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. In vitro dissolution and ex vivo isolated perfused rat lung tests demonstrate dramatically slowed release with increasing nanofilm thickness, regardless of the nature of the material. Ex situ 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, in vitro 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.

Atomic Layer Coating to Inhibit Surface Crystallization of Amorphous Pharmaceutical Powders

“…Additionally, wettability in aqueous media is a concern with hydrophobic drugs, and ALC coatings may offer a new approach to address this limitation. Release behavior of ALC-coated particles is also an area warranting extensive future study, as drug release behavior has been shown to be both increased or delayed depending on coating properties. ,,,,, In the context of ASD dissolution, where the drug release behavior is complex and dependent upon wettability, drug loading, polymer ionization state, hydration/phase separation kinetics, and matrix crystallization kinetics among many other factors, − the mechanisms of drug release in the presence of an ALC coating warrant future investigation.…”

“…This technique modifies the surface properties of the substrate, imparting improved barrier properties, wetting, or adhesion, and has been widely used to deposit thin films on inorganic substrates in semiconductor, solar cell, ceramic, and medical device applications . Recent studies have demonstrated the feasibility of ALC to modify the particulate properties of organic pharmaceutical materials, such as improved powder flowability. ,− Beyond powder handling improvement, ALC has the potential to impart benefits to the physical stability of pharmaceutical materials. A recent study from our research group demonstrated long-term physical stability (crystallization inhibition) at accelerated storage conditions (40 °C and 75% RH) with a high DLASD composed of 70% ezetimibe and 30% hydroxypropyl methylcellulose acetate succinate (HPMCAS)…”

Stability of Inhaled Ciprofloxacin-Loaded Poly(2-ethyl-2-oxazoline) Nanoparticle Dry Powder Inhaler Formulation in High Stressed Conditions

“…In both studies, the stored formulations demonstrated comparably stable states at low temperatures and RH. Thus, particle-engineered techniques have been applied to develop more stable formulations in adverse conditions including spray-dried particles, drug-polymer conjugates and drug-loaded polymeric NPs [ 15 , 16 , 17 ]. However, it is still very important to determine the optimized conditions to store the DPI formulations to retain their aerosolization properties.…”

Characterization of Membrane-Type Dissolution Profiles of Clinically Available Orally Inhaled Products Using a Weibull Fit and a Mechanistic Model

“…The dissolution rate can impact the rate and extent of absorption of a poorly soluble compound or a modified release compound of the inhaled drug; therefore, it is of high importance that the dissolution profiles that are measured using a membrane-type dissolution test are well understood. 13 Such an understanding can be achieved through mathematical modeling. More or less empirical expressions, such as the Weibull distribution function, are often used to analyze dissolution data.…”