(361f) Mathematical Modeling of Drug Release from Bi-Layered Polymer Capsules in the Eye

Wet age-related macular degeneration (wet AMD) is a chronic disease that involves new blood vessel formation in the eye due to excessive production of vascular endothelial growth factor (VEGF). Wet AMD progressively affects the central retina, and, if left untreated, it can cause vision loss. Wet AMD is the leading cause of visual impairment in the Western World, and the third leading cause worldwide. Wet AMD is not curable; however, current therapies are based on anti-VEGF drugs. The most common administration route of anti-VEGF therapeutics is intravitreal injections. The monthly injections are plagued by poor patient compliance, high costs, and possible complications such as retinal detachment. To address this, several drug delivery systems (DDS) have been proposed in the literature to extend anti-VEGF release in the eye and reduce the frequency of injections. In this work, focus is on an injectable bi-layered capsule for sustained delivery of anti-VEGF [1]. The DDS is composed of two polymeric layers: an inner chitosan layer and an outer polycaprolactone (PCL) layer. In the present work, we detail our efforts at mathematical modeling of drug release from the prototype DDS designed to treat wet-AMD.

First, we used our data for core-shell spherical microparticles [2] to estimate the material specific parameters for chitosan and PCL fabricated by layered electrospinning. We numerically solved the diffusion equation in spherical coordinates in MATLAB for two layers with different diffusion coefficients. Nonlinear least squares curve fitting was used to determine these diffusion coefficients as well as the initial burst release. We then reconstructed the same system in COMSOL Multiphysics to compare the capabilities of the MATLAB and COMSOL optimization routines for curve fitting in advance of extending to more complicated geometries. We used this process to verify our numerical techniques for integrating the amount of drug remaining in each layer of the microspheres and for calculating the objective function for minimizing the sum of squared errors between the experimental data and the model predictions for cumulative drug release over time [2]. We then built a COMSOL model with the dimensions of the DDS intended for eye drug delivery, which is a bi-layered cylinder with a hollow core for drug loading. Transport of dilute species is the only physics enabled in COMSOL as we first focus on the diffusive transport of drug from the DDS into the in vitro medium. The boundary condition is set to zero on the top and bottom of the DDS, simulating impermeable boundaries, consistent with the fabrication techniques of sealing the end caps of the device. The DDS is assumed to be under perfect sink conditions, therefore the concentration on the outside is kept at zero. Fick’s second law is used to model the unsteady-state diffusion in 3 dimensions. Diffusion coefficients of PCL and chitosan were used as estimated from the spherical data. We compare our mathematical predictions to the experimental data [1]. Additionally, our fabrication technique of salt-leaching the outer PCL layer allows us to modulate the DDS porosity. We are fitting the experimental data for the various salt leaching conditions to correlate the impacts of the initial porosity on the subsequent drug release trajectories. We will consider a few candidate models for the effects of porosity in impacting the drug release from the DDS and use COMSOL optimization module to estimate the relevant parameters. The refined model will use the inputs conditions of drug loading, DDS geometry, and initial porosity to determine the cumulative release profile, the amount of time a therapeutic dose is released, and the amount of time to completely deplete the DDS.

In the future, we aim to combine the model with new in vitro and in vivo experimental data to predict and optimize the design of this DDS by tuning its thickness and porosity, so that its drug release is extended as much as possible while keeping it in a therapeutic range. Simulating pharmacokinetics of the released drug in the eye is also part of the future plan for this project.

References:

1. Jiang, P., Chaparro, F. J., Cuddington, C. T., Palmer, A. F., Ohr, M. P., Lannutti, J. J., Swindle-Reilly, K. E. Injectable biodegradable bi-layered capsule for sustained delivery of bevacizumab in treating wet age-related macular degeneration. J Controlled Release 320, 442-456, doi:10.1016/j.jconrel.2020.01.036 (2020).

2. Jiang, P., Jacobs, K. M., Ohr, M. P. & Swindle-Reilly, K. E. Chitosan-Polycaprolactone Core-Shell Microparticles for Sustained Delivery of Bevacizumab. Mol Pharm 17, 2570-2584, doi:10.1021/acs.molpharmaceut.0c00260 (2020).

Acknowledgment: This work was supported by the National Institutes of Health grant R35GM133763, the University at Buffalo, and Ohio Lions Eye Research Foundation.