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Ayumi Yoshimatsu, Chiho Yabuta, Akira Ohtori, Mitsuyoshi Azuma; Influence of Physicochemical Properties on Drug Delivery across Sclera into Choroid-Retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5057. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal injections are currently used to deliver drugs to the retina and other tissues in the back of eye. Topical instillation of ophthalmic drugs would be more comfortable for patients and lower the risk of infection. Reports indicate that topical instillation of some compounds indeed diffuse from the posterior periocular tissues across sclera and reach the posterior choroid-retina. The specific physicochemical properties of such drugs would be important for their permeability, diffusivity and partitioning into ocular tissues, but such data are limited. Thus, the purpose of the present study was to determine the influence of physicochemical properties of selected drugs on their passage across sclera into choroid-retina.
Model compounds were selected to range in molecular weight (MW) from 300 to 10,000 and included a wide range of lipophilicity. Sclera and sclera-choroid-retina were excised from rabbit globes, and were mounted side-by-side in Ussing diffusion chambers. Model compounds in buffer were added to the donor chamber adjacent to sclera, while buffer solution alone was present in the receptor chamber. Permeation rates, time lags, and permeability across sclera or sclera-choroid-retina preparations were determined by pharmacokinetics modeling. Diffusion and partition coefficients were then calculated based on a bilayer membrane model.
Cumulative transport of drug across sclera and sclera-choroid-retina increased as drug concentration in donor solution increased except for compound of MW 10,000. Permeability was negatively correlated with MW in sclera and sclera-choroid-retina. Drug diffusivity in sclera and choroid-retina decreased as MW increased, and diffusion coefficients in choroid-retina were 3 to 10 times less than that in sclera. Partition coefficients into choroid-retina increased as lipophilicity increased. This relationship was not observed for sclera.
Optimal modification of ocular drugs used for topical instillation needs to decrease MW and to balance solubility with lipophilicity.
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