Dexamethasone nano-embedded sodium hyaluronate microparticles for treatment of COVID-19 acute respiratory distress syndrome

Abstract

Dexamethasone (DX) is a synthetic glucocorticoid employed in a wide range of diseases asimmunosuppressant. Recent studies reported that DX could be administered orally or intravenouslyfor the treatment of acute respiratory distress syndrome in patients with COVID-19 phase-3infection caused by an overreaction of their immune system, reducing 28-day mortality in patientsmechanically ventilated or receiving oxygen [1]. Nevertheless, the long-term systemicadministration of dexamethasone led to severe side effects, highlighting the urgent need of newstrategies for its delivery [2][3]. The aim of this work was to develop a new formulation for inhalationbased on DX-nanoparticles. High molecular weight sodium hyaluronate (HA, 750 kDa) was employedto coat DX nanoparticles to exploit HA targeting to CD44 receptors on pulmonary macrophages andits anti-inflammatory effects[4]. DX-nanoparticles were obtained by anti-solvent precipitation usingwater as anti-solvent dripped into an alcoholic solution of drug. The suspension was spray-dried toobtain a dry powder. Size distribution and morphology of microparticles were investigated by laserdiffraction and scanning electron microscopy. Nanoparticle characteristics and composition wereassessed after powder redispersion in physiological medium by dynamic light scattering and X-rayscattering techniques. Results revealed the release of quite polydisperse nanoparticles (PdI = 0.3-0.4) with size around 290 nm in water and 180 nm in phosphate buffer. SAXS results showednanoparticles with a DX-rich crystalline core stabilized in solution by the presence of a shell of HAchains partially embedded in the core. After particle redispersion in water the aerodynamicbehavior of the obtained suspension was assessed in vitro using a device for aerosol therapyobtaining a Fine Particle Fraction of 87.5 +- 0.7% while the Emitted Fraction was 26.4 +-2.9%. Thelatter figure represents a limit that may be overcome by nebulizing directly the nanosuspension inthe pipe of a ventilator.