TWI655948B - Microporous zirconium silicate for the treatment of hyperkalemia - Google Patents

Abstract

The present invention relates to the development of novel microporous zirconium silicates which remove selected toxins, such as potassium or ammonium ions, from the gastrointestinal tract at elevated rates without undesirable side effects. Preferred formulations are designed to avoid increasing the pH of the patient's urine and/or to avoid potential entry of particles into the patient's blood. High purity crystals for the preparation of ZS-9 exhibiting an enhanced degree of potassium ion exchange capacity are also disclosed. These compositions are particularly useful in the treatment of hyperkalemia.

Description

Microporous zirconium citrate for hyperkalemia treatment

The present application claims priority to U.S. Provisional Serial No. 61/800,182, filed on March 15, 2013, the entire disclosure of which is incorporated herein.

The present invention relates to a pharmaceutical composition comprising a novel zirconium citrate (ZS) composition which is formulated at a specific dosage to remove selected toxins, such as potassium or ammonium ions, from the gastrointestinal tract without undesirable side effects. Things. Preferred formulations are designed to remove particles and prevent the particles from potentially entering the bloodstream and potentially increasing the pH in the patient's urine. The formula is also designed to release less sodium into the blood. These compositions are particularly useful for the treatment of hyperkalemia and kidney disease. A microporous ZS composition having enhanced purity and potassium exchange capacity (KEC) is also disclosed. It is also to explore ways to treat acute, subacute and long-term hyperkalemia. Disclosed herein is the use of the microporous ZS composition described above for the advantageous dosing regimen for the treatment of different forms of hyperkalemia.

Acute hyperkalemia is a life-threatening condition caused by increased serum potassium levels. Potassium is a ubiquitous ion that is found in many systems in the human body. It is the most abundant intracellular cation and is extremely important for many physiological systems including maintenance of cell membrane potential, homeostasis of cell volume, and transmission of action potentials. Its main dietary sources are vegetables (tomato and potatoes), fruits (oranges, bananas) and meat. When the kidney is the main potassium concentration regulator, the potassium concentration in normal plasma is between 3.5 and 5.0 mmol/L. Kidney elimination of potassium is passive (through the glomerulus) by active reabsorption in the proximal tubule and the ascending limb of the loop of Henle. It is the active excretion of potassium in the distal tubules and collecting ducts of systems controlled by aldosterone.

Increased extracellular potassium ion concentration results in depolarization of the cell membrane potential. This deionization turns on some voltage-gated sodium ion channels, but not enough to generate an action potential. After a short period of time, the open sodium ion channel is inactive and becomes difficult to control, increasing the threshold for generating an action potential. This causes damage to the neuromuscular-, heart-, and gastrointestinal system, and this damage is responsible for the visible symptoms of hyperkalemia. The biggest concern is the impact on the heart system, where damage to the heart system can lead to fatal arrhythmias, such as cardiac arrest or ventricular fibrillation. Because of the possibility of a fatal arrhythmia, hyperkalemia represents an acute metabolic emergency that requires immediate treatment.

Hyperkalemia may develop when excessive serum potassium is produced (mistaken, tissue breakdown). The most common ineffective elimination leading to hyperkalemia may be hormones (such as aldosterone deficiency), drugs (treated with ACE-inhibitors or angiotensin receptor blockers) or more commonly due to renal function of decline or Further heart failure. Hyperkalemia is most common due to renal insufficiency and is closely related to renal failure and serum potassium (S-K) concentrations. In addition, many different commonly used drugs cause hyperkalemia, such as ACE-inhibitors, angiotensin receptor blockers, potassium-sparing diuretics (eg, amiloride), NSAIDs (like ibuprofen, naphthalene) Probiotics, celecoxib), heparin and certain cytotoxic and/or antibiotic drugs (like cyclosporine and trimethoprim). Finally, beta-blockers, digoxin or succinylcholine are other well-known causes of hyperkalemia. In addition, a further degree of congestive heart disease, large gauge damage, burns or intravascular hemolysis leads to hyperkalemia, such as metabolic acidosis, which is usually part of diabetic ketoacidosis.

Symptoms of hyperkalemia are somewhat non-specific and often include signs of generalized weakness, palpitations and muscle weakness or arrhythmias, such as palpitations, Brady-tachycardia or dizziness/fainting. However, hyperkalemia is usually diagnosed during routine blood screening for medical conditions or after developmental complications such as arrhythmia or sudden death. The diagnosis is clearly established by S-K measurements.

Treatment depends on the SK concentration. In the milder case (SK between 5 and 6.5 mmol/l), with potassium-binding resin (Kai Keng Ning San (kayexalate Emergency treatment combined with dietary recommendations (low potassium diet) and possible treatment of medication is the standard of care; if SK is higher than 6.5 mmol/l or arrhythmia occurs, it is required to urgently reduce potassium and closely monitor it in the hospital environment. The following are commonly used treatments:

●Kai Keng Li Ning , combined with the potassium resin in the intestine and thus increased defecation, thereby reducing the SK concentration. However, Kay Kaolin The display can cause intestinal obstruction and potential rupture. In addition, it is necessary to induce diarrhea while treating. These factors are reduced by Kay Kaolin The palatability of treatment.

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

● Calcium supplementation. Calcium is not lower than the S-K concentration, but it reduces myocardial excitability and thus stabilizes the myocardium, reducing the risk of arrhythmia.

● Bicarbonate. Bicarbonate ions will promote the exchange of K+ with Na+, thus resulting in the promotion of a sodium-potassium pump.

● Dialysis (in severe cases).

The only way to actually increase the amount of potassium that is removed from the body is Kai Kaolin However, because of the need to induce diarrhea, Kay Kaolin It can not be used on a long-term basis, and even if it is used under acute conditions, the need to induce diarrhea, combined with only a slight effect and odor and taste, reduces its practicability.

The use of ZS or titanium citrate microporous ion exchangers to self-move the body in addition to toxic cations and anions or dialysis is described in U.S. Patent Nos. 6,579,460, 6,099,737 and 6,332,985, all incorporated herein by reference. Other examples of microporous ion exchangers are found in U.S. Patent Nos. 6,814,871, 5,891,417 and 5,888,472, all incorporated herein.

The present inventors have discovered that known ZS compositions, when used in the treatment of hyperkalemia, may exhibit undesirable effects when used to remove potassium in vivo. In particular, the administration of the ZS molecular sieve composition has been combined with the incidence of mixed leukocyte inflammation, minimal acute bladder inflammation, and observations of unidentified crystals in the renal pelvis and urine in animal studies, while increasing the pH in urine. . Additionally, known ZS compositions have problems with crystalline impurities and undesirable low cation exchange capacity.

The present invention discloses novel ZS molecular sieves to address the problems associated with existing hyperkalemia treatments, and novel methods of treating hyperkalemia using such novel compositions. See U.S. Patent Application Serial No. 13/371,080 (U.S. Patent Application Publication No. 2012-0213847 A1). In addition, the inventors have disclosed a novel manufacturing process for preparing a ZS absorbent having a particle size distribution by avoiding and/or reducing the need to screen ZS crystallization. See U.S. Provisional Application No. 61/658,117. Finally, the inventors disclose novel divalent cations (e.g., calcium or magnesium) in the form of ZS carriers that are particularly useful in the treatment of patients with hypocalcemia suffering from hyperkalemia. See Magnesium Fruit Provisional Application No. 61/670,415. The calcium carrier form of ZS disclosed in the '415 Provisional Case may additionally contain magnesium or contain magnesium as an alternative to calcium. These disclosures are hereby incorporated by reference in their entirety.

The inventors have found that the delivery of ZS in hyperkalemia treatment can be improved by the use of novel forms of administration. In particular, the inventors have found that the specific administration form of ZS can significantly reduce the serum potassium concentration of a patient having hyperkalemia to a normal concentration when administered to a target subject suffering from an increased concentration of potassium. The inventors have also discovered that a particular dose can maintain a reduction in potassium concentration in a patient for an extended period of time.

A cation exchange composition or product comprising ZS, when formulated and administered in a particular pharmaceutical dosage, can significantly reduce serum potassium concentration in patients with elevated potassium concentrations. In one embodiment, the patient exhibiting elevated potassium concentration is a patient suffering from chronic or acute kidney disease. In another embodiment, the patient exhibiting elevated potassium concentration has acute or chronic hyperkalemia.

In one embodiment, the dose of the composition can range from about 1 to about 20 grams of ZS, preferably from about 8 to about 15 grams, and more preferably about 10 grams. In other embodiments, the composition is administered in a total dose ranging from about 1 to about 60 grams, preferably from about 24 to about 45 grams, and more preferably from about 30 grams.

In other embodiments, the composition comprises a molecular sieve having a microporous structure consisting of at least one of a ZrO ₂ octahedral unit and a SiO ₂ tetrahedral unit and a GeO ₂ tetrahedral unit. These molecular sieves have experimental formulas:

A _P M _X Zr _1-X Si _n Ge _y O _m wherein A is an exchangeable cation selected from the group consisting of potassium ion, sodium ion, strontium ion, strontium ion, calcium ion, magnesium ion, hydronium ion or a mixture thereof, M is Choose free 铪 (4+), tin (4+), 铌 (5+), titanium (4+), 铈 (4+), 锗 (4+), 鐠 (4+) and 鋱 (4+) At least one frame metal in the group, "p" has a value from about 1 to about 20, "x" has a value from 0 to less than 1, "n" has a value from about 0 to about 12, and "y" has a value of about From 0 to about 12, "m" has a value from about 3 to about 36, and 1 ≦ n + y ≦ 12. Niobium can replace niobium, zirconium or combinations thereof. Because the composition is substantially insoluble in body fluids (at neutral or alkaline pH), it can be taken orally to remove toxins from the gastrointestinal system.

In other embodiments, the molecular sieves provided have an elevated cation exchange capacity, particularly a potassium ion exchange capacity. The elevated cation exchange capacity is suspended by the special process and lifted and more fully suspended in the reactor structure of the entire reaction, as described in U.S. Patent Application Serial No. 13/371,080 (U.S. Patent Application No. 2012-0213847 A1). In one embodiment of the invention, the modified ZS-9 crystalline composition (ie, the composition in which the predominantly crystalline form is ZS-9) has a potassium ion exchange capacity greater than about 2.5 meq/g, preferably at 2.7 and The potassium ion exchange capacity between 3.7 meq/g is preferably between 3.05 and 3.35 meq/g. ZS-9 with a potassium ion exchange capacity of 3.1 meq/g has been manufactured on a commercial scale and has achieved the desired clinical results. ZS-9 crystallization with a potassium ion exchange capacity of 3.2 meq/g is also expected to achieve the desired clinical effect and provide an improved dosing regimen. The target of 3.1 and 3.2 meq/g can be achieved with a tolerance of ±15%, preferably ±10%, and most preferably ±5%. The high capacity form of the ZS-9 is ideal, although it is more difficult to produce on a commercial scale. These higher capacity forms of ZS-9 have an increased exchange capacity of greater than 3.5 meq/g, preferably greater than 4.0 meq/g, more preferably between 4.3 and 4.8 meq/g, furthermore Between 4.4 and 4.7 meq/g and optimal is about 4.5 meq/g. A ZS-9 crystal having a potassium ion exchange capacity in the range between 3.7 and 3.9 meq/g was produced according to the following Example 14.

In one embodiment, the composition exhibits a median particle size greater than 3 microns, and less than 7% of the particles in the composition have a diameter of 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, and more preferably less than 3% of the particles in the composition. Having 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, and further 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. The best system has no particles or only traces having a diameter of less than 3 microns.

Particles having an intermediate and average particle size of preferably greater than 3 microns and up to the size of 1000 microns are also possible in certain applications. Preferably, the median particle size is in the range of from 5 to 1000 microns, more preferably from 10 to 600 microns, more preferably from 15 to 200 microns and most preferably from 20 to 100 microns.

In one embodiment, the composition exhibiting a median particle size and having a proportion of particles having a diameter less than the above 3 micrometers in the composition also exhibits a sodium content of less than 12% by weight. Preferably, the sodium content is less than 9% by weight, more preferably less than 6% by weight, more preferably less than 3% by weight, and more preferably 0.05% by weight of sodium. Within the range of 3%, and the optimum is 0.01% by weight or less or as low as possible.

