Hot "Dissolving" Extrusion of Lurasidone with Natural Liquid Small Molecule for Amorphous Solid Dispersion Based Self-Assembled Submicron Emulsion

Nowadays, approximate to 90% of new drug candidates under development are poorly bioavailable due to their low solubility and/or permeability. Herein, a natural liquid small molecule trans-anethole (TA) is introduced into the drug-polymer system lurasidone (LUS)-poly (1-vinylpyrrolidone-co-vinyl acetate) (VA64), notably improving the compatibility of components for the successful preparation of amorphous solid dispersion (ASD) and facilitating the formation of self-emulsifying drug delivery system (SEDDS) during dissolution. LUS-TA-VA64 ASD shows enhanced supersaturation with a long maintenance time of at least 24 h over pure LUS. The strong non-covalent force between VA64 (as emulsifier) and TA (as oil phase)/ water promotes the self-assembly of submicron emulsion and ensures its stability for at least 10 h. Compared to the commercial salt form of LUS, the ASD shows twofold increase in peak plasma concentration (Cmax) and area under plasma concentration-time profiles (AUC), 1.5-fold increase in peak time (Tmax), and twofold decrease in AUC-based coefficient of variation (CV) (59%-> 26%) after a single oral dose to a rabbit. The joint use of amorphous solid dispersion (ASD) with self-emulsifying delivery system by using natural liquid small molecules as bridge is achieved first, establishing an innovative model of self-assembled submicron emulsion with amphiphilic polymer as emulsifiers and liquid small molecules as oil phase to improve solubility and permeability of water-insoluble drugs.image