Formulation by design approach for development of ultrafine self-nanoemulsifying systems of rosuvastatin calcium containing long-chain lipophiles for hyperlipidemia management.

The present work entails systematic development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) of rosuvastatin calcium containing long-chain lipophiles using QbD-driven Formulation by Design (FbD) approach. Elements of quality target product profile (QTPP) were defined and critical material attributes (CQAs) earmarked. Excipient screening was performed for selecting a suitable long-chain lipophile along with a surfactant and a cosolvent. Maximal drug solubility was observed in Peceol (i.e., lipid), Tween 80 (i.e., surfactant) and Transcutol HP (i.e., cosolvent), which during pseudoternary phase titration study indicated maximal nanoemulsion region at 1:1 ratio of surfactant: cosolvent mixture. Risk analysis and factor screening study indicated selection of excipient levels as the critical material attributes (CMAs). D-optimal mixture design was used for systematic optimization of L-SNEDDS, which exhibited emulsification time of 131s, globule size <100nm and faster drug release rate >80% in 15min. Ex vivo permeability showed >70% permeation of drug across the rat intestine, while in situ perfusion study indicated up to 1.8 and 2.1-folds improvement in permeability and absorptivity parameters of the drug from optimized L-SNEDDS over the plain drug suspension. In vivo pharmacokinetic studies revealed 1.8- and 5.7-folds enhancement in AUC and C, and 0.33-folds reduction in T of drug from the optimized L-SNEDDS vis-à-vis the pure plain drug suspension. In vivo pharmacodynamic studies also indicated superior antihyperlipidemic activity of optimized L-SNEDDS in normalizing serum lipid levels. Overall, the research work construed significant role of long-chain lipophiles in enhancing biopharmaceutical attributes of the L-SNEDDS of rosuvastatin.