In one embodiment, the invention comprises an individual pharmaceutical dosage comprising a component in the form of a capsule, tablet or powder. In other embodiments of the invention, the pharmaceutical product is encapsulated in a kit of individual unit doses sufficient to maintain a low serum potassium concentration. Dosages can range from about 1 to 60 grams or any integer or integer range herein. For example, a dose of 1.25-20 grams of ZS, preferably 2.5-15 grams of ZS, more preferably 5-10 grams of ZS of individual capsules, tablets, bagged powder. In other embodiments, the ZS can be a single individual unit dose of about 1.25-45 grams of capsule, tablet, bagged powder. In other embodiments, the product may be consumed once a day, three times a day, every two days, or every week.

The composition of the present invention can be used for symptoms of kidney disease or kidney (e.g., chronic or acute) and kidney disease, such as hyperkalemia (e.g., chronic or acute), including the administration of a composition to a patient in need thereof. The dosage administered can range from about 1.25 to 20 grams of ZS, preferably from about 2.5 to about 15 grams, more preferably about 10 grams. In other embodiments, the total dose of the composition may range from about 1 to 60 grams (14 to 900 mg/kg/day), preferably from 24 to 36 grams (350 to 520 mg/kg). Day), more preferably 30 grams (400 mg/Kg/day).

The inventors have disclosed novel ZS molecular sieve absorbents that are treated in the treatment with molecular sieve absorbents, such as those used in the treatment of hyperkalemia. ZS has a microporous framework structure composed of a ZrO ₂ octahedral unit and a SiO ₂ tetrahedral unit. Figure 1 is a polyhedral diagram showing the structure of microporous ZS Na2.19ZrSi3.01O9.11.2.71H2O (MW 420.71). The black polygon depicts the octahedral zirconia unit while the light-colored polygon depicts the tetrahedral cerium oxide unit. The cations are not shown in Figure 1.

The microporous exchanger of the present invention has a large capacity and a strong affinity, i.e., selectivity, for potassium or ammonium. Eleven types of ZS, ZS-1 to ZS-11, which have different affinity for each pair of ions, have been developed. See, for example, U.S. Patent No. 5,891,417. UZSi-9 (or known ZS-9) is a particularly effective ZS absorber for absorbing potassium and ammonium. These ZS have experimental formulas:

A _P M _X Zr _1-X Si _n Ge _y O _m (I)

Wherein A is an exchangeable cation selected from the group consisting of potassium ions, sodium ions, strontium ions, strontium ions, calcium ions, magnesium ions, hydronium ions or mixtures thereof, and M is selected from the group consisting of ruthenium (4+) and tin (4+). At least one frame metal of the group consisting of 铌(5+), titanium (4+), 铈(4+), 锗(4+), 鐠(4+), and 鋱(4+), "p" has A value of from about 1 to about 20, "x" has a value from 0 to less than 1, "n" has a value from about 0 to about 12, "y" has a value from about 0 to about 12, and "m" has a value of from about 3 to A value of about 36, and 1≦n+y≦12. Niobium can replace niobium, zirconium or combinations thereof. Since ruthenium and other metals are usually present in trace amounts, it is preferred that x and y are zero or both are close to zero. Because the composition is substantially insoluble in body fluids (at neutral or alkaline pH), it can be taken orally to remove toxins from the gastrointestinal system. The inventors of the present invention have noted that ZS-8 has increased solubility compared to other forms of ZS (i.e., ZS-1-ZS-7 and ZSi-9-ZS-11). The presence of a soluble form of ZS comprising ZS-8 is undesirable because the soluble form of ZS may promote the concentration of zirconium and/or citrate in the urine. The amorphous form of ZS can also be substantially soluble. Therefore, it is desirable to reduce the proportion of amorphous materials to a precisely feasible range.

The zirconium metal salt is prepared by hydrothermal crystallization of a reaction mixture prepared by combining a reaction source of zirconium, hafnium and/or hafnium, optionally one or more M metals, at least one alkali metal reduction and water. Alkali metal is used as a template reagent. Any zirconium compound hydrolyzable to zirconium oxide or zirconium hydroxide can be used. Specific examples of such compounds include azoxide zirconium such as zirconium n-propoxide, zirconium hydroxide, zirconium acetate, zirconium oxychloride, zirconium chloride, zirconium phosphate and zirconyl nitrate. Sources of these cerium oxides include colloidal cerium oxide, gas phase cerium oxide, and sodium citrate. Sources of antimony include antimony oxide, alkoxide, and antimony tetrachloride. The source of the alkali comprises potassium hydroxide, sodium hydroxide, barium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, barium carbonate, sodium ethylenediamine tetraacetic acid (EDTA), potassium. EDTA, 铷EDTA and 铯EDTA. Sources of M metals include M metal oxides, alkoxides, halides, acetates, nitrates, and sulfates. Specific examples of M metal sources include, but are not limited to, alkoxide titanium, titanium tetrachloride, titanium trichloride, titanium dioxide, tin tetraisopropoxide, bismuth isopropoxide, hydrazine hydrate, bismuth isopropoxide, Barium chloride, barium oxychloride, barium chloride, barium oxide and barium sulfate.

In general, the hydrothermal treatment to prepare the zirconium metal salt or titanium metal salt ion exchange composition of the present invention comprises forming a reaction mixture in which the molar ratio of the oxide is represented by the following formula:

aA ₂ O:bMO _q/2 :1-bZrO ₂ :cSiO ₂ :dGeO ₂ :eH ₂ O wherein "a" has a value of from about 0.25 to about 40, and "b" has a value of from about 0 to about 1, "q " is the valence of M, "c" has a value of from about 0.5 to about 30, "d" has a value of from about 0 to about 30, and "e" has a value of from about 10 to about 3,000. The reaction mixture provides the desired mixture by mixing the desired zirconium, hafnium source, and optionally rhodium, alkali metal, and optionally M metal in any order. This also requires that the mixture have an alkaline pH and preferably a pH of at least 8. The basicity of the mixture is controlled by the addition of an excess of the alkali hydroxide and/or other components of the mixture to the basic compound. The resulting reaction mixture is then reacted under autogenous pressure in a sealed reaction vessel at a temperature of from about 100 ° C to about 250 ° C for a period of from about 1 to about 30 days. After the dispensing time, the mixture was filtered to separate the solid product washed with deionized water, acid or dilute acid and dried. Many drying techniques can be used, such as vacuum drying, tray drying, fluid bed drying. For example, the filtered material can be dried in air under vacuum.

Following the ready-made reference materials, different structural types of ZS molecular sieves and zirconium-lanthanum molecular sieves have been given any designation of ZS-1, where "1" indicates the frame structure type "1". That is, one or more ZS and/or zirconium-lanthanum molecular sieves having different experimental formulas may have the same structural type.

The X-ray patterns presented in the following examples were obtained using standard X-ray powder diffraction techniques and reported in U.S. Patent No. 5,891,417. The source of radiation is a high intensity X-ray tube operating at 45 Kv and 35 ma. The diffraction pattern from copper K-alpha radiation is obtained by a corresponding computer-based technique. Flat compressed powder samples were scanned at 2° (20) per minute. The interplanar spacing (d) in angstroms is obtained from the position of the diffraction peak expressed as 2θ, where θ is the Bragg angle when viewed from the digitized data. The intensity is determined by the integral area of the diffraction peak after the background is cut off, "I ₀ " is the intensity of the strongest line or peak, and "I" is the intensity of each of the other peaks.

As will be known to those of ordinary skill in the art, the determination of the parameter 2θ is affected by human and machine errors, and the combination may impose an uncertainty of about ±0.4 for each reported 2θ value. Of course, this uncertainty is also reflected in the reported value of the d-spacing calculated from θ. This inaccuracy is common in the entire field and is not sufficient to rule out differences between existing crystalline materials and between prior art compositions. In some reported X-ray patterns, the relative intensities of the d-spacings are indicated by the symbols strong, strong, medium, and weak, vs, s, m, and w, respectively. At 100xI/I ₀ , the above reference numerals are defined as w=0-15; m=15-60; s=60-80 and vs=80-100.

In some examples, the purity of the synthetic product can be evaluated with reference to its X-ray powder diffraction pattern. Thus, for example, if the sample is considered pure, then only the X-ray pattern of the sample is expected without the line caused by crystalline impurities, and not that no amorphous material is present.

The crystalline composition of the present invention can be characterized by its X-ray powder diffraction pattern, and this can have an X-ray pattern comprising the d-spacing and intensity described in the following table. The X-ray patterns of ZS-1, ZS-2, ZS-6, ZS-7, ZS-8 and ZS-11 are reported in U.S. Patent No. 5,891,417, which is reported below:

The X-ray diffraction pattern of ZS-9 of high purity and high KEC prepared according to Example 14 (XRD shown in Fig. 12) has the following characteristic d-spacing range and intensity:

The formation of ZS involves the reaction of sodium citrate with zirconium acetate in the presence of sodium hydroxide water. The reaction is usually carried out in a small reaction vessel of 1-5 gallons. Smaller reaction vessels have been used to make various crystals of ZS containing ZS-9. The inventors understand that ZS-9 made in such small reactors has insufficient or undesirable low cation exchange capacity (CEC).

The inventors have found that the use of a plate-like structure in a crystallization vessel and proper positioning relative to a stirrer produces a crystalline product of ZS-9 exhibiting crystal purity (as indicated by XRD and FTIR) and unpredictable high potassium ion exchange capacity. In a smaller scale reactor (5 gallons), the cooling coil is positioned in the reactor to provide a plate-like structure. The cooling coil is not used for heat exchange. Many types of cooling coils are available and different designs may have some effect on the results presented here, however the inventors used a coiled coil that was twisted along the inner wall of the reactor.

The inventors have found that the crystallization reaction to produce ZS-9 is particularly beneficial from the baffle when the baffle is properly positioned relative to the agitator. The inventors initially produced ZS-9 with a significant concentration of unwanted ZS-11 impurities. See Figures 10 through 11. This incomplete reaction is believed to be caused by a significant amount of solids remaining near the bottom of the reaction vessel. Even with conventional agitation, these solids near the bottom of the container remain. When properly positioned, the baffle and agitator enhance the reaction conditions in the reactor by creating the force to lift the crystals in the vessel, allowing the necessary heat exchange and agitation to produce ZS-9 in high purity form. In one embodiment, a baffle can be placed in combination with the agitator to provide sufficient lifting force throughout the container regardless of the size of the reactor used. For example, if the reactor size is increased (eg, 200 liters of reactor) and the reaction capacity is increased, the baffles will be sized to accommodate the new reactor capacity. Figures 12 to 13 show XRD and FTIR spectra of high purity ZS-9 crystals. As shown in Table 3 below, this crystalline phase exhibits a higher degree of potassium ion exchange capacity (KEC) than the less pure ZS-9 composition. In an embodiment of the invention, the ZS-9 crystals have a potassium ion exchange capacity between 2.7 and 3.7 meq/g, preferably between 3.05 and 3.35 meq/g. ZS-9 with a potassium ion exchange capacity of 3.1 meq/g has been manufactured on a commercial scale and has achieved the desired clinical results. ZS-9 crystallization with a potassium ion exchange capacity of 3.2 meq/g is also expected to achieve the desired clinical effect and provide an improved dosing regimen. The target of 3.1 and 3.2 meq/g can be achieved with a tolerance of ±15%, preferably ±10%, and most preferably ±5%. The high capacity form of the ZS-9 is ideal, although it is more difficult to produce on a commercial scale. These higher capacity forms of ZS-9 have an increased exchange capacity of greater than 3.5 meq/g, preferably greater than 4.0 meq/g, more preferably between 4.3 and 4.8 meq/g, furthermore Between 4.4 and 4.7 meq/g and optimal is about 4.5 meq/g. A ZS-9 crystal having a potassium ion exchange capacity in the range between 3.7 and 3.9 meq/g was produced according to the following Example 14.

Another unpredictable benefit from the use of a reactor having a standard agitator in combination with a baffle is the high crystal purity, high potassium ion exchange capacity ZS-9 crystallization can be produced without the use of any seed crystals. Previous attempts have been made to utilize seed crystals in the manufacture of homogeneous crystals of high crystal purity with a single crystalline form. Therefore, the ability to eliminate the use of seed crystals is an unpredictable improvement over the previous process.

The microporous composition of the present invention as described has a framework structure of at least one of an octahedral ZrO ₃ unit, a tetrahedral SiO ₂ unit and a tetrahedral GeO ₂ unit, and an optional octahedral MO ₃ unit. This framework results in a system of intracrystalline pores having a uniform pore size, i.e., a crystallographically uniform pore structure of pores. The pore size can vary greatly from about 3 Egypt.

