Abstract

Particle agglomeration is a major challenge to enhance inhaled drug deposition into the lungs. Current inhalants either use drug-loaded lactose or “soft agglomerated spheroids” or “co-suspended spheres” to address it, not solved the problem at the source. Novel technologies should be introduced to fundamentally tackle it. Supercritical fluid particle design is such new technology. Using the 3S-improved supercritical anti-solvent process, bionic inhalation crystalline microspheres of budesonide-based series were obtained for the first time, and successful in the trial production, including single-component (budesonide), dualcomponent (budesonide/formoterol) and triple-component (budesonide/glycopyrrolate/formoterol) formulas. They look like red blood cells, and their unique bionic texture was observed and disclosed here for the first time under a high-resolution scanning electron microscope, their surfaces are covered with dense nanowhiskers, while the underlying self-similar ring-like intertwined texture. Such “nano-inmicro” structure make them lightweight, hydrophobic, tough, self-lubricating, with minimal aggregation, excellent dispersion and aerodynamic performance, outstanding results in the in vitro carrier-free inhalation assessments. They allow directly inhaled without further processing, laying a solid foundation for a new generation of efficient and simplified carrier free inhalant. Further research found that their changes in the morphology and physical properties are synchronously related to the changes in their surface energy. Surface energy profiles intuitively reflect subtle changes in their morphological and physical properties.

Keywords: Supercritical fluid particle design; Bionic inhalation crystalline microsphere; “Nano in micro” structure; Carrier free inhalant; Surface energy