Oral (poly)peptide delivery: On the emulsifying properties of inverted lipid phases under gastrointestinal conditions

This study explores the emulsification behavior and oral delivery performance of dry and wet inverted lipid phases (ILP_dry and ILP_wet) with and without emulsifying agents. A central aim was to assess whether reverse micelle-based lipid systems enable sufficient self-emulsification in the gastrointestinal (GI) tract under physiological bile salt conditions to facilitate systemic absorption of polypeptides.

ILP_dry and ILP_wet formulations containing reverse micelles, as well as corresponding self-emulsifying systems (se-ILP_dry and se-ILP_wet) incorporating a non-ionic surfactant, were developed. Emulsification capacity was evaluated via turbidity measurements in bile salt-containing media (5-20 mM). Emulsification kinetics of se-ILP were assessed in water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). In vivo performance was evaluated in rats using horseradish peroxidase (HRP) as a model polypeptide.

ILP_dry and ILP_wet exhibited limited emulsification and poor oral bioavailability (1.54 % and 0.89 %, respectively). In contrast, se-ILP showed rapid and complete emulsification across all media and significantly enhanced bioavailability (12.10 % for se-ILP_dry and 9.24 % for se-ILP_wet). ILP_dry demonstrated superior bile salt stability compared to ILP_wet.

Reverse micelle-based ILP require emulsifying excipients for efficient GI emulsification and peptide transport. ILP_dry and se-ILP_dry outperformed wet systems, likely due to reduced water uptake and improved structural integrity.