Combining modeling of drug uptake and release of cyclosporine in contact lenses to determine partition coefficient and diffusivity

Ophthalmic drug delivery via eye drops is inefficient because only about 1-5% of the drug permeates the cornea during the short residence time of a few minutes. Contact lenses are receiving considerable attention for delivering ophthalmic drugs because of higher bioavailability and the possibility of sustained release from hour to days, and possibly longer. The drug release durations from contact lenses are typically measured in vitro and it is challenging to relate the in vitro release to in vivo release, particularly for hydrophobic drugs which may not exhibit sink release in vitro and in vivo. The in vitro release can be fitted to diffusion equation to determine the partition coefficient and diffusivity, which can then be utilized to model in vivo release. The Higuchi equation is frequently used to model the short time release from a contact lens to determine diffusivity with the implicit assumption that the release is under sink conditions and the starting concentration in the lens was uniform. Both conditions may be violated when measuring release of hydrophobic drugs from contact lenses because the diffusivity and partition coefficient, and also the time needed for equilibrium are not known a priori. Here we develop a method to use the data for both loading and release of cyclosporine, which is a common hydrophobic ophthalmic drug, to determine the partition coefficient and diffusivity. The proposed approach does not require sink conditions and also does not require the lens to be fully equilibrated during loading, which may take almost a month for lenses considered here. The model is based on solving the diffusion equation in the gel along with a mass balance in the fluid. The model equations are solved numerically by finite difference. When the value of partition coefficient is high, such as it is for cyclosporine, the dynamic data is only sensitive to a ratio of partition coefficient and diffusivity, and this ratio had to first be determined from the loading data. Then the two unknown parameters were obtained by minimizing the error between the model prediction and experimental data. The method was used to determine D and K for several silicone hydrogel formulations with varying ratio of hydrogel and silicone fractions. [Display omitted]