目的:西地那非碱和波生坦一水合物共同用于肺动脉高压(PAH)的慢性治疗。两种药物都难溶于水,和它们的生物利用度被限制在约。50%。因为波生坦是一种弱酸,而西地那非是一种弱碱,我们假设它们的共非晶化可以:(i)提高它们在胃肠液中的溶解度,(ii)能够达到过饱和和(iii)确保过饱和溶液的稳定。如果成功,这可以加速新的固定剂量组合药物的开发。
方法:使用高能球磨制备共无定形制剂。使用XRD评估了它们的固态特性,DSC,FT-MIR,和介电谱。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。
结果:结果表明,在西地那非碱(Tg=64-78°C)中对波生坦进行分子分散的二元制剂可以在高能球磨过程中制造。当西地那非负荷低于50重量%时。%,该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。
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.