目的 研究佐匹克隆的生物药剂学分类系统（BCS），并对原研和3家仿制企业原料的关键理化性质进行对比评价，为佐匹克隆片剂的一致性评价提供依据。方法 检测pH 6.8和pH 7.4的磷酸盐缓冲液中佐匹克隆的固有溶出速率；分别采用差示扫描量热法（DSC）和X射线粉末衍射法对佐匹克隆的晶型进行考察；采用高效液相色谱（HPLC）法测定佐匹克隆不同pH介质中的平衡溶解度及表观油水分配系数；分别采用平行人工膜渗透性模型（PAMPA）和Caco-2细胞模型，考察佐匹克隆的有效渗透性。对佐匹克隆的BCS进行初步判定，并考察原研与仿制企业原料的差异。结果 原研与仿制企业的佐匹克隆晶型为同一晶型，为对映异构体形成的无水非中心对称的正交晶型化合物；佐匹克隆在酸性介质中溶解度最高，为高溶解度药物；表观油水分配系数结果表明，佐匹克隆在胃内几乎无吸收，在不同肠段存在不同程度的吸收；PAMPA和Caco-2细胞模型均判定佐匹克隆为高渗透性药物，P-gp转运体参与佐匹克隆的肠道转运过程。原研与仿制企业原料的固有溶出速率、晶型、溶解度、表观油水分配系数和有效渗透性基本一致。结论 佐匹克隆为BCS Ⅰ类药物；原研与仿制企业原料的关键理化性质基本一致；为佐匹克隆片的体外溶出行为评价和体内外相关性研究提供数据支撑。

Objective To determine the biopharmaceutics classification system (BCS) of zopiclone and compare the key physicochemical characteristics of the original and generic drug materials. Methods The intrinsic dissolution rates of zopiclone in pH 6.8 and pH 7.4 phosphate buffer were measured; The crystal form of zopiclone was investigated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD); The equilibrium solubility and apparent oil-water partition coefficient of zopiclone in different pH media were determined by high performance liquid chromatography (HPLC); Parallel artificial membrane permeability model (PAMPA) and Caco-2 cell model were used to investigate the effective permeability of zopiclone. The BCS of zopiclone was preliminarily determined, and the differences of raw materials between original research and imitation enterprises were investigated. Results The crystal form of zopiclone from original research and imitation enterprises was the same crystal form, which was an anhydrous noncentrosymmetric orthorhombic compound formed by enantiomer; Zopiclone had the highest solubility in acid medium, which was a high solubility drug. The results of apparent oil-water partition coefficient showed that zopiclone had almost no absorption in the stomach, and there were different degrees of absorption in different intestinal segments. Both Pampa and Caco-2 cell models showed that zopiclone was a highly permeable drug. P-gp transporter was involved in the intestinal transport process of zopiclone. There was no significant difference in the intrinsic dissolution rate, crystal form, solubility, apparent oil-water partition coefficient and effective permeability between the original and generic drug materials, although there were obvious differences in the synthesis process. Conclusion Zopiclone is classified into class Ⅰ in the BCS. By comparing the key parameters of the original and generic drug materials, the data support can be provided for the in vitro dissolution behavior evaluation and in vitro and in vivo correlation research of zopiclone tablets.

R945

国家“重大新药创制”科技重大专项资助项目（2017ZX09101001）