Preface xvii
List of Contributors xix
Part I Understanding of Physiology and Anatomy - Factors Influencing Drug Release and Absorption from MR Formulations 1
1a Composition of Gastric Fluids Under Fasting and Fed Conditions 3
Jens Van Den Abeele and Patrick Augustijns
1a.1 Gastric Volume 3
1a.2 Gastric Acid 3
1a.3 Buffer Capacity 4
1a.4 Mucus/Viscosity 5
1a.5 Enzymes 5
1a.6 Surface Tension 6
1a.7 Osmolality 6
1a.8 Duodenogastric Reflux 7
References 7
1b Composition of the Small Intestinal Contents Under Fasting and Fed Conditions 11
Edmund S. Kostewicz
1b.1 Small Intestinal Volume 11
1b.2 pH Profile Along the Small Intestine 12
1b.3 Composition of the Luminal Contents 12
1b.3.1 Bile 13
1b.3.2 Phospholipids 13
1b.3.3 Monoglycerides and Free Fatty Acids 13
1b.4 Other Characteristics of Small Intestinal Fluids 14
1b.4.1 Buffer Capacity 14
1b.4.2 Osmolality 14
1b.4.3 Surface Tension 14
1b.4.4 Ionic Strength 15
1b.4.5 Viscosity 15
1b.5 Influence of Age, Gender, and Disease on the Small Intestinal Composition 15
References 16
1c The Luminal Environment in the Proximal Colon 19
Maria Vertzoni and Christos Reppas
1c.1 Volume of Luminal Contents 19
1c.1.1 Liquid Contents 19
1c.1.2 Aspirated Contents and Liquid Fractions 20
1c.2 Luminal pH Values 20
1c.2.1 Data Collected with Telemetric Capsules 20
1c.2.2 Data Collected with Aspirated Samples 20
1c.3 Buffer Capacity 22
1c.4 Characteristics of Liquid Fraction of Contents 22
1c.5 Concluding Remarks 22
References 23
2 Gastrointestinal Transit and Hydrodynamics Under Fasting and Fed Conditions 25
Mirko Koziolek
2.1 Introduction 25
2.2 Imaging Techniques Used for Assessment of Transit Times and Hydrodynamics 25
2.3 Oral Cavity and Esophagus 25
2.4 Stomach 26
2.5 Small Intestine 29
2.6 Large Intestine 31
2.7 Whole Gut Transit Time 32
2.8 Therapy- Related Effects on GI Transit 33
2.9 Motility Disorders Affecting the GI Transit of Oral Dosage Forms 33
2.10 Patient- Related Effects on GI Transit 34
2.10.1 Age 34
2.10.2 Gender 35
2.10.3 Dietary and Smoking Habits 35
2.11 Conclusion 36
References 36
3 Intestinal Epithelium and Drug Transporters 39
Karelle Ménochet, Hugues Chanteux, Jamie Henshall, Jean- Marie Nicolas, Sara Wright, Judith van Asperen, and Anna- Lena Ungell
3.1 Introduction: Oral Drug Absorption General Mechanisms and Influencing Factors 39
3.2 Expression of Drug Transporters in the Intestinal Epithelium 40
3.3 Uptake Transporters Present at the Intestinal Level 40
3.4 Regional Distribution of Uptake Transporters 42
3.5 Efflux Transporters at the Intestinal Level 42
3.6 Regional Distribution of Efflux Transporters 43
3.7 Impact of the Regional Distribution of Enzymes and Transporters in the Intestine on the Enzyme/Transporter Interplay 43
3.8 Species Differences in Regional Expression of Uptake and Efflux Transporters 44
3.9 Models for Regional Assessment of Intestinal Permeability 45
3.10 Use of PBPK to Integrate Formulation and Permeation Knowledge 46
3.11 Impact of Regional Solubility and Permeability Along the Intestine 47
3.12 Formulation Excipients and Their Potential Modulatory Effects on Transporters 48
3.13 Other Confounding Factors Affecting Drug Intestinal Absorption 51
3.14 Drug-Drug Interactions 52
3.15 Conclusion and Future Challenges 53
References 53
4 The Interplay Between Drug Release and Intestinal Gut- Wall Metabolism 65
