Adsorbents for dialysis and adsorption systems for regenerative dialysis

Abstract

Disclosed herein is a material for use in adsorption-based dialysis, the material comprising acidic and / or neutral cation exchange particles, alkaline anion exchange particles, and one or more of an alkali metal carbonate, a water-insoluble alkaline earth metal carbonate, and a water-insoluble polymeric ammonium carbonate. Also disclosed herein are uses of the material and its preparation.

Description

[Technical field]

[0001] The present invention relates to sorbents for dialysis and sorption systems for regenerative dialysis, which may include, but are not limited to, hemodialysis, peritoneal dialysis, liver dialysis, pulmonary dialysis, water purification, and regeneration of biological fluids. [Background technology]

[0002] The listing or discussion of a prior-published document in this specification should not be considered an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0003] Chronic kidney disease (CKD) often results in imbalances in serum bicarbonate and sodium concentrations. Patients commonly suffer from metabolic acidosis with low bicarbonate and low serum pH, but untreated CKD can lead to dangerously high serum sodium due to accumulation of dietary sodium. These imbalances pose significant risks to central nervous system and cardiovascular health. Thus, the fundamental goal of dialysis is the correction of serum sodium and acid-base balance to maintain blood homeostasis.

[0004] In conventional peritoneal dialysis, such as CAPD or APD, sodium is corrected by maintaining a negative concentration gradient between the dialysate (Na:132mmol / L) and the patient's serum sodium concentration (approximately Na:138mmol / L), and removing sodium by diffusing from the blood into the dialysate. This concentration gradient is further increased by the transport of ultrafiltrate to the peritoneum (where the sodium concentration is low, further diluting the dialysate). Bicarbonate is corrected by maintaining a positive alkaline balance (net transfer of alkali from the dialysate to the patient's serum) using a high concentration of lactate ions (Lac:40mmol / L) in the dialysate, as lactate diffuses into the patient's bloodstream and is metabolized to bicarbonate in the liver. Thus, in conventional peritoneal dialysis, sodium and bicarbonate are managed by somewhat different mechanisms, which do not directly affect each other.

[0005] In the current adsorption dialysis system consisting of urease, zirconium phosphate (ZP), and hydrous zirconium oxide (HZO), bicarbonate and sodium regulation are directly related, so Na + and HCO3 - There are limitations regarding simultaneous optimization of the balance. The first method to regulate sodium in adsorption dialysis is removal by ion exchange with hydrogen-loaded ZP (ZP-H): ZP-H + Na + → ZP-Na + H + It is. However, this ion exchange process occurs much more readily in the presence of a base (e.g., bicarbonate ion): ZP-H + HCO3 - + Na + → ZP-Na + H2O + CO2

[0006] Depending on the pH of the entire dialysate, CO2 may escape to the air, resulting in a net loss of alkali in the dialysate. While utilizing an exclusively acidic H-loaded ZP may be favorable for sodium regulation and removal of other unwanted cations (such as ammonium), the subsequent loss of bicarbonate and the resulting drop in pH may cause an overall deterioration of bicarbonate balance. This is illustrated by the molar fractions of aqueous carbonic acid, bicarbonate, and carbonate in solution versus pH shown in Figure 1, and the molar fractions of aqueous ammonium and ammonia in solution versus pH shown in Figure 2.

[0007] Typically, the effects of low pH and low bicarbonate concentrations are counterbalanced by adding a basic salt (such as sodium bicarbonate) to the sorbent and / or by utilizing an alkaline anion exchanger (e.g., OH-loaded HZO).

[0008] A limitation of the sodium bicarbonate approach is that this salt dissolves easily in aqueous dialysate, resulting in a rapid increase in dialysate sodium and pH at the beginning of treatment. In this case, direct addition of a soluble sodium salt would not have the desired effect on sodium regulation, since a hemodialysate concentration gradient is desired to remove sodium from the patient in peritoneal dialysis. Furthermore, this approach does not provide a sustained increase in pH over the course of treatment, which would be desirable from the perspective of bicarbonate in the patient; this is because, as noted above, bicarbonate stability is pH dependent. The use of alkaline HZO is advantageous in helping to neutralize the acidic dialysate and removing phosphate leached from the ZP-H: HZO-OH + H + + X - → HZO-X + H2O (pH << 7, X = Cl, PO4, F)

[0009] However, the amount of HZO required to act as a buffer is not insignificant and can have a significant impact on the size and weight of the sorbent cartridge. Furthermore, the reaction rate between HZO and H is fast, so this buffering capacity is easily depleted; this means that the pH and bicarbonate concentration are only maintained at the beginning of the treatment.

[0010] This method of regulating sodium is HCO3 - Enhanced removal and simultaneously Na + This means that excess HCO3 - Removal can lead to metabolic acidosis, which can be harmful to the patient, causing many unhealthy symptoms. Current medical practice has other ways to address metabolic acidosis, and these (such as oral sodium bicarbonate tablets) can be used as adjunctive therapy, but these solutions run into the same problem; namely, Na + This means that Na will be added to the blood system. + Therefore, there is a need for improved methods of bicarbonate management, specifically, a suitable alternative to sodium bicarbonate and alkaline HZO for adsorption dialysis. Summary of the Invention

[0011] Adsorption compositions consisting of different percentages of neutral ZP (NZP), acidic ZP (AZP), alkaline HZO (NaHZO), and the substantially insoluble salts CaCO3 and Ca(OH)2 are disclosed herein that surprisingly solve some or all of the problems identified above.

[0012] Aspects and embodiments of the present invention are presented in the following sequentially numbered sections.

[0013] [Serial number item 1] A material for use in adsorption-based dialysis comprising: Acidic and / or neutral cation exchange particles; Alkaline anion exchange particles; and one or more of an alkali metal carbonate, a water-insoluble alkaline earth metal carbonate, and a water-insoluble polymeric ammonium carbonate; Materials containing.

[0014] [Serial number item 2] 1. A material according to serial number 1, wherein the material further comprises one or both of Ca(OH)2 and Mg(OH)2.

[0015] [Serial number item 3] A material according to serial number 1 or 2, wherein the acidic and / or neutral cation exchange particles are acidic and / or neutral water-insoluble metal phosphates, optionally wherein the metal is one or more selected from the group consisting of titanium, zirconium, and hafnium.

[0016] [Serial number item 4] A material according to serial number 3, wherein the metal is zirconium.

[0017] [Serial number item 5] A material according to any one of the preceding serial numbers, wherein the alkaline anion exchange particles comprise a partially hydrated amorphous water-insoluble metal oxide in its hydroxide counterion form; and / or carbonate counterion form; and / or acetate counterion form; and / or lactate counterion form, wherein the metal is one or more selected from the group consisting of titanium, zirconium, and hafnium, and optionally wherein the anion exchange particles are alkaline hydrous zirconium oxide.

[0018] [Serial number item 6] A material according to any one of the preceding serial numbers, comprising: (a) the water-insoluble alkaline earth metal carbonate is one or more selected from the group consisting of CaCO3 and MgCO3; and / or (b) the alkali metal carbonate is KCO; and / or (c) the water-insoluble polymeric ammonium carbonate is one or more selected from the group consisting of sevelamer carbonate, polymer-bound tetraalkylammonium carbonate, and 3-(trialkylammonium) alkyl (e.g., propyl) functionalized silica gel carbonate; material.

[0019] [Serial number item 7] A material according to any one of the preceding serial numbers, wherein the material comprises: 30-79 wt% acidic and / or neutral cation exchange particles; 20-65 wt% alkaline anion exchange particles; Includes; moreover, one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and insoluble polymeric ammonium carbonates in a total amount of 0.1 to 10 wt %; and Ca(OH)2 and / or Mg(OH)2 in a total amount of 0-5 wt% Including, materials.

[0020] [Serial number item 8] 1. A material according to sequence number 7, wherein the material comprises: 31-75 wt% acidic and / or neutral cation exchange particles; 23-63 wt% alkaline anion exchange particles; Includes; moreover, one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.1 to 5 wt %; and Ca(OH)2 and / or Mg(OH)2 in a total amount of 0-4 wt% Including, materials.

[0021] [Serial number item 9] A material according to sequence number 7 or 8, wherein the material comprises: 50-64 wt% acidic and / or neutral cation exchange particles; 35-45wt% alkaline anion exchange particles, Includes; moreover, one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.3 to 5 wt %, Including, materials.

[0022] [Serial number item 10] 1. A material according to sequence number 9, wherein the material comprises: 53-60 wt% acidic and / or neutral cation exchange particles; 39-44 wt% alkaline anion exchange particles; Including, moreover, one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.5 to 3 wt %, Including, materials.

[0023] [Serial number item 11] A material according to sequence number 7 or 8, wherein the material comprises: 45-59 wt% acidic and / or neutral cation exchange particles; 40-54 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.5 to 5 wt %, Including, materials.

[0024] [Serial number item 12] 1. A material according to serial number 11, wherein the material comprises: 48-56 wt% acidic and / or neutral cation exchange particles; 42-50 wt% alkaline anion exchange particles; Including, moreover, one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 1 to 2 wt %, Including, materials.

