法莫替丁口服脉冲控释微丸的研究
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摘要
随着时间生物学的发展，人们认识到人体的许多生理现象如血压、
心率、肾功能、胃酸分泌以及某些疾病如高血压、哮喘、风湿性关节
炎等均具有节律性。定时给药系统可以根据人体需要释放药物，通过
按需给药达到最佳疗效。本文以法莫替丁为模型药物，根据人体在晚
间21：00～22：00间胃酸分泌达高峰的生理节律，制备了日服一次，释药
两次的法莫替丁脉冲控释微丸胶囊剂。
建立了紫外分光光度法用于法莫替丁的制剂含量、释放度及基本
性质的测定。对与处方设计密切相关的原料药的一些性质进行了考察。
由所测表观油/水分配系数结果可知，法莫替丁脂溶性很小，故在文献
报道的基础上，采用固相萃取的方法提取血样中的法莫替丁，建立了
高效液相色谱法检测体内血药浓度，此法灵敏度高、专属性强、绝对
回收率较高。
采用大鼠在体回流实验方法研究了法莫替丁在肠道的吸收情况。
其于十二指肠、空肠、回肠和结肠的吸收速率常数分别为0.0541h~(-1)，
0.0518h~(-1)，0.0500h~(-1)，0.0467h~(-1)，各值间无明显差别；并初步推断法莫替
丁在大鼠体内主要以被动扩散方式吸收。故制成定时释放制剂是可行
的。
本制剂分为两部分。速释微丸由挤出滚圆造粒机直接制得，本文
对其工艺进行了优化。定时释放微丸制剂采用有机酸诱导机制，即在
丸芯中加入有机酸，外层用水不溶性膜材进行包衣。丸芯亦由挤出滚
圆法制得，微丸的包衣采用微型流化床包衣机，本文对其工艺进行了
考察。由于定时释放微丸的释药行为由丸芯中有机酸与外层衣膜共同
决定，故处方设计需同时兼顾这两方面。在单因素考察的基础上，应
用L_9(3~4)正交设计试验优化处方，筛选出了符合要求的定时释放微丸制
剂。将速释微丸与定时释放微丸按剂量混合后装入胶囊，制成了可释
沈阳药科大学硕士学位论文 摘要
药两次的法莫替丁脉冲控释微丸制剂。
本文对法莫替丁定时释放微丸的释药动力学进行了研究，其体外
释放行为符合零级动力学过程。包衣小丸属膜控型释药系统，释药机
制是通过连续膜的溶解／扩散和通过水性通道的扩散共同起作用。定时
释放微丸为有机酸诱导型给药系统，其体外溶出曲线为典型的“ S”型
曲线，即药物在初期一段时间内不释放，之后再快速释放出来。本文
上 通过大量实验对产生此种释药行为的机理进行了探讨。
本文以普通片为对照，利用HPLC法分别测定了三名健康受试者
口服法莫替丁定时释放微丸胶囊剂与脉冲控释微丸胶囊剂的药时曲线
并计算了药动学参数和相对生物利用度。定时释药微丸的时滞显著增
加，达峰时间明显滞后，说明其在体内具有显著的定时释放作用，相
对生物利用度为95．22％。脉冲控释微丸胶囊剂的药时曲线出现双峰（第
一次为速释微丸所致，第二次为定时释放微丸所致），达峰时间分别
为1．sh及12h，达峰浓度分另为82．1及44．3ng／ml，相对生物禾用度为
93．83％。体内外相关性结果表明，定时释放微丸胶囊剂的体外释放百
分率与体内吸收百分率间具有较好的相关性O＝0．9869卜
With the development of chronobiology ,it is realized that many physiological phenomena such as blood pressure ,heart-beating rate, gastric acid secretion and many disease symptoms such as hypertension, asthma, rheumatic arthritis exhibit circadian rhythms. Time-controlled delivery system releases drug and achieves an effective drug level at the required time so that optimum therapy can be obtained.
