【作者】 陈小军；

【导师】 孙志良；

【作者基本信息】 湖南农业大学 ， 基础兽医， 2005， 硕士

【摘要】 硫酸阿米卡星传统制剂的主要缺点是生物半衰期短,用量大,且具有耳、肾和神经肌肉阻滞等毒副作用,而脂质体剂型能有效延长药物的半衰期,减少用量,降低毒副作用。本文在研究了有关单—因素对硫酸阿米卡星脂质体包封率和稳定性的影响的基础上,运用正交设计法优化了脂质体的制备工艺和处方。结果表明,硫酸阿米卡星脂质体的最佳处方为:磷脂:胆固醇=1.5:1,药物:（磷脂+胆固醇）=1:15,PBS液的pH值为7.0,脂相:水相=3:1,以乙醚为有机溶剂,采用逆相蒸发法制备。在此条件下所制备的脂质体包封率为64.8%,具有较好的稳定性。 为研究硫酸阿米卡星脂质体在家兔体内的代谢动力学,给家兔一次静注硫酸阿米卡星脂质体（12.5mg/kg）,在24 h内不同时间点取血样测定血药浓度。结果表明:药-时曲线符合一室开放模型,其主要药代动力学参数分别为:生物半衰期(t_1/2)7.40h,表观分布容积（V_d）39.46mL,药时曲线下面积（AUC）6899.51h.μg/mL,清除率（Cl_B）3.82mL/h。结果显示硫酸阿米卡星脂质体制剂能有效地延长药物的作用时间。 对硫酸阿米卡星脂质体作了安全性评价。急性毒性试验结果表明,硫酸阿米卡星脂质体对小白鼠的最大耐受量大于750mg/kg.bw,80只小白鼠随机分为4组,即140mg/kg.bw、70mg/kg.bw、35mg/kg.bw和阴性对照组,相当于临床用量的28、14、7倍,连续4w腹腔注射后,进行血液学、血清生化学和组织病理学检查,结果与对照组无显著性差异。结果表明,硫酸阿米卡星脂质体在治疗剂量范围内安全可靠。 本文考察了硫酸阿米卡星脂质体的体外抑菌效果,并比较了硫酸阿米卡星脂质体和硫酸阿米卡星对大肠杆菌、链球菌、巴氏杆菌、金葡菌的最小抑菌浓度和最小杀菌浓度.结果表明:硫酸阿米卡星脂质体对大肠杆菌、链球菌、巴氏杆菌、金葡菌的最低抑菌浓度分别约为游离硫酸阿米卡星的1/3.5、1/7、1/2、1/2,最低杀菌浓度分别约为游离阿米卡星的1/4、1/4、1/1.8、1/4,证明硫酸阿米卡星脂质体的体外抗菌作用明显优于游离药物。 为了研究硫酸阿米卡星脂质体的临床疗效,探讨其临床适应症,用硫酸阿米卡星脂质体与硫酸阿米卡星进行了对比试验,观察了其临床治疗效果。选择某链更多还原

【Abstract】 The main shortcoming of the traditional preparation of amikacinsulfate is its short elimination half-life ,great consumption and toxicity of ear , kidney and neural muscle. Liposomal amikacinsulfate can improve above-mentioned index. On the basis of evaluating separately the influence of several factors on the encapsulation efficiency and stability ,the orthogonal design was utilized to optimize the preparation and formulation of liposomal amikacinsulfate. The results showed that the ideal ratio for lecithinxholesterol is 1.5:1, the ratio for amikacinsulfate :（lecithin+cholesterol） is 1:15 and pH of PBS is 7.0, the ratio for organic solvent PBS is 3:1. The encapsulation efficiency is 64.8%,and its stability is satisfying.The experiment was conducted in rabbit s body to investigate pharmacokinetics about liposomal amikacinsulfate. A dose of 12.5mg/kg.bw liposomal amikacinsulfate was given iv to rabbits and blood samples were collected at different time during 24 hours to measure the drug concentration. The results showed that drug concentration-time curve conformed to one compartment-open model. Its main pharmacokinetical parameters were t_1/27.40 h, Vd 39.46 mL, AUC 6899.51 h.μg/mL、 ClB3.82mL/h.Acute toxicity of liposomal amikacinsulfate in mice showed maximum tolerance capacity of liposomal amikacinsulfate was higher than 750 mg/kg. bw. 80 mice were randomly divided into 4 groups .140,70,35,0 mg/kg.bw liposomal amikacinsulfate were supplied to each group by i.p for 4 weeks in succession in order to investigate its subchronic toxicity . The results indicated that toxicity of liposomal amikacinsulfate was significantly lower than that of conventional amikacinsulfate.Liposomal amikacinsulfate,was compared its MIC and MBC against E.coli, streptococcus, pasteurella multocid and staphylococcus aureus with free amikacinsulfate in order to study its antibacterial effect in vitro .The MIC of liposomal amikacinsulfate against the bacterias mentioned above were 1/3.5,1/7,1/2,1/2 of that of free amikacinsulfate, and the MBC were 1/4,1/4,1/1.8,1/4 of it. The results showed the antibacterial effect of liposomal amikacinsulfate was superior to free amikacinsulfate.In order to study clinical application of liposomal amikacinsulfate, A pig farm infected with streptococcosis suis was sellected to conducte clinical trail compared with conventional amikacinsulfate. 216 pigs were divided into five goups. Pigs of the更多还原