Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Eur J Pharm Sci. 2017 Nov 15;109:638-649. doi: 10.1016/j.ejps.2017.09.022. Epub 2017 Sep 14.
The purpose of the study was to develop a parenteral docetaxel lipid microsphere to inhibit its 7-epidocetaxel conversion in vitro and in vivo. 7-epidocetaxel conversion as the main indicator was investigated to optimize the formulation and process. 10% medium-chain triglyceride/long-chain triglyceride (3:1) as the oil phase, egg lecithin E80 as the emulsifier and 0.02% NaHSO as the acidity regulator were selected to prepare docetaxel lipid microsphere. This study found that pH and temperature were dominant factors on the epimerization of docetaxel in lipid microsphere, and that optimum conditions were a pH of 5.3 and thermal sterilization conditions of 121°Cautoclaving for 8min. According to the degradation kinetics, docetaxel lipid microsphere had a wider pH range where 7-epidocetaxel(%) stayed at low levels than Docetaxel for Injection, and might improve the docetaxel stability by loading drug in lecithin layer instead of altering the degradation mechanism. Docetaxel lipid microsphere decreased epimerization in plasma in vitro obviously. Pharmacokinetics of docetaxel and 7-epidocetaxel were investigated to quantify the 7-epidocetaxel conversion in vivo. The resulrs indicated that there was less conversion of docetaxel in lipid microspheres than in Docetaxel for Injection. The convert ratios were 0.61% and 3.04% respectively. In conclusion, lipid microsphere is a promising delivery system for intravenous administration of docetaxel with decreased 7-epidocetaxel conversion.
本研究旨在开发一种紫杉醇脂质微球，以抑制其在体内外的 7-表紫杉醇转化。以 7-表紫杉醇转化率为主要指标，优化处方和工艺。选择 10%中链甘油三酯/长链甘油三酯（3:1）为油相，卵磷酯 E80 为乳化剂，0.02%NaHSO4 为酸度调节剂，制备紫杉醇脂质微球。本研究发现，pH 值和温度是影响脂质微球中紫杉醇差向异构化的主要因素，最佳条件为 pH 值 5.3 和 121°C 热压灭菌 8min。根据降解动力学，紫杉醇脂质微球在较低水平保持 7-表紫杉醇（%）的 pH 值范围较宽，与注射用紫杉醇相比，可能通过将药物载入磷脂层而不是改变降解机制来提高紫杉醇的稳定性。紫杉醇脂质微球明显减少了体外血浆中的差向异构化。研究了紫杉醇和 7-表紫杉醇的药代动力学，以定量测定体内 7-表紫杉醇的转化率。结果表明，脂质微球中紫杉醇的转化率低于注射用紫杉醇。转化率分别为 0.61%和 3.04%。结论：脂质微球是一种有前途的紫杉醇静脉给药传递系统，可降低 7-表紫杉醇的转化率。