Upon synthesis, the microporous composition of the present invention will comprise some alkali metal templating agent in the pores. Such metals are described as exchangeable cations, meaning that they can be exchanged with other (secondary) A' cations. In general, the A exchangeable cation can be selected from other alkali metal cations (K ⁺ , Na ⁺ , Rb ⁺ , Cs ⁺ ), alkaline earth cations (Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Ba ²⁺ ) A' cation exchange of hydrogen ions or mixtures thereof. It should be understood that the A' cation is different from the A cation. The microporous composition is contacted by a method for exchanging a cation with another cation and a solution which is conventional in the art and which is contained under exchange conditions to contain the desired cation (usually in excess of moir). Generally, the exchange conditions are included at a temperature of from about 25 ° C to about 100 ° C and for a period of from about 20 minutes to about 2 hours. The use of water to exchange ions and the replacement of sodium ions with hydronium ions may take more time and takes 8 to 10 hours. The particular cation (or mixture thereof) present in the final product will depend on the particular application and the particular composition employed. A specific composition is an ion exchanger in which the A' cation is a mixture of Na ⁺ , Ca ^{+ 2} and H ⁺ ions.

When ZS-9 is formed according to such processes, it can be recovered in the form of Na-ZS-9. When the manufacturing process is carried out at a pH greater than 9, the sodium content of Na-ZS-9 is about 12% to 13% by weight. Na-ZS-9 is unstable in hydrochloric acid (HCl) at a concentration above 0.2 M at room temperature and will undergo structural collapse after exposure overnight. At the same time, ZS-9 was slightly stable in 0.2 M hydrochloric acid at room temperature, and the material rapidly lost crystallinity at 37 °C. The Na-ZS-9 system is stable at room temperature in a solution of 0.1 M hydrochloric acid and/or a pH of between about 6 and 7. Under these conditions, the sodium concentration was reduced from 13% to 2% via overnight treatment.

The conversion of Na-ZS-9 to H-ZS-9 can be accomplished by a water wash and ion exchange process, i.e., ion exchange using a dilute acid such as 0.1 M hydrochloric acid or water washing. Washing with water will reduce the pH of the ZS and protonate the visible portion of the ZS, thereby reducing the sodium in the ZS. As long as the protonation of ZS will effectively keep the pH down to the extent of ZS decomposition, it may be desirable to perform initial ion exchange in a higher concentration of strong acid. Additional ion exchange can be accomplished by washing in water or dilute acid to further reduce the sodium concentration in the ZS. ZS made in accordance with the present invention exhibits a sodium content of less than 12% by weight. Preferably, it is less than 9% by weight of sodium, more preferably less than 6% by weight of sodium, and even more preferably less than 3% by weight of sodium, preferably The sodium content is in the range of 0.05% to 3% by weight, and is preferably 0.01% by weight or less or as low as possible. When the protonated ZS system is prepared according to such techniques, the potassium ion exchange capacity decreases relative to the unprotonated crystals. The ZS prepared in this way has a potassium ion exchange capacity of greater than 2.8. In a preferred aspect, the potassium ion exchange capacity is in the range of 2.8 to 3.5 meq/g, more preferably in the range of 3.05 to 3.35 meq/g, and most preferably about 3.2 meq/g. The potassium ion exchange capacity target of about 3.2 meq/g contains small fluctuations in the potassium ion exchange capacity expected to be measured between ZS crystals of different batches.

It has been found that protonation can result in loss of cation exchange capacity when ZS crystals produced under optimal crystallization conditions are protonated. The inventors have found that in the scale-up manufacturing process of ZS-9 with lower crystallization conditions than optimal conditions, the protonation of the resulting ZS crystals produces an increased cation exchange capacity relative to the unprotonated form. Suboptimal crystallization conditions pose a challenge to maintaining adequate agitation of the larger reaction vessel. For example, when the size of the reaction vessel is increased from 50 gallons to 125 gallons, ZS-9 crystals with crystallized impurities are produced. However, the KEC evaluation of the protonated H-ZS-9 crystals provided by this new method is greater than 3.1 meq/g, preferably in the range of 3.2 to 3.5 meq/g, which is expected to be large.

Potassium forms, such as Na-ZS-9 ion exchangers, are effective in the removal of excess potassium ions from the gastrointestinal tract of patients treated with hyperkalemia. When the sodium form is applied to a patient, the replacement of sodium ions by the hydronium ion on the exchanger results in an undesirable increase in the pH of the stomach and gastrointestinal tract of the patient. By in vitro testing, it takes about 20 minutes to acid in the acid to stabilize the sodium ion exchanger.

The hydrated form generally has the same effect as the sodium form in removing potassium ions from the body while avoiding some of the disadvantages of the sodium form that involves a change in pH in the patient. For example, the hydrogenated form has the advantage of avoiding excessive release of sodium from the body upon administration. This alleviates edema due to excessive sodium concentrations, especially when used to treat acute conditions. In addition, patients who are given a hydrated form to treat long-term conditions will benefit from lower sodium concentrations, particularly those at risk of congestive heart failure. In addition, it is believed that the hydrated form will have the effect of avoiding an unwanted increase in the pH of the patient's urine.

The present inventors have found that the lack of calcium-added ZS composition can be used to extract excess calcium from a patient, which makes such compositions useful for the treatment of hyperkalemia in hypercalcemic patients, and for high blood calcium. Treatment. The calcium content of the compositions prepared by the processes described in the U.S. Provisional Serial No. 61/670,415, which is incorporated herein by reference in its entirety, is generally very low, i.e., less than 1 ppm. The inventors have found that hyperkalemia treatment with such compositions is also associated with the removal of significant amounts of calcium from the body of the patient. Therefore, such compositions are particularly useful in patients with hypercalcemia or hypercalcemia who suffer from hyperkalemia.

The composition of the present invention can be prepared by previously loading the above ZS composition with calcium ions. The composition preloaded with calcium ions causes the composition to not absorb calcium when administered to the patient. Alternatively, magnesium can also be preloaded into the ZS.

Preloading the ZS system with calcium (and/or magnesium) is accomplished by contacting ZS with a dilute solution of either calcium or magnesium ions, preferably calcium or magnesium at a concentration ranging from about 10 to 100 ppm. The preloading step can be accomplished simultaneously with the step of exchanging the hydronium ion and sodium ions discussed above. Alternatively, the preloading step can be accomplished by contacting the ZS crystals with a solution containing calcium or magnesium at any stage of its manufacture. Preferably, the ZS composition comprises a potassium or magnesium concentration in the range of from 1 to 100 ppm, preferably from 1 to 30 ppm, and still more preferably from 5 to 25 ppm.

Preloaded ZS does not cause a reduction in potassium absorption capacity and therefore does not detract from the use of such compositions in hyperkalemia treatment. It is believed that calcium and/or magnesium ions cannot completely penetrate the pores of ZS because of their size. Instead, the loaded calcium or magnesium is only maintained on the surface of the ZS. This added calcium or magnesium causes the body to absorb calcium or magnesium from the patient's body and is therefore preferred in clinical applications of hyperkalemia.

In other embodiments, the protonated ZS can be linked to a hydroxyl-loaded anion exchanger that facilitates the removal of sodium, potassium, ammonium, hydrogen, and phosphate, such as zirconia (OH-ZO). Without being bound by theory, the hydrogen released from the protonated ZS and the hydroxide released from the OH-ZO combine to form water, thereby reducing the concentration of "counter-ions" that weaken other ion binding. The bonding ability of the cation to the anion exchanger should be increased by application together. This form of ZS is useful for the treatment of many types of diabetes. In one embodiment, the composition is used to remove sodium, potassium, ammonium, hydrogen, and phosphate from the gut and from patients with renal failure.

ZS-9 crystals have a broad particle size distribution. It is theorized that small particles less than 3 microns in diameter may be absorbed into the blood of a patient, resulting in the potential for particles to accumulate in the patient's urethra, particularly the unwanted effects of the patient's kidneys. Commercially available ZS systems are obtained by filtering out portions of the particles that are less than 1 micron. However, it has been found that small particles remain on the filter cake and removal of particles having a diameter of less than 3 microns requires the use of additional screening techniques.

The inventors have found that screening can be used to remove particles having a diameter of less than 3 microns, and the removal of such particles can be beneficial for a therapeutic product comprising a ZS composition of the invention. A number of techniques for screening particles can be used to achieve the objectives of the present invention, including manual screening, air jet screening, sieving or filtration, floating screens, or any other known method of particle classification. The ZS composition, which is the subject of screening techniques, presents a desired particle size distribution that avoids the potential complications associated with the use of ZS treatment. In general, as long as the particles are too small, the size distribution of the particles is not important. The ZS composition of the present invention exhibits a median particle size greater than 3 microns, and less than 7% of the particles in the composition have a diameter of 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, and more preferably less than 3% of the particles in the composition. Having 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, and further 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. The best system has no particles or only traces having a diameter of less than 3 microns. Particles having a median particle size of preferably greater than 3 microns and up to the size of 1000 microns are also possible in certain applications. Preferably, the median particle size is in the range of from 5 to 1000 microns, more preferably from 10 to 600 microns, more preferably from 15 to 200 microns and most preferably from 20 to 100 microns.

The particle screening can be carried out before, during or after the ion exchange process in which the sodium content of the ZS material is reduced to 12% or less as described above. Reduction of the sodium ion content to less than 3% can occur through many steps of the binding screen or can occur completely before or after the screening step. Particles having a sodium content of less than 3%, with or without particle size as described herein, may be effective.

In addition to screening or sieving, the desired particle size distribution may use granulation or other agglomeration techniques to produce particles of appropriate size.

In other embodiments, the ZS composition can further comprise atoms or molecules attached to its surface to produce grafted crystals. The grafted atoms or molecules are attached to the surface of the ZS, preferably by stabilizing the covalent bond. In one embodiment, the organic citrate moiety is grafted onto the surface of the ZS composition through a reactive group such as a sterol group (≡Si-O-H) on the crystalline surface. This can be done, for example, by using an aprotic solvent. In other embodiments, the alkoxydecane can be grafted and the corresponding alcohol will need to be used to carry out the reaction. The free stanol groups on the recognition surface can be carried out, for example, by infrared spectroscopy. In other embodiments, if the grafted material lacks reactive groups on its surface, pickling can be used to promote its formation. After successful grafting, the ZS composition can further comprise a composition having a labeled radioisotope such as, but not limited to, C or Si. In another embodiment, the ZS composition may also contain non-exchangeable atoms, such as Zr, Si or O isotopes that may be used in mass balance studies.

It is also within the scope of the invention that such microporous ion exchange compositions can be used in powder form or in a variety of shapes by methods known in the art. Examples of various shapes include pellets, extrudates, spheres, pellets, and irregularly shaped particles. It is also foreseen that the various forms can be wrapped in a variety of known containers. This may include capsules, plastic bags, bags, bags, sachets, dose bags, vials, bottles or any other loading device that is generally known to those skilled in the art.

The microporous ion exchange crystals of the present invention can be combined with other materials to produce a composition that provides the desired utility. The ZS composition can be combined with foods, drugs, devices and compositions for treating various diseases. For example, the ZS compositions of the present invention can be combined with toxin reducing compounds, such as charcoal, to accelerate the removal of toxins and poisons. In other embodiments, the ZS crystals may be present as a combination of two or more ZS forms of ZS-1 to ZS-11. In one embodiment, the combination of ZS may comprise ZS-9 and ZS-11, preferably ZS-9 and ZS-7, further preferably ZS-9, ZS-11 and ZS-7. In other embodiments of the invention, the ZS combination may comprise a mixture or mixture of ZS-9, wherein ZS-9 is present greater than at least 40%, preferably greater than at least 60%, and even more preferably greater than or equal to 70% The remaining portion may comprise a mixture of other forms of ZS crystals (i.e., ZS-1 to ZS-11) or other amorphous forms. In other embodiments, the mixing of ZS-9 may comprise greater than about 50% to 75% of ZS-9 crystals and greater than about 25% to 50% of ZS-7 crystals and the remainder of other forms of ZS crystals, The remaining ZS crystals do not contain ZS-8 crystals.

As stated, the composition has particular utility in the absorption of various toxins from body fluids, dialysate and mixtures thereof. As used herein, body fluids will include, but are not limited to, blood and gastrointestinal fluids. Also, the body means any mammalian body including, but not limited to, humans, cows, pigs, sheep, monkeys, gorillas, horses, dogs, and the like. The method of the invention is particularly suitable for the removal of toxins from the human body.

The zirconium metal salt can also be formulated into pellets or other shapes that can be taken orally and transmitted as an ion exchanger to extract toxins from the gastrointestinal fluid through the intestinal tract and eventually discharged. In one embodiment, the ZS composition can be formed into wafers, pellets, powders, medical foods, suspended powders or layered structures comprising two or more ZS. In order to protect the ion exchanger from the high acid content in the stomach, the shaped article may be coated with various coatings that are insoluble in the stomach but are soluble in the intestine. In one embodiment, the ZS can be shaped into a capsule that is subsequently coated or embedded in an enteric coating or used in a site specific delivery.

