Release date:2023/9/7 17:12:13

Peptides and proteins play an increasingly important role in the treatment of many diseases, but oral administration of peptides remains a challenge. Due to poor bioavailability in oral administration, peptides and proteins usually need to be administered by injection, thus affecting patient compliance, especially in chronic diseases that require long-term treatment. Since the discovery of insulin in 1921, several attempts to develop oral insulin formulations have failed, demonstrating the difficulty as well as the challenge of developing oral peptides and proteins.

Glucagon-like peptide-1 receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. GLP-1RAs can effectively control blood glucose through its effects on appetite and gastric emptying, while favoring weight loss.  Most GLP-1 RA agents are administered via subcutaneous (SC) injection. Although GLP-1 drugs have been iterated from short-acting to long-acting, the frequency of once-weekly injections still fails to deliver an optimal experience. For chronic diseases such as diabetes and obesity, the convenience and adherence advantages of oral administration are self-evident.

Strategies for the oral delivery of peptides are broadly categorized into four methods: (1) permeation enhancers (PEs), (2) nanoparticles, (3) lipid-based drug delivery systems (self-emulsifying drug delivery systems (SEDDS)) or hydrophobic ion-pairing, and (4) microneedle devices. Among these, permeation enhancers (PEs) are one of the most widely tested strategies to improve oral delivery of therapeutic peptides. Two oral peptides approved to date, Rybelsus® and Mycapssa®, have been successfully converted to oral dosage forms using the PEs strategy, and research is underway for the development of oral dosage forms of many peptide drugs through a similar strategy.

PEs can be categorized into chemical and peptide PEs based on material standards, and paracellular and transcellular PEs based on mechanistic standards. Representative examples of chemical PEs that are being applied to various peptides and currently being studied include medium-chain fatty acids (MCFAs), Eligen™ technology-based PEs (SNAC, 5-CNAC, 4-CNAB), EDTA, bile salt, acyl carnitine, and alkylmaltoside. Today, we will focus on analyzing the role of SNAC in oral semaglutide.

A Brief History of SNAC

SNAC is a synthetic N-acylated amino acid derivative of salicylic acid, developed by Emisphere's Eligen™ technology. As intestinal permeation enhancers (PEs), SNAC adheres to the gastric mucosa along with peptides to facilitate permeation absorption. Oral semaglutide (Rybelsus®), the first oral peptide drug developed based on the PEs strategy, was approved by the FDA and EMA in September 2019 and March 2020, respectively, bringing SNAC into the global public eye.

Figure 1. Structure of SNAC

Eligen® SNAC technology, proprietary oral drug delivery platform of Emisphere, enables the transport of therapeutic molecules including large peptides and proteins across biological membranes such as those of the gastrointestinal tract. This technology conducted carrier libraries to develop carriers that increase hydrophobicity through non-covalent interactions with the payload (drug), which aims to increase transcellular absorption. Eligen B12 (vitamin B12), which was approved as an FDA medical food in 2015, was the first product to be commercialized using SNAC.

Subsequently in 2017, Novo Nordisk transferred the Eligen™ technology from Emisphere and applied it to the development of an oral GLP-1 RA. The precedent approval of Eligen B12, and the FDA GRAS of SNAC gained in the process, have made the development of the current Rybelsus® product much easier.

What Is the Mechanism of Action of SNAC in Semaglutide?

Instead of applying enteric coating technology, Rybelsus® constitutes an oral formulation of semaglutide together with SNAC, which is capable of embedding itself in cell membranes based on its lipophilicity, helping semaglutide and SNAC to be rapidly absorbed by the cells and enabling semaglutide to achieve a certain oral bioavailability.

The absorption of semaglutide is mainly due to the indirect effect of SNAC. First, As the tablet is eroded, on the one hand, SNAC causes a local increase in pH via a buffering action, which protect semaglutide from enzymatic degradation by reducing the conversion of pepsinogen to pepsin; on the other hand, SNAC promotes the monomerization of semaglutide by changing the polarity of the solution in which the tablets are dissolved, thus weakening the hydrophobic interactions that would otherwise facilitate the semaglutide oligomerization. Next, SNAC is bound to the lipid membrane of gastric cells, which in turn allows semaglutide to pass across the cell, an effect that is temporary and reversible.


Figure 2. Mechanism of absorption and protection of the semaglutide molecule. [2]

A single oral dose of Rybelsus® demonstrated that the erosion and absorption of the tablet was in the stomach, which is different from the absorption of most orally administered drugs in the small intestine. Scientists devise a formulation of Rybelsus in which complete tablet erosion (CTE) occurs in the stomach by local disintegration by sinking to the lower part of the stomach through optimization of the formulation. Plasma semaglutide concentrations were similar in dogs undergoing pyloric ligation (to prevent intestinal absorption) compared to non-ligated dogs, with plasma concentrations in the splenic vein being significantly higher than in the portal vein, providing further evidence that the stomach is the site of absorption.


Oral peptides have gradually become the future trend of peptide drug development.While SNAC, as a permeation enhancer, leads the way in the development of oral peptides from scratch, whether it can replicate the excellent track record of semaglutide tablets to other peptide drugs needs to be carefully considered. The longer half-life of semaglutide and its broader therapeutic window provides a solid foundation for its safe and effective clinical results. From Emisphere's early development process, it is clear that SNAC is not omnipotent, and a better understanding of its mechanism of action is needed in order to find better scenarios for its use and more compatible partner drugs.

[1] Kim JC, Park EJ, Na DH. Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals. Pharmaceuticals (Basel). 2022 Dec 19;15(12):1585. doi: 10.3390/ph15121585. PMID: 36559036; PMCID: PMC9781085.
 [2] Aroda VR, Blonde L, Pratley RE. A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes. Rev Endocr Metab Disord. 2022 Oct;23(5):979-994. doi: 10.1007/s11154-022-09735-8. Epub 2022 Jul 15. PMID: 35838946; PMCID: PMC9515042.

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