Inhalation Sciences, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Inhalation Sciences, Stockholm, Sweden.
Eur J Pharm Biopharm. 2019 Jun;139:213-223. doi: 10.1016/j.ejpb.2019.03.005. Epub 2019 Mar 9.
The surface area of the air/liquid interface in the lungs is substantial, so deposited doses of aerosol medicines per interface surface area when administered via the inhalation route is always quite low. However, in most in vitro systems used for dissolution testing of dry powder inhalables, the dose per surface area is generally much higher. The aim of this study was to investigate in one in vitro lung dissolution system, the DissolvIt, the manner in which the deposited dose per test surface area of drug particles influences the simulated dissolution- and absorption rate. Here we used the dissolution test method DissolvIt to investigate the influence on dissolution behavior by varying the deposited surface density of tested drugs. Dry powders of three different active pharmaceutical ingredients with different solubilities were used; salmeterol, budesonide and fluticasone propionate. It was found that by varying the dose density from 0.23 to 29 µg/cm the dissolution- and absorption rate of test particles was affected for all three substances, with decreasing relative dissolution rates above certain dose limits. The effect was much more prominent with the least soluble fluticasone propionate. In contrast, in a real lung it has been shown that a tenfold increase of the even less soluble fluticasone furoate did not affect the pulmonary dissolution- and absorption as measured in the ex vivo isolated perfused rat lung. This indicates that the deposited particle dose on the test surface used must be carefully considered in all in vitro dissolution testing apparatuses used for inhalation drugs, especially when aiming for in vitro-in vivo correlations. Conclusive data show that in the DissolvIt system consistent normalized dissolution- and absorption data can be obtained if the deposition density of test substance are kept below 1 µg/cm and the variability between the initial drug doses is smaller than 10-15% expressed as standard deviation.
肺部气/液界面的表面积相当大，因此通过吸入途径给予时，每个界面表面积沉积的气溶胶药物剂量总是相当低。然而，在大多数用于干粉吸入剂溶解测试的体外系统中，每个表面积的剂量通常要高得多。本研究的目的是在一个体外肺溶解系统，即 DissolvIt 中，研究沉积剂量与药物颗粒的测试表面积的比值如何影响模拟的溶解和吸收速率。在这里，我们使用 DissolvIt 溶解测试方法来研究通过改变测试药物的沉积表面密度对溶解行为的影响。使用了三种具有不同溶解度的不同活性药物成分的干粉；沙美特罗、布地奈德和丙酸氟替卡松。结果发现，通过将剂量密度从 0.23 到 29μg/cm 变化，测试颗粒的溶解和吸收速率受到所有三种物质的影响，在某些剂量限制以上，相对溶解速率降低。对于最不溶性的丙酸氟替卡松，这种影响更为显著。相比之下，在真实肺部中已经表明，即使是更不易溶解的糠酸氟替卡松的十倍增加也不会影响离体灌流大鼠肺中测量的肺部溶解和吸收。这表明在所有用于吸入药物的体外溶解测试设备中，必须仔细考虑用于测试表面的沉积颗粒剂量，特别是当旨在建立体外-体内相关性时。明确的数据表明，如果将测试物质的沉积密度保持在 1μg/cm 以下，并且初始药物剂量之间的变异性（表示为标准偏差）小于 10-15%，则在 DissolvIt 系统中可以获得一致的归一化溶解和吸收数据。
