马来酸罗格列酮胃漂浮型缓释片剂的实验研究
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摘要
马来酸罗格列酮为第二代噻唑烷二酮类降糖新药，主要通过增加胰岛
素敏感性来发挥药效，用于治疗2型糖尿病。该药自1999年5月被美国FDA批
准上市以来，具有很好的市场前景。有关该药物新剂型的研究未见诸报道，
本论文将该药物设计制成一日一次的胃滞留缓控释片，通过延长药物在胃
内的滞留时间，使缓释片达到与普通速释片生物等效的目的。
胃滞留缓释片根据流体动力学平衡体系原理制成的一种新型给药体
系。本论文在制剂处方前和预实验的研究基础上，以体外漂浮和药物释放
为筛选指标，采用单因素考察和正交设计等方法对处方、制备工艺及体外
释放条件等进行优化筛选。有关释药机理的研究结果表明体外释放过程符
合Higuchi方程，释放机制为异常扩散；制剂稳定性研究结果提示，该制剂
应在避光和干燥的条件下贮存。
采用γ闪烁照相技术对口服~(99m)Tc标记的滞留片和普通片胃内滞留情况
进行初步动态观察，实验结果表明，口服胃滞留片后，药片在胃内滞留达3
小时以上，且不发生崩解。
人体药动学研究表明，普通片的药动学参数与文献报道的数据基本类
似，单剂量缓释片和普通片生物等效，且体内外具有一定的相关性。
本论文对马来酸罗格列酮缓控释新剂型开发进行了有益的尝试。
EXPEREMENTAL STUDIES OF ROSIGLITAZONE
MALEATE INTRAGASTRIC FLOATING SUSTAINED
RELEASE TABLET
FENG HAO (Pharmaceutics)
CHEN DAWEI WANG ZHIM]7N
ABSTRACT
Rosiglitazone maleate was an oral anti-diabetic agent, belonged to new
thiazolidinediones(TZD), which reduces insulin resistance, an underlying defect
of type 2 diabetes. It showed a very good market perspective since Avandia was
approved by Food and Drug Administration (FDA) in May , 1999. The new
dosage forms of rosiglitazone maleate have not been reported. A new
intragastric floating sustained release tablet was designed in this thesis, which
aimed to delay the gastrointestinal residence time, decease administrated times
within day, and have a bio-equivalent to the fast-released tablet.
Gastric floating sustained-released tablet was a novel oral dosage form,
designed by the principle of hydrodynamically balanced system. On basis of
pre-experiments and pharmaceutical pre-formulation studies, the amount and
types of expicents, prepared methods and drug release in vitro of the
prescription were determined by buoyant and drug releasing conditions as
screening index with orthogonal design test and single-factor test methods.
Drug releasing process of testing tablet in media was accorded to Higuchi
equation, and the releasing mechanism was anomalous diffusion. Stability
studies indicated that the preparation should be stored in the dry and light-
prevented environment.
To observe the dynamic changes in gastric retention, Rg-M sustained-
release tablet and control tablet (Avandia) were radio-labeled with 99mTc, their
behavior in stomach were detected by i -ray camera techniques. The testing
tablet was remained in the stomach for more than 3h without disintegrating.
Pharmacokinetic parameters of control and sustained-releasing tablets
were studied. The pharmacokinetic parameters of control group (Avandia) in
healthy volunteers were similar to that of published. It was suggested that these
3
two preparations were bioequivalent in single oral administration. The
cumulative releasing of Rg-M in vitro was related to the absorption fraction in
vzvo.
Our thesis will be benefit for the development of sustained release dosage
forms of rosiglitazone maleat.
素敏感性来发挥药效，用于治疗2型糖尿病。该药自1999年5月被美国FDA批
准上市以来，具有很好的市场前景。有关该药物新剂型的研究未见诸报道，
本论文将该药物设计制成一日一次的胃滞留缓控释片，通过延长药物在胃
内的滞留时间，使缓释片达到与普通速释片生物等效的目的。
胃滞留缓释片根据流体动力学平衡体系原理制成的一种新型给药体
系。本论文在制剂处方前和预实验的研究基础上，以体外漂浮和药物释放
为筛选指标，采用单因素考察和正交设计等方法对处方、制备工艺及体外
释放条件等进行优化筛选。有关释药机理的研究结果表明体外释放过程符
合Higuchi方程，释放机制为异常扩散；制剂稳定性研究结果提示，该制剂
应在避光和干燥的条件下贮存。
采用γ闪烁照相技术对口服~(99m)Tc标记的滞留片和普通片胃内滞留情况
进行初步动态观察，实验结果表明，口服胃滞留片后，药片在胃内滞留达3
小时以上，且不发生崩解。
人体药动学研究表明，普通片的药动学参数与文献报道的数据基本类
似，单剂量缓释片和普通片生物等效，且体内外具有一定的相关性。
本论文对马来酸罗格列酮缓控释新剂型开发进行了有益的尝试。
EXPEREMENTAL STUDIES OF ROSIGLITAZONE
MALEATE INTRAGASTRIC FLOATING SUSTAINED
RELEASE TABLET
FENG HAO (Pharmaceutics)
CHEN DAWEI WANG ZHIM]7N
ABSTRACT
Rosiglitazone maleate was an oral anti-diabetic agent, belonged to new
thiazolidinediones(TZD), which reduces insulin resistance, an underlying defect
of type 2 diabetes. It showed a very good market perspective since Avandia was
approved by Food and Drug Administration (FDA) in May , 1999. The new
dosage forms of rosiglitazone maleate have not been reported. A new
intragastric floating sustained release tablet was designed in this thesis, which
aimed to delay the gastrointestinal residence time, decease administrated times
within day, and have a bio-equivalent to the fast-released tablet.
