两种不同剂量药物缓释微丸的研究
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摘要
本文分别以大剂量药物盐酸二甲双胍和小剂量药物阿司匹林为模型药物，以Eudragit~(?)NE30D为膜材，利用国产挤出滚圆机和小型流化床包衣机，成功地制备了具有良好缓释作用的缓释微丸，对国内口服缓控释制剂的研制开发和质量控制具有一定的参考价值。
制备大剂量盐酸二甲双胍缓释微丸有一定难度，一要素丸含药量大，二要使包上的衣膜厚度适宜。本文采用正交设计优化出最佳工艺，在处方单因素考察的基础上确定了最佳处方。在此基础上通过采用适当地“外加”少量润湿剂的方法，进一步改善了微丸的圆整度和收率，制备出含药量高达60％的素丸。经过对影响包衣微丸释放的工艺和处方因素考察，确定了最佳包衣工艺和包衣液处方组成。通过按适当比例混合两种不同释药速率的包衣微丸，得到了缓释作用明显的胶囊剂，并对该制剂进行了质量评价和初步稳定性试验，最后还探讨了其释药机理。
制备小剂量阿司匹林素丸的过程中，阿司匹林不稳定、易分解。本文通过考察各影响因素，优化出最佳制丸工艺和处方，在一定程度上解决了阿司匹林的不稳定性；通过优化包衣工艺和包衣液处方，调整衣膜厚度和致孔剂用量，成功地制备了具有缓释特征的包衣微丸，并对该制剂进行了质量评价和初步稳定性试验，还探讨了其释药机理。家犬体内药动学实验结果表明：自制缓释胶囊剂与普通片相比，缓释特征明显且体内外具有较好的相关性。
This thesis is to report that sustained-release pellets with well sustained-release effect were successfully prepared by domestic extrusion-spheronization machine and small-scale fluid-bed coater and using high-dose drug Metformin Hydrochloride(MH) and low-dose drug Aspirin(ASP)as model drug and Eudragit?NE30D as coating material, so that this work has referential value for R&D and quality controll of oral sustained-release and controlled-release pharmaceuticals in China.
There are certain difficulties in preparing the high-dose MH sustained-release pellets, in which one is that the pellet core has to contain high drug content and the other is that the coating membrane thickness has to be suitable to ensure an expectable effect. The orthogonal design to optimize the best technological process was adopted and the most desirable formulation was determined based on single-factor study. On the basis of the previous work, pellet cores with high drug content (60%) were prepared by "properly" adding small amount of moistening agent in the spinning spheronizer which has further improved the pellets' sphericity and
productivity. By studying on the technological and formulational factors that effect the release behavior of coated pellets, the best coating process and formulation were determined. The desirable MH capsule providing a clear sustained-release effect was obtained by mixing two kinds of coated pellets having different release rate in proper proportion. Also, quality evaluation and stability tests of the preparation were done, and at last drug release mechanism was discussed.
In the process of making low-dose ASP pellets, ASP was unstable and easy to resolve. The best technology and formulation were optimized in making pellet cores through the study of effecting factors that might be concerned and as a result, the problem of ASP's unstability has been solved to a certain extent. Coated pellets with promising sustained-release properties have been successfully prepared by the optimization of both coating process and coating formulation and also through the selection of coating membrane thickness and amount of pore former. Also, quality evaluation and stability tests of the preparation were done, and drug release mechanism was discussed. The pharmacokinetics results in-vivo from experimental dogs showed that self-made sustained-release capsule has an obvious sustained-release character in comparison with the conventional-tablet on market and the co-relationship between the absorption in-vivo and the dissolution in-vitro is significant.
