吲达帕胺微孔渗透泵片的制备及质量研究
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摘要
吲达帕胺(Indapamide,简称INDP)为磺胺类利尿药,具有利尿和钙拮抗作用,是一种强效、长效的降压药,临床上还用于充血性心力衰竭时水钠潴留的治疗。目前,国内外市场上只有普通片、缓释片和缓释胶囊三种剂型。渗透泵制剂具有恒速释药的特性,且释放不受介质pH值、胃肠道蠕动等因素的影响,更有利于保持体外释放与体内吸收的相关性。但目前,多应用在水溶性药物的研究上。本文以吲达帕胺为难溶性药物的模型,研究将其制备成微孔渗透泵(Micro-porous osmotic pump,简称Mpop)片剂的方法。
在处方前研究的基础上,首先对处方和工艺进行了单因素考察。结果表明,促渗剂、致孔剂、增塑剂和包衣膜厚度对药物释放有显著影响。通过正交试验设计,优化筛选出16小时释药的最佳处方。同时,确定了关键的工艺参数。以微晶纤维素(MCC)、可压性淀粉、乳糖、氯化钠、羟丙基甲基纤维素(HPMC)K4M、十二烷基硫酸钠为片芯材料;以醋酸纤维素(CA)、聚乙二醇-400(PEG-400)、邻苯二甲酸二乙酯(DEP)的丙酮溶液为包衣液;喷雾速率为5 ml·min-1,包衣温度30℃,包衣锅转速30 rpm,制备了吲达帕胺微孔渗透泵型控释片。其16小时累积释放率到达90%,线性相关系数达到0.99。
释药机制的研究证明INDP MPOP片的释药动力主要为衣膜内外的渗透压差。其体外释药行为符合零级释药模型。释放介质的pH值、溶出方法和转速,对药物释放均无显著性的影响。
查阅文献资料和试验,建立高效液相色谱方法用于测定含量、有关物质和体外释放度,对片剂质量进行评价。稳定性试验结果显示,INDP MPOP片除在高湿条件略有吸潮外,在光照、高温、留样及加速试验中均表现出了良好的稳定性。
建立高效液相-质谱联用色谱法测定家犬血浆中的药物浓度。采用双周期随机交叉试验设计,以市售吲达帕胺缓释片为参比制剂,测定了INDP MPOP片在家犬体内的相对生物利用度和药代动力学参数。通过血药浓度-时间曲线下面积(AUC)、达峰浓度(Cmax)和达峰时间(Tpeak)等参数的比较,方差分析和双向单侧T检验结果显示,自制微孔渗透泵片和市售缓释片生物等效。自制片的相对生物利用度为106%。对MPOP片的体内吸收分数与体外释放百分率进行线性回归,证明体外释药特性与体内吸收有良好的相关性。
Indapamide (INDP) is a non-thiazide sulphonamide diuretic drug marketed by Servier, generally used in the treatment of hypertension, as well as decompensated cardiac failure. So far there are only conventional tablets,sustained release tablets and capsules in domestic and foreign markets. Osmotic pump tablets have a constant release rate and the release rate is pH-independent and agitation-independent which lead to comparable in vitro/in vivo correlation. But they are usually applieable for soluble drugs. In this study, micro-porous osmotic pump (MPOP) tablets were prepared using INDP as the model of indissoluble drugs.
Based on the comprehensive pre-formulation research, single-factor tests were carried out to inspect the influence of formulation and manufacture process on the release of indapamide. The results suggested that osmotic pressure promoting agent, pore former, plasticizer and coating weight had marked effect on the drug release. By orthogonal experimental design, optimal formulation modified to release drug over 16h was obtained. Meanwhile, the parameters of coating technique were determined. Microcrystalline cellulose(MCC), amylum pregelatinisatum, lactose, sodium chloride and hypromellose(HPMC) were used to make the tablet core. Cellulose acetate (CA), PEG-400, diethyl phthalate (DEP) and acetone were selected as the coating solution. Tablets were coated by pan-spray method, and the coating process was described as the spray speed of 5 ml·min-1, coating temperature 30℃. Cumulative drug release of the best formulation at 16 h exceeded 90% and the linear correlation coefficient exceeded 0.99.
