喷雾干燥方法制备对乙酰氨基酚缓释微球的工艺研究
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摘要
本文研究以对乙酰氨基酚为模型药，利用喷雾干燥方法制备缓释微球的工艺。该方法可以将药物与载体材料的溶液一步制成微球，操作方便，时间短，效率高，工艺重现性好，有利于工业化生产，并且制备的微球具有很好的缓释作用。
以缓释微球的载药量、流动性和体外释放度为指标，考察了喷雾干燥方法制备缓释微球的工艺和处方，分别对载体材料的种类、载体材料与药物的比例、进风温度、空气压力、进料速度、载体材料的浓度、增塑剂的种类、增塑剂的用量、抗粘着剂的种类和抗粘着剂的用量等因素进行了考察。最后确定用乙基纤维素为载体材料，并且载体材料与药物的比例为4：1，处方条件：蓖麻油50％，载体材料的浓度4％；喷雾干燥制备缓释微球的工艺条件：进风温度120℃，空气压力0.4MPa，进料速度10ml／min。
利用生物显微镜观察缓释微球的外观形态、粒径及其粒度分布，并且用固定圆锥法测定其流动性。微球的外观为圆整球形，平均粒径为4.5μm，粒度分布均匀，流动性好。稳定性试验表明，缓释微球的外观、色泽、粒度、载药量和体外释放度均无显著变化。
采用紫外—可见分光光度法测定缓释微球的载药量和体外释放度，结果表明，缓释微球的载药量为20.19％，在pH 6.8的磷酸盐缓冲液中可持续稳定地释放12 h，其体外释放度在1 h不少于15.％，在2 h不超过40％，在12 h为90％以上，并且释放介质的pH值对缓释微球的体外释放度影响不大。
采用高效液相色谱法测定血浆中对乙酰氨基酚的浓度，经大鼠体内药物动力学研究表明，缓释微球达峰时间延长，峰值降低，血药浓度平稳，具有明显的缓释效果，相对生物利用度F_R％=97.38％，并且缓释微球与市售普通片具有生物等效性。
This paper prepared sustained-released microspheres by spray drying method using paracetarnol as model drug. The advantages of spray drying method were as follows: one-step, convenient, rapid, high-yield, reproducible and advantageous to the production of industrialization. The effectiveness of sustained-released of mierospheres prepared by spray drying method was very good.
Selecting drug content, flowability and in vitro release of sustained-released microspheres as criteria, the technology and prescription of spray drying including kind of carrying agent materials, ratio of carrying agent materials and drug, inlet temperature, air pressure, spray-rate of feed, concentration of carrying agent materials, kind of plasticizer, weight of plasticizer, kind of antiadherents, weight of antiadherents and so on were investigated. Sustained-released microspheres were prepared using ethylcellulose as carrying agent materials and the ratio of carrying agent materials and drug was 4: 1. The prescription conditions were as follows: castro oil 50％, concentration of carrying agent materials 4％. The technology conditions of spray drying were as follows: inlet temperature 120℃, air pressure 0.4 MPa, spray-rate of feed 10 ml/min.
The appearance, particle diameter and particle size distribution of sustained-released microspheres were observed using biological microscope. The flowability of sustained-released microspheres was determined by fixed conus method. The appearance of mierospheres was globe. The mean diameter of microspheres was 4.5μm and the particle size distribution of microspheres was uniform. The flowability of microspheres was good. Stability test indicated that the external appearance, colour, particle size, drug content and in vitro release of sustained-released microspheres were no significant change.
Drug content and in vitro release of sustained-released microspheres were determined by ultraviolet-visible light detector. Drug content of microspheres Was 20.19％. Microspheres could be released for 12 h in pH 6.8 phosphate buffer saline and the dissolution was not less than 15％in 1 h, more than 40％in 2 h, not less than 90％in 12 h. In vitro release of sustained-released microspheres was not effect by the pH of release medium.
Concentration of paracetamol in the blood plasma was determined by HPLC. In vivo research of pharmacokinetics in rat indicated that T_(peak) of sustained-released microspheres was extended and C_(max) was degraded. Plasma concentration of microspheres was stable. Microspheres have the effectiveness of sustained-released obviously. Relative bioavailability of microspheres was 97.38％. Sustained-released microspheres and conventional tablet were bioequiavailability.
