【作者】 刘扬；

【导师】 张学农；

【作者基本信息】 苏州大学 ， 药物化学， 2008， 硕士

【摘要】 目的:本课题旨在药剂学基本理论的指导下,熟悉去甲斑蝥素的理化性质和大鼠在体肠吸收特性。以去甲斑蝥素为模型药物制备骨架型和膜控型缓释微丸。并对缓释微丸进行初步药动学研究。方法:(1)通过文献,掌握去甲斑蝥素已知理化性质,建立去甲斑蝥素分析测试方法,测定了溶解度,油水分配系数。通过图谱考察去甲斑蝥素的存在状态。(2)以去甲斑蝥素原料药溶液为对照,考察去甲斑蝥素低分子量壳聚糖纳米粒中药物的大鼠在体肠吸收特性。采用大鼠在体回流方法,利用紫外分光光度法和HPLC法分别测定酚红和去甲斑蝥素的含量。(3)采用挤出-滚圆技术制备去甲斑蝥素骨架型缓释微丸,研究了机器及处方因素对去甲斑蝥素骨架型缓释微丸的制备和释放度的影响,采用正交试验,通过综合打分法,多元回归分析确定最优处方。(4)采用流化床包衣法对去甲斑蝥素微丸进行缓释包衣,确定最佳机器参数,通过均匀设计优化包衣液处方。并对最佳处方进行重现和释放曲线数据拟合。(5)使用HPMC、乳糖等辅料,制备去甲斑蝥素凝胶型骨架片,研究了HPMC、乳糖用量及乙醇浓度和用量对缓释片剂释放的影响。采用正交试验确定最佳处方。(6)建立去甲斑蝥素体内分析方法,运用3P97计算药动学参数。结果:(1)全面掌握去甲斑蝥素理化性质,建立了一套可行的分析测试方法。去甲斑蝥素在水中以去甲斑蝥酸的形式存在。去甲斑蝥素溶解度较大,油水分配系数随pH值升高而下降。(2)不同药物浓度70、80、90μg/ml大鼠在体肠吸收时,去甲斑蝥素低分子量壳聚糖纳米粒的吸收百分数和吸收速率常数均比原料药高。(3)以微晶纤维素(MCC) 9.877%、乙基纤维素(EC):硬脂酸(Stearic acid)=1:1.5、粘合剂1%羟丙甲纤维素(HPMC)13ml、80℃烘干制得的去甲斑蝥素骨架型缓释微丸具有较好的缓释效果。(4)通过U7(74)均匀设计试验,4因素7水平,得出最佳包衣液处方配比:增塑剂24%,致孔剂14%,抗粘剂20%,抗静电剂0.060%。最佳处方曲线拟合Ritger-Peppas方程。(5)单因素考察中HPMC用量增加,释放度减慢;乳糖对释放度影响不大;乙醇用量相同时,药物释放随乙醇浓度的增大而加快。乙醇浓度相同时,药物释放随乙醇用量的增大而减慢。正交试验最佳处方为(100片)HPMC12g,乳糖1.5g,乙醇浓度90%,用量10ml。(6)缓释微丸的达峰时间为4.49h,而片剂达峰时间为2.42h,达峰时间延长2h。与片剂比较相对生物利用度为104.5%。结论:(1)HPLC分析法稳定准确,由理化性质得出去甲斑蝥素设计成缓释制剂可行。(2)不同的药物浓度对去甲斑蝥素在大鼠全肠道的吸收无显著影响,药物的吸收呈一级动力学过程,吸收机制为被动扩散;去甲斑蝥素在肠道中上部有较好的吸收,提示适于制备日服一次的缓释给药系统;去甲斑蝥素低分子量壳聚糖纳米粒能促进去甲斑蝥素在大鼠小肠的吸收。(3)采用挤出-滚圆技术,通过缓释材料制备的去甲斑蝥素骨架型缓释微丸,其体外释药缓慢、持续、平稳。(4)以EC为主要包衣材料,HPMC为致孔剂制得的缓释包衣微丸,释放缓慢,为扩散和溶蚀相结合的释药模式。(5)HPMC作为凝胶骨架片主要材料,其用量是释放度的决定因素。(6)在体内微丸与片剂相比有一定缓释作用。更多还原

【Abstract】 Objective: Guide by the theory of pharmaceutics, the physico-chemical property of NCTD and absorption characteristic of intestine in rats was mastered. The matrix-diffusion type and membrane-moderated type sustained-release NCTD pellets were prepared.The pharmacokinetics of sustained–release pellets was investigated.Methods:(1) The physico-chemical property of NCTD was mastered by documents. HPLC method was utilized to determine the NCTD content in pellets and release of sustained-release pellets. The dissolubility and n-octyl alcohol /water partition coefficient were determined. The existence condition of NCTD was investigation by spectrums. (2) The intestine in rats was cannudated for in situ recirculation, UV and HPLC were used to determine the concentrations of UV spectrums of phenol red and NCTD, respectively.The absorption of NCTD was studied at different intestine segments, and with different concentration of NCTD. (3) Extrusion-spheronization method was used to prepare pellets. The effects of process variables and formulation variables on pellets preparation and drug release were investigated. (4)A fluid bed spray processor was adopted for coating the pellets of NCTD. The best parameter of machines was controlled. The best coating solution was optimized with uniform design test. The best results were repeated and the data of release curve was fitted.(5)The matrix tablets of NCTD were prepared with HPMC and lactose. The effect of the amount of HPMC and lactose on the release of tablets was studied. The best formulation was optimized with orthogonal experiment. (6)The analytical method of NCTD in vivo was established。The pharmacokinetics parameters was obtained with 3P97.Results: (1) The solubility of NCTD in water is big. The n-octyl alcohol /water partition coefficient decreases when pH increases. (2) The absorption rate constants (Ka) at duodenum, jejunum, ileum, and colon were 0.0306,0.0278, 0.0151, 0.0044h-1, respectively. Ka from intestine at NCTD concentration of 70, 80, 90μg/ml were 0.0499, 0.0525, 0.0489h-1. (3) The main factors affecting the release rate were the type of material applied and the temperature of drying. Release of the drug from pellets was in accordance with Higuchi equation.(4)The best formulation of coating solution: plasticizer 24%,HPMC14%,antisticking agent20%,anstatic agent0.060%.The curve fitting of the best formulation is Ritger-Peppas equation. (5)The best result(100 tablets):HPMC12g,lactose 1.5g,the concentration of alcohol is 90%,the amount of alcohol is 10ml.(6) The Tmax of pellets is 4.49h and the Tmax of tablets is 2.42.The relative bioavailability is 104.5%。Conclusion: (1) The method of HPLC is stable and accurate. It is possible that the sustained-release preparations were designed with NCTD.(2) The concentration of NCTD had no distinctive effect on the absorption kinetics. The absorption of NCTD was a first-order process with passive diffusion mechanism. NCTD was well absorbed at the superior and middle segments of intestine in rats, which indicate that NCTD could be prepared as sustained-release dosage form for administration once a day.(3) The method and the formulation are successful in providing slow and steady release of NCTD from sustained—release pellets.(4)The coating sustained-release pellets with EC release slowly. The type of drug release of the sustained-release pellets is diffusion and corrosion. (5)As the main material of gel-matrix tablets, the HPMC is determinative factor of drug release. (6) The pellets release slowly in vivo compared with tablets.更多还原