Jagiellonian University, Medical College, Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, PL-30688 Cracow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University in Cracow, PL-31530, Poland.
Jagiellonian University, Institute of Physics, PL-30348 Cracow, Poland.
Int J Pharm. 2024 Aug 15;661:124312. doi: 10.1016/j.ijpharm.2024.124312. Epub 2024 Jun 13.
Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs.
The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs.
It was shown that binary formulations in which bosentan was molecularly dispersed in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS.
西地那非碱和波生坦一水合物在肺动脉高压（PAH）的慢性治疗中联合使用。这两种药物在水中的溶解度都很差，生物利用度约为 50%。由于波生坦是一种弱酸，而西地那非是一种弱碱，我们假设它们的共晶化可以：（i）提高在胃肠道液中的溶解度，（ii）达到过饱和状态，（iii）确保过饱和溶液的稳定。如果成功，这将加速新的固定剂量组合药物的开发。
共无定形制剂采用高能球磨法制备。使用 XRD、DSC、FT-MIR 和介电谱评估其固态性能。还分析了粒度分布和表面润湿性。应用偏光显微镜和扫描电子显微镜来评估这些粉末的微观结构。开发了一种新的 HPLC-DAD 方法，用于同时定量两种药物。
表明可以在高能球磨过程中制造其中波生坦分子分散在西地那非碱中的二元制剂（Tg=64-78°C）。当西地那非负载低于 50wt.%时，制剂显示出最大的热稳定性，并在 PBS 中形成持久的波生坦过饱和度。