As also described above, although the compositions of the present invention are synthesized with various exchangeable cations (A), they are preferably secondary cations (A') which are more compatible with blood or which do not adversely affect blood. Exchange cations. Preferred cations for this reason are sodium, calcium, hydronium ions and magnesium. Preferred compositions comprise sodium and calcium; sodium and magnesium sodium; calcium and hydronium ions; sodium, magnesium, and hydronium ions; calcium sodium, magnesium, and hydronium ions. The relative amounts of sodium and calcium can vary widely and depend on the microporous composition and the concentration of such ions in the blood. As discussed above, when sodium is an exchangeable cation, it is desirable to replace the sodium ion with a hydrated ion, thereby reducing the sodium content of the composition.

ZS crystals, as described in the entire disclosure of U.S. Application Serial No. 13/371,080, the disclosure of which is incorporated herein by reference. This increased capacity crystallization can also be used in accordance with the present invention. The dosage used to formulate the pharmaceutical compositions according to the present invention will be adjusted according to the cation exchange capacity as determined by one of ordinary skill in the art. Accordingly, the amount of crystallization used in the formulation will vary based on this determination. Because of its higher cation exchange capacity, fewer doses may be required to achieve the same utility.

The compositions of the invention are useful for treating diseases or conditions involving elevated serum potassium concentrations. Such diseases may include, for example, chronic or acute kidney disease; chronic, acute or subacute hyperkalemia. For patients suffering from a disease or condition with elevated serum potassium concentrations, the invention is administered at a specific potassium reduction dose. The dose administered may be ZS in the range of about 1.25-15 grams (~18-215 mg/Kg/day), preferably 8-12 grams (~100-170 mg/Kg/day), more preferably. It is 10 grams (~140 mg/Kg/day) three times a day. In other embodiments, the total dose of the composition can be in the range of about 15-45 grams (~215-640 mg/Kg/day), preferably 24-36 grams (~350-520 mg/Kg/ Day), more preferably 30 grams (~400 mg/Kg/day). When administered to a subject, the compositions of the present invention are capable of reducing the serum potassium concentration to a normal concentration of approximately 3.5-5 mmol/L. The molecular sieve of this product is capable of specifically removing potassium without affecting other electrolytes (ie, no hypomagnesemia or no hypocalcemia). The use of this product or composition is accomplished with the aid of no laxatives or other resins to remove excess serum potassium.

Acute hyperkalemia requires immediate reduction of serum potassium concentrations to normal or near normal concentrations. Molecular sieves of the invention having a KEC in the range of about 1.3-2.5 meq/g will be capable of reducing elevated concentrations of potassium to within the normal range for about 1-8 hours after administration. In one embodiment, the product of the invention is capable of reducing the elevated concentration for at least 1, 2, 4, 6, 8, 10 hours after administration. The dosage required to reduce the elevated potassium concentration may range from about 5 to about 15 grams, preferably from about 8 to about 12 grams, and more preferably about 10 grams. Molecular sieves having a higher KEC in the range of about 2.5-4.7 meq/g will be more efficient at absorbing potassium. Thus, the dosage required to reduce the elevated potassium concentration can range from about 1.25 to 6 grams. The schedule for administering the dose can be at least once a day, more often three times a day.

Long-term and subacute hyperkalemia treatments will require maintenance doses to maintain potassium concentrations close to normal serum potassium concentrations or to normal serum potassium concentrations. Therefore, the administration of the product of the present invention will be lower than the administration of a patient suffering from acute blood potassium. In one embodiment, a composition comprising a molecular sieve having a KEC in the range of from about 2.5 to about 4.7 meq/g will be dosed in the range of from about 1 to about 5 grams, preferably from about 1.25 to about 5 grams, preferably about 2.5-5 grams, preferably about 2-4 grams, more preferably about 2.5 grams. A smaller composition comprising a molecular sieve having a KEC in the range of about 2.5 to 4.7 meq/g will be accepted, and the dosage will be arranged in the range of about 0.4 to 2.5 grams, preferably about 0.8 to 1.6 grams, preferably About 1.25-5 grams, preferably about 2.5-5 grams, more preferably about 1.25 grams. Patients following this subset are important factors in maintaining normal potassium concentrations. Thus, the dosage regimen will therefore be an important consideration. In one embodiment, the dose will be administered to the patient at least three times a day, preferably once a day.

The composition or product of the present invention can be configured in a manner that is convenient to administer. For example, the compositions of the present invention can be formulated into tablets, capsules, powders, granules, crystals, sachets, or any dosage form conventionally known to those skilled in the art. The various forms may be formulated to contain 5-15 grams, preferably about 8-12 grams, more preferably about 10 grams of individual doses administered daily, weekly or monthly; or may be formulated to contain Between 15-45 grams, preferably about 24-36 grams or more, a single dose of about 30 grams. In other embodiments, individual dosage forms can be at least greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, or 40 grams. If the dosage form is a tablet, it may be formulated as granules, granules or as a sustained release dosage form. The capsule can be configured as a discrete, delayed release or dose package for administration three times a day. The powder can be formulated to dissolve and contained in a plastic pouch or pouch. Those of ordinary skill in the art will recognize that the above dosage forms are not limited and that other forms of solids may also be used to administer the products or compositions of the present invention.

Surprisingly, the administration of the composition of the present invention at a dose of about 10 grams (~140 mg/Kg/day) as described in detail for three times a day (i.e., 30 grams (~400 mg/kg/day)) can be reduced. Reduce the potassium concentration in serum for an extended period of time. The inventors have found that when the product or composition of the present invention is administered three times a day at a dose of about 10 grams, the effect of reducing and the serum potassium concentration to the normal range is maintained for 5 days after two days of emergency treatment. However, it is expected that the products of the present invention will be discharged in a relatively rapid manner.

The ZS of the present invention may be modified by other drugs or treatments and/or combined with other drugs or therapies if the subject has multiple conditions or diseases. For example, in one embodiment, the subject may be hyperkalemia and chronic kidney disease, wherein a Na-ZS composition may be used. In another embodiment, the ZS composition for treating chronic kidney disease may further comprise sodium bicarbonate in combination with the protonated form of ZS. In other embodiments, a subject with hyperkalemia and chronic heart failure may require the use of a protonated ZS composition. In other embodiments, the treatment of hyperkalemia and chronic heart disease will require no more than 10% sodium, preferably 2% sodium is present in the ZS.

In other embodiments of the invention, the ZS described herein can be further combined with activated carbon. Activated carbon has the utility of attracting organic molecules that circulate within the host system. See, for example, HSGD Haemosorbents for medical device applications, Nikolaev V. G. Presentation, London. Therefore, the combination of activated carbon and ZS will serve as a combination product with the ability to remove excess potassium and organic molecules. The activated carbon will comprise a plurality of absorbent pores in the range of from about 8 angstroms to about 800 angstroms in diameter, preferably at least about 50 angstroms in diameter. The ZS of the present invention in combination with activated carbon will be useful for the treatment of many diseases and/or conditions that require the removal of excess organic molecules such as, but not limited to, lipids, proteins and toxins. For example, the carbon comprising the ZS composition of the present invention is a pyrimidine, a methyl guanidine, a guanidine, an o-hydroxy hippuric acid, a p-hydroxy hippuric acid, a parathyroid hormone, a guanidine, a phenol, a guanidine. Useful for the removal of terpenoids, pesticides, carcinogenic heterocyclic amines, ascorbic acid conjugates, trihalomethanes, dimethylarginine, methylamines, organochloramines, polyamines or combinations thereof . Activated carbon in combination with ZS is also useful in absorbing elevated concentrations of bile acids, albumin, ammonia, creatinine and bilirubin. To further enhance the adsorption of the activated carbon with the coated ZS, the composition may further coat the albumin layer, the lipid layer, the DNA layer, and the heparin layer with an additional adsorption effect in the range of about 12% to about 35%.

Activated carbon and ZS compositions will appear like hyperkalemia, acute and chronic gastric mucositis, acute and chronic enteritis, gastritis of hyperacidity, summer diarrhea, catarrhal jaundice, food-related toxic infections, kidney disease, dysentery , cholera, typhoid, enterobacteria vector, heartburn, nausea, acute viral hepatitis, chronic active hepatitis and cirrhosis, complicated hepatitis, mechanical jaundice, liver-kidney failure, hepatic coma or a combination of multiple diseases or conditions Useful for subject treatment.

In other embodiments, the ZS compositions described herein can be used in a variety of methods comprising administering a composition described herein to a subject described herein to remove excess potassium concentration. In other embodiments of the invention, the method can comprise administering a ZS conjugate as described herein and can further comprise an added composition to aid in the removal of potassium while simultaneously removing other materials, such as, but not limited to, from a subject. In addition to toxins, proteins or ions.

In order to more fully illustrate the invention, the following examples are set forth. It is to be understood that the examples are merely illustrative and not intended to be a limitation of the broad scope of the invention as set forth in the appended claims.

Example 1

By mixing 2058 g of colloidal silicon dioxide (DuPont regarded as Ludox ^TM AS-40), 2210 g of KOH in 7655 g H ₂ O to prepare a solution. After vigorous stirring for a few minutes, 1471 g of zirconium acetate solution (22.1 wt.% ZrO2) was added. The mixture was stirred for a further 3 minutes and the resulting gel was transferred to a stainless steel reactor and hydrothermally reacted at 200 ° C for 36 hours. The reactor was cooled to room temperature and the mixture was vacuum filtered to isolate a solid that was washed with deionized water and dried in air.

The solid reaction product was analyzed and found to contain 21.2 wt% Si, 21.5 wt% Zr, K 20.9 wt% K, loss on ignition (LOI) 12.8 wt%, which was given K _2.3 ZrSi _3.2 O _9.5 *3.7H ₂ The chemical formula of O. This product is considered sample A.

Example 2

By mixing 121.5 grams of colloidal cerium oxide (DuPont sees Ludox AS-40), 83.7 g of NaOH in order to prepare a solution of 1051 g H ₂ O. After vigorous stirring for a few minutes, 66.9 g of zirconium acetate solution (22.1 wt.% ZrO2) was added. The mixture was stirred for a further 3 minutes and the resulting gel was transferred to a stainless steel reactor and hydrothermally reacted at 200 ° C and stirred for 72 hours. The reactor was cooled to room temperature and the mixture was vacuum filtered to isolate a solid that was washed with deionized water and dried in air.

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.%, which was given Na _2.0 ZrSi _2.0 O _9.0 *3.5H ₂ O Chemical formula. This product is considered sample B.

Example 3

Slowly add colloidal cerium oxide solution (60.08 g) over a period of 15 minutes (DuPont considers Ludox AS-40) to 64.52 grams of KOH is dissolved in a stirred solution of 224 grams of deionized water. Subsequently, 45.61 g of zirconate (15-16 wt.% Zr from Aldrich, in dilute acetic acid) was added. When this addition was complete, 4.75 grams of aqueous Nb ₂ O ₅ (30 wt.% LOI) was added and stirred for a further 5 minutes. The resulting gel was transferred to a stirred autoclave reactor and hydrothermally treated at 200 ° C for 1 day. After this time, the reactor was cooled to room temperature, the mixture was vacuum filtered, the solid was washed with deionized water and dried in air.

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.%, which was given K _2.14 Zr _0.71 Nb Chemical formula of _0.29 Si ₃ O _9.2 *2.32H ₂ O. A portion of the electronically scanned (SEM) sample, containing crystalline EDAX, indicates the presence of yttrium, zirconium and hafnium frame elements. This product is considered sample C.

Example 4

A solution was prepared by mixing 141.9 g of NaOH granules in a solution of 774.5 g of water to which 303.8 g of sodium citrate was added and stirred. To this mixture, 179.9 g of zirconium acetate (15% of Zr in a 10% acetic acid solution) was added dropwise. After thorough mixing, the mixture was transferred to a Hastelloy (Hastalloy ^TM) reactor, and heated under autogenous pressure to 200 ℃ and stirred 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 a 0.001 M NaOH solution and then dried at 100 ° C for 16 hours. Analysis by X-ray powder diffraction indicated that the product was pure ZS-11.