[0025] [Serial number item 13] A material according to sequence number 7 or 8, wherein the material comprises: 50-70 wt% acidic and / or neutral cation exchange particles; 30-49 wt% alkaline anion exchange particles; 0.2 to 3 wt % of one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates; Including, moreover Ca(OH)2 and / or Mg(OH)2 in a total amount of 0.2-2 wt%. Including, materials.

[0026] [Serial number item 14] 1. A material according to serial number 13, wherein the material comprises: 53-67 wt% acidic and / or neutral cation exchange particles; 33-46 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.2 to 2 wt %; Ca(OH)2 and / or Mg(OH)2 in a total amount of 0.2-1.5 wt%. Including, materials.

[0027] [Serial number item 15] A material according to any one of the preceding serial numbers, wherein the material comprises: the cation exchange particles are acidic and / or neutral water-insoluble metal phosphates; The anion exchange particles are alkaline hydrous zirconium oxide; and one or more of the alkali metal carbonate, the water-insoluble alkaline earth metal carbonate, and the water-insoluble polymeric ammonium carbonate is CaCO3 and / or MgCO3, optionally wherein the material further comprises Ca(OH)2; material.

[0028] [Serial number item 16] A material according to any one of the preceding serial items, wherein the material further comprises an organic compound absorbing agent, wherein the organic compound absorbing agent is present in an amount of 10-40 wt %, based on the total weight of the components recited in item 1, and optionally wherein the organic compound absorbing agent is present in an amount of 15-25 wt %, such as 18-23 wt %, such as 19-21 wt %, based on the total weight of the components recited in item 1.

[0029] [Serial number item 17] A material according to serial number 16, wherein the organic compound absorbent is activated carbon.

[0030] [Serial number item 18] A material according to any one of the preceding serial items, wherein the material further comprises neutral hydrous zirconium oxide, wherein the neutral hydrous zirconium oxide is present in an amount of 0.1 to 10 wt. %, based on the total weight of the components recited in serial item 1, and optionally wherein the neutral hydrous zirconium oxide is present in an amount of 0.5 to 5 wt. %, based on the total weight of the components recited in serial item 1.

[0031] [Serial number item 19] 1. A material according to serial number 4 and any one of serial numbers 5-18 subordinate to serial number 4, wherein both acid zirconium phosphate and neutral zirconium phosphate are present, the acid zirconium phosphate being present in an amount from 55 to 80 wt% of the total amount of zirconium phosphate in the material, to which the amount of neutral zirconium phosphate is present such that the amount of zirconium phosphate adds up to 100 wt% zirconium phosphate.

[0032] [Serial number item 20] Material according to sequence number 19, comprising: (a) the acid zirconium phosphate is present in an amount between 59 and 70 wt.% of the total amount of zirconium phosphate in the material, to which the amount of the neutral zirconium phosphate is added to provide 100 wt.% zirconium phosphate; (b) the acid zirconium phosphate is present in an amount between 75 and 78 wt% of the total amount of zirconium phosphate in the material, to which the amount of neutral zirconium phosphate is added to amount to 100 wt% zirconium phosphate; material.

[0033] [Serial number item 21] A material according to any one of the preceding serial numbers, comprising: (a) combining all of the components together to provide a single layer of material; or (b) combining one or more of the alkali metal carbonate, water-insoluble alkaline earth metal carbonate, and water-insoluble polymeric ammonium carbonate, and, when present, the metal hydroxide, with the cation exchange particles to form a first layer, with the anion exchange particles being provided as a second layer; material.

[0034] [Serial number item 22] A material according to any one of the preceding paragraphs, comprising one or both of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate.

[0035] [Serial number item 23] A cartridge for use in adsorption dialysis, comprising a material as described in any one of serial numbers 1 to 22. [Brief description of the drawings]

[0036] [Figure 1] The mole fraction of hydrous carbonic acid, bicarbonate, and carbonate versus the pH of the solution. [Diagram 2] The mole fraction of ammonium hydroxide and ammonia versus the pH of the solution. [Diagram 3] FIG. 1 is a schematic diagram of a sorbent cartridge according to an embodiment of the present invention used in the examples disclosed herein. [Figure 4] This is the experimental setting. [Diagram 5] The different constituent amounts of Ca(OH)2 and their overall contribution to the dialysate pH profile during the 7 hour treatment. [Figure 6] 1 shows a sorbent cartridge according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Surprisingly, it has been discovered that the bicarbonate and sodium concentrations in the dialysate of adsorption-based dialysis can be altered by the addition of certain metal carbonates and / or certain metal hydroxide salts.

[0038] Thus, in a first aspect of the present invention there is provided a material for use in adsorption-based dialysis comprising: Acidic and / or neutral cation exchange particles; Alkaline anion exchange particles; and One or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates.

[0039] In certain embodiments, the above materials may further include one or both of Ca(OH)2 and Mg(OH)2.

[0040] In embodiments herein, the term "comprising" may be interpreted as requiring the recited features, but does not limit the presence of other features. Alternatively, the term "comprising" may also relate to a situation in which only the recited components / features are intended to be present (e.g., the term "comprising" may be replaced by the terms "consisting of" or "essentially consisting of"). It is expressly intended that both broader and more restrictive interpretations may apply to all aspects and embodiments of the present invention. In other words, the term "comprising" and its synonyms may be replaced by the terms "consisting of" or "essentially consisting of" and its synonyms, and vice versa.

[0041] The phrase "consisting essentially of" and its different equivalents may be construed herein to refer to a material in which minor impurities may be present. For example, the material may be 90% or more pure (such as greater than 95% pure, such as greater than 97% pure, such as greater than 99% pure, such as greater than 99.9% pure, such as greater than 99.99% pure, such as greater than 99.999% pure, 100% pure, etc.).

[0042] As used herein, the term "sorbent" refers broadly to a class of materials characterized by their ability to absorb a desired target substance.

[0043] The term "metabolic waste" as used herein refers to any component, typically a toxic component, in the dialysate that is produced by metabolism and that is desired to be removed in the dialysate detoxification process. Typical metabolic waste products include, but are not limited to, phosphate, urea, creatinine, and uric acid.

[0044] As used herein, the term "essential cations" refers to cations other than sodium ions that are present in the dialysis solution and are essential for its safety and effective use. These ions are typically calcium and magnesium ions, although potassium ions may also be present. Calcium, magnesium, and potassium are removed by the sorbent and therefore require reintroduction into the regenerated dialysis solution to reconstitute the dialysis solution.

[0045] The term "cation equivalent" or "total cation equivalent" refers to the sum of all positive charge equivalents in solution, excluding protons. Cation equivalent is measured as mEq / L.

[0046] As will be appreciated by those of skill in the art, the term "sodium" or its symbol "Na" is used herein to refer to sodium ions rather than elemental sodium itself. Thus, the terms "sodium," "Na," "sodium ions," and "Na + " are used synonymously. Similarly, the terms "calcium," "magnesium," and "potassium," or their symbols "Ca," "Mg," and "K," are used herein to represent calcium ions, magnesium ions, and potassium ions, respectively.

[0047] The term "source of dialysate effluent" herein refers to the source of dialysate, from which the dialysate is generated. The source may be a source of effluent where regeneration of biological fluid occurs by exchange across a membrane. For example, if the dialysis process is hemodialysis, the source of dialysate effluent would be the dialyzer in a hemodialysis machine. In such a machine, the flow of blood and dialysate from the patient is countercurrent, and exchange occurs across a membrane that separates the flows. Alternatively, the source may be the patient, as in the case of peritoneal dialysis, where the dialysate is forced into the patient's peritoneal cavity to allow the exchange to occur.

[0048] As used herein, the term "cation exchange particle" refers to a particle capable of capturing or immobilizing cations or positively charged molecular species when contacted with such species, typically by passing a solution of such species over the surface of the particle.

[0049] As used herein, the term "anion exchange particle" refers to a particle capable of capturing or immobilizing anions or negatively charged molecular species when contacted with such species, typically by passing a solution of such species over the surface of the particle.

[0050] The term "uremic toxin-treating enzyme" as used herein refers to an enzyme capable of reacting with uremic toxins as a substrate. For example, the uremic toxin-treating enzyme may be an enzyme capable of reacting with urea as a substrate, uric acid as a substrate, or creatinine as a substrate. Whether a uremic enzyme has its function in vitro can be determined, for example, by reacting the enzyme with uremic toxins in a solution and measuring the decrease in the concentration of the uremic toxins. Examples of uremic toxin-treating enzymes include, but are not limited to, urease (reacts with urea), uricase (reacts with uric acid), or creatininase (reacts with creatinine).

[0051] The term "uremic toxins" as used herein, as will be well understood by those skilled in the art, refers to compounds including one or more waste products generated by the breakdown of proteins, nucleic acids, etc. Non-limiting examples of uremic toxins include urea, uric acid, creatinine, and beta-2 (β2) microglobulin. In healthy individuals, uremic toxins are normally excreted from the body through urine. However, in certain individuals, uremic toxins are not cleared from the body at a sufficiently rapid rate, resulting in a disease or condition characterized by uremic toxicity, i.e., elevated levels of at least one uremic toxin compared to normal physiological levels of uremic toxins. Non-limiting examples of disorders associated with uremic toxins include renal disease or insufficiency, gout, and uremic toxicity in subjects undergoing chemotherapy.

