光敏性多西他赛脂质体的制备、处方优化和体外释放度研究

Preparation,prescription optimization and in vitro release of photosensitive docetaxel liposome

目的:以富勒烯丙二酸衍生物(DMA-C60)-多西他赛为模型药物,构建光敏性脂质体,增强抗肿瘤效果。系统研究脂质体(LP)的制备工艺、理化性质、处方优化和体外释放特性。方法:采用Bingle环加成反应和酯水解反应合成了DMA-C60,采用傅立叶变换红外光谱(FT-IR)对产物表征定性;采用薄膜法制备DMA-C60-DTX脂质体;超滤离心法测量DTX包封率和载药量;采用激光纳米粒度测定仪测定粒径、粒径分布和Zeta电位;透射电镜测定脂质体外观形态;利用差示扫描量热法(DSC)考察LP中原料药DTX及脂质材料的晶形存在状态;采用透析袋法测量体外释放度并拟合释放模型。结果:采用FTIR表征定性DMA-C60合成成功。最优处方得到的DMA-C60-DTX-LP,平均粒径约为170 nm,Zeta电位约为-30 mV,DTX包封率(85.76±2.60)%,DMA-C60包封率约为89%;透射电镜观察DMA-C60-DTX-LP呈类球形,粒径大小约为170 nm,分布均匀且与所测粒径大小相符;DSC显示DTX原料药几乎以无定型的状态存在于脂质内核中;DMA-C60的加入并不影响DTX的释放,60 h内累计释放百分数为80%,DTX在LP中体外释放行为可用Ritger-Peppas释放动力学方程进行描述。结论:光敏性多西他赛脂质体载药量和包封率较高、脂质体外观呈类球形,粒径较小且分布均匀,体外释放具有一定的缓释作用。

OBJECTIVE To explore the formulation of fullerene malonic acid derivative-docetaxel combined photosensitive liposome(DMA-C60-DTX-LP)and assess its physicochemical properties,formulation optimization and in vitro release characteristics.METHODS Diadduct malonic acid fullerene derivatives(DMA-C60)was synthesized by Bingle cycloaddition reaction and ester hydrolysis reaction and Fourier transform infrared spectroscopy(FT-IR)utilized for phenotypic identification.DMA-C60-DTX-LP was constructed by thin-film dispersion.DTX entrapment efficiency and drug loading were measured by ultrafiltration.Particle size,particle size distribution and Zeta potential were measured by laser nanometry;transmission electron microscope for observing the appearance of lipostomas.Differential scanning calorimetry(DSC)was utilized for evaluating crystal form of original drug DTX in LP.And in vitro release behaviors of DMA-C60-DTX-LP were examined by dialysis bag method.RESULTS The particle size of DMA-C60-DTX-LP was approximately 170 nm through optimal formulation and its Zeta potential around-30 mV measured by a laser nanoparticle meter.Encapsulation rates of DTX and DMA-C60 were(85.76±2.60)%and 89%;DMA-C60-DTX-LP was a uniform quasi-spherical particle with a particle size of 170 nm.DTX bulk drug was almost completely amorphous in lipid core detected by DSC,release of DTX unaffected by an addition of DMA-C60 and a cumulative release percentage of 80%within 60h.Also Ritger-Peppas release kinetic equation was utilized for examining in vitro release behavior of DTX.CONCLUSION DMA-C60-DTX-LP offers a high drug loading and encapsulation efficiency.With a spherical particle size with a uniform distribution,its in vitro release shows some slow-release effect.