漂浮型脉冲释放系统的研究
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摘要
本课题将胃漂浮技术应用于脉冲释放制剂,设计研究漂浮型脉冲释放制剂。漂浮型脉冲释放制剂的特点和优势在于:(1)包衣型和溶蚀塞型脉冲制剂的体内时滞主要受到与消化液接触时间的影响,漂浮型脉冲释放制剂增加制剂在消化道的滞留时间,利用胃液充分的优势,有利于提高脉冲释药时间控制的稳定性,增加脉冲制剂对控时时间不同的时辰节律性疾病的适应性。(2)根据生物药剂学的原理,药物的主要吸收部位在小肠,脉冲释放制剂的体内过程比较复杂,体内延迟释放时间较长(多大于肠溶时间),一般在小肠下端至大肠部分,以致吸收不规则,个体差异比较大。胃漂浮型脉冲释放制剂可以增加制剂在消化道的滞留时间,可以避免出现制剂脉冲释放发生时已经通过药物吸收部位的问题。
口服漂浮型脉冲释放制剂的关键和难点在于,要同时控制预定的延迟释放时间和制剂在消化液中的漂浮性能。胃滞留技术发展至今,已经出现了胃漂浮系统、胃内膨胀系统、生物粘附系统、磁场定位等方法,其中以胃漂浮技术最为成熟。而胃漂浮技术多数采用的是根据水平衡动力学(HBS)的原理,制备亲水凝胶骨架片,利用水凝胶材料分子量大,水化速度慢,产生的漂浮性能好的特点,达到漂浮的效果。但是,漂浮型脉冲释放制剂由于还需要实现控制预定的延迟释放时间后迅速释药,因此无法直接采用亲水凝胶骨架片技术制备口服漂浮型脉冲释放制剂。
本研究主要探讨三类口服漂浮型脉冲释放制剂:
一类为口服漂浮型脉冲释放胶囊:本实验研制的漂浮型脉冲释放胶囊,制剂的组成是:非渗透性胶囊体,胶囊内依次为助漂浮剂、含药片、溶蚀塞,胶囊口部可盖有可溶性胶囊帽。这一脉冲装置的关键是整个胶囊体内部完全处于封闭状态,助漂浮剂使胶囊整体密度小于1,实现制剂始终在体内漂浮;并且溶蚀塞溶蚀完全之前,胶囊内的药片始终是干燥的,而在溶蚀塞溶蚀之后,含药片才与水接触膨胀,并在溶出介质水动力冲刷下,被抛射出来,迅速崩解释药,形成脉冲释药。对体外实验筛选出的处方进行了人体体内的γ-闪烁扫描观察试验,结果表明:在受试过程中,参比制剂在1~1.5小时后屏幕监视表明已经胃排空,而受试制剂仍停留在胃中。此后,受试制剂和参比制剂的距离开始拉大。受试制剂在
3.5小时内的位置基本恒定,3.5小时后受试制剂开始从胃内向肠道中移动。本研究制备的口服漂浮型脉冲释放胶囊在体内均实现了一定的漂浮和脉冲控时效果。对比口服漂浮型脉冲释放胶囊的体内外释药“时滞”可以发现体内Tlag(4.26±0.25)hr较体外Tlag(238.1±18.3) min测得值基本相符。
另一类为漂浮型脉冲释放片:本实验设计的漂浮型脉冲释放片,采用干包衣法制备,它包括二个部分:一是外部由具疏水和亲水性材料混合组成的具有控时效果的干包衣层,二是内含高效崩解剂和主药的片芯。本研究设计漂浮型脉冲释放片主要考虑制剂的密度小于胃液的密度,即制剂的整体密度小于1。因此用作干包衣材料的阻挡水分的蜡质材料的筛选作为本部分制剂研究的主要内容。研究表明影响药物释放滞后时间和制剂漂浮性能的处方因素有:片芯的崩解剂及其赋形剂种类和用量;外层颗粒的用量和比例;片剂的硬度等。通过均匀设计考察确定了体外控时3、4、5小时的漂浮型脉冲设计的处方,并研究了释放条件因素(释放介质pH、粘度以及转速)和制剂因素(外包衣用量、致孔剂的量、外包衣颗粒大小)对漂浮性能和脉冲效果的影响。本研究采用γ-闪烁扫描法作为考察漂浮型脉冲释放制剂体内过程的方法,考察了研制的漂浮型脉冲释放制剂的在体内的漂浮特征和脉冲释放特征。研究结果表明:参比制剂在胃内的滞留时间平均在(1.17±0.29)小时,而受试制剂在胃内的滞留时间(1.67±0.29)小时,显然这类漂浮型脉冲释放制剂在体内没有实现漂浮特征,即没有实现本课题的设计目标。
再一类是双层漂浮型脉冲释放片:采用双层片技术,其中一层是漂浮层,采用兼具漂浮和粘附的亲水性凝胶骨架材料以及发泡剂组成;另一层为脉冲释放层,采用干包衣法(包芯片)技术完成。为增加漂浮脉冲片的漂浮可靠性,在片剂的一个侧面增加一个漂浮层,其由高粘度羟丙甲基纤维素、卡波姆和碳酸氢钠等材料组成。释药机理:在初始状态时,双层片脉冲片部分和漂浮部分在径向大小上没有区别;在与SGF接触后时,由于NaHCO3与HCl反应生成CO2气体,双层片的漂浮层迅速膨胀,漂浮层带着脉冲片达到液面上部,由于漂浮层具有一定粘附性,会将制剂粘附在胃粘膜;随着时间的推移,脉冲释放片的外包衣不断溶蚀,脉冲释放片的片芯吸水膨胀后形成脉冲释药;到最后时,脉冲释放片释药完毕,只剩下上层的漂浮部分,该部分在胃的蠕动作用下,经过一定时间后也会经消化道排出体外。本研究将γ-闪烁扫描法作为初步考察漂浮型脉冲释放制剂
体内过程的首选方法,以期确定研制的漂浮型脉冲释放制剂的在体内的漂浮特征和脉冲释放特征。对比口服双层漂浮型脉冲释放片的体内外释药“时滞”可以发现体内Tlag(4.33±0.15)hr与体外Tlag(242.1±6.2)min 测得值基本相符。特别值得指出的是,采用双层漂浮型脉冲释放片的胃滞留时间长,在脉冲释放发生前,三例志愿者供试片均没有发生胃排空。双层漂浮型脉冲释放片是本研究三种制剂中漂浮时间长,可控性最好的制剂,已经完全达到设?
Using current release technology, it is possible for many drugs oral delivery for a pulsed or pulsatile release, which is defined as the rapid and transient release of a certain amount of molecules within a short time-period immediately after a predetermined off-release period. However, the substance must be absorbed well throughout the whole regions of the gastrointestinal tract since the GI region where drug released could not be controlled for the current pulsatile release system. A significant obstacle may arise if there is a narrow window for drug absorption in the gastrointestinal tract, or the drug is poorly soluble in the