Investigation about the drug release mechanism proved that the release kinetics derives from the difference of the osmotic pressure across the membrance. The release behavior in vitro of the INDP MPOP complied with zero order release rule. The type of dissolution medium, dissolution method and rotation speed had less effect. According to literatures, UV spectrophotometer and high-performance liquid chromatography(HPLC) were developed for in vitro assay during the studies of content, related substance and release. The stability test results showed that INDP MPOP is a little wet under high humidity, whereas good stability was found under light, high temperature, the accelerating test and room temperature.
High-performance liquid chromatography-mass spectrometry (HPLC-MS) method was preformed to detect the concentration of INDP in Plasma of dogs, using sustained release tablets as the reference and by the two Periods cross-over design for determining the pharmacokinetics and bioavailability in six healthy dogs. By comparing the pharmacokinetic parameters of the test and refrence tablets, such as AUC, Cmax, Tpeak and T1/2, the results of analysis of varianee and the two one-sided test showed they were bio-equivalent. The relative bioavailability was 106%. Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.
在处方前研究的基础上,首先对处方和工艺进行了单因素考察。结果表明,促渗剂、致孔剂、增塑剂和包衣膜厚度对药物释放有显著影响。通过正交试验设计,优化筛选出16小时释药的最佳处方。同时,确定了关键的工艺参数。以微晶纤维素(MCC)、可压性淀粉、乳糖、氯化钠、羟丙基甲基纤维素(HPMC)K4M、十二烷基硫酸钠为片芯材料;以醋酸纤维素(CA)、聚乙二醇-400(PEG-400)、邻苯二甲酸二乙酯(DEP)的丙酮溶液为包衣液;喷雾速率为5 ml·min-1,包衣温度30℃,包衣锅转速30 rpm,制备了吲达帕胺微孔渗透泵型控释片。其16小时累积释放率到达90%,线性相关系数达到0.99。
释药机制的研究证明INDP MPOP片的释药动力主要为衣膜内外的渗透压差。其体外释药行为符合零级释药模型。释放介质的pH值、溶出方法和转速,对药物释放均无显著性的影响。
查阅文献资料和试验,建立高效液相色谱方法用于测定含量、有关物质和体外释放度,对片剂质量进行评价。稳定性试验结果显示,INDP MPOP片除在高湿条件略有吸潮外,在光照、高温、留样及加速试验中均表现出了良好的稳定性。
建立高效液相-质谱联用色谱法测定家犬血浆中的药物浓度。采用双周期随机交叉试验设计,以市售吲达帕胺缓释片为参比制剂,测定了INDP MPOP片在家犬体内的相对生物利用度和药代动力学参数。通过血药浓度-时间曲线下面积(AUC)、达峰浓度(Cmax)和达峰时间(Tpeak)等参数的比较,方差分析和双向单侧T检验结果显示,自制微孔渗透泵片和市售缓释片生物等效。自制片的相对生物利用度为106%。对MPOP片的体内吸收分数与体外释放百分率进行线性回归,证明体外释药特性与体内吸收有良好的相关性。
Indapamide (INDP) is a non-thiazide sulphonamide diuretic drug marketed by Servier, generally used in the treatment of hypertension, as well as decompensated cardiac failure. So far there are only conventional tablets,sustained release tablets and capsules in domestic and foreign markets. Osmotic pump tablets have a constant release rate and the release rate is pH-independent and agitation-independent which lead to comparable in vitro/in vivo correlation. But they are usually applieable for soluble drugs. In this study, micro-porous osmotic pump (MPOP) tablets were prepared using INDP as the model of indissoluble drugs.
Based on the comprehensive pre-formulation research, single-factor tests were carried out to inspect the influence of formulation and manufacture process on the release of indapamide. The results suggested that osmotic pressure promoting agent, pore former, plasticizer and coating weight had marked effect on the drug release. By orthogonal experimental design, optimal formulation modified to release drug over 16h was obtained. Meanwhile, the parameters of coating technique were determined. Microcrystalline cellulose(MCC), amylum pregelatinisatum, lactose, sodium chloride and hypromellose(HPMC) were used to make the tablet core. Cellulose acetate (CA), PEG-400, diethyl phthalate (DEP) and acetone were selected as the coating solution. Tablets were coated by pan-spray method, and the coating process was described as the spray speed of 5 ml·min-1, coating temperature 30℃. Cumulative drug release of the best formulation at 16 h exceeded 90% and the linear correlation coefficient exceeded 0.99.
