Biopharmaceutics: From Fundamentals to Industrial Practice (Advances in

Description: Explore the latest research in biopharmaceutics from leading contributors in the field In Biopharmaceutics - From Fundamentals to Industrial Practice, distinguished Scientists from the UK's Academy of Pharmaceutical Sciences Biopharmaceutica Focus Group deliver a comprehensive examination of the tools used within the field of biopharmaceutics and their applications to drug development. This edited volume is an indispensable tool for anyone seeking to better understand the field of biopharmaceutics as it rapidly develops and evolves. Beginning with an expansive introduction to the basics of biopharmaceutics and the context that underpins the field, the included resources go on to discuss how biopharmaceutics are integrated into product development within the pharmaceutical industry. Explorations of how the regulatory aspects of biopharmaceutics function, as well as the impact of physiology and anatomy on the rate and extent of drug absorption, follow. Readers will find insightful discussions of physiologically based modeling as a valuable asset in the biopharmaceutics toolkit and how to apply the principles of the field to special populations. The book goes on to discuss: * Thorough introductions to biopharmaceutics, basic pharmacokinetics, and biopharmaceutics measures * Comprehensive explorations of solubility, permeability, and dissolution * Practical discussions of the use of biopharmaceutics to inform candidate drug selection and optimization, as well as biopharmaceutics tools for rational formulation design * In-depth examinations of biopharmaceutics classification systems and regulatory biopharmaceutics, as well as regulatory biopharmaceutics and the impact of anatomy and physiology Perfect for professionals working in the pharmaceutical and biopharmaceutical industries, Biopharmaceutics - From Fundamentals to Industrial Practice is an incisive and up-to-date resource on the practical, pharmaceutical applications of the field. Edited by Hannah Batchelor, Strathclyde Institute of Pharmacy and Biomedical Sciences. List of Contributors xv Foreword xvii 1 An Introduction to Biopharmaceutics 1 Hannah Batchelor 1.1 Introduction 1 1.2 History of Biopharmaceutics 1 1.3 Key Concepts and Definitions Used Within Biopharmaceutics 3 1.4 The Role of Biopharmaceutics in Drug Development 6 1.5 Conclusions 8 2 Basic Pharmacokinetics 9 Hamid A. Merchant 2.1 Introduction 9 2.2 What is 'Pharmacokinetics'? 9 2.3 Pharmacokinetic Profile 10 2.4 Bioavailability 12 2.5 Drug Distribution 13 2.6 Volume of Distribution 15 2.7 Elimination 16 2.7.1 Metabolism 16 2.7.2 Excretion 17 2.8 Elimination Half-Life (t¿) 19 2.9 Elimination Rate Constant 20 2.9.1 Clearance 20 2.10 Area Under the Curve (AUC) 21 2.11 Bioequivalence 22 2.12 Steady State 23 2.13 Compartmental Concepts in Pharmacokinetics 24 2.14 Concept of Linearity in Pharmacokinetics 25 2.15 Conclusions 28 3 Introduction to Biopharmaceutics Measures 31 Hannah Batchelor and Pavel Gershkovich 3.1 Introduction 31 3.2 Solubility 31 3.3 Dissolution 33 3.4 Permeability 34 3.5 Absorptive Flux 35 3.6 Lipinsky's Rule of 5 35 3.6.1 Molecular Weight 36 3.6.2 Lipophilicity 36 3.6.3 Hydrogen Bond Donors/Acceptors 37 4 Solubility 39 Hannah Batchelor 4.1 Definition of Solubility 39 4.2 The Importance of Solubility in Biopharmaceutics 39 4.3 What Level of Solubility Is Required? 40 4.4 Solubility-Limited Absorption 41 4.5 Methods to Assess Solubility 41 4.6 Brief Overview of Forces Involved in Solubility 42 4.6.1 van der Waals Interactions 42 4.6.2 Hydrogen Bonding 42 4.6.3 Ionic Interactions 43 4.7 Solid-State Properties and Solubility 43 4.8 pH and Drug Solubility 43 4.9 Solvents 44 4.9.1 Biorelevant Solubility 45 4.9.2 Buffer System - Phosphate vs Bicarbonate 45 4.9.3 Solubilisation by Surfactants 45 4.9.4 Solubilisation During Digestion 47 4.9.5 Excipients and Solubility 47 4.10 Risk of Precipitation 48 4.11 Solubility and Link to Lipophilicity 49 4.12 Conclusions 49 5 Permeability 51 Chris Roe and Vanessa Zann 5.1 Introduction 51 5.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters 51 5.2.1 Enzymes 52 5.2.2 Drug Transporters 54 5.2.3 Efflux Transporters 55 5.2.4 Transporters of Greatest Relevance to Oral Biopharmaceutics 56 5.2.5 Regulatory Overview of Transporter Effects on Biopharmaceutics 58 5.2.6 Regional Expression and Polymorphism of Intestinal Transporters and Impact of Drug Variability 58 5.