盐酸去甲万古霉素-PNIPAAm-PEO纳米粒在兔眼内的毒理学和药代动力学研究  

Pharmacokinetics characterization and toxicology of PNIPAAm-PEO nanoparticles loaded norvancomycin in rabbit eyes

作　　者：王丽曌 陈翔[2] 王雨生[2] 陈晓农[3] 王庆伟[4] 

机构地区：[1]西安爱尔古城眼科医院 [2]第四军医大学西京医院眼科全军眼科研究所,西安710032 [3]北京化工大学材料科学与工程学院,100029 [4]第四军医大学唐都医院药剂科,西安710032

出　　处：《中华实验眼科杂志》2014年第3期200-205,共6页Chinese Journal Of Experimental Ophthalmology

基　　金：全军医药卫生科研项目（06M261）;陕西省自然科学基金项目（2004C246）;本研究获得德国洪堡基金会（Alexander yon Humboldt Foundation）仪器设备捐赠（V-8151/02085）资助志谢本研究获得德国洪堡基金会（Alexanderyon Humboldt Foundation）仪器设备捐赠（V.815I/02085）资助;本实验所用NV原药由华北制药集团新药研究开发有限责任公司惠赠,特此感谢

摘　　要：背景 传统给药方法治疗眼内炎症时,药物难以透过血-视网膜屏障而达到有效的治疗浓度,局部药物缓释系统可以减少用药剂量并降低药物的毒性作用,构建载药药物缓释系统对眼内感染性疾病的治疗具有重要意义. 目的 评价多聚体材料聚N-异丙基丙烯酰胺-聚氧化乙烯（PNIPAAm-PEO）构建的盐酸去甲万古霉素-PNIPAAm-PEO（NV-PNIPAAm-PEO）纳米粒在兔眼玻璃体腔内注射给药后的眼部毒理学和眼内药代动力学特征,为眼后节给药治疗感染性眼病提供依据. 方法 NV-PNIPAArn-PEO纳米粒平均载药量约为质量分数22％,用无菌生理盐水配成质量浓度为20 g/L的凝胶液.新西兰白兔41只采用随机数字表法分为实验组31只和对照组10只,将20 g/L NV-PNIPAAm-PEO凝胶液0.1 ml注射入实验组兔的一侧眼玻璃体腔内,对照组注入等容量的生理盐水.分别于给药后的第1、2、3、7、14、21和28天进行眼前后节裂隙灯显微镜和B型超声检查,记录实验眼的视网膜电图（ERG）反应,对角膜、虹膜、玻璃体和视网膜组织行组织病理学检查,以评价NV-PNIPAAm-PEO对眼部组织结构和功能的影响.将兔眼角膜和视网膜脉络膜制备组织匀浆,收集兔房水、玻璃体和血浆样本,用高效液相色谱分析（HPLC）法检测上述各组织中的药物质量浓度.结果 NV-PNIPAAm-PEO玻璃体腔内注射后1～28 d,裂隙灯显微镜下可见眼前后节组织正常,B型超声检查未见异常；最大混合ERG b波振幅、a波振幅和峰潜时在两组间的差异均无统计学意义（P＞0.05）.视网膜组织病理学检查表明,两组兔玻璃体腔内注射后视网膜结构均正常.HPLC法分析表明,注射后1～28d,兔眼角膜组织中药物质量分数均低于检测水平下限,血浆药物质量浓度最高为（0.34±0.11） mg/L,房水药物质量浓度为（0.08±0.04）～（2.16±0.07） mg/L,视网膜脉络膜中药物质量分数为（0.11±0.02）～（2.54±0.38）μg/Background The penetration of bacterial agents into the vitreous cavity is difficult because of the existence of blood-retina barrier.So conventional drug therapy is not enough effective on endophthalmitis.Drug delivery systems can decrease drug dose and reduce the drug toxicity.To construct nano controlled-release system of anti-bacterial agents is very important for the treatment of intraocular infectious diseases.Objective This study was to investigate the toxicology and intraocular pharmacoklnetics of intravitreal PNIPAAm-PEO loaded norvancomycin nanoparticles （NV-PNIPAAm-PEO） in normal rabbit eyes.Methods NV-PNIPAAm-PEO was constructed with the drug-loading rate about 22％,and then the drug gelatin solution （20 g/L） was prepared using normal saline solution.Forty-one New Zealand albino rabbits were randomized divided into experimental group and control group.20 g/L drug gelatin solution 0.1 ml was monocularly injected into the vitreous cavity in the experimental group,and the equal volume of sterilized normal saline solution was used in the control group.In 1 day,2,3,7,14,21 and 28 days after injection,ocular anterior and posterior segments were examined by slit lamp microscope and Bsonography,and electroretinogram （ERG） was recorded and the histopathological examination was performed to evaluate the biotoxicity of the drug.Norvancomycin contents in the cornea homogenate,aqueous humor,vitreous,retinochoroid homogenate were detected by high performance liquid chromatography （HPLC） system.Results The anterior and posterior segments were normal by the slit lamp microscope and B-sonography 1-28 days after injection of NV-PNIPAAm-PEO.In 7,14,21 and 28 days after injection,there were no statistically significant difference in the a-wave latency and amplitude of max-ERG between the two groups,as well as the b-wave amplitude（P＞0.05）.The histopathological examination showed that the retinal structure was normal in both groups.HPLC assay showed that the norvancomycin level was gradually declined

关 键 词：眼 抗生素 药代动力学 盐酸去甲万古霉素 眼内炎 药物治疗 注射 玻璃体内 聚N-异丙基丙烯酰胺-聚氧化乙烯 纳米微粒 色谱法 高效液相 革兰阳性细菌 毒理学 兔 

分 类 号：R965[医药卫生—药理学]