Four pharmaceutical cocrystals of naringenin were obtained, which demonstrate improved dissolution performance.

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.

Sinomenine (SIN) is a benzyltetrahydroisoquinoline-type alkaloid isolated from the dried plant root and stem of Sinomenium acutum (Thumb.) Rehd.et Wils, which shows potent anti-inflammatory and analgesic effects. As a transforming disease-modifying anti-rheumatic drug, SIN has been used to treat rheumatoid arthritis over twenty-five years in China. In recent years, SIN is also in development for use against other disorders, including colitis, pain, traumatic brain injury, and uveitis. However, its commercial hydrochloride (SIN-HCl) shows low oral bioavailability and certain allergic reactions in patients, due to the release of histamine. Therefore, a large number of pharmaceutical strategies have been explored to address these liabilities, such as prolonging release behaviors, enhancing skin permeation and adsorption for transdermal delivery, targeted SIN delivery using new material or conjugates, and co-amorphous technology. This review discusses these different delivery strategies and approaches employed to overcome the limitations of SIN for its efficient delivery, in order to achieve improved bioavailability and reduced side effects. The potential advantages and limitations of SIN delivery strategies are elaborated along with discussions of potential future SIN drug development strategies.