(C) Means to enhance penetration: (1) Prodrugs as a means to improve the delivery of peptide drugs

Abstract

A major obstacle to the application of peptides as clinically useful drugs is their poor biomembrane penetration, rapid enzymatic degradation and short biological half-lives. A possible approach to solve these delivery problems of peptide drugs is derivatization of the peptides to produce prodrugs or transport forms which are more lipophilic than the parent peptides and capable of protecting these against degradation by enzymes present at the mucosal barrier or in the blood. The potential utility of this prodrug approach is reviewed and illustrated with a number of specific examples including prodrugs of the pyroglutamyl group, the α-aminoamide moiety, the peptide bond itself and of several amino acid- and small peptide-like drugs. Recently developed prodrugs of the tripeptide thyrotropin-releasing hormone are given special attention. It is concluded that the prodrug technology alone or in combination with appropriate formulation techniques may offer a promising means to improve the delivery characteristics of several peptide drugs.