使用 HFA134a 或 HFA152a 推进剂作为 pMDI 吸入给药后福莫特罗、甘草酸苷和二丙酸倍氯米松的药代动力学特征比较:Sprague-Dawley 大鼠模型药物暴露的临床前评估。

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Alessandro Fioni, Giandomenico Brogin, Paola Puccini, Andrew Dennis Allen, Daniela Miglietta, Erika Cuoghi, Enrico Zambelli, Loredana Battipaglia
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引用次数: 0

摘要

背景:一些地区批准了福莫特罗、甘草酸苷和二丙酸倍氯米松的固定组合作为加压计量吸入器(pMDI)制剂,用于治疗哮喘和慢性阻塞性肺病。目前的 pMDI 使用氢氟烷烃(HFA)作为推进剂,如 1,1,1,2-四氟乙烷(HFA134a),其全球变暖潜能值(GWP)较高,但为减少对气候的影响,其使用量正在逐步降低。要减少 pMDI 产品的碳足迹,同时保留 pMDIs 作为一种治疗选择,一种方法是使用低全球升温潜能值推进剂(如 1,1-二氟乙烷 (HFA152a))重新配制当前的 pMDIs。然而,在重新配制 pMDI 时需要考虑制药、临床和监管方面的挑战。我们对啮齿动物进行了非临床研究,以支持配方工作并优化人体生物等效性研究的设计。研究方法使用吸入塔给 Sprague-Dawley 大鼠吸入福莫特罗、甘草酸苷和二丙酸倍氯米松(BDP)的固定组合 pMDI 以及两种推进剂 HFA134a 或 HFA152a,以评估推进剂对活性成分 PK 曲线的影响。给药后,对每只大鼠进行连续血样采集,并通过 HPLC-MS/MS 对等分血浆进行分析。结果显示大鼠吸入固定三合一 pMDI 后,福莫特罗、甘草酸苷和 BDP 与两种推进剂的 PK 曲线相似。对三种活性成分的暴露参数 Cmax 和 AUClast 进行了比较,结果表明两个治疗组之间的全身暴露量没有显著的统计学差异。代谢物 17-monopropionate 倍氯米松的动物间变异性较高,这可能是由于代谢物生成的个体差异造成的。结论:考虑到这些数据,可以得出结论:在新开发的制剂中用 HFA152a 取代推进剂 HFA134a 对大鼠使用吸入塔吸入福莫特罗、甘草酸苷和 BDP 后的血浆 PK 曲线没有显著影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Comparison of Formoterol, Glycopyrrolate, and Beclomethasone Dipropionate Pharmacokinetic Profile after Inhaled Administration as pMDI Using HFA134a or HFA152a Propellant: Preclinical Assessment of Drug Exposure in Sprague-Dawley Rat Model.

Background: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate is approved in some geographic areas as pressurized metered dose inhaler (pMDI) formulation for the treatment of asthma and chronic obstructive pulmonary disease. Current pMDIs use hydrofluoroalkanes (HFAs) as a propellant, such as 1,1,1,2-tetrafluoroethane (HFA134a), that have a high global warming potential (GWP), but their use is being progressively lowered to reduce impact on climate. One option to reduce the carbon footprint of the pMDI products while preserving pMDIs as a therapeutic option is reformulating the current pMDIs using low GWP propellants, such as 1,1-difluoroethane (HFA152a). Nevertheless, pharmaceutical, clinical, and regulatory challenges need to be considered when reformulating a pMDI. A nonclinical study in rodents has been performed to support the formulation work and optimize the design of the bioequivalence study in humans. Methods: A fixed combination of formoterol, glycopyrrolate, and beclomethasone dipropionate (BDP) as pMDI with the two propellants HFA134a or HFA152a was administered by inhalation to Sprague-Dawley rats, using inhalation tower, to assess the impact of the propellant on the PK profile of the active components. After administration, serial blood samples were taken from each rat, and plasma aliquots were analyzed by HPLC-MS/MS. Results: Inhalation administration to rats of the fixed triple combination as pMDI showed similar PK profile for formoterol, glycopyrrolate, and BDP with the two propellants. Exposure parameters Cmax and AUClast of the three active ingredients were compared, showing no statistically significant differences in the systemic exposure between the two treatment groups. Higher interanimal variability was observed for the metabolite beclomethasone 17-monopropionate, likely due to individual differences in the metabolite generation. Conclusions: Considering these data, it was possible to conclude that replacing propellant HFA134a with HFA152a in a newly developed formulation had no significant impact on the plasmatic PK profile of formoterol, glycopyrrolate, and BDP in rats after inhalation administration using inhalation towers.

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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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