According to the fact that gastric acid secretion reaches its climax at 21:00?2:00 in the evening, we prepared an orally applicable time-controlled release capsule(TRC)using famotidine as the model drug, which was administered in the morning while reaching plasma concentration climax in the evening. At the same time, we prepared normal pellets which released drug immediately after administration. The two types of pellets were put into one capsule together in proportion in order to prepare famotidine pulsed release capsule(PRC)which released drug two times a day while being administered only once.
Ultraviolet spectrophotomatry method was developed for assay during the study of physicochemical properties, content and drug release. Some physicochemical properties of famotidine were investigated, which were connected closely with phannaceutic form design. In order to increase extraction recovery, we use solid phase extraction (SPE)to extract famotidine from human plasma. Precise and reliable HPLC method was developed for in vivo assay.
To clarify the absorption of famotidine from gastrointestine, the absorption was studied by utilizing the rat intestinal absorption recirculating method in situ. No significant difference of value of Ka was absorbed among duodenum, jejunum, ileum and colon. The mechanism of intestinal absorption was studied with different drug concentrations, which suggested that the intestinal absorption of famotidine was via passive transport mechanism.
The pharmaceutic form design was devided into two parts. Nomal pellets
3
ABSTRACT
were prepared by extrusion-spheronization. Time-controlled release pellets were 搊rganic acid-induced type drug delivery system? The core pellets, which contained organic acid, were prepared by extrusion-spheronization also and the coating process was performed on a mini-fluidized bed spray coater. Because the drug release behavior was dependent on both organic acid and the polymer, orthogonal design test was used to obtain optimal formulation. We also studied some factors which affected the release of the drug from the time-controlled release pellets.
The release profile of TRC pellets in vitro complied with zero order kinetics. The coated pellets were film-controlled release sysf em. The organic acidinduced drug delivery system has a typical sigmodical release profile which achieved a prolonged lag time, followed by rapid release. We studied the drug release mechanism on the basis of lots of experiment results.
Plasma concentration-time profiles in three healthy volunteers after oral administration of TRC, PRC and normal pellets were determined by HPLC and the pharinacokinetic parameters of the three types of formulations were calculated. The lag time of TRC was dramatically prolonged and t~ was obviously delayed, indicating that TRC had positive effect of time-controlled release system. The plasma concentration-time profiles of PRC had two peaks. T,~1 and tm~2 were 1.5h and 12h. Cmaxi and Cm~ were 82.1 ng/ml and 44.3 nglml. The comparative bioavailabiity were 95.22% and 93.83% .Obvious correlation (r=O.9869) existed between absorption fraction in vivo and the release percentage in vitro.
心率、肾功能、胃酸分泌以及某些疾病如高血压、哮喘、风湿性关节
炎等均具有节律性。定时给药系统可以根据人体需要释放药物，通过
按需给药达到最佳疗效。本文以法莫替丁为模型药物，根据人体在晚
间21：00～22：00间胃酸分泌达高峰的生理节律，制备了日服一次，释药
两次的法莫替丁脉冲控释微丸胶囊剂。
建立了紫外分光光度法用于法莫替丁的制剂含量、释放度及基本
性质的测定。对与处方设计密切相关的原料药的一些性质进行了考察。
由所测表观油/水分配系数结果可知，法莫替丁脂溶性很小，故在文献
报道的基础上，采用固相萃取的方法提取血样中的法莫替丁，建立了
