Design of high dose lopinavir loading self-nanoemulsifying drug delivery systems using supersaturation and solidification strategies.

Abstract

Lopinavir (LPV) is a clinically relevant antiretroviral drug that is challenging to optimally formulate and deliver due to its low solubility and poor permeability. Self-nanoemulsifying drug delivery systems (SNEDDS) offer potential for LPV but suffer from low loading levels and instability. Here we employ supersaturation and solidification to improve these challenges. Optimised LPV-loaded liquid-SNEDDS (Capmul® PG8:Labrasol®:propylene glycol, 80:15:5 w/w) were supersaturated using a heating and cooling method at loading levels 80%, 150% and 200% of the LPV equilibrium solubility. Solid-SNEDDS were prepared by physical adsorption of liquid-SNEDDS onto different silica carriers (Parteck® SLC, Aerosil® R974, and Aerosil® 300). The biorelevant solubilisation properties were evaluated using two-stage dissolution and fed vs fasted lipolysis. Compared to crystalline LPV, liquid-SNEDDS increased LPV release 9-fold and 5-fold in gastric and intestinal dissolution, and 3-fold and 6-fold under fasted and fed lipolysis, respectively. Solidification altered the release and sustained LPV solubilisation, i.e. a progressive sustained release from Parteck® SLC, slow attenuated release from Aerosil® R974 and rapid release from Aerosil® 300. Together, these findings demonstrate that increased LPV loading can reduce formulation burden while retaining substantial biorelevant performance, but that performance following solidification is strongly dependent on silica carrier architecture.

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