Investigation about the drug release mechanism proved that the release kinetics derives from the difference of the osmotic pressure across the membrance. The release behavior in vitro of the INDP MPOP complied with zero order release rule. The type of dissolution medium, dissolution method and rotation speed had less effect. According to literatures, UV spectrophotometer and high-performance liquid chromatography(HPLC) were developed for in vitro assay during the studies of content, related substance and release. The stability test results showed that INDP MPOP is a little wet under high humidity, whereas good stability was found under light, high temperature, the accelerating test and room temperature.
High-performance liquid chromatography-mass spectrometry (HPLC-MS) method was preformed to detect the concentration of INDP in Plasma of dogs, using sustained release tablets as the reference and by the two Periods cross-over design for determining the pharmacokinetics and bioavailability in six healthy dogs. By comparing the pharmacokinetic parameters of the test and refrence tablets, such as AUC, Cmax, Tpeak and T1/2, the results of analysis of varianee and the two one-sided test showed they were bio-equivalent. The relative bioavailability was 106%. Obvious correlation was observed between absorption percentage in vivo and release rate in vitro.
引文
[1]胡还甫,衣伟锋,余林岚.渗透泵控释制剂释药影响因素研究概况[J].实用医药杂志,2010.27(1):81-83.
[2]宋金春,吕桦,以盛.渗透泵型择时释药系统的研究进展[J].中国药房,2009.20(10):792-794.
[3]欧阳斌,刘科秋.渗透泵制剂的研究进展[J].中国药房,2007.18(28):2227-2229.
[4]刘睿,刘志东,高国义.丹酚酸B渗透泵控释片的制备[J].中国新药杂志,2010.19(2):142-146.
[5] Kumar G., Gupta D.. Development and in vitro evaluation of smotically controlled oral drug delivery system of carvedilol [J].International Journal of Pharmaceutical Sciences and Drug Research, 2009. 1(2): 80-82.
[6]赵学玲,李强,龚显峰等.微孔渗透泵片的药物传递机制[J].药学学报,2007.42(2):226-230.
[7]张继稳,陈军,高美华等.控释制剂释放动力学评价理论研究[J].中国药科大学,2008.39(1):28-31.
[8]朱兰,顾鹏,李健等.口服缓控释制剂研究进展及临床应用[J].现代预防医学,2008.35(10):1893-1895.
[9]王文苹,谢秀琼,杨大坚等.口服渗透泵控释给药系统研究新进展[J].中国中药杂志,2008.33(5):598-600.
[10]颜琨,梅兴国.渗透泵给药系统设计原理、关键技术与发展动态[J].国际药学研究杂志,2010.37(2):92-94.
[11]周晓丽,朱金屏.渗透泵剂型的研究进展[J].中国医药工业杂志,2009.40(1):52-54.
[12]金玲宇,张宇,韩飞等.包衣处方对盐酸文拉法辛微孔渗透泵型控释片体外释药的影响[J].沈阳药科大学学报,2008.25(8):594-597.
[13]张辉,王文苹.赤芍总苷微孔渗透泵控释片的处方优化研究[J].中国中药杂志,2008.33(19):2185-2187.
[14]杨秀丽,孙进,何仲贵.格列吡嗪油水分配系数和平衡溶解度的测定[J].中国药剂学杂志,2009.7(3):121-126.
[15]谢英花,曹德英.己酮可可碱渗透泵控释片的研制[J].河北科技大学学报,2010.31(2):142-146.
[16]宋金春,以盛,吕桦等.磷酸川芎嗪微孔渗透泵片的研制及释药机制研究[J].中国药房,2008.19(6):420-424.
[17]钟玲,吴伟,臧志和.芦丁渗透泵片的体外释放度方法研究[J].时珍国医国药,2010.21(1):131-133.
[18] Hui L., Xing-Gang Y., Shu-Fang N., et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation [J]. International Journal of Pharmaceutics, 2007. 332: 115-124.
[19]张志宏,孙光美,杨星钢等.木糖醇作为渗透泵制剂新辅料的双重作用研究[J].中国新药杂志,2009.18 (23):2264-2266.
[20]李肖屹,尹蓉莉,钟玲等.人参总皂苷渗透泵片体外释药的影响因素[J].华西药学杂志,2008.23(4):438-439.