高效液相色谱法检测体内血药浓度，此法灵敏度高、专属性强、绝对
回收率较高。
采用大鼠在体回流实验方法研究了法莫替丁在肠道的吸收情况。
其于十二指肠、空肠、回肠和结肠的吸收速率常数分别为0.0541h~(-1)，
0.0518h~(-1)，0.0500h~(-1)，0.0467h~(-1)，各值间无明显差别；并初步推断法莫替
丁在大鼠体内主要以被动扩散方式吸收。故制成定时释放制剂是可行
的。
本制剂分为两部分。速释微丸由挤出滚圆造粒机直接制得，本文
对其工艺进行了优化。定时释放微丸制剂采用有机酸诱导机制，即在
丸芯中加入有机酸，外层用水不溶性膜材进行包衣。丸芯亦由挤出滚
圆法制得，微丸的包衣采用微型流化床包衣机，本文对其工艺进行了
考察。由于定时释放微丸的释药行为由丸芯中有机酸与外层衣膜共同
决定，故处方设计需同时兼顾这两方面。在单因素考察的基础上，应
用L_9(3~4)正交设计试验优化处方，筛选出了符合要求的定时释放微丸制
剂。将速释微丸与定时释放微丸按剂量混合后装入胶囊，制成了可释
沈阳药科大学硕士学位论文 摘要
药两次的法莫替丁脉冲控释微丸制剂。
本文对法莫替丁定时释放微丸的释药动力学进行了研究，其体外
释放行为符合零级动力学过程。包衣小丸属膜控型释药系统，释药机
制是通过连续膜的溶解／扩散和通过水性通道的扩散共同起作用。定时
释放微丸为有机酸诱导型给药系统，其体外溶出曲线为典型的“ S”型
曲线，即药物在初期一段时间内不释放，之后再快速释放出来。本文
上 通过大量实验对产生此种释药行为的机理进行了探讨。
本文以普通片为对照，利用HPLC法分别测定了三名健康受试者
口服法莫替丁定时释放微丸胶囊剂与脉冲控释微丸胶囊剂的药时曲线
并计算了药动学参数和相对生物利用度。定时释药微丸的时滞显著增
加，达峰时间明显滞后，说明其在体内具有显著的定时释放作用，相
对生物利用度为95．22％。脉冲控释微丸胶囊剂的药时曲线出现双峰（第
一次为速释微丸所致，第二次为定时释放微丸所致），达峰时间分别
为1．sh及12h，达峰浓度分另为82．1及44．3ng／ml，相对生物禾用度为
93．83％。体内外相关性结果表明，定时释放微丸胶囊剂的体外释放百
分率与体内吸收百分率间具有较好的相关性O＝0．9869卜
With the development of chronobiology ,it is realized that many physiological phenomena such as blood pressure ,heart-beating rate, gastric acid secretion and many disease symptoms such as hypertension, asthma, rheumatic arthritis exhibit circadian rhythms. Time-controlled delivery system releases drug and achieves an effective drug level at the required time so that optimum therapy can be obtained.
According to the fact that gastric acid secretion reaches its climax at 21:00?2:00 in the evening, we prepared an orally applicable time-controlled release capsule(TRC)using famotidine as the model drug, which was administered in the morning while reaching plasma concentration climax in the evening. At the same time, we prepared normal pellets which released drug immediately after administration. The two types of pellets were put into one capsule together in proportion in order to prepare famotidine pulsed release capsule(PRC)which released drug two times a day while being administered only once.
Ultraviolet spectrophotomatry method was developed for assay during the study of physicochemical properties, content and drug release. Some physicochemical properties of famotidine were investigated, which were connected closely with phannaceutic form design. In order to increase extraction recovery, we use solid phase extraction (SPE)to extract famotidine from human plasma. Precise and reliable HPLC method was developed for in vivo assay.
To clarify the absorption of famotidine from gastrointestine, the absorption was studied by utilizing the rat intestinal absorption recirculating method in situ. No significant difference of value of Ka was absorbed among duodenum, jejunum, ileum and colon. The mechanism of intestinal absorption was studied with different drug concentrations, which suggested that the intestinal absorption of famotidine was via passive transport mechanism.
The pharmaceutic form design was devided into two parts. Nomal pellets
3
ABSTRACT
were prepared by extrusion-spheronization. Time-controlled release pellets were 搊rganic acid-induced type drug delivery system? The core pellets, which contained organic acid, were prepared by extrusion-spheronization also and the coating process was performed on a mini-fluidized bed spray coater. Because the drug release behavior was dependent on both organic acid and the polymer, orthogonal design test was used to obtain optimal formulation. We also studied some factors which affected the release of the drug from the time-controlled release pellets.
