Géraldine Piel

The industrial translation of liposome production processes remains challenging, particularly in achieving scalability while maintaining critical quality attributes and formulation stability. In this study, a supercritical CO2-based PGSS process was successfully transferred from the laboratory to the pilot scale (50 to 500 mL reactor). Using a Quality by Design approach and a design of experiments on a simplified soy phosphatidylcholine formulation, we identified optimal production process parameters. These parameters were then validated and transferred to other drug-encapsulating liposome formulations, demonstrating process robustness. Under these conditions, liposomes measuring less than 200 nm and polydispersity indices close to 0.30 were reproducibly obtained at pilot scale. The process was successfully applied to drug-loaded formulations, achieving high encapsulation efficiencies while maintaining suitable physicochemical properties. Cryo-TEM confirmed the formation of consistent vesicular structures. Importantly, lipid chemical stability was preserved, with minimal hydrolysis and no significant increase in oxidation, even for unsaturated lipids. Overall, this study demonstrates the robustness, scalability, and relevance of the PGSS process as a solvent-free, single-step technology for liposome production.

Combination therapy with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) is the clinical cornerstone of asthma management. However, therapeutic efficacy is frequently compromised by high drug hydrophobicity, which enhances entrapment within the pulmonary mucus and promotes recognition and clearance from alveolar macrophages. This results in reduced drug availability at the target site, requiring higher doses or more frequent administrations.To overcome these biological barriers and improve the therapeutic outcomes, we report the systematic optimization of a liposomal formulation for the co-delivery of ciclesonide (CIC) and indacaterol maleate (IND). Among various PEGylated lipids, DSPE-PEG was chosen because its amine function maximizes IND encapsulation via amine-phosphate interactions and its 18-carbon chain exhibited superior biocompatibility with macrophages compared to C14 and C16 analogs. Incorporating DSPE-PEG at 15% ensured robust mucopenetration and macrophage evasion, significantly improving the ex vivo relaxation effect of IND compared to the drug solution. DLPC was utilized as the main phospholipid since its high degree of unsaturation (two double bonds) was essential for achieving high encapsulation efficiency of both hydrophobic payloads, efficient epithelial cell uptake and improved ex vivo efficacy and potency of IND. In an OVA-induced murine model, the optimized formulation markedly attenuated airway hyperresponsiveness and suppressed the type 2 inflammatory cascade, including upstream epithelial-derived alarmins, downstream inflammatory cytokines and inflammatory cell recruitment. Notably, liposomal encapsulation also provided a potential dose-sparing effect for both compounds, suggesting that efficient pulmonary delivery of ICS/LABA via lipid nanoparticles is a promising asthma management strategy and may be applicable to other respiratory diseases.

Dexamethasone-loaded liposomes composed of DSPC/Chol/PEG (85/10/5 mol%) and dispersed in a 16.25% Poloxamer 407 (P407) hydrogel were developed as a local therapeutic strategy for sound trauma-induced sensorineural hearing loss (SNHL). Physicochemical and rheological characterization demonstrated that the formulation remains injectable at room temperature and undergoes rapid in situ gelation within 8.0 ± 3.8 minutes in the middle ear cavity at 37°C. Incorporation of liposomes into the 16.25% P407 hydrogel significantly prolonged the in vitro release of encapsulated dexamethasone compared to the free drug solution. Cryogenic transmission electron microscopy (cryo-TEM) revealed multilamellar and multivesicular liposomal vesicles, consistent with sustained release behavior. The formulation was well tolerated by HEI-OC1 cells and cochlear explants and conferred a significant otoprotective effect, as evidenced by preservation of synaptic surface area following kainic acid-induced excitotoxic injury.