盐酸二甲双胍缓释片的研究
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摘要
盐酸二甲双胍是广泛应用于非胰岛素依赖型(Ⅱ型)糖尿病的降糖药，口服后主要通过降低肝及外周组织对胰岛素的敏感度来降低血糖水平，对腺体的正常分泌无影响，还可以降低血清脂肪水平，提高纤维蛋白的活性。本文采用HPMC作为基本骨架材料，结合其他辅料，制备了日服1次的盐酸二甲双胍缓释片。
本文在处方前研究工作的基础上，以药物释放度为筛选指标，通过单因素实验和正交设计实验，确定了体外释放8小时的盐酸二甲双胍缓释片的制备工艺和优化处方。对采用优化处方制备的三批样品进行了质量评价和初步稳定性实验，还采用Higuchi模型研究了盐酸二甲双胍缓释片的释药机理。
分别采用压制包衣技术，有机溶剂包衣技术和水性包衣技术，结合骨架缓释技术，对体外释放12小时的盐酸二甲双胍缓释片进行了研究。在固定片芯处方的基础上，考察了不同包衣技术的的处方影响因素。最终采用水性包衣技术，通过调节包衣液处方中羟丙基甲基纤维素水溶液与乙基纤维素水分散体Surelease的比例，并加入癸二酸二丁酯作为增塑剂，成功地控制了盐酸二甲双胍的释放，并对薄膜包衣的缓释作用机制进行了探讨。
以盐酸二甲双胍普通片为参比制剂，对自制的盐酸二甲双胍缓释片进行了家犬体内药动学研究，结果表明，口服单剂量缓释片和普通片生物等效，且缓释片体内外具有一定的相关性。
Metformin hydrochloride ( MH ) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus ( NTDDM or type-2 diabetes). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissues sensitivity to insulin without affecting the secretion of this hormone. It also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity. Combining with other filers , a sustained release tablet (SRT) of once daily administration was prepared by using hydropropyl methylcellulose as basic matrix material.
On the basis of pharmaceutical preformulation studies , the preparation technique and optimized formulation of MH SRT , which extend the drug release to 8 hours in vitro , were determined by single-factor test and orthogonal design test according to cumulative percent of drug release. The test of quality and the basic stability of three batches of tablets prepared by optimized formulation were carried out . The Higuchi model were used to study the releasing mechanism of MH sustained release tablets .
Combing with matrix-sustained release technique ,the MH SRT ,which extend the drug release to 12 hours in vitro were studied respectively by using press coating technique, organic solvent coating technique and pseudolatex coating technique. The effecting factors of different coating techniques were studied basing on the unchanging of tablet formulation. Finally the latex coating technique were adopted . By changing the percentage of hydropropyl methylcellulose and Surelease(ethylcellulose pseudolatex) in coating solution with dibutyl sebacate as plastics , the release of MH were successfully controlled . By the time ,the sustained release mechanism of film coating were studied.
The pharmacokinetics of MH SRT and commercial tablet in dogs were studied. The results showed that these two dosage forms were bioequivalent by single oral administration The IVIVC(in vitro-in vivo correlation) was also encouraging.
本文在处方前研究工作的基础上，以药物释放度为筛选指标，通过单因素实验和正交设计实验，确定了体外释放8小时的盐酸二甲双胍缓释片的制备工艺和优化处方。对采用优化处方制备的三批样品进行了质量评价和初步稳定性实验，还采用Higuchi模型研究了盐酸二甲双胍缓释片的释药机理。
分别采用压制包衣技术，有机溶剂包衣技术和水性包衣技术，结合骨架缓释技术，对体外释放12小时的盐酸二甲双胍缓释片进行了研究。在固定片芯处方的基础上，考察了不同包衣技术的的处方影响因素。最终采用水性包衣技术，通过调节包衣液处方中羟丙基甲基纤维素水溶液与乙基纤维素水分散体Surelease的比例，并加入癸二酸二丁酯作为增塑剂，成功地控制了盐酸二甲双胍的释放，并对薄膜包衣的缓释作用机制进行了探讨。
以盐酸二甲双胍普通片为参比制剂，对自制的盐酸二甲双胍缓释片进行了家犬体内药动学研究，结果表明，口服单剂量缓释片和普通片生物等效，且缓释片体内外具有一定的相关性。
Metformin hydrochloride ( MH ) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus ( NTDDM or type-2 diabetes). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissues sensitivity to insulin without affecting the secretion of this hormone. It also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity. Combining with other filers , a sustained release tablet (SRT) of once daily administration was prepared by using hydropropyl methylcellulose as basic matrix material.
On the basis of pharmaceutical preformulation studies , the preparation technique and optimized formulation of MH SRT , which extend the drug release to 8 hours in vitro , were determined by single-factor test and orthogonal design test according to cumulative percent of drug release. The test of quality and the basic stability of three batches of tablets prepared by optimized formulation were carried out . The Higuchi model were used to study the releasing mechanism of MH sustained release tablets .
Combing with matrix-sustained release technique ,the MH SRT ,which extend the drug release to 12 hours in vitro were studied respectively by using press coating technique, organic solvent coating technique and pseudolatex coating technique. The effecting factors of different coating techniques were studied basing on the unchanging of tablet formulation. Finally the latex coating technique were adopted . By changing the percentage of hydropropyl methylcellulose and Surelease(ethylcellulose pseudolatex) in coating solution with dibutyl sebacate as plastics , the release of MH were successfully controlled . By the time ,the sustained release mechanism of film coating were studied.
