Method of treating chronic kidney disease

Abstract

The present invention discloses pharmaceutical-grade ferric organic compounds having enhanced dissolution rate. These ferric organic compounds, including but are not limited to ferric citrate, are useful for treating chronic kidney disease.

What is claimed is: 
     
         1 . A method of treating a subject having chronic kidney disease, comprising administering to said subject an effective amount of a ferric organic compound having a dissolution rate of at least approximately 2 mg/cm 2 /min. 
     
     
         2 . The method of  claim 1 , wherein the dissolution rate of the ferric organic compound is from approximately 2.5 mg/cm 2 /min to approximately 3.0 mg/cm 2 /min. 
     
     
         3 . The method of  claim 1 , wherein the dissolution rate of the ferric organic compound is from approximately 3.0 mg/cm 2 /min to approximately 3.5 mg/cm 2 /min. 
     
     
         4 . The method of  claim 1 , wherein the dissolution rate of the ferric organic compound is from approximately 3.5 mg/cm 2 /min to approximately 4.0 mg/cm 2 /min. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the ferric organic compound is prepared according a method comprising the steps of:
 a) obtaining a ferric iron salt;   b) adding an alkaline metal hydroxide to the ferric iron salt under conditions suitable to produce a mixture comprising polyiron oxide;   c) isolating a precipitate from the mixture;   d) adding an organic acid to the precipitate;   e) heating the organic acid and the precipitate, thereby forming a ferric organic acid solution; and   f) precipitating a ferric organic compound from the ferric organic acid solution by an organic solvent.   
     
     
         6 . The method of  claim 5 , wherein the alkaline metal hydroxide is sodium hydroxide or potassium hydroxide. 
     
     
         7 . The method of  claim 5  or  6 , wherein the alkaline metal hydroxide is added at a rate of less than 20 ml/min., and the alkaline metal hydroxide is added to the ferric iron salt at a temperature of less than 40° C. 
     
     
         8 . The method of any one of  claims 5 - 7 , wherein the organic acid and the precipitate are heated to a temperature of between about 80° C. to about 90° C., and precipitating the ferric organic compound from the ferric organic acid solution by an organic solvent comprises cooling the ferric organic acid solution to less than 30° C. before adding the organic solvent. 
     
     
         9 . The method of any one of  claims 5 - 8 , wherein the organic acid is in crystalline form. 
     
     
         10 . The method of any one of  claims 5 - 9 , wherein the organic acid is selected from the group consisting of citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid. 
     
     
         11 . The method of any one of  claims 5 - 10 , wherein the organic solvent is selected from the group consisting of ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran. 
     
     
         12 . The method of any one of  claims 5 - 11 , wherein the ferric iron salt is ferric chloride hexahydrate, the alkaline metal hydroxide is sodium hydroxide, and the organic acid is crystalline citric acid. 
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the subject is a human or an animal. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the chronic kidney disease includes any stage of chronic kidney disease and end stage renal disease 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the subject is undergoing renal dialysis. 
     
     
         16 . The method of any one of  claims 1 - 15 , wherein the ferric organic compound is administered at a dose of about 2-20 gm/day 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein the ferric organic compound is administered orally or any other appropriate route. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein the ferric organic compound is formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein treatment with the ferric organic compound results in decreased serum level of one or more substances in the subject, said substances are selected from the group consisting of creatinine, BUN, phosphorus, and calcium and phosphorus product (CaxP). 
     
     
         20 . The method of any one of  claims 1 - 18 , wherein treatment with the ferric organic compound results in preventing, reversing, maintaining or delaying one or more conditions in the subject, said conditions are selected from the group consisting of progression of chronic kidney disease, development of hyperparathyroidism, development of bone disorder, development of cardiovascular disease, calcium phosphate precipitation in renal tissue, kidney stone formation, and development of metabolic acidosis. 
     
     
         21 . A method of treating a subject having chronic kidney disease, comprising administering to said subject an effective amount of a ferric organic compound. 
     
