去甲斑蝥素缓释微丸的制备
|
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。
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.
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。
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.
引文
[1] 程宇慧,廖工铁,候世祥,等.去甲斑蝥素钠白蛋白微球的研究[J].药学学报,1993,28(5):384～388.
[2] 潘卫三,孙稳健,胡晋.去甲斑蝥素毫微型胶囊制备方法的研究[J].沈阳药学院学报,1994,11(2):124～127.
[3] 李柏,咸春成,张南征,等.不同因素对去甲斑蝥素-泊洛沙姆 407 缓释制剂体外释放度的影响[J].中国医院药学杂志,1999,19(9):517～519.
[4] 梁福佑,张胜华,潘颖,等.去甲斑蝥素用于单克隆抗体为载体的肿瘤导向治疗实验研究[J].首都医科大学学报,1999,20(1):5～8.
[1] 吴建梅,任天池.去甲斑蝥素脂质体的制备及理化性质研究[J].中国药学杂志,2005,40(19):1485～1489.
[2] Xiaohua Liu,Wan Sia Heng,Paul,et al. Novel polymeric microspheres containing norcantharidin for chemoembolization[J].Journal of Controlled release,2006,116(1):35～41.
[3] 郑俊民主编.经皮给药新剂型.人民卫生出版社.1997, 255.
[4] 邵瑞莹,唐星,刘彦生.离子交换色谱法测定去甲基斑蝥素乳剂的含量[J].中国新药杂志,2005,14(7):885～887.
[5] 王广生,李荣昌,窦培延.去甲斑蝥素在胃肠液中的存在状态[J].药学通报,1984,19(8):24～26.
[1] 刘明,陈束叶,杨天府,等.大鼠对阿魏酸哌嗪的在体肠吸收[J].华西药学杂志,2006,21(4):350～352.
[1] 毕殿洲主编.药剂学第四版.北京:人民卫生出版社[M].1999,77～78.
[2] 陆彬主编,药物新剂型与新技术.北京:人民卫生出版社[M].1998,300～301.
[3] 刘定远主编.医药数理统计方法.北京:人民卫生出版社[M].1999, 252～259.
[4] 蔡翠芳,毕殿洲,毛世瑞.挤出滚圆法制备氢溴酸右美沙芬骨架缓释微丸[J].沈阳药科大学学报,2003,20(5):313～316.
[1] 曾昭钧主编.匀设计及其应用.北京:中国医药科技出版社[M].2005
[2] 崔福德主编.药剂学第六版.北京:人民卫生出版社[M].2007
[3] 杨宏图,常翠,宁德俄.盐酸雷尼替丁控释微丸的制备和释药机理的研究[J].中国药师,2003,6(3):136～138.
[4] 施路,李三鸣,宋红光,等.不同包衣条件下银杏缓释微丸体外释放考察[J].沈阳药科大学学报,2005,22(3):176～180.
[5]曾环想,肖全英,盘卫三,等.法莫替丁缓释微丸的悬浮包衣法制备[J].中国医药工业杂志,2002,33(9):442～444.
[6]匡长春,罗顺德,何文,等.乙基纤维素-壳聚糖包衣膜处方的优化[J].广东药学院学报,2004,20(6):605～609. 第五部分 去甲斑蝥素水凝胶型缓释骨架片的制备
[1] 张娜,徐彦先,黄桂华,等.氯氮平缓释片的制备及释药特性的研究[J].中国现代应用药学杂志,2000,17(3):202～204.
[2]高迎春,张亮,王晓娟,等.卡托普利混合骨架片的处方筛选[J].中国医院药学杂志,2004,24(3):159～160.
[3] 颜耀东等.缓释控释制剂的设计与开发[M].中国医药科技出版社.北京.2007.69. 第六部分 去甲斑蝥素缓释微丸胶囊药动学初步研究
[1] 邵瑞莹,唐星.高效液相一质谱法联用测定大鼠体内去甲基斑蝥素血药浓度[J].药物分析杂志,2005,25(6):607～609.
[2] 王立新,何海冰,唐星,等.去甲基斑蝥素钠脂质微球体内外评价[J].药学学报,2006,41(8):784～788.
[3] 张莉,向东,洪诤,等.肝靶向去甲斑蝥素微乳的研究[J].药学学报,2004,39(8):650～655.
