Hu Dandan, Chen Xin, Li Duanxiu, Zhang Hailu, Duan Yanwen, Huang Yong
Xiangya International Academy of Translational Medicine, Central South University, Changsha 410013, China.
Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
Pharmaceutics. 2022 Mar 10;14(3):603. doi: 10.3390/pharmaceutics14030603.
Matrine (MAR), oxymatrine (OMAR), and sophoridine (SPD) are natural alkaloids with varying biological activities; matrine was recently used for the treatment of coronavirus disease 2019 (COVID-19). However, the short half-lives and rapid elimination of these matrine-type alkaloids would lead to low oral bioavailability and serious side effects. Herein, resveratrol (RES) was selected as a co-former to prepare their co-amorphous systems to improve the therapeutic index. The formation of co-amorphous MAR-RES, OMAR-RES, and SPD-RES was established through powder X-ray diffraction and modulated temperature differential scanning calorimetry. Furthermore, Fourier transform infrared spectroscopy and NMR studies revealed the strong molecular interactions between resveratrol and these alkaloids, especially OMAR-RES. Matrine, oxymatrine, and sophoridine in the co-amorphous systems showed sustained release behaviors in the dissolution experiments, due to the recrystallization of resveratrol on the surface of co-amorphous drugs. The three co-amorphous systems exhibited excellent physicochemical stability under high relative humidity conditions. Our study not only showed that minor structural changes of active pharmaceutical ingredients may have distinct molecular interactions with the co-former, but also discovered a new type of sustained release mechanism for co-amorphous drugs. This promising co-amorphous drug approach may present a unique opportunity for repurposing these very promising drugs against COVID-19.
苦参碱（MAR）、氧化苦参碱（OMAR）和槐定碱（SPD）是具有不同生物活性的天然生物碱；苦参碱最近被用于治疗2019冠状病毒病（COVID-19）。然而，这些苦参碱型生物碱的半衰期短且消除迅速，会导致口服生物利用度低和严重的副作用。在此，选择白藜芦醇（RES）作为共形成剂来制备它们的共无定形体系，以提高治疗指数。通过粉末X射线衍射和调制温度差示扫描量热法确定了共无定形MAR-RES、OMAR-RES和SPD-RES的形成。此外，傅里叶变换红外光谱和核磁共振研究揭示了白藜芦醇与这些生物碱之间的强分子相互作用，尤其是OMAR-RES。在溶出实验中，共无定形体系中的苦参碱、氧化苦参碱和槐定碱表现出缓释行为，这是由于白藜芦醇在共无定形药物表面重结晶所致。这三种共无定形体系在高相对湿度条件下表现出优异的物理化学稳定性。我们的研究不仅表明活性药物成分的微小结构变化可能与共形成剂有不同的分子相互作用，还发现了一种共无定形药物的新型缓释机制。这种有前景的共无定形药物方法可能为重新利用这些非常有前景的药物对抗COVID-19提供独特的机会。
