Semipermeable membrane and semipermeable membrane module

Abstract

A semipermeable membrane comprising a sulfonated polyarylene ether copolymer, wherein the sulfonated polyarylene ether copolymer includes a repeating unit of a hydrophobic segment represented by formula (1) and a repeating unit of a hydrophilic segment represented by formula (2) as copolymer components, and the solvation energy density of the entire semipermeable membrane is 170-225 kJ･mol-1･nm-3.

Description

Semipermeable membranes and semipermeable membrane modules

[0001] The present invention relates to a semipermeable membrane and a semipermeable membrane module.

[0002] In recent years, blood purification therapies using membrane separation technologies such as hemodialysis, hemofiltration, and hemodiafiltration have become more widely used not only for patients with chronic renal failure but also for patients with acute renal failure, and are now widely used in emergency departments, ICUs, etc.

[0003] In addition, COVID-19 infection can cause acute kidney injury, in which the kidneys suddenly stop functioning, or a cytokine storm, in which large amounts of inflammatory mediators circulate in the blood as a severe immune response to the virus. It is known that 15-30% of patients with severe COVID-19 symptoms develop acute kidney injury, and 67% develop organ dysfunction syndrome, which is thought to be caused by high levels of circulating cytokines.

[0004] Continuous renal replacement therapy (CRRT) is known for treating acute renal failure, organ dysfunction syndrome, etc., and involves gradually correcting body fluids (by reducing the circulating flow rate) over a longer period of time than is typically achieved with hemodialysis or hemofiltration. CRRT is used not only to replace kidney function, such as by removing fluids, removing waste products, and correcting electrolyte balance, but also to remove inflammatory mediators. For example, a single treatment of 24 to 48 hours is performed under conditions of a blood flow rate of 50 to 150 mL / min and a filtration rate of 5 to 50 mL / min.

[0005] A known example of a semipermeable membrane (blood treatment device) used in CRRT is Sepxylis® manufactured by Baxter Corporation. The semipermeable membrane used in Sepxylis contains a copolymer of acrylonitrile and sodium methacrylate sulfonate as its constituent material. This semipermeable membrane is thought to be primarily capable of adsorbing positively charged cytokines because its negatively charged sulfonate groups ionically bond with the amino groups of positively charged cytokines (see Artificial Organs, Vol. 43, No. 3, pp. 233-237, 2014 (Non-Patent Document 1)).

[0006] Furthermore, Japanese Patent No. 6817240 (JP 2018-171431 A (Patent Document 1)) discloses a hollow fiber membrane for blood purification that is blood compatible and capable of adsorbing cytokines. This hollow fiber membrane contains polymethyl methacrylate and sodium parastyrenesulfonate and has negatively charged sulfonate groups, and is therefore thought to be capable of adsorbing mainly positively charged cytokines.

[0007] Furthermore, Japanese Patent Laid-Open Publication No. 2001-70767 (Patent Document 2) discloses an ultrafiltration membrane for surface water treatment, which is made of a composition containing polyethersulfone, polyvinylpyrrolidone, and sulfonated polyethersulfone. However, this is an ultrafiltration membrane for water treatment, and there is no mention of a membrane for medical use.

[0008] Furthermore, International Publication No. 2018 / 025979 (Patent Document 3) describes that when the hydration energy density, etc. of a copolymer is within a predetermined range, the "copolymer" is excellent at inhibiting the adhesion of proteins, etc., and describes that the copolymer is used as a material for medical separation membranes.

[0009] Japanese Patent No. 6817240 (JP 2018-171431 A) Japanese Patent No. 2001-70767 International Publication No. 2018 / 025979

[0010] Artificial Organs, Vol. 43, No. 3, pp. 233-237, 2014

[0011] The above-mentioned conventional semipermeable membranes for continuous renal replacement therapy have a problem in that although they have a high adsorption capacity (removal performance) for positively charged substances, they have a low adsorption capacity for negatively charged substances.

