IMPROVED ORAL-DRUG DELIVERY - SOLUBILITY LIMITATIONS OVERCOME BY THE USE OF PRODRUGS

This chapter describes a strategy to improve the oral delivery of poor ly water-soluble drugs by chemical derivatization to a water-soluble p rodrug. The strategy utilizes esterification of a drug hydroxyl, amine or carboxyl group with a moiety (progroup) designed to introduce an i onizable function or reduce intermolecular interactions responsible fo r low solubility. The use of spacer groups to introduce derivatizable functions and/or to position ionizable progroups for unhindered hydrol ysis is also described. Prodrug strategies coupling drug solubilizatio n with membrane carrier targeting and the use of collapsible and bifun ctional prodrugs are outlined. These approaches are illustrated with s tudies utilizing model compounds to test the strategy as well as examp les from various therapeutic classes of drugs in which aqueous solubil ity limits drug absorption.