Oral formulations of cytidine analogs and methods of use thereof

Abstract

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein.

1 - 30 . (canceled) 
     
     
         31 . A method for treating acute myelogenous leukemia, comprising orally administering once daily to a human subject in need thereof a pharmaceutical composition comprising 180 mg to 360 mg of 5-azacytidine and at least one pharmaceutically acceptable excipient, wherein the composition is a non-enteric-coated tablet, and wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to the human subject. 
     
     
         32 . The method of  claim 31 , wherein the tablet is an immediate release tablet. 
     
     
         33 . The method of  claim 32 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         34 . The method of  claim 32 , wherein the amount of 5-azacytidine is 200 mg. 
     
     
         35 . The method of  claim 32 , which achieves an area-under-the-curve value of about 150 ng×hr/mL to about 340 ng×hr/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         36 . The method of  claim 35 , which achieves an area-under-the-curve value of about 230 ng×hr/mL to about 280 ng×hr/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         37 . The method of  claim 36 , which achieves an area-under-the-curve value of about 240 ng×hr/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         38 . The method of  claim 37 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         39 . The method of  claim 37 , which achieves a maximum plasma concentration of about 140 ng/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         40 . The method of  claim 39 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         41 . The method of  claim 39 , which achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject. 
     
     
         42 . The method of  claim 32 , which achieves a maximum plasma concentration of about 120 ng/mL to about 240 ng/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         43 . The method of  claim 42 , which achieves a maximum plasma concentration of about 130 ng/mL to about 160 ng/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         44 . The method of  claim 43 , which achieves a maximum plasma concentration of about 140 ng/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         45 . The method of  claim 44 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         46 . The method of  claim 44 , which achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject. 
     
     
         47 . The method of  claim 46 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         48 . The method of  claim 32 , which achieves a median time to maximum plasma concentration of 5-azacytidine of less than about 90 minutes following oral administration to the human subject. 
     
     
         49 . The method of  claim 48 , which achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject. 
     
     
         50 . The method of  claim 49 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         51 . The method of  claim 49 , which achieves an area-under-the-curve value of about 240 ng×hr/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         52 . The method of  claim 51 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         53 . The method of  claim 31 , wherein the tablet does not comprise a methacrylic acid copolymer. 
     
     
         54 . The method of  claim 53 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         55 . The method of  claim 32 , wherein the pharmaceutical composition is orally administered for fourteen consecutive days. 
     
     
         56 . The method of  claim 55 , wherein after the fourteen consecutive days of orally administering the pharmaceutical composition, the pharmaceutical composition is not administered for the next fourteen consecutive days. 
     
     
         57 . The method of  claim 55 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         58 . The method of  claim 32 , wherein the pharmaceutical composition is orally administered for seven consecutive days. 
     
     
         59 . The method of  claim 58 , wherein the amount of 5-azacytidine is 200 mg. 
     
     
         60 . A method for treating acute myelogenous leukemia, comprising orally administering once daily to a human subject in need thereof a pharmaceutical composition comprising 300 mg of 5-azacytidine and at least one pharmaceutically acceptable excipient,
 wherein the composition is a non-enteric-coated tablet,   wherein the composition achieves an area-under-the-curve value of about 240 ng×hr/mL of 5-azacytidine following oral administration to the human subject,   wherein the composition achieves a maximum plasma concentration of about 140 ng/mL of 5-azacytidine following oral administration to the human subject,   wherein the composition achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject,   wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to the human subject, and   wherein the tablet is an immediate release tablet.