Use of a zirconium silicate for the treatment of hyperkalemia

Description

STATE OF THE ART (i) Field of the Invention

[0001] The present invention relates to the use of novel microporous zirconium silicate compositions for the treatment of hyperkalemia, which are formulated to remove toxins, e.g., potassium ions or ammonium ions, from the gastrointestinal tract at an increased rate without causing undesirable side effects. Preferred formulations are designed to avoid the potential entry of particles into the bloodstream and the potential increase in urine pH in patients. These compositions are particularly useful in the therapeutic treatment of hyperkalemia. Also described are microporous zirconium silicate compositions having increased purity and potassium exchange capacity (KEC), and methods and devices for making such microporous zirconium silicate compositions.

(i) Description of the related technique

[0002] Acute hyperkalemia is a serious, life-threatening condition resulting from elevated serum potassium levels. Potassium is a ubiquitous ion involved in numerous processes in the human body. It is the most abundant intracellular cation and is critically important for numerous physiological processes, including maintenance of cell membrane potential, cell volume homeostasis, and transmission of action potentials. Major dietary sources include vegetables (tomatoes and potatoes), fruits (oranges, bananas), and meat. Normal plasma potassium levels are between 3.5-5.0 mmol/l, with the kidney being the main regulator of potassium levels. Potassium elimination in the kidney is passive (via the glomeruli) with active reabsorption in the proximal tubules and ascending limb of the loop of Henle. Active potassium secretion occurs in the distal tubules and collecting duct, both processes being controlled by aldosterone.

[0003] Increased extracellular potassium levels lead to a depolarization of the cell's membrane potential. This depolarization opens some voltage-gated sodium channels, but is not sufficient to generate an action potential. After a short period of time, the open sodium channels inactivate and become refractoriness, raising the threshold for generating an action potential. This leads to damage to the neuromuscular, cardiac, and gastrointestinal organ systems, and this damage is responsible for the symptoms seen with hyperkalemia. Of greatest concern is the effect on the cardiac system, where damage to cardiac conduction can lead to fatal cardiac arrhythmias such as asystole or ventricular fibrillation. Because of the potential for fatal cardiac arrhythmias, hyperkalemia represents an acute metabolic emergency that must be corrected promptly.

[0004] Hyperkalemia can develop when there is excessive production of serum potassium (oral intake, tissue breakdown). Inefficient elimination, which is the most common cause of hyperkalemia, may be hormonal (as with aldosterone), pharmacological (treatment with ACE inhibitors or angiotensin receptor blockers), or, more commonly, due to decreased renal function or advanced heart failure. The most common cause of hyperkalemia is renal failure, and there is a close correlation between the degree of renal failure and serum potassium (SKP) levels. In addition, a large number of different commonly used drugs cause hyperkalemia, such as ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics (e.g., amiloride, spironolactone), NSAIDs (such as ibuprofen, naproxen, celecoxib), heparin, and certain cytotoxic and/or antibiotic drugs (such as cyclosporine and trimethoprim). Finally, beta-blockers, digoxin, or succinylcholine are other well-known causes of hyperkalemia. In addition, advanced stages of congestive heart disease, massive trauma, burns, or intravascular hemolysis cause hyperkalemia, as well as metabolic acidosis, most often as part of diabetic ketoacidosis.

[0005] Symptoms of hyperkalemia are somewhat nonspecific and generally include weakness, palpitations, and muscle weakness or signs of cardiac arrhythmia, such as palpitations, bradytachycardia, or dizziness/fainting. Often, however, hyperkalemia is discovered during routine blood tests for a medical condition or after serious complications, such as cardiac arrhythmias or sudden death, have developed. The diagnosis is apparently made by measuring the ECG.

[0006] Treatment depends on the SCC level. In mild cases (SCC between 5-6.5 mmol/l), acute treatment with a potassium-binding resin (Kayexalate®), combined with dietary advice (low-potassium diet) and possible modification of drug treatment (if treated with drugs that cause hyperkalemia) is the standard of care; if SCC is above 6.5 mmol/l or if arrhythmias are present, urgent potassium lowering and careful monitoring in hospital are required. The following treatments are commonly used:

• Kayexalate®, a potassium-binding resin in the intestine that increases fecal excretion, thereby reducing SK levels. However, Kayexalate® has been shown to cause intestinal obstruction and potential rupture. Furthermore, diarrhea must be induced simultaneously with treatment. These factors have reduced the appeal of Kayexalate® treatment.

• Insulin IV (+ glucose to prevent hypoglycemia), which moves potassium into the cells and away from the blood.

• Calcium supplementation. Calcium does not reduce SC, but it reduces myocardial excitability and thus stabilizes the myocardium, reducing the risk of cardiac arrhythmias.

• Bicarbonate. The bicarbonate ion will stimulate the exchange of K+ for Na+, which leads to stimulation of the sodium-potassium ATPase.

• Dialysis (in severe cases).

[0007] The only pharmacological modality that actually increases potassium elimination from the body is Kayexalate®; however, due to the need to induce diarrhea, Kayexalate® cannot be administered on a chronic basis, and even in the acute setting, the need to induce diarrhea, combined with only marginal efficacy and a foul odor and taste, limit its usefulness.

[0008] The use of microporous zirconium silicate or titanium silicate ion exchangers for removing toxic cations and anions from blood or dialysate is described in U.S. Patent Nos. 6,579,460, 6,099,737, and 6,332,985. Additional examples of microporous ion exchangers are found in U.S. Patent Nos. 6,814,871, 5,891,417, and 5,888,472. WO 02/062356 describes compounds and methods for treating patients exhibiting high serum toxin levels, particularly using zirconium silicate sorbents.

[0009] Borun et al. ("Hydrothermal Synthesis of Sodium Zirconium Silicates and Characterization of Their Properties", Chem. Mater. 1997, 9, 1856-1864) discloses data on a large number of sodium zirconium silicates formed under hydrothermal conditions (180-190°C).

[0010] Navascues et al. (“Reconstruction of umbite framework variants by atomistic simulations using XRD and sorption data”, Chemical Engineering and Processing, 47, (2008), 1139-1149) discloses the synthesis and characterization of Zr-umbite, Sn-umbite and Ti-umbite crystals using experimental and simulation techniques.

[0011] Anonymous ("Catapleiite Mineral Data", retrieved from the Internet: URL:https://web.archive.org/web/20020811184524/http://www.webmineral.com:80/data/ Catapleiite.shtml [retrieved 2018-02-06]) discloses and characterizes a catapleiite crystal.

[0012] Anonymous („Mineralienatlas Eexikon - Kataple“, Retrieved from the Internet:

URL:https://www.mineralienatlas.de/lexikon/index.php/MineraiData? minerai=Katapleit [retrieved on 201802-06]) discloses and characterizes various catapleitite crystals.

[0013] The inventors have discovered that known zirconium silicate compositions may exhibit adverse effects when used in vivo for potassium removal in the treatment of hyperkalemia. Specifically, the use of zirconium silicate molecular sieves has been associated with an increased incidence of mixed leukocytic inflammation, minimal acute bladder inflammation, and the observation of unidentified crystals in the renal pelvis and urine in animal studies, as well as an increase in urine pH. Furthermore, known zirconium-silicate compositions have had problems with crystalline impurities and an undesirably low cation exchange capacity.

[0014] The inventors have discovered novel molecular sieves of zirconium silicate to solve the problems associated with existing hyperkalemia treatments and new methods of treating hyperkalemia using these novel compositions.

SUMMARY OF THE INVENTION

[0015] The invention relates to a composition for use in the treatment of hyperkalemia, as defined in the appended claims.