Adam S. Darwich, Oliver J. Hatley, Andrés Olivares- Morales, Farzaneh Salem, Alison Margolskee, and Amin Rostami- Hodjegan
4.1 The Role of Gut Wall Metabolism in Determining Oral Bioavailability 65
4.1.1 Cytochrome P450's (CYPs) 66
4.1.2 Uridine 5¿- Diphosphate Glucuronosyltransferases (UGTs) 68
4.1.3 Sulfotransferases (SULTs) 68
4.1.4 Other Drug- Metabolizing Enzymes in the Gut- Wall 68
4.1.5 Luminal Degradation in the Gut 69
4.2 Factors Affecting Gut Wall Metabolism 69
4.2.1 Absorption 69
4.2.2 Mucosal Blood Flow 70
4.2.3 Protein Binding 70
4.2.4 Metabolic Drug-Drug Interactions 70
4.2.5 Intestinal Transporter- Metabolism Interplay 70
4.3 Preclinical and Clinical In Vivo and In Situ Models for Studying Intestinal Metabolism 71
4.4 In Vitro Assays for Studying Intestinal Metabolism 72
4.5 Models for Studying Bacterial Degradation 74
4.6 In Vitro-In Vivo Extrapolation of Metabolic Clearance and In Silico Models for Predicting In Vivo Gut Wall Metabolism 75
4.7 Oral Extended- Release Formulations and Gut Wall Metabolism 76
4.8 Excipient Effects on Gut Wall Metabolism 77
4.9 Considerations for Intestinal Metabolism in Special Populations 77
4.10 Summary 79
References 79
Part II Design of MR Formulations - Considerations, Mechanisms and Technologies 87
5 Preformulation Considerations for Design of Oral Modified- Release Products 89
Christel A. S. Bergström and René Holm
5.1 Introduction 89
5.2 Purpose of MR Formulations 90
5.3 Means to Obtain MR Drug Products 91
5.3.1 Physicochemical Characterization of the Drug Substance and its Impact on the Design of Modified- release Dosage Forms 92
5.4 Ionization Constant - pK a 93
5.5 Lipophilicity 93
5.6 Solubility 93
5.7 Chemical Stability 93
5.8 Solid State Characterization 94
5.9 Compatibility with Excipients 94
5.10 Permeability and Metabolism 94
5.10.1 Additional Early Drug Substance Testing 95
5.11 Regional Absorption 95
5.12 Microbial Stability 96
5.12.1 Early Performance Testing of Formulations 96
5.13 Quality by Design (QbD) for MR formulations 97
5.14 Conclusions 98
References 98
6 The Application of Biopharmaceutics Classification Systems to Modified- Release Formulations 103
James M. Butler
6.1 Introduction 103
6.2 The Use of Biopharmaceutics Classification Systems in Oral Drug Development 103
6.3 The Application of Classification Systems to MR Drug Product Development - An Evidence- Based Approach 104
6.3.1 Test Sets Used 104
6.3.2 Where Do Successfully Marketed Modified- Release Products Fit in Solubility/Permeability Classification Systems? 108
6.3.3 Classification System Categorization and Relative Colonic Bioavailability Data 109
6.3.4 The Significance of Dissolution Rate and Solubility in the Colon 109
6.3.5 Does Ionization State Matter? 111
6.3.6 Managing Low Solubility (DCS IIA/IIB) 112
6.3.7 Managing Low Permeability (DCS III/IV) 112
6.3.8 Beyond Permeability and Solubility: Other Factors Affecting MR Feasibility 112
6.3.8.1 Time- period for Drug Release and Absorption 113
6.3.8.2 Bacterial Metabolism in the Colon 113
6.3.8.3 Uptake Transporters 113
6.3.8.4 Gut Wall First- Pass Metabolism 113
6.3.8.5 Efflux Transporters 113
6.3.9 Relative Bioavailability in the Colon (F rel Colon) as a Guide to Extended- Release Formulation Feasibility 113
6.3.10 The Properties of Drugs for Delayed- Release (Gastro Protection) 113