Example 5

37.6 g of NaOH pellets were added to the vessel and dissolved in a solution of 848.5 g of water, and 322.8 g of sodium citrate was added to the solution and mixed. To this mixture, 191.2 g of zirconium acetate (15% of Zr in 10% acetic acid) was added dropwise. After thorough mixing, the mixture was transferred to a Hastelloy reactor which was heated to 200 ° C under autogenous conditions and stirred for 72 hours. After cooling, the product was filtered, washed with a 0.001 M NaOH solution, and then dried at 100 ° C for 16 hours. Analysis by X-ray powder diffraction indicated that the product was ZS-9 (i.e., a composition mainly in the crystalline form of ZS-9).

Example 6

About 57 grams (non-volatile free base, batch 0063-58-30) of Na-ZS-9 was suspended in about 25 milliliters of water. The 0.1 N HCl solution was gradually added, gently stirred, and the pH was monitored with a pH meter. A total of about 178 ml of 0.1 N HCl was added and stirred, and the mixture was filtered, and then further washed with an additional 1.2 liters of 0.1 N hydrochloric acid. The material was filtered, dried and washed with DI water. The resulting material had a pH of 7.0. The H-ZS-9 powder was ion exchanged from this three-part batch and produced with <12% Na of 0.1 N HCl.

As illustrated in this example, batch ion exchange with a dilute strong acid can reduce the sodium content of the NA-ZS-9 composition to the desired range.

Example 7

Approximately 85 grams (non-volatile free base, batch 0063-59-26) of Na-ZS-9 in 31 liters of DI water in 2 liter increments for 3 days until the pH of the cleaning solution 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 obtained from batch ion exchange and water rinse had <12% Na.

As illustrated in this example, water washing can reduce the sodium content of the NA-ZS-9 composition to the desired range.

Example 8

Individual batches of ZS-9 crystals were analyzed using light scattering diffraction techniques. Particle size distribution and other measurement parameters are shown in Figures 2 through 4. d (0.1), d (0.5), and d (0.9) represent 10%, 50%, and 90% dimensional values. The cumulative particle size distribution is shown in Figures 4 through 6. It can be seen from the graph that the cumulative volume of particles has a diameter ranging from about 0.3% to about 6% below 3 microns. In addition, different ZS-9 batches have different particle size distributions with varying degrees of particle size having a diameter of less than 3 microns.

Example 9

The crystals of ZS-9 are screened to remove the bulk of the small diameter particles. The particle size distribution of the ZS-9 crystals obtained by screening using different sizes was analyzed. As shown in the following figures, the proportion of particles having a diameter of less than 3 microns can be reduced and eliminated using a suitable mesh size screen. Without sieving, about 2.5% of the particles have a diameter of less than 3 microns. See Figure 5. By screening with a 635 mesh screen, the proportion of particles having a diameter of less than 3 microns was reduced to about 2.4%. See Figure 6. The proportion of particles having a diameter of less than 3 microns was further reduced to about 2% via screening with a 450 mesh screen. See Figure 7. The proportion of particles having a diameter of less than 3 microns was further reduced to about 0.14% by screening with a 325 mesh screen. See Figure 8. Finally, the 230 mesh screen reduces the proportion of particles below 3 microns to 0%. See Figure 9.

The screening technique presented in this example illustrates that a particle size distribution of ZS-9 providing little or no particles below 3 microns can be obtained. It will be appreciated that ZS-9 according to Example 5 or H-ZS-9 according to Example 6 and Example 7 can be screened as taught in this example to provide the desired particle size distribution. In particular, the preferred particle size distribution disclosed herein can be obtained using techniques used in the ZS-9 and H-ZS-9 paradigms.

Example 10

A 14-day repeated dose oral toxicity test and response to Beagle was performed. This GLP-compliant oral toxicity study was conducted on Beagle to assess the potential oral toxicity of ZS-9 when administered at 6 hour intervals, 12 hours, 3 times a day, in food, for at least 14 consecutive days. In the main study, ZS-9 was applied to 3/dogs/sex/dose at a dose of 0 (control), 325, 650 or 1300 mg/kg/dose. An additional 2 dogs/sex/dos was assigned to the recovery study, receiving either 0 or 1300 mg/kg/dose at the same time as the primary study animals, and additionally maintaining discontinuation of treatment for 10 days. The correction factor of 1.1274 is used to correct the water content of ZS-9. A dose record is used to confirm the accuracy of the dosing.

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 course of treatment, the required amount of substance to be tested (according to the recently recorded weight) is mixed with ~100 grams of wet dog food and supplied to the dog at 6 hour intervals. Additional dry food is provided as the last daily dose is consumed. Each dog receives a quantity of wet dog food. Body weights were recorded on arrival and on Days -2, -1, 6, 6, and 20. Two clinical observations per day were performed during the acclimation, treatment, and recovery periods. The consumption of both dry and wet feeds was measured daily during the treatment period. Blood and urine samples before the test (-1 day) and day 13 were collected for serum chemical analysis, hematology, coagulation, and urinalysis parameters. Ophthalmologic examinations were performed before the test (Day -6/7) and Day 7 (female) or Day 8 (male). ECG assessments were performed before the test (Day-1) and Day 11. At the end of the study (Day 14 - Major Study and Day 24 - Recovery Study), a necropsy was performed, the weight of the organ designated by the protocol was weighed, and the selected tissue was microscopically examined.

It is good to allow 325, 650 and 1300 mg ZS-9/kg/dose and food to be administered orally three times a day at 6 hour intervals, 14 days during 12 hours. The clinical symptoms were limited to the second week of treatment at 325 mg/kg/dose in some dogs and accepted The feces of all animals at 650 mg/kg/dose were assumed to be observations of the white material of the test article. No adverse effects on body weight, weight change, food intake, hematology and coagulation parameters or ophthalmoscopy and ECG assessment.

The administration of ZS-9 is not visible to the naked eye. Under the microscope, minimal mild focal and/or multifocal inflammation was observed in the kidneys of the treated animals, but not in the control animals. At 650 and 1300 mg/kg, lesions have similar morbidity and severity and are less frequent and severe at 325 mg/kg. In some dogs, inflammation is unilateral rather than bilateral and in some cases associated with inflammation of the bladder and ureter origin. These observations indicate that in addition to direct injury to the kidney, changes in the urine composition of dogs treated with ZS-9- may result in increased susceptibility to subclinical urinary tract infections, even if no microbes are observed in these tissues. . In restoring animals, these inflammations are completely resolved in females and partially resolved in males, meaning that irrespective of inflammation, they are reversible with discontinuation of administration.

The incidence of elevated leukocyte inflammation observed in the beagle treated with ZS-9 is summarized below.

The following summary of the lowest acute cystitis and unexplained crystallization was also observed in the renal pelvis and urine at a dose of 650 mg/kg/dose.

Crystallization was not identified in the females of group 2 or 4 or males treated with ZS-9.

It was noted in both experiments that the urine pH was increased compared to the control group and that the change in urine pH and/or the urine composition affecting the solubility of the urine solutes caused urinary tract irritation and/or increased urine. The formation of susceptibility to road infections (UTIs).

The insolubility of urine crystals (long fine clusters) and test articles in combination with particle size data makes these crystals less likely to be ZS-9.

Example 11

Crystals of ZS-9 and specific "unscreened ZS-9" were prepared. The ZS-9 crystalline samples were screened according to the procedure of Example 10, and the screened samples were designated as "ZS-9 > 5 microns." Other Examples of ZS-9 Crystals The ion exchange of the procedure of Example 6 above was followed by screening according to the procedure of Example 10. The obtained H-ZS-9 crystal was designated as "ZS-9+>5 μm".

The following 14-day study design was designed to show the effect of particle size and particle form on the pH of the urine and the crystallization present in the urine. The above compounds were orally administered to the beagle by mixing with the wet dog food. The program is administered three times a day in the following manner during a 12-hour interval of 6 hours:

The table below summarizes this observation, toxicokinetic evaluation, laboratory tests (hematology, urinalysis), and terminal procedures.

During the study period, in the female dogs, the test samples were unscreened ZS-9, ZS-9>5μm and ZS-9+>5μm at 6 hours intervals for 12 hours, for 14 consecutive days, three times a day, using the wet grain carrier from the diet. Ingestion. The dose concentration is 100 or 600 mg/kg/dose.

All animals survived a 14-day dosing cycle. There were no test article-related changes in mortality, weight, weight gain, organ weight, as seen by the naked eye, or in clinical chemistry or blood gas parameters. The ZS-9-related findings were based on an increase in the proportion of sodium excretion and an increase in the pH of the urine in animals receiving the 6000 mg/kg/dose dose or in the unscreened ZS-9, and a reduction in the proportion of potassium excretion and 600 mg. /kg/dose Urea nitrogen/creatinine ratio in urine of unscreened ZS-9, ZS-9 > 5 μm and ZS-9 + > 5 μm administered animals.

Compared with the control group, the urine pH of the animals treated with 600 mg/kg/dose unscreened ZS-9 and ZS-9>5 μm satisfactorily increased significantly, at 100 mg/kg/dose and 600 mg/ Not observed in kg/dose ZS-9+>5 μm treated animals. The urine pH of these animals increased from 5.33 to ~7.67 on day 7, and increased from 5.83 to ~7.733 on day 13. The lack of effect on the urine pH of animals treated with protonated ZS-9 (ZS-9+>5 μm) at 600 mg/kg/dose indicates that ZS-9 was loaded with a higher dose of sodium (unscreened ZS-9) The increase in the pH of the urine of animals treated with ZS-9>5 μm) is the result of hydrogen absorption in the gastrointestinal tract.

All differences found in urine volume and specific gravity are considered to be within acceptable ranges for normal physiological and/or surgical related variations. Partial changes between the urine components of the treatment group in biochemical (protein, ketone, etc.) and microscopy (crystals, blood cells, etc.) are also considered to be within acceptable limits for biological and/or operational related changes. At all study intervals, triple phosphate crystals (magnesium ammonium phosphate) were observed in most animals, and a small amount of calcium oxalate crystals was also observed in some animals. These two crystal types are considered to be a normal finding on dogs. No pattern was observed, and the crystals observed in any animal were associated with treatment or test objects. No unexplained crystallization was observed in the urine precipitate of any animal.

On days 7 and 13, the sodium excretion ratio was increased relative to the pre-dose interval in all cohorts containing the control group. Animals receiving 600 mg/kg/dose unscreened ZS-9, ZS-9>5 μm and ZS-9+>5 μm tend to be slightly larger (up to 116% relative to the control group) among other treatment groups or control animals. The observed increase. The increase observed in these three groups occasionally reached a magnitude above the expected range and was attributed to the test article. No significant differences were observed between the changes observed in the three groups. The sodium excretion ratio of animals treated with 600 mg/kg/dose protonated ZS-9 did not differ. These changes are attributed to the test article and do not take into account toxicological disadvantages.

Compared with the control group, animals treated with 600 mg/kg/dose unscreened ZS-9, ZS-9>5 μm and ZS-9+>5 μm and 100 mg/kg/dose ZS-9>5 μm on day 7 and A significantly reduced proportion of potassium excretion was observed in 13 days. Most of these values reached statistical significance on days 7 and 13 relative to the control group. These reductions are due to the pharmacological effects of the test article.

On days 7 and 13, all groups containing the control group had a relatively slight increase in the urea nitrogen/creatinine ratio relative to the pre-dose interval. Compared with the control group, the ratio of urea nitrogen/creatinine on the 7th day and the 13th day of the animals receiving 600mg/kg/dose unscreened ZS-9, ZS-9>5μm and ZS-9+>5μm was slightly reduced ( Up to 26%). Although the group mean values were not significantly different from their pre-test values, most of the changes observed on the 7th and 13th day groups were statistically significant compared to the control group. These findings are believed to be related to the test article. Although there were occasional statistically significant differences between the other endpoints, the effects of creatinine clearance, calcium/creatinine ratio, magnesium/creatinine ratio, or urine osmotic pressure test article were confirmed in any treatment cohort.

The test lines seen under the microscope in the kidney were observed at 600 mg/kg/dose. The most common findings are minimal to slightly mixed leukocyte infiltration (lymphocytes, plasma cells, macrophages, and/or neutrophils), as well as minimal to mild tubular regeneration (from attenuated epithelial cells, with Plump nuclear epithelial cells and cytoplasmic basophilic slightly enlarged tubular lining). Minimal pyelitis (infiltration of neutrophils, lymphocytes, and plasma cells in the submucosal layer of the renal pelvis) and minimal tubular degeneration/necrosis (by eosinophils with pyknosis or nuclear rupture and epithelial cells contained in shedding and/or Or inflammatory cells in the lumen of the lumen, in a dog receiving 1/3 of 600 mg/kg/dose unscreened ZS-9 and receiving 1/600 of 600 mg/kg/dose ZS-9>5 μm Observed in 3 dogs. Minimal pyelonephritis and mixed leukocyte infiltration in the urethra or ureter are also present in some dogs given ZS-9 > 5 μm.

