BIORELEVANT DISSOLUTION TEST METHODS

Transcription

1 BIORELEVANT DISSOLUTION TEST METHODS FOR MODIFIED RELEASE DOSAGE FORMS Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich Chemische und Pharmazeutische Wissenschaften der Johann Wolfgang Goethe-Universität in Frankfurt am Main von Sandra Klein aus Büdingen Frankfurt am Main, 2005 (D F 1)

2 Vom Fachbereich Chemische und Pharmazeutische Wissenschaften der Johann Wolfgang Goethe-Universität als Dissertation angenommen Dekan: Prof. Dr. Harald Schwalbe 1. Gutachter: Prof. Dr. Jennifer B. Dressman 2. Gutachter: Prof. Dr. Manfred Schubert-Zsilavecz 3. Gutachter: Prof. Dr. Hans E. Junginger Datum der Disputation:

3 Berichte aus der Pharmazie Sandra Klein Biorelevant Dissolution Test Methods for Modified Release Dosage Forms Shaker Verlag Aachen 2005

4 Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the internet at Zugl.: Frankfurt am Main, Univ., Diss., 2005 Copyright Shaker Verlag 2005 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publishers. Printed in Germany. ISBN ISSN Shaker Verlag GmbH P.O. BOX D Aachen Phone: 0049/2407/ Telefax: 0049/2407/ Internet: info@shaker.de

5 Für meine Eltern Willy & Waltraud Klein

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7 DANKSAGUNG Die vorliegende Arbeit entstand im Rahmen meiner Tätigkeit als wissenschaftliche Angestellte am Institut für Pharmazeutische Technologie der Johann Wolfgang Goethe-Universität Frankfurt am Main. Meiner Doktormutter, Frau Professor Jennifer B. Dressman danke ich ganz herzlich für die ausgezeichnete wissenschaftliche Betreuung. Sie ist mir ein großes Vorbild und gab mir nicht nur die Möglichkeit, wissenschaftliches Arbeiten zu erlernen und zu diskutieren, sondern auch die Chance, viele weitere Wissenschaftler kennen zu lernen und Forschungsergebnisse bei diversen internationalen Kongressen vorzustellen. Many thanks to Professor Christos Reppas, Maria Vertzoni and Nikoletta Fotaki from the Department of Pharmacy at the University of Athens for their valuable input in the development of a biorelevant dissolution test set-up. Herrn Werner G. Müller und der Firma Erweka GmbH danke ich für die apparative und finanzielle Unterstützung, die es mir unter anderem möglich machte, bei mehreren internationalen Dissolution-Workshops als Referentin tätig zu sein. Bedanken möchte ich mich bei allen Mitarbeitern am Institut für Pharmazeutische Technologie, besonders bei meinen ehemaligen und aktuellen Kollegen aus der Arbeitsguppe: Dr. Edmund Kostewicz, Dr. Karen Schamp, Dr. Annette Scholz, Dr. Alexander Glomme, Dr. Christian Leuner, Dr. Erika Stippler, Dr. Martin Wunderlich, Karen Beltz, Marc Lindenberg, Matthias Fischbach, Frank Seiler, Ekarat Jantratid, Corina Becker, Kevin Kiehm, Kathrin Nollenberger, Thomas Zöller und Niels Janssen. Mein besonderer Dank gilt meinem Laborkollegen und guten Freund Thomas (Tom) Fürst, ohne dessen unkomplizierte Art so mancher Labortag nur halb so viel Spass gemacht hätte. Weiterhin möchte ich mich herzlich bei meinem ehemaligen Kollegen Dr. Markus Rudolph bedanken, der mir insbesondere zu Beginn meiner Arbeit viele wertvolle Denkanstöße gab.

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9 Table of contents TABLE OF CONTENTS TABLE OF CONTENTS...I LIST OF FIGURES... V LIST OF TABLES...XIII ABBREVIATIONS...XXI 1 INTRODUCTION ORAL MODIFIED-RELEASE (MR) DOSAGE FORMS RELEVANT ANATOMY OF THE GASTROINTESTINAL TRACT RELEVANT PHYSIOLOGY OF THE GASTROINTESTINAL TRACT Upper GI tract: Stomach Upper GI tract: Small intestine Colon DISSOLUTION METHODS FOR MODIFIED-RELEASE DOSAGE FORMS Drug dissolution and bioavailability Official test methods Objectives for improving the biorelevance of dissolution methods USP apparatus BIORELEVANT DISSOLUTION MEDIA Media to simulate gastric conditions in the fasted state Media to simulate proximal small intestinal conditions in the fasted state Media to simulate gastric conditions in the fed state Media to simulate proximal small intestinal conditions in the fed state AIMS OF THE THESIS I

