Design and Development of Dry Powder Cyclodextrin Complexes of Zinc Diethyldithiocarbamate for Pulmonary Drug Delivery.

Background: Pulmonary drug delivery represents a promising approach for the potential localised treatment of respiratory of non-small-cell lung cancer (NSCLC). However, the efficient delivery of poorly water-soluble drugs remains challenging due to limited solubility and inadequate aerodynamic performance. This study aimed to develop and characterise inhalable dry powder formulations of zinc diethyldithiocarbamate (Zn(DDC)2) complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) for potential pulmonary administration. Methods: Formulations were prepared by freeze-drying and spray-drying, with leucine incorporated at 0%, 5%, and 10% w/w. Formulations were prepared via freeze-drying and spray-drying with leucine incorporation (0%, 5% and 10% w/w) to evaluate their physicochemical properties, flowability and aerodynamic performance. Results: Spray-dried formulations exhibited significantly lower densities (as low as 1.03 ± 0.71 g/cm3), enhanced flowability, improved aerosolisation and higher fine particle fraction (FPF) values (up to 40.12 ± 0.60%) compared to freeze-dried powders (20.03 ± 2.79%). The incorporation of leucine further reduced powder density down to 0.72 ± 0.34 g/cm3 and increased surface corrugation as shown in SEM images, improving aerosolisation performance, with FPF values up to 76.77 ± 1.18%. Next Generation Impactor (NGI) analysis confirmed that leucine-containing formulations exhibited a greater proportion of particles within the respirable aerodynamic diameter range (1-5 μm), suggesting suitability for deep lung deposition. Conclusions: These results demonstrate that spray-dried Zn(DDC)2-cyclodextrin powders, particularly those modified with 10% leucine, offer excellent potential for pulmonary delivery in NSCLC therapy. Further in vivo studies are warranted to evaluate therapeutic efficacy and safety.