Porous membranes containing sorbent particles for improved urea capture

Abstract

The present invention relates to methods for preparing membranes containing sorbent particles that capture urea. The invention also relates to the sorbent-containing membranes themselves and methods of using the membranes. The membranes are useful for carrying out continuous reactions with small molecules such as urea, for example, to remove urea from solution.

Description

Detailed Description of the Invention

[0001] [Technical field to which the invention belongs] The present invention relates to methods for preparing membranes containing sorbent particles that capture urea. The invention also relates to the sorbent-containing membranes themselves and methods of using the membranes. The membranes are useful for carrying out continuous reactions with small molecules such as urea, for example, to remove urea from solution.

[0002] [Background technology] Patients with end-stage kidney disease (ESKD) or severe acute renal failure undergo dialysis (either hemodialysis or HD or peritoneal dialysis or PD) to replace kidney function. Although lifesaving, traditional dialysis has significant drawbacks. The process is time-consuming and inefficient in removing waste molecules and excess water, significantly contributing to reduced quality of life, serious health problems, and a high mortality rate (15-20% per year). The cost of treatment is very high.

[0003] In dialysis, patient fluids are typically dialyzed against a dialysis fluid, which is then discarded. It is desirable to regenerate the dialysis fluid to allow for the use of smaller volumes. In efforts to miniaturize, patient fluids are dialyzed against a relatively small volume of dialysis fluid, called dialysate. During this process, waste solutes from the patient fluid migrate toward the dialysate by diffusion and / or convection, often through a membrane, such as a semipermeable membrane. If the waste solutes are later removed from the dialysate, it can be reused, which is called dialysate regeneration. Efficient regeneration of dialysate reduces the need for large volumes of dialysis fluid, making dialysis more practical to perform, reducing resource dependency, and reducing waste streams.

[0004] A compact artificial kidney machine would represent a major breakthrough in renal replacement therapy. Worldwide, the number of dialysis patients is estimated at 3.4 million (see www.fresenius.com / media_library / Fresenius_Annual_Report_2018.pdf). Currently, approximately 89% of dialysis patients use HD technology either at a center (>96%) or at home (<4%) (see ERA-EDTA Registry Annual Report 2017). While center HD requires long, frequent visits to the hospital (approximately three times per week, 4 hours per session), home HD offers greater flexibility and autonomy. However, home HD still requires bulky dialysis machines and a large supply of dialysis fluid (at least 20 L per treatment) or a bulky fixed water purification system. User-friendly, lightweight HD devices that do not rely on a fixed water supply or large amounts of dialysis fluid would increase patient mobility, allowing patients to remain active in their social lives and move freely.

[0005] The large fluctuations in water balance and uremic toxin levels between dialysis treatments with standard three times weekly HD can be attenuated by continuous or more frequent HD, which may improve patient outcomes (Nesrallah GE et al., J Am Soc Nephrol 2012;23:696-705; Susantitaphong P et al., Am J Kidney Dis 2012;59:689-99; Ting GO, et al., Am J Kidney Dis 2003;42:1020-35). A more liberal diet is permitted. Significant cost savings are achieved through reduced need for dialysis personnel and related infrastructure, fewer medications, and fewer hospitalizations due to reduced complications.

[0006] PD is currently used by approximately 11% of dialysis patients (see Fresenius 2018 Annual Report). While PD offers the opportunity for continuous dialysis, in contrast to HD, this technique has several major drawbacks: low uremic toxin removal (Evenepoel P et al., Kidney Int 2006;70:794-9), time-consuming exchange procedures, and a high rate of technical failure due to a high incidence of peritoneal infection (peritonitis) and membrane failure (median technical survival time is 3.7 years) (Perl J et al., Clin J Am Soc Nephrol 2012;7:1145-54). Low dialysis efficiency is primarily due to the rapid dissipation of the concentration gradient between dwelling plasma and peritoneal dialysate, thereby limiting solute transport (Gotch FA. "Kinetic modeling of continuous flow peritoneal dialysis." Semin Dial 2001;14:378-83). Miniature PD devices that continuously regenerate dialysate and thereby maintain the plasma-dialysate concentration gradient significantly enhance PD efficiency. This allows for a reduction in the number of time-consuming exchanges while still improving waste solute removal. Additionally, reducing the number of connections reduces the risk of contamination and lowers the rate of peritonitis (De Fijter CW, et al. Adv Perit Dial 1991;7:186-9; Piraino B, Sheth H. Blood Purif 2010;29:145-9). Continuous glucose infusion with miniature PD devices reduces functional deterioration of the peritoneal membrane by avoiding the extremely toxic glucose concentrations applied in conventional PD (Gotch 2001). By preventing the two major causes of technical failure in conventional PD (recurrent infection and functional loss of the peritoneal membrane), miniartificial kidneys significantly prolong technical survival.

[0007] Therefore, a user-friendly wearable or portable dialysis machine that provides dialysis outside of a hospital would represent a major leap forward for dialysis patients, significantly improving their quality of life. The machine would allow for continuous or more frequent dialysis, which would improve the removal of waste solutes and excess fluid, thus improving patient health. The miniaturized design, independent of a fixed water supply, would provide patients with freedom and autonomy.

[0008] In recent years, miniaturized prototype dialysis devices have been constructed that adequately remove several organic waste solutes and waste ions. However, to date, no suitable strategy for urea removal exists that allows for miniaturization to truly wearable proportions, which is one of the major obstacles to the successful realization of miniaturized artificial kidney devices. Urea is the waste solute with the highest daily production (the major waste product of nitrogen metabolism) and exerts toxic effects at high plasma concentrations. However, urea is difficult to capture and has low reactivity.

[0009] Adsorbents particularly suitable for urea adsorption have been known for a long time. DE 2305186 A1 / US 3933753 A disclose a polymeric composition with a polystyrene-like scaffold featuring glyoxal moieties. This composition captured up to 1 mmol / g of urea. This was further developed as described in US 4012317, and WO 2004078797 A1 discloses a similar ketoaldehyde material that reaches a urea capture capacity of 1.5 mmol / g.

[0010] EP121275A1 / US4897200A discloses a ninhydrin-type adsorbent. At clinically relevant urea concentrations, a urea retention capacity of 1.2 mmol / g dry adsorbent was demonstrated in 8 hours. However, for effective miniaturization, a higher urea retention capacity is required. WO2019110557 discloses a ninhydrin-type adsorbent with a urea retention capacity of more than 2 mmol / g.

[0011] US4178241A discloses polystyrene-type adsorbents with para-thio, para-nitro, or para-amino moieties. For the thio moieties, urea uptake was again shown to be about 1.5 mmol / g. Creatinine was also shown to be uptaken at well over 90% of the daily production in a normal adult for each functional group.

[0012] Membranes are well known for filtration, and membranes have also been proposed for urea removal. WO2017116515A1 discloses the use of charged membranes to improve urea separation from dialysate and suggests the use of electro-oxidation of the separated urea. A drawback of this method is the generation of reactive oxygen species as a by-product.

[0013] Membranes have also been used to remove other waste solutes from fluids. Geremia et al. (DOI: 10.1016 / j.actbio.2019.04.009) describe membranes containing activated carbon particles. While these membranes can capture uremic toxins, activated carbon is a poor urea scavenger, and urea capture has not been demonstrated. This poor capture is confirmed by Cheah et al. (Materials Chemistry and Physics, 175 (2016), 151-157), who describe silica-based materials with amine or hydroxyl groups for the noncovalent capture of urea as an alternative.

[0014] WO2014007716 describes a macroporous copper-chitosan polymer membrane for the adsorption of urea from dialysis solutions. This membrane captures urea, but its performance is low. In addition, the membrane can only have a non-covalent interaction with urea through the copper, which is also non-covalently bound to itself, so removal is easily via reversible capture.

[0015] WO2011102807A1 discloses epoxide-coated substrates. Epoxides can be used to recover solutes from solution. They are also used to immobilize urease enzymes, which aid in the treatment of urea. Disadvantages of urease enzymes include their sensitivity to environmental factors, their expensive and laborious preparation, and the fact that their reaction produces toxic ammonium, which then requires removal using cation exchangers, including materials such as zirconium phosphate, which add extra weight to the device in which they are used and can undesirably trap calcium or potassium. WO2016126596 uses a very different substrate, namely reduced graphene oxide. High urea capture capacity was demonstrated, but the captured urea represented less than 15% of the initial urea concentration.

[0016] To enable the development of improved artificial kidney devices, there is a continuing need for easily prepared materials that capture higher amounts of urea, do not risk leaching components or captured urea into the dialysate, do not produce harmful by-products, and have improved kinetics to capture urea faster, and combine the advantages of membranes with those of dedicated urea sorbents, reducing the total weight required for the device.

[0017] [Summary of the Invention] The present invention is based on the surprising discovery that the performance of a urea adsorbent is improved when the adsorbent particles are embedded in a porous membrane matrix. The urea adsorbent's capture capacity is increased and the capture kinetics are improved. Accordingly, the present invention relates to a membrane comprising embedded particulate material, the membrane being a porous polymer membrane, the particulate material comprising a urea adsorbent, and the particle size of the particulate material is up to 250 μm according to its largest diameter. Preferably, the particulate material is present in the membrane in an amount ranging from 5% to 80% by weight, more preferably from 25% to 70% by weight, based on the total dry weight of the membrane and the particulate material. Preferably, the particle size of the particulate material is up to 150 μm, more preferably up to 85 μm according to its largest diameter. Preferably, the membrane is in the form of a hollow fiber, a solid fiber, or a flat sheet. More preferably, the membrane is a hollow fiber. Preferably, the membrane comprises at least one polymer selected from polysulfone, polyethersulfone, polyphenylenesulfone, polyarylethersulfone, polyamide, polyetherimide, polyimide, polyethylene-co-vinyl alcohol, polyethylene-co-vinyl acetate, cellulose acetate, cellulose triacetate, polyvinylidene fluoride, polyvinyl chloride, polyacrylonitrile, polyurethane, polyetheretherketone, and / or polyacrylic acid. More preferably, it comprises polyethersulfone and / or polyvinylpyrrolidone. Preferably, the membrane has a flow rate of at least 1 L / (m 2The urea adsorbent has a water permeability of (°C / °F). Preferably, the urea adsorbent is an adsorbent that covalently traps urea. Preferably, the urea adsorbent is a polymeric composition comprising a polymer backbone grafted with moieties capable of covalently trapping urea, the moieties preferably comprising two or more adjacent carbonyl groups or hydrates thereof. Preferably, the urea adsorbent is selected from a ninhydrin-type adsorbent, a phenylglyoxalaldehyde-type adsorbent, and / or a triformylmethyl-type adsorbent. In preferred embodiments, the particulate material further comprises activated carbon particles, ion exchange particles such as ion exchange resin particles or ion exchanged silica particles, silica particles such as unmodified silica particles or alkylated silica particles, zeolite particles, ceramic particles, polymer particles such as porous polymer particles or non-porous polymer particles, and / or molecularly imprinted particles, and / or the membrane further comprises a hydrophilic additive, preferably an additive such as polyvinylpyrrolidone, chitosan, polyethylene glycol, dextran, glycerol, diethylene glycol, octanol, oxalic acid, maleic acid, tartaric acid, fumaric acid, lithium chloride, and / or calcium chloride.

[0018] There is also provided a membrane as defined above for use as a medicament, preferably for use in the treatment of a disease or condition associated with urea accumulation.

[0019] Furthermore, there is provided a method for preparing a membrane as defined above, comprising the steps of: i. providing urea sorbent particles having a size according to a maximum diameter of up to 250 μm; ii. mixing the urea sorbent particles with a polymeric material in a solvent for the polymeric material to obtain a mixture; iii. extruding or casting the mixture to form a membrane; and iv. Optionally, solidifying the film, preferably by phase inversion. A method is provided that includes:

[0020] Additionally, there is provided a method for removing nucleophilic waste solutes from a fluid, comprising: i) providing a fluid containing a nucleophilic waste solute; and iia) contacting a fluid with a membrane according to any one of claims 1 to 10; or iib) contacting said fluid with a dialysis fluid through a membrane, wherein said dialysis fluid is in contact with a membrane according to any one of claims 1 to 10; and iii) optionally recovering said fluid. A method is provided, comprising:

[0021] The present invention further provides a cartridge for use in a dialysis machine, comprising a membrane as defined above. The present invention also provides a dialysis machine comprising a membrane as defined above or a cartridge as defined above.

[0022] [Description of the embodiment] The present invention seeks to provide improved adsorbent materials with increased capacity and capture rates for nucleophilic waste solutes, of which urea is a key example. Adsorbents are materials that capture target substances; in this case, the adsorbent captures nucleophiles such as urea. The inventors have invented membranes with high urea capture capacity and fast binding kinetics, making them suitable for applications in dialysis. The membranes contain adsorbent particles. The improved adsorbent membranes, which can be called mixed matrix membranes (MMMs) because they contain particulate material embedded in a polymer matrix, enable the miniaturization of adsorbent cartridges and are therefore an important step toward miniaturized artificial kidney devices.

[0023] The present invention is based on the surprising discovery that the performance of a urea sorbent is improved when the sorbent particles are embedded in a porous membrane matrix. Not only is the urea sorbent's loading capacity increased, but the loading kinetics are also improved. Thus, the present invention provides a membrane comprising embedded particulate material, wherein the membrane is a porous polymer membrane; The particulate material comprises a urea adsorbent. The particle size of the particulate material is up to 250 μm according to the maximum diameter A membrane is provided.

[0024] Such membranes with embedded urea adsorbent particles are hereinafter referred to as "membranes of the present invention." Generally, the membranes of the present invention achieve faster kinetics for the removal of nucleophilic waste solutes, particularly urea, compared to other systems, such as free adsorbent particles. Furthermore, the membranes of the present invention have higher performance for removing nucleophilic waste solutes, particularly urea, compared to other systems. Surprisingly, the amount of urea adsorbed by the membrane is greater than when the adsorbent particles are not embedded in the membrane but dispersed in an aqueous urea solution.

[0025] The membrane of the present invention comprises embedded particulate material.Those skilled in the art are familiar with membranes having embedded particulate material, for example, from WO2019175366 or WO2014007716 or Geremia et al. (DOI: 10.1016 / j.actbio.2019.04.009).Generally, embedded particulate material refers to particles that are captured by the polymer matrix that constitutes the membrane.Embedded particulate material may be completely surrounded by the membrane matrix, or may be partially exposed on the surface of the polymer.

[0026] film The membranes may be advantageously used in (hemo)dialysis for the removal of urea, where blood is directed through a membrane or through a semipermeable membrane that separates it from a small amount of dialysis fluid, which is then contacted with the membrane of the invention. The sorbent particles in the membrane then capture nucleophilic waste solutes, such as urea, so that diffusion of these solutes across the (semipermeable) membrane continues and is not slowed down by saturation.