10 Table of contents 3 DISSOLUTION MEDIA TO SIMULATE THE POSTPRANDIAL STOMACH BACKGROUND MATERIALS AND METHODS Meal composition Materials Meal and media preparation Characterization of the physicochemical properties Statistical analysis RESULTS AND DISCUSSION Adjustment of the viscosity CONCLUSION ACKNOWLEDGEMENT DISSOLUTION MODELS TO PREDICT THE IN VIVO BEHAVIOR OF MODIFIED RELEASE DOSAGE FORMS STANDARD MATERIALS AND EQUIPMENT Standard materials Standard equipment COMPOSITION OF STANDARD DISSOLUTION MEDIA Standard dissolution media for simulating gastric conditions Media to simulate small intestinal conditions Media to simulate colonic conditions IN VITRO DISSOLUTION PROFILE COMPARISON Calculation of difference factor f f 2 factor calculation Criteria for f 1 and f 2 calculation in the present thesis COMPARISON OF DRUG RELEASE FROM METOPROLOL MR DOSAGE FORMS IN SINGLE BUFFERVERSUS A PH-GRADIENT DISSOLUTION TEST Metoprolol II

11 Table of contents Background Materials and methods Results and discussion Summary Acknowledgement EVOLUTION OF BIODIS METHODOLOGY: SELECTION OF ADEQUATE INSTRUMENT PARAMETERS Background Materials and methods Results and discussion Summary DEVELOPING A DISSOLUTION SYSTEM TO PREDICT DRUG RELEASE FROM DRUG DELIVERY SYSTEMS INTENDED FOR SITE-SPECIFIC RELEASE Mesalazine Budesonide Background Materials and methods Results Discussion Conclusion Acknowledgement PREDICTING FOOD EFFECTS ON DRUG RELEASE FROM EXTENDED- RELEASE ORAL DOSAGE FORMS:THEOPHYLLINE Theophylline Background Materials and methods Results and discussion Summary PREDICTING THE IN VIVO RELEASE BEHAVIOR OF A NOVEL PH- AND TIME-BASED MULTI-UNIT COLONIC DELIVERY SYSTEM III

12 Table of contents Selection of caffeine as a marker molecule Background Materials and methods Results and discussion Acknowledgement SUMMARY ZUSAMMENFASSUNG APPENDICES EXPERIMENTAL DATA LITERATURE IV

13 List of figures LIST OF FIGURES FIGURE 1.2.1: ANATOMY OF THE HUMAN GI TRACT... 7 FIGURE 1.2.2: ANATOMY OF THE HUMAN STOMACH... 8 FIGURE 1.3.1: INTERDIGESTIVE MOTILITY PATTERN OF THE STOMACH (MMC) (ADAPTED FROM AGA UNDERGRADUATE TEACHING PROJECT (HENDRIX)) FIGURE 1.3.2: INTERDIGESTIVE MOTILITY PATTERN IN THE STOMACH IS INTERRUPTED BY FEEDING (ADAPTED FROM AGA UNDERGRADUATE TEACHING PROJECT (HENDRIX)) FIGURE 1.3.3: GASTRIC EMPTYING OF A NONCALORIC FUID (PHYSIOLOGICAL SALINE, 0.9 % NACL (ADAPTED FROM BRENER,(BRENER 1983)) FIGURE 1.3.4: GASTRIC EMPTYING OF LIQUID AND SOLID COMPONENTS OF A MEAL (ADAPTED FROM CAMILLERI,(CAMILLERI ET AL 1985)) FIGURE 1.3.5: HUMAN INTESTINAL INTRALUMINAL VOLUMES AND ELECTROLYTE CONTENT FOLLOWING A HYPOTONIC (STEAK) MEAL AND A HYPERTONIC (MILK AND DOUGH-NUT) MEAL (ADAPTED FROM FORDTRAN (FORDTRAN & LOCKLEAR 1966)) FIGURE 1.4.1: USP APPARATUS 3(BIODIS )- COMPLETE SETUP FIGURE 1.4.2: USP APPARATUS 3: GLASS CYLINDER MOVING FROM ONE VESSEL TO ANOTHER FIGURE 3.3.1: TYPICAL FLOW CURVES OF STANDARD BREAKFAST MEALS (--- FDA OFFICE OF GENERIC DRUGS PREPARATION, GLAXOSMITHKLINE PREPARATION), N=3, MEAN VALUES ARE SHOWN) FIGURE 3.3.2: RHEOLOGICAL PROFILES OF ENSURE PLUS (-) AND ENSURE PLUS MIXTURES CONTAINING DIFFERENT AMOUNTS OF PECTIN ( 0.25 %, 0.45 %, 0.46 %, 0.50 %, AND 0.75 % PECTIN; N=3, MEAN VALUES ARE SHOWN) V

