Model-based optimization of drug release rate from a size distributed population of biodegradable polymer carriers

Abstract

In the present study, a comprehensive polymer degradation-drug diffusion model is developed to describe the polymer degradation kinetics and quantify the release rate of an active pharmaceutical ingredient (API) from a size-distributed population of drug-loaded poly(lactic-co-glycolic) acid (PLGA) carriers in terms of material and morphological properties of the drug carriers. To take into account the spatial-temporal variation of the drug and water diffusion coefficients, three new correlations are developed in terms of spatial-temporal variation of the molecular weight of the degrading polymer chains. The first one relates the diffusion coefficients with the time-spatial variation of the molecular weight of PLGA and initial drug loading and, the second one with the initial particle size, and the third one with evolution of the particle porosity due to polymer degradation. The derived model, comprising a system of partial differential and algebraic equations, is numerically solved using the method of lines and validated against published experimental data on the drug release rate from a size distributed population of piroxicam-PLGA microspheres. Finally, a multi-parametric optimization problem is formulated to calculate the optimal particle size and drug loading distributions of drug-loaded PLGA carriers to realize a desired zero-order drug release rate of a therapeutic drug over a specified administration period of several weeks. It is envisaged that the proposed model-based optimization approach will aid the optimal design of new controlled drug delivery systems and, consequently, the therapeutic outcome of an administered drug.

Keywords: Controlled drug delivery; Drug diffusion; Drug loading distribution; Particle size distribution; Poly(lactic-co-glycolic acid); Polymer degradation kinetics; Zero-order drug release rate; drug-loaded PLGA microspheres; model-based optimal design of DDS.