Cirilli Roberto, Guglielmi Paolo, Formica Francesca Romana, Casulli Adriano, Carradori Simone
Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, 00185 Rome, Italy.
J Pharm Biomed Anal. 2017 May 30;139:1-7. doi: 10.1016/j.jpba.2017.01.057. Epub 2017 Feb 20.
Albendazole (ABZ) is a sulfanyl-benzimidazole anthelmintic drug used worldwide in the treatment and prevention of parasitic diseases in animals and humans. Following oral administration, ABZ is rapidly oxidized into the pharmacologically active chiral sulfoxide metabolite known as ricobendazole (RBZ). As its achiral precursor, RBZ shows very low intestinal absorption due to its poor solubility in water (0.06mgmL). To the best of our knowledge, there is no known example in human medicine of a water-soluble salt form of racemic or enantiomerically pure RBZ. In the present study, we describe in detail the preparation of the sodium (Na) salt of the enantiomers of RBZ through a two-step process: i) the multi-milligram resolution of RBZ by HPLC on the amylose-based Chiralpak IG chiral stationary phase under polar organic mode; ii) the salification of the isolated enantiomers of RBZ by reaction with sodium hydroxide solution. The spectroscopic and chiroptical properties of the RBZ-Na enantiomers were determined. Due to their unique solubility in 0.01M phosphate buffer at physiological pH (14.49mgmL) and the high sample throughput obtained on semipreparative separation of the non-salified form, it is potentially possible to develop new anthelmintic enantiopure formulations with improved pharmacokinetic properties and lower toxicity.
阿苯达唑（ABZ）是一种硫烷基苯并咪唑驱虫药，在全球范围内用于治疗和预防动物及人类的寄生虫病。口服后，ABZ会迅速氧化为具有药理活性的手性亚砜代谢物，即瑞苯达唑（RBZ）。作为其非手性前体，RBZ由于在水中的溶解度较差（0.06mg/mL），肠道吸收非常低。据我们所知，在人类医学中，尚无外消旋或对映体纯的RBZ水溶性盐形式的已知实例。在本研究中，我们详细描述了通过两步法制备RBZ对映体钠盐的过程：i）在极性有机模式下，在基于直链淀粉的Chiralpak IG手性固定相上通过HPLC对RBZ进行多毫克级拆分；ii）将分离出的RBZ对映体与氢氧化钠溶液反应进行成盐。测定了RBZ-Na对映体的光谱和旋光性质。由于它们在生理pH值下于0.01M磷酸盐缓冲液中具有独特的溶解度（14.49mg/mL），并且在非盐化形式的半制备分离中获得了高样品通量，因此有可能开发出具有改善的药代动力学性质和更低毒性的新型驱虫对映体纯制剂。