[0012] Therefore, an object of the present invention is to provide a semipermeable membrane that has a high adsorption capacity for inflammatory mediators (both negatively charged substances and positively charged substances).

[0013] [1] A semipermeable membrane comprising a sulfonated polyarylene ether copolymer, wherein the sulfonated polyarylene ether copolymer comprises, as copolymerization components, a repeating unit of a hydrophobic segment represented by the following formula (1) and a repeating unit of a hydrophilic segment represented by the following formula (2):

[0014]

[0015]

[0016] R １ and R ２ is "-SO ３ M" where M represents a metal element, and the solvation energy density of the entire semipermeable membrane is 170 to 225 kJ mol －１ ・nm －３ That is, a semipermeable membrane.

[0017] [2] The semipermeable membrane according to [1], wherein the constituent ratio (molar ratio) of the formula (1) is 0.40 to 0.70, the constituent ratio (molar ratio) of the formula (2) is 0.30 to 0.60, and the sum of the constituent ratio (molar ratio) of the formula (1) and the constituent ratio (molar ratio) of the formula (2) is 1.00.

[0018] [3] The semipermeable membrane according to [1] or [2], comprising polyethersulfone, the sulfonated polyarylene ether copolymer, and polyvinylpyrrolidone.

[0019] [4] The semipermeable membrane according to [3], wherein the content ratio (mass ratio) of polyethersulfone / sulfonated polyarylene ether copolymer / polyvinylpyrrolidone in the entire semipermeable membrane is 75 to 90 / 7 to 22 / 3 to 18.

[0020] [5] The semipermeable membrane according to any one of [1] to [4], which is for continuous renal replacement therapy.

[0021] [6] The semipermeable membrane according to any one of [1] to [5], which has a non-uniform structure in the thickness direction.

[0022] [7] A semipermeable membrane module comprising the semipermeable membrane according to any one of [1] to [6].

[0023] [8] The semipermeable membrane module according to [7], which has a non-uniform structure in the thickness direction.

[0024] According to the present invention, it is possible to provide a semipermeable membrane having a high adsorption capacity for both negatively charged substances and positively charged substances.

[0025] 1 is a graph showing the relationship between the solvation energy density of the entire membrane and the cytokine removal rate in an example.

[0026] Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to these.

[0027] <Semipermeable membrane> <Solvation energy density> The solvation energy density of the entire semipermeable membrane of this embodiment is 170 to 225 kJ mol －１ ・nm －３ and preferably 175 to 220 kJ mol －１ ・nm －３ and more preferably 178 to 215 kJ mol －１ ・nm －３ and more preferably 180 to 210 kJ mol －１ ・nm －３ is.

[0028] In this specification, solvation energy refers to the amount of energy change that occurs when a target substance (solute) is placed in water (solvent). The unit of solvation energy is, for example, J mol －１ is used.

[0029] The solvation energy density of the copolymer is calculated based on the following formula (1).

[0030]

[0031] In formula (1), the "solvation energy of monomer unit i" is the absolute value of the energy of monomer unit i in water minus the energy of monomer unit i in vacuum, N represents the total number of monomer species constituting the copolymer, and i represents an integer of 1 to N.

[0032] The solvation energy density of a homopolymer is also calculated based on the formula (1) when N=1 (i.e., the following formula (2)). －１ ・nm －３ ) = {solvation energy of monomer unit} / {volume of monomer unit} Equation (2)

[0033] The "solvation energy of a monomer unit" refers to the absolute value of the value obtained by subtracting the energy of the monomer unit in vacuum from the energy of the monomer unit in water.

[0034] The energy of a monomer unit in vacuum and in water can be calculated in the following way.

[0035] First, the molecular model of the above monomer unit is structurally optimized. Density functional theory (DFT) is used for structural optimization. B3LYP is used as the functional and 6-31G(d,p) as the basis function. opt is set as the keyword to be written in the input file.