[0027] Membrane technology is well developed, and those skilled in the art can select the appropriate type of membrane in which the urea adsorbent is embedded, or in other words, the appropriate polymer matrix in which the urea adsorbent is embedded, to develop an MMM (see "Basic Principles of Membrane Technology", Second edition by M. Mulder, Kluwer Academic publishers, ISBN 0-7923-4247-x; and "Biomedical membranes and bioartificial organs", D. Stamatialis, Ed., World Scientific / Oxford press, ISBN 978-981-3221-75-8 (2018)). Suitable membranes are made from polymers and therefore comprise or consist of a polymer matrix. The membrane is porous and can be macroporous, microporous, or nanoporous. Dense (non-porous) membranes are not suitable because such membranes do not allow sufficient access of particulate matter to the fluid. Based on the application and the relative importance of permeability within it, microfiltration, ultrafiltration, nanofiltration, and reverse osmosis membranes can be defined as having decreasing pore sizes. The required transmembrane pressure increases as the pore size decreases.

[0028] For applications where urea removal is the primary objective, microfiltration and / or ultrafiltration are preferred. In general, lower permeability can help improve the kinetics of urea binding, as it increases the retention of passing molecules and provides more time for solutes to bind to the embedded sorbent particles.

[0029] The membrane of the present invention is particularly suitable for use in liquid filtration, and therefore, preferred membranes are filtration membranes, more preferably liquid filtration membranes that are porous membranes.Filtration membranes can be microfiltration membranes, ultrafiltration membranes, nanofiltration membranes, and reverse osmosis membranes.In preferred embodiments, the membrane is a microfiltration membrane, an ultrafiltration membrane, or a nanofiltration membrane.In preferred embodiments, the membrane is a microfiltration membrane or an ultrafiltration membrane.In preferred embodiments, the membrane is a nanofiltration or reverse osmosis membrane.In some preferred embodiments, for example, when used in water treatment, the membrane is a reverse osmosis membrane.

[0030] Microfiltration membranes are known in the art. They typically have a flow capacity of about 500-5000 L / (m 2 They have a water permeability of 1000 kJ / cm² (1000 kJ / cm²) and are typically operated at pressures in the range of 0 to 1 bar. Examples of microfiltration membranes are organic membranes made using polymers including cellulose acetate (CA), polysulfone, polyvinylidene fluoride, polyethersulfone, and / or polyamide. Inorganic membranes are less preferred because they are not easily prepared using the methods of the present invention.

[0031] Ultrafiltration membranes are also known and have pore sizes ranging from 0.1 μm to 0.01 μm. They are capable of retaining proteins, endotoxins, viruses, and silica. Ultrafiltration has diverse applications ranging from wastewater treatment to pharmaceutical applications and dialysis treatments. They typically have a flow rate of about 50 to 800 L / (m 2 They have a water permeability of 1000 kJ / s (·h·Bar), and they are typically operated at pressures ranging from 0.2 to 10 bar. Examples of ultrafiltration membranes are organic membranes made using polymers including polysulfone, polyethersulfone, polypropylene, cellulose acetate, and / or polylactic acid.

[0032] Nanofiltration membranes are also known and have pore sizes between 0.001 μm and 0.01 μm. They are capable of filtering multivalent ions, synthetic dyes, sugars, and certain salts. They typically have a flow rate of about 1 to 15 L / (m 2They have a water permeability of 1000 kJ / cm² (1000 kJ / cm²) and are typically operated at pressures in the range of 5 to 20 bar. Examples of nanofiltration membranes are organic membranes made using polymers including ethylene vinyl alcohol, polysulfone, polyethersulfone, polyvinylidene fluoride, polyamide, and / or polyethylene terephthalate.

[0033] Reverse osmosis is the finest membrane separation process available, with pore sizes ranging from 0.0001 μm to 0.001 μm. Reverse osmosis can retain almost all molecules except small hydrophilic molecules such as water and urea. Because of the pore size, the osmotic pressure required is significantly greater than for other filtration techniques. Typically, the permeability is about 1-5 L / (m 2 ·h·Bar) and are typically operated at pressures in the range of 8-100 bar. An example of a reverse osmosis membrane is an organic membrane made using cellulose triacetate (CTA).

[0034] In a preferred embodiment, at least 1 L / (m 2 In another preferred embodiment, the membrane has a water permeability of at least 50, more preferably 100, even more preferably 150, even more preferably 200, even more preferably 250, and most preferably 300 L / (m 2 In another highly preferred embodiment, the water permeability is at least 500 L / (m 2 ·h·Bar). Preferably up to 5000 L / (m 2 ·h·Bar), more preferably at most 3500, even more preferably at most 2500, even more preferably at most 1500, even more preferably at most 800, even more preferably at most 500, even more preferably at most 400, even more preferably at most 250, even more preferably at most 150, even more preferably at most 75, even more preferably at most 50, 25, 15, 10 or 5 L / (m 2 10 to 1000 L / (m 2 Water permeabilities in the range of about 10 to about 500 L / (m 2·h·Bar) is more suitable, and 50~400L / (m 2 ·h·Bar) is more suitable.

[0035] In a preferred embodiment, the membrane of the present invention comprises at least one polymer selected from the group consisting of polysulfone, polyethersulfone, polyphenylenesulfone, polyarylethersulfone, polyamide, polyetherimide, polyimide, polyethylene-co-vinyl alcohol, polyethylene-co-vinyl acetate, cellulose derivatives such as cellulose acetate or cellulose triacetate, polyvinylidene fluoride, polyvinyl chloride, polyacrylonitrile, polyurethane, polyetheretherketone, polysaccharides such as chitosan, and polyacrylic acid. More preferably, the membrane comprises polyethersulfone and / or polyvinylpyrrolidone, preferably both.

[0036] As those skilled in the art know, mixtures of polymers can result in attractive membranes. In a preferred embodiment, the membrane of the present invention comprises a total amount of polymer in the range of 20% to 95% by weight, preferably in the range of 30% to 75% by weight, more preferably in the range of 40% to 60% by weight, based on the dry weight of the membrane including the particles. Advantageously, the membrane comprises a first polymer such as an EVA polymer such as polyethersulfone (PES, see Pavlenko et al., Nature Scientific Reports, 6 (2016) 34429), ethylene vinyl alcohol (see Tetala & Stamatialis, Sep. Pur. Tech., 104 (2013) 214-220) or a polyimide such as polyimide P84 (see Kopec et al., Sep. Pur. Tech., 80 (2011) 306-314), preferably PES, in an amount ranging from 10% to 50% by weight, more preferably in an amount ranging from 20% to 40% by weight, most preferably about 30% by weight, based on the dry weight of the membrane including the particles. Preferably, the membrane comprises a second polymer, such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or polyethylene oxide (PEO), preferably PVP, in an amount ranging from 1% to 30% by weight, more preferably from 10% to 20% by weight, and most preferably about 14% by weight, based on the dry weight of the membrane containing the particles. Those skilled in the art will recognize that a variety of polymers can be used, particularly when a polymer solvent and non-solvent are present to enable liquid-induced phase separation, and preferably when the particulate material is not soluble in the polymer solvent.

[0037] The membrane morphology can be controlled using methods known in the art. In a preferred embodiment, the membrane of the present invention is provided, wherein the membrane is in the form of a hollow fiber, a full fiber, or a flat sheet. Preferably, the membrane is a hollow fiber.

[0038] The membranes of the present invention can be referred to as mixed matrix membranes (MMMs). MMMs can have one, two, three, or more layers. The membranes of the present invention can be asymmetric or symmetric. In a preferred embodiment, the MMM has two layers, and the particulate material is present in the layer of the bilayer mixed matrix membrane closest to the dialysate. In other preferred embodiments, the particulate material is present in all layers. In other preferred embodiments, the membrane has only a single layer, which can be useful when the permeability and mechanical stability of the membrane obviate the need for multiple layers.

[0039] In a preferred embodiment, the membrane comprises a polymer having a molecular weight in the range of 1,000 to 1,000,000 grams per mole (g / mol), preferably in the range of 30,000 to 500,000 g / mol. Preferably, the polymer weight is a number-average polymer weight. The membranes of the present invention preferably have a molecular weight cut-off (MWCO) in the range of 0.5 to 1,000 kilodaltons (kDa), more preferably in the range of 5 to 50 kDa, or up to 40, more preferably up to 30, more preferably up to 25, and most preferably up to 20 kDa. In a preferred embodiment, the MWCO is about 20 kDa to about 50 kDa. In other preferred embodiments, such as those requiring high-flux membranes, the MWCO is about 20 kDa. In other preferred embodiments, such as those requiring medium cut-off membranes, the MWCO is about 50 kDa.

[0040] In some embodiments, the membranes of the present invention have an average pore size in the range of 1 to 2000 nm, more preferably 1 to 500 nm. The pore size is preferably at least 1 nm, more preferably at least 2 nm, and most preferably at least about 3 nm. A low pore size is preferred for dialysis applications because it helps retain blood proteins such as albumin. Preferably, a pore size of about 3 nm combined with a MWCO of about 10 to 50 kDa, such as about 20 kDa, is used. Pore size can be determined using known techniques, such as gas adsorption or MWCO determination by filtration of a mixture of molecules of various sizes, preferably MWCO determination.

[0041] The membrane of the present invention preferably has a thickness of at least 50 cm -1 , more preferably at least 100 cm -1 The membranes of the present invention preferably can withstand a maximum flow rate of a mixture, preferably a filtrate such as dialysate or plasma filtrate, where the mixture contains a nucleophilic waste solute, such as urea, in the range of 10 to 1000 milliliters per minute (mL / min), most preferably 300 to 800 mL / min. The maximum flow rate is preferably at least 10, more preferably at least 50, even more preferably at least 75, even more preferably at least 100, more preferably at least 250, and more preferably at least 300 mL / min. The maximum flow rate is preferably at most 1000, more preferably at most 750, even more preferably at most 600, even more preferably at most 500, more preferably at most 400, and more preferably at most 350 mL / min. For typical dialysis applications, a flow rate of 100 mL / min is sufficient. For home dialysis, a flow rate of 300 mL / min is preferred.

[0042] The membrane of the present invention preferably has a flow rate of 60 to 600 milliliters per square meter per hour per millimeter of mercury (mL m -2 h -1 mmHg -1 ), more preferably 100 to 400 mL m -2 h -1 mmHg -1 in the range of 250 to 350 mL m -2 h -1 mmHg -1 Ultrafiltration coefficient K in the range uf Preferably, K uf is at least 10, more preferably at least 50, more preferably at least 60, more preferably at least 75, more preferably at least 100 mL m -2 h -1 mmHg -1 Preferably, K ufis at most 400, more preferably at most 350, more preferably at most 300, more preferably at most 250, more preferably at most 200, more preferably at most 150, more preferably at most 100 mL m -2 h -1 mmHg -1 is.

[0043] The membranes of the present invention preferably have a swelling degree in the range of 1% to 15%, preferably 1% to 5%, most preferably about 2%. Preferably, the membranes do not swell substantially, more preferably swell less than 1%, such as at most 3%, even more preferably at most 1.5%, most preferably at most 0.5%.

[0044] The membranes of the present invention preferably have a urea uptake capacity of at least 1.8 mmol / g, more preferably at least 2.0, even more preferably at least 2.5, even more preferably at least 2.6, even more preferably at least 2.7, even more preferably at least 2.8, more preferably 2.9, and even more preferably 3 mmol / g. The membranes of the present invention can preferably uptake at least 0.75 mmol / g, more preferably 0.8 mmol / g, of urea after 1 hour. The membranes of the present invention can preferably uptake at least 1.8 mmol / g, more preferably 2 mmol / g, of urea after up to 16 hours. This urea uptake is preferably as described elsewhere herein, more preferably at 70°C, and most preferably as described in the Examples.

[0045] Urea adsorbent The membrane of the present invention comprises a particulate material, the particulate material comprising at least a urea adsorbent, and in a preferred embodiment, the particulate material consists of a urea adsorbent.

[0046] The adsorbent is a material that captures a target substance; in this case, the adsorbent is a urea adsorbent, thus capturing urea. Urea adsorbents are well known in the art, as described in the Background of the Invention section. The two main modes of urea binding are covalent binding and adsorption, particularly physical adsorption. Covalent binding is sometimes referred to as chemical adsorption. Preferably, the urea adsorbent for use in the membrane of the present invention is a urea adsorbent that covalently captures urea. In another preferred embodiment, multiple types of urea adsorbents are used, with at least one urea adsorbent covalently capturing urea. Preferably, the capture comprises covalent capture of urea, and at least 10% of the urea capture is covalent capture of urea. More preferably, the binding comprises at least 50% covalent capture of urea, more preferably at least 70%, more preferably at least 80%, and even more preferably at least 90% covalent capture of urea. In another preferred embodiment, substantially all of the urea capture is covalent urea capture. Urea adsorbents for use in the present invention preferably have a urea uptake capacity of greater than 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1, 1.1, 1.2, 1.3, 1.4, 1, or 1.5 mmol of urea per gram of adsorbent. More preferably, the adsorbent has a urea uptake capacity of greater than 0.1 mmol of urea per gram of adsorbent; even more preferably, the adsorbent has a urea uptake capacity of greater than 0.5 mmol of urea per gram of adsorbent; more preferably, the adsorbent has a urea uptake capacity of greater than 1 mmol, even more preferably, greater than 1.5 mmol, or even more preferably, greater than 2 mmol of urea per gram of adsorbent, for example, greater than 2.5 mmol or 2.6 mmol of urea per gram of adsorbent. The valency of urea uptake can be assessed using spectroscopic techniques.

[0047] Examples of urea adsorbents include ninhydrin-type adsorbents (e.g., EP121275A1; US4897200A; WO2019110557); phenylglyoxalaldehyde (PGA)-type adsorbents (e.g., DE2305186A1; US3933753A; US4012317; WO2004078797A1; EP19210947); and triformylmethyl (TFM)-type adsorbents (the capture of urea by TFM is described in Jong et al., ACS Omega 2019, 4, aldehyde-type adsorbents, such as those described in WO 2014007716; copper-composite-type adsorbents, such as those described in WO 2014007716; para-functionalized polystyrene-type adsorbents, characterized by para-thio, para-nitro, or para-amino moieties (e.g., US 4178241 A); silica-type adsorbents with free hydroxyl or amino moieties (e.g., Cheah et al. (Materials Chemistry and Physics, 175 (2016), 151-157); epoxide-coated adsorbents (e.g., WO2011102807A1); enzyme-type adsorbents such as particles with immobilized urease enzymes (e.g., WO2011102807A1); and reduced graphene-type adsorbents (e.g., WO2016126596). Examples of urea adsorbents that covalently capture urea include ninhydrin-type adsorbents; phenylglyoxalaldehyde (PGA)-type adsorbents; triformylmethyl (TFM)-type adsorbents; epoxide-coated adsorbents; and reduced graphene-type adsorbents.

