【作者】 孙娥；

【导师】 丁安伟； 张丽；

【作者基本信息】 南京中医药大学 ， 中药学， 2007， 硕士

【摘要】 荆芥内酯(ST)是我们从中药材荆芥中提取、分离得到的一具有明显生物活性的单体化合物，药效学研究结果表明，ST具有很强的抗病毒活性以及明显的抗炎、解热、镇痛等作用。但ST溶解度较小，常规制剂工艺很难解决其因溶解性差而导致的制剂生物利用度低的问题。纳米技术以其独特的“小尺寸效应”为人类开拓了一片认识事物的新天地，利用纳米科技可将生物降解性和生物相容性的聚合物作为药物的载体，提高药物在靶部位或吸收部位的浓度，改变其体内分布和药动学过程，达到增加吸收、提高疗效和降低毒性的作用。因此，本课题利用纳米技术，合成新型的纳米药物载体材料携带药物ST，制成新型的中药ST纳米制剂来改善这一问题，达到提高药物的疗效、控制药物释放的目的。本论文分别对纳米分散系及纳米药物载体材料聚乳酸乙醇酸的研究进展进行了文献综述，实验部分主要完成了以下研究：1．采用熔融缩聚法，以等摩尔乙醇酸(GA)、D，L-乳酸(D，L-LA)为原料，直接合成高分子材料聚乳酸乙醇酸(PLGA50／50)，并对其进行了系统表征。通过改变聚合温度、反应时间、催化剂的种类和用量等因素，成功合成了分子量在4900～22000范围的PLGA50／50。同时研究了PLGA50／50(M_η=10000)共聚物的体外降解行为，证实PLGA材料具有可降解性，其降解规律符合本体降解特征。2．采用溶剂-非溶剂法成功制得ST纳米粒，并运用单因素法探索出纳米粒制备的一般规律性，改变工艺条件可制备粒径为150nm左右，包封率为40％左右的ST纳米粒。在单因素考察基础上，利用正交设计优选出最佳制备工艺为乳化剂泊洛沙姆浓度0.5％、PLGA用量25mg、ST用量20mg、油相丙酮体积10mL、水相体积20mL、注射孔径4~#，制得的ST纳米粒形态圆整，大小均匀，平均粒径67.6nm，分散度0.0144，包封率为50.86％，载药量达27.56％。3．采用冷冻干燥技术，以10％甘露醇作为支架剂，制得最佳ST-NP冻干针剂，并对冻干工艺参数进行了优化。同时考察了ST-NP冻干针剂的相关理化性质，并建立其质量评价方法。通过比较ST-NP胶体溶液和冻干针剂的稳定性，表明冻干针剂的稳定性较好，且宜在4℃条件下避光保存。4．以抗炎为指标，采用小鼠耳廓肿胀法和腹腔染料渗出法，对ST-NP粉针剂进行初步药效学研究。结果表明，ST-NP冻干针剂具有显著的抗急性炎症作用，抗炎效果明显优于游离ST药物，提示以纳米粒为载体负载药物可促进药物的吸收，提高药物的疗效。5．采用透析法，模拟人体生理环境，考察了ST-NP粉针剂在24小时内的体外释药行为，并拟合出释放曲线。ST-NP冻干针剂0.25h内突释量为46.34％，24h内累积释药量达79.48％，表明ST-NP冻干针剂具有明显的缓释作用。更多还原

【Abstract】 Schizonepetin(ST) is an effective ingredient which has been extracted from theChinese crude drug schizonepetae. Pharmacodynamics findings indicate that, ST obviouslypossesses the affect of antiviral activity, anti-inflammatory, relieving fever and pain.However, ST has tiny dissolubility, and common praeparatum technology is difficult tosolve the problem of low bioavailability. Nanotechnology has opened up a new space forpeople to know things because of its distinct "quantum effect". By the nanotechnology, wecan apply biodegradable and biocompatible polymer for pharmacal carrier in order to raisethe drug concentration at target site or absorption position, change body distribution andpharmacokinetics process, and increase absorption, improve curative effect and lowertoxicity. Therefore, this topic applied nanotechnology to improve this problem. Wesynthesized a new type of nanometer material to carry ST, and preparated traditionalChinese medicine ST nano-praeparatum to improve pharmacal curative effect and controlpharmacal release.This thesis summarized the research progress of nano-disperse systems anddrug-loaded nano-material poly(lactic acid-glycolic acid). The experiment part mainlycompleted the researches below:Starting from equimolar glycolic acid(GA) and D,L-lactic acid(D,L-LA), themacromolecule materials polylactic-co-glycolic acid(PLGA50/50) was directly synthesizedvia the melt polycondensation, and was systematically characterized. By changing thefactors of polymerized temperature, reaction time, the type and dosage of catalyst, wesuccessfully synthesized PLGA50/50 possessing the molecular weight from 4900～22000.Meanwhile, we studied on the degradation behavior of PLGA50/50 in vitro. It wasconfirmed that, PLGA was degradable and its degradation regularity accorded withnoumenon degradation characteristic.ST nanoparticles were successfully prepared with solvent-nonsolvent method. We usedthe single factor tests to search for the general regularity about nanoparticles’ preparation. Changing these factors, the mean diameter of ST nanoparticles was about 150nm, and theencapsulation ratio was about 40％. Based on the single factor investigation, we used theorthogonal design for seeking the optimum formulation and technics, that was 0.5％emulsifier of poloxamer, 25mg PLGA, 20mg ST, 10mL oil phase of acetone, 20mL aqueousphase and 4~# injection antilinear. The shape of ST nanoparticles with the optimum technicswas roundness, size was well-distributed, the mean diameter was 67.6nm, the dispersity was0.0144, the encapsulation ratio was 50.86％and the loading dosage reached to 27.56％.With the supporting agent of 10％manicol, we used freeze drying to obtain the bestST-NP lyophilization injection. In addition, we also optimized the parameters oflyophilization process. Meanwhile, we studied correlated physico-chemical properties ofST-NP lyophilization injection and established its qulity evaluation methods. Throughcomparing the stability of ST-NP colloid solution and lyophilization injection, wediscovered that lyophilization injection had the better stability and was fit to store awayfrom light at 4℃.With the index of anti-inflammation, we used the methods of the swelling of mice’sauricle and exudation of dye in mice’s abdominal cavity to research on initialpharmacodynamics of ST-NP lyophilization injection. The results indicated that, ST-NPlyophilization injection had marked anti-acute inflammatory effect, and better than pure STmedicine. It was proved that nanoparticles carring ST can promote the absorption of ST, andimprove its curative effect.Simulating anthropometric physiological environment, we used the dislysis method toinvestigate the release behaviors of ST-NP lyophilization injection in vitro for 24 hours, anddrew the release curve. ST-NP lyophilization injection had released 46.34％dosage during0.25h, and cumulative release dosage reached to 79.48％during 24h. It signified that ST-NPlyophilization injection had marked slow-release effect.更多还原