Method for removing lead ions from a body fluid

Abstract

A method for removing Pb2+toxins from body fluids is disclosed. The method involves contacting the body fluid, which includes blood and gastrointestinal fluids, with an ion exchange composition to remove the metal toxins from the body fluid. Alternatively, the blood can be contacted with a dialysis solution and then with the ion exchange composition. The ion exchange composition is represented by the empirical formula: A m Ti a Nb 1‑a Si x O y having any one of the following: tavorite, sitinakite, tavorite-sitinakite paragenetic topology, or mixtures thereof. Also disclosed is a composition comprising the ion exchange composition described above in combination with a body fluid or a dialysis solution. The ion exchange composition can be supported by a porous network of biocompatible polymers such as carbohydrates or proteins.

Description

[0001] CLAIM

[0002] This application claims priority to U.S. Provisional Application No. 63 / 085,784, filed September 30, 2020, which is incorporated herein in its entirety. TECHNICAL FIELD

[0003] The present invention relates to an in vitro or in vivo method for removing Pb2+ions from body fluids. Either the gastro-intestinal fluids or any other body fluid is directly contacted with a metallate ion exchange composition which is able to selectively remove the toxins or the blood or other body fluids are first contacted with a dialysis solution and then with the metallate ion exchange composition. 2+ BACKGROUND

[0004] ​In mammals (e.g., humans), most other organs of the body also fail soon after the kidneys and / or liver are unable to remove metabolic waste products from the body. Therefore, extensive efforts have been made to find safe and effective methods for removing toxins from the blood of patients by extracorporeal treatment. Many methods have been proposed for removing small molecule toxins, protein-bound molecules, or larger molecules believed to be responsible for coma and liver failure diseases. Some of these toxic compounds have been identified as urea, creatine, ammonia, phenol, thiols, short-chain fatty acids, aromatic amino acids, pseudoneurotransmitters (octopamine), neuroinhibitors (glutamate), and bile salts. Among these compounds, phenol and thiols, as well as bilirubin and bacterial endotoxins, also appear as strong protein-bound toxins and are therefore more difficult to effectively remove from the blood. Intermediate molecular weight toxins with a molecular weight of 300 to 10,000 can also be present and are difficult to effectively remove. Various ways of treating blood containing such toxins have been demonstrated in the art. The classical method is of course dialysis. Dialysis is defined as the removal of a substance from a liquid by diffusion across a semipermeable membrane into a second liquid. Dialysis of blood outside the body (hemodialysis) is the basis of the "artificial kidney". The treatment program commonly used today is similar to the program developed by Kolff in the early 1940s. Since the 1940s, several disclosures have been made involving improvements to the artificial kidney or artificial liver. Thus, US 4,261,828 discloses an apparatus for blood detoxification. The apparatus comprises a housing filled with adsorbents such as charcoal or resins and optionally an enzyme carrier. To prevent direct contact between the blood and the adsorbents, the adsorbents can be coated with a coating that allows the penetration of the substances to be adsorbed, also preventing direct contact between the blood corpuscle blood components and the adsorbents. US 4,581,141 discloses a composition for dialysis containing surface adsorbing substances, water, a suspending agent, urease, calcium-loaded cation exchanger, aliphatic carboxylic acid resin, and a metabolizable organic acid buffer. The calcium-loaded cation exchanger can be a calcium-exchanged zeolite. EP 0046971A1 discloses that zeolite W can be used for hemodialysis to remove ammonia. Finally, US 5,536,412 discloses a blood filtration and plasma filtration device in which blood flows through the interior of hollow fiber membranes and during the flow of blood, an adsorbent suspension is circulated against the outer surface of the hollow fiber membranes. Another step involves alternately removing and reintroducing the plasma portion of the blood into the interior of the membranes, thereby effecting removal of toxins. The adsorbents can be activated carbon as well as ion exchangers such as zeolites or cation exchange resins.

[0005] There are problems associated with the adsorbents disclosed in the above patents. For example, charcoal does not remove any water, phosphates, sodium, or other ions. A disadvantage of zeolites is that they can partially dissolve in the dialysis solution, allowing aluminum and / or silicon to enter the blood. In addition, zeolites can adsorb sodium, calcium, and potassium ions from the blood, requiring the addition of these ions back into the blood.

[0006] More recently, examples of microporous ion exchangers that are substantially insoluble in fluids such as body fluids, especially blood, have been developed, namely zirconium-based silicates and titanium-based silicates of US 5,888,472, US 5,891,417, and US 6,579,460. The use of these microporous ion exchangers of zirconium-based silicates or titanium-based silicates to remove toxic ammonium cations from blood or dialysate is described in US 6,814,871, US 6,099,737, and US 6,332,985. In addition, some of these compositions, such as UZSi-9, were found to also be selective in potassium ion exchange and can remove potassium ions from body fluids to treat the disease hyperkalemia, and were regulated to do so more effectively. The use in treating hyperkalemia is discussed in US 8,802,152, US 9,457,050, US 9,662,352, US 9,844,567, US 9,861,658, US 10,413,569, and US 10,398,730, which refer to material optimization such as crystal size, cation form, pH control, ion exchange capacity, dosage form, material combinations such as ZS-9 and ZS-1, reaction form to produce a product free of undesirable impurities, and simultaneous treatment of hyperammonemia with hyperkalemia. US 8,808,750, US 8,877,255, and US 9,913,860 discuss dosing and combinations of zirconium silicate materials for hyperkalemia treatment, including ZS-9 and ZS-7 combinations without ZS-8. US 9,707,255 discusses simultaneous treatment of hyperkalemia and hypercalcemia, and the introduction of a Ca-exchange version of ZS-9 that does not absorb too much Ca from the body. The ex vivo use of these materials, for example in dialysis, is described in US 9,943,637.

[0007] Blood compatible polymers have also been incorporated into devices for the treatment of body fluids. US 9033908 discloses a small benchtop and wearable device for removing toxins from blood. The device has an adsorptive filter which utilizes nanoparticles embedded in a porous blood compatible polymer matrix. The toxic materials targeted by this device and filter system are potassium, ammonia, phosphate, urea and uric acid. Similarly, a 3-D printed hydrogel matrix composed of cross-linked poly(ethylene glycol) diacrylate tethered with polydiacetylene-based nanoparticles has been demonstrated to be successful in removing the toxin honeybee venom (Nat. Commun., 5, 3774 2014).

[0008] In addition to toxins derived from metabolic waste, humans are susceptible to environmental toxins that can enter the body, for example, by ingestion, absorption through the skin, or inhalation. One such toxic metal is lead. For many years, lead was a key component of gasoline in the form of tetraethyl lead and was a key component of paints. Currently, lead is no longer used or is used sparingly in these industries, but environmental hazards still exist. Remodeling activities in older homes that were painted with lead-containing paints generate dust that can be inhaled or end up in the soil nearby, and in which lead is leached into groundwater or absorbed by plants. Unreliable or unregulated water supplies represent a risk of exposure to Pb 2+ toxicity, most notably the recent situation in Flint, Michigan, USA, where some residents were found to have dangerously high Pb 2+ levels in their blood after exposure to a new municipal water supply. Lead contamination is associated with many adverse health conditions, including affecting the nervous and urinary systems and inducing learning and developmental disorders in exposed children. Removal of lead from the blood of afflicted patients would reduce further exposure and damage.

[0009] Chelation therapy has also been used for Pb 2+ poisoning. The chelator CaNa2EDTA has been used to remove Pb 2+ from the blood, but this complex is poorly absorbed by the gastrointestinal tract and must typically be administered intravenously. This chelate has been observed to mobilize Pb 2+ , transferring it to other tissues, including the brain (Int. J. Environ. Res. Public Health, 2010, 7, 2745-2788). Dimercaptosuccinic acid (DMSA) is considered a detoxifying agent for heavy metal poisoning and has been used to treat Co 2+ , Cd 2+ and Pb 2+Poisoning (see US 5519058). Issues with chelation therapy include toxic side effects, non-selective binding of metals, and diffusion of the toxin through the body. Supported chelators, i.e. chelators bound to resins, have been used for heavy metal removal in a dialysis mode, where blood is on one side of a semi-permeable membrane and resin-supported chelators are on the other side (see US 4612122).