[0048] The inventors have achieved good results using urea adsorbents, which are polymeric compositions comprising a polymer backbone grafted with moieties capable of covalently trapping urea. The moieties preferably comprise two or more adjacent carbonyl groups or hydrates thereof that covalently trap urea. In a preferred embodiment, a membrane comprising such an adsorbent is provided. Further characteristics and definitions are provided later in this specification. Moieties having two or more adjacent carbonyl groups may also be hydrates thereof, as these groups often undergo spontaneous hydration and dehydration in equilibrium at ambient conditions. It should be understood that when C(=O) moieties are directly bonded to adjacent C(=O) moieties, the adjacent carbonyl groups need not be directly adjacent. Cases where two or more carbonyl moieties can participate in the same resonance-stabilized isomer, such as when two or more carbonyl moieties are separated only by an unsaturated carbon or double bond, should also be considered. Examples of suitable moieties are shown in the table below, with reference names and numbers provided below. [Table A]

[0049] In Table A above, an asterisk indicates the site at which the indicated moiety is attached to the polymer backbone. X represents a linker moiety containing 1 to 10 backbone atoms selected from C, N, O, and S, substituted with H to full valence. Examples of X can be -CH2-, -O-CH2CH2-, and phenyl. X is preferably -CH2-. These moieties can be further substituted, for example, with C1-6 hydrocarbon, or C1-6 alkoxy, or nitro, nitrile, amino, hydroxyl, carboxyl, phosphate moieties, and the like. Variations in the structure of the adsorbents are possible, and the use of such adsorbents in membranes is encompassed by the present invention.

[0050] Examples 1, 2, 3, and 4 from Table A above are moieties that, when linked to a polymer backbone, constitute ninhydrin-type adsorbents. Examples 6, 7, and 8 from Table A above are moieties that, when attached to a polymer backbone, constitute PGA-type adsorbents. Example 10 from Table A above is a moiety that, when attached to a polymer backbone, constitutes a TFM-type adsorbent. Examples 1 and 4 coexist in equilibrium at ambient conditions, as do Examples 7 and 8.

[0051] In a particularly preferred embodiment, the urea adsorbent is selected from a ninhydrin-type adsorbent, a phenylglyoxalaldehyde-type adsorbent, and / or a triformylmethyl-type adsorbent. In another preferred embodiment, the urea adsorbent is selected from a ninhydrin-type adsorbent and / or a TFM-type adsorbent. In another preferred embodiment, the urea adsorbent is selected from a ninhydrin-type adsorbent and / or a PGA-type adsorbent. In another preferred embodiment, the urea adsorbent is selected from a TFM-type adsorbent and / or a PGA-type adsorbent. In a particularly preferred embodiment, the adsorbent is a ninhydrin-type adsorbent. In a particularly preferred embodiment, the adsorbent is a TFM-type adsorbent. In a particularly preferred embodiment, the adsorbent is a PGA-type adsorbent.

[0052] The particle size of the particulate material is at most 250 μm according to the maximum diameter. Preferably, the particle size according to the maximum diameter is at most 200 μm, more preferably at most 180 μm, more preferably at most 160 μm, more preferably at most 150 μm, more preferably at most 130 μm, more preferably at most 110 μm, more preferably at most 100 μm, even more preferably at most 90 μm, even more preferably at most 80 μm, and even more preferably at most 70 μm. In a preferred embodiment, the membrane of the present invention is provided, wherein the particle size of the particulate material is at most 150 μm according to the maximum diameter, preferably at most 85 μm, more preferably at most 70 μm.

[0053] In a preferred embodiment, the adsorbent particles have a regular, particularly spherical, or irregular shape. The adsorbent particles are preferably porous and more preferably have a surface area-to-weight ratio as described in Pavlenko et al., Nature Scientific Reports, 6 (2016) 34429. The adsorbent particles may be applied as flakes, fibers, powders, or a combination thereof. Examples of powders include, but are not limited to, metal powders, plastic powders, normal-phase silica, fumed silica, and activated carbon. The particles are preferably substantially round or spherical, resulting from grinding or pulverizing the granulated adsorbent. Smaller particles allow for thinner films to be formed. Therefore, the particles preferably have a maximum diameter of at most 65 μm or 63 μm, more preferably at most 60 μm, even more preferably at most 50 μm, and most preferably at most 40 μm. The maximum diameter is preferably at least 5 μm, more preferably at least 10 μm, even more preferably at least 15 μm, and most preferably at least 20 μm. For example, a range of 20 to 40 μm is highly preferable.

[0054] In preferred embodiments, the sizes in the previous two paragraphs relate to the size of the urea sorbent and not to the size of other particles contained in the particulate material. Most preferably, the sizes relate to all particulate matter.

[0055] In a preferred embodiment, the adsorbent particles have a minimum dimension of at most 100 μm, preferably at most 63 μm, and more preferably in the range of 0.05 μm to 60 μm. It is understood that the adsorbent particles may be, inter alia, spherical or ellipsoidal. Preferably, the adsorbent particles are substantially spherical. In that case, the minimum dimension is the diameter of the adsorbent particle. If the adsorbent particles are ellipsoidal, the maximum dimension of the adsorbent particles is preferably at most 150 μm, more preferably at most 100 μm, even more preferably at most 80 μm, and most preferably at most 63 μm.

[0056] Preferably, the adsorbent particles have a size in their smallest dimension in the range of 0.05 μm to 100 μm, more preferably in the range of 0.1 μm to 63 μm, even more preferably in the range of 0.5 μm to 60 μm, even more preferably in the range of 1 μm to 50 μm, and most preferably in the range of 5 μm to 45 μm.

[0057] It will be understood that the size of the adsorbent particles can be determined and / or controlled by using techniques such as grinding, milling, cutting, and / or sieving, which are standard procedures in the art. The size of the particles can be determined, for example, using light scattering or microscopy, such as electron microscopy, as shown in the examples. In preferred embodiments, the size of the particles is determined using electron microscopy. In preferred embodiments, at least 80% of the particles are smaller than the size recited according to their largest diameter, more preferably at least 90% are smaller than the recited size, even more preferably at least 95%, even more preferably at least 99%, and most preferably 100% are smaller than the recited size.

[0058] In a preferred embodiment, the particulate material is present in the membrane in the range of 5% to 80% by weight, preferably 25% to 70% by weight, based on the total dry weight of the membrane and particulate material.

[0059] Preferably, at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70% by weight of the specified material is present. More preferably, at least 10, even more preferably, at least 15, even more preferably, at least 20, and most preferably, at least about 25% by weight of the specified material is present. Preferably, at most 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10% by weight of the specified material is present. More preferably, at most 60%, even more preferably, at most 50%, even more preferably, at most 40%, and most preferably, at most about 30% by weight of the specified material is present.

[0060] In preferred embodiments, the weight percentages in the previous two paragraphs relate to the weight percentage of the urea sorbent and not to the weight percentage of other particles contained in the particulate material. Most preferably, the weight percentages relate to all particulate matter.

[0061] In a preferred embodiment, at least one sorbent particle is at least 0.5 m 2 / g, more preferably at least 0.8m 2 / g, and even more preferably at least 1 m 2 / g, and even more preferably at least 1.5m 2 / g, most preferably at least 5m 2 / g. Preferably, the BET surface area of ​​the adsorbent particles is 0.5 m 2 / g~10000m 2 / g, more preferably in the range of 10m 2 / g~2500m 2 / g range.

[0062] In a preferred embodiment, at least one adsorbent particle has an average pore diameter in the range of 0.1 to 250 nm, most preferably 25 to 150 nm. In a preferred embodiment, at least one adsorbent particle has an average pore volume in the range of 0.001 to 0.12 mL / g, more preferably 0.01 to 0.10 mL / g, most preferably 0.02 to 0.09 mL / g. In a preferred embodiment, at least one additional adsorbent particle is embedded in the membrane of the present invention. The additional adsorbent particle may advantageously have the same size, shape, BET surface area, and / or pore size as the adsorbent particle defined herein above. In a preferred embodiment, the total amount of adsorbent particles embedded in the membrane is in the range of 5 wt.% to 80 wt.%, preferably 25 wt.% to 70 wt.%, more preferably 40 wt.% to 60 wt.%, based on the dry weight of the membrane including the particles.

[0063] Further details on adsorbents In the context of this invention, a sorbent is a polymeric composition that can be a dissolved or partially dissolved solid, suspended solid, colloidal suspension, aggregate, resin, or polymer. It can bind to nucleophilic waste solutes, and urea sorbents bind at least urea, allowing the sorbent to be subsequently recovered from the mixture. Binding can be covalent or non-covalent, such as by electrostatic or hydrophobic interactions.

[0064] A PGA-type adsorbent is an adsorbent containing a PGA-type moiety. PGA is phenylglyoxalaldehyde or 1-phenylethane-1,2-dione or phenyloxalaldehyde. The PGA-type moiety is preferably a short aliphatic structure, preferably having only two carbon atoms, attached to an aromatic ring or aromatic ring system, preferably a phenyl or substituted phenyl moiety (e.g., substituted on a polymer backbone), characterized by two adjacent carbonyl groups (or their hydrates). Glyoxalaldehyde and its hydrates are easily converted into each other, and it should be understood that a reference to PGA generally also includes a reference to its hydrate. Generally, glyoxalaldehyde hydrates are formed in non-dry environments, and glyoxalaldehyde can be dehydrated by heating. In aqueous environments, both species generally coexist in equilibrium. Preferred examples of PGA-type moieties are selected from the group consisting of ortho-oxalaldehyde phenyl, meta-oxalaldehyde phenyl, and para-oxalaldehyde phenyl, and hydrates thereof, wherein the phenyl ring may be further substituted as needed. In some embodiments, the PGA-type moiety is selected from the group consisting of ortho-oxalaldehyde phenyl and meta-oxalaldehyde phenyl. In other embodiments, the PGA-type moiety is selected from the group consisting of ortho-oxalaldehyde phenyl and para-oxalaldehyde phenyl. In some embodiments, the PGA-type moiety is selected from the group consisting of meta-oxalaldehyde phenyl and para-oxalaldehyde phenyl. Most preferably, the PGA-type moiety is para.

[0065] PGA-type adsorbents suitable for use in the present invention are well suited to binding nucleophilic waste solutes with high binding capacity. These solutes react with the PGA-like moieties contained in the adsorbent. Preferably, the PGA-type adsorbents have a urea uptake capacity of greater than 1.60 mmol, preferably greater than 1.80 mmol, and more preferably greater than 2.00 mmol of urea per gram of adsorbent.

[0066] Ninhydrin-type adsorbents are adsorbents containing a ninhydrin-type moiety. Ninhydrin is 2,2-dihydroxy-1H-indene-1,3(2H)-dione, also known as 2,2-dihydroxyindan-1,3-dione and 1,2,3-indantrione hydrate. The ninhydrin-type moiety is preferably a hydrate of a five-membered ring structure with three adjacent carbonyl groups fused to two adjacent positions of an aromatic ring or aromatic ring system, preferably fused to a phenyl moiety. Preferred examples of ninhydrin-type moieties are selected from the group consisting of 4-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl, 5-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl, 6-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl, and 7-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl. More preferred ninhydrin-type moieties are selected from the group consisting of 5-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl and 6-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl. Since ninhydrin has an axis of symmetry, in the absence of other substituents, 5-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl and 6-[2,2-dihydroxy-1H-indene-1,3(2H)]-dionyl are identical.

[0067] Ninhydrin-type adsorbents suitable for use in the present invention are suitable for capturing nucleophilic waste solutes. These solutes react with the ninhydrin-like moieties contained in the adsorbent. Preferably, the ninhydrin-type adsorbents have a urea capture capacity of greater than 1.4 mmol, preferably greater than 2.1 mmol, of urea per gram of adsorbent.

[0068] Urea is a small, highly polar molecule that is highly soluble in water (400 mg / ml) and in protic organic solvents such as methanol, ethanol, and glycerol due to its polarity and ability to participate in hydrogen bond formation. Urea's role in biochemistry is essential, and it is an industrially important molecule, including as a nitrogen source for fertilizers and as a polymer precursor, making it often important to remove urea from fluid solutions.

[0069] PGA type adsorbents for use in the present invention preferably have a stoichiometric concentration of 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2030, 2030, 2031, 20 0.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 mmol of urea. More preferably, the sorbent has a urea scavenging capacity of greater than 1.60 mmol of urea per gram of sorbent; even more preferably, the sorbent has a urea scavenging capacity of greater than 1.80 mmol of urea per gram of sorbent; even more preferably, the sorbent has a urea scavenging capacity of greater than 2.00, even more preferably greater than 2.20, and even more preferably greater than 2.40, 2.45, 2.50, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9 mmol of urea per gram of sorbent, such as greater than 2.5 or 2.6 mmol of urea per gram of sorbent.

[0070] The ninhydrin-type sorbents preferably have a urea scavenging capacity of greater than 1.5 mmol of urea per gram of sorbent. In more preferred embodiments of this aspect, the sorbents have a urea scavenging capacity of greater than 1.6 mmol of urea per gram of sorbent. In even more preferred embodiments, the ninhydrin-type sorbents have a urea scavenging capacity of greater than 1.6 mmol of urea per gram of sorbent. In even more preferred embodiments, the ninhydrin-type sorbents have a urea scavenging capacity of greater than 1.6 mmol of urea per gram of sorbent. having a urea scavenging capacity of greater than 15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 or 4.9 mmol of urea. More preferably, the adsorbent has a urea scavenging capacity of greater than 2.10 mmol of urea per gram of adsorbent; even more preferably, the adsorbent has a urea scavenging capacity of greater than 2.20 mmol of urea per gram of adsorbent; most preferably, the adsorbent has a urea scavenging capacity of greater than 2.40 mmol of urea per gram of adsorbent, such as greater than 2.5 mmol or greater than 2.6 mmol of urea per gram of adsorbent.

[0071] In this regard, the urea trapping capacity of the adsorbent is preferably the maximum urea trapping capacity, which can be determined after incubating the adsorbent with excess urea in solution (such as about 30 mM) at about 70°C for about 24 hours. The amount of bound urea can be determined by directly analyzing the amount of urea bound to the adsorbent, by analyzing the difference in the amount of urea present in the solution before and after exposure to the adsorbent, or by regenerating the adsorbent by dissociating the bound urea and subsequently determining the amount of urea released. Urea concentration can be determined by any method known in the art, such as elemental analysis, as described in WO2004078797A1. Alternatively, the amount of ammonia released by the urease enzyme can be used to indirectly quantify urea concentration. Alternatively, a PAB reagent solution containing approximately 4% (w:v) 4-(dimethylamino)benzaldehyde and 4% (v:v) sulfuric acid in absolute ethanol can be used for UV-VIS analysis (422 nm) of urea reaction adducts using a pre-prepared calibration curve, as described in WO2016126596A1. Various kits for determining urea concentration are commercially available and include instructions for use. The urea-trapping capacity of the adsorbent is preferably that of the free adsorbent as particles not yet embedded in the membrane of the present invention.

