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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.

SUBMITTER: La Zara D

PROVIDER: S-EPMC8155342 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Atomic layer deposition (ALD) of alumina using trimethylaluminum (TMA) has technological importance in microelectronics. This process has demonstrated a high potential in applications of protective coatings on Cu surfaces for control of diffusion of Cu in Cu2S films in photovoltaic devices and sintering of Cu-based nanoparticles in liquid phase hydrogenation reactions. With this motivation in mind, the reaction between TMA and oxygen was investigated on Cu(111) and Cu2O/Cu(111) surfaces. TMA did not adsorb on the Cu(111) surface, a result consistent with density functional theory (DFT) calculations predicting that TMA adsorption and decomposition are thermodynamically unfavorable on pure Cu(111). On the other hand, TMA readily adsorbed on the Cu2O/Cu(111) surface at 473 K resulting in the reduction of some surface Cu(1+) to metallic copper (Cu(0)) and the formation of a copper aluminate, most likely CuAlO2. The reaction is limited by the amount of surface oxygen. After the first TMA half-cycle on Cu2O/Cu(111), two-dimensional (2D) islands of the aluminate were observed on the surface by scanning tunneling microscopy (STM). According to DFT calculations, TMA decomposed completely on Cu2O/Cu(111). High-resolution electron energy loss spectroscopy (HREELS) was used to distinguish between tetrahedrally (Altet) and octahedrally (Aloct) coordinated Al(3+) in surface adlayers. TMA dosing produced an aluminum oxide film, which contained more octahedrally coordinated Al(3+) (Altet/Aloct HREELS peak area ratio ? 0.3) than did dosing O2 (Altet/Aloct HREELS peak area ratio ? 0.5). After the first ALD cycle, TMA reacted with both Cu2O and aluminum oxide surfaces in the absence of hydroxyl groups until film closure by the fourth ALD cycle. Then, TMA continued to react with surface Al-O, forming stoichiometric Al2O3. O2 half-cycles at 623 K were more effective for carbon removal than O2 half-cycles at 473 K or water half-cycles at 623 K. The growth rate was approximately 3-4 Å/cycle for TMA+O2 ALD (O2 half-cycles at 623 K). No preferential growth of Al2O3 on the steps of Cu(111) was observed. According to STM, Al2O3 grows homogeneously on Cu(111) terraces.

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

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