[0052] The term "uremic toxin-treating enzyme particles" as used herein refers to uremic toxin-treating enzymes in particulate form, which may be immobilized on a biocompatible solid support via covalent or physical bonds, cross-linking, or encapsulation, or any other means.

[0053] The term "soluble source" as used herein refers to a compound that is distinct from the other components of the adsorbent and may be added to or mixed with the other components, or that is present as a distinct layer or in a distinct compartment of the adsorbent. A "soluble source" is typically added to the adsorbent in the form of solid particles that combine with other solid particles in the adsorbent.

[0054] As used herein, the term "biocompatibility" refers to the property of a material not eliciting an adverse biological response in the human or animal body.

[0055] As used herein, the term "homogeneous" refers to a substantially homogeneous mixture, meaning a mixture in which the various components have the same proportions throughout a given sample, resulting in a uniform mixture. The composition of the mixture is substantially the same throughout, although it will be understood that in mixtures of solid particles, there may be regions of incomplete mixing within the sample.

[0056] The term "particle size" refers to the diameter or equivalent diameter of a particle. The term "average particle size" means that some particles are larger than a particular size and some particles are smaller than a particular size, but most particles are close to the particular particle size. The peak in the particle distribution has a particular size. Thus, for example, if the average particle size is 50 microns, there are particles larger than 50 microns and particles smaller than 50 microns.

[0057] The terms "regenerate" or "regenerated" herein refer to the detoxification of the dialysate by the sorbent breaking down uremic toxins and / or by the sorbent absorbing uremic toxins.

[0058] As used herein, the term "regenerated dialysate" refers to dialysate that has been detoxified by the sorbent breaking down uremic toxins and / or by the sorbent absorbing uremic toxins.

[0059] As used herein, the terms "reconstitute" or "reconstituted" refer to the act of converting regenerated dialysate to essentially the same state and chemical composition as fresh dialysate prior to dialysis.

[0060] As used herein, the term "reconstituted dialysate" refers to dialysate that has been converted to essentially the same condition and chemical composition as fresh dialysate prior to dialysis.

[0061] The term "predominantly" as used herein refers to a situation or condition that occurs to a large extent or in a major proportion, without excluding the possibility that another situation or condition also occurs to some extent, to a minimal extent. For example, it may be >80% or >90% or >95% or more than 99%. For the avoidance of doubt, the possibility that only that situation or condition occurs to the exclusion of all others is also intended to be included in the term.

[0062] The term "substantially" does not exclude "completely", for example a composition that is "substantially free of Y" may be completely free of Y. If desired, the term "substantially" may be omitted from the definition of the invention.

[0063] The term "about" herein with respect to formulation component concentrations typically refers to the mean value ±5% of the stated value, more typically + / -4% of the stated value, more typically ±3% of the stated value, more typically + / -2% of the stated value, even more typically ±1% of the stated value, and even more typically + / -0.5% of the stated value.

[0064] Throughout this disclosure, certain embodiments may be disclosed in range form. It should be understood that the description in range form is merely for convenience and conciseness. It should not be considered as an inflexible range limitation on the disclosed range. Thus, the description of a range should be considered to include all possible subranges specifically disclosed as well as individual numbers within that range. For example, the description of a range such as 1-6 should be considered to include specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This is true regardless of the breadth of the range.

[0065] The acidic and / or neutral water-insoluble metal phosphate can be any metal phosphate with a solubility of 10 mg / L or less in water. Examples of suitable acidic and / or water-insoluble neutral metal phosphates include those in which the metal is selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof. In certain embodiments referred to herein, the acidic and / or neutral water-insoluble metal phosphate can be acidic and / or neutral zirconium phosphate. The preparation process of neutral zirconium phosphate and acidic zirconium phosphate is the same, except that the pH of the buffer and its ratio with respect to sodium zirconium carbonate are changed to suit the desired pH value. Both are prepared by mixing sodium zirconium carbonate with a phosphate buffer solution having the desired pH value in an appropriate ratio, which can be easily determined by one skilled in the art.

[0066] The term "and / or" herein, when used in reference to two specific materials, such as "acid and / or neutral zirconium phosphate," is intended to allow for the use of any combination of the above components, or the components individually. That is, the term "acid and / or neutral zirconium phosphate" includes the following embodiments: · Only acid zirconium phosphate is present; · Only neutral zirconium phosphate is present; or Both acidic and neutral zirconium phosphates exist. Acidic and / or neutral water-insoluble metal phosphates may be used as ion exchange materials and are particularly useful as adsorption materials in regenerative kidney dialysis. For example, zirconium phosphate in the sodium or hydrogen form acts as a cation exchanger and ammonium (NH + ), Calcium (Ca 2+ ), potassium (K + ), and magnesium (Mg 2+In exchange for the absorption of these cations, zirconium phosphate absorbs two other cations, namely sodium (Na + ) and hydrogen (H + ). Neutral zirconium phosphate, when mixed with acidic zirconium phosphate, helps maintain the proper in situ pH. Without intending to be limited by theory, it is believed that neutral zirconium phosphate, along with CaCO3 and Ca(OH)2, helps maintain bicarbonate balance in the dialysate.

[0067] In one embodiment, acidic and / or neutral water-insoluble metal phosphates are configured to exchange ammonium ions primarily for hydrogen ions and to exchange essential cations for sodium ions by setting a low pH during synthesis. To optimize this property, the cation exchange particles are typically set to a low pH and a low sodium loading during synthesis. In one embodiment, the cation exchanger is synthesized in the presence of an acid. The pH is adjusted and set to a desired level, such as by titration with a base (such as sodium hydroxide) to raise the pH to a level that provides the desired differential exchange behavior. The titration is also used to provide cation exchange particles with sufficient sodium loading to allow sodium to be exchanged for calcium, magnesium, and potassium, if desired. In one embodiment, the cation exchange material is zirconium phosphate. Zirconium phosphate may be synthesized by conventional processes, such as from basic zirconium sulfate (BZS) or from zirconium carbonate, for example, by reaction with phosphoric acid. If other acids are used, it is essential to provide a source of phosphate groups. Typically, the pH is set by titration of the reaction product with a base in the range of 3.5 to 5.0, advantageously about 4.5.

[0068] Acid zirconium phosphate may also be prepared, for example, according to the method disclosed in U.S. Patent No. 6,818,196; the entire contents of this reference are incorporated herein by reference. Briefly, acid zirconium phosphate can be prepared by heating zirconium oxychloride (ZOC) with soda ash to form sodium zirconium carbonate, which is treated with caustic soda to form alkaline hydrous zirconium oxide. The aqueous slurry of alkaline hydrous zirconium oxide can then be heated while phosphoric acid is added. The aqueous slurry of acid zirconium phosphate can also be titrated with a basic material (such as caustic soda) until a desired pH (e.g., a pH of about 5 to about 7) is reached.

[0069] The average particle size of the acidic and / or neutral zirconium phosphate particles may be in the range of about 10 microns to about 1000 microns, about 100 microns to about 900 microns, about 200 microns to about 900 microns, about 300 microns to about 800 microns, about 400 microns to about 700 microns, 500 microns to about 600 microns, about 25 microns to about 200 microns, or about 25 microns to about 150 microns, or about 25 microns to about 80 microns, or about 25 microns to about 50 microns, or about 50 microns to about 100 microns, or about 125 microns to about 200 microns, or about 150 microns to about 200 microns, or about 100 microns to about 175 microns, or about 100 microns to about 150 microns, or about 150 microns to about 500 microns, or about 250 microns to about 1000 microns. The acidic and / or neutral zirconium phosphate particles may be immobilized on any known support material capable of providing immobilization to the zirconium phosphate particles. In one embodiment, the support material may be a biocompatible matrix. In one embodiment, the immobilization of the acidic and / or neutral zirconium phosphate particles is achieved by physically concentrating the particles in a volume. In one embodiment, the immobilization of the acidic and / or neutral zirconium phosphate particles is achieved by sintering zirconium phosphate or a mixture of zirconium phosphate and a suitable ceramic material. The biocompatible matrix may be a homogeneous matrix made of one material or a composite matrix made of at least two materials.

[0070] The anion exchange particles may be comprised of partially hydrated amorphous water-insoluble metal oxides in hydroxide, carbonate, acetate, and / or lactate counterion types, where the metal is selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof. In one embodiment, the metal is zirconium. The anion exchange particles may be zirconium oxide particles. Preferably, the anion exchange particles are hydrous zirconium oxide particles.

[0071] Alkaline hydrous zirconium oxide or NaHZO refers to the alkaline form of hydrous zirconium oxide (ZrO(OH)2) in which the zirconium oxide is hydroxide. NaHZO may have the following chemical and physical properties: Composition: Sodium + x ZrO2(OH - ) y · n H2O Ion exchange formula: ZrO2·OH -

[0072] Here, Na + x is 1 and OH - For H2O, y can be 2 to 4, and for H2O, n can be 4 to 6, and x, y, and n can be any fractional part of these ranges, optionally greater than or less than these ranges. The NaHZO is, for example, a Na:ZrO2 (molar ratio) in the range of about 0.5:1.5 to about 1.5:0.5 (such as about 1:1). + and / or may have, for example, about 3 to about 12 mEq OH - / 10g NaHZO, about 5~10mEq OH - / 10g NaHZO, or about 6 to about 9 mEq OH - The pH of the NaHZO, in water (1 g / 100 mL), can be, for example, about pH 7 to about 14, about pH 9 to about 12, or about pH 10 to about 11. As can be seen from the formula above, the purpose of the alkaline hydrous zirconium oxide is to release hydroxide ions.

