Oral peptide delivery gains rest on chemical design and formulation together

Oral peptide delivery still depends on chemistry and formulation working together, drug developers told Pharmaceutical Technology in a feature published on Nov. 2. Scientists at Arecor, WuXi AppTec and Sai Life Sciences described how changes to a peptide's backbone, side chains and ring structure can help it survive the gut. They also said each change brings tradeoffs in solubility, potency and manufacturing. The article cites recent FDA approvals of engineered oral peptides as proof the approach can work. It also notes that few such medicines have reached patients so far.

Why the gut blocks peptide pills

Oral peptide delivery is hard because the digestive tract is built to break proteins down. The feature cites published reviews that put oral bioavailability for peptides as low as 1% to 2%, meaning only a tiny share of a swallowed amount reaches the blood. Jan Jezek, chief scientific officer at Arecor, told the magazine that swallowed peptides meet sharp swings in pH and many protein cutting enzymes. Molecules that survive must then cross a mucus layer and the cells lining the intestine, and some face breakdown in the liver as well. William Fang of WuXi TIDES, part of WuXi AppTec, named the same two main barriers: poor passage across the gut wall and instability inside the gastrointestinal tract.

Developers have tried several ways around these barriers. The article lists enzyme inhibitors, permeation enhancers that briefly open a path across the gut lining, nanoparticle carriers and self emulsifying formulations. A separate route is to change the peptide itself, often called peptide engineering, through steps such as lipidation, cyclization and PEGylation. The commercial stakes are large. A Grand View Research forecast cited in the feature projects the peptide therapeutics market growing from $164 billion in 2026 to $294.6 billion by 2033, an 8.7% yearly rate; that is a market estimate, not a measured result. Much of the recent interest follows the success of GLP 1 drugs, and our report on the first GLP 1 pill shows how one reached the market.

Chemical modification shifts peptide weak points

Chemical modification does not turn a peptide into a small molecule, according to Santosh Kulkarni, vice president of medicinal chemistry at Sai Life Sciences. Instead, it moves the weak points. He told the magazine that bonds prone to enzyme attack "can be removed or shielded," while tuning charge and hydrogen bonding can help a molecule enter cell membranes. Fang singled out macrocyclization, including peptide stapling, which holds a peptide in a fixed shape. "Constraining the peptide's conformation improves its resistance to proteolytic enzymes," he said. Other tools named in the feature include N-methylation, D-amino acid swaps, unnatural amino acids, lipidation, glycosylation and prodrugs. These changes can improve stability or extend half life, the article reports, but chemistry alone rarely solves oral peptide delivery.

In one oral weight management program described by Fang, more than 1,700 cyclic peptides were made and screened to find two candidates.

Cyclization is not a guaranteed fix either. Jezek said ring structures can hide polar groups and help some peptides pass through membranes, but success still depends on a balance of polarity, rigidity, solubility and target binding. Improving one property can damage another. "Increasing stability provides little benefit if a peptide cannot cross the intestinal epithelium," he said. For that reason, teams often screen large libraries. In one oral weight management program described by Fang, more than 1,700 cyclic peptides were made and screened to find two candidates. That screen produced 10 hits and 3 leads along the way, and the final pick was chosen for potency, stability and ease of development together, he said. Jezek added that computational tools and artificial intelligence could help rank candidates earlier.

Approved oral peptides back the engineering approach

The feature points to several approved drugs as evidence that engineered peptides can work by mouth. Jezek described Merck's enlicitide, sold as Lipfendra, as a macrocyclic peptide built for potency, stability, solubility and oral uptake. The drug is the first oral PCSK9 inhibitor and is approved alongside diet and exercise to lower LDL cholesterol in adults with hypercholesterolemia, according to an FDA announcement dated July 17, 2026. Jezek also named Johnson & Johnson's icotrokinra, sold as Icotyde. The article says this macrocyclic peptide, which contains natural and non canonical amino acids, won FDA approval in March 2026 for moderate to severe plaque psoriasis in eligible adults and adolescents. We have also covered a topical icotrokinra formulation tested only in early skin and animal work.

Kulkarni cited Mycapssa, octreotide capsules from Chiesi that are approved for maintenance treatment in selected people with acromegaly. Octreotide is naturally cyclic and resists enzymes, and the product pairs it with an enteric capsule and a short acting permeation enhancer, he said. He presented it as a case where molecule and formulation were designed to work as a pair. The article also lists oral GLP 1 tablets from Novo Nordisk and Eli Lilly among recent examples of the method. Readers should note that not every oral GLP 1 drug is a peptide. Orforglipron, for example, acts on the GLP 1 receptor as a small molecule, so its route to the market did not rely on peptide engineering at all.

Manufacturing limits shape the next designs

Each added change also creates work in the plant, Fang told the magazine. Unusual amino acids that are not sold commercially can create supply risk, and closing rings gets harder as molecules become more constrained. He said roughly 20% of peptides are hydrophobic enough to need excess reagents and long reaction times during synthesis, which produces incomplete chains that are harder to purify. Every extra modification adds testing, from measuring D-isomer impurities to confirming the sequence of multi ring structures. With demand for metabolic disease peptides at metric ton scale, small losses grow large, he said. Kulkarni added that new substitutions can create new metabolites or immune targets that need more safety work before a candidate moves forward.

Fang said running supply, process development, testing and formulation in parallel can speed things up. He said this parallel work took one WuXi AppTec oral cyclic peptide roughly 2.5 years to go from the lead optimization stage to being ready for GMP production, and that changes to the synthesis route lifted crude purity by over 70% and yield by over 140%. These are company figures and were not independently checked. Looking ahead, Fang and Kulkarni described bicyclic and tricyclic designs that combine several constraints in one molecule. Kulkarni said success in oral peptide delivery should be judged on more than absorption, including variability, food effects, dose burden and gut safety. The full interviews appear in the Pharmaceutical Technology feature.

Conclusion

Oral peptide delivery remains a problem of balance rather than a single fix, according to the developers interviewed. Approvals for enlicitide and icotrokinra show that engineered macrocyclic peptides can reach patients, but the experts said chemistry must be matched with formulation and manufacturing from the start. The feature reported no new trial data or regulatory decisions. Readers should treat its program figures as company accounts and watch for peer reviewed data on multi ring designs.