The release profile of TRC pellets in vitro complied with zero order kinetics. The coated pellets were film-controlled release sysf em. The organic acidinduced drug delivery system has a typical sigmodical release profile which achieved a prolonged lag time, followed by rapid release. We studied the drug release mechanism on the basis of lots of experiment results.
Plasma concentration-time profiles in three healthy volunteers after oral administration of TRC, PRC and normal pellets were determined by HPLC and the pharinacokinetic parameters of the three types of formulations were calculated. The lag time of TRC was dramatically prolonged and t~ was obviously delayed, indicating that TRC had positive effect of time-controlled release system. The plasma concentration-time profiles of PRC had two peaks. T,~1 and tm~2 were 1.5h and 12h. Cmaxi and Cm~ were 82.1 ng/ml and 44.3 nglml. The comparative bioavailabiity were 95.22% and 93.83% .Obvious correlation (r=O.9869) existed between absorption fraction in vivo and the release percentage in vitro.
引文
[1] 张静，平其能．口服择时释药系统．药学进展，1999，23(5)：265～269
[2] Ryuzo Ishino, Hisoyuki Yoshino, Yoshiyuki Hirakawa. Design and preparation of pulsatile release tablet as a new oral delivery system. Chem Pharm Bull, 1992, 40(11): 3036～3041
[3] 张强．脉冲定时给药系统的研究与应用．科技部生命科学技术发展中心主办 第四届中国新医药博士论坛论文集(摘要)．北京：1999：15～18
[4] Pozzi F, Furlani P, Dazzaninga A, et al. The time clock system: a new oral dosage form for fast and complete release of drug after a predetermined lagtime. J Controlled Release, 1994, 31(1): 99～104
[5] Ishino R, Yoshino H, Hirakana Y, et al. Absorption of diltiazem in beagle dog from pulsatile release tablet. Chem Pharm Bull, 1992, 40(11): 3049～3055
[6] Binns J, Steve H, Mewen J, et al. The tolerability of multiple oral doses of pulsincap capsules in healthy volunteers. J Controlled Release, 1996, 38: 151～157
[7] Schmltz Peter, kleinebudde Peter. A new multiparticulate delayed release system. Part Ⅰ: Dissolution properties and release mechanism. J Controlled Release, 1997, 47(2): 181～189
[8] 钱方，蒋雪涛，王安文．微丸的进展．中国医药工业杂志，1996，27(1)：41～46
[9] 龙孝庆，卢丹，许美蓉．缓释微丸工业研究．中国医药工业杂志，1996，27(4)：163～165
[10] Ueda S, Yamaguchi H, Kotani M, et al. Development of a novel drug release system: time-controlled explosion system (TES). Chem Pharm Bull, 1994, 42(2): 359～363
[11] 郝钦，岗艳云，朱家壁．硝酸异山梨酯脉冲控释微丸的研制．中国医药工业杂志，1999，30(3)：109～112
[12] Narisawa S, Nagata M, Danyoshi C, et al. An organic acid-induced sigmoidal release system for oral controlled-release preparations. Pharm Res, 1994, 1(1): 111～116
