Industry Insight

Oral peptides are becoming an attractive drug candidate due to their efficacy and potency. How are parenteral drug products impacting the distribution of this new candidate?

By Andrew Lewis, Quotient Sciences

Peptides are attractive drug candidates due to their potency and specificity, but because they are prone to enzymatic degradation and poor permeability, parenteral administration methods like intramuscular (IM) or subcutaneous (SC) injection have been the primary way that they have been delivered to patients. Advances in IM and SC drug delivery have focused on reducing the frequency of injections, reducing injection pain, and making self-administration easier with the use of pens and auto-injector devices. Still, challenges remain in achieving full patient adherence (eg, needle fear), while manufacturing availability and associated supply chains for parenteral drug products are also becoming increasingly constrained.

After years of research and innovation, more peptide products are now being optimised for oral administration. The non-invasive nature, convenience and familiarity of oral solid dosage forms (OSD) make them an appealing option for patients. The approval of oral semaglutide not only demonstrated the technical and commercial feasibility of oral peptide delivery but also sparked further research in this area, opening new possibilities for similar approaches with other peptides.

In drug development, enabling technologies are often used to maximise systemic absorption and achieve therapeutic drug levels of a peptide following oral administration.

Some of the technologies and strategies that can be used include:

• Peptide engineering: where peptides can be specifically designed to mitigate susceptibility to enzymatic degradation, enhance their permeation across epithelial barriers and optimise pharmacokinetic receptor-mediated trans-epithelial transport, which in turn allows peptides to be actively transported across the intestinal epithelium
• And ingestible devices: such as the RaniPill Capsule by Rani Therapeutics, for targeted delivery and release to the intestine via transenteric injection.

The most widely used and best-validated approach to enable oral delivery of therapeutic peptides is co-formulation with a permeation enhancer (PE) to increase peptide absorption across the intestinal epithelium. For example, SNAC is the permeation enhancer used in Rybelsus to promote semaglutide absorption, while Mycapssa (oral octreotide, marketed by Chiesi US, Inc.) employs the Transient Permeation Enhancer (TPE) technology, which utilises the medium-chain fatty acid (MCFA) sodium caprylate (C8) to augment the absorption of the somatostatin analogue octreotide.1,2

Such formulations are unlike traditional tablet formulations: a significant amount of PE is often required and will limit other excipients that can be included to improve processability and delivery. Additionally, many PEs are waxy, with low melting points that result in poor flow characteristics and compressibility. These properties can pose significant challenges during manufacturing processes and affect the long-term stability of the product. Careful design of the formulation and manufacturing process is often required to address these issues. Particular attention must be paid to the granulation, lubrication and coating steps to ensure the manufacturability and scalability of the final product.

While enabling technologies are helping to revolutionise oral peptide delivery, the poor correlation between preclinical models and humans makes it difficult to predict how oral peptide formulations will perform when administered. The challenge for oral peptides is achieving maximum bioavailability and appropriate safety and tolerability. Higher bioavailability increases the likelihood of achieving therapeutic levels and reduces the amount of peptide required, thereby lowering the cost of goods. Optimising drug and permeation enhancer release from the formulation is also crucial to ensure efficacy and potentially reduce side effects. In the case of incretin mimetics, GI disturbances like nausea and vomiting are common adverse events that can be Cmax-related. These side effects can be potentially minimised using modified-release formulations. Adaptive clinical trial designs and flexible drug product strategies can help bridge the gap between preclinical models and humans. If critical formulation variables can be identified, it is possible to produce demonstration batches that bracket a formulation ‘design space.’ This concept gives flexibility to manufacture and dose any formulation within a set range. Variables that can be explored include the levels of permeation enhancer, the peptide dose and the ratio of peptide to permeation enhancer; each of these adjusted to maximise the performance of the formulation. When coupled with on-demand drug product manufacturing, formulations can be optimised in response to emerging clinical data, thereby improving the chances of success.

Oral peptide delivery, once considered the holy grail of drug delivery, is now proven to be feasible, providing developers with another option to improve treatments for patients. The success of the GLP-1 analogues has resulted in a surge of interest in oral peptide delivery as companies in an increasingly competitive space look for more patient-friendly dosage forms that can make starting and maintaining a treatment programme easier.

Continued advancements in drug delivery technologies will be crucial for improving oral peptides’ bioavailability, convenience and efficacy. Technologies that can achieve higher bioavailabilities and/or reduce food effects will enable more oral peptide products to be developed. Likewise, ingestible devices are achieving impressive bioavailabilities and show promise as long as long-term safety and reproducibility of delivery are demonstrated.

The increased availability of oral peptides benefits patients, caregivers and healthcare providers downstream, broadening access to treatments while improving the patient experience by removing fear of injections and the associated discomfort of administering an IM or SC injection. This promising development opens new horizons in GLP-1 treatment for not only obesity and diabetes but to related conditions, such as preventing complications like chronic kidney disease and end-stage renal disease that often occur alongside obesity, and beyond.

References

1. Antza C, et al (2019), ‘The development of an oral GLP-1 receptor agonist for managing type 2 diabetes: evidence to date’, Drug design, development and therapy, 13, 2985–2996
2. Brayden D J, et al (2021), ‘Transient Permeation Enhancer (TPE) technology for oral delivery of octreotide: a technological evaluation’, Expert Opinion on Drug Delivery, 18(10), 1501–1512