Looking behind the Solubilization Curtain: Microdialysis Provides Near-Real-Time Noncolloidal Drug Concentrations during In Vitro Lipolysis.

Lipid-based formulations can enhance the oral absorption of poorly water-soluble drugs. Their performance is typically evaluated by in vitro lipolysis. For this, samples are usually prepared by centrifugation, and formulation performance is evaluated based on the concentration in the aqueous phase. However, several studies have questioned the predictiveness of the in vitro lipolysis method. A reason for the in vitro-in vivo mismatch may be that centrifugation cannot separate truly dissolved drug molecules from molecules associated with colloidal assemblies such as mixed micelles. The present study tested microdialysis as an alternative sampling technique for in vitro lipolysis by which truly dissolved drug molecules (i.e., the free fraction) can be separated from colloid-associated drug molecules. Thereby, a better mechanistic understanding of the formulation performance will possibly be achieved. Indomethacin and a medium-chain type IIIB lipid-based formulation were used as model drug and model formulation, respectively. Microdialysis sampling was found compatible with lipolysis medium with bile salts, phospholipids, and pancreatic enzymes. In a proof-of-concept study, microdialysis provided near-real-time concentrations of free indomethacin during the in vitro lipolysis process and revealed supersaturation of indomethacin. However, indomethacin supersaturation was also observed under nonlipolytic conditions. Based on microdialysis data, digestion would not influence the formulation performance. In contrast, conventional samples showed that lipolysis significantly decreased the solubilization capacity of the formulation. Other examples have been described in the literature where oral absorption from lipid-based formulations had been independent of digestion even though data from in vitro lipolysis with conventional sampling indicated the opposite. Overall, microdialysis is a promising and complementary sampling technique for the evaluation of lipid-based formulations by in vitro lipolysis.