Preparation Of Uniform-sized PLGA Particles And Exploration In Long-term Release System And Pickering Emulsions

Poly(D,L-lactic-co-glycolic acid) (PLGA) has been used in form of nano/micro-particle in drug delivery due to its compatibility and biodegradability. It has been reported that the particle size plays an important role in the biomedical applications. For example, micro-particles are useful as long-term release system injected subcutaneously. However, the conventional preparation method often leads to large particles with broad size distribution, which will cause poor reproducibility, drug efficacy and so forth. To overcome this issue, premix membrane emulsification was used to prepare uniform-sized PLGA microspheres and investigate the effects of preparation methods on their performance, such as drug release, polymer degradation and pharmacology. Besides, this technique was also utilized to prepare uniform-sized PLGA particles with sub-micron size, and explored the mechanism of formation and stabilization of Pickering emulsions stabilized by PLGA particles.This thesis is divided into five parts:(1) To overcome the difficulty of preparing uniform-sized drug-loaded PLGA microspheres with several micro-size, premix membrane emulsification combined with double emulsion method was employed. Exenatide was used as model peptide. After careful optimization, we obtained the microspheres with high encapsulation efficiency and constant release rate. The stability of the peptide was also highly preserved.(2) Based on the above optimization, the influences caused by primary emulsion preparation (ultrasonication and homogenization) on release behavior, polymer degradation, pharmacology and so forth were further discussed. It was found that the microspheres whose primary emulsion were prepared by ultrasonication (UMS) had slow release rate, low microclimate pH (μpH), which might be harmful for the encapsulated protein drugs. Contrarily, those prepared by homogenization (HMS) had high μpH and constant release rate within first 2 weeks in vivo, but slowed down since then.(3) The differences of solidification methods (solvent evaporation, solvent extraction and co-solvent) on the performance of exenatide-loaded PLGA microspheres were further explored, such as release behavior, polymer degradation, pharmacokinetics and so forth. The microspheres solidified by solvent evaporation (EVM) effectively reduced the blood glucose as exenatide solution with high biosafety and low metabolic burden.(4) During release period, the interaction between peptide and materials greatly affects the bioactivity of the peptide. Here, exenatide as model acidic peptide was used to explore its interaction with PLGA. It was found that acylation occurred between exenatide and PLGA, and then different dications were used to investigate their effects on acylation inhibition. By QCM-D, the inhibition mechanism was demonstrated:Ca2+did not inhibit the acylation; Mn2+ partly restrained the action. While Zn2+ could form complex with exenatide and shield more binding sites, leading to generation of less acylated derivatives.(5) Pickering emulsions were prepared by using sub-micron sized PLGA particles as stabilizer. It was found that PLGA particles acted as a surfactant in the interface lowing interfacial intension, and formed a particle-layer to inhibit the coalescence of the droplets.In this thesis, we took advantages of premix membrane emulsification to prepare uniform-sized PLGA particles with micron and sub-micron size. We achieved a new formulation for exenatide-loaded PLGA microspheres realizing long-term release and proposed a new method and mechanism for stability of acidic peptide. Besides, we further expanded the application of PLGA particles in Pickering emulsions, which opens a novel approach in the biopharmaceutical area.