The challenge of oral peptide delivery is formidable. Peptides are rapidly shredded by digestive enzymes, their hydrophilic nature blocks passage through the fatty membranes of intestinal cells, and their large molecular size restricts transport between cells. Only a handful of oral peptide products have ever reached the market, including Rybelsus (oral semaglutide) and Mycapssa (oral octreotide), both approved in the late 2010s. The research team, led by Camille Dumont and Vincent Jannin, set out to build a formulation platform that addresses the enzymatic and permeability barriers simultaneously rather than one at a time.

The first tier of protection begins with a chemical trick known as hydrophobic ion pairing. Exenatide, the model GLP-1 analog used in the study, carries several positively charged amino acids under acidic conditions. By mixing the peptide with an anionic surfactant, sodium docusate, at a 1:4 molar ratio, the researchers neutralized those charges and created a lipophilic salt. The transformation was dramatic: the partition coefficient, log P, shifted from −2.9 ± 0.3 for unmodified exenatide to 0.9 ± 0.2 for the paired form, meaning the peptide’s affinity for oily environments increased roughly a thousandfold. Precipitation efficiency at this optimal ratio reached 97.6% ± 4.0%, and FT-IR spectroscopy confirmed the counter-ion pairing.

With the peptide now chemically disguised as a fat-loving molecule, the team screened a panel of lipid excipients for solubility. The clear winner was Labrafac MC60, a glycerol monocaprylocaprate that dissolves the paired exenatide at 9.54 mg/g while the unmodified acetate form remained below the quantification limit in most oils. Labrafac MC60 is itself a documented promoter of intestinal permeability, giving the excipient a dual role as both solubilizer and absorption enhancer. The researchers then built a self-emulsifying formulation around it: 85% Labrafac MC60, 10% Kolliphor RH40, and 5% propylene glycol, a composition that disperses in water as monodispersed droplets with a final particle size of 106 nm.

Particle size matters for intestinal absorption. Droplets below roughly 100 to 150 nm can diffuse through the mucus layer lining the gut and make close contact with the epithelial surface. The optimized formulation, designated F9, was loaded with 6 mg/g of solubilized paired exenatide, set deliberately at 80% of the measured solubility to prevent premature drug release upon dilution in gastrointestinal fluids, and supplemented with 20 mg/g of sodium caprate, a well-characterized medium-chain fatty acid that transiently fluidizes epithelial membranes to promote uptake.

The second tier of protection was tested in vitro against alpha-chymotrypsin, the most active pancreatic enzyme against exenatide. Unformulated exenatide was completely degraded within minutes of exposure. When the peptide was dissolved in the lipid formulation as its hydrophobic ion pair, however, approximately 80% of the drug remained intact after 60 minutes, a result consistent with the sequestration of the paired peptide inside lipid droplets that physically limit enzymatic access. Sodium caprate appeared to add a modest protective benefit during the first five minutes of the assay, though the 60-minute recovery was similar whether the enhancer was present or absent.

Stability testing revealed a subtler picture. Over four weeks of storage, impurity formation was significantly higher for the solubilized paired peptide than for a suspended acetate form, particularly at room temperature, and the addition of sodium caprate accelerated degradation at 25 degrees Celsius. The authors attribute this to the higher reactivity of molecules in a dissolved state and note that the finding raises questions about whether complete solubilization is even necessary when the formulation will be released into the relatively small fluid volume of the small intestine, where high local concentrations of drug and enhancer would co-localize at the absorption site.

The capsule itself proved to be an engineering problem worth solving. Standard Enprotect capsules, which feature a hypromellose structural layer and a hypromellose acetate succinate enteric layer, developed holes in their caps within 30 minutes in acid when filled with the placebo lipid formulation, an incompatibility traced to the HPMC inner layer. The team responded by manufacturing customized bilayer capsules using a patented double-dipping process, swapping the inner polymer for gelatin while retaining the HPMC-AS enteric outer layer. Dissolution testing with esomeprazole pellets as an acid-sensitive marker showed no release during two hours in 0.1 N hydrochloric acid and complete release within 30 minutes after transfer to pH 6.8 buffer, meeting USP delayed-release criteria. Disintegration tests with the actual formulation confirmed the same behavior: capsules stayed sealed through the acid phase and opened within five minutes at intestinal pH.

The coordinated release is central to the two-tier concept. Because the enteric shell prevents premature dilution in gastric fluids, the lipid formulation arrives in the small intestine intact, where lower fluid volumes favor close mucosal contact and prevent the peptide from partitioning out of its protective droplets. The capsule shell guards the payload during gastric transit, while the lipid droplets shield the peptide from intestinal proteases, and the permeation enhancers are co-released precisely where absorption occurs. The researchers emphasize that this is a proof-of-concept built entirely on in vitro evidence; extended stability studies, long-term capsule compatibility testing, and in vivo pharmacokinetic and pharmacodynamic studies remain necessary to determine whether the enzymatic protection translates into improved bioavailability and therapeutic efficacy.

Even so, the platform offers a scalable and mechanistically guided framework for oral peptide delivery. The formulation achieves encapsulation capacity of up to 3.3 mg of exenatide in a size 0 capsule, with corresponding doses of 2.5 mg and 4.7 mg in size 1 and size 00 capsules, and the authors suggest it could be adapted to a range of peptide APIs with a simpler formulation pathway than post-filling enteric coating. If future animal and human studies confirm the promise, the work could contribute to a future in which the most effective treatments for diabetes and obesity are delivered not by needle but by a carefully engineered capsule that knows exactly where and when to open.

Subject of Research: Drug Delivery

Article Title: A two-tier protection strategy for oral delivery of GLP-1 peptides: lipid-based formulation combined with enteric capsules

Article References: Dumont, C., Gonzalez, V., Klatt, P., Picco, S., Nombret, D., Agisson, M., Uku, E., Saurel, T., & Jannin, V. (2026). A two-tier protection strategy for oral delivery of GLP-1 peptides: lipid-based formulation combined with enteric capsules. Frontiers in Drug Delivery, 6, Article 1770094. https://doi.org/10.3389/fddev.2026.1770094

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1770094

Keywords: GLP-1, oral drug delivery, exenatide, lipid-based formulation, enteric capsules, peptides, two-tier, protection, strategy, oral, delivery, lipid-based