obtained by simply mixing the compound (A-1) with the coating polymer without forming a covalent bond between them. The conditions for mixing the compound (A-1) with the coating polymer can be appropriately set depending on the type of compound (A-1) and the coating polymer used. When mixing the compound (A-1) with the coating polymer, the compound (A-1) 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 coating polymer. Within the above range, a coating agent (C1) can be produced that can impart sufficient CPP adsorption performance to the dialysis membrane and stably fix electron-donating groups to the dialysis membrane.

[0080] The compound (A-1) and the coating polymer can be mixed in the presence of a solvent. Examples of the solvent 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. For example, when the coating polymer is soluble in an organic solvent, the mixed solvent 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 coating polymer is soluble in both an organic solvent and water, the mixed 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 suitable solvent depending on the properties of the coating polymer, the production of the coating agent (C1) can be stabilized.

[0081] The mixing temperature for compound (A-1) and the coating polymer is preferably 0 to 80°C, more preferably 10 to 70°C, and even more preferably 20 to 60°C. The mixing time may be any time that allows compound (A-1) and the coating polymer to be sufficiently mixed and for compound (A-1) to be dispersed throughout the coating polymer.

[0082] When the dialysis membrane has an electron-donating group in the above embodiment (ii) and the compound (A) is the above compound (A-2), it is preferable to use the compound (A-2) as a coating agent (C2) and fix it to the semipermeable membrane by coating.

[0083] The coating agent (C2) can be produced, for example, by reacting the compound (A-1) with a base polymer. The reaction conditions can be appropriately set depending on the type of the first functional group that the compound (A-1) may have and the type of the second functional group that the base polymer may have. In the reaction between the compound (A-1) and the base polymer, the compound (A-1) 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 base polymer. Within the above range, a coating agent (C2) can be produced that can impart sufficient CPP adsorption performance to the dialysis membrane and stably fix electron-donating groups to the dialysis membrane.

[0084] The reaction between compound (A-1) and the base polymer can also be carried out in the presence of a solvent. Examples of the solvent 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. For example, when the base polymer is soluble in an organic solvent, preferred reaction solvents are hydrocarbon solvents (preferably hexane and toluene), ether solvents (preferably tetrahydrofuran), alcohol solvents (preferably 2-propanol), and ketone solvents (preferably acetone). When the base polymer is soluble in both an organic solvent and water, preferred reaction solvents are aqueous solvents (preferably water), hydrocarbon solvents (preferably toluene), ether solvents (preferably tetrahydrofuran), and alcohol solvents (preferably 2-propanol). By selecting a suitable solvent depending on the properties of the base polymer, the production of the coating agent (C2) can be stabilized.

[0085] The reaction temperature of the compound (A-1) with the base polymer 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 of the compound (A-1) with the base polymer proceeds stably.

[0086] The reaction time between the compound (A-1) and the base polymer 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 compound (A-1) and the base polymer proceeds sufficiently.

[0087] The coating agents (C1) and (C2) are preferably both organic solvent-soluble and water-soluble due to the properties of the coating polymer or base polymer. If the coating agent is both organic solvent-soluble and water-soluble, the coating layer formed using the coating agent can be made less susceptible to elution during blood treatment, and it is easy to form a coating layer that minimizes damage to the semipermeable membrane caused by solvents (especially organic solvents). As a result, a dialysis membrane suitable for CPP adsorption treatment can be obtained.

[0088] The inventors' investigations have revealed that the organic solvent solubility and water solubility of a coating agent are correlated with the organic solvent solubility and water solubility of the polymers (coating polymer and / or base polymer) that constitute the coating agent. In other words, if the polymers that constitute the coating agent are soluble in organic solvents, the coating agent tends to be soluble in organic solvents, and if the polymers that constitute the coating agent are soluble in water, the coating agent tends to be soluble in water. Therefore, if the properties of the polymers that constitute the coating agent are known, the properties of the coating agent can also be understood to a certain extent.

[0089] The coating amount of the coating agent (C1) and / or (C2) may be appropriately set so that the molar concentration of the electron-donating group in the dialysis membrane and the content (total content) of the coating layer in the dialysis membrane fall within the above-mentioned ranges.