制备大剂量盐酸二甲双胍缓释微丸有一定难度，一要素丸含药量大，二要使包上的衣膜厚度适宜。本文采用正交设计优化出最佳工艺，在处方单因素考察的基础上确定了最佳处方。在此基础上通过采用适当地“外加”少量润湿剂的方法，进一步改善了微丸的圆整度和收率，制备出含药量高达60％的素丸。经过对影响包衣微丸释放的工艺和处方因素考察，确定了最佳包衣工艺和包衣液处方组成。通过按适当比例混合两种不同释药速率的包衣微丸，得到了缓释作用明显的胶囊剂，并对该制剂进行了质量评价和初步稳定性试验，最后还探讨了其释药机理。
制备小剂量阿司匹林素丸的过程中，阿司匹林不稳定、易分解。本文通过考察各影响因素，优化出最佳制丸工艺和处方，在一定程度上解决了阿司匹林的不稳定性；通过优化包衣工艺和包衣液处方，调整衣膜厚度和致孔剂用量，成功地制备了具有缓释特征的包衣微丸，并对该制剂进行了质量评价和初步稳定性试验，还探讨了其释药机理。家犬体内药动学实验结果表明：自制缓释胶囊剂与普通片相比，缓释特征明显且体内外具有较好的相关性。
This thesis is to report that sustained-release pellets with well sustained-release effect were successfully prepared by domestic extrusion-spheronization machine and small-scale fluid-bed coater and using high-dose drug Metformin Hydrochloride(MH) and low-dose drug Aspirin(ASP)as model drug and Eudragit?NE30D as coating material, so that this work has referential value for R&D and quality controll of oral sustained-release and controlled-release pharmaceuticals in China.
There are certain difficulties in preparing the high-dose MH sustained-release pellets, in which one is that the pellet core has to contain high drug content and the other is that the coating membrane thickness has to be suitable to ensure an expectable effect. The orthogonal design to optimize the best technological process was adopted and the most desirable formulation was determined based on single-factor study. On the basis of the previous work, pellet cores with high drug content (60%) were prepared by "properly" adding small amount of moistening agent in the spinning spheronizer which has further improved the pellets' sphericity and
productivity. By studying on the technological and formulational factors that effect the release behavior of coated pellets, the best coating process and formulation were determined. The desirable MH capsule providing a clear sustained-release effect was obtained by mixing two kinds of coated pellets having different release rate in proper proportion. Also, quality evaluation and stability tests of the preparation were done, and at last drug release mechanism was discussed.
In the process of making low-dose ASP pellets, ASP was unstable and easy to resolve. The best technology and formulation were optimized in making pellet cores through the study of effecting factors that might be concerned and as a result, the problem of ASP's unstability has been solved to a certain extent. Coated pellets with promising sustained-release properties have been successfully prepared by the optimization of both coating process and coating formulation and also through the selection of coating membrane thickness and amount of pore former. Also, quality evaluation and stability tests of the preparation were done, and drug release mechanism was discussed. The pharmacokinetics results in-vivo from experimental dogs showed that self-made sustained-release capsule has an obvious sustained-release character in comparison with the conventional-tablet on market and the co-relationship between the absorption in-vivo and the dissolution in-vitro is significant.
引文
[1] Isaac Ghebre-Sellassie. Pharmaceutical Pelletization Technology Marcel Dekker, Inc. 1989, 1
[2] 平其能．现代药剂学．中国医药科技出版社，1998，411～413
[3] 钱方，蒋雪涛，王安文．微丸的进展．中国医药工业杂志，1996，27(1)：41～46
[4] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，294
