Development and in vitro and ex vivo characterization of a twin nanoparticulate system to enhance ocular absorption and prolong retention of dexamethasone in the eye: from lab to pilot scale optimization

Abstract

Conventional eye drops show low bioavailability (below 20%) due to the eye's inherent tissue barriers and unique microenvironment. Recent advancements in pharmaceutical nanotechnology have explored various nanoparticle systems, such as micelles, liposomes, and nanoemulsions, to enhance corneal permeation and prolong drug retention. In this study, we propose a twin nanoparticulate system, combining the advantages of two nanoparticles to improve drug targeting and therapeutic efficacy. A dexamethasone-loaded liposome–microemulsion (LME) twin nanoparticulate system was developed using high-pressure homogenization and successfully scaled up. Both liposomes and microemulsions were of similar size (∼60 nm) and displayed uniform distribution (polydispersity index < 0.2) upon combination. The final formulation was hypo-osmolar (osmolality < 100 mOsm per Kg), making it ideal for dry eye relief. Drug release was extended for up to 8 h, following a non-Fickian diffusion pattern. The LME formulation, tested under different conditions (2–8 °C and 25 °C with 60% relative humidity), was found to be stable for 6 months. It showed no cytotoxicity in human corneal epithelial cells up to 10 μM drug concentration. Fluorescence microscopy revealed rapid nanoparticle uptake by cells within 5 minutes. Human corneal epithelial cells showed a marked reduction in inflammatory biomarkers (IL-6, IL-8, and TNF-α) after drug-loaded LME treatments, compared to the control. Corneal tissue imaging confirmed prolonged retention of nanoparticles within the tissue. A whole eye ex vivo permeation study demonstrated higher drug concentrations in the aqueous humour of LME drug-treated rabbit eyes compared to a reference product. This twin nanoparticulate system, loaded with dexamethasone, offers a promising next-generation treatment for dry eye disease (DED).