6.3.11 The Properties of Drugs for Targeting Local Release in the Lower GI Tract 114
6.4 Summary 114
References 114
7 Technologies and Mechanisms for Oral Modified Release by Monolithic and Multiparticulate Delivery Systems 119
Gaia Colombo, Stavros Politis, and Alessandra Rossi
7.1 Introduction 119
7.2 Mechanism of Drug Release 121
7.3 Manufacturing Processes 124
7.3.1 Pelletization Processes 124
7.3.1.1 Extrusion-spheronization 124
7.3.1.2 Layering Techniques 125
7.3.1.3 Direct Pelletization from Powders (Wet Granulation) 126
7.3.2 Particulate Production from Liquid Systems (Globulation Methods) 127
7.3.2.1 Pelletization Methods Utilizing Melts 127
7.3.2.2 Spray Drying and Spray Congealing 127
7.3.2.3 Jet Cutting (Prilling) 128
7.3.3 Compression Methods 128
7.4 Formulation Screening and Characterization 128
7.5 Conclusions and Perspectives 131
References 131
8 Lipid- based Formulations 137
Joseph P. O'Shea, Caitriona M. O'Driscoll, and Brendan T. Griffin
8.1 Introduction 137
8.2 Mechanisms of Lipid- mediated Improvements in Bioavailability 138
8.2.1 Increased Drug Solubilization and Dissolution in the GIT 138
8.2.2 Increased Intestinal Permeability, Reduced First- pass Metabolism, and Intestinal Efflux 140
8.2.3 Promotion of Intestinal Lipid Absorption and Lymphatic Uptake 141
8.3 Lipid- based Formulations for Controlled Release 142
8.3.1 Solid Lipid Excipient Matrices 142
8.3.2 Solid Lipid Nanoparticles 143
8.4 Design of Lipid- based Formulations 144
8.4.1 Excipient Type and Selection 144
8.4.2 Drug Loading 146
8.4.3 Formulation Types and the Lipid Formulation Classification System 146
8.5 Formulation Screening and Characterization 146
8.5.1 Drug Solubility in Lipid- based Formulations 146
8.5.2 Self- emulsification and the Effect of Dispersion 149
8.5.3 Impact of Digestion 150
8.5.4 Assessing Supersaturation and Precipitation 151
8.5.5 Identifying Formulation Limiting Factors and the Lipid Formulation Performance Classification System (LF- PCS) 152
8.5.6 Characterization of Nanoparticulate Lipid- based Formulations 152
8.5.7 Preclinical to Clinical Dose Scaling and Developing In Vitro and In Vivo Correlations 153
8.6 Industrial Considerations on LBF 154
8.7 Emerging Applications of Lipid- based Formulations 154
8.8 Conclusions 155
References 155
9 Strategies for MR Formulation Development: Mesoporous Silica 161
Georgios K. Eleftheriadis, Eleni Kontogiannidou, Christina Karavasili, and Dimitrios G. Fatouros
9.1 Introduction 161
9.2 Technologies 161
9.2.1 The Template Method in Synthesis of Mesoporous Silica 161
9.2.1.1 M41S Mesoporous Materials 161
9.2.1.2 SBA Mesoporous Materials 162
9.2.2 Factors Affecting Drug Loading 162
9.3 Characterization 163
9.4 Stability of Drug Carrier 165
9.5 Silica- based Materials for the Modified Release of Poorly Soluble Drugs - In Vitro/In Vivo Applications 166
9.5.1 pH- sensitive Silica- based Systems 167
9.5.2 Surface- modification of Silica- based Materials 169
9.5.3 Lipid Formulations of Silica- based Materials 169
9.6 Toxicological Assessment 171
9.6.1 In vitro Toxicity 171
9.7 Conclusions and Future Directions 173
References 173
10 Hot- Melt Extrusion Technology for Modified- Release (MR) Formulation Development 181
Harpreet Sandhu, Siva Ram Kiran Vaka, Dipen Desai, Paras Jariwala, Aruna Railkar, Wantanee Phuapradit, and Navnit Shah
10.1 Introduction 181
10.2 HME Technology Overview 182