[21] Chao W., Fei Ch., Ji-zhong L., et al. A novel osmotic pump tablet using core of drug-resin complexes for time-controlled delivery system [J].The Pharmaceutical Society of Japan, 2008. 128(5): 773-782.
[22] Vincent M., Joerg O., Nicoletta L., et al. Oral osmotically driven systems: 30 years of development and clinical use [J]. European Journal of Pharmaceutics and Biopharmaceutics, 2009. 73(3): 311-323.
[23]李肖屹,尹蓉莉,钟玲等.人参总皂苷渗透泵片制备及体外释放度考察[J].医学研究杂志,2009.38(1):66-68.
[24]钟玲,臧志和.三七总皂苷微孔渗透泵控释片体外释放度研究[J].中成药,2007.29(6):823-824.
[25]许小红,黎聪,徐霞.三七总皂苷微孔渗透泵片的制备[J].中国医院药学杂志,2010.30(6):457-458.
[26]吴蘅,杨星钢,李杰等.星点设计一效应面法优化苯扎贝特渗透泵片处方[J].中国药房,2009.20(13):1000-1002.
[27]邵正飞,王洪光,翟翠云.星点设计一效应面法优化二甲双胍片的缓释包衣工艺[J].华西药学杂志,2010.25(3):260-262.
[28]翟国松,张伟,李琳等.盐酸阿夫唑嗪微孔渗透泵控释片的研制及释药影响因素考察[J].中国药剂学杂志,2007.5(5):231-233.
[29]尹飞,李威,潘卫三.盐酸二甲双胍渗透泵控释片的制备及体外释放度考察[J].实用药物与临,2009.12(3):194-195.
[30]刘辉,漆正林,刘宏等.盐酸文拉法辛微孔型渗透泵片的制备工艺研究[J].医药导报,2009.28(10):1332-1334.
[31]魏萍,尹蓉莉,李东芬等.淫羊藿总黄酮微孔渗透泵控释片的制备及体外释药因素的考察[J].成都中医药大学学报,2009.32(4):78-80.
[32] Prakash Rao B., Geethal M., Purushothama N., et al.Optimization and development of swellable controlled porosity osmotic pump tablet for theophylline[J]. Tropical Journal of Pharmaceutical Research, 2009. 8 (3): 247-255.
[33] Tzahi C., Amy Ch., Menachem E.. Forward osmosis: principles, applications, and recent developments [J]. Journal of Membrane Science , 2006. 281: 70-87.
[34]刘石磊,谢向阳,黄何松等.原料药粒径对盐酸普萘洛尔渗透泵片释药行为的影响[J].中国药房,2010.21(5):435-436.
[35]王英申嫣.阿魏酸钠单层渗透泵控释片的研制[J].当代医学,2009.15(31):6-7.
[36]刘辉,张宜,符旭东等.布地奈德固体分散体增溶型渗透泵片的研制及其释药机制[J].中国药师,2009.12(1):5-7.
[37]张宇,刘清飞,罗国安等.单硝酸异山梨酯渗透泵型控释片的制备及体外释药机制考察[J].中国新药杂志,2007.16(21):1784-1786.
[38]陈存香,李三鸣,李红菊等.法莫替丁单室单层渗透泵片的制备[J].中国新药杂志,2007.16(13):1035-1036.
[39]赵诤,卢骏,冯岩等.格列齐特渗透泵控释片的制备及犬体内药动学[J].中国医药工业杂志,2009.40(8):592-594.
[40]唐蕾,张文彬,唐仕炜等.枸橼酸坦度螺酮渗透泵型控释片的制备及体外释药因素的考察[J].华西药学杂志,2009.24(3):232-234.
[41]胡客峰,马凤余,张虹等.黄杨宁渗透泵型控释片的设计及释放度的研究[J].中国实验方剂学杂志,2007.13(12):18-20.
[42]王文苹,谢秀琼,杨大坚等.均匀设计法优化秋水仙碱渗透泵控释片的衣膜处方[J].中成药,2008.30(5):661-663.
[43]张丹,孙英华,刘艳等.均匀设计法制备苦参碱渗透泵型控释片[J].沈阳药科大学学报,2007.24(1):16-18.
[44]钟玲,郭小丽,臧志和.芦丁渗透泵片片芯的处方组成研究[J].医药导报,2009.28(12):1600-1602.