[0016] The molecular sieves of zirconium silicate and zirconium germanate have a microporous structure composed of ZrO, an octahedral unit and at least one S1O2 tetrahedral unit and a GeCE tetrahedral unit. These molecular sieves have the empirical formula:

ApM_xMr._xSynGeyOm (I) where A is a replaceable cation selected from potassium ion, sodium ion, methylene ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, M is at least one metal framework selected from the group consisting of hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+) and terbium (4+), "p" has a value from 1 to 20, "x" has a value from 0 to less than 1, "n" has a value from 0 to 12, "y" has a value from 0 to 12, "m" has a value from 3 to 36 and 1 < n + y < 12. Germanium can replace silicon, zirconium, or combinations thereof. Since the preparations are essentially insoluble in body fluids (at neutral or basic pH), they can be ingested orally to remove toxins in the gastrointestinal system.

[0017] The zirconium silicate of formula (I) exhibits a mean particle size greater than 3 microns and less than 7% of the particles in the composition have a diameter less than 3 microns. Preferably, less than 5% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 4% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 3% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 2% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 1% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 0.5% of the particles in the composition have a diameter of less than 3 microns. Most preferably, none of the particles or only traces have a diameter smaller than 3 microns.

[0018] The mean and average particle size is preferably greater than 3 microns, and particles as large as 1000 microns are possible for certain applications. Preferably, the mean particle size is in the range of 5 to 1000 microns, more preferably 10 to 600 microns, more preferably 15 to 200 microns, and most preferably 20 to 100 microns.

[0019] The zirconium silicate of formula (I) exhibits a mean particle size and particle fragment size in the composition having a diameter of less than 3 microns, as described above, also exhibiting a sodium content below 12% by weight. Preferably, the sodium content is below 9% by weight, more preferably the sodium content is below 6% by weight, more preferably the sodium content is below 3% by weight, more preferably the sodium content is in the range of 0.05 to 3% by weight, and most preferably 0.01% or less by weight, or as low as possible.

[0020] In one embodiment, the invention includes a pharmaceutical product comprising the composition in the form of a capsule or tablet.

[0021] In one embodiment, a molecular sieve is provided that has an increased cation exchange capacity, particularly potassium exchange capacity. The increased cation exchange capacity is achieved by a specialized process and reactor configuration that lifts and more thoroughly suspends the crystals during the reaction. In one embodiment of the present invention, the UZSi-9 crystals had a potassium exchange capacity of greater than 2.5 meq/g, more preferably greater than 3.5 meq/g, more preferably greater than 4.0 meq/g, more preferably between 4.3 and 4.8 meq/g, more preferably between 4.4 and 4.7 meq/g, and most preferably about 4.5 meq/g. UZSi-9 crystals having a potassium exchange capacity in the range of 3.7-3.9 were produced according to Example 13 below.

[0022] The compositions of the present invention are used in the treatment of hyperkalemia, which comprises administering the composition to a patient in need thereof. The dosage administered may vary, depending on whether the treatment is for chronic or acute hyperkalemia. The dosage for the treatment of acute hyperkalemia is higher than that for the treatment of chronic hyperkalemia. For the treatment of acute hyperkalemia, the dosage is preferably in the range of about 0.7 to 1,500 mg/kg/day, more preferably about 500 to 1,000 mg/kg/day, and most preferably about 700 mg/kg/day. A typical daily dosage for the treatment of acute hyperkalemia, depending on the potassium exchange capacity, in a human will range from about 50 mg to 60 g per day, more preferably about 1 mg to 30 g per day, more preferably 3 to 9 g per day, and most preferably about 3 g per day. For the treatment of chronic hyperkalemia, the dosage is preferably in the range of 0.25 to 100 mg/kg/day, more preferably 10 to 70 mg/kg/day, and most preferably about 50 mg/kg/day. A typical daily dosage for the treatment of chronic hyperkalemia in a human patient ranges from about 0.020 to 10 g per day, more preferably 0.1 to 1 g per day, and most preferably about 0.5 g per day.

[0023] For higher KEC compositions, the dosage will usually be lower due to the increased efficacy of the composition in lowering the potassium level in the patient. For the treatment of acute hyperkalemia, the dosage preferably ranges from about 0.7 to 800 mg/kg/day, more preferably from about 280 to 500 mg/kg/day, and most preferably about 390 mg/kg/day. A typical daily dose for the treatment of acute hyperkalemia, depending on the potassium exchange capacity, in a human will range from about 50 mg to 33 g per day, more preferably from about 1 mg to 30 g per day, more preferably 3 to 9 mg per day. g per day, and most preferably about 3 g per day. For the treatment of chronic hyperkalemia, the dose is preferably in the range of 0.25 to 55 mg/kg/day, more preferably from 5 to 40 mg/kg/day, and most preferably about 30 mg/kg/day. A typical daily dose for the treatment of chronic hyperkalemia in a human patient ranges from about 0.020 to 5 g per day, more preferably from 0.05 to 0.7 g per day, and most preferably about 0.5 g per day.

[0024] Compositions according to the invention can be prepared by subjecting a zirconium silicate composition as described above to screening or a combination of screening and process ion exchange, as described further herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025]

Figure 1 is a polyhedral drawing showing the structure of microporous zirconium silicate Na₂ i₉ZrSi₃ oh0₉ n.«2.71H₂O (MW 420.71)

Figure 2 shows the particle size distribution of ZS-9 series 5332-04310-A ​​according to Example 8.

Figure 3 shows the particle size distribution of ZS-9 series 5332-15410-A according to Example 8.

Figure 4 shows the particle size distribution of ZS-9 from a preclinical batch according to Example 8.

Figure 5 shows the particle size distribution of batch 5332-04310A without checking according to Example 9.

Figure 6 shows the particle size distribution of the 5332-04310A 635 mesh series according to Example 9.

Figure 7 shows the particle size distribution of the 5332-04310A 450 mesh series according to Example 9.

Figure 8 shows the particle size distribution of the 5332-04310A 325 mesh series according to Example 9.

Figure 9 shows the particle size distribution of batch 5332-04310A 230 according to Example 9.

Figure 10: XRD pattern for ZS-9 prepared according to Example 12.

Figure 11: FTIR diagram for ZS-9 prepared according to Example 12.

Figure 12: XRD pattern for ZS-9 prepared according to Example 13.

Figure 13: FTIR diagram for ZS-9 prepared according to Example 13.

Figure 14: Example of a chromatogram of a blank solution

Figure 15: Example of a chromatogram of a standard solution for testing.

Figure 16: Example of a sample chromatogram.

Figure 17: Reaction vessel with standard stirring device.

Figure 18: Reaction vessel with grooves for the production of reinforced ZS-9

Figure 19: Detail of the groove design for a 200-L reaction vessel for the production of enhanced ZS-9

DETAILED DESCRIPTION OF THE INVENTION

[0026] The inventors have discovered novel molecular sieve absorbers with zirconium silicate that solve the problems of adverse effects in the therapeutic use of molecular sieve absorbers, for example, in the treatment of hyperkalemia. Zirconium silicate has a microporous framework structure composed of ZrO₂ octahedral units and SiO₂ tetrahedral units. Figure 1 is a polyhedral drawing showing the structure of microporous zirconium silicateNa₂ i₉ZrSi₃ oh0₉ n.*2.71H₂O (MV 420.71) Dark polygons represent octahedral zirconium oxide units, while light polygons represent tetrahedral silica units. Cations are not shown in Figure 1.

[0027] The microporous exchanger of the invention has a high capacity and a strong affinity, i.e., selectivity, for potassium or ammonium. Eleven types of zirconium silicates are available, UZSi-1 through UZSi-11, each of which has developed different affinities for the ions. See, e.g., U.S. Patent No. 5,891,417. UZSi-9 (otherwise known as ZS-9) is a particularly effective zirconium silicate absorber for absorbing potassium and ammonia. These zirconium silicates have the empirical formula:

ApM_xMr._xAnd_nGe_andOm (I) where A is a replaceable cation selected from potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, M is at least one metal framework selected from the group consisting of hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+) and terbium (4+), "p" has a value of about 1 to about 20, "x" has a value of 0 to less than 1, "n" has a value of about 0 to about 12, "y" has a value of 0 to about 12, "m" has a value of about 3 to about 36, and 1 < n + y < 12. Germanium may replace silicon, zirconium, or combinations thereof. It is preferred that x and y be zero, or both tend to zero, since germanium and other metals are often present in trace amounts. Since the preparations are essentially insoluble in body fluids (at neutral or basic pH), they can be ingested orally to remove toxins from the gastrointestinal system.