14 List of figures FIGURE 3.3.3: RHEOLOGICAL PROFILES OBSERVED FOR ENSURE PLUS ( ), THE STANDARD BREAKFAST MEALS ( STANDARD BREAKFAST 1, STANDARD BREAKFAST 2) AND THE ENSURE PLUS MIXTURE CONTAINING 0.45 % PECTIN ( PREPARED WITH AN ULTRATURRAX, PREPARED WITH A COLLOID MILL; N=6, MEAN VALUES ARE SHOWN)...79 FIGURE 4.4.1: STRUCTURAL FORMULA OF METOPROLOL...99 FIGURE 4.4.2: DRUG RELEASE FROM OF BELOK-ZOK (WITH PERMISSION OF ASTRAZENECA GMBH) FIGURE 4.4.3: DISSOLUTION PROFILES OF METOPROLOL AL 200 RETARD AND METOPROLOL-RETARD RATIOPHARM 200 GENERATED WITH USP APPARATUS 2(OPEN SYMBOLS) AND USP APPARATUS 3(CLOSED SYMBOLS) FIGURE 4.4.4: DISSOLUTION PROFILES OF BELOC-ZOK 95 MG AND METODURA Z 100 MG GENERATED WITH USP APPARATUS 2(OPEN SYMBOLS) AND USP APPARATUS 3(CLOSED SYMBOLS) FIGURE 4.4.5: DISSOLUTION PROFILES OF VARIOUS CONVENTIONAL ER FORMULATIONS OF METOPROLOL USING A PH-GRADIENT METHOD FIGURE 4.4.6: DISSOLUTION PROFILES OF NOVEL ER FORMULATIONS OF METOPROLOL USING A PH-GRADIENT METHOD FIGURE 4.4.7: DISSOLUTION PROFILES OF DIFFERENT DOSAGE STRENGTHS OF NOVEL ER FORMULATIONS OF METOPROLOL USING A PH-GRADIENT METHOD FIGURE 4.4.8: COMPARISON OF DRUG RELEASE FROM DIFFERENT TYPES OF METOPROLOL ER FORMULATIONS FIGURE 4.5.1: DRUG RELEASE RATE OF THE BUDESONIDE TEST FORMULATION AT RECIPROCATING RATES OF 10 AND 20 DPM USING DIFFERENT MESH SCREEN SIZES AT TOP AND BOTTOM OF THE GLASS CYLINDERS FIGURE 4.5.2: DRUG RELEASE RATE OF THE BUDESONIDE TEST FORMULATION AT RECIPROCATING RATES OF 10 AND 20 DPM USING DIFFERENT MESH SCREEN SIZES AT TOP AND BOTTOM OF THE GLASS CYLINDERS VI

15 List of figures FIGURE 4.5.3: DRUG RELEASE RATE OF THE BUDESONIDE TEST FORMULATION AT RECIPROCATING RATES OF 10 AND 20 DPM USING DIFFERENT MESH SCREEN SIZES AT TOP AND BOTTOM OF THE GLASS CYLINDERS FIGURE 4.6.1: STRUCTURAL FORMULA OF MESALAZINE FIGURE 4.6.2: STRUCTURAL FORMULA OF BUDESONIDE FIGURE 4.6.3: LOCALIZATION OF THE INFLAMED AREAS IN CROHN S DISEASE (ON THE LEFT HAND) AND ULCERATIVE COLITIS (ON THE RIGHT HAND). 133 FIGURE 4.6.4: PREPARATION OF DIFFERENT FASSIF MEDIA FROM A CONCENTRATE FIGURE 4.6.5: DISSOLUTION BEHAVIOR OF DIFFERENT MESALAZINE DOSAGE FORMS IN SIFSP PH FIGURE 4.6.6: DISSOLUTION BEHAVIOR OF DIFFERENT MESALAZINE DOSAGE FORMS IN HOSPHATE BUFFER PH FIGURE 4.6.7: DISSOLUTION BEHAVIOR OF DIFFERENT MESALAZINE DOSAGE FORMS IN PHOSPHATE BUFFER PH FIGURE 4.6.8: DISSOLUTION BEHAVIOR OF DIFFERENT MESALAZINE DOSAGE FORMS: SALOFALK 250 MG, CLAVERSAL 250 MG, PENTASA 250 MG, ASACOLITIN 400 MG DURING A SIMULATED GI-PASSAGE USING A PH-GRADIENT METHOD (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) FIGURE 4.6.9: DISSOLUTION BEHAVIOR OF SALOFALK 250 MG, CLAVERSAL 250 MG, PENTASA 250 MG, ASACOLITIN 400 MG IN A PHYSIOLOGICALLY BASED PH-GRADIENT METHOD UTILIZING COMPENDIAL MEDIA (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) FIGURE : DISSOLUTION BEHAVIOR OF SALOFALK 500 MG, CLAVERSAL 500 MG, PENTASA 500 MG, SALOFALK GRANUSTIX 500 MG IN A PHYSIOLOGICALLY BASED PH-GRADIENT METHOD UTILIZING COMPENDIAL MEDIA (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) VII