[0010] Zeolites have been proposed for the treatment of chronic lead poisoning, taken in pill form in US 20180369279A1, but zeolites have limited stability, especially in the gastrointestinal tract.

[0011] Recently, the applicant disclosed in co-pending application 16 / 506377 metallosilicate ion exchangers for the removal of Pb 2+ , Cd 2+ , Cr 3+ and Co 2+ from body fluids. The compositions demonstrated Pb 2+ uptake include titanium-based silicates with the pharmacosiderite and sitinakite topology. Pharmacosiderite is an iron-arsenate mineral and many compositions with the pharmacosiderite topology are known (Micropor. Mesopor. Mater., 151, 2012, 13-25). Among the known compositions, Tripathi et al. have disclosed Ge and Nb substituted titanium silicate pharmacosiderites to optimize Cs + uptake in ion exchange, see J. Solid State Chem., 177, 2004, 2903-2915. In US 5,667,695, the claimed germanium-containing pharmacosiderite ion exchanger takes up a variety of metals, including Pb 2+ , but only exhibits Cs + uptake in solutions with pH = 13. Similarly, sitinakite is a titanium silicate mineral first reported in Zap. Vseross Mineral O-va, 121, 1992, 94-99. Anthony et al. first discovered a synthetic form of sitinakite, TAM-5, and noted its favorable Cs + and Sr 2+ ion exchange properties (see Ind. Eng. Chem. Res., 33, 1994, 2702). The synthesis, crystal structure and Cs +The ion exchange properties are described (see Chem. Mater., 6, 1994, 2364-2368). In US 6110378, Anthony et al. reported metal-doped titanium silicate sitinakite, focusing on Nb as a dopant and its better chelation of Cs compared to undoped materials. + The ability to [discuss] niobium substitution in sitinakite and the resulting Cs. + Further studies on the ion exchange properties are reported in Micropor. Mesopor. Mater., 55, 2002, 1-13. A recent review of the ion exchange properties of titanium silicate-based materials demonstrates the broad utility of this family, but the utility of titanium silicates with ferromagnetic and sitinakite topologies has been overwhelmingly focused on for the removal of Cs from radioactive waste stored in high-pH solutions. + and Sr 2+ (See Chemical Engineering Journal, 317, 2017, 570-585).

[0012] The topologies of sitinakite and ferroalloy are similar in two dimensions but different in the third. Both structures are composed of [Ti₄O₄]. 8+ The structure consists of cubane units, which are incorporated into the ferroalloy topology via [SiO4]. 4- The tetrahedra are connected in three main directions, creating a cubic three-dimensional 8-ring porous structure. In sitinakite, the bridging SiO4 tetrahedra exist in the a- and b- directions, but not along the c- direction, where the Ti4O4 groups are connected by a pair of oxygen ions (two O ions). 2- ) for SiO4 4- Connection. This produces one-dimensional 8-ring pores along the c-direction and 6-ring pores along the a- and b-directions. The different pore structures are determined by the cations present during the synthesis process. When K + In this reaction mixture, a poisonite structure will be formed. When the cation used in the synthesis is Na... + At this time, a sitinakite structure is formed. Recognizing the similarity in topological structure and chemical relationship between sitinakite and ferritinite, Bedard disclosed a mixed K-type ferritin-sitinakite symbiotic structure in US 5,858,243. + -Na +Synthesis, the patent incorporated by reference. The relationship between the parsonsite and sitinakite structures is confirmed in the present disclosure and by transmission electron microscopy observation of the intergrown material. Some parsonsite and sitinakite coexist with the parsonsite-sitinakite intergrowth. The ability of the claims is limited to the removal of multiple metals from a contaminated liquid stream and no utility in the human body is contemplated. The contaminants listed in the claims of US 5,858,243 include Pb 2+ but like parsonsite and sitinakite, the intergrowth was tested for Cs + uptake in a 0.6 M NaOH solution, under which conditions Pb 2+ will not dissolve or be able to participate in the ion exchange process.

[0013] Applicants have developed a method for removing Pb 2+ toxins from a fluid using a crystalline metallosalt ion exchanger that is substantially insoluble in the fluid, such as a body fluid (especially a gastrointestinal fluid) or a dialysis solution. These ion exchangers have the following empirical formula on an anhydrous basis:

[0014] A m Ti a Nb 1-a Si x O y

[0015] where A is an exchangeable cation selected from potassium ion, sodium ion, lithium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion, or mixtures thereof, “m” is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.00, “a” is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, “1-a” is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, where a + (1-a) = 1, “x” is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and “y” is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and is characterized in that the ion exchanger has a parsonsite topology, a sitinakite topology, an intergrowth of these two topologies, or mixtures thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing in the range of and between 100%, where when the material has a parsonsite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0016] Table A

[0017]

[0018] or wherein when the material has a sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0019]

[0020] or wherein when the material is a sitinakite-arseniosiderite intergrowth or a mixture of any combination of sitinakite, arseniosiderite and sitinakite-arseniosiderite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and 100% relative intensity.

[0021] Since these compositions are substantially insoluble in body fluids (at neutral and acidic or basic pH), they can be ingested orally to remove toxins from the gastrointestinal system as well as for removing toxins from the blood, in particular Pb 2+ . SUMMARY

[0022] As stated, the present invention relates to a process for removing Pb 2+ from a fluid selected from the group consisting of body fluids, dialysis fluid solutions and mixtures thereof, the process comprising contacting the fluid containing the toxin with a crystalline metalate ion exchanger selected from the group consisting of titanium silicate, niobium-titanium silicate or mixtures thereof, the metalate ion exchanger having the following empirical formula on an anhydrous basis:

[0023] A m Ti a Nb 1-a Si x O y

[0024] wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that the metal salt has any one of the fukalite topology, the sitinakite topology, intergrowths of these two topologies, or mixtures thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing between and a relative intensity of 100%, wherein when the material has the fukalite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0025] Table A

[0026]

[0027] or wherein when the material has the sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0028]

[0029] or when the material is an intergrowth of fukalite-sitinakite or a mixture of any combination of fukalite, sitinakite, and fukalite-sitinakite phases, the diffraction pattern has at least one peak with a d-spacing between and a relative intensity of 100%. The body fluid treated by the present invention includes blood, gastrointestinal fluid, and dialysis fluid. As known to those skilled in the art, blood can include whole blood, plasma, or other components of blood.

[0030] Another embodiment of the present invention is a combination of a body fluid or dialysis fluid solution and a crystalline metal salt ion exchanger selected from titanium silicate, niobium-titanium silicate, or mixtures thereof, the metal salt ion exchanger having the following empirical formula on an anhydrous basis:

[0031] A m Ti a Nb 1-a Si x Oy

[0032] wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.5, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that the metal salt has a ferrorométopo topology, a sitinakite topology, a paragenesis of both topologies or mixtures thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing in the range of and between 4.80 and 5.20 A, a relative intensity of 100%, wherein when the material has a ferrorométo topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0033] Table A

[0034]

[0035] or wherein when the material has a sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0036]

[0037] or when the material is a ferrorométo-sitinakite paragenesis or a mixture of any combination of ferrorométo, sitinakite and ferrorométo-sitinakite paragenetic phases, the diffraction pattern has at least one peak with a d-spacing in the range of and between 4.80 and 5.20 A, a relative intensity of 100%, wherein when the material has a ferrorométo topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0038] Another embodiment of the present invention is a device comprising a crystalline metal salt ion exchanger selected from titanium silicate, niobium-titanium silicate and mixtures thereof, the composite metal salt having the following empirical formula on an anhydrous basis:

[0039] A m Ti a Nb 1-a Si x O y

[0040] wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.5 to 1.5, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that the complex metal salt has a pharmacosiderite topology, a sitinakite topology, a paragenesis of both topologies or mixtures thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing in the range of and between 6.8 and 7.2 A, a relative intensity of 100%, wherein when the material has a pharmacosiderite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0041] Table A

[0042]

[0043] or wherein when the material has a sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0044]

[0045] or wherein when the material is a pharmacosiderite-sitinakite paragenesis or a mixture of pharmacosiderite, sitinakite and pharmacosiderite-sitinakite paragenetic phases in any combination, the diffraction pattern has at least one peak with a d-spacing in the range of and between 6.8 and 7.2 A, a relative intensity of 100%, wherein when the material has a pharmacosiderite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0046] The device is configured for contacting a body fluid or a dialysate solution to remove Pb 2+ ions. The device of the present invention containing the metalate ion exchanger described above can be an adsorptive filter on a wearable device or a device remote from the individual. The crystalline metalate ion exchanger can be supported or embedded in a porous biocompatible matrix, which includes polymers as well as porous and mesoporous metal oxides and metal silicates. In particular, natural or biopolymers such as crosslinked carbohydrates or proteins are envisaged as useful polymers for the present invention.