[0028] Zirconium metals are prepared by hydrothermal crystallization of a reaction mixture obtained by combining a reactive source of zirconium, silicon and/or germanium, optionally one or more M metals, at least one alkali metal, and water. The alkali metal acts as a templating agent. Any zirconium compound that can be hydrolyzed to zirconium oxide or zirconium hydroxide can be used. Specific examples of these compounds include zirconium alkoxides, for example, zirconium n-propoxide, zirconium hydroxide, zirconium acetate, zirconium oxychloride, zirconium chloride, zirconium phosphate and zirconium oxynitrate. Sources of silica include colloidal silica, fumed silica and sodium silicate. Sources of germanium include germanium oxide, germanium alkoxides and germanium tetrachloride. Alkaline sources include potassium hydroxide, sodium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, sodium halide, potassium halide, rubidium halide, cesium halide, sodium ethylenediamine tetraacetate (EDTA), potassium EDTA, rubidium EDTA, and cesium EDTA. Sources of M metals include metal oxides, alkoxides, halide salts, acetate salts, nitrate salts, and sulfate salts. Specific examples of M-source metals include, but are not limited to, titanium alkoxides, titanium tetrachloride, titanium trichloride, titanium dioxide, tin tetrachloride, tin isopropoxide, niobium isopropoxide, hydrous niobium oxide, hafnium isopropoxide, hafnium chloride, hafnium oxychloride, cerium chloride, cerium oxide, and cerium sulfate.

[0029] Generally, the hydrothermal process used to prepare the zirconium metallate or titanium metallate ion exchanger compositions of the present invention involves forming a reaction mixture which is expressed in terms of molar oxide ratios by the formulas:

aA₂O: b MO₄ 2:1 -bZrO2:CS1O2:dGeCE:eEEO where "a" has a value of about 0.25 to about 40, "b" has a value of about 0 to about 1, "x" is the valence of M, "c" has a value of about 0.5 to about 30, "d" has a value of about 0 to about 30 and "e" has a value of 10 to about 3000. The reaction mixture is prepared by mixing the desired sources of zirconium, silicon and optionally germanium, an alkali metal and an optional M metal in any order to obtain the desired mixture. It is also necessary that the mixture has a basic pH and preferably a pH of at least 8. The basicity of the mixture is controlled by adding an excess of alkali hydroxide and/or basic compounds of other ingredients of the mixture. After the reaction mixture is formed, it is then reacted at a temperature of about 100°C to about 250°C for a period of about 1 to about 30 days in a closed reaction vessel under autogenous pressure. After the time has elapsed, the mixture is filtered to separate the solid product, which is washed with deionized water, acid or dilute acid, and dried. A number of drying techniques can be used, including vacuum drying, pan drying, and fluidized bed drying. For example, the filtered material can be dried in an air oven under vacuum.

[0030] To provide ready reference, the different types of zirconium silicate molecular sieves and zirconium germanate molecular sieves have been given the arbitrary designation UZSi-1 where “1” represents the framework structure of type “1”. That is, one or more zirconium silicate and/or zirconium nemetate molecular sieves with different empirical formulas may have the same type of structure.

[0031] The X-ray patterns shown in the following examples were obtained using standard X-ray diffraction techniques and are described in U.S. Patent No. 5,891,417. The radiation source was a high-intensity X-ray tube operating at 45 Kv and 35 ma. The diffraction pattern of the K-alpha radiation was obtained by appropriate computer techniques. The flat samples of compressed powder were continuously scanned at 2°(20) per minute. The interplanar spacings (d) in Angstroms are obtained from the positions of the diffraction peaks expressed as 2Θ, where θ is the Bragg angle as observed from the digitized data. The intensities are determined from the integrated area of ​​the diffraction peaks after background subtraction, "1" being the intensity of the strongest line or peak, and "1" being the intensity of every other peak.

[0032] As will be appreciated by those skilled in the art, the determination of parameter 28 is subject to both human and mechanical error, which in combination can impose an uncertainty of about ± 0.4 on each reported value of 20. This uncertainty is, of course, also manifested in the reported d-spacing values, which are calculated from the 0 value. This imprecision is general throughout the system and is not sufficient to prevent the subject crystalline materials from being distinguished from each other, nor from prior art compositions. In some reported X-ray patterns, the relative d-spacing intensities are designated by the notations vs, s, miw, which represent very strong, strong, medium and weak. In terms of 100xI/I_the The above labels are defined as w=0-15; m=15-60; s=60-80 and vs=80-100.

[0033] In certain cases, the purity of a synthesized product can be assessed by reference to its X-ray powder diffraction pattern. Thus, for example, if a sample is listed as pure, the intention is only that the X-ray pattern of the sample be free of lines attributable to crystalline impurities, not that there are no amorphous materials present.

[0034] The crystalline compositions of the present invention can be characterized by their powder X-ray diffraction patterns, and such may have one of the X-ray patterns having the d-spacings and intensities listed in the following tables. The X-ray pattern for ZS-11 as disclosed in U.S. Patent No. 5,891,417 is as follows:

<td colspan="2">Table 1 - UZSi-11</td>

<td>d(A)</td><td>I</td>

<td> 6,0-6,8</td><td>w-m</td>

<td> 5,5-6,3</td><td>m</td>

<td> 5,4-6,2</td><td>vs</td>

<td> 5,2-6,0</td><td>m</td>

<td> 2,7-3,5</td><td>s</td>

<td> 2,5-3,3</td><td>m</td>

The X-ray diffractogram for high purity, high KEC ZS-9, as made according to Example 13 (XRD shown in Figure 13), had the following d-spacing and intensity characteristics:

<td colspan="2">Table 2 - UZSi-9</td>

<td>d(A)</td><td>I</td>

<td> 5,9-6,7</td><td>m</td>

<td> 5,3-6,1</td><td>m-s</td>

<td> 2,7-3,5</td><td>vs</td>

<td> 2,0-2,8</td><td>w-m</td>

<td> 1,6-2,4</td><td>In</td>

[0035] The formation of zirconium silicate involves the reaction of sodium silicate and zirconium acetate in the presence of sodium hydroxide and water. The reaction is typically carried out in small reaction vessels on the order of 1-5 gallons. Smaller reaction vessels have been used to produce various crystalline forms of zirconium silicate including ZS-9. The inventors have recognized that ZS-9 produced in these smaller reactors had inadequate or undesirably low cation exchange capacity (CEC).

[0036] The inventors have discovered that the use and proper positioning of a groove-like structure relative to the stirrer in the crystallization vessel produces a UZSi-9 crystal that exhibits crystal purity (as demonstrated by XRD and FTIR spectra) and an unexpectedly high potassium exchange capacity. In smaller scale reactors (5 gal), cooling coils are placed inside the reactor to provide the groove-like structure. Cooling coils are not used for heat exchange. Several types of cooling coils are available and different designs may have some effect on the results shown here, but the inventors used snake-type coils that coil along the inner wall of the reactor vessel.

