挤出—滚圆技术制备大剂量药物缓释微丸的研究
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摘要
挤出-滚圆技术是工业药剂学上的一项重要制丸方法，载药量高是其一大优势。国内外报道，采用包衣锅制丸法、流化床制丸法或其它方法制备的微丸载药量一般为20—50％，而采用挤出滚圆技术制备的微丸，载药量可达80％以上。另外，对于同时含有不同释放速率的微丸制剂以及复方微丸制剂，通常采用制备两种或两种以上不同的微丸，然后灌装于同一胶囊的方式，但不同的微丸往往在堆密度及体积大小等方面存在差异，采用上述工艺，微丸灌装时必将导致药物含量均匀度问题，而本研究采用集速释-缓释于一体的GFN微丸很好地解决了这方面的难题。因此，该法是制备大剂量药物微丸很有价值的方法，同时亦为复方微丸制剂的研制提供一个新的思路。
愈创木酚甘油醚(guaifenesin，GFN)系临床长期使用的传统祛痰药，其口服后的祛痰药理作用机理是刺激胃粘膜，反射性引起支气管分泌增加，同时降低痰的粘度，达到其药效。长期以来国内主要使用该药的复方制剂，且需每日给药3—4次；迄今为止，尚无该药缓释制剂的报道。2002年GFN缓释双层片于美国批准上市，商品名为Mucinex~(?)，剂量600mg，每12h给药一次，提高了患者的顺应性，且祛痰效果良好。
本研究以GFN为模型药物，采用挤出-滚圆技术制备载药量80％的骨架微丸。以微丸圆整度、脆碎度及18—24目微丸收率为微丸质量评价指标，考察了影响挤出-滚圆制备GFN载药微丸的工艺因素及处方因素。结果表明：挤出速度、滚圆速度及滚圆时间对微丸质量均有较大影响，在挤出速度75rpm、滚圆速度800rpm及滚圆时间4min的条件下制备的80％GFN载药微丸质量良好，能满足后续微丸包衣的质量要求。
选用乙基纤维素水分散体(Surelease)及丙烯酸树脂水分散体(Eudragit NE30D)为GFN微丸缓释包衣材料，应用流化床包衣技术，对GFN微丸进行缓释包衣及外层速释药层的制备；考察不同的处方因素对释放度的影响。鉴于Eudragit NE30D为微丸包衣有一明显“时滞”(Lag time)现象，将导致与实验设计1h内释药量达25％水平相距甚远，而Surelease为GFN微丸缓释衣膜的控释效果较好，膜材增重至7—8％即可符合设计的要求，本研究最终采用Surelease为GFN微丸的缓释包衣材料。
Extrusion-Spheronization is an important method to prepare pellets in industrial pharmaceutics fields. Compared with other drug-loading methods such as rotary coater pelletization and fluid-bed pelletization . Extrusion-spheronization possesses its high drug-loading advantage (more than 80%) especially. It has been approved to be an excellent technique to prepare the pellets with high drug-loading.
Guaifenesin(GFN) has been used as the traditional expectorant in the clinical therapeutics. Its expectorant mechanism is based on increasing the excreta of bronchia with irritating gastrointestinal mucus and enhancing the output of respiratory tract fluid by reducing adhesivenesss and surface tension, facilitating the removal of viscous mucus. Conventional dosage forms of Guaifenesin with 3-4 administrations per day have been used for long time due to its short t_(1/2), and GFN sustained release dosage forms have not been reported yet in China.FDA approved the Guaifenesin tablets( Mucinex?, 600mg ) with 12hr sustained release in 2002,It was got high evaluated in clinical effects.
In this study, about 80% drug loading matrix pellets of Guaifenesin prepared by extrusion-spheronization technology. The pellet quality was evaluated in terms of sphericity, friability and yields. The results showed that extrusion speed, spheronization speed and spheronization time were all important, and optimized technical parameters of 80% Guaifenesin pellets were as following:e.g. 75rpm of extrusion speed, 800rpm of spheronization speed and 4min of spheronization time.
Ethyl cellulose aqueous dispersion (Surelease(?)) and Acrylic acid resin aqueous dispersion (Eudragit(?) NE30D) were chosen as the film coating materials to prepare the Guaifenesin sustained release pellets with fluid-bed coating technology. Surelease was decided to be the final coating material for the reason of obvious "lag time" of Eudragit(?)NE30D which caused the drug release content was far less than the designed level- 25% at the first hour in Vitro.