intestine. Furthermore, the majority of drugs are preferentially absorbed in the upper part of the small intestine and the relatively brief gastric emptying time in humans, which normally averages 2–3 h through the major absorption zone (stomach or upper part of the intestine),can result in incomplete drug absorption from the pulsatile release system with more than 3 h lag time. Thus may lead to diminished efficacy of the administered dose. So the real issue in the development of oral pulsatile release dosage forms is not just to a achieve lag-time before release, but to prolong the presence of the dosage forms in the stomach or somewhere in the upper small intestine until the drug is released after a predetermined period.
On the other hand, pulsatile drug delivery is recognized as a satisfactory based on clinical cases and chronopharmacology theory. But how to appropriately control the predetermined lag time in vivo always brings about great puzzles in the research. Most pulsatile delivery systems are reservoir devices covered with a barrier coating, which dissolves, erodes or ruptures after a certain time period, followed by rapid drug release from the reservoir. Several single-unit pulsatile dosage forms with a capsular design have been developed, releasing the drug in a pulsatile fashion either after ejection or erosion of a plug or a capsule half. The working mechanism of these current pulsatile release systems is based on the exploitation of the peculiar interaction between a swellable or erodible hydrophilic polymeric coating and the aqueous gastrointestinal fluids. Time of interaction between the dosage form and the aqueous gastrointestinal fluids is a critcal factor for the lag time of the pulsatile release system. While considering the role of the influence of the biological environment on the release performance of pulsatile delivery system, control of placement of a dosage form in a specific region of the GI tract before the drug released offers numerous advantages, especially for include a reproducible of its lag time in vivo.
Overall, These considerations have led to the development of oral pulsatile release dosage forms possessing gastric retention capabilities. Oral pulsatile release dosage forms with hydrodynamically balanced systems possessing gastric retention
capabilities have a bulk density lower than gastric fluids and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, interaction between the system and the aqueous gastrointestinal fluids would be retained until the release of drug. After the release of drug, the residual system is emptied from the stomach. This results in an increase in the gastric residence time and a better control of the lag time of the oral pulsatile release system.
We developed three kinds of oral pulsatile release dosage forms possessing gastric retention capabilities.
