Page 70 - 《中国药房》2021年3期

川芎嗪眼用脂质体温敏凝胶的制备及体内外特性评价 Δ

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李 维 ，陈 梁 ，尹 丹 ，杨 昊 ，周佳仪 ，宋 雨 ，张 艳 ，邹 亮 （1.成都大学基础医学院，成都
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610106；2.成都中医药大学药学院，成都 611137；3.成都大学药学院，成都 610052；4.成都大学国家农业农村
部杂粮加工重点实验室，成都 610106）
中图分类号 R943；R285.5 文献标志码 A 文章编号 1001-0408（2021）03-0320-08
DOI 10.6039/j.issn.1001-0408.2021.03.12
摘 要 目的：制备川芎嗪眼用脂质体温敏凝胶，考察其体内外特性。方法：采用硫酸铵梯度法制备川芎嗪脂质体，以正交试验优
化制备工艺，并以泊洛沙姆P407为凝胶基质进一步制成温敏凝胶。采用无膜溶出模型对该凝胶的溶蚀性和体外释药特性进行研
究；采用改良Franz扩散池考察其角膜透过性，并进一步测定角膜水化值；采用MTT法评价该凝胶对人角膜上皮细胞HCE-T增殖
的影响；采用苏木素-伊红染色法和Draize眼部刺激评分考察该凝胶对家兔角膜的刺激性，并观察其眼部组织学变化。结果：川芎
嗪脂质体的最优制备工艺为药脂比1∶10（m/m）、硫酸铵溶液浓度0.2 mol/L、磷脂与胆固醇质量比4∶1、孵育温度45 ℃；再以23％质
量分数的泊洛沙姆P407作为凝胶基质制得川芎嗪眼用脂质体温敏凝胶。该凝胶具有良好的胶凝温度；其溶蚀和体外释药均呈零
级动力学特征，且体外释药主要与溶蚀相关（R ＝0.993 4）。该凝胶6 h内累计透过量为43.3％；角膜水化值为72.98％。低、中质量
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浓度（1、5 mg/L）的川芎嗪眼用脂质体温敏凝胶对HCE-T细胞无明显增殖毒性，但其在高质量浓度（10 mg/L）时显示出一定的细胞
毒性。该凝胶对家兔角膜的Draize眼部刺激平均评分属于无刺激范围，且家兔角膜组织学未见异常变化。结论：所制备的川芎嗪
眼用脂质体温敏凝胶具有适宜的胶凝温度，对角膜渗透性好、刺激性小。
关键词 川芎嗪眼用脂质体；温敏凝胶；制备工艺；体外释药特性；人角膜上皮细胞HCE-T；眼部刺激性；角膜组织学

Preparation and in vivo and in vitro Characteristic Evaluation of Ligustrazine Ophthalmic Liposome
Thermosensitive Gel
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LI Wei ，CHEN Liang ，YIN Dan ，YANG Hao ，ZHOU Jiayi ，SONG Yu ，ZHANG Yan ，ZOU Liang（1. Basic
Medical School，Chengdu University，Chengdu 610106，China；2. College of Pharmacy，Chengdu University of
TCM，Chengdu 611137，China；3. College of Pharmacy ，Chengdu University，Chengdu 610052，China；4. Key
Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs，Chengdu University，
Chengdu 610106，China）
ABSTRACT OBJECTIVE：To prepare Liguatrazine opthalmic liposome thermosensitive gel，and to investigate its in vivo and in
vitro characteristics. METHODS：The ammonium sulfate gradient method was used to prepare Liguatrazine liposomes. The
preparation technology was optimized by using orthogonal test. Using poloxamer P407 as gel matrix，Liguatrazine liposomes were
prepared into thermosensitive gel. A membraneless model was used to study the dissolution and in vitro drug release of the gel. The
modified Franz diffusion cell was used to investigate corneal permeability and further determine corneal hydration value. The effects
of the gel on the proliferation of human corneal epithelial cell HCE-T. HE staining and Draize test were used to investigate the
stimulatory effects of the gel on corneal cells of the rabbit，and the histological changes of the eyes were observed. RESULTS：The
optimal preparation technology of Liguatrazine liposome was drug-lipid ratio of 1 ∶ 10（m/m），the ammonium sulfate concentration
of 0.2 mol/L，phospholipid-cholesterol ratio of 4 ∶ 1（m/m），incubation temperature of 45 ℃. Then ligustrazine opthalmic liposome
thermosensitive gel was prepared with 23％ poloxamer P407 as gel matrix. The gel had good gelatinization temperature. The in
vitro drug release and dissolution showed zero-order kinetic characteristics，and in vitro drug release of the gel was mainly related
to dissolution（R ＝0.993 4）. The cumulative transcorneal permeability of the gel was 43.3％ within 6 hours and corneal hydration
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value was 72.98％. Low and medium concentrations（1，5 mg/L）of Ligustrazine opthalmic liposome thermosensitive gel had no
obvious proliferation toxicity to HCE-T cells，but it showed cytotoxicity at high concentration（10 mg/L）. The mean Draize eye
Δ 基金项目：四川省科技计划项目（No.2019YJ0661）；四川省科技 irritation score of the gel on rabbit cornea was within
创 新 苗 子 工 程 资 助 项 目（No.2019061）；成 都 市 医 学 科 研 课 题 non-stimulation，and there was no abnormal change in rabbit
（No.2018001） corneal histology. CONCLUSIONS： Prepared Ligustrazine
＊助教，硕士。研究方向：新型药物递送系统及其质量评价技 opthalmic liposome thermosensitive gel has a suitable phase
术。电话：028-84814286。E-mail：liweivirlee@163.com transition temperature，good corneal permeability，and low
# 通信作者：教授，博士。研究方向：中药新制剂、新剂型、新技 corneal irritation.
术。电话：028-84616061。E-mail：zouliangcdu@126.com

·320 · China Pharmacy 2021 Vol. 32 No. 3 中国药房 2021年第32卷第3期