Chemical Engineering Spring Seminar Series: Dr. David Brayden

Oral administration of peptides: The quest to improve bioavailability

The oral administration of peptides and proteins remains one of the great challenges in pharmaceutical science. Efficacy depends on patients committing to take essential medicines and this is built upon the convenience of a dosing regimen using a patient-friendly route of administration. Large molecules have problems negotiating the GI tract to achieve systemic delivery due to instability against metabolizing enzymes and low permeability across the epithelium. To date, just five linear peptides aimed at systemic delivery have been approved by the FDA, the most recent being oral semaglutide (Rybelsus®, Novo Nordisk, 2019) and oral octreotide (Mycappsa®, Chiasma Ltd, 2020). These approvals heralded a renewed interest in the field, built around developing Glucagon-1-like peptide 1 (GLP-1) mimetics for Type II diabetes and obesity, alone or as a dual agonist with other gut peptides. Relative success to date for oral peptides has been achieved with standard oral dosage forms made with permeation enhancers, but these will only work for niche peptides with high potency and long half-lives.

My group has been working on the mechanism of action of the intestinal permeation enhancers that typically are used to enable these formulations, albeit that oral bioavailability with the above products is less than 1%. We have focussed on comparisons between sodium caprate and SNAC, both medium-chain fatty acid derivatives, and found that they have multimodal actions suggesting a dual effects on tight junctions and the intestinal epithelial plasma membrane depending on the concentration and the bioassay. We also have contributed to the search for other permeation enhancers (alone and combination) that can be used with peptides in oral dosage forms including the Gattefosse excipients, Labrasol® and Labrafac™. We are working on a nanotechnology concept, where we have achieved 7% bioavailability for insulin in a rat model using a core-shell construct based on silica coating over a core of peptide and the excipients, L-arginine, and zinc. Finally, devices may eventually be able to increase the oral bioavailability of peptides by an order of magnitude over permeation enhancers according to data from animal models, but clinical testing is at an early stage and the toxicology and the regulatory pathway for these types of technologies have yet to be addressed. I will touch on aspects and examples of these multiple approaches in my talk at Northeastern.

David Brayden is Full Professor of Advanced Drug Delivery at the School of Veterinary Medicine and a Fellow of the UCD Conway Institute. Following a Ph.D. in Pharmacology at the University of Cambridge, UK (1989), and a post-doctoral research fellowship at Stanford University, CA (1991), he set up Elan Corporation’s pharmacology laboratory in Dublin (1991). At Elan, he became a senior scientist and project manager of several of Elan’s Joint-Venture drug delivery research collaborations with US biotech companies. In 2001, he joined UCD as a college lecturer in veterinary pharmacology and was appointed Senior Lecturer (2005), Associate Professor (2006), and Full Professor (2014). He completed a successful Principle Investigator Grant from SFI on the topic of oral delivery of novel mucoadhesive polymeric peptide conjugates (2005-2009). Professor Brayden was the Director of an SFI Research Cluster grant (The Irish Drug Delivery Research Network), that was awarded 7.2 million euro by SFI from 2007-2013. He was the Deputy Coordinator of an EU 7th Framework grant on oral nanomedicines (www.TRANS-INT.eu), 2012-2017. In 2014, he was one of four Principal Investigators (Co-PIs) on the successful SFI Centre bid in Medical Devices (CURAM), worth over 40 million EUR over 6 years, which was renewed for 6 years in 2021. He is the coordinator of the Horizon Europe consortium grant, BUCCAL-PEP, which was awarded 4m EUR and runs from 2022-2026. He is the author or co-author of more than 300 research publications and patents. Professor Brayden serves on the Editorial Advisory Boards of Drug Discovery Today, Advanced Drug Delivery Reviews and the Journal of Veterinary Pharmacology and Therapeutics. In 2021 he was appointed Chief Editor of “Frontiers in Drug Delivery”. He was Chairman of the UK-Ireland Chapter of the Controlled Release Society (2003-2006), Co-Chair of the Veterinary Programmes at the CRS international conferences (2003-2006), and served on the CRS Board of Scientific Advisors (2006-2009) and the CRS Annual Meeting Programme Committee (2015, 2016). At UCD, he was Chairman of the Animal Research Ethics Committee (2005-2007) and was a member of the UCD Research Ethics Committee (2006-2011) and was elected by Academic Council to the UCD Promotions and Tenure Committee (2010-2012) and to the UCD Academic Council for Academic Centres Committee, ACCAC (2019-). He was Director of Research for the School of Agriculture, Food Science and Veterinary Medicine (2007-2008) and Head of the Veterinary Biosciences Section from 2013-2017. On the teaching side, he coordinates undergraduate and postgraduate modules on Biological Fluids and Drug Discovery and Development and contributes to a module on Cell Communication. He contributes Professional Ethics material to the Conway Institute Core Research Skills modules and also coordinates a 4th level online module on Drug Discovery and Development. In 2015, he was made an Adjunct Professor at NUI Galway to support his Co-PI role in the SFI CURAM Centre. He was elected as a Fellow of both the Controlled Release Society (2012) and the American Association of Pharmaceutical Scientists (2017). In 2021, he was appointed by the Minister of Health to the National Research Ethics Committee (Clinical Trials A). He acts as a consultant to selected Pharma and Biotech companies.