[0036] Next, the energy in vacuum and the energy in water are calculated for the optimized structure. Density functional theory is used to calculate the energy in vacuum. B3LYP is used as the functional and 6+31G(d,p) is used as the basis function. Density functional theory is used to calculate the energy in water. B3LYP is used as the functional and 6+31G(d,p) is used as the basis function. Furthermore, to calculate the energy in water, a continuum dielectric model is used, and the following keywords are used: SCRF=(PCM, G03Defaults, Read, Solvent=Water) Radii=UAHF Alpha=1.20

[0037] The "solvation energy of a monomer unit" is calculated as the absolute value of the value obtained by subtracting the energy of the monomer unit in vacuum (SCF energy) from the energy of the monomer unit in water (SCF energy). The SCF energy is the value of E written on the line labeled "SCF Done:".

[0038] The volume of the monomer unit can be calculated by, for example, COSMO calculation using quantum chemistry calculation software "Gaussian16" manufactured by Gaussian Corporation. Density functional theory is used for structural optimization in COSMO calculation. BVP86 is used as the functional, TZVP is used as the basis function, and DGA1 is used as the fitting basis. Furthermore, the following keywords are used: SCRF=(CPCM, READ) Radii=klamt The volume can be calculated by performing a single-point calculation on the structure optimized by COSMO calculation. BVP86 is used as the functional, TZVP is used as the basis function, and DGA1 is used as the fitting basis. Furthermore, the following keywords are used: SCRF=COSMORS

[0039] The "molar fraction of monomer units" in the above formula (1) can be calculated from the peak area obtained by measurement using a nuclear magnetic resonance (NMR) device. If the mole fraction cannot be calculated by NMR measurement due to overlapping of peaks or other reasons, the mole fraction may be calculated by elemental analysis.

[0040] (Solvation Energy Density of the Entire Semipermeable Membrane) In this specification, the solvation energy density of the entire semipermeable membrane is the volume average value of the solvation energy densities of the components constituting the semipermeable membrane.

[0041] For example, when the semipermeable membrane is composed of polyethersulfone, sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone, the solvation energy density of the entire semipermeable membrane is the volume average value of the solvation energy density of SPN calculated based on the above formula (1), the solvation energy density of polyethersulfone calculated based on the above formula (2), and the solvation energy density of polyvinylpyrrolidone calculated based on the above formula (2).

[0042] In general, the solvation energy tends to be larger when there are more polarized functional groups, such as carbonyl groups (e.g., ester groups or amide groups), in the molecule compared to alkyl groups. Furthermore, for the same solvation energy, the smaller the volume of the monomer, the larger the solvation energy density.

[0043] Therefore, the solvation energy density of the entire semipermeable membrane can be adjusted by adjusting the type of polymer constituting the semipermeable membrane and the molar fraction of each polymer. For example, when the semipermeable membrane is composed of polyethersulfone, SPN, and polyvinylpyrrolidone, the solvation energy density of the entire semipermeable membrane can be adjusted by adjusting the molar fraction of each of the polyethersulfone, SPN, and polyvinylpyrrolidone. The solvation energy density of the entire copolymer (e.g., SPN) can be adjusted by adjusting the molar fraction of each monomer unit constituting the copolymer.

[0044] <Composition of Semipermeable Membrane> The semipermeable membrane of this embodiment contains a sulfonated polyarylene ether copolymer (hereinafter, sometimes abbreviated as "SPN"). SPN is a negatively charged polymer.

[0045] The semipermeable membrane of this embodiment preferably contains polyethersulfone (a hydrophobic polymer), sulfonated polyarylene ether copolymer (SPN: a negatively charged polymer), and polyvinylpyrrolidone (a hydrophilic polymer).

[0046] (Polyethersulfone) Polyethersulfone is a compound containing a structural unit represented by the following formula (3): Polyethersulfone is expected to have the effect of adsorbing inflammatory mediators through hydrophobic interaction.