[0037] The inventors have discovered that the crystallization reaction used to produce UZSi-9 particularly benefits from grooves that are properly positioned relative to the stirrer. The inventors initially produced UZSi-9 with known levels of the unwanted impurity UZSi-11. See Figures 10-11. It is believed that this incomplete reaction is the result of significant amounts of solids remaining near the bottom of the reaction vessel. These solids remain near the bottom of the vessel even with conventional stirring. When properly positioned, the grooves and stirrer improve the reaction conditions by creating forces within the reactor that lift the crystals in the vessel, providing the necessary heat transfer and mixing to produce the high-purity UZSi-9 form. Figures 11-12 show the XRD and FTIR spectra of high-purity UZSi-9 crystals. As shown in Table 3 below, these crystals exhibit significantly higher levels of potassium exchange capacity (KEC) than the less pure ZS9 compositions. In one embodiment of the present invention, the UZSi-9 crystals had a potassium exchange capacity of greater than 2.5 meq/g, more preferably greater than 3.5 meq/g, more preferably greater than 4.0 meq/g, more preferably between 4.3 and 4.8 meq/g, more preferably between 4.4 and 4.7 meq/g, and most preferably about 4.5 meq/g. UZSi-9 crystals having a potassium exchange capacity in the range of 3.7-3.9 were produced according to Example 13 below.

[0038] Another unexpected benefit that has arisen from the use of a standard stirred reactor in combination with the troughs is that ZS-9 crystals of high crystal purity, with a high potassium exchange capacity, can be produced without the use of seed crystals. Previous attempts to produce homogeneous crystals having high crystal purity of a single crystal form have used seed crystals. The ability to eliminate the use of a seed crystal is therefore an unexpected improvement over previous methods.

[0039] As noted, the microporous compositions of the present invention have a framework structure of octahedral ZrOs units, at least one of a tetrahedral S1O2 unit and a tetrahedral OeOgj unit, and optionally an octahedral MOz unit. This framework results in a microporous structure that has an intracrystalline pore system with uniform pore diameters, i.e., the pore sizes are crystallographically regular. The pore diameters can vary considerably from about 3 angstroms and above.

[0040] As synthesized, the microporous compositions of the present invention will contain some alkali metal agents in the pores. These metals are described as exchangeable cations, meaning that they can be exchanged with other (secondary) A' cations. Generally, the exchangeable cations can also be exchanged with A' cations selected from other alkali metal cations (K⁺, That⁺, Rb⁺, Cs⁺), alkaline earth metal cations (Mg²⁺, As²⁺, Sr²⁴, No²⁺), hydronium ions or mixtures thereof. It is understood that the A' cation is distinct from the A cation. The methods used to exchange one cation for another are well known in the art and involve contacting the microporous compositions with a solution containing the desired cation (usually in molar excess) under exchange conditions. Typically, the exchange conditions involve a temperature of from about 25°C to about 100°C and a time of from about 20 minutes to about 2 hours. The use of ion exchange water to replace sodium ions with hydronium ions can require a longer time, from eight to ten hours. The specific cation (or mixture of cations) present in the final product will depend on the particular application and the specific composition used. One particular composition is an ion exchanger where the A' cation is a mixture of Na⁺, As⁺² i H⁺ June.

[0041] When ZS-9 is formed according to these processes, it can be obtained in the form of Na-ZS-9. The sodium content of Na-ZS-9 is approximately 12 to 13% by weight when the production process is carried out at a pH greater than 9. Na-ZS-9 is unstable in hydrochloric acid (HCl) concentrations above 0.2 M at room temperature, and will undergo structural collapse after overnight exposure. While ZS-9 is slightly stable in 0.2 M HCl at room temperature, at 37°C the material rapidly loses crystallinity. At room temperature, Na-ZS-9 is stable in solutions of 0.1 M HCl and/or pH between approximately 6 to 7. Under these conditions, the Na level was reduced from 13% to 2% after overnight treatment.

[0042] The conversion of Na-ZS-9 to H-ZS-9 can be achieved by a combination of a water washing process and an ion exchange process, i.e., ion exchange using a dilute strong acid, e.g., 0.1 M HCl, or a water wash. The water wash will lower the pH and protonate a significant fraction of the zirconium silicate, thereby reducing the weight fraction of Na in the zirconium silicate. It may be desirable to perform an initial ion exchange in a strong acid using higher concentrations, as long as protonation of the zirconium silicate effectively keeps the pH from dropping to levels at which the zirconium silicate decomposes. Additional ion exchange can be achieved by rinsing in water or dilute acids to further reduce the sodium level in the zirconium silicate. Zirconium silicate made in accordance with the present invention exhibits a sodium content below 12% by weight. Preferably, the sodium content is below 9% by weight, more preferably the sodium content is below 6% by weight, more preferably the sodium content is below 3% by weight, more preferably the sodium content is in the range of 0.05 to 3% by weight, and most preferably 0.01% or below % by weight, or as low as possible.

[0043] An ion exchanger in the sodium form, for example, Na-ZS-9, is effective in removing excess potassium ions from the gastrointestinal tract of a patient in the treatment of hyperkalemia. When administered to a patient in the sodium form, hydronium ions replace sodium ions on the exchanger, resulting in an undesirable increase in pH in the stomach and gastrointestinal tract of the patient. In in vitro testing, it takes about twenty minutes in acid to stabilize the sodium ion exchanger.

[0044] The hydronium form typically has equivalent efficacy to the sodium form for removing potassium ions in vivo while avoiding some of the disadvantages of the sodium form related to changes in pH in the patient's body. For example, the hydrogenated form has the advantage of avoiding excessive release of sodium into the body after administration. This may alleviate edema resulting from excessive sodium levels, particularly when used in the treatment of acute conditions. Furthermore, patients receiving hydronium form for the treatment of chronic conditions will benefit from lower sodium levels, particularly in patients at risk of congestive heart failure. Furthermore, it is believed that the hydronium form will have the effect of avoiding an undesirable increase in the pH of the patient's urine.

[0045] ZS-9 crystals have a broad particle size distribution. It is theorized that small particles, less than 3 microns in diameter, could potentially be absorbed into the patient's bloodstream, resulting in adverse effects such as particle accumulation in the patient's urinary tract, and particularly in the patent's renal system. Commercially available zirconium silicates are manufactured in a manner that filters out some of the particles below 1 micron. However, it was discovered that small particles were retained in the filter cake, and that the elimination of particles smaller than 3 microns in diameter required the use of additional screening techniques.

[0046] The inventors have discovered that screening can be used to remove particles having a diameter of less than 3 microns and that the removal of such particles is useful for therapeutic products containing zirconium silicate compositions of the invention. Many particle screening techniques can be used to achieve the objectives of the invention, including hand screening, air jet screening, sieving or filtering, flotation, or any other known means of particle classification. Zirconium silicate compositions that have been subjected to screening techniques exhibit a desirable particle size distribution that avoids potential complications involving the therapeutic use of zirconium silicates. In general, the particle size distribution is not critical, as long as excessively small particles are removed. The zirconium silicate of formula (I) of the present invention exhibits a mean particle size greater than 3 microns, and less than 7% of the particles in the composition have a diameter less than 3 microns. Preferably, less than 5% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 4% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 3% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 2% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 1% of the particles in the composition have a diameter of less than 3 microns, more preferably less than 0.5% of the particles in the composition have a diameter of less than 3 microns. Most preferably, none of the particles or only traces have a diameter smaller than 3 microns. The median particle size is preferably greater than 3 microns and particles reaching sizes of 1000 microns are possible for certain applications. Preferably, the median particle size is in the range of 5 to 1000 microns, more preferably 10 to 600 microns, more preferably 15 to 200 microns, and most preferably 20 to 100 microns.

[0047] Particle screening may be performed before, during, or after the ion exchange process, as described above, where the sodium content of the zirconium silicate material is reduced to below 12%. The reduction of the sodium content to below 3% may occur in several steps in conjunction with the screening, or may occur entirely before or after the screening step. Particles having a sodium content below 3% may be effective with or without particle size screening, as described herein.

[0048] In addition to screening or sieving, the desired particle size distribution can be achieved by using granulation or other agglomeration techniques to produce particles of the appropriate size.

[0049] It is also within the scope of the invention that these microporous ion exchanger compositions can be used in powder form or can be formed into various shapes by methods well known in the art. Examples of these various shapes include pellets, extrudates, spheres, pellets and irregularly shaped particles.

