缓释、控释制剂药动学理论研究及其在大环内酯类药物生物利用度研究中的应用
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摘要
目的 建立缓释、控释制剂的药物动力学理论系统，探讨其应用价值，并
将相关原理和方法用于提高大环内酯类制剂的生物利用度研究。
方法 1．以Kalman滤波法计算缓释、控释制剂的体内释放动力学；
2．以拉普拉斯变换为线性微分方程求解工具，分析经典药动学尚未全面探讨
的血管外零级释放和一级释放药动学；
3．以零级释放过程逼近连续的药物释放过程，在血管外零级释放药动学基础
上，提出缓释、控释制剂药动学评价方法：“剂量分割法”（Zhang'S Dose-Division
method）。
4．以经典释放的药动学为基础，基于“缓释、控释制剂的释放动力学皆由不
同剂量的速释、零级释放和一级释放组成”的假设，提出缓释、控释制剂评价方
法：“释放分割法”（Zhang's Release-Division method）。
5．以剂量分割法和释放分割法为手段，建立缓释、控释制剂的多剂量给药药
动学、体内释放动力学、吸收动力学评价方法。
6．以剂量分割法和释放分割法分别进行缓释、控释制剂的体内外相关性方法
研究。
7．以释放过程的相似性研究和释放分割法为基础，分别建立缓释、控释制剂
释放行为的单一指标评价方法：缓释度、控释度。
8．研究常见的非经典释放：Higuchi释放、双指数释放、脉冲释放等非经典
释放的药动学。
9．以缓释、控释制剂药动学方法对生物利用度异常的大环内酯类制剂的的生
物利用度偏低和差异大的原因，并为提高其生物利用度的体外研究提供依据。
10．对口服生物利用度最低的大环内酯药物阿奇霉素，设计新剂型，并用抗生
素的微生物测定法测定其在狗中的生物利用度。
结果 1．Kalman滤波法可以给出缓释、控释制剂的体内释放动力学，本法
为非模型依赖性方法，但计算过程抽象。
2．给出血管外零级释放、一级释放的药动学，其吸收部位药物残留量的动力
学在释放结束时符合速释制剂药动学。血管外零级释放吸收部位残留量：
X_s=K_0/K_a（1-e~(-k_at)）
血管外一级释放吸收部位残留量：
X_s=(k_rD)/(k_a-k_r)（e~(-k_rt)-e~(-k_at)）
首次提出一级释放多剂量给药药动学，并给出一级释放达峰时间计算公式，
沈阳药科大学博士学位论文 摘 要
该公式的 100 刀00次预测准确性为 99．91％（RSD二0刀041％卜
、＝～
3．剂量分割法可以在速释制剂药动学参数基础上，给出任意缓释、控释制剂
的药动学，是缓释、控释制剂药动学基础方法。
4．释放分割法采用经典释放可以有效表达非经典释放过程及其药动学，是评
价缓释、控释制剂药动学的基础方法。
5．初步建立了缓释、控释制剂的多剂量给药药物动力学方法、吸收动力学和
体内释放动力学方法。
6．与现行的体外释放度－体内吸收度的相关性评价方法相比，提出的五种A水
平的体内外相关性方法（体内外释放度相关性、体内外吸收度相夫性、体内外血
药浓度相关性、基于相似性方法的体内外缓释度或控释度的相关性、基于释放分
割法的体内外缓释度或控释度的相关性）均有一定的方法学依据；方法学研究表
明，现行体外释放度与体内吸收度的相关性因方法学缺陷，容易导致相关性方程
失真（截距过大）和误判（相关系数良好卜
7基于相似性的缓释度p 厂 控释度rSI）和基于释放分割法的缓释度
旧RDX控释度＊RD）是评价缓释、控释制剂释放特征及其内在质量的单一度量指
标，易于进行质量控制、稳定性评价和体内药动学评估，并进行统计学比较。
8．通过剂量分割法和释放分割法推算非典型释放的药动学，给出HyuChj释
放的分割模数。
9．罗红霉素片、克拉霉素胶囊生物利用度的体内外影响因素的实验表明，导
致大环内酯类制剂生物利用度异常的因素包括：吸收程度低（可能因素为酸降解、
原形药物在肠道内不溶解），释放缓慢（游离大环内酯类药物逼酸后，颗粒表层的粘
性增大，不利于药物的释放）；据此设计阿奇霉素高效片的处方工艺。
10．与普通片相比，阿奇霉素高效片在狗中的相对生物利用度分别为：胃内 pH
为人工胃液条件下，F叫45％＊叫2；P＜0刀1）；胃内 pH为近7．3的磷酸盐缓冲对
时，F二122％（n＝12，P＜0＊1卜 胃内叫 未经调整时，F二128％（n二12；P＜0＊5）。
结论 本文从生物药剂学原理出发，指出同一药物的速释制剂和缓释、控
释制剂的清除速率应一致，一般情况下，其吸收速率也一致，制剂间的药动学差
异主要由制剂的释放特征决定。对现行的缓释、控释制剂体内外评价方法提出疑
问，并分析了现行速释制剂药动学评价方法中的错误、以及将速释制剂药动学套
用至缓释、控释制剂时的不足。
以缓释、控释制剂药动学基础评价方法“剂量分割法”、“释放分割法”和数
学分离法为基础，初步建立了缓释、控释制剂药动学评价体系，包括缓释、控释
2
沈阳药科大学博士学位论文 摘 ?
