Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery: A preclinical and clinical study

Current oral formulations of macromolecules including peptides typically rely on single permeation enhancer (PE) to promote absorption and thus bioavailability. In this work, we combined two PEs, namely sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and sodium caprate (C10), in one tablet formulation to potentially gain a synergistic effect for enhanced gastric absorption of a GLP-1 analogue and a PCSK9 inhibitor. Permeability tests on a gastric organoids-based cell model showed that the combination of SNAC and C10 can significantly improve peptide permeability compared to either SNAC or C10 alone. Tablet formulations were then designed, adjusting the total PE amount, relative ratio between SNAC and C10, and the peptide dose. To facilitate drug and PE release, a diluent was added. Upon oral administration in beagle dogs, the lead formulations made of SNAC/C10/diluent demonstrated higher bioavailability than either SNAC, SNAC/diluent and C10/diluent formulations for both peptides. Finally, the SNAC/C10/diluent formulation with PCSK9 inhibitor was tested in human, where it displayed similar bioavailability to the SNAC/diluent reference, thereby suggesting a low translatability between pre-clinical and clinical data when C10 was involved. This may be attributed to the difference in physiology, gastric pH environment as well as C10 concentration and colloidal form in the gastric lumen between dogs and humans. Hence, additional studies are needed for a better understanding of the clinical translation of C10-based peptide formulations.