Abstract：
Pazopanib (PZ) is a multikinase inhibitor, which is mainly used in the treatment of soft tissue sarcoma and advanced renal cancer. However, because of its water insolubility, oral bioavailability is poor. At the same time, photo lability and high dose oral administration lead to severe hepatotoxicity, which is limited in clinical application. In this paper, the novel pazopanib-fumarate disodium glycyrrhizinate nanocrystalline micelles are successfully prepared by liquid-assisted ball milling. The prepared cocrystals and nanocrystalline micelle structures are systematically characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier Transform Infrared Spectrometer (FTIR) analysis. In vitro solubility and dissolution experiments show that the solubility and dissolution of nanocrystalline micelles are significantly improved under different simulated physiological conditions. The accelerated stabilization experiments show that the nanocrystalline micelles have good physical and chemical stability and showed excellent stability in water (Zeta potential was 62.39 mV). In addition, the in vivo bioavailability of nanocrystalline micelles is 3 times higher than that of PZ, and the therapeutic threshold (> 20 μg/mL) is up to 30 h. This new strategy provides a feasible solution to the undesirable properties of PZ.
摘要：
帕唑帕尼（PZ）是一种多激酶抑制剂，主要用于治疗软组织肉瘤和晚期肾癌。然而,因为它不溶于水，口服生物利用度较差。同时,光不稳定性和高剂量口服给药导致严重的肝毒性，这在临床应用中受到限制。在本文中,通过液体辅助球磨成功制备了新型的富马酸帕唑帕尼-甘草酸二钠纳米胶束。通过X射线衍射(XRD)对制备的共晶和纳米晶胶束结构进行了系统表征,差示扫描量热法(DSC)和傅里叶变换红外光谱仪(FTIR)分析。体外溶解度和溶出度实验表明，在不同的模拟生理条件下，纳米晶胶束的溶解度和溶出度都有显著提高。加速稳定实验表明，纳米晶胶束具有良好的物理和化学稳定性，在水中表现出优异的稳定性（Zeta电位为62.39mV）。此外,纳米胶束的体内生物利用度是PZ的3倍,治疗阈值(>20μg/mL)长达30小时。这种新策略为PZ的不良性质提供了可行的解决方案。
