药学学报, 2019, 54(6): 1115-1122
引用本文:
黄平情, 高利利, 于颖超, 王奕博, 吴慧敏, 陈功森, 倪健, 曲昌海. 左卡尼汀温敏原位凝胶的制备及质量评价[J]. 药学学报, 2019, 54(6): 1115-1122.
HUANG Ping-qing, GAO Li-li, YU Ying-chao, WANG Yi-bo, WU Hui-min, CHEN Gong-sen, NI Jian, QU Chang-hai. Preparation and quality evaluation of levocarnitine thermosensitive in situ gel[J]. Acta Pharmaceutica Sinica, 2019, 54(6): 1115-1122.

左卡尼汀温敏原位凝胶的制备及质量评价
黄平情, 高利利, 于颖超, 王奕博, 吴慧敏, 陈功森, 倪健, 曲昌海
北京中医药大学中药学院, 北京 100029
摘要:
本文以左卡尼汀为模型药物,制备了一种用于治疗初发型干眼病的新型制剂-左卡尼汀温敏原位凝胶。以泊洛沙姆407和泊洛沙姆188为凝胶基质,透明质酸钠和羧甲基纤维素钠为生物黏附性材料,采用转子法测定胶凝温度,星点设计-效应面法优化处方;并对最优处方的pH值、黏度值及胶凝温度等进行测定,透析膜透过法考察制剂体外释放,裂隙灯显微镜观察制剂在兔眼表的滞留性。结果表明,原位凝胶的最优处方中,泊洛沙姆407和泊洛沙姆188用量分别为20.81%和3.46%,透明质酸钠为0.02%,羧甲基纤维素钠为0.10%;室温下pH值为6.90 ±0.06,黏度在27℃开始发生突跃,泪液稀释前后的胶凝温度分别为(26.37 ±0.06)℃和(33.57 ±0.21)℃;体外单位面积释放速率在前240 min内低于溶液剂(P<0.05),600 min时累积释放度可达80%以上;原位凝胶制剂滴眼给药后,在家兔眼表的滞留时间为25 min左右,约为溶液剂的5倍。动物实验按照国际动物实验指导原则进行并获得北京中医药大学实验动物中心伦理学委员会批准。本文所制得的左卡尼汀温敏原位凝胶性状良好,具有缓释特性并显著提高了药物在家兔眼表的滞留时间。
关键词:    左卡尼汀      原位凝胶      干眼      高渗      眼表滞留     
Preparation and quality evaluation of levocarnitine thermosensitive in situ gel
HUANG Ping-qing, GAO Li-li, YU Ying-chao, WANG Yi-bo, WU Hui-min, CHEN Gong-sen, NI Jian, QU Chang-hai
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
Abstract:
In this paper, a new type of preparation for treatment of initial dry eye disease, thermosensitive in situ gel, was prepared using levocarnitine as a model drug. Poloxamer 407 and poloxamer 188 were used as the gel matrix, and sodium hyaluronate and sodium carboxymethylcellulose were used as bioadhesive materials. Gelation temperature was determined by a rotor method and the prescription was optimized by central composite design-response surface methodology. The pH value, viscosity value and gelation temperature of the optimal prescription were measured. The release of the drug in vitro was examined by dialysis membrane permeation, and retention time of the thermosensitive in situ gel preparation on the rabbit's ocular surface was observed by a slit lamp microscope. The results showed that the dosage of the poloxamer 407 and poloxamer 188 were 20.81% and 3.46%, respectively, and sodium hyaluronate was 0.02%, sodium carboxymethyl cellulose was 0.10% of the optimal formulation of levocarnitine thermosensitive in situ gel. The pH value was 6.90 ±0.06 at room temperature and the viscosity value started to rise sharply at 27℃ of the optimal formulation. The gelation temperature of the optimal preparation before and after dilution by simulated tear fluid were (26.37 ±0.06)℃ and (33.57 ±0.21)℃, respectively. In the first 240 min, in vitro release rate per unit area of levocarnitine thermosensitive in situ gel was lower than that of solution (P<0.05), and after 600 min, the cumulative release rate of levocarnitine thermosensitive in situ gel could reach more than 80%. The retention time of the thermosensitive in situ gel preparation on rabbit's ocular surface reached about 25 min, at least 5 times as much as that of the solution. The animal experiment was conducted following the National Institutes of Health Guidelines for the use of experimental animals, and approved by the Ethics Committee of the Experimental Animal Center of Beijing University of Chinese Medicine. The levocarnitine thermosensitive in situ gel showed good characteristics and sustained release property and significantly improved the retention time of the drug on the rabbit's ocular surface.
Key words:    levocarnitine    in situ gel    dry eye disease    hyperosmosis    ocular surface retention   
收稿日期: 2019-01-08
DOI: 10.16438/j.0513-4870.2019-0024
基金项目: 北京市科技计划十病十药专项资助项目(Z171100001717027).
通讯作者: 倪健, 曲昌海
Email: njtcm@263.net;quchanghai@bucm.edu.cn
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