[13] 徐葆元．法莫替丁—强效H_2受体拮抗剂．重庆医药，1988，17(5)：34～35
[14] 谢红光，周宏灏．法莫替丁的抗溃疡作用与临床应用．湖南医学，1992，9(4)：225～226
[15] 徐传福，尚福堂，戴承钰．一种新的组胺H_2受体阻滞剂—法莫替丁．中国医院药学杂志，1988，8(11)：526～527
[16] 何绍雄编．时间药理学与时间治疗学．天津：天津科学技术出版社，1994：192
[17] Lemmer B. Implications of Chronopharmacokinetics for drug delivery: antiasthmatics, H_2-blockers and cardiovascular active drugs. Adv Drug Deliv Rev, 1991, 1:83
[18] 曾环想，潘卫三，陈济民．法莫替丁缓释片的制备工艺及体外释放特性的研究．中国药学杂志，1997，32(4)：213～216
[19] 卢铮，陈济民．HPLC法测定人血浆中法莫替丁的浓度．药物分析杂志，1997，17(2)：107～109
[20] 曾环想，陈静，吴涛．法莫替丁缓释片的生物利用度研究．中国药学杂志，1999，34(8)：545～549
[21] W.C.Vincek. Analytical method for the quantification of famotidine, an H_2-receptor blocker, in plasma and urine. J Chromatogra, 1985, 338(2): 438～443
[22] 李惠明，宣坚钢．法莫替丁片的紫外分光光度测定法．中国医药工业杂志，1993，24(7)：319～321
[23] Naji M. Najib, Mohammad S. Suleiman. Determination of some parameters influencing the dissolution rate of famotidine. Int J Pharm,1990, 61(3): 173～178
[24] 李发美主编．医药高效液相色谱技术．北京：人民卫生出版社，1999：488～489
[25] Yasuhiko Imai, Shin-ichiro Kobayashi. A simple method for quantification of famotidine in human plasma and urine by paired-ion HPLC. Biomedical Chromatogra, 1992, 6:222～223
[26] Wanwimolnik, A.R.Zoert. Sensitive HPLC determination of famotidine in plasma. J Chromatogra, 1991, 372:227～238
[27] Schurger N, Bijdendijk J, Tukker JJ. Comparison of four experimental techniques for studing drug absorption kinetics in the anesthetized rat in situ. J Pharm Sci, 1986, 75(2): 117～128
[28] Artursson P, karisson J. Correlation between oral drug absorption in humans and apparent drug permeability cofficients in human intestinal epithelial(caco-2)cells. Biochem Biophys Res Commun, 1991,175(3): 880～885
[29] 陆彬主编．药剂学实验．北京：人民卫生出版社，1994：131～135
[30] 毛凤斐，屠锡德，朱家壁．黄芩甙大鼠小肠吸收研究．南京药学院，1984，15(1)：61～66
[31] 何力，何进．大蒜油及其包合物小肠吸收的研究．药物实践杂志，1997，15(3)：154～157
[32] 黄志宏，方积乾主编．数理统计方法．北京：人民卫生出版社，1987：143～147
[33] 林田敏部，有田隆一著编，朱家壁译．生物药剂学．北京：人民卫生出版社，1979：37
[34] 胡一桥，Josef T. Ramipril．在大鼠小肠内转运机制的研究．中国药科大学学报，1993，24(6)：338～344
[35] L．拉赫曼，H．A．利伯曼，J．L．卡凡希主编．北京医学院药学系译．工业药剂学理论与实践．北京：化学工业出版社，1984：72～73
[36] 杨正管，朱家壁，岗艳云．盐酸地尔硫卓大鼠肠吸收动力学及在口服缓释制剂设计的意义．中国药科大学学报，1998，29(3)：179～182
[37] Berardi RR, Rogers HJ, Morrisom PJ, et al. Comparison of famotidine with omitidine and ranitidine. Clin Pharm, 1988, 14(5): 271～284
[38] 平其能主编．现代药剂学．北京：中国医药科技出版社，1998：472
[39] Yuen KH, Deshmukh AA, Newton JM, et al. Gastrointestinal transit and absorption of theophylline from a multiparticulate controlled release formulation. Int J Pharm, 1993, 97:61～77
[40] 莫韫，张钧寿．结肠靶向给药系统研究进展．中国新药杂志，1999，8(6)：368～371
[41] 包泳初，陈庆华，刘伟伦，等．挤出滚圆法制备药用微丸Ⅱ．制备工艺．中国医药工业杂志，1999，30(1)：18～20
