Predicting oral performance of lipid-based formulations using in vitro methods

Sammanfattning: Oral administration of drugs is widely considered preferable to other methods by end-users and healthcare providers alike; however, not all drug compounds are inherently suited for it because some molecules are not well-absorbed by the intestine. Good absorption requires both dissolution and permeation. For instance, highly lipophilic compounds (which have good permeability over intestinal mucosa) are prone to poor absorption following oral administration due to their poor solubility in water. Contemporary drug discovery methods tend to produce many such compounds. Thus, there is a need for enabling formulations that can increase solubility and by extension the absorption of lipophilic compounds from the intestinal tract. Lipid-based formulations (LBFs) have been proven to improve oral absorption and bioavailability for poorly water-soluble but highly permeable drug compounds. However, lipid excipients are not strictly inert, as they are also digested in and absorbed from the gastro-intestinal tract, and there is a complex interplay between physiological and physical processes that makes it difficult to rationally select an optimal composition of lipid excipients for any given drug. Empirical selection is also difficult because of the difficulty of capturing these processes in vitro. Animal studies are useful, but carry a heavy burden of high expense and ethical considerations. For these reasons, LBF development would be improved by the availability of better predictive tools.This thesis aims to improve in vitro methodology for understanding drug release and absorption processes for LBFs, focusing on self-emulsifying drug delivery systems (SEDDS), with the goal of helping better drug products reach the market. The general approach was to investigate a lipolysis-permeation method by which different LBF compositions can be assayed, hopefully in a manner more predictive of the in vivo situation than currently offered by current lipolysis assays, which do not incorporate simultaneous absorption. Special focus was put on artificial membranes, but cell monolayers were also investigated as absorptive membranes. Many parameters were discovered to significantly impact the assay outcomes, such as lipase product, lipase activity, buffer composition, stirring and fluid flow and absorptive membrane properties. The issue of predicting oral performance of LBFs is not yet solved, and much work remains. However, this thesis has identified both an artificial membrane (LiDo) that is suitable for lipolysis-permeation assays and important considerations for further development of this assay model.