以缓释微球的载药量、流动性和体外释放度为指标，考察了喷雾干燥方法制备缓释微球的工艺和处方，分别对载体材料的种类、载体材料与药物的比例、进风温度、空气压力、进料速度、载体材料的浓度、增塑剂的种类、增塑剂的用量、抗粘着剂的种类和抗粘着剂的用量等因素进行了考察。最后确定用乙基纤维素为载体材料，并且载体材料与药物的比例为4：1，处方条件：蓖麻油50％，载体材料的浓度4％；喷雾干燥制备缓释微球的工艺条件：进风温度120℃，空气压力0.4MPa，进料速度10ml／min。
利用生物显微镜观察缓释微球的外观形态、粒径及其粒度分布，并且用固定圆锥法测定其流动性。微球的外观为圆整球形，平均粒径为4.5μm，粒度分布均匀，流动性好。稳定性试验表明，缓释微球的外观、色泽、粒度、载药量和体外释放度均无显著变化。
采用紫外—可见分光光度法测定缓释微球的载药量和体外释放度，结果表明，缓释微球的载药量为20.19％，在pH 6.8的磷酸盐缓冲液中可持续稳定地释放12 h，其体外释放度在1 h不少于15.％，在2 h不超过40％，在12 h为90％以上，并且释放介质的pH值对缓释微球的体外释放度影响不大。
采用高效液相色谱法测定血浆中对乙酰氨基酚的浓度，经大鼠体内药物动力学研究表明，缓释微球达峰时间延长，峰值降低，血药浓度平稳，具有明显的缓释效果，相对生物利用度F_R％=97.38％，并且缓释微球与市售普通片具有生物等效性。
This paper prepared sustained-released microspheres by spray drying method using paracetarnol as model drug. The advantages of spray drying method were as follows: one-step, convenient, rapid, high-yield, reproducible and advantageous to the production of industrialization. The effectiveness of sustained-released of mierospheres prepared by spray drying method was very good.
Selecting drug content, flowability and in vitro release of sustained-released microspheres as criteria, the technology and prescription of spray drying including kind of carrying agent materials, ratio of carrying agent materials and drug, inlet temperature, air pressure, spray-rate of feed, concentration of carrying agent materials, kind of plasticizer, weight of plasticizer, kind of antiadherents, weight of antiadherents and so on were investigated. Sustained-released microspheres were prepared using ethylcellulose as carrying agent materials and the ratio of carrying agent materials and drug was 4: 1. The prescription conditions were as follows: castro oil 50％, concentration of carrying agent materials 4％. The technology conditions of spray drying were as follows: inlet temperature 120℃, air pressure 0.4 MPa, spray-rate of feed 10 ml/min.
The appearance, particle diameter and particle size distribution of sustained-released microspheres were observed using biological microscope. The flowability of sustained-released microspheres was determined by fixed conus method. The appearance of mierospheres was globe. The mean diameter of microspheres was 4.5μm and the particle size distribution of microspheres was uniform. The flowability of microspheres was good. Stability test indicated that the external appearance, colour, particle size, drug content and in vitro release of sustained-released microspheres were no significant change.
Drug content and in vitro release of sustained-released microspheres were determined by ultraviolet-visible light detector. Drug content of microspheres Was 20.19％. Microspheres could be released for 12 h in pH 6.8 phosphate buffer saline and the dissolution was not less than 15％in 1 h, more than 40％in 2 h, not less than 90％in 12 h. In vitro release of sustained-released microspheres was not effect by the pH of release medium.
Concentration of paracetamol in the blood plasma was determined by HPLC. In vivo research of pharmacokinetics in rat indicated that T_(peak) of sustained-released microspheres was extended and C_(max) was degraded. Plasma concentration of microspheres was stable. Microspheres have the effectiveness of sustained-released obviously. Relative bioavailability of microspheres was 97.38％. Sustained-released microspheres and conventional tablet were bioequiavailability.
引文
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[2] 潘永康主编．现代干燥技术[M]．北京：化学工业出版社，1998．9．
[3] 蔡薇，韩静，李智．喷雾干燥技术在中药领域中的应用及进展[J]．沈阳药科大学学报，2006，23(9)：613-616．
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[5] 李英霞，邹彪，田景振，等．喷雾干燥技术[J]．山东中医杂志，2000，19(6)：68-69．
[6] 曹顺达．喷雾干燥在中成药生产中的应用[J]．海峡药学，1996，8(1)：84．
[7] 耿炤，陶建生．喷雾干燥技术及其在中药制药中的应用[J]．中成药，2004，26(1)：66-68．
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[11] 邹龙贵．流化床技术在制药工业应用的现状及前景[J]．机电信息，2005，(16)：10-17．
[12] T. Kristmundsdottir, O.S. Oudmundsson, .K Ingvarsdottir. Release of diltiazem from Eudragit microparticles prepared by spray-drying [J]. Int J Pharm, 1996, 137: 159-165.
[13] 谈金辉，刘文涵，单胜艳．药物微胶囊技术及其应用[J]．天津化工，2003，17(6)：4-7．
[14] 张永成，方岩雄，范会强，等．医药微胶囊技术[J]．河北化工，2002，(6)：6-10．
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[16] Bodmeier R., Chen H.. Preparation of biodegradable poly'(±) lactide microparticles using a spray-drying technique [J]. Pharm. Pharmacol, 1988, 40: 754-757.
