Drug-loaded Polylactide Microspheres Design And Preparation

In the treatment of diseases with drugs, all the factors including therapeutic effects, concentration, maintained time, absorption, excretion and toxicity of drugs in a body must be considered. Because traditional pharmaceuticals have been unable to meet the requirements of people on health and continuous developing medical technology, the study of controlled release drug delivery system is becoming the focus of pharmaceutical preparations. Recently, much concern has been put on the research of poly(lactic acid)(PLA) microspheres drug loading system. However, because of the hydrophobicity of PLA, drug loading PLA microspheres would be phagocytized by macrophage in the mononuclear phagocyte system (MPS) immediately when it is intravenously injected into a body. The phagocytosis of macrophage on PLA microspheres reduced the circulation time of drug in blood, which resulted in the limited application of PLA microspheres in drug delivery system. Fortunately, the introduction of hydrophilic groups in the PLA main chain or coating microspheres with hydrophilic materials can improve the hydrophilicity of PLA microspheres.In this work, a chitosan derivative, N-maleic acylation chitosan (NMCS), was synthesized. Capsules with hydrophilic shell, polymerized-N-maleoylchitosan (p-NMCS), and hydrophobic core, PLA, were successfully prepared using PVA emulsifier and oil in water (O/W) interface radical polymerization method. The structure of the capsule carrier was investigated by Fourier Transform Infrared Spectroscopy (FTIR). The particle size and polydispersity was investigated by Dynamic Light Scattering (DLS). The morphology of the particles was investigated by Field Emission Scanning Electron Microscopy (FESEM) and Transmission Electron Microscope (TEM). The drug loading content, entrapment efficiency and in vitro release kinetic of the capsules with four different ratio of PLA to p-NMCS (0,1/3,1/1,3/1) were also studied. The result revealed that the PLA/p-NMCS microcapsules showed regular spherical morphology with a hydrophilic shell and hydrophobic core structure. The ratio of PLA to p-NMCS in the PLA/p-NMCS microcapsules was found affecting the drug loading content and entrapment efficiency. In vitro release kinetic results indicated that the p-NMCS microcapsules had a faster release rate comparing with that of the PLA/p-NMCS core-shell microcapsules, suggesting the release mechanism of the p-NMCS microcapsules was a diffusion-driven process, while the release mechanism of the PLA/p-NMCS microcapsules with high ratio of PLA to p-NMCS (not less than1/1) was a combined diffusion and degradation-driven process.In order to obtain PLA particles with small and controlled particle size, an effective and biocompatible surfactant butanedioic acid,2-sulfo,1,4-ditridecyl ester, sodium salt (1:1)(BASDE) was used in O/W emulsion-evaporation process for the preparation of PLA particles. The size and polydispersity of the PLA particles was investigated by DLS. The morphology of the PLA particles was investigated by TEM. The cytocompatibility of the PLA particles was studied by MTT assay. The drug loading content, entrapment efficiency and in vitro release kinetic of the PLA particles with different particle size, theoretic drug loading and drug concentration in the organic phase were studied systematically. The result indicated that the PLA particles had a regular spherical morphology with controlled particle size and narrower size distribution, and showed good water suspension dispersion stability. Moreover, because of the excellent emulsification capability of BASDE to PLA, the obtained PLA particles presented excellent cell compatibility. With the increment of particle size and theoretical drug loading, the drug entrapment efficiency reduced. With the increment of particle size and the decrement of the theoretical drug loading, the drug release rate decreased. The drug concentration in organic phase played little effect on drug release rate. The result also revealed that the drug release of the PLA particles with a size of50to550nm was controlled by Fickian diffusion mechanism within10days.Fluorescence PLA particles labeled with RhB were prepared by surface polymerization. In order to study the influence of biocompatible and amphiphilic molecules on the macrophage phagocytosis, PLA/poly(ethylene glycol)(PEG), PLA/pluronic127, PLA/acrylic polyethers (APEG) and PLA/poly(vinyl alcohol)(PVA) particles were prepared respectively. The structures of the particle carriers were investigated by FTIR. The size and polydispersity of the particles was investigated by DLS. The morphology of the PLA particles was investigated by a TEM. The fluorescent labeling efficiency was studied by Fluorescence spectra. The influence of particle size and surface on macrophage phagocytosis was studied by a Fluorescence microscopy. The influence of particle surface on protein adsorption was studied by an Electrochemical Impedance Spectroscopy (EIS). The result showed the fluorescence particles displayed strong fluorescence effects. The particle size and surface had some influence on fluorescent labeling effect. The internalization of RhB-labelled PLA particles by macrophages and the EIS result showed that the PLA/PEG particles had excellent resistance ability to macrophage phagocytosis and albumin adsorption, revealing that the PLA/PEG particles could have broad application prospects in the field of drug delivery system.