[0050] As noted, these compositions have particular utility in the adsorption of various toxins from fluids selected from body fluids, dialysate solutions, and mixtures thereof. As used herein, body fluids will include, but are not limited to, blood and gastrointestinal fluids. By body is meant any mammalian body, including, but not limited to, humans, cows, pigs, sheep, monkeys, gorillas, horses, dogs, etc. The current process is particularly suitable for removing toxins from the human body.

[0051] Zirconium metals can be formed into pills or other forms that can be taken orally and collect toxins in the gastrointestinal fluid as the ion exchanger passes through the intestines and is ultimately excreted. To protect the ion exchangers from the high acidity of the stomach, the shaped objects can be coated with various coatings that do not dissolve in the stomach, but dissolve in the intestines.

[0052] As also noted, although the present compositions are synthesized with various exchangeable cations ("A"), it is desirable to exchange the cation with secondary cations (A¹) that are more compatible with the blood or do not adversely affect the blood. For this reason, the preferred cations are sodium, calcium, hydronium, and magnesium. Preferred compositions are those containing sodium and calcium ions or sodium, calcium, and hydronium ions. The relative amounts of sodium and calcium can vary considerably and depend on the micropore composition and the concentration of these ions in the blood. As discussed above, when sodium is a replaceable cation, it is desirable to replace sodium ions with hydronium ions, thereby reducing the sodium content of the composition.

[0053] The compositions of the present invention are used in the treatment of hyperkalemia, which comprises administering the composition to a patient in need thereof. The dosage administered may vary, depending on whether the treatment is for chronic or acute hyperkalemia. The dosage for the treatment of acute hyperkalemia is higher than that for the treatment of chronic hyperkalemia. For the treatment of acute hyperkalemia, the dosage is preferably in the range of about 0.7 to 1,500 mg/kg/day, more preferably about 500 to 1,000 mg/kg/day, and most preferably about 700 mg/kg/day. A typical daily dosage for the treatment of acute hyperkalemia, depending on the potassium exchange capacity, in a human will range from about 50 mg to 60 g per day, more preferably about 1 mg to 30 g per day, more preferably 3 to 9 mg per day. g per day, and most preferably about 3 g per day. For the treatment of chronic hyperkalemia, the dosage is preferably in the range of 0.25 to 100 mg/kg/day, more preferably 10 to 70 mg/kg/day, and most preferably about 50 mg/kg/day. A typical daily dosage for the treatment of chronic hyperkalemia in a human patient ranges from about 0.020 to 10 g per day, more preferably 0.1 to 1 g per day, and most preferably about 0.5 g per day.

[0054] For higher KEC compositions, the dosage will usually be lower due to the increased efficacy of the composition in lowering the potassium level in the patient. For the treatment of acute hyperkalemia, the dosage preferably ranges from about 0.7 to 800 mg/kg/day, more preferably from about 280 to 500 mg/kg/day, and most preferably about 390 mg/kg/day. A typical daily dose for the treatment of acute hyperkalemia, depending on the potassium exchange capacity, in a human will range from about 50 mg to 33 g per day, preferably from about 1 mg to 30 g per day, preferably 3 to 9 g per day, and most preferably about 3 g per day. For the treatment of chronic hyperkalemia, the dose is preferably in the range of 0.25 to 55 mg/kg/day, more preferably from 5 to 40 mg/kg/day, and most preferably about 30 mg/kg/day. A typical daily dose for the treatment of chronic hyperkalemia in a human patient ranges from about 0.020 to 5 g per day, more preferably from 0.05 to 0.7 g per day, and most preferably about 0.5 g per day.

[0055] In order to more fully illustrate the invention, the following examples are set forth. It is to be understood that the examples are for illustrative purposes only and are not intended to unduly limit the broad scope of the invention as set forth in the appended claims.

REFERENCE EXAMPLE 1

[0056] The solution was prepared by mixing 2058 g of colloidal silica (DuPont Corp, identified as Ludox™ AS-40), 2210 g of KOH in 7655 g of H2O. After several minutes of vigorous mixing, 1471 g of zirconium acetate solution (22.1% by weight ZrO2) was added. This mixture was mixed for another 3 minutes and the resulting gel was transferred to a stainless steel reactor and hydrothermally reacted for 36 hours at 200°C. The reactor was cooled to room temperature and the mixture was filtered under vacuum to isolate solids which were washed with deionized water and air dried.

[0057] The solid reaction product was analyzed and found to contain 21.2 wt% Si, 21.5 wt% Zr, 20.9 wt% K, loss on ignition (LOI) 12.8 wt%, giving the formula K2 3ZrSi3 2O9 5*3.7H2O. This product was identified as sample A.

REFERENCE EXAMPLE 2

[0058] The solution was prepared by mixing 121.5 g of colloidal silica (DuPont Corp, identified as Ludox® AS-40), 83.7 g of NaOH in 1051 g of H2O. After several minutes of vigorous stirring, 66.9 g of zirconium acetate solution (22.1% by weight ZrO2) was added. This was stirred for 3 minutes and the resulting gel was transferred to a stainless steel reactor and hydrothermally reacted with stirring for 72 hours at 200°C. The reactor was cooled to room temperature and the mixture was filtered under vacuum to isolate solids which were washed with deionized water and air dried.

[0059] The solid reaction product was analyzed and found to contain 22.7 wt% Si, 24.8 wt% Zr, 12.8 wt% Na, LOI 13.7 wt%, giving the formula Na2oZrSis 0O90 *3.5НгО. This product was identified as sample B.

REFERENCE EXAMPLE 3

[0060] A solution (60.08 g) of colloidal silica (DuPont Corp, identified as Ludox® AS-40) was slowly added over a period of 15 minutes to the stirred 64.52 g KOH dissolved in 224 g deionized H2O. This was followed by the addition of 45.61 g zirconium acetate (Aldrich 15-16% by weight Zr, in dilute acetic acid). When this addition was complete, 4.75 g of aqueous Nb2Os (30% by weight LOI) was added and stirred for an additional 5 minutes. The resulting gel was transferred to a stirred autoclave reactor and hydrothermally treated for 1 day at 200° C. After this time, the reactor was cooled to room temperature, the mixture was filtered under vacuum, the solid was washed with deionized water and air dried.

[0061] The solid reaction product was analyzed and found to contain 20.3 wt% Si, 15.6 wt% Zr, 20.2 wt% K, 6.60 wt% Nb, LOI 9.32 wt%, giving the formula K2 i4Zro ?iNbo 29 S13O9 2*2.32НгО. Scanning Electron (SEM) of a portion of the sample, including ED AX crystals, indicated the presence of niobium, zirconium, and silicon framework elements. This product was identified as sample C.

REFERENCE EXAMPLE 4

[0062] To a solution prepared by mixing 141.9 g of NaOH pellets in 774.5 g of water, 303.8 g of sodium silicate were added with stirring. To this mixture, 179.9 g of zirconium acetate (15% Zr in 10% acetic acid solution) was added dropwise. After thorough mixing, the mixture was transferred to a Hastalloy™ reactor and heated to 200°C under atmospheric pressure with stirring for 72 hours. At the end of the reaction time, the mixture was cooled to room temperature, filtered and the solid product was washed with 0.001 M NaOH solution and then dried at 100°C for 16 hours. X-ray powder diffraction analysis showed that the product was pure ZS-11.

REFERENCE EXAMPLE 5

[0063] A solution of 37.6 g NaOH pellets dissolved in 848.5 g water was added to the vessel and 322.8 g sodium silicate was added to the solution with stirring. To this mixture was added dropwise 191.2 g zirconium acetate (15% Zr in 10% acetic acid). After thorough stirring, the mixture was transferred to a Hastalloy™ reactor and the reactor was heated to 200°C under anoxic conditions with stirring for 72 hours. After cooling, the product was filtered, washed with 0.001 M NaOH solution and then heated at 100°C for 16 hours. X-ray diffraction analysis of the explosion showed that the product was ZS-9.