[1] 陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998,12(8):9.
[2] 钱方,蒋子涛,王安文.微丸的进展[J ].中国医药工业杂志,1996 ,27 (1):41.
[3] 金红花,张恒弼.缓释微丸制剂研究近况[J].药学实践杂志,1996,14 (2):103.
[4] Laicher A,Fuchs WS. Pellet technology. sustained-release pellets in hard gelatin capsules-a suitable dosage form for theophylline[J]. Arzneimittelforschung, 1998, 48(5): 540
[5] Pillay V, Fassihi R. In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract.Ⅰ .Comparison of pH-responsive drug release and associated kinetics[J]. Journal of Controlled Release, 1999,59(2):229. [6 ] 陈庆华.现代微丸制备与包衣装置的类型与应用[J].中国医药工业杂志,1996,27(3):13.
[7] 刘红,沈灵佳.萘普生肠溶微丸的制备及其体外特性研究[J] .中国医院药学杂志,2004(2):58.
[8] Chris V, Lieven B, Paul RJ. Extrusion-spheronisation. Int J Pharm, 1995,116(2):131.
[9] 潘家祯,孙晓明,朱大滨,等.挤出滚圆法制备药用微丸[J] .中国医药工业杂志,1998,29(8):378.
[10] 陈庆华.现代微丸制备与包衣装置的类型与应用[J].中国医药工业杂志,1996,27(3):13.
[11] 黄坤,张陈炎,袁彦洁,等.流化床制粒法制备中药纯浸膏包衣微丸的工艺研究[J].中国药业,2005,14(7):53.
[12] Per Borgquist, Gunnar Zackrisson, Bernt Nilsson, et al. Simulation and parametric study of a film - coated controlled – release pharmaceutical [J]. Journal of Controlled Release, 2002, 80: 229.
[13] 陈庆华.现代微丸制备与包衣装置的类型与应用[J].中国医药工业杂志,1996,27 (3) :134.
[14] Vecchio C ,Fabiani F ,Sangalli ME , et al.Rotary tangential spray technique for aqueous film coating of indobufen pellets [ J ].Drug Dev IndPharm,1998 ,24(3) :269.
[15] P.W.S. Heng, L.W. Chan, E.S.K. Tang. Use of swirling airflow to enhance coating performance of bottom spray fluid bed coaters[J].International Journal of Pharmaceutics,2006,327:26.
[16] 阳长明,侯世祥,张志荣,等.缓释与控释小丸的研究进展[J] .华西药学杂志,2001,16(2):121.
[17] 于少云,王洪光,刘璐,等.微丸进展[J].中国新药杂志,1999,8(12):802.
[18] Zheng W, McGinity JW. Influence of Eudragit NE 30 blended with Eudragit L 30 D255 on the release of phenyl-propanolamine hydrochloride from coated pellets [J ]. DrugDev Int Pharm , 2003 , 29(3) :357.
[19] Cole G, Hogan,H, et al. Pharmaceutical Coating Technology [M].中国医药科技出版社,2003,8(6):422.
[20] Mehta KA , Kislalioglu MS , Phuapradit W, et al . Release performance of a poorly soluble drug from a novel , Eudragit based multi-unit erosion matrix [ J ]. Int J Pharm ,2001 , 213(1/ 2) :7 .
[21] Santos H , Veiga F , Pina M, et al . Physical properties of chitosan pellets produced by extrusion spheronisation : influence of formulation variables[J ]. Int J Pharm , 2002 , 246(1/ 2) :153.
[22] Munday DL. Film coated pellets containing verapamil hydrochloride :enhanced dissolution into neutral medium[J ].Drug Dev Int Pharm ,2003 ,29(5) :575.
[1] Lawrence X.Y, Lipka E, Crison JR, et al. Transport approaches to the biopharmaceutical design of oral drug delivery system: prediction of intestinal absorption[J]. Adv Drug Del Rev,1996,19:359.
[2] Stewart BH, Chan OH, Jeryk N, et al. Descrimination between drug candidates using models for evaluation of instestinal absorption[J]. Adv Drug Del Rev, 1997,23:27.
[3] 汤继辉,胡容峰,常宫. 丹皮酚大鼠在体小肠吸收动力学研究[J].中国实验方剂学杂志,2006,12(7):35.