First, a multifunctional drug delivery system, which was designed as a pulsatile and floating drug delivery system , was developed and evaluated. Such drug delivery system is developed from the pulsatile system described by Krogel and Bodmeier. The novel system consists of a hydrophilic matrix tablet placed within an impermeable polymeric cylinder closed with an erodible drug-free plug and an air-filled space or floating material filled at the bottom. When
口服漂浮型脉冲释放制剂的关键和难点在于,要同时控制预定的延迟释放时间和制剂在消化液中的漂浮性能。胃滞留技术发展至今,已经出现了胃漂浮系统、胃内膨胀系统、生物粘附系统、磁场定位等方法,其中以胃漂浮技术最为成熟。而胃漂浮技术多数采用的是根据水平衡动力学(HBS)的原理,制备亲水凝胶骨架片,利用水凝胶材料分子量大,水化速度慢,产生的漂浮性能好的特点,达到漂浮的效果。但是,漂浮型脉冲释放制剂由于还需要实现控制预定的延迟释放时间后迅速释药,因此无法直接采用亲水凝胶骨架片技术制备口服漂浮型脉冲释放制剂。
本研究主要探讨三类口服漂浮型脉冲释放制剂:
一类为口服漂浮型脉冲释放胶囊:本实验研制的漂浮型脉冲释放胶囊,制剂的组成是:非渗透性胶囊体,胶囊内依次为助漂浮剂、含药片、溶蚀塞,胶囊口部可盖有可溶性胶囊帽。这一脉冲装置的关键是整个胶囊体内部完全处于封闭状态,助漂浮剂使胶囊整体密度小于1,实现制剂始终在体内漂浮;并且溶蚀塞溶蚀完全之前,胶囊内的药片始终是干燥的,而在溶蚀塞溶蚀之后,含药片才与水接触膨胀,并在溶出介质水动力冲刷下,被抛射出来,迅速崩解释药,形成脉冲释药。对体外实验筛选出的处方进行了人体体内的γ-闪烁扫描观察试验,结果表明:在受试过程中,参比制剂在1~1.5小时后屏幕监视表明已经胃排空,而受试制剂仍停留在胃中。此后,受试制剂和参比制剂的距离开始拉大。受试制剂在
3.5小时内的位置基本恒定,3.5小时后受试制剂开始从胃内向肠道中移动。本研究制备的口服漂浮型脉冲释放胶囊在体内均实现了一定的漂浮和脉冲控时效果。对比口服漂浮型脉冲释放胶囊的体内外释药“时滞”可以发现体内Tlag(4.26±0.25)hr较体外Tlag(238.1±18.3) min测得值基本相符。
另一类为漂浮型脉冲释放片:本实验设计的漂浮型脉冲释放片,采用干包衣法制备,它包括二个部分:一是外部由具疏水和亲水性材料混合组成的具有控时效果的干包衣层,二是内含高效崩解剂和主药的片芯。本研究设计漂浮型脉冲释放片主要考虑制剂的密度小于胃液的密度,即制剂的整体密度小于1。因此用作干包衣材料的阻挡水分的蜡质材料的筛选作为本部分制剂研究的主要内容。研究表明影响药物释放滞后时间和制剂漂浮性能的处方因素有:片芯的崩解剂及其赋形剂种类和用量;外层颗粒的用量和比例;片剂的硬度等。通过均匀设计考察确定了体外控时3、4、5小时的漂浮型脉冲设计的处方,并研究了释放条件因素(释放介质pH、粘度以及转速)和制剂因素(外包衣用量、致孔剂的量、外包衣颗粒大小)对漂浮性能和脉冲效果的影响。本研究采用γ-闪烁扫描法作为考察漂浮型脉冲释放制剂体内过程的方法,考察了研制的漂浮型脉冲释放制剂的在体内的漂浮特征和脉冲释放特征。研究结果表明:参比制剂在胃内的滞留时间平均在(1.17±0.29)小时,而受试制剂在胃内的滞留时间(1.67±0.29)小时,显然这类漂浮型脉冲释放制剂在体内没有实现漂浮特征,即没有实现本课题的设计目标。
再一类是双层漂浮型脉冲释放片:采用双层片技术,其中一层是漂浮层,采用兼具漂浮和粘附的亲水性凝胶骨架材料以及发泡剂组成;另一层为脉冲释放层,采用干包衣法(包芯片)技术完成。为增加漂浮脉冲片的漂浮可靠性,在片剂的一个侧面增加一个漂浮层,其由高粘度羟丙甲基纤维素、卡波姆和碳酸氢钠等材料组成。释药机理:在初始状态时,双层片脉冲片部分和漂浮部分在径向大小上没有区别;在与SGF接触后时,由于NaHCO3与HCl反应生成CO2气体,双层片的漂浮层迅速膨胀,漂浮层带着脉冲片达到液面上部,由于漂浮层具有一定粘附性,会将制剂粘附在胃粘膜;随着时间的推移,脉冲释放片的外包衣不断溶蚀,脉冲释放片的片芯吸水膨胀后形成脉冲释药;到最后时,脉冲释放片释药完毕,只剩下上层的漂浮部分,该部分在胃的蠕动作用下,经过一定时间后也会经消化道排出体外。本研究将γ-闪烁扫描法作为初步考察漂浮型脉冲释放制剂
体内过程的首选方法,以期确定研制的漂浮型脉冲释放制剂的在体内的漂浮特征和脉冲释放特征。对比口服双层漂浮型脉冲释放片的体内外释药“时滞”可以发现体内Tlag(4.33±0.15)hr与体外Tlag(242.1±6.2)min 测得值基本相符。特别值得指出的是,采用双层漂浮型脉冲释放片的胃滞留时间长,在脉冲释放发生前,三例志愿者供试片均没有发生胃排空。双层漂浮型脉冲释放片是本研究三种制剂中漂浮时间长,可控性最好的制剂,已经完全达到设?
