The Impact of Temperature on the Formation, Release Mechanism, and Degradation of PLGA-based In-Situ Forming Implants

This study explores the impact of varying temperatures on the release behavior of Triptorelin Acetate (TA) from a PLGA-based in-situ forming implant (ISFI) and polymer degradation. Formulations were prepared using the in situ forming method in an acetate buffer (pH=6.8) and then exposed to temperatures of 4 to 60°C. The drug release and polymeric depot behavior were evaluated using HPLC, SEM, GPC, Rheometer, and pH measurements. A modified Gallagher-Corrigan Model-based mathematical model was applied to fit the in-vitro data, and the activation energy for peptide release in diffusional and erosional phases was calculated using the Arrhenius equation. The results revealed that matrices formed at 37, 45, and 53°C exhibited a highly porous structure, resulting from rapid phase inversion and surface pore closing. This led to a reduction in TA burst release, observed as 38%, 27%, and 15% at 37°C, 45°C, and 53°C respectively. Conversely, matrices at 4 and 25 °C demonstrated a faster initial release, followed by the formation of dense structures. The accelerated drug release profiles at 45 and 53°C showed a shortened ultimate drug release duration and a good correlation with the real-time results at 37°C. Due to the discernible PLGA matrices degradation at different temperatures, biphasic and tri-phasic release patterns were observed. The experimental release results aligned well with the proposed mathematical model, and the drug release kinetic parameters were estimated. Thus, in in-vitro studies, the release medium temperature plays a significant role in the drug-release behavior of ISFIs.