伊维菌素微乳的安全性评价及质量标准研究

发布时间：2018-08-27 14:37

【摘要】：伊维菌素微乳制剂是一种新型高效、广谱、低毒和对多种动物体内外寄生虫有高效驱杀作用的新制剂,是以纳米乳为载体,以80%以上水为溶剂制成。本论文对该制剂的安全性评价、制剂含量测定方法的建立、稳定性试验、制剂的无菌检查进行了研究。1.对新型伊维菌素微乳制剂进行了过敏性试验、溶血试验、肌肉刺激性试验、热原检查、注射途径的急性毒性试验、亚慢性毒性试验等安全性评价试验。结果显示:制剂对豚鼠和大鼠的过敏性反应均为阴性,无致敏性;制剂未出现溶血和红细胞凝聚现象;制剂对家兔股四头肌未见明显刺激作用;热原限度符合规定,无致热原;制剂对大鼠腹腔注射的LD50为3.8256g/kg,95%可信限为3.4639 g/kg~4.2251 g/kg,对小鼠腹腔注射的LD50为3.2200 g/kg,95%可信限为1.8197 g/kg~5.6979 g/kg,高于伊维菌素原料药对小鼠腹腔注射的的LD50(24.2493 mg/kg);亚慢性毒性试验,各给药剂量组大鼠的体重、血液学指标、生化指标与对照组比较均无显著性差异,显示伊维菌素微乳制剂对大鼠长期给药无明显毒副作用,临床用药安全。以上结果证明:新型伊维菌素微乳制剂安全可靠,可应用于兽医临床。2.建立了新型伊维菌素微乳制剂中伊维菌素的高效液相色谱法的含量测定方法。伊维菌素的色谱条件为Hypersil ODS2(5um,4.6mm x 250mm)色谱柱,流动相为甲醇:乙腈:水=35:60:5(v/v),柱温30℃,进样量10μl,检测波长244 nm,流速1mL·min-1。用该方法检测3批制剂中伊维菌素的含量为标示量的94%~100%,方法准确可靠、选择性好、重现性好、操作简便、快速,可用于伊维菌素微乳制剂中伊维菌素的含量测定。3.对新型伊维菌素微乳制剂的中试产品进行了高温、高湿、强光照射和加速试验。结果表明,在以上条件下伊维菌素的含量没有明显变化,样品正立、倒立、平放放置对含量无明显影响,即橡胶塞可用于该制剂的封装。试验结果证明该制剂易于存储和运输。4.对新型伊维菌素微乳制剂进行无菌检查,进行了无菌检查的方法验证试验,确立了该制剂无菌检查的方法,并对3批伊维菌素微乳制剂进行了无菌检查,结果显示,阳性对照菌均在24h内生长良好,阴性对照均澄清,无菌生长,3批供试品均澄清,无菌生长,无菌检查试验结果符合规定。
[Abstract]:Ivermectin microemulsion is a novel preparation with high efficiency, broad spectrum, low toxicity and high efficiency in killing parasites in vivo and in vitro. It is prepared with nanometer emulsion as carrier and more than 80% water as solvent. In this paper, the safety evaluation, determination method, stability test and aseptic examination of the preparation were studied. The safety evaluation tests such as hypersensitivity test hemolysis test muscle irritation test pyrogen test acute toxicity test of injection route subchronic toxicity test and so on were carried out on the new Ivermectin microemulsion. The results showed that the allergic reaction of the preparation to both guinea pigs and rats was negative without sensitization, no hemolysis and erythrocyte condensation, no obvious stimulation to the quadriceps femoris muscle of rabbits, no pyrogen limit and no pyrogen. The LD50 of intraperitoneal injection was 3.8256g / kg 95% confidence limit was 3.4639 g/kg~4.2251 / kg, the LD50 confidence limit of mice was 3.2200 g / kg 95% confidence limit was 1.8197 g/kg~5.6979 / kg, which was higher than that of Ivermectin API LD50 (24.2493 mg/kg). There was no significant difference in body weight, hematological index and biochemical index between each dosage group and control group, which showed that Ivermectin microemulsion had no obvious side effect on long-term administration of Ivermectin in rats, and was safe in clinical use. The results show that the new Ivermectin microemulsion is safe and reliable and can be used in veterinary clinic. A HPLC method for the determination of ivermectin in new Ivermectin microemulsion was established. The chromatographic conditions of ivermectin were as follows: Hypersil ODS2 (5umn 4.6mm x 250mm) column, mobile phase: methanol: acetonitrile: water 35: 60: 5 (v / v), column temperature 30 鈩，

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