Paulus_2025_Eur.J.Pharm.Sci_210_107125

A recent in vivo study investigated the impact of supersaturation, lipid chain length, and lipase- and precipitation inhibition on the oral absorption of cinnarizine from type I Lipid-based formulations (LBFs). The aim of the current work was to investigate these formulations using the pH-stat lipolysis model, a well-established method for in vitro investigation of LBFs. This method allows the determination of the extent of lipolysis and of the drug distribution during lipolysis. The pH-stat experiment revealed that LBFs containing medium-chain triglycerides (MCT) were digested more than those containing long-chain triglycerides (LCT). Notably, digestion decreased by at least 75 % in the presence of the lipase inhibitor orlistat. XRPD measurements indicated the presence of amorphous cinnarizine upon precipitation. No correlation was found between the drug concentration in the aqueous phase (in vitro area under the curve (AUC)) and the in vivo AUC (R(2) = 0.022). However, when considering the drug concentration in the micellar phases, a stronger correlation was observed (R(2) = 0.17), which further improved when only considering MCT-based formulations (R(2) = 0.85). The poor correlation for LCT-based formulations could be attributed to their poor dispersibility in aqueous media. Overall, an acceptable correlation was found for MCT-based supersaturated formulations considering the drug concentration in the micellar phases. For potential improvement in predictability for supersaturated type I LBFs containing LCT, one will need to discuss whether the observed poor dispersibility in aqueous media is an artefact of the current lipolysis workflow.