Most of the changes in the kidney occur in the cerebral cortex and are occasionally randomized in the medulla, ranging from lesions to multiple lesions (up to 4 lesions). These foci are of variable size, most irregular, occasionally linear (extending from the outer cortex to the medulla), and involve less than 5% of the kidney parenchyma in a given section. Most lesions consisted of minimal to mild leukocyte mixing with minimal to mild tubular infiltration, with minimal to minor tubular regeneration in some lesions without mixed leukocyte infiltration. Some of these lesions (two dogs given 600 mg/kg/dose unscreened ZS-9 and one dog given 600 mg/kg/dose ZS-9 > 5 μm) contained a small amount of denatured/necrotic tubules. Pyelitis is present in four dogs (one dog given 600 mg/kg/dose unscreened ZS-9 and three dogs given 600 mg/kg/dose ZS-9 > 5 μm).

Infiltration of mixed leukocytes was also present in the submucosal layer of bilateral ureters administered to dogs 600 mg/kg/dose ZS-9>5 μm and given 600 mg/kg/dose unscreened ZS-9, 600 mg/kg/dose ZS -9> 5 μm animal urethra submucosa. The incidence and/or severity of leukocyte infiltration in renal parenchyma is higher in dogs with pyelitis compared to dogs without pyelitis. In some dogs, the presence and multifocality of pyelonephritis and/or mixed leukocyte infiltration in the urethra and ureter, a random distribution of inflammatory infiltrating kidneys, reminiscent of an up-and-down urinary tract infection, and presented at 600 mg/kg The kidneys found in /dose may be an indirect effect of the test article.

In dogs given 600 mg/kg/dose unscreened ZS-9, the kidneys of two of the three dogs were affected by one or more of the above mentioned findings. All three dogs given 600 mg/kg/dose ZS-9 > 5 μm contained renal lesions with pyelitis and mixed leukocyte infiltration in the submucosal layer of the urethra or ureter. In dogs given 600 mg/kg/dose ZS-9+>5 μm, there was minimal mixed leukocyte infiltration and tubular regeneration in only one left kidney in one dog, while the other dog had minimal lesions with minimal tubular regeneration.

Test-related findings (directly or indirectly) were not present in female dogs given 100 mg/kg/dose unscreened ZS-9 (ZS-9, ZS-9 > 5 μm, ZS-9 + > 5 μm). Occasional lesions or two minimal tubular regenerations occurred in three animals without evidence of mixed leukocyte infiltration or tubular degeneration/necrosis. Similar lesions/focal points of renal tubular regeneration also appeared in the control group. Tumor regeneration was observed to be slightly smaller in the female dogs given less doses of unscreened ZS-9 and was not associated with mixed leukocyte infiltration or tubular degeneration/necrosis. There is no evidence of crystallization in any of the test sections. Tubular mineralization in nipple and glomerular lipid deposition is a background study in beagle and is not considered to be associated with test articles.

600mg/kg/dose unscreened ZS-9, ZS-9>5μm and ZS-9+>5μm have minimal to mild mixed leukocyte infiltration in the kidney sometimes with minimal to mild tubular regeneration and occasional minimal tubular degeneration / Necrosis-related, mixed leukocyte infiltration in the ureter and / or urethra and minimal pyelitis in unscreened ZS-9 and ZS-9 > 5 μm dogs.

No increase in urine pH in dogs treated with 600 mg/kg/dose ZS-9+>5 μm combined with reduced incidence of microscopic studies in these dogs and unscreened ZS supplemented with potassium at 600 mg/kg/dose 9 Treated dogs indicate that urine pH and/or potassium removal due to increased pharmacological effects of the test article may have increased susceptibility to background damage from urine crystals and bacteria.

Based on these results, the no-observable-effect-level (NOEL) was 100 mg/kg/dose unscreened ZS-9, ZS-9>5 μm, and ZS-9+>5 μm. The dose of no-observable-adverse-effect-level (NOAEL) was determined to be 600 mg/kg/dose for unscreened ZS-9, and 600 mg for ZS-9 (ZS-9>5 μm) for screening. The /kg/dose and the screened and protonated ZS-9 (ZS-9+>5 μm) were 600 mg/kg/dose.

Example 12

ZS-9 was crystallized and prepared by reaction in a standard 5-G crystallization vessel.

The reactants were prepared as follows. The 22-L Morton flask was equipped with an overhead stirrer, thermocouple and balanced addition funnel. Deionized water (3.25 liters) was added to the flask. Stirring was started at about 100 rpm and sodium hydroxide (090 g NaOH) was added to the flask. The contents of the flask exotherm when sodium hydroxide is dissolved. The solution was stirred and cooled to below 34 °C. Sodium citrate solution (5672.7 g) was added. To this solution was added a solution of zirconium acetate (3309.5 g) for more than 43 minutes. The resulting suspension was stirred for a further 22 minutes. Seed crystals of ZS-9 (223.8 g) were added to the reaction vessel and stirred for about 17 minutes.

The mixture was transferred to a 5-G Parr pressure vessel with the aid of deionized water (0.5 liters). The container has a smooth wall and a standard blender. There is no cooling coil in the reactor. The vessel was sealed and the reaction mixture was stirred at about 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 reaction was then cooled to 80 ° C for 12.6 hours. The resulting white solid was filtered with the help of deionized water (18 L). The solid was washed with deionized water (125 L) until the pH of the eluted filtrate was less than 11 (9.73). The wet cake was dried under vacuum (25 inches of Hg) at 95-105 °C for 48 hours to afford 2577.9 g of ZS-9 (107.1%) as a white solid.

The XRD pattern of ZS-9 obtained in this example is shown in Fig. 10. The FTIR spectrum of this material is shown in Figure 11. These XRD and FTIR spectra are characterized by the appearance of absorption peaks typically associated with the crystalline form of ZS-11. In addition, the peak associated with ZS-9 exhibits significant diffusion due to crystal impurities (such as ZS-11 crystals present in the ZS-9 composition). For example, the FTIR spectrum shows significant absorption around 764 and 955 cm ^-1 . The XRD pattern of this example shows significant noise and undefined peaks at 2, 25, and 42.5 values.

Example 13

The ZS-9 crystals in this example were protonated.

Deionized water (15.1 liters) was charged to a 100 L reaction vessel under vacuum and stirring (60-100 rpm). ZS-9 crystals (2.7 kg) were added to a 100 liter vessel containing deionized water and allowed to react for a period of 5-10 minutes. Record the initial pH reading.

In a separate 50 liter glass jar, the preparation of the hydrochloric acid solution included the step of charging deionized water (48 liters) followed by hydrochloric acid (600 ml) to a large glass vial. The hydrochloric acid solution was charged into a 100 liter reaction vessel over a period of 1.5-2 hours. The hydrochloric acid solution was added to the reaction mixture until the pH reached a range of about 4.45 to 4.55. The reaction mixture was continuously mixed for 30-45 minutes. If the pH is greater than 4.7, additional hydrochloric acid solution is added until the pH is in the range of about 4.45 to 4.55. The reaction was stirred for another 15-30 minutes.

The crystals of protonated ZS-9 were filtered through a Buchner funnel having a 2 micron stainless steel mesh screen having a diameter of about 18 inches. The resulting filter cake was rinsed three times with about 6 liters of deionized water to remove any excess hydrochloric acid. The filter cake containing the protonated crystals is dried in a vacuum oven at about 95-105 ° C for a period of 12 to 24 hours. Drying continues until the percentage difference in net weight loss does not exceed 2% during the 2 hour period. Once the product is properly dried, the resulting crystallization is the sample quality.

Example 14

High capacity ZS-9 crystals were prepared according to the following representative examples.

The reactants were prepared as follows. The 22-L Morton flask was equipped with an overhead stirrer, thermocouple, and balanced addition funnel. Deionized water (8,600 grams, 477.37 moles) was added to the flask. The mixture was stirred at about 145-150 rpm and sodium hydroxide (661.0 g, 16.53 moles of NaOH, 8.26 moles Na2O) was added to the flask. The contents of the flask were heated from 24 ° C to 40 ° C over a period of 3 minutes while dissolving sodium hydroxide. The solution was stirred for 1 hour to allow the initial exotherm to subside. A solution of sodium citrate solution (5,017 g, 22.53 moles SO2, 8.67 moles Na2O) was added. To this solution, a zirconium acetate solution (2,080 g, 3.76 moles of zirconium dioxide) was added over 30 minutes through a device in an addition funnel. The resulting suspension was stirred for a further 30 minutes.

The mixture was transferred to a 5-G Parr pressure vessel model 4555 with the aid of deionized water (500 grams, 27.75 moles). The reactor was equipped with a cooling coil having a crucible structure to provide a plate-like structure in the reactor adjacent to the agitator. The heat exchange fluid is not charged in the cooling coil because it is used in this reaction to provide only the plate-like structure of the adjacent agitator.

The vessel was sealed and the reaction mixture was stirred at about 230-235 rpm and heated from 21 ° C to 140-145 ° C for 7.5 hours and held at 140-145 ° C for 10.5 hours, then heated to 210-215 ° C for 6.5 hours, where The maximum pressure of 295-300 psi is then maintained at 210-215 ° C for 41.5 hours. Subsequently, the reactor was cooled to 45 ° C over a period of 4.5 hours. The resulting white solid was filtered with the help of deionized water (1.0 kg). The solid was washed with deionized water (40 L) until the pH of the eluted filtrate was less than 11 (10.54). A representative portion of the wet cake was dried overnight at 100 ° C under vacuum (25 inches of Hg) to yield 1376 g of ZS-9 (87.1%) as a white solid.

The XRD pattern of the obtained ZS-9 is shown in Fig. 12. The FTIR spectrum of this material is shown in Figure 13. When compared to Example 12 (Figs. 10-11), these XRD and FTIR spectra show well-defined peaks without diffusion and no peaks associated with other crystalline forms other than ZS-9 (eg ZS) -11 peak). This example illustrates how the appearance of the plate-like structure within the reactor greatly and unexpectedly improves the quality of such resulting crystals. While not wishing to be bound by theory, the inventors understand that during the reaction, the baffles provide additional turbulence to lift solids (i.e., crystals) and result in a more uniform suspension of crystals in the reaction vessel. This improved suspension allows for a more complete reaction to the desired crystalline form and reduces the presence of unwanted ZS crystalline forms in the final product.

Example 15

The KEC of ZS (ZS-9) is determined according to the following plan.

Such HPLC test methods have the ability to introduce solvent gradients and cation exchange assays. The column was IonPac CS12A, analyzed (2 x 250 mm). The flow rate was 0.5 ml/min with a run time of about 8 minutes. The column temperature was set to 35 °C. The injection volume was 10 μL and the cleaning syringe was 250 μL. The pump is operated in isocratic mode and the solvent is DI water.

A stock standard solution was prepared by accurately weighing and recording approximately 383 mg of potassium chloride (ACS grade) which was transferred to a 100 ml plastic volumetric flask. The material was dissolved and diluted with a diluent to a volume and mixed. The storage standard solution has a K+ concentration of 2000 ppm (2 mg/mL). Samples were prepared by accurately weighing, recording and transferring approximately 112 mg of ZS-9 to 20 ml plastic bottles. 20.0 ml of 2000 ppm potassium storage standard solution was pipetted into the vial and the container was closed. Place the vial on the wrist shaker and shake for at least 2 hours, but no more than 4 hours. The sample preparation solution was filtered into a plastic container through a 0.45 pm PTFE filter. Transfer the sample solution from 750 PL to a 100 ml plastic volumetric flask. The sample was diluted to a volume with DI water and mixed. The initial K+ concentration was 15 ppm (1 SpgImL).

The sample was injected into the HPLC. Figure 14 shows an example of a blank solution chromatogram. Figure 15 shows an example of a chromatogram of a test standard solution. Figure 16 shows an example of a chromatogram of a sample. Potassium ion exchange capacity is calculated using the following formula:

Potassium ion exchange capacity of KEC in mEq/g. The initial concentration of potassium (ppm) is IC. The final concentration of potassium (ppm) is FC. The equivalent weight (atomic/valence) is Eq wt. The standard amount (liter) in the sample preparation is V. The ZS-9 weight (mg) used for sample preparation is Wt _spl . The percentage (%) of the water content is % water.

According to the procedure of Example 12, three samples of ZS-9 manufactured without a baffle (for example, an internal cooling coil structure), potassium ion exchange capacity (KEC) was tested according to the above procedure. Similarly, three samples of ZS-9 made according to Example 14 were tested according to this procedure in a reactor having a cooling coil used as a baffle. The results in Table 3 indicate that the procedure of Example 14 and the presence of baffles within the crystallizer resulted in a significant increase in potassium ion exchange capacity.

