羟丙基甲基纤维素邻苯二甲酸酯（HPMCP）的合成新工艺及其水分散体的制备
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摘要
以邻苯二甲酸酐对羟丙基甲基纤维素(HPMC)功能化改性,分别在经典的冰醋酸体系和新型的有机溶剂体系合成了符合药典要求的羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)粉末,IR测试结果表明粉末为目标产物。重点考察了有机溶剂体系下各因素对酯化反应的影响。实验证明,通过调节邻苯二甲酸酐的用量可以控制HPMCP粉末的苯甲酸甲酰基含量。反应温度太高容易引发第二羧基参与到酯化反应中,温度太低催化剂活性不能得到充分发挥,所得到的产品的苯甲酸甲酰基含量过低。有机溶剂体系比冰醋酸体系具有更大优点,主要表现在:反应收率高;溶剂对设备无腐蚀;后处理过程简易,游离酸含量易达标;溶剂可回收利用,无溶剂外排所带来的环境污染等问题。
以自制的HPMCP为起始物,在不使用任何有机溶剂的情况下,采用水乳化方法,成功制备了HPMCP的乳液水分散体。TEM测试表明所得HPMCP水分散体乳胶粒为近似光滑球形。DLS测试表明,乳化剂用量较多时可得到粒径更加均一的乳胶粒。HPMCP水分散体游离膜具有良好的成膜性能,SEM表征游离膜具有良好的致密性。拉伸测试表明,粒度均匀的HPMCP水分散体具有较好的力学性能。以HPMC作为乳化剂,比Tween80为乳化剂的水分散体,可以赋予游离膜材料更为优良的力学性能。不同苯甲酸甲酰基含量的HPMCP水分散体游离膜样品在模拟人工胃液中2小时内均不溶解,这符合药典中对于肠溶包衣材料的要求。HPMCP游离膜样品在模拟人工肠液中的溶解速率随HPMCP中苯甲酸甲酰基含量的增加而增大。
Hydroxypropyl methylcellulose phthalate (HPMCP) was prepared in classic Glacial Acetic Acid-Sodium Acetate system and new organic solvent system respectively, with HPMC as starting material and phthalic anhydride as functional graft monomer, which meet for the requirements of the Pharmacopoeia. IR test indicated that the product is the target product HPMCP. The experiments proved that the phthalyl content can be controlled by the dosage of phthalic anhydride. The reaction temperature should not be too high or too low, while high temperature will cause the reaction of the second carboxyl and low temperature can not provide enough power to the catalyst. By comparison, organic system has more benefits than Glacial Acetic Acid-Sodium Acetate system. It has higher yield than the Glacial Acetic Acid-Sodium Acetate system. The solvent it used does not corrode the equipment. It’s easier to wash the product and easier to control the content of free acid in organic system. The solvent can be recycled and so avoid the environment pollution caused by solvent discharge.
Hydroxypropyl methylcellulose phthalate (HPMCP) prepared was used as the starting material to prepare HPMCP water dispersion by water emulsion method, during which none of the organic solvent was used. TEM test showed HPMCP water dispersion latex particle is near-spherical. DLS test indicated that with the increase of the dosage of emulsification, the latex particle has more uniform micelle particles. SEM test showed that HPMCP water dispersion dissociate film has high compact-ability. Stretching test indicated that the HPMCP water dispersion with better particle size distribution have better mechanical property. The water dispersion with HPMC as emulsifier has excellent mechanical property. HPMCP water dispersion dissociate film has better film forming property, and HPMCP water dispersion dissociate films with different phthalyl contents were all insoluble in the simulated gastric fluid within 2 hours, which meets the requirement of China pharmacopeia. The solution rate of HPMCP water dispersion dissociate film can be accelerated with increasing the phthalyl content.
