Optimization of Performance Variables of Exemestane Nanosuspension Using Box-Behnken Design to Improve Dissolution and Oral Bioavailability.

PURPOSE

Present investigation was aimed to fabricate nanocrystal of exemestane, an anticancer drug with poor dissolution properties and oral bioavailability.

METHODS

Influence of various process parameters on the formulation of exemestane nanosuspension using media milling technique were investigated in the trial batches. Box-Behnken design was applied with independent variables identified in the preliminary studies, viz. X1 -Milling time, X2 -Amount of stabilizer and X3 -Amount of milling agent. In vitro dissolution and in vivo studies were carried out. Solid state characterization (PXRD, SEM, and DSC) studies demonstrated physical changes in drug due to nano-crystallization. Accelerated stability studies of optimized formulation were carried out.

RESULTS

Individual process attributes exhibited a significant effect on the average particle size of exemestane nanosuspension. Dissolution studies revealed enhancement in drug release rate as compared to pure exemestane powder. The in vivo pharmacokinetic parameters of exemestane nanosuspension showed significant improvement in Cmax and AUC0-t, about 283.85% and 271.63%, respectively suggesting amelioration in oral bioavailability by 2.7-fold as compared to pure exemestane. Accelerated stability studies of the optimized formulation suggested stability of the nanocrystals for at least a six-month period.

CONCLUSION

Nanocrystals prepared by media milling technique were successful in improving the poor dissolution properties and oral bioavailability of exemestane.