Using current release technology, it is possible for many drugs oral delivery for a pulsed or pulsatile release, which is defined as the rapid and transient release of a certain amount of molecules within a short time-period immediately after a predetermined off-release period. However, the substance must be absorbed well throughout the whole regions of the gastrointestinal tract since the GI region where drug released could not be controlled for the current pulsatile release system. A significant obstacle may arise if there is a narrow window for drug absorption in the gastrointestinal tract, or the drug is poorly soluble in the intestine. Furthermore, the majority of drugs are preferentially absorbed in the upper part of the small intestine and the relatively brief gastric emptying time in humans, which normally averages 2–3 h through the major absorption zone (stomach or upper part of the intestine),can result in incomplete drug absorption from the pulsatile release system with more than 3 h lag time. Thus may lead to diminished efficacy of the administered dose. So the real issue in the development of oral pulsatile release dosage forms is not just to a achieve lag-time before release, but to prolong the presence of the dosage forms in the stomach or somewhere in the upper small intestine until the drug is released after a predetermined period.
On the other hand, pulsatile drug delivery is recognized as a satisfactory based on clinical cases and chronopharmacology theory. But how to appropriately control the predetermined lag time in vivo always brings about great puzzles in the research. Most pulsatile delivery systems are reservoir devices covered with a barrier coating, which dissolves, erodes or ruptures after a certain time period, followed by rapid drug release from the reservoir. Several single-unit pulsatile dosage forms with a capsular design have been developed, releasing the drug in a pulsatile fashion either after ejection or erosion of a plug or a capsule half. The working mechanism of these current pulsatile release systems is based on the exploitation of the peculiar interaction between a swellable or erodible hydrophilic polymeric coating and the aqueous gastrointestinal fluids. Time of interaction between the dosage form and the aqueous gastrointestinal fluids is a critcal factor for the lag time of the pulsatile release system. While considering the role of the influence of the biological environment on the release performance of pulsatile delivery system, control of placement of a dosage form in a specific region of the GI tract before the drug released offers numerous advantages, especially for include a reproducible of its lag time in vivo.
Overall, These considerations have led to the development of oral pulsatile release dosage forms possessing gastric retention capabilities. Oral pulsatile release dosage forms with hydrodynamically balanced systems possessing gastric retention
capabilities have a bulk density lower than gastric fluids and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, interaction between the system and the aqueous gastrointestinal fluids would be retained until the release of drug. After the release of drug, the residual system is emptied from the stomach. This results in an increase in the gastric residence time and a better control of the lag time of the oral pulsatile release system.
We developed three kinds of oral pulsatile release dosage forms possessing gastric retention capabilities.
First, a multifunctional drug delivery system, which was designed as a pulsatile and floating drug delivery system , was developed and evaluated. Such drug delivery system is developed from the pulsatile system described by Krogel and Bodmeier. The novel system consists of a hydrophilic matrix tablet placed within an impermeable polymeric cylinder closed with an erodible drug-free plug and an air-filled space or floating material filled at the bottom. When
引文
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[20] Sheth P.R,Tossouinion J. The hydrodynamically balanced system (HBSTM) :A novel drug delivery system for oral use . Drug. Devel. Ind. Pharm. 1984; 10(2):313-339
[21] 石明德,高汝荔,候惠民.等. 漂浮片剂在胃内的初步动态观察. 中国医药工业杂志 1990;21(4):162-164
[22] F.Pozzi,P. Furlani,A. Gazzaniga et.al. The Time Clock system:a new oral dosage form for fast and complete release of drug after a predetermined lag time. J. controlled release. 1994;31(1):99-108
[23] S.S. Davis,J.G. Hardy and J.W. Fara. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27:886-892
[24] 邹豪,蒋雪涛,尚玉琨等,r-示综扫描照相术观察脉冲释放片在体内的释放 实用核医学杂志2001,17(12):881
[25] 邹豪,马伯良,蒋雪涛等,盐酸维拉帕米脉冲释放片的设计和制备 第二军医大学学报 1999,20(4):256-8
[26] 邹豪,郭涛,蒋雪涛等,盐酸维拉帕米脉冲释放片人体内药代动力学及生物利用度研究 第二军医大学学报2000,21(10):977
[27] F. Atyabi, H. L. Sharma, H.A.H. Mohammad et. al,In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins, J. Controlled. Release, 1996;42:105~113
