Engineering nanoliposomal tiotropium bromide embedded in a lactose-arginine carrier forming Trojan-particle dry powders for efficient pulmonary drug delivery: A combined approach of in vitro-3D printing and in silico-CFD modeling.

Nanocarrier-based dry powders for lung disease treatment are crucial, with in vitro and in silico research being pivotal to their success. This study introduces a method for creating Tiotropium-bromide liposomal inhalation dry powder, termed "Trojan-particles," utilizing thin-film hydration and spray-drying with lactose-arginine carriers. Encapsulating tiotropium-bromide in nanoliposomes enhances lung treatment via liposomes' unique features. This formulation was examined through in vitro-3D-printing and in silico-CFD analysis. Nanoliposomes and powder were evaluated for physicochemical attributes, aerosolization, encapsulation-efficiency (EE%), and release. Both liposomes (90 nm) and powder particles (3 µm) were spherical. Liposomes had an EE% over 95 % and a zeta-potential of -28.3 mV. The optimal formulation was tested in vitro at 30, 60, and 90 L/min using a 3D-printed airway replica. CFD analysis evaluated particle deposition in steady and realistic inhalation with monodisperse and polydisperse particles. Based on realistic airway geometry, model utilized k-ω-SST turbulence model for the continuous phase and Lagrangian-DEM for the discrete phase, analyzed through ANSYS Fluent. The 20 %-arginine nanoliposomal-tiotropium formulation outperformed others due to arginine's dispersibility and therapeutic benefits, including nitric oxide conversion. The formulation competes with commercial dry powders due to its chemical, biochemical advantages, and Trojan-based physical traits, reducing exhalation risk. Simulation data aligned with experimental findings, showing that higher inhalation flows increase particle deposition in airways due to greater inertia and turbulence. At 60 L/min, the polydisperse model matched experimental data better than the monodisperse model. Alongside improving dry powder performance via a nanoliposomal formulation, this research highlights the development of a novel CFD method for their assessment.