Development of Particulate Formulations for Controlled Drug Delivery

Microparticles and nanoparticles are widely investigated for controlled delivery of drug compounds. The aim of the research presented in this thesis was to develop and conduct preliminary evaluations of microparticle and nanoparticle-based formulations for sustained and targeted delivery respectively. The author successfully prepared microparticles and nanoparticles of controlled size and distribution using a modified hydrogel template method for microparticles and an antisolvent precipitation method for nanoparticles. In the first part of this thesis, model compounds risperidone, methylprednisolone acetate and paclitaxel were formulated into polymeric microparticles without the use of heat or other harsh processing conditions. The resulting formulations contained amorphous drug and were stable for at least 2 months at 4 °C. Various processing and formulating parameters were tested to determine the optimal combination that would produce microparticle formulation with minimized initial burst release and long sustained release. Results indicate that control of initial burst release is dependent on polymer-drug compatibility and drug distribution within the polymeric matrix. The latter factor is influenced greatly by solvent removal kinetics and drug solubility in the solvent system. The optimized formulation for risperidone, methylprednisolone acetate and paclitaxel demonstrated initial release of 7.2±2.8%, 0.0±1.1% and 12.0±2.5% respectively, which is relatively low considering the high drug loading achieved in these formulations (\u3e 25% w/w). The in vitro release of methylprednisolone acetate and paclitaxel occurred over a 15-day period, while approximately 60% risperidone was released at the end of a 21-day evaluation period. In the second part of this thesis, the nanocrystal form of model compound paclitaxel was prepared and various polymer, surfactant or serum protein-based stabilizers were evaluated for their ability to produce stable formulations. The successful formulation contains paclitaxel nanocrystals stabilized by serum protein transferrin with a drug content of 55~60%, which is significantly higher than the drug content in currently marketed paclitaxel formulation Abraxane®. This formulation was stable for at least 3 months stored at 4 °C. In in vitro dissolution studies, the formulation resulted in significant dissolution enhancement compared to control paclitaxel with over 25% released in 50 hours compared to less than 5% released in control. Interestingly, the formulation showed slower dissolution compared to paclitaxel nanocrystals without transferrin. This was attributed to the transferrin binding to paclitaxel molecules, and is potentially advantageous in prolonging circulation and preventing premature release of paclitaxel