Royal College of Surgeons in Ireland
Systemic delivery of peptides by the oral route.....pdf (5.59 MB)

Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches

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journal contribution
posted on 2021-07-12, 16:33 authored by DJ Brayden, TA Hill, DP Fairlie, Sam MaherSam Maher, RJ Mrsny
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.


Science Foundation Ireland (SFI) CÚRAM Centre for Medical Devices, grant number 13/RC/2073

SFI BiOrbic Centre for Bioeconomy, grant number 16/RC/3889

EU Regional Development Fund

NHMRC (1128908, 1143601)

NHMRC Senior Principal Research Fellowship (1117017)

ARC (DP180103244, CE200100012)



The original article is available at

Published Citation

Brayden DJ, Hill TA, Fairlie DP, Maher S, Mrsny RJ. Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches. Adv Drug Deliv Rev. 2020;157:2-36.

Publication Date

29 May 2020

PubMed ID



  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Chemistry and Pharmaceutical Sciences


Elsevier BV


  • Published Version (Version of Record)