愈创木酚甘油醚(guaifenesin，GFN)系临床长期使用的传统祛痰药，其口服后的祛痰药理作用机理是刺激胃粘膜，反射性引起支气管分泌增加，同时降低痰的粘度，达到其药效。长期以来国内主要使用该药的复方制剂，且需每日给药3—4次；迄今为止，尚无该药缓释制剂的报道。2002年GFN缓释双层片于美国批准上市，商品名为Mucinex~(?)，剂量600mg，每12h给药一次，提高了患者的顺应性，且祛痰效果良好。
本研究以GFN为模型药物，采用挤出-滚圆技术制备载药量80％的骨架微丸。以微丸圆整度、脆碎度及18—24目微丸收率为微丸质量评价指标，考察了影响挤出-滚圆制备GFN载药微丸的工艺因素及处方因素。结果表明：挤出速度、滚圆速度及滚圆时间对微丸质量均有较大影响，在挤出速度75rpm、滚圆速度800rpm及滚圆时间4min的条件下制备的80％GFN载药微丸质量良好，能满足后续微丸包衣的质量要求。
选用乙基纤维素水分散体(Surelease)及丙烯酸树脂水分散体(Eudragit NE30D)为GFN微丸缓释包衣材料，应用流化床包衣技术，对GFN微丸进行缓释包衣及外层速释药层的制备；考察不同的处方因素对释放度的影响。鉴于Eudragit NE30D为微丸包衣有一明显“时滞”(Lag time)现象，将导致与实验设计1h内释药量达25％水平相距甚远，而Surelease为GFN微丸缓释衣膜的控释效果较好，膜材增重至7—8％即可符合设计的要求，本研究最终采用Surelease为GFN微丸的缓释包衣材料。
Extrusion-Spheronization is an important method to prepare pellets in industrial pharmaceutics fields. Compared with other drug-loading methods such as rotary coater pelletization and fluid-bed pelletization . Extrusion-spheronization possesses its high drug-loading advantage (more than 80%) especially. It has been approved to be an excellent technique to prepare the pellets with high drug-loading.
Guaifenesin(GFN) has been used as the traditional expectorant in the clinical therapeutics. Its expectorant mechanism is based on increasing the excreta of bronchia with irritating gastrointestinal mucus and enhancing the output of respiratory tract fluid by reducing adhesivenesss and surface tension, facilitating the removal of viscous mucus. Conventional dosage forms of Guaifenesin with 3-4 administrations per day have been used for long time due to its short t_(1/2), and GFN sustained release dosage forms have not been reported yet in China.FDA approved the Guaifenesin tablets( Mucinex?, 600mg ) with 12hr sustained release in 2002,It was got high evaluated in clinical effects.
In this study, about 80% drug loading matrix pellets of Guaifenesin prepared by extrusion-spheronization technology. The pellet quality was evaluated in terms of sphericity, friability and yields. The results showed that extrusion speed, spheronization speed and spheronization time were all important, and optimized technical parameters of 80% Guaifenesin pellets were as following:e.g. 75rpm of extrusion speed, 800rpm of spheronization speed and 4min of spheronization time.
Ethyl cellulose aqueous dispersion (Surelease(?)) and Acrylic acid resin aqueous dispersion (Eudragit(?) NE30D) were chosen as the film coating materials to prepare the Guaifenesin sustained release pellets with fluid-bed coating technology. Surelease was decided to be the final coating material for the reason of obvious "lag time" of Eudragit(?)NE30D which caused the drug release content was far less than the designed level- 25% at the first hour in Vitro.
引文
[1] 黄胜炎．药物制剂新进展，国家经贸委医药工业信息中心站．2001：43-50．
[2] 平其能．现代药剂学．中国医药科技出版社，1998：412-413．
[3] 陈挺，陈庆华．盐酸苯丙醇胺微丸的制备工艺研究[J]．中国医药工业杂志，1999，30(8)：345-348．
[4] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，294-295．
[5] 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[J]．中国医药工业杂志，1998，29(8)：378—380．
[6] Newtom JM. Extrusion and Extruders, Encyclopedia of Pharmaceutical Technology, Marcel Dekker, Inc 2002:1220-1247
[7] 李永庆，田子新，赵文等．高效液相色谱法测定雷登泰口服液中愈创木酚甘油醚、盐酸伪麻黄碱、氢溴酸右美沙芬的含量[J]．药物分析杂志，2000，20(2)：97-98．
[8] 安国升，李玉珍．HPLC法测定愈创木酚甘油醚的血药浓度[J]．中国药学杂志，1995，30(6)：317-320。
[9] Wilcox ML, Stewart JT, HPLC determination of guaifenesin with selected medications on underivatized silica with an aqueous-organic mobile phase [J]. J Pharma Biom Analy, 2000, 23: 909-916
[10] Nkahara, 1966:US Pat.3,277,520.