[0090] When a dialysis membrane having a coating layer formed on the surface of a semipermeable membrane is produced using coating agent (C1) and / or (C2), the combination of the coating polymer or base polymer with compound (A-1) can be freely selected, making it possible to form a wide variety of coating layers. Furthermore, a dialysis membrane having electron-donating groups can be produced more easily by forming a coating layer on the surface of the semipermeable membrane having electron-donating groups, rather than by forming a membrane-forming polymer constituting the semipermeable membrane having electron-donating groups. Furthermore, forming a coating layer using coating agent (C2) makes it difficult for the electron-donating groups to escape from the dialysis membrane, allowing the dialysis membrane to have electron-donating groups with high stability.

[0091] The coating layer on the surface of the semipermeable membrane may be formed using a coating composition containing the coating agent (C1) and / or (C2). Use of the coating composition makes it easier to form the coating layer.

[0092] The coating composition may further contain a solvent. When the coating composition contains a solvent, the coating composition can be easily coated onto the semipermeable membrane, and the coating agent can be uniformly fixed on the surface of the semipermeable membrane. 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 (C1) and / or (C2) to be fixed on the surface of the semipermeable membrane by the simple process of coating, without impairing the properties of the coating agent (C1) and / or (C2).

[0093] The solvent used in the coating composition can also be selected depending on the properties of the coating polymer and / or base polymer. When the coating polymer or base polymer 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 coating polymer or base polymer is soluble in 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 coating polymer and / or base polymer, the coating agent (C1) and / or (C2) can be fixed to the surface of the semipermeable membrane by the simple procedure of coating while taking advantage of the properties of the coating agent (C1) and / or (C2).

[0094] The solvent used in the coating composition can also be selected depending on the type of semipermeable membrane to be coated. For example, when the semipermeable membrane is 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 type of semipermeable membrane, the coating agent (C1) and / or (C2) can be fixed to the surface of the semipermeable membrane by a simple operation of coating without impairing the properties of the semipermeable membrane.

[0095] 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.

[0096] The concentration of the coating agents (C1) and (C2) 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 agents (C1) and (C2) are adequately coated on the surface of the semipermeable membrane, and the CPP adsorption performance is fully exhibited.

[0097] The coating composition is produced by mixing the coating agent (C1) and / or (C2) with a solvent and additives as needed. Alternatively, the coating composition can be produced by producing the coating agent (C1) and / or (C2) and then using the resulting coating agent-containing liquid as a raw material for the coating composition. In the former case, the components can be appropriately mixed so that the coating agent (C1) and / or (C2) reaches the desired concentration. In the latter case, the concentration of the coating agent (C1) and / or (C2) in the coating composition can be adjusted by adjusting the amount of reaction solvent before producing the coating agent or by adding a solvent after producing the coating agent.

[0098] A method for producing a dialysis membrane having a coating layer on its surface preferably includes a step of contacting a semipermeable membrane with a coating composition containing coating agents (C1) and / or (C2) at 0 to 50°C for 0.1 to 2 hours. This contact step allows the coating agent (C1) and / or (C2) to be applied to the semipermeable membrane. The contacting method is not particularly limited, but examples include immersing the semipermeable membrane in the coating composition or passing the coating composition through the semipermeable membrane. If the semipermeable membrane is housed in a container, the shape of the container can be utilized during contact between the coating composition and the semipermeable membrane. For example, by utilizing the structure of a dialyzer in which hollow fiber membranes are housed in a container, the inner surface of the hollow fiber membrane can be coated by passing the coating composition through the hollow portion of the hollow fiber membrane from the treatment liquid inlet of the dialyzer. The contact temperature between the coating composition and the semipermeable membrane is preferably 5 to 40°C, more preferably 10 to 35°C. The contact time between the coating composition and the semipermeable membrane 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, a dialysis membrane with sufficient CPP adsorption performance can be produced without impairing the properties of the semipermeable membrane. The method for producing a dialysis membrane having a coating layer on its surface may further include a step of removing excess coating composition after the contact step by, for example, applying compressed air to the semipermeable membrane or performing a separation step such as filtration. The method for producing a dialysis membrane having a coating layer on its surface may further include a step of drying the semipermeable membrane coated with the coating composition after the contact step.

[0099] As a method for producing a dialysis membrane having a coating layer on the surface thereof, particularly when the semipermeable membrane is a hollow fiber membrane, a preferred method is to form a coating layer by passing a coating composition containing the coating agent (C1) and / or (C2) and water through the hollow fiber membrane to coat the inner surface of the hollow fiber membrane.