Aims To establish systematic pharmacokinetic (P1<) theories of the controlled/sustained release (CSR) dosage forms, and to apply the principles and methods to the macrolides with poor bioavailabilities (BA).
Methods 1. The in viva release kinetics of a CSR dosage form was processed by Kalman Filter method.
2. The PK of the non-parenteral zero-order release and the first-order release was analyzed mainly by means of the Laplace Transform.
3. A new tool of the P1< of the CSR dosage forms, the Zhang抯 Dose-Division method, was proposed based on the basis that any drug release profile can be simulated by a series of zero-order release doses administered by the same way.
4. A novel kinetic tool for evaluation of the CSR dosage forms was proposed as the Zhang抯 Release-Division method by the hypothesis that all the CSR dosage forms are all formed by and therefore can be divided into the classical releases.
5. The P1< of the CSR dosage forms administered with repeating doses, in vivo release kinetics, and in vitro absorption kinetics were methodologically established by the Dose-Division method and the Release-Division method.
6. The methodology study was processed by the Dose-Division method and the Release-Division method to propose five categories of in vitro versus in vivo Level A correlation methods, namely, the correlation of the in vitro release versus the in vivo release, the in vitro absorption expectance versus the in viva absorption, the in vitro plasma drug level expectance versus the in viva plasma concentration, the in vitro Sustained Release Index versus the in viva Sustained Release Index, and the in vitro Controlled Release Index versus the in viva Controlled Release Index.
7. Two single-parameter method to evaluate the release of the CSR dosage forms were established, one by the Similarity method, and the other by the Release Division method. The release profiles of the CSR dosage
4
Abstracts
forms can be simply evaluated by the Controlled Release Index (CSI) or the Sustained Release Index (55/) respectively by the Similarity method; or by the Controlled Release Index (CRD) or the Sustained Release Index (SRD) respectively by Release-Division method. The single parameter evaluation method makes it possible to control the release quality and evaluate the release stability of the CSR dosage forms quantitatively and statistically. The CSI and SSI, or CRD and SRD are correlated with the PK behaviors of the CSR dosage forms.
8. The PK profiles of non-typical releases, such as Higuchi release, double exponential release, and pulse-style release, were predicted by the Dose-Division method and the Release-Division method.
9. The poor BA of macrolides were analyzed by the Pk theory of the CSR dosage forms to reveal the role the in vivo release and in vivo absorption of the macrolides played in the BA. That the poor stability in an acid solution, and the slow release in a neutralized solution after agglomeration in the stomach decreased the BA of the macrolides.
10. The dosage form design should be targeted on overcoming the BA influencing parameters. The BA validation test was processed in dogs by the microbiological test of antibiotics.
Results 1. The kalman Filter was able to process the in vivo release profile of the CSR dosage forms, but the method was too abstract to be accepted and not easy to control for it is a totally computerized process.
2. The releases (non-parenterai zero-order release, and the first-order release) were elucidated. The residue in the absorption site after the release finished plays an important role for understand the Pk of CSR dosage forms and behaves as an immediate release.
The residue dose of non-parenteral zero-order release is:
X~
The residue dose of non-parenteral first-order release is:
k_D ekt)
~I鐥k, ?
It is possible the first time to report the PK of the repeating doses of the first-order release, the peak plasma concentration time (tmax) formula of the same release.
