The challenge of proteolytic enzymes in intestinal peptide delivery

• Published in: Journal of controlled release 1997-05, Vol.46 (1-2), p.39-57
• Main Authors: Langguth, P., Bohner, V., Heizmann, J., Merkle, H.P., Wolffram, S., Amidon, G.L., Yamashita, S.
• Format: Article
• Language: English
• Subjects: Bioavailability; Biological and medical sciences; Controlled release; General pharmacology; Intestine; Medical sciences; Peptide delivery; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Proteolytic enzymes
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(96)01586-6

The former general belief that all peptides and proteins are entirely decomposed in the gastrointestinal tract before absorption occurs turns out to be a misconception. Today several lines of evidence suggest that some proteins and peptides are capable of traversing the intestinal epithelium in intact form, however with yet unpredictable and often insufficient bioavailability, due to severe presystemic degradation in the gastrointestinal tract. Initial steps in the development of drug delivery systems for peroral peptide and protein administration involve systematic case by case investigations on proteolytic degradation mechanisms and kinetics as well as segmental differences in degradation rate and intestinal permeability using a variety of techniques such as incubations with pancreatic enzymes, mucosaI homogenates, brush-border membrane vesicles, intestinal rings and perfusion experiments. LHRH agonists, e.g. buserelin and immunoactive thymopoietin fragments are examples of compounds readily degraded by pancreatic trypsin, chymotrypsin and carboxypeptidases whereas metkephamid, a pentapeptide has been shown to completely resist proteases of pancreatic origin. Investigations on brush-border membrane-catalyzed degradation of several enkephalin analogs demonstrate the versatility of the enzyme systems involved in the degradation and also the saturability of the reaction rate. The latter findings imply that at higher peptide doses (concentrations) the fraction absorbed can be expected to increase due to a saturability of the degradation process. For proteolytically labiIe compounds, appropriate means to stabilize the molecule within the gastrointestinal tract are mandatory in order to improve the fraction absorbed unchanged. These may involve a stabilization of the molecule itself, e.g. by inserting unnatural d-amino acids into the molecule, N-methylation of peptide bonds or cyclization, examples of which are presented. On the other hand, coadministration of protease inhibitors may significantly enhance the bioavailability of a proteolytically labiIe peptide. A delivery system is presented which simultaneously releases a peptide together with an aminopeptidase inhibitor and a pH-modifier in the lower gastrointestinal tract, resulting in an improvement in absolute bioavailability from 0.2% to 4%.