[0100] It is preferable that the inherent function of the semipermeable membrane is not significantly impaired even after coating. For example, 2The 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).

[0101] <Uses> The dialysis membrane of the present invention can adsorb CPPs while also performing other blood treatments, such as optimizing mineral concentrations. The dialysis membrane of the present invention can also be used for body fluids other than blood, such as cerebrospinal fluid, ascites, lymph, intra-articular fluid, bone marrow fluid, and liquid components derived from living organisms, including fractions obtained from these fluids.

[0102] It is known that some calcium ions in blood exist as CPPs, which can be causative agents of vascular calcification and chronic inflammation. It has also been reported that in patients with chronic kidney disease, the amount of CPPs in the blood increases with the decline in renal function, and that these CPPs cannot be removed by conventional dialysis. Removing CPPs from the blood is significant in solving various problems caused by these CPPs.

[0103] Compared to the use of a conventional CPP adsorber, the dialysis membrane of the present invention can suppress the loss of minerals such as calcium and magnesium from the treated liquid while adsorbing and removing CPPs. This is because the dialysis membrane of the present invention allows hemodialysis to be performed simultaneously with the adsorption and removal of CPPs. When a conventional CPP adsorber and a dialyzer are used, these devices are connected together. However, when a CPP adsorber and a dialyzer are connected together in this manner, it is not possible to completely eliminate the risk of the loss of minerals from the treated liquid, i.e., blood, and the amount of extracorporeal blood in the extracorporeal blood circulation is increased, and the handling of the device including the CPP adsorber and dialyzer is complicated. In contrast, blood treatment using the dialysis membrane of the present invention can suppress the loss of minerals while removing CPPs from blood. Furthermore, the amount of blood removed can be reduced, thereby reducing the processing load, and the number of treatment devices used can be reduced, thereby reducing the handling complexity of the device.

[0104] <<Dylaizer>> The dialysis membrane according to the present invention can be filled into a container and used as a dialyzer. The shape of the container is not particularly limited as long as it has an inlet and outlet for a liquid (e.g., an inlet and outlet for blood, and an inlet and outlet for dialysate). However, when the dialysis membrane is a hollow fiber membrane, a cylindrical container is preferred. When the dialysis membrane is composed of a hollow fiber membrane, it is preferable to use a hollow fiber membrane bundle in which multiple hollow fiber membranes are bundled. The number of hollow fiber membranes in the hollow fiber membrane bundle can be set appropriately and may be, for example, 300 to 100,000, 500 to 50,000, or 1,000 to 30,000.

[0105] In addition to adsorbing CPPs due to the CPP adsorption performance of the dialysis membrane, a dialyzer having the dialysis membrane of the present invention can also be used in extracorporeal blood treatments such as hemodialysis, hemofiltration, hemodiafiltration, blood component fractionation, oxygenation, and plasma separation. In particular, the dialyzer is preferably used in one blood treatment selected from the group consisting of hemodialysis, hemofiltration, and hemodiafiltration, in addition to adsorbing CPPs, and more preferably in performing CPP adsorption and hemodialysis simultaneously.

[0106] A dialyzer includes a container having a liquid inlet and outlet, and a dialysis membrane filled in the container. The liquid inlet and outlet may each be one or more. For example, a dialyzer has a configuration in which blood introduced through a blood inlet of the container and dialysate introduced through a dialysate inlet are brought into contact with each other via the dialysis membrane. In the case of a dialysis membrane in which the semipermeable membrane is a hollow fiber membrane, the liquid to be treated (blood) can be passed through the inside (hollow portion) of the hollow fiber membrane, and the dialysate can be passed through the outside of the hollow fiber membrane. The dialysate is not particularly limited, but examples thereof include ordinary dialysate and dialysate having a composition that can suppress the reduction of minerals in the liquid to be treated (blood).

[0107] <<Dialysis System>> The present disclosure also encompasses a dialysis system including the dialyzer and a pump that supplies a liquid to the dialyzer. By including the pump in the dialysis system, the liquid to be treated (blood) can be efficiently supplied to the dialyzer.

