Validation of a General In Vitro Approach for Prediction of Total Lung Deposition in Healthy Adults for Pharmaceutical Inhalation Products
Validation of a General In Vitro Approach for Prediction of Total Lung Deposition in Healthy Adults for Pharmaceutical Inhalation Products
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DOI：
10.1089/jamp.2012.0986
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发表时间：
2013-12-01
影响因子：
3.4
通讯作者：
Svensson, Marten
中科院分区：
文献类型：
--
作者：
Olsson, Bo;Borgstrom, Lars;Svensson, Marten
背景：尽管许多人尝试关联体外和体内结果，但仍缺乏根据体外数据预测吸入药物肺部沉积的有效方法。通过使用类似体内的体外设置并在体外和体内分析同一批的吸入器，我们希望创造一种可以同时分析体外和体内结果信息的情况。方法：对九种含有布地奈德或 AZD4818 的吸入产品进行了评估。其中包括两个加压计量吸入器 (pMDI)、一个 pMDI 加一个储雾器、四个干粉吸入器和两个剂量雾化器。在体外，由解剖学上正确的入口喉部组成的类似体内的装置连接到一个流动系统，该系统可以重放通过喉部到过滤器或冲击器的实际吸入流量曲线。在体内，通过药代动力学方法测量健康成人的肺总沉积量。结果和结论：我们可以证明，在真实递送条件下，在真实喉咙模型中逃逸过滤的药物量可以预测在没有显着呼气质量的情况下受过训练的健康成人受试者的典型肺总沉积量。我们可以进一步证明，通过使用代表与典型情况的实际偏差的喉部模型和流量剖面的组合，铸前沉积的变化反映了受试者之间肺沉积的变化。此外，我们还证明，通过简单的过滤器或通过使用混合入口以固定流速操作的级联冲击器收集的铸造前沉积物，以适应通过吸入器的可变流量分布，同样可以很好地预测肺部沉积剂量。此外，通过该方法测量的铸造前粒度分布可能与通过计算模型预测呼气分数和区域肺沉积相关。
Background: A validated method to predict lung deposition for inhaled medication from in vitro data is lacking in spite of many attempts to correlate in vitro and in vivo outcomes. By using an in vivo-like in vitro setup and analyzing inhalers from the same batches, both in vitro and in vivo, we wanted to create a situation where information from the in vitro and in vivo outcomes could be analyzed at the same time.Method: Nine inhalation products containing either budesonide or AZD4818 were evaluated. These comprised two pressurized metered dose inhalers (pMDIs), a pMDI plus a spacer, four dry powder inhalers, and two dosimetric nebulizers. In vitro, an in vivo-like setup consisting of anatomically correct inlet throats were linked to a flow system that could replay actual inhalation flow profiles through the throat to a filter or to an impactor. In vivo, total lung deposition was measured in healthy adults by pharmacokinetic methods.Results and Conclusion: We could show that the amount of drug escaping filtration in a realistic throat model under realistic delivery conditions predicts the typical total lung deposition in trained healthy adult subjects in the absence of significant exhaled mass. We could further show that by using combinations of throat models and flow profiles that represent realistic deviations from the typical case, variations in ex-cast deposition reflect between-subject variation in lung deposition. Further, we have demonstrated that ex-cast deposition collected either by a simple filter or by a cascade impactor operated at a fixed flow rate using a mixing inlet, to accommodate a variable flow profile through the inhaler, predicts equally well the lung deposited dose. Additionally, the ex-cast particle size distribution measured by this method may be relevant for predicting exhaled fraction and regional lung deposition by computational models.