Background/Objectives: Oral delivery of semaglutide (Rybelsus) relies on sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) to enhance peptide absorption. However, formulation constraints and SNAC's localized gastric mechanism have prompted the exploration of alternative enhancers. This study evaluated whether sodium caprate (C10), a well-characterized medium-chain fatty acid (MCFA), could achieve systemic exposure comparable to SNAC-based formulations when co-formulated in an immediate-release (IR) tablet. Methods: Preformulation studies assessed the physicochemical properties and buffering capacity of C10. Mechanistic feasibility was evaluated through Caco-2 transport studies and rat pharmacokinetic (PK) trials using aqueous suspensions, comparing the concentration-dependent effects of C10 and SNAC. Based on these findings, three IR tablet architectures (monolayer, bilayer, and dry compression-coated) were developed. The optimized formulation was evaluated in beagle dogs (14 mg semaglutide) and compared with the SNAC-based reference product. Results: C10 exhibited sufficient buffering capacity to neutralize acidic environments. In Caco-2 and rat PK studies, C10 enhanced semaglutide absorption in a concentration-dependent manner, yielding exposure levels equivalent to SNAC at matched doses. Among the tablet designs, the monolayer tablet showed the highest dissolution similarity (f2 = 67.8) to Rybelsus. In beagle dogs, the optimized monolayer formulation produced pharmacokinetic parameters, including Cmax, AUClast, and t1/2, that overlapped with those of the SNAC-based reference drug product under matched dosing conditions. Conclusions: These results demonstrate that C10 can effectively support oral semaglutide delivery when incorporated into a rationally designed IR tablet. The findings support the feasibility of MCFA-based permeation enhancer platforms as formulation alternatives to SNAC for oral peptide therapeutics.
