Impact of hydrophobic ion pair type and self-nanoemulsifying drug delivery systems composition on the oral delivery of salmon calcitonin

Salmon calcitonin (sCT) is a peptide with poor enzymatic stability and permeability, limiting its oral delivery. This study investigated how hydrophobic ion pair (HIP) type and self-nanoemulsifying drug delivery systems (SNEDDS) composition influence the oral delivery of sCT, and whether in vitro findings correlate with in vivo outcomes. HIPs were prepared with sodium caprate (C10) or sodium docusate (DOC) and incorporated into two SNEDDS differing in a single excipient: F1 contained 10% lysophosphatidylcholine (LPC), a natural permeation enhancer, while F2 replaced LPC with propylene glycol.In vitro, sCT:C10 provided no protection against trypsin, whereas sCT:DOC did (p < 0.05 vs native sCT). Incorporating HIPs into SNEDDS enhanced sCT proteolytic stability against trypsin relative to native sCT, but the extent was formulation-dependent, with F1 showing lower protection than F2 for the same HIP. Permeability in Caco-2 cells was mainly driven by SNEDDS, with F1 consistently showing lower FD4 transport than F2, indicating no additional benefit from LPC.In vivo, sCT:C10 showed no significant difference in relative pharmacological activity (PA_rel) over native sCT, whereas sCT:DOC significantly increased activity. HIP-loaded SNEDDS enhanced sCT activity compared with native sCT, yet F1 did not improve activity beyond F2. Among all groups, sCT:DOC in F2 achieved the highest PA_rel (8.8 ± 0.8%), indicating more favourable conditions for sCT oral delivery. In addition, in vitro trends correlated well with in vivo outcomes. Overall, HIP type and SNEDDS composition significantly influenced oral sCT delivery, highlighting the need to co-optimize these parameters to achieve effective oral peptide delivery.