pH对盐酸苯环壬酯鼻喷剂的质量影响及其纤毛毒性研究  

Effect of pH on quality of ciliary toxicity of phenylnonanoate hydrochloride nasal spray

作　　者：董雪 马愉蔓 李蒙 张慧 王增明 刘楠 郑爱萍 王梅[1] DONG Xue;MA Yuman;LI Meng;ZHANG Hui;WANG Zengming;LIU Nan;ZHENG Aiping;WANG Mei(College of Pharmacy,Xinjiang Medical University,Urumqi 830017,China;Beijing Institute of Pharmacology and Toxicology,Beijing 110108,China)

机构地区：[1]新疆医科大学药学院,乌鲁木齐830017 [2]军事医学研究院国家安全特需药品全国重点实验室,北京110108

出　　处：《新疆医科大学学报》2025年第1期88-94,100,共8页Journal of Xinjiang Medical University

基　　金：国家重点研发计划项目(2023YFC2706102)。

摘　　要：目的考察不同pH对盐酸苯环壬酯鼻喷剂质量的影响及其对纤毛的刺激性,为制剂pH范围制定与安全性评价提供依据。方法筛选稳定的pH调节剂,制备pH值为3.5、4.0、4.5、5.0和5.5的盐酸苯环壬酯鼻喷剂,置于高温(60±2)℃与光照(4500±500)Lx条件下,于5、10、30 d后取样观察制剂性状,通过高效液相色谱法检测苯甲醇、盐酸苯环壬酯及有关物质含量,与0 d相比评估不同pH条件下盐酸苯环壬酯鼻喷剂的稳定性。取9只牛蛙,建立离体牛蛙上鄂纤毛模型,随机分为阴性对照组(生理盐水)、鼻喷剂组(盐酸苯环壬酯鼻喷剂)、阳性对照组(1%脱氧胆酸钠),每组各3只,分别滴加0.1 mL于黏膜上,对各组纤毛运动时间进行测定,计算相对运动百分率。取18只大鼠,随机分为阴性对照组(生理盐水)、鼻喷剂组(盐酸苯环壬酯鼻喷剂)、阳性对照组(1%脱氧胆酸钠),每组各6只,分别滴注50μL于大鼠左右鼻腔,每天给药1次,连续7 d,通过苏木精-伊红染色法对各组鼻黏膜病理学变化进行考察。结果柠檬酸-柠檬酸钠作为pH调节剂用于盐酸苯环壬酯鼻喷剂的制备。盐酸苯环壬酯鼻喷剂pH为5.5时,制剂析出,可见不溶性颗粒,pH3.5、4.0、4.5、5.0样品性状无色澄明,苯甲醇与盐酸苯环壬酯含量在98%~102%之间,有关物质项下未知杂质1、未知杂质2含量小于0.3%,未见增长,未检出其他杂质。离体牛蛙纤毛毒性考察结果可知,与阴性对照组相比,鼻喷剂组相对运动百分率约为74.93%,纤毛可复摆。大鼠鼻黏膜刺激性考察结果可知,鼻喷剂组上皮细胞形态结构完整,纤毛排列整齐,与阴性对照组相比无显著性差异。结论盐酸苯环壬酯鼻喷剂pH值在3.5~5.0范围内稳定性良好,无明显纤毛毒性,是一种安全稳定的晕动病防治新剂型。Objective The effects of different pH on the quality of phencycline nonyl hydrochloride nasal spray and its irritation to cilia were investigated,which provided a basis for the formulation of pH range and safety evaluation of preparations.Methods Stable pH adjusters were screened,phencycline hydrochloride nasal sprays with pH values of 3.5,4.0,4.5,5.0 and 5.5 were prepared,placed at high temperature 60℃±2℃and light(4500±500)Lx,samples were taken after 5,10 and 30 days to observe the preparation properties,benzyl alcohol,phencycline hydrochloride and related substances were detected by high performance liquid chromatography,and the stability of phencycline hydrochloride nasal spray under different pH conditions was evaluated compared with 0 d.9 bullfrogs were randomly divided into negative control group(normal saline),nasal spray group(phencycline hydrochloride nasal spray)and positive con-trol group(1%sodium deoxycholate),with 3 bullfrogs in each group,and 0.1 mL was added dropwise to the mucosa,and the cilia motility time of each group was measured and the relative motility percentage was calculated.18 rats were randomly divided into negative control group(normal saline),nasal spray group(phencycline hydrochloride nasal spray)and positive control group(1%sodium deoxycholate),6 rats in each group,and 50μL was instilled into the left and right nasal cavities of the rats,administered once a day for 7 days,and the pathological changes of the nasal mucosa in each group were investigated by hematoxylin-eosin staining.Results Citrate-sodium citrate was used as a pH adjuster in the preparation of phencycline hydrochloride nasal spray.When the pH of phencycline hydrochloride nasal spray was 5.5,the preparation was precipitated,insoluble particles could be seen,the pH 3.5,4.0,4.5,5.0 samples were colorless and clear,the content of benzyl alcohol and phencycline hydrochloride was 98%~102%,and the content of unknown impurity 1 and unknown impurity 2 under the relevant substances was less than 0.3%,no growth was found

关 键 词：盐酸苯环壬酯 pH稳定性 鼻喷剂 纤毛毒性 

分 类 号：R943[医药卫生—药剂学]