[45]刘海洲,刘均洪,张媛媛等.罗红霉素渗透泵型控释片处方工艺研究[J].抗感染药学,2009.6(1):20-22.
[46] Shahla J., Reza F.. Development of a controlled release low dose class II drug-Glipizide [J]. International Journal of Pharmaceutics, 2006. 312: 24-32.
[47] Mishra B., Makesh K., Sankar C.. Oral push-pull osmotic pumps of pentazocinehydrochloride: development and evaluation [J]. Indian Journal of Pharmaceutical Sciences, 2006. 68 (1): 85-87.
[48]葛乐乐,范辉.特拉唑嗪单芯渗透泵片研制及其控制释放的因素[J].中国医院药学杂志,2007.27(6):740-742.
[49]尹飞,李威,潘卫三.盐酸二甲双胍渗透泵控释片的制备及体外释放度考察[J].实用药物与临床,2009.12(3):194-195.
[50]曹高忠,傅红兴,张福志等.盐酸沙格雷酯渗透泵控释片的研制[J].中国医院药学杂志,2008.28(13):1056-1957.
[51]吴敏,周朝森,高秀蓉等.岩白菜素渗透泵片释药机理研究[J].时珍国医国药,2010.21(4):861-863.
[52]王汝兴,张宇丽,陈大为.酮基布洛芬单室渗透泵片在家犬体内的药动学和相对生物利用度[J].中国医院药学杂志,2008.28(2):106-108.
[53]王超,陈飞,洪丽娟等.盐酸普萘洛尔渗透泵片的制备及Beagle犬体内药动学研究[J].中国新药杂志,2008.17(2):146-147.
[54]李红菊,张向荣等.丙烯酸树脂RSIO0和丙烯酸树脂RLIO0混合包衣制备法莫替丁渗透泵控释片[J].沈阳药科大学学报,2007.24(7):398-400.
[55]薛立安,李元波,郭丹丹等.复方丹参泡腾性渗透泵片的制备及释药机制研究[J].中国中药杂志,2009.34(7):848-850.
[56]温利民,年四昀,鲜飞鹏.格列吡嗪渗透泵片的水分散体包衣法研制及其体外[J].制剂技术,2009.18 (22):44-47.
[57]胡容峰,韩玲玲,彭代银等.六味地黄控释片的处方优化及同步释放的研究[J].中医药现代化,2010.12 (2):217-219.
[58]罗晓健,辛洪亮,饶小勇等.泡腾技术在药物制剂中的研究进展[J].中国中药杂志,2008.33 (8):973-975.
[59]万常伟,傅红兴,徐艳艳等.渗透泵控释胶囊的制备与释药影响因素研究[J].医药导报,2010.29(4):511-513.
[60]何燕,曾祥腾,潘卫三.体外条件对不同类型灯盏花素缓控释制剂释放行为的影响[J].药学学报,2008.43(11):1161-1164.
[61]韩翠艳,徐楠,盛长江.乌拉地尔渗透泵片的制备[J].制剂技术,2008.19(22):1721-1723.
[62] Mahalaxmi R., Phanidhar S., Ravi k., et al. Enhancement of dissolution of glipizide from controlled porosity osmotic pump using a wicking agent and a solubilizing agent [J]. International Journal of PharmTech Research, 2009. 1(3): 705-711.
[63]陶丽娟,宫学晶.小剂量与常规剂量吲达帕胺治疗老年高血压的疗效比较[J].医学创新研究,2008.5(23):29-33.
[64]魏娟英.吲达帕胺的不良反应[J].浙江中西医结合杂志,2010.20(1):41-43.
[65]杨启兵.吲达帕胺的不良反应与合理用药建议[J].药学与l临床研究,2008.16(3):222-224.
[66]王金,吴志刚,杜青.吲达帕胺冻干口腔崩解片在Beagle犬体内药物动力学研究[J].河北北方学院学报(医学版),2009.26(5):21-25.
[67]甘方良,崔晓宇,李芳芳等.吲达帕胺缓释胶囊人体药动学和生物等效性试验[J].中国医院药学杂志,2008.28(24):2107-2109.
[68]田娟,周彦彬,冉黎灵等. HPLC测定非冷冻人全血中吲达帕胺及相对生物利用度[J].药物分析杂志,2008.28(8):1244-1246.