[4] 梁桂贤,刘谦民.药物肠吸收研究方法近况[J].国外医药—合成药·生化药·制剂分册,1998,19(4):251.
[5] Brown JR,Collett JH, Attwood D, et al. Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayexs and everted gut sacs[J].Int.l Pharm,2002,245(1-2):133.
[6] 梁文权.生物药剂学与药物动力学[M]. 北京:人民卫生出版社,2003. 53.
[7] 沈凯,王景田.药物肠吸收实验研究进展[J].中国新药杂志,2003,12(12):988.
[8] 杨海涛,王广基. Caco-2 单层细胞模型及其在药学中的应用[J]. 药学学报,2000,35(10):797.
[9] 聂淑芳, 潘卫三, 李 伟, 等.长春西汀的大鼠在体肠吸收研究[J].中国医药工业杂志,2006,36(10): 625.
[10] 刘太明,蒋学华. 黄芩苷和黄芩素大鼠在体胃、肠的吸收动力学研究[J].中国中药杂志, 2006,31(12):999.
[11] 周庆颂,蒋学华,樊新星. 不同相对分子质量灯盏乙素-PEG 酯大鼠在体小肠吸收动力学的研究[J].中国药学杂志,2006,41(5):375.
[12] 吕占国,陈大为,苑振亭,等.石杉碱甲的大鼠在体小肠吸收动力学[J].中国药剂学杂志,2003,1(3):96.
[13] 李岩,郭涛,颜鸣. 泛昔洛韦大鼠在体肠吸收动力学研究[J].解放军药学学报,2006,22(5):3325.
[14] 刘明,陈束叶,杨天府,等.大鼠对阿魏酸哌嗪的在体肠吸收[J].华西药学杂志,2006,21(4):350.
[15] 陈军辉,陈俊 . 苯丙醇胺肠吸收特性的研究 [J]. 中国医院药学杂志,2002.20(2):73.
[16] 张学农,陈靖,张强.阿苯达唑纳米粒体外释药及大鼠在体吸收动力学相关性研究[J].中国药学杂志,2003,38(12):932.
[17] 游本刚,杨明世,范玉玲,等.尼群地平大鼠在体肠吸收动力学研究[J].中国药学杂志,2004,39(3):214.
[2] 潘卫三,孙稳健,胡晋.去甲斑蝥素毫微型胶囊制备方法的研究[J].沈阳药学院学报,1994,11(2):124～127.
[3] 李柏,咸春成,张南征,等.不同因素对去甲斑蝥素-泊洛沙姆 407 缓释制剂体外释放度的影响[J].中国医院药学杂志,1999,19(9):517～519.
[4] 梁福佑,张胜华,潘颖,等.去甲斑蝥素用于单克隆抗体为载体的肿瘤导向治疗实验研究[J].首都医科大学学报,1999,20(1):5～8.
[1] 吴建梅,任天池.去甲斑蝥素脂质体的制备及理化性质研究[J].中国药学杂志,2005,40(19):1485～1489.
[2] Xiaohua Liu,Wan Sia Heng,Paul,et al. Novel polymeric microspheres containing norcantharidin for chemoembolization[J].Journal of Controlled release,2006,116(1):35～41.
[3] 郑俊民主编.经皮给药新剂型.人民卫生出版社.1997, 255.
[4] 邵瑞莹,唐星,刘彦生.离子交换色谱法测定去甲基斑蝥素乳剂的含量[J].中国新药杂志,2005,14(7):885～887.
[5] 王广生,李荣昌,窦培延.去甲斑蝥素在胃肠液中的存在状态[J].药学通报,1984,19(8):24～26.
[1] 刘明,陈束叶,杨天府,等.大鼠对阿魏酸哌嗪的在体肠吸收[J].华西药学杂志,2006,21(4):350～352.
[1] 毕殿洲主编.药剂学第四版.北京:人民卫生出版社[M].1999,77～78.
[2] 陆彬主编,药物新剂型与新技术.北京:人民卫生出版社[M].1998,300～301.
[3] 刘定远主编.医药数理统计方法.北京:人民卫生出版社[M].1999, 252～259.
[4] 蔡翠芳,毕殿洲,毛世瑞.挤出滚圆法制备氢溴酸右美沙芬骨架缓释微丸[J].沈阳药科大学学报,2003,20(5):313～316.
