Overcoming the obstacles associated with oral delivery of peptides
08 March 2016
Image: Dr Mark Auty, Teagasc
Authors: Joanne Heade, David Brayden, UCD School of Veterinary Medicine and UCD Conway Institute; Sinéad Bleiel, AnaBio Technologies Ltd
Peptides are an interesting drug class with huge therapeutic potential. Some of the more well-known commercially successful peptides on the market include: hormones (calcitonin), growth hormone inhibitors (octreotide), and anti-diabetics (insulin and GLP1- agonists).
Peptides such as these possess high potency and are inherently very selective, which means they will interact largely with a specific target, reducing the chances of adverse effects occurring due to off-target interactions.
Unfortunately these favourable characteristics come at a price, as peptides are generally unsuitable for delivery by the more convenient oral route. Due to their susceptibility to enzymatic degradation in the gastrointestinal tract (GIT), pH-related instability, high molecular weight, and hydrophilic nature, poorly permeable peptides are invariably delivered by parenteral routes  as opposed to via the skin (topical or transdermal) or through the gastrointestinal tract (enteral).
For this reason, AnaBio Technologies Ltd initiated a collaboration with Professor David Brayden in University College Dublin, to address oral administration of therapeutics with an efficacious, economical dose delivery response.
Although there are some orally available peptide drugs on the market and in clinical development, the GIT and intestinal wall represent primary barriers to oral drug delivery. Interferon for example (20kDa), is too large to cross the gut wall meaning orally delivered therapeutic peptides have to be sized between 0.9 kDa and 6 kDa.
The tight junctions between the cells of the intestinal epithelium restrict the passage of molecules larger than 200Da . The hydrophilic nature of many peptides also prevents them from crossing the lipid bilayers of the epithelial cells. Together, these obstacles make it difficult for peptides to reach the bloodstream in a biologically active form.
Protection of sensitive cargoes
The first obstacle encountered by a peptide-drug is the acidic environment of the stomach where most peptides will be denatured and lose biological activity. The next phase of digestion involves proteolytic enzymes which are designed to break down peptides into smaller peptides or single amino acids. AnaBio Technologies Ltd is an Irish company formed in 2011 by Dr Sinéad Bleiel, who seek to find solutions to this problem.
AnaBio’s core technologies are patented micro-encapsulation systems made from food-derived macro-nutrients. These technologies are designed to protect sensitive cargoes during processing, storage, stomach and small intestinal delivery, with subsequent liberation at the intestinal target site.
For example, dairy and vegetable proteins have been utilised to protect bioactives during thermal processing, shelf-life and (in vivo) intestinal transit for enhanced absorption and bioavailability . To date AnaBio has successfully commercialised patented technologies in the food, feed and pharmaceutical sectors. AnaBio seeks further success in oral delivery of therapeutic peptides.
Permeation enhancement at the gut wall
The oral delivery of peptides is a difficult task, and one that requires collaboration to achieve success. For this reason, AnaBio initiated a collaboration with Professor David Brayden in UCD School of Veterinary Medicine and Conway Institute.
By utilising the AnaBio encapsulation technology, a peptide can be formulated to reach the intestinal wall in an intact biologically active form. This has been verified by AnaBio by utilsing in vitro and ex vivo models for selected peptides of interest.
The next obstacle is the selectively permeable intestinal epithelium. Prof Brayden’s group in UCD has been investigating delivery strategies for peptide-drugs for over 10 years, focusing particularly on improving permeability at the intestinal wall. This is achieved by using excipients known as permeation enhancers, which can improve drug absorption by reversibly perturbing the intestinal epithelium and/or interacting with the proteins that regulate the tight junctions.
The Brayden group has been testing the potential of medium chain fatty acids (MCFA) to act as intestinal permeation enhancers using tissue mucosae mounted in Ussing chambers. Natural MCFA are found in many foods including milk, coconut oil and palm kernel oil, but typically not in quantities sufficient enough to induce permeation enhancement. By using higher concentrations of MCFA than those found in food, the Brayden group has demonstrated improved transport of marker molecules and peptides across ex vivo intestinal tissue [5, 6].
These MCFA have also been found to be largely non-toxic to colonic cells in vitro and only mildly damaging to ex vivo intestinal tissue . This damage has been shown to be reversible in vivo as the intestinal epithelium is capable of rapid repair .
The AnaBio – UCD collaboration has helped bring together the oral delivery expertise in UCD and encapsulation expertise of AnaBio. The Irish Research Council (IRC) supports this collaboration and enables Joanne Heade to perform research with a commercial objective. This collaboration aims to formulate a delivery system for therapeutic peptides which are both highly unstable and poorly permeable.
Building upon positive protected preliminary findings, this project will look to create tablets of prototype formulations, which is a key aspect of oral drug delivery that is often overlooked. To this end a third collaborator on this project is Dr Sam Maher from RCSI School of Pharmacy, who can offer pharmaceutical formulation experience.
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