琥珀酰明胶注射液工艺优化及质量安全性评价  

Process optimization and safety evaluation of succinylated gelatin injection

作　　者：程志明 周婷硕 周慧 秦凯 刘貌林 张宇[1] CHENG Zhiming;ZHOU Tingshuo;ZHOU Hui;QIN Kai;LIU Maolin;ZHANG Yu(School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China;Jilin Changyuan Pharmaceutical Co.,Ltd.,Changchun 130103,China)

机构地区：[1]沈阳药科大学药学院,辽宁沈阳110016 [2]吉林省长源药业有限公司,吉林长春130103

出　　处：《中国药剂学杂志(网络版)》2025年第2期57-75,共19页Chinese Journal of Pharmaceutics:Online Edition

摘　　要：目的 对琥珀酰明胶注射液明胶原料进行质量控制,优化琥珀酰明胶注射液的处方和工艺,并对该产品及其参比制剂进行质量研究以及安全性评价。方法 比较《中华人民共和国药典》(Ch P 2020)、《欧洲药典》(EP 10.4)、《美国药典》(USP 43)和《日本药典》(JP 17)中明胶的质控标准,确定检验项目和限度,对明胶进行质量检验,并控制原辅料的内毒素水平。采用正交实验对琥珀酰明胶注射液的水解、酰化反应工艺进行参数考察,并通过体外溶血试验、全身主动过敏试验、血管刺激性试验进行安全性评价。结果 (1)明胶质量检验结果符合质量标准规定,原辅料的内毒素水平合格;(2)确认琥珀酰明胶注射液的工艺参数:氢氧化钠4.5 g(10 mol·L^(-1)),水解时间90 s,保温时间(40±20)min,丁二酸酐0.5 g,用水量30%,酰化温度80℃;(3)自制制剂的p H值、琥珀酰化度、琥珀酰明胶含量、氯含量、钠含量、胶体渗透压与参比制剂没有显著差异,具有一致性;自制制剂的游离琥珀酸和重均分子量与参比制剂有差异,其中,游离琥珀酸含量低于参比制剂,重均分子量高于参比制剂,但在质量标准范围内;(4)自制琥珀酰明胶注射液及其参比制剂对兔血红细胞均无溶血和凝集作用,豚鼠给予琥珀酰明胶注射液及其参比制剂全身致敏性评价结果均为阴性,日本大耳白兔多次静脉注射给予琥珀酰明胶注射液及其参比制剂均未见药物相关刺激性。结论明胶质量能够满足琥珀酰明胶注射液的研究;自制的琥珀酰明胶注射液的质量可控性和安全可靠性较好,自制制剂能够满足质量标准的要求,与参比制剂的安全性比较,未见明显差异。Objective To control the quality of gelatin,active pharmaceutical ingredient of succinylated gelatin injection,quality standards were investigated.Orthogonal experiments and safety evaluation were carried out to study the formulation process of succinylated gelatin injection,and to investigate the quality and the safety of succinylated gelatin injection and reference preparation.Methods The quality standards of gelatin in the Pharmacopoeia of ChP 2020,EP 10.4,USP 43,and JP 17 were compared to determine the test items and limits,and conduct quality inspection on gelatin,meanwhile,endotoxin level of raw material and accessories were controlled.The orthogonal design of L9(34)was used to explore the hydrolytic reactions and acylating reaction of succinylated gelatin injection.By the tests of hemolysis,active systemic anaphylaxis(ASA)and stimulation on blood vessel were used to exam the uniformity of succinylated gelatin injection and reference preparation.Results(1)The gelatin test results met the quality standards,and the endotoxin level of raw material and accessories were qualified.(2)The optimal formulation was determined from results of the orthogonal experiment as follow:sodium hydroxide was 4.5 g(10 mol·L-1),hydrolysis time was 90 s,the insulation time was(40±20)min,succinic anhydride was 0.5 g,the water consumption was 30%,and acylation temperature was 80℃.(3)There is no significant difference between the succinylated gelatin injection and reference preparation in pH value,colloid osmotic pressure,succinylation rate,succinylated gelatin,chlorine and sodium.The free succinic acid and the weight average molecular weight were both in accord with quality standard,although the free succinic acid of succinylated gelatin injection was slightly lower than that of reference preparation while its weight average molecular weight was slightly higher than that of reference preparation.(4)No evidences of hemolyzation or aggregation on rabbit erythrocyte in vitro,allergic reaction on guinea pig or vascular irritation ef

关 键 词：琥珀酰明胶注射液 工艺研究 质量标准 安全性评价 

分 类 号：R94[医药卫生—药剂学]