[1] 曾昭钧主编.匀设计及其应用.北京:中国医药科技出版社[M].2005
[2] 崔福德主编.药剂学第六版.北京:人民卫生出版社[M].2007
[3] 杨宏图,常翠,宁德俄.盐酸雷尼替丁控释微丸的制备和释药机理的研究[J].中国药师,2003,6(3):136～138.
[4] 施路,李三鸣,宋红光,等.不同包衣条件下银杏缓释微丸体外释放考察[J].沈阳药科大学学报,2005,22(3):176～180.
[5]曾环想,肖全英,盘卫三,等.法莫替丁缓释微丸的悬浮包衣法制备[J].中国医药工业杂志,2002,33(9):442～444.
[6]匡长春,罗顺德,何文,等.乙基纤维素-壳聚糖包衣膜处方的优化[J].广东药学院学报,2004,20(6):605～609. 第五部分 去甲斑蝥素水凝胶型缓释骨架片的制备
[1] 张娜,徐彦先,黄桂华,等.氯氮平缓释片的制备及释药特性的研究[J].中国现代应用药学杂志,2000,17(3):202～204.
[2]高迎春,张亮,王晓娟,等.卡托普利混合骨架片的处方筛选[J].中国医院药学杂志,2004,24(3):159～160.
[3] 颜耀东等.缓释控释制剂的设计与开发[M].中国医药科技出版社.北京.2007.69. 第六部分 去甲斑蝥素缓释微丸胶囊药动学初步研究
[1] 邵瑞莹,唐星.高效液相一质谱法联用测定大鼠体内去甲基斑蝥素血药浓度[J].药物分析杂志,2005,25(6):607～609.
[2] 王立新,何海冰,唐星,等.去甲基斑蝥素钠脂质微球体内外评价[J].药学学报,2006,41(8):784～788.
[3] 张莉,向东,洪诤,等.肝靶向去甲斑蝥素微乳的研究[J].药学学报,2004,39(8):650～655.
[1] 陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998,12(8):9.
[2] 钱方,蒋子涛,王安文.微丸的进展[J ].中国医药工业杂志,1996 ,27 (1):41.
[3] 金红花,张恒弼.缓释微丸制剂研究近况[J].药学实践杂志,1996,14 (2):103.
[4] Laicher A,Fuchs WS. Pellet technology. sustained-release pellets in hard gelatin capsules-a suitable dosage form for theophylline[J]. Arzneimittelforschung, 1998, 48(5): 540
[5] Pillay V, Fassihi R. In vitro release modulation from crosslinked pellets for site-specific drug delivery to the gastrointestinal tract.Ⅰ .Comparison of pH-responsive drug release and associated kinetics[J]. Journal of Controlled Release, 1999,59(2):229. [6 ] 陈庆华.现代微丸制备与包衣装置的类型与应用[J].中国医药工业杂志,1996,27(3):13.
[7] 刘红,沈灵佳.萘普生肠溶微丸的制备及其体外特性研究[J] .中国医院药学杂志,2004(2):58.
[8] Chris V, Lieven B, Paul RJ. Extrusion-spheronisation. Int J Pharm, 1995,116(2):131.
[9] 潘家祯,孙晓明,朱大滨,等.挤出滚圆法制备药用微丸[J] .中国医药工业杂志,1998,29(8):378.
[10] 陈庆华.现代微丸制备与包衣装置的类型与应用[J].中国医药工业杂志,1996,27(3):13.
[11] 黄坤,张陈炎,袁彦洁,等.流化床制粒法制备中药纯浸膏包衣微丸的工艺研究[J].中国药业,2005,14(7):53.
[12] Per Borgquist, Gunnar Zackrisson, Bernt Nilsson, et al. Simulation and parametric study of a film - coated controlled – release pharmaceutical [J]. Journal of Controlled Release, 2002, 80: 229.
[13] 陈庆华.现代微丸制备与包衣装置的类型与应用[J].中国医药工业杂志,1996,27 (3) :134.
[14] Vecchio C ,Fabiani F ,Sangalli ME , et al.Rotary tangential spray technique for aqueous film coating of indobufen pellets [ J ].Drug Dev IndPharm,1998 ,24(3) :269.
