New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis

Abstract

Correspondence: Christophe Duret Université Libre de Bruxelles (ULB), Boulevard du triomphe campus de la plaine (accès 2), Service de pharmacie galénique et biopharmacie, bat BC niveau 6, Brussels, Belgium Tel +32 650 5331 Fax +32 650 5269 Email cduret@ulb.ac.be Purpose: Itraconazole (ITZ) dry powders for inhalation (DPI) composed of nanoparticles (NP) embedded in carrier microparticles were prepared and characterized. Methods: DPIs were initially produced by reducing the ITZ particle size to the nanometer range using high-pressure homogenization with tocopherol polyethylene 1000 succinate (TPGS, 10% w/w ITZ) as a stabilizer. The optimized nanosuspension and the initial microsuspension were then spray-dried with different proportions of or in the absence of mannitol and/or sodium taurocholate. DPI characterization was performed using scanning electron microscopy for morphology, laser diffraction to evaluate the size-reduction process, and the size of the dried NP when reconstituted in aqueous media, impaction studies using a multistage liquid impactor to determine the aerodynamic performance and fine-particle fraction that is theoretically able to reach the lung, and dissolution studies to determine the solubility of ITZ. Results: Scanning electron microscopy micrographs showed that the DPI particles were composed of mannitol microparticles with embedded nano-or micro-ITZ crystals. The formulations prepared from the nanosuspension exhibited good flow properties and better fine-particle fractions, ranging from 46.2% ± 0.5% to 63.2% ± 1.7% compared to the 23.1% ± 0.3% that was observed with the formulation produced from the initial microsuspension. Spray-drying affected the NP size by inducing irreversible aggregation, which was able to be minimized by the addition of mannitol and sodium taurocholate before the drying procedure. The ITZ NP-based DPI considerably increased the ITZ solubility (58 ± 2 increased to 96 ± 1 ng/mL) compared with that of raw ITZ or an ITZ microparticle-based DPI (,10 ng/mL). Conclusion: Embedding ITZ NP in inhalable microparticles is a very effective method to produce DPI formulations with optimal aerodynamic properties and enhanced ITZ solubility. These formulations could be applied to other poorly water-soluble drugs and could be a very effective alternative for treating invasive pulmonary aspergillosis.

Inhalable nanoparticulate powders for respiratory delivery

“…In enhanced condensation growth (ECG), a submicron size particle aerosol is inhaled with a saturated or supersaturated stream of air that is above body temperature. The inhaled air is cooled in the respiratory track that leads to condensation into the droplets, growth, and enhanced lung deposition 75,76 . On the other hand, excipient enhanced growth (EEG) occurs on aerosol particles that contain a hygroscopic excipient which then absorbs humidity from the lungs leading to aerosol particle growth 75 .…”

Preparation, optimization, and in vitro simulated inhalation delivery of carvedilol nanoparticles loaded on a coarse carrier intended for pulmonary administration

“…Moreover, the optimized CAR nanosuspension formula was lyophilized in the presence of mannitol, which was intended to perform a dual action: cryoprotectant and coarse carrier for nanoparticles. 27,28 The lyophilized powder was then incorporated in DPI intended for pulmonary administration. The in vitro emitted doses of CAR were evaluated using a DPI sampling apparatus with a critical flow controller and the aerodynamic characteristics were evaluated using an Andersen MKII cascade impactor (ACI).…”

Formulation and delivery of itraconazole to the brain using a nanolipid carrier system

“…Chen et al formulated ITZ nanoparticles using human serum albumin for parenteral delivery; 7 Kim et al designed ITZ-loaded lipid nanoparticles to achieve controlled release when administered intravenously; 13 Pardeike et al formulated ITZ-loaded lipid nanoparticles for pulmonary application; 10 and Duret et al embedded ITZ-loaded nanoparticles in inhalable microparticles for the treatment of pulmonary aspergillosis. 22 However, to the best of our knowledge, the preparation of ITZ-loaded lipid nanoparticles for brain-targeted delivery has not yet been evaluated.…”