Oral delivery of calcitonin-ion pairs: In vivo proof of concept for a highly lipophilic counterion

Hydrophobic ion pairing and subsequent incorporation into self-emulsifying drug delivery systems (SEDDS) is a promising strategy to orally deliver hydrophilic macromolecular drugs. Within this study, hydrophobic ion pairs (HIP) between salmon calcitonin (sCT) and highly lipophilic sulfosuccinate counterions were formed and compared to frequently applied commercially available counterions. Bis(isotridecyl) sulfosuccinate resulted in HIPs of the highest lipophilicity and in significantly higher solubility in lipophilic co-solvents. Thus, bis(isotridecyl) sulfosuccinate allowed efficient solubilization of sCT in a SEDDS preconcentrate based on a lipophilic co-solvent and an indigestible lipid, but omitting hydrophilic co-solvents. In addition to the increased solubility in the lipidic matrix, markedly reduced dissociation in biorelevant media resulted in high distribution coefficients between oil droplet and FaSSGF or FaSSIF (logD) of 2.98 +/- 0.12 or 2.77 +/- 0.14, respectively. The composition of the lipidic matrix preserved integrity of the oil droplets after emulsification and subsequent lipolysis, allowing to fully exploit the potential of the HIP attributed to the high logD. Oral administration of the HIP-loaded SEDDS resulted in an excellent relative pharmacological activity of 13.8 +/- 5.6 % measured as hypocalcaemic effect in rats.

Automated summary

Hydrophobic ion pairing and incorporation into SEDDS is a promising strategy for oral delivery of hydrophilic macromolecular drugs. In this study, hydrophobic ion pairs (HIP) between sCT and highly lipophilic sulfosuccinate counterions were formed. The use of bis(isotridecyl) sulfosuccinate resulted in the highest lipophilicity and improved solubility in lipophilic co-solvents. The HIP-loaded SEDDS showed excellent pharmacological activity in rats, with a relative hypocalcaemic effect of 13.8 +/- 5.6%.