PROTEASE INHIBITORS AND PENETRATION ENHANCERS AS APPROACHES TO MODIFY PEPTIDE ABSORPTION

The proteolytic and penetration barriers are formidable barriers that must be overcome in considering any non-parenteral route of peptide and protein drug delivery. While chemical modification of the primary structure has been successful in protecting peptides from proteolysis, this is not so in the case of proteins because of their structural complexity. Consequently, the use of protease inhibitors must be considered. The selection of protease inhibitors depends on the principal proteases mediating the degradation of a given peptide or protein, their subcellular compartmentalization, their ability to reach the target and the mechanisms by which the peptide or protein crosses the mucosal epithelial layer. In addition to protease inhibitors, penetration enhancers are also required. Penetration enhancers act by diverse mechanisms, including fluidization of the plasma membrane, loosening of the tight junctions between cells, inhibition of proteases and increasing the thermodynamic activity of proteins prone to self-association. Before protease inhibitors and penetration enhancers can be used on a routine basis, however, their short- and long-term effects on the well-being of the mucosal cells and the rest of the body must be ascertained. This paper will review the experience with protease inhibitors and penetration enhancers to date, address the concerns with their routine use and examine some alternative approaches to promote mucosal peptide and protein absorption. © 1990.