[0072] In the PGA-type or ninhydrin-type adsorbent, preferably, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the polymerized monomers are PGA-type or ninhydrin-type monomers. Preferred PGA-type or ninhydrin-type adsorbents are those in which at least 30%, preferably at least 50%, more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the polymerized monomers are PGA-type or ninhydrin-type monomers. Even more preferred PGA-type or ninhydrin-type adsorbents are those in which at least 50% and up to 90% of the polymerized monomers are PGA-type or ninhydrin-type monomers. In a more preferred embodiment, 55% to 90% of the polymerized monomers are PGA-type or ninhydrin-type monomers. In an even more preferred embodiment, 70% to 90% of the polymerized monomers are PGA-type or ninhydrin-type monomers. In a most preferred embodiment, 70% to 80% of the polymerized monomers are PGA-type or ninhydrin-type monomers. The amount of PGA-type or ninhydrin-type monomers can be assessed using conventional techniques known in the art, such as solid-state NMR or IR spectroscopy. In certain embodiments, 100% of the polymerized monomers are PGA-type or ninhydrin-type monomers.

[0073] In a preferred embodiment, the PGA- or ninhydrin-type adsorbent of the present invention can be obtained by polymerization, preferably suspension polymerization. In a preferred embodiment, the PGA- or ninhydrin-type adsorbent can be obtained by polymerization, and a crosslinking monomer of up to 50%, preferably up to 35%, more preferably up to 25%, even more preferably up to 20%, and most preferably up to 10% is used.

[0074] During polymerization to produce the adsorbent, comonomers that are not PGA-type or ninhydrin-type monomers or their precursors may also be present. A comonomer is an additional monomer that undergoes polymerization and is covalently incorporated into the resulting polymer. Such resulting polymers are often referred to as copolymers, but for clarity, this specification refers only to the polymer itself when the context makes clear whether copolymers can also be referenced. In the context of the present invention, two classes of comonomers are particularly relevant: hydrophilic comonomers and crosslinking comonomers.

[0075] In a preferred embodiment, the sorbent comprises at least one comonomer, preferably styrene, isopropenylbenzene, divinylbenzene, vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, acrylonitrile, 2-hydroxyethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl 2-methylprop-2-enoate, 2-hydroxypropyl prop-2-enoate, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, telechelic N,N'-alkylenebisacrylamides such as N,N'-methylenebisacrylamide (NMAA), N-isopropylacrylamide (NIPAm), divinyl sulfone, butadiene, methacrylonitrile, vinyl sulfonamide, N-alkylvinylsulfonamides such as N-methylvinylsulfonamide, and N,N-dialkylvinylsulfonamides such as N,N-dimethylvinylsulfonamide. In a more preferred embodiment, the comonomer is selected from the group consisting of divinylbenzene, vinylbenzenesulfonic acid, acrylic acid, (meth)acrylonitrile, vinylsulfonamide, N-alkylvinylsulfonamide, N,N-dialkylvinylsulfonamide, and 2-hydroxyethyl 2-methylprop-2-enoate (HEMA). Even more preferably, the comonomer is selected from the group consisting of divinylbenzene and vinylbenzenesulfonic acid. Most preferably, both divinylbenzene and vinylbenzenesulfonic acid are present. In the context of this specification, divinylbenzene can be either 1,2-diethenylbenzene, 1,3-diethenylbenzene, or 1,4-diethenylbenzene, or a mixture thereof. 1,4-diethenylbenzene or a mixture containing 1,4-diethenylbenzene is preferred because it provides more extensive crosslinking and improves the solvent permeability of the resulting polymer.In the present context, vinylbenzenesulfonic acid can be either 2-vinylbenzenesulfonic acid, 3-vinylbenzenesulfonic acid, or 4-vinylbenzenesulfonic acid, or mixtures thereof. 4-vinylbenzenesulfonic acid is preferred due to its favorable polymerization kinetics.

[0076] For crosslinked adsorbents, it is preferred that at least one crosslinking comonomer be present. Crosslinking comonomers generally have two or more reactive moieties capable of participating in a polymerization reaction. Preferably, such crosslinking comonomers are selected from the group consisting of divinylbenzene, telechelic N,N'-alkylenebisacrylamides such as N,N'-methylenebisacrylamide (NMAA), divinyl sulfone, and butadiene, with divinylbenzene preferably being provided during polymerization to form the adsorbent. In the context of this specification, the amount of crosslinking is defined as the amount of crosslinking comonomer present in the polymerization mixture during the formation of the adsorbent. A greater amount of crosslinking results in a denser adsorbent. A lesser amount of crosslinking results in a more porous or macroporous adsorbent. Preferably, a maximum of 10% crosslinking comonomer is present. More preferably, a maximum of 5% crosslinking comonomer is present. Even more preferably, for a cross-linked adsorbent, 0.1% to 5% cross-linking comonomer is present, more preferably 0.2% to 4% cross-linking comonomer is present, even more preferably 0.4% to 4% cross-linking comonomer is present, and most preferably 0.8% to 3% cross-linking comonomer is present, for example, about 1% to about 2%, or about 2%.

[0077] Adsorbents containing hydrophilic comonomers are referred to herein as hydrophilic adsorbents. The hydrophilic comonomer allows aqueous solvents to more easily permeate the adsorbent, which in turn allows nucleophilic waste solutes to more easily permeate the adsorbent. This allows the interior of the adsorbent to participate in binding nucleophilic waste solutes. A balance exists, since hydrophilic comonomers generally cannot bind nucleophilic waste solutes in the same way that PGA- or ninhydrin-type moieties can. Thus, increasing the hydrophilic comonomer content makes PGA- or ninhydrin-type moieties more effective, but reduces their number.

[0078] For hydrophilic adsorbents, it is preferred that at least one hydrophilic comonomer is present. Preferably, such hydrophilic comonomers are vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, 2-hydroxyethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl 2-methylprop-2-enoate, 2-hydroxyethyl prop-2-enoate, 2-hydroxypropyl prop-2-enoate, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, and N-isopropylacrylamide (NIPAm), more preferably vinylbenzenesulfonic acid, acrylic acid, methacrylic acid, 2-hydroxyethyl 2-methylprop-2-enoate (HEMA), 2-hydroxypropyl Preferably, the comonomer is selected from the group consisting of 2-methylprop-2-enoate, 2-hydroxyethyl prop-2-enoate, 2-hydroxypropyl prop-2-enoate, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide (HPMA), N-(2-hydroxyethyl)acrylamide, and N-(2-hydroxypropyl)acrylamide, and more preferably, vinylbenzenesulfonic acid is present. Those skilled in the art will understand that some comonomers, such as methyl methacrylate, can be easily post-modified to become hydrophilic by hydrolysis of their esters. Preferably, up to 60% of the hydrophilic comonomer is present. More preferably, up to 50% of the hydrophilic comonomer is present.Even more preferably, with respect to the hydrophilic adsorbent, 0% to 50% hydrophilic comonomer is present, more preferably 0% to 40% hydrophilic comonomer is present, even more preferably 5% to 40% hydrophilic comonomer is present, even more preferably 10% to 35% hydrophilic comonomer is present, even more preferably 15% to 35% hydrophilic comonomer is present, and most preferably 20% to 30% hydrophilic comonomer, for example about 25%.

[0079] Schematic examples of suitable adsorbents are shown below. The square brackets separate the different monomer types contained in the adsorbent. The monomers are preferably present as random or statistical copolymers. Suitable amounts for the different monomer types are described elsewhere herein. [Table B]

[0080] Further membrane properties Further additives may be present in the membrane, such as in the polymer matrix, as known in the art. For example, in a preferred embodiment, the membrane of the present invention, wherein the particulate material further comprises activated carbon particles, ion-exchange particles such as ion-exchange resin particles or ion-exchanged silica particles, silica particles such as unmodified silica particles or alkylated silica particles, zeolite particles, ceramic particles, polymer particles such as porous or non-porous polymer particles, and / or molecularly imprinted particles; and / or The membrane may further comprise a hydrophilic additive, preferably an additive such as polyvinylpyrrolidone, chitosan, polyethylene glycol, dextran, glycerol, diethylene glycol, octanol, oxalic acid, maleic acid, tartaric acid, fumaric acid, lithium chloride, and / or calcium chloride.

[0081] Thus, in a preferred embodiment, the membrane of the present invention further comprises at least one hydrophilic additive. The addition of a hydrophilic additive to the membrane can help adjust membrane morphology, improve membrane water transport, reduce membrane fouling, increase membrane hemocompatibility, or a combination thereof. Preferably, the hydrophilic additive is present in an amount ranging from 0.01% to 50% by weight, more preferably from 0.5 to 10% by weight, based on the dry weight of the membrane including the particles. More preferably, the additive is present at at least 1, preferably 2, more preferably 5, and even more preferably 10% by weight. More preferably, the additive is present at a maximum of 15%, more preferably 8%, and more preferably 3% by weight.

[0082] The hydrophilic additive is preferably selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, dextran, glycerol, diethylene glycol, octanol, oxalic acid, maleic acid, tartaric acid, fumaric acid, lithium chloride, and calcium chloride. Most preferably, the hydrophilic additive is polyvinylpyrrolidone. The polyvinylpyrrolidone preferably has a molecular weight in the range of 2500 to 2,500,000 g / mol, more preferably in the range of 2500 to 500,000 g / mol.

[0083] Membranes generally have two major surfaces. In the case of a sheet, these are opposing surfaces of a plane that roughly defines the sheet. Both of these surfaces can be viewed as exterior surfaces. In the case of hollow fibers, the exterior and interior surfaces are the two major surfaces. The interior surface defines the boundary between the membrane itself and its lumen. Full fibers have no pores and therefore no interior surface in this sense, but may have a porous structure that provides surface area. This surface area does not separate the membrane from the lumen. The surface may be smooth or rough, and may be non-pleated or pleated, as known in the art. Pleat refers to ribs that protrude from the surface. Preferably, the pleats are substantially or completely parallel. Preferably, the pleats are along the longest dimension of the membrane. The pleats preferably protrude at least 5%, more preferably at least 10%, even more preferably 20%, even more preferably 30%, and most preferably at least 40% of the average membrane thickness. The corrugations preferably project at most 150% relative to the average membrane thickness, more preferably at most 100%, even more preferably 75%, still more preferably 60%, and most preferably at most 50%. In preferred embodiments, at least one surface is smooth. In preferred embodiments, only one surface is smooth. In preferred embodiments, both surfaces are smooth. In preferred embodiments, at least one surface is pleated. In preferred embodiments, only one surface is pleated. In preferred embodiments, both surfaces are pleated. If the surface is an exterior surface, it is highly preferred that it is smooth, most preferably smooth and non-pleated. If the surface is an interior surface, it is highly preferred that it is pleated, most preferably pleated and smooth. As is known, pleats increase surface area and may therefore be preferred for any surface where increased surface area is desired.

[0084] In a preferred embodiment, at least one additional type of sorbent particle is included in the membrane of the present invention. The additional sorbent particle may advantageously have the same size, shape, BET surface area, and / or pore size as the urea sorbent particle defined elsewhere herein. Preferably, the at least one additional sorbent is selected from the group consisting of activated carbon particles, ion exchange resins, unmodified silica particles, C2-derivatized silica particles, C4-derivatized silica particles, C6-derivatized silica particles, C8-derivatized silica particles, C 16 - derivatized silica particles, ion-exchanged silica particles, zeolites, zirconia such as zirconium phosphate or zirconium oxide or zirconium oxyhydroxide or zirconium carbonate, ceramic particles, porous polymer particles, non-porous polymer particles, and molecularly imprinted particles. It is understood herein that the ion exchange resin may be a weak or strong cation exchange resin or a weak or strong anion exchange resin.

[0085] In a preferred embodiment, the additional adsorbent particles are activated carbon particles, which is particularly advantageous because activated carbon particles are capable of removing waste solutes (especially compounds other than urea) from the mixture.

[0086] The activated carbon particles preferably have an average pore size in the range of 0.1 to 20 nm, most preferably 1 to 5 nm. In another aspect, the activated carbon particles preferably have a size in the range of 0.1 to 100 μm, preferably in the range of 0.1 to 30 μm, and most preferably the activated carbon particles are smaller than 25 μm. In some embodiments, the activated carbon particles have a pore size of 100 to 10,000 square meters per gram (m 2 / g), most preferably 2000m 2The activated carbon particles have a Brunauer-Emmet-Teller (BET) surface area of ​​1 / g. The activated carbon particles are optionally impregnated with at least one inorganic impregnant selected from the group consisting of iodine, silver, aluminum, manganese, zinc, iron, lithium, and calcium. Preferably, the aluminum, manganese, zinc, iron, lithium, and calcium are in their cationic form. In a preferred embodiment, no such impregnation is present. The activated carbon particles are preferably selected from the group consisting of AC Norit A Supra particles and CMK3 particles.

[0087] Membrane production The membrane of the present invention can be prepared using techniques known in the art. Particle-containing membranes are known in the art, for example, from WO2006019293A1 or Geremia et al. (DOI:10.1016 / j.actbio.2019.04.009). The manufacturing method for preparing the membrane of the present invention differs in that it uses urea adsorbent particles having a size of up to 250 μm according to the maximum diameter. Thus, in one aspect, the present invention provides a method for preparing the membrane of the present invention, i. providing urea sorbent particles having a size according to a maximum diameter of up to 250 μm; ii. mixing the urea sorbent particles with a polymeric material in a solvent for the polymeric material to obtain a mixture; iii. extruding or casting the mixture to form a membrane; and iv. Solidifying the film, preferably by phase inversion. A method is provided that includes: Such methods are referred to herein as the manufacturing methods of the present invention.

[0088] In step i, urea sorbent particles are provided. These particles are defined herein above. In a preferred embodiment, the particles have a size of up to 200 μm, preferably up to 150 μm, more preferably up to 100 μm, even more preferably up to 70 μm, and even more preferably up to 50 μm, along their maximum diameter. The particles can be manufactured as part of the method of the present invention or obtained from commercial sources. In a preferred embodiment, the particles are sized as part of step i. This sizing involves bringing the particles into a desired size range. Sizing can be performed by milling, grinding, crushing, or cutting, or any other material processing method known in the art. Sizing can also include sieving, which is a convenient method for ensuring an upper size cutoff. Preferred urea sorbent particles swell by up to 20% along their longest axis when suspended in a liquid. More preferably, the particles swell by up to 15%, even more preferably by up to 10%, even more preferably by up to 5%, and most preferably by up to 2%. It is highly preferred that the particles do not swell substantially when suspended in a liquid, which improves the mechanical stability of the resulting film after successive wetting and dewetting or during storage.

[0089] In step ii), the urea sorbent particles are mixed with the polymeric material in a solvent for the polymeric material. The resulting suspension contains the dissolved polymer that will later constitute the membrane, with the sorbent particles suspended therein. Mixing can be carried out using any known method, such as those described below or illustrated in the Examples. Preferably, mixing is carried out for at least 1, 2, 3, 4, 5, 6, 12, 18, 24, 36, 48, 72 hours or more. Preferably, mixing is carried out for up to 120 hours, more preferably up to 96 or 72 hours, e.g., 72 hours. Preferably, the urea sorbent particles are individually suspended in the solvent without forming agglomerates. Additional components of the membrane of the present invention, such as additional particles or additives for the membrane, can be conveniently added here. These additional components are part of the mixture obtained in step ii.