[0073] The average particle size of the alkaline hydrous zirconium oxide particles may be in the range of about 10 microns to about 1000 microns, about 100 microns to about 900 microns, about 200 microns to about 900 microns, about 300 microns to about 800 microns, about 400 microns to about 700 microns, 500 microns to about 600 microns, about 10 microns to about 200 microns, or about 10 microns to about 100 microns, or about 10 microns to about 30 microns, or about 10 microns to about 20 microns, or about 20 microns to about 50 microns, or about 25 microns to about 50 microns, or about 30 microns to about 50 microns, or about 40 microns to about 150 microns, or about 80 microns to about 120 microns, or about 160 microns to about 180, or about 25 microns to about 250, or about 250 microns to about 500, or about 250 microns to about 1000. The zirconium oxide particles may be immobilized on any known support material capable of providing immobilization of the zirconium oxide particles. In one embodiment, the immobilization of the zirconium oxide particles may be by physically concentrating the particles in a volume. In one embodiment, the immobilization of the zirconium oxide particles is achieved by sintering zirconium oxide or a mixture of zirconium oxide and a suitable ceramic material. In one embodiment, the support material is a biocompatible substrate. The biocompatible substrate may be a carbohydrate-based polymer, an organic polymer, a polyamide, a polyester, a polyacrylic acid, a polyether, a polyolefin, or an inorganic polymer or ceramic material. The biocompatible substrate may be at least one of cellulose, Eupergit, silicon dioxide, nylon, polycaprolactone, and chitosan.

[0074] In one embodiment, the alkaline hydrous zirconium oxide particles may be replaced by any particles capable of absorbing phosphate ions and other anions. Preferably, the particles are capable of absorbing anions selected from the group including phosphate, fluoride, nitrate, and sulfate ions. The zirconium oxide particles may also release ions such as acetate, lactate, bicarbonate, and hydroxide in exchange for the absorbed anions.

[0075] Alkaline hydrous zirconium oxide can be prepared by reacting a zirconium salt (e.g., BZS or an aqueous solution thereof) with an alkali metal (or an alkali metal compound) at ambient temperature to form a precipitate of alkaline hydrous zirconium oxide. The alkaline hydrous zirconium oxide particles can be filtered and washed to remove all anions of the zirconium salt, and then air dried or oven dried at a mild temperature to a moisture level of, for example, about 30-40 weight percent LOD or less to form a free-flowing powder. Although other LODs are achievable, the use of higher temperatures and / or longer drying times (e.g., 24-48 hours) to achieve lower moisture levels (i.e., <20 weight percent LOD) may convert zirconium hydroxide bonds to zirconium oxide bonds, reducing the adsorptive capacity and alkalinity of the anion exchange material.

[0076] Alkaline hydrous zirconium oxide can also be prepared according to the method disclosed in, for example, US Patent Application Publication No. 2006 / 0140844; this reference is incorporated herein by reference in its entirety in combination with the teachings provided herein. Briefly, this method of preparing alkaline hydrous zirconium oxide involves adding an aqueous solution of ZOC titrated with concentrated hydrochloric acid to an aqueous solution of caustic soda. The addition of hydrochloric acid can prevent excessive gelling during the precipitation process and promote particle growth. Neutral hydrous zirconium oxide can be prepared by modifying the method described herein for producing basic zirconium oxide. For example, this may be achieved by adjusting the pH of the aqueous slurry by treatment with sodium zirconium carbonate and sodium hydroxide to obtain neutral hydrous zirconium oxide.

[0077] As can be seen from the above, the essential element of the sorbents disclosed herein is the presence of water-insoluble alkaline earth metal carbonates, alkali metal carbonates, water-insoluble polymeric ammonium carbonates, and combinations thereof. In certain embodiments referred to herein: (a) the water-insoluble alkaline earth metal carbonate may be selected from one or more of the group consisting of CaC03 and MgC03; (b) the alkali metal carbonate may be KCO; and / or (c) The water-insoluble polymeric ammonium carbonate may be selected from one or more of the group consisting of sevelamer carbonate, polymer-bound tetraalkylammonium carbonate, and 3-(trialkylammonium) alkyl (e.g., propyl) functionalized silica gel carbonate.

[0078] The term "alkyl" as used herein may refer to a linear or branched C1-C6 alkyl group, and may specifically include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, and t-butyl groups.

[0079] Without intending to be limited by theory, it is believed that the water-insoluble alkaline earth metal carbonate, alkali metal carbonate, water-insoluble polymeric ammonium carbonate, and combinations thereof in the sorbent act as a direct source of bicarbonate and act as a buffer with a mild pH.Similarly, it is believed that Ca(OH)2 and Ca(OH)2 act in a similar manner when included in the formulation.For example, when CaCO3 (or MgCO3) is present, it acts as a direct source of bicarbonate and acts as a buffer with a mild pH, while Ca(OH)2 (or Mg(OH)2; if present) is more basic and helps to further increase the pH of the dialysate.High pH promotes the conversion of CO2 generated during urea hydrolysis or by reaction with ZP to bicarbonate.

[0080] The corresponding overall chemical reaction can be expressed as shown below for the calcium species mentioned above: CaCO3(s) + H2O (l) + CO2(g) < = > Ca 2+ (aq) + 2HCO3 - (aq) Ca(OH)2(s) + H2O (l) + 2CO2(g) < = > Ca 2+ (aq) + 2HCO3 - (aq) It will be appreciated that similar reactions occur when the other materials listed above are substituted for these calcium species. The bicarbonate conversion depends on the equilibrium pH, as well as the dissociation constants and dissolution rates of CaCO3 and Ca(OH)2.

[0081] In patients with low serum urea, when less CO2 is produced by urea hydrolysis, the low urea cartridge structure allows CaCO3 (or MgCO3) to convert HCO3 - It plays an important role in regulating the balance of HCO3 -In such cases, additional CaCO3 (or MgCO3) can help regulate pH and increase the conversion of HCO3 to HCO3 while maintaining the stability of the HCO3 or CO2 already in solution. - The term "low urea cartridge design" as used herein refers to a cartridge designed to reduce the urea concentration to between 3 mM and 5.5 mM.

[0082] In the high urea cartridge structure, Ca(OH)2 is HCO3 - It plays an important role in regulating the balance. When treating patients with high serum urea, there is more CO2 in the dialysis fluid because more urea is hydrolyzed. Urea + H2O → Urease → 2NH3+ CO2

[0083] As used herein, the term "high urea cartridge design" refers to a cartridge designed to reduce the urea concentration to between 5 mM and 8 mM.

[0084] The effect of Ca(OH)2 on bicarbonate balance is perhaps most clearly demonstrated in Examples 6 and 7. In Example 7, the addition of 2.5 g of Ca(OH)2 to the adsorption composition resulted in a higher bicarbonate balance than the composition of Example 6 (absent Ca(OH)2).

[0085] The addition of Ca(OH)2 helps improve the pH level of the dialysis solution, thereby reducing CO2 to HCO3 - Promotes the conversion to

[0086] Ca(OH)2 and CaCO3 are the overall HCO3 - It contributes to balance, but if added in excess, Na + and ammonium removal is reduced. When Ca(OH)2 and CaCO3 are dissolved, the dialysate contains Ca2 + In that case, Ca2 +is selectively bound by zirconium phosphate (or other water-insoluble metal phosphates), thereby consuming some of the ion exchange capacity used to regulate sodium and ammonia. Therefore, in designing an optimal adsorption composition containing Ca(OH)2 and CaCO3, it is important to consider Na + Balance, HCO3 - Balance and factors such as pH that affect ammonium binding capacity all need to be considered.

[0087] In some embodiments of the invention as referred to herein, the carbonate present in the sorbent may be an insoluble carbonate. In other words, in some embodiments of the invention as referred to herein, the material may comprise one or more of water-insoluble alkaline earth metal carbonates and water-insoluble polymeric ammonium carbonates. This may advantageously prevent rapid dissolution of carbonate during dialysis, allowing the sorbent to provide a steady source of bicarbonate throughout the course of the sorption process. As a result, the use of a water-insoluble carbonate is believed to mean that the sorbent can provide a steady supply of bicarbonate ions throughout the course of the dialysis treatment, without causing a sudden rise in sodium concentration or a sudden rise in pH at the beginning of the treatment.

[0088] Particle size can affect the dissolution rate and therefore can be a factor in regulating the bicarbonate conversion rate, the sorbent pH, and the dialysate pH. This is a design factor to be considered. Any particle size suitable for CaCO3 can be used herein. For example, about 1 μm to about 100 μm. The particle size distribution suitable for CaCO3 particles can be a distribution in which the D90 can be about 38 μm, the D50 can be about 16 μm, and the D10 can be about 5 μm. Any particle size suitable for Ca(OH)2 can be used herein. For example, about 1 μm to about 80 μm. The particle size distribution suitable for Ca(OH)2 particles can be a distribution in which the D90 can be about 30 μm, the D50 can be about 11 μm, and the D10 can be about 3 μm.

