Preparation, in-vitro and in-vivo evaluation of spray-dried ternary solid dispersion of biopharmaceutics classification system class II model drug.

OBJECTIVES: The objective of this study was to investigate the impact of a novel spray-dried ternary solid dispersion (TSD) on the dissolution rate and bioavailability of a biopharmaceutics classification system (BCS) class II model drug, atorvastatin calcium trihydrate (ATC), and evaluate its in-vitro and in-vivo performance. METHODS: TSD of ATC was prepared by spray-drying method employing ethanol/water solvent systems. The TSD formulations, composed of hydroxypropyl methylcellulose (HPMC E5) and nicotinamide, were optimized by rotatable central composite design. Physicochemical characterization along with dissolution, stability and pharmacokinetic study of optimized TSD was evaluated. KEY FINDINGS: The optimized TSD was found to be amorphous with spherical shape morphology. It exhibited a fourfold increase in dissolution rate in comparison to ATC, with a considerable enhancement in oral bioavailability (relative bioavailability of 134.11%). Physicochemical characterization and dissolution study of optimized TSD at the end of stability studies clearly indicated that the stability of optimized TSD was due to hydrogen bonding between drug and HPMC E5 and nicotinamide. This bonding remained unaffected even under stressful conditions of high temperature and humidity. CONCLUSION: The TSD exhibits a significant increase in dissolution rate, and for this reason should be useful as an efficacious tool to enhance the bioavailability of BCS class II drug molecule, ATC.

Formulation, optimization and in vitro-in vivo evaluation of febuxostat nanosuspension.

The purpose of the present study was to develop febuxostat nanosuspension and investigate its effect on febuxostat solubility, dissolution rate and oral bioavailability. The wet media milling technique was adopted with a combination of hydroxypropyl methylcellulose (HPMC E3) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as surface stabilizers for the generation of nanocrystals. Rotatable central composite design (CCD) was selected for nanosuspension optimization. The critical parameters were bead volume, milling time, polymer and surfactant concentrations; whereas particle size, polydispersity index (PDI) and zeta potential were taken as responses. The presence of crystallinity was confirmed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy and transmission electron microscopy revealed small and uniform plate like morphology. A significant increase was observed in saturation solubility and dissolution rate of the optimized nanosuspension in all the pH conditions tested. Oral bioavailability of FXT and optimized FNC was evaluated in SD rats. The nanosuspension exhibited enhanced Cmax (26.48±2.71 vs. 19.85±2.96µg/mL) and AUC0-∞ (222.29±9.81 vs. 100.32±9.36µgh/mL) with a 221.6% increase in relative bioavailability. Thus, FNC is a viable approach to enhance the bioavailability of FXT, a BCS Class II drug.