[0047]

[0048] (Sulfonated Polyarylene Ether Copolymer) The sulfonated polyarylene ether copolymer is a compound containing a repeating unit of a hydrophobic segment represented by the following formula (1) and a repeating unit of a hydrophilic segment represented by the following formula (2).

[0049]

[0050]

[0051] In the above formula (2), R １ and R ２Each of the is independently "-SO ３ M" or "-SO ３ H" where M represents a metal element.

[0052] The constituent ratio (molar ratio) of the above formula (1) is preferably 0.40 to 0.70, more preferably 0.45 to 0.67, and even more preferably 0.50 to 0.60. The constituent ratio (molar ratio) of the above formula (2) is preferably 0.30 to 0.60, more preferably 0.33 to 0.55, and even more preferably 0.40 to 0.50. The sum of the constituent ratio (molar ratio) of the above formula (1) and the constituent ratio (molar ratio) of the above formula (2) is 1.00.

[0053] When the above-mentioned composition ratio is within the above-mentioned range, the effects of both the hydrophilic segment and the hydrophobic segment are such that the interaction between the SPN and its adsorbed water present on the surface of the semipermeable membrane and the positively and negatively charged substances and their adsorbed water becomes appropriate, resulting in a semipermeable membrane having high adsorption capacity for both positively and negatively charged substances.

[0054] The sulfonated polyarylene ether copolymer may be any of a random copolymer, a block copolymer, an alternating copolymer, and the like.

[0055] There is no particular limitation on M (metal element), but examples thereof include sodium, potassium, and lithium.

[0056] In the sulfonated polyarylene ether copolymer, R １ and R ２ is "-SO ３ Na" or "-SO ３ It is more preferable that it is "K".

[0057] The sulfonated polyarylene ether copolymer is a material that undergoes little change over time during long-term use of the membrane.

[0058] The sulfonated polyarylene ether copolymer can be obtained by conventional methods. For example, 2,6-dichlorobenzonitrile, 3,3'-disulfo-4,4'-dichlorodiphenyl sulfone metal salt, and 4,4'-biphenol are reacted in the presence of a basic compound to polymerize via an aromatic nucleophilic substitution reaction, resulting in a copolymer comprising a hydrophobic segment represented by the above formula (1) and a hydrophilic segment represented by the above formula (2). The polymerization can be carried out at a temperature ranging from 0 to 350°C, with a temperature of 50 to 250°C being preferred. Temperatures below 0°C tend to prevent the reaction from proceeding sufficiently, while temperatures above 350°C tend to cause decomposition of the polymer. The reaction can be carried out without a solvent, but is preferably carried out in a solvent. Usable solvents include, but are not limited to, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, diphenyl sulfone, and sulfolane, as long as they are stable solvents in aromatic nucleophilic substitution reactions. Examples of basic compounds include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. However, any compound capable of converting aromatic diols to an active phenoxide structure can be used without limitation. In aromatic nucleophilic substitution reactions, water may be produced as a by-product. In this case, toluene or other solvents can be added to the reaction system to form an azeotrope and remove the water from the system, regardless of the polymerization solvent. A water-absorbing material such as a molecular sieve can also be used to remove the water from the system. When the aromatic nucleophilic substitution reaction is carried out in a solvent, it is preferable to charge the monomers so that the resulting polymer concentration is 5 to 50% by mass. If the concentration is less than 5% by mass, the degree of polymerization tends to be difficult to increase. On the other hand, if the concentration is more than 50% by mass, the viscosity of the reaction system tends to be too high, making post-treatment of the reactant difficult. After the polymerization reaction is completed, the solvent is removed from the reaction solution by evaporation, and the residue is washed as necessary to obtain the desired polymer (sulfonated polyarylene ether copolymer).Alternatively, the reaction solution may be added to a solvent in which the polymer has low solubility, thereby precipitating the polymer as a solid, and the polymer may be obtained by filtering the precipitate.

[0059] (Polyvinylpyrrolidone) Polyvinylpyrrolidone is a polymer of monomers containing at least N-vinylpyrrolidone.