[0047] These and other objects and embodiments will become more apparent after a reading of the detailed description. DETAILED DESCRIPTION

[0048] As stated, the Applicant has developed a new method for removing toxins from fluids selected from the group consisting of body fluids and dialysis fluid solutions. An essential element of the method of the present invention is an ion exchanger having a large capacity and a strong affinity (i.e. selectivity) for Pb 2+ These compositions are identified as coming from titanium silicate and niobium-titanium silicate and mixtures thereof, the complex metallophosphate having an empirical formula on an anhydrous basis of:

[0049] A m Ti a Nb 1-a Si x O y

[0050] The composition has a framework structure consisting of at least [TiO 3 / 3 O 3 / 2 ] - octahedral units, SiO 4 / 2 tetrahedral units and optionally NbO 3 / 3O 3 / 2 octahedral units. "A" is an exchangeable cation selected from the group consisting of potassium ion, lithium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that are Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that are Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.5, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and is characterized in that the complex metallophosphate has a pharmacosiderite topology, a sitinakite topology, a paragenesis of the two topologies or mixtures thereof, exhibiting an x-ray diffraction pattern having at least one peak with a d-spacing between and 100% relative intensity, wherein when the material has a pharmacosiderite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0051] Table A

[0052]

[0053] or wherein when the material has a sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0054]

[0055] or when the material is a parsettensite-sitinakite intergrowth or a mixture of any combination of parsettensite, sitinakite and parsettensite-sitinakite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and and a relative density of 100%.

[0056] Crystalline titanyl silicates and niobium-titanium silicates having a parsettensite topology, a sitinakite topology, an intergrowth of both topologies or mixtures thereof are obtained by hydrothermal crystallization of a reaction mixture prepared by mixing reactive sources of titanium, silicon and optionally Nb, at least one alkali metal, a hydroxide source and water. The alkali metal acts as a templating agent. Specific examples of titanium metal sources include, but are not limited to, titanium alkoxides, titanium tetrachloride, titanium trichloride and titanium dioxide. Silica sources include colloidal silica, fumed silica, tetraethyl orthosilicate, sodium silicate and potassium silicate. Alkali sources include, but are not limited to, nitrates, halides, acetates, carbonates and hydroxides, including potassium hydroxide, sodium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, sodium halide, potassium halide, rubidium halide, cesium halide and lithium acetate. Nb sources include niobium isopropoxide, niobium ethoxide, niobium oxide hydrate, ammonium niobium oxalate, niobium oxalate. Hydroxide sources include quaternary ammonium hydroxides, ROH, specific examples of which are tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide and tetrabutylammonium hydroxide. Typically, the hydrothermal process for making crystalline titanyl silicates, niobium-titanium silicates and mixtures thereof having a parsettensite topology, a sitinakite topology, an intergrowth of both topologies or mixtures thereof of the present invention comprises forming a reaction mixture represented in terms of molar ratios of oxides as follows:

[0057] r R 2 / s O:p A2O:TiO2:a Nb2O5:b SiO2:c H2O

[0058] where "R" is one or more quaternary ammonium cations, "s" is the charge on the quaternary ammonium cation and is either 1 or 2, "r" has a value of 0 to 25, "p" has a value of 0.5 to 25, "a" has a value of 0 to 1.5, "b" has a value of 0.25 to 20, and "c" has a value of 10 to 5000. The reaction mixture is prepared by mixing the desired titanium source, silicon source, optional Nb source, optional quaternary ammonium hydroxide source, and alkali metal source in any order to give the desired mixture. The mixture must also have a basic pH and preferably a pH of at least 10. The basicity of the mixture is controlled by the addition of excess alkali metal hydroxide, quaternary ammonium hydroxide, and / or basic compound of the other components of the reaction mixture. After the reaction mixture is formed, it is then reacted under autogenous pressure in a sealed reaction vessel at a temperature of 100°C to 200°C for a period of 1 to 30 days. After the allotted time, the mixture is filtered to isolate the solid product, which is washed with deionized water and dried in an oven or just in air. As described, the compositions of the present invention have a framework of octahedral units, SiO 3 / 3 O 3 / 2 ] - octahedral units, SiO 4 / 2 tetrahedral units, and optional NbO 3 / 3 O 3 / 2 octahedral units, having a tobermorite topology, a sitinakite topology, a co-crystal of these two topologies, or a mixture thereof.

[0059] Upon synthesis, the compositions of the present invention will contain some alkali metal templating agents in the pores and at other charge balancing locations. These metals are described as exchangeable cations, which means that they can be exchanged with other (secondary) A' cations. Typically, the A exchangeable cations can be exchanged with A' cations selected from the group consisting of other alkali metal cations (K + , Na + , Rb + , Cs + ), alkaline earth metal cations (Mg 2+ , Ca 2+ ), hydronium (H + ), or mixtures thereof. It should be understood that the A' cations are different from the A cations. Methods for exchanging one cation for another are well known in the art and involve contacting the composition under exchange conditions with a solution containing the desired cation in molar excess. Exchange conditions include temperatures of 25°C to 100°C and times of 20 minutes to 2 hours. The particular cation (or mixture thereof) that is present in the final product will depend on the particular use of the composition and the particular composition used. One particular composition is an ion exchanger, where the A' cations are Na + , Ca 2+and H + a mixture of ions.

[0060] As noted above, the materials of the present application are prepared at high pH, and thus can increase the pH of any liquid to which they are exposed. Body fluids such as gastrointestinal fluids are acidic throughout the digestive tract, reaching a pH as low as 1.0 in the lower stomach. Blood has a pH of 7.4. Both of these types of body fluids would experience a pH increase if exposed directly to the materials synthesized in the present application. It is therefore preferred to ion exchange the materials of the present application. In a preferred embodiment, the as-synthesized ion exchanger having the tobermorite topology, the sitinakite topology, a paragenesis of both topologies, or a mixture thereof is treated with an acid to form an ion exchanger of the proton / hydrated hydrogen ion type, which avoids a pH increase upon contact with body fluids. In another embodiment, the as-synthesized ion exchanger having the tobermorite topology, the sitinakite topology, a paragenesis of both topologies, or a mixture thereof can be ion exchanged with Na + or Ca 2+ cations, or both. In a third embodiment, the as-synthesized ion exchanger having the tobermorite topology, the sitinakite topology, a paragenesis of both topologies, or a mixture thereof can be first ion exchanged with an acid, and subsequently ion exchanged with Na + or Ca 2+ or both. If the patient being treated for Pb 2+ poisoning is hypocalcemic, a Ca 2+ exchanged form of the ion exchanger having the tobermorite topology, the sitinakite topology, a paragenesis of both topologies, or a mixture thereof would be advantageous to avoid lowering the Ca 2+ level in the patient.

