Study On The Preparation Of Biodegradable Microparticle And Its In Vitro Drug Release Kinetics

In recent years, biodegradable polymeric microparticles have attracted more and more attentions as sustained /controlled drug delivery systems. They have many advantages such as small size, diversity and functionality of materials and multiple dose administration, etc. They will be promising in clinical applications because they can release drugs with a controlled speed and thus greatly improve the effectiveness and safety of drugs. This research aimed to investigate the effect of polymer microstructure on controlled drug delivery from Poly (dl-lactide-co-glycolic acid)-methoxypoly (ethyleneglycol) (PLGA-mPEG) microparticles during polymer degradation process. An experimental and theoretical framework was created for the guidance of microparticle application.PLGA-mPEG microparticles were prepared by O/W solvent evaporation method. MTX, a small hydrophobic drug, was employed as the model drug. The influences of manufacturing parameters on the properties of microparticles were investigated. O/W solvent evaporation method was further optimized by orthogonal design. Microparticles with high encapsulation efficiency and well sustained drug release were prepared. The analytical results indicated that MTX had high compatibility with PLGA-mPEG.Under a certain drug loading capacity, the MTX release from PLGA-mPEG microparticles showed a triphasic pattern: an initial burst release, followed by a lag period and a subsequently second burst release. The degradation of microparticles induced both physicochemical and morphological changes, and these changes played important roles on the drug release kinetics. For each drug release phase, the controlling factor which correlated with polymer degradation was different. The incorporation of hydrophilic mPEG chain, acting as a surface modifier of hydrophobic PLGA network, increased the polymer hydrolysis rate as well as drug release rate. mPEG chain also enhanced the mechanical strength of PLGA-mPEG microparticles. It reduced the risk of severe drug burst release caused by particle collapse and shortened the lag period of drug release. The degradation behavior of microparticles could be affected by many external factors. These factors regulated the drug release indirectly by working on the polymer degradation process. In this study, the effects of four external factors, copolymer composition, drug loading, particle size and incubation medium, on the degradation of PLGA-mPEG microparticles were investigated. For each factor, the mechanism of controlling drug release was analyzed. Expanded means of regulating the drug release from PLGA-mPEG microparticles were then developed to achieve the desired drug release rate.Mass transfer models considering drug diffusion, hydrolysis of polymer chains and matrix erosion were developed for different drug release phases. A diffusion-degradation-erosion model was proposed and successfully described the whole MTX release from PLGA-mPEG microsparticles. The effects of external factors on drug release kinetics were analyzed and the trends of influences were well predicted according to the model.PLGA-mPEG was also applied for encapsulating salbutamol sulphate (SBS) and lysozyme (LYS), by utilizing the compatibility of PLGA-mPEG with hydrophilic or biomacromolecular drugs. Aiming at solving problems of microparticles encapsulating water soluble drugs, such as low encapsulation efficiency, severe initial burst release, and lag release of active biomolecules at the end of incubation period, etc, additives and manufacturing technique improvements were applied to improve the properties of hydrophilic drug-loaded microparticles.