流化床法制备氨茶碱缓释微丸的研究
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摘要
本文以流化床包衣造粒的方法制备了氨茶碱缓释微丸并对制剂的药动学性质作了相关研究。通过差示扫描量热法结合X-射线粉末衍射法和傅立叶变换红外光谱法考察了药物与辅料的配伍兼容性;采用单因素摸索的方法确定了空白丸心的制备工艺并且对丸心的粉体动力学性质作了评价;同样单因素方法确定了氨茶碱缓释微丸的包衣处方和制备工艺,制得12h持续释放的缓释制剂,通过体外释放试验并对释放曲线进行曲线方程拟合,研究了微丸的缓释机理;以家兔为实验动物,对制备的缓释微丸进行了药动学研究。结果表明,流化床造粒包衣法制备的氨茶碱缓释微丸体外释放行为符合一级动力学方程;与市售氨茶碱片相比,自制缓释微丸的T_(max)显著延长,C_(max)明显降低,达到了良好的缓释效果;动物体内分数和体外释放度试验拟合较好,可以用体外试验取代体内试验作为质量监测的方法;药动学实验结果表明自制的缓释微丸生物利用度良好。
Film coating technique carried on by a fluidized bed spray coater is always used for preparing sustained-release pellets, which is more simple technology, less equipment need, less costs and more output capacity. Besides, the apparent fluidity of products made by fluidized bed is well, and there is no dust and mass during production. In this dissertation, aminophylline which is used for treating asthma, has been made in to sustained-release pellets. And the study was aiming at validation in vivo, consisting of preparation methods for pellets, the sustained- release system of coated pellets, pharmacokinetics. Results showed: the sustained-release pellets had good appearance and the drug was released in vivo over 12h.
The drug-excipient compatibility was studied between aminophylline and self-made blank pellets, using the pellets on market as the reference. Differential scanning calorimetry (DSC) was used as a screening technique besides with FT-IR spectroscopy and X-ray powder diffractometry. Aminophylline was found to be compatibility with self-made blank pellets but pellets on market. The studies of release seemed to sustain the result.
UV spectrophotometry was developed for in vitro assay during the studies of release , and the plasma concentration in rabbits was monitored by using the HPLC ultraviolet method.
Blank pellets were layered by exipients in liquid phase which was also used for drug carrying. The effects of process variables were investigated. Finally the content of the drug in the pellets is 36%.
Ethyl Cellulose was used for pellets coating. The effects of process variables and formulation variables on coating pellets preparation were investigated. And The results showed: the coated pellets had a marked sustained release property. The description of release profiles suggested that among the different kinetics, the first-order became the most appropriate model to describe release kinetics.
Using the aminophylline pills on market as the reference, the pharmacokinetics in rabbits of self-made sustained-release pellets were studied. The result indicated that Tmax was longer, whereas Cmax was lower than the pills on market. Furthermore, the results showed that the sustained release preparation had satisfactory sustained release effects and there was good correlation between absorption percent in vivo and accumulative release in vitro. And the aminophylline sustained release pellets show a good bioavailability.
Film coating technique carried on by a fluidized bed spray coater is always used for preparing sustained-release pellets, which is more simple technology, less equipment need, less costs and more output capacity. Besides, the apparent fluidity of products made by fluidized bed is well, and there is no dust and mass during production. In this dissertation, aminophylline which is used for treating asthma, has been made in to sustained-release pellets. And the study was aiming at validation in vivo, consisting of preparation methods for pellets, the sustained- release system of coated pellets, pharmacokinetics. Results showed: the sustained-release pellets had good appearance and the drug was released in vivo over 12h.
The drug-excipient compatibility was studied between aminophylline and self-made blank pellets, using the pellets on market as the reference. Differential scanning calorimetry (DSC) was used as a screening technique besides with FT-IR spectroscopy and X-ray powder diffractometry. Aminophylline was found to be compatibility with self-made blank pellets but pellets on market. The studies of release seemed to sustain the result.