[17] B. Baras, M.-A. Benoit, J. Gillard. Parameters influencing the antigen release from spray-dried poly (DL-lactide) microparticles [J]. Int J Pharm, 2000, 200: 133-145.
[18] Conte U., Conti B., Giunchedi P., et al. Spray dried polylactide microsphere preparation: influence of the technological parameters [J]. Drug Dev Ind Pharm, 1994, 20: 235-258.
[19] Pascal Le Corre, Jean Pierre Estebe, Rozenn Clement, et al. Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep [J]. Int J Pharm, 2002, 238: 191-203.
[20] A. Ganza-Gonzalez, S. Anguiano-Igea, F. J. Otero-Espinar, et al. Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide [J] . European Journal of Pharmaceutics and Biopharmaceutics, 1999, 48: 149-155.
[21] Ping He, Stanley S. Davis, Lisbeth Illum. Chitosan microspheres prepared by spray drying [J]. Int J Pharm, 1999, 187: 53-65.
[22] 李风前，陆彬，曾仁杰．喷雾干燥在药物微囊化中的应用[J]．国外医药：合成药、生化药、制剂分册，1999，20(1)：57-60．
[23] 沈岚，徐德生，冯怡．喷雾干燥技术制备微囊的研究进展[J]．中成药，2005，27(2)：207-209．
[24] Zgoulli S, Brek V, Barre G, et al. Microencapsulation of erythromycin and clarithromycin using a spray-drying technique [J]. J Microencapsul, 1999, 16 (5) : 565-571.
[25] Giunchedi P, Gavini E, Bonacucina G, et al. Tablettod polylactide microspheres prepared by a W/O emulsion spray drying method [J]. J Microencapsul, 2000, 17 (6): 711-720.
[26] 孙伟张，曾仁杰，景利，等．喷雾干燥法制备阿司匹林肠溶微囊的实验研究[J]．中国医院药学杂志，2000，20(7)：391-393．
[27] 中国药典2005年版．二部[S]．2005．
[28] Shozo Miyazaki, Wataru Kubo, Kunihiko Itoh, et al. The effect of taste masking agents on in situ gelling pectin formulations for oral sustainod delivery of paracetamol and ambroxol [J]. Int J Pharm, 2005, 297: 38-49.
[29] Wataru Kubo, Shozo Miyazaki, David Attwood. Oral sustainod delivery of paracetamol from in situ-gelling gellan and sodium alginate formulations [J]. Int J Pharm, 2003, 258: 55-64.
[30] 陈庆华，于书文．对乙酰氨基酚乙基纤维素微囊的制备及其特性研究[J]．中国医药工业杂志，1990，21(7)：300-303．
[31] 王建华，陈慧云，杨永，等．口服缓/控释药物制剂技术研究进展[J]．中国药业，2005，14(8)：14-15．
[32] Ritschel WA. Handbook of Basic Pharmacokinetics [M]. Illinois: Hamilton Press INC, 1980.
[33] Hoffman A. Pharmacodynamic aspects of sustained roelease preparations [J]. Adv Drug Delivery Rev, 1998, 33: 185-186.
[34] 盛朝晖．口服缓控释剂的临床评价[J]．中国医院药学杂志，2005，25(6)：558-559．
[35] 李玲 译．心血管药物控释剂释放系统[J]．心血管病学进展，1995，16(6)：375．
[36] Broadhead J., Rouan S.K.E., Rhodes C.T.. The spray-drying of pharmaceuticals [J]. Drug Dev Ind Pharm, 1992, 18: 1169-1206.
[37] 黄立新，王宗濂，唐金鑫．我国喷雾干燥技术研究及进展[J]．化学工程，2001，29(2)：51-55．
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[41] 俞媛．布比卡因聚乳酸缓释微球的研究[D]．第二军医大学，2001．5．
[42] A. Billon, B. Bataille, G. Cassanas, et al. Development of spray-dried acetaminophen microparticles using experimental designs [J]. Int J Pharm, 2000, 203: 159-168.
