School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.
Medical College, Qinghai University, Xining, Qinghai 810001, P. R. China.
ACS Infect Dis. 2020 May 8;6(5):802-810. doi: 10.1021/acsinfecdis.9b00231. Epub 2019 Oct 17.
Alveolar echinococcosis (AE) is a chronic infectious parasitic disease that is fatal and still being neglected. Currently, the AE treatment recommended by the WHO is complete excision of the lesions, followed by the oral administration of albendazole (ABZ), the only effective first-line anti-AE drug, for two years. Unfortunately, complete excision of AE lesions is impossible in most cases, leaving the long-term use of ABZ as the only alternative. However, only about one-third of patients experience complete remission or cure with such treatments, largely because of the low oral bioavailability of ABZ caused by its very low solubility. To improve the oral bioavailability of ABZ, a novel nanocrystalline (NC) formulation of ABZ was obtained by spray-drying ABZ with a triblock copolymer poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (Poloxamer 188), and its physical structure was confirmed by scanning electron microscopy (SEM), small-angle X-ray scattering (SAXS), wide-angle X-ray diffraction (WAXRD), and polarized optical microscopy (POM). The significantly reduced ABZ crystallite size coupled with prolonged ABZ supersaturation significantly improved the drug dissolution performance compared with that of the commercial ABZ oral product (Albenda), and the NC formulation showed an approximately 4.2-fold higher AUC than Albenda in a pharmacokinetic comparison in Beagle dogs as measured by the plasma concentration of albendazole sulfoxide, the active antiparasitic metabolite. Even more encouragingly, after 30 days of once-daily oral administration of the NC and Albenda formulations to SD rats with hepatic alveolar echinococcosis, the NC formulation demonstrated a cyst inhibition effect 3.7-fold greater than that of Albenda. We therefore conclude that the NC formulation could potentially be developed into an improved anti-AE drug therapy.
泡型包虫病（AE）是一种致命的慢性传染性寄生虫病，但仍未得到重视。目前，世界卫生组织推荐的 AE 治疗方法是完全切除病变，然后口服唯一有效的一线抗 AE 药物阿苯达唑（ABZ），持续两年。不幸的是，在大多数情况下，完全切除 AE 病变是不可能的，这使得 ABZ 的长期使用成为唯一的选择。然而，只有约三分之一的患者通过这种治疗方法获得完全缓解或治愈，这主要是由于 ABZ 的极低溶解度导致其口服生物利用度极低。为了提高 ABZ 的口服生物利用度，我们通过将 ABZ 与三嵌段共聚物聚（环氧乙烷）-聚（环氧丙烷）-聚（环氧乙烷）（泊洛沙姆 188）喷雾干燥，获得了 ABZ 的新型纳米晶（NC）制剂，并通过扫描电子显微镜（SEM）、小角 X 射线散射（SAXS）、广角 X 射线衍射（WAXRD）和偏光显微镜（POM）确认了其物理结构。与商业 ABZ 口服制剂（Albenda）相比，ABZ 结晶度显著减小，ABZ 过饱和度延长，这显著提高了药物的溶解性能，在比格犬的药代动力学比较中，NC 制剂的 AUC 约为 Albenda 的 4.2 倍，这是通过 Albendazole sulfoxide 的血浆浓度来衡量的，Albendazole sulfoxide 是一种活性抗寄生虫代谢物。更令人鼓舞的是，在 SD 大鼠肝泡型包虫病模型中，每日一次口服 NC 制剂和 Albenda 制剂 30 天后，NC 制剂的囊泡抑制作用比 Albenda 制剂强 3.7 倍。因此，我们得出结论，NC 制剂有可能开发成为一种改良的抗 AE 药物治疗方法。
