鼻黏膜给药装置中5种抗氧剂提取方法的建立及其在鼻喷流感减毒活疫苗中的迁移

Development of methods for extraction of five kinds of antioxidants in nasal mucosal drug delivery device and migration of antioxidants in live attenuated influenza vaccines for nasal spraying

目的通过5种抗氧剂提取和迁移试验,分析鼻喷流感减毒活疫苗与鼻黏膜给药装置之间的相容性,以保证药品的安全性和有效性。方法采用高效液相色谱法(high performance liquid chromatography,HPLC)考察5种抗氧剂(3114、1010、330、1076、168)在鼻黏膜给药装置胶塞和鼻喷装置中的含量,以及在鼻喷流感减毒活疫苗中的迁移量。依据添加剂的人每日允许摄入量(permitted daily exposure,PDE),评估鼻喷流感减毒活疫苗中5种抗氧剂是否存在安全性风险。并对5种抗氧剂的提取方法进行专属性、检测限及定量限、线性及范围、重复性和准确性验证。结果胶塞中检出抗氧剂3114和1076,未检出其他3种抗氧剂;鼻喷装置中检出抗氧剂3114、1010和1076,未检出其他2种抗氧剂,符合《欧洲药典》对5种抗氧剂的限度要求。3批鼻喷流感减毒活疫苗在加速[(25±2)℃放置0、5、10 d]和长期稳定性(2~8℃放置3、6个月)试验条件下,均未检出5种抗氧剂。每日摄入量低于PDE值,方法灵敏度满足分析评价阈值(analysis and evaluation threshold,AET)的测定要求,对患者的安全性风险较小。5种抗氧剂的提取方法专属性、线性、重复性良好,准确性较高。结论鼻喷流感减毒活疫苗与鼻黏膜给药装置相容性良好。

Objective To analyze the compatibility between live attenuated influenza vaccine for nasal spraying and nasal mucosal drug delivery device by the extraction and migration tests on five kinds of antioxidants so as to ensure the safety and effectiveness of the drug.Methods High performance liquid chromatography(HPLC)was used to investigate the contents of five antioxidants(3114,1010,330,1076 and 168)in the rubber stopper of nasal mucosal drug delivery device and the nasal spray device,as well as the migration amount in live attenuated influenza vaccine for nasal spraying.Based on the permitted daily exposure(PDE)of additives,the safety risks of the five antioxidants in live attenuated influenza vaccine for nasal spraying were evaluated.The extraction methods for five antioxidants were verified for specificity,limit of detection(LOD),limit of quantitation(LOQ),linear range,reproducibility and accuracy.Results Antioxidants 3114 and 1076 were detected in the rubber stoppers,while no the other three antioxidants were detected;however,antioxidants 3114,1010 and 1076 were detected in the nasal spray device,while no the other two antioxidants were detected,which met the limit requirements for five antioxidants in the European Pharmacopoeia.In accelerated[storage at(25±2)℃for 0,5 and 10 d]and long-term(storage at 2~8℃for 3 and 6 months)stability tests,no any of the five kinds of antioxidants were detected in three batches of live attenuated influenza vaccine for nasal spraying.The daily intakes of the antioxidants were less than the PDE,indicating that the sensitivities of developed methods met the requirements for analysis and evaluation threshold(AET),and also indicating low safety risks of the antioxidants.The extraction methods for five antioxidants showed good specificity,linearity,reproducibility and accuracy.Conclusion Live attenuated influenza vaccine for nasal spraying is compatible with the nasal mucosal drug delivery device.