[0108] In a dialysis system, blood drawn from a patient is passed through a dialyzer to perform blood treatment, including adsorption and removal of CPPs. The blood drawing rate (blood flow rate Qb) can be adjusted as needed, and in the case of humans, it can be adjusted to 50 mL / min or more and 550 mL / min or less. The frequency of blood treatment 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 per treatment.

[0109] By adsorbing and removing CPPs from the blood in this way, blood phosphorus levels can be effectively reduced, making it possible to treat diseases whose symptoms can be alleviated or treated by reducing blood phosphorus levels. Examples of diseases whose symptoms can be alleviated or treated by reducing blood phosphorus levels 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.

[0110] A dialysis system will now be described with reference to FIG. 1 . 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 modifications are within the technical scope of the present invention. FIG. 1 is a schematic diagram showing an example of a dialysis system. The dialysis system preferably includes a dialyzer 1 and a pump 10. The figure shows an enlarged cross-sectional view of a main portion of the dialyzer 1. As shown in this enlarged cross-sectional view, the dialyzer 1 preferably includes a dialysis membrane 21 packed in a container 22. Specifically, the dialysis membrane in FIG. 1 is composed of a hollow fiber membrane having electron-donating groups on its surface. The dialyzer 1 is similar in configuration to a general dialyzer except for the dialysis membrane 21. The dialysis membrane 21 is mounted on a support 23 and housed in a container 22 having a blood inlet 25 a, a blood outlet 25 b, a dialysate inlet, and a dialysate outlet. 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.

[0111] A dialysate supply device 2 is connected to the dialyzer 1. The dialysate is supplied from the dialysate supply device 2 to the dialyzer 1 through a dialysis line II-A, passes through the dialyzer 1 from the downstream side to the upstream side, and then returns to the dialysate supply device 2 through a dialysis line II-B and is treated as waste liquid.

[0112] The dialysis system may further include an arterial pressure monitor 11 and a venous pressure monitor 12. By including these, blood processing can be performed more safely. The dialysis system may include the arterial pressure monitor 11 upstream of the dialyzer 1. The dialysis system may also include the venous pressure monitor 12 downstream of the dialyzer 1.

[0113] A dialysis system may include one or more dialyzers. When a dialysis system includes two or more dialyzers, the dialysis membranes filled in the dialyzers may be the same or different. When a dialysis system includes two or more dialyzers, the two or more dialyzers may be installed in series or in parallel.

[0114] This application claims the benefit of priority based on Japanese Patent Application No. 2024-056275, filed on March 29, 2024. The entire contents of the specification of Japanese Patent Application No. 2024-056275, filed on March 29, 2024, are incorporated herein by reference.

[0115] 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".

[0116] <1. Solubility in Organic Solvents> Solubility in organic solvents was evaluated by adding 0.1 wt % of a 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 deemed to be soluble in organic solvents. In the evaluation of organic solvent solubility in the table below, "Good" means that the solute is soluble in organic solvents, and "Poor" means that the solute is not soluble in organic solvents.

[0117] <2. Water Solubility> Solubility in aqueous solvents was evaluated by adding 0.1 wt % of a 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 content remained, the weight of the solid content was measured. If the solid content of the solute remaining in the aqueous solvent was 0 to 0.001 wt %, the substance was deemed to be water-soluble. In the water solubility evaluation in the table below, "Good" means water-soluble, and "Poor" means water-insoluble.

[0118] 3. Evaluation of CPP Adsorption Performance The CPP adsorption performance of the dialysis membrane was evaluated by the following method: First, bovine serum albumin (Sigma-Aldrich) was dissolved at a concentration of 40 mg / mL in phosphorus-free DMEM (Thermo Fisher Scientific) and bovine-derived Fetuin-A (Sigma-Aldrich) was dissolved at a concentration of 0.5 mg / mL in calcium-free DMEM (Thermo Fisher Scientific), respectively, and the solutions were then 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®, 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). The fluorescence of the high molecular weight fraction containing CPP was quantified using a near-infrared scanner (Odyssey CLx Imaging System). Adsorption treatment was performed by circulating the CPP-containing solution through the dialysis membrane (flow rate 200 mL / min, 37°C, 60 minutes). The CPP-containing solution was used in an amount such that the ratio of the volume of the dialysis membrane to the volume of the CPP-containing solution (volume of the dialysis membrane:volume of the CPP-containing solution) was 1:1.0 to 1:1.5. The amount of CPP in the CPP-containing solution after the adsorption treatment was quantified in the same manner as above, and the CPP adsorption rate was calculated based on the following formula (1): 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 : Amount of CPP in the CPP-containing solution after adsorption treatment)