[0060] The polyvinylpyrrolidone preferably contains a structural unit represented by the following formula (4).

[0061]

[0062] The polyvinylpyrrolidone that can be used is, for example, one manufactured by BASF with a weight average molecular weight of 9,000 (K17), 450,000 (K60), or 1,200,000 (K90).

[0063] The content ratio of polyethersulfone / sulfonated polyarylene ether copolymer / polyvinylpyrrolidone in the entire semipermeable membrane is preferably 75 to 90 / 7 to 22 / 3 to 18% by mass.

[0064] The semipermeable membrane preferably has a non-uniform structure in the thickness direction (asymmetric structure), and more preferably has a dense layer on the inner surface side and a structure in which the pore size increases continuously or discontinuously from the inner surface to the outer surface (asymmetric structure).

[0065] An example of a semipermeable membrane having an asymmetric structure (asymmetric membrane) is a membrane in which the dense layer is a separation active layer that essentially determines the pore size of the semipermeable membrane. Although the pore size of the dense layer cannot be measured directly, the dense layer is defined as the molecular weight cutoff of SC dextran measured using a semipermeable membrane having a dense layer. In the present invention, the molecular weight cutoff of SC dextran measured in this manner is preferably 100 kDa or less. From the viewpoint of membrane durability (filtration stability), the semipermeable membrane is preferably an asymmetric membrane.

[0066] In addition, the semipermeable membrane having an asymmetric structure may have different constituent components in the thickness direction of the membrane.

[0067] In hollow fiber membranes having an asymmetric structure, the porosity of the inner surface is preferably different from the porosity of the outer surface. The porosity of the outer surface of the hollow fiber membrane is preferably 29% or more, more preferably 30% or more. The porosity of the outer surface of the hollow fiber membrane is determined from an image taken with a scanning electron microscope (SEM) as described below.

[0068] Examples of the semipermeable membrane include nanofiltration membranes (NF membranes), ultrafiltration membranes (UF membranes), and microfiltration membranes (MF membranes). The semipermeable membrane is preferably an ultrafiltration membrane.

[0069] Typically, the pore size of an NF membrane is about 1 to 2 nm, the pore size of an UF membrane is about 2 to 100 nm, and the pore size of an MF membrane is about 0.1 μm or more.

[0070] The shape of the semipermeable membrane is not particularly limited. The semipermeable membrane may be a flat membrane or a hollow fiber membrane (hollow fiber type semipermeable membrane), but is preferably a hollow fiber membrane. Hollow fiber membranes are advantageous in that they can increase the membrane area per module compared to flat membranes.

[0071] The semipermeable membrane of this embodiment is preferably a semipermeable membrane for continuous renal replacement therapy that has the ability to remove inflammatory mediators.

[0072] Inflammatory mediators are physiologically active substances (algesic substances, prostanoids, cytokines) released from leukocytes, mast cells, macrophages, etc. that infiltrate damaged tissue or inflammatory sites. Inflammatory mediators include positively charged substances and negatively charged substances. Examples of positively charged substances include interleukin-8 (IL-8), interleukin-10 (IL-10), transforming growth factor β (TGF-β), monocyte chemotactic factor 1 (MCP1), platelet-derived growth factor (PDGF), etc. Examples of negatively charged substances include interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1β (IL-1β), HMGB1 (High Mobility Group Box 1), tumor necrosis factor α (TNF-α), etc.

[0073] <Semipermeable membrane module> The present invention also relates to a semipermeable membrane module (membrane separator, membrane separation device) including the semipermeable membrane. The semipermeable membrane module is not particularly limited as long as it is a separator (separation device) that can perform separation (solid-liquid separation, liquid-liquid separation, etc.) using the semipermeable membrane.

[0074] In a semipermeable membrane module using the hollow fiber membrane (for example, the continuous slow hemofilter described above), it is preferable that the dialysis fluid flows outside the hollow fiber membrane and the blood flows inside the hollow fiber membrane (hollow portion).