The high capacity ZS prepared according to Example 14 would have a slightly lower potassium ion exchange capacity via protonation using the technique of Example 13. The protonated ZS prepared in this way was found to have a potassium ion exchange capacity of about 3.2 meq/g. Accordingly, high capacity ZS was found to increase the protonation capacity prepared using this procedure. This indicates that the protonated ZS can be prepared to have a potassium ion exchange capacity in the range of from 2.8 to 3.5 meq/g, preferably from 3.05 to 3.35 meq/g, and most preferably 3.2 meq/g.

Example 16

It is possible to use an internal cooling coil to provide a plate-like structure in the reactor with only a small reactor on the order of 5-gallon, since larger reactors cannot be easily lifted with cooling coils and usually do not use cooling trays. tube.

The inventors have designed a reactor for the mass production of high purity, high KEC ZS-9 crystals. Large scale reactors typically use a jacket for achieving heat exchange in the reaction chamber rather than a coil suspended within the reaction chamber. A conventional 200-L reactor 100 is shown in Figure 17. Reactor 100 has a smooth wall and an agitator 101 that extends into the center of the reaction chamber. Reactor 100 also has a thermowell 102 and a bottom outlet valve 103. The inventors have devised an improved reactor 200, Fig. 18, which also has an agitator 201, a thermowell 202 and a bottom outlet valve 203. The improved reactor 200 has a baffle structure 204 on its side wall surface, which in combination with the agitator 201 provides significant lift and suspension of crystallization during the reaction and creates high purity, high KEC ZS-9 crystals. The modified reactor may be packaged with a cooling or heating jacket for controlling the reaction temperature during crystallization in addition to the baffle structure 204. Details of an exemplary and non-limiting baffle design are shown in Figure 19. Preferably, the reactor has a volume of at least 20 liters, more preferably 200 liters or more, or further in the range of 200 liters to 30,000 liters.

Example 17

Several doses of ZS-9 were studied in the treatment of human subjects with hyperkalemia. A total of 90 subjects were included in the study. This study involved three phases of dose escalation for each phase of ZS. The ZS-9 line used in these studies was prepared according to Example 12. The crystals of the appropriately sized distribution of ZS-9 are obtained by air classification to obtain a distribution having crystals greater than or equal to 97% greater than 3 microns. The screening is such that the ZS crystals exhibit a median particle size greater than 3 microns and less than 7% of the particles in the composition are less than 3 microns in diameter. The ZS-9 crystal was judged to have a KEC of about 2.3 meq/g. Protonation causes the ZS crystals to exhibit a sodium content of less than 12% by weight. The study utilized 3 grams of deuterated microcrystalline cellulose that could not be distinguished from ZS as a placebo.

Each patient in the study received a 3 gram dose of placebo or ZS, taken three times a day with meals. Both ZS and placebo are administered as a powder suspended in water for consumption at mealtimes. At each stage of the study, there was a 2:1 ratio between the ZS population and the subjects in the placebo. In the first phase, 18 patients were randomized to receive a three-day dose of 0.3 g of ZS or placebo taken with the meal. In the second phase, 36 patients were randomized to receive 3 grams of ZS or placebo for 3 days. In the third phase, 36 patients were randomized to receive a three-day dose of 10 grams of ZS or placebo taken with the meal. A total of 30 patients received a placebo and 60 patients received various doses of ZS. The diet is essentially unrestricted, and patients are allowed to choose the food they want from a variety of local restaurants or standard indoor weight loss clinics.

Screening values for potassium ("K") were determined by measuring serum K+ three times at 30 minute intervals and calculating the mean (times 0, 30 and 60 minutes) on day 0. Before the first dose, the baseline potassium concentration was calculated as the mean of these values and the serum K+ on the first day. If the screening K value is less than 5.0 meq/l, the subject is not included in the study.

On Days 1-2 of the study, all subjects received study medication from the start of the meal three times a day (the first meal was delayed until 1.5 hours after the first dose on Day 1). After the start of treatment, serum potassium concentration was evaluated for 48 hours 4 hours after each dose. If the K concentration tends to be normal, the subject was discharged from the clinic for 48 hours without further study drug treatment. If the K concentration is still elevated (K > 5.0 meq/l), the subject is treated for another 24 hours of study medication, then reassessed and discharged at 72 hours or 96 hours. All subjects received at least 48 hours of study drug treatment, but a small number received up to 96 hours of study drug treatment. The primary efficacy endpoint of the study was the difference in the rate of change in potassium concentration in the study drug treatment between the first 48 hours of placebo treatment and the ZS treatment subject. Table 4 provides the p values for the various populations at the 24 and 48 hour endpoints. Patients who received 300 mg of ZS three times a day did not differ statistically from placebo at the 24-hour or 48-hour endpoint. Patients who received 3 grams of ZS showed statistical differences only during the 48 hour period, indicating that this particular dose is relatively effective in lowering serum potassium levels. Unexpectedly, those patients who received 10 grams of ZS three times a day showed the greatest decrease in potassium concentration at both concentration and speed. Potassium is reduced by a considerable extent, with a reduction of about 0.5 meq/g at a dose of about 3 grams, and a reduction of about 0.5-1 meq/g at a dose of 10 grams.

The subject was then tracked daily for 7 days (168 hours). All patients, as long as the patient ingested the test article, performed 24-hour urine collection on the day before the study (Day 0). Table 5 provides the difference in the rate of change in serum potassium concentration between subjects treated with placebo and between different subjects at 7 days of study. Patients receiving 300 mg of drug did not have a statistically significant reduction in potassium concentration relative to placebo during the 7-day period. Patients receiving 3 grams of drug did not have a statistically significant reduction in potassium concentration after the initial 24 hour period. Patients who received 3 grams of drug had the most statistically significant reduction in serum potassium concentration over a 7 day period. These data indicate that a prolonged reduction in potassium is achieved when at least 10 grams of ZS is administered, while a single (ie, one day) dose is suitable for a significant reduction in potassium concentration. It is also possible to effectively reduce the potassium concentration once a dose of 3, 4 or 5 grams is administered once a day.

Comparison of treatment groups demonstrated no significant differences in any parameters including age, gender, weight, serum creatinine concentration, estimated glomerular filtration rate ("GFR"), potassium concentration, and the cause of chronic kidney disease ("CKD"). difference.

Figure 20 shows the change in serum potassium after the first 48 hours of ingestion of placebo, 0.3 grams of ZS per dose (population 1), 3 grams of ZS per dose (population 2), 10 grams per dose of ZS (population 3). The slope of potassium versus time for patients given ZS was significantly different from place 2 (0.5 meq/L/48 hours, P<0.05) and group 3 (1 meq/L/48 hours, P<0.0001) placebo.

The time to normalize serum potassium in group 3 was significantly less than in the placebo group (P=0.040). There were no significant differences between the results of the other groups and the placebo. Figure 21 compares the timing of administration of a 10 gram dose of ZS versus placebo to reduce serum potassium by 0.5 meq/L. Serum K fall time was significantly shorter in subjects given ZS compared to placebo (P = 0.042).

An increase in serum K from 48 hours to 144 hours from the study was also reviewed after discontinuation of administration of the study drug. The rate of increase in serum potassium is roughly proportional to the rate of decrease in serum potassium during drug intake, as shown in Figure 22.

24-hour urinary K+ excretion analysis showed a significant reduction in urinary K excretion of approximately 20 meq/day at 10 gram doses of ZS (P < 0.002), while all other groups of excretion remained unchanged or increased, as shown in Figure 23. Show.

Analysis of the K/creatinine ratio in urine samples per day confirmed the same trend as 24 h urinary K+ excretion. Group 3 had a decreasing trend in the urinary K/creatinine ratio, while other groups remained unchanged or increased. Independent analysis showed no change in creatinine clearance or daily creatinine excretion in any population during the study period.

Analysis of 24-hour urine samples also allowed daily urinary sodium excretion. As shown in Figure 24, sodium excretion was generally stable in all cohorts. Although there was no significant change in any cohort, there was a greater increase in sodium excretion in group 1 and control patients compared to group 3 urine.

Urea nitrogen ("BUN") was tested as a measure of the effect of ZS binding to the production of ammonium by bacterial urease in the gut. From study day 2 to study day 7, BUN had a dose-related and statistically significant reduction in response to serum K (between 0.035 [study day 2] and <0.001 [study day 5-7] p value) . This is also accompanied by a decrease in the excretion of urine urea.

At 10 g doses of ZS three times a day (p-values from 0.047 to 0.001 on days 2-6 of the study), there is still a statistical analysis of serum calcium in the normal range (from 9.5 mg/dL to 9.05 mg/dL) Significantly reduced, but no subject developed into hypocalcemia; there was no significant change in serum magnesium, serum sodium, blood bicarbonate or any other electrolyte at any dose of ZS. There was a tendency for blood creatinine to decrease, which became statistically significant on day 6 of the study (P = 0.048). There were no dose-related changes in renal parameters including urinary sediment, assessment of glomerular filtration rate ("GFR") or renal function markers NGAL and KIM-1.

This randomized and double-blind clinical trial demonstrated that a moderate intake of ZS significantly reduced serum potassium concentrations in patients with stage 3 CKD. No diarrhea is given with ZS, so the removal of potassium is purely based on the combination of ZS versus K in the intestine rather than diarrhea.

Oral sodium polystyrene sulfonate ("SPS") treatment always results in sodium loading in the patient. Sodium is released in a ratio of 1:1 to all cations (K, hydrogen, calcium, magnesium, etc.). ZS is partially loaded with sodium and partially loaded with hydrogen to produce a near physiological pH (7 to 8). At this initial pH, there is a small release of sodium and some absorption of hydrogen during the binding of K. Urine sodium excretion does not increase during the intake of ZS, so the use of ZS should not cause excessive sodium in the patient.

A maximum dose of about 10 grams per day (about 30 grams per day or about 0.4 g/kg/day) is surprising in the rapidity of ZS action on serum K and the reduction in the effectiveness of K-excretion in urine. This also caused urine K to decrease by about 40% from baseline at the next day. Therefore, it appears that, like in animals, ZS is effective at least in reducing the body K stored in humans, and is more likely to be due to the high K concentration in human feces.

Example 18

High capacity ZS (ZS-9) was prepared according to Example 14. This material was protonated according to the technique described in Example 13. The material is screened such that the ZS crystals exhibit greater than 3 microns and the particles in the composition are less than 7% having a median diameter of less than 3 microns in diameter. The ZS crystals exhibit a sodium content of less than 12% by weight. Dosage forms are prepared at a concentration of 5 grams, 10 grams, and 15 grams per patient. The ZS in this example has an elevated potassium ion exchange capacity greater than 2.8. In a preferred aspect, the potassium ion exchange capacity is in the range of 2.8 to 3.5 meq/g, more preferably in the range of 3.05 to 3.35 meq/g, and most preferably about 3.2 meq/g. The target for a potassium ion exchange capacity of about 3.2 meq/g contains small fluctuations in the potassium ion exchange capacity expected to be measured between ZS crystals in different batches.

When administered according to the schedule established in Example 17, ZS-9 will be provided for a similar reduction in potassium serum concentration. Since ZS-9 has an elevated KEC, considering the increased cation exchange capacity, the dose administered to the subject in need will be reduced. Therefore, patients suffering from an increase in serum potassium concentration beyond the normal range will be administered 1.25, 2.5, 5, and 10 grams of ZS-9 three times a day.

Other embodiments and uses of the invention will be apparent to those skilled in the art. All of the references cited herein, including all U.S. and foreign patents and patent applications, are hereby incorporated by reference in its entirety herein in its entirety. It is intended that the specification and embodiments be regarded as

Example 19

ZS (ZS-2) is prepared according to the known techniques of U.S. Patent Nos. 6,814,871, 5,891,417 and 5,888,472, which are discussed above. The ZS-2 x-ray winding pattern has the following characteristic d-spacing range and intensity:

In one aspect of the present example, ZS-2 crystals were prepared using a baffled reactor as described in Example 14. This material was protonated according to the technique described in Example 13. The ZS crystals are screened to exhibit greater than 3 microns and the particles in the composition are less than 7% having a median diameter of less than 3 microns in diameter. The ZS crystals exhibit a sodium content of less than 12% by weight. Dosage forms are prepared at a concentration of 5 grams, 10 grams, and 15 grams per patient. ZS-2 crystallization prepared according to this example helps to reduce serum potassium and can be made using alternative techniques for making ZS-2. This alternative manufacturing technique can provide benefits in certain situations.

