title: Sustained release ophthalmic dexamethasone: In vitro in vivo correlations derived from the PK-Eye.
abstract: Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20±0.02mg in a 50μL volume of TIPS microparticles resulted in a clearance t1/2of 9.6±0.3days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t1/2of 48h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye.
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1 V9EL, UK; UCL School of Pharmacy, London, WC1N 1AX, UK.
authors.forename: Sahar
authors.initials: S
authors.lastname: Awwad
authors.affiliation: UCL Division of Medicine, London, WC1E 6JJ, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Day
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1 V9EL, UK.
authors.forename: Peng T
authors.initials: PT
authors.lastname: Khaw
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1 V9EL, UK; UCL School of Pharmacy, London, WC1N 1AX, UK. Electronic address: ucnvsbr@ucl.ac.uk.
authors.forename: Steve
authors.initials: S
authors.lastname: Brocchini
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN 46208, USA. Electronic address: hfadda@butler.edu.
authors.forename: Hala M
authors.initials: HM
authors.lastname: Fadda
mesh_terms: D060433:Administration, Ophthalmic; D000465:Algorithms; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D005123:Eye / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D058449:Intravitreal Injections; D008953:Models, Anatomic; D053758:Nanoparticles; D010539:Permeability; D012160:Retina / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D003907:Dexamethasone
keywords: In vitro in vivo correlations; Ocular drug delivery; PLGA; Pharmacokinetics; Sustained release