Mechanistic Model\nfor Drug Release from PLGA-Based\nBiodegradable Implants for <i>In Vitro</i> Release Testing:\nDevelopment and Validation

Several factors can affect drug release from polylactide\ncoglycolide\n(PLGA)-based formulations, including polymer and drug properties,\nformulation components, manufacturing processes, and environmental <i>in vitro</i> or <i>in vivo</i> conditions. To achieve\noptimal release profiles for specific drug delivery applications,\nit is crucial to understand the mechanistic processes that determine\ndrug release from PLGA-based formulations. In the current study, we\ndeveloped a mechanistic model for the <i>in vitro</i> drug\nrelease of PLGA-based solid implants. The model accounts for all known\ncritical quality attributes (CQAs) and considers the most important\nrelease rate processes, including water or dissolution medium influx\ninto the porous structure of the implant, initial noncatalytic hydrolysis\nof PLGA, autocatalytic hydrolysis, dissolution of oligomers and monomers\ninto the aqueous medium, the liberation of the trapped solid drug\nfrom the polymer matrix, dissolution of the solid drug into the wetted\npore network, diffusion of the dissolved drug out of the implant,\nand distribution of the dissolved drug into the dissolution medium.\nThe model has been validated using <i>in vitro</i> release\ndata obtained from implants of four drugs (buserelin, afamelanotide,\nbrimonidine, and nafarelin). The model presented in this manuscript\nprovides valuable insights into the kinetics and mechanism of drug\nrelease from PLGA-based solid implants and has demonstrated the potential\nfor optimizing formulation design. The <i>in vitro</i> release\nmodel, coupled with physiologically based pharmacokinetic (PBPK) modeling,\ncan predict the <i>in vivo</i> performance of implants and\ncan be used to support bioequivalence studies in a drug development\nprogram.