[0090] The mixture of step ii preferably has a viscosity of at least 1.5 Pa·s, more preferably at least 10 Pa·s, and most preferably at least about 12.5 Pa·s, for example about 15 Pa·s. The mixture of step ii preferably has a viscosity of at most 150 Pa·s, more preferably at most 100 Pa·s, even more preferably at most 50 Pa·s, and most preferably at most 25 Pa·s, for example at most 20 Pa·s. Viscosity can be determined using any method known in the art. Preferably, a Stormer viscometer is used.

[0091] In step iii, the mixture of dissolved polymer and suspended urea sorbent is extruded, such as by coextrusion, or cast to form a membrane. Suitable details for this step are described below and shown in the examples.

[0092] In optional step iv, the formed film is solidified. This can be done using any known method, such as those described below or shown in the examples. The manufacturing method of the present invention preferably includes step iv.

[0093] Further details of the method are preferably as follows: The method of the present invention preferably includes a coextrusion process using a spinning head having at least two concentrically arranged outlet openings, in which stream (A) containing particulate material and stream (B) of polymeric material in a solvent for the polymeric material are fed separately and simultaneously through two adjacent outlet openings, after which the two streams are subjected to phase inversion, preferably a two-step phase inversion process, to obtain the membrane of the present invention as a fiber having a porous layer. Preferably, stream (A) is a mixture containing 0 to 50 wt.% of polymer matrix and 1 to 100 wt.% of particulate material. Preferably, stream (B) contains 3 to 50 wt.% of polymeric material. Preferably, the two-step phase inversion process includes using a three-layer spinneret in which stream (C), a liquid, vapor, or gas, preferably a liquid, is fed through the third, outermost outlet opening, allowing for control of the pore size of the outer porous layer. It is further preferred that stream (A) is fed through the spinning head inside stream (B). Furthermore, preferably, a polymeric material stream (D) in a solvent for the polymeric material is coextruded, where the outlet opening to which stream (A) is fed is sandwiched between the outlet openings to which streams (B) and (D) are fed, and then the three streams are subjected to phase inversion to obtain the membrane of the present invention as a fiber having three porous layers. After the phase inversion step, preferably, a heat treatment, chemical treatment, stretching, or further functionalization step is carried out to activate the particles, fix the porous structure of the fiber, or reduce the size of the pores in the porous fiber.

[0094] Coextrusion is understood to be the simultaneous extrusion of separate materials using a spinning head with multiple openings. Phase inversion is understood to be phase separation, which can be induced by changing the temperature of a homogeneous solution (thermal phase separation), evaporating a solvent from a polymer solution containing a nonvolatile nonsolvent (evaporation-induced phase separation), infiltrating a nonsolvent vapor (vapor-induced phase separation), or immersing a homogeneous polymer solution in a nonsolvent bath (immersion-induced phase separation). In the present manufacturing method, the latter is preferred. It is preferable to use a two-stage phase inversion method, as described on page 11, lines 2-20 of WO-A-2004 / 003268. In summary, before entering the coagulation bath, the exterior of the nascent membrane, here in the form of fibers, is contacted with a selected medium, resulting in a change in the composition of the exterior of the layer. This is considered the first step of the phase separation process. Once the membrane enters the coagulation bath, the nascent fibers undergo further phase separation and their structure is terminated. This is considered the second step of phase separation. Using a three-layer spinneret such as that described in WO-A-93 / 12868, in a first step, a stream of liquid, vapor, gas, or vapor / gas mixture can be fed through the third, outermost outlet opening, allowing for control of the pore size of the outer porous layer. However, it is considered within the scope of the present invention to provide a method for preparing membranes as hollow fibers with controlled pore size in the inner wall. In that case, the liquid, vapor, or gas stream is fed instead through the innermost outlet opening of the spinning head.

[0095] Simple tube-in-orifice spinnerets can also be used in the manufacturing method of the present invention, but they offer less flexibility in modifying the porosity of the fiber surface because no exit orifices are left to control the porosity of the outer layer in the first coagulation step. Instead of using a three-layer spinneret to control the porosity of the outer surface, the nascent fiber can be spun through a "chimney" or enclosed box in which the atmosphere is controlled by a continuous flow of steam, gas, or steam / gas mixture. When a high-temperature coagulation bath is used, the steam evaporating from the coagulation bath can also be used to influence the pore structure of the outer layer.

[0096] In the coextrusion process, stream (A) containing particulate material and stream (B) of polymeric material in a solvent for the polymeric material are fed separately and simultaneously through two adjacent spinning head outlet openings. Streams (A) and (B) ultimately result in the first and second porous layers of fibers, respectively. Stream (A) is preferably a mixture containing 0 to 50 wt% polymer matrix based on the total weight of stream (A). The appropriate amount of particles depends on the type of polymer used and its concentration. Generally, the amount of particles can vary between 1 and 95 wt%. Thus, stream (A) contains 0 to 50 wt% polymeric material and 1 to 100 wt% particulate material, with the remainder being solvent, the weights being based on the total weight of stream (A). More preferably, stream (A) contains 0.5 to 50 wt% polymeric material and 1 to 95 wt% particulate material. It is therefore possible to prepare fibers comprising 100% by weight of functionalized particulate matter entrapped within a second porous shell layer in a single preparation step, preferably choosing membrane dimensions with an inner diameter of less than 0.5 mm.

[0097] More preferably, stream (A) comprises 3 to 50 wt. %, most preferably 5 to 20 wt. % of the polymeric material. Preferably, the matrix polymer concentration is less than 12 wt. %, more preferably less than 10 wt. %. The amount of particles in stream (A), based on its dry weight, is more preferably 1 to 97 wt. % of stream (A), typically greater than 30 wt. %, even more preferably greater than 40 wt. %, most preferably 50 to 90 wt. %. The preferred concentration depends on the particular polymer and particulate material used and the desired amount of particles in the first porous layer of the resulting fiber.

[0098] Stream (B) contains 3 to 50 wt. %, preferably 5 to 25 wt. %, of polymeric material. In one embodiment, stream (B) is further supplied with 1 to 95 wt. % of functionalized particulate material according to stream (A) to obtain porous fibers having two adjacent layers of particulate material entrapped in a polymer matrix, where the particulate material and / or polymer matrix of both layers may be different. For both streams (A) and (B), it applies that the polymeric material should be dissolved in a suitable solvent. Therefore, the type of solvent depends on the choice of polymer. Taking into account the phase inversion process, preferably, a solvent that is sufficiently miscible with water is used. One or more solvents can also be used together in combination with a non-solvent. Suitable solvents include, but are not limited to, N-methylpyrrolidone (NMP), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), formamide (FA), tetrahydrofuran (THF), ε-caprolactam, butyrolactone, especially 4-butyrolactone, sulfolane, cyclohexanone, and triethyl phosphate. Preferred solvents are NMP, DMAc, DMF, DMSO, THF, ε-caprolactam, and 4-butyrolactone. Because the polymers in streams (A) and (B) are selected independently of each other, the solvents may be different. Mixtures of solvents and non-solvents, as well as additive components of any nature, can be added to the coagulation bath to affect the morphological structure of either layer. Additives can be added to streams (A) and / or (B), for example, to affect viscosity, act as pore-forming agents, enhance pore connectivity, reduce or prevent macrovoid formation, and / or introduce hydrophilic properties. Possible additives include, but are not limited to, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyethylene oxide (PEO), dextran, glycerol, diethylene glycol, (higher) alcohols such as octanol, carboxylic acids or organic acids such as oxalic acid, maleic acid, tartaric acid, fumaric acid, salts such as LiCl and CaCl2. Other additives are described herein above.It is within the ability of one skilled in the art to evaluate and apply the appropriate (mixtures) of (non-)solvents, additives, and process conditions to produce fibers with the desired properties. The additives and / or non-solvents can partially replace the solvent and can vary between 0.01 and 50% by weight.

[0099] If a membrane in the form of a fiber is to be obtained in which the first porous layer with trapped particulate material forms the inner layer, stream (A) is fed through the spinning head inside stream (B), and vice versa for embodiments in which the second porous layer is the outer layer of the fiber. For embodiments in which a hollow core and / or a third or even more layers are required, it will be clear to those skilled in the art to adapt the spinning head to have the required number of outlet openings and select the order in which the streams need to be fed to these openings. To achieve a hollow core, it is known in the art to apply stream (C) of pore liquid through, for example, a needle, which is the innermost opening. If the fiber requires the retention of a third polymer layer, this layer is formed from stream (D), for which the same conditions and constraints apply as for stream (B). In these cases, in the coextrusion process, a stream (D) of polymeric material in a solvent for the polymeric material is coextruded with stream (A) and stream (B), the outlet opening to which stream (A) is fed is sandwiched between the outlet openings to which streams (B) and (D) are fed, and the three streams then undergo phase inversion.

[0100] As mentioned above, the phase inversion process preferably includes a coagulation medium. Water is the preferred coagulation medium. Other examples of possible coagulation media and non-solvents are methanol, ethanol, propanol, butanol, ethylene glycol, acetone, and methyl ethyl ketone. To achieve the desired porosity in the fiber, a mixture of non-solvents and solvents is used in combination with variations in physical process parameters such as temperature, production rate, humidity, air gap length, drawing, and winding speed.

[0101] To achieve the desired membrane porosity, a mixture of non-solvent and solvent is used in combination with variations in physical process parameters such as temperature, production rate, humidity, void length, drawing, and winding speed. For fibers, membrane porosity is primarily controlled by the flow of a liquid, vapor, or gas stream through an outlet opening adjacent to the stream that ultimately forms the shell layer of the fiber. The selection of this stream's composition and contact time before entering the coagulation bath determines whether the shell layer will be dense or porous. When the stream that ultimately forms the shell layer comes into contact with air of appropriate humidity, the surface of the outer layer becomes dense. To achieve optimal accessibility of the entrapped adsorbent particles, a suitable medium is preferably flowed along the stream that ultimately forms the shell layer during spinning. Preferably, the medium is a liquid mixture of a solvent and a non-solvent for the polymer. Preferably, the non-solvent is water.

[0102] Alternatively, a gas stream containing a non-solvent for the polymer can be applied. However, if steam is used, the stream that ultimately forms the fiber shell layer must contain a non-volatile solvent, so that solvent emissions into the vapor path are small compared to the inward diffusion of the non-solvent vapor. Mixtures of two non-solvents, or a solvent and a non-solvent vapor, can also be used to affect fiber formation. In the case of a gas or vapor stream, the non-solvent is preferably water vapor. Those skilled in the art can easily determine the desired amount of water vapor in the gas stream to produce the first phase inversion effect. The porosity of the first porous layer can be controlled by varying the concentration of the polymeric material, the amount and type of additives, and the size, content, and functionality of the particulate material, as explained in more detail on page 10, lines 4-26 of WO-A-2004 / 003268.

[0103] Thus, the method effectively comprises contacting the adsorbent particles and polymer defined herein with a solvent to form a mixture, extruding or casting the mixture, and subsequently solidifying the mixture to form a membrane. Those skilled in the art are aware of methods for preparing membranes, particularly mixed matrix membranes. An overview of membrane preparation techniques is provided, for example, by Ladewig and Al-Shaeli (Fundamentals of Membrane Bioreactors - Chapter 2: Fundamentals of Membrane Processes, Springer 2017, pages 13-37). A non-limiting example of a membrane preparation method is phase inversion. Phase inversion can be further specified by various techniques, such as precipitation by solvent evaporation, precipitation by controlled evaporation, thermal precipitation, precipitation from the gas phase, and immersion precipitation. The latter is also known as non-solvent-induced phase inversion. In a preferred embodiment, the solidification is non-solvent-induced phase inversion, and preferably the non-solvent is water. In that case, it is understood that after extrusion or casting, the mixture is substantially immediately contacted with water, for example, by using a water bath. Preferably, the extrusion of the mixture is carried out using a spinneret. A particularly suitable method that can be applied to produce the membrane of the present invention is described in EP1518011. In particular, the conditions described in

[0019] to

[0051] therein are advantageous.

[0104] Preferably, the polymer used to prepare the membranes of the invention is at least one polymer selected from the group consisting of polysulfone, polyethersulfone, polyphenylenesulfone, polyarylethersulfone, polyamide, polyetherimide, polyimide, polyethylene-co-vinyl alcohol, polyethylene-co-vinyl acetate, cellulose acetate, cellulose triacetate, polyvinylidene fluoride, polyvinyl chloride, polyacrylonitrile, polyurethane, polyetheretherketone, and polyacrylic acid. Most preferably, the method comprises contacting adsorbent particles as defined herein with polyethersulfone and polyvinylpyrrolidone.

[0105] In a preferred embodiment, the polymer concentration in the mixture from which the membrane is prepared is in the range of 3% to 50% by weight, preferably 5% to 35% by weight, and most preferably 10% to 20% by weight, relative to the total weight of polymer and solvent (i.e., excluding the weight of the adsorbent particles). Most preferably, the mixture contains 5% to 15% by weight of polyethersulfone and 1% to 5% by weight of polyvinylpyrrolidone, relative to the total weight of polymer and solvent.

[0106] In a preferred embodiment, the solvent is selected from the group consisting of N-methylpyrrolidone (NMP), dimethylacetamide (DMAc), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), formamide (FA), tetrahydrofuran (THF), ε-caprolactam, butyrolactone, sulfolane, cyclohexanone, and triethyl phosphate. NMP is the most preferred solvent. It is also preferred that the mixture consists essentially of the adsorbent particles, polymer, and solvent as defined herein.

[0107] Membrane-containing device The membranes of the present invention can be advantageously used in renal replacement therapies such as peritoneal dialysis or hemodialysis. During such use, the membranes are typically present in a cartridge that can be replaceably inserted into a (hemo)dialysis machine. Accordingly, the present invention provides a cartridge for use in a dialysis machine, comprising the membranes of the present invention. Such a dialysis machine may be a hemodialysis machine or a machine for regenerating peritoneal dialysate in peritoneal dialysis. Accordingly, the present invention provides a dialysis machine comprising the membranes of the present invention or the cartridges of the present invention. Such a dialysis machine may be a hemodialysis machine or a machine for regenerating peritoneal dialysate in peritoneal dialysis.