[0089] Any suitable amount of the above components can be used in the adsorbents disclosed herein. The materials can be, for example, any material that comprises: 30-79 wt% acidic and / or neutral cation exchange particles; 20-65 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.1 to 10 wt %; and Ca(OH)2 and / or Mg(OH)2 in a total amount of 0-5 wt%. In a more specific embodiment, this may be a material comprising: 30-79 wt% acidic and / or neutral zirconium phosphate; 20-65 wt% alkaline hydrous zirconium oxide; 0.1-10 wt% CaCO3 and / or MgCO3; and 0-5 wt% Ca(OH)2, The material may be a material containing

[0090] For example, the material may be: 31-75 wt% acidic and / or neutral cation exchange particles; 23-63 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.1 to 5 wt %; and Ca(OH)2 and / or Mg(OH)2 in a total amount of 0-4 wt%. In a more specific embodiment, the adsorbent may be a material comprising: 31-75 wt% acidic and / or neutral zirconium phosphate; 23-63 wt% alkaline hydrous zirconium oxide; 0.1-5wt% CaCO3 and / or MgCO3 and 0-4 wt% Ca(OH)2, The adsorbent may be a material comprising:

[0091] The exact design of the materials disclosed herein may vary depending on the expected concentration of urea in the dialysis fluid of the subject being treated. For example, in subjects where urea may be expected to be at low concentrations (e.g., 3-5.5 mM), the material may be: 50-64 wt% acidic and / or neutral cation exchange particles; 35-45 wt% alkaline anion exchange particles; and one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.3 to 5 wt %, For example, the adsorbent may be a material comprising: 50-64 wt% acidic or neutral water-insoluble metal phosphates; 35-45 wt% alkaline hydrous zirconium oxide; and 0.3-5 wt% CaCO3 and / or MgCO3, The adsorbent may comprise:

[0092] For example, the material may be: 53-60 wt% acidic and / or neutral cation exchange particles; 39-44 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.5 to 3 wt %, For example, the adsorbent may be a material comprising: 53-60 wt% acidic or neutral water-insoluble metal phosphates; 39-44 wt% alkaline hydrous zirconium oxide; and 0.5-3 wt% CaCO3 and / or MgCO3, The adsorbent may comprise:

[0093] Alternatively, suitable materials for use at low urea concentrations are: 45-59 wt% acidic and / or neutral cation exchange particles; 40-54 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.5 to 5 wt %, For example, the adsorbent may be a material comprising:

[0094] 45-59 wt% acidic and / or neutral water-insoluble metal phosphates; 40-54 wt% alkaline hydrous zirconium oxide; and 0.5-5 wt% CaCO3 and / or MgCO3, The adsorbent may comprise:

[0095] For example, the material may be: 48-56 wt% acidic and / or neutral cation exchange particles; 42-50wt% alkaline anion exchange particles, Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 1 to 2 wt %, For example, the adsorbent may be a material comprising: 48-56 wt% acidic and / or neutral water-insoluble metal phosphates; 42-50 wt% alkaline hydrous zirconium oxide; and 1-2 wt% CaCO3 and / or MgCO3, The adsorbent may comprise:

[0096] In subjects where urea may be expected to be in high concentrations (e.g., 5-8 mM), the material: 50-70 wt% acidic and / or neutral cation exchange particles; 30-49 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.2 to 3 wt %; and Ca(OH)2 and / or Mg(OH)2 in a total amount of 0.2-2 wt%. For example, the adsorbent may be a material comprising: 50-70 wt% of acidic and / or neutral water-insoluble metal phosphates; 30-49 wt% alkaline hydrous zirconium oxide; 0.2-3 wt% CaCO3 and / or MgCO3; and 0.2-2 wt% Ca(OH)2, The adsorbent may comprise:

[0097] For example, the material may be: 53-67 wt% acidic and / or neutral cation exchange particles; 33-46 wt% alkaline anion exchange particles; Including, moreover one or more of alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates in a total amount of 0.2 to 2 wt %; and Ca(OH)2 and / or Mg(OH)2 in a total amount of 0.2-1.5 wt%. For example, the adsorbent may be a material comprising: 53-67 wt% acidic and / or neutral water-insoluble metal phosphates; 33-46 wt% alkaline hydrous zirconium oxide; 0.2-2 wt% CaCO3 and / or MgCO3; and 0.2-1.5 wt% Ca(OH)2, The adsorbent may comprise: In certain of the above embodiments, the acidic and / or neutral water-insoluble metal phosphate may be an acidic and / or neutral zirconium phosphate.

[0098] In certain embodiments as referred to herein: The cation exchange particles are acidic and / or neutral water insoluble metal phosphates and alkaline hydrous zirconium oxide; Anion exchange particles; and The one or more of the alkali metal carbonate, the water-insoluble alkaline earth metal carbonate, and the water-insoluble polymeric ammonium carbonate is CaCO3 and / or MgCO3, optionally where the material further comprises Ca(OH)2.

[0099] The sorbent may be prepared in any suitable manner, for example, all components may be combined together to provide the material as a single layer, or one or more of the alkali metal carbonate, water-insoluble alkaline earth metal carbonate, and water-insoluble polymeric ammonium carbonate, and the metal hydroxide, if present, may be combined with the cation exchange particles to form a first layer, with the anion exchange particles provided as a second layer.

[0100] The above material may also further comprise an organic compound absorbent. The organic compound absorbent may be combined with one or more other materials to form a composite layer or may form different layers. The organic compound absorbent may be selected from the group consisting of activated carbon, molecular sieves, zeolites, and diatomaceous earth, among others. The organic compound absorbent particles may be activated carbon particles. In one embodiment, the organic compound absorbent of the first layer may be an activated carbon filter pad. In another embodiment, the organic compound absorbent comprises activated carbon particles.

[0101] The average particle size of the activated carbon particles may be in the range of about 10 microns to about 1000 microns, about 10 microns to about 250 microns, about 20 microns to about 200 microns, about 25 microns to about 150 microns, about 50 microns to about 100 microns, about 25 microns to about 250 microns, or about 100 microns to about 200 microns, or about 100 microns to about 150 microns, or about 150 microns to about 300 microns, or about 200 microns to about 300 microns, or about 400 microns to about 900 microns, or about 500 microns to about 800 microns, or about 600 microns to about 700 microns, or about 250 microns to about 500 microns, or about 250 microns to about 1000 microns.

[0102] In one embodiment, the activated carbon particles can be replaced by any particles that can absorb organic compounds.Preferably, the particles can absorb organic compounds and / or organic metabolites selected from the group including creatinine, uric acid and other small and medium-sized organic molecules without releasing anything by exchange.The activated carbon particles can also be physically packed into a certain volume for space saving purposes.In one embodiment, the activated carbon particles are physically packed into an activated carbon filter pad.

[0103] When the organic compound absorbent is present as part of the material, it may be present in an amount of 10-40 wt% based on the total weight of the most abundantly listed components in the material (i.e., a material containing 30-79 wt% acidic and / or neutral zirconium phosphate; 20-65 wt% alkaline hydrous zirconium oxide; 0.1-10 wt% CaCO3 and / or MgCO3; and 0-5 wt% Ca(OH)2). For example, the organic compound absorbent may be present in an amount of 15-25 wt% (such as 18-23 wt%, such as 19-21 wt%) based on the total weight of the most abundantly listed components in the material.

[0104] The materials disclosed herein may also further include neutral hydrous zirconium oxide, which may be obtained by a process similar to that described herein for making alkaline hydrous zirconium oxide. When present in the compositions described herein, the neutral hydrous zirconium oxide may be present in an amount of 0.1-10 wt.% based on the total weight of the most predominant component listed in the material (i.e., a material comprising 30-79 wt.% acidic and / or neutral zirconium phosphate; 20-65 wt.% alkaline hydrous zirconium oxide; 0.1-10 wt.% CaCO3 and / or MgCO3; and 0-5 wt.% Ca(OH)2). For example, the neutral hydrous zirconium oxide may be present in an amount of 0.5-5 wt.% based on the total weight of the most predominant component listed in the material.

[0105] The neutral hydrous zirconium oxide may be combined with one or more other materials to form a composite layer or to form a separate layer. For example, it may be mixed with the alkaline hydrous zirconium oxide. Neutral hydrous zirconium oxide may be used as a substitute for alkaline hydrous zirconium oxide, which may provide similar balance results. However, the use of alkaline hydrous zirconium oxide is preferred compared to neutral hydrous zirconium oxide, since neutral hydrous zirconium oxide may provide chloride ions to the patient. However, an appropriate amount of neutral hydrous zirconium oxide may be added to the adsorbent material.

[0106] In certain embodiments of the present invention, the CaCO3 and / or MgCO3 in the materials described herein may be CaCO3 only.

[0107] In certain embodiments as described herein, the acidic and / or water insoluble metal phosphate can be an acidic zirconium phosphate. In other embodiments, the acidic and / or water insoluble metal phosphate can be an acidic zirconium phosphate and a neutral zirconium phosphate. Any suitable ratio of acidic and neutral zirconium phosphates can be used in the applications described herein. Examples of suitable ratios include, but are not limited to, where the acidic zirconium phosphate is present in an amount of 55-80 wt% of the total amount of zirconium phosphate in the material, with the neutral zirconium phosphates adding up to a total of 100 wt%. For example, the acid zirconium phosphate may be present in an amount of 59-70 wt% of the total zirconium phosphates in the material, which together with the neutral zirconium phosphates make up 100 wt%; or the acid zirconium phosphate may be present in an amount of 75-78 wt% of the total zirconium phosphates in the material, which together with the neutral zirconium phosphates make up 100 wt%.