[5] Chris V, Lieven B, Paul RJ. Extrusion-spheronization. Int J Pharm, 1995, 116(2):131
[6] 潘家祯，孙晓明，朱大滨等．挤出滚圆法制备药用微丸Ⅰ设备的工作原理及特点．中国医药工业杂志，1998，29(8)：378～380
[7] 包泳初，陈庆华，刘伟伦等．挤出滚圆法制备药用微丸Ⅱ制丸工艺．中国医药工业杂志，1999，30(1)：18～21
[8] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，266
[9] 陈庆华．现代微丸制备与包衣装置的类型与应用．中国医药工业杂志，1996，27(3)：134～138
[10] Lippold BH, Sutter BK and Lippold BC. Parameters controlling drug release from pellets coated with aqueous ethyl cellulose dispersion. Int J Pharm 1989, 54:15
[11] Turkoglu M and Sakr A. Mathematical modeling and optimization of a rotary fluidized-bed coating process. Int J Pharm 1992, 88:75
[12] 张彦文，郎奕．盐酸二甲双胍片剂质量评价．中国医院药学杂志，2000，20(12)：721～722
[13] 亢泽坤，张丽华．二甲双胍与其它口服降糖药物作用比较．河北医药，1994，16(6)：374
[14] 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
[15] 谢晓慧，甄健存，赵怀全．5个不同企业的盐酸二甲双胍片体外溶出度考察．中国药学杂志，2001，36(7)：481～482
[16] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，301
[17] Umpragn K, Chitropas P, Amarekajorm S. Influence of process variables on physical properties of the pellets. Drug Dev Ind Pharm 1999, 25(1): 45
[18] C. W. Woodruff and N. O. Nuessle. Effect of processing variables on particles obtained by extrusion-spheronization process Ind J Pharm Sci, 1972, 61: 787～790
[19] H.A. Doshi and R. Shrivastava. Preparation of Pellets: Extruding and Spheronizing Machines Study. Ind J Pharm Sci, 1993, 55(2): 55～58
[20] L. Baert and J. P. Remon. Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion-spheronization. Int J Pharm, 1993, 95(1): 135～141
[21] J. F. Pinto, G. Buckton and J. M. Newton. The influence of four selected processing and formulation factors on the production of spheres by extrusion and spheronisation. Int J Pharm, 1992, (83): 187～196
[22] Vervaet C, Baert L and Remon J P. Enhancement of in-vitro drug release by using polyethylene glycol 400 and PEG-40 hydrogenated castor oil in pellets made by extrusion spheronization, Int J Pharm. 1994, 108:207～212
[23] 梁超峰，欧阳允，陈平等．润湿粘合剂对小丸制备的影响．中国医药工业杂志，2000，31(4)：159～161
[24] Schmidt C, Kleinebudde P. Influence of the granulation step on pellets prepared by extrusion-spheronization. Chem Parm Bull, 1999, 47(3): 405～412
[25] Van SG and Rhodos CT. The sustained release coating of solid dosage forms: a historical review. Drug Dev Ind Phar, 1995, 21(1): 93～118
[26] Zhang GH, Schwartz JB, Schnaare RL, et al. Bead coating Ⅱ: effect of
spheronization technique on drug release from coated spheres. Drug Dev Ind Pharm, 1991, 17(1): 67～81
[27] Marcel V, Jozua L, Anton LG. Current understanding of the deformation of latex particles during film formation. Pharm Res, 1994, 11(10): 1474
[28] Derbin GM, Palsson BO, Mansfield JF, et al. Release behavior from ethylcellulose-coated pellets: thermomechanical and electron microbeam studies. Pharm Tech, 1996, 20(9): 70
[29] 卢元东，王登明．膜控释药的机理及影响因素．国外医药-合成药、生化药、制剂分册，1992，13(5)：296～299
[30] Yang ST and Ghebre SI. The effect of product bed temperature on the microstructure of Aquacoat-hased controlled-release coatings. Int J Pharm, 1990, 60:109～124
[31] Harris MR, Ghebre SI and Nesbitt RU. Water-based coating process for sustained release. Pharm Tech 1986, 10:102～107
[32] Russell UN. Effect of formulation components on drug release from mulfiparticulates. Drug Dev Ind Pharm, 1994, 20(20): 3207～3236
