Peptides are attractive drug candidates because of their potency and specificity; and, since the launch of the first synthetic peptide drug in the 1970s, more than 80 peptide drugs have been approved worldwide to treat conditions including diabetes, cancer and cardiovascular diseases.1
Owing to the susceptibility of peptides to enzymatic degradation and their poor permeability, delivery has often relied on parenteral administration methods such as intramuscular (IM) or subcutaneous (SC) injection.
Numerous advances in drug delivery have focused on reducing the frequency of injections (depot formulations), reducing injection pain (narrow gauge needles) and making injections easier to self-administer (injection pens and autoinjectors).
Developments such as these have provided improved options for patients and caregivers and enabled self-administration.
However, patient adherence remains a challenge. For example, recipients may fear needles or experience discomfort when larger or more frequent doses are administered by IM or SC injection to obtain a therapeutic effect.
Additionally, the global manufacturing landscape and the associated supply chain for parenteral drug products continue to face capacity challenges and are becoming increasingly constrained.
Following several decades of research in both academia and industry, innovations in peptide drug delivery are enabling more products to be optimised for oral administration.
The increased availability of oral peptide products has the potential to significantly benefit patients, caregivers and healthcare providers. Even so, the challenges associated with achieving therapeutic drug levels of a peptide following oral administration are considerable.
Optimising oral peptide products
With an estimated 63.2% of patients experiencing varied levels of needle fear, developing alternative administration methods for peptide products is one strategy to increase adherence and potentially improve patient outcomes.2
For example, in diabetes and obesity, incretin analogues are achieving impressive control of blood glucose and weight loss, respectively, but most need to be injected.
In contrast, the non-invasive nature, convenience and familiarity of oral dosage forms make them attractive treatment options for patients, making it easier for them to start and maintain their treatment.
The approval of oral semaglutide (marketed as Rybelsus by Novo Nordisk) demonstrated both the technical and commercial feasibility of oral peptide delivery.
The glucagon-like peptide 1 (GLP-1) agonist, initially developed for diabetes and now being used to treat obesity, is stimulating further research into this area and creating new possibilities for similar approaches with other peptides.
These factors contribute to an increased global demand for oral proteins and peptides, projected to grow from $1.7 billion in 2023 to $3.3 billion by 2032 at a compound annual growth rate (CAGR) of 7.51%.3
Overcoming challenges in oral peptide delivery
Advances in drug delivery technology and peptide engineering have made oral peptide delivery increasingly feasible. Several enabling technologies have been developed and often combined to maximise systemic absorption and achieve therapeutic drug levels.
- Peptide engineering allows peptides to be specifically designed to mitigate susceptibility to enzymatic degradation, enhance their permeation across epithelial barriers and optimise pharmacokinetics. For example, researchers can swap amino acids that are susceptible to proteolytic enzymes with alternative amino acid sequences or create cyclic structures to protect them from enzymatic degradation in the gastrointestinal (GI) tract.
- Permeation enhancers are incorporated to increase peptide absorption across the intestinal epithelium. For example, SNAC is the permeation enhancer used in Rybelsus to promote semaglutide absorption, whereas Mycapssa (oral octreotide, marketed by Chiesi USA, Inc.) employs the transient permeation enhancer (TPE) technology that utilises the medium-chain fatty acid (MCFA) sodium caprylate (C8) to augment the absorption of the somatostatin analogue octreotide.4,5
- Ingestible devices have been developed, including the RaniPill Capsule by Rani Therapeutics that, once swallowed and activated, inject microneedles into the GI epithelium — acting to both protect the peptide and overcome the barrier to absorption.
- Receptor mediated transepithelial transport allows peptides to be actively transported across the intestinal epithelium. For example, targeting the neonatal Fc receptor on intestinal cells has been shown (preclinically at least) to enable active transport across the epithelium to systemically deliver insulin.
The most widely used and best-validated approach to enable the oral delivery of therapeutic peptides is coformulation with a permeation enhancer (PE).
Such formulations are unlike traditional tablet formulations as, usually, quite significant amounts of PE are required; this limits the number of other excipients that can be included to improve processability and delivery.
Many PEs are waxy in nature and have low melting points, frequently exhibiting poor flow characteristics and compressibility. These properties can pose significant challenges during manufacturing processes and affect the long-term stability of the product.
To address these issues, careful design of the formulation and manufacturing process is often required — especially the granulation, lubrication and coating steps — to ensure the manufacturability and scalability of the final product.
Adopting a design-based approach
Although 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.
Given that approximately 90% of drugs fail during the clinical trial phase, developing strategies to address this is imperative.6
For oral peptides, the challenge is to achieve maximum bioavailability with appropriate safety and tolerability. A high level of bioavailability not only increases the chances that therapeutic levels can be achieved, but also reduces the amount of peptide required in the product, ultimately reducing the cost of goods.
In addition, optimising drug and permeation enhancer release from the formulation is crucial to ensure efficacy and potentially reduce side-effects.
In the case of incretin mimetics, for example, GI disturbances such as nausea and vomiting are common adverse events that can be Cmax related and, potentially, minimised using modified release formulations.
Adaptive clinical trial designs coupled with flexible drug product strategies can help to bridge the gap between preclinical models and humans.
If a performance-critical formulation variable can be identified (such as levels of a permeation enhancer), demonstration batches can be produced to bracket a formulation design space; this gives the drug developer the flexibility to manufacture and dose any formulation within that design space.
When coupled with on-demand manufacturing, formulations can be optimised in response to the emerging clinical data, thereby improving the chances of success.
This approach is particularly powerful in oral peptide delivery, wherein the differences in physiology between humans and preclinical models can significantly affect product performance.
Variables that can be explored include the levels of permeation enhancer, the peptide dose and the ratio of peptide to permeation enhancer … and each of these can then be adjusted to maximise the performance of the formulation.
The future of oral peptide delivery
Advancements in oral delivery of peptides promise to transform the treatment landscape for patients and healthcare providers downstream.
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.
Continued advancements in drug delivery technologies will be crucial to improve the bioavailability, convenience and efficacy of oral peptides. Technologies that can achieve higher bioavailabilities and/or reduce food effects will enable more oral peptide products to be developed.
In relation to this, ingestible devices are achieving impressive bioavailabilities and show real promise if long-term safety and reproducibility of delivery can be demonstrated.
Oral peptide delivery, once considered to be the holy grail of drug delivery, is now proven to be feasible, providing developers with another option to improve treatments for the benefit of patients.
References
- L. Wang, et al., “Therapeutic Peptides: Current Applications and Future Directions,” Sig. Transduct. Target Ther. 7, 48 (2022).
- K. Alsbrooks and K. Hoerauf, “Prevalence, Causes, Impacts and Management of Needle Phobia: An International Survey of a General Adult Population,” PLOS One 17(11), e0276814 (2022).
- www.imarcgroup.com/oral-proteins-peptides-market.
- C. Antza, et al., “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 (2019).
- D.J. Brayden and S. Maher, “Transient Permeation Enhancer® (TPE®) Technology for Oral Delivery of Octreotide: A Technological Evaluation,” Expert Opinion on Drug Delivery 18(10), 1501–1512 (2021).
- D. Sun, et al., “Why 90% of Clinical Drug Development Fails and How to Improve It? Acta Pharm. Sin. B 12(7), 3049–3062 (2022).
- www.fda.gov/drugs/information-drug-class/incretin-mimetic-drugs-type-2-diabetes#:~:text=These%20drugs%20work%20by%20mimicking,adults%20with%20type%202%20diabetes.
