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 . A method for treating non-Hodgkin's lymphoma, comprising orally administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of 5-azacytidine and at least one pharmaceutically acceptable excipient, wherein the composition is a non-enteric coated tablet. 
     
     
         2 . The method of  claim 1 , wherein the composition further comprises a permeation enhancer. 
     
     
         3 . The method of  claim 2 , wherein the permeation enhancer is D-alpha-tocopheryl polyethylene glycol 1000 succinate. 
     
     
         4 . The method of  claim 3 , wherein the D-alpha-tocopheryl polyethylene glycol 1000 succinate is present in the composition at about 2% by weight relative to the total weight of the formulation. 
     
     
         5 . The method of  claim 1 , wherein the method further comprises not co-administering a cytidine deaminase inhibitor with the 5-azacytidine. 
     
     
         6 . The method of  claim 1 , wherein the composition is a single unit dosage form. 
     
     
         7 . The method of  claim 1 , wherein the at least one pharmaceutically acceptable excipient is selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate. 
     
     
         8 . The method of  claim 1 , wherein the tablet comprises a sugar coating, a film coating, or a compression coating. 
     
     
         9 . The method of  claim 8 , wherein the film coating is a cellulose ether polymer. 
     
     
         10 . The method of  claim 9 , wherein the cellulose ether polymer is hydroxypropyl methyl-cellulose, hydroxypropyl cellulose, or methyl-cellulose. 
     
     
         11 . The method of  claim 1 , wherein the amount of 5-azacytidine is at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, or at least about 400 mg. 
     
     
         12 . The method of  claim 1 , wherein the amount of 5-azacytidine is at least about 20 to 1000 mg. 
     
     
         13 . The method of  claim 1 , which has been shown to achieve an area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to the subject. 
     
     
         14 . The method of  claim 1 , which has been shown to achieve an area-under-the-curve value of at least about 400 ng-hr/mL following oral administration to the subject. 
     
     
         15 . The method of  claim 1 , which has been shown to achieve a maximum plasma concentration of at least about 100 ng/mL following oral administration to the subject. 
     
     
         16 . The method of  claim 1 , which has been shown to achieve a maximum plasma concentration of at least about 200 ng/mL following oral administration to the subject. 
     
     
         17 . The method of  claim 1 , which has been shown to achieve a time to maximum plasma concentration of less than about 180 minutes following oral administration to the subject. 
     
     
         18 . The method of  claim 1 , which has been shown to achieve a time to maximum plasma concentration of less than about 90 minutes following oral administration to the subject. 
     
     
         19 . The method of  claim 1 , wherein the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma.