注射用亚锡依替菲宁药盒的制备与应用

目的 对注射用亚锡依替菲宁的制备工艺进行改进,并将该药盒应用于临床.方法 将2,6-二乙基苯胺与氯乙酰氯经酰化反应得中间体氯乙酰(2,6-二乙基)苯胺,中间体与亚胺基二乙酸缩合反应生成(2,6-二乙基乙酰苯胺基)亚氨二乙酸(即依替菲宁).改变反应温度,并采用重结晶纯化方法以提高收率.40 mg依替菲宁与0.4 mg氯化亚锡制备得到药盒.依照《中华人民共和国药典》进行质量检测,检查药盒的性状、鉴别、澄明度、酸度、亚锡含量、依替菲宁含量、无菌情况、细菌内毒素.以99Tcm标记亚锡依替菲宁,检测标记物99Tcm的放化纯.观察99Tcm-依替菲宁临床显像效果.结果 合成的依替菲宁经红外光谱、氢谱、质谱等方法确证.红外光谱( KBr,cm-1):3308、3010、1706、1665、1535和1471;氢谱(CD3OD;相对位移,×10-6):1.16、2.57、3.62、3.67、7.11和7.20;质谱m/z:323(M+).成功制备注射用亚锡依替菲宁药盒.产品为白色粉末,易溶于水,加氯化钠溶液后澄清无色,pH值为4.6,细菌内毒素含量＜75内毒素单位(EU)/瓶.标记物99Tcm-依替菲宁经纸层析方法测定,其放化纯为96％,达到临床使用要求.患者显像肝胆图像清晰,表明该药可应用于肝胆疾病的诊断.结论 改进后的药盒制备方法合理可行,制备得到的药盒满足临床显像要求.

The preparation of an etifenin and stannous chloride kit for hepatobiliary imaging

Objective To improve the synthesis of etifenin and stannous chloride for injection in clinical practice. Methods N-ehloraeetyl-2,6-diethylaniline was obtained by reaction of ehloroaeetyl chlo- ride with （2,6-diethyl） aniline. It was condensed by iminodiaeetie acid to generate （2,6-diethylacetani- lide） iminodiaeetate （etifenin）. The reaction temperature was changed and the product was＇reerystallized for purification. The ligand, 40 mg etifenin, and the reducing agent, 0.4 mg SnC12 , were reacted in the kit. Quality control analysis was performed according to the Chinese Pharmacopoeia. The radiochemieal pu- rity of the labeled compound, 99Tcm-etifenin, and its use in hepatobiliary imaging was studied. Results The synthetic ligand was confirmed by infrared spectroscopy（IR） , 1 H-nuclear magnetic resonance （ NMR）, mass spectroscopy （MS） and elemental analysis. IR peaks （KBr, em-1） were located at： 3308, 3010, 1706, 1665, 1535, 1471 ; l H-NMR（ CD30D, ppm） peaks were ： 1.16, 2.57, 3.62, 3.67, 7.11,7.20 ; MS m/z was 323 （ M ＋ ）. The ligand and reducing agent were lyophilized to form a sterile nonpyrogenie kit. The quality satisfied the Chinese Pharmacopoeia standard, including the identity test, pH （4.6） , tin con- tent, etifenin content, sterile test and endotoxin test （the content was 〈 75 endotoxin unit （EU）/bottle）. The radiochemieal purity of 99Tcm-etifenin was 96%. The hepatobiliary imaging by 99Tcm-etifenin was of high quality. Conclusion The modified synthesis of etifenin and stannous chloride for injection is simple and feasible. The improved etifenin and stannous chloride kit could be applied to clinical imaging.