16 List of figures FIGURE : DISSOLUTION PROFILES OF PENTASA 500 MG MICROSPHERES GENERATED WITH THE PH-GRADIENT METHOD, USING DIFFERENT GASTRIC RESIDENCE TIMES: 30 MIN, 60 MIN, 120 MIN, (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) FIGURE : DISSOLUTION BEHAVIOR OF SALOFALK 500 MG, CLAVERSAL 500 MG, PENTASA 500 MG, SALOFALK GRANUSTIX 500 MG IN A BIORELEVANT PH-GRADIENT (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) FIGURE : MEAN % DRUG RELEASED FROM MESALAZINE TABLETS (CLAVERSAL 500 MG (C 500): GREY COLUMNS AND SALOFALK 500 MG (S 500): WHITE COLUMNS) IN DIFFERENT REGIONS OF THE GI DRUG, ESTIMATED FROM THE DISSOLUTION PROFILES AND ASSUMING A GET OF 60 MIN IN THE BIORELEVANT PH-GRADIENT FIGURE : MEAN % DRUG RELEASED FROM MESALAZINE MICROGRANULES (PENTASA 500 MG (P 500): GREY COLUMNS AND SALOFALK GRANUSTIX 500 MG (SG 500): WHITE COLUMNS) IN DIFFERENT REGIONS OF THE GI DRUG, ESTIMATED FROM THE DISSOLUTION PROFILES AND ASSUMING A GET OF 30 MIN IN THE BIORELEVANT PH-GRADIENT FIGURE : DISSOLUTION PROFILES OF DIFFERENT BUDESONIDE DOSAGE FORMS IN SIMULATED INTESTINAL FLUID (SIFSP) USP AT PH 6.8 (CLOSED SYMBOLS) AND PH 7.5 (OPEN SYMBOLS) FIGURE : DISSOLUTION BEHAVIOR OF: BUDENOFALK 3 MG AND ENTOCORT 3 MG DURING A SIMULATED GI-PASSAGE USING A PH-GRADIENT METHOD (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) FIGURE : DISSOLUTION BEHAVIOR OF BUDENOFALK 3 MG, ENTOCORT 3 MG, IN A PHYSIOLOGICALLY BASED PH-GRADIENT METHOD USING COMPENDIAL MEDIA (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) FIGURE : DISSOLUTION BEHAVIOR OF BUDENOFALK 3 MG, ENTOCORT 3 MG, IN A BIORELEVANT PH-GRADIENT (SHADED PART: DRUG RELEASE IN THE SMALL INTESTINE) VIII

17 List of figures FIGURE : MEAN % DRUG RELEASED FROM BUDESONIDE MICROSPHERES (BUDENOFALK (B) 3 MG: GREY COLUMNS AND ENTOCORT (E) 3 MG: WHITE COLUMNS) IN DIFFERENT REGIONS OF THE GI DRUG, ESTIMATED FROM THE DISSOLUTION PROFILES AND ASSUMING A GET OF 30 MIN FIGURE 4.7.1: STRUCTURAL FORMULA OF THEOPHYLLINE FIGURE 4.7.2: PREPARATION OF TWO DIFFERENT FESSIF PH 6.5 MEDIA FROM A CONCENTRATE FIGURE 4.7.3: PHASE SEPARATION AFTER CENTRIFUGATION OF ENSURE PLUS SAMPLES FIGURE 4.7.4: DISSOLUTION BEHAVIOR OF DIFFERENT THEOPHYLLINE ER DOSAGE FORMS CREATED WITH THE PADDLE APPARATUS IN SIFSP PH FIGURE 4.7.5: DISSOLUTION BEHAVIOR OF DIFFERENT THEOPHYLLINE ER DOSAGE FORMS CREATED WITH THE BIODIS APPARATUS IN SIFSP PH FIGURE 4.7.6: DISSOLUTION PROFILES OF UNILAIR 300 PELLETS UNDER FASTED AND FED STATE CONDITIONS FIGURE 4.7.7: DISSOLUTION PROFILES OF AEROBIN 300 NORMO PELLETS UNDER FASTED AND FED STATE CONDITIONS FIGURE 4.7.8: DISSOLUTION PROFILES OF THEOPHYLLIN AL 300 RETARD PELLETS UNDER FASTED AND FED STATE CONDITIONS FIGURE 4.7.9: DISSOLUTION PROFILES OF THEOPHYLLIN AZU 300 MG PELLETS RETARD UNDER FASTED AND FED STATE CONDITIONS FIGURE : DISSOLUTION PROFILES OF CONTIPHYLLIN 300 MG TABLETS UNDER FASTED AND FED STATE CONDITIONS FIGURE : DISSOLUTION PROFILES OF TROMPHYLLIN RETARD 300 MG TABLETS UNDER FASTED AND FED STATE CONDITIONS FIGURE : DISSOLUTION PROFILES OF CONTIPHYLLIN 300 MG AND TROMPHYLLIN RETARD 300 MG TABLETS RESULTING FROM THE INFINITY POINT TEST FIGURE : DRUG RELEASE RATES OF CONTIPHYLLIN 300 MG AND TROMPHYLLIN RETARD 300 MG TABLETS UNDER FED STATE GASTRIC CONDITIONS IX

