The first orally available peptide drug to reach the market was Cyclosporin A in 1990 to treat rheumatoid arthritis, psoriasis, Crohn’s disease, and nephrotic syndrome. Since then, the demand for oral peptide delivery, along with the oral delivery of other small molecule drug products such as protein therapeutics, has increased exponentially. Back in 2016, the peptide therapeutics market was valued at approximately 643 million USD, and by 2028 it is expected to reach over 833 million USD. But it is the recent breakthrough in orally available peptides that is set to really up-the-ante for industry growth and development. Key players within the field include AstraZeneca, Novo Nordisk, Novartis, CARA Therapeutics, Enteris BioPharma, Chiasma, Oramed, and Diabetology. But why are oral peptides such a hot topic right now?
Besides safety, improving patient experience is the top priority of peptide therapeutics today. Key therapeutic areas for peptide drugs include metabolic disorders such as diabetes, oncology, and immunotherapy. However, around 95% of all peptides are delivered parenterally, meaning there are currently only 4 drug products that are being administered orally. Along with protein therapeutics, many peptides require parenteral administration to avoid degradation by stomach enzymes. Parenteral administration refers to non-oral administration techniques such as injections. Injections, however, can be a significant deterrent for patients, significantly decreasing medicinal compliance rates. As a result, oral delivery has become especially desirable as a less invasive form of administration and, extensive efforts have been made to develop more consumer-friendly delivery strategies. In this article, we take a look at some of the challenges of oral peptide delivery as well as exciting pipeline developments to overcome these.
The Challenges of Oral Peptide Delivery: Digestive Enzymes and Degradation
The biggest challenge for delivering orally available peptide therapeutics is achieving bioavailability. Bioavailability refers to the extent and speed to which a drug can enter the systemic circulation and access the target site of action. Increasing the rate of bioavailability is difficult when considering the physiological barriers found in the gastrointestinal tract (GT). The GT is responsible for food digestion, nutrient uptake, and is the first-line defence against toxins. According to Nigel Davies, Principal Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, “the gastrointestinal tract is the hurdle nature has put in place to limit the oral absorption of peptides, however science and technology advances are helping us overcome this”. Along with protein therapeutics, many oral peptides risk degradation by stomach enzymes such as protease, trypsin, and chymotrypsin. Degradation refers to the process by which the drug products, upon entering the digestive system via the mouth, essentially get broken down and their therapeutic potency compromised by the naturally occurring chemical reactions in the gut.
GT mucus can also hinder the transport of peptide therapeutics. Mucus is a slippery aqueous secretion that has a protective function and creates a diffusional gel barrier. It captures foreign moieties and external pathogens and thus ultimately affects the fate of the therapeutic. Brush border enzymes are a further obstacle. Located in the small intestines, these further cleave the peptides. The intestinal epithelium is the single-cell layer forming the luminal surface lining of both the small and large intestine, and likewise limits the systematic oral bioavailability of peptides. To overcome these challenges associated with the route of administration, scientists are making strides to develop numerous novel approaches and technologies to increase the oral bioavailability of peptide therapeutics.
Pushing the Boundaries of Oral Peptide Delivery: Advances in Technology
1.) Transient Permeation Enhancers: Transient Permeation Enhancers (TPEs) can enable systematic absorption following oral administration. TPEs comprise of excipients (a substance that serves as the vehicle for a drug) and affect the permeability of the intestinal epithelium. This occurs either by opening the tight junctions to enable paracellular absorption or by disturbing the epithelial cell membrane to therefore facilitate transcellular absorption. To prevent and protect the peptide against enzymatic degradation, TPEs are often administered with protease inhibitors and PH modifiers. Most delivery technologies such as TPE are also made with a polymer barrier of enteric coating to prevent intestinal dissolution. Examples of different types of TPEs are bile salts, fatty acids and salts, acylated amino acids, and polymers. Other popular TPEs include Acyl carnitines, alkyl saccharides, and medium-chain mono-, di-, and triglycerides.
2.) Lipid Nanocarriers: Lipid Nanocarriers are fast becoming an increasingly developed technology for oral drug delivery. Lipidisation can improve the intestinal permeability of peptide drugs, by enhancing their transport across the epithelial and thus reducing the chances of degradation. For Andreas Bernkop-Schnürch, Chairman for Pharmaceutical Technology and Head of the Department of Pharmaceutical Technology at the University of Innsbruck, “self-emulsifying lipid nanocarriers possess the highest relevance within the industry because they are both affordable and simple to make”. Their oily properties mean lipid nanocarriers are often encapsulated in soft gelatine coatings, which undergo an aqueous dilution upon reaching and reacting to the gastrointestinal fluids. Lipid nanocarriers therefore significantly increase the bioavailability of oral peptide delivery and are preferable due to the protective effect they provide for peptides towards a presystemic metabolism and absorption enhancing properties.
3.) PEGlyation: PEGlyation refers to the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG). PEG is a non-immunogenic and non-toxic polymer that can be used to overcome the challenges of specific biopharmaceuticals. It is possible to take a PEGlyation approach to optimise the oral delivery of peptides. PEGlyation protects the structural integrity of peptides by created a barrier from protease enzymes which thus allows for oral therapeutics to reach the epithelial lining and bloodstream. The advantages of this approach include improved half-life, lower toxicity, and lower cost of manufacturing.
Research and innovation in the advancement of oral peptide delivery are gaining momentum. Driven by a desire to make the administration of peptide therapeutics easier and less invasive, the pharmaceutical industry is committed to optimising the patient experience. To address the all-too-real phenomenon of needle-phobia and the implications it has on patient reluctance and medicinal avoidance, scientists are fast developing novel oral solutions. One such exciting breakthrough came in the form of Novo Nordisk’s advancements in semaglutide delivery. Semaglutide is a peptide-drug used to treat diabetes and obesity. Previously it was only available as an injection, however, in 2020, its oral use was approved for market. Chiasma’s Ocreotide capsule which was developed using TPE technology and is used in the treatment of carcinoid syndrome also received FDA approval in 2020. At Oxford Global, we believe that these exciting developments mean it will only be a matter of time before technological innovation provide an oral alternative for every peptide drug on the market.