Microporous zirconium silicate and diuretics for the reduction of potassium and treatment of chronic kidney and/or chronic heart disease

Abstract

The present invention relates to novel methods of using microporous zirconium silicate to reduce the risk of hyperkalemia and to lower aldosterone levels in the treatment of chronic kidney disease and/or chronic heart disease with therapies comprising diuretics. The invention provides a safe way to reduce the risk of hyperkalemia and to lower aldosterone. The invention also relates to treatment of other conditions that can occur either alone or in connection with hyperkalemia, chronic kidney disease, and/or chronic heart disease.

1 . A method of treating chronic kidney disease comprising administering to a patient in need thereof an individual pharmaceutical dosage comprising zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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 1 to about 12, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         2 . A method of treating chronic kidney disease comprising administering to a patient in need thereof a diuretic and a zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+) titanium (4+), cerium (4+) germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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 1 to about 12, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         3 . The method of  claim 2 , wherein the diuretic is a loop diuretic, a thiazine diuretic, a potassium sparring diuretic, or combinations thereof. 
     
     
         4 . The method of  claim 3 , wherein the potassium sparring diuretics is selected from spironolactone, eplerenone, canrenone, amiloride, triamterene, benzamil or pharmaceutically acceptable salts thereof. 
     
     
         5 . The method of  claim 2 , wherein the diuretic is administered as part of an ongoing therapy for the treatment of chronic kidney disease or chronic heart failure. 
     
     
         6 . The method of  claim 5 , wherein the ongoing therapy includes treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocking (ARB). 
     
     
         7 . The method of  claim 2 , wherein the zirconium silicate exhibits a median particle size of greater than 3 microns and less than 7% of the particles in the composition have a diameter less than 3 microns, and the composition exhibits a sodium content below 12% by weight. 
     
     
         8 . The method of  claim 2 , wherein the sodium content is between 0.05 to 3% by weight. 
     
     
         9 . The method of  claim 2 , wherein the sodium content is less than 0.01% by weight. 
     
     
         10 . The method of  claim 2 , wherein less than 4% of the particles in the composition have a diameter less than 3 microns. 
     
     
         11 . The method of  claim 2 , wherein less than 1% of the particles in the composition have a diameter less than 3 microns. 
     
     
         12 . The method of  claim 2 , wherein the median particle size ranges from 5 to 1000 microns. 
     
     
         13 . The method of  claim 2 , wherein the median particle size ranges from 20 to 100 microns. 
     
     
         14 . The method of  claim 2 , wherein the composition exhibits an x-ray powder diffraction spectrum indicating at least the following d-spacing values:
 a first d-spacing within the range of 2.7-3.5 angstroms having a first intensity value,   a second d-spacing within the range of 5.3-6.1 having a second intensity value, wherein the second intensity value is less than the first intensity value,   a third d-spacing within the range of 1.6-2.4 angstroms having a third intensity value,   a fourth d-spacing within the range of 2.0-2.8 angstroms having a fourth intensity value, and   a fifth d-spacing within the range of 5.9-6.7 angstroms having a fifth intensity value, wherein the third, fourth, and fifth intensity values are each lower than the first and second intensity values.   
     
     
         15 . The method of  claim 2 , wherein the dosage is in the range of approximately 8-12 g. 
     
     
         16 . The method of  claim 15 , wherein the dosage is approximately 10 g. 
     
     
         17 . The method of  claim 2 , wherein the zirconium silicate exhibits a cation exchange capacity greater than 2.8 meq/g. 
     
     
         18 . The method of  claim 17 , wherein the potassium exchange capacity is between 2.8 and 3.5 meq/g. 
     
     
         19 . The method of  claim 17 , wherein the composition exhibits a median particle size of greater than 3 microns and less than 7% of the particles in the composition have a diameter less than 3 microns, and the composition exhibits a sodium content below 12% by weight. 
     
     
         20 . The method of  claim 17 , wherein the composition exhibits an x-ray powder diffraction spectrum indicating at least the following d-spacing values:
 a first d-spacing within the range of 2.7-3.5 angstroms having a first intensity value,   a second d-spacing within the range of 5.3-6.1 having a second intensity value, wherein the second intensity value is less than the first intensity value,   a third d-spacing within the range of 1.6-2.4 angstroms having a third intensity value,   a fourth d-spacing within the range of 2.0-2.8 angstroms having a fourth intensity value, and   a fifth d-spacing within the range of 5.9-6.7 angstroms having a fifth intensity value, wherein the third, fourth, and fifth intensity values are each lower than the first and second intensity values.   
     
     
         21 . The method of  claim 20 , wherein the potassium exchange capacity is greater than 2.8 meq/g. 
     
     
         22 . The method of  claim 20 , wherein the potassium exchange capacity is between 2.8 and 3.5 meq/g. 
     
     
         23 . The method of  claim 20 , wherein the potassium exchange capacity is between 3.05 and 3.35 meq/g. 
     