Gastric floating sustained-released tablet was a novel oral dosage form,
designed by the principle of hydrodynamically balanced system. On basis of
pre-experiments and pharmaceutical pre-formulation studies, the amount and
types of expicents, prepared methods and drug release in vitro of the
prescription were determined by buoyant and drug releasing conditions as
screening index with orthogonal design test and single-factor test methods.
Drug releasing process of testing tablet in media was accorded to Higuchi
equation, and the releasing mechanism was anomalous diffusion. Stability
studies indicated that the preparation should be stored in the dry and light-
prevented environment.
To observe the dynamic changes in gastric retention, Rg-M sustained-
release tablet and control tablet (Avandia) were radio-labeled with 99mTc, their
behavior in stomach were detected by i -ray camera techniques. The testing
tablet was remained in the stomach for more than 3h without disintegrating.
Pharmacokinetic parameters of control and sustained-releasing tablets
were studied. The pharmacokinetic parameters of control group (Avandia) in
healthy volunteers were similar to that of published. It was suggested that these
3
two preparations were bioequivalent in single oral administration. The
cumulative releasing of Rg-M in vitro was related to the absorption fraction in
vzvo.
Our thesis will be benefit for the development of sustained release dosage
forms of rosiglitazone maleat.
引文
[1] L.A. Sorbera, X. Rabasseda, J. Castaner, et. al. Rosiglitazone Maleate. Drugs of the future. 1998,22(9):977-985
[2] 赵圣印．糖尿病治疗药的研究进展．国外医药-合成药生化药制剂分册。1999，20(3)：130-135
[3] 丁禄霞．胰岛素增敏剂的开发与临床应用．国外医药-合成药生化药制剂分册．2000，21(2)：93-96
[4] 邓安春摘．抗糖尿病新药罗格列酮和吡格列酮．国外医学药学分册。2000，27(1)：15-16
[5] Chustecka Z. New Drugs for Diabetes—Rosiglitazone and Pioglitazone. Scrip. (2451): 28-29
[6] 连云港康缘制药股份公司．马来酸罗格列酮药代动力学研究综述．二类新药申报资料(22)：5-12
[7] J.L. Tossounian, W.J. Mergens and P.R. Sheth. Bioefficient Product-A novel Delivery System. Drug Dev. and Ind. Phar. 11(5):1019-1050
[8] Hofmann AF, Jeffrey M.D, Charles M.D, et. al. Drug Dev Ind Pharm, 1983;9(7): 1077-1109
[9] P. Sheth, J. Tossounian, The hydrodynamically balanced syetem(HBS~(TM)):A novel drug delivery system for oral use. Drug Dev. and Ind. Phar, 1984;10(2):313-339
[10] 刘崇悌．胃内漂浮给药系统．药学通报，1987；22 (5)：300-302
[11] H.M. Ingani, Timmermans, A.J. Moes. Conception and in vivo investigation of peroral sustained release floating dosage forms with enhanced gastrointestinal transit. Int. J. Pharm. 1987;35:157-164
[12] 吴伟，周全．胃内滞留漂浮型给药系统的研究概况与进展．国外医药-合成药生化药制剂分册．1998，19(2)：123-128
[13] 钱传训，曾平，肖新芳．安定胃内漂浮缓释片的研制．中国医院药学杂志．1989；9(11)：547-549
[14] 曹德英，张立德，张莉等．盐酸曲马多胃漂浮缓释片的研究．中国医药工业杂志．1999；30(4)：154-156
[15] 朱于村，屠锡德．盐酸雷尼替丁胃内滞留漂浮型缓释片的制备及药物动力学研究．中国药科大学学报。1990；21(5)：271-275
[16] 徐琛，屠锡德．复方硫酸庆大霉素胃内滞留漂浮型缓释片的研究．中国药科大学学报。1999；30(5)：335-339
[17] 胡容峰，屠锡德，谢鹏雁．呋喃唑酮胃漂浮缓释片的研究．中国医药工业杂志．1992；23(1)：10-11
[18] 范田园，魏树礼．地西泮动力学平衡胶囊研究．中国药学杂志．1999；37(7)：459-461
[19] 侯惠民，朱金屏．胃漂浮缓释片Ⅰ硝苯啶胃漂浮缓释片的制备与性质。中国医药工业杂志．1991；22(3)：106-108
