Molecular modelling and multisimplex optimization of tocotrienol-rich Self Emulsified Drug Delivery Systems

The objective of this study was to optimize a novel tocotrienol (TRF)-rich Self Emulsified Drug Delivery System (SEDDS). In the first part, an unusual phenomenon was investigated. It was observed that by substituting Tween® 80 with Cremophor® EL in the SEDDS it was possible to emulsify > 55% TRF (by weight of the formulation) into submicron (<200 nm) emulsion. With Tween®, only 17.5% of the loaded TRF could be emulsified into crude emulsion. The superiority of Cremophor® was attributed to the special arrangement of the surfactant at the oil/water interface, which was confirmed by modelling and docking studies. In the second part of this study, the composition of the secondary ingredients in the TRF-rich SEDDS were optimized by the modified Multisimplex® approach. SEDDS were manufactured at pre-defined step-size and tested for their dissolution behavior. Testing was performed sequentially until the optimum composition that can emulsify 50% of the loaded TRF into a stable < 150 nm submicron emulsion was obtained. Optimization end-point was identified when the “membership value” approached 1, which was confirmed by a second Multisimplex® run. Overall, this study demonstrated the utility of docking studies and the Multisimplex® approach in product development when little is known about the experimental “design space”.