The formula wa
将相关原理和方法用于提高大环内酯类制剂的生物利用度研究。
方法 1．以Kalman滤波法计算缓释、控释制剂的体内释放动力学；
2．以拉普拉斯变换为线性微分方程求解工具，分析经典药动学尚未全面探讨
的血管外零级释放和一级释放药动学；
3．以零级释放过程逼近连续的药物释放过程，在血管外零级释放药动学基础
上，提出缓释、控释制剂药动学评价方法：“剂量分割法”（Zhang'S Dose-Division
method）。
4．以经典释放的药动学为基础，基于“缓释、控释制剂的释放动力学皆由不
同剂量的速释、零级释放和一级释放组成”的假设，提出缓释、控释制剂评价方
法：“释放分割法”（Zhang's Release-Division method）。
5．以剂量分割法和释放分割法为手段，建立缓释、控释制剂的多剂量给药药
动学、体内释放动力学、吸收动力学评价方法。
6．以剂量分割法和释放分割法分别进行缓释、控释制剂的体内外相关性方法
研究。
7．以释放过程的相似性研究和释放分割法为基础，分别建立缓释、控释制剂
释放行为的单一指标评价方法：缓释度、控释度。
8．研究常见的非经典释放：Higuchi释放、双指数释放、脉冲释放等非经典
释放的药动学。
9．以缓释、控释制剂药动学方法对生物利用度异常的大环内酯类制剂的的生
物利用度偏低和差异大的原因，并为提高其生物利用度的体外研究提供依据。
10．对口服生物利用度最低的大环内酯药物阿奇霉素，设计新剂型，并用抗生
素的微生物测定法测定其在狗中的生物利用度。
结果 1．Kalman滤波法可以给出缓释、控释制剂的体内释放动力学，本法
为非模型依赖性方法，但计算过程抽象。
2．给出血管外零级释放、一级释放的药动学，其吸收部位药物残留量的动力
学在释放结束时符合速释制剂药动学。血管外零级释放吸收部位残留量：
X_s=K_0/K_a（1-e~(-k_at)）
血管外一级释放吸收部位残留量：
X_s=(k_rD)/(k_a-k_r)（e~(-k_rt)-e~(-k_at)）
首次提出一级释放多剂量给药药动学，并给出一级释放达峰时间计算公式，
沈阳药科大学博士学位论文 摘 要
该公式的 100 刀00次预测准确性为 99．91％（RSD二0刀041％卜
、＝～
3．剂量分割法可以在速释制剂药动学参数基础上，给出任意缓释、控释制剂
的药动学，是缓释、控释制剂药动学基础方法。
4．释放分割法采用经典释放可以有效表达非经典释放过程及其药动学，是评
价缓释、控释制剂药动学的基础方法。
5．初步建立了缓释、控释制剂的多剂量给药药物动力学方法、吸收动力学和
体内释放动力学方法。
6．与现行的体外释放度－体内吸收度的相关性评价方法相比，提出的五种A水
平的体内外相关性方法（体内外释放度相关性、体内外吸收度相夫性、体内外血
药浓度相关性、基于相似性方法的体内外缓释度或控释度的相关性、基于释放分
割法的体内外缓释度或控释度的相关性）均有一定的方法学依据；方法学研究表
明，现行体外释放度与体内吸收度的相关性因方法学缺陷，容易导致相关性方程
失真（截距过大）和误判（相关系数良好卜
7基于相似性的缓释度p 厂 控释度rSI）和基于释放分割法的缓释度
旧RDX控释度＊RD）是评价缓释、控释制剂释放特征及其内在质量的单一度量指
标，易于进行质量控制、稳定性评价和体内药动学评估，并进行统计学比较。
8．通过剂量分割法和释放分割法推算非典型释放的药动学，给出HyuChj释
放的分割模数。
9．罗红霉素片、克拉霉素胶囊生物利用度的体内外影响因素的实验表明，导
致大环内酯类制剂生物利用度异常的因素包括：吸收程度低（可能因素为酸降解、
原形药物在肠道内不溶解），释放缓慢（游离大环内酯类药物逼酸后，颗粒表层的粘
性增大，不利于药物的释放）；据此设计阿奇霉素高效片的处方工艺。
10．与普通片相比，阿奇霉素高效片在狗中的相对生物利用度分别为：胃内 pH
为人工胃液条件下，F叫45％＊叫2；P＜0刀1）；胃内 pH为近7．3的磷酸盐缓冲对
时，F二122％（n＝12，P＜0＊1卜 胃内叫 未经调整时，F二128％（n二12；P＜0＊5）。
结论 本文从生物药剂学原理出发，指出同一药物的速释制剂和缓释、控
释制剂的清除速率应一致，一般情况下，其吸收速率也一致，制剂间的药动学差
异主要由制剂的释放特征决定。对现行的缓释、控释制剂体内外评价方法提出疑
问，并分析了现行速释制剂药动学评价方法中的错误、以及将速释制剂药动学套
用至缓释、控释制剂时的不足。
以缓释、控释制剂药动学基础评价方法“剂量分割法”、“释放分割法”和数
学分离法为基础，初步建立了缓释、控释制剂药动学评价体系，包括缓释、控释
2
沈阳药科大学博士学位论文 摘 ?
Aims To establish systematic pharmacokinetic (P1<) theories of the controlled/sustained release (CSR) dosage forms, and to apply the principles and methods to the macrolides with poor bioavailabilities (BA).
Methods 1. The in viva release kinetics of a CSR dosage form was processed by Kalman Filter method.
2. The PK of the non-parenteral zero-order release and the first-order release was analyzed mainly by means of the Laplace Transform.
3. A new tool of the P1< of the CSR dosage forms, the Zhang抯 Dose-Division method, was proposed based on the basis that any drug release profile can be simulated by a series of zero-order release doses administered by the same way.
4. A novel kinetic tool for evaluation of the CSR dosage forms was proposed as the Zhang抯 Release-Division method by the hypothesis that all the CSR dosage forms are all formed by and therefore can be divided into the classical releases.
