Canagliflozin loaded SMEDDS: formulation optimization for improved solubility, permeability and pharmacokinetic performance

摘要

The aim of the present investigation is to systematically optimize and develop microemulsion preconcentrates to improve the solubility and oral bioavailability profile of canagliflozin employing D-optimal mixture design. Preconcentrate constituents, i.e. oils, surfactants and co-surfactants were selected on the basis of solubility studies and their concentration range capable of influencing the formation of microemulsions was determined. D-optimal mixture design was employed for studying the interaction behavior of desired responses and optimized using desirability approach. The optimized formulation was evaluated for its in vitro, ex vivo and in vivo behavior to determine the dissolution rate, permeation rate and oral bioavailability of the drug. The optimized formulation containing Lauroglycol FCC (80 mg), Tween 80 (300 mg) and Transcutol P (120 mg) showed desired attributes of measured responses with minimum experimental variation and desirability value of 0.751. The morphological behavior showed unifo m nano-structured globules with negligible aggregation as confirmed in transmission electron microscopy. Ex vivo permeation rate of the drug across excised intestinal segments (duodenum, jejunum, ileum and colon) was observed to be 3.51, 5.62, 4.52 and 2.98 folds higher, respectively, as compared to drug powder and marketed tablets Compared with the pure drug and commercial tablets, enhanced in vitro dissolution rate of optimized formulation was observed, resulting in 2.56 fold enhancement in Cmax and AUC0_24h following oral administration in fasting wistar rats. Establishment of level A IVTVC for the developed SMEDDS indicated excellent goodness of fit between the in vitro drug release and in vivo drug absorbed. Accelerated stability studies indicated stability of the optimized formulation over 3 months storage.