10.2.1 Feeding of Raw Materials 182
10.2.1.1 Single- screw Extruders: Flood Feeding 183
10.2.1.2 Twin- screw Extruders: Starve Feeding 183
10.2.2 Conveying and Melting 183
10.2.3 Mixing 183
10.2.3.1 Dispersive Mixing 183
10.2.3.2 Distributive Mixing 184
10.2.4 Venting 184
10.2.5 Die Pressurization 184
10.2.6 Pumping and Shaping 184
10.2.7 Postprocessing 184
10.2.8 Process Monitoring and Statistical Process Controls 184
10.3 General Considerations in Developing MR Dosage Forms Using HME Processing 185
10.4 Material Considerations for MR- HME Application 187
10.5 Dosage Form Design and Case Studies 189
10.5.1 Powder/Granules/Multiparticulates 190
10.5.2 Compressed Tablets 193
10.6 Characterization of HME Products 195
10.6.1 Rheological Techniques 196
10.6.2 Use of Diffraction- Based Methods 196
10.6.3 Spectroscopic Methods 196
10.6.4 Thermal Methods 197
10.6.5 Microscopic Techniques 197
10.6.6 Chemical Properties 198
10.6.7 In Vitro Dissolution/Release Properties 198
10.7 Summary 200
References 200
11 Gattefosse: Strategies for MR Formulation Development - Lipids 205
Yvonne Rosiaux, Vincent Jannin, and Cécile Morin
11.1 Introduction 205
11.2 Lipids Used in SR Matrix 205
11.2.1 Names and Structures 205
11.2.2 Physicochemical Properties 206
11.2.3 Physiological Properties 206
11.3 Processing Lipid SR Matrix 206
11.3.1 Direct Compression (DC) 206
11.3.1.1 Impact of Dual Hydrophilic/Hydrophobic Matrix 206
11.3.1.2 Impact of Filler 207
11.3.1.3 Impact of Tablet Size 207
11.3.1.4 Comparison with Polymer Matrices 207
11.3.2 Granulation 207
11.3.3 Melt and Mix Methods 208
11.3.4 Hot Melt Coating 208
11.4 Understanding Drug Release from Lipid Matrix 208
11.4.1 Drug Release Mechanism 208
11.4.2 Optimizing Drug Release with Formulation and Process Parameter Adjustments 209
11.4.3 Drug Release Prediction 209
11.5 Characterizing Lipid SR Matrix 210
11.5.1 In Vitro Characterization 210
11.5.2 In Vivo-In Vitro Correlation (IVIVC) 210
11.5.3 Resistance and Alcohol 210
11.5.4 Stability 211
11.6 Conclusions 211
References 211
12 Polymethacrylates for Modified- Release Formulations 215
Miriam Robota, Felix Hofmann, and Meike Pistner
12.1 Introduction 215
12.2 Polymethacrylate Polymers and Their Application in Modified- Release Dosage Forms 215
12.3 Protective Coatings 218
12.4 Gastro- Resistant Coatings 221
12.5 EUDRACAP(TM) Functional Ready-To-Fill Capsules for Fast Track Development of Sensitive Drugs 224
12.6 Modified- Release Technology 224
12.7 Modified- Release Formulations for Gastrointestinal Targeting 228
12.7.1 Duodenal Drug Release 228
12.7.2 Colonic Drug Release 228
12.7.3 Modulated Drug Release 230
12.8 Matrix Tablets as an Alternative to Modified- Release Multiparticulate Dosage Forms 231
12.9 Alcohol- Resistant Formulation Concepts with EUDRAGIT® Polymers 232
12.10 Conclusion 232
References 233
13 Strategies for Modified Release Oral Formulation Development 235
Aurélien Sivert, Randy Wald, Chris Craig, and Hassan Benameur
13.1 Introduction 235
13.2 Controlled- Release Drug Delivery Systems 235
13.2.1 Osmotic Tablets 236
13.2.1.1 Formulation, Characterization, and Evaluation 236
13.2.1.2 Manufacturing and Process Considerations 237
13.2.2 Multiparticulate Systems 238
13.2.2.1 Formulation, Characterization, and Evaluation of Spray- Layered Multiparticulates 238
