Jacobsen Ann-Christin, Krupa Anna, Brandl Martin, Bauer-Brandl Annette
Drug Transport & Delivery Group, Department of Physics, Chemistry & Pharmacy, University of Southern Denmark, Odense 5230, Denmark.
Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Collegium Medicum, Krakow 30-6088, Poland.
Pharmaceutics. 2019 May 10;11(5):227. doi: 10.3390/pharmaceutics11050227.
Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. Freeze-drying from hydro-alcoholic solutions was used to prepare amorphous formulations. The screening approach was tested on amorphous and crystalline tadalafil formulations with and without Soluplus. The workflow consisted of: 1) dispersion of the formulations; 2) incubation within the two-compartment plate, where a dialysis membrane separated donor (dispersed formulation) and acceptor; 3) sampling (donor and acceptor), where donor samples were centrifuged to remove non-dissolved material; and 4) quantification by UHPLC-UV. To identify optimal screening conditions, the following parameters were varied: dispersion medium (buffer / biomimetic media), acceptor medium (buffer / surfactant solutions), and incubation time (1, 3, and 6 h). Surfactants (acceptor) increased tadalafil permeation. Biomimetic medium (donor) enhanced dissolution, but not permeation, except for freeze-dried tadalafil, for which the permeated amount increased. The predictiveness was evaluated by comparing dissolution-/permeation-results with in vivo bioavailability. In general, both dissolution and permeation reflected bioavailability, whereof the latter was a better predictor. High-throughput dissolution/permeation is regarded promising for formulation screening.
早期制剂筛选可以缓解高级口服药物制剂（如无定形固体分散体）的研发进程。传统上，溶出度用于预测无定形固体分散体的性能。在此，我们描述了一种高通量方法，该方法使用两室96孔板同时筛选药物的溶出度和渗透率。采用从水醇溶液中冻干的方法制备无定形制剂。该筛选方法在有无Soluplus的无定形和结晶他达拉非制剂上进行了测试。工作流程包括：1）制剂的分散；2）在两室板中孵育，其中透析膜将供体（分散制剂）和受体隔开；3）取样（供体和受体），供体样品进行离心以去除未溶解的物质；4）通过超高效液相色谱-紫外检测进行定量。为了确定最佳筛选条件，对以下参数进行了变化：分散介质（缓冲液/仿生介质）、受体介质（缓冲液/表面活性剂溶液）和孵育时间（1、3和6小时）。表面活性剂（受体）增加了他达拉非的渗透率。仿生介质（供体）提高了溶出度，但除了冻干他达拉非（其渗透量增加）外，并未提高渗透率。通过将溶出度/渗透率结果与体内生物利用度进行比较来评估预测性。总体而言，溶出度和渗透率均反映了生物利用度，其中后者是更好的预测指标。高通量溶出度/渗透率被认为在制剂筛选方面具有前景。