18 List of figures FIGURE : SIZE AND SHAPE OF A CONTIPHYLLIN 300 MG TABLET (LEFT HAND SIDE) COMPARED TO A TROMPHYLLIN RETARD 300 MG TABLET (RIGHT HAND SIDE) FIGURE : CONTIPHYLLIN 300 MG AND TROMPHYLLIN RETARD 300 MG TABLETS BEFORE AND AFTER A TEST DURATION OF 4 HOURS (2 HOURS IN BLANK FESSIF AND 2 HOURS IN SGF PH 2.0) FIGURE : CONTIPHYLLIN 300 MG AND TROMPHYLLIN RETARD 300 MG TABLETS BEFORE AND AFTER A TEST DURATION OF 2 AND 4 HOURS IN ENSURE PLUS FIGURE 4.8.1: STRUCTURAL FORMULA OF CAFFEINE FIGURE 4.8.2: SCHEMATIC ILLUSTRATION OF THE MULTIUNIT DELIVERY SYSTEM EUDRAGIT RL/RS 30 D, FS 30 D (ADOPTED FROM BOTT ET AL. (BOTT 2004)) FIGURE 4.8.3: DISSOLUTION BEHAVIOR OF PROTOTYPE A(PH AND TIME- DEPENDENT RELEASE) AND PROTOTYPE B(PH-DEPENDENT RELEASE) IN THE PHYSIOLOGICAL BASED PH-GRADIENT OF SET-UP # 1, (SHADED PART REPRESENTS DRUG RELEASE IN THE SMALL INTESTINE) FIGURE 4.8.4: DISSOLUTION BEHAVIOR OF PROTOTYPE A(PH AND TIME- DEPENDENT RELEASE) AND PROTOTYPE B(PH-DEPENDENT RELEASE) IN THE PHYSIOLOGICAL BASED PH-GRADIENT OF SET-UP # 2, (SHADED PART REPRESENTS DRUG RELEASE IN THE SMALL INTESTINE) FIGURE 4.8.5: CALCULATED FRACTION ABSORBED FROM PROTOTYPE A(TIME- AND PH-DEPENDENT RELEASE) AND PROTOTYPE B(PH-DEPENDENT RELEASE) FOLLOWING ORAL APPLICATION FIGURE 4.8.6: COMPARISON OF THE MEAN FRACTION ABSORBED IN VIVO AND THE MEAN FRACTION RELEASED IN VITRO UNDER TEST CONDITIONS OF SET-UP #1 OVER THE SAME TIME RANGE FIGURE 4.8.7: COMPARISON OF THE MEAN FRACTION ABSORBED IN VIVO AND THE MEAN FRACTION RELEASED RELEASED IN VITRO UNDER TEST CONDITIONS OF SET-UP #2 OVER THE SAME TIME RANGE X

19 List of figures FIGURE 4.8.8: RELATIONSHIP BETWEEN THE MEAN FRACTION ABSORBED IN VIVO AND THE MEAN FRACTION RELEASED IN VITRO UNDER CONDITIONS OF SET-UP # 1 AND B. THE LINE REPRESENTS THE LINEAR REGRESSION OF THE DATA WHERE F ABS = F REL AND R 2 = FOR PROTOTYPE A AND F ABS = F REL AND R 2 = FOR PROTOTYPE B FIGURE 4.8.9: RELATIONSHIP BETWEEN THE MEAN FRACTION ABSORBED IN VIVO AND THE MEAN FRACTION RELEASED IN VITRO UNDER CONDITIONS OF SET-UP # 2 AND B. THE LINE REPRESENTS THE LINEAR REGRESSION OF THE DATA WHERE F ABS = F REL AND R 2 = FOR PROTOTYPE A AND F ABS = F REL AND R 2 = FOR PROTOTYPE B FIGURE 7.1.1: MESALAZINE STANDARD CURVES FROM HPLC METHOD VALIDATION FIGURE 7.1.2: THEOPHYLLINE STANDARD CURVES FROM HPLC METHOD VALIDATION FIGURE 7.1.3: MEAN PLASMA CURVES (N=12) RESULTING FROM PROTOTYPE A (PH- AND TIME-BASED MULTI-UNIT FORMULATION) AFTER ADMINISTRATION IN THE FASTED STATE FIGURE 7.1.4: MEAN PLASMA CURVES (N=12) RESULTING FROM PROTOTYPE B (PH-BASED MULTI-UNIT FORMULATION) AFTER ADMINISTRATION IN THE FASTED STATE FIGURE 7.1.5: MEAN PLASMA CURVES (N=12) RESULTING FROM PROTOTYPE A( ) AND B( ) AFTER ADMINISTRATION IN THE FASTED STATE XI

