Department of Pharmacy, University of Copenhagen , DK-2100 Copenhagen, Denmark.
Department of Micro- and Nanotechnology, Technical University of Denmark , DK-2800 Lyngby, Denmark.
Mol Pharm. 2017 Dec 4;14(12):4154-4160. doi: 10.1021/acs.molpharmaceut.7b00422. Epub 2017 Aug 16.
Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.
如今，许多药物候选物的水溶性较低，因此可能表现出较低的口服生物利用度，这给制剂和药物传递带来了重大挑战。提高这些药物生物利用度的一种方法是使用超饱和药物传递策略。本研究的目的是开发一种视频显微镜方法，使用新颖的视频显微镜小尺度装置来评估沉淀抑制剂对低溶解度药物他达拉非的超饱和溶液的影响。基于初步研究，选择 29 的过饱和度来研究他达拉非在 FaSSIF 中的过饱和度。将不同量的羟丙基甲基纤维素 (HPMC) 预先溶解在 FaSSIF 中，得到四个不同的浓度，然后使用溶剂转移法创建超饱和系统。通过视频显微镜监测他达拉非从超饱和溶液中的沉淀情况，作为时间的函数。使用商业上可获得的软件可以进行单颗粒分析；然而，为了研究整个沉淀颗粒群体（即它们在视场中的数量和覆盖面积），开发了一种图像分析算法（多颗粒分析）。在 FaSSIF 中添加 0.01%（w/v）HPMC 可显著延长他达拉非沉淀的诱导时间，在 0.1%（w/v）HPMC 时达到最大抑制效果，之后添加更多的 HPMC 不会进一步增加诱导时间。单颗粒和多颗粒分析得出了相同的 HPMC 浓度对沉淀抑制作用的排名。开发的小尺度方法可以评估沉淀抑制剂的效果，从而加快选择合适的沉淀抑制剂和使用浓度的过程。