[0119] <4. Evaluation of Mineral Reduction Rate> The mineral reduction rate by the dialysis membrane or adsorber was evaluated by the following method. A CPP-containing solution was prepared in the same manner as in item 3 above. The amount of minerals in the CPP-containing solution before CPP adsorption treatment was quantified by the Arsenazo III method for Ca and the xylidine blue method for Mg. An adsorption treatment was carried out by circulating 3.2 L of the CPP-containing solution through the dialysis membrane or adsorber (37°C, 240 minutes). The flow rate conditions for the dialysis membrane (dialyzer) were a CPP-containing solution side flow rate of 200 mL / min and a dialysate side flow rate of 500 mL / min, and the flow rate condition for the adsorber was 200 mL / min. The amount of minerals in the CPP-containing solution after adsorption treatment was quantified in the same manner as above, and the mineral reduction rate was calculated based on the following formula (2): Mineral reduction rate (%) = (Q C -Q D ) / Q C ×100...(2) (In formula (2), Q C : Amount of Ca or Mg in the CPP-containing solution before adsorption treatment, Q D (Calcium or magnesium amount in the CPP-containing solution after the adsorption treatment) Using the calculated mineral reduction rate, evaluation was performed according to the following criteria: <Criteria> ◯ (Good): Mineral reduction rate is less than 50% × (Poor): Mineral reduction rate is 50% or more

[0120] 5. Dialysis Performance Evaluation (Clearance) Measurement of the clearance of the dialysis membrane was performed 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 / min, QD: 500 mL / min. Furthermore, when the performance standard value of urea clearance for a type I hemodialyzer of 125 mL / min or more described in the "Function Classification of Blood Purifiers (Hollow Fiber Type) 2013" established by the Japanese Society for Dialysis Therapy was met, the clearance performance was evaluated as being maintained, and this is indicated by "○" in the table below.

[0121] 6. Content of Monomer Having Electron-Donating Group The content of structural units derived from a monomer having an electron-donating group in the compound (A-2) used as a coating agent in the coating composition was determined by the following method. 31The reactivity of compound (A-1) with the base polymer was calculated from the peak area of ​​the electron-donating group derived from compound (A-1) in compound (A-2) contained in the coating composition by PNMR analysis. The content of the monomer containing the electron-donating group among the monomers constituting compound (A-2) was calculated using the obtained reactivity.

[0122] 7. Molar concentration of electron-donating groups in dialysis membranes Approximately 1 g of dialysis membrane was weighed out into a conical beaker, and sulfuric acid and nitric acid were added to the membrane, 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. The molar concentration of the electron-donating groups in the membrane was calculated from the measured value.

[0123] Synthesis Example 1 Alendronate sodium trihydrate (Tokyo Chemical Industry Co., Ltd., CAS No.: 121268-17-5) was added to 1M NaOH and stirred, followed by addition of water to prepare a 0.16 g / mL solution. 3.0 g of poly(methyl vinyl ether-alt-maleic anhydride) (Sigma-Aldrich, CAS No.: 9011-16-9, Mw: 216,000) was added to 150 mL of this solution, and water was added to bring the total weight to 300 g. The mixture was stirred at 45°C for 6 hours to obtain Coating Composition 1. Coating Composition 1 contains an electron-donating polymer compound (compound (A-2)) produced by reacting alendronate sodium trihydrate with poly(methyl vinyl ether-alt-maleic anhydride) as a coating agent. The evaluation results for the solubility of the polymer and the calculated content of the monomer containing an electron-donating group are shown in Table 1.

[0124] Synthesis Example 2 Coating composition 2 was obtained in the same manner as in Synthesis Example 1, except that poly(methyl vinyl ether-alt-maleic anhydride) was changed to poly(ethylene-alt-maleic anhydride) (Sigma-Aldrich, CAS number: 9006-25-2).

[0125] Synthesis Example 3 To 0.1 g of neridronic acid (manufactured by Biosynth, CAS number: 79778-41-9) and 0.1 g of poly(methyl vinyl ether-alt-maleic anhydride) (manufactured by Sigma-Aldrich, CAS number: 9011-16-9), water was added so that the total amount was 10 g, and the mixture was stirred at 45° C. for 6 hours, to obtain Coating Composition 3.

