【作者】 冯明芳；

【导师】 丁平田； 何仲贵； 赵春顺；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2007， 硕士

【摘要】 3-正丁基苯酞（3-n-butylphthal ide，简称NBP）是从芹菜籽挥发油中分离得到的抗脑缺血的有效成分，经化学合成后用于临床试验的新药。本文旨在研究一种能将NBP静脉注射给药的制剂，即NBP静脉注射用亚微乳，利用脑透析技术验证该制剂是否可以透过血脑屏障（blood-brain barrier，BBB）进入脑组织，测定NBP的脑脊液浓度和血清浓度，研究该制剂脑内和血内药物浓度的相关性。建立NBP静脉注射用亚微乳的体外分析方法，考察pH与温度对NBP的影响。单因素考察NBP亚微乳处方组分及用量，优化NBP静脉注射用亚微乳的制备工艺，在此基础上，采用正交设计法筛选处方。对最优处方所制制剂进行稳定性考察。建立NBP静脉注射用亚微乳脑透析液和血清的体内分析方法，采用脑透析技术及大鼠血清药物浓度的测定评价该制剂脑内和体内药动学行为及二者的相关性。利用HPLC法测定NBP静脉注射用亚微乳中NBP的含量，该法专属性强、准确度高、重现性好，利用该法测定NBP在pH 5～11范围内，对热稳定。单因素考察确定了NBP亚微乳的载药量为5％，对处方稳定性影响最主要的是乳化剂（E-80）、助乳化剂（COE2）及稳定剂（ST），对这三个因素进行正交设计筛选处方。按优化后的处方和工艺制备的NBP亚微乳外观为乳白色，无油滴，无分层，pH为7.5～8.5，平均粒径为128.0±3.4 nm（n=3），Zeta电位为-34.3±5.3mv（n=3），样品能耐受高压灭菌。在4、25、40℃条件下放置3个月，除平均粒径略有增大，以及40℃下乳剂略为变黄外，其他各项指标无明显变化。采用脑透析技术测定大鼠脑内NBP浓度。按增量法计算探针的回收率。比较了NBP两种制剂和两种剂量的脑内浓度，结果表明，给予不同剂量的NBP亚微乳，其脑内峰浓度随给药剂量的增大而增大；给予相同剂量的NBP乙醇液和NBP亚微乳，前者较后者脑内达峰时间短，消除快。血清药物浓度测定结果表明，NBP乙醇液和NBP亚微乳在体内均呈双隔室模型分布，二者T_1／2。分别为17.2007±2.6308 min，17.0438±4.5502 min；T_1／2β分别为233.38±134.43 min，382.11±206.82 min，说明NBP乙醇液在体内消除较快。与脑内浓度结果相联系，对NBP乙醇液来说，NBP脑内浓度随血清内浓度的降低而降低；对NBP亚微乳来说，NBP脑内浓度随血清浓度的降低先增大后减小。自制NBP静脉注射用亚微乳平均粒径小，粒径分布范围窄，性质稳定，符合静脉注射要求。体内实验证实该制剂可以到达脑部发挥药效。更多还原

【Abstract】 3-n-Butylphthalide（NBP）, a novel cerebral antiischemic agent, was isolated and identified from several plants including celery oil. The main objective of this research was to study an intravenous formulation of NBP- NBP submicron emulsion for intravenous administration. We determined the uptake of NBP into the brain to investigate whether the NBP submicron emulsion can cross the blood-brain-barrier with the method of brain microdialysis. We also determined NBP concentration in serum to study the correlation of NBP content both in brain and blood.A method for determining NBP submicron emulsion in vitro was developed. The effect of pH and temperature on NBP was investigated. The constituent and content of NBP submicron emulsion formulation was studied by one-factor experiment. Processing parameters were studied and optimized., and then the optimized formulation was selected through orthogonal experimental design. The stability of the optimized formulation was also inspected. The methods for detecting NBP both in brain dialysate and serum were established. Pharmacokinetics in brain and blood were studied by intracerebral microdialysis and serum content determination., and the correlation of both was also investigated.A specified HPLC method was developed for the determination of NBP in vitro. NBP was stable under heating within the pH range from 5 to 11. The content of NBP in the formulation was 5％, and the emulsifier（E-80）, coemulsifier（COE2）, stabilizer（ST）had obviously effect on the stability of NBP submicron emulsion. The best formulation was selected by orthogonal experimental design. A fine and stable NBP submicron emulsion was acquired under good processing control. The average particle size was 128.0±3.4 nm（n=3）and the zeta potential was -34.3±5.3 mv（n=3）. NBP submicron emulsion was stable after sterilization. All the property parameters of NBP submicron emulsion were almost the same under the condition of 4, 25, 40℃except that the colour of the NBP submicron emulsion under 40℃was a little yellow and the average size under all conditions was slightly increased.The intracerebral NBP content in rats was determined using brain microdialysis technique. The recovery of probes was calculated by the way of recovery by gain. Two preparations and two doses of NBP were compared in brain. For NBP submicron emulsion, the concentrain of NBP in brain increased when the rats administered more drugs. For NBP ethanol solution and NBP submicron emulsion, the former reached the maximum concentration faster than the latter and also eliminated more quickly than the latter.It indicated from the serum NBP concentration that both the NBP submicron emulsion and NBP ethanol solution exhibited two-compartment distribution. T_1/2α values were 17.2007±2.6308 min and 17.0438±4.5502 min, respectively. T_1/2β values were 233.38±134.43 min and 382.11±206.82 min, respectively. NBP ethanol solution eliminated more rapidly than NBP submicron emulsion.When correlated the NBP concentration both in brain and serum, we fotmd that the concentration of NBP in brain decreased with the NBP concentration in serum for NBP ethanol solution; the concentration of NBP in brain increased first and then decreased with the NBP concentration in serum for NBP submicron emulsion.The self-made NBP submicron emulsion for intravenous administration with small size and narrow size distribution was stable and can be used for intravenous administration. The in vivo study proved that NBP submicron emulsion can distributed into brain and acted on it.更多还原