Modification of the tri-phasic drug release pattern of leuprolide acetate-loaded poly(lactide-co-glycolide) microparticles

Abstract

Leuprolide acetate-loaded poly(lactide-co-glycolide) (PLGA RG503H) microparticles prepared by the solvent evaporation method had a tri-phasic drug release pattern over a duration of up to 2 months. An initial release was followed by a slow drug release phase and a final rapid drug release. The objective of this study was to identify parameters, which shift the release profile from the tri-phasic to a more continuous release profile. Varying formulation and processing parameters (e.g., drug loading, volume of the external aqueous phase, using low molecular weight PLGA, different microparticle drying methods) affected the initial release (burst) but did not influence the drug release thereafter. The addition of the hydrophilic polymer polyvinylpyrrolidone (PVP) led to the formation of more porous microparticles. This influenced the initial release but did not change the tri-phasic drug release pattern. The inclusion of medium chain triglycerides (MCT) successfully shifted the tri-phasic pattern to a continuous release profile. MCT accelerated the leuprolide release in the second, slow release phase and reduced it in the final rapid release phase. MCT led to the formation of microparticles with an irregular surface and a highly porous inner structure. Differential scanning calorimetry (DSC) revealed a high encapsulation efficiency of MCT (88–105%) in the microparticles and an unchanged glass transition temperature ( T g) of PLGA.