以自制的HPMCP为起始物,在不使用任何有机溶剂的情况下,采用水乳化方法,成功制备了HPMCP的乳液水分散体。TEM测试表明所得HPMCP水分散体乳胶粒为近似光滑球形。DLS测试表明,乳化剂用量较多时可得到粒径更加均一的乳胶粒。HPMCP水分散体游离膜具有良好的成膜性能,SEM表征游离膜具有良好的致密性。拉伸测试表明,粒度均匀的HPMCP水分散体具有较好的力学性能。以HPMC作为乳化剂,比Tween80为乳化剂的水分散体,可以赋予游离膜材料更为优良的力学性能。不同苯甲酸甲酰基含量的HPMCP水分散体游离膜样品在模拟人工胃液中2小时内均不溶解,这符合药典中对于肠溶包衣材料的要求。HPMCP游离膜样品在模拟人工肠液中的溶解速率随HPMCP中苯甲酸甲酰基含量的增加而增大。
Hydroxypropyl methylcellulose phthalate (HPMCP) was prepared in classic Glacial Acetic Acid-Sodium Acetate system and new organic solvent system respectively, with HPMC as starting material and phthalic anhydride as functional graft monomer, which meet for the requirements of the Pharmacopoeia. IR test indicated that the product is the target product HPMCP. The experiments proved that the phthalyl content can be controlled by the dosage of phthalic anhydride. The reaction temperature should not be too high or too low, while high temperature will cause the reaction of the second carboxyl and low temperature can not provide enough power to the catalyst. By comparison, organic system has more benefits than Glacial Acetic Acid-Sodium Acetate system. It has higher yield than the Glacial Acetic Acid-Sodium Acetate system. The solvent it used does not corrode the equipment. It’s easier to wash the product and easier to control the content of free acid in organic system. The solvent can be recycled and so avoid the environment pollution caused by solvent discharge.
Hydroxypropyl methylcellulose phthalate (HPMCP) prepared was used as the starting material to prepare HPMCP water dispersion by water emulsion method, during which none of the organic solvent was used. TEM test showed HPMCP water dispersion latex particle is near-spherical. DLS test indicated that with the increase of the dosage of emulsification, the latex particle has more uniform micelle particles. SEM test showed that HPMCP water dispersion dissociate film has high compact-ability. Stretching test indicated that the HPMCP water dispersion with better particle size distribution have better mechanical property. The water dispersion with HPMC as emulsifier has excellent mechanical property. HPMCP water dispersion dissociate film has better film forming property, and HPMCP water dispersion dissociate films with different phthalyl contents were all insoluble in the simulated gastric fluid within 2 hours, which meets the requirement of China pharmacopeia. The solution rate of HPMCP water dispersion dissociate film can be accelerated with increasing the phthalyl content.
引文
[1]乐晓磊,费解.羟丙基甲基纤维素邻苯二甲酸酯[J].纤维素醚工业,2002,10(3):24~26
[2]张宪康,沈建平,李育.肠溶性药用辅料HPMCP的合成研究[J].中国医药工业杂志,1993,24(3):104~107
