Peptide (small protein) medicines play an essential role in treating many serious diseases. Yet delivering them in a simple and effective way remains a scientific challenge. When taken orally, peptides are easily broken down by digestive enzymes, poorly absorbed through the gut, and largely removed by the liver before they can work.
One promising alternative is to deliver peptides through the lining of the mouth — particularly the inside of the cheek (buccal mucosa) or under the tongue (sublingual mucosa). These areas are rich in blood vessels and are generally well accepted by patients, making them a promising needle-free option.
However, the mouth is not an easy gateway. Saliva can quickly wash medicines away, natural enzymes may still break down peptides, and the mouth lining itself forms a tight protective barrier that limits how much drug can pass through. Achieving reliable and consistent absorption has therefore been a major hurdle.
To tackle this challenge, BUCCAL-PEP team member Sandeep Karki and colleagues at UCD explored the latest advances in the field in their new review paper published in Drug Delivery and Translational Research. The team examined the wide range of formulation strategies researchers have developed to improve peptide delivery through the mouth.
Permeation enhancers, mucoadhesive polymers and layered films
These approaches include substances that temporarily loosen the mouth lining to help drugs pass through (permeation enhancers), sticky materials that help dosage forms stay in place longer (mucoadhesive polymers), and layered thin films that carefully control how the drug is released. The review also highlights newer systems incorporating nanoparticles, which can protect delicate peptides from breakdown and help them cross the mouth lining more effectively.
Sandeep explains: “Our review systematically examines oromucosal films as a platform for delivering peptide medicines through the mouth, such as via the cheek (buccal) or under the tongue (sublingual). It focuses on how formulation design and key physicochemical properties of peptides can be used to overcome the biological barriers of the buccal and sublingual mucosa.”
Producing this review required carefully analysing and comparing a large body of scientific literature on buccal and sublingual peptide delivery. As Sandeep notes, “Results from multiple studies were brought together to identify common trends and challenges, and the findings were organised into a clear framework linking formulation design to potential clinical performance.”
Formulation strategies
A central theme quickly emerged: peptide delivery through the mouth lining is inherently difficult due to the strong biological barriers of the oral tissues and the relatively large molecular size of peptides. Yet there is reason for optimism. “However, these challenges can be addressed through rational formulation strategies and the appropriate use of permeation enhancers, making oromucosal delivery a promising non-injectable route,” Sandeep comments.
Importantly, the review emphasises that success does not come from a single ingredient or design tweak. “The key message is that successful peptide delivery through these routes requires an integrated formulation strategy rather than a single intervention. A clear understanding of oromucosal anatomy and physiology, together with the physicochemical properties of peptides, is essential to guide formulation choices, including film architecture, permeation enhancers, and nanocarrier systems.” Beyond the laboratory science, the team also stresses the importance of early consideration of safety, patient acceptability, and regulatory feasibility — all crucial factors in moving from promising research to real clinical applications.
One of the most compelling insights from the review relates to the power of structured film design. As Sandeep explains: “One of the most striking observations is the increasing evidence that rational film design, together with the appropriate use of permeation enhancers plays a critical role in improving peptide delivery. In particular, multilayer and nanoparticle-embedded mucoadhesion, and directional release, which helps overcome the anatomical and physiological barriers of the oral mucosa. When combined with a carefully selected polymer matrix, these structured film designs can work synergistically with permeation enhancers to improve peptide protection and mucosal transport, compared to conventional single-layer films, while ensuring patient comfort and safety.”
Building on this knowledge
Within BUCCAL-PEP, development of a multi-layer film is already underway. The insights from this review are helping to refine and optimise these systems, bringing the project another step closer to effective, patient-friendly peptide delivery through the mouth. More data — and exciting developments — are on the way.
Curious to read the full publication? Check it out here:
Sandeep Karki
Sandeep is a PhD student at University College Dublin (UCD)
Graphical abstract of the review paper