5. The P1< of the CSR dosage forms administered with repeating doses, in vivo release kinetics, and in vitro absorption kinetics were methodologically established by the Dose-Division method and the Release-Division method.
6. The methodology study was processed by the Dose-Division method and the Release-Division method to propose five categories of in vitro versus in vivo Level A correlation methods, namely, the correlation of the in vitro release versus the in vivo release, the in vitro absorption expectance versus the in viva absorption, the in vitro plasma drug level expectance versus the in viva plasma concentration, the in vitro Sustained Release Index versus the in viva Sustained Release Index, and the in vitro Controlled Release Index versus the in viva Controlled Release Index.
7. Two single-parameter method to evaluate the release of the CSR dosage forms were established, one by the Similarity method, and the other by the Release Division method. The release profiles of the CSR dosage
4
Abstracts
forms can be simply evaluated by the Controlled Release Index (CSI) or the Sustained Release Index (55/) respectively by the Similarity method; or by the Controlled Release Index (CRD) or the Sustained Release Index (SRD) respectively by Release-Division method. The single parameter evaluation method makes it possible to control the release quality and evaluate the release stability of the CSR dosage forms quantitatively and statistically. The CSI and SSI, or CRD and SRD are correlated with the PK behaviors of the CSR dosage forms.
8. The PK profiles of non-typical releases, such as Higuchi release, double exponential release, and pulse-style release, were predicted by the Dose-Division method and the Release-Division method.
9. The poor BA of macrolides were analyzed by the Pk theory of the CSR dosage forms to reveal the role the in vivo release and in vivo absorption of the macrolides played in the BA. That the poor stability in an acid solution, and the slow release in a neutralized solution after agglomeration in the stomach decreased the BA of the macrolides.
10. The dosage form design should be targeted on overcoming the BA influencing parameters. The BA validation test was processed in dogs by the microbiological test of antibiotics.
Results 1. The kalman Filter was able to process the in vivo release profile of the CSR dosage forms, but the method was too abstract to be accepted and not easy to control for it is a totally computerized process.
2. The releases (non-parenterai zero-order release, and the first-order release) were elucidated. The residue in the absorption site after the release finished plays an important role for understand the Pk of CSR dosage forms and behaves as an immediate release.
The residue dose of non-parenteral zero-order release is:
X~
The residue dose of non-parenteral first-order release is:
k_D ekt)
~I鐥k, ?
It is possible the first time to report the PK of the repeating doses of the first-order release, the peak plasma concentration time (tmax) formula of the same release.
The formula wa
引文
1 Rowland M，Tozer TN．著，彭彬译．临床药动学．湖南科学技术出版社．长沙．1999．P2
2 Chien YW.，Novel Drug Delivery Systems. Marcel Dekker, Inc. New York. 1992:p750
3 Gibaldi M, Perrier D. Pharmacokinetics. (2nd edition). Marcel Dekker, Inc. New York and Basel. 1982. Absorption kinetics and Bioavailability Studies, sustained release. P188-195
4 Silber M, Bialer M, and Yacobi A. Pharmacokinetic/pharmacodynamic Basis of Controlled Drug Delivery. From: Joseph R. Robinson, Vincent H. L. Lee (ed). Controlled Drug Delivery, fundamentals and applications. Marcel Dekker, Inc., New York, 1987. P213-252
5 Theeuwes F and Bayne W. Dosage form index: an objective criterion for evaluation of controlled release drug delivery systems. J. Pharm. Sci. 66:1388 (1977)
6 Rhodes CT. Drug Delivery Systems: Effects of phamacoKinetics on Design, Evaluation, and Production. From: Peter G. Welling, Francis L.S. Tse. Phramacokinetics: regulatory, industrial, academic perspectives (2nd ed). Marcel Dekker, Inc. New York. 1995. P39-58
7 刘昌孝，孙瑞元．药物评价实验设计与统计学基础．军事医学科学出版社．北京．1999．缓(控)释制剂的生物利用度实验．P153-159
8 李家泰．临床药理学．人民卫生出版社．北京．1991．药代动力学基本原理和计算方法(缺缓释、控释制剂)．P105-166
9 徐叔云，张均田，魏伟，李俊．现代实用临床药理学．华夏出版社．北京．1996．药物体内过程和药动学．P13-32
10 周怀梧．数理医药学．上海科学技术出版社．上海．1983
11 Blume HH, Midha KK. (ed) Bio-International 2: Bioavailability, Bioequivalence and Pharmacokinetic Studies. Medpharm Scientific Publishers Stuttgart. 1995.
12 Midha KK, Blume HH, (ed) Bio-International: Bioavctilability, Bioequivalence and Pharmacokinetic Studies. Medpharm Scientific Publishers Stuttgart. 1993.
