【作者】 肖莉；

【导师】 张韻慧；

【作者基本信息】 天津大学 ， 药物分析， 2005， 硕士

【摘要】 尼莫地平是1,4-双氢吡啶类钙通道拮抗剂,其药理特性是能有效地调节细胞内钙水平,使之保持正常的生理功能。对脑血管的作用尤为突出,能有效预防和治疗蛛网膜下腔出血所引起的脑血管痉挛造成的脑组织缺血性损害,对离体或体内的脑动脉,正常或缺血脑动脉均有扩张作用。因其水溶性差、口服生物利用度低,导致临床给药次数频繁,患者服药不便,且易因血药浓度积累引起毒副作用。本课题研究的目标是应用现代药物制剂新技术,制备尼莫地平微球,从而达到缓释作用,减少服用剂量及毒副刺激作用,同时,建立相应的检测方法。本研究中采用溶剂提取法制备了尼莫地平聚乳酸微球,通过正交实验,考察了各因素对微球性质的影响。实验结果表明:聚乳酸浓度、乳化剂浓度、投药比及油水两相体积比等均可成为微球的粒径大小、包封率、载药量及产率的影响因素。优选后的制备工艺为:聚乳酸的浓度为7.5%,乳化剂明胶的浓度为1.5%,尼莫地平:聚乳酸为2:3,油水相体积比为5:40。通过对最佳制备工艺的验证实验表明了以上工艺的重现性和稳定性是可靠的。稳定性实验表明:37℃密闭保存,微球会产生粘连破坏。4℃及25℃下密闭保存,微球的形态、载药量及包封率均较稳定。这现象与聚乳酸的玻璃化温度(40-55℃)有关。因此,微球贮存条件应为不高于25℃密闭保存。体外释药研究表明,释药过程可用零级方程拟合。微球的载药量及制备过程中的因素会对其释药性产生影响。以聚乳酸为载体材料制备的尼莫地平微球具有明显的缓释作用,能够达到延长药效作用时间及减少给药次数的目的。更多还原

【Abstract】 Nimodipine is a dihydropyridine calcium channel blocker, which regulatesintracellular calcium level effectively to maintain normal physiological functions. Itdemonstrates a marked specificity for cerebral vessels. Major interests have focusedon its use in the prevention and treatment of the cerebral ischemic lesions thatfrequently occur in patients with subarachnoid haemorrhages as a result of sustainedcerebral vasospasm and the inhibition of transmembrane calcium influx. However,there are several unfavorable characteristics for this drug. Because of its lower watersolubility, oral bioavailability is lower and variable.In this work, the main goal is to prepare Nimodipine PLA microspheres , whichcan not only prolong acting time, decrease the dose but also minimize side effect, then,a series of novel study method are developed for the microspheres.A solvent extraction method was employed to prepare the Nimodipine PLAmicrospheres. The influences in the process of preparing PLA microspheres werestudied according to an orthogonal-design of experiments. The polymeric theconcentration of internal phase, the concentration of dispersing agent, the ratio ofnimodipine: PLA, volume ratio of oil phase to water phase could affect microspheressize, drug encapsulating efficiency and drug content. The optimum preparationmethod is: the PLA concentration is 7.5%, the gelatin concentration is 1.5%, the ratioof nimodipine: PLA is 2:3, the volume ratio of oil phase to water phase is 5:40. Therepeated tests of optimum preparing method proved that its stability is good.The study on stability indicates that when stored at 37℃, the microspheres fusedand aggregated;while stored at 4℃ or room temperature under sealed condition forsix months, surface morphology, drug content and in vitro release of microsphereswere not altered. It possibly related to the glasstransition temperature for PLA.Studies on the release in vitro showed that the release kinetics of nimodipinefrom PLA microspheres could be described by zero-order equation. The release ratewas related to drug content and some factors for preparation.In conclusion, a new Nimodipine-PLA microspheres that can prolonged actingtime and decrease side effects was developed.更多还原