[28] J. Timmermans and A. J. Moes. Factors controlling the buoyancy and gastric rentention capabilities of floating matix capsules: New data for reconsidering the controversy. J. Pharm. Sci. 1994,83(1):18~24
[29] R. Groning, M. Merner and M. georgarakis. Acyclovir serum concentration following peroral administration of a magnetic depot tablets and influence of extracorporal magnets to control gastrointestinal transit, Eur. J. Pharm. Biopharm. 1998;46:285~291
[30] G.M.Clarke, J.M.Newton, M.B.Short, Comparative gastrointestinal transit of pellet systems of varying density, Int. J. Pharm, 1995;114:1~11
[31] N.Mazer,E. Abisch, J.C.gfeller et.al, Intragastric behavior and absorption kinetics of a normal and floating modified-release of isradipine under fasted and fed consitions, J. Pharm. Sci,1988;77(8):647~657
[32] J.L.Tossunian,W.J.Mergens and P.R.Sheth. Bioefficient products: A novel delivery system, Drug Dev. Ind. Pharm. 1985;11(5):1019~1050
[33] J. Timmermans and A.J.Moes, How well do floating dosage forms float? Int. J. Pharm. 1990;62:207~216
[34] 奚念朱主编 药剂学,第三版,北京,人民卫生出版社,1980:318~320
[35] 邹豪,马伯良,郭涛,等 盐酸维拉帕米脉冲释放片的研究 药学学报 1999,34(11):862-7
[36] Zouhao,Ma boliang, Jiang xuetao, et al,Design and preparation of press-coated tablets for pulsed release of verapamil. J Med Coll PLA 1999;14(4):266~269
[37] P.R.Sheth, and J.Tossounian. Thehydrodynamically balanced system (HBS): a novel drug delivery system for oral use. Drug Dev. Ind. Pharm. 1984;10(2):313~339
[38]朱盛山主编 药物新剂型 北京,化学工业出版社 2003:236~239
[39] Polli JE,Rekhi GS,Augsburger LL,et al. Methods to compare dissolution profiles and a rational for wide dissolution specifications for Metoprolol Tartrate tablets. J. Pharm. Sci. 1997,86(6):690
[40] 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. 中国药学杂志. 2000,35(2):130
[41] Pillay V,Fassihi R. Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternatibe method. J control Rel 1998,55(1):45
[42] Guidance for Industry: Immediate release solid oral dosage forms :Scale–up and post–approval changes (SUPACIR): Chemistry,Manufacturing and Controls, In vitro dissolution testing, and in vivo bioequivalence documentation .US Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research , November 1995.
[43] Human Medicines Evaluation Unit, EMEA ,Notes for guidance on quality of modified release products :A. Oral dosage forms ;B. Transdermal dosage forms ;Section I (Quality ) ,1999
[44] Moore JW,Flanner HH. Mathematical comparison of dissolution profiles. Pharm Technol 1996,20(1):64
[45] Pozzi F., Furlani P., Gazzaniga A. et al. The time clock system: a new oral dosage form for the fast and complete release of drug after a predetermined lag time. J. of control release, 1994; 31(1):99～108
[46] 罗明生,高天惠 主编. 药剂辅料大全. 成都:四川科学技术出版社 1995年.
[47] Ian R Wilding ,S.S. Davis ,Massoud Bakhshaee et.al. Gastrointestinal transit and systemic absorption of captopril from a pulsed-release formulation. Pharm. Res. 1992;9(5):654-657
[48] Brahma N. Singh, Kwon H. Kim Floating drug delivery systems: an approach to oral controlled
drug delivery via gastric retention J. of control release 2000;63:235–259
[49] V.S. Gerogiannis, D.M. Rekkas, P.P. Dallas, Floating and swelling characteristics of various excipients used in controlled release technology, Drug Dev. Ind. Pharm. 1993;19:1061–1081.
[50] M. Oth, M. Franz, J. Timmermans, A. Moes, The bilayer floating capsule: a stomach-directed drug delivery system for misoprostol, Pharm. Res. 1992; 9: 298–302.
[51] J. Timmermans, B. Van Gansbeke, A.J. Moes, Assessing by gamma scintigraphy the in vivo buoyancy of dosage forms known size and floating force profiles as a function of Proc. 5th Int. Conf. Pharm. Technol., vol. I, APGI, Paris, 1989, 42–51.
[52] N. Mazer, E. Abisch, J.C. Gfeller, R. Laplanche, P. Bauerfeind, M. Cucala, M. Lukachich, A. Blum, Intragastric behavior and absorption kinetics of a normal and ‘floating’ modified-release capsule of isradipine under fasted and fed conditions, J. Pharm. Sci. 1988; (8) :647–657.
[53] G.A. Agyilirah, M. Green, R. DuCret, G.S. Banker, Evaluation of the gastric retention properties of a cross-linked polymer coated tablet versus those of a non-disintegrating tablet, Int. J. Pharm. 1991; 75:241–247.
[54] S. Sangekar, W.A. Vadino, I. Chaudry, A. Parr, R. Beihn, G. Digenis, Evaluation of the effect of food and specific gravity of tablets on gastric retention time, Int. J. Pharm. 1987;35:187–191.
[55] S. Desai, S. Bolton, A floating controlled-release drug delivery systems: in vitro–in vivo evaluation, Pharm. Res. 1993;10:1321–1325.
[56] H.M. Ingani, J. Timmermans, A.J. Moes, Conception and in vivo investigation of peroral sustained release floating dosage forms with enhanced gastrointestinal transit, Int. J. Pharm. 1987; 35:157–164.
