King's College London , Institute of Pharmaceutical Science , London SE1 9NH , U.K.
Inhalation Sciences Sweden AB , Hälsovägen 7-9 , 141 57 Huddinge , Sweden.
Mol Pharm. 2019 Mar 4;16(3):1245-1254. doi: 10.1021/acs.molpharmaceut.8b01200. Epub 2019 Feb 15.
The dissolution of inhaled drug particles in the lungs is a challenge to model using biorelevant methods in terms of (i) collecting a respirable emitted aerosol fraction and dose, (ii) presenting this to a small volume of medium that is representative of lung lining fluid, and (iii) measuring the low concentrations of drug released. We report developments in methodology for each of these steps and utilize mechanistic in silico modeling to evaluate the in vitro dissolution profiles in the context of plasma concentration-time profiles. The PreciseInhale aerosol delivery system was used to deliver Flixotide aerosol particles to Dissolv It apparatus for measurement of dissolution. Different media were used in the Dissolv It chamber to investigate their effect on dissolution profiles, these were (i) 1.5% poly(ethylene oxide) with 0.4% l-alphaphosphatidyl choline, (ii) Survanta, and (iii) a synthetic simulated lung lining fluid (SLF) based on human lung fluid composition. For fluticasone proprionate (FP) quantification, solid phase extraction was used for sample preparation with LC-MS/MS analysis to provide an assay that was fit for purpose with a limit of quantification for FP of 312 pg/mL. FP concentration-time profiles in the flow-past perfusate were similar irrespective of the medium used in the Dissolv It chamber (∼0.04-0.07%/min), but these were significantly lower than transfer of drug from air-to-perfusate in isolated perfused lungs (0.12%/min). This difference was attributed to the Dissolv It system representing slower dissolution in the central region of the lungs (which feature nonsink conditions) compared to the peripheral regions that are represented in the isolated lung preparation. Pharmacokinetic parameters ( C, T, and AUC) were estimated from the profiles for dissolution in the different lung fluid simulants and were predicted by the simulation within 2-fold of the values reported for inhaled FP (1000 μg dose) administered via Flixotide Evohaler 250 μg strength inhaler in man. In conclusion, we report methods for performing biorelevant dissolution studies for orally inhaled products and illustrate how they can provide inputs parameters for physiologically based pharmacokinetic (PBPK) modeling of inhaled medicines.
吸入药物颗粒在肺部的溶解是使用生物相关方法建模的一个挑战，特别是在以下方面：（i）收集可吸入的发射气溶胶部分和剂量，（ii）将其呈现给代表肺衬里液的小体积介质，以及（iii）测量释放的药物的低浓度。我们报告了这些步骤中每一步的方法学发展，并利用机制的计算模型来评估在体内药物浓度-时间曲线的背景下的体外溶解曲线。PreciseInhale 气溶胶输送系统用于将 Flixotide 气溶胶颗粒输送到 Dissolv It 装置以进行溶解测量。不同的介质在 Dissolv It 室中使用，以研究它们对溶解曲线的影响，这些介质包括（i）1.5%聚（氧化乙烯）和 0.4% l-α磷脂酰胆碱，（ii）Survanta，以及（iii）基于人肺液成分的合成模拟肺衬里液（SLF）。对于氟替卡松丙酸酯（FP）的定量，使用固相萃取进行样品制备，并用 LC-MS/MS 分析进行分析，提供了一种适合目的的测定方法，其对 FP 的定量限为 312 pg/mL。在流动灌注液中的 FP 浓度-时间曲线无论在 Dissolv It 室中使用哪种介质（约 0.04-0.07%/min）都相似，但与在离体灌注肺中从空气到灌注液的药物转移（0.12%/min）相比，这些曲线显著较低。这种差异归因于 Dissolv It 系统代表了肺部中央区域（具有非溶解条件）的溶解速度较慢，而在离体肺制剂中代表了周边区域。在不同的肺液模拟物中进行溶解的曲线的药代动力学参数（C、T 和 AUC）进行了估计，并通过模拟进行了预测，与报告的通过 Flixotide Evohaler 250 μg 强度吸入器吸入的 FP（1000 μg 剂量）的体内药代动力学参数（2 倍以内）。总之，我们报告了进行生物相关的吸入产品溶解研究的方法，并说明了它们如何为吸入药物的生理相关药代动力学（PBPK）建模提供输入参数。
