Abstract
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.
Highlights
Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and Guangdong Institute of Semiconductor Micro-Nano Manufacturing Technology, Foshan 528200, China
We discovered that the three co-amorphous systems showed sustained release behavior, enabling the future development and clinical evaluation of a more convenient oral delivery route than continuous infusion for these excellent drug candidates against
The crystallized resveratrol on the surface of co-amorphous samples during the dissolution process formed a “shell-like” structure, which may hinder the release of matrine-type alkaloids and realizes the sustained release
Summary
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to over 5 million deaths worldwide as of early December 2021 [1]. We test the hypothesis if resveratrol can be used as a new co-former for the formation of co-amorphous drug systems with matrine, oxymatrine, and sophoridine, due to the potential synergistic effects against SARS-CoV-2. These new solid formulations have been prepared and systematically characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), modulated temperature differential scanning calorimetry (mDSC), scanning electron microscopy (SEM), and nuclear magnetic resonance (NMR) spectroscopy. Our study results in three new co-amorphous drug systems with great anti-COVID-19 potential, and suggests a promising translational route for natural products from traditional Chinese medicines
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