Controlled Pulmonary Delivery of Carrier-Free Budesonide Dry Powder by Atomic Layer Deposition.

Abstract

Ideal controlled pulmonary drug delivery systems provide sustained release by retarding lung clearance mechanisms and efficient lung deposition to maintain therapeutic concentrations over prolonged time. Here, we use atomic layer deposition (ALD) to simultaneously tailor the release and aerosolization properties of inhaled drug particles without the need for lactose carrier. In particular, we deposit uniform nanoscale oxide ceramic films, such as Al₂O₃, TiO₂, and SiO₂, on micronized budesonide particles, a common active pharmaceutical ingredient for the treatment of respiratory diseases. <i>In vitro</i> dissolution and <i>ex vivo</i> isolated perfused rat lung tests demonstrate dramatically slowed release with increasing nanofilm thickness, regardless of the nature of the material. <i>Ex situ</i> transmission electron microscopy at various stages during dissolution unravels mostly intact nanofilms, suggesting that the release mechanism mainly involves the transport of dissolution media through the ALD films. Furthermore, <i>in vitro</i> aerosolization testing by fast screening impactor shows a ∼2-fold increase in fine particle fraction (FPF) for each ALD-coated budesonide formulation after 10 ALD process cycles, also applying very low patient inspiratory pressures. The higher FPFs after the ALD process are attributed to the reduction in the interparticle force arising from the ceramic surfaces, as evidenced by atomic force microscopy measurements. Finally, cell viability, cytokine release, and tissue morphology analyses verify a safe and efficacious use of ALD-coated budesonide particles at the cellular level. Therefore, surface nanoengineering by ALD is highly promising in providing the next generation of inhaled formulations with tailored characteristics of drug release and lung deposition, thereby enhancing controlled pulmonary delivery opportunities.