FIRST 6

[0064] Approximately 57 g (volatile free, batch 0063-58-30) of Na-ZS-9 was suspended in approximately 25 mL of water. A solution of 0.1N HCl was added gradually with gentle stirring, and the pH was monitored with a pH meter. Approximately 178 mL of 0.1N HCl was added continuously with stirring, the mixture was filtered, and further washed with an additional 1.2 liters of 0.1N HCl wash. The material was filtered, concentrated, and washed with DI water. The pH of the resulting material was 7.0. The H-ZS-9 burst resulting from these three ion exchange runs with 0.1 N HCl has &lt;12% Na.

[0065] As illustrated in this example, batch ion exchange with dilute strong acid is capable of reducing the sodium content of the NA-ZS-9 composition within the desired range.

FIRST 7

[0066] Approximately 85 grams (volatile free, batch 0063-59-26) of Na-ZS-9 was washed with approximately 31 liters of DI water in 2 liter increments over 3 days until the pH of the wash reached 7. The material was filtered, dried, and washed with DI water. The pH of the resulting material was 7. The H-ZS-9 powder resulting from the ion exchange from the batch and water wash had &lt;12% Na.

[0067] As illustrated in this example, water rinsing is capable of reducing the sodium content of the NA-ZS-9 composition within the desired range.

FIRST 8

[0068] Separate batches of ZS-9 crystals were analyzed by light diffraction techniques. The particle size distribution and other parameters are shown in Figures 2-4. The values ​​of d(0.1), d(0.5) and d(0.9) represent the 10%, 50% and 90% size values. The cumulative particle size distribution is shown in Figures 4-6. As can be seen from the following figures, the cumulative volume of particles having a diameter below 3 microns ranges from approximately 0.3% to approximately 6%. Additionally, different ZS-9 series have different particle size distributions with varying levels of particles having a diameter of less than 3 microns.

FIRST 9

[0069] ZS-9 crystals were screened to remove small diameter particles. The resulting particle size distribution of ZS-9 crystals, screened using different sized sieves, was analyzed. As illustrated in the following figures, a fraction of particles having a diameter below 3 microns can be reduced and eliminated by using the appropriate mesh size of the sieve. Without screening, approximately 2.5% of the particles had a diameter below 3 microns. See Figure 5. After screening with a 635 mesh sieve, the fraction of particles having a diameter below 3 microns was reduced to approximately 2.4%. See Figure 6. After screening with a 450 mesh sieve, the fraction of particles having a diameter below 3 microns was further reduced to approximately 2%.

See Figure 7. When a 325 mesh screen is used, the fraction of particles below 3 microns in diameter is further reduced to approximately 0.14%. See Figure 8. Finally, a 230 mesh screen reduces the fraction of particles below 3 microns to 0%. See Figure 9.

[0070] The screening techniques presented in this example illustrate that a particle size distribution can be obtained for ZS-9 that provides little or no particles below 3 microns. It should be noted that ZS-9 according to Example 5 or H-ZS-9 according to Examples 6 and 7 can be screened as described in this example to obtain the desired particle size distribution. Specifically, the desired particle size distribution described herein can be obtained using the techniques in this example for ZS-9 and H-ZS-9.

FIRST 10

[0071] A 14-day repeated dose oral toxicity study was conducted in beagle dogs with recovery. A GLP-compliant oral toxicity study was conducted in beagle dogs to evaluate the potential oral toxicity of ZS-9 when administered at 6-hour intervals over a 12-hour period, three times daily, in the diet, for at least 14 consecutive days. In the main study, ZS-9 was administered to 3/dog/sex/dose at doses of 0 (control), 325, 650, or 1300 mg/kg/dose. An additional 2 dogs/sex/dose, assigned to the recovery study, received 0 or 1300 mg/kg/dose concurrently with the animals in the main study and were maintained on treatment for an additional 10 days. A correction factor of 1.1274 was used to correct the ZS-9 for water content. Dose records were used to confirm the accuracy of dose administration.

[0072] During the acclimation period (Day -7 to Day -1) the dogs were trained to eat 3 portions of wet dog food at 6-hour intervals. During the treatment, the required amount of test material (based on the last recorded body weight) was mixed with 100g of wet dog food and offered to the dogs at 6-hour intervals. Additional dry food was offered after the last daily dose was consumed. Each dog received the same amount of wet dog food. Body weights were recorded on arrival and on Days -2, -1, 6, 13 and 20. Clinical observations were made twice daily during the acclimation, treatment and recovery periods. Wet and dry food consumption was measured daily during the treatment period. Blood and urine samples for serum chemistry, hematology, coagulation parameters and urinalysis were collected before the test (Day -1) and on Day 13. Ophthalmological examinations were performed before the test (Day -6/7) and on Day 7 (females) or 8 (males).

Electrocardiographic assessments were performed before the test (Day -1) and on Day 11. At the end of the study (Day 14 - main study and Day 24 - recovery study), necropsy examinations were performed, protocol-specified organ weights were measured, and selected tissues were examined microscopically.

[0073] Oral administration of 325, 650 and 1300 mg ZS-9/kg/dose with food, three times daily at 6 hour intervals over a 12 hour period for 14 days was well tolerated. Clinical signs were limited to the observation of white material, presumed to be test material, in the feces of some dogs at the 325 mg/kg/dose and in all animals receiving > 650 mg/kg/dose during the second week of treatment. There were no adverse effects on body weight, body weight change, food consumption, hematological and coagulation parameters, or ophthalmoscopic and ECG assessments.

[0074] There were no macroscopic findings associated with ZS-9 administration. Microscopically, minimal to mild focal and/or multifocal inflammation was observed in the kidneys of treated animals, but not in control animals. Lesions were of similar frequency and severity at 650 and 1300 mg/kg and were less frequent and severe at 325 mg/kg. In some dogs, the inflammation was unilateral, rather than bilateral, and in some cases it was associated with inflammation of the bladder and the beginning of the ureters. Taken together, these observations suggest that factors other than direct renal injury, such as changes in composition of dogs treated with ZS-9, may lead to increased susceptibility to subclinical urinary tract infections, even though no organisms were observed in these tissues. In animals that recovered, inflammation completely resolved in females and partially resolved in males, indicating that, regardless of the cause of the inflammation, it was reversible upon cessation of dosing. The increased incidence of mixed leukocytic inflammation observed in Beagle dogs treated with ZS-9 is summarized below.

<td colspan="10">Overview of kidney inflammation</td>

<td colspan="10">Terminal necropsy (TN): Day 14</td>

<td colspan="2">Dose</td><td colspan="2">0 mg/kg</td><td colspan="2">325 mg/kg</td><td colspan="2">650 mg/kg</td><td colspan="2">1,3θθ mg/kg</td>

<td colspan="2">Pol</td><td>M</td><td>With</td><td>M</td><td>With</td><td>M</td><td>With</td><td>M</td><td>With</td>

<td colspan="2">Number of animals</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td>

<td rowspan="3">Left kidney</td><td>Incidence</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 2/3</td><td> 2/3</td><td> 3/3</td><td> 3/3</td><td> 3/3</td>

<td>minimal</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 2/3</td><td> 2/3</td><td> 2/3</td><td> 3/3</td><td> 1/3</td>

<td>medium</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 1/3</td><td> 0/3</td><td> 2/3</td>

<td colspan="10"></td>

<td rowspan="3">Right kidney</td><td>Incidence</td><td> 0/3</td><td> 0/3</td><td> 1/3</td><td> 1/3</td><td> 2/3</td><td> 3/3</td><td> 2/3</td><td> 2/3</td>

<td>minimal</td><td> 0/3</td><td> 0/3</td><td> 1/3</td><td> 1/3</td><td> 2/3</td><td> 1/3</td><td> 2/3</td><td> 0/3</td>

