Dynamic changes in the distribution equilibrium of drugs in microemulsions associated with drug absorption facilitate the absorption improvement for drugs with low water-solubility by self-microemulsifying drug delivery system (SMEDDS)

Mechanisms for absorption improvement of drugs with low water-solubility by self-microemulsifying drug delivery system (SMEDDS) are still controversial except for solubility improvement. We attempted to clarify the mechanisms by utilizing model drugs classified as biopharmaceutics classification system class II. In the in-vitro transport study for microemulsions (MEs) formed from SMEDDS, the permeation clearance (CL_perm,free^SMEDDS) calculated based on free drug concentrations in MEs, was significantly larger than the CL_perm^soln for aqueous solution. However, pretreatment of intestinal mucosa with drug-free MEs did not change CL_perm^soln so much. The contribution of endocytosis to drug absorption from MEs was negligible. Instead, our novel egg phosphatidylcholine-monolayer-chloroform partition study revealed that drugs were continuously released from ME droplets, and that the distribution equilibrium of drugs in ME dynamically shifted from ME droplets to aqueous phase associated with their partitioning into chloroform phase (i.e. drug absorption). CL_perm,free^SMEDDS did not reflect the continuous drug release or the much larger amount of drugs available for absorption than revealed as free concentrations and thereby overestimated the permeation clearance. The absorption improvement by SMEDDS could be attributed to the dynamic changes in the distribution equilibrium of drugs in MEs associated with drug absorption, i.e., the continuous drug release from ME droplets.