School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China.
School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Research Center for Pharmaceutical Preparations, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan, 430065, PR China.
Int J Pharm. 2024 Oct 25;664:124592. doi: 10.1016/j.ijpharm.2024.124592. Epub 2024 Aug 17.
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.
共无定形物（CM）是提高难溶性药物水溶解度的一种很有前途的技术，但在溶解过程中经常会出现凝胶现象，严重威胁其溶解度/溶解性能。因此，设计有利的 CM 系统以减轻甚至避免凝胶现象的不利影响是非常重要的。在这项研究中，构建了圣草酚（TAX）和氧化苦参碱（OMT）的 CM 系统（TAX-OMT CM）以提高 TAX 的溶解度和溶解性能。有趣的是，TAX-OMT CM 在溶解过程中逐渐聚集并明显胶凝，但 TAX 在 TAX-OMT CM 中的溶解度和溶解明显增强，与结晶 TAX 相比。因此，系统地探讨了 TAX-OMT CM 胶凝后的潜在增溶机制。一方面，通过相溶解度、荧光光谱和等温滴定量热法验证了 TAX-OMT CM 中两种成分的络合作用。另一方面，通过粉末 X 射线衍射、傅里叶变换红外光谱、扫描电子显微镜对 TAX-OMT CM 溶解评价后的残余固体进行了彻底表征，结果表明 TAX-OMT CM 具有抗结晶性。此外，分子模拟表明了 TAX-OMT CM 单独和 TAX-OMT 复合物在水溶液中的分子间相互作用。最后，大鼠药代动力学研究表明，口服 TAX-OMT CM（1:2）后 TAX 的生物利用度约为结晶 TAX 的 5.5 倍。综上所述，本研究揭示了 CM 系统的络合和抗结晶作用对胶凝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一种有效的策略。
