Li Long, Yin Xian-Hong, Diao Kai-Sheng
Sichuan Kelun Pharmaceutical Research Institute Co., Ltd. Chengdu 610000 China
College of Chemistry and Chemical Engineering, Guangxi University for Nationalities Nanning 530006 China.
RSC Adv. 2020 Oct 2;10(59):36125-36134. doi: 10.1039/d0ra06608g. eCollection 2020 Sep 28.
PEC is a new generation of phosphamide ester anti-hepatitis B virus drug. It is a prodrug of tenofovir and can be rapidly metabolized to tenofovir. However, its poor solubility in water (0.219 mg mL at 25 °C) has limited its oral bioavailability. In this study, we aimed to improve the solubility and consequently the oral bioavailability of PEC a cocrystal. A cocrystal of PEC with fumaric acid (FUA) (PEC-FUA, 1 : 1) was successfully obtained and characterized. The crystal structure of this cocrystal was tested using a single crystal X-ray diffraction method. The intrinsic dissolution rate (IDR) characterization was performed in a pH 6.8 buffer. The solubility of this cocrystal in 0.1 M HCl (pH 1.0) and pH 6.8 phosphate buffers was investigated, and the results showed that the solubility of the cocrystal was 3.8 and 4.0 times that of free PEC, respectively. We also studied the pharmacokinetics of beagle dogs. The mean AUC of the cocrystal is about 4.2 times that of free PEC, indicating that the solubility and bioavailability of PEC can indeed be improved by forming the cocrystal. It may become an ideal solid form of an active pharmaceutical ingredient suitable for pharmaceutical preparations, and it can be further studied later.
PEC是新一代磷酰胺酯类抗乙肝病毒药物。它是替诺福韦的前体药物，可迅速代谢为替诺福韦。然而，其在水中的溶解度较差（25℃时为0.219mg/mL），限制了其口服生物利用度。在本研究中，我们旨在通过形成共晶体来提高PEC的溶解度，进而提高其口服生物利用度。成功获得并表征了PEC与富马酸（FUA）的共晶体（PEC-FUA，1∶1）。采用单晶X射线衍射法对该共晶体的晶体结构进行了测试。在pH 6.8缓冲液中进行了固有溶解速率（IDR）表征。研究了该共晶体在0.1M HCl（pH 1.0）和pH 6.8磷酸盐缓冲液中的溶解度，结果表明，共晶体的溶解度分别是游离PEC的3.8倍和4.0倍。我们还研究了比格犬的药代动力学。共晶体的平均AUC约为游离PEC的4.2倍，表明通过形成共晶体确实可以提高PEC的溶解度和生物利用度。它可能成为适合药物制剂的活性药物成分的理想固体形式，后续可进一步研究。
