【作者】 秦金淼；

【导师】 李引乾；

【作者基本信息】 西北农林科技大学 ， 基础兽医学， 2009， 硕士

【摘要】 多潘立酮作为第二代促胃动力药,在人医上已得到广泛应用,但在兽医临床上少有报道。本试验的目的在于研制出以多潘立酮为主药的微乳制剂,并对其进行质量控制、稳定性、安全性以及药效学研究,以探求此剂型在兽医临床上应用的可能性,为其在兽医临床上的应用提供科学依据。1.空白微乳的研制以吐温80(Tween80)、司盘80(Span80)和聚氧乙烯氢化蓖麻油(RH-40)为表面活性剂,丙二醇、甘油、无水乙醇为助表面活性剂,再添加不同比例的油相(液体石蜡、蓖麻油、乙酸乙酯和肉豆蔻酸异丙酯)和水相制备微乳。通过绘制伪三元相图筛选微乳处方。结果表明,RH-40/IPM/蒸馏水(Km=9:1、8:2)体系形成的微乳区最大,稳定性好,故作为药用空白微乳的最佳处方。2.多潘立酮微乳的制备及质量评价通过滴定法绘制伪三元相图,根据相图优选处方,并考察了微乳的形态粒径和理化性质。用紫外分光光度(UV-Vis)法测定微乳中多潘立酮的含量。结果表明,制备出的多潘立酮微乳处方是RH-40/IPM/多潘立酮/蒸馏水(Km=9:1)。微乳稳定,透射电镜下呈圆球形,分布均匀,平均粒径为12.4 nm。在1μg/mL～50μg/mL浓度范围内,浓度与吸光度的线性关系良好,平均回收率为99.41±1.17%,RSD为1.18%(n=5)。该处方设计合理,方法可靠。3.多潘立酮微乳的稳定性及LD50的测定分别在4℃、室温(25℃)、38℃条件下对多潘立酮微乳进行热稳定性实验,光照条件下进行光稳定性实验,离心加速实验考察其乳液的均一稳定性。结果表明,多潘立酮微乳对热、光不稳定,离心加速后稳定性好,因此多潘立酮微乳应低温避光保存。选用昆明种小鼠,经口灌胃一次给药,统计死亡率,用改良寇氏法计算半数致死量(LD50),并观察毒性作用,为临床用量的确定提供科学的依据。结果显示,多潘立酮微乳对小鼠的口服LD50为899.91 mg/kg,其95 %可信区间为850.94 mg/kg～951.92 mg/kg,表明多潘立酮微乳属于低毒性的药物。4.多潘立酮微乳的药效学研究对多潘立酮微乳进行了家兔在体、离体肠管运动试验,并观察了其对山羊胃肠蠕动的影响。结果显示,多潘立酮微乳能明显加快家兔在体肠管蠕动,大剂量时甚至发生剧烈收缩;对家兔离体肠管平滑肌有兴奋作用,可促进小肠的运动;对山羊胃肠蠕动频率的影响进一步表明,该药对瘤胃和小肠蠕动频率均明显提高,并在2 h达最高值,于2 h后逐渐下降,且这种作用可以持续8 h以上。更多还原

【Abstract】 Domperidone was producted as the second generation of gastro-kinetic agent, and used widely in medicine for human, but few reports on veterinary medicine. The aim of the research is to prepare domperidone microemulsion, and perform the study on quality control, stability, safety and pharmacodynamics, which can find the possibility in veterinary clinic and provide scientific basis for apllication.1. Study on the blank microemulsionIn order to prepare the microemulsion, the Tween80, Span80 and RH40 were used as surfactant, the propylene glycol, glycerol and dehydrated alcohol were used as cosurfactant, the liquid paraffin, castor oil, acetoacetate and IPM were used as oil, the formulations of the microemulsion was optimized by using the pseudo-ternary phase diagram. The results indicated that the region of blank microemulsion system of RH-40/IPM/water (Km=9:1, 8:2) was the biggest, and the stability was good. So it was definited as the best formulation of blank microemulsion.2. Preparation and quality evaluation of domperidone microemulsionThe optimum formulation was investigated by using titration to prepare the Pseudo-ternary phase diagram, testing the size of distribution and physico-chemical property of domperidone microemulsion. The content of domperidone was determined by UV-Vis.The results showed that the domperidone microemulsion delivery could be prepared using RH-40/ IPM/domperidone/Water(Km=9:1). The average size of domperidone microemulsion was 12.4 nm. Calibration curve was linear in the range of 1μg/mL~50μg/mL, the average recovery was 99.41±1.17%, with RSD of 1.18%(n=5). The formulation is reasonable and the method is accurate.3. Stability and LD50 tests of domperidone microemulsionHeat stability of domperidone microemulsion was studied at 4℃, room temperature and 38℃. Photo-stability and uniform stability of microemulsion were studied by low temperature with light exposure and centrifugation respectively. The results showed that the domperidone microemulsion wasn’t stable to heat and light but stable to centrifugation and low temperature(4℃). These results suggested that domperidone microemulsion should be stored at low temperature (4℃)and away from light. The acute oxicity test of domperidone microemulsion in mice in taking orally was carried out in order to establish base for further research and development, then provid science foundation for clinical dosage. The toxic effect was observed and the LD50 were calculated by Karber method. The results suggeted that LD50 of domperidone microemulsion in mice was 899.91mg/kg, and 95% average incredible range of its LD50 was 850.94mg/kg～951.92mg/kg, The results indicated that domperidone microemulsion was the drug of low toxicity.4. The pharmacodynamics study on domperidone microemulsionThe tests of intestine movement in vivo and in vitro was done on rabbit, and the effect of domerdone microemulsion on rumen and small intestine peristalsis in goat was observed. The results showed that the intestine contracted obviously when domperidone microemulsi was dropped, the construction became impetuous with dose increased. The tracing results of domperidone microemulsion’s effect on rabbit’s intestine in vitro showed that the tension increment of small intestine increased obviously when the drug was administrated, which can stimulate the tension of smooth muscle and enhance the movement of the small intestine. The result of microemulsion’s effect on goat further indicated that the peristalsis frequency in small intestine and rumen increased obviously after administration, peaked 2 hours later, then decreased gradually. The whole process lasted over 5 hours.更多还原