Engineering nano-embedded microparticles as formulation platform for site-specific drug delivery to the respiratory tract

Effective drug delivery to the lung often implies selective spatial deposition of the active molecule in a specific lung region, such as the bronchi for asthma therapy or the alveoli for combating infections of the deep lung. Depending on the site of action, platform formulations adaptable to spatio-selective delivery are valuable. A Design of Experiments approach was employed to systematically analyze the influence of selected spray drying parameters on mannitol particle characteristics. Additionally, one candidate was formulated with varying concentrations of leucine as an aerosolization enhancer. Based on their physicochemical characteristics, three different lead formulations – tailored for tracheobronchial, bronchial, and alveolar deposition – were identified for further nanoparticle encapsulation to develop a pulmonary delivery platform based on spray-dried amphiphilic cyclodextrin nano-in-microparticles. The formulations exhibited mean geometric particle diameters of 1.31 to 1.71 μm and favorable aerosolization performance, with mass median aerodynamic diameters of 4.69 ± 0.22, 3.79 ± 0.17 and 2.18 ± 0.55 μm, respectively. Physicochemical characterization of the incorporated nanoparticles revealed hydrodynamic diameters below 200 nm, narrow size distributions, and stable negative surface charges. Moreover, biocompatibility and time-dependent intracellular uptake of the formulations were verified using human in vitro models of bronchi and deep lung. The novel formulations can serve as an adaptive platform enabling targeted delivery of challenging drug candidates and advanced pulmonary therapeutics. • Spray-dried nano-in-microparticles enable site-specific respiratory targeting. • Targeting of (tracheo-) bronchial and alveolar region by nano-in-microparticles. • Spray drying parameters affect microparticle diameter, flowability and yield. • Nano-in-microparticles exhibit improved aerodynamic properties for lung application. • Optimized process parameters enable site-specific targeting of bronchi and lung.