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人类免疫缺陷病毒（HIV）膜融合抑制剂能够抑制病毒与细胞膜融合过程，于感染初期发挥阻断作用，在艾滋病预防中具有较大优势。然而由于其半衰期短，需频繁给药才能达到有效的血药浓度，造成患者顺应性差，且一旦用药中断感染风险极大。因此，亟需开发长效预防制剂满足临床需求。针对此问题，本论文采用聚乳酸-羟基乙酸共聚物（PLGA）包埋膜融合抑制剂，并使用快速膜乳化技术结合溶剂挥发法，系统考察制备工艺对微球粒径及载药等性质的影响，旨在制备粒径均一、高载药量、高包埋缓释微球。具体研究内容分为以下三个部分：（1）针对脂肽膜融合抑制剂的两亲特性，对药物形态、亲疏水性、乳化性等性质进行系统分析，根据药物性质确定了适宜的微球包埋方式为W1/O/W2复乳结合溶剂挥发法。（2）采用快速膜乳化技术结合复乳法制备载药微球，考察了预复乳方式、过膜压力、外水相稳定剂浓度、油相PLGA浓度、内水相药物浓度、初乳制备方式等因素对微球性质的影响，最终制备获得了粒径为14 μm，Span<0.9，载药量>8%，包埋率>95%的膜融合抑制剂缓释微球。（3）对最优工艺下制备的载药微球进行性能评价，通过圆二色光谱法和体外抗病毒实验考察包埋前后药物结构和活性变化，结果证明制备工艺对药物结构和活性均无影响；体外释放实验证明载药微球释放速率平稳；体内药代动力学分析显示，所制备的微球可在大鼠体内持续释放24天；并通过血液生化分析检测发现所制备的微球对大鼠心、肝和肾功能无影响，初步证明生物安全性良好。综上，采用快速膜乳化法结合复乳法制备的粒径均一的载膜融合抑制剂微球缓释效果良好，有望应用于艾滋病的长效预防中。;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 condition.This 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 μm, 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-98-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.
|靳惠娟. HIV膜融合抑制剂长效缓释微球的制备及应用研究[D]. 中国科学院大学,2020.|
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