13.2.2.2 Manufacturing and Process Considerations of Spray- Layered Multiparticulates 239
13.2.2.3 Formulation, Characterization, and Evaluation of Lipid- Based Multiparticulates 239
13.2.2.4 Manufacturing and Process Considerations of Lipid- Based Multiparticulates 241
13.3 Dual- Release Drug Delivery Systems and Fixed- Dose Combination 242
13.3.1 DuoCap(TM) Capsule- in- Capsule Technology 242
13.3.1.1 Formulation, Characterization, and Evaluation 242
13.3.1.2 Manufacturing and Process Considerations 243
13.4 Site- Specific Drug Delivery Systems 243
13.4.1 Postgastric- Targeted Release 243
13.4.1.1 Delayed- Release Acid- Resistant Capsules (DRcaps ®) 244
13.4.1.2 Enteric Drug Delivery Capsules (enTRinsic(TM)) 246
13.4.2 Encode(TM) Colonic Drug Delivery System 247
13.4.2.1 Formulation, Characterization, and Evaluation 248
13.4.2.2 Manufacturing and Process Considerations 249
13.5 Conclusion/Future Perspectives 249
References 249
Part III Evaluation of MR Formulations 253
14 Dissolution Equipment and Hydrodynamic Considerations for Evaluating Modified- Release Behavior 255
Sandra Klein
14.1 Introduction 255
14.2 Compendial Dissolution Equipment 255
14.2.1 USP Apparatus 1 - Basket Apparatus 256
14.2.2 USP Apparatus 2 - Paddle Apparatus 257
14.2.3 USP Apparatus 3 - Reciprocating Cylinder 261
14.2.4 USP Apparatus 4 - Flow- Through Cell 261
14.3 USP Apparatus 7 - Reciprocating Holder 263
14.4 Noncompendial Dissolution Equipment 264
14.4.1 Dynamic Monocompartmental Models 264
14.4.1.1 Rotating Beaker Apparatus 264
14.4.1.2 Apparatus for Simulating GI Forces Acting on a Dosage Form 265
14.4.1.3 Dynamic Gastric Model 265
14.4.1.4 Dynamic Colon Model 266
14.4.2 Dynamic Multicompartmental Models 266
14.4.2.1 Dissolution Stress Test Device 266
14.4.2.2 In Vitro Gastrointestinal Model (TIM) 268
14.5 Summary and Conclusion 268
References 269
15 The Role and Applications of Dissolution Media for the Investigation of Modified-Release Formulations 273
Cord J. Andreas and Edmund S. Kostewicz
15.1 Introduction 273
15.2 Compendial Media 274
15.3 Biorelevant Media 275
15.3.1 Concept of Different Levels of Complexity for Dissolution Media 277
15.3.2 Case Example Level I Media 278
15.3.3 Case Example Level II Media 278
15.3.4 Case Example Level III Media 279
15.3.5 Application of Levels Concept 280
15.3.6 Bicarbonate Buffer 280
15.4 Biphasic Dissolution Media 282
15.5 Summary and Outlook 283
References 283
16 Biorelevant Dissolution Testing to Forecast the In Vivo Performance of Modified- Release Formulations 289
Mirko Koziolek
16.1 Introduction 289
16.2 Factors Affecting the In Vivo Performance of MR Products 289
16.2.1 Physiological Aspects 289
16.3 Drug- Related Aspects 290
16.4 Formulation- Related Aspects 290
16.5 Biorelevant In Vitro Dissolution Test Methods 290
16.6 General Remarks on Dissolution Media 290
16.7 General Remarks on Dissolution Test Devices 291
16.8 Dissolution Test Methods for the Simulation of Regional Transit Conditions 292
16.8.1 Simulation of Fasted State Administration of Oral MR Products 292
16.8.2 Simulation of Fed State Administration of Oral MR Products 296
16.9 Criteria for the Selection of a Suitable Biorelevant In Vitro Dissolution Method 299
16.10 Conclusion 300
References 300
17 In Vitro and Ex Vivo Dissolution Tests for Considering Dissolution in the Lower Intestine 305
Constantinos Markopoulos and Maria Vertzoni
