野黄芩苷内水相增稠多囊脂质体的制备及其稳定性的初步考察

Preparation and Preliminary Stability of Scutellarin Internal Phase Thickened Multivesicular Liposomes

多囊脂质体结构中具有许多非同心的、由类脂及磷脂双分子层分割成的水性囊泡,作为药物载体具有良好的缓释作用,但在制备、贮存及用药过程中易发生内部囊泡破裂、聚合,药物渗漏等现象,对其体内外过程造成不利影响。本试验以野黄芩苷为模型药物,采用复乳法制备多囊脂质体,内水相中加入羟丙甲纤维素(HPMC)以增加内水相黏度,减弱内水相流动性,增强内部囊泡机械强度,避免囊泡破裂、聚合,减少药物渗漏。以包封率为指标,采用单因素及正交试验优化工艺和处方。结果表明,乳化时间8 min、氮气流速6 L/min,HPMC在内水相中的浓度为0.2%,大豆磷脂、胆固醇、三油酸甘油酯和十八胺在油相中的浓度分别为1.5%、1%、0.7%和0.45%,聚乙烯醇及葡萄糖在外水相中的浓度为0.5%和3%。比较了野黄芩苷普通多囊脂质体(内水相不含HPMC)及内水相增稠多囊脂质体在室温下放置30 d期间的包封率及粒子形态变化情况,初步评价本品的稳定性。结果显示,与野黄芩苷普通多囊脂质体相比,本品在试验期间形态光滑圆整,未见磷脂碎片,包封率改变不明显。并且,与普通多囊脂质体相比,野黄芩苷内水相增稠多囊脂质体在含3%葡萄糖的pH 6.8磷酸盐缓冲液中的释药速率明显减慢。

Multivesicular liposomes（MVL）, an effective sustained-delivery system, consist of numerous nonconcentric closely-packed internal aqueous chambers separated by lipid bilayer. However, the physical and chemical instabilities（leakage of the encapsulated drug, vesicle aggregation and hydrolysis of phospholipids） of multivesicular liposomes are major problems during the preparation, storage and usage due to their aqueous state. In this study, scutellarin was selected as a model drug and scutellarin internal phase thickened multivesicular liposomes（SITMVLs）were prepared by double emulsion method. In this formulation, hydroxypropyl methyl cellulose（HPMC） was encapsulated into its internal aqueous chambers as a thickener, which was supposed to reduce the fluidity of the interior aqueous phase and enhance mechanical strength of internal chambers, thereby avoiding repture/aggregation of internal aqueous chambers. The process and formulation were optimized by single factor test and orthogonal experiment with encapsulation efficiency as the index. The results showed that the encapsulation efficiency was the highest when the first emulsifying time was 8 min and the nitrogen flow rate was 6 L/min. The optimal formulation was as follows： the HPMC concentration in the internal aqueous phase was 0.2%; the concentrations of soy lecithin, cholesterol, triolein, octadecyl amine in oil phase were 1.5%, 1%, 0.7% and 0.45%, respectively; the concentrations of polyvinyl alcohol and glucose in the external water phase was 0.5% and 3%, respectively. The encapsulation efficiency and particle size of SITMVLs and the common scutellarin multivesicular liposomes（SMLVs） which had no HPMC in the internal aqueous chamber were compared to evaluate the preliminary stability of SITMVLs. The results showed that the shapes of SITMVLs were smooth and spherical during the storage at room temperature for 30 d, and no debris was observed in the light micrographs. Moreover, the changes of encapsulation efficiency for SITMVLs was also unobvious. Finally, the drug release from SITMVLs was significantly slower than that of SMLVs in pH 6.8 phosphate buffer containing 3% glucose.