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 - 65 . (canceled) 
     
     
         66 . A pharmaceutical composition for oral administration comprising 180 mg to 360 mg of 5-azacytidine and at least one pharmaceutically acceptable excipient, wherein the composition is a non-enteric film-coated tablet, and wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to a human subject. 
     
     
         67 . A pharmaceutical composition for oral administration comprising 180 mg to 360 mg of 5-azacytidine and at least one pharmaceutically acceptable excipient, wherein the composition is an immediate release film-coated tablet and releases the 5-azacytidine substantially in the stomach following oral administration to a human subject. 
     
     
         68 . The composition of  claim 67 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         69 . The composition of  claim 67 , wherein the amount of 5-azacytidine is 200 mg. 
     
     
         70 . 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 film-coated tablet, and wherein a therapeutically effective amount of 5-azacytidine is not absorbed through oral mucosa upon administration to the human subject. 
     
     
         71 . 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 an immediate release film-coated tablet and releases the 5-azacytidine substantially in the stomach following oral administration to the human subject. 
     
     
         72 . The method of  claim 71 , wherein the film coat is the only coat of the tablet. 
     
     
         73 . The method of  claim 71 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         74 . The method of  claim 71 , wherein the amount of 5-azacytidine is 200 mg. 
     
     
         75 . The method of  claim 71 , 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. 
     
     
         76 . The method of  claim 75 , 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. 
     
     
         77 . The method of  claim 76 , which achieves an area-under-the-curve value of about 240 ng×hr/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         78 . The method of  claim 77 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         79 . The method of  claim 77 , which achieves a maximum plasma concentration of about 140 ng/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         80 . The method of  claim 79 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         81 . The method of  claim 79 , which achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject. 
     
     
         82 . The method of  claim 71 , 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. 
     
     
         83 . The method of  claim 82 , 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. 
     
     
         84 . The method of  claim 83 , which achieves a maximum plasma concentration of about 140 ng/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         85 . The method of  claim 84 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         86 . The method of  claim 84 , which achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject. 
     
     
         87 . The method of  claim 86 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         88 . The method of  claim 71 , 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. 
     
     
         89 . The method of  claim 88 , which achieves a median time to maximum plasma concentration of 5-azacytidine of about 60 minutes following oral administration to the human subject. 
     
     
         90 . The method of  claim 89 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         91 . The method of  claim 89 , which achieves an area-under-the-curve value of about 240 ng×hr/mL of 5-azacytidine following oral administration to the human subject. 
     
     
         92 . The method of  claim 91 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         93 . The method of  claim 71 , wherein the tablet does not comprise a methacrylic acid copolymer. 
     
     
         94 . The method of  claim 93 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         95 . The method of  claim 72 , wherein the pharmaceutical composition is orally administered for fourteen consecutive days. 
     
     
         96 . The method of  claim 95 , wherein after the fourteen consecutive days of orally administering the pharmaceutical composition, the pharmaceutical composition is not administered for the next fourteen consecutive days. 
     
     
         97 . The method of  claim 95 , wherein the amount of 5-azacytidine is 300 mg. 
     
     
         98 . The method of  claim 72 , wherein the pharmaceutical composition is orally administered for seven consecutive days. 
     
     
         99 . The method of  claim 98 , wherein the amount of 5-azacytidine is 200 mg. 
     
     
         100 . 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 an immediate release film-coated tablet and releases the 5-azacytidine substantially in the stomach following oral administration to the human subject, 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, and 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. 
     
     
         101 . The method of  claim 100 , wherein the film coat is the only coat of the tablet. 
     
     
         102 . The method of  claim 100 , wherein the tablet does not comprise a methacrylic acid copolymer.