Optimizing spray-dried liposomes for pulmonary delivery: impact of lipids composition and of drying parameters using experimental design.

Liposomes are promising carriers for pulmonary drug delivery due to their biocompatibility and controlled-release properties. However, their stability in aqueous suspension is limited, leading to aggregation and reduced therapeutic efficiency. Converting liposomal dispersions into dry powders for inhalation (DPIs) is a potential strategy to overcome these limitations. Spray-drying (SD) is particularly attractive for this purpose, offering precise control over particle properties along with speed, cost-efficiency, and scalability. Yet, the thermal and mechanical stresses involved in this process and their effects on liposomal integrity remain poorly understood, limiting its broader application. In this study, we developed a systematic framework integrating Design of Experiments (DOE) with scale-up-oriented processing, combining supercritical fluid technology (PGSS) for liposome formation with subsequent spray-drying of high solid content suspensions. Two complementary DoE approaches were applied: DOEA optimized drying parameters and carbohydrate type, testing trehalose and hydroxypropyl-β-cyclodextrin (HPβCD), while DOEB assessed the effects of active pharmaceutical ingredients (APIs) hydrophobicity, lipid composition (1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) percentage), and carbohydrate-to-liposome ratio. Optimized spray-dried powders exhibited preserved liposome structure (mean diameter < 200 nm, narrow polydispersity index (PdI), near-neutral zeta potential (ZP)), favorable aerodynamic properties (∼3 µm, extra-fine particle fraction (eFPF) > 20% and fine particle fraction (FPF) > 60%), low residual moisture (<5%), and high drying yields (>75%). Mechanistic insights revealed that HPβCD significantly protects liposomes during atomization, while drug retention was governed by PEGylated lipid content, lipid-to-carbohydrate ratio, and API hydrophobicity. Co-encapsulation of clinically relevant drug combinations (formoterol/budesonide and ciclesonide/indacaterol) produced uniform powders with efficient aerosolization, highlighting the therapeutic potential of these formulations. Collectively, these results establish a robust, scalable, and reproducible approach for designing liposomal DPIs, balancing formulation composition, excipient selection, and process parameters. This study demonstrates that strategic integration of scalable technologies can reconcile structural stability, aerodynamic performance, and manufacturability, paving the way for the industrial translation of liposomal dry powders for targeted pulmonary therapies, including asthma and chronic obstructive pulmonary disease (COPD).