Drug Transport Across Pulmonary Epithelial Cell Monolayers: Effects of Particle Size, Apical Liquid Volume, and Deposition Technique
Drug Transport Across Pulmonary Epithelial Cell Monolayers: Effects of Particle Size, Apical Liquid Volume, and Deposition Technique
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DOI：
10.1089/jamp.2009.0757
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发表时间：
2010-06-01
影响因子：
3.4
通讯作者：
Lehr, Claus-Michael
中科院分区：
文献类型：
--
作者：
Bur, Michael;Huwer, Hanno;Lehr, Claus-Michael
背景资料：肺细胞培养物越来越多地用于预测吸入后的体内药物吸收，类似于已经建立的用于预测口服药物吸收的肠细胞培养模型。然而，与肠屏障相反，所谓的肺的空气-血液屏障仅覆盖有液体薄膜，气溶胶颗粒沉积在液体薄膜上。本研究的目的是研究当以干粉制剂沉积在体外肺上皮细胞上时，这种顶端液膜与药物吸收率的相关性。方法：选择布地奈德和硫酸沙丁胺醇作为模型药物，对于每种药物，使用三种通用气雾剂粉末制剂。将人支气管上皮细胞系Calu-3的过滤生长单层用作模型，使用不同体积的顶端液体。尽管两种药物中的每一种在体内被证明是生物等效的，但通用干粉制剂在体外显示出显著不同的上皮转运速率，这取决于顶端液体的量和沉积技术，并表明气溶胶颗粒在顶端液体体积中的溶解是总吸收速率的速率限制。然而，我们发现，在多级液体撞击器中雾化和沉积后，制剂的吸收速率相似，该多级液体撞击器更真实地模拟了药物晶体从载体乳糖中的分离及其在从干粉吸入器吸入后在呼吸道中的空气动力学粒度依赖性沉积。这些数据表明，需要改进的体外测试系统，以允许沉积的气溶胶颗粒的空气-液体界面培养的细胞单层，同时考虑到空气动力学特性。
Background: Pulmonary cell cultures are increasingly used to predict in vivo drug absorption after inhalation, similar to intestinal cell culture models that have already been well established to predict oral drug absorption. In contrast to the intestinal barrier, however, the so-called air-blood barrier of the lung is covered only with a thin film of liquid, on which the aerosol particles are deposited. The aim of this study was to investigate the relevance of this apical liquid film on the drug absorption rate when deposited as a dry powder formulation on pulmonary epithelial cells in vitro.Methods: Budesonide and salbutamol sulfate were chosen as model drugs, and for each drug three generic aerosol powder formulations were used. Filter-grown monolayers of the human bronchial epithelial cell line Calu-3 were used as a model, using various volumes of apical liquid.Results and Conclusions: Although proven to be bioequivalent in vivo for each of the two drugs, the generic dry powder fomulations showed strikingly different epithelial transport rates in vitro, depending on the amount of apical liquid and the deposition technique, and suggesting that the dissolution of the aerosol particles in the apical liquid volume was rate limiting for the overall absorption rate. However, we found that the absorption rates of the formulations were similar after aerosolization and deposition in a multistage liquid impinger, which simulates more realistically the detachment of the drug crystals from the carrier lactose and their aerodynamic particle size-dependent deposition in the respiratory tract following inhalation from a dry powder inhaler. These data demonstrate the need for improved in vitro test systems to allow deposition of aerosol particles on the air-liquid interface cultivated cell monolayers by simultaneously taking into account aerodynamic properties.