Example 20

A number of batches of protonated ZS crystals were prepared using the reactor described in Example 16.

Batches of protonated ZS crystals are typically made according to the following representative examples.

The reactants were prepared as follows. As shown in Figure 17, sodium citrate (56.15 kg) was added to a 200-L reactor and charged with deionized water (101.18 kg). Sodium hydroxide (7.36 kg) was added to the reactor and allowed to dissolve in the reactor during rapid agitation over a period of more than 10 minutes until sodium hydroxide was completely dissolved. Ethyl zirconium acetate (23 kg) was added to the reactor in the presence of continuous stirring and stirred for 30 minutes. The reactants were mixed at a rate of 150 rpm and the reactor was set to 210 ° C ± 5 ° C 60 hours period.

After the reaction period, the reactor was cooled to 60 ° C - 80 ° C, and the slurry of the reaction was filtered, washed and dried at a temperature of about 100 ° C. 4 hours period. To prepare dry crystallization for protonation, deionized water (46 liters) was charged to re-slurry the crystallization. 15% HCl (about 5-7 kg of 15% HCl solution) was mixed with the slurry for a period of 25 to 35 minutes. After the protonation reaction, the reactants are again filtered and dried, and about Wash with 75 liters of deionized water.

Exemplary details of many protonated ZS crystal batches made using the above process are shown in Table 7:

The XRD pattern of H-ZS-9 obtained above is provided in Figures 25 to 28. Such XRD patterns indicate that H-ZS-9 can be manufactured with a commercially significant batch number of desired potassium ion exchange capacity. Batch 5602-2-26812-A achieved the most uniform crystal distribution. It was found that when the crystallization conditions resulted in a highly uniform particle size distribution, the subsequent protonation step reduced the cation exchange capacity from 3.4 to 3.1 meq/g. In contrast, batches 5602-28312-A, 5602-29112-A, and 5602-29812-A exhibited a less uniform particle size distribution. The less uniform particle size distribution is due to the increased fill ratio of the reactor. When the proportion of the filler reaches 80-90%, the particle size distribution becomes less uniform. However, it was unexpected that the subsequent protonation of these batches resulted in a significant increase in potassium ion exchange capacity. Since the reaction according to the present invention can be carried out by means of protonation to increase the potassium ion exchange capacity, it is expected that a higher capacity of ZS-9 can be obtained in a commercially significant amount compared to others, which would be considered to be possible.

The phase quantification of the different batches of the diffraction pattern used to determine the protonated ZS crystalline sample was also performed in the Rigaku MiniFlex 600 using the Rietveld method. The phase composition produced by the manufacturing method using a 200-L reactor is described in Table 8 and the XRD data is described in Figures 25 to 29.

The diffraction pattern is used to mass produce the ZS-9 and ZS-7 crystalline mixtures in addition to a series of amorphous crystals. It was found that the ZS crystallization prepared in the larger 200 liter reactor according to the above method resulted in no detectable concentration of ZS-8 crystals and a lower concentration of amorphous crystals than in the previous method. Because of the undesired higher solubility of ZS-8 crystals and consequent increase in the concentration of zirconium in the urine, it is highly desirable that the ZS-8 crystals disappear. In particular, the concentration of zirconium in the urine is usually about 1 ppb. The application of the zirconium silicate containing the ZS-8 impurity results in a zirconium content in the urine of between 5 and 50 ppb. The presence of ZS-8 can be confirmed by X-ray diffraction as shown in Fig. 30. ZS-9 crystallization according to this example is expected to reduce the concentration of zirconium in urine by eliminating impurities of soluble ZS-8 and minimizing the amorphous content.

Example 21

Batches of protonated zirconium crystals described in Example 20 were used in the study to treat human subjects suffering from hyperkalemia. The composition of ZS is generally characterized as having a mixture of ZS-9 and ZS-7, wherein ZS-9 is present at about 70% and ZS-7 is present at about 28% (hereinafter referred to as ZS-9/ZS-7). All of the characterized ZS-9/ZS-7 crystals lack a detectable amount of ZS-8 crystals. The subject was administered the ZS-9/ZS-7 composition according to the method described in Example 17. A summary of the results is provided in Table 9.

Surprisingly, the glomerular filtration rate (GFR) administered to the subject of the ZS-9/ZS-7 composition was unexpectedly high relative to the patient's baseline. Without being bound by any particular theory, the inventors conclude that improved GFRs and reduced creatinine concentrations (see Table 9 above) are due to the absence of ZS-8 impurities in the ZS-9/ZS-7 composition. As is generally known in the previous case, ZS-8 crystals have been characterized as having a higher solubility and are therefore capable of systemic circulation. The inventors believe that this may be the reason for the elevated BUN and creatinine concentrations in the zirconium crystals described in the previous paragraph.

This clinical trial showed that ingestion of a suitable amount of ZS-9/ZS-7 surprisingly and unexpectedly reduced creatinine levels in patients.

Other embodiments and uses of the present invention will be apparent to those of ordinary skill in the art. All references cited herein, including all U.S. and U.S. patents and patent applications, are hereby expressly incorporated by reference in their entirety. It is intended that the specification and embodiments be regarded as illustrative only,

100, 200. . . reactor

101, 201. . . Blender

102, 202. . . Thermowell

103, 203. . . Bottom outlet valve

204. . . Baffle structure

Figure 1 is a polyhedral diagram showing the structure of microporous ZS Na2.19ZrSi3.01O9.11.2.71H2O (MW 420.71).

Figure 2 is a particle size distribution of ZS-9 lot 5332-04310-A according to Example 8.

Figure 3 is a particle size distribution of ZS-9 batch 5332-15410-A according to Example 8.

Figure 4 is a particle size distribution of the ZS-9 clinical batch according to Example 8.

Figure 5 is a particle size distribution of the batch 5332-04310-A w/o screen according to Example 9.

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

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

Figure 8 is a particle size distribution of the batch 5332-04310-A 325 mesh according to Example 9.

Figure 9 is a particle size distribution of the 5332-04310-A 230 mesh according to Example 9.

Figure 10 is an XRD pattern of ZS-9 prepared according to Example 12.

Figure 11 is an FTIR spectrum of ZS-9 prepared according to Example 12.

Figure 12 is an XRD pattern of ZS-9 prepared according to Example 14.

Figure 13 is an FTIR spectrum of ZS-9 prepared according to Example 14.

Figure 14 is an example of a Blanck Solution Chromatogram.

Figure 15 is an example of an Assay Standard Solution Chromatogram.

Figure 16 is an example of a sample chromatogram.

Figure 17 is a reaction vessel with a standard agitator unit.

Figure 18 is a reaction vessel with a baffle for enhancing the manufacture of ZS-9.

Figure 19 is a detail of the baffle design used to enhance the 200-L reaction vessel manufactured by ZS-9.

Figure 20 is the treatment cycle of ZS-9 against placebo after more than 48 hours of ingestion.

Figure 21 is a comparison of the time of serum K reduction.

Figure 22 is a comparison of the increase in serum K of the following treatments.

Figure 23 is the rate at which K is expelled from the urine.

Figure 24 is a daily urinary sodium excretion.

Figure 25 is an XRD pattern of H-ZS-9 prepared according to Example 20 Batch 5602-26812.

Figure 26 is an XRD pattern of H-ZS-9 prepared according to Example 20 Batch 5602-28312.

Figure 27 is an XRD pattern of H-ZS-9 prepared according to Example 20 Batch 5602-29112.

Figure 28 is an XRD pattern of H-ZS-9 prepared according to Example 20 Batch 5602-29812.

Figure 29 is an XRD data of ZS crystals produced according to Example 20.

Figure 30 is an XRD data showing the presence of ZS-8 impurities.

Claims (24)

A zirconium silicate composition comprising zirconium silicate of formula (I): A _P M _X Zr _1-X Si _n Ge _y O _m (I) wherein A is potassium ion, sodium ion, strontium ion, strontium ion, Calcium ion, magnesium ion, hydronium ion or a mixture thereof, M is at least one framework metal, wherein the framework metal is lanthanum (4+), tin (4+), lanthanum (5+), titanium (4+), lanthanum (4+), 锗(4+), 鐠(4+), 鋱(4+) or a mixture thereof, "p" has a value of about 1 to about 20, and "x" has a value of 0 to less than 1, "n" has a value of from about 0 to about 12, "y" has a value of from about 0 to about 12, "m" has a value of from about 3 to about 36, and 1 ≦ n + y ≦ 12, wherein the zirconium silicate consists The material contained ZS-9 and ZS-7 and there was no detectable amount of ZS-8. The zirconium ruthenate composition as described in claim 1, wherein the X-ray diffraction pattern of ZS-9 is: The zirconium ruthenate composition as described in claim 1 wherein ZS-7 has an X-ray diffraction pattern of: The zirconium ruthenate composition as described in claim 1 wherein ZS-8 has an X-ray diffraction pattern of: The zirconium ruthenate composition of claim 1, wherein the zirconium ruthenate composition comprises ZS-9 in a weight percentage ranging from about 50% to about 75%. The zirconium ruthenate composition of claim 1, wherein the zirconium ruthenate composition comprises ZS-7 in a weight percentage ranging from about 25% to about 50%. Zirconium citrate composition as described in claim 1 of the patent application, wherein ZS- 9 exhibits a median particle size greater than 3 microns, and less than 7% of the particles in the zirconium ruthenate composition have a diameter of less than 3 microns, and the zirconium silicate composition exhibits a sodium content of less than 12% by weight. The zirconium ruthenate composition as described in claim 1, wherein ZS-9 is partially protonated. The zirconium silicate composition according to claim 1, wherein the protonated ZS-9 has a potassium ion exchange capacity of more than 3.1 meq/g. The zirconium ruthenate composition according to claim 1, wherein the protonated ZS-9 has a potassium ion exchange capacity ranging from 3.2 meq/g to 3.5 meq/g. A zirconium ruthenate composition as described in claim 1, wherein the protonated ZS-9 has a potassium ion exchange capacity of > 2.46 meq/g. The zirconium ruthenate composition of claim 1, wherein the protonated ZS-9 has a sodium content of less than 12%. A zirconium silicate composition comprising zirconium silicate of formula (I): A _P M _X Zr _1-X Si _n Ge _y O _m (I) wherein A is potassium ion, sodium ion, strontium ion, strontium ion, Calcium ion, magnesium ion, hydronium ion or a mixture thereof, M is at least one framework metal, wherein the framework metal is lanthanum (4+), tin (4+), lanthanum (5+), titanium (4+), lanthanum (4+), 锗(4+), 鐠(4+), 鋱(4+) or a mixture thereof, "p" has a value of about 1 to about 20, and "x" has a value of 0 to less than 1, "n" has a value of from about 0 to about 12, "y" has a value of from about 0 to about 12, "m" has a value of from about 3 to about 36, and 1 ≦ n + y ≦ 12, wherein zirconium citrate comprises weight The percentage ranges from about 50% to about 75% ZS-9 and the weight percentage ranges from about 25% to about 50% ZS-7. The zirconium ruthenate composition as described in claim 13 wherein ZS-9 has an X-ray diffraction pattern of: The zirconium ruthenate composition as described in claim 13 wherein ZS-7 has an X-ray diffraction pattern of: The zirconium ruthenate composition as described in claim 13 wherein the X-ray diffraction pattern of ZS-8 is: The zirconium ruthenate composition of claim 13, wherein the zirconium ruthenate composition comprises ZS-9 in a weight percentage ranging from about 50% to about 75%. The zirconium ruthenate composition of claim 13, wherein the zirconium ruthenate composition comprises ZS-7 in a weight percentage ranging from about 25% to about 50%. The zirconium ruthenate composition of claim 13, wherein ZS-9 exhibits a median diameter greater than 3 microns, and less than 7% of the zirconium ruthenate composition has a diameter of less than 3 microns, And the zirconium silicate composition exhibits a sodium content of less than 12% by weight. A zirconium ruthenate composition as described in claim 13 wherein ZS-9 is partially protonated. A zirconium ruthenate composition as described in claim 13 wherein the protonated ZS-9 has a potassium ion exchange capacity greater than 3.1 meq/g. The zirconium silicate composition according to claim 13 wherein the protonated ZS-9 has a potassium ion ranging from 3.2 meq/g to 3.5 meq/g. Exchange capacity. A zirconium ruthenate composition as described in claim 13 wherein the protonated ZS-9 has a potassium ion exchange capacity of > 2.46 meq/g. A zirconium ruthenate composition as described in claim 13 wherein the protonated ZS-9 has a sodium content of less than 12%.