Oral Drug Delivery for Modified Release Formulations Oral Drug Delivery for Modified Release Formulations Edited by Edmund S. Kostewicz Fraunhofer Institute for Translational Medicine and Pharmacology ITMP Frankfurt, Germany Maria Vertzoni National and Kapodistrian University of Athens Athens, Greece Heather A. E. Benson Curtin University of Technology Perth, WA, Australia Michael S. Roberts University of South Australia/University of Queensland Brisbane, QLD, Australia This edition first published 2022 © 2022 John Wiley & Sons, Inc. 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, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Edmund S. Kostewicz, Maria Vertzoni, Heather A. E. Benson and Michael S. 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Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging- in- Publication Data Names: Kostewicz, Edmund S., editor. | Vertzoni, Maria, editor. | Benson, Heather A. E., editor. | Roberts, Michael S., 1949- editor. Title: Oral drug delivery for modified release formulations / edited by Edmund S Kostewicz, Maria Vertzoni, Heather A E Benson, Michael S Roberts. Description: Hoboken, NJ : Wiley, 2022. | Includes bibliographical references and index. Identifiers: LCCN 2021025872 (print) | LCCN 2021025873 (ebook) | ISBN 9781119772699 (cloth) | ISBN 9781119772705 (Adobe PDF) | ISBN 9781119772712 (epub) Subjects: MESH: Delayed-Action Preparations | Administration, Oral | Drug Delivery Systems Classification: LCC RS199.5 (print) | LCC RS199.5 (ebook) | NLM QV 786 | DDC 615/.6–dc23 LC record available at https://lccn.loc.gov/2021025872 LC ebook record available at https://lccn.loc.gov/2021025873 Cover image: © yodiyim/iStock/Getty Images; yulia_lavrova/Shutterstock Cover design by Wiley Set in 9.5/12.5pt STIXTwoText by Straive, Pondicherry, India 10 9 8 7 6 5 4 3 2 1 v Contents 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 vi Contents 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-L ena 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 Contents vii 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-R elease 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 93 a 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-B ased Approach 104 viii Contents 6.3.1 Test Sets Used 104 6.3.2 Where Do Successfully Marketed Modified-R elease 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 Colon) as a Guide to Extended- Release Formulation Feasibility 113 rel 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-p ass 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