17.1 Introduction 305
17.2 Dissolution Tests for pH- responsive Delivery Systems 306
17.2.1 Dissolution Tests Using Compendial Apparatuses 306
17.2.2 Dissolution Tests Using Noncompendial Apparatuses 310
17.3 Dissolution Tests for Enzyme- triggered Delivery Systems 313
17.3.1 Dissolution Tests Using Enzyme- supplemented Compendial Media 314
17.3.2 Dissolution Tests Using Rat Cecal Contents 315
17.3.3 Dissolution Tests Using Human Fecal Contents 316
17.3.4 Dissolution Tests Using Bacteria- containing Media 318
17.4 Conclusion 319
References 319
18 Preclinical Evaluation - Animal Models to Evaluate MR Formulations 325
René Holm
18.1 Introduction 325
18.2 When to Use Nonclinical Models in the Development of Modified-release Formulations 325
18.3 Physiological Factors in Animals Used to Investigate Modified- release Formulations 326
18.3.1 The Stomach 326
18.3.2 The Small Intestine 327
18.3.3 The Large Intestine 329
18.4 Intestinal Site- specific Administration in Animals 330
18.5 Evaluation of Modified- release Formulations in Animal Models 330
18.5.1 Rodents - Rats 331
18.5.2 Dogs 331
18.5.3 Pigs and Mini- Pigs 333
18.5.4 Monkeys 333
18.6 Conclusions 334
References 335
19 In Vitro-In Vivo Correlations for Modified Release Formulations 341
Ivana Tomic and Jean- Michel Cardot
19.1 Introduction 341
19.2 Definitions of IVIVC 341
19.3 Correlation Levels 341
19.4 Considerations in IVIVC Development 342
19.4.1 In Vivo Absorption 343
19.4.2 In Vitro Dissolution Methodology 344
19.5 IVIVC Models 344
19.6 Predictability of IVIVC 348
19.7 Use of IVIVC 350
19.7.1 Setting In Vitro Dissolution Limits 350
19.7.2 Optimization of Formulations 350
19.7.3 Dissolution and IVIVC as a Surrogate for In Vivo Data 351
19.8 Limitations of an IVIVC 352
19.9 Conclusion 352
Acknowledgment 353
References 353
20 Application of the Simcyp Population- based PBPK Simulator to the Modelling of MR Formulations 355
Nikunjkumar Patel, Shriram M. Pathak, and David B. Turner
20.1 Introduction 355
20.2 The ADAM Oral Absorption Model 357
20.3 Handling of Modified Release Formulations 358
20.4 System Information 361
20.5 MR Case Studies/Examples 363
20.5.1 Introduction 363
20.5.2 Bottom- up Methods 363
20.5.3 Virtual Bioequivalence, Biowaivers, and Setting Dissolution Specifications 364
20.5.4 Physiologically Based IVIVC 367
20.6 Conclusion 370
References 370
21 PK- Sim® for Modeling Oral Drug Delivery of Modified- Release Formulations 375
Donato Teutonico, Michael Block, Lars Kuepfer, Juri Solodenko, Thomas Eissing, and Katrin Coboeken
21.1 General Introduction on PK- Sim® and MoBi® 375
21.2 Gastrointestinal Transit and Absorption Model 376
21.3 Formulations Available in PK- Sim® 380
21.4 Dissolved Form 380
21.5 Zero and First- order Release and Lint80 Release 381
21.6 Weibull 381
21.7 Particle Dissolution 382
21.7.1 Direct Use of MR In Vitro Release Profiles 383
21.8 Dissolution Media and Transit Times 383
21.9 Case Studies 384
21.9.1 Use of a Fitted In Vitro Dissolution Function as a Direct Drug Input 384
21.9.2 Prediction of Plasma Concentration After Administration of an Enteric- coated Tablet 386
21.10 Outlook 386
References 388
22 Clinical Evaluation - In Vivo Bioequivalence Assessment of MR Formulations 391
Konstantina Soulele and Panos Macheras
22.1 Introduction/Historical Background 391
22.2 Clinical Evaluation of New and Generic Modified- Release Formulations 392
