CHAPTER 16: Technologies for Oral Delivery of Peptides

The oral route for the delivery of peptides offers safety, ease of use and increased patient compliance for chronic indications. However, with a few special exceptions, most peptide drugs marketed today are injectable. The intestinal epithelium and the mucus layer are barriers to the transport of molecules greater than two or three amino acids in size, and intestinal proteolytic enzymes derived either from the pancreas or from the intestinal brush border membranes rapidly cleave peptide bonds. For most peptides, poor intestinal permeability, susceptibility to proteolytic degradation, short half-life, propensity to aggregate and size offer significant challenges to oral delivery. For a commercially viable oral product these limitations need to be overcome by formulation development or peptide structure modification. Structural modification strategies such as cyclization, addition of unnatural amino acids, blocking of N- and C-termini, etc. to stabilize peptides and increase their protease resistance have been developed to accomplish this. Several formulation enhancements are also employed, including the addition of protease inhibitors and permeation enhancers, conjugation to peptide transporters and/or encapsulation in micro- or nano-spheres. Using one or more of these strategies to increase paracellular or transcellular transport, a variety of peptide molecules are currently in preclinical or different stages of clinical development. Further increases in bioavailability, decreases in inter- and intrapatient variability, and evidence of long-term safety of formulation excipients remain the foci for further efforts to fully realize the potential for the oral delivery of peptides.