[0075] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0076] (Preparation of sulfonated polyarylene ether copolymer (SPN)) 3,3'-disulfo-4,4'-dichlorodiphenyl sulfone disodium salt, 2,6-dichlorobenzonitrile, 4,4'-biphenol, potassium carbonate, and molecular sieves were weighed into a four-neck flask and flushed with nitrogen. NMP was added and the mixture was stirred at 150°C for 50 minutes, after which the reaction temperature was raised to 195-200°C and the reaction was continued until the viscosity of the system had sufficiently increased. The mixture was then allowed to cool, and the precipitated molecular sieves were removed, and the polymer was precipitated in water. The obtained polymer was washed in boiling water for 1 hour and then carefully washed with pure water to completely remove residual potassium carbonate. The polymer after removing the potassium carbonate was then dried to obtain sulfonated polyarylene ether copolymer (SPN).

[0077] The SPN (copolymer of the above formula (1) and formula (2)) used in each of the examples and comparative examples was any of SPN15, SPN33, SPN44, SPN55, and SPN65 shown in Table 1. These SPNs were prepared by varying the charging ratio of 3,3'-disulfo-4,4'-dichlorodiphenyl sulfone disodium salt and 2,6-dichlorobenzonitrile in the preparation of the above SPNs. In SPN15, the molar ratio of (1) was 0.85, and the molar ratio of (2) was 0.15. In SPN33, the molar ratio of (1) was 0.67, and the molar ratio of (2) was 0.33. In SPN44, the molar ratio of (1) was 0.56, and the molar ratio of (2) was 0.44. In SPN55, the molar ratio of (1) is 0.45, and the molar ratio of (2) is 0.55. In SPN65, the molar ratio of (1) is 0.35, and the molar ratio of (2) is 0.65.

[0078] (Preparation of hollow fiber membranes of Examples 1 to 3 and Comparative Examples 4 and 5) Polyethersulfone (PES, manufactured by Sumitomo Chemical), sulfonated polyarylene ether copolymer (SPN obtained above), polyvinylpyrrolidone K-90 (PVP, manufactured by Nippon Shokubai), 46.2 mass% of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 30.8 mass% of triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were heated and dissolved uniformly. The charging ratios of polyethersulfone (PES), sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone (PVP) are as shown in Table 1. The obtained spinning solution was discharged from a tube-in-orifice nozzle heated to 55 ° C. together with a hollow forming material (NMP / TEG / water = 12 / 8 / 80), passed through a 200 mm dry section isolated from the outside air by a spinning tube, and then coagulated in a 74 ° C. coagulation bath (NMP / TEG / water = 24 / 16 / 60), passed through a water washing bath at 80 ° C., and then wound up at a spinning speed of 37 m / min with a reeling machine. The obtained hollow fiber membrane (bundle) was washed with warm water at 70 ° C. to remove excess solvent, etc., and then immersed in a 60 mass% glycerin solution at 60 ° C. to fill the pores with an aqueous glycerin solution. The excess glycerin aqueous solution adhering to the hollow fiber membrane surface was removed by centrifugal deliquoring and then dried at 60 ° C. The obtained hollow fiber membrane had a dense layer on the inner surface side, an inner diameter of 0.240 mm, and an outer diameter of 0.350 mm.

[0079] (Preparation of hollow fiber membranes of Examples 4 to 6) Polyethersulfone (PES, manufactured by Sumitomo Chemical), sulfonated polyarylene ether copolymer (SPN obtained above), polyvinylpyrrolidone K-90 (PVP, manufactured by Nippon Shokubai), 46.8 mass% N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 31.2 mass% triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were heated and uniformly dissolved. The charging ratios of polyethersulfone (PES), sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone (PVP) are as shown in Table 1. Other conditions were the same as in Example 1, and hollow fiber membranes were produced.

