Excipients: the unsung heroes of next‑generation oral peptide delivery

In recent years, there have been several seismic shifts in the pharma landscape, with a key one being the introduction of new and increasingly complex modalities as uptake of targeted treatment options grows.

One of the modalities at the forefront of this revolution is the peptide family of drugs, which is gaining significant notoriety due to the rapid rise to fame of the glucagon-like peptide 1 receptor agonist (GLP-1RA) class of medicines. Since their market debut, the GLP-1RAs have joined the ranks as some of the most commercially successful medicines in pharma’s history, as patients, physicians and payers increasingly recognise their paradigm-shifting potential in the cardiometabolic market.

While the active pharmaceutical ingredients (APIs) found in GLP-1RAs soak up a large portion of the credit for a drug’s success, their counterparts – the excipients – don’t usually garner the same attention.

This is despite their key role in optimising the delivery and preventing the degradation of an API, stabilising a formulation, making it more palatable to the end user and more.

Arguably one of the most notable excipient innovation success stories is that of peptide-shielding sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, or SNAC, which is found in Novo’s GLP-1RA pill, oral Wegovy (semaglutide). By incorporating SNAC in oral Wegovy, Novo was able to overcome the challenges linked to oral peptide delivery, as the excipient technology was able to shield the active peptide from degradation in the highly acidic stomach environment. This meant that enough semaglutide could be absorbed in the gut to have a meaningful therapeutic effect – offering patients a new, injection-free treatment option for conditions like obesity and type 2 diabetes.

With excipients playing a key role in delivering increasingly sought-after peptides, but work still to be done in improving their delivery, formulators are looking for new ways to cater their excipient approaches to create optimal oral peptide therapies.

Though pharma’s interest in peptides is blooming, formulating with these complex molecules often presents several challenges for a formulator, notes Victor Mendelez-Colon, R&D head of applications at life science tools specialist, Avantor.

“Peptides combine several different properties; they’re relatively large, often hydrophilic and charged, susceptible to enzymatic degradation, and can have physical stability issues such as aggregation,” Mendelez-Colon comments.

In the case of oral peptide delivery, Mendelez-Colon says that four main obstacles prevail: the active ingredient’s degradation in the gut or the formulation itself, poor absorption by the body and a lack of permeability into target cells.

Because of these barriers, he states that effective peptide delivery often requires an excipient-system design, in which a combination of suitable excipients play a fundamental role in creating the right microenvironment within the formulation for the effective delivery, absorption and activity of the peptide.

On the topic of absorption, Evonik Health Care’s Dr Susanne Schwechheimer, manager advanced technologies & services, oral drug delivery solutions and Dr Marcel Arndt, head of drug delivery and applications, also point to the differences in peptide optimal absorption windows, which can be influenced by factors like their size, vulnerability to degradation, food intake, permeability and stability. The optimal absorption window, they say, is highly important to consider on a peptide-by-peptide basis to ensure the bioavailability of a formulation.

Meanwhile, Lori Ditty, Lubrizol’s global marketing manager, notes that patient centricity concerns are also at play, as larger orally administered medications like tablets can be a choking hazard for patients with swallowing difficulties, as well as those who find taking pills a challenge already. With this in mind, Ditty says that a formulator’s excipient choices should also centre around the patient experience, and how they can help to improve it.

While excipients have traditionally been viewed as ingredients that stabilise a bulk formulation, Mendelez-Colon notes that this dynamic is now shifting, as excipients play an increasingly active role in drug delivery mechanism itself.

With this change playing out in real time, he says the formulator’s question is now less ‘which excipient should I use’, and more ‘which combination will create the right microenvironment for this particular peptide therapy’.

The evolving use of excipients, Mendelez-Colon says, is taking excipient development in new directions – with focus now moving towards multifunctional formulations that marry permeation enhancement, pH control, protection from enzymes and release control. On top of this, formulators are exploring best practices for co-localisation, which is where a peptide and its associated absorption enhancer reach their target together at the right concentration to ensure treatment potency.

Schwechheimer and Arndt echo Mendelez-Colon’s sentiments on growing excipient responsibilities, though they caveat that formulators should be thinking about if their approach has any impact on manufacturing complexity and scalability, as well as development costs linked to the drug in question. “As peptide-based drugs evolve, particularly in a highly competitive field like the incretin therapies, successful products will increasingly depend on the ability to combine complementary technologies, while maintaining manufacturability and commercial scalability,” they comment.

With a multi-excipient approach becoming the new standard, it’s important to determine what ingredients may work best with a specific active peptide when developing a product. Because of this, Mendelez-Colon notes that many are now leaning towards more data-driven workflows, with advancements in artificial intelligence (AI) and preclinical new approach methodologies (NAMs) like organoids helping to accelerate the screening process for more efficient formulation development.

Ditty adds that including an excipient into animal toxicity studies could also streamline development in these early stages – allowing companies to identify and mitigate safety concerns and data gaps at an early stage.

With his eye on the future, Mendelez-Colon predicts that drugmakers will increasingly co-design peptides and their associated formulations, meaning peptide sequence, stability and excipient compatibility will likely be considered an optimised in tandem.

With excipient technology advancing at a rapid pace, Mendelez-Colon, Schweccheimer and Ardnt agree that there are several up-and-coming approaches which hold potential to shape the next generation of peptide delivery.

All three believe that permeation enhancement continues to be a strong area of innovation, as companies look to create options that can mimic SNAC’s success in oral Wegovy.

1. Biffa internal savings data, average saving (January - August 2023)
2. Nisbets internal savings data, average saving (January – September 2023)
3. Compliance365 internal data, average  savings
4. HEINEKEN UK data, Calculations based on SmartDispense® active accounts each year since 2015 with 10 lines
5. Independent test results based on subterranean and ground floor pub cellars of varying sizes
6. Independent test results based on subterranean and ground floor pub cellars of varying sizes

Mendelez-Colon also points to the work in refining excipient systems rather than simply adding more quantities of an enhancer, which he says is being explored through the control of local pH, as well as the effective co-localisation of active ingredients and their enhancers.

Meanwhile, Schweccheimer and Ardnt tout the early potential of intestinal protease inhibition, which could be used to prolong how long an ingredient stays in the gut – and thus its chance of absorption – by blocking certain types of digestive enzymes. At the 2026 Controlled Release Society (CRS) conference, Novo presented data highlighting the potential of a modified Bowman-Birk inhibitor, found naturally in legumes and cereal grains, as a component of oral peptide formulations.

However, they caveat that the toxicological profile of intestinal protein inhibitors has, thus far, limited their application beyond the preclinical setting.

Looking ahead, Mendelez-Colon predicts we will see more excipients that perform a defined molecular or biological function, such as interacting with the mucus barrier in the gut, rather than simply stabilising a bulk formulation. Meanwhile, Schweccheimer and Ardnt foresee that advancements in excipient technology, especially permeation enahncers, will come in tandem with new peptide engineering approaches that improve stability and resistance to degradation.