Co-无定形(CM)是提高不溶性药物水溶性的一种有前途的技术。但是在溶解过程中经常发生凝胶现象,严重威胁其溶解度/溶解性能。因此,设计良好的CM系统以减轻甚至避免凝胶现象的不利影响非常重要。在这项研究中,构建了紫杉素(TAX)和氧化苦参碱(OMT)的CM体系(TAX-OMTCMs),以提高TAX的溶解度和溶解性能。有趣的是,TAX-OMTCM在溶解过程中逐渐聚集并明显胶凝,但与结晶TAX相比,TAX-OMTCMs中TAX的溶解度和溶出度显著增强。因此,系统地探讨了TAX-OMTCMs凝胶化后的增溶机理。首先,通过相溶解度验证了TAX-OMTCM中两种组分之间的络合,荧光光谱法和等温滴定量热法。对于另一个,通过粉末X射线衍射彻底表征了溶解评估后TAX-OMTCM的残留固体,傅里叶变换红外光谱,扫描电子显微镜,这表明了TAX-OMTCMs的抗结晶性能。此外,分子模拟证明了TAX-OMTCMs单独和TAX-OMT复合物在水溶液中的分子间相互作用。最后,大鼠的药代动力学研究表明,口服后TAX-OMTCM(1:2)中TAX的生物利用度比结晶TAX高约5.5倍。总的来说,这项研究揭示了CM体系的络合和抗结晶作用对凝胶化后保持增溶行为的重要性,为提高药物CM系统的吸收性能提供了有效的策略。
Co-amorphous (CM) is a promising technology for enhancing the aqueous solubility of insoluble drugs, but the gelation phenomenon has often occurred during the dissolution process and seriously threatened their solubility/dissolution performance. Therefore, it\'s quite important to design favorable CM systems to alleviate or even avoid the adverse effects of gelation phenomenon. In this study, CM systems of taxifolin (TAX) and oxymatrine (OMT) (TAX-OMT CMs) were constructed to improve the solubility and dissolution properties of TAX. Interestingly, TAX-OMT CMs gradually aggregated and obviously gelled during dissolution, but the solubility and dissolution of TAX in TAX-OMT CMs were significantly enhanced compared to crystalline TAX. Consequently, the underlying solubilization mechanisms of TAX-OMT CMs after gelation were systematically explored. For one thing, the
complexation between the two components in TAX-OMT CMs was verified by phase solubility, fluorescence spectroscopy and isothermal titration calorimetry. For another, the residual solids of TAX-OMT CMs after dissolution evaluation were thoroughly characterized by means of powder X-ray diffraction, fourier transform infrared spectroscopy, scanning electron microscopy, which showed the anti-crystallization property of TAX-OMT CMs. Furthermore, molecular simulation demonstrated the intermolecular interactions of TAX-OMT CMs alone and TAX-OMT complexes in aqueous solution. Finally, pharmacokinetics study in rats suggested that the bioavailability of TAX in TAX-OMT CM (1:2) was approximately 5.5-fold higher than that of crystalline TAX after oral administration. Collectively, this study reveals the importance of
complexation and anti-crystallization effects of CM systems on maintaining solubilization behavior after gelation, providing an effective strategy to improve the absorption performance of pharmaceutical CM systems.