<td>medium</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 0/3</td><td> 2/3</td><td> 0/3</td><td> 2/3</td>

<td colspan="10"></td>

<td rowspan="3">Both kidneys</td><td>Incidence</td><td> 0/6</td><td> 0/6</td><td> 1/6</td><td> 3/6</td><td> 4/6</td><td> 6/6</td><td> 5/6</td><td> 5/6</td>

<td>minimal</td><td> 0/6</td><td> 0/6</td><td> 1/6</td><td> 3/6</td><td> 4/6</td><td> 3/6</td><td> 5/6</td><td> 1/6</td>

<td>medium</td><td> 0/6</td><td> 0/6</td><td> 0/6</td><td> 0/6</td><td> 0/6</td><td> 3/6</td><td> 0/6</td><td> 4/6</td>

<td colspan="10"></td>

<td colspan="2" rowspan="2">Sum of severity scores</td><td> 0</td><td> 0</td><td> 2</td><td> 3</td><td> 4</td><td> 9</td><td> 5</td><td> 9</td>

<td colspan="2"> 0</td><td colspan="2"> 5</td><td colspan="2"> 13</td><td colspan="2"> 14</td>

<td colspan="2">Middle group severity scores</td><td colspan="2"> 0,00</td><td colspan="2"> 0,83</td><td colspan="2"> 2,17</td><td colspan="2"> 2,33</td>

[0075] Minimal acute bladder inflammation and unidentified crystals were also observed in the renal pelvis and urine of females dosed at 650 mg/kg/dose as shown below.

<td colspan="4">Overview of crystals observed at 650 mg/kg/dose</td>

<td>Animal number</td><td> 4420</td><td> 4421</td><td> 4422</td>

<td>Unidentified crystals in urine</td><td> +</td><td> -</td><td> +</td>

<td>Crystals in the renal pelvis</td><td> -</td><td> +</td><td> -</td>

<td>Acute bladder inflammation</td><td> +</td><td> +</td><td> -</td>

[0076] Crystals were not identified in groups of 2 or 4 females, or in any male treated with ZS-9.

[0077] In both studies, urine pH was observed to be increased compared to controls and it was hypothesized that the change in urine pH and/or urine composition affected the solubility of solutes in urine, resulting in crystal formation that caused urinary tract irritation and/or increased susceptibility to urinary tract infections (UTIs).

[0078] The description of the urinary crystals (long, thin, spiny clusters) combined with the particle size profile and insolubility of the material tested, makes it unlikely that these crystals are ZS-9.

FIRST 11

[0079] ZS-9 crystals were prepared and designated “ZS-9 unscreened”. Screening according to the procedures of Example 10 was performed on a sample of ZS-9 crystals and the screened sample was designated “ZS-9 >5pm.” A second sample of ZS-9 crystals was ion-exchanged according to the procedures of Example 6 above and then screened according to the procedures of Example 10. The resulting H-ZS-9 crystals were designated “ZS9 + >5pm.”

[0080] The following 14-day study was designed to demonstrate the effect of particle size and particle shape on urinary pH and the presence of crystals in the urine. The above compounds were administered orally to beagles by mixing them with wet dog food. The regimen was administered 3 times daily at 6-hour intervals over a 12-hour period as follows:

DESIGN STUDIO

[0081]

<td>Group</td><td>mg/kg/twelve*</td><td>Females</td>

<td>Control</td><td> 0</td><td> 3</td>

<td>ZS-9 unscreened</td><td> 750</td><td> 3</td>

<td>ZS-9 &gt;5pm</td><td> 750</td><td> 3</td>

<td>ZS-9 + &gt;5 pm</td><td> 750</td><td> 3</td>

<td>ZS-9 unscreened</td><td> 100</td><td> 3</td>

<td>ZS-9 &gt;5pm</td><td> 100</td><td> 3</td>

<td>ZS-9 + &gt;5 pm</td><td> 100</td><td> 3</td>

<td>NaHCO₃</td><td> 50</td><td> 3</td>

<td colspan="3">* uncorrected for water ZS-9+ = pH neutral crystal</td>

<td>Total number of dogs</td><td colspan="2">24 females</td>

<td>Age</td><td>5 months old upon arrival</td>

<td>Acclimation</td><td>&gt; 10 days</td>

<td>Formulation of test materials</td><td>Mixed with wet dog food</td>

<td>Application of test materials</td><td>Within 30 minutes of application</td>

<td>Dose formulation analysis</td><td>Dose records will be used to confirm dosing. The weight of any remaining wet food will be recorded.</td>

[0082] The following table shows the observations, toxicokinetics assessment, laboratory tests (hematology, urinalysis) and terminal procedures.

Observations

[0083]

<td>Mortality and signs of ill health or</td><td>Twice a day (after treatment and in the evening) including</td>

<td>reaction to treatment</td><td>fecal assessments</td>

<td>Detail of the review</td><td>During acclimation, weekly during testing</td>

<td>Body weights</td><td>Dolazak, Dan -1, Dan 7 i 14</td>

<td>Food consumption</td><td>Daily (wet and dry food)</td>

<td>Oftahnoloscopy ja</td><td>Without</td>

Toxicokinetics (for potential Zr analysis) [0084]

<td>3 X 1 ml whole blood/sample</td><td>Day -1: For the dose</td>

<td>with recorded sample weights</td><td>Day 3: Before dose and 4 hours after second dose</td>

Laboratory tests

[0085]

<td>Hematology/Clinical Chemistry (see list)</td><td>Pretreatment and during weeks 1 and 2 of the study</td>

<td>Urinalysis (see list)</td><td>Pretreatment and during weeks 1 and 2 of the study (metabolic cage, urine sample kept cold) Remaining urine aliquots were kept frozen for possible future Zr analysis</td>

Terminate procedure [0086]

<td>Necropsy</td><td>All animals regardless of the manner of death.</td>

<td></td><td>All tissues collected in NBF (see list)</td>

<td>Histopathology</td><td>Sarno urinami tract (bubreg i basika)</td>

[0087] These tests show that the zirconium silicates of the present invention are particularly suitable for the treatment of hyperkalemia.

FIRST 12

[0088] UZSi-9 crystals were prepared by reaction in a standard 5-G crystallization vessel.

[0089] The reactants were prepared as follows. A 22-L Morton flask was equipped with a top stirrer, thermocouple, and equalizing addition funnel. The flask was filled with deionized water (3.25 L). Stirring was started at approximately 100 rpm and sodium hydroxide (1091 g NaOH) was added to the flask. The contents of the flask exothermed as a sodium hydroxide solution. The solution was stirred and cooled to less than 34°C. Sodium silicate solution (5672.7 g) was added. To this solution was added a solution of zirconium acetate (3309.5 g) over a period of 43 minutes. The resulting suspension was stirred for an additional 22 minutes. ZmaZS-9 crystals (223.8 g) were added to the reaction vessel and stirred for approximately 17 minutes.

[0090] The mixture was transferred to a 5-G Parr pressure vessel with the aid of deionized water (0.5 L). The vessel had smooth walls and a standard stirrer. The reactor did not have a cooling coil present. The vessel was sealed and the reaction mixture was stirred at approximately 275-325 rpm and heated to 185 +/- 10°C for 4 hours, then held at 184-186°C and soaked for 72 hours. Finally, the reactants were then cooled to 80°C for 12.6 hours. The resulting white solid was filtered using deionized water (18L). The solids were washed with deionized water (125 L) until the pH of the eluting filtrate was less than 11 (9.73). The wet cake was dried under vacuum (25 inches Hg) for 48 hours at 95-105°C to give 2577.9 g (107.1%) of ZS-9 as a white solid.