[0108] In addition to the membranes of the present invention, such cartridges and dialysis devices are known in the art. In certain embodiments, the cartridge is a disposable cartridge. In certain embodiments, the cartridge is a regenerative cartridge (e.g., when the sorbent is a ninhydrin-type sorbent that can be regenerated under acidic conditions, such as those described in WO2019110557). The cartridge may also be referred to as a cassette. The cartridge is preferably adaptable for use with a variety of different types of components and arranged in various ways. The cartridge may include additional sorbents or membranes. By removing nucleophilic waste solutes, the cartridge at least partially regenerates the dialysate and / or filtrate used during dialysis. The cartridge preferably includes a body having a fluid inlet and a fluid outlet. The interior of the cartridge is preferably configured and arranged so that fluid entering the interior through the inlet flows through the membrane and subsequently through the outlet.

[0109] The membrane used in the dialysis device is preferably semi-permeable. It can be in the form of a sheet, acting as a wall or part of a wall to separate two volumes. It can also be in the form of a fiber bundle connecting the two volumes. A very suitable fiber bundle is described in WO2006019293, which describes a bundle of hollow or solid fibers with multiple coaxially arranged porous layers.

[0110] A dialysis machine is a closed, sterile system. It comprises one or two fluid circuits. It typically comprises two circuits: a so-called patient loop, through which a subject's fluid, such as blood or peritoneal dialysis fluid, flows; and a so-called regeneration loop, through which dialysis fluid, such as dialysate and / or filtrate, is circulated through the cartridge as described above. The two circuits are separated from each other by a (semi-permeable) membrane through which waste solutes can diffuse or pass from the subject's fluid into the dialysis fluid. Air, moisture, pathogens, and fluids from the environment surrounding the dialysis machine cannot enter the fluid circuits. The dialysis system only allows fluids (e.g., ultrafiltrate) and air to exit or enter these fluid circuits under controlled conditions.

[0111] The present invention also relates to a cartridge comprising the membrane of the present invention. Preferably, the cartridge is suitable for use in a dialysis device. The cartridge preferably comprises a housing in which the membrane is disposed. Preferably, the cartridge is configured such that during normal use, the membrane comes into contact with a relevant fluid or mixture as defined herein for a treatment or non-therapeutic method for removing amine- or amide-containing compounds, respectively. Typically, the cartridge comprises at least one inlet and at least one outlet for fluid inflow or outflow, respectively.

[0112] The present invention also relates to a dialysis device comprising the membrane of the present invention or the cartridge described herein. Preferably, the dialysis device is a portable or wearable artificial kidney device. In a preferred embodiment, the dialysis device comprises at least one inlet and at least one outlet for fluid inflow and outflow, respectively. The dialysis device also preferably comprises a means for maintaining the temperature of the membrane of the present invention at an elevated temperature, preferably in the range of 20°C to 90°C, more preferably in the range of 35°C to 80°C, and most preferably in the range of 36°C to 75°C.

[0113] Medical Use In a fourth aspect, the present invention provides a medical use of the membrane of the present invention.Accordingly, this aspect provides a membrane of the present invention for use as a medicine, preferably for use in the treatment of diseases or conditions associated with urea accumulation or inadequate removal of urea.Such membranes are herein referred to as products for use according to the present invention.In this same use, there are provided the above-mentioned cartridge and the above-mentioned dialysis device, each of which contains the membrane (for use) of the present invention.

[0114] In the article of manufacture for use of the present invention, the article of manufacture comprises a sorbent as described, which is a substance or composition, chemical or composition of chemicals, that achieves a medical effect, wherein the treatment involves the removal of urea from the plasma of a patient suffering from a condition as described herein. This effect is achieved by the specific binding agent for urea, which is the chemical and sorbent.

[0115] In particular embodiments of this aspect, the invention provides a membrane of the invention for use as a medicament for use in the treatment of diseases or conditions associated with ammonia accumulation or inadequate removal of ammonia. In further particular embodiments of this aspect, the invention provides a membrane of the invention for use as a medicament, the membrane for sequestering urea. In further particular embodiments of this aspect, the invention provides a membrane of the invention for use as a medicament, the membrane for sequestering ammonia.

[0116] Treatment of disease or condition can be the improvement, suppression, prevention, delay, cure or prevention of disease or condition or its symptoms, and preferably the suppression of the symptoms of disease or condition.Urea may accumulate or may not be fully removed in the case of renal failure.Examples of diseases or conditions associated with urea accumulation or inadequate removal of urea include end-stage renal disease (ESKD); severe acute renal failure; for example, increased hepatic production of urea due to gastrointestinal bleeding; increased protein catabolism due to trauma, such as major surgery or extreme starvation accompanied by muscle destruction; increased renal reabsorption of urea due to any cause of renal hypoperfusion, such as congestive heart failure, shock, severe diarrhea; iatrogenic conditions caused by drug therapy that increases urea production, such as urea infusion for diuresis, treatment with tetracycline or corticosteroids; chronic renal failure; and urinary outflow obstruction.

[0117] The products for use of the present invention are suitable for use in a method of treatment, which may comprise contacting a fluid from a subject, preferably a subject in need thereof, with a membrane of the present invention, preferably with an effective amount of the product for use of the present invention.

[0118] With respect to dialysis therapy, the present invention can be used in a variety of different dialysis therapies to treat renal failure. Dialysis therapy, as used throughout this specification and similar terms, is meant to include and encompass any and all forms of treatment for removing waste products, toxins, and excess water from a subject suffering from a disease or condition. Blood therapies, such as hemodialysis, hemofiltration, and hemodiafiltration, include both intermittent therapy and continuous therapy, such as that used in continuous renal replacement therapy (CRRT). Continuous therapy includes, for example, slow continuous ultrafiltration (SCUF), continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), continuous arteriovenous hemodiafiltration (CAVHDF), continuous ultrafiltration cyclic intermittent hemodialysis, and the like. The present invention can also be used during peritoneal dialysis, including, for example, continuous ambulatory peritoneal dialysis, automated peritoneal dialysis, continuous flow peritoneal dialysis, and the like. Furthermore, while the present invention may, in certain embodiments, be utilized in methods of providing dialysis therapy to subjects with acute or chronic renal failure or disease, it should be understood that the present invention may also be used for acute dialysis needs, for example, in an emergency room setting. However, it should be understood that the compositions of the present invention may be effectively utilized in a variety of different applications (physiological and non-physiological) in addition to dialysis.

[0119] In particular, the membranes of the present invention are intended for use in the treatment and / or prevention of a disease selected from the group consisting of uremia and azotemia in a subject. In a preferred embodiment, the disease is uremia. Uremia is a condition in which the blood has undesirably high levels of urea. The condition can be either chronic or acute. It is understood that during treatment and / or prevention, the membranes of the present invention can be in contact with one or more associated fluids (e.g., a subject's blood, or spent fluid resulting from subjecting a subject to hemodialysis, hemofiltration, or any one of hemodiafiltration or peritoneal dialysis). Hemodialysis, hemofiltration, and hemodiafiltration and peritoneal dialysis are commonly used methods for removing solutes from a patient's blood. In a hemodialysis setup, blood flows through one side of a dialysis membrane and dialysate flows through the other side of the membrane. In hemodialysis, solutes flow through the membrane into the dialysate primarily due to concentration differences (i.e., diffusion). In hemofiltration, dialysate is not used. Instead, positive hydrostatic pressure moves water and solutes across the filtration membrane from the blood compartment to the filtrate compartment, where they are expelled. Solutes and water move across the membrane and are removed from the blood by convection, driven by the hydrostatic pressure difference. A substitution fluid is added to the blood (before and / or after the blood contacts the dialysis membrane) to replenish the water transported across the membrane. Hemodiafiltration is a combination of hemodialysis and hemofiltration. Thus, blood flows on one side of the dialysis membrane, dialysate flows on the other side, substitution fluid is added to the blood (before and / or after the blood contacts the dialysis membrane), and solute transport from the blood to the dialysate is based on both diffusion and convection. In a typical hemodialysis, hemofiltration, or hemodiafiltration treatment, the blood is returned to the patient after contacting the dialysis membrane. The spent fluid that has contacted the membrane of the present invention can be reused, for example, as dialysate or substitution fluid, since the membrane removes amine-containing compounds, particularly urea, from the spent fluid. This is particularly advantageous in small dialysis systems, such as portable and wearable artificial kidney machines, since a smaller volume of fluid is needed to perform the therapy. The spent fluid may be directly recirculated during treatment or stored for later use. In the case of hemodialysis, this spent fluid is spent dialysate.In the case of hemofiltration, the spent fluid is water containing solutes that is forced onto the membrane in contact with the subject's blood due to convection. In the case of hemodiafiltration, the spent fluid is one or more of spent dialysate, where water containing solutes is forced onto the membrane in contact with the subject's blood due to convection. In a preferred embodiment, the membrane is for use in the treatment and / or prevention, preferably treatment, of a disease selected from the group consisting of uremia and azotemia in a subject, the subject undergoing hemodialysis, hemofiltration, or hemodiafiltration or peritoneal dialysis, and the membrane is in contact with the spent fluid as defined herein, preferably not in direct contact with the subject's blood. In a preferred embodiment, the membrane is maintained at an elevated temperature during treatment, preferably in the range of 20°C to 90°C, more preferably in the range of 35°C to 80°C, and most preferably in the range of 36°C to 75°C. In a preferred embodiment, the subject is human. The subject can be of any gender, and similarly, treatment is not limited to subjects of a particular age or any other characteristics. Preferably, the treatment is selected from the group consisting of hemodialysis, hemofiltration, and hemodiafiltration and peritoneal dialysis. For either treatment, the treatment time is preferably in the range of 1 to 36 hours, more preferably in the range of 1 to 24 hours. Most preferably, when the treatment is hemodialysis, the treatment period is 4 to 8 hours. The present disclosure also relates to a method for treating and / or preventing a disease selected from the group consisting of uremia and azotemia, preferably uremia, in a subject as defined herein, comprising contacting the blood of said subject and / or contacting spent fluid resulting from subjecting said subject to any one of hemodialysis, hemofiltration, hemodiafiltration, or peritoneal dialysis with a membrane of the present invention. The treatment and / or prevention is preferably as disclosed herein above.

[0120] How to use The membranes of the invention are surprisingly effective at capturing nucleophilic solutes, preferably nucleophilic waste solutes. In a fifth aspect, the invention provides a method for removing nucleophilic waste solutes from a fluid, comprising: i) providing a fluid containing a nucleophilic waste solute; iia) contacting said fluid with a membrane of the invention or a cartridge of the invention, or alternatively iib) contacting said fluid with a dialysis fluid through a membrane, said dialysis fluid being in contact with the membrane of the invention or the cartridge of the invention; iii) optionally recovering the fluid The present invention provides a method comprising:

[0121] Hereinafter, such a method is referred to as the capture method of the present invention. The method can be a continuous process in which the supply of a fluid containing nucleophilic waste solutes is a continuous flow of fluid. In such a case, step iii) is preferably not optional but is also performed continuously. The capture method of the present invention always includes step i), step ii) (either step iia) or step iib), and optionally step iii). The membrane in step iib is preferably not a membrane of the present invention or is a membrane of the present invention that is further present in the membrane of the present invention referred to as such in step iib.

[0122] Nucleophilic waste solutes are dissolved substances that are nucleophilic and whose removal is desirable. For example, in human blood, urea is a waste solute. In unpurified water intended for drinking water, most organic nucleophiles are waste solutes. Examples of nucleophilic waste solutes are ammonia, urea, creatinine, and small organic amines, thiols, or alcohols. The chemical binding properties make the membranes of the present invention well suited for a variety of different applications that are subjected to physiological and / or non-physiological conditions. In one embodiment, the membranes of the present invention can be used to remove metabolic, proteinaceous, and other substances, such as urea, creatinine, uric acid, and / or uremic toxins, biological substances, proteinaceous substances, and the like, from blood, peritoneal dialysis fluid, and / or solutions used to dialyze and / or filter blood, such as dialysate and / or filtrate. Due to their relevance as described elsewhere herein, highly preferred nucleophilic waste solutes are urea and ammonia. In a preferred embodiment, the nucleophilic waste solute is ammonia. In another preferred embodiment, the nucleophilic waste solute is urea.

[0123] In step i), a fluid containing a nucleophilic waste solute is provided. This may be wastewater to be purified, a waste solvent to be purified, but also a (body) fluid from a subject (e.g., blood or peritoneal dialysis fluid). When the fluid in step i) is a fluid from a subject, it is preferably blood or peritoneal dialysis fluid, most preferably blood, and is preferably a fluid previously obtained from the subject.

[0124] In step ii), there are two options. In one option, step iia), the fluid itself is directly contacted with the membrane of the present invention, the composition of the present invention, or the membrane or cartridge of the present invention. Step iia) is well suited to purifying solvents or fluids not intended for consumption or medical purposes after removal of waste solutes. Step iib) separates the capture membrane of the present invention from the fluid provided in step i) by using dialysis fluid and / or filtrate. Step iib) is particularly suited to removing nucleophilic waste solutes from pharmaceutical solutions or fluids obtained from a subject (e.g., a subject's body fluid). The contact preferably lasts for 24 hours, 12 hours, 6 hours, 4 hours, 3 hours, 2 hours, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute or less. The contacting may also be in a continuous flow through the adsorbent, in which case the total amount of waste solute removed is more valuable.

[0125] The additional membrane for use in separating the fluid in step iib) is preferably a semipermeable membrane. These are known in the art and may be, for example, the semipermeable membranes present in conventional (hemo)dialysis machines. The membranes of the present invention as described above may also be used. Dialysis fluids are known in the art and may range from ultrapure water to physiological buffers. Non-limiting examples of dialysis fluids are media containing known amounts of, for example, Na, K, Ca, Mg, Cl, acetate, HCO3, and glucose (e.g., those available from MDN Netherlands GmbH (Neubrandenburg, Germany) or Baxter (Deerfield, Illinois, USA) or Dirinco BV (Oss, the Netherlands)).

[0126] In optional step iii), the fluid is recovered. The membranes of the present invention are porous or macroporous, and often swellable in aqueous media, so that fluids can flow through and permeate them. Recovery of the fluid that has come into contact with the adsorbent is easily achieved by filtration, centrifugation, or removal of the cartridge containing the adsorbent. Recovery of the fluid allows for further treatment thereof or its return to the subject. In a preferred embodiment within this aspect, the fluid is recovered.

[0127] Preferably, when the fluid is collected in step iii), the relevant physiological parameters are then analyzed and adjusted, if appropriate. Examples are ion concentration, osmolality, pH, and in particular Na concentration, Ca concentration, and Mg concentration. Therefore, a preferred step iii) is to collect the fluid, after which at least one of the fluid pH, fluid sodium concentration, fluid magnesium concentration, and fluid calcium concentration is determined and optionally adjusted to a reference value. The preferred reference value is a physiological value corresponding to the type of fluid. The adjustment can be performed by any suitable method known in the art. The adjustment is preferably performed when a deviation from the reference value is detected.

[0128] In a preferred embodiment of the capture method, at least 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2 0.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.70, 2.80, 2.90, 3.00 or 3.10 mmol of nucleophilic waste solutes are removed; preferably at least 1.55, 1.56, 1.57, 1.58, 1.59, 1.60 mmol, more preferably at least 2.20, even more preferably at least 2.50, and most preferably at least 2.55 mmol of nucleophilic waste solutes are removed per gram of sorbent. This removal preferably involved the removal of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more of the initial concentration of the particular nucleophilic waste solute from the fluid provided in step i), more preferably at least 50% or more.