[3] Kokubo; Hiroyasu; Minemura. Base for coating solid enteric pharmaceutical preparations, US 5700929, 1996-04-29
[4] KIM I H , PARKJ H , CHEONG I W, et al . Swelling and drug release behavior of tablets coated with aqueous hydroxypropyl methylcellulose phthalate (HPMCP) nanoparticles [J]. J Controlled Release, 2003, 89: 225~233
[5] Jensen J L, Appel L E, Clair J H, et al. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/mthacrylate copolymer latexes [J]. Journal of Pharmaceutical Sciences, 1995, 84(5): 530~533
[6] Raghunathan Y, Amsel L, Hinsvark O, et al. Sustained release drug delivery system, I: coated ion-exchange resin system for phenylpropanolamine and other drugs [J]. Journal of Pharmaceutical Science, 1981, 70(4): 379~384
[7] Borodkin S, Sundberg D P. Polycarboxylic acid ion-exchange resin adsorbates for taste coverage in chewable tablets [J]. Journal of Pharmaceutical Science, 1971, 60(10): 1523~1527
[8]牟晓红.羟丙基甲基纤维素酞酸酯假胶乳的制备及应用于消炎痛肠溶包衣片的质量评价[J].沈阳药科大学学报,1996,13(3):157~163
[9]陈挺,陈庆华.乙基纤维素水性包衣技术Ⅱ热处理对衣膜性质的影响[J].中国医药工业杂志,2000,31(7):298~302
[10]张俐娜.天然高分子改性材料及应用,北京:化学工业出版社,2003,1
[11]李捷玮,刘吉祥.常用药物辅料手册.第二军医大学出版社,2006,序言
[12]侯世祥.中药液体制剂研究中的药用辅料及其应用技术[J].世界科学技术—中医药现代化,2005,7(2):40~44
[13]卞筱泓.纤维素类肠溶包衣材料的研究,[硕士学位论文],中国药科大学,2001,4
[14] Ferrero Rodriguez, C., Bruneau, N., Barra J., et al., Hydrophilic cellulose derivatives as drug delivery carriers: Influence of substitution type on the properties of compressed matrix tablets, Handbook of Pharmaceutical Controlled Releas Technology, Donald L. Wise(ed), Marcel Dekker, New York, Basel, (2000) 1~30
[15]杨季,毕茹,王征.肠溶包衣材料的发展及其应用[J].中国药学杂志,2006,6,41(12):885~889
[16]张跃军,刘小平.肝泰肠溶片的制备工艺探讨[J].山东医药工业,1990,9 (4):152161
[17]吕植孝.肠溶丙烯酸树脂Ⅱ号在生产中的应用[J].中国药学杂志,1989,24(9):547~549
[18]黄族和.用褐藻胶制肠溶片剂的方法[J].发明专利公报,1989,5(25):3
[19]郑素娥.褐藻胶新型软胶丸的研究[J].医药工业,1988,19(4):162~165
[20]杜德才.肠溶包衣材料在药物制剂中的应用[J].中国药业,2001,10(5):62~63
[21]郑俊民.片剂包衣的工艺和原理.北京:中国医药科技出版社,2000:13
[22] SINGH M, O’HAGAN D. The preparation and characterization of polymeric antigen delivery systems for oral administration [J]. Adv Drug Deliv Rev, 1998, 34 : 285~304
[23]祁荣.吲哚美辛HPMCP肠溶片的制备及溶出度考察[J].沈阳药科大学学报,2001,18(6):395~397
[24] WANG X Q, DAI J D, CHEN Z, et al. Bioavailability and pharmacokinetics of cyclosporine A2loaded pH2sensitive nanoparticles for oral administration [J]. J Controlled Release, 2004, 97: 421~429
[25] ZANIBONI H, FELL J, COLETT J. Production and characterization of enteric beads [J]. Int J Pharm, 1995, 12: 151~155
[26] J.Siepmann, N.A.Pappas. Advanced Drug Delivery Reviews, 2001, (48): 139~157
[27]国家药典委员会.中华人民共和国药典,北京:化学工业出版社,2000
[28]刘啸武.羟丙基甲基纤维素生产技术和发展前景[J].江汉石油职工大学学报,2004,17(6):58~60