[33] 黄庆珍，路建华．阿司匹林话百年．中国药事，1997，11(4)：282
[34] 钱春梅，李亚莉，王云彩等．小剂量阿司匹林缓释胶囊的研制．西北药学杂志，1999，14(5)：210～211
[35] Nagatsuka K, Uyama O, Nakabayashi S, et al. A new approach to antithrombic therapy-evaluation of combined therapy of thromboxane synthymse inhibitor and very low dose of aspirin. Pharm Tech 1985, 16(5): 806
[36] Vanags D, Rodgers SE. Lloyd JV, et al. The anfiplatelet effect of daily low dose enteric-coated aspirin in man: a time course of onset and recovery. Thrombosis Research, 1990, 59(6): 995
[37] 周鹏，胡大一．如何正确应用阿司匹林．中国医刊，2001，36(8)：60～61
[38] 种兆忠，徐秋萍．血小板与缺血性脑卒中及抗血小板药物作用评价．中国药学杂志，2000，35(10)：653～654
[39] 徐波，马冀．小剂量阿司匹林药理研究．黑龙江医药，1999，12(1)：34
[40] 林宁，肖学成，王汉文等．阿司匹林胃漂浮型缓释胶囊的制备及药物动力学研究．中国医院药学杂志，1994，14(6)：243～246
[41] 常锦荣．阿司匹林缓释片的释放特性．西北药学杂志，1999，14(2)：70
[42] Blangue D, Sternagel H, Podczeck F, et al. Some factors influencing the formation and in vitro drug release from matrix pellets prepared by extrusion-spheronization. Int J Pharm 1995, 119(2): 203～211
[43] 辛学福，张型竹．阿司匹林的不良反应．山东医药，1984，24(10)：54
[44] Seegers JM, Olling M, Jager LD, et al. Interactions of aspirin with acetaminophen and affeine in rat stomach pharmacokinetics of absorption and accumulation in gastric mucosa. J Pharm Sci, 1980, 69:900
[45] 吴越，吴葆杰．ASP的药代动力学．中国药理通报，1988，4：335
[46] 宗红心，赵钰，李竞．阿司匹林缓释片的研制及药代动力学．中国药学杂志，2000，35(2)：110～113
[47] 杜江波，张媚，陆红等．阿司匹林肠溶缓释胶囊的人体药代动力学及生物利用度研究．中国药房，1998，9(2)：73～74
[48] 邓树海，刘兆平．药物动力学—理论与实践．北京：人民卫生出版社，1998：23～24
[49] 魏树礼主编．生物药剂学与药物动力学．北京：北京医科大学、中国协合医科大学联合出版社，1997：58～60
[50] 乔海灵，张莉蓉，张启堂等，阿司匹林缓释片健康人体药动学．中国医院药学杂志，2000，20(10)：584～587
[51] 吕万良，屠锡德．小剂量阿司匹林缓释微丸药代动力学及生物等效性研究．中国药科大学学报，1993，24(6)：334～337
[2] 平其能．现代药剂学．中国医药科技出版社，1998，411～413
[3] 钱方，蒋雪涛，王安文．微丸的进展．中国医药工业杂志，1996，27(1)：41～46
[4] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，294
[5] Chris V, Lieven B, Paul RJ. Extrusion-spheronization. Int J Pharm, 1995, 116(2):131
[6] 潘家祯，孙晓明，朱大滨等．挤出滚圆法制备药用微丸Ⅰ设备的工作原理及特点．中国医药工业杂志，1998，29(8)：378～380
[7] 包泳初，陈庆华，刘伟伦等．挤出滚圆法制备药用微丸Ⅱ制丸工艺．中国医药工业杂志，1999，30(1)：18～21
[8] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，266
[9] 陈庆华．现代微丸制备与包衣装置的类型与应用．中国医药工业杂志，1996，27(3)：134～138
[10] Lippold BH, Sutter BK and Lippold BC. Parameters controlling drug release from pellets coated with aqueous ethyl cellulose dispersion. Int J Pharm 1989, 54:15
[11] Turkoglu M and Sakr A. Mathematical modeling and optimization of a rotary fluidized-bed coating process. Int J Pharm 1992, 88:75
[12] 张彦文，郎奕．盐酸二甲双胍片剂质量评价．中国医院药学杂志，2000，20(12)：721～722
[13] 亢泽坤，张丽华．二甲双胍与其它口服降糖药物作用比较．河北医药，1994，16(6)：374
[14] 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
[15] 谢晓慧，甄健存，赵怀全．5个不同企业的盐酸二甲双胍片体外溶出度考察．中国药学杂志，2001，36(7)：481～482
[16] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，301
[17] Umpragn K, Chitropas P, Amarekajorm S. Influence of process variables on physical properties of the pellets. Drug Dev Ind Pharm 1999, 25(1): 45
[18] C. W. Woodruff and N. O. Nuessle. Effect of processing variables on particles obtained by extrusion-spheronization process Ind J Pharm Sci, 1972, 61: 787～790
[19] H.A. Doshi and R. Shrivastava. Preparation of Pellets: Extruding and Spheronizing Machines Study. Ind J Pharm Sci, 1993, 55(2): 55～58
[20] L. Baert and J. P. Remon. Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion-spheronization. Int J Pharm, 1993, 95(1): 135～141
