Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide

Purpose Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. Methods As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS 2 ), and compared to the commercial acetate salt (OCT.OAc 2 ) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS 2 and OCT.OAc 2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. Results LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS 2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS 2 . However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS 2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS 2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. Conclusion The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.