[29]祁荣.肠溶包衣材料羟丙甲纤维素邻苯二甲酸酯的研究. [硕士学位论文],2001,6:11
[30]邵自强等.纤维素醚,化学工业出版社,2007,9,第一版:69
[31]秦冬梅.羟丙基甲基纤维素在药剂学中的应用[J].安徽医药,2004,8(3):172~174
[32] P.H.Emmett, Catalysis, Vol.1~7, Reinhold Pub.Corp.,New York,1954~1960
[33] D. L. Trimm, Design of Industrial Catalysts, Elsevier Scientific Pub.Co.,Amsterdam, 1980
[34] J.R.Anderson and M. Boudart, Catalysis, Science and Technology, Vol.5, Springer-Verlag. Berlin, 1984
[35]黄宪,王彦广等.新编有机合成化学,化学工业出版社,2003,1,第一版:428
[36]高鸿宾.有机化学,高等教育出版社,1999,9,第三版:377
[37]吕恩雄.固体超强酸催化剂的制备及应用[J].精细石油化工,1994,3:49~53
[38]王红艳,周苏闽.纳米超强酸催化酯化反应研究[J].淮阴师范学院学报. 2003,2(1):42~45
[39] Saravanan P and Singh V K. Tetrahedrom Lett. 1999,40:2611
[40]李小永,王丽琼.三氟甲磺酸酮(Ⅱ)手性衍生物:不对称合成中的一类高效催化剂[J].有机化学,2004,24(10):1159~1167
[41]郑燕升,粟晖.三乙胺催化合成维生素E琥珀酸单酯的研究[J].精细石油化工,2006,23(5):39~41
[42]郑燕升,粟晖.三乙胺催化合成维生素E乙酸酯的研究[J].广西工学院学报,2006,17(3):33-35,40
[43]徐莹,常杰.固体碱催化剂上生物油催化酯改性[J].石油化工,2006,35(17):615~618
[44]崔福德.药剂学.人民卫生出版社,2003年7月,第五版:143
[45]陆彬.药物新剂型与新技术.人民卫生出版社,2002年2月,第一版:261
[46] CHANG RONG-KUN, HSIAO C H, ROBINSON J. A review of aqueous coating techniques and preliminary data on release from a theophylline product[J]. Pharm Technol, 1987, 11(3): 56
[47] WilliamsⅢR O, Liu J P. Influence of processing and curing conditions on beads coated with an aqueous dispersion of cellulose acetate phthalate [J]. Eur J Pharm Biopharm, 2000, 49 (3): 243~252
[48] Raffin F, Durn C, Jacob M, et al. Permeability to hydrogen ions of an enteric coating polymer and interaction of film formulation factors [J]. Int J Pharm, 1996, 145 (3): 247~252
[49] Muhammad N A, Boisvert W, Harris M R, et al. Evaluation of hydroxyl propylmethylcellulose phthalate 50 as film forming polymer from aqueous dispersion system [J ]. Drug Dev Ind Pharm, 1992, 18 (16):1787~1797
[50] Watano S, Wada I, Miyanami K, et al. Modeling and simulation of drug release from granule coated with an aqueous-based system of acrylic copolymer [J]. Chem Pharm Bull, 1995, 43 (5): 877~880
[51]陈挺,陈庆华.乙基纤维素水性包衣技术Ⅰ.水分散体与有机溶剂包衣的比较[J].中国医药工业杂志.2000,31(1):7~12
[52]奚念珠.药剂学.北京:人民卫生出版社,1997,74~75
[53]王红梅,陈巍,施伟.芦荟酚类化合物研究[J].中草药,2003,34(6):499~501
[54]封士兰,潘宣,张晓光.兔耳草化学成分研究[J].中草药,2000,31(7):500~501.
[55]刘怡,沈岚.羟丙基甲基纤维素邻苯二甲酸酯在药物制剂中的应用[J].亚太传统医药, 2005,(3):92
[56]程玉红.羟丙基甲基纤维素酞酸酯及其水分散体的制备与表征,[硕士学位论文],南开大学,2004.6~7
[57]许加星.HPMCP合成及其水分散体的制备.[学士学位论文],天津大学,2006.6~7
[58]国家药典委员会.中华人民共和国药典,北京:化学工业出版社,2000,附录Ⅹ崩解时限检查法
[59]国家药典委员会.中华人民共和国药典,北京:化学工业出版社,2000,附录ⅩD释放度测定法
[60]胡金生,曹同玉,刘庆普.乳液聚合,北京:化学工业出版社,1987,16~26;续1,139~144
[61] T. C.巴顿著,郭隽奎等译.涂料流动和颜料分散(第二版).北京:化学工业出版社,1988,233~236
[62]何曼君等.高分子物理.上海:复旦大学出版社.1990:244~247