[0126] Synthesis Example 4 Coating composition 4 was obtained in the same manner as in Synthesis Example 3, except that neridronic acid was changed to disodium pamidronate (manufactured by Tokyo Chemical Industry Co., Ltd., CAS number: 57248-88-1).

[0127] Synthesis Example 5 Coating composition 5 was obtained in the same manner as in Synthesis Example 1, except that the amount of the alendronate sodium trihydrate solution (0.16 g / mL) used was changed from 150 mL to 0.19 mL.

[0128] Synthesis Example 6 Coating composition 6 was obtained in the same manner as in Synthesis Example 1, except that the amount of the alendronate sodium trihydrate solution (0.16 g / mL) used was changed from 150 mL to 18.8 mL.

[0129] Synthesis Example 7 Coating composition 7 was obtained in the same manner as in Synthesis Example 1, except that the amount of alendronate sodium trihydrate solution (0.16 g / mL) used was changed from 150 mL to 75 mL.

[0130] Synthesis Example 8 Coating composition 8 was obtained in the same manner as in Synthesis Example 1, except that the concentration of the alendronate sodium trihydrate solution was changed to 0.25 g / mL and the amount of this solution used was changed to 264 mL.

[0131]

[0132] Example 1 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) containing a hollow fiber membrane (cellulose triacetate membrane) to pre-clean the inner surface. Next, coating composition 1 (300 g) produced in Synthesis Example 1 was passed through the blood inlet at a flow rate of 50 mL / min for 30 minutes, and then compressed air was pumped in to discharge the coating composition 1 remaining inside the dialyzer. The dialyzer was then dried at 37°C for 24 hours to obtain a dialysis membrane 1 in which the surface of the hollow fiber membrane was coated with a coating agent.

[0133] Example 2 A dialysis membrane 2 was obtained in the same manner as in Example 1, except that the dialyzer used was changed to a dialyzer having a hollow fiber membrane (polyethersulfone membrane) inside (manufactured by Nipro Corporation, PES-15SGαeco, polyethersulfone (PES), inner diameter: 200 μm, membrane thickness: 40 μm).

[0134] Example 3 Dialysis membrane 3 was obtained in the same manner as in Example 1, except that the dialyzer used was changed to a dialyzer having a hollow fiber membrane (polysulfone membrane) inside (manufactured by Fresenius Medical Care Japan, FX-S 140, polysulfone (PS), inner diameter: 185 μm, membrane thickness: 35 μm).

[0135] Example 4 A dialysis membrane 4 was obtained in the same manner as in Example 1, except that the coating composition used was changed to Coating Composition 5.

[0136] Example 5 A dialysis membrane 5 was obtained in the same manner as in Example 1, except that the coating composition used was changed to Coating Composition 6.

[0137] Example 6 A dialysis membrane 6 was obtained in the same manner as in Example 1, except that the coating composition used was changed to Coating Composition 7.

[0138] Example 7 A dialysis membrane 7 was obtained in the same manner as in Example 1, except that the coating composition used was changed to Coating Composition 8.

[0139] Comparative Example 1 An uncoated hollow fiber membrane (cellulose triacetate membrane) present in a dialyzer (manufactured by Nipro Corporation, FB-150Uβeco, cellulose triacetate (CTA), inner diameter: 200 μm, membrane thickness: 15 μm) was used as dialysis membrane X.

[0140] (Comparative Example 2) An alkaline aqueous solution was added to 40 mL of porous cellulose beads (molecular weight exclusion limit: 5,000,000, particle size: 400-500 μm) to bring the total volume to 80 mL, and then 30 mL of epichlorohydrin was added and the mixture was allowed to react at 40°C for 2 hours. After the reaction, the beads were thoroughly washed with water to obtain epoxidized cellulose beads. An aqueous solution of alendronic acid was added to the obtained epoxidized cellulose beads and the mixture was shaken at 50°C for 5 hours or more. The mixture was then thoroughly washed with water to obtain alendronic acid-immobilized cellulose beads. 30 g (dry weight) of the obtained alendronic acid-immobilized cellulose beads was packed into a container (volume: 250 mL) to obtain CPP adsorber X.

