Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
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DOI：
10.1021/acs.molpharmaceut.9b00289
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发表时间：
2019-07-01
影响因子：
4.9
通讯作者：
Lennernas, Hans
中科院分区：
文献类型：
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作者：
Eriksson, Johanna;Thorn, Helena;Lennernas, Hans
许多吸入药物的水溶性差，溶出速率通常是整个吸收过程中的限速步骤。为了提高对肺部药物溶出度的了解，将四种难溶性吸入化合物（AZD 5423（一种发育非甾体糖皮质激素）、布地奈德、糠酸氟替卡松（FF）和丙酸氟替卡松（FP））以悬浮液或干粉形式给予已建立的离体灌注4大鼠肺（IPL）模型。研究了AZD 5423的两种粒度分布（d50 = 1.2 μ m和d50 = 2.8 μ m）。将混悬液和干粉中药物的肺吸收率与溶液的历史吸收数据进行比较，以提高对溶解度差的吸入药物的整体肺吸收过程的影响的理解。使用基于生理学的生物制药计算机模型分析实验IPL数据并估计溶出参数（K-离体）。将类似的计算机模拟方法应用于文献中的体外溶出数据，以获得体外溶出参数（Kin vitro）。当FF、FP和AZD 5423的较大颗粒作为混悬液给药时，药物溶出是整个吸收过程中的限速步骤。然而，布地奈德的情况并非如此，布地奈德具有最高的水溶性（61 μ M），AZD 5423的颗粒较小，可能是因为可用于溶解的表面积增加（d50 = 1.2 μ m）。根据药物的溶解度对估计的溶出参数进行排序，并且k（离体）和k（体外）之间具有良好的一致性。所有化合物的干燥粉末比悬浮液吸收更慢，表明润湿是干燥粉末溶解的重要参数。在计算机模拟模型中引入润湿因子，以解释混悬液和干粉之间吸收曲线的差异，其中AZD 5423的润湿性最差，其次是FP和FF。IPL模型与计算机模拟模型相结合是一种有用的工具，可用于研究肺溶出度，并提高对难溶性吸入化合物溶出度相关参数的理解。
Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.