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21 List of tables LIST OF TABLES TABLE 1.1.1: CLASSIFICATION OF COMMON MR DOSAGE FORMS (RACHEV ET AL 1989; LANGER 1990; FLORENCE & JANI1994; COLOMBO1996A; GANDHI ET AL 1999)... 5 TABLE 1.3.1: SEGMENTS OF THE GI TRACT AND THEIR CORRESPONDING FUNCTIONS TABLE 1.3.2: CONSEQUENCES OF FOOD INTAKE ON GASTRIC ENVIRONMENT TABLE 1.3.3: MEAN GASTRIC EMPTYING (GET50%) TIMES FOR SINGLE UNIT AND MULTIPLE UNIT DOSAGE FORMS UNDER DIFFERENT DOSING CONDITIONS (MEAN VALUES ARE GIVEN) TABLE 1.3.4: MEAN PH VALUES IN THE FASTED STATE SMALL INTESTINE TABLE 1.3.5: RANGE OF PH VALUES MEASURED THE FED STATE SMALL INTESTINE TABLE 1.3.6: FOOD-INDUCED CHANGES IN THE SMALL INTESTINE TABLE 1.4.1: OFFICIAL DISSOLUTION APPARATUS ACCORDING TO THEIR USP CLASSIFICATION TABLE 1.4.2: VARIABLE DISSOLUTION PARAMETERS USING USP APPARATUS 3 AND THEIR CORRESPONDING IN VIVO ASPECTS TABLE 1.5.1: SAMPLE COMPOSITION FOR SIMULATING FASTED STATE GASTRIC CONDITIONS ( SGFPLUS ) TABLE 1.5.2: COMPOSITION OF THE BIORELEVANT MEDIUM USED TO SIMULATE FASTED STATE CONDITIONS IN THE SMALL INTESTINE (RECOMMENDED VOLUME FOR DISSOLUTION STUDIES IS 500 ML) TABLE 1.5.3: COMPOSITION OF THE BIORELEVANT MEDIUM USED TO SIMULATE FED STATE CONDITIONS IN THE SMALL INTESTINE (RECOMMENDED VOLUME FOR DISSOLUTION STUDIES IS 1000 ML) TABLE 3.2.1: COMPOSITION OF STANDARD BREAKFAST MEAL 1 # TABLE 3.2.2: COMPOSITION OF STANDARD BREAKFAST MEAL 2* TABLE 3.2.3: INGREDIENTS OF THE STANDARD BREAKFAST MEALS TABLE 3.3.1: PHYSICOCHEMICAL PARAMETERS OF STANDARD BREAKFAST MEALS, ENSURE AND ENSURE PLUS XIII

22 List of tables TABLE 3.3.2: COMPOSITION AND NUTRITIVE VALUES OF ENSURE PLUS DRINK (VANILLA FLAVOR)*...77 TABLE 4.1.1: STANDARD CHEMICALS USED FOR IN VITRO STUDIES...84 TABLE 4.1.2: STANDARD EQUIPMENT USED FOR IN VITRO STUDIES...85 TABLE 4.1.3: STANDARD EQUIPMENT USED FOR PREPARATION AND ANALYSIS OF DISSOLUTION MEDIA...85 TABLE 4.1.4: STANDARD EQUIPMENT USED FOR UV ANALYSIS...86 TABLE 4.1.5: STANDARD EQUIPMENT USED FOR HPLC ANALYSIS...86 TABLE 4.2.1: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF SGFSP AT VARIOUS PH VALUES...88 TABLE 4.2.2: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF SGF PLUS...88 TABLE 4.2.3: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF PHOSPHATE BUFFER PH TABLE 4.2.4: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF PHOSPHATE BUFFER PH TABLE 4.2.5: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF SIFSP (USP 24) PH TABLE 4.2.6: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF PHOSPHATE BUFFER PH TABLE 4.2.7: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF SIFSP (USP 23) PH TABLE 4.2.8: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF BLANK FASSIF*...92 TABLE 4.2.9: COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF BLANK FESSIF*...93 TABLE : COMPOSITION AND PHYSICOCHEMICAL PROPERTIES OF SCOF...94 TABLE 4.4.1: FORMULATIONS STUDIED TABLE 4.4.2: AGITATION CONDITIONS IN USP DISSOLUTION APPARATUS 3 ESTIMATED TO BE EQUIVALENT TO USP APPARATUS 2(ADAPTED FROM ROHRS ET AL.) TABLE 4.4.3: MEDIA AND RESIDENCE TIMES USED TO SIMULATE GASTROINTESTINAL PASSAGE IN THE FASTED STATE XIV

23 List of tables TABLE 4.4.4: F 1 AND F 2 VALUES FROM AGITATION SPEED COMPARISON TABLE 4.4.5: F 2 VALUES FROM COMPARISON OF CONVENTIONAL METOPROLOL ER FORMULATIONS TABLE 4.4.6: F 2 VALUES FROM COMPARISON OF DIFFERENT STRENGTHS OF BELOC-ZOK TABLE 4.4.7: F 2 VALUES FROM COMPARISON OF DIFFERENT STRENGTHS OF METODURA Z TABLE 4.4.8: F 2 VALUES FROM COMPARISON OF CONVENTIONAL AND ZERO-ORDER TYPES OF METOPROLOL ER FORMULATIONS TABLE 4.4.9: F 2 VALUES FROM COMPARISON OF ZERO-ORDER MULTIPARTICULATES AND MATRICES OF SAME STRENGTH TABLE 4.5.1: COMBINATIONS OF MESH SCREEN SIZES USED IN THE INSTRUMENT PARAMETER STUDY TABLE 4.5.2: APPLICABILITY OF DIFFERENT COMBINATIONS OF MESH SIZES TABLE 4.6.1: COMPOSITION OF MARKETED MESALAZINE DOSAGE FORMS TABLE 4.6.2: COMPOSITION OF MARKETED BUDESONIDE DOSAGE FORMS TABLE 4.6.3: FORMULATIONS STUDIED TABLE 4.6.4: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN THE STUDY MESALAZINE # TABLE 4.6.5: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN THE STUDY MESALAZINE # TABLE 4.6.6: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN THE STUDY MESALAZINE # TABLE 4.6.7: PH VALUES AND BILE SALT CONCENTRATIONS USED TO SIMULATE PASSAGE THROUGH THE FASTED SMALL INTESTINE TABLE 4.6.8: COMPOSITION OF SODIUM HYDROXIDE SOLUTION FOR FASSIF MEDIA TABLE 4.7.1: USP 24 TEST METHODS FOR THEOPHYLLINE EXTENDED-RELEASE PREPARATIONS (USP 2002) TABLE 4.7.2: FORMULATIONS STUDIED TABLE 4.7.3: COMPOSITION OF THE THEOPHYLLINE FORMULATIONS STUDIED XV

