Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides

The objective of the current work is to develop systematically optimized self-nanoemulsifying drug delivery systems (SNEDDS) using long chain triglycerides (LCT's) and medium chain triglycerides (MCT's) of ezetimibe employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. Equilibrium solubility studies indicated the choice of Maisine 35-1 and Capryol 90 as lipids, and of Labrasol and Tween 80 as emulgents for formulating the LCT and MCT systems, respectively. Ternary phase diagrams were constructed to select the areas of nanoemulsion, and the amounts of lipid (X1) and emulgent (X2) as the critical factor variables. The SNEDDS were systematically optimized using 32 central composite design and the optimized formulations located using overlay plot. TEM studies on reconstituted SNEDDS demonstrated uniform shape and size of globules. The nanometer size range and high negative values of zeta potential depicted non-coalescent nature of the optimized SNEDDS. Thermodynamic studies, cloud point determination and accelerated stability studies ascertained the stability of optimized formulations. In situ perfusion (SPIP) studies in Sprague Dawley (SD) rats construed remarkable enhancement in the absorptivity and permeability parameters of SNEDDS vis-à-vis the conventional marketed product. In vivo pharmacodynamic studies in SD rats indicated significantly superior modification in plasma lipid levels of optimized SNEDDS vis-à-vis marketed product, inclusion complex and pure drug. The studies, therefore, indicate the successful formulation development of self-nanoemulsifying systems with distinctly improved bioavailability potential of ezetimibe.

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► Marked bioavailability enhancement potential of SNEDDS as adjudged from in vivo pharmacodynamic studies.
► Exploration of the mechanism of absorption enhancement employing in situ SPIP studies.
► Superior bioavailability enhancement of ezetimibe using LCT's vis-à-vis MCT's.
► Robustness of the SNEDDS formulation using accelerated stability, thermodynamic and rheological studies.