13 Wagner JG and Nelson E. Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J. Pharm. Sci., 53, 1392-1404(1964)
14 国家药典委员会．缓释、控释制剂指导原则．中华人民共和国药典(2000版二部)．化学工业出版社．北京．2000．P200-202
15 United States Pharmacopoeia (ed.24). In vitro and in vivo evaluation, p2051-2055
16 Loo JCK and Riegelman S. J. Pharm. Sci., 57, 918(1968).
17 Heinzel G. Data fit of a sustained release oral dosage form after repeated dosing using freed disposition parameters derived from the i. v. data fit. Topfit 2.0 Part 5:Compartmental analysis examples. P69-72
18 Heinzel G, Woloszczak R, Thomann P. Topfit 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the P.C., Part 5. Gustav Fischer, 1993, Stuttgart. Determination of the absorption profile by means of a user defined compartment model. P73-80
19 国家药典委员会. 释放度测定法. 中华人民共和国药典(2000 版二部). 化学工业出版社．北京．2000. P77-78
20 Carstensen JT. Drug Stability: Principles and Practices. (2nd edition). Physical testing. Marcel Dekker, Inc. New York. 1995:P408-486
21 Carstensen JT. Drug Stability: Principles and Practices. (2nd edition). 1993 ICH Guidelines. Marcel Dekker, Inc. New York. 1995: P538-550
22 Krowczynski L. Extended-release dosage forms. Florida, CRC Press, Inc. 1987. P56
23 Meier J, Nuesch E, Schmidt R. Pharmacokinetic criteria for evaluation of retard formulation. Eur J Clin Pharmacol., 1974: 7:429
24 Umesh V. Banakar, Chetan D. Lathia and John H. Wood. interpretation of dissolution rate data and techniques of in vivo dissolution. From: Umesh V. Banakar. Pharmaceutical Dissolution Testing (Chapter 6). Marcel Dekker, Inc. New York. 1992:p189-250
25 Leeson LJ, Adair D, Clevenger J, and Chiang N. The in vitro development of extended-release solid oral dosage forms. J. Pharmacokinet. Biopharm. 13:493-514, 1985
26 Williams RL, Upton RA, Ball L, et al. Development of a new controlled-release formulation of chlorphenirarnine maleate using in vitro/in vivo correlations. J. Pharm Sci. 80:22-25,1991.
27 张继稳，屠锡德．均匀设计在马来酸噻吗洛尔缓释片研究中的应用．中国药科大学学报．1996，27(6)：350-354
28 Dighe, SV. Development of dissolution tests for immediate release and modified release oral dosage forms. In: Blume HH and Midha KK(ed). Bio-International 2, bioavailability, bioequivalence and pharmacokinetic studies. Medpharm scientific publishers, Stuttgart, 1995. Pp247-255
29 Skelly JP, Shiu GF. In vitro/in vivo correlations in biopharmaceutics: scientific and regulatory implications. Eur J Drug Metab and Pharmacokin. 1993:18,121-129
30 Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet. 1992: 23(2) ; 106-31
31 Bryskier A, Labro, MT. Macrolides. New therapeutic prospects. Presse Medicale. 1994; 23(38) , 1762-6
32 Kirst HA. Semi-synthetic derivatives of erythromycin. Progress in Medicinal Chemistry. 1993; 30; 57-88
33 Mordi MN, Pelta MD, Boote V, et al. Acid-catalyzed degradation of clarithromycin and erythromycin B: a comparative study using NMR spectroscopy. J Med Chem. 2000;43(3) ; 467-74
34 Erah PO, Goddard AF, Barrett DA, et al. The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection.J Antimicrob Chemother. 1997;39(1) ;5-12
35 Erah PO , Barrett DA, Shaw PN. Ion-pair high-performance liquid chromatographic assay method for the assessment of clarithromycin stability in aqueous solution and in gastric juice. J Chromatogr B Biomed Appl. 1996; 682(1) ;73-8
36 Gill CJ, Abruzzo GK, Flattery AM et al. In vivo evaluation of three acid-stable azalide compounds, L-701,677, L-708,299 and L-708,365 compared to erythromycin, azithromycin and clarithromycin. J Antibiot (Tokyo). 1995; 48(10) ; 1141-7
37 Periti P,Mazzei T, Mini E, Novelli A. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I). Clin Pharmacokinet. 1989; 16(4) ;193-214
38 Yonemochi E, Kitahara S, Maeda S et al. Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. Eur J Pharm Sci. 1999;7(4) ;331-8
39 Nakagawa Y, Itai S, Yoshida T, Nagai T. Physicochemical properties and stability in the acidic solution of a new macrolide antibiotic, clarithromycin, in comparison with erythromycin. Chem Pharm Bull (Tokyo). 1992; 40(3) ;725-8
40 Lode H, Borner K, Koeppe P et al. Azithromycin-review of key chemical, pharmacokinetic and microbiological features. J Antimicrob Chemother. 1996;37 Suppl C;1-8