24 List of tables TABLE 4.7.4: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN THE FASTED STATE THEOPHYLLINE STUDY TABLE 4.7.5: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN THE FED STATE THEOPHYLLINE STUDY TABLE 4.7.6: PH VALUES AND BILE SALT CONCENTRATIONS USED TO SIMULATE PASSAGE THROUGH THE FED SMALL INTESTINE TABLE 4.7.7: F 2 VALUES FROM COMPARISON OF THEOPHYLLINE ER FORMULATIONS IN THE PADDLE APPARATUS (SIFSP PH 6.8, 50 RPM, N=3) TABLE 4.7.8: F 1 VALUES FROM COMPARISON OF THEOPHYLLINE ER FORMULATIONS IN THE PADDLE APPARATUS (SIFSP PH 6.8, 50 RPM, N=3) TABLE 4.7.9: F 2 VALUES FROM COMPARISON OF THEOPHYLLINE ER FORMULATIONS IN THE BIODIS APPARATUS (SIFSP PH 6.8, 10 DPM, N=3) TABLE : F 1 VALUES FROM COMPARISON OF THEOPHYLLINE ER FORMULATIONS IN THE BIODIS APPARATUS (SIFSP PH 6.8, 10 DPM, N=3) TABLE : DIMENSIONS AND WEIGHT OF A CONTIPHYLLIN 300 MG TABLET (LEFT HAND SIDE) COMPARED TO A TROMPHYLLIN RETARD 300 MG TABLET (RIGHT HAND SIDE) TABLE 4.8.1: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN SET-UP # TABLE 4.8.2: DISSOLUTION MEDIA AND TRANSIT TIMES USED IN SET-UP # TABLE 7.1.1: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 2, SIFSP PH 6.8, 100 RPM TABLE 7.1.2: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 2, SIFSP PH 6.8, 100 RPM TABLE 7.1.3: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH 6.8, 10 DPM TABLE 7.1.4: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH 6.8, 10 DPM TABLE 7.1.5: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM TABLE 7.1.6: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM XVI

25 List of tables TABLE 7.1.7: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM TABLE 7.1.8: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM TABLE 7.1.9: METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM TABLE : METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM TABLE : METOPROLOL RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT,10 DPM TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, VARYING TOP AND BOTTOM MESH AND RECIPROCATING RATE TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, VARYING TOP AND BOTTOM MESH AND RECIPROCATING RATE TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, VARYING TOP AND BOTTOM MESH AND RECIPROCATING RATE TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, VARYING TOP AND BOTTOM MESH AND RECIPROCATING RATE TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, VARYING TOP AND BOTTOM MESH AND RECIPROCATING RATE TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, VARYING TOP AND BOTTOM MESH AND RECIPROCATING RATE TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 2, SGF PH 1.2 AND PHOSPHATE BUFFER PH 7.2, 100 RPM TABLE : MESALAZIN RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH XVII

26 List of tables TABLE : MESALAZIN RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH TABLE : MESALAZIN RELEASE DATA (% RELEASE), USP APPARATUS 3, PHOSPHATE BUFFER PH TABLE : MESALAZIN RELEASE DATA (% RELEASE), USP APPARATUS 3, PHOSPHATE BUFFER PH TABLE : MESALAZIN RELEASE DATA (% RELEASE), USP APPARATUS 3, PHOSPHATE BUFFER PH TABLE : MESALAZIN RELEASE DATA (% RELEASE), USP APPARATUS 3, PHOSPHATE BUFFER PH TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, BIORELEVANT PH-GRADIENT, MESALAZINE # TABLE : MESALAZINE RELEASE DATA (% RELEASE), USP APPARATUS 3, BIORELEVANT PH-GRADIENT, MESALAZINE # TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, BUDESONIDE # XVIII