[69]张强,武凤兰.药剂学[M] .北京:北京大学医学出版社,2005. 385～387
[70]国家药典委员会.中国药典2005版第二部附录[M].北京:化学工业出版社,2005.
[71] The Merck Index Thirteenth Edition德国默克《默克索引》.
[72]陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998,24-51
[73]方开泰,马长兴正交与均匀试验设计[M].北京:科学出版社,2001
[74]广东艾美斯医药信息有限责任公司.抗高血压药物市场研究报告[M]. 2001
[75]李磊. 2008至2009年我院口服抗高血压药物临床用药分析[J].河北医药,2010.32(21):3085-3086.
[2]宋金春,吕桦,以盛.渗透泵型择时释药系统的研究进展[J].中国药房,2009.20(10):792-794.
[3]欧阳斌,刘科秋.渗透泵制剂的研究进展[J].中国药房,2007.18(28):2227-2229.
[4]刘睿,刘志东,高国义.丹酚酸B渗透泵控释片的制备[J].中国新药杂志,2010.19(2):142-146.
[5] Kumar G., Gupta D.. Development and in vitro evaluation of smotically controlled oral drug delivery system of carvedilol [J].International Journal of Pharmaceutical Sciences and Drug Research, 2009. 1(2): 80-82.
[6]赵学玲,李强,龚显峰等.微孔渗透泵片的药物传递机制[J].药学学报,2007.42(2):226-230.
[7]张继稳,陈军,高美华等.控释制剂释放动力学评价理论研究[J].中国药科大学,2008.39(1):28-31.
[8]朱兰,顾鹏,李健等.口服缓控释制剂研究进展及临床应用[J].现代预防医学,2008.35(10):1893-1895.
[9]王文苹,谢秀琼,杨大坚等.口服渗透泵控释给药系统研究新进展[J].中国中药杂志,2008.33(5):598-600.
[10]颜琨,梅兴国.渗透泵给药系统设计原理、关键技术与发展动态[J].国际药学研究杂志,2010.37(2):92-94.
[11]周晓丽,朱金屏.渗透泵剂型的研究进展[J].中国医药工业杂志,2009.40(1):52-54.
[12]金玲宇,张宇,韩飞等.包衣处方对盐酸文拉法辛微孔渗透泵型控释片体外释药的影响[J].沈阳药科大学学报,2008.25(8):594-597.
[13]张辉,王文苹.赤芍总苷微孔渗透泵控释片的处方优化研究[J].中国中药杂志,2008.33(19):2185-2187.
[14]杨秀丽,孙进,何仲贵.格列吡嗪油水分配系数和平衡溶解度的测定[J].中国药剂学杂志,2009.7(3):121-126.
[15]谢英花,曹德英.己酮可可碱渗透泵控释片的研制[J].河北科技大学学报,2010.31(2):142-146.
[16]宋金春,以盛,吕桦等.磷酸川芎嗪微孔渗透泵片的研制及释药机制研究[J].中国药房,2008.19(6):420-424.
[17]钟玲,吴伟,臧志和.芦丁渗透泵片的体外释放度方法研究[J].时珍国医国药,2010.21(1):131-133.
[18] Hui L., Xing-Gang Y., Shu-Fang N., et al. Chitosan-based controlled porosity osmotic pump for colon-specific delivery system: Screening of formulation variables and in vitro investigation [J]. International Journal of Pharmaceutics, 2007. 332: 115-124.
[19]张志宏,孙光美,杨星钢等.木糖醇作为渗透泵制剂新辅料的双重作用研究[J].中国新药杂志,2009.18 (23):2264-2266.
[20]李肖屹,尹蓉莉,钟玲等.人参总皂苷渗透泵片体外释药的影响因素[J].华西药学杂志,2008.23(4):438-439.
[21] Chao W., Fei Ch., Ji-zhong L., et al. A novel osmotic pump tablet using core of drug-resin complexes for time-controlled delivery system [J].The Pharmaceutical Society of Japan, 2008. 128(5): 773-782.
[22] Vincent M., Joerg O., Nicoletta L., et al. Oral osmotically driven systems: 30 years of development and clinical use [J]. European Journal of Pharmaceutics and Biopharmaceutics, 2009. 73(3): 311-323.
[23]李肖屹,尹蓉莉,钟玲等.人参总皂苷渗透泵片制备及体外释放度考察[J].医学研究杂志,2009.38(1):66-68.