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[45] 郭涛主编．新编药物动力学[M]．北京：中国科学技术出版社，2005．1．
[2] 潘永康主编．现代干燥技术[M]．北京：化学工业出版社，1998．9．
[3] 蔡薇，韩静，李智．喷雾干燥技术在中药领域中的应用及进展[J]．沈阳药科大学学报，2006，23(9)：613-616．
[4] 王元清，严建业，杨红艳．喷雾干燥技术及其在中药制剂中的应用[J]．时珍国医国药，2005，16(2)：161-162．
[5] 李英霞，邹彪，田景振，等．喷雾干燥技术[J]．山东中医杂志，2000，19(6)：68-69．
[6] 曹顺达．喷雾干燥在中成药生产中的应用[J]．海峡药学，1996，8(1)：84．
[7] 耿炤，陶建生．喷雾干燥技术及其在中药制药中的应用[J]．中成药，2004，26(1)：66-68．
[8] 王喜忠，于才渊，周才君．喷雾干燥[M]．北京：化学工业出版社，2003．2．
[9] 于才渊，王宝和，王喜忠编著．干燥装置设计手册[M]．北京：化学工业出版社，2005．5．
[10] 刘明乐，曹敬兰，白德记．自动喷雾干燥制粒装置[J]．中成药，1995，17(9)：41．
[11] 邹龙贵．流化床技术在制药工业应用的现状及前景[J]．机电信息，2005，(16)：10-17．
[12] T. Kristmundsdottir, O.S. Oudmundsson, .K Ingvarsdottir. Release of diltiazem from Eudragit microparticles prepared by spray-drying [J]. Int J Pharm, 1996, 137: 159-165.
[13] 谈金辉，刘文涵，单胜艳．药物微胶囊技术及其应用[J]．天津化工，2003，17(6)：4-7．
[14] 张永成，方岩雄，范会强，等．医药微胶囊技术[J]．河北化工，2002，(6)：6-10．
[15] 曲军，郝勇，于新蕊，等．中药新剂型研究与应用进展[J]．中草药，1999，30(12)：946-949．
[16] Bodmeier R., Chen H.. Preparation of biodegradable poly'(±) lactide microparticles using a spray-drying technique [J]. Pharm. Pharmacol, 1988, 40: 754-757.
[17] B. Baras, M.-A. Benoit, J. Gillard. Parameters influencing the antigen release from spray-dried poly (DL-lactide) microparticles [J]. Int J Pharm, 2000, 200: 133-145.
[18] Conte U., Conti B., Giunchedi P., et al. Spray dried polylactide microsphere preparation: influence of the technological parameters [J]. Drug Dev Ind Pharm, 1994, 20: 235-258.
[19] Pascal Le Corre, Jean Pierre Estebe, Rozenn Clement, et al. Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep [J]. Int J Pharm, 2002, 238: 191-203.
[20] A. Ganza-Gonzalez, S. Anguiano-Igea, F. J. Otero-Espinar, et al. Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide [J] . European Journal of Pharmaceutics and Biopharmaceutics, 1999, 48: 149-155.
[21] Ping He, Stanley S. Davis, Lisbeth Illum. Chitosan microspheres prepared by spray drying [J]. Int J Pharm, 1999, 187: 53-65.
[22] 李风前，陆彬，曾仁杰．喷雾干燥在药物微囊化中的应用[J]．国外医药：合成药、生化药、制剂分册，1999，20(1)：57-60．
[23] 沈岚，徐德生，冯怡．喷雾干燥技术制备微囊的研究进展[J]．中成药，2005，27(2)：207-209．
[24] Zgoulli S, Brek V, Barre G, et al. Microencapsulation of erythromycin and clarithromycin using a spray-drying technique [J]. J Microencapsul, 1999, 16 (5) : 565-571.
[25] Giunchedi P, Gavini E, Bonacucina G, et al. Tablettod polylactide microspheres prepared by a W/O emulsion spray drying method [J]. J Microencapsul, 2000, 17 (6): 711-720.
[26] 孙伟张，曾仁杰，景利，等．喷雾干燥法制备阿司匹林肠溶微囊的实验研究[J]．中国医院药学杂志，2000，20(7)：391-393．
[27] 中国药典2005年版．二部[S]．2005．
[28] Shozo Miyazaki, Wataru Kubo, Kunihiko Itoh, et al. The effect of taste masking agents on in situ gelling pectin formulations for oral sustainod delivery of paracetamol and ambroxol [J]. Int J Pharm, 2005, 297: 38-49.
[29] Wataru Kubo, Shozo Miyazaki, David Attwood. Oral sustainod delivery of paracetamol from in situ-gelling gellan and sodium alginate formulations [J]. Int J Pharm, 2003, 258: 55-64.
[30] 陈庆华，于书文．对乙酰氨基酚乙基纤维素微囊的制备及其特性研究[J]．中国医药工业杂志，1990，21(7)：300-303．
[31] 王建华，陈慧云，杨永，等．口服缓/控释药物制剂技术研究进展[J]．中国药业，2005，14(8)：14-15．
[32] Ritschel WA. Handbook of Basic Pharmacokinetics [M]. Illinois: Hamilton Press INC, 1980.
[33] Hoffman A. Pharmacodynamic aspects of sustained roelease preparations [J]. Adv Drug Delivery Rev, 1998, 33: 185-186.
[34] 盛朝晖．口服缓控释剂的临床评价[J]．中国医院药学杂志，2005，25(6)：558-559．
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