目的: 测定定量型吸入气雾剂参比制剂和受试制剂各3批的喷雾模式和喷雾形态、递送剂量,判断参比制剂和受试制剂体外雾化形态和剂量的等效性。方法: 采用激光成像系统测定硫酸沙丁胺醇吸入气雾剂的喷雾模式和喷雾形态,以喷射角度和喷射宽度作为喷雾形态的评价参数,以椭圆比和喷射面积作为喷雾模式的评价参数,对结果进行体外群体等效性分析。结合递送剂量测定结果,判断参比制剂和受试制剂的体外等效性。结果: 参比制剂和受试制剂喷射角度几何平均值的比值分别为98.2%(3 cm)、97.1%(6 cm),喷射宽度几何平均值的比值分别为97.4%(3 cm)、98.4%(6 cm),对3 cm和6 cm处的椭圆比、喷射面积、喷射角度、喷射宽度分别进行群体等效分析,得到各参数的95%置信区间的上限值,椭圆比均为-0.02(3 cm和6 cm),喷射面积分别为-0.01(3 cm)和-0.02(6 cm),喷射角度均为-0.02(3 cm和6 cm),喷射宽度均为-0.02(3 cm和6 cm)。参比制剂和受试制剂的递送剂量相差较大,受试制剂的递送剂量均一性较好。结论: 参比制剂和受试制剂在喷雾模式和喷雾形态项目评价为等效,但递送剂量均一性经非参数检验判定为不等效。本文为仿制制剂的处方、工艺和雾化装置筛选提供依据,为仿制制剂的体外雾化形态的等效性评价提供参考,为吸入制剂的仿制药品研发和体外评价提供思路。
Objective: To determine spray pattern, plume geometry and delivered dose of the reference products and the tested products of salbutamol sulfate inhalation aerosol, and judge the atomization characteristic equivalence in vitro of the reference and test products. Methods: Spray pattern and plume geometry of salbutamol sulfate inhalation aerosol were determined by Spray VIEW. Plume geometry was evaluated with plume angle and plume width. Spray pattern was evaluated with spray area and ovality. The results were analyzed by population bioequivalence (PBE).Combined with the results of delivered dose, equivalence in vitro of the reference products and the tested products was further judged. Results: The ratios of the average of the geometric mean of plume angle of the reference and the test products were 98.2%(3 cm), 97.1%(6 cm), respectively, and the average of the geometric mean of plume width were 97.4%(3 cm) and 98.4%(6 cm), respectively. The spray area, ovality, plume angle and plume width at 3 cm and 6 cm were analyzed by PBE. The upper limits of the 95% confidence interval of ovality were -0.02(3 cm) and -0.02(6 cm), respectively. The upper limits of the 95% confidence interval of spray area were -0.01 (3 cm) and -0.02 (6 cm), respectively. The upper limits of the 95% confidence interval of plume angle were -0.02(3 cm) and-0.02(6 cm), respectively. The upper limits of the 95% confidence interval of plume width were-0.02(3 cm) and -0.02(6 cm), respectively. The delivered dose of the reference products and the test products were different, and the delivered dose of the test products was more uniform. Conclusion: The reference and the test products are equivalent in spray pattern and plume geometry, but the uniformity of delivery dose is non-equivalent by nonparametric test. It provides choices for the formulation, process and atomization device screening of generic products, offers the evaluation method of atomization characteristic in vitro, and provides ideas for the development and evaluation in vitro of generic products.
[1] 薛峰, 金方.吸入制剂在哮喘和慢性阻塞性肺疾病治疗中的作用及地位[J].世界临床药物, 2012, 33(4):245
XUE F, JIN F. Role of inhalations in asthma and chronic obstructive pulmonary disease treatment[J].World Clin Drugs, 2012, 33(4):245
[2] 翁琳琳, 唐黎明, 陈桂良.吸入给药制剂的质量控制及其安全性研究进展[J].药物分析杂志, 2013, 33(5):724
WENG LL, TANG LM, CHEN GL. The progress of the research on quality control and safety evaluation of inhalation preparations[J]. Chin J Pharm Anal, 2013, 33(5):724
[3] SUNITA L. An overview on:pharmaceutical aerosols[J].Int Res J Pharm, 2012, 3(9):68
[4] NEWMAN SP. Principles of metered-dose inhaler design[J].Respirat Care, 2005, 50(9):1177
[5] 徐景娜, 周学海, 杨敏, 等.肺部吸入制剂的研究概况[J].药物评价研究, 2019, 42(12):2305
XU JN, ZHOU XH, YANG M, et al. Research progress of pulmonary inhalations[J]. Drug Eval Res, 2019, 42(12):2305
[6] 周学海, 张成飞, 杨敏, 等.肺部吸入制剂评价方法研究进展[J].药物评价研究, 2019, 42(9):1891
ZHOU XH, ZHANG CF, YANG M, et al. Research progress of evaluation methods for pulmonary inhalation preparations[J].Drug Eval Res, 2019, 42(9):1891
[7] 王妍, 姜锦秀, 胡筱芸, 等.喷雾模式及喷雾形态用于口腔吸入及鼻用制剂的质量评价[J].药物评价研究, 2019, 42(12):2325
WANG Y, JIANG JX, HU XY, et al. Research progress of spray pattern and plume geometry for orally inhaled andnasal drug products evaluation[J].Drug Eval Res, 2019, 42(12):2325