[2]张宪康,沈建平,李育.肠溶性药用辅料HPMCP的合成研究[J].中国医药工业杂志,1993,24(3):104~107
[3] Kokubo; Hiroyasu; Minemura. Base for coating solid enteric pharmaceutical preparations, US 5700929, 1996-04-29
[4] KIM I H , PARKJ H , CHEONG I W, et al . Swelling and drug release behavior of tablets coated with aqueous hydroxypropyl methylcellulose phthalate (HPMCP) nanoparticles [J]. J Controlled Release, 2003, 89: 225~233
[5] Jensen J L, Appel L E, Clair J H, et al. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/mthacrylate copolymer latexes [J]. Journal of Pharmaceutical Sciences, 1995, 84(5): 530~533
[6] Raghunathan Y, Amsel L, Hinsvark O, et al. Sustained release drug delivery system, I: coated ion-exchange resin system for phenylpropanolamine and other drugs [J]. Journal of Pharmaceutical Science, 1981, 70(4): 379~384
[7] Borodkin S, Sundberg D P. Polycarboxylic acid ion-exchange resin adsorbates for taste coverage in chewable tablets [J]. Journal of Pharmaceutical Science, 1971, 60(10): 1523~1527
[8]牟晓红.羟丙基甲基纤维素酞酸酯假胶乳的制备及应用于消炎痛肠溶包衣片的质量评价[J].沈阳药科大学学报,1996,13(3):157~163
[9]陈挺,陈庆华.乙基纤维素水性包衣技术Ⅱ热处理对衣膜性质的影响[J].中国医药工业杂志,2000,31(7):298~302
[10]张俐娜.天然高分子改性材料及应用,北京:化学工业出版社,2003,1
[11]李捷玮,刘吉祥.常用药物辅料手册.第二军医大学出版社,2006,序言
[12]侯世祥.中药液体制剂研究中的药用辅料及其应用技术[J].世界科学技术—中医药现代化,2005,7(2):40~44
[13]卞筱泓.纤维素类肠溶包衣材料的研究,[硕士学位论文],中国药科大学,2001,4
[14] Ferrero Rodriguez, C., Bruneau, N., Barra J., et al., Hydrophilic cellulose derivatives as drug delivery carriers: Influence of substitution type on the properties of compressed matrix tablets, Handbook of Pharmaceutical Controlled Releas Technology, Donald L. Wise(ed), Marcel Dekker, New York, Basel, (2000) 1~30
[15]杨季,毕茹,王征.肠溶包衣材料的发展及其应用[J].中国药学杂志,2006,6,41(12):885~889
[16]张跃军,刘小平.肝泰肠溶片的制备工艺探讨[J].山东医药工业,1990,9 (4):152161
[17]吕植孝.肠溶丙烯酸树脂Ⅱ号在生产中的应用[J].中国药学杂志,1989,24(9):547~549
[18]黄族和.用褐藻胶制肠溶片剂的方法[J].发明专利公报,1989,5(25):3
[19]郑素娥.褐藻胶新型软胶丸的研究[J].医药工业,1988,19(4):162~165
[20]杜德才.肠溶包衣材料在药物制剂中的应用[J].中国药业,2001,10(5):62~63
[21]郑俊民.片剂包衣的工艺和原理.北京:中国医药科技出版社,2000:13
[22] SINGH M, O’HAGAN D. The preparation and characterization of polymeric antigen delivery systems for oral administration [J]. Adv Drug Deliv Rev, 1998, 34 : 285~304
[23]祁荣.吲哚美辛HPMCP肠溶片的制备及溶出度考察[J].沈阳药科大学学报,2001,18(6):395~397
[24] WANG X Q, DAI J D, CHEN Z, et al. Bioavailability and pharmacokinetics of cyclosporine A2loaded pH2sensitive nanoparticles for oral administration [J]. J Controlled Release, 2004, 97: 421~429
[25] ZANIBONI H, FELL J, COLETT J. Production and characterization of enteric beads [J]. Int J Pharm, 1995, 12: 151~155
[26] J.Siepmann, N.A.Pappas. Advanced Drug Delivery Reviews, 2001, (48): 139~157
[27]国家药典委员会.中华人民共和国药典,北京:化学工业出版社,2000