[57] M.R. Franz, M.P. Oth, Sustained release, bilayer buoyant dosage form, US Patent 5, 232, 704, August 3, 1993.
[58] M. Ichikawa, S. Watanabe, Y. Miyake, A new multiple-unit oral floating dosage systems. I: Preparation and in vitro evaluation of floating and sustained-release characteristics, J. Pharm. Sci. 1991;80:1062–1066.
[59] K. Asrani, Evaluation of bioadhesive properties of poly(acrylic acid) polymers and design of a novel floating bioadhesive drug delivery system, Doctoral thesis, St. John’s University, Jamaica, NY, 1994.
[60] A.O. Nur and Jun S. Zhang, Captoptil floating and/or bioadhesive tablets: Design and drug release kinetics. Drug Dev. Ind. Pharm. 2000;26(9):965~969
[61] M.R. Jimenez-Castellanos, H. Zia and C.T. Rhodes, Design and testing in vitro of a bioadhesive and floating drug delivery for oral application, Int. J. Pharm. 1994;105:65~70
[62] N.Ozdemir,S.Ordu and Y. Ozkan, Studies of floating dosage forms of fursemide: In vitro and in vivo evaluations of bilayer tablet formulation, Drug Dev. Ind. Pharm. 2000;26(8):857~866
[63] B.C. Thanoo, M.C. Sunny and A. jayakrishnan, Oral sustained-release drug delivery systems using polycabornate microsphere capable of floating on the gastric fluid, J. Pharm. Pharmacol. 1993;45:21~24
[64] A.S. Michaels, J.D. Bashwa, A. Zaffaroni, Integrated device for administering beneficial drug at programmed rate, US Patent 3, 901, 232, August 26, 1975.
[65] A.S. Michaels, Drug delivery device with self actuated mechanism for retaining device in selected area, US Patent 3, 786, 813, January 22, 1974.
[66] Tobyn MJ, Johnson JR, Dettmar PW. Factors affecting in vitro gastric mucoadhesion I. Test conditions and instrumental parameters. Eur J Pharm Biopharm, 1995;41(4):235-241.
[67] 陈夏景,王浩,贺芬等. 芬太尼口腔粘附片的处方研究. 中国医药工业杂志,1997;8 (3): 129-131.
[68] Blanco-Fuente H,Anguiano-Igeas, Otero-Espinar FJ. In vitro bioadhesive of carbopol hydrogels. Int J Pharm, 1996;142(3):169-174.
[69] Garcia,J.J. Aramayona,M.A. Bregante , et.al. Simultaneous determination of verapamil and norverapamil in biological samples by high-performance liquid chromatography using ultraviolet detection. J.Chromatogr. B. 1997;693(2):377-382
[70] Ph. Hubert and J.Crommon. HPLC determination of verapamil and norverapamil in plasma using automated solid phase extraction for sample preparation and fluorometric detection J. Liquid Chromatogr. 1994;17(10):2147～2170
[71] Darina Romanova. Determination of verapamil and its metabolites in plasma using HPLC. Die Pharmazie. 1994; 49(H10): 779～2170
[72] Wieslaw Sawicki, A validated method for the determination of verapamil and norverapamil in human plasma. J. pharm. Biomed. Anal. 2001;25:689~695
[74] C.A. Lau-Cam, D. Piemontese, Sinplified reversed-phase HPLC method with spectrophotometric detection for the assay of verapamil in rat plasma. J. pharm. Biomed. Anal. 1998;16:1029~1035
[2] P. Colombo, U. Conte, A. Gazzaniga, et al. Drug release modulation by physical restrictions of matrix swelling, Int. J. Pharm. 1990,63:43-48
[3] P. Colombo, P.L.Catellani, N.A. Peppas, et. al Swelling characteristics of hydrophilic matrices for controlled release: new dimensionless number to describe the swelling and release behavior, Int. J. Pharm. 1992,88:99-109
[4]I. Krogel, R. Bodmeier Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinde J. Control. Release 1999,61:43-50
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[17]J.Binns,H.N.E.Stevens,J.McEwen, et. al. The tolerability of multiple oral doses of PulsincapTM capsules in healthy volunteers. J. Control. Release. 1996;38:151-158
[18] Takadai K. Controlled-release preparations. US Patent: 5637319,1997-06-10
[19] Hofmann AF,Pressman JH,Code CF et.al Controlled entry of orally administed drugs:physiological considerations. Drug Devel. Ind. Pharm. 1983;9(7):1077-1079
[20] Sheth P.R,Tossouinion J. The hydrodynamically balanced system (HBSTM) :A novel drug delivery system for oral use . Drug. Devel. Ind. Pharm. 1984; 10(2):313-339
[21] 石明德,高汝荔,候惠民.等. 漂浮片剂在胃内的初步动态观察. 中国医药工业杂志 1990;21(4):162-164
