title: In vitro, ex vivo and in vivo characterization of PLGA nanoparticles loading pranoprofen for ocular administration.
abstract: 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 1.5mg/mL, PF-F2NPs with cPF 1mg/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(®), PF 1mg/mL) and free drug solution (PF dissolved in PBS, 1.5mg/mL). The mean particle size of both formulations was around 350nm, with polydispersity index below 0.1, and a net negative charge of -7.41mV and -8.5mV 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, 1.5mg/mL). Concentrations up to 75μg/mL exhibited no toxicity to Y-79 cells, whereas at 150μg/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 1μg/mL to 100μg/mL, the cell viability was similar to control values after 24h and 48h 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 QP (amounts of PF permeated in the cornea) and significantly reduced the ocular edema compared to the tested formulations. The QR (amounts of PF retained in the cornea) of the PF-F1NPs was greater than that obtained for PF-F2NPs.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Biopharmaceutical and Pharmacokinetic Unit, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cañadas
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Biopharmaceutical and Pharmacokinetic Unit, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain; Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Helen
authors.initials: H
authors.lastname: Alvarado
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Biopharmaceutical and Pharmacokinetic Unit, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Calpena
authors.affiliation: Department of Biology and Environment, University Trás-os-Montes and Alto Douro, Vila Real, Portugal; Centre for the Research and Technology and Agro-Environmental and Biological Sciences, University Trás-os-Montes and Alto Douro, Vila Real, Portugal.
authors.forename: Amélia M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: ebsouto@ff.uc.pt.
authors.forename: Eliana B
authors.initials: EB
authors.lastname: Souto
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: García
authors.affiliation: Department of Chemical and Instrumental Analysis, Faculty of Chemistry and Pharmacy, University of El Salvador, Ciudad Universitaria, San Salvador, El Salvador.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Abrego
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001578:Benzopyrans / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000517:prevention & control; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009883:Ophthalmic Solutions / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011422:Propionates / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D009883:Ophthalmic Solutions; D011422:Propionates; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C043940:pyranoprofen; D019344:Lactic Acid
keywords: Anti-inflammatory efficacy; Corneal permeation; Cytotoxicity cell; Nanoparticles; Poly (lactic/glycolic) acid (PLGA); Pranoprofen