[42] 陆彬主编．药物新剂型与新技术．北京：人民卫生出版社，1998：301
[43] 毕殿洲主编．药剂学．第四版．北京：人民卫生出版社，1999：76
[44] Zhang GH, Schwartz JB, Schnaare RL, et al. Bead coating Ⅱ: effect of spheronization technique on drug release from spheres. Drug Dev Ind Pharm, 1991, 17(1): 67～81
[45] 宋洪涛．复方中药麝香保心pH依赖型梯度释药微丸的研究．[学位论文]．沈阳药科大学中药制剂教研室，2001：106
[46] 陈挺译．丙烯酸聚合物在缓释制剂上的应用．罗姆公司宣传材料，2001：17
[47] 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)：130～131
[48] Baert L, Remon JP. Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion spheronization. Int J Pharm, 1993, 95:135～137
[49] 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．中国医药工业杂志，1998，29(8)：378～380
[50] Schmidt Peter C., Niemann Frank. Some factors influencing the formation and in vitro drug release from pellets prepared by extrusion/spheronization. Int J Pharm, 1995, 119(2): 203～211
[51] Judit Predah. Evaluation of mathematical models describing drug release from lipophilic matrices. Int J Pharm, 1996, 145(1): 61～64
[52] 平其能主编．现代药剂学．北京：中国医药科技出版社，1998，177～179
[53] R.S.Okor. Effect of polymer cation content on certain film properties. J Pharm Pharmacol, 1982, 34:83～86
[54] 陆彬主编．药物新剂型与新技术．北京：人民卫生出版社，1998：290～292
[55] 平其能主编．现代药剂学．北京：中国医药科技出版社，1998：501～502
[56] 陈挺译．丙烯酸聚合物在缓释制剂上的应用．罗姆公司宣传材料，2001：4
[57] 孙毓庆主编．分析化学实验．北京：人民卫生出版社：1994，67～70
[58] Shinji Narisawa, Minako Nagata, Yoshiyuki Hirakawa. An organic acidinduced sigmoidal release system for oral conorolled-release preparations. J Pharm Sci, 1996, 85(2): 184～188
[59] Jim H.Kac, Gordon L.Amidon, Ping I.Cel. PH-dependent swelling and solute diffusion characteristics of poly hydrogels. Pharm Res, 1988, 9: 592～597
[60] 郑俊民主编．药用高分子材料学．北京：中国医药科技出版社，2000：73～74
[61] 魏树礼主编．生物药剂学与药物动力学．北京：北京医科大学、中国协合医科大学联合出版社，1997：52～55
[62] 邓树海，刘兆平．药物动力学—理论与实践．北京：人民卫生出版社，1998：23～24
[63] 魏树礼主编．生物药剂学与药物动力学．北京：北京医科大学、中国协合医科大学联合出版社，1997：58～60
[2] Ryuzo Ishino, Hisoyuki Yoshino, Yoshiyuki Hirakawa. Design and preparation of pulsatile release tablet as a new oral delivery system. Chem Pharm Bull, 1992, 40(11): 3036～3041
[3] 张强．脉冲定时给药系统的研究与应用．科技部生命科学技术发展中心主办 第四届中国新医药博士论坛论文集(摘要)．北京：1999：15～18
[4] Pozzi F, Furlani P, Dazzaninga A, et al. The time clock system: a new oral dosage form for fast and complete release of drug after a predetermined lagtime. J Controlled Release, 1994, 31(1): 99～104
[5] Ishino R, Yoshino H, Hirakana Y, et al. Absorption of diltiazem in beagle dog from pulsatile release tablet. Chem Pharm Bull, 1992, 40(11): 3049～3055
[6] Binns J, Steve H, Mewen J, et al. The tolerability of multiple oral doses of pulsincap capsules in healthy volunteers. J Controlled Release, 1996, 38: 151～157
