In vitro, ex vivo and in vivo characterization of PLGA nanoparticles loading pranoprofen for ocular administration

Pranoprofen (PF) is a NSAID considered as a safe anti-inflammatory treatment for strabismus and/or cataract surgery. The drug has been formulated in poly (lactic/glycolic) acid (PLGA) nanoparticles (PF-F1NPs with cPF 1.5 mg/mL, PF-F2NPs with cPF 1 mg/mL) produced by solvent displacement technique and tested the in vitro cytotoxicity, ex vivo corneal permeation, in vivo ocular tolerance and in vivo anti-inflammatory efficacy of PF-F1NPs, PF-F2NPs, in comparison to eye drops conventional dosage form (Oftalar (R), PF 1 mg/mL) and free drug solution (PF dissolved in PBS, 1.5 mg/mL). The mean particle size of both formulations was around 350 nm, with polydispersity index below 0.1, and a net negative charge of -7.41 mV and -8.5 mV for PF-F1NPs and PF-F2NPs, respectively. Y-79 human retinoblastoma cell line was used to evaluate the cytotoxicity of PF-F1NPs and PF-F2NPs, which were compared to blank NPs and free drug solution (PF dissolved in PBS, 1.5 mg/mL). Concentrations up to 75 mu g/mL exhibited no toxicity to Y-79 cells, whereas at 150 mu g/mL a decrease of about 80% on the cell viability was observed after exposing the cells to PF-F1NPs. When treating the Y-79 cells with concentrations of PF-F2NPs between 1 mu g/mL to 100 mu g/mL, the cell viability was similar to control values after 24 h and 48 h of exposure. An ex vivo corneal permeation study was carried out in New Zealand rabbits. A very similar profile has been observed for the permeation of PF through the cornea when administered as eye drops and as free drug solution, which was kept much lower in comparison to PF-NPs formulations. The permeated amount of PF from the PF-F1NPs was slightly smaller than from PF-F2NPs, attributed to the increase of viscosity of the formulations with the increase of cPVA concentration. New Zealand white rabbits were also used to evaluate the irritancy of PF-F1NPs and PF-F2NPs, which demonstrated to be well-tolerated to the eye (i.e. the mean total score (MTS) was 0). PF-F2NPs exhibited the highest Q(P) (amounts of PF permeated in the cornea) and significantly reduced the ocular edema compared to the tested formulations. The Q(R) (amounts of PF retained in the cornea) of the PF-F1NPs was greater than that obtained for PF-F2NPs. (C) 2016 Elsevier B.V. All rights reserved.