Ethanol-Based Proliposomes Incorporating Dexamethasone for The Treatment of COVID-19 Acute Respiratory Distress Syndrome (ARDS) Using Medical Nebulizers
Abstract
Background/Objective: Systemic dexamethasone has demonstrated mortality
reduction in COVID-19-related acute respiratory distress syndrome (ARDS). The aim
of this study is to use ethanol-based proliposome technology to formulate inhalable
liposomes encapsulating dexamethasone for localized anti-inflammatory effect in the
lung.
Methods: Ethanol-based proliposomes were prepared using equimolar ratios of
cholesterol and one of three phospholipids: soya-phosphatidylcholine(SPC),
hydrogenated SPC(HSPC), or dipalmitoyl-phosphatidylcholine(DPPC). Hydration of
proliposomes was followed by probe-sonication to generate small unilamellar vesicles
(SUVs), then followed by the determination of particle size, zeta-potential, entrapment
efficiency, and drug release. Aerosol characterization studies were performed using
three different nebulizers (air-jet, ultrasonic, and mesh) delivered to a two-stage
impinger. Finally, cytokine release was measured in peripheral blood mononuclear
cells stimulated with lipopolysaccharide and treated with the formulation.
Results: The prepared SUVs had particle size <100 nm, polydispersity index (PDI)
<0.3, and slightly negative zeta-potential. SPC liposomes had significantly (pvalue<
0.05) lower particle size and PDI compared to HSPC and DPPC liposomes, and
entrapped significantly more dexamethasone (p-value<0.05). The air-jet nebulizer was
the superior nebulizer in terms of mass, drug, and lipid output and fine particle fraction, and was the least physically disruptive to liposomes. All three formulations were
successfully delivered using the air-jet nebulizer; however, SPC liposomes had
significantly higher drug output rate, respirable dose, and underwent less aggregation.
Cytokine release studies demonstrated that liposomal dexamethasone suppressed
cytokine release in a manner superior to free dexamethasone.
Conclusion: SUVs with small particle size and low PDI were successfully prepared
and delivered using different nebulizers. Of the three investigated formulations, SPC
liposomes delivered using the air-jet nebulizer are the most promising for further
development. Future studies will be dedicated to scaling up this formulation and testing
it using in vivo models of acute lung injury.
DOI/handle
http://hdl.handle.net/10576/45007Collections
- COVID-19 Research [822 items ]
- Master in Pharmacy [58 items ]