22.2.1 Pharmacokinetic Studies 392
22.2.2 The Modified- Release Formulations in the Milieu of the Gastrointestinal Tract 394
22.2.3 Influence of Drug Properties 394
22.2.4 Influence of Physiological Factors 395
22.2.5 Food Effect and Drug Interactions 395
22.2.6 The Use of In Vitro/In Vivo Correlations (IVIVC) in Clinical Evaluation of Controlled- Release Formulations 396
22.2.7 Bioequivalence of MR Products: An Ever- Evolving Field 397
22.2.8 Approaches and Metrics Associated with the Modified- Release Bioequivalence Assessment 398
22.2.9 Current Regulatory Requirements for the Demonstration of Bioequivalence of MR Formulations 400
22.3 Summary 403
References 403
23 US Regulatory Considerations for Modified Release Products 409
Hao Zhu, Ramana S. Uppoor, and Mehul Mehta
23.1 Introduction 409
23.2 Clinical Development Programs for Nongeneric MR Dosage Forms 410
23.2.1 Clinical Development Programs for Obtaining Efficacy and Safety Information 410
23.2.1.1 Bioequivalence Trials 410
23.2.1.2 Bioavailability Trials in Combination with PK/PD Trials or with Clinical Efficacy and Safety Trials 412
23.2.2 Clinical Development Program for Product Characterization 413
23.2.2.1 In Vivo Evaluation of Multiple Strengths 413
23.2.2.2 Assessment of Food Effect 414
23.2.2.3 Assessment of Alcohol Effect 414
23.2.2.4 Dosage Instructions in Patients with Changed Clearance 415
23.2.3 Modeling and Simulations to Support Product Development 416
23.3 Considerations for Clinical Development Programs for Generic MR Products 417
23.4 Studies to Support Postapproval Changes for MR Products 418
23.4.1 Different Levels of Postapproval Changes 418
23.4.2 Additional In Vitro Dissolution Evaluations 418
23.4.3 In vitro/In Vivo Correlations (IVIVC) 418
23.5 Summary 421
Disclaimer 421
References 422
24 Regulatory Assessment, European Perspective 425
Malin Filler and Anders Lindahl
24.1 Introduction 425
24.2 Quality of Oral Extended- Release Products 425
24.2.1 Pharmaceutical Development 425
24.2.1.1 Quality Target Product Profile and Critical Quality Attributes 426
24.2.1.2 Manufacturing Process 427
24.2.1.3 Dissolution Method and Discriminatory Power 427
24.2.1.4 Bioavailability Studies 428
24.2.2 In Vitro-In Vivo Correlation 428
24.2.3 Setting Specifications 429
24.2.3.1 Case (A) Level A IVIVC is Established 429
24.2.3.2 Case (B) No IVIVC is Established 429
24.2.4 Control Strategy 429
24.3 Quality by Design in Pharmaceutical Development 429
24.3.1 Risk Assessment 430
24.3.2 Design Space 430
24.3.3 Control Strategy 430
24.4 Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms 431
24.4.1 Rationale for Development 431
24.4.1.1 Pharmacokinetic Studies 431
24.4.1.2 Prolonged Residence Time in the Stomach 433
24.4.1.3 Clinical Studies 434
24.4.1.4 Generic Modified Release Formulations 435
24.5 Concluding Remarks 436
References 437
25 Industry Perspectives for the Evaluation of MR Formulations 439
Irena Tomaszewska and Mark McAllister
25.1 Introduction 439
25.2 Commercially Marketed MR Products - Historical Trends and Emerging Themes 439
25.3 Early- stage MR Product Development 440
25.4 Current Themes for Industrial MR Product Evaluation: (1) Dissolution Acceleration 444
25.5 Current Themes for Industrial MR Product Evaluation: (2) Hydro- ethanolic Studies 447
25.6 Conclusion 449
References 449
Index 455