[0061] In some cases, when quaternary ammonium cations are used in synthesis typically as a source of hydroxide, quaternary ammonium cations can be incorporated into the product. This is not typically the case because the quaternary ammonium cations are typically displaced by alkali metal cations that have a higher affinity to bind into the ion exchanger having the toxicolite topology, the sitinakite topology, intergrowths of both topologies, or mixtures thereof. However, if any quaternary ammonium ions are present, they must be removed from the product. This can typically be achieved by the ion exchange methods mentioned above. Sometimes, the quaternary ammonium ions can be trapped in the pores and it can not be possible to remove the quaternary ammonium cations by ion exchange; decomposition by calcination will be required. Typically, calcination consists of heating the sample to a temperature of 400-600 °C for 2-24 hours after flowing air or flowing nitrogen followed by flowing air. In this method, the quaternary ammonium cations are decomposed and replaced by residual protons. Once the calcination is complete, the sample can be ion exchanged into the desired A' cation composition as described above.

[0062] It is also within the scope of the present invention that these ion exchange compositions can be used in powder form or can be formed into various shapes by means well known in the art. Examples of these various shapes include pellets, extrudates, spheres, spheroids and irregularly shaped particles. This has been demonstrated previously in US 6,579,460 B1 and US 6,814,871 B1. The crystalline ion exchange compositions of the present invention can also desirably be supported in a porous network, including intercalation into or binding to a hemocompatible porous network, such as in an adsorptive filter as disclosed in US 9,033,908 B2. The porous network can consist of natural or synthetic polymers and biopolymers as well as mesoporous metal oxides and silicates. Suitable natural polymers (biopolymers) can include crosslinked carbohydrates or proteins made from oligomeric and polymeric carbohydrates or proteins. The biopolymers are preferably polysaccharides. Examples of polysaccharides include alpha-glucans with 1,3-, 1,4- and / or 1,6-bonds. Among these polysaccharides, the "starch family" (including amylose, amylopectin and dextrin) is particularly preferred, but pullulan, elsinan, reuteran and other alpha-glucans are also suitable, although the proportion of 1,6-bonds is preferably lower than 70%, more preferably lower than 60%. Other suitable polysaccharides include beta-1,4-glucans (cellulose), beta-1,3-glucans, xyloglucans, glucomannans, galactans and galactomannans (guar gum and locust bean gum), other gums, including heterogamous gums such as xanthan gum, ghatti, carrageenan, alginate, pectin, beta-2,1 - and beta-2,6-fructans (inulin and Ievan) and the like. A preferred cellulose is carboxymethyl cellulose (CMC, e.g. AKUCELL from AKZONobel). Carbohydrates that can thus be used are carbohydrates consisting only of C, H and O atoms, such as for example glucose, fructose, sucrose, maltose, arabinose, mannose, galactose, lactose as well as oligomers and polymers of these sugars, cellulose, dextrin (such as maltodextrin), agarose, amylose, amylopectin and gums (e.g. guar gum). Preferably, oligomeric carbohydrates from DP2 on or polymeric carbohydrates from DP50 on are used. These carbohydrates can be naturally occurring polymers such as starches (amylose, amylopectin), cellulose and gums or their derivatives which can be formed by phosphorylation or oxidation. The starches can be cationically or anionically modified starches. Examples of suitable (modified) starches that can be modified are corn starch, potato starch, rice starch, tapioca starch, banana starch and manioc starch. Other polymers (e.g. caprolactone) can also be used.In certain embodiments, the biopolymer is preferably a cationic starch, most preferably an oxidized starch (e.g., C6 oxidized with hypochlorite). The level of oxidation can be freely selected to suit the application of the sorbent material. Very suitably, the level of oxidation is between 5% and 55%, most preferably between 25% and 35%, still more preferably between 28% and 32%. Most preferably, the oxidized starch is cross-linked. A preferred cross-linking agent is a diepoxide. The level of cross-linking can be freely selected to suit the application of the sorbent material. Very suitably, the level of cross-linking is between 0.1% and 25%, more preferably between 1% and 5%, and most preferably between 2.5% and 3.5%. Proteins that can be used include albumin, ovalbumin, casein, myosin, actin, globulin, hemoglobin, myoglobin, gelatin, and small peptides. In the case of proteins, proteins obtained from hydrolysates of plant or animal material can also be used. A particularly preferred protein polymer is gelatin or a gelatin derivative.

[0063] As noted, these compositions have the ability to sorb various Pb 2+ the fluid is selected from the group consisting of a body fluid, a dialysis fluid solution, and mixtures thereof. As used herein and in the claims, a body fluid will include, but is not limited to, blood, plasma, and gastrointestinal fluids. Also, a composition means that it can be used to treat the body fluids of any mammal, including, but not limited to, humans, cows, pigs, sheep, monkeys, gorillas, horses, dogs, etc. The method of the present invention is particularly suited for removing toxins from the human body. There are a number of ways in which the fluid can be brought into direct or indirect contact with the desired ion exchanger and thus have the toxins removed. One technique is hemoperfusion, which involves packing the ion exchange composition described above into a column through which blood is flowed. One such system is described in U.S. Patent No. 4,261,828. As described in the '828 patent, the ion exchange composition is preferably formed into a desired shape, such as a sphere. In addition, the ion exchange composition particles can be coated with a compound, such as a cellulose derivative, which is compatible with blood but impermeable to the blood cell blood components. In one particular case, the spheres of the desired ion exchange composition described above can be packed into hollow fibers, thus providing a semipermeable membrane. It should also be noted that more than one type of ion exchange composition can be mixed and used in the method to enhance the efficiency of the method.

[0064] Another way to perform the method is by preparing a suspension or slurry of the molecular sieve adsorbent by means known in the art, such as described in U.S. Patent No. 5,536,412. The apparatus described in the '412 patent can also be used to perform the method. The method essentially involves passing a fluid containing metal toxins (e.g., blood) through the interior of a hollow fiber and circulating an adsorbent suspension through the outer surface of the hollow fiber membrane during said passing. Simultaneously, intermittent pulses of positive pressure are applied to the adsorbent solution such that the fluid alternately exits and re-enters the interior of the hollow fiber membrane, thereby removing toxins from the fluid.

[0065] Another type of dialysis is peritoneal dialysis. In peritoneal dialysis, the peritoneal cavity or abdomen (belly) is filled via a catheter inserted into the peritoneal cavity with a dialysis fluid or solution that contacts the peritoneum. Toxins and excess water flow from the blood through the peritoneum into the dialysis fluid, which is a membrane that surrounds the organs outside the belly. The dialysis fluid is left in the body for a time sufficient to remove the toxins (dwell time). After the desired dwell time, the dialysis fluid is removed from the peritoneal cavity through the catheter. There are two types of peritoneal dialysis. In continuous ambulatory peritoneal dialysis (CAPD), dialysis is performed throughout the day. This method involves leaving a dialysis solution in the peritoneal cavity and periodically removing spent dialysis fluid (containing toxins) and refilling the cavity with fresh dialysis solution. This is done several times during the day. The second type is automated peritoneal dialysis or APD. In APD, the dialysis solution is exchanged by a device overnight while the patient is sleeping. In both types of dialysis, a fresh dialysis solution must be used for each exchange.

[0066] The crystalline titania silicates and titania-niobium metallosilicate ion exchangers of the present invention can be used to regenerate the dialysis fluid solution used in peritoneal dialysis, thereby further reducing the amount of dialysis fluid required to clean the blood and / or the amount of time required for an exchange. This regeneration is performed by any of the above-described means for conventional dialysis. For example, in the indirect contact method, the dialysis fluid from the peritoneal cavity (i.e., the first dialysis fluid that has absorbed the metal toxins transferred across the peritoneum) is now contacted with a membrane and a second dialysis solution and metal toxins are transferred across the membrane, thereby purifying the first dialysis solution, i.e., the purified dialysis solution. The second dialysis solution containing the metal toxins is flowed through at least one adsorbent bed containing at least one of the ion exchangers described above, thereby removing the metal toxins and producing a purified second dialysis solution. It is generally preferred that the second dialysis solution be continuously circulated through the adsorbent bed until the toxic metal ions (i.e., Pb 2+ ) have been removed. It is also preferred that the first dialysis solution be circulated through the peritoneal cavity, thereby increasing the efficiency of toxic metal removal and reducing the overall dwell time.

