Modeling and Design of Chitosan-PCL Bi-Layered Microspheres for Intravitreal Controlled Release.

Background/Objectives: Chronic retinal diseases usually require repetitive local dosing. Depending on factors such as dosing frequency, mode of administration, and associated costs, this can result in poor patient compliance. A better alternative involves using controlled-release drug delivery systems to reduce the frequency of intravitreal dosing and extend drug release. However, reaching the market stage is a time-consuming process. Methods: In this study, we employed two computational approaches to model and estimate the parameters governing the diffusion-controlled drug release from bi-layered microspheres. The case study involved microspheres composed of a chitosan core and a polycaprolactone (PCL) shell. The model drugs were bovine serum albumin and bevacizumab (an agent that slows neovascularization due to retinal disorders). Drug release from the microspheres is described by a mathematical model that was solved numerically using the finite difference and the finite element approaches. The parameter estimation was performed by nonlinear least-squares regression. Results: We used the estimated parameters to simulate the cumulative release under various conditions and optimize the device design to guide future experimental efforts and improve the duration of release beyond a target daily therapeutic release rate from the microspheres. Conclusions: We investigated the effects of polymeric layer sizes on drug release and provided recommendations for optimal sizes. We provide straightforward computational tools for others to reuse in designing bi-layered microspheres for intravitreal drug delivery needs in the treatment of chronic ocular neovascularization.