[8] CHEN Y, YOUNG PM, MURPHY S, et al. High-speed laser image analysis of plume angles for pressurised metered dose inhalers: the effect of nozzle geometry[J]. AAPS PharmSciTech, 2017, 18(3):782
[9] KHALE A, BAJAJ A. Formulation and development of metered dose inhalations of salbutamol in solution form[J].Ind J Pharm Sci, 2012, 73(5):543
[10] 陈桂良, 侯惠民.大鼠肺部给药后血浆中沙丁胺醇浓度的LC-MS/MS测定[J].中国医药工业杂志, 2006, 37(6):411
CHEN GL, HOU HM. Determination of salbutamol in rat plasma after pulmonary administration by LC-MS/MS[J].Chin J Pharm, 2006, 37(6):411
[11] 张雪梅.左旋硫酸沙丁胺醇肺部吸入给药的制剂与药效与作用研究[D].广州:华南理工大学, 2013
ZHANG XM. The Study on Preparation and Pharmacodynamics of R-Salbutamol Sulfate for Pulmonary Inhalation[D].Guangzhou: South China University of Technology, 2013
[12] FDA. Drugdatabases: draftguidanceonbudesonide[EB/OL].(2012-09)[2021-09-13].https://www.accessdata.fda.gov/drugsatfda_docs/psg/Budesonide_Inhalation_Sus_20929_RC_09-12.pdf
[13] NEWCOMB A, FARINA DJ. Understanding the importance and effects of shakingonp MDI performance[J].J Aerosol Med Pulm, 2016, 29(3):A20
[14] GUO CN, DOUB WH. The influence of actuation parameters on in vitro testing of nasal spray products[J].J Pharm Sci, 2006, 95(9):2029
[15] LIU XF, DOUB WH, GUO CN. Evaluation of metered dose inhaler spray velocities using Phase Doppler Anemometry(PDA)[J].Int J Pharm, 2012, 423(2):235
[16] FDA. Drug databases: draft guidance on albuterol sulfate[EB/OL].(2020-03)[2021-09-13]. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_020503.pdf
[17] 臧云娜, 俞森, 杨劲.FDA对吸入制剂与纳米注射剂体外群体生物等效性研究相关指导原则[J].中国新药杂志, 2018, 27(10):1116
ZANG YN, YU S, YANG J. Related guidelines about in vitro population bioequivalence of locally acting inhaled drug products and nanoparticulate intravenous formulations in FDA[J].Chin J New Drugs, 2018, 27(10):1116
[18] 魏宁漪, 周颖, 陈翠翠, 等.硫酸沙丁胺醇吸入气雾剂递送剂量测定方法比较[J].中国新药杂志, 2018, 27(4):405
WEI NY, ZHOU Y, CHEN CC, et al. Comparison of measurement methods of delivered-doseuniformity of salbutamol sulfate inhalation aerosol[J].Chin J New Drugs, 2018, 27(4):405
[19] FDA. Drug databases: metered dose inhaler(MDI) and dry powderinhaler(DPI) drug products quality considerations[EB/OL].(2018-04-19)[2021-09-13]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/metered-dose-inhaler-mdi-and-dry-powder-inhaler-pidrug-products-quality-considerations
[20] 国家药品监督管理局药品审评中心.国内药品技术指导原则:经口吸入制剂仿制药药学和人体生物等效性研究指导原则[EB/OL].(2020-12-16)[2021-09-13]. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=086bbc1572ed7f747e169a3948edd916
Center For Drug Evaluation.Technical guiding principles of domestic drugs: guidelines for bioequivalence studies of generic oral inhalation formulations[EB/OL].(2020-12-16)[2021-09-13]. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=086bbc1572ed7f747e169a3948edd916
[21] SMYTH H, BRACE G, BARBOUR T, et al. Spray pattern analysis for metered dose inhalers: effect of actuator design[J].Pharm Res, 2006, 23(7):1591
[22] 管苹, 张成飞, 周学海, 等.吸入制剂体外群体生物等效性的研究进展[J].药物评价研究, 2019, 42(12):2309
GUAN P, ZHANG CF, ZHOU XH, et al. Research progress of in vitro population bioequivalence for inhaled drug products[J].Drug Eval Res, 2019, 42(12):2309
[23] 陈桂良, 侯惠民.以氯氟烃(CFC)和氢氟烷(HFA)为抛射剂的沙丁胺醇气雾剂的特性比较[J].药物分析杂志, 2006, 26(1):144
CHEN GL, HOU HM. Comparison of in vitro performance CFC propellant salbutamol pressurized metered - dose inhaler(s-pMDI) with HFA propellant s-pMDI[J]. Chin J Pharm Anal, 2006, 26(1):144
[24] TZOU TZ, PACHUTA RR, COY RB, et al. Drug form selection in albuterol-containing metered-dose inhaler formulations and its impact on chemical and physical stability[J]. J Pharm Sci, 1997, 86(12):1352
[25] 陈哲, 李雯燕, 倪晓凤, 等.呼吸系统吸入制剂研发现状的系统评价[J].中国药房, 2021, 32(14):1671
CHEN Z, LI WY, NI XF, et al. Research and development status quo of respiratory inhalation preparations: a systematic review[J].Chin Pharm, 2021, 32(14):1671