[28]刘啸武.羟丙基甲基纤维素生产技术和发展前景[J].江汉石油职工大学学报,2004,17(6):58~60
[29]祁荣.肠溶包衣材料羟丙甲纤维素邻苯二甲酸酯的研究. [硕士学位论文],2001,6:11
[30]邵自强等.纤维素醚,化学工业出版社,2007,9,第一版:69
[31]秦冬梅.羟丙基甲基纤维素在药剂学中的应用[J].安徽医药,2004,8(3):172~174
[32] P.H.Emmett, Catalysis, Vol.1~7, Reinhold Pub.Corp.,New York,1954~1960
[33] D. L. Trimm, Design of Industrial Catalysts, Elsevier Scientific Pub.Co.,Amsterdam, 1980
[34] J.R.Anderson and M. Boudart, Catalysis, Science and Technology, Vol.5, Springer-Verlag. Berlin, 1984
[35]黄宪,王彦广等.新编有机合成化学,化学工业出版社,2003,1,第一版:428
[36]高鸿宾.有机化学,高等教育出版社,1999,9,第三版:377
[37]吕恩雄.固体超强酸催化剂的制备及应用[J].精细石油化工,1994,3:49~53
[38]王红艳,周苏闽.纳米超强酸催化酯化反应研究[J].淮阴师范学院学报. 2003,2(1):42~45
[39] Saravanan P and Singh V K. Tetrahedrom Lett. 1999,40:2611
[40]李小永,王丽琼.三氟甲磺酸酮(Ⅱ)手性衍生物:不对称合成中的一类高效催化剂[J].有机化学,2004,24(10):1159~1167
[41]郑燕升,粟晖.三乙胺催化合成维生素E琥珀酸单酯的研究[J].精细石油化工,2006,23(5):39~41
[42]郑燕升,粟晖.三乙胺催化合成维生素E乙酸酯的研究[J].广西工学院学报,2006,17(3):33-35,40
[43]徐莹,常杰.固体碱催化剂上生物油催化酯改性[J].石油化工,2006,35(17):615~618
[44]崔福德.药剂学.人民卫生出版社,2003年7月,第五版:143
[45]陆彬.药物新剂型与新技术.人民卫生出版社,2002年2月,第一版:261
[46] CHANG RONG-KUN, HSIAO C H, ROBINSON J. A review of aqueous coating techniques and preliminary data on release from a theophylline product[J]. Pharm Technol, 1987, 11(3): 56
[47] WilliamsⅢR O, Liu J P. Influence of processing and curing conditions on beads coated with an aqueous dispersion of cellulose acetate phthalate [J]. Eur J Pharm Biopharm, 2000, 49 (3): 243~252
[48] Raffin F, Durn C, Jacob M, et al. Permeability to hydrogen ions of an enteric coating polymer and interaction of film formulation factors [J]. Int J Pharm, 1996, 145 (3): 247~252
[49] Muhammad N A, Boisvert W, Harris M R, et al. Evaluation of hydroxyl propylmethylcellulose phthalate 50 as film forming polymer from aqueous dispersion system [J ]. Drug Dev Ind Pharm, 1992, 18 (16):1787~1797
[50] Watano S, Wada I, Miyanami K, et al. Modeling and simulation of drug release from granule coated with an aqueous-based system of acrylic copolymer [J]. Chem Pharm Bull, 1995, 43 (5): 877~880
[51]陈挺,陈庆华.乙基纤维素水性包衣技术Ⅰ.水分散体与有机溶剂包衣的比较[J].中国医药工业杂志.2000,31(1):7~12
[52]奚念珠.药剂学.北京:人民卫生出版社,1997,74~75
[53]王红梅,陈巍,施伟.芦荟酚类化合物研究[J].中草药,2003,34(6):499~501
[54]封士兰,潘宣,张晓光.兔耳草化学成分研究[J].中草药,2000,31(7):500~501.
[55]刘怡,沈岚.羟丙基甲基纤维素邻苯二甲酸酯在药物制剂中的应用[J].亚太传统医药, 2005,(3):92
[56]程玉红.羟丙基甲基纤维素酞酸酯及其水分散体的制备与表征,[硕士学位论文],南开大学,2004.6~7
[57]许加星.HPMCP合成及其水分散体的制备.[学士学位论文],天津大学,2006.6~7
[58]国家药典委员会.中华人民共和国药典,北京:化学工业出版社,2000,附录Ⅹ崩解时限检查法
[59]国家药典委员会.中华人民共和国药典,北京:化学工业出版社,2000,附录ⅩD释放度测定法
[60]胡金生,曹同玉,刘庆普.乳液聚合,北京:化学工业出版社,1987,16~26;续1,139~144
[61] T. C.巴顿著,郭隽奎等译.涂料流动和颜料分散(第二版).北京:化学工业出版社,1988,233~236
[62]何曼君等.高分子物理.上海:复旦大学出版社.1990:244~247