Supersaturated LFCS type III self-emulsifying delivery systems of sorafenib tosylate with improved biopharmaceutical performance: QbD-enabled development and evaluation.

The current studies investigate the application of quality by design-enabled type III self-emulsifying delivery system (Type III-SEDDS) of sorafenib tosylate (SFN) in improving its biopharmaceutical attributes. Initially, lipidic and emulsifying excipients were selected by carrying out solubility and phase titration experiments. After screening studies using Taguchi OA design, Type III-SEDDS were further optimised using D-optimal mixture design. The prepared formulations were assessed for globule size, zeta potential and percent of drug release. Following graphical optimisation, the optimum formulation was earmarked and further supersaturated to form saturated Type III-SEDDS (Sat-Type III-SEDDS) using a combination of HPMC and PVP to improve the stability of the formulation for a prolonged period. In vitro drug release of Type III-SEDDS study indicated approximately 8-fold improvement in dissolution rate over the pure powder drug. Cell uptake studies demonstrated higher uptake of dye-loaded Type III-SEDDS formulations in Caco-2 cells vis-à-vis plain dye. Cytotoxicity assay on Hep G2 cells revealed significant reduction in cell growth with Type III- and Sat-Type III-SEDDS vis-à-vis the pure drug. Furthermore, in situ permeation studies carried out using Wistar rats exhibited nearly 8.3- to 10.2-fold augmentation in permeation and absorption parameters of the drug from the Type III- and Sat-Type III-SEDDS, respectively, vis-à-vis the pure drug. Pharmacokinetic studies indicated nearly 3.98- and 3.62-fold improvement in AUC0-72, and 8.01- and 5.42-fold in Cmax, along with 0.25-fold decrease in Tmax of the drug from Type III- and Sat-Type III-SEDDS, respectively, in comparison with the SFN suspension. Furthermore, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time points for Sat-Type III-SEDDS and pure drug, whereas the Type III-SEDDS exhibited a nonlinear relationship. Stability studies indicated the robustness of Sat-Type III-SEDDS, when stored at 25 °C for 3 months. Overall, the manuscript documents the successful systematic development of SFN-loaded Sat-Type III-SEDDS with distinctly improved biopharmaceutical performance. Graphical abstract.