Pinto Joana T, Cachola Inês, F Pinto João, Paudel Amrit
Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria.
iMed.ULisboa-Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Pharmaceutics. 2021 Feb 24;13(3):297. doi: 10.3390/pharmaceutics13030297.
The use of physiologically based pharmacokinetic (PBPK) models to support drug product development has become increasingly popular. The in vitro characterization of the materials of the formulation provides valuable descriptors for the in silico prediction of the drug's pharmacokinetic profile. Thus, the application of an in vitroin silico framework can be decisive towards the prediction of the in vivo performance of a new medicine. By applying such an approach, this work aimed to derive mechanistic based insights into the potential impact of carrier particles and powder bulk properties on the in vivo performance of a lactose-based dry powder inhaler (DPI). For this, a PBPK model was developed using salbutamol sulphate (SS) as a model drug and the in vitro performance of its low-dose blends (2% /) with different types of lactose particles was investigated using different DPI types (capsule versus reservoir) at distinct airflows. Likewise, the influence of various carrier's particle and bulk properties, device type and airflow were investigated in silico. Results showed that for the capsule-based device, low-dose blends of SS had a better performance, when smaller carrier particles (Dv ≈ 50 μm) with about 10% of fines were used. This resulted in a better predicted bioavailability of the drug for all the tested airflows. For the reservoir type DPI, the mean particle size (Dv) was identified as the critical parameter impacting performance. Shear cell and air permeability or compressibility measurements, particle size distribution by pressure titration and the tensile strength of the selected lactose carrier powders were found useful to generate descriptors that could anticipate the potential in vivo performance of the tested DPI blends.
基于生理药代动力学（PBPK）模型来支持药物产品开发已变得越来越普遍。制剂材料的体外特性可为药物药代动力学特征的计算机模拟预测提供有价值的描述符。因此，体外-计算机模拟框架的应用对于预测新药的体内性能可能具有决定性作用。通过应用这种方法，本研究旨在深入了解载体颗粒和粉末堆积性质对基于乳糖的干粉吸入器（DPI）体内性能的潜在影响。为此，以硫酸沙丁胺醇（SS）作为模型药物开发了一个PBPK模型，并使用不同类型的DPI（胶囊型与储库型）在不同气流条件下研究了其与不同类型乳糖颗粒的低剂量混合物（2%/）的体外性能。同样，还在计算机模拟中研究了各种载体颗粒和堆积性质、装置类型及气流的影响。结果表明，对于基于胶囊的装置，当使用较小的载体颗粒（体积平均直径Dv≈50μm）且细粉含量约为10%时，SS的低剂量混合物表现更好。这使得在所有测试气流条件下药物的预测生物利用度更高。对于储库型DPI，平均粒径（Dv）被确定为影响性能的关键参数。发现剪切细胞和透气率或可压缩性测量、压力滴定法测定的粒度分布以及所选乳糖载体粉末的抗张强度有助于生成可预测测试DPI混合物潜在体内性能的描述符。
