【作者】 王胜浩；

【导师】 曾苏； 陈国神；

【作者基本信息】 浙江大学 ， 药物分析， 2002， 硕士

【摘要】 采用O／W乳剂——有机溶剂挥发技术，以生物降解材料乳酸-乙醇酸共聚物（PLGA）（9:1）及左炔诺孕酮（LNG）的氯仿溶液作油相，聚乙烯醇（PVA）水溶液为水相，电动搅拌，分别在常温（25℃）和低温（0～5℃）条件下挥发有机溶剂，制备PLGA（9:1）-LNG的常温法和低温法微球。比较了二种微球制备方法的粒径分布、得率、微球外观、微球粘均分子量、药物含量、载药量等，并对表面更致密的低温法微球进行了体内外药物释放特性研究和评价。 5批低温法微球的平均得率为47.6％，载药量为19.65％，药物含量97.87％。6批常温法微球的平均得率为44.6％，载药量为17.29％，药物含量86.50％。微球中LNG的含量的测定参照中国药典方法，溶剂为无水乙醇，最大吸收波长为240nm，吸收系数E_1cm^1％为544，方法回收率为100.7+1.47％，RSD=1.46％。 库尔特记数器测定低温法和常温法两种PLGA-LNG微球的粒径分布，结果表明微球的粒径分布主要集中在25～64μm之间，常温法制备的微球，该区域占74.4％，低温法微球占65.0％。 低温法微球聚合物粘均分子量（Mv）为4.66×10^-4、常温法为4.75×10^-4。 扫描电镜对两种微球扫描结果显示，低温法微球表面光滑致硕士论文：生物降解型左炔诺孕酮微球的制备及体内外释药特性研究密，常温法微球表面有小孔。 低温法微球体外药物释放经计算机数学模型拟合（零级释放、一级释放以及 Ilig［JChi方程），显示 PLGA（9：1）－U4G微球的体外释放更符合 Ill＝uchi 方程，为 Mt／M＿二0．11 6t”‘，本方程的 R＝0．989，经F检验，F二1056．058，P＜0．001。 低温法微球的体外释放及大鼠的体内释药试验显示：PI石A（9：l）－LNG微球具有相似的体内外释药特性，即存在双峰现象，而巨双峰之间均有一较为平稳的释药区间，该区间约占整个释药过程的70％。LNG微球在大鼠的MRT为65．12d，持续显效时间为168天(血药浓度大于体内抗生育起效浓度(0．lug／ml》。生物降解型Pn八（9：】）－1。M微球在大鼠的血药浓度数据由放射免疫法测得，RI八方法灵敏度为mgg／管，批内、批间 防D分别为5．1矾和6．31％，提取回收率＞90％。微球体外释药的介质为 25％(V／叶乙醇，采用 UV分 光 光 度 法 测 定 药 物 浓 度，以 标 准 曲 线A＝0·0147＋0·0397C（r＝0．9999）计算微球释药最（方注的线性歹 围：0．sug／ml—6．OPg／ml，检坝波长为248urn）。 研究表明：低温法微球药物载药量、药物含量均高于常温法微球，尤其是低温法微球表面光滑而致密，而常温法微球表面有明显孔隙，因此宜采川（）／W乳剂一低温（0～5℃）下挥发有机溶剂的微囊化技术制备生物降解型w石A（9：l）－l。NG微球。依据微球的药物载药量、药物含量、电镜下微球表面的致密性和微球体外释药反映体内药物释放的二个特点：双峰及维持平稳区域较氏时间等多个指标，可对左炔诺孕酮长效微球的质量进行初步控制。更多还原

【Abstract】 The levonorgestrel (LNG) copolymer of lactic and glycolic acid (PLGA) (9:1) microsphere is a new dosage form for parenteral administration of LNG , it was prepared using o/w emulsion organic solvent evaporation at low temperature(0 ~ 5癈) and room temperature(25癱),respectively. The effect of these two kinds of preparation methods on the characteristics of microspheres, such as the surface of microspheres, the molecular weight, the content, the distribution of particle and the loading drug percent, were studied. The results showed that the surface of microspheres prepared by low temperature method was more smooth and compact than that of microspheres prepared by room temperature method, and the content and the loading drug percent were higher than that of room temperature microspheres.The content of PLGA-LNG microspheres was determined by UV spectrophotometer method at 240nm (E1%1cm=544,ethnol), the average recovery was 100.7±1.47%(RSD=1.46%).In order to evaluate on the characteristics of the microspheres prepared by low temperature method in detail, the release in vitroand in vivo was tested, respectively.Pharmacokinetics of levonorgestrel (LNG) in the form of injectable biodegradable PLGA(9:1) microspheres containing LNG was determined in rats by RIA method, the limit of detection(LOD) of this RIA method was 10pg/tube, the average inter-day precision of the assay was 5.15% and the intra-day precision was 6.31%, and the average extraction recovery was more than 90%. The drug release in vitro was determined by UV spectrophotometric method. 25%(v/v) alcohol was used as the media solution. The regression equation wasA=0.0147+0. 0397C(r=0.9999) and the linearity ranges from 0.5 to 6jag/ml. the A max for measurement was set at 248nm.The release profiles of microspheres showed a similar biphasic release pattern between in vitro and in vivo, the first phase of the release was diffusion controlled, and a secondary rise in the drug level due to the onset of degradation of the PLGA. Between the first phase and the secondary phase, there was about 70% steady release in vitro and in vivo. The first phase peak plasma LNG level of the microspheres was low , and its MRT of the microspheres was 65.12d ,the time of lasting action was longer than 168 days. The drug release from PLGA (9:1) microspheres in vitro correlated well with that in vivo. The microspheres have remarkably long-acting control release action.We attempted to correlate the in vitro release datum of low temperature method to fit a recognized mathematical model by computer, the results showed that the release kinetics for LNG from PLGA(9:1) microspheres was approached the Higuchi equation, compared to zero order kinetics pattern and the first order kinetics pattern, the Higuchi equation was Mt/M ?=0. 116t1/2(F=1056. 058, P<0. 001; R=0. 989)In conclusion, the content and the loading drug percent for the microspheres prepared by the low temperature method were higher than that for the room temperature microspheres. Especially, the surface of microspheres made by the low temperature method was more smooth and compact than that of microsphere prepared by the room temperature method, there are many pores on the surface of microsphere prepared by the room temperature method. So, the preparation of microspheres should be used o/w emulsion organic solvent evaporation at low temperature(0 ~ 5 癈). The following parameters such as the loading drug percent, the content , the degree of smooth and compact on microsphere surface, and the characteristics of release in vitro with two peaks and steady drug release area could be used to evaluate and control the quality of PLGA(9:1)-LNG microspheres.更多还原