[22] F.Pozzi,P. Furlani,A. Gazzaniga et.al. The Time Clock system:a new oral dosage form for fast and complete release of drug after a predetermined lag time. J. controlled release. 1994;31(1):99-108
[23] S.S. Davis,J.G. Hardy and J.W. Fara. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27:886-892
[24] 邹豪,蒋雪涛,尚玉琨等,r-示综扫描照相术观察脉冲释放片在体内的释放 实用核医学杂志2001,17(12):881
[25] 邹豪,马伯良,蒋雪涛等,盐酸维拉帕米脉冲释放片的设计和制备 第二军医大学学报 1999,20(4):256-8
[26] 邹豪,郭涛,蒋雪涛等,盐酸维拉帕米脉冲释放片人体内药代动力学及生物利用度研究 第二军医大学学报2000,21(10):977
[27] F. Atyabi, H. L. Sharma, H.A.H. Mohammad et. al,In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins, J. Controlled. Release, 1996;42:105~113
[28] J. Timmermans and A. J. Moes. Factors controlling the buoyancy and gastric rentention capabilities of floating matix capsules: New data for reconsidering the controversy. J. Pharm. Sci. 1994,83(1):18~24
[29] R. Groning, M. Merner and M. georgarakis. Acyclovir serum concentration following peroral administration of a magnetic depot tablets and influence of extracorporal magnets to control gastrointestinal transit, Eur. J. Pharm. Biopharm. 1998;46:285~291
[30] G.M.Clarke, J.M.Newton, M.B.Short, Comparative gastrointestinal transit of pellet systems of varying density, Int. J. Pharm, 1995;114:1~11
[31] N.Mazer,E. Abisch, J.C.gfeller et.al, Intragastric behavior and absorption kinetics of a normal and floating modified-release of isradipine under fasted and fed consitions, J. Pharm. Sci,1988;77(8):647~657
[32] J.L.Tossunian,W.J.Mergens and P.R.Sheth. Bioefficient products: A novel delivery system, Drug Dev. Ind. Pharm. 1985;11(5):1019~1050
[33] J. Timmermans and A.J.Moes, How well do floating dosage forms float? Int. J. Pharm. 1990;62:207~216
[34] 奚念朱主编 药剂学,第三版,北京,人民卫生出版社,1980:318~320
[35] 邹豪,马伯良,郭涛,等 盐酸维拉帕米脉冲释放片的研究 药学学报 1999,34(11):862-7
[36] Zouhao,Ma boliang, Jiang xuetao, et al,Design and preparation of press-coated tablets for pulsed release of verapamil. J Med Coll PLA 1999;14(4):266~269
[37] P.R.Sheth, and J.Tossounian. Thehydrodynamically balanced system (HBS): a novel drug delivery system for oral use. Drug Dev. Ind. Pharm. 1984;10(2):313~339
[38]朱盛山主编 药物新剂型 北京,化学工业出版社 2003:236~239
[39] Polli JE,Rekhi GS,Augsburger LL,et al. Methods to compare dissolution profiles and a rational for wide dissolution specifications for Metoprolol Tartrate tablets. J. Pharm. Sci. 1997,86(6):690
[40] 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. 中国药学杂志. 2000,35(2):130
[41] Pillay V,Fassihi R. Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternatibe method. J control Rel 1998,55(1):45
[42] Guidance for Industry: Immediate release solid oral dosage forms :Scale–up and post–approval changes (SUPACIR): Chemistry,Manufacturing and Controls, In vitro dissolution testing, and in vivo bioequivalence documentation .US Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research , November 1995.
[43] Human Medicines Evaluation Unit, EMEA ,Notes for guidance on quality of modified release products :A. Oral dosage forms ;B. Transdermal dosage forms ;Section I (Quality ) ,1999
[44] Moore JW,Flanner HH. Mathematical comparison of dissolution profiles. Pharm Technol 1996,20(1):64
[45] Pozzi F., Furlani P., Gazzaniga A. et al. The time clock system: a new oral dosage form for the fast and complete release of drug after a predetermined lag time. J. of control release, 1994; 31(1):99～108
[46] 罗明生,高天惠 主编. 药剂辅料大全. 成都:四川科学技术出版社 1995年.
[47] Ian R Wilding ,S.S. Davis ,Massoud Bakhshaee et.al. Gastrointestinal transit and systemic absorption of captopril from a pulsed-release formulation. Pharm. Res. 1992;9(5):654-657
[48] Brahma N. Singh, Kwon H. Kim Floating drug delivery systems: an approach to oral controlled
drug delivery via gastric retention J. of control release 2000;63:235–259
[49] V.S. Gerogiannis, D.M. Rekkas, P.P. Dallas, Floating and swelling characteristics of various excipients used in controlled release technology, Drug Dev. Ind. Pharm. 1993;19:1061–1081.
[50] M. Oth, M. Franz, J. Timmermans, A. Moes, The bilayer floating capsule: a stomach-directed drug delivery system for misoprostol, Pharm. Res. 1992; 9: 298–302.