[0067] A direct contact method can also be performed in which a first dialysate solution is introduced into the peritoneal cavity and then flowed through at least one bed containing at least one ion exchanger. As described above, this can be performed as CAPD or APD. The composition of the dialysate solution can be varied in order to ensure proper electrolyte balance in the body. This, along with the various equipment used to perform dialysis, is well known in the art.

[0068] Titanium silicate and titanium silicate-niobium metallasalt ion exchangers can also be shaped into pills or other shapes that can be ingested orally and absorb toxins in the gastrointestinal fluids as the ion exchanger passes through the intestinal tract and is eventually excreted. To protect the ion exchanger from the high acid content of the stomach, the shaped article can be coated with various coatings that will not dissolve in the stomach but will dissolve in the intestines.

[0069] As has also been stated, although the compositions of the present invention are synthesized with a variety of exchangeable cations ("A"), it is preferred to exchange the cations with secondary cations (A') that are more compatible with blood or do not adversely affect blood. For this reason, the preferred cations are sodium, calcium, hydronium and magnesium. The preferred compositions are those containing sodium and calcium or sodium, calcium and hydronium ions. The relative amounts of sodium and calcium can vary significantly and depend on the concentration of these ions in the composition and blood.

[0070] The x-ray patterns presented in the following examples were obtained using standard x-ray powder diffraction techniques. The irradiation source was a high intensity x-ray tube operating at 45 kV and 35 mA. The diffraction pattern from the copper K-alpha irradiation was obtained by suitable computer-based techniques. Flat, compressed powder samples were scanned continuously from 2° to 56° (2 theta). The interplanar spacing (d) was obtained from the position of the diffraction peaks expressed as theta, where theta is the Bragg angle as observed from the digitized data. Intensity was determined from the integrated area of the diffraction peak after background subtraction, "I" is the intensity of the strongest line or peak, and "I" is the intensity of each of the other peaks. o

[0071] As will be appreciated by those skilled in the art, the determination of the parameter 2 theta is subject to both human and mechanical error, the combination of which can impart an uncertainty of ±0.4° to each reported 2 theta value. This uncertainty is of course also embodied in the reported d-spacing values, which are calculated from the 2 theta values. This imprecision is ubiquitous in the art and is insufficient to eliminate the differentiation of the crystalline materials of the present invention from each other and from the compositions of the prior art. In the reported x-ray patterns, the relative intensities of the d-spacings are indicated by the symbols vs, s, m and w, which stand for very strong, strong, medium and weak, respectively. According to 100 x I / I o The above nomenclature is defined as:

[0072] ​w > 0 - 15, m > 15 - 60: s > 60 - 80 and vs > 80 - 100.

[0073] In certain instances, the purity of a synthetic product can be assessed with reference to its x-ray powder diffraction pattern. Thus, for example, if a sample is described as pure, it is intended only to mean that the x-ray pattern of the sample contains no lines attributable to crystalline impurities, not that there is no amorphous material present.

[0074] In order to more fully demonstrate the present application, the following examples are presented. It is to be understood that these examples are merely illustrative and do not in any way limit the broad scope of the present application as set forth in the appended claims.

[0075] Example

[0076] Example 1

[0077] In a Teflon beaker, 306.73 g of KOH (87.8%) was dissolved in 576.49 g of deionized water under high speed Heidolph agitation and the mixture was stirred until it reached room temperature. To this solution was added 240.34 g of Ludox AS-40 (40% Si02) via a dropping funnel under vigorous agitation, resulting in a translucent solution that became clear after homogenization for 2 hours. To this clear solution was added 234.44 g of Ti(OiPr)4(97%) via a dropping funnel while continuing the vigorous overhead stirring. Upon further agitation, the reaction mixture became a white opaque colloidal suspension. The reaction mixture was loaded into a 2 L Parr stirred autoclave and digested at 175 °C for 120 hours while stirring at 300 RPM under autogenous pressure. The solid product was isolated by centrifugation, washed with deionized water and dried at 100 °C. The powder x-ray diffraction pattern indicated that the titania product had the tridymite topology; representative diffraction lines are shown in Table 1 below. Elemental analysis showed the stoichiometry of the solid to be K 1.40 TiSi 1.01 .

[0078] Table 1

[0079]

[0080] Example 2

[0081] In a Teflon beaker, 358.87 g KOH (87.8%) was dissolved in 674.49 g of deionized water under high speed Heidolph agitation and the mixture was stirred until it reached room temperature. To this solution, 281.20 g Ludox AS-40 (40% Si02) was added via dropping funnel while vigorous overhead stirring was continued. A clear solution was formed after 2 hours of homogenization. To the clear solution, 274.29 g Ti(OiPr)4(97%) was added via dropping funnel while overhead stirring was continued. After stirring for an additional 25 minutes, a white opaque gel-like suspension was obtained. The reaction mixture was loaded into a 2 L Parr stirred autoclave and digested at 175°C for 120 hours while stirring at 300 RPM under autogenous pressure. The solid product was isolated by centrifugation, washed with deionized water and dried at 100°C. The powder X-ray diffraction pattern indicated that the titania silicate had a tridymite topology; representative diffraction lines are listed in Table 2 below. Elemental analysis indicated that the product had the stoichiometry Na 0.01 K 0.97 TiSi 0.86 .

[0082] Table 2

[0083]

[0084] Example 3

[0085] In a Teflon beaker, 358.87 g KOH (87.8%) was dissolved in 674.49 g of deionized water under high speed Heidolph agitation and the mixture was stirred until it reached room temperature. To this solution, 281.20 g Ludox AS-40 (40% Si02) was added via dropping funnel while vigorous overhead stirring was continued. A clear solution was formed after 2 hours of homogenization. To the clear solution, 274.29 g Ti(OiPr)4(97%) was added via dropping funnel while overhead stirring was continued. After stirring for an additional 25 minutes, a white opaque gel-like suspension was obtained. The reaction mixture was loaded into a 2 L Parr stirred autoclave and digested at 175°C for 120 hours while stirring at 300 RPM under autogenous pressure. The solid product was isolated by centrifugation, washed with deionized water and dried at 100°C. The powder X-ray diffraction pattern indicated that the titania silicate had a tridymite topology; representative diffraction lines are listed in Table 2 below. Elemental analysis indicated that the product had the stoichiometry Na 2) , a clear solution was formed after 1 hour of homogenization. To this clear solution, 22.71 g of hydrated Nb205powder (55.2% Nb) was added and homogenized for 1 hour, resulting in a smooth white suspension. Subsequently, 115.45 g Ti(OiPr)4(97%) was added via dropping funnel while overhead stirring was continued. After stirring for an additional 25 minutes, a white opaque suspension was obtained. The reaction mixture was transferred and sealed in a 2 L Parr stirred reactor and digested at 175°C for 120 hours while stirring at 300 RPM under autogenous pressure. The solid product was isolated by centrifugation, washed with deionized water and dried at 100°C. The powder X-ray diffraction pattern indicated that the titania silicate-niobium had a tridymite topology. Representative diffraction lines are given in Table 3 below. Elemental analysis indicated that the product had the stoichiometry K 1.31 Ti 0.77 Nb 0.23 Si 0.91 .

