Oral Semaglutide with Sodium Caprate Achieves Equivalent Absorption to SNAC-Based Formulations in Dogs
Background
Oral delivery of peptide therapeutics like semaglutide faces significant challenges due to enzymatic degradation and poor intestinal permeation. Current oral semaglutide (Rybelsus) relies on sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) as an absorption enhancer, primarily acting in the stomach. However, formulation constraints and SNAC's localized mechanism necessitate exploring alternative permeation enhancers. This study investigates sodium caprate (C10), a well-characterized medium-chain fatty acid (MCFA), as a potential alternative to achieve comparable systemic exposure.
Study Design
Researchers first assessed sodium caprate (C10)'s physicochemical properties and buffering capacity. Mechanistic feasibility was evaluated via Caco-2 cell transport studies and rat pharmacokinetic (PK) trials using aqueous suspensions, comparing C10's concentration-dependent effects against SNAC. Based on these findings, three immediate-release (IR) tablet designs (monolayer, bilayer, and dry compression-coated) were developed. The optimized monolayer formulation, containing 14 mg semaglutide, was then tested in beagle dogs and directly compared to the SNAC-based reference product (Rybelsus) under matched dosing conditions.
Results
Sodium caprate (C10) demonstrated sufficient buffering capacity to neutralize acidic environments, a crucial property for gastric stability. In both Caco-2 cell and rat PK studies, C10 enhanced semaglutide absorption in a concentration-dependent manner, achieving exposure levels equivalent to SNAC at matched doses. Among the developed tablet architectures, the monolayer tablet exhibited the highest dissolution similarity to Rybelsus, with an f2 value of 67.8. This optimized monolayer formulation, when administered to beagle dogs, produced pharmacokinetic parameters—including Cmax, AUClast, and t1/2—that significantly overlapped with those of the SNAC-based reference drug product.
These results confirm that C10 can effectively support oral semaglutide delivery when incorporated into a rationally designed immediate-release tablet, demonstrating its potential as a viable alternative to SNAC.
Key Findings
- Sodium caprate (C10) exhibited sufficient buffering capacity to stabilize semaglutide in acidic environments.
- C10 enhanced semaglutide absorption in Caco-2 cells and rats, achieving exposure equivalent to SNAC at matched doses.
- An optimized monolayer tablet formulation with C10 showed high dissolution similarity (
f2 = 67.8) to Rybelsus. - In beagle dogs, the C10-based oral semaglutide formulation produced PK parameters (Cmax, AUClast, t1/2) comparable to SNAC-based Rybelsus.
Why It Matters
This research provides a critical step towards diversifying the toolkit for oral peptide delivery, potentially reducing reliance on SNAC and its associated formulation challenges. The findings suggest that MCFA-based permeation enhancers like sodium caprate could enable new oral peptide formulations, offering greater flexibility in tablet design and potentially broader applicability across various peptide therapeutics. While currently preclinical, this work lays the groundwork for future human trials, moving closer to more accessible and patient-friendly oral peptide options beyond injectables. It highlights a promising alternative for enhancing absorption, which could impact how future oral GLP-1 agonists or other peptides are formulated and dosed.
semaglutide
sodium caprate
oral delivery
absorption enhancer
pharmacokinetics
formulation