title: An assessment of the ocular safety of excipient maleic acid following intravitreal injection in rabbits.
abstract: Maleic acid was formulated in 0.7% saline and injected intravitreally in rabbits in order to evaluate ocular safety and tolerability. Maleic acid was formulated within a narrow pH range (2-3), administered in a fixed volume (100 µl), and concentrations ranged from 0.00 to 2.00 mg/eye (0.00 to 12.30 mM vitreous). Ocular evaluations were conducted at 2, 4, and 8 days post injection. Ocular irritation responses were observed at doses from 0.50 mg/eye (3.07 mM vitreous) to 2.00 mg/eye (12.30 mM vitreous) and included conjunctival redness and scleral swelling. Chemosis was observed at 2.00 mg/eye (12.30 mM vitreous). Funduscopic evaluations revealed enlarged retinal blood vessels and optic disk swelling at doses ≥1.50 mg/eye (9.22 mM vitreous), retinal folds and retinal discoloration at 2.00 mg/eye (12.30 mM vitreous). Histopathologic evaluations on days 4 and 8 post injection revealed retinal degeneration at doses ≥1.0 mg/eye (6.15 mM vitreous), conjunctival inflammation at doses ≥1.5 mg/eye (9.22 mM vitreous), and retinal pigment epithelial hypertrophy, optic nerve demyelination, anterior chamber fluid, and conjunctival fibrosis at 2.00 mg/eye (12.30 mM vitreous) maleic acid. The data suggest that maleic acid formulations at ≥1.00 mg/eye (6.15 mM vitreous) were not suitable for intraocular indications.
authors.affiliation: Drug Safety Research and Development, La Jolla Laboratories, Pfizer Inc., San Diego, California, USA. shirley.aguirre@pfizer.com
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Aguirre
authors.forename: Walter
authors.initials: W
authors.lastname: Collette
authors.forename: Hovhannes J
authors.initials: HJ
authors.lastname: Gukasyan
authors.forename: Wenhu
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005079:Excipients / Q000008:administration & dosage / Q000633:toxicity*; D005123:Eye / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects; D058449:Intravitreal Injections / Q000379:methods*; D008298:Maleates / Q000008:administration & dosage / Q000633:toxicity*; D009887:Ophthalmoscopy / Q000379:methods; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000503:physiopathology; D012164:Retinal Diseases / Q000139:chemically induced / Q000503:physiopathology*; D018570:Risk Assessment; D014785:Vision, Ocular / Q000187:drug effects*
chemical_list: D005079:Excipients; D008298:Maleates; C030272:maleic acid