title: Barrier analysis of periocular drug delivery to the posterior segment.
abstract: Periocular administration is a potential way of delivering drugs to their targets in posterior eye segment (vitreous, neural retina, retinal pigment epithelium (RPE), choroid). Purpose of this study was to evaluate the role of the barriers in periocular drug delivery. Permeation of FITC-dextrans and oligonucleotides in the bovine sclera was assessed with and without Pluronic gel in the donor compartment. Computational model for subconjunctival drug delivery to the choroid and neural retina/vitreous was built based on clearance concept. Kinetic parameters for small hydrophilic and lipophilic drug molecules, and a macromolecule were obtained from published ex vivo and in vivo animal experiments. High negative charge field of oligonucleotides slows down their permeation in the sclera. Pluronic does not provide adequate rate control to modify posterior segment drug delivery. Theoretical calculations for subconjunctival drug administration indicated that local clearance by the blood flow and lymphatics removes most of the drug dose which is in accordance with experimental results. Calculations suggested that choroidal blood flow removes most of the drug that has reached the choroid, but this requires experimental verification. Calculations at steady state using the same subconconjunctival input rate showed that the choroidal and vitreal concentrations of the macromolecule is 2-3 orders of magnitude higher than that of small molecules. The evaluation of the roles of the barriers augments to design new drug delivery strategies for posterior segment of the eye.
authors.affiliation: Faculty of Health Sciences, University of Eastern Finland, Finland.
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Ranta
authors.affiliation: Faculty of Health Sciences, University of Eastern Finland, Finland.
authors.forename: Eliisa
authors.initials: E
authors.lastname: Mannermaa
authors.affiliation: Division of Biopharmacy and Pharmacokinetics, University of Helsinki, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Lummepuro
authors.affiliation: Centre for Drug Research, University of Helsinki, Finland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Subrizi
authors.affiliation: Centre for Drug Research, University of Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Laukkanen
authors.affiliation: Centre for Drug Research, University of Helsinki, Finland.
authors.forename: Maxim
authors.initials: M
authors.lastname: Antopolsky
authors.affiliation: Centre for Drug Research, University of Helsinki, Finland; Department of Chemistry, Aalto University, Finland.
authors.forename: Lasse
authors.initials: L
authors.lastname: Murtomäki
authors.affiliation: Centre for Drug Research, University of Helsinki, Finland.
authors.forename: Margit
authors.initials: M
authors.lastname: Hornof
authors.affiliation: Centre for Drug Research, University of Helsinki, Finland. Electronic address: Arto.urtti@helsinki.fi.
authors.forename: Arto
authors.initials: A
authors.lastname: Urtti
mesh_terms: D000818:Animals; D001682:Biological Availability; D002417:Cattle; D002829:Choroid / Q000098:blood supply / Q000378:metabolism; D003911:Dextrans / Q000493:pharmacokinetics; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D010539:Permeability; D057972:Posterior Eye Segment / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D012590:Sclera / Q000378:metabolism*
chemical_list: D003911:Dextrans; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate