Abstract
The capability to predict corneal permeability based on physicochemical parameters has always been a desirable objective of ophthalmic drug development. However, previous work has been limited to cases where either the diversity of compounds used was lacking or the performance of the models was poor. Our study provides extensive quantitative structure-property relationship (QSPR) models for corneal permeability predictions. The models involved in vitro corneal permeability measurements of 189 diverse compounds. Preliminary analysis of data showed that there is no significant correlation between corneal-PAMPA (Parallel Artificial Membrane Permeability Assay) permeability values and other pharmacokinetically relevant in silico drug transport parameters like Caco-2, jejunal permeability and blood-brain partition coefficient (logBB). Two different QSPR models were developed: one for corneal permeability and one for corneal membrane retention, based on experimental corneal-PAMPA permeability data. Partial least squares regression was applied for producing the models, which contained classical molecular descriptors and ECFP fingerprints in combination. A complex validation protocol (including internal and external validation) was carried out to provide robust and appropriate predictions for the permeability and membrane retention values. Both models had an overall fit of R2 > 0.90, including R2-values not lower than 0.85 for validation runs, and provide quick and accurate predictions of corneal permeability values for a diverse set of compounds.
Highlights
The eye is a challenging target of therapy
We investigated the relationships between corneal-parallel artificial membrane permeability assay (PAMPA) permeability and membrane retention values (MR) in comparison with experimental log of calculated Caco-2 permeability (Caco-2) permeability data and calculated physicochemical properties, such as molecular weight (MW), topological polar surface area (TPSA) and lipophilicity descriptors, in the case of 50 structurally and physicochemically diverse compounds [43]
Due to weak correlations (R2 = 0.018−0.506) we concluded that corneal permeability cannot be predicted based on only these physicochemical descriptors and for this reason, a larger measured permeability dataset is needed to be able to carry out a quantitative structure-property relationship (QSPR) analysis
Summary
Because of its complicated anatomic structure and small absorptive surface, it is difficult to achieve therapeutic drug levels in the interior of the eye by topical dosage forms (eye drops, ointments, in-situ gel-forming systems, etc.). More invasive ones such as intraocular injections or implants can be very useful for maintaining high drug levels in both the anterior and posterior segment [1,2,3]. The intraocular injections (usually targeting the vitreous) are still the most commonly used posterior segment therapies since there are no other efficient delivery routes for reaching high drug levels in the posterior with minimal systemic side effects [9]
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