The pharmacokinetics of MH SRT and commercial tablet in dogs were studied. The results showed that these two dosage forms were bioequivalent by single oral administration The IVIVC(in vitro-in vivo correlation) was also encouraging.
引文
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[2] 陈睿杰 刘允坚．糖尿病治疗药物的研究现状．广东药学院学报，2001，17(2)：131[3]
[4] 李颖编译．口服抗糖尿病药物的选用，国外医学--制剂分册，1998，19(6)：336
[5] 冯继明，尹湘津，蔡健等．二甲双胍治疗非胰岛素依赖性糖尿病．新药与临床，1997，16(1)：19-20
[6] 亢则坤，张丽华．二甲双胍与其他口服降糖药物作用比较．河北医药，1994，16(6)：374
[7] 王敬先，康晨霞．降血糖新药—盐酸二甲双胍．中国药理学通报，1996，12(4)：334
[8] 中国制药信息．2000，16(6)：27
[9] Pharma Marketletter. 2000, 7(3): 23
[10] Scrip. 2000, (2518), 22
[11] 平其能等．现代药剂学，北京，中国医药科技出版社，1998年，1-9
[12] R. Konrad, A. Christ, G. Zessin et al. The use of ultrasound and penetrometer to characterize the advancement of swelling and eroding fronts in HPMC matrices. Int. J. Pharm. 1998, 163: 123-131
[13] 王振国，董皎，韩艳丽等．羟丙基甲基纤维素的凝胶特性及其对曲尼司特缓释片释放行为的影响．药学学报，2000，35(1)：48-51
[14] P. Colombo, P. catellani, N. A. Peppas et al. Swelling characteristics of hydrophilic matrices for controlled release: new dimensionless number to describe the swelling and release behaviour. Int. J. Pharm. 1992,88:99-109
[15] Thomas D. Reynolds, Stevin H. Gehrke, Ajaz S. Hussain et al. Polymer erosion and drug release characterization of hydroxypropyl methycellulose matrices. J. Pharm. Sci. 1998, 87(9):1115-1122
[16] F. Veiga, T. Salsa & E. Pina. Influence of technological variables on the release of theophylline from hydrophilic matrix tablets. Drug Dev. Ind. Pharm. 1997, 23(6): 547-551
[17] T. Salsa, F. Veiga & M. E. Plna. Oral controlled-release dosage forms. I. Cellulose ether polymers in hydrophilic matrices. Drug Dev. Ind. Pharm. 1997, 23(9): 928-938
[18] 董志超，蒋雪涛．羟丙基甲基纤维素在凝胶骨架片中的应用．国外医药—合成药、生化药、制剂分册，1994，14(1)：41-44
[19] 董志超，蒋雪涛．羟丙基甲基纤维素的性质对药物亲水性骨架片溶出度的影响．药学学报，1994，29(12)：920-924
[20] 董志超，蒋雪涛．羟丙基甲基纤维素的物理性质对口服骨架型制剂释放的影响．国外医药—合成药、生化药、制剂分册，1995，16(2)：103-105
[21] 吕丹，裴元英．羟丙基甲基纤维素-卡波普缓释亲水凝胶骨架片的研制和释药影响因素的考察．中国药学杂志，2001，36(9)：603-606
[22] 吴涛．硫酸沙丁胺醇渗透泵型控释片及其人工神经网络辅助处方设计的研究．沈阳药科大学博士学位论文
[23] M. C. Bonferoni, S. Rossi & F. Ferrari et al. On the employment of λ carrageenan in a matrix system. Ⅲ. Optimization of a λ carrageenan-HPMC hydrophilic matrix. J. Controlled. Release. 1998, 51: 231-239
[24] Adrian Bodea, Sorin E. Leucuta. Optimization of hydrophilic matrix tablets using a D-optimal design. Int. J. Pharm. 1998,153:247-255
[25] G. J. Xu, F. Fang & R. H. Zhang et al. A research on aspirin sustained-release formulation. Drug Dev. Ind. Pharm. 1997, 23(8):741-747
[26] 陆兵，徐国杰，张汝华．偏离度—缓控释制剂处方优化的指标．中国医药工业杂志，1999，30(8)：348-351
[27] Jeffrey W. Moore, Henry H. Flanner, Mathematical comparison of dissolution profiles. Pharm. Tech. 1996, 6: 64-74
[28] 夏锦辉，刘昌孝．固体药物制剂的体外溶出度的统计学评价分析．中国药学杂志，2000，35(2)：130-131
[29] 方积乾主编．医药数理统计方法(第二版)版．人民卫生出版社，1995年9月
[30] 齐美玲，郑俊民，张汝华．盐酸尼卡地平缓释片的研究．中国医药工业杂志，2000，31(6)：260-262
[31] 徐晖，丁平田，郑俊民．聚合物系统中药物的非扩散控制释放．药学学报，2000，35(9)：710-714
[32] T Higuchi. J. Pharm. Sci. 1961, 50:874
[33] T, Higuchi. Mechanism of sustained-action medication, theoretical analysis of rate of release of solid drugs dipersed in solid matrices. J. Pharm. Sci. 1963, 12: 1145-1149
[34] Koichim Tahara, Ken Yamamoto & oshiaki Nishihata. Overall mechanism behind matrix sustained release tablets prepared with hydroxyprpyl methylcellulose 2910. J. Controlled. Release. 1995, 35: 59-66
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