QbD-based formulation development and evaluation of lipid-cellulose-based extended-release multi-particulates of cinitapride and its in-silico PBPK modeling

The study aims to develop and optimize extended-release cinitapride matrix pellets using lipid wax glyceryl monostearate (GMS) and ethyl cellulose (EC) for treating functional dyspepsia and gastrointestinal reflux disease. Pellets were prepared using the extrusion spheronization technique by applying central composite design (CCD), keeping EC-7cps (matrix former), spheronization speed, and time as variables. The drug release, sphericity, and aspect ratio were quality parameters. The predicted optimized formulation was evaluated for chemical interaction, thermal stability, accelerated stability, and surface morphology. EC effectively controlled the overall Cinitapride release for up to 12 h, but burst release was reduced by sintering the matrix pellets. A direct relationship was observed between the sphericity and aspect ratio of the pellets with the spheronization speed and time. F_pred followed the Korsmeyer-Peppas model, demonstrating a non-fickian diffusion at all pH levels. The bioavailability of F_pred was compared with reference immediate release tablet by applying in silico PBPK modeling and comparable relative bioavailability. The PBPK predicted C_max, T_max, AUC_0-t, and AUC_0-∞ was 361.93 pg/mL, 6.88 h, 4567.8 pg/mL/h, and 5204.7 pg/mL/h, respectively. Lipid-cellulose-based extended-release Cinitapride matrix pellets were successfully prepared and can be effectively used as a single dose regimen for treating functional dyspepsia and gastrointestinal reflux disease.