[0080] (Preparation of hollow fiber membranes of Examples 7 to 12 and Comparative Examples 1, 2, 6, and 7) Polyethersulfone (PES, manufactured by Sumitomo Chemical), sulfonated polyarylene ether copolymer (SPN obtained above), polyvinylpyrrolidone K-90 (PVP, manufactured by Nippon Shokubai), 48.0% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 32.0% by mass of triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were heated and uniformly dissolved. The charging ratios of polyethersulfone (PES), sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone (PVP) are as shown in Table 1. Other conditions were the same as in Example 1, and hollow fiber membranes were produced.

[0081] (Preparation of hollow fiber membrane of Example 13) Polyethersulfone (PES, manufactured by Sumitomo Chemical), sulfonated polyarylene ether copolymer (SPN obtained above), polyvinylpyrrolidone K-90 (PVP, manufactured by Nippon Shokubai), 47.4 mass% N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 31.6 mass% triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were heated and dissolved uniformly. The charging ratios of polyethersulfone (PES), sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone (PVP) are as shown in Table 1. A hollow fiber membrane was produced under the same conditions as in Example 1, except for the above.

[0082] (Preparation of hollow fiber membrane of Example 14) Polyethersulfone (PES, manufactured by Sumitomo Chemical), sulfonated polyarylene ether copolymer (SPN obtained above), polyvinylpyrrolidone K-90 (PVP, manufactured by Nippon Shokubai), 46.8 mass% N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 31.2 mass% triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were heated and dissolved uniformly. The charging ratios of polyethersulfone (PES), sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone (PVP) are as shown in Table 1. A hollow fiber membrane was produced under the same conditions as in Example 1, except for the above.

[0083] (Preparation of hollow fiber membrane of Comparative Example 3) Polyethersulfone (PES, manufactured by Sumitomo Chemical), sulfonated polyarylene ether copolymer (SPN obtained above), polyvinylpyrrolidone K-90 (PVP, manufactured by Nippon Shokubai), 45.0 mass% N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 30.0 mass% triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation) were heated and uniformly dissolved. The charging ratios of polyethersulfone (PES), sulfonated polyarylene ether copolymer (SPN), and polyvinylpyrrolidone (PVP) are as shown in Table 1. A hollow fiber membrane was produced under the same conditions as in Example 1, except for the above.

[0084] The compositions (composition ratios) of the components constituting the semipermeable membranes of the above Examples and Comparative Examples, and the solvation energy densities of the entire semipermeable membranes (and the solvation energy densities of the SPNs) are as shown in Table 1. The solvation energy density was measured as described above.

[0085] (Fabrication of a semipermeable membrane module) The bundle of hollow fiber membranes obtained as described above was placed in a cylindrical container having two nozzles for introducing and discharging a liquid, and urethane resin was poured into both ends. Thereafter, the hardened urethane resin portion was cut off to process the end surfaces so that the hollow fiber membranes were open, and the membrane area in terms of the inner surface was 1.7 m. ２ Next, header caps having nozzles for introducing (discharging) blood were attached to both ends of the semipermeable membrane module.

[0086] <Evaluation Test> (Measurement of Cytokine Removal Rate) The cytokine (IL-6 and IL-8) removal rates were measured using semipermeable membrane modules (hollow fiber membrane modules) prepared using the hollow fiber membranes of the above Examples and Comparative Examples. Specifically, the cytokine removal rates were measured as follows. A blood sample was prepared by adding 24 μg each of IL-6 and IL-8 to 1,000 mL of heparin-added porcine whole blood. The blood sample was circulated for 1 hour using the semipermeable membrane modules (continuous slow hemofilters) of the above Examples and Comparative Examples at a blood flow rate (Qb) of 100 mL / min and a filtrate flow rate (Qf) of 10 mL / min. After circulation, the entire blood sample was collected, and the IL-6 and IL-8 in the blood sample were measured using enzyme-linked immunosorbent assay (ELISA). The reduction rates of IL-6 and IL-8 were calculated from the measured values ​​and the amounts added to the blood sample, and these values ​​were used as the removal rates (adsorption rates) of IL-6 and IL-8, respectively.

