In vitro-in vivo correlation of PLGA microspheres: Effect of polymer source variation and temperature

Development of Level A in vitro-in vivo correlations (IVIVCs) remains challenging for complex long-acting parenterals, such as poly(lactic-co-glycolic acid) PLGA microspheres. The nature of the PLGA polymer excipient has a dominant influence on the performance of PLGA microspheres. These microsphere systems typically exhibit multiphasic in vitro/in vivo release/absorption characteristics and may also show interspecies differences (animal model versus human data). These issues contribute to the difficulties in the development of IVIVCs for PLGA microsphere systems. To gain a better understanding of how to achieve IVIVCs for PLGA microspheres, microsphere formulations with similar as well as different release characteristics were prepared using PLGAs from different sources. Efforts were then made to establish IVIVCs for these formulations using in vitro release profiles obtained at both 37°C (human body temperature) and 39°C (rabbit body temperature) with in vivo data obtained from an animal model (rabbit). Risperidone was selected as the model drug; microsphere formulations were prepared under the same processing methods using apparently similar PLGAs from different sources. Owning to the different physicochemical properties of the PLGAs (such as inherent viscosity, monomer ratio (L/G ratio) and blockiness), the formulations exhibited significant differences in critical quality attributes (such as particle size, particle size distribution, porosity and pore size) and consequently had different in vitro and in vivo performance. IVIVCs were developed and it was shown that model predictability improved when IVIVCs were established using those formulations with comparable release characteristics. In addition, IVIVCs were established with Tscaling factors close to 1 using in vitro release profiles acquired at 39°C, emphasizing the importance of considering the body temperature in understanding interspecies differences. The present work provides a comprehensive understanding of the impact of the PLGA source variation on IVIVC development and predictability for complex long-acting parenterals such as PLGA microspheres. [Display omitted]