Combined protection for glaucoma and ocular surface diseases: New nanohybrid platforms with sustained in vivo hypotensive activity

Abstract

Purpose : Hypotensive topical formulations entail the first line for glaucoma treatment, eventually leading to poor patient compliance due to secondary ocular surface effects. This work aimed to develop osmoprotective latanoprost-loaded microemulsions (Lt-MEs) as a potential glaucoma treatment with extended activity.

Methods : Microemulsions (MEs) with or without hyaluronic acid (HA)/dextran (DX) were characterized and latanoprost entrapment efficacy (EE) assessed. In vitro tolerance and osmoprotective efficacy, cell internalization (coumarin-loaded) as well as cell-MEs distribution were carried out in human corneal (HCECs) and conjunctival epithelial cells (HcEpiC). In vivo hypotensive efficacy was conducted in New Zealand male albino rabbits to determine intraocular pressure reduction (△IOP), maximum percentage of △IOP (IOPmax), and relative ocular bioavailability (ROB). These experiments were carried out according to the ARVO Statement as well as the European community council directive (86/609/EEC) and Spanish regulations (PROEX 114.4/21).

Results : Developed hybrid MEs exhibited physicochemical properties suitable for ocular surface administration. Nanovesicles (inner phase) were 21.85±3.48nm for those without HA and 30.51±3.20nm with HA. Lt-MEs exhibited an EE ≥ 98%. High viability (>80%) at 1h and 4h exposure was obtained in HCECs and HcEpiC cells. Besides, all MEs avoided cell death in HCECs under hypertonic stress (470 mOsm/L) for 16h showing high cell survival (50.28±2.83%) in comparison with cells without receiving MEs (19.75±4.91%). Cell fluorescence was extended up to 11 days after 5-min exposure to all coumarin-loaded MEs. Also, extensive accumulation of nanovesicles was localized in different cellular regions. A single dose of Lt-MEs (25 µL) in rabbits decreased IOP between 4-6 (△IOPmax=23.39±5.23%) and 9-13 days (△IOPmax=29.78±4.96%) for those without and with polymers, respectively. MEs exhibited a ROB between 4.5 and 19 times higher than the marketed formulation. The MEs without mucoadhesive polymers presented AUC(0-t’)=139.31±15.92%●h increasing to AUC(0-t’)=271.50±38.25%●h (MEs-HA) and AUC(0-t’)=157.40±37.84%●h (MEs-DX).

Conclusions : New developed MEs were able to protect corneal cells under hypertonic stress and decrease IOP overtime, thus entailing a new potential strategy for the combined treatment of ocular surface diseases and glaucoma.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.