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.