[0086] Table 3

[0087]

[0088] Example 4

[0089] In a Teflon beaker, 45.70 g of KOH (87.3%) was dissolved in 87.07 g of deionized water under high speed Heidolph stirring and the resulting solution was stirred until it reached room temperature. To this solution, 35.42 g of Ludox AS-40 (SiO240%) was added by pipette under vigorous stirring and a clear solution was formed after homogenization for 45 minutes. To this clear solution, 2.85 g of hydrated Nb2O5powder (55.2% Nb) was added and allowed to mix for 1 hour, resulting in a smooth white suspension. Next, 28.97 g of Ti(OiPr)4(97%) was added by pipette while overhead stirring was continued. After stirring for an additional 25 minutes, the reaction mixture remained as a white opaque suspension. The reaction mixture was loaded into a 300 cc Parr stirred autoclave and stirred at 300 RPM under autogenous pressure at 175°C for 120 hours. The solid product was isolated by centrifugation, washed with deionized water and dried at 100°C. The powder X-ray diffraction pattern indicated that the titania-niobate had the titania-ferrihydrite topology. Representative diffraction lines are shown in Table 4 below. Elemental analysis indicated that the product had the stoichiometry K 1.06 Ti 0.86 Nb 0.14 Si 0.89 .

[0090] Table 4

[0091]

[0092]

[0093] Example 5

[0094] The Na + ion-exchanged version of the as-synthesized material was prepared as follows. 15 g of the as-synthesized Ti-silicate ferrihydrite material from Example 1 was added to 750 ml of 2 M NaCl solution, stirred at 75°C for 1.5 hours and isolated by filtration. This process was repeated two more times and the solid was washed with deionized water after the last exchange. After the final exchange, the solid was dried at 100°C. The powder X-ray diffraction pattern indicated that the ferrihydrite topology was retained in the ion-exchanged product. Representative diffraction lines are shown in Table 5 below. Elemental analysis showed that most of the K +has been removed, the resulting product has a stoichiometry of K 0.026 Na 0.80 TiSi 0.85 .

[0095] Table 5

[0096]

[0097] Example 6

[0098] The Ca 2+ exchanged product was obtained in the following manner. 11.5 g of as-synthesized Ti-silicate torberite material from Example 1 was added to 333 ml of 1 M CaCl2exchange solution and stirred at 85 °C for 1.5 hours and isolated by filtration. This process was repeated two more times and the solid was washed with deionized water after the last exchange. The final washed product was dried at 100 °C. The powder X-ray diffraction pattern indicated that the torberite topology was retained in the Ca 2+ exchanged product. Representative diffraction lines are shown in Table 6 below. Elemental analysis showed that most of the K + has been removed, the resulting product has a stoichiometry of K 0.13 Ca 0.47 TiSi 0.72 .

[0099] Table 6

[0100]

[0101] Example 7

[0102] The Na + exchanged ion exchanger was obtained in the following manner. 19.35 g of deionized water was treated with 1 M nitric acid to obtain a pH of 1.5. Then 2.15 g of ground Na + exchanged Ti-silicate torberite material from Example 5 was suspended in this solution. The suspension was further treated with 1 M nitric acid in a dropwise manner while monitoring the pH until the pH of the suspension was stable at 1.5 for 20 minutes. This pH stabilization required 9.43 g of 1 M nitric acid. The neutralized material was isolated by filtration, washed with deionized water and dried at 100 °C. The powder X-ray diffraction pattern indicated that the torberite topology was retained in the acid neutralized product. Representative diffraction lines are shown in Table 7 below. Elemental analysis gave a stoichiometry of K 0.027 Na 0.0.057 TiSi 0.81, indicating that most of the cations have been removed, leaving a product in the predominantly hydronium ion (H + ) exchanged form.

[0103] Table 7

[0104]

[0105]

[0106] Example 8

[0107] The Ca 2+ exchanged ion exchanger was obtained in the acid neutralized form by treating 22.50 g of deionized water with 1 M nitric acid to obtain a pH of 1.5. Then 2.50 g of the ground Ca 2+ exchanged Ti-silicate berlinite material was suspended in this solution. While monitoring the pH, the suspension was further treated with 1 M nitric acid in a dropwise fashion until the pH of the suspension stabilized at 1.5 for 20 minutes. This pH stabilization required 14.97 g of 1 M nitric acid. The neutralized material was isolated by filtration, washed with deionized water and dried at 100 °C. The powder X-ray diffraction pattern indicated that the berlinite topology was retained in the acid neutralized product. Representative diffraction lines are shown in Table 8 below. Elemental analysis gave the product stoichiometry as K 0.125 Ca 0.006 TiSi 0.92 , indicating that most of the cations have been removed, leaving a product in the predominantly hydronium ion (H + ) exchanged form.

[0108] Table 8

[0109]

[0110] Example 9

[0111] The as-synthesized product was obtained in its acid-exchanged form in a neutralization procedure carried out as a one-step acid treatment using nitric acid at room temperature. 180 g of the as-synthesized Ti-silicate torberite material from Example 2 was suspended in 1620 g of deionized water while stirring vigorously. The initial pH of the resulting slurry was 12.01. While monitoring the pH, aliquots of 1 M HNO3 totaling 26.92 g were added to the stirred slurry over the course of about 1 hour until the pH was reduced to and remained consistent in the range of 1.2 to 1.5. The slurry remained at this pH range for 30 minutes after addition, indicating that the pH had stabilized. The product was isolated by filtration, washed with 10 liters of deionized water, and dried at 100 °C. The effectiveness of this acid treatment to remove undesirable alkalinity from the sample was evaluated by checking the pH of a 1 : 1000 solid:deionized water (by weight) slurry before and after acid neutralization. The as-synthesized sample of Example 2 produced a pH of 10.91 in this test, which was reduced to a pH of 4.07 after acid treatment, a value more compatible with body fluids, particularly gastrointestinal fluids. Powder X-ray diffraction patterns indicated that the torberite topology was retained in the acid-treated product, representative diffraction lines are shown in Table 9 below. 0.195 TiSi 0.82 , indicating that most of the cations had been removed, leaving the product in the form of predominantly hydrated hydrogen ions (H + ) exchange.

[0112] Table 9

[0113]

[0114] Example 10

[0115] As shown in Example 9, in cases where it is desirable to adjust the pH of the ion exchanger to obtain compatibility, it is also desirable to have the ion exchanger in a suitable cationic form, which is typically dependent on the patient being treated. The Na + exchanged form of the acid-neutralized material from Example 9 was prepared in the following manner. 5 g of the acid-exchanged Ti-silicate torberite material from Example 9 was slurried in a solution prepared by dissolving 5 g of NaCl in 45 g of deionized water, stirred at 80 °C for 1.5 hours, and isolated by filtration. This process was repeated two more times and the solid was washed with deionized water after the last exchange. After the final exchange, the solid was dried at 100 °C. Powder X-ray diffraction patterns indicated that the torberite topology was retained in the Na + exchanged ion exchange product. Representative diffraction lines are shown in Table 10 below.

[0116] Table 10

[0117]

[0118] Example 11

[0119] Na + exchange form, in this case, Ca 2+ ion exchange form. 5 g of the acid exchanged Ti-silicate zeolite material from Example 9 was slurried in a solution (prepared by dissolving 5 g of CaCl2in 45 g of deionized water), stirred at 80 °C for 1.5 hours and isolated by filtration. This process was repeated two more times and the solid washed with deionized water after the last exchange. After the final exchange, the solid was dried at 100 °C. The powder x-ray diffraction pattern indicated that the sitinakite topology was retained in the Ca + exchanged ion exchange product. Representative diffraction lines are shown in Table 11 below.

[0120] Table 11

[0121]

[0122] Example 12

[0123] A solution was prepared by dissolving 3.90 g of NaOH (98%) pellets in 111.17 g of deionized water, stirring with a Heidolph stirrer until cool. With continued vigorous stirring, 2.39 g of Nb2O5powder (55.2% Nb) was added. After 15 minutes of continued vigorous stirring, 9.05 g of tetraethyl orthosilicate (98%) was added slowly by pipette. After 15 minutes of continued vigorous overhead stirring, 13.49 g of Ti(OiPr)4(28.0% as TiO2) was added to the reaction mixture by pipette, which immediately formed additional visible precipitate. The white reaction mixture was homogenized for an additional 15 minutes, then was divided into 45 ml Teflon-lined Parr reaction vessels which were digested under autogenous pressure at various conditions. The products were isolated by centrifugation, washed 3 times with deionized water, and dried in an oven at 100 °C overnight. The isolated products after digestion were characterized by x-ray diffraction and identified as sitinakite after 18 hours at 200 °C in a roller oven. Representative x-ray diffraction lines for the product are shown in Table 12. Elemental analysis gave the stoichiometry as Na 0.45 Nb 0.24 Ti 0.76 Si 0.55 .