41 Lode H. The pharmacokinetics of azithromycin and their clinical significance. Eur J Clin Microbiol Infect Dis. 1991;10(10) ; 807-12
42 Fiese EF, Steffen SH. Comparison of the acid stability of azithromlycin and erythromycm A. J Antimicrob Chemother. 1990; 25 Suppl A; 39-47
43 Rodvold KA. Clinical pharmacokinetics of clarithromycin. Clin Pharmacokinet.1999; 37(5); 385-98
44 Chantot JF, Bryskier A, Gasc JC. Antibacterial activity of roxithromycin: a laboratory evaluation. J Antibiot (Tokyo). 1986; 39(5); 660-8
45 Luke DR, Foulds G. Disposition of oral azithromycin in humans. Clin Pharmacol Ther. 1997; 61(6); 641-8
46 Foulds G, Luke DR, Teng R. et al. The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chernother. 1996; 37Suppl C;37-44
47 Boeckh M, Lode H, Hoffken A et al. Pharrnacokinetics of roxithromycin and influence of H2-blockers and antacids on gastrointestinal absorption. Eur J Clin Microbiol Infect Dis. 1992 11(5), 465-8
48 Kees F, Holstege A, Ittner K et al. Pharmacokinetic interaction between proton pump inhibitors and roxithrornycin in volunteers. Alimentary Pharmacology and Therapeutics. 2000; 14(4); 407-12
49 Singlas E. Clinical pharmacokinetics of azithromycin. Pathol Biol (Paris). 1995; 43(6); 505-11
50 相秉仕．计算药学． 中国医药科技出版社．北京．1990. p109
51 Rutan SC, Bouveresse E, Andrew KN et al. Correction for drift in multivariate systems using the Kalman filter. Chemo Int Lab Sys 1996: 35: 199-211.
52 Andrew KN, Rutan SC, Worsfold PJ. Application of Kalman filter to multivariate calibration and drift correction. Anal Chim Acta 1999: 388: 315-325.
53 Chen J, Rutan SC. Identification and Quantification of Overlapped Peaks in Liquid Chromatography with UV Diode Array Detection Using an Adaptive Kalman Filter. Anal Chim Acta 1996: 335:1-10
54 Hayashi Y, Rutan SC. Accuracy, Precision and Information of the Adaptive Kalman Filter in Chromatography. Anal. Chim. Acta. 1993: 271:91-100
55 Gerow DD, Rutan SC. Background Correction for Fluorescence Detection in Thin Layer Chromatography Using Factor Analysis and the Adaptive Kalman Filter. Anal Chem 1988, 60, 847-852
56 相秉仕．计算药学． 中国医药科技出版社．北京．1990. p154-59
57 Higuchi T, J. Soc. Cosmet. Chem., 11,85 (1960)
58 Banakar UV. Pharmaceutical Dissolution Testing: theory of dissolutiorn Marcel Dekker, Inc. New York. 1992:p290-291
59 廖工铁主编．靶向给药制剂．肝靶向米托葸醌毫微球研究．成都．四川科学技术出版社．1997．P236
60 Broad NW, Carmody AF, Feely LC, Witner BC. A controlled release formulation for poorly soluble basic drugs. WO98/56357
61 马剑文，韩永平，沈克温主编．现代药品检验学．人民军医出版社．北京．1997．p745-750
62 Shepard RM, Falkner FC. Pharmacokinetics of azithromycin in rats and dogs. J Antimicrob Chemother 1990 Jan 25 Suppl A 49-60
63 郭蓓宁，张菁，张婴元．Azithromycin 临床药物动力学研究．中国抗生素杂志．1996；21(5)；376-379
64 陈桂荣，王利杰，杨继芳，王鹏．甘氨酸茶碱钠缓释片体外释放与体内吸收的相关性研究．中国临床药理学杂志．2000；16(3)：217-219
2 Chien YW.，Novel Drug Delivery Systems. Marcel Dekker, Inc. New York. 1992:p750
3 Gibaldi M, Perrier D. Pharmacokinetics. (2nd edition). Marcel Dekker, Inc. New York and Basel. 1982. Absorption kinetics and Bioavailability Studies, sustained release. P188-195
4 Silber M, Bialer M, and Yacobi A. Pharmacokinetic/pharmacodynamic Basis of Controlled Drug Delivery. From: Joseph R. Robinson, Vincent H. L. Lee (ed). Controlled Drug Delivery, fundamentals and applications. Marcel Dekker, Inc., New York, 1987. P213-252
5 Theeuwes F and Bayne W. Dosage form index: an objective criterion for evaluation of controlled release drug delivery systems. J. Pharm. Sci. 66:1388 (1977)
6 Rhodes CT. Drug Delivery Systems: Effects of phamacoKinetics on Design, Evaluation, and Production. From: Peter G. Welling, Francis L.S. Tse. Phramacokinetics: regulatory, industrial, academic perspectives (2nd ed). Marcel Dekker, Inc. New York. 1995. P39-58
7 刘昌孝，孙瑞元．药物评价实验设计与统计学基础．军事医学科学出版社．北京．1999．缓(控)释制剂的生物利用度实验．P153-159
8 李家泰．临床药理学．人民卫生出版社．北京．1991．药代动力学基本原理和计算方法(缺缓释、控释制剂)．P105-166
9 徐叔云，张均田，魏伟，李俊．现代实用临床药理学．华夏出版社．北京．1996．药物体内过程和药动学．P13-32
10 周怀梧．数理医药学．上海科学技术出版社．上海．1983
11 Blume HH, Midha KK. (ed) Bio-International 2: Bioavailability, Bioequivalence and Pharmacokinetic Studies. Medpharm Scientific Publishers Stuttgart. 1995.
