Biodegradable Microparticle and In Situ Microparticle Systems

1\. Microparticles prepared by the solvent evaporation (cosolvent) method: Adjusting parameters, which affected the PLGA precipitation kinetics, provided efficient ways to increase the encapsulation efficiency and control the initial release. Addition of NaCl to the external aqueous phase increased the encapsulation efficiency. The presence of ethanol in the external phase led to porous microparticles with an increased initial release but a decreased encapsulation efficiency. The initial release also decreased with decreasing volume of the external phase and homogenization speed, as well as with covering the preparation apparatus; however, these variations showed no significant effect on the encapsulation efficiency. Varying formulation and processing parameters (e.g., drug loading, volume of the external phase, using low molecular weight PLGA) affected the initial release of microparticles but not the drug release thereafter. The inclusion of medium chain triglycerides (MCT) successfully shifted the tri-phasic release pattern of microparticles to a continuous release profile. MCT led to the formation of microparticles with an irregular surface and a highly porous inner structure. Differential scanning calorimetry (DSC) revealed a high entrapment of MCT in the microparticles and an unchanged glass transition temperature (Tg) of the PLGA. 2\. In situ microparticle (ISM) system: ISM showed a high initial release due to the high porosity of microparticles. The initial release could be reduced by increasing the polymer concentration, increasing the volume and viscosity of the oil phase, and decreasing the drug loading. Introducing a partial water-miscible solvent reduced the initial release from ISM, which could be attributed to the formation of less porous microparticles. In vivo study in rabbits showed a suppression of testosterone until day 29 after single administration of ISM prepared with a solvent mixture of 80% w/w NMP and 20% w/w triacetin. For ISM, the low molecular weight PLGA resulted in a lower initial release than the high molecular weight PLGA. ISM prepared with PLGA combinations showed a decreasing initial release with increasing low molecular weight PLGA content. A slower solvent diffusion from the low molecular weight PLGA solution droplets into the release medium led to a less porous structure of the resulting microparticles, thus explaining the lower initial release. PLGA with free carboxylic acid endgroups led to a slower drug release compared to PLGA with esterified end groups. 6-month controlled release leuprolide ISM could be obtained by blending poly(lactides) (PLA) with different molecular weights.