[0087] The measurement results of the cytokine removal rate are shown in Table 1. Note that blank spaces in Table 1 indicate that no measurement was performed. Figure 1 is a graph showing the relationship between the solvation energy density of the entire membrane (semipermeable membrane) and the cytokine removal rate for those results in Table 1 for which measurement results of the cytokine removal rate are available.

[0088]

[0089] From the results shown in Table 1 and Figure 1, the removal rate of IL-8 was 170 kJ mol when the solvation energy density of the entire membrane (semipermeable membrane) was 170 kJ mol. －１ ・nm －３ This is thought to be because, since IL-8 has a positive charge, when the ratio of the hydrophilic portion (the repeating unit of the hydrophilic segment represented by the above formula (2)) of the sulfonated polyarylene ether copolymer (SPN) increases (the solvation energy density of the entire semipermeable membrane increases), the amount of IL-8 adsorbed to the semipermeable membrane increases.

[0090] The removal rate of IL-6 was also improved when the solvation energy density of the entire semipermeable membrane was 170 to 225 kJ / mol. －１ ・nm －３It can be seen that if the ratio of the hydrophobic portion of SPN (the repeating unit of the hydrophobic segment represented by the following formula (1)) is increased (the solvation energy density of the entire semipermeable membrane is reduced), the adsorption amount of IL-6 to the semipermeable membrane increases. However, if the ratio of the hydrophobic portion of SPN is too high, the effect of electrostatic repulsion by the sulfonic acid group increases, and the adsorption amount of IL-6 to the semipermeable membrane decreases.

[0091] In particular, the solvation energy density of the entire film is approximately 170 to 180 kJ mol －１ ・nm －３ It can be seen that the removal rate of IL-8 drops sharply due to a decrease in solvation energy density within this range. In the present invention, based on this finding, the lower limit of the range of solvation energy density of the entire semipermeable membrane is set, and within this range, high adsorption capacity (removal performance) is exhibited for both negatively charged substances (e.g., negatively charged cytokines such as IL-6) and positively charged substances (e.g., positively charged cytokines such as IL-8).

Claims

1. 1. A semipermeable membrane comprising a sulfonated polyarylene ether copolymer, The sulfonated polyarylene ether copolymer contains, as copolymerization components, a repeating unit of a hydrophobic segment represented by the following formula (1) and a repeating unit of a hydrophilic segment represented by the following formula (2): 【Chemical 1】 【Chemistry 2】 R １ and R ２ is "-SO ３ M" where M represents a metal element; The solvation energy density of the entire semipermeable membrane is 170 to 225 kJ mol －１ ・nm －３ That is, a semipermeable membrane.

2. The constituent ratio (molar ratio) of the formula (1) is 0.40 to 0.70, the constituent ratio (molar ratio) of the formula (2) is 0.30 to 0.60, and the sum of the constituent ratio (molar ratio) of the formula (1) and the constituent ratio (molar ratio) of the formula (2) is 1.

00. The semipermeable membrane according to claim 1.

3. 3. The semipermeable membrane of claim 1, comprising polyethersulfone, the sulfonated polyarylene ether copolymer, and polyvinylpyrrolidone.

4. The semipermeable membrane according to claim 3, wherein the content ratio (mass ratio) of polyethersulfone / sulfonated polyarylene ether copolymer / polyvinylpyrrolidone in the entire semipermeable membrane is 75 to 90 / 7 to 22 / 3 to 18.

5. The semipermeable membrane according to claim 1 or 2, which is for continuous renal replacement therapy.

6. The semipermeable membrane according to claim 1 or 2, which has a non-uniform structure in the thickness direction.

7. A semipermeable membrane module comprising the semipermeable membrane described in claim 1 or claim 2.

8. The semipermeable membrane module according to claim 7, which is for continuous renal replacement therapy.

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