Enhancing leuprolide penetration through enterocytes via the ER-Golgi pathway using lipophilic complexation

Oral delivery of peptide drugs remains one of the most formidable challenges in the frontier of pharmaceutical research. Peptide drugs typically suffer from exceptionally low oral bioavailability, primarily attributed to rigorous enzymatic degradation within the gastrointestinal (GI) tract, limited ability to traverse the enterocyte barrier, and significant first-pass hepatic metabolism. Absorption of peptide drugs via the lymphatic route could potentially bypass intracellular lysosome degradation and hepatic first-pass metabolism. In this study, we present a strategy to enhance the lymphatic absorption of the model peptide leuprolide (LEU) by diverting its intracellular trafficking towards the endoplasmic-reticulum (ER)-Golgi pathway. Complexes were formed between LEU and lipophilic excipient and then formulated as an oral emulsion. We observed that the penetration of LEU in the emulsion across the Caco-2 cell monolayer model was diverted from the endosome-lysosome pathway, and LEU entered the bloodstream via the mesenteric lymph nodes (MLNs). The data obtained illustrates that the lipophilic LEU complexes could improve enterocyte permeability and bypass lysosomal degradation, and the change of absorption pathway may reduce hepatic first pass metabolism.