Intraluminal enzymatic hydrolysis of API and lipid or polymeric excipients

Abstract

The role of intraluminal enzymes for the hydrolysis of active pharmaceutical ingredients (API), prodrugs and pharmaceutical excipients will be reviewed. Carboxylesterases may hydrolyze ester-based API, prodrugs and ester-bond containing polymer excipients, whereas lipases digest lipid formulation excipients, such as mono-, di- and triglycerides. To clarify the conditions that should be mimicked when designing in vitro studies, we briefly review the upper gastrointestinal physiology and provide new data on the inter-individual variability of enzyme activities in human intestinal fluids. Afterwards, the methodology for studying enzymatic hydrolysis of API, prodrugs, lipid and polymeric excipients, as well as the main results that have been obtained, are summarized. In vitro digestion models used to characterize lipid formulations are well described, but data about the hydrolysis of lipid excipients (including surfactants) has been scarce and contradictory. Data on API and prodrug hydrolysis by esterases is available; however, inconsistent use of enzyme types and concentrations limits structure-stability relationships. Hydrolysis of polymer excipients in the lumen has not been significantly explored, with only qualitative data available for cellulose derivates, polyesters, starches, etc. Harmonization of the methodology is required in order to curate larger enzymatic hydrolysis datasets, which will enable mechanistic understanding and theoretical prediction.