UV spectrophotometry was developed for in vitro assay during the studies of release , and the plasma concentration in rabbits was monitored by using the HPLC ultraviolet method.
Blank pellets were layered by exipients in liquid phase which was also used for drug carrying. The effects of process variables were investigated. Finally the content of the drug in the pellets is 36%.
Ethyl Cellulose was used for pellets coating. The effects of process variables and formulation variables on coating pellets preparation were investigated. And The results showed: the coated pellets had a marked sustained release property. The description of release profiles suggested that among the different kinetics, the first-order became the most appropriate model to describe release kinetics.
Using the aminophylline pills on market as the reference, the pharmacokinetics in rabbits of self-made sustained-release pellets were studied. The result indicated that Tmax was longer, whereas Cmax was lower than the pills on market. Furthermore, the results showed that the sustained release preparation had satisfactory sustained release effects and there was good correlation between absorption percent in vivo and accumulative release in vitro. And the aminophylline sustained release pellets show a good bioavailability.
引文
[1] 平其能.现代药剂学[M].北京:中国医药科技出版社,1998,411.
[2] 邹贵龙.微丸的制备方法简介[J].中国医药工业杂志,2005,36(2):127~128.
[3] 伍成祥,徐锋.浅析微丸在固体口服缓释控释制剂中的应用[J].山东医药工业杂志,2000,19(5):36~37.
[4] 张俊贞, 杜文力.口服缓控释制剂研究现状[J].药学服务与研究,2003 Jun,3(2):93~95.
[5] 尤孝庆,卢丹,许美蓉.缓释微丸工艺研究[J].中国医药工业杂志,1996,27(4):163~165.
[6] 奚念朱.药剂学[M].北京:人民卫生出版社,1989:288.
[7] 张东利,郝东升,舒安庆,张维蔚.流化床喷雾造粒技术进展[J].化学工业与工程,2005,22(4),289~295.
[8] 刘善奎,钟延强,孙其荣,张卫星. 丙烯酸树脂系列辅料在药物新剂型中的应用[J].药学实践杂志,2002,20(1):12~14.
[9] 张光杰.药用辅料应用技术[M] . 北京:中国医药科技出版社.1991 :134.
[10] 郭波红,程怡. 乙基纤维素在缓控释制剂中的应用研究[J].中医药学刊,2002,20(5):601~603.
[11] 陈庆华,矍文,闻萍,等.乙基纤维素作为包衣材料在缓释盐酸苯丙醇胺树脂上的应用[J]. 中国药学杂志,1998 ,33 (1) :25.
[12] 温志红,杜华,谢庆玲,熊文虹,麦玲玲.成功抢救大剂量氨茶碱中毒 1 例[J].中国实用医药,2007,2(32):207.
[13] 徐富坤.国产缓释微丸面世[J].上海医药,2001,22(212):48
[14] 许让贤,吴建华,陈晓根.急诊支气管哮喘病人发病特点分析[J].浙江临床医学,2002,4(6):421.
[15] 中华医学会呼吸病学会哮喘学组.支气管哮喘定义、诊断.中华结核和呼吸志,1993,16(S):5～10.
[16] 国家药典委员会.中华人民共和国药典 2005 版二部[M].北京:化学工业出版社,2005,617.
[17] P. Corvi Moraa, M. Cirri b, P. Murab, Differential scanning calorimetry as a screening technique in compatibility studies of DHEA extended release formulations. Journal of Pharmaceutical and Biomedical Analysis,2006,3-10:4～11.
[18] A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke’s Analysisof Drugs and Poisons, 3rd ed., Pharmaceutical Press, London,2004.
[19] 苏德森,王思玲.物理药剂学[M].北京:化学工业出版社,2002:52.
[20] 张青,黄德音,戎霭伦. X 射线粉末衍射技术在酞菁同质多晶异构体研究中的应用[J].化学通报,2000,11:50～53.
[21] Peter A T, F reedman H S. Analytical Chemistry of Synthetic Co lour ants. Glasgow ,N Z: Blackie Academic & Professional, an imprint of Chapman & Hall, 1995: 1～5.