[7] Schmltz Peter, kleinebudde Peter. A new multiparticulate delayed release system. Part Ⅰ: Dissolution properties and release mechanism. J Controlled Release, 1997, 47(2): 181～189
[8] 钱方，蒋雪涛，王安文．微丸的进展．中国医药工业杂志，1996，27(1)：41～46
[9] 龙孝庆，卢丹，许美蓉．缓释微丸工业研究．中国医药工业杂志，1996，27(4)：163～165
[10] Ueda S, Yamaguchi H, Kotani M, et al. Development of a novel drug release system: time-controlled explosion system (TES). Chem Pharm Bull, 1994, 42(2): 359～363
[11] 郝钦，岗艳云，朱家壁．硝酸异山梨酯脉冲控释微丸的研制．中国医药工业杂志，1999，30(3)：109～112
[12] Narisawa S, Nagata M, Danyoshi C, et al. An organic acid-induced sigmoidal release system for oral controlled-release preparations. Pharm Res, 1994, 1(1): 111～116
[13] 徐葆元．法莫替丁—强效H_2受体拮抗剂．重庆医药，1988，17(5)：34～35
[14] 谢红光，周宏灏．法莫替丁的抗溃疡作用与临床应用．湖南医学，1992，9(4)：225～226
[15] 徐传福，尚福堂，戴承钰．一种新的组胺H_2受体阻滞剂—法莫替丁．中国医院药学杂志，1988，8(11)：526～527
[16] 何绍雄编．时间药理学与时间治疗学．天津：天津科学技术出版社，1994：192
[17] Lemmer B. Implications of Chronopharmacokinetics for drug delivery: antiasthmatics, H_2-blockers and cardiovascular active drugs. Adv Drug Deliv Rev, 1991, 1:83
[18] 曾环想，潘卫三，陈济民．法莫替丁缓释片的制备工艺及体外释放特性的研究．中国药学杂志，1997，32(4)：213～216
[19] 卢铮，陈济民．HPLC法测定人血浆中法莫替丁的浓度．药物分析杂志，1997，17(2)：107～109
[20] 曾环想，陈静，吴涛．法莫替丁缓释片的生物利用度研究．中国药学杂志，1999，34(8)：545～549
[21] W.C.Vincek. Analytical method for the quantification of famotidine, an H_2-receptor blocker, in plasma and urine. J Chromatogra, 1985, 338(2): 438～443
[22] 李惠明，宣坚钢．法莫替丁片的紫外分光光度测定法．中国医药工业杂志，1993，24(7)：319～321
[23] Naji M. Najib, Mohammad S. Suleiman. Determination of some parameters influencing the dissolution rate of famotidine. Int J Pharm,1990, 61(3): 173～178
[24] 李发美主编．医药高效液相色谱技术．北京：人民卫生出版社，1999：488～489
[25] Yasuhiko Imai, Shin-ichiro Kobayashi. A simple method for quantification of famotidine in human plasma and urine by paired-ion HPLC. Biomedical Chromatogra, 1992, 6:222～223
[26] Wanwimolnik, A.R.Zoert. Sensitive HPLC determination of famotidine in plasma. J Chromatogra, 1991, 372:227～238
[27] Schurger N, Bijdendijk J, Tukker JJ. Comparison of four experimental techniques for studing drug absorption kinetics in the anesthetized rat in situ. J Pharm Sci, 1986, 75(2): 117～128
[28] Artursson P, karisson J. Correlation between oral drug absorption in humans and apparent drug permeability cofficients in human intestinal epithelial(caco-2)cells. Biochem Biophys Res Commun, 1991,175(3): 880～885
[29] 陆彬主编．药剂学实验．北京：人民卫生出版社，1994：131～135
[30] 毛凤斐，屠锡德，朱家壁．黄芩甙大鼠小肠吸收研究．南京药学院，1984，15(1)：61～66
[31] 何力，何进．大蒜油及其包合物小肠吸收的研究．药物实践杂志，1997，15(3)：154～157
[32] 黄志宏，方积乾主编．数理统计方法．北京：人民卫生出版社，1987：143～147