     
         24 . The method of  claim 23 , wherein the composition exhibits a median particle size of greater than 3 microns and less than 7% of the particles in the composition have a diameter less than 3 microns, and the composition exhibits a sodium content below 12% by weight. 
     
     
         25 . The method of  claim 2 , wherein the composition comprises ZS-9 and ZS-7 and lacks detectable amounts of ZS-8. 
     
     
         26 . The method of  claim 25 , wherein the ZS-9 has an X-ray diffraction pattern of 
       
         
           
                 
                 
               
                     
                 
                   d(Å) 
                   I 
                 
                     
                 
                   5.9-6.7 
                   m 
                 
                   5.3-6.1 
                   m-s 
                 
                   2.7-3.5 
                   vs 
                 
                   2.0-2.8 
                   w-m 
                 
                   1.6-2.4 
                   w 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         27 . The method of  claim 25 , wherein the ZS-7 has an X-ray diffraction pattern of 
       
         
           
                 
                 
               
                     
                 
                   d(Å) 
                   I 
                 
                     
                 
                   6.8-7.6 
                   vs 
                 
                   5.6-6.4 
                   m 
                 
                   3.7-4.5 
                   m 
                 
                   3.6-4.4 
                   m 
                 
                   2.6-3.4 
                   s-vs 
                 
                   2.5-3.3 
                   m 
                 
                   2.4-3.2 
                   vs 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         28 . The method of  claim 25 , wherein the ZS-8 has an X-ray diffraction pattern of 
       
         
           
                 
                 
               
                     
                 
                   d(Å) 
                   I 
                 
                     
                 
                   12.0-13.2 
                   vs 
                 
                   3.9-4.7 
                   m 
                 
                   2.8-3.6 
                   m 
                 
                   2.3-3.1 
                   m 
                 
                   2.2-3.0 
                   w 
                 
                   2.1-2.9 
                   w 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         29 . The method of  claim 25 , wherein the composition comprises ZS-9 at a weight percent ranging from about 50% to about 75%. 
     
     
         30 . The method of  claim 25 , wherein the composition comprises ZS-7 at a weight percent ranging from about 25% to about 50%. 
     
     
         31 . The method of  claim 25 , wherein the ZS-9 exhibits a median particle size of greater than 3 microns and less than 7% of the particles in the composition have a diameter less than 3 microns, and the composition exhibits a sodium content below 12% by weight. 
     
     
         32 . The method of  claim 25 , wherein the ZS-9 is partially protonated. 
     
     
         33 . The method of  claim 32 , wherein the protonated ZS-9 has a potassium exchange rate of greater than 3.1 meq/g. 
     
     
         34 . The method of  claim 32 , wherein the protonated ZS-9 has a potassium exchange rate in the range of 3.2 to 3.5 meq/g. 
     
     
         35 . The method of  claim 32 , wherein the protonated ZS-9 has a potassium exchange rate of 3.2 meq/g. 
     
     
         36 . The method of  claim 32 , wherein the protonated ZS-9 has a sodium content of less than 12%. 
     
     
         37 . The method of  claim 2 , wherein the zirconium silicate comprises ZS-9 at a weight percent ranging from about 50% to about 75%, and ZS-7 at a weight percent ranging from about 25% to about 50%. 
     
     
         38 . The method of  claim 2 , wherein the patient diagnosed with chronic kidney disease is also diagnosed with chronic heart disease. 
     
     
         39 . A method of treating chronic heart disease comprising administering to a patient in need thereof an individual pharmaceutical dosage comprising zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         40 . A method for reducing aldosterone comprising administering to a patient in need thereof an individual pharmaceutical dosage comprising zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         41 . A method for treating hyperphosphatemia comprising administering to a patient in need thereof an individual pharmaceutical dosage comprising zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         42 . A method for treating chronic kidney or chronic heart disease comprising administering to a patient in need thereof a first agent selected from an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), and a second agent comprising zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         43 . The method of  claim 42 , wherein the first agent is an ACE inhibitor selected from captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril, fosinopril, or pharmaceutically acceptable salts thereof. 
     
     
         44 . The method of  claim 42 , wherein the first agent is an ARB selected from valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, or pharmaceutically acceptable salts thereof. 
     
     
         45 . The method of  claim 1  further comprising administering an ACE inhibitor and an ARB. 
     
     
         46 . The method of  claim 1  further comprising administering a telmisartan and ramapril. 
     
     
         47 . A method for treating chronic kidney or chronic heart disease comprising administering to a patient in need thereof a first agent comprising an aldosterone antagonist, and a second agent comprising zirconium silicate of formula (I):
   A p M x Zr 1-x Si n Ge y O m   (I)
   
       where
 A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, 
 M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, 
 “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, 
 “y” has a value from 0 to about 12, 
 “m” has a value from about 3 to about 36 and 1≦n+y≦12. 
 
     
     
         48 . The method of  claim 37 , wherein the aldosterone antagonist is selected from spironolactone, eplerenone, canrenone, prorenone, mexrenone, or pharmaceutically acceptable salts thereof.