Preparation and evaluation of dexamethasone-loaded polymeric micelles using thermosensitive copolymers for ocular drug delivery

Abstract

The ocular bioavailability of most topically administered drugs is less than 5%. Micelles as nanoparticulate drug delivery systems have been examined as a tool for improving topical delivery of hydrophobic drugs to the eye. Objectives: The objective of this study was to develop and characterize dexamethasone (DEX) -loaded polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) and polylactide-polycaprolactone-polyethylene glycol- polycaprolactone-polylactide (PLA-PCL-PEG-PCL-PLA) based micelles to enhance the corneal permeability of DEX as a poorly water-soluble drug. Methods: PCL-PEG-PCL copolymers were synthesized by ring opening polymerization of ε- caprolactone. The resulting purified copolymers were utilized for copolymerization with lactide. The synthesized copolymers were characterized by nuclear magnetic spectroscopy (NMR), gel permeation chromatography (GPC), and Fourier transform infrared spectroscopy (FTIR) methods. DEX was loaded into the copolymers and the obtained DEX-loaded micelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). In vitro cytotoxicity of the micelles obtained was investigated on L929 cells. Drug release behavior and membrane permeability were also determined. Finally, the anti-inflammatory impact of the DEX-loaded PCL-PEG-PCL micelles was investigated on endotoxin-induced uveitis in rabbits. Results: NMR, GPC, and FTIR analyses provided complete characterization of the copolymers. Aqueous solutions of the resulting PCL-PEG-PCL copolymers rapidly formed a gel in situ at 34°C. TEM and DLS results verified the formation of spherical tri- and penta-block micelles, the sizes of which were approximately 37 and 65 nm, respectively. The micelles exhibited suitable compatibility on L929 cells. The release profile showed an initial burst release followed by a sustained release phase. The micelles showed higher corneal permeability of DEX in comparison to a marketed eye drop. The DEX-loaded PCL-PEG-PCL micelles could reduce the clinical symptoms of uveitis after a lag-time. Conclusion: The results showed that PCL-PEG-PCL and PLA-PCL-PEG-PCL-PLA based copolymers can be used as a platform for the treatment of anterior eye disease.