[0141] Using the dialysis membranes 1 to 7 and dialysis membrane X, adsorption performance evaluation, mineral reduction rate evaluation, and / or dialysis performance evaluation were carried out (Examples 1 to 7, Comparative Example 1). The mineral reduction rate evaluation was also carried out using adsorber X (Comparative Example 2). The results are shown in Table 2.

[0142]

[0143] As shown in Table 2, all of dialysis membranes 1 to 7 had CPP adsorption performance, and it was confirmed that the resulting dialysis membranes were capable of adsorbing CPPs. As can be seen from the results of Example 4 (dialysis membrane 4 using coating composition 5), it was confirmed that sufficient CPP adsorption performance was exhibited when the electron-donating groups per gram of dialysis membrane were 0.4 μmol or more. It was also confirmed that the dialysis membranes, even after having electron-donating groups, exhibited their inherent dialysis performance regardless of the semipermeable membrane material. Furthermore, it was confirmed that the dialysis membrane of the present invention was capable of removing CPPs from the treated liquid while suppressing the reduction of minerals compared to the case where a CPP adsorber was used.

[0144] Dialysis membranes produced in the same manner as in Example 1 except that the coating composition used was changed to one of Coating Compositions 2 to 4 were also confirmed to exhibit good CPP adsorption performance and dialysis performance while suppressing mineral reduction, similar to dialysis membranes 1 to 7.

[0145] 1: Dialyzer 2: Dialysis fluid supply device 10: Pump 11: Arterial pressure monitor 12: Venous pressure monitor 21: Dialysis membrane 22: Container 23: Support 25a: Blood inlet 25b: Blood outlet I: Blood line II-A, II-B: Dialysis fluid lines

Claims

1. A dialysis membrane used for blood treatment including the adsorption of calcium protein particles, which are complexes of calcium phosphate and protein, comprising a semipermeable membrane that is a hollow fiber membrane or a flat membrane, wherein the membrane-forming polymer constituting the semipermeable membrane 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 in a portion other than the main chain terminal, and / or the semipermeable membrane contains, in addition to the semipermeable membrane, a compound (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 dialysis membrane according to claim 1, wherein the compound (A) is a low molecular weight compound containing an electron-donating group and having a molecular weight of 1,000 or less, or an electron-donating polymer compound which is a reaction product of the low molecular weight compound containing an electron-donating group and a base polymer, and a coating layer is formed on the surface of the semipermeable membrane, the coating layer being composed of a polymer mixture composed of the electron-donating low molecular weight compound and a coating polymer, or the electron-donating polymer compound.

3. The dialysis membrane of claim 1, wherein the dialysis membrane has at least one phosphono group as an electron-donating group.

4. The dialysis membrane according to claim 1, wherein the molar concentration of the electron-donating group contained in the dialysis membrane is 0.4 μmol or more per gram of the dialysis membrane.

5. The dialysis membrane according to claim 1, wherein the membrane-forming polymer is at least one selected from the group consisting of cellulose, cellulose triacetate, polysulfone, polyethersulfone, polyester-based polymer alloy, polyacrylonitrile, polymethyl methacrylate, and ethylene-vinyl alcohol copolymer.

6. A dialyzer comprising a dialysis membrane according to any one of claims 1 to 5 packed in a container having an inlet and an outlet for a liquid.

7. A dialysis system comprising the dialyzer according to claim 6 and a pump for supplying a liquid to the dialyzer.

8. A method for producing a dialysis membrane according to claim 2, comprising a step of coating the surface of a semipermeable membrane, which is a hollow fiber membrane or a flat membrane, with a coating agent comprising the polymer mixture or the electron-donating polymer compound.

9. The manufacturing method according to claim 8, wherein the coating agent is soluble in both organic solvents and water.

10. The method according to claim 8, wherein the electron-donating low molecular weight compound further has at least one first functional group selected from the group consisting of an amino group, a thiol group, and a hydroxy group, and the base polymer has 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 the method comprises the step of reacting the electron-donating low molecular weight compound with the base polymer to produce the electron-donating polymer compound.

11. The method according to claim 8, wherein the semipermeable membrane is a hollow fiber membrane, and the inner surface of the hollow fiber membrane is coated by passing a coating composition containing the coating agent and water through the hollow fiber membrane.

Images