From bench to humans: formulation development of a poorly water soluble drug to mitigate food effect.
This study presents a formulation approach that was shown to mitigate the dramatic food effect observed for a BCS Class II drug. In vitro (dissolution), in vivo (dog), and in silico (GastroPlus®) models were developed to understand the food effect and design strategies to mitigate it. The results showed that such models can be used successfully to mimic the clinically observed food effect. GastroPlus® modeling showed that food effect was primarily due to the extensive solubilization of the drug into the dietary lipid content of the meal. Several formulations were screened for dissolution rate using the biorelevant dissolution tests. Surfactant type and binder amount were found to play a significant role in the dissolution rate of the tablet prototypes that were manufactured using a high-shear wet granulation process. The performance of the lead prototypes (exhibiting best in vitro dissolution performance) was tested in dogs and human subjects. A new formulation approach, where vitamin E TPGS was included in the tablet formulation, was found to mitigate the food effect in humans.
Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey, 08901, USA, preetanshu.pandey@bms.com.
Preetanshu
P
Pandey
Rhye
R
Hamey
Dilbir S
DS
Bindra
Zongyun
Z
Huang
Neil
N
Mathias
Timothy
T
Eley
John
J
Crison
Brian
B
Yan
Robert
R
Perrone
Chandra
C
Vemavarapu
D000818:Animals; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D018565:Food-Drug Interactions; D006801:Humans; D012995:Solubility