Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs

This chapter describes a strategy to improve the oral delivery of poorly water-soluble drugs by chemical derivatization to a water-soluble prodrug. The strategy utilizes esterification of a drug hydroxyl, amine or carboxyl group with a moiety (progroup) designed to introduce an ionizable function or reduce intermolecular interactions responsible for low solubility. The use of spacer groups to introduce derivatizable functions and/or to position ionizable progroups for unhindered hydrolysis is also described. Prodrug strategies coupling drug solubilization with membrane carrier targeting and the use of collapsible and bifunctional prodrugs are outlined. These approaches are illustrated with studies utilizing model compounds to test the strategy as well as examples from various therapeutic classes of drugs in which aqueous solubility limits drug absorption.