Oral Drug Delivery for Modified Release Formulations

Edmund S. Kostewicz, PhD is at the Fraunhofer Institute for Translational Medicine and Pharmacology in Frankfurt, Germany.Maria Vertzoni, PhD is an Assistant Professor of Pharmaceutical Technology and Biopharmaceutics at National and Kapodistrian University of Athens, Greece. Heather A.E. Benson, PhD is an adjunct Associate Professor at the Curtin Medical School, Curtin University, Australia, where she leads the Skin Delivery Research Group. Michael S. Roberts, PhD is a Professor of Therapeutics & Pharmaceutical Science at the University of South Australia, and a Professor of Clinical Pharmacology & Therapeutics at the University of Queensland, Australia.

• Preface xviiList of Contributors xixPart I Understanding of Physiology and Anatomy – Factors Influencing Drug Release and Absorption from MR Formulations 11a Composition of Gastric Fluids Under Fasting and Fed Conditions 3Jens Van Den Abeele and Patrick Augustijns1a.1 Gastric Volume 31a.2 Gastric Acid 31a.3 Buffer Capacity 41a.4 Mucus/Viscosity 51a.5 Enzymes 51a.6 Surface Tension 61a.7 Osmolality 61a.8 Duodenogastric Reflux 71b Composition of the Small Intestinal Contents Under Fasting and Fed Conditions 11Edmund S. Kostewicz1b.1 Small Intestinal Volume 111b.2 pH Profile Along the Small Intestine 121b.3 Composition of the Luminal Contents 121b.4 Other Characteristics of Small Intestinal Fluids 141b.5 Influence of Age, Gender, and Disease on the Small Intestinal Composition 151c The Luminal Environment in the Proximal Colon 19Maria Vertzoni and Christos Reppas1c.1 Volume of Luminal Contents 191c.2 Luminal pH Values 201c.3 Buffer Capacity 221c.4 Characteristics of Liquid Fraction of Contents 221c.5 Concluding Remarks 222 Gastrointestinal Transit and Hydrodynamics Under Fasting and Fed Conditions 25Mirko Koziolek2.1 Introduction 252.2 Imaging Techniques Used for Assessment of Transit Times and Hydrodynamics 252.3 Oral Cavity and Esophagus 252.4 Stomach 262.5 Small Intestine 292.6 Large Intestine 312.7 Whole Gut Transit Time 322.8 Therapy- Related Effects on GI Transit 332.9 Motility Disorders Affecting the GI Transit of Oral Dosage Forms 332.10 Patient- Related Effects on GI Transit 342.11 Conclusion 363 Intestinal Epithelium and Drug Transporters 39Karelle Ménochet, Hugues Chanteux, Jamie Henshall, Jean- Marie Nicolas, Sara Wright, Judith van Asperen, and Anna-Lena Ungell3.1 Introduction: Oral Drug Absorption General Mechanisms and Influencing Factors 393.2 Expression of Drug Transporters in the Intestinal Epithelium 403.3 Uptake Transporters Present at the Intestinal Level 403.4 Regional Distribution of Uptake Transporters 423.5 Efflux Transporters at the Intestinal Level 423.6 Regional Distribution of Efflux Transporters 433.7 Impact of the Regional Distribution of Enzymes and Transporters in the Intestine on the Enzyme/Transporter Interplay 433.8 Species Differences in Regional Expression of Uptake and Efflux Transporters 443.9 Models for Regional Assessment of Intestinal Permeability 453.10 Use of PBPK to Integrate Formulation and Permeation Knowledge 463.11 Impact of Regional Solubility and Permeability Along the Intestine 473.12 Formulation Excipients and Their Potential Modulatory Effects on Transporters 483.13 Other Confounding Factors Affecting Drug Intestinal Absorption 513.14 Drug–Drug Interactions 523.15 Conclusion and Future Challenges 534 The Interplay Between Drug Release and Intestinal Gut- Wall Metabolism 65Adam S. Darwich, Oliver J. Hatley, Andrés Olivares- Morales, Farzaneh Salem, Alison Margolskee, and Amin Rostami- Hodjegan4.1 The Role of Gut Wall Metabolism in Determining Oral Bioavailability 654.2 Factors Affecting Gut Wall Metabolism 694.3 Preclinical and Clinical In Vivo and In Situ Models for Studying Intestinal Metabolism 714.4 In Vitro Assays for Studying Intestinal Metabolism 724.5 Models for Studying Bacterial Degradation 744.6 In Vitro–In Vivo Extrapolation of Metabolic Clearance and In Silico Models for Predicting In Vivo Gut Wall Metabolism 754.7 Oral Extended- Release Formulations and Gut Wall Metabolism 764.8 Excipient Effects on Gut Wall Metabolism 774.9 Considerations for Intestinal Metabolism in Special Populations 774.10 Summary 79Part II Design of MR Formulations – Considerations, Mechanisms