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.

Keywords: atomic layer deposition; budesonide; controlled release; dry powder inhaler; inhalation; isolated perfused rat lung; particle-to-cell deposition.

Figure 1

Linear growth of SiO₂, TiO₂, and Al₂O₃ on micronized budesonide as a function of the ALD cycles. (a, d, g) TEM images of budesonide particles coated by (a) SiO₂, (d) TiO₂, and (g) Al₂O₃via ALD. The film thicknesses were measured by ImageJ. (b, e, h) Evolution of film thickness with the number of cycles for (b) SiO₂, (e) TiO₂, and (h) Al₂O₃ ALD. The error bars indicate 95% confidence intervals. (c, f, i) Evolution of the amount of deposited material, measured by ICP-OES and normalized with respect to the budesonide amount, with the number of cycles for (c) SiO₂, (f) TiO₂, and (i) Al₂O₃ ALD.

Figure 2

High-angle annular dark-field (HAADF) images and energy dispersive X-ray spectroscopy (EDX) mappings of (a) Si, O, and C in SiO₂-coated budesonide after 100 cycles, (b) Ti, O, and C in TiO₂-coated budesonide after 50 cycles, and (c) Al, O, and C in Al₂O₃-coated budesonide after 50 cycles.

Figure 3

In vitro dissolution profiles of uncoated and ALD-coated budesonide after aerosolization using mACI, distinguished by ALD material: (a) SiO₂, (b) TiO₂, and (c) Al₂O₃. Increasing film thicknesses result in slower dissolution rates for each ALD material. The error bars indicate standard deviations.

Figure 4

Drug release: in vitro dissolution and ex vivo IPRL absorption. (a) In vitro dissolution profiles of uncoated and ALD-coated budesonide after aerosolization using mACI. The error bars indicate standard deviations. (b) Ex vivo absorption profiles of uncoated and ALD-coated budesonide using isolated perfused rat lung (IPRL). The error bars indicate 95% confidence intervals. (c) Correlation of the time required for 50% drug release/absorption (t50) between in vitro and ex vivo. (d) TEM images of uncoated and ALD-coated budesonide after 5 and 30 min dissolution in sodium phosphate buffer. After 5 min bubbles from the medium are present only in the uncoated particles, and after 30 min they also appear in the ALD-coated particles. While after 30 min already a budesonide amount ranging from ∼30% to ∼55% is released from the ALD-coated particles, the films are still intact.

Figure 5

In vitro aerosolization and correlation with interparticle force. (a) Fine particle fraction (FPF), % of loaded mass below 5 μm, of uncoated and ALD-coated budesonide with different film thicknesses, resulting from different numbers of cycles, of SiO₂, TiO₂, and Al₂O₃ after long-term storage for 8–10 months at 20 °C and ∼0% RH and after storage for 1 month at 40 °C and 75% RH. The measurements were carried out at a flow rate of 30 L/min for 8 s using the monodose inhaler. The error bars indicate standard deviations. (b) Contact forces of uncoated and ALD-coated budesonide. The error bars indicate 95% confidence intervals. (c) Correlation between FPF and interparticle force after long-term storage for 8–10 months at 20 °C and ∼0% RH. The FPF decreases with increasing contact forces.

Figure 6

Safety and efficacy assessment. (a) Cell viability after treatment with uncoated and ALD-coated budesonide in the concentration range of 20–1000 μM for 48 h on A549 cells. The error bars indicate standard errors. (b) Cytokine analysis of IL-8, G-CSF, IP-10, and MCP-1 and (c) histology analysis of lung tissue morphology upon exposure of 3D human bronchial epithelial cells to air and uncoated and Al₂O₃-coated budesonide for 24 h with and without cytomix (0.2 mg/mL LPS and 500 ng/mL TNF-α).