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Jenni J. Hakkarainen, Agne Ziniauskaite, Vytautas Cepla, Ramunas Valiokas, Giedrius Kalesnykas; Comparison and validation of ex vivo and in vitro corneal permeability models. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5087.
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© ARVO (1962-2015); The Authors (2016-present)
Early drug discovery and development require the accurate estimation of the permeability properties of topical ocular pharmaceutical formulations across the corneal barrier. The aim of this study was to compare the gold standard ex vivo rabbit corneal permeability model with our novel and validated in vitro model for corneal permeability.
The apparent permeability coefficient (Papp) was estimated for nine fluorescent reference standards (Rhodamine B, Rhodamine 123, Rhodamine 6G, Rhodamine 110 chloride, 6-carboxyfluorescein, FITC-dextrans mol. wt 4000 and 70 000, resorufin, DAPI) and six clinically used ocular drugs (brinzolamide, dexamethasone, chloramphenicol, timolol, pilocarpine and betaxolol) using a vertical diffusion chamber system. Reference standards were selected based on lipophilicity and physicochemical properties.
The ophthalmic drug molecules used for this initial validation of our in vitro model exhibited a wide range of corneal permeability. Correlation analysis was performed by comparing ex vivo and in vitro Papp values with several physicochemical parameters such as molecular weight, lipophilicity, and polar surface area. Significant differences between the permeability properties of in vitro and ex vivo models were identified. Specifically, using an in vitro model with a stratified corneal epithelium overestimated the Papp values of lipophilic molecules compared with the ex vivo model (Pappvalues ranged from 0.07 to 42 × 10-6 cm/s and from impermeable to 27 × 10-6 cm/s, respectively). The prediction of Papp values was improved in an in vitro model containing a double-layered structure mimicking both the stratified epithelium and the stroma (Papp ranged from 0.2 to 34.6 × 10-6 cm/s).
Our data suggest that in vitro corneal permeability models require a multilayered corneal structure in order to adequately predict corneal permeability of drugs and experimental compounds.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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