[0129] The membranes of the present invention can also be used to remove amine- or amide-containing compounds from a mixture. Preferably, the compound is urea. It is also preferred that the mixture is as defined herein for a non-therapeutic method for removing amine- or amide-containing compounds. It is understood that this use is preferably a non-therapeutic use.

[0130] The present invention also relates to a non-therapeutic method for removing amine- or amide-containing compounds from a mixture, comprising contacting the mixture with a membrane of the present invention. Preferably, the compound is urea. In a preferred embodiment, the mixture is an aqueous solution, such as a patient sample. Potential uses include, for example, removing amine-containing compounds from patient samples such as blood or urine or dialysates such as peritoneal dialysis fluids to prepare the sample for further analysis. In other applications, the aqueous solution may contain, for example, large amounts of urea and biomolecules, such as proteins, that denature under these conditions. In a preferred embodiment, in the non-therapeutic method, the membrane is maintained at an elevated temperature, preferably in the range of 20°C to 90°C, more preferably in the range of 37°C to 80°C, and most preferably in the range of 60°C to 75°C.

[0131] General definition In this specification and claims, the verb "to comprise" and its conjugations are used in their open-ended sense to mean that the items following the word are included, but not that items not specifically mentioned are excluded. Furthermore, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of that element is present, unless the context clearly requires that only one of that element is present. Thus, the indefinite article "a" or "an" typically means "at least one." The terms "about" or "approximately," when used in connection with a numerical value (e.g., about 10), mean "about" or "approximately." Preferably, means that a value may be within 5% of a given value. As used herein, "subject" means any animal, preferably a mammal, and most preferably a human. In a preferred embodiment, the subject is a non-human.

[0132] In the context of the present invention, a decrease or increase in an evaluated parameter refers to a change of at least 5% in the value corresponding to that parameter. More preferably, a decrease or increase in value refers to a change of at least 10%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, or 100%. In this latter case, there may no longer be a detectable value associated with the parameter.

[0133] The use of a substance as a medicament described herein can also be interpreted as the use of said substance in the manufacture of a medicament.Similarly, whenever a substance is used for treatment or as a medicine, it can also be used for the manufacture of a medicine for treatment.Products for use are suitable for use in methods of treatment.

[0134] Throughout this specification, when percentages are used to describe the amounts of monomers and comonomers in a mixture, molar percentages are intended unless otherwise stated or clearly evident from the context.

[0135] Throughout this application, (hemo)dialysis refers to both hemodialysis and dialysis. In general, dialysis machine can refer to any type of dialysis machine described herein.

[0136] The present invention has been described above with reference to several exemplary embodiments. Modifications and alternative implementations of several parts or elements are possible and fall within the scope of protection defined in the appended claims. All citations to literature and patent documents are incorporated herein by reference. [Brief explanation of the drawings]

[0137] [Figure 1]Scanning electron microscope images of mixed matrix membranes prepared as described in Example 2 are shown. Figure 1A is a cross-sectional image of the membrane's MMM pleated lumen morphology. Figure 1B is a magnified image of the wall of the MMM, showing the finger-like macrovoid structure. The adsorbent particles are well dispersed without agglomeration and are well surrounded by the polymer solution (white arrows). Figures 1C and 1D show the lumen (inner layer) and outer layer of the MMM, respectively, showing a very thin dense layer with no visible pores on the lumen surface (Figure 1E) or outer surface (Figure 1F). The outer dense layer (Figure 1D) is slightly thicker (0.5 μm) compared to the inner dense layer (0.2 μm). [Figure 2] Figure 1 shows the water permeability at various pressures for MMMs prepared as described in Example 2. Data are expressed as mean ± SE (n = 6). A linear fit gave a water permeability equal to 238 ± 9 L / (m h Bar). [Figure 3] FIG. 1 shows the kinetics of urea uptake measured at 37° C., 50° C., and 70° C. using ninhydrin-type adsorbent particles in suspension (containing approximately 2.5 mmol of ninhydrin per g of adsorbent) with a mean diameter ± SD of 483 ± 282 μm (n = 30). [Figure 4] Urea uptake results (n=3) obtained over time for ninhydrin-type adsorbent particles (containing approximately 2.5 mmol / g of ninhydrin) in suspension before (standard deviation of diameter ±483 ±282 μm) and after (diameter <63 μm) grinding and sieving. [Figure 5] Urea uptake results (mean ± standard deviation) obtained over time for ninhydrin-type adsorbents (diameter <63 μm) in suspension and MMMs containing such adsorbent particles. [Figure 6] Urea isotherm binding (n=3) on adsorbent-containing MMM prepared as described in Example 2 and on control hollow fibers (HF, PES / PVP) without adsorbent particles, prepared as described in Example 2.2. [Figure 7]Figure 1 shows the results of dynamic urea uptake using MMM-containing sorbent particles prepared as described in Example 2. In this experiment, the urea solution was continuously recirculated through the membrane for 4 hours (n=5). The urea uptake at 4 hours (indicated by an asterisk) was normalized by the amount of urea eluted from the MMM. [Figure 8] Figure 1 shows the kinetics of urea capture using MMMs containing PGA-type sorbent particles prepared in the form of hollow fibers as described in Example 2. Here, the urea solution is continuously recirculated through the MMMs (n = 2) or continuously stirred with crushed sorbent particles (n = 3). The PGA-type sorbent in the membrane exhibits faster urea capture behavior than the free PGA-type sorbent that has been crushed to obtain smaller particles.

[0138] [Example] Example 1 - Preparation of Adsorbent 1.1 Preparation of ninhydrin-type adsorbent Adsorbents of this type are known in the art and can be prepared, for example, as described in EP121275A1, US4897200A, or WO2019110557.

[0139] 1.2 Preparation of PGA-type adsorbent Adsorbents of this type are known in the art and can be prepared, for example, as described in US3933753A or WO2004078797A1, or can be produced as follows:

[0140] 1.2.1 Preparation of precursor monomers [ka] In a three-necked round-bottom flask, p-(ethynylphenyl)ethanone (10.0 g, 69.4 mmol) was suspended in EtOH (350 mL) and Lindlar's catalyst (300 mg, 3 wt%) was added. The air was replaced with H2, and the suspension was stirred at room temperature for 2-16 h. To monitor the conversion (and thus prevent over-reduction of VPE to alkanes), samples were taken frequently from the reaction mixture, and the conversion was monitored after evaporation of EtOH under reduced pressure. 1 The conversion was determined by H-NMR (CDCl). After >90% conversion, the H-filled balloon was removed and the reaction mixture was concentrated under reduced pressure. The crude product was redissolved in CHCl and purified by filtration over Hyflo. The filtrate was concentrated under reduced pressure to give crude pVPE (p-(vinylphenyl)ethanone) as a yellow liquid in 99% yield (10.1 g, 69.0 mmol). Melting point: 29 °C, enthalpy of fusion: 90.6 J / g. 1 H-NMR (CDCl3, 600 MHz) δ7.92 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.75 (dd, J = 17.6 Hz, 10.9Hz, 1H), 5.87 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.9 Hz, 1H), 2.59 (s, 3H).

[0141] 1.2.2 Polymerization of precursor monomers A two-phase suspension polymerization was used. Briefly, the aqueous phase was prepared by adding NaCl (11 mg), polymethacrylic acid sodium salt solution (452 ​​mg of 10% gel in water), and CaHPO (84 mg) to water (15 mL). The organic phase consisted of VPE (2.1 g, 14.4 mmol, 2 mL), porogen (2.9 mL, heptane / toluene), 80% technical-grade divinylbenzene (3-6 mol%), and a 50% benzoyl peroxide blend with dicyclohexyl phthalate (174 mg, 0.36 mmol, 2.5 mol%). After mixing and polymerization (heating at 73 °C in an oil bath under mechanical stirring for 16 h), the resulting suspension was cooled to room temperature and poured onto a filter (200 μm cutoff, Veco BV). The residue was washed with acetone and water and finally dried over P2O5 under vacuum to give pVPE (1.1-1.9 grams, 52-90% yield).

[0142] 1.2.3 Preparation of PGA-type adsorbents based on poly-VPE The resulting crude pVPE mixture was then further converted to a PGA-type adsorbent. The acetyl aromatic groups in the pVPE beads were halogenated and subsequently converted to PGAH-groups by Kornblum oxidation in a one-pot operation. In a glass reactor equipped with a Teflon blade stirrer, pVPE beads (60.0 g) were swollen in DMSO (600 mL, 8.45 mol) under continuous stirring for 30 minutes, after which 48% aqueous HBr solution (175 mL, 1.55 mol) was slowly added. One of the reactor outlets was capped with a septum containing a needle to allow the escape of the formed Me2S. The suspension was stirred at 80 °C for 8 hours, after which the reaction mixture was filtered (200 μm cutoff, Veco BV). The residue was washed with water until the pH of the filtrate was >5. The residue was dried over PO5 under vacuum to yield a PGA-type adsorbent (55.2 grams).

[0143] Example 2 - Preparation of Adsorbent-Containing Membrane 2.1 General Method for Preparing Adsorbent-Containing Membranes The desired amount of polymer was weighed and completely dissolved in ultra-high-purity NMP. After stirring for 3 days, dry adsorbent particles with a maximum diameter of 120 μm were added, and the suspension was then stirred on a roller bank for 4 hours. The resulting suspension was then cast into water to form a sheet membrane or extruded through a spinneret to form fibers.

[0144] 2.2 Preparation of PES / PVP membrane containing ninhydrin-type adsorbent Prior to membrane preparation, ninhydrin-type or PGA-type adsorbents with a mean diameter of 483 ± 282 μm ± standard deviation (e.g., approximately 2.5 mmol of ninhydrin per gram of particles) were ground using a mortar and pestle. The ground adsorbent particles were then sieved through a 63 μm sieve. Hollow fiber (HF) mixed matrix membranes (MMMs) were prepared using adsorbent particles embedded in a PES / PVP polymer matrix. HF MMMs were prepared by a dry-wet spinning technique. The polymer dope solution was prepared by dissolving Ultrason E6020 PES (BASF, Ludwigshafen, Germany) and PVP K90 (molecular weight approximately 360 kDa, Sigma-Aldrich Chemie GmbH, Munchen, Germany) in ultrapure N-methylpyrrolidone (NMP) (Acros Organics, Geel, Belgium). The particles were added to the dope solution to obtain a final particle weight equal to 55% of the dry weight of the membrane. The PES / PVP / adsorbent polymer solution was stirred at 60 °C for 2 days to ensure proper dispersion of the particles in the polymer solution. It was then transferred to a stainless steel syringe and degassed for 24 hours. The concentrations of PES, PVP, and adsorbent used in this study, as well as the spinning parameters, are specified in Table 1. After degassing, the syringe was connected to a high-pressure syringe pump and a spinneret for preparing HF (specifications in Table 1). Ultrapure water was used as the pore-forming solution. The air gap between the spinneret and the coagulation bath was adjusted to 5.5 cm. The HF was allowed to gravity fall into the water coagulation bath. The fabricated membrane was washed with deionized water and stored in deionized water for further use.

[0145] [Table 1]

[0146] Example 3 - Identification of Adsorbent-Containing Membrane 3.1 Scanning Electron Microscopy (SEM) The morphology of HF MMM (prepared as described in Example 2.2) was analyzed by SEM (JEOL JSM-IT 100, Tokyo, Japan). Film samples were dried in air and fractured in liquid nitrogen for cross-sectional imaging. Prior to SEM imaging, the samples were gold sputtered (Cressington 108 auto sputter, (Cressington Scientific Instruments, Watford, UK)). A cross-sectional image of the MMM (Figure 1A) shows the pleated lumen morphology of the membrane. While the pleated morphology may indicate certain instabilities in the membrane-forming system, the grooves are well aligned axially with the flow direction. Such pleats generally do not impede mass transfer along the fiber, flow velocity, or transmembrane pressure. In addition, the presence of grooves on the lumen side of the fiber increases the active surface area, which provides benefits for the membrane's filtration and diffusion performance. Furthermore, the membrane's thick walls allow more particles per unit length to be embedded in the polymer matrix, thus enhancing the trapping properties of the MMM. From the magnified view of the wall of the MMM (Figure 1B), the finger-like macrovoid structure typical of SEM membranes can be seen in the lumen and exterior of the membrane, but disappears along the center of the wall cross section, where more particles are hosted in the polymer matrix. The adsorbent particles are well dispersed without agglomeration, and they are well surrounded by the polymer solution (white arrows in Figure 1B). Both the luminal and outer layers of the MMM (Figures 1C and 1D, respectively) exhibit a very thin dense layer with no visible pores on the luminal surface (Figure 1E) or outer surface (Figure 1F). However, the outer dense layer (Figure 1D) is slightly thicker (0.5 µm) compared to the inner dense layer (0.2 µm). For this reason, the selective layer of the membrane, which determines the molecular weight cutoff and filtration properties of the membrane, is thought to be the outer dense layer.

[0147] 3.2 Water transport experiment The MMM was also characterized for its water transport properties. 2 A membrane module consisting of 3 HFs with a total surface area of ​​1000 m was used. A two-component epoxy adhesive (Griffon Combi Snel-Rapide, Bison International, Goes, The Netherlands) was used for module preparation. Prior to the water transport experiments, the HF modules (n=6) were prewetted with EtOH for 30 min at a transmembrane pressure (TMP) of 0.2 Bar and precompressed with ultrapure water for 30 min at a TMP of 0.6 Bar. The amount of permeate water was then measured over time at TMPs of 0.2, 0.4, and 0.6 Bar. The resulting water permeabilities were expressed as flux (L / (m 2 MMM was calculated as the slope of the linear fit of TMP (bar) versus L / (m 2 The ultrafiltration coefficient (K) of the MMM is uf ) is 309 mL / (h·mmHg·m 2 ) The water flux through the membrane increases proportionally with pressure without compression or destruction of the HF MMM. Overall, these results suggest that the MMM has excellent morphological and filtration properties for use in ultrafiltration.

[0148] Example 4 - Urea Capture Using an Adsorbent-Containing Membrane 4.1 Static capture of urea 4.1.1 Effect of temperature on urea capture kinetics using ninhydrin-type adsorbents To study the effect of temperature on the capture reaction between urea and ninhydrin groups (approximately 2.5 mmol / g of adsorbent) in ninhydrin particles prepared from cross-linked polystyrene (PS-Nin), urea kinetic capture experiments were performed at 37°C, 50°C, and 70°C. The free particles used in this experiment have a mean diameter ± standard deviation of 483 ± 282 μm (N = 30). Adsorbent beads (15 mg) were incubated with a urea solution (1.5 mL, 30 mM) in PBS. Samples (n = 3 for each time point) were placed in an oven on a rotator at 37, 50, or 70°C. After 1, 2, 4, 8, 16, and 24 h, the urea concentration in the supernatant was analyzed using an AU 5800 routine chemistry analyzer (Beckman Coulter, Brea, CA) using a coupled enzyme reaction to yield a colorimetric (570 nm) product proportional to the urea concentration. The amount of bound urea was calculated from the amount of urea consumed in solution via mass balance. The results in Figure 3 are shown as mean ± standard deviation. At higher temperatures, the urea capture kinetics was faster. Indeed, at 70 °C, the particles bound 1.4 ± 0.0 mmol / g of urea over 24 h, which is much higher than the binding at 50 °C and 37 °C. Saturation of the ninhydrin moiety with urea was not achieved in 24 h, even at 70 °C. Here, the maximum achievable saturation was established to be 1.6–1.7 mmol / g for the particles. Given the faster capture kinetics at 70 °C, subsequent urea capture experiments were performed at 70 °C.

[0149] 4.1.2 Particle size effect on urea uptake kinetics To study the effect of particle size on urea capture, urea kinetic binding experiments were performed at 70 °C on PS-Nin particles with an average diameter of 483 ± 282 μm (approximately 2.5 mmol / g ninhydrin) and the same particles after grinding and sieving with diameters less than 63 μm (Example 2.2). Larger sorbent beads (15 mg) were incubated with urea solution (1.5 mL, 30 mM) in PBS (pH 7.4). The ground and sieved particles were incubated in urea solution (1.5 mL, 30 mM) in dialysate (pH 7.4). Samples (n = 3 for each time point) were shaken at 70 °C, and after 1, 2, 4, 8, 16, and 24 hours, the supernatant was collected by filtration. Urea concentrations were determined using the enzymatic assay Urea FS. * The binding kinetics of urea was determined by a HPLC (Diasys, Holzheim, Germany) or an AU 5800 routine chemistry analyzer (Beckman Coulter, Brea, CA). Both methods are based on a coupled enzymatic reaction that results in a colorimetric product proportional to the urea concentration. The amount of bound urea was calculated from the amount of urea consumed in solution via mass balance. The results in Figure 4 are shown as mean ± standard deviation. Urea uptake kinetics was much faster on smaller particles compared to larger particles. At 4 h, urea uptake on smaller particles was more than twice as fast as that on larger particles. The urea uptake kinetics on small particles was very fast for the first 4 h and then slowly decreased. Over a 24-h period, urea binding was equivalent to 1.7 ± 0.1 mmol / g urea on smaller particles and 1.4 ± 0.0 mmol / g on larger particles. Despite the higher surface area, the maximum binding capacity (2.5 mmol / g) was not reached. Thus, particle size has a strong effect on binding kinetics but a much smaller effect on binding capacity.

[0150] 4.1.3 Urea uptake kinetics for MMM containing sorbent particles To study the effect of particle incorporation into the polymer matrix of MMM, urea kinetic binding experiments were performed at 70 °C on ground PS-Nin particles (approximately 2.5 mmol / g ninhydrin) with a diameter of less than 63 μm and MMM prepared as described in Example 2.2. Adsorbent beads (15 mg) and MMM (27 mg, containing 15 mg of embedded particles) were incubated with urea solution (1.5 mL, 30 mM) in dialysate (pH 7.4) and shaken at 70 °C. After 1, 2, 4, 8, 16, and 24 h, the supernatant was collected (via filtration of the particles) and the urea concentration in the supernatant was determined using an enzymatic assay (Urea FS). * The urea uptake was determined using a centrifuge (Diasys, Holzheim, Germany). Via mass balance, the amount of bound urea was calculated from the urea consumption in solution. Each time point was represented by three different samples (n = 3) (Figure 5). The results in Figure 5 are shown as the mean ± standard deviation. The urea uptake kinetics are very similar over an 8-hour period for particles in suspension and particles in MMM. Interestingly, at 8 hours of urea uptake, particles in suspension enter a plateau, while particles embedded in MMM maintain binding. At 24 hours, urea uptake on particles in suspension equals 1.7 ± 0.1 mmol / g, while on particles embedded in MMM it is 2.1 ± 0.1 mmol / g. After longer times, urea uptake on particles in MMM can reach saturation (maximum uptake capacity is approximately 2.5 mmol / g). This demonstrates how the polymer matrix does not limit the ability of urea to reach the particles. Clearly, binding is further enhanced compared to free adsorbent particles. Further improved urea uptake was demonstrated using a PGA-type sorbent in hollow fiber MMM. In a comparative experiment, a volume of MMM containing 88 mg of PGA-type sorbent was contacted with 30 mM urea in PBS buffer at 70 °C using a recirculation setting with a flow rate of 5 mL / min (total volume of 25 mL). As shown in Figure 8, urea uptake was determined at various time points (n = 2 for t = 6–8 h; n = 1 for t = 1). As a comparison, a static batch experiment was performed using 5 mg of the same PGA-type sorbent in a total volume of 1 mL of the same urea solution continuously stirred at 70 °C, and urea uptake was determined at various time points (n = 3). The results in Figure 8 demonstrate that the binding kinetics of the PGA-type sorbent in MMM are faster than those of the crushed sorbent under stirring.

[0151] 4.1.4 Urea isotherm binding to MMM and control membranes Urea uptake at various concentrations was measured using MMM (prepared as described in Example 2.2) and PES / PVP control HF. The PES / PVP control HF was prepared by the dry-wet spinning technique as described in Acta Biomaterialia 90 (2019) 100-111. Briefly, a polymer dope solution was prepared by dissolving Ultrason E6020 PES (15 wt%) (BASF, Ludwigshafen, Germany) and PVP K90 (7 wt%) (molecular weight approximately 360 kDa, Sigma-AldrichChemie GmbH, Munchen, Germany) in ultra-high-purity NMP (78 wt%) (AcrosOrganics, Geel, Belgium). The polymer solution was mixed on a roller bench for 3 days, then transferred to a stainless steel syringe and degassed for 24 hours. The syringe was then connected to a high-pressure syringe pump and the designed spinneret. The pumping rate of the dope solution was set to 0.4 mL / min. Ultrapure water was used as the pore-forming solution, and the pumping speed of the pore solution was set at 1.2 mL / min. The air gap between the spinneret and the coagulation bath was adjusted to 10 cm. A collection wheel (speed 8.3 m / min) was used to collect the produced HF. The fabricated membrane was washed with deionized water and stored for further use. 27 mg of MMM (15 mg particles in MMM) and 27 mg of control HF were incubated with 1.5 mL of urea solution in dialysate (pH 7.4) at different concentrations. The samples were placed in a horizontal shaking water bath at 70°C. After 24 hours, the supernatant was collected and used for the enzyme assay (Urea FS). * The urea concentration in the supernatant was determined using a sorbent (Diasys, Holzheim, Germany). Via mass balance, the amount of bound urea was calculated from the amount of urea consumed in solution. Results in Figure 6 are shown as mean ± standard deviation (N = 3). The graph shows the binding capacity (mmol / g) versus equilibrium urea concentration (mM). The PES / PVP control HF did not capture urea, suggesting that only the adsorbent particles inside the MMM are responsible for urea capture. Interestingly, at an equilibrium concentration of 90.1 mmol / g, urea uptake on MMM equals 3.4 ± 0.1 mmol / g, exceeding the expected value for one-on-one binding to ninhydrin. This higher binding of urea can be explained through multilayer binding of urea, where urea molecules adsorb via hydrogen bonding (physisorption) onto urea covalently bound (chemisorption) to the ninhydrin moiety of the particle.

[0152] 4.1.5 Dynamic binding of urea 23.3cm 2Urea capture under dynamic conditions was studied using a membrane module composed of 3 HFs (prepared as described in Example 2) with a total surface area of ​​1000 nm and a total amount of particles embedded in a PES / PVP matrix equal to 77 mg. A two-component epoxy adhesive (Griffon Combi Snel-Rapide, Bison International, Goes, The Netherlands) was used to prepare the modules. Prior to the dynamic urea capture experiments, the HF modules (n = 5) were kept in deionized water. The urea dynamic experiments were performed using a dedicated setup (Convergence, Enschede, The Netherlands) in filtration mode (TMP = 0.15 Bar) with a 30 mM urea solution in the dialysate continuously recirculated through the fibers at a flow rate of 20 mL / min. The capture experiments (n = 5) were carried out at 70 °C for 4 h. To maintain the temperature of the urea solution in the recirculation system at 70 °C, the feed solution was heated to 70 °C, the tubing was insulated, and the HF modules were immersed in a water bath heated to 90 °C. Samples of the urea solution were collected every hour for quantification. At the end of the capture experiment, the HF module was removed from the 90°C water bath and emptied. 24.5 mL of room temperature MilliQ water was recirculated through the module at a flow rate of 20 mL / min for 1 hour to recover any urea that may have eluted from the MMM. Enzyme assay (Urea FS * Urea concentrations were quantified using a urea analyzer (Diasys, Holzheim, Germany). The binding results are shown in Figure 7. Over a 4-hour period, the membrane was able to capture 3.4 ± 0.3 mmol / g, and saturation did not appear to be reached. When the capture experiment was performed in dynamic mode, the capture kinetics was much faster compared to static conditions. Not only was the kinetics faster, but the total amount of urea bound to the adsorbent particles was also higher. The amount of urea bound per gram of particles in MMM was greater than the total amount of ninhydrin moieties in the particles (approximately 2.5 mmol / g). 1) All ninhydrin moieties in the particles were saturated, and 2) urea molecules adsorbed via hydrogen bonding (physisorption) onto the urea covalently bonded (chemisorbed) to the ninhydrin moieties of the particles, thus forming a multilayer bond enabled by the resulting surface saturated with covalently bound urea. At the end of the experiment, the MMM modules (n=2) were rinsed with MilliQ water, and 0.05 mmol was detected after 1 hour. Urea uptake at 4 hours, normalized to the amount of urea eluted from the MMM, is shown by an asterisk in Figure 7. It was expected that all urea physisorbed in the system would be eluted during longer rinse times. This experiment confirms that, under dynamic conditions, urea uptake on the MMM is a combination of chemisorption and physisorption. Because urea did not bind to the control membrane without adsorbent particles, the combined binding is an effect of the membranes of the present invention. In conclusion, recirculation and filtration of the urea solution through the membrane improves binding kinetics and total binding. Furthermore, once the maximum chemisorption capacity is reached, urea adsorption can continue, likely due to hydrogen bonding of urea molecules to the newly formed surface of covalently bound urea.

Claims

1. 1. A membrane including embedded particulate material, comprising: the membrane is a porous polymer membrane; the particulate material comprises a urea adsorbent; the particulate material has a maximum diameter of up to 250 μm; and A membrane wherein the urea adsorbent is a urea covalently trapping adsorbent, and wherein at least 10% of the urea trapping is covalent trapping of urea.

2. 10. The membrane of claim 1, wherein the particulate material is present in the membrane in a range of 5% to 80% by weight, based on the total dry weight of the membrane and the particulate material.

3. 3. The membrane of claim 1, wherein the particulate material has a maximum diameter of at most 150 μm.

4. The membrane of any one of claims 1 to 3 in the form of a hollow fiber, a full fiber, or a flat sheet.

5. 5. The membrane of any one of claims 1 to 4, wherein the membrane comprises at least one polymer selected from polysulfone, polyethersulfone, polyphenylenesulfone, polyarylethersulfone, polyamide, polyetherimide, polyimide, polyethylene-co-vinyl alcohol, polyethylene-co-vinyl acetate, cellulose acetate, cellulose triacetate, polyvinylidene fluoride, polyvinyl chloride, polyacrylonitrile, polyurethane, polyetheretherketone, and / or polyacrylic acid.

6. At least 1 L / (m ２ 6. The membrane of claim 1, having a water permeability of 0.05 MPa (0.05 MPa) in increments of 0.05 MPa (0.05 MPa).

7. 7. The membrane of any one of claims 1 to 6, wherein the urea adsorbent is a covalently trapping adsorbent of urea, and wherein at least 50% of the urea trapping is covalent trapping of urea.

8. 8. The membrane of claim 7, wherein the urea adsorbent is a polymeric composition comprising a polymer backbone grafted with moieties capable of covalently trapping urea.

9. 9. The membrane of claim 1, wherein the urea adsorbent is selected from ninhydrin-type adsorbents, phenylglyoxalaldehyde-type adsorbents, and / or triformylmethyl-type adsorbents.

10. A membrane according to any one of claims 1 to 9, the particulate material further comprises activated carbon particles, ion-exchange particles, silica particles, zeolite particles, ceramic particles, polymer particles, and / or molecularly imprinted particles; and / or The membrane further comprises an additive.

11. A membrane according to any one of claims 1 to 10 for use in medical applications.

12. A method for preparing a membrane according to any one of claims 1 to 10, comprising: i. providing urea sorbent particles having a maximum diameter of up to 250 μm; ii. mixing the urea sorbent particles with a polymeric material in a solvent for the polymeric material to obtain a mixture; and iii. Extruding or casting the mixture to form a membrane A method comprising:

13. iv. A step of solidifying the film. The method of claim 12 further comprising:

14. 1. A method for removing nucleophilic waste solutes from a fluid, comprising: i) providing a fluid containing a nucleophilic waste solute; and ii) contacting said fluid with a membrane according to any one of claims 1 to 10, or alternatively iib) contacting said fluid with a dialysis fluid through a membrane, said dialysis fluid being in contact with a membrane according to any one of claims 1 to 10. A method comprising:

15. iii) recovering the fluid. The method of claim 14 further comprising:

16. A cartridge for use in a dialysis machine comprising a membrane according to any one of claims 1 to 10.

17. A dialysis device comprising a membrane according to any one of claims 1 to 10 or a cartridge according to claim 16.

18. 10. The membrane of claim 1, wherein the particulate material is present in the membrane in a range of 25% to 70% by weight, based on the total dry weight of the membrane and the particulate material.

19. 5. The membrane of claim 4, wherein the membrane is in the form of a hollow fiber.

20. 6. The membrane of claim 5, wherein the membrane comprises polyethersulfone and / or polyvinylpyrrolidone.

21. 9. The membrane of claim 8, wherein the moiety capable of covalently trapping urea comprises two or more adjacent carbonyl groups or hydrates thereof.

22. 11. The membrane of claim 10, the ion exchange particles are ion exchange resin particles or ion exchange silica particles, the silica particles are unmodified silica particles or alkylated silica particles; the polymer particles are porous or non-porous polymer particles; The membrane, wherein the additive is a hydrophilic additive.

23. 23. The membrane of claim 22, The membrane, wherein the hydrophilic additive is polyvinylpyrrolidone, chitosan, polyethylene glycol, dextran, glycerol, diethylene glycol, octanol, oxalic acid, maleic acid, tartaric acid, fumaric acid, lithium chloride, and / or calcium chloride.

24. 14. The method of claim 13, wherein in step iv, the film is solidified by phase inversion.

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