[11] Tomer G, Newton JM. Water movement evaluation during extrusion of wet powder masses by collecting extrudate fractions[J].Int J Pharm, 1999;182:71-77
[12] Vervaet C, Baert L, Remen JP.Extrusion-Spheronization.A literature review [J].Int.J.Pharm. 1995.116:131-146
[13] Tomer G., Podczeck F., Newton JM..The influence of type and quantity of model drug on the extrusion-spheronization of mixtures with microcrystallinecellulose Ⅰ. Extrusion parameters[J].Int J Pharm, 2001, 217: 237-248.
[14] Tomer G., Podczeck F., Newton JM..The influence of model drugs on the preparation of pellets by extrusion-spheronization: Ⅱ spheronization parameters[J].Int J Pharm, 2002, 231: 107-119
[15] Blanque D,Sternagel H,Podczeck F et al. Some factors influencing the formation and in vitro drug release from matrix pellets prepared by extrusion spheronization[J].Int J Pharm, 1995, 119: 203-211
[16] Alvarez L, Concheiro A.Powdered cellulose as excipient for extrusion-spheronization pellets of a cohesive hydrophobic drug[J].Eur J Pharmaand Biopharma,2003,55:291-295.
[17] Jover I, Podczeck F, Newtonx M. Evaluation, by a Statistically Designed Experiment, of an Experimental Gradeof Microcrystalline Cellulose, Avicel 955, as a Technology To Aid the Production of Pellets with High Drug Loading[J].J Pharm Sci, 1996,85(7):700-707.
[18] Hileman GA, Goskonda SR, Spalitto AJ et al.A factorial approach to high dose product development my an Extrusion/Spheronization process[J].Drug Dev Ind Pharm,1993,19(4):483-491
[19] Sonaglio D,Bataille B,Ortigosa C et al.Approach to the development of high dose paracetamol spheres by extrusion/spheronization,Pharmazie, 1997,52:129-134
[20] Boutell S, Newton JM, Bloor JR.et al. The influence of liquid binder on the liquid mobility andpreparation of spherical granules by the process ofextrusion/spheronization[J]. Int J Pharma, 2002, 238: 61-76.
[21] 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[J]．中国医药工业杂志，1999，30(1)：1821-1826．
[22] 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[J]．中国药学杂志，2003，35(2)：130—136
[23] 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
[24] Koida Y, Takahata H,Kobayashi M,et al.Studies on dissolution mechanism of srugs from ethylcellulose microcapsules[J].Chem Pharm Bull, 1987,35(4): 1538-1545
[25] Vecchio C,Fabiani F, Sangalli ME et al.Drug Dev Ind Pharm,1997;23:345-361.
[26] 赵陆华，黄剑，刘艳华．复方美愈缓释片的高效液相色谱法分析[J]．中国现代应用药学杂志，2002，16(6)：491-496．．
[27] Wagner DL, Patel VS. Steady-state human pharmacokinetics and bioavailability of guaifenesin and pseudoephedrine in a sustained-release tablet relative to immediate-release liquids[J]. Int J Pharm, 1995, 114: 171-178..
