目的 研究佐匹克隆的生物藥劑學分類系統(tǒng)（BCS），并對原研和3家仿制企業(yè)原料的關鍵理化性質進行對比評價，為佐匹克隆片劑的一致性評價提供依據。方法 檢測pH 6.8和pH 7.4的磷酸鹽緩沖液中佐匹克隆的固有溶出速率；分別采用差示掃描量熱法（DSC）和X射線粉末衍射法對佐匹克隆的晶型進行考察；采用高效液相色譜（HPLC）法測定佐匹克隆不同pH介質中的平衡溶解度及表觀油水分配系數；分別采用平行人工膜滲透性模型（PAMPA）和Caco-2細胞模型，考察佐匹克隆的有效滲透性。對佐匹克隆的BCS進行初步判定，并考察原研與仿制企業(yè)原料的差異。結果 原研與仿制企業(yè)的佐匹克隆晶型為同一晶型，為對映異構體形成的無水非中心對稱的正交晶型化合物；佐匹克隆在酸性介質中溶解度最高，為高溶解度藥物；表觀油水分配系數結果表明，佐匹克隆在胃內幾乎無吸收，在不同腸段存在不同程度的吸收；PAMPA和Caco-2細胞模型均判定佐匹克隆為高滲透性藥物，P-gp轉運體參與佐匹克隆的腸道轉運過程。原研與仿制企業(yè)原料的固有溶出速率、晶型、溶解度、表觀油水分配系數和有效滲透性基本一致。結論 佐匹克隆為BCS Ⅰ類藥物；原研與仿制企業(yè)原料的關鍵理化性質基本一致；為佐匹克隆片的體外溶出行為評價和體內外相關性研究提供數據支撐。

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

國家“重大新藥創(chuàng)制”科技重大專項資助項目（2017ZX09101001）