Oral Drug Delivery for Modified Release Formulations

ORAL DRUG DELIVERY FOR MODIFIED RELEASE FORMULATIONS Provides pharmaceutical development scientists with a detailed reference guide for the development of MR formulations Oral Drug Delivery for Modified Release Formulations is an up-to-date review of the key aspects of oral absorption from modified-release (MR) dosage forms. This edited volume provides in-depth coverage of the physiological factors that influence drug release and of the design and evaluation of MR formulations. Divided into three sections, the book begins by describing the gastrointestinal tract (GIT) and detailing the conditions and absorption processes occurring in the GIT that determine a formulation’s oral bioavailability. The second section explores the design of modified release formulations, covering early drug substance testing, the biopharmaceutics classification system, an array of formulation technologies that can be used for MR dosage forms, and more. The final section focuses on in vitro, in silico, and in vivo evaluation and regulatory considerations for MR formulations. Topics include biorelevant dissolution testing, preclinical evaluation, and physiologically-based pharmacokinetic modelling (PBPK) of in vivo behaviour. Featuring contributions from leading researchers with expertise in the different aspects of MR formulations, this volume: Provides authoritative coverage of physiology, physicochemical determinants, and in-vitro in-vivo correlation (IVIVC) Explains the different types of MR formulations and defines the key terms used in the field Discusses the present status of MR technologies and identifies current gaps in research Includes a summary of regulatory guidelines from both the US and the EU Shares industrial experiences and perspectives on the evaluation of MR dosage formulations Oral Drug Delivery for Modified Release Formulations is an invaluable reference and guide for researchers, industrial scientists, and graduate students in general areas of drug delivery including pharmaceutics, pharmaceutical sciences, biomedical engineering, polymer and materials science, and chemical and biochemical engineering.

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 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.4 Other Characteristics of Small Intestinal Fluids 14 1b.5 Influence of Age, Gender, and Disease on the Small Intestinal Composition 15 1c The Luminal Environment in the Proximal Colon 19 Maria Vertzoni and Christos Reppas 1c.1 Volume of Luminal Contents 19 1c.2 Luminal pH Values 20 1c.3 Buffer Capacity 22 1c.4 Characteristics of Liquid Fraction of Contents 22 1c.5 Concluding Remarks 22 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 2.11 Conclusion 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 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 4.2 Factors Affecting Gut Wall Metabolism 69 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 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 5.4 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 5.11 Regional Absorption 95 5.12 Microbial Stability 96 5.13 Quality by Design (QbD) for MR formulations 97 5.14 Conclusions 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 6.4 Summary 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 7.4 Formulation Screening and Characterization 128 7.5 Conclusions and Perspectives 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 8.3 Lipid- based Formulations for Controlled Release 142 8.4 Design of Lipid- based Formulations 144 8.5 Formulation Screening and Characterization 146 8.6 Industrial Considerations on LBF 154 8.7 Emerging Applications of Lipid- based Formulations 154 8.8 Conclusions 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 9.3 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 9.6 Toxicological Assessment 171 9.7 Conclusions and Future Directions 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 10.3 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 10.6 Characterization of HME Products 195 10.7 Summary 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 11.3 Processing Lipid SR Matrix 206 11.4 Understanding Drug Release from Lipid Matrix 208 11.5 Characterizing Lipid SR Matrix 210 11.6 Conclusions 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 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 12.8 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 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 13.3 Dual- Release Drug Delivery Systems and Fixed- Dose Combination 242 13.4 Site- Specific Drug Delivery Systems 243 13.5 Conclusion/Future Perspectives 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 14.3 USP Apparatus 7 – Reciprocating Holder 263 14.4 Noncompendial Dissolution Equipment 264 14.5 Summary and Conclusion 268 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 15.4 Biphasic Dissolution Media 282 15.5 Summary and Outlook 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 16.3 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 16.9 Criteria for the Selection of a Suitable Biorelevant In Vitro Dissolution Method 299 16.10 Conclusion 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 17.3 Dissolution Tests for Enzyme- triggered Delivery Systems 313 17.4 Conclusion 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 18.4 Intestinal Site- specific Administration in Animals 330 18.5 Evaluation of Modified- release Formulations in Animal Models 330 18.6 Conclusions 334 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 19.5 IVIVC Models 344 19.6 Predictability of IVIVC 348 19.7 Use of IVIVC 350 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 20.6 Conclusion 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 21.8 Dissolution Media and Transit Times 383 21.9 Case Studies 384 21.10 Outlook 386 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 22.3 Summary 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 23.3 Considerations for Clinical Development Programs for Generic MR Products 417 23.4 Studies to Support Postapproval Changes for MR Products 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 24.3 Quality by Design in Pharmaceutical Development 429 24.4 Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms 431 24.5 Concluding Remarks 436 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