[21] J. F. Pinto, G. Buckton and J. M. Newton. The influence of four selected processing and formulation factors on the production of spheres by extrusion and spheronisation. Int J Pharm, 1992, (83): 187～196
[22] Vervaet C, Baert L and Remon J P. Enhancement of in-vitro drug release by using polyethylene glycol 400 and PEG-40 hydrogenated castor oil in pellets made by extrusion spheronization, Int J Pharm. 1994, 108:207～212
[23] 梁超峰，欧阳允，陈平等．润湿粘合剂对小丸制备的影响．中国医药工业杂志，2000，31(4)：159～161
[24] Schmidt C, Kleinebudde P. Influence of the granulation step on pellets prepared by extrusion-spheronization. Chem Parm Bull, 1999, 47(3): 405～412
[25] Van SG and Rhodos CT. The sustained release coating of solid dosage forms: a historical review. Drug Dev Ind Phar, 1995, 21(1): 93～118
[26] Zhang GH, Schwartz JB, Schnaare RL, et al. Bead coating Ⅱ: effect of
spheronization technique on drug release from coated spheres. Drug Dev Ind Pharm, 1991, 17(1): 67～81
[27] Marcel V, Jozua L, Anton LG. Current understanding of the deformation of latex particles during film formation. Pharm Res, 1994, 11(10): 1474
[28] Derbin GM, Palsson BO, Mansfield JF, et al. Release behavior from ethylcellulose-coated pellets: thermomechanical and electron microbeam studies. Pharm Tech, 1996, 20(9): 70
[29] 卢元东，王登明．膜控释药的机理及影响因素．国外医药-合成药、生化药、制剂分册，1992，13(5)：296～299
[30] Yang ST and Ghebre SI. The effect of product bed temperature on the microstructure of Aquacoat-hased controlled-release coatings. Int J Pharm, 1990, 60:109～124
[31] Harris MR, Ghebre SI and Nesbitt RU. Water-based coating process for sustained release. Pharm Tech 1986, 10:102～107
[32] Russell UN. Effect of formulation components on drug release from mulfiparticulates. Drug Dev Ind Pharm, 1994, 20(20): 3207～3236
[33] 黄庆珍，路建华．阿司匹林话百年．中国药事，1997，11(4)：282
[34] 钱春梅，李亚莉，王云彩等．小剂量阿司匹林缓释胶囊的研制．西北药学杂志，1999，14(5)：210～211
[35] Nagatsuka K, Uyama O, Nakabayashi S, et al. A new approach to antithrombic therapy-evaluation of combined therapy of thromboxane synthymse inhibitor and very low dose of aspirin. Pharm Tech 1985, 16(5): 806
[36] Vanags D, Rodgers SE. Lloyd JV, et al. The anfiplatelet effect of daily low dose enteric-coated aspirin in man: a time course of onset and recovery. Thrombosis Research, 1990, 59(6): 995
[37] 周鹏，胡大一．如何正确应用阿司匹林．中国医刊，2001，36(8)：60～61
[38] 种兆忠，徐秋萍．血小板与缺血性脑卒中及抗血小板药物作用评价．中国药学杂志，2000，35(10)：653～654
[39] 徐波，马冀．小剂量阿司匹林药理研究．黑龙江医药，1999，12(1)：34
[40] 林宁，肖学成，王汉文等．阿司匹林胃漂浮型缓释胶囊的制备及药物动力学研究．中国医院药学杂志，1994，14(6)：243～246
[41] 常锦荣．阿司匹林缓释片的释放特性．西北药学杂志，1999，14(2)：70
[42] Blangue D, Sternagel H, Podczeck F, et al. Some factors influencing the formation and in vitro drug release from matrix pellets prepared by extrusion-spheronization. Int J Pharm 1995, 119(2): 203～211
[43] 辛学福，张型竹．阿司匹林的不良反应．山东医药，1984，24(10)：54
[44] Seegers JM, Olling M, Jager LD, et al. Interactions of aspirin with acetaminophen and affeine in rat stomach pharmacokinetics of absorption and accumulation in gastric mucosa. J Pharm Sci, 1980, 69:900
[45] 吴越，吴葆杰．ASP的药代动力学．中国药理通报，1988，4：335
[46] 宗红心，赵钰，李竞．阿司匹林缓释片的研制及药代动力学．中国药学杂志，2000，35(2)：110～113
[47] 杜江波，张媚，陆红等．阿司匹林肠溶缓释胶囊的人体药代动力学及生物利用度研究．中国药房，1998，9(2)：73～74
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