Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability

Sanyog Jain, Venkata Appa Reddy, Sumit Arora, Kamlesh Patel
Drug Delivery and Translational Research 2016, 6 (5): 498-510
Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and -23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model. Graphical Abstract Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability.

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