     
         22 . The method of  claim 21 , wherein the ferric organic compound is administered orally. 
     
     
         23 . The method of  claim 21 , wherein the subject is a human or an animal. 
     
     
         24 . The method of  claim 21 , wherein the subject is having any stage of chronic kidney disease, or is undergoing renal dialysis. 
     
     
         25 . The method of  claim 21 , wherein the ferric organic compound is formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup. 
     
     
         26 . The method of  claim 21 , wherein the ferric organic compound has a dissolution rate of at least approximately 2 mg/cm 2 /min. 
     
     
         27 . The method of any one of  claims 21 - 26 , wherein treatment with the ferric organic compound results in decreased serum level of one or more substances in the subject, said substances are selected from the group consisting of creatinine, BUN, phosphorus, calcium and phosphorus product (CaxP). 
     
     
         28 . The method of any one of  claims 21 - 26 , wherein treatment with the ferric organic compound results in preventing, reversing, maintaining or delaying one or more conditions in the subject, said conditions are selected from the group consisting of progression of chronic kidney disease, development of hyperparathyroidism, development of bone disorder, development of cardiovascular disease, calcium phosphate precipitation in renal tissue, kidney stone formation, and development of metabolic acidosis. 
     
     
         29 . The method according to any one of  claims 21 - 28 , wherein the ferric organic compound is ferric citrate. 
     
     
         30 . A therapeutic regimen for a subject having chronic kidney, the regiment comprising a pharmaceutical composition comprising an acceptable carrier and an effective amount of ferric organic compound having a dissolution rate of at least 2 mg/cm 2 /min., wherein the pharmaceutical composition is administered in single or multiple doses regimens. 
     
     
         31 . The therapeutic regimen of  claim 30 , wherein the dissolution rate of the ferric organic compound is from approximately 2.5 mg/cm 2 /min to approximately 3.0 mg/cm 2 /min. 
     
     
         32 . The therapeutic regimen of  claim 30 , wherein the dissolution rate of the ferric organic compound is from approximately 3.0 mg/cm 2 /min to approximately 3.5 mg/cm 2 /min. 
     
     
         33 . The therapeutic regimen of  claim 30 , wherein the dissolution rate of the ferric organic compound is from approximately 3.5 mg/cm 2 /min to approximately 4.0 mg/cm 2 /min. 
     
     
         34 . The therapeutic regimen of any one of  claims 30 - 33 , wherein at least a portion of the pharmaceutical composition is administered orally. 
     
     
         35 . The therapeutic regimen of  claim 30 , wherein the chronic kidney disease includes any stage of chronic kidney disease and end stage renal disease. 
     
     
         36 . The therapeutic regimen of any one of  claims 30 - 35 , further comprising renal dialysis or peritoneal dialysis. 
     
     
         37 . The therapeutic regimen of any one of  claims 30 - 36 , wherein the ferric organic compound is formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup. 
     
     
         38 . The therapeutic regimen according to any one of  claims 30 - 37 , wherein the ferric organic compound is ferric citrate. 
     
     
         39 . A pharmaceutical composition for treating a subject having chronic kidney disease, the composition comprising an effective amount of a ferric organic compound having a dissolution rate of at least approximately 2 mg/cm 2 /min. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the dissolution rate of the ferric organic compound is from about 2 mg/cm 2 /min to about 4 mg/cm 2 /min. 
     
     
         41 . The pharmaceutical composition of  claim 39  or  40 , wherein the ferric organic compound is ferric citrate. 
     
     
         42 . The pharmaceutical composition of any one of  claims 39 - 41 , wherein the composition is in a form suitable for oral administration. 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the form suitable for oral administration is a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup. 
     
     
         44 . A use of the pharmaceutical composition of any one of  claims 39 - 43  in preparation of a medicament for treating a subject having chronic kidney disease. 
     
     
         45 . The use of  claim 44 , wherein the subject is having any stage of chronic kidney disease, or is undergoing renal dialysis.