27 List of tables TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, BUDESONIDE # TABLE : BUDESONIDE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH-GRADIENT, BUDESONIDE # TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 2, SIFSP PH 6.8, 50 RPM TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 2, SIFSP PH 6.8, 50 RPM TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 2, SIFSP PH 6.8, 50 RPM TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH 6.8, 10 DPM TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH 6.8, 10 DPM TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, SIFSP PH 6.8, 10 DPM TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FASTED STATE PH-GRADIENT, COMPENDIAL MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FASTED STATE PH-GRADIENT, COMPENDIAL MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FASTED STATE PH-GRADIENT, COMPENDIAL MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FASTED STATE PH-GRADIENT, BIORELEVANT MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FASTED PH-GRADIENT BIORELEVANT MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FASTED STATE PH-GRADIENT, BIORELEVANT MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FED STATE PH-GRADIENT, COMPENDIAL MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FED STATE PH-GRADIENT, COMPENDIAL MEDIA XIX

28 List of tables TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FED STATE PH-GRADIENT, COMPENDIAL MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FED STATE PH-GRADIENT, BIORELEVANT MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FED STATE PH-GRADIENT BIORELEVANT MEDIA TABLE : THEOPHYLLINE RELEASE DATA (% RELEASE), USP APPARATUS 3, FED STATE PH-GRADIENT, BIORELEVANT MEDIA TABLE : THEOPHYLLINE PEAK AREAS RESULTING FROM THE REFERENCE STANDARD USED FOR THE INFINITY POINT RELIABILITY TEST TABLE : THEOPHYLLINE PEAK AREAS RESULTING FROM INFINITY POINT RELIABILITY TEST, USP APPARATUS 3, 240 MIN ENSURE PLUS (STOMACH), 480 MIN SGF (INFINITY POINT MEASUREMENT) TABLE : DRUG RELEASE (% RELEASE) FROM CONTIPHYLLIN 300 MG AND TROMPHYLLIN RETARD 300 MG UNDER SIMULATED POSTPRANDIAL GASTRIC CONDITIONS (ENSURE PLUS ) TABLE : CAFFEINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH- GRADIENT, SET-UP # TABLE : CAFFEINE RELEASE DATA (% RELEASE), USP APPARATUS 3, PH- GRADIENT, SET-UP # TABLE : SINGLE PLASMA DATA RESULTING FROM PROTOTYPE A(PH- AND TIME-BASED MULTI-UNIT FORMULATION) AFTER ADMINISTRATION IN THE FASTED STATE TABLE : SINGLE PLASMA DATA RESULTING FROM PROTOTYPE B(PH-BASED MULTI-UNIT FORMULATION) AFTER ADMINISTRATION IN THE FASTED STATE XX

29 Abbreviations ABBREVIATIONS 5-ASA APAP AUC BCS BP CD CHOs C max CMC C min CNS COLD c ss CTT dpm DR ER et al f abs FaSSIF 5-aminosalicylic acid Acetaminophen Area under curve Biopharmaceutical classification scheme British Pharmacopoeia Crohn s disease Carbohydrates Maximal plasma concentration Critical micelle concentration Minimal plasma concentration Central nervous system Chronic obstructive lung diseases Steady state concentration Colonic transit time Dips per minute (unit) Dissolution rate Extended release et alii (and others) Fraction absorbed Fasted state simulating intestinal fluid XXI

30 Abbreviations FDA FeSSIF f rel g GET GI GMP GRAS HPLC HPMC IBD IR ISA IVIVC JP k el kg l LU μg μl μm Food and Drug Administration Fed state simulating intestinal fluid Fraction released Grams (unit) Gastric emptying time Gastrointestinal Good manufacturing practice Generally regarded/recognized as safe High performance liquid chromatography Hydroxypropylmethylcellulose Intestinal bowel disease(s) Immediate release Intrinsic sympathomimetic activity In vitro in vivo correlation Japanese Pharmacopoeia Elimination rate constant (unit) Kilogram(s) Litre(s) (unit) Lactoseureide Microgram(s) (unit) Microlitre(s) (unit) Micrometers (unit) XXII

31 Abbreviations m m/m [%] mbar meq MHPC min ml MMC MMM mmol mn MR N nm OCTT PA PEG PhEur PMMA PTF PTFE R 2 Meter(s) (unit) Mass percent (unit) Millibar (unit) Milli equivalent(s) Methylhydroxypropylcellulose Minute(s) (unit) Millilitre(s) (unit) Migrating motility/myoelectricity complex Magnetic marker monitoring Millimol (unit) MilliNewton (unit) Modified release Normal (concentration) Nanometres (unit) Orocecal transit time Polyamide Polyethylenglycol European Pharmacopoeia poly(methacryl)methacrylate(s) Peak-through-fluctuation Teflon Regression coefficient XXIII

32 Abbreviations rpm SCoF SD SFCA SGF SGFsp SI SIF SIFsp SITT SR SUPAC TEC t max UC USP UV vs ZOK Rounds per minute (unit) Simulated colonic fluid Standard deviation Short-chain fatty acid Simulated gastric fluid Simulated gastric fluid sine pepsin Small intestine / small intestinal Simulated intestinal fluid Simulated intestinal fluid sine pancreatin Small intestinal transit time Sustained release Scale up and post approval changes Triethyl citrate Time to maximal plasma concentration Ulcerative colitis United States Pharmacopoeia Ultraviolet versus Zero order kinetics XXIV