[51] J. Timmermans, B. Van Gansbeke, A.J. Moes, Assessing by gamma scintigraphy the in vivo buoyancy of dosage forms known size and floating force profiles as a function of Proc. 5th Int. Conf. Pharm. Technol., vol. I, APGI, Paris, 1989, 42–51.
[52] N. Mazer, E. Abisch, J.C. Gfeller, R. Laplanche, P. Bauerfeind, M. Cucala, M. Lukachich, A. Blum, Intragastric behavior and absorption kinetics of a normal and ‘floating’ modified-release capsule of isradipine under fasted and fed conditions, J. Pharm. Sci. 1988; (8) :647–657.
[53] G.A. Agyilirah, M. Green, R. DuCret, G.S. Banker, Evaluation of the gastric retention properties of a cross-linked polymer coated tablet versus those of a non-disintegrating tablet, Int. J. Pharm. 1991; 75:241–247.
[54] S. Sangekar, W.A. Vadino, I. Chaudry, A. Parr, R. Beihn, G. Digenis, Evaluation of the effect of food and specific gravity of tablets on gastric retention time, Int. J. Pharm. 1987;35:187–191.
[55] S. Desai, S. Bolton, A floating controlled-release drug delivery systems: in vitro–in vivo evaluation, Pharm. Res. 1993;10:1321–1325.
[56] H.M. Ingani, J. Timmermans, A.J. Moes, Conception and in vivo investigation of peroral sustained release floating dosage forms with enhanced gastrointestinal transit, Int. J. Pharm. 1987; 35:157–164.
[57] M.R. Franz, M.P. Oth, Sustained release, bilayer buoyant dosage form, US Patent 5, 232, 704, August 3, 1993.
[58] M. Ichikawa, S. Watanabe, Y. Miyake, A new multiple-unit oral floating dosage systems. I: Preparation and in vitro evaluation of floating and sustained-release characteristics, J. Pharm. Sci. 1991;80:1062–1066.
[59] K. Asrani, Evaluation of bioadhesive properties of poly(acrylic acid) polymers and design of a novel floating bioadhesive drug delivery system, Doctoral thesis, St. John’s University, Jamaica, NY, 1994.
[60] A.O. Nur and Jun S. Zhang, Captoptil floating and/or bioadhesive tablets: Design and drug release kinetics. Drug Dev. Ind. Pharm. 2000;26(9):965~969
[61] M.R. Jimenez-Castellanos, H. Zia and C.T. Rhodes, Design and testing in vitro of a bioadhesive and floating drug delivery for oral application, Int. J. Pharm. 1994;105:65~70
[62] N.Ozdemir,S.Ordu and Y. Ozkan, Studies of floating dosage forms of fursemide: In vitro and in vivo evaluations of bilayer tablet formulation, Drug Dev. Ind. Pharm. 2000;26(8):857~866
[63] B.C. Thanoo, M.C. Sunny and A. jayakrishnan, Oral sustained-release drug delivery systems using polycabornate microsphere capable of floating on the gastric fluid, J. Pharm. Pharmacol. 1993;45:21~24
[64] A.S. Michaels, J.D. Bashwa, A. Zaffaroni, Integrated device for administering beneficial drug at programmed rate, US Patent 3, 901, 232, August 26, 1975.
[65] A.S. Michaels, Drug delivery device with self actuated mechanism for retaining device in selected area, US Patent 3, 786, 813, January 22, 1974.
[66] Tobyn MJ, Johnson JR, Dettmar PW. Factors affecting in vitro gastric mucoadhesion I. Test conditions and instrumental parameters. Eur J Pharm Biopharm, 1995;41(4):235-241.
[67] 陈夏景,王浩,贺芬等. 芬太尼口腔粘附片的处方研究. 中国医药工业杂志,1997;8 (3): 129-131.
[68] Blanco-Fuente H,Anguiano-Igeas, Otero-Espinar FJ. In vitro bioadhesive of carbopol hydrogels. Int J Pharm, 1996;142(3):169-174.
[69] Garcia,J.J. Aramayona,M.A. Bregante , et.al. Simultaneous determination of verapamil and norverapamil in biological samples by high-performance liquid chromatography using ultraviolet detection. J.Chromatogr. B. 1997;693(2):377-382
[70] Ph. Hubert and J.Crommon. HPLC determination of verapamil and norverapamil in plasma using automated solid phase extraction for sample preparation and fluorometric detection J. Liquid Chromatogr. 1994;17(10):2147～2170
[71] Darina Romanova. Determination of verapamil and its metabolites in plasma using HPLC. Die Pharmazie. 1994; 49(H10): 779～2170
[72] Wieslaw Sawicki, A validated method for the determination of verapamil and norverapamil in human plasma. J. pharm. Biomed. Anal. 2001;25:689~695
[74] C.A. Lau-Cam, D. Piemontese, Sinplified reversed-phase HPLC method with spectrophotometric detection for the assay of verapamil in rat plasma. J. pharm. Biomed. Anal. 1998;16:1029~1035