Pulmonary delivery of anti-infectives from natural sources: Development and characterization of liposomal sanggenon formulations

Sanggenon C (SGC) and sanggenon D (SGD) are stereoisomeric natural products with promising anti-infective potential, especially against pathogens involved in acute respiratory infections. However, their bulky structures, poor aqueous solubility, and low oral bioavailability present major therapeutic challenges. Inhalation enables direct delivery to the site of infection while minimizing systemic exposure. Liposomal formulations DMPC:DMPG (2:1 w/w) of SGC and SGD, prepared via ethanol injection, achieved high drug loadings (> 3.5 mg/mL). Drug-lipid interactions were evaluated via DSC, Langmuir trough studies, SAXS, and cryo-TEM, showing incorporation of the compounds in the lipid bilayer. While stereochemistry-dependent differences were evident in vesicle size and thermotropic behavior, other biophysical data indicated that these differences were largely mitigated upon formulation. Liposomal formulations showed an excellent stability during nebulization with a vibrating mesh nebulizer (mass median aerodynamic diameters: 1.30-1.35 µm) and the high affinity of the compounds for the lipid bilayer resulted in a sustained in vitro release profile (8-9 % after 240 h). The retention of the drugs in the liposomes also significantly reduced cytotoxicity at 24 h compared to neat compounds. These findings highlight the importance of stereochemistry in drug-membrane interaction, yet their similar formulation performance suggests that both compound formulations are promising candidates for pulmonary anti-infective therapy.