[0108] It will be appreciated that the components of the materials used in the adsorption-based dialysis described herein may be provided as individual layers or may be combined together in any suitable manner. In certain embodiments of the invention, all of the materials may be combined together to provide a single layer of material. In other embodiments of the invention, CaCO3 and / or MgCO3, and, if present, Ca(OH)2, may be mixed with the acidic and / or neutral zirconium phosphate to form a first layer, with alkaline hydrous zirconium oxide being the second layer.

[0109] It should be noted that CaCO3 and / or MgCO3, and Ca(OH)2 when present (and equivalent materials herein above; i.e.: alkali metal carbonates, water-insoluble alkaline earth metal carbonates, and water-insoluble polymeric ammonium carbonates, and Mg(OH)2), can cause problems when present as a single homogeneous layer, because when present as a homogeneous layer, these materials can form very dense sludge, which restricts flow in the sorbent cartridge. Therefore, it is preferred to mix these materials with at least one of alkaline zirconium phosphate and hydrous zirconium oxide (or combine them, if activated carbon or other organic compound sorbent material is present in the sorbent).

[0110] It will be appreciated that the materials disclosed herein may be used in a sorbent cartridge to configure the interior of the cartridge to achieve the desired effects referred to herein, i.e., the materials that form part of the sorbent may be provided as a single homogenous mixed layer or as two distinct layers, as discussed above.

[0111] Examples of configurations that may be used include, but are not limited to, those shown in Figures 3 and 6-8.

[0112] 3A shows a configuration in which the sorbent cartridge 300 contains the materials described herein in a single composite layer 310 sandwiched between a layer of urease 320 and a layer of activated carbon 330. Each layer is separated from the other by filter paper 340.

[0113] FIG. 3 b shows a different configuration in which the material is combined with a portion of the urease present in the adsorbent 350 as well as a different urease layer 340 .

[0114] Note that in both configurations, it is intended that the dialysate enters the cartridge at the end closest to the urease 360 ​​and exits at the end furthest from the urease 370.

[0115] The term "urease" herein is a synonym of the term "uremic toxin-treating enzyme," and both refer to an enzyme capable of reacting with uremic toxins as a substrate. For example, the uremic toxin-treating enzyme may be an enzyme capable of reacting with urea as a substrate, uric acid as a substrate, or creatinine as a substrate. Whether a uremic enzyme has this function in vitro can be determined, for example, by reacting the enzyme with uremic toxins in a solution and measuring the decrease in the concentration of the uremic toxins. Examples of uremic toxin-treating enzymes include, but are not limited to, urease (reacts with urea), uricase (reacts with uric acid), or creatininase (reacts with creatinine).

[0116] The term "uremic toxins" as used herein, as will be well understood by those skilled in the art, refers to compounds including one or more waste products resulting from the breakdown of proteins, nucleic acids, etc. Non-limiting examples of uremic toxins include urea, uric acid, creatinine, and beta-2 (β2) microglobulin. In healthy individuals, uremic toxins are normally excreted from the body through urine. However, in certain individuals, uremic toxins are not cleared from the body at a sufficiently rapid rate, resulting in a disease or condition characterized by uremic toxicity, i.e., elevated levels of at least one uremic toxin compared to normal physiological levels of uremic toxins. Non-limiting examples of disorders associated with uremic toxins include renal disease or insufficiency, gout, and uremic toxicity in subjects undergoing chemotherapy.

[0117] The term "uremic toxin-treating enzyme particles" as used herein refers to uremic toxin-treating enzymes in particulate form, which may be immobilized on a biocompatible solid support via covalent or physical bonds, cross-linking, or encapsulation, or any other means.

[0118] The uremic toxin-treating enzyme may be immobilized on any known support material capable of providing immobilization for the uremic toxin-treating enzyme particles. Immobilization may be by physical means, such as by adsorption on alumina. In one embodiment, a non-immobilized enzyme is used. Alternatively, other methods are used to convert urea to ammonia.

[0119] In one embodiment, the support material is a biocompatible matrix to which the enzyme is covalently attached. The biocompatible material may be a carbohydrate-based polymer, an organic polymer, a polyamide, a polyester, or an inorganic polymeric material. The biocompatible matrix may be a homogeneous matrix made of one type of material or a composite matrix made of at least two types of materials.

[0120] The biocompatible matrix may be at least one of cellulose, Eupergit, silicon dioxide (eg, silica gel), zirconium phosphate, zirconium oxide, nylon, polycaprolactone, and chitosan.

[0121] In one embodiment, the immobilization of the uremic toxin-treating enzyme on the biocompatible substrate is carried out by an immobilization technique selected from the group consisting of glutaraldehyde activation, activation with epoxy groups, epichlorohydrin activation, bromoacetic acid activation, cyanogen bromide activation, thiol activation, and N-hydroxysuccinimide and diimide-amide linkage. The immobilization technique used may also include the use of silane-based linkers such as (3-aminopropyl)triethoxysilane, (3-glycidyloxypropyl)trimethoxysilane, or (3-mercaptopropyl)trimethoxysilane. The surface of the biocompatible substrate may be further functionalized with reactive and / or stabilizing layers such as dextran or polyethylene glycol, and may be further functionalized with suitable linkers and stabilizer molecules such as ethylenediamine, 1,6-diaminohexane, thioglycerol, mercaptoethanol, and trehalose. The uremic toxin-treating enzymes may be used in purified form or in the form of a crude extract, such as a urease extract from jack beans or other suitable urease source.

[0122] The uremic toxin-treating enzyme particles may be capable of converting urea into ammonium carbonate. In one embodiment, the uremic toxin-treating enzyme is at least one of urease, uricase, and creatininase. In a preferred embodiment, the uremic toxin-treating enzyme is urease.

[0123] In one embodiment, the uremic toxin-treating enzyme particles are urease particles.

[0124] In one embodiment, the average particle size of the uremic toxin-treating enzyme particles is in the range of about 10 microns to about 1000 microns, about 100 microns to about 900 microns, about 200 microns to about 900 microns, about 300 microns to about 800 microns, about 400 microns to about 700 microns, 500 microns to about 600 microns, about 25 microns to about 250 microns, about 25 microns to about 100 microns, about 25 microns to about 500 microns, about 250 microns to about 1000 microns, about 125 microns to about 200 microns, about 150 microns to about 200 microns, about 100 microns to about 175 microns, and about 100 microns to about 150 microns.

[0125] In one embodiment, 1000 to 10000 units of urease are immobilized on the biocompatible substrate. The total weight of the immobilized urease and substrate ranges from about 0.5 g to about 30 g.

[0126] 6 shows a further sorption cartridge 600 according to the invention, in which CaCO3 and Ca(OH)2 (if present) are mixed with hydrous zirconium oxide to form a layer 610 (as according to the invention) sandwiched between a layer of activated carbon 620 and a layer of zirconium phosphate 630. Another layer 640 of urease is also present, with each layer separated by filter paper 650. The dialysate is intended to enter cartridge 600 through port 660 and exit through port 670.

[0127] 7 shows a further sorption cartridge 700 according to the invention, in which CaCO3 is mixed with zirconium phosphate to form layer 710, and Ca(OH)2 (if present) is combined with hydrous zirconium oxide to form layer 720 sandwiched between activated carbon layer 730 and CaCO3 and zirconium phosphate layer 710. A separate urease layer 740 is also present, with each layer separated by filter paper 750. The dialysate is intended to enter cartridge 700 through port 760 and exit through port 770.

[0128] 8 shows a further sorption cartridge 800 according to the invention, in which CaCO3 and Ca(OH)2 (if present) are mixed with zirconium phosphate (as according to the invention) to form layer 810. This layer is sandwiched between an activated carbon layer 820 and a hydrous zirconium oxide layer 830. There is also a separate urease layer 840, with each layer separated by filter paper 50. The dialysate is intended to enter cartridge 800 through port 860 and exit through port 870.

[0129] Further aspects and embodiments of the present invention are discussed below with reference to the non-limiting examples.

[0130] Working Example

[0131] Materials and Methods

[0132] All chemicals for synthetic dialysate preparation (NaCl, NaHCO3, CaCl2·2H2O, MaCl2·6H2O, KCl, glucose monohydrate, urea, creatinine, and NaH2PO4·2H20), as well as CaCO3 and Ca(OH)2, were purchased from Sigma-Aldrich (USA). Amorphous acid zirconium phosphate (pH: 3.8–4.3), amorphous neutral zirconium phosphate (pH: 5.8–6.1), amorphous hydrous zirconium oxide (pH: 11.0–11.5), and immobilized urease were prepared as described below. Activated charcoal powder (NDS Centaur) was purchased from Calgon. All reagents and materials were used without further purification. The pH of all samples was recorded with a Sartorius PB-10 benchtop pH meter. The concentrations of all test substances (sodium, bicarbonate, urea, ammonia, etc.) were measured using a Vitros-250 chemistry analyzer.