[20] 侯惠民，朱金屏，熊全美等．PVP、PVA为辅料的胃漂浮缓释片研究Ⅱ地尔硫卓胃漂浮缓释片．中国医药工业杂志．1991；22(4)：156-158
[21] Menon, Wolfgang A. Adel S. Development and Evaluation of a Monolithic Floating Dosage Form for 5-Furosemide. J. Pharm. Sci. 1994;83(2):239-245
[22] Norman Mazer, Eva Abisch, Jean-C.G. et. al. Intragastric Behavior and Absorption Kinetics of a Normal and '"Floating "Modified-Release Capsule of Isradipine under Fasted and Fed Condition. J. Pharm. Sci. 1988,77(8):647-657
[23] Brahma N, Kwon H. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Controlled Release. 2000;63:235-259
[24] Gerogiannis VS, Rekkas DM, Dallas PP et al. Floating and Swelling Characteristics of Various Excipents used in Controlled Release Technology. Drug Development and Pharmacy. 1993;19(9):1061-1081
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[2] 赵圣印．糖尿病治疗药的研究进展．国外医药-合成药生化药制剂分册。1999，20(3)：130-135
[3] 丁禄霞．胰岛素增敏剂的开发与临床应用．国外医药-合成药生化药制剂分册．2000，21(2)：93-96
[4] 邓安春摘．抗糖尿病新药罗格列酮和吡格列酮．国外医学药学分册。2000，27(1)：15-16
[5] Chustecka Z. New Drugs for Diabetes—Rosiglitazone and Pioglitazone. Scrip. (2451): 28-29
[6] 连云港康缘制药股份公司．马来酸罗格列酮药代动力学研究综述．二类新药申报资料(22)：5-12
[7] J.L. Tossounian, W.J. Mergens and P.R. Sheth. Bioefficient Product-A novel Delivery System. Drug Dev. and Ind. Phar. 11(5):1019-1050
[8] Hofmann AF, Jeffrey M.D, Charles M.D, et. al. Drug Dev Ind Pharm, 1983;9(7): 1077-1109
[9] P. Sheth, J. Tossounian, The hydrodynamically balanced syetem(HBS~(TM)):A novel drug delivery system for oral use. Drug Dev. and Ind. Phar, 1984;10(2):313-339
[10] 刘崇悌．胃内漂浮给药系统．药学通报，1987；22 (5)：300-302
[11] H.M. Ingani, Timmermans, A.J. Moes. Conception and in vivo investigation of peroral sustained release floating dosage forms with enhanced gastrointestinal transit. Int. J. Pharm. 1987;35:157-164
[12] 吴伟，周全．胃内滞留漂浮型给药系统的研究概况与进展．国外医药-合成药生化药制剂分册．1998，19(2)：123-128
[13] 钱传训，曾平，肖新芳．安定胃内漂浮缓释片的研制．中国医院药学杂志．1989；9(11)：547-549
[14] 曹德英，张立德，张莉等．盐酸曲马多胃漂浮缓释片的研究．中国医药工业杂志．1999；30(4)：154-156
[15] 朱于村，屠锡德．盐酸雷尼替丁胃内滞留漂浮型缓释片的制备及药物动力学研究．中国药科大学学报。1990；21(5)：271-275
[16] 徐琛，屠锡德．复方硫酸庆大霉素胃内滞留漂浮型缓释片的研究．中国药科大学学报。1999；30(5)：335-339
[17] 胡容峰，屠锡德，谢鹏雁．呋喃唑酮胃漂浮缓释片的研究．中国医药工业杂志．1992；23(1)：10-11
[18] 范田园，魏树礼．地西泮动力学平衡胶囊研究．中国药学杂志．1999；37(7)：459-461
[19] 侯惠民，朱金屏．胃漂浮缓释片Ⅰ硝苯啶胃漂浮缓释片的制备与性质。中国医药工业杂志．1991；22(3)：106-108
[20] 侯惠民，朱金屏，熊全美等．PVP、PVA为辅料的胃漂浮缓释片研究Ⅱ地尔硫卓胃漂浮缓释片．中国医药工业杂志．1991；22(4)：156-158
[21] Menon, Wolfgang A. Adel S. Development and Evaluation of a Monolithic Floating Dosage Form for 5-Furosemide. J. Pharm. Sci. 1994;83(2):239-245
[22] Norman Mazer, Eva Abisch, Jean-C.G. et. al. Intragastric Behavior and Absorption Kinetics of a Normal and '"Floating "Modified-Release Capsule of Isradipine under Fasted and Fed Condition. J. Pharm. Sci. 1988,77(8):647-657
[23] Brahma N, Kwon H. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Controlled Release. 2000;63:235-259
[24] Gerogiannis VS, Rekkas DM, Dallas PP et al. Floating and Swelling Characteristics of Various Excipents used in Controlled Release Technology. Drug Development and Pharmacy. 1993;19(9):1061-1081
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