[33] 林田敏部，有田隆一著编，朱家壁译．生物药剂学．北京：人民卫生出版社，1979：37
[34] 胡一桥，Josef T. Ramipril．在大鼠小肠内转运机制的研究．中国药科大学学报，1993，24(6)：338～344
[35] L．拉赫曼，H．A．利伯曼，J．L．卡凡希主编．北京医学院药学系译．工业药剂学理论与实践．北京：化学工业出版社，1984：72～73
[36] 杨正管，朱家壁，岗艳云．盐酸地尔硫卓大鼠肠吸收动力学及在口服缓释制剂设计的意义．中国药科大学学报，1998，29(3)：179～182
[37] Berardi RR, Rogers HJ, Morrisom PJ, et al. Comparison of famotidine with omitidine and ranitidine. Clin Pharm, 1988, 14(5): 271～284
[38] 平其能主编．现代药剂学．北京：中国医药科技出版社，1998：472
[39] Yuen KH, Deshmukh AA, Newton JM, et al. Gastrointestinal transit and absorption of theophylline from a multiparticulate controlled release formulation. Int J Pharm, 1993, 97:61～77
[40] 莫韫，张钧寿．结肠靶向给药系统研究进展．中国新药杂志，1999，8(6)：368～371
[41] 包泳初，陈庆华，刘伟伦，等．挤出滚圆法制备药用微丸Ⅱ．制备工艺．中国医药工业杂志，1999，30(1)：18～20
[42] 陆彬主编．药物新剂型与新技术．北京：人民卫生出版社，1998：301
[43] 毕殿洲主编．药剂学．第四版．北京：人民卫生出版社，1999：76
[44] Zhang GH, Schwartz JB, Schnaare RL, et al. Bead coating Ⅱ: effect of spheronization technique on drug release from spheres. Drug Dev Ind Pharm, 1991, 17(1): 67～81
[45] 宋洪涛．复方中药麝香保心pH依赖型梯度释药微丸的研究．[学位论文]．沈阳药科大学中药制剂教研室，2001：106
[46] 陈挺译．丙烯酸聚合物在缓释制剂上的应用．罗姆公司宣传材料，2001：17
[47] 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)：130～131
[48] Baert L, Remon JP. Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion spheronization. Int J Pharm, 1993, 95:135～137
[49] 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．中国医药工业杂志，1998，29(8)：378～380
[50] Schmidt Peter C., Niemann Frank. Some factors influencing the formation and in vitro drug release from pellets prepared by extrusion/spheronization. Int J Pharm, 1995, 119(2): 203～211
[51] Judit Predah. Evaluation of mathematical models describing drug release from lipophilic matrices. Int J Pharm, 1996, 145(1): 61～64
[52] 平其能主编．现代药剂学．北京：中国医药科技出版社，1998，177～179
[53] R.S.Okor. Effect of polymer cation content on certain film properties. J Pharm Pharmacol, 1982, 34:83～86
[54] 陆彬主编．药物新剂型与新技术．北京：人民卫生出版社，1998：290～292
[55] 平其能主编．现代药剂学．北京：中国医药科技出版社，1998：501～502
[56] 陈挺译．丙烯酸聚合物在缓释制剂上的应用．罗姆公司宣传材料，2001：4
[57] 孙毓庆主编．分析化学实验．北京：人民卫生出版社：1994，67～70
[58] Shinji Narisawa, Minako Nagata, Yoshiyuki Hirakawa. An organic acidinduced sigmoidal release system for oral conorolled-release preparations. J Pharm Sci, 1996, 85(2): 184～188
[59] Jim H.Kac, Gordon L.Amidon, Ping I.Cel. PH-dependent swelling and solute diffusion characteristics of poly hydrogels. Pharm Res, 1988, 9: 592～597
[60] 郑俊民主编．药用高分子材料学．北京：中国医药科技出版社，2000：73～74
[61] 魏树礼主编．生物药剂学与药物动力学．北京：北京医科大学、中国协合医科大学联合出版社，1997：52～55
[62] 邓树海，刘兆平．药物动力学—理论与实践．北京：人民卫生出版社，1998：23～24
[63] 魏树礼主编．生物药剂学与药物动力学．北京：北京医科大学、中国协合医科大学联合出版社，1997：58～60