Pharmaceutical Technology & Development Inhalation, Operations , AstraZeneca R&D , Pepparedsleden 1 , Mölndal 43183 , Sweden.
Pharmaceutical Sciences, IMED , AstraZeneca R&D , Pepparedsleden 1 , Mölndal 43183 , Sweden.
Mol Pharm. 2018 Nov 5;15(11):5319-5326. doi: 10.1021/acs.molpharmaceut.8b00796. Epub 2018 Oct 22.
Pulmonary dissolution of poorly soluble drug substances (DSs) may limit the drug absorption rate and consequently influence clinical performance. Dissolution rate is thus an important quality attribute, and its influence on in vivo drug release must be characterized, understood, and controlled early in the development process. The aim of this study is to establish an in vitro dissolution method with the capability to capture therapeutically relevant differences in the dissolution rate between drug batches and drug compounds. A method was developed by which a biorelevant aerosol fraction was captured on a filter using a sedimentation technique in a modified Andersen cascade impactor to avoid particle agglomeration. Subsequently, the filters were transferred to a commercial Transwell system where dissolution in 3 mL of phosphate buffer at pH 6.8 with 0.5% sodium dodecyl sulfate (SDS) occurred at sink conditions. Dissolved DS was quantified over time using UPLC-UV. Dissolution data was obtained on a series of micronized and aerosolized lipophilic DSs, budesonide, fluticasone furoate (FF), fluticasone propionate (FP), and AZD5423. The latter is a lipophilic AstraZeneca development compound available in two different mass median diameters (MMD), 1.3 (AZD5423) and 3.1 μm (AZD5423). Dissolution data were evaluated using a Weibull fit and expressed as t, the time to dissolution of 63% of the initial dose. The following rank-order of t was obtained (mean t and MMD in brackets), budesonide (10 min, 2.1 μm) = AZD5423 (10 min, 1.3 μm) < AZD5423 (19 min, 3.1 μm) < FP (38 min, 2.4 μm) < FF (63 min, 2.5 μm). The method could differentiate between different drug compounds with different solubility but similar particle size distribution, as well as between the same drug compound with different particle size distributions. Furthermore, a relation between the in vitro dissolution rate ( t) and mean pulmonary absorption time in man (literature data) was observed, indicating clinical relevance. It is thus concluded, that the method may be useful for the characterization and ranking of DSs and drug products in early development, as well as being a potential tool for the control of dissolution as a potential quality attribute.
肺部对难溶性药物物质（DS）的溶解可能会限制药物吸收速率，从而影响临床性能。因此，溶解速率是一个重要的质量属性，必须在开发过程的早期对其影响体内药物释放的特性进行表征、理解和控制。本研究的目的是建立一种能够捕捉药物批次和药物化合物之间治疗相关溶解速率差异的体外溶解方法。开发了一种方法，通过该方法，使用改良的安德森级联撞击器中的沉降技术，将生物相关气溶胶部分捕获在过滤器上，以避免颗粒团聚。随后，将过滤器转移到商业 Transwell 系统中，在 pH 6.8 的磷酸盐缓冲液中以 3 mL 进行溶解，其中含有 0.5%十二烷基硫酸钠（SDS），在溶出条件下进行溶解。使用 UPLC-UV 随时间定量测定溶解的 DS。对一系列微米化和雾化的亲脂性 DS、布地奈德、糠酸氟替卡松（FF）、丙酸氟替卡松（FP）和 AZD5423 进行了溶解数据获取。后者是一种亲脂性阿斯利康开发化合物，有两种不同的质量中值直径（MMD），1.3（AZD5423）和 3.1μm（AZD5423）。使用 Weibull 拟合评估溶解数据，并表示为 t，即初始剂量的 63%溶解所需的时间。得到以下 t 的排序（括号中为平均 t 和 MMD），布地奈德（10 分钟，2.1μm）=AZD5423（10 分钟，1.3μm）<AZD5423（19 分钟，3.1μm）<FP（38 分钟，2.4μm）<FF（63 分钟，2.5μm）。该方法可区分具有不同溶解度但相似粒径分布的不同药物化合物，以及具有不同粒径分布的相同药物化合物。此外，还观察到体外溶解速率（t）与人体平均肺吸收时间（文献数据）之间的关系，表明具有临床相关性。因此，该方法可用于早期开发中 DS 和药物产品的特征描述和排序，也可作为控制溶解作为潜在质量属性的潜在工具。
