Systemic Delivery of Peptides by the Oral Route: Formulation and Medicinal Chemistry Approaches

David J Brayden, T. A. Hill, D. P. Fairlie, S. Maher, Randy Mrsny

Research output: Contribution to journalReview articlepeer-review

154 Citations (SciVal)


In its 33 years, ADDR has published regularly on the po5tential of oral delivery of biologics especially peptides and proteins. In the intervening period, analysis of the preclinical and clinical trial failures of many purported platform technologies has led to reflection on the true status of the field and reigning in of expectations. Oral formulations of semaglutide, octreotide, and salmon calcitonin have completed Phase III trials, with oral semaglutide being approved by the FDA in 2019. The progress made with oral peptide formulations based on traditional permeation enhancers is against a background of low and variable oral bioavailability values of ~1%, leading to a current perception that only potent peptides with a viable cost of synthesis can be realistically considered. Desirable features of candidates should include a large therapeutic index, some stability in the GI tract, a long elimination half-life, and a relatively low clearance rate. Administration in nanoparticle formats have largely disappointed, with few prototypes reaching clinical trials: insufficient particle loading, lack of controlled release, low epithelial particle uptake, and lack of scalable synthesis being the main reasons for discontinuation. Disruptive technologies based on engineered devices promise improvements, but scale-up and toxicology aspects are issues to address. In parallel, medicinal chemists are synthesizing stable hydrophobic macrocyclic candidate peptides of lower molecular weight and with potential for greater oral bioavailability than linear peptides, but perhaps without the same requirement for elaborate drug delivery systems. In summary, while there have been advances in understanding the limitations of peptides for oral delivery, low membrane permeability, metabolism, and high clearance rates continue to hamper progress.

Original languageEnglish
Pages (from-to)2-36
Number of pages35
JournalAdvanced Drug Delivery Reviews
Early online date29 May 2020
Publication statusPublished - 2020

Bibliographical note

Funding Information:
DB is funded by the Science Foundation Ireland (SFI) CÚRAM Centre for Medical Devices , grant number 13/RC/2073 , by the SFI BiOrbic Centre for Bioeconomy , grant number 16/RC/3889 , and by the EU Regional Development Fund . DF was supported by grants from the ARC ( DP180103244 , CE200100012 ) and NHMRC ( 1128908 , 1143601 ) and an NHMRC Senior Principal Research Fellowship ( 1117017 ). We thank Maciek Doczyk of the SFI CÚRAM Centre at NUI Galway for the artwork in Fig. 4 .

Publisher Copyright:
© 2020 The Authors


  • Drug-device combination products
  • Epithelial permeability
  • Nanoparticles
  • Oral bioavailability
  • Oral peptide delivery
  • Tight junctions

ASJC Scopus subject areas

  • Pharmaceutical Science


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