[0133] Preparation 1: Preparation of zirconium phosphate

[0134] Zirconium phosphate was synthesized by conventional methods, for example, by reaction of an aqueous mixture of basic zirconium sulfate and phosphoric acid as described in U.S. Patent No. 3,850,835, or from an aqueous mixture of sodium zirconium carbonate and phosphoric acid as described in U.S. Patent No. 4,256,718.

[0135] The product was titrated to a solution pH of 3.8-6.1. 5M sodium hydroxide solution was added stepwise to the aqueous slurry of zirconium phosphate until the desired pH was reached. After titration, the zirconium phosphate was washed and air-dried until the filtrate was within acceptable limits for leachables.

[0136] Preparation 2: Preparation of hydrous zirconium oxide

[0137] Hydrous zirconium oxide was synthesized by conventional methods, for example, by reaction of an aqueous mixture of sodium zirconium carbonate and sodium hydroxide as described in U.S. Patent No. 4,256,718. In carrying out such synthesis, an aqueous slurry of hydrous zirconium carbonate was prepared and titrated with 5M sodium hydroxide until the pH of the slurry was 11-12. In some cases, the hydrous zirconium oxide was then washed until the leachable concentration of the filtrate was within acceptable levels, and then air dried.

[0138] Example 1

[0139] Preparation of sorbent cartridges

[0140] The sorbent cartridges consisted of the materials listed in Tables 1-3 below. Zirconium phosphate (ZP) was prepared according to Preparation 1. Hydrous zirconium oxide (HZO) was prepared as described in Preparation 2. Immobilized urease (IU) was prepared as described in Examples 1 and 2 of WO2011 / 102807; this reference is incorporated herein by reference in its entirety. Activated carbon (AC) with particle sizes of 50-200 microns was used. Calcium carbonate (CaCO3) and calcium hydroxide (Ca(OH)2) were purchased commercially and had particle sizes ranging from 1-100 μm. The sorbent cartridges used to obtain the experimental results described below consisted of empty polypropylene flash columns packed with the above sorbent materials (Figure 3). [Table 1] [Table 2] [Table 3]

[0141] The immobilized urease catalyzes the hydrolysis of urea to ammonia and carbon dioxide. Zirconium phosphate acts as a cation exchanger, and Ca ++ , Mg ++ , and NH4 + In exchange for Na + or H + Hydrous zirconium oxide acts as a zwitterionic ion exchanger, primarily binding negatively charged species such as phosphate and fluoride. The additives CaCO3 and Ca(OH)2 act as sources of carbonate and alkali to help maintain the pH and bicarbonate balance within the desired range. Activated carbon, a very fine porous material with an exceptionally large surface area, adsorbs heavy metals, small water-soluble uremic toxins such as creatinine and medium-sized molecules such as uric acid, B2-microglobulin, and protein-bound uremic toxins. The adsorption cartridges and materials were prepared as described below.

[0142] In the examples herein, the columns were packed with: (1) AC layer, followed by a filter paper separator; (2) a mixture of ZP, HZO and CaCO3 / Ca(OH)2, followed by a filter paper separator; and (3) Immobilized urease layer.

[0143] The column was then inverted and incorporated into the experimental setup with the dialysate effluent first flowing into the IU layer and out via the AC layer.

[0144] It will be appreciated that different configurations of layer combinations and orderings may be used for the cartridge (FIGS. 3 and 7-9).

[0145] General method 1

[0146] Compositions A-H were tested using a proprietary method hereafter referred to as "General Method 1," which involved pumping two different solutions through the sorbent in a dynamic mix ratio calculated to more closely mimic the changing composition of dialysate during normal in vivo use.

[0147] In the above, these solutions contain mixtures of sugars, salts, toxins (e.g., urea, creatinine, phosphate and other toxins) mixed in unique ratios. The use of dynamic dialysis solutions is believed to provide more precise results than traditional mimicking dialysis solutions, thus allowing for more precise testing of sorbents.

[0148] Major electrolytes such as sodium and bicarbonate balance were calculated according to the following formula: Sodium balance = (C Na Drain -C Na pre ) * V drain Bicarbonate balance = C HCO3 Drain * V drain -C HCO3 SD * VSD used where C Na Drain = sodium concentration in the liquid collected at the end of the experiment C Na pre = Average sodium concentration in synthetic dialysis fluid V drain = Volume of liquid collected at the end of the experiment C HCO3 Drain = Bicarbonate concentration in the liquid collected at the end of the experiment C HCO3 SD = Bicarbonate concentration in synthetic dialysis fluid V SD used = Volume of synthetic bicarbonate-containing dialysis solution used in the experiment

[0149] Example 2

[0150] To obtain the results in Table 4, compositions A, B, and C from Example 1 were used in General Method 1 with urea influxes of 7.9-8.6 mM. [Table 4]

[0151] A negative balance indicates removal from the dialysate.

[0152] Compositions B and C are "high urea" cartridges, prepared by mixing equal proportions of acid zirconium phosphate and hydrous zirconium oxide with varying amounts of calcium carbonate (Composition A is a comparative example and does not contain CaCO3). The desired sodium and bicarbonate balance can be achieved by adjusting the amount of calcium carbonate, as can be seen in Table 4, where a better bicarbonate balance was obtained by increasing the amount of calcium carbonate from 0 g to 3.1 g.

[0153] As can be seen from the data in Table 4, CaCO3 is HCO3 -By serving as a source of ions and a sodium balance, bicarbonate balance increases with successive increases in CaCO3 content because ZP preferably binds calcium while retaining low binding capacity for other cations.

[0154] Example 3

[0155] To obtain the results in Table 5, compositions D and E from Example 1 were used in General Method 1 with a urea input of 8.1 mM. [Table 5] The amount of ammonia removed was calculated by multiplying the amount of urea removed by 17. The amount of urea removed was also calculated by multiplying the difference between the influent urea concentration (mmol / L) and the effluent urea concentration (mmol / L) by the amount of liquid passed through the cartridge (14 L). The above data shows that an increase of 1 g (approximately 10 mmol) of CaCO3 added to the sorbent reduces ammonia binding by 10 mmol.

[0156] Example 4

[0157] To obtain the results in Table 6, compositions F, G, and H from Example 1 were used in General Method 1 with a urea inflow of 5.0-5.2 mmol / L. [Table 6]

[0158] Compositions F-H can be considered to form "low urea" cartridges intended to handle urea loads of 3-5 mmol / L. Successive increases in CaCO3 content are accompanied by an increase in bicarbonate balance. However, in this case, the effect on the sodium balance was less compared to the composition used in Example 2; this is due to the lower amount of AZP. AZP is H +Since these compositions contain ions, they are able to adsorb more sodium and ammonium ions. Therefore, the reduction in AZP may explain the above differences. However, since the ammonium ion release is less in these compositions, the reduction in the amount of AZP (compared to the amount used in Examples 2 and 3) is sufficient to maintain the desired sodium and bicarbonate balance.

[0159] Example 5

[0160] To obtain the results in Tables 7 and 8, compositions I and J from Example 1 were used in General Method 1 with urea influxes ranging from 2.3 to 5.2 mM. [Table 7] [Table 8]

[0161] As can be seen from the table, sodium and bicarbonate balance increased at the urea concentrations of these "low urea" cartridges. Example 6 Example 7

[0162] pH Profile

[0163] As mentioned above, Examples 2-5 were carried out under unique conditions. The influent dialysate composition was varied to mimic the dialysate chemistry of the peritoneal environment. For this purpose, the initial dialysate was essentially fresh dialysate at pH 5.2, whereas the influent dialysate was progressively changed thereafter to a synthetic dialysate effluent at pH 7.4.

[0164] During the course of the experiment, a maximum pH of 7.5 was reached. After incorporating the pH improvement mechanism, the level is not unlimited. When designing a new adsorption structure, the effluent pH must be within a pH range of 5 to 8 to be physiologically acceptable. In addition to considering metabolic acidosis, low pH levels can lead to high pCO2 (CO2 partial pressure) levels in the dialysate, with concomitant CO2 dissolution. Exposing the patient to a high pCO2 dialysate can lead to gas formation in the peritoneum (pneumoperitoneum), causing potential abdominal pain and discomfort.

[0165] The compositions of CaCO3 and Ca(OH)2 described herein are + Balance and HCO3 - This will have a direct impact on the final balance performance of the sorbent in terms of balance as well as in terms of pH which will affect pCO2 levels.

[0166] The following further compositions were prepared and incorporated into cartridges according to general method 1 (proprietary method). (1) Acidic ZP (145.2g) / Neutral ZP (36.3g) / Alkaline HZO (148.5) / AC (70g) Ca(OH)2 (4g) (2) Acidic ZP (145.2g) / Neutral ZP (36.3g) / Alkaline HZO (148.5) / AC (70g) 4g CaCO3 1g Ca(OH)2 (3) Acidic ZP (145.2g) / Neutral ZP (36.3g) / Alkaline HZO (148.5) / AC (70 g) 3g CaCO3 1.75g ​​Ca(OH)2

[0167] Figure 5 shows the effect of different Ca(OH)2 amounts on the pH profile over the course of a 14L mimetic treatment treatment. With increasing amounts of Ca(OH)2 (Exp311 vs. Exp304 / 306), the effect of increasing pH is longer. Since it takes time for urea to diffuse from the blood into the dialysate, it was expected that the CO2 produced by urea hydrolysis would increase in the later stages of the dialysis treatment. Therefore, the HCO3- It is desirable to also increase the pH profile later in the treatment to maximize the effect of Ca(OH)2 on balance.