[22] L.S.勃克斯.X-射线光谱分析[M].北京:冶金工业出版社,1973,5.
[23] 吴谨光等.近代傅立叶变换红外光谱技术[M].北京:科学技术文献出版社:54～55.
[24] 苏德森,王思玲.物理药剂学[M].北京:化学工业出版社,2002,57.
[25] 易小红,邹同华. 差示扫描量热法在食品热物性测量中的应用[J].剂量与测试技术,2006,33(9):22～24.
[26] 金丽.差示扫描量热技术在淀粉研究中的应用[J].国外科技,2000,36(77):26～28.
[27] Anett Flemming, Katharina M. Picker-Freyer. Compaction of lactose drug mixtures: Quantification of the extentof incompatibility by FT-Raman spectroscopy. European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 802–810.
[28] 邹梅娟,于杰,程刚.氨茶碱缓释片的制备[J].中国药剂学杂志,2007,5(1):1～5.
[29] K.J. Hartauer, J.K. Guillory, A comparison of diffuse reflectance FT-IR spectroscopy and DSC in the characterization of a drug excipients interaction, Drug Dev. Ind. Pharm. 17 (4) (1991):617–630.
[30] 黄先菊,高林,马玲.紫外分光光度法检测氨茶碱在家兔中的血药浓度[J].湖北省卫生职工医学院学报,2004,17(3):80～82.
[31] 国家药典委员会.中华人民共和国药典 2005 版二部[M].北京:化学工业出版社,2005,617.
[32] 国家药典委员会.中华人民共和国药典 2005 版二部[M].北京:化学工业出版社,2005,附录 71.
[33] 张汝华主编.工业药剂学[M].北京:中国医药科技出版社,1999,39.
[34] 孙英华.苦参素缓释微丸的研究.沈阳药科大学学位论文,2004:20.
[35] 陈挺,靳松,陈庆华.乙基纤维素水分散体包衣微丸的体外释药研究[M].中国药科大学学报,2000,31(1):25～28.
[36] 陈挺,陈庆华.乙基纤维素水性包衣技术Ⅰ水分散体与有机溶剂包衣方法的比较[M].中国医药工业杂志,2000,31(1):7～12.
[37] 曾环想,肖全英,潘卫三,陈济民.法莫替丁缓释微丸的悬浮包衣法制备[M].中国医药工业杂志,2002,33(9):442～444.
[38] 毕殿洲.药剂学第四版[M].北京:人民卫生出版社,1999,422～425.
[39] Richard W. Korsmeyer, Robert Gurny, Eric Doelker. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 1983, 15(1):25-35.
[40] Judit Dredan, Istvan Antal. Evaluation of mathematical models describing drug release from lipophilic matrices. Int. J. Pharm. 1996, 145(1):61-64.
[41] Ozturk A, Oztuk S, Palsson B et al. Mechanism of release from pellets coated with an ethylcellulose-based film. J Control Rel, 1990,14(3):203-213.
[42] 卢元东,王登明.膜控释药的机理及影响因素[J].国外医药-合成药、生化药、制剂分册,1992,13(5):296～299.
[43] 林宁,肖学成,王蓉,丁广林.双氯芬酸纳缓释微丸在家兔体内的药动学研究[J].中国医院药学杂志,2002,22(7):402～404.
[44] 王丽萍,温实,胡宝生.尼美舒利缓释微丸在家兔体内吸收与体外溶出相关性研究[J].中国药师,2005,8(1):10～12.
[45] 杨积坪,裕海明.反相高效液相色谱法测定氨茶碱人体血药浓度[M].安徽医药,2006,10(4):263-264.
[46] M.S. Latha, K. Rathinam, P.V. Mohanan, A. Jayakrishnan. Bioavailability of theophylline from glutaraldehyde cross-linked casein microspheres in rabbits followingoral administration. Journal of Controlled Release 34 (1995) 1-7.
[47] 平其能主编.现代药剂学[M].北京:中国医药科技出版社,1998,413.
