Sustained Release of Co-Amorphous Matrine-Type Alkaloids and Resveratrol with Anti-COVID-19 Potential.

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.