Oral dosage formulations of active pharmaceutical ingredients and methods of preparing the same

Abstract

A method of forming a multi-particulate dosage form using rotary granulation is described in which polyethylene oxide is employed as s binder in a rotary granulation process. A multi-particulate oral dosage form comprises a plurality of pellets, the pellets comprising a core having disposed thereon a core composition layer. The core composition layer comprises an active pharmaceutical ingredient and a binder, wherein the binder comprises a polyethylene oxide. In other embodiments, the binder comprises a 1:2:1 bis (butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate.

1 . A method of making a multi-particulate oral dosage form, comprising 
 mixing an active pharmaceutical ingredient, a binder comprising polyethylene oxide, and a dispersing agent to form a coating mixture, and    atomizing the coating mixture in the presence of a plurality of cores in a fluidized bed with a rotor-disk granulator to produce a plurality of pellets, the pellets comprising the core having disposed thereon a core composition layer comprising the active pharmaceutical ingredient and the binder.    
     
     
         2 . The method of  claim 1 , wherein the dispersing agent comprises water:alcohol in a ratio of 15:85 to 95:5.  
     
     
         3 . The method of  claim 2 , wherein the alcohol comprises ethanol.  
     
     
         4 . The method of  claim 1 , wherein a ratio of binder to active pharmaceutical ingredient is about 1:30 to about 1:5.  
     
     
         5 . The method of  claim 1 , wherein the binder comprises about 0.2 wt % to about 12 wt % of the total weight of the core and the core composition layer.  
     
     
         6 . The method of  claim 1 , wherein the pellets comprise about 10 wt % to about 98 wt % of the core, about 2 wt % to about 85 wt % of the active pharmaceutical ingredient, and about 0.1 wt % to about 20 wt % of the binder, all based on the total weight of the core and the core composition layer.  
     
     
         7 . The method of  claim 1 , wherein the coating mixture further comprises a plasticizer.  
     
     
         8 . The method of  claim 1 , wherein the core comprises a sugar sphere.  
     
     
         9 . The method of  claim 1 , further comprising coating the pellets with an additional coating, wherein the additional coating comprises a controlled-release coating, a seal coating, or a combination comprising one or more of the foregoing coatings.  
     
     
         10 . The method of  claim 1 , wherein the active pharmaceutical ingredient is water soluble.  
     
     
         11 . The method of  claim 1 , wherein greater than or equal to about 30% of the active pharmaceutical ingredient is dissolved in the dispersing agent in the coating mixture.  
     
     
         12 . The method of  claim 1 , wherein the active pharmaceutical ingredient is about 50% to about 100% dissolved in the dispersing agent in the coating mixture.  
     
     
         13 . The method of  claim 1 , wherein rotary granulation is performed in half the time required for a comparable process in which polyvinylpyrrolidone is employed as a binder.  
     
     
         14 . A multi-particulate oral dosage form, comprising a plurality of pellets, the pellets comprising a core having disposed thereon a core composition layer, the core composition layer comprising an active pharmaceutical ingredient and a binder, wherein the binder comprises polyethylene oxide, wherein a ratio of polyethylene oxide to active pharmaceutical ingredient is about 1:30 to about 1:5.  
     
     
         15 . The multi-particulate oral dosage form of  claim 14 , wherein the binder comprises about 0.2 wt % to about 12 wt % of the total weight of the core and the core composition layer.  
     
     
         16 . The multi-particulate oral dosage form of  claim 14 , comprising about 10 wt % to about 98 wt % of the core, about 2 wt % to about 85 wt % of the active pharmaceutical ingredient, and about 0.1 wt % to about 20 wt % of the binder, all based on the total weight of the core and the core composition layer.  
     
     
         17 . The multi-particulate oral dosage form of  claim 14 , further comprising an additional coating layer, wherein the additional coating layer comprises a controlled-release coating, a seal coating, or a combination comprising one or more of the foregoing coatings.  
     
     
         18 . The multi-particulate oral dosage form of  claim 14 , wherein the API is water soluble.  
     
     
         19 . A multi-particulate oral dosage form, comprising a plurality of pellets, the pellets comprising a core having disposed thereon a core composition layer, the core composition layer comprising an active pharmaceutical ingredient and a binder, wherein the binder comprises a 1:2:1 (butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate).  
     
     
         20 . The multi-particulate oral dosage form of  claim 19 , wherein the ratio of binder to active pharmaceutical ingredient in the core composition layer is about 1:30 to about 1:5.