12 Midha KK, Blume HH, (ed) Bio-International: Bioavctilability, Bioequivalence and Pharmacokinetic Studies. Medpharm Scientific Publishers Stuttgart. 1993.
13 Wagner JG and Nelson E. Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J. Pharm. Sci., 53, 1392-1404(1964)
14 国家药典委员会．缓释、控释制剂指导原则．中华人民共和国药典(2000版二部)．化学工业出版社．北京．2000．P200-202
15 United States Pharmacopoeia (ed.24). In vitro and in vivo evaluation, p2051-2055
16 Loo JCK and Riegelman S. J. Pharm. Sci., 57, 918(1968).
17 Heinzel G. Data fit of a sustained release oral dosage form after repeated dosing using freed disposition parameters derived from the i. v. data fit. Topfit 2.0 Part 5:Compartmental analysis examples. P69-72
18 Heinzel G, Woloszczak R, Thomann P. Topfit 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the P.C., Part 5. Gustav Fischer, 1993, Stuttgart. Determination of the absorption profile by means of a user defined compartment model. P73-80
19 国家药典委员会. 释放度测定法. 中华人民共和国药典(2000 版二部). 化学工业出版社．北京．2000. P77-78
20 Carstensen JT. Drug Stability: Principles and Practices. (2nd edition). Physical testing. Marcel Dekker, Inc. New York. 1995:P408-486
21 Carstensen JT. Drug Stability: Principles and Practices. (2nd edition). 1993 ICH Guidelines. Marcel Dekker, Inc. New York. 1995: P538-550
22 Krowczynski L. Extended-release dosage forms. Florida, CRC Press, Inc. 1987. P56
23 Meier J, Nuesch E, Schmidt R. Pharmacokinetic criteria for evaluation of retard formulation. Eur J Clin Pharmacol., 1974: 7:429
24 Umesh V. Banakar, Chetan D. Lathia and John H. Wood. interpretation of dissolution rate data and techniques of in vivo dissolution. From: Umesh V. Banakar. Pharmaceutical Dissolution Testing (Chapter 6). Marcel Dekker, Inc. New York. 1992:p189-250
25 Leeson LJ, Adair D, Clevenger J, and Chiang N. The in vitro development of extended-release solid oral dosage forms. J. Pharmacokinet. Biopharm. 13:493-514, 1985
26 Williams RL, Upton RA, Ball L, et al. Development of a new controlled-release formulation of chlorphenirarnine maleate using in vitro/in vivo correlations. J. Pharm Sci. 80:22-25,1991.
27 张继稳，屠锡德．均匀设计在马来酸噻吗洛尔缓释片研究中的应用．中国药科大学学报．1996，27(6)：350-354
28 Dighe, SV. Development of dissolution tests for immediate release and modified release oral dosage forms. In: Blume HH and Midha KK(ed). Bio-International 2, bioavailability, bioequivalence and pharmacokinetic studies. Medpharm scientific publishers, Stuttgart, 1995. Pp247-255
29 Skelly JP, Shiu GF. In vitro/in vivo correlations in biopharmaceutics: scientific and regulatory implications. Eur J Drug Metab and Pharmacokin. 1993:18,121-129
30 Periti P, Mazzei T, Mini E, Novelli A. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet. 1992: 23(2) ; 106-31
31 Bryskier A, Labro, MT. Macrolides. New therapeutic prospects. Presse Medicale. 1994; 23(38) , 1762-6
32 Kirst HA. Semi-synthetic derivatives of erythromycin. Progress in Medicinal Chemistry. 1993; 30; 57-88
33 Mordi MN, Pelta MD, Boote V, et al. Acid-catalyzed degradation of clarithromycin and erythromycin B: a comparative study using NMR spectroscopy. J Med Chem. 2000;43(3) ; 467-74
34 Erah PO, Goddard AF, Barrett DA, et al. The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection.J Antimicrob Chemother. 1997;39(1) ;5-12
35 Erah PO , Barrett DA, Shaw PN. Ion-pair high-performance liquid chromatographic assay method for the assessment of clarithromycin stability in aqueous solution and in gastric juice. J Chromatogr B Biomed Appl. 1996; 682(1) ;73-8
36 Gill CJ, Abruzzo GK, Flattery AM et al. In vivo evaluation of three acid-stable azalide compounds, L-701,677, L-708,299 and L-708,365 compared to erythromycin, azithromycin and clarithromycin. J Antibiot (Tokyo). 1995; 48(10) ; 1141-7
37 Periti P,Mazzei T, Mini E, Novelli A. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I). Clin Pharmacokinet. 1989; 16(4) ;193-214
38 Yonemochi E, Kitahara S, Maeda S et al. Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. Eur J Pharm Sci. 1999;7(4) ;331-8
39 Nakagawa Y, Itai S, Yoshida T, Nagai T. Physicochemical properties and stability in the acidic solution of a new macrolide antibiotic, clarithromycin, in comparison with erythromycin. Chem Pharm Bull (Tokyo). 1992; 40(3) ;725-8
40 Lode H, Borner K, Koeppe P et al. Azithromycin-review of key chemical, pharmacokinetic and microbiological features. J Antimicrob Chemother. 1996;37 Suppl C;1-8
41 Lode H. The pharmacokinetics of azithromycin and their clinical significance. Eur J Clin Microbiol Infect Dis. 1991;10(10) ; 807-12
42 Fiese EF, Steffen SH. Comparison of the acid stability of azithromlycin and erythromycm A. J Antimicrob Chemother. 1990; 25 Suppl A; 39-47
43 Rodvold KA. Clinical pharmacokinetics of clarithromycin. Clin Pharmacokinet.1999; 37(5); 385-98
44 Chantot JF, Bryskier A, Gasc JC. Antibacterial activity of roxithromycin: a laboratory evaluation. J Antibiot (Tokyo). 1986; 39(5); 660-8
45 Luke DR, Foulds G. Disposition of oral azithromycin in humans. Clin Pharmacol Ther. 1997; 61(6); 641-8
46 Foulds G, Luke DR, Teng R. et al. The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chernother. 1996; 37Suppl C;37-44
47 Boeckh M, Lode H, Hoffken A et al. Pharrnacokinetics of roxithromycin and influence of H2-blockers and antacids on gastrointestinal absorption. Eur J Clin Microbiol Infect Dis. 1992 11(5), 465-8
48 Kees F, Holstege A, Ittner K et al. Pharmacokinetic interaction between proton pump inhibitors and roxithrornycin in volunteers. Alimentary Pharmacology and Therapeutics. 2000; 14(4); 407-12
49 Singlas E. Clinical pharmacokinetics of azithromycin. Pathol Biol (Paris). 1995; 43(6); 505-11
50 相秉仕．计算药学． 中国医药科技出版社．北京．1990. p109
51 Rutan SC, Bouveresse E, Andrew KN et al. Correction for drift in multivariate systems using the Kalman filter. Chemo Int Lab Sys 1996: 35: 199-211.
52 Andrew KN, Rutan SC, Worsfold PJ. Application of Kalman filter to multivariate calibration and drift correction. Anal Chim Acta 1999: 388: 315-325.
53 Chen J, Rutan SC. Identification and Quantification of Overlapped Peaks in Liquid Chromatography with UV Diode Array Detection Using an Adaptive Kalman Filter. Anal Chim Acta 1996: 335:1-10
54 Hayashi Y, Rutan SC. Accuracy, Precision and Information of the Adaptive Kalman Filter in Chromatography. Anal. Chim. Acta. 1993: 271:91-100
55 Gerow DD, Rutan SC. Background Correction for Fluorescence Detection in Thin Layer Chromatography Using Factor Analysis and the Adaptive Kalman Filter. Anal Chem 1988, 60, 847-852
56 相秉仕．计算药学． 中国医药科技出版社．北京．1990. p154-59
57 Higuchi T, J. Soc. Cosmet. Chem., 11,85 (1960)
58 Banakar UV. Pharmaceutical Dissolution Testing: theory of dissolutiorn Marcel Dekker, Inc. New York. 1992:p290-291
59 廖工铁主编．靶向给药制剂．肝靶向米托葸醌毫微球研究．成都．四川科学技术出版社．1997．P236
60 Broad NW, Carmody AF, Feely LC, Witner BC. A controlled release formulation for poorly soluble basic drugs. WO98/56357
61 马剑文，韩永平，沈克温主编．现代药品检验学．人民军医出版社．北京．1997．p745-750
62 Shepard RM, Falkner FC. Pharmacokinetics of azithromycin in rats and dogs. J Antimicrob Chemother 1990 Jan 25 Suppl A 49-60
63 郭蓓宁，张菁，张婴元．Azithromycin 临床药物动力学研究．中国抗生素杂志．1996；21(5)；376-379
64 陈桂荣，王利杰，杨继芳，王鹏．甘氨酸茶碱钠缓释片体外释放与体内吸收的相关性研究．中国临床药理学杂志．2000；16(3)：217-219