[24]钟玲,臧志和.三七总皂苷微孔渗透泵控释片体外释放度研究[J].中成药,2007.29(6):823-824.
[25]许小红,黎聪,徐霞.三七总皂苷微孔渗透泵片的制备[J].中国医院药学杂志,2010.30(6):457-458.
[26]吴蘅,杨星钢,李杰等.星点设计一效应面法优化苯扎贝特渗透泵片处方[J].中国药房,2009.20(13):1000-1002.
[27]邵正飞,王洪光,翟翠云.星点设计一效应面法优化二甲双胍片的缓释包衣工艺[J].华西药学杂志,2010.25(3):260-262.
[28]翟国松,张伟,李琳等.盐酸阿夫唑嗪微孔渗透泵控释片的研制及释药影响因素考察[J].中国药剂学杂志,2007.5(5):231-233.
[29]尹飞,李威,潘卫三.盐酸二甲双胍渗透泵控释片的制备及体外释放度考察[J].实用药物与临,2009.12(3):194-195.
[30]刘辉,漆正林,刘宏等.盐酸文拉法辛微孔型渗透泵片的制备工艺研究[J].医药导报,2009.28(10):1332-1334.
[31]魏萍,尹蓉莉,李东芬等.淫羊藿总黄酮微孔渗透泵控释片的制备及体外释药因素的考察[J].成都中医药大学学报,2009.32(4):78-80.
[32] Prakash Rao B., Geethal M., Purushothama N., et al.Optimization and development of swellable controlled porosity osmotic pump tablet for theophylline[J]. Tropical Journal of Pharmaceutical Research, 2009. 8 (3): 247-255.
[33] Tzahi C., Amy Ch., Menachem E.. Forward osmosis: principles, applications, and recent developments [J]. Journal of Membrane Science , 2006. 281: 70-87.
[34]刘石磊,谢向阳,黄何松等.原料药粒径对盐酸普萘洛尔渗透泵片释药行为的影响[J].中国药房,2010.21(5):435-436.
[35]王英申嫣.阿魏酸钠单层渗透泵控释片的研制[J].当代医学,2009.15(31):6-7.
[36]刘辉,张宜,符旭东等.布地奈德固体分散体增溶型渗透泵片的研制及其释药机制[J].中国药师,2009.12(1):5-7.
[37]张宇,刘清飞,罗国安等.单硝酸异山梨酯渗透泵型控释片的制备及体外释药机制考察[J].中国新药杂志,2007.16(21):1784-1786.
[38]陈存香,李三鸣,李红菊等.法莫替丁单室单层渗透泵片的制备[J].中国新药杂志,2007.16(13):1035-1036.
[39]赵诤,卢骏,冯岩等.格列齐特渗透泵控释片的制备及犬体内药动学[J].中国医药工业杂志,2009.40(8):592-594.
[40]唐蕾,张文彬,唐仕炜等.枸橼酸坦度螺酮渗透泵型控释片的制备及体外释药因素的考察[J].华西药学杂志,2009.24(3):232-234.
[41]胡客峰,马凤余,张虹等.黄杨宁渗透泵型控释片的设计及释放度的研究[J].中国实验方剂学杂志,2007.13(12):18-20.
[42]王文苹,谢秀琼,杨大坚等.均匀设计法优化秋水仙碱渗透泵控释片的衣膜处方[J].中成药,2008.30(5):661-663.
[43]张丹,孙英华,刘艳等.均匀设计法制备苦参碱渗透泵型控释片[J].沈阳药科大学学报,2007.24(1):16-18.
[44]钟玲,郭小丽,臧志和.芦丁渗透泵片片芯的处方组成研究[J].医药导报,2009.28(12):1600-1602.
[45]刘海洲,刘均洪,张媛媛等.罗红霉素渗透泵型控释片处方工艺研究[J].抗感染药学,2009.6(1):20-22.
[46] Shahla J., Reza F.. Development of a controlled release low dose class II drug-Glipizide [J]. International Journal of Pharmaceutics, 2006. 312: 24-32.
[47] Mishra B., Makesh K., Sankar C.. Oral push-pull osmotic pumps of pentazocinehydrochloride: development and evaluation [J]. Indian Journal of Pharmaceutical Sciences, 2006. 68 (1): 85-87.