[48] 魏树礼主编.生物药剂学与药物动力学[M].北京:北京医科大学-中国协和医科大学联合出版社,1997:58～60.
[49] 体内药物分析
[50] 汤毅,韩有贵,黄昌全.兔体内氨茶碱时辰药代动力学的实验研究[J].第一军医大学学报,1990,10(2):205～207.
[51] 刘天培.时辰药物动力学[M].国外医学·药学分册,1985,12(3):180.
[2] 邹贵龙.微丸的制备方法简介[J].中国医药工业杂志,2005,36(2):127~128.
[3] 伍成祥,徐锋.浅析微丸在固体口服缓释控释制剂中的应用[J].山东医药工业杂志,2000,19(5):36~37.
[4] 张俊贞, 杜文力.口服缓控释制剂研究现状[J].药学服务与研究,2003 Jun,3(2):93~95.
[5] 尤孝庆,卢丹,许美蓉.缓释微丸工艺研究[J].中国医药工业杂志,1996,27(4):163~165.
[6] 奚念朱.药剂学[M].北京:人民卫生出版社,1989:288.
[7] 张东利,郝东升,舒安庆,张维蔚.流化床喷雾造粒技术进展[J].化学工业与工程,2005,22(4),289~295.
[8] 刘善奎,钟延强,孙其荣,张卫星. 丙烯酸树脂系列辅料在药物新剂型中的应用[J].药学实践杂志,2002,20(1):12~14.
[9] 张光杰.药用辅料应用技术[M] . 北京:中国医药科技出版社.1991 :134.
[10] 郭波红,程怡. 乙基纤维素在缓控释制剂中的应用研究[J].中医药学刊,2002,20(5):601~603.
[11] 陈庆华,矍文,闻萍,等.乙基纤维素作为包衣材料在缓释盐酸苯丙醇胺树脂上的应用[J]. 中国药学杂志,1998 ,33 (1) :25.
[12] 温志红,杜华,谢庆玲,熊文虹,麦玲玲.成功抢救大剂量氨茶碱中毒 1 例[J].中国实用医药,2007,2(32):207.
[13] 徐富坤.国产缓释微丸面世[J].上海医药,2001,22(212):48
[14] 许让贤,吴建华,陈晓根.急诊支气管哮喘病人发病特点分析[J].浙江临床医学,2002,4(6):421.
[15] 中华医学会呼吸病学会哮喘学组.支气管哮喘定义、诊断.中华结核和呼吸志,1993,16(S):5～10.
[16] 国家药典委员会.中华人民共和国药典 2005 版二部[M].北京:化学工业出版社,2005,617.
[17] P. Corvi Moraa, M. Cirri b, P. Murab, Differential scanning calorimetry as a screening technique in compatibility studies of DHEA extended release formulations. Journal of Pharmaceutical and Biomedical Analysis,2006,3-10:4～11.
[18] A.C. Moffat, M.D. Osselton, B. Widdop (Eds.), Clarke’s Analysisof Drugs and Poisons, 3rd ed., Pharmaceutical Press, London,2004.
[19] 苏德森,王思玲.物理药剂学[M].北京:化学工业出版社,2002:52.
[20] 张青,黄德音,戎霭伦. X 射线粉末衍射技术在酞菁同质多晶异构体研究中的应用[J].化学通报,2000,11:50～53.
[21] Peter A T, F reedman H S. Analytical Chemistry of Synthetic Co lour ants. Glasgow ,N Z: Blackie Academic & Professional, an imprint of Chapman & Hall, 1995: 1～5.
[22] L.S.勃克斯.X-射线光谱分析[M].北京:冶金工业出版社,1973,5.
[23] 吴谨光等.近代傅立叶变换红外光谱技术[M].北京:科学技术文献出版社:54～55.
[24] 苏德森,王思玲.物理药剂学[M].北京:化学工业出版社,2002,57.
[25] 易小红,邹同华. 差示扫描量热法在食品热物性测量中的应用[J].剂量与测试技术,2006,33(9):22～24.
