Dapagliflozin (DAP), which improves glycemic control in patients with type 2 diabetes mellitus, has poor physical properties against heat and moisture, thus hindering its manufacturing potential. The superior physicochemical properties of a recently developed cocrystal of DAP and citric acid (DAP cocrystal) in comparison with those of DAP and Forxiga^®, a patented solvate form with propandiol monohydrate, were identified via structural analysis and moisture sorption isotherm. For the first time, the formulation, manufacturability, and in vivo bioavailability of DAP cocrystals were successfully investigated to develop oral dosage forms that substitute Forxiga^®. The intrinsic dissolution rate of DAP cocrystal was controlled by varying particle size distribution. Unlike the direct compression (DC), roller compaction (RC) was more preferable to obtain good flowability of dry granules for a continuous manufacturing system. The cocrystal structure was maintained throughout the stability assessment period. In Vitro dissolution pattern differences of the optimized DAP cocrystal tablet with RC and the reference tablet, Forxiga^® 10 mg, were pharmaceutically equivalent within 5% in four different media. Furthermore, comparative pharmacokinetic analysis confirmed that a 10 mg DAP cocrystal tablet with RC was bioequivalent to a 10 mg Forxiga^® tablet, as assessed in beagle dogs and human volunteers.

中文翻译：

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Dapagliflozin共结晶在Beagle犬和人类志愿者中的可制造性和体内比较药代动力学

Dapagliflozin（DAP）可改善2型糖尿病患者的血糖控制，其抗热和湿气的物理性能较差，因此阻碍了其生产潜力。DAP和柠檬酸（DAP共晶体）的与这些DAP和Forxiga的比较最近开发的共晶体的优良的物理化学性质^®，一溶剂化物的专利形式丙二醇一水合物，分别通过结构分析和吸湿等温线确定。首次，制剂，可制造性和体内DAP共结晶的生物利用度被成功的研究以口服剂型替代Forxiga ^®。DAP共晶的固有溶解速率通过改变粒径分布来控制。与直接压缩（DC）不同，对于连续生产系统，为了获得干燥颗粒的良好流动性，更优选辊压（RC）。在整个稳定性评估期间，共晶结构得以保持。与RC和参考片剂，Forxiga优化DAP共晶片剂的体外溶出模式差异^® 10毫克，分别在四个不同的媒体5％内的药学上等效的。此外，比较药代动力学分析证实，与RC 10毫克DAP共晶片剂是生物等效的10毫克Forxiga ^®片剂，如在比格犬和人类志愿者评估。