[15] P.W.S. Heng, L.W. Chan, E.S.K. Tang. Use of swirling airflow to enhance coating performance of bottom spray fluid bed coaters[J].International Journal of Pharmaceutics,2006,327:26.
[16] 阳长明,侯世祥,张志荣,等.缓释与控释小丸的研究进展[J] .华西药学杂志,2001,16(2):121.
[17] 于少云,王洪光,刘璐,等.微丸进展[J].中国新药杂志,1999,8(12):802.
[18] Zheng W, McGinity JW. Influence of Eudragit NE 30 blended with Eudragit L 30 D255 on the release of phenyl-propanolamine hydrochloride from coated pellets [J ]. DrugDev Int Pharm , 2003 , 29(3) :357.
[19] Cole G, Hogan,H, et al. Pharmaceutical Coating Technology [M].中国医药科技出版社,2003,8(6):422.
[20] Mehta KA , Kislalioglu MS , Phuapradit W, et al . Release performance of a poorly soluble drug from a novel , Eudragit based multi-unit erosion matrix [ J ]. Int J Pharm ,2001 , 213(1/ 2) :7 .
[21] Santos H , Veiga F , Pina M, et al . Physical properties of chitosan pellets produced by extrusion spheronisation : influence of formulation variables[J ]. Int J Pharm , 2002 , 246(1/ 2) :153.
[22] Munday DL. Film coated pellets containing verapamil hydrochloride :enhanced dissolution into neutral medium[J ].Drug Dev Int Pharm ,2003 ,29(5) :575.
[1] Lawrence X.Y, Lipka E, Crison JR, et al. Transport approaches to the biopharmaceutical design of oral drug delivery system: prediction of intestinal absorption[J]. Adv Drug Del Rev,1996,19:359.
[2] Stewart BH, Chan OH, Jeryk N, et al. Descrimination between drug candidates using models for evaluation of instestinal absorption[J]. Adv Drug Del Rev, 1997,23:27.
[3] 汤继辉,胡容峰,常宫. 丹皮酚大鼠在体小肠吸收动力学研究[J].中国实验方剂学杂志,2006,12(7):35.
[4] 梁桂贤,刘谦民.药物肠吸收研究方法近况[J].国外医药—合成药·生化药·制剂分册,1998,19(4):251.
[5] Brown JR,Collett JH, Attwood D, et al. Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayexs and everted gut sacs[J].Int.l Pharm,2002,245(1-2):133.
[6] 梁文权.生物药剂学与药物动力学[M]. 北京:人民卫生出版社,2003. 53.
[7] 沈凯,王景田.药物肠吸收实验研究进展[J].中国新药杂志,2003,12(12):988.
[8] 杨海涛,王广基. Caco-2 单层细胞模型及其在药学中的应用[J]. 药学学报,2000,35(10):797.
[9] 聂淑芳, 潘卫三, 李 伟, 等.长春西汀的大鼠在体肠吸收研究[J].中国医药工业杂志,2006,36(10): 625.
[10] 刘太明,蒋学华. 黄芩苷和黄芩素大鼠在体胃、肠的吸收动力学研究[J].中国中药杂志, 2006,31(12):999.
[11] 周庆颂,蒋学华,樊新星. 不同相对分子质量灯盏乙素-PEG 酯大鼠在体小肠吸收动力学的研究[J].中国药学杂志,2006,41(5):375.
[12] 吕占国,陈大为,苑振亭,等.石杉碱甲的大鼠在体小肠吸收动力学[J].中国药剂学杂志,2003,1(3):96.
[13] 李岩,郭涛,颜鸣. 泛昔洛韦大鼠在体肠吸收动力学研究[J].解放军药学学报,2006,22(5):3325.
[14] 刘明,陈束叶,杨天府,等.大鼠对阿魏酸哌嗪的在体肠吸收[J].华西药学杂志,2006,21(4):350.
[15] 陈军辉,陈俊 . 苯丙醇胺肠吸收特性的研究 [J]. 中国医院药学杂志,2002.20(2):73.
[16] 张学农,陈靖,张强.阿苯达唑纳米粒体外释药及大鼠在体吸收动力学相关性研究[J].中国药学杂志,2003,38(12):932.
[17] 游本刚,杨明世,范玉玲,等.尼群地平大鼠在体肠吸收动力学研究[J].中国药学杂志,2004,39(3):214.