[0168] General method 2

[0169] Further experiments were performed using the following method: Synthetic dialysate effluent of known electrolyte and toxin concentrations was pumped at a constant flow rate through a cartridge containing the sorbent material (Figure 4).

[0170] Preparation of synthetic dialysis solution

[0171] 14 L of synthetic dialysate was used in a single pass experiment using the setup shown in Figure 4 with the various cation and anion concentrations in the synthetic dialysate shown in Table 9. Urea was added at the desired final urea concentration, typically in the concentration range of 3 mmol / L to 8 mmol / L. [Table 9]

[0172] Synthetic dialysis solutions having the above concentrations were prepared by mixing the salts in the amounts listed below in Table 10. The pH of the synthetic dialysis solutions was adjusted to 7.4-7.6 by adding 5N HCl. [Table 10]

[0173] Example 7

[0174] To demonstrate the effect of influent urea concentration and the importance of calcium carbonate in managing bicarbonate and sodium balance, four experiments were performed under single-pass conditions using low urea cartridges (general method 2). The compositions of the sorbents tested are shown in Table 11. [Table 11]

[0175] When experiment 1 was performed using the base formulation of low urea cartridges (LUC) without calcium carbonate, a high negative bicarbonate balance (-83 mmol) was observed; this was because there was no additional bicarbonate source in the form of calcium carbonate.

[0176] In experiments 1 to 3, the basic formulation of the sorbent and the composition of the inflowing dialysate were kept the same, but only the amount of calcium carbonate in the sorbent was increased from 0 g (experiment 1) to 6 g (experiment 3). An increase in the average bicarbonate balance from -83 mmol to -10 mmol (column 3) was observed, indicating the importance of calcium carbonate in maintaining neutral bicarbonate balance. Also, by increasing the amount of calcium carbonate, the sodium balance increases because additional sodium ions are released in exchange for calcium ions contributed by calcium carbonate.

[0177] Experiment 4 was performed with the aim of demonstrating the effect of influent urea concentration on bicarbonate and sodium balance. Experiments 3 and 4 were performed under similar conditions with the same sorbent composition. However, in comparison to experiment 3, the influent urea concentration was reduced in experiment 4 (5.61 mmol / L vs. 3 mmol / L). At higher influent urea concentrations, a higher sodium balance is observed due to the increased availability of ammonium ions (derived from urea) that can be exchanged for sodium. The higher the urea, the higher the bicarbonate balance due to its contribution.

[0178] Four further experiments (Experiment 5 to Experiment 8) were performed using high urea cartridges, the results of which are shown in Table 12. [Table 12]

[0179] It can be seen that the trends shown in these results (Experiments 1 to 8 in Example 7) are consistent with the results of Examples 2 to 5, which used a (more precise) proprietary method.

Claims

1. 1. A material for use in adsorption-based dialysis comprising: Acidic and / or neutral cation exchange particles; alkaline anion exchange particles; and one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate; Materials containing.

2. The material is Ca(OH) ２ and Mg(OH) ２ 10. The material of claim 1, further comprising one or both of:

3. The material described in claim 1, wherein the acidic and / or neutral cation exchange particles are acidic and / or neutral water-insoluble metal phosphates, and optionally the metals are one or more selected from the group consisting of titanium, zirconium, and hafnium.

4. The material described in claim 3, wherein the metal is zirconium.

5. The material of claim 1, wherein the alkaline anion exchange particles comprise a partially hydrated amorphous water-insoluble metal oxide in its hydroxide-counterion form; and / or carbonate-counterion form; and / or acetate-counterion form; and / or lactate-counterion form, wherein the metal is one or more selected from the group consisting of titanium, zirconium, and hafnium, and optionally the anion exchange particles are alkaline hydrous zirconium oxide.

6. (a) the water-insoluble alkaline earth metal carbonate is CaCO ３ and MgCO ３ one or more selected from the group consisting of: and / or (b) the water-insoluble polymeric ammonium carbonate is one or more selected from the group consisting of sevelamer carbonate, polymer-bound tetraalkylammonium carbonate, and 3-(trialkylammonium) alkyl (e.g., propyl)-functionalized silica gel carbonate; The material of claim 1.

7. The material comprising: 30 to 79 wt % acidic and / or neutral cation exchange particles; 20 to 65 wt % alkaline anion exchange particles; Including; moreover, one or more of a water-insoluble alkaline earth metal carbonate and an insoluble polymeric ammonium carbonate in a total amount of 0.1 to 10 wt %; and Ca(OH) ２ and Mg(OH) ２ One or both of these in a total amount of 0 to 5 wt %, The material of claim 2 comprising:

8. The material comprising: 31 to 75 wt % acidic and / or neutral cation exchange particles; 23 to 63 wt % alkaline anion exchange particles; Including; moreover, one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate in a total amount of 0.1 to 5 wt %; and Ca(OH) ２ and Mg(OH) ２ One or both of these in a total amount of 0 to 4 wt %, The material of claim 7, comprising:

9. The material comprising: 50-64 wt % acidic and / or neutral cation exchange particles; 35 to 45 wt % alkaline anion exchange particles; Including; moreover, one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate in a total amount of 0.3 to 5 wt %, The material of claim 1 comprising:

10. The material is 53-60 wt % acidic and / or neutral cation exchange particles; 39 to 44 wt % alkaline anion exchange particles; Including; moreover, one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate in a total amount of 0.5 to 3 wt %, The material of claim 9 comprising:

11. The material comprising: 45-59 wt % acidic and / or neutral cation exchange particles; 40 to 54 wt % alkaline anion exchange particles; Including; moreover one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate in a total amount of 0.5 to 5 wt %, 10. The material of claim 1, comprising:

12. The material comprising: 48-56 wt % acidic and / or neutral cation exchange particles; 42 to 50 wt % alkaline anion exchange particles; Including; moreover, one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate in a total amount of 1 to 2 wt %, The material of claim 11 , comprising:

13. The material comprising: 50-70 wt % acidic and / or neutral cation exchange particles; 30-49 wt % alkaline anion exchange particles; 0.2 to 3 wt % of one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate; Including; moreover Ca(OH) ２ and Mg(OH) ２ One or both of these in a total amount of 0.2 to 2 wt %, The material of claim 7, comprising:

14. The material comprising: 53-67 wt % acidic and / or neutral cation exchange particles; 33 to 46 wt % alkaline anion exchange particles; Including; moreover one or more of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate in a total amount of 0.2 to 2 wt %; and Ca(OH) ２ and Mg(OH) ２ One or both of these in a total amount of 0.2 to 1.5 wt %, The material of claim 13 comprising:

15. The material comprising: the cation exchange particles are acidic and / or neutral water-insoluble metal phosphates; the anion exchange particles are alkaline hydrous zirconium oxide; and At least one of the water-insoluble alkaline earth metal carbonate and the water-insoluble polymeric ammonium carbonate is CaCO ３ and / or MgCO ３ and optionally the material is Ca(OH) ２ further comprising: The material of claim 1.

16. The material of claim 1, further comprising an organic compound absorbent, wherein the organic compound absorbent is present in an amount of 10 to 40 wt % based on the total weight of the components recited in claim 1, and optionally the organic compound absorbent is present in an amount of 15 to 25 wt % (such as 18 to 23 wt %, such as 19 to 21 wt %) based on the total weight of the components recited in claim 1.

17. The material of claim 16, wherein the organic compound absorbent is activated carbon.

18. (a) the material further comprises neutral hydrous zirconium oxide, the neutral hydrous zirconium oxide being present in an amount of 0.1 to 10 wt % based on the total weight of the components recited in claim 1, and optionally the neutral hydrous zirconium oxide being present in an amount of 0.5 to 5 wt % based on the total weight of the components recited in item 1; and / or (b) (i) combining all of the above components together to provide a single layer material; or (ii) one or more of the water-insoluble alkaline earth metal carbonates and water-insoluble polymeric ammonium carbonates, and, when present, Ca(OH) ２ and Mg(OH) ２ is combined with the cation exchange particles to form a first layer, with the anion exchange particles being provided as a second layer. The material of claim 1.

19. A method of manufacturing a material comprising the steps of: providing an acid zirconium phosphate and a neutral zirconium phosphate in an amount that is 55-80 wt % of the total amount of zirconium phosphate in said material; and providing a material comprising: a) a material having an acid zirconium phosphate and a neutral zirconium phosphate; Optionally: (a) the acid zirconium phosphate is present in an amount of 59-70 wt % of the total amount of zirconium phosphate in the material, to which the amount of the neutral zirconium phosphate is present in an amount that adds up to 100 wt % zirconium phosphate; or (b) the acidic zirconium phosphate is present in an amount of 75-78 wt % of the total amount of zirconium phosphate in the material where it is present, to which the amount of the neutral zirconium phosphate is present in an amount that adds up to 100 wt % zirconium phosphate; 5. The material of claim 4.

20. The material of claim 1, comprising one or both of a water-insoluble alkaline earth metal carbonate and a water-insoluble polymeric ammonium carbonate.

21. A cartridge for use in adsorption dialysis, comprising the material of claim 1.

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