By: Sam Maher
Oral delivery of therapeutic peptides has been a constant source of frustration for delivery and formulation scientists over the last 50 years. Peptides are poorly absorbed via the oral route due to digestion and poor movement across the gut wall. For a long time the problem was limited to insulin and the non-peptide heparin, but today there are 60+ peptide drugs marketed worldwide, the majority of which are delivered using needles. Effort to enable more convenient oral delivery is associated with a minefield of proof-of-concept delivery systems, which to date have failed to translate into successful oral formulations. The extensive literature on oral peptide delivery has helped to shape specialities such as biopharmaceutics, although the volume of delivery systems that fail to deliver on their promise—especially those that have progressed to clinical testing—has raised concerns about whether peptides can be delivered via the oral route.
It is worth emphasising that there are nine peptides that have been successfully marketed via the oral route, and these provide valuable information on potential future innovation. In short, all of these peptides are cyclised or chemically modified to limit digestion. Seven are intended to act in the digestive tract and only two reach systemic targets: desmopressin and cyclosporin. These peptides are atypical, and hence have not been lauded as milestones in oral peptide delivery, but they do provide information that could promote innovation and future success.
Desmopressin (DDAVP®, Teva) is successful because it is potent, has a long plasma half-life, a wide therapeutic index, and is relatively small and stable. Even still, only 0.17% is absorbed in to the systemic circulation. Few peptides meet these requirements with low potency, large size, and lower half-life significantly impacting potential oral activity (Table 1). The ultimate question is can a delivery system or structural modification enable administration via the oral route for peptides that do not share these properties.
|Peptide||Disadvantages (Vs Desmopressin)||Advantages (Vs Desmopressin)||Route of administration|
|Octreotide||· Low potency||· ―||· Injectable|
|Exenatide||· Large size||· ―||· Injectable|
|GLP-1||· Large size
· Short half life
|· ―||· Injectable*|
|Insulin glargine||· Low potency
· Large size
|· ―||· Injectable|
|Insulin||· Low potency
· Large size
· Short half-life
|· ―||· Injectable|
|Semaglutide||· Large size||· Long half-life||· Injectable/Oral*|
|Cyclosporin||· Low potency||· Lipophilic||· Oral|
Table 1: Comparison of peptides of interest in oral delivery versus desmopressin (* in development)
Whether to focus on drug or delivery system in discovery was the subject of debate at the 2016 AAPS Annual Meeting session Where to Invest? The Drug or the Delivery System?, presented by Christopher A. Lipinski and Marshall Crew. The most challenging peptides could benefit from a dual focus where modification reduces the demand on the delivery system. For example, semaglutide (Novo Nordisk) is a potent, long acting GLP-1 analogue that has been combined with a delivery system that has been successful with more challenging macromolecules (Eligen®, Emisphere).
Most marketed peptides have good solubility in water, a property that sometimes confers poor movement across the gut wall. Cyclosporin on the other hand has low water solubility and, concurrently, much improved permeability across the gut wall; but only if poor solubility is corrected using a delivery system (e.g., Neoral®, Novartis). Approximately 27% of cyclosporin is absorbed into the systemic circulation despite being bigger than desmopressin (0.17%) and several injectable peptides (e.g., octreotide). The challenge therefore is: can peptides be physically or chemically modified to make them more like cyclosporin, and if so, can the modified peptide be combined with a suitable drug delivery system? Promising prototypes are beginning to emerge in the scientific literature, and these warrant rational consideration without bias based on past failures in oral peptide delivery.