Preparation And Application Of HIV Fusion Inhibitor Loaded PLGA Microspheres

Human immunodeficiency virus(HIV)fusion inhibitor can effectively block HIV from getting into and infecting CD4+T cell,which stops HIV multiplication in the human body at the first stage and exerts greater preventive effect.Due to its short half-life,frequent administration is required,because HIV can easily infect cells once the drug is interrupted.However,there is still no long-acting AIDS prevention drug approved.Therefore,the purpose of this study is to prepare a fusion inhibitor loaded PLGA microspheres as a sustained-release system for long-term AIDS prevention Premix membrane emulsification technique combined with solvent evaporation method was used to prepare microspheres,and the effect of preparation conditions on particle size and drug loading efficiency of microspheres was investigated systematically.Finally,microspheres with narrow size distribution,high drug loading efficiency and high encapsulation efficiency were obtained under optimum preparation conditionThis thesis is divided into three parts:(1)Due to the amphiphilicity of lipopeptide fusion inhibitors(LP-98),the morphology,hydrophilicity,and emulsibility of lipopeptide were investigated to determine the appropriate embedding method.Finally,W1/O/W2 double emulsion method was chosen according to the drug properties.(2)Premix membrane emulsification technique combined with solvent evaporation method was used to prepare microspheres.After the optimization of the pre-double emulsion method,trans-membrane pressure,PVA concentration,PLGA concentration,LP-98 concentration and primary emulsion preparation method,LP-98 loaded microspheres with a diameter of 14 ?m,Span of 0.9,drug loading efficiency of 8%,and encapsulation efficiency of 95%were obtained.(3)The performance of LP-98-loaded microspheres prepared under optimum condition were evaluated comprehensively.Circular dichroism spectroscopy and in vitro antiviral test were used to analyze the structure and biological activity of LP-98,and the results showed that the embedding process had no negative effect.The release behavior of microspheres was investigated by in vivo and in vitro release experiments.Pharmacokinetic studies showed that LP-98-loaded microspheres were capable to continuously release for 24 days in rats without obvious damage to heart,liver and kidney.In summary,the LP-9 8-loaded microspheres prepared by premix membrane emulsification technique combined with double emulsion method exhibited a stable sustained release effect,which revealed a promising potential for long-term AIDS prevention.