[26] 金丽.差示扫描量热技术在淀粉研究中的应用[J].国外科技,2000,36(77):26～28.
[27] Anett Flemming, Katharina M. Picker-Freyer. Compaction of lactose drug mixtures: Quantification of the extentof incompatibility by FT-Raman spectroscopy. European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 802–810.
[28] 邹梅娟,于杰,程刚.氨茶碱缓释片的制备[J].中国药剂学杂志,2007,5(1):1～5.
[29] K.J. Hartauer, J.K. Guillory, A comparison of diffuse reflectance FT-IR spectroscopy and DSC in the characterization of a drug excipients interaction, Drug Dev. Ind. Pharm. 17 (4) (1991):617–630.
[30] 黄先菊,高林,马玲.紫外分光光度法检测氨茶碱在家兔中的血药浓度[J].湖北省卫生职工医学院学报,2004,17(3):80～82.
[31] 国家药典委员会.中华人民共和国药典 2005 版二部[M].北京:化学工业出版社,2005,617.
[32] 国家药典委员会.中华人民共和国药典 2005 版二部[M].北京:化学工业出版社,2005,附录 71.
[33] 张汝华主编.工业药剂学[M].北京:中国医药科技出版社,1999,39.
[34] 孙英华.苦参素缓释微丸的研究.沈阳药科大学学位论文,2004:20.
[35] 陈挺,靳松,陈庆华.乙基纤维素水分散体包衣微丸的体外释药研究[M].中国药科大学学报,2000,31(1):25～28.
[36] 陈挺,陈庆华.乙基纤维素水性包衣技术Ⅰ水分散体与有机溶剂包衣方法的比较[M].中国医药工业杂志,2000,31(1):7～12.
[37] 曾环想,肖全英,潘卫三,陈济民.法莫替丁缓释微丸的悬浮包衣法制备[M].中国医药工业杂志,2002,33(9):442～444.
[38] 毕殿洲.药剂学第四版[M].北京:人民卫生出版社,1999,422～425.
[39] Richard W. Korsmeyer, Robert Gurny, Eric Doelker. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 1983, 15(1):25-35.
[40] Judit Dredan, Istvan Antal. Evaluation of mathematical models describing drug release from lipophilic matrices. Int. J. Pharm. 1996, 145(1):61-64.
[41] Ozturk A, Oztuk S, Palsson B et al. Mechanism of release from pellets coated with an ethylcellulose-based film. J Control Rel, 1990,14(3):203-213.
[42] 卢元东,王登明.膜控释药的机理及影响因素[J].国外医药-合成药、生化药、制剂分册,1992,13(5):296～299.
[43] 林宁,肖学成,王蓉,丁广林.双氯芬酸纳缓释微丸在家兔体内的药动学研究[J].中国医院药学杂志,2002,22(7):402～404.
[44] 王丽萍,温实,胡宝生.尼美舒利缓释微丸在家兔体内吸收与体外溶出相关性研究[J].中国药师,2005,8(1):10～12.
[45] 杨积坪,裕海明.反相高效液相色谱法测定氨茶碱人体血药浓度[M].安徽医药,2006,10(4):263-264.
[46] M.S. Latha, K. Rathinam, P.V. Mohanan, A. Jayakrishnan. Bioavailability of theophylline from glutaraldehyde cross-linked casein microspheres in rabbits followingoral administration. Journal of Controlled Release 34 (1995) 1-7.
[47] 平其能主编.现代药剂学[M].北京:中国医药科技出版社,1998,413.
[48] 魏树礼主编.生物药剂学与药物动力学[M].北京:北京医科大学-中国协和医科大学联合出版社,1997:58～60.
[49] 体内药物分析
[50] 汤毅,韩有贵,黄昌全.兔体内氨茶碱时辰药代动力学的实验研究[J].第一军医大学学报,1990,10(2):205～207.
[51] 刘天培.时辰药物动力学[M].国外医学·药学分册,1985,12(3):180.