[0124] Table 12

[0125]

[0126] Example 13

[0127] A solution was prepared by dissolving 29.07 g of NaOH (98%) pellets in 815.27 g of deionized water. With vigorous overhead stirring using a high speed mechanical stirrer, 49.13 g of colloidal silica (Ludox AS-40, 40% Si02) was added slowly but all at once. After about one hour of mixing, 106.53 g of Ti(OiPr)4(97%) was rapidly added to the colloidal translucent suspension via a single pour, which immediately formed a precipitate. The reaction mixture was homogenized for an additional 5 minutes and loaded into a Parr 2 L autoclave. The mixture was digested at 200 °C for 24 hours under autogenous pressure. The solid product was isolated by centrifugation, washed 3 times with deionized water, and dried in an oven at 100 °C overnight. The product was identified as a sitinakite by X-ray diffraction. Representative x-ray diffraction lines for the product are shown in Table 13. Elemental analysis provided the stoichiometry of the product as Na TM TiSi 0.83 TiSi 0.55 .

[0128] Table 13

[0129]

[0130] Example 14

[0131] A Nb-Ti sitinakite / parisite intergrowth was prepared according to Example 5 of US 5,935,552. X-ray diffraction indicated that the product was a sitinakite / parisite intergrowth. Elemental analysis provided the stoichiometry of the product as Na 0.58 TiSi 0.26 TiSi 0.81 TiSi 0.19 TiSi 0.63 .

[0132] Table 14

[0133]

[0134] Example 15

[0135] This is a method for preparing a titanate / sitinakite intergrowth adapted from Example 5 of US 5,932,552. A solution was prepared by dissolving 8.58 g of NaOH (98%) pellets and 4.02 g of KOH (87%) pellets in 342.4 g of deionized water with stirring. Next, 33.0 g of Ti(OiPr)4(97%) was added and stirred for 15 minutes. Then, 27.0 g of TEOS (98%) was added and stirred for 15 minutes. The resulting opaque gel was loaded into a 0.6 L stirred Parr reactor. The temperature of the reaction mixture was increased to 200°C over 4 hours and held for 72 hours with continuous stirring. The solid product was isolated by centrifugation, washed with deionized water, and dried at 90°C. Powder X-ray diffraction analysis indicated that the product was a sitinakite / titanate intergrowth. Representative diffraction lines for the product are shown in Table 15. Elemental analysis gave the product stoichiometry as Na 0.64 K 0.27 TiSi 0.81 .

[0136] Table 15

[0137]

[0138] Example 16: Removal of Pb from solution 2+ ions

[0139] The samples disclosed in Examples 1-15 were tested to determine their ability to selectively adsorb Pb 2+ ions from a solution that also contained essential electrolytes found in vivo, including Na, K, Mg, and Ca. The test solution was prepared by dissolving sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, and lead nitrate in a sodium acetate buffer solution. A 1 L sodium acetate buffer solution was prepared by dissolving 4.18 g of sodium acetate and 2.49 g of acetic acid in 1 L of deionized water. The buffer solution was used to maintain a constant pH of 4.7 during the test. The test solution was first analyzed by ICP to contain concentrations of 3000 ppm Na + , 300 ppm K + , 25 ppm Mg 2+ , 25 ppm Ca 2+ , and 200 ppb Pb 2+ or 15 ppm Pb 2+Any of the above. For this test, 100 mg of titanium silicate or titanium silicate- niobate toxic ironstone ion exchanger was placed in a 125 mL plastic bottle with 100 mL of test solution. The capped bottle was rolled at room temperature for 2 hours. Once the ion exchanger was in contact with the test solution for the desired amount of time, the solid / solution suspension was passed through a 0.2 μιη syringe filter to remove solids and then the solution was analyzed using ICP. The K d value for the distribution of metal between the solution and the solid was calculated using the following equation:

[0140]

[0141] Where: V = volume of waste mimic (mL)

[0142] Ac = concentration of cations adsorbed on the ion exchanger (g / mL)

[0143] W = mass of ion exchanger being evaluated (g)

[0144] Sc = concentration of cations in the supernatant after reaction (g / mL)

[0145] Table 16 below summarizes the results of the Pb 2+ uptake studies, giving the initial and final Pb 2+ concentrations and K d values. The ion exchangers disclosed in this application removed at least 50% of the Pb 2+ from the test solutions. The ion exchangers did not remove significant amounts of the supplemental essential electrolytes Na + , K + , Mg 2+ , or Ca 2+ .

[0146] Table 16

[0147]

[0148] Specific Embodiments

[0149] While the following is described in conjunction with the specific embodiments, it will be understood that it is intended to cover not only the descriptions but also the

[0150] A first embodiment of the present application is a method for removing Pb 2+ from a body fluid, the method comprising contacting a fluid containing a toxin with an ion exchanger to remove the toxin from the fluid by ion exchange between the ion exchanger and the body fluid, the crystalline metalate ion exchanger being selected from the group consisting of titanium silicate and niobate-titanium silicate or mixtures thereof, the metalate having the following empirical formula on an anhydrous basis:

[0151] Am Ti a Nb 1-a Si x O y

[0152] wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the molar fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the molar fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.5 to 7.38, and characterized in that the metal salt has a tavorite topological structure, a sitinakite topological structure, a paragenesis of both topological structures or mixtures thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing in the range of and between 4.80 and 5.20 A, a relative intensity of 100%, wherein when the material has a tavorite topological structure, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0153] Table A

[0154]

[0155] or wherein when the material has a sitinakite topological structure, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0156] Table B

[0157]

[0158] or wherein when the material is a tavorite-sitinakite paragenesis or a mixture of tavorite, sitinakite and tavorite-sitinakite paragenetic phases in any combination, the diffraction pattern has at least one peak with a d-spacing in the range of and between 4.80 and 5.20 A, a relative intensity of 100%, wherein when the material has a tavorite topological structure, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0159] Specific embodiments

[0160] One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein the body fluid is selected from the group consisting of: whole blood, plasma or other components of blood, gastrointestinal fluid, dialysate fluid, gastrointestinal fluid, and a dialysate solution containing blood, plasma, other components of blood, or gastrointestinal fluid. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein a = 1. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein a = 0.5. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein A is a hydrated hydrogen ion (H + ). One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein A is sodium. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein A is calcium. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein A is a mixture of calcium and sodium. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein A is a mixture of calcium, sodium, and a hydrated hydrogen ion (H + ). One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein the ion exchanger is packed into hollow fibers incorporated into a membrane. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein the ion exchanger is contained on particles coated with a coating comprising a cellulose derivative composition. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein the method is a hemoperfusion method, wherein the body fluid is passed through a column containing the ion exchanger. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein the dialysate solution is introduced into a peritoneal cavity and then flowed through at least one adsorbent bed containing at least one of the ion exchangers. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the first embodiment in this paragraph, wherein the ion exchanger is formed into a shaped article for oral ingestion, and then the ion exchanger is ingested by a mammal and the Pb 2+The toxins are ion exchanged between each other and then excreted with the ion exchanger containing the toxins. One embodiment of the present invention is one, any or all of the previous embodiments in this paragraph up to the first embodiment in this paragraph, wherein the shaped article is coated with a coating that is insoluble under gastric conditions.