[28] 刘欢，只德广，高晶，等．复方愈麻美芬缓释片在B犬内的药物动力学研究[J]．沈阳药科大学学报，2004，21(5)：328-335．．
[29] 杜玥，钟大放，肇丽梅，等．愈美分散片人体药动学及制剂生物等效性研究[J]．沈阳药科大学学报，2001，18(3)：157-164．．
[2] 平其能．现代药剂学．中国医药科技出版社，1998：412-413．
[3] 陈挺，陈庆华．盐酸苯丙醇胺微丸的制备工艺研究[J]．中国医药工业杂志，1999，30(8)：345-348．
[4] 陆彬．药物新剂型与新技术．人民卫生出版社，1998，294-295．
[5] 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[J]．中国医药工业杂志，1998，29(8)：378—380．
[6] Newtom JM. Extrusion and Extruders, Encyclopedia of Pharmaceutical Technology, Marcel Dekker, Inc 2002:1220-1247
[7] 李永庆，田子新，赵文等．高效液相色谱法测定雷登泰口服液中愈创木酚甘油醚、盐酸伪麻黄碱、氢溴酸右美沙芬的含量[J]．药物分析杂志，2000，20(2)：97-98．
[8] 安国升，李玉珍．HPLC法测定愈创木酚甘油醚的血药浓度[J]．中国药学杂志，1995，30(6)：317-320。
[9] Wilcox ML, Stewart JT, HPLC determination of guaifenesin with selected medications on underivatized silica with an aqueous-organic mobile phase [J]. J Pharma Biom Analy, 2000, 23: 909-916
[10] Nkahara, 1966:US Pat.3,277,520.
[11] Tomer G, Newton JM. Water movement evaluation during extrusion of wet powder masses by collecting extrudate fractions[J].Int J Pharm, 1999;182:71-77
[12] Vervaet C, Baert L, Remen JP.Extrusion-Spheronization.A literature review [J].Int.J.Pharm. 1995.116:131-146
[13] Tomer G., Podczeck F., Newton JM..The influence of type and quantity of model drug on the extrusion-spheronization of mixtures with microcrystallinecellulose Ⅰ. Extrusion parameters[J].Int J Pharm, 2001, 217: 237-248.
[14] Tomer G., Podczeck F., Newton JM..The influence of model drugs on the preparation of pellets by extrusion-spheronization: Ⅱ spheronization parameters[J].Int J Pharm, 2002, 231: 107-119
[15] Blanque D,Sternagel H,Podczeck F et al. Some factors influencing the formation and in vitro drug release from matrix pellets prepared by extrusion spheronization[J].Int J Pharm, 1995, 119: 203-211
[16] Alvarez L, Concheiro A.Powdered cellulose as excipient for extrusion-spheronization pellets of a cohesive hydrophobic drug[J].Eur J Pharmaand Biopharma,2003,55:291-295.
[17] Jover I, Podczeck F, Newtonx M. Evaluation, by a Statistically Designed Experiment, of an Experimental Gradeof Microcrystalline Cellulose, Avicel 955, as a Technology To Aid the Production of Pellets with High Drug Loading[J].J Pharm Sci, 1996,85(7):700-707.
[18] Hileman GA, Goskonda SR, Spalitto AJ et al.A factorial approach to high dose product development my an Extrusion/Spheronization process[J].Drug Dev Ind Pharm,1993,19(4):483-491
[19] Sonaglio D,Bataille B,Ortigosa C et al.Approach to the development of high dose paracetamol spheres by extrusion/spheronization,Pharmazie, 1997,52:129-134
[20] Boutell S, Newton JM, Bloor JR.et al. The influence of liquid binder on the liquid mobility andpreparation of spherical granules by the process ofextrusion/spheronization[J]. Int J Pharma, 2002, 238: 61-76.
[21] 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[J]．中国医药工业杂志，1999，30(1)：1821-1826．
[22] 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[J]．中国药学杂志，2003，35(2)：130—136
[23] 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
[24] Koida Y, Takahata H,Kobayashi M,et al.Studies on dissolution mechanism of srugs from ethylcellulose microcapsules[J].Chem Pharm Bull, 1987,35(4): 1538-1545
[25] Vecchio C,Fabiani F, Sangalli ME et al.Drug Dev Ind Pharm,1997;23:345-361.
[26] 赵陆华，黄剑，刘艳华．复方美愈缓释片的高效液相色谱法分析[J]．中国现代应用药学杂志，2002，16(6)：491-496．．
[27] Wagner DL, Patel VS. Steady-state human pharmacokinetics and bioavailability of guaifenesin and pseudoephedrine in a sustained-release tablet relative to immediate-release liquids[J]. Int J Pharm, 1995, 114: 171-178..
[28] 刘欢，只德广，高晶，等．复方愈麻美芬缓释片在B犬内的药物动力学研究[J]．沈阳药科大学学报，2004，21(5)：328-335．．
[29] 杜玥，钟大放，肇丽梅，等．愈美分散片人体药动学及制剂生物等效性研究[J]．沈阳药科大学学报，2001，18(3)：157-164．．