Cocrystals of Quercetin with Improved Solubility and Oral Bioavailability

Flavonoids have been studied extensively due to the observation that diets rich in these compounds are associated with lower incidences of many diseases. One of the most studied flavonoids, quercetin, is also the most abundant of these compounds in the plant kingdom. Numerous therapeutic bioactivities have been identified in vitro. However, its in vivo efficacy in pure form is limited by poor bioavailability, primarily due to its low solubility and consequent low absorption in the gut. Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. Here, we synthesized and evaluated four new cocrystals of quercetin (QUE): quercetin:caffeine (QUECAF), quercetin:caffeine:methanol (QUECAF·MeOH), quercetin:isonicotinamide (QUEINM), and quercetin:theobromine dihydrate (QUETBR·2H2O). Each of these cocrystals exhibited pharmacokinetic properties that are vastly superior to those of quercetin alone. Cocrystallization was able to overcome the water insolubility of quercetin, with all four cocrystals exhibiting some degree of solubility. The QUECAF and QUECAF·MeOH cocrystals increased the solubility of QUE by 14- and 8-fold when compared to QUE dihydrate. We hypothesized that this improved solubility would translate into enhanced systemic absorption of QUE. This hypothesis was supported in our pharmacokinetic study. The cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold.黄酮类化合物（Flavonoids）已被广泛研究，因为有研究发现富含此类化合物的膳食与多种疾病的较低发病率相关。研究最为广泛的黄酮类化合物之一槲皮素（quercetin），也是植物界中含量最为丰富的此类化合物。目前已在体外实验中证实其多种治疗性生物活性。然而，纯态槲皮素的体内药效受限于较差的生物利用度，这主要源于其低溶解性，进而导致肠道吸收效率低下。共晶技术（Cocrystallization）近年来作为改善化合物理化性质的手段受到广泛关注。本研究合成并评估了四种新型槲皮素共晶：槲皮素-咖啡因（QUECAF）、槲皮素-咖啡因-甲醇（QUECAF·MeOH）、槲皮素-异烟酰胺（QUEINM）以及槲皮素-可可碱二水合物（QUETBR·2H₂O）。上述四种共晶均展现出远优于纯态槲皮素的药代动力学特性。共晶技术成功解决了槲皮素的水不溶性问题，四种共晶均具备一定程度的水溶性。与槲皮素二水合物相比，QUECAF与QUECAF·MeOH共晶可使槲皮素的溶解度分别提升14倍与8倍。我们推测，溶解度的提升将转化为槲皮素全身吸收效率的增强。该假设在本研究的药代动力学实验中得到了验证。四种共晶的表现均优于槲皮素二水合物，其生物利用度最高可提升近10倍。