[0161] A second embodiment of the present invention is a composition comprising a combination of a body fluid, a dialysate solution or a mixture of a body fluid and a dialysate solution, which composition further comprises an ion exchanger, the crystalline metalate ion exchanger being selected from titanium silicate and niobium-titanium silicate or mixtures thereof, the metalate having the following empirical formula on an anhydrous basis, respectively:

[0162] A m Ti a Nb 1-a Si x O y

[0163] wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydron ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the molar fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the molar fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that the metalate has a ferroromilite topology, a sitinakite topology, a paragenesis of both topologies or mixtures thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing in the range of and between 6.9 A and 7.1 A, a relative intensity of 100%, wherein when the material has a ferroromilite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0164] Table A

[0165]

[0166] or wherein when the material has a sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0167] Table B

[0168]

[0169] or wherein when the material is a parsettite-sitinakite intergrowth or a mixture of any combination of parsettite, sitinakite and parsettite-sitinakite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and and a relative density of 100%. One embodiment of the present invention is one, any or all of the preceding embodiments in this paragraph through the second embodiment in this paragraph, wherein the body fluid is whole blood, plasma, other blood components or gastrointestinal fluids.

[0170] A third embodiment of the present invention is a device comprising a matrix of a support material containing an ion exchanger, the crystalline metalate ion exchanger being selected from titanium silicate and niobium-titanium silicate or mixtures thereof, the metalate having on an anhydrous basis the empirical formula:

[0171] A m Ti a Nb 1-a Si x O y

[0172] wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydron ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the molar fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the molar fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that the metalate has a parsettite topology, a sitinakite topology, an intergrowth of these two topologies or mixtures thereof, exhibiting an x-ray diffraction pattern having at least one peak with a d-spacing between and and a relative density of 100%, wherein when the material has a parsettite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A:

[0173] Table A

[0174]

[0175] or wherein when the material has a sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B:

[0176] Table B

[0177]

[0178] or wherein when the material is a parsettite-sitinakite intergrowth or a mixture of any combination of parsettite, sitinakite, and parsettite-sitinakite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and a relative density of 100%.

[0179] One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the third embodiment in this paragraph, wherein the matrix comprises a porous network comprising a biocompatible polymer and a metal oxide and a silicate. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the third embodiment in this paragraph, wherein the biocompatible polymer comprises a cross-linked carbohydrate or a protein. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the third embodiment in this paragraph, wherein the biocompatible polymer is a polysaccharide selected from an alpha-glucan having 1,3-linkages, 1,4-linkages, or 1,6-linkages. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the third embodiment in this paragraph, wherein the biocompatible polymer is a carbohydrate selected from glucose, fructose, sucrose, maltose, arabinose, mannose, galactose, lactose, and oligomers and polymers comprising one or more of the carbohydrates. One embodiment of the application is one, any or all of the preceding embodiments in this paragraph up to the third embodiment in this paragraph, wherein the biocompatible polymer comprises a protein selected from albumin, ovalbumin, casein, myosin, actin, globulin, hemoglobin, myoglobin, gelatin, and small peptides.

[0180] While the application has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. It is therefore intended that whatever is described herein is to be considered merely in an illustrative sense and that the true scope of the application is to be determined by the appended claims, and that equivalents thereof are to be included within the scope of the appended claims. It is further intended that equivalents, modifications, and variations of the application as herein described are within the scope of the application.

[0181] In the foregoing, all temperatures are in degrees Celsius, and all parts and percentages are by weight, unless otherwise indicated.

Claims

1. Use of a crystalline metalate ion exchanger for the manufacture of a device for removing Pb 2+ toxins or mixtures thereof, said device bringing a body fluid containing said toxins into contact with said crystalline metalate ion exchanger to remove said toxins from said body fluid by ion exchange between said ion exchanger and said body fluid, said crystalline metalate being selected from titanium silicate and niobium-titanium silicate or mixtures thereof, said metalate having on an anhydrous basis the empirical formula: A m Ti a Nb 1-a Si x O y wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that, The metal salt has a toxic ferrite topology, a sitinakite topology, a paragenesis of both topologies or a mixture thereof, exhibits an x-ray diffraction pattern with at least one peak with a d-spacing between and 100%, wherein when the material has the toxic ferrite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A: Table A: Peaks and d-spacings of the toxic ferrite topology Table A or wherein when the material has the sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B: Table B or wherein when the material is a parsettensite-sitinakite intergrowth or a mixture of any combination of parsettensite, sitinakite and parsettensite-sitinakite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and a relative density of 100%.

2. The use of claim 1, wherein the body fluid is selected from the group consisting of: whole blood, plasma or other components of blood, gastrointestinal fluids, dialysate fluid, gastrointestinal fluids and dialysate solutions containing blood, plasma, other components of blood or gastrointestinal fluids.

3. The use of claim 1, wherein the crystalline metalate ion exchanger has the torbernite topology, the sitinakite topology or the topology of a torbernite and sitinakite intergrowth.

4. The use of claim 1, wherein the crystalline metalate ion exchanger is a composite consisting of a mixture of any combination of the torbernite, sitinakite, torbernite-sitinakite intergrowth topologies.

5. The use of claim 1, wherein a = 1.

6. Use according to claim 1, wherein A is a hydronium ion (H + ), calcium, sodium or mixtures thereof.

7. The use of claim 1, wherein the crystalline metalate ion exchanger is formed into a shaped article for oral ingestion, then ion-exchanges between the crystalline metalate ion exchanger and the Pb 2+ toxins contained in the gastrointestinal fluids contained in the mammal's intestines, and then excretes the crystalline metalate ion exchanger containing the toxins.

8. A composition comprising a combination of a body fluid, a dialysate solution or a mixture of the body fluid and the dialysate solution, the combination further comprising a crystalline metalate ion exchanger selected from the group consisting of titanium silicate and niobium-titanium silicate or mixtures thereof, the metalate having the empirical formula on an anhydrous basis: A m Ti a Nb 1-a Si x O y wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that, The metal salt has a toxic ferrite topology, a sitinakite topology, a paragenesis of both topologies or a mixture thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing between and 100%, wherein when the material has the toxic ferrite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A: Table A or wherein when the material has the sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B: Table B or wherein when the material is a parsettensite-sitinakite intergrowth or a mixture of any combination of parsettensite, sitinakite and parsettensite-sitinakite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and a relative density of 100%.

9. An apparatus for removing Pb from a body fluid 2+ toxins or mixtures thereof, the apparatus contacting a body fluid containing the toxins with the crystalline metalate ion exchanger to remove the toxins from the body fluid by ion exchange between the ion exchanger and the body fluid, the apparatus comprising a matrix containing a support material for the crystalline metalate ion exchanger, the crystalline metalate ion exchanger being selected from titanium silicate and niobium-titanium silicate or mixtures thereof, the metalate having the empirical formula on an anhydrous basis: A m Ti a Nb 1-a Si x O y wherein A is an exchangeable cation selected from lithium ion, potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, "m" is the molar ratio of A to total metal elements (total metal elements = Ti + Nb) and has a value of 0.10 to 2.0, "a" is the mole fraction of total metal elements that is Ti and has a value of 0.25 to 1, "1-a" is the mole fraction of total metal elements that is Nb and has a value of 0 to 0.75, wherein a + (1-a) = 1, "x" is the molar ratio of Si to total metal elements and has a value of 0.25 to 1.50, and "y" is the molar ratio of O to total metal elements and has a value of 2.55 to 7.38, and characterized in that, The metal salt has a toxic ferrite topology, a sitinakite topology, a paragenesis of both topologies or a mixture thereof, exhibits an x-ray diffraction pattern having at least one peak with a d-spacing between and a relative density of 100%, wherein when the material has the toxic ferrite topology, the diffraction pattern has at least the peaks and d-spacings listed in Table A: Table A: Peaks and d-spacings of the toxic ferrite topology Table A or wherein when the material has the sitinakite topology, the diffraction pattern has at least the d-spacings and intensities listed in Table B: Table B or wherein when the material is a parsettensite-sitinakite intergrowth or a mixture of any combination of parsettensite, sitinakite and parsettensite-sitinakite intergrowth phases, the diffraction pattern has at least one peak with a d-spacing between and a relative density of 100%.

10. The device of claim 9, wherein the matrix comprises a porous network containing a biocompatible polymer and metal oxides and silicates, wherein the biocompatible polymer comprises a cross-linked carbohydrate or protein.

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