and Technologies 875 Preformulation Considerations for Design of Oral Modified- Release Products 89Christel A. S. Bergström and René Holm5.1 Introduction 895.2 Purpose of MR Formulations 905.3 Means to Obtain MR Drug Products 915.4 Ionization Constant – pK a 935.5 Lipophilicity 935.6 Solubility 935.7 Chemical Stability 935.8 Solid State Characterization 945.9 Compatibility with Excipients 945.10 Permeability and Metabolism 945.11 Regional Absorption 955.12 Microbial Stability 965.13 Quality by Design (QbD) for MR formulations 975.14 Conclusions 986 The Application of Biopharmaceutics Classification Systems to Modified- Release Formulations 103James M. Butler6.1 Introduction 1036.2 The Use of Biopharmaceutics Classification Systems in Oral Drug Development 1036.3 The Application of Classification Systems to MR Drug Product Development – An Evidence- Based Approach 1046.4 Summary 1147 Technologies and Mechanisms for Oral Modified Release by Monolithic and Multiparticulate Delivery Systems 119Gaia Colombo, Stavros Politis, and Alessandra Rossi7.1 Introduction 1197.2 Mechanism of Drug Release 1217.3 Manufacturing Processes 1247.4 Formulation Screening and Characterization 1287.5 Conclusions and Perspectives 1318 Lipid- based Formulations 137Joseph P. O’Shea, Caitriona M. O’Driscoll, and Brendan T. Griffin8.1 Introduction 1378.2 Mechanisms of Lipid- mediated Improvements in Bioavailability 1388.3 Lipid- based Formulations for Controlled Release 1428.4 Design of Lipid- based Formulations 1448.5 Formulation Screening and Characterization 1468.6 Industrial Considerations on LBF 1548.7 Emerging Applications of Lipid- based Formulations 1548.8 Conclusions 1559 Strategies for MR Formulation Development: Mesoporous Silica 161Georgios K. Eleftheriadis, Eleni Kontogiannidou, Christina Karavasili, and Dimitrios G. Fatouros9.1 Introduction 1619.2 Technologies 1619.3 Characterization 1639.4 Stability of Drug Carrier 1659.5 Silica- based Materials for the Modified Release of Poorly Soluble Drugs – In Vitro/In Vivo Applications 1669.6 Toxicological Assessment 1719.7 Conclusions and Future Directions 17310 Hot- Melt Extrusion Technology for Modified- Release (MR) Formulation Development 181Harpreet Sandhu, Siva Ram Kiran Vaka, Dipen Desai, Paras Jariwala, Aruna Railkar, Wantanee Phuapradit, and Navnit Shah10.1 Introduction 18110.2 HME Technology Overview 18210.3 General Considerations in Developing MR Dosage Forms Using HME Processing 18510.4 Material Considerations for MR- HME Application 18710.5 Dosage Form Design and Case Studies 18910.6 Characterization of HME Products 19510.7 Summary 20011 Gattefosse: Strategies for MR Formulation Development – Lipids 205Yvonne Rosiaux, Vincent Jannin, and Cécile Morin11.1 Introduction 20511.2 Lipids Used in SR Matrix 20511.3 Processing Lipid SR Matrix 20611.4 Understanding Drug Release from Lipid Matrix 20811.5 Characterizing Lipid SR Matrix 21011.6 Conclusions 21112 Polymethacrylates for Modified- Release Formulations 215Miriam Robota, Felix Hofmann, and Meike Pistner12.1 Introduction 21512.2 Polymethacrylate Polymers and Their Application in Modified- Release Dosage Forms 21512.3 Protective Coatings 21812.4 Gastro- Resistant Coatings 22112.5 EUDRACAP Functional Ready-To-Fill Capsules for Fast Track Development of Sensitive Drugs 22412.6 Modified- Release Technology 22412.7 Modified- Release Formulations for Gastrointestinal Targeting 22812.8 Matrix Tablets as an Alternative to Modified- Release Multiparticulate Dosage Forms 23112.9 Alcohol- Resistant Formulation Concepts with EUDRAGIT® Polymers 23212.10 Conclusion 23213 Strategies for Modified Release Oral Formulation Development 235Aurélien Sivert, Randy Wald, Chris Craig, and Hassan Benameur13.1 Introduction 23513.2 Controlled- Release Drug Delivery Systems 23513.3 Dual- Release Drug Delivery Systems and Fixed- Dose Combination 24213.4 Site- Specific Drug Delivery Systems 24313.5 Conclusion/Future Perspectives 249Part III Evaluation of MR Formulations 25314 Dissolution Equipment and Hydrodynamic Considerations for Evaluating Modified- Release Behavior 255Sandra Klein14.1 Introduction 25514.2 Compendial Dissolution Equipment 25514.3 USP Apparatus 7 – Reciprocating Holder 26314.4 Noncompendial Dissolution Equipment 26414.5 Summary and Conclusion 26815 The