冯双双,钞艳惠,何海冰,唐星
FENG Shuang-shuang,CHAO Yan-hui,HE Hai-bing,TANG Xing

• 1:沈阳药科大学药学院

摘要(Abstract)：

目的以聚乙二醇-聚己内酯(polyethylene glycol-b-poly caprolactone,m PEG-b-PCL)为聚合物,硬脂酸单双甘油酯(geleol mono and diglycerides Nf,GMD)为固体脂质,制备拉洛他赛共聚物脂质杂合纳米粒(larotaxel-solid lipid core-contained polymeric nanoparticles,LTX-cSLNs)并评价其性能。方法采用透析法制备LTX-cSLNs,以粒径、多分散系数(polydispersity index,PDI)、载药量(drug loading content,wDL)和包封率(entrapment efficiency,wEE)为评价指标,采用单一因素法筛选最优处方工艺。采用高效液相色谱法测定LTX-cSLNs的wDL和wEE,激光散射粒度测定仪测定粒径和电位,采用透射电镜观察形态,采用差示扫描量热法测定GMD在纳米粒内核的存在形式。同时以不含GMD的纳米粒(larotaxel-solid lipid core-uncontained polymeric nanoparticles,LTX-u SLNs)作为对照,比较两种制剂在临界聚集质量浓度(critical aggregation concentration,ρCAC)以及体内外性能的差异。结果 LTXcSLNs帯有脂质内核,平均粒径为56.8 nm,zeta电位为-13.56 m V,wDL为12.9%,wEE为81.46%,ρCAC为0.126 mg·L~(-1)。LTX-cSLNs能够延缓累积释放量达12%,药时曲线下面积(AUC0-t)提高近16.7%。结论 LTX-cSLNs具有高载药量、高稳定性以及良好的体内外性能。
Objective In this study,polymeric nanoparticles with lipid cores were developed for intravenous administration of larotaxel(LTX) using polyethylene glycol-b-poly caprolactone(m PEG-b-PCL) and geleol mono and diglycerides Nf(GMD) as building blocks.Methods LTX-solid lipid corecontained nanoparticles(LTX-c SLNs) were prepared via dialysis method with GMD incorporated physically in the cores.The formulation was further optimized by the single factor test with particle size,drug loading content(wDL) and entrapment efficiency(wEE) as indexes.The prepared nanoparticles were characterized by using highperformance liquid chromatography(HPLC),dynamic light scattering(DLS) and transmission electron microscopy(TEM).Critical aggregation concentration(ρCAC) was determined withpyrene fluorescence probe.The physicalstate of GMD in the nanoparticle core wasdetermined by differential scanning calorimetry(DSC).In this study,nanoparticles(u SLNs) without solid-lipid core were also prepared by the same method and used as control.The in vitro drug release profiles and in vivo pharmacokinetics of LTX-u SLNs and LTXc SLNs were also evaluated and compared.Results The optimized formulation was composed of 20 mg of m PEG-b-PCL,2 mg of GMD and 4 mg of LTX and was prepared at 60 ℃ with addition of water at the speed of 0.1 m L·min- 1and stirring speed of 400 r·min- 1.DSC study revealed that GMD existed in solid state when blended with PCL homopolymer.TEMshowed that c SLNs were spherical in shape with lipid core embedded in the nanoparticles.The wDLand wEEof the optimal formulation was 12.9% and 81.46%,respectively.The mean particles size and zeta potential of LTX-c SLNs was 56.8 nm and- 13.56 m V,respectively.Critical aggregation concentration(ρCAC) of c SLNs was 1.26 × 10- 4g·L~(-1).LTX-c SLNs showed a sustained release profile during the period of 168 h release study and the release rate was found 12% slower than that of the LTX-u SLNs.In addition,the area under the plasma drug concentration-time curve(AUC0-t) of LTX-c SLNs was 16.7% larger than that of LTX-u SLNs.Conclusions The incorporation of GMD into nanoparticles could improve the performance of LTX nanoparticles with respect to in vitro drug release and in vivo pharmacokinetic profile.

关键词(KeyWords)： 聚乙二醇-聚己内酯;硬脂酸单双甘油酯;共聚物脂质杂合纳米粒;体外释放;药时曲线下面积;拉洛他赛
polyethylene glycol-b-poly caprolactone;geleol mono and diglycerides Nf;solid lipid-contained nanoparticles;in vitro release;area under the curve;larotaxel

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 冯双双,钞艳惠,何海冰,唐星
FENG Shuang-shuang,CHAO Yan-hui,HE Hai-bing,TANG Xing

DOI: 10.14066/j.cnki.cn21-1349/r.2017.01.003

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