【作者】 侯冬枝；

【导师】 谢长生；

【作者基本信息】 华中科技大学 ， 材料科学与工程， 2004， 博士

【摘要】 近年来越来越多事实表明,仅仅发展新药不足以保证药物治疗的进步,发展合适的药物载体系统可以克服目前存在的一些问题,还可能实现药物控释和定点释药。1990初开发的固体脂质纳米粒SLN(solid lipid nanoparticles)系统,认为其合并了聚合物纳米粒和O/W脂肪乳的优点;同时避免了二者的明显缺点。因而成为药剂学领域热门研究课题之一。由于所选用材料性能,制备工艺参数和SLN中药物和脂质的结构特征,均会对包封药物载体的体内行为产生关键作用,因此,本文从材料学角度,运用材料分析和药剂分析相结合的方法,改进了高剪切乳化超声法,在不添加有机溶剂的前提下,制备出具有相当稳定性能、较高包封率、足够载药量和缓控释作用的SLN体系。该工艺是将熔融乳化法和高速搅拌及超声技术结合起来的方法,要求两次搅拌和超声均要在水浴中进行,并始终保持制备温度不低于脂质熔点10℃以上。实验中发现,只用高剪切法制备的样品很快发生分层,上层浑浊,下层澄清,所得混悬液的平均粒径较大,下层平均粒径小于上层的,但多分散系数均较大;长时间大功率超声制备的样品,颗粒呈双模分布,没有观察到大于微米级颗粒,但超声探头易于产生Ti金属污染样品;只进行一次高剪切和超声的试样平均粒径约165nm(略大于改进工艺制备的),为半透明乳白色液体,但颗粒呈多模分布,存在较大颗粒。用改进工艺制备的纳米体系,平均粒径102nm,颗粒分布非常集中,呈单模分布,可长时间贮存,是很难得的胶体稳定系统。模型药米非司酮,是一种临床常用的抗早孕药物。实验中通过表面活性剂复配,制备出了平均粒径约100nm,可以长期稳定的SLN胶体系统。所制备的载药SLN试样,XRD和DSC分析表明,结晶度均较原始基材的明显降低,认为纳米化过程中伴随有非晶化的现象,破坏规则的晶格点阵结构,缺陷增加,从而为外来药物提供存在空间。研究认为一定质量的载体材料,只能够容纳一定量的外来药物分子,过多投药量并不能持续提高包封率。随投药量增加,体系平均粒径逐渐增大,认为与体系中游离药物对表面活性剂的消耗有关,Zeta电位变化趋势亦大致随投药量而增加。当较高投药量时,SLN体系中存在大量游离药物,DSC分析表明,其物理状态发生改变,不再以原料药的结晶状态存在了。添加20%海藻<WP=4>糖的SLN体系冻干后包封率仍可达到73%,粒径247nm(冻干前为109nm),取得了较好冻干效果。纳米混悬液样品的体外释放性能差异不大,只有平均粒径在微米量级试样,相对于纳米混悬液显示出初期的迅速释放,且在较短时间内(24hr)几乎达到完全释放(91%)。因此纳米载体系统可以延长药物的释放。雷公藤内酯醇的复合SLN微观结构中,固体脂质和液态油两种复合材料仍然以两种状态存在:因其表现为各自的熔融性状(低温和常温DSC研究)和分子运动状态(NMR检测)。并没有形成一种新的低共熔物,或者油相分子插入到片状固态脂质分子层之间,改变其两层结构(SAXS研究),甘油酯分子的整体排布不因为液相油的出现而受到影响。双链结构得以保持。由于复合纳米粒相对于固体基材制备纳米粒发生了长程变化(SAXS分析)和分子运动自由度改变(NMR分析)以及结晶结构的打乱(DSC分析),因此认为两种基材的混合物在生成纳米粒时,也并非各自生成了固态SLN和液体的纳米乳。由此推测本实验室制备含油纳米粒的微观结构,应该如Müller教授所示模型那样,液态油形成了更加微细的纳米油室,周围包被着固体脂质,而整个球形颗粒还处于纳米尺度。试样长期贮存稳定性实验表明,相对于新鲜制备试样(102nm),贮存三个月的粒径只有限增加(106nm),半年后平均粒径增加不显著(126nm)。尚需指出的是,其间试样多分散系数在不断增加。更多还原

【Abstract】 More and more facts showed that developing new drug could not support the therapy progress yet during recent years, the appropriate drug carrier system could overcome the problems existed at present and also satisfy the special requirement of control release and drug target delivery. At the beginning of 1990s, solid lipid nanoparticle (SLN) system was introduced as a novel carrier system, and was regarded as combined advantages of polymer nanoparticle and the O/W fat emulsion, simultaneity avoided the obviously disadvantages of the two systems. Therefore SLN was turned into one of the hotspots in the field of pharmacy.For the property of the materials,the parameter of the preparation and the structure characteristics of the drug and lipid in the SLN should all play crucial roles on the vivo performance of drug carrier, from the point of view of materials investigation,the pharmaceutical method was united in present work. Without adding organic solvent,modified high shear and ultrasound method was employed to produce the drug loaded SLN system with considerate physical stability, preferably entrapment efficiency (EE%) and favorable release properties. The modified method used in experiments was combined melt homogenization method with high shear and ultrasound techniques to produce SLN colloidal system, and two times high shears and ultrasounds should be performed in water bath with the temperature not less than 10℃ above the lipid melt point.The sample prepared with high shear method delaminated soon, and superstratum was turbid with the lager mean particle size than clarifying underlayer. The two suspension systems were lied average particle in lager size range and with big polydispersity index at all. The one produced by the ultrasound method with long time presented two model distribution of particle, and there was no micro particle observed, but the metal Ti pollution should be taken into account for the long time probe ultrasound. The mean particle size of sample prepared with once high shear and ultrasound was larger than that of modified method, the system was performed several model distribution with the semitransparent nanosuspension of mean particle size of 165nm, and lager particles in micron range was detected. The nano system prepared by modified method presented single model of very narrow particle distribution, with mean particle size of 102nm, and the system performed excellent physical stability. Model drug mifepristone was an effective abortifacient. Combined several <WP=6>surfactants the sample was produced with average particle size of about 100nm, and also showed favorable long term storing stability. It was regarded that regular crystal lattice was substituted with defects, for the crystallization of SLN samples was decreased sharply than that of the matrix from XRD and DSC investigations. As a result it could supply place to accommodate foreign drug. Certain amount of materials could only accommodate certain amount of foreign drug molecular, and extra drug adding could not improve the EE%. With the increase of drug adding, average particle size and Zeta potential of system were improved for the amount of free drug increased, and the physical state of free drug was also altered from crystalline state to amorphism resulting from DSC measurements. The EE% of the lyophilization sample added 20% trehalose was as high as 73% with mean particle size of 247nm (versus 109nm before lyophilization). The vitro release property of nano systems did not show remarkable difference, but micron system performed rapid release at the beginning compared the nanosuspensions, with almost complete release (about 91%) at the first 24hr. therefore, the nano carrier systems could prolong the release of drug encapsulated in them.In the structure of triptolide SLN prepared with mixed materials, two matrixes were still existed in two states: liquid oil and solid lipid, for the respective melting property of low and normal temperature DSC investigations and different molecular mobile state of NMR measurements. The更多还原