[0091] The XRD pattern of ZS-9 obtained in this example is shown in Figure 10. The FTIR pattern of this material is shown in Figure 11. These XRD and FTIR spectra are characterized by the presence of absorption peaks that are typically associated with the ZS-11 crystalline form. In addition, the peaks associated with ZS-9 show significant broadening due to crystalline impurities (e.g., the presence of ZS-11 crystals in the ZS-9 composition). For example, the FTIR spectra show significant absorption around 764 and 955 cm¹The XRD pattern for this example shows significant noise and poorly defined peaks at 2-theta values ​​of 7.5, 32 and 42.5.

FIRST 13

[0092] High-capacity UZSi-9 crystals were prepared according to the following representative example.

[0093] The reactants were prepared as follows. A 22-L Morton flask was equipped with a top stirrer, thermocouple, and equalizing addition funnel. The flask was charged with deionized water (8,600 g, 477.37 mol). Stirring was started at approximately 145-150 rpm and sodium hydroxide (661.0 g, 16.53 mol NaOH, 8.26 mol Na2O) was added to the flask. The contents of the flask were exothermed from 24°C to 40°C over a period of 3 minutes while the sodium hydroxide dissolved. The solution was stirred for one hour to allow the initial exotherm to subside. A solution of sodium silicate (5.017 g, 22.53 mol SO2, 8.67 mol Na20) was added. To this solution, using an addition funnel, was added a solution of zirconium acetate (2.080 g, 3.76 mol Zr02) over 30 minutes. The resulting suspension was stirred for an additional 30 minutes.

[0094] The mixture was transferred to a 5-G Parr Model 4555 pressure vessel using deionized water (500g, 27.75 moles). The reactor was equipped with a cooling coil that had a serpentine configuration to provide a groove-like structure in the reactor adjacent to the stirrer. The cooling coil was not filled with heat exchange fluid, as it was used in this reaction only to provide a groove-like structure adjacent to the stirrer.

[0095] The vessel was sealed and the reaction mixture was stirred at approximately 230-235 rpm and heated from 21°C to 140-145°C over 7.5 hours and held at 140-145°C for 10.5 hours, then heated to 210-215°C over 6.5 hours, where a maximum pressure of 295-300 psi was achieved, then held at 210-215°C for 4 1.5 hours. The reactor was then cooled to 45°C over a period of 4.5 hours. The resulting white solid was filtered using deionized water (1.0 KG). The solids were washed with deionized water (40 L) until the pH of the eluting filtrate was not less than 11 (10.54). A representative portion of the wet cake was dried under vacuum (25 inches Hg) overnight at 100°C to afford 1.376 g (87.1%) of ZS-9 as a white solid.

[0096] The XRD pattern of the obtained ZS-9 is shown in Figure 12. The FTIR pattern of this material is shown in Figure 13. These XRD and FTIR spectra, when compared to those of Example 12 (Figures 10-11), showed well-defined peaks without broadening and the absence of peaks associated with non-ZS-9 crystal forms (e.g., ZS-11 peaks). This example demonstrates how the presence of a groove-like structure within the reactor drastically and unexpectedly improves the quality of the crystals thus obtained. Without wishing to be bound by theory, the inventors understand that the grooves provide additional turbulence that lifts the solids (i.e., crystals) and results in a more uniform suspension of the crystals in the reaction vessel as the reaction proceeds. This improved suspension allows for a more complete reaction to the desired crystal form and reduces the presence of undesired zirconium silicate crystal forms in the final product.

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[0097] The potassium exchange capacity (KEC) of zirconium silicate (ZS-9) was determined according to the following protocol.

[0098] This test procedure used HPLC capable of introducing a solvent gradient and detecting cation exchange. The column was an lonPac CS12A, Analytical (2 x 250 mm). The flow rate was 0.5 mL/min with a residence time of approximately 8 minutes. The column temperature was set at 35°C. The injection volume was 10 uL and the needle wash was 250 uL. The pump was operated in isocratic mode and the solvent was DI water.

[0099] The stock standard was prepared by accurately weighing and recording the weight of approximately 383 mg of potassium chloride (ACS grade), which was transferred to a 100-mL plastic volumetric flask. The material was dissolved and diluted to volume with diluent, followed by mixing. The stock standard had a K⁺concentration of 2000 ppm (2 mg/mL). Samples were prepared by accurately measuring, recording, and transferring approximately 112 mg of ZS-9 into a 20 mL plastic container. 20.0 mL of a 2000 ppm potassium standard solution was pipetted into the vial and the container was capped. The sample vials were placed on an articulating mixer and shaken for at least 2 hours, but not more than 4 hours. The sample preparation solution was filtered through a 0.45 pm PTFE filter into a plastic container. 750 pL of the sample solution was transferred to a 100 mL plastic volumetric flask. The sample was diluted to volume with DI water and mixed. Initial K⁺ the concentration was 15 ppm (1 Spg1mL).

[0100] The samples were injected into the HPLC. Figure 14 shows an example of a chromatogram of a blank solution. Figure 15 shows an example of a chromatogram of a standard solution for analysis. Figure 16 shows an example of a sample chromatogram. The potassium exchange capacity was calculated using the following formula:

(IC - FC) x I/

<img file="RS58490B2_D0001.tif" />

KEC is the potassium exchange capacity in mEq/g. The initial potassium concentration (ppm) is IC. The final potassium concentration (ppm) is FC. The equivalent weight (atomic weight/valence) is Eq wt. The volume (L) of the standard in the sample preparation is V. The weight of ZS-9 (mg) used in the sample preparation is Wtspi. The percent water content (%) (LOD) is %water.

[0101] Three samples of ZS-9 produced according to the procedures of Example 12, i.e., in a reactor without grooves (e.g., internal cooling coil structure), were tested for potassium exchange capacity (KEC) according to the above procedure. Similarly, three samples of ZS-9 produced according to Example 13 in a reactor with cooling coils serving as grooves were tested according to this procedure. The results in Table 3 below show that the procedure of Example 13 and the presence of grooves within the crystal vessel resulted in a dramatic increase in potassium exchange capacity.

<td colspan="4">Table 3 Potassium exchange capacity (KEC)</td>

<td colspan="2">Example 12 (bez zljebova)</td><td colspan="2">Example 13 (with grooves)</td>

<td>Lot 5368-10311A</td><td>2.3 meq/gm</td><td>Lot 2724-9A</td><td>3.9 meq/gm</td>

<td>Lot 5368-12211A</td><td>value of 1.7 meq/gm</td><td>Lot 2724-13D</td><td>3.8 meq/gm</td>

<td>Lot 5368-13811A</td><td>value of 1.8 meq/gm</td><td>Lot 2724-18F</td><td>3.8 meq/gm</td>

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[0102] The use of an internal cooling coil to provide a groove-like structure within the reactor is only feasible for small reactors on the order of 5 gallons, as larger reactors cannot be easily equipped and do not typically use cooling coils.

[0103] The inventors have constructed a reactor for the large-scale production of high-purity, high-KEC ZS-9 crystals. Large-scale reactors typically use a jacket to achieve heat transfer to the reaction chamber, rather than a coil suspended within the reaction chamber. A conventional 200-L reactor 100 is shown in Figure 17. The reactor 100 has smooth walls and a stirrer 101 extending into the center of the reaction chamber. The reactor 100 also has a heating chamber 102 and a bottom outlet valve 103. The inventors have constructed an improved reactor 200, Figure 18, which also has a stirrer 201, a thermowell 202, and a bottom outlet valve 203. The improved reactor 200 has groove structures 204 on the side walls, which in combination with the stirrer 201 provide significant lift and suspension of the crystals during the reaction, and the formation of high purity and high KEC ZS-9 crystals. The improved reactor may also include a cooling or heating jacket to control the reaction temperature during crystallization in addition to the trough structures 204. Details of a suitable and non-limiting trough design are shown in Figure 19. The reactor is preferably at least 20-L in volume, more preferably 200-L or more, or in the range of 200-L to 30,000-L.

[0104] It is intended that the specification and examples be considered as exemplary only, and that the true scope of the invention is indicated by the following claims.