[48]葛乐乐,范辉.特拉唑嗪单芯渗透泵片研制及其控制释放的因素[J].中国医院药学杂志,2007.27(6):740-742.
[49]尹飞,李威,潘卫三.盐酸二甲双胍渗透泵控释片的制备及体外释放度考察[J].实用药物与临床,2009.12(3):194-195.
[50]曹高忠,傅红兴,张福志等.盐酸沙格雷酯渗透泵控释片的研制[J].中国医院药学杂志,2008.28(13):1056-1957.
[51]吴敏,周朝森,高秀蓉等.岩白菜素渗透泵片释药机理研究[J].时珍国医国药,2010.21(4):861-863.
[52]王汝兴,张宇丽,陈大为.酮基布洛芬单室渗透泵片在家犬体内的药动学和相对生物利用度[J].中国医院药学杂志,2008.28(2):106-108.
[53]王超,陈飞,洪丽娟等.盐酸普萘洛尔渗透泵片的制备及Beagle犬体内药动学研究[J].中国新药杂志,2008.17(2):146-147.
[54]李红菊,张向荣等.丙烯酸树脂RSIO0和丙烯酸树脂RLIO0混合包衣制备法莫替丁渗透泵控释片[J].沈阳药科大学学报,2007.24(7):398-400.
[55]薛立安,李元波,郭丹丹等.复方丹参泡腾性渗透泵片的制备及释药机制研究[J].中国中药杂志,2009.34(7):848-850.
[56]温利民,年四昀,鲜飞鹏.格列吡嗪渗透泵片的水分散体包衣法研制及其体外[J].制剂技术,2009.18 (22):44-47.
[57]胡容峰,韩玲玲,彭代银等.六味地黄控释片的处方优化及同步释放的研究[J].中医药现代化,2010.12 (2):217-219.
[58]罗晓健,辛洪亮,饶小勇等.泡腾技术在药物制剂中的研究进展[J].中国中药杂志,2008.33 (8):973-975.
[59]万常伟,傅红兴,徐艳艳等.渗透泵控释胶囊的制备与释药影响因素研究[J].医药导报,2010.29(4):511-513.
[60]何燕,曾祥腾,潘卫三.体外条件对不同类型灯盏花素缓控释制剂释放行为的影响[J].药学学报,2008.43(11):1161-1164.
[61]韩翠艳,徐楠,盛长江.乌拉地尔渗透泵片的制备[J].制剂技术,2008.19(22):1721-1723.
[62] Mahalaxmi R., Phanidhar S., Ravi k., et al. Enhancement of dissolution of glipizide from controlled porosity osmotic pump using a wicking agent and a solubilizing agent [J]. International Journal of PharmTech Research, 2009. 1(3): 705-711.
[63]陶丽娟,宫学晶.小剂量与常规剂量吲达帕胺治疗老年高血压的疗效比较[J].医学创新研究,2008.5(23):29-33.
[64]魏娟英.吲达帕胺的不良反应[J].浙江中西医结合杂志,2010.20(1):41-43.
[65]杨启兵.吲达帕胺的不良反应与合理用药建议[J].药学与l临床研究,2008.16(3):222-224.
[66]王金,吴志刚,杜青.吲达帕胺冻干口腔崩解片在Beagle犬体内药物动力学研究[J].河北北方学院学报(医学版),2009.26(5):21-25.
[67]甘方良,崔晓宇,李芳芳等.吲达帕胺缓释胶囊人体药动学和生物等效性试验[J].中国医院药学杂志,2008.28(24):2107-2109.
[68]田娟,周彦彬,冉黎灵等. HPLC测定非冷冻人全血中吲达帕胺及相对生物利用度[J].药物分析杂志,2008.28(8):1244-1246.
[69]张强,武凤兰.药剂学[M] .北京:北京大学医学出版社,2005. 385～387
[70]国家药典委员会.中国药典2005版第二部附录[M].北京:化学工业出版社,2005.
[71] The Merck Index Thirteenth Edition德国默克《默克索引》.
[72]陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998,24-51
[73]方开泰,马长兴正交与均匀试验设计[M].北京:科学出版社,2001
[74]广东艾美斯医药信息有限责任公司.抗高血压药物市场研究报告[M]. 2001
[75]李磊. 2008至2009年我院口服抗高血压药物临床用药分析[J].河北医药,2010.32(21):3085-3086.