Biodegradable microparticles and in situ forming implants/microparticles containing drugs in different physical states

Abstract

PLGA drug delivery systems have been widely investigated as carriers for sustained drug release. But incorporating nanosized drugs or excipients into these systems was not been systematically studied until now. This research aimed first to understand the specific properties of PLGA microparticles loaded with nanosized drug when compared to micronized and dissolved drug. Then optimize the manufacturing process and formulation parameters of PLGA drug delivery systems incorporating nanosized drugs. And finally, investigate the possibility of using sugar particles and an optimized manufacturing process to prepare porous PLGA drug delivery systems. Quasi-linear release was obtained by encapsulating 10 % nanosized dexamethasone into PLGA 502H and 503H microparticles. Quick wetting process and homogenous distribution of nanosized drugs inside microparticles helped to form a uniform inner network and thus eliminated the lag phase. Dexamethasone, hydrocortisone and dexamethasone sodium phosphate nanosuspensions (200 – 300 nm) were successfully prepared by wet bead milling in dichloromethane using PLGA as a milling stabilizer, and then encapsulated inside the microparticles. Most microparticles’ encapsulation efficiencies were larger than 80 %. By changing PLGA types, selecting microparticle sizes, varying drug loadings, and using PLGA blends, the release profiles could be modified and a quasi-linear release without a lag phase was obtained. Incorporating nanosized dexamethasone into PLGA in situ forming systems increased systems’ viscosities, which resulted in better physical stability for at least 3 months, a smaller burst release, increased drug release during lag phase and a longer release period, compared to dissolved and micronized dexamethasone. The usage of nanosized/micronized sugar particles as porogen can introduce porosity within PLGA microparticles containing dexamethasone using S/O/W method. The porosity of the microparticles is caused both by the influx of water into the oil droplets and the encapsulation and subsequent dissolution of sugar particles during the manufacturing process. Overall, the introduction of nanosized/micronized sugar particles resulted in porous PLGA microparticles with high encapsulation efficiency. Designed porosity and pore size, as well as modifiable in vitro drug release could be achieved via the selection of appropriate particle size and weight fraction of nanosized/micronized sugar particles. The successful completion of this research can instruct the development of PLGA formulations. Firstly, this work will aid future research in PLGA microparticles in terms of choosing drug particle sizes and dispersion states. Secondly, this study will be helpful in the design and development of PLGA formulations loaded with drug nanocrystals in a simplified process by combining non-aqueous wet bead milling and subsequent microencapsulation. Further, this study presents a newly developed PLGA in situ forming system incorporating nanosized drug. Finally, this research is also an important step toward the development of porous PLGA microparticles using nanosized sugar particles as porogen which can adjust the drug release.