A Edward1, M R Prausnitz. 1. Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts 02155, USA. aurelie.edwards@tufts.edu
Abstract
PURPOSE: To develop a theoretical model to predict the passive, steady-state permeability of cornea and its component layers (epithelium, stroma, and endothelium) as a function of drug size and distribution coefficient (phi). The parameters of the model should represent physical properties that can be independently estimated and have physically interpretable meaning. METHODS: A model was developed to predict corneal permeability using 1) a newly developed composite porous-medium approach to model transport through the transcellular and paracellular pathways across the epithelium and endothelium and 2) previous work on modeling corneal stroma using a fiber-matrix approach. RESULTS: The model, which predicts corneal permeability for molecules having a broad range of size and lipophilicity, was validated by comparison with over 150 different experimental data points and showed agreement with a mean absolute fractional error of 2.43, which is within the confidence interval of the data. In addition to overall corneal permeability, the model permitted independent analysis of transcellular and paracellular pathways in epithelium, stroma and endothelium. This yielded strategies to enhance corneal permeability by targeting epithelial paracellular pathways for hydrophilic compounds (phi < 0.1 - 1), epithelial transcellular pathways for intermediate compounds, and stromal pathways for hydrophobic compounds (phi > 10 - 100). The effects of changing corneal physical properties (e.g., to mimic disease states or animals models) were also examined. CONCLUSIONS: A model based on physicochemical properties of the cornea and drug molecules can be broadly applied to predict corneal permeability and suggest strategies to enhance that permeability.
PURPOSE: To develop a theoretical model to predict the passive, steady-state permeability of cornea and its component layers (epithelium, stroma, and endothelium) as a function of drug size and distribution coefficient (phi). The parameters of the model should represent physical properties that can be independently estimated and have physically interpretable meaning. METHODS: A model was developed to predict corneal permeability using 1) a newly developed composite porous-medium approach to model transport through the transcellular and paracellular pathways across the epithelium and endothelium and 2) previous work on modeling corneal stroma using a fiber-matrix approach. RESULTS: The model, which predicts corneal permeability for molecules having a broad range of size and lipophilicity, was validated by comparison with over 150 different experimental data points and showed agreement with a mean absolute fractional error of 2.43, which is within the confidence interval of the data. In addition to overall corneal permeability, the model permitted independent analysis of transcellular and paracellular pathways in epithelium, stroma and endothelium. This yielded strategies to enhance corneal permeability by targeting epithelial paracellular pathways for hydrophilic compounds (phi < 0.1 - 1), epithelial transcellular pathways for intermediate compounds, and stromal pathways for hydrophobic compounds (phi > 10 - 100). The effects of changing corneal physical properties (e.g., to mimic disease states or animals models) were also examined. CONCLUSIONS: A model based on physicochemical properties of the cornea and drug molecules can be broadly applied to predict corneal permeability and suggest strategies to enhance that permeability.