Role and Applications of Dissolution Media for the Investigation of Modified-Release Formulations 273Cord J. Andreas and Edmund S. Kostewicz15.1 Introduction 27315.2 Compendial Media 27415.3 Biorelevant Media 27515.4 Biphasic Dissolution Media 28215.5 Summary and Outlook 28316 Biorelevant Dissolution Testing to Forecast the In Vivo Performance of Modified- Release Formulations 289Mirko Koziolek16.1 Introduction 28916.2 Factors Affecting the In Vivo Performance of MR Products 28916.3 Drug- Related Aspects 29016.4 Formulation- Related Aspects 29016.5 Biorelevant In Vitro Dissolution Test Methods 29016.6 General Remarks on Dissolution Media 29016.7 General Remarks on Dissolution Test Devices 29116.8 Dissolution Test Methods for the Simulation of Regional Transit Conditions 29216.9 Criteria for the Selection of a Suitable Biorelevant In Vitro Dissolution Method 29916.10 Conclusion 30017 In Vitro and Ex Vivo Dissolution Tests for Considering Dissolution in the Lower Intestine 305Constantinos Markopoulos and Maria Vertzoni17.1 Introduction 30517.2 Dissolution Tests for pH- responsive Delivery Systems 30617.3 Dissolution Tests for Enzyme- triggered Delivery Systems 31317.4 Conclusion 31918 Preclinical Evaluation – Animal Models to Evaluate MR Formulations 325René Holm18.1 Introduction 32518.2 When to Use Nonclinical Models in the Development of Modified-release Formulations 32518.3 Physiological Factors in Animals Used to Investigate Modified- release Formulations 32618.4 Intestinal Site- specific Administration in Animals 33018.5 Evaluation of Modified- release Formulations in Animal Models 33018.6 Conclusions 33419 In Vitro–In Vivo Correlations for Modified Release Formulations 341Ivana Tomic and Jean- Michel Cardot19.1 Introduction 34119.2 Definitions of IVIVC 34119.3 Correlation Levels 34119.4 Considerations in IVIVC Development 34219.5 IVIVC Models 34419.6 Predictability of IVIVC 34819.7 Use of IVIVC 35019.8 Limitations of an IVIVC 35219.9 Conclusion 352Acknowledgment 353References 35320 Application of the Simcyp Population- based PBPK Simulator to the Modelling of MR Formulations 355Nikunjkumar Patel, Shriram M. Pathak, and David B. Turner20.1 Introduction 35520.2 The ADAM Oral Absorption Model 35720.3 Handling of Modified Release Formulations 35820.4 System Information 36120.5 MR Case Studies/Examples 36320.6 Conclusion 37021 PK- Sim for Modeling Oral Drug Delivery of Modified- Release Formulations 375Donato Teutonico, Michael Block, Lars Kuepfer, Juri Solodenko, Thomas Eissing, and Katrin Coboeken21.1 General Introduction on PK- Sim® and MoBi® 37521.2 Gastrointestinal Transit and Absorption Model 37621.3 Formulations Available in PK- Sim® 38021.4 Dissolved Form 38021.5 Zero and First- order Release and Lint80 Release 38121.6 Weibull 38121.7 Particle Dissolution 38221.8 Dissolution Media and Transit Times 38321.9 Case Studies 38421.10 Outlook 38622 Clinical Evaluation – In Vivo Bioequivalence Assessment of MR Formulations 391Konstantina Soulele and Panos Macheras22.1 Introduction/Historical Background 39122.2 Clinical Evaluation of New and Generic Modified- Release Formulations 39222.3 Summary 40323 US Regulatory Considerations for Modified Release Products 409Hao Zhu, Ramana S. Uppoor, and Mehul Mehta23.1 Introduction 40923.2 Clinical Development Programs for Nongeneric MR Dosage Forms 41023.3 Considerations for Clinical Development Programs for Generic MR Products 41723.4 Studies to Support Postapproval Changes for MR Products 41823.5 Summary 421Disclaimer 421References 42224 Regulatory Assessment, European Perspective 425Malin Filler and Anders Lindahl24.1 Introduction 42524.2 Quality of Oral Extended- Release Products 42524.3 Quality by Design in Pharmaceutical Development 42924.4 Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms 43124.5 Concluding Remarks 43625 Industry Perspectives for the Evaluation of MR Formulations 439Irena Tomaszewska and Mark McAllister25.1 Introduction 43925.2 Commercially Marketed MR Products – Historical Trends and Emerging Themes 43925.3 Early- stage MR Product Development 44025.4 Current Themes for Industrial MR Product Evaluation: (1) Dissolution Acceleration 44425.5 Current Themes for Industrial MR Product Evaluation: (2) Hydro- ethanolic Studies 44725.6 Conclusion 449References 449Index 455