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment 59 5.3.1 In Silico Tools: Predictive Models for Permeability 59 5.3.2 in vitro Tools 60 5.3.2.1 PAMPA 60 5.3.2.2 Cell Lines 61 5.3.3 ex vivo Tools 63 5.3.3.1 Ussing Chambers 63 5.3.3.2 Everted Intestinal Sac/Ring 65 5.3.4 In Situ Tools 66 5.3.4.1 Closed-Loop Intestinal Perfusion 66 5.3.4.2 Single-Pass Intestinal Perfusion 66 5.3.4.3 Intestinal Perfusion with Venous Sampling 67 5.3.4.4 Vascularly Perfused Intestinal Models 67 5.4 in vivo Tools 67 5.5 Conclusion 69 6 Dissolution 75 Hannah Batchelor and James Butler 6.1 Introduction 75 6.2 Purpose of Dissolution Testing 75 6.2.1 Dissolution Versus Solubility 76 6.3 History of Dissolution Testing 77 6.4 Compendial (Pharmacopeial) Dissolution Apparatus 78 6.4.1 USP1 and 2 Apparatus 78 6.4.2 USP3 Apparatus 79 6.4.3 USP4 Apparatus 80 6.4.4 USP5 Apparatus 82 6.4.5 USP6 Apparatus 82 6.4.6 USP7 Apparatus 82 6.4.7 Intrinsic Dissolution Rate (IDR) Apparatus 83 6.4.8 Micro-dissolution Apparatus 83 6.5 Dissolution Media Selection 83 6.5.1 Biphasic Dissolution Media 84 6.6 Dissolution Agitation Rates 84 6.7 Reporting Dissolution Data 85 6.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC) 86 6.8.1 Convolution and Deconvolution of Dissolution Data 87 6.9 Evolution of Biorelevant Dissolution Testing 88 6.9.1 Biorelevant Dissolution Media 88 6.9.2 Dissolution Testing to Mimic GI Transit 93 6.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions 94 6.9.4 Dissolution Testing to Incorporate Permeability 95 6.10 Conclusions 96 7 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation 103 Linette Ruston 7.1 Introduction 103 7.2 Oral Product Design Considerations During Early Development 103 7.3 Biopharmaceutics in Drug Discovery 105 7.3.1 Pre-Clinical Studies 106 7.4 Biopharmaceutics Assessment 107 7.4.1 Solubility 107 7.4.2 Permeability 107 7.4.3 Dissolution 108 7.4.4 Biopharmaceutics Classification System 108 7.4.5 Lipophilicity 109 7.4.6 pKa 109 7.4.7 Molecular Size 109 7.4.8 Crystallinity 109 7.4.9 In Vivo Pre-Clinical Studies 109 7.4.10 In Silico Modelling 110 7.4.11 Human Absorption/Dose Prediction 110 7.5 Output of Biopharmaceutics Assessment 110 7.5.1 New Modalities/Complex Delivery Systems Within Early Development 112 7.6 Influence/Optimise/Design Properties to Inform Formulation Development 112 7.6.1 Fraction Absorbed Classification System 113 7.7 Conclusion 114 8 Biopharmaceutics Tools for Rational Formulation Design 117 Panagiota Zarmpi, Mark McAllister, James Butler, and Nikoletta Fotaki 8.1 Introduction 117 8.2 Formulation Development to Optimise Drug Bioavailability 118 8.3 Traditional Formulation Strategies 119 8.3.1 Decision Making for Conventional or Enabling Formulations 119 8.4 Decision Trees to Guide Formulation Development 119 8.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS) 119 8.4.2 Decision Trees Based on Developability Classification System (DCS) 121 8.4.3 Expanded Decision Trees 122 8.5 Computational Tools to Guide Formulation Strategies 124 8.5.1 Statistical Tools 124 8.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 125 8.6 Decision- Making for Optimising Enabling Formulations 125 8.7 Decision Trees for Enabled Formulations 127 8.7.1 Statistical Tools 128 8.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 128 8.8 System-Based Formulation Strategies 128 8.8.1 Quality by Design 128 8.8.2 Tools to Identify Quality Target Product Profile 129 8.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM) 131 8.9.1 Tools to Identify Quality Target Product Profile 131 8.10 Conclusions 132 9 Biopharmaceutic Classification System 139 Hannah Batchelor and Talia Flanagan 9.1 Description and History of the BCS 139 9.2 BCS-Based Criteria for Solubility, Dissolution and Permeability 139 9.3 BCS-Based Biowaivers 141 9.4 Regulatory Development of BCS-Based Biowaivers 142 9.5 International Harmonisation of BCS-Based Biowaiver Criteria - ICH M9 143 9.5.1 Application of BCS-Based Biowaivers 144 9.5.1.1 Drug Product Type 144 9.5.1.2 Composition 145 9.5.1.3 Dissolution Similarity 145 9.6 BCS as a Development Tool 146 9.6.1 Candidate Selection 146 9.6.2 Solid Form Selection 146 9.6.3 Product Development 146 9.7 Beyond the BCS 147 9.7.1 Biopharmaceutic Drug Disposition Classification System (BDDCS) 148 9.7.2 Developability Classification System 148 9.7.3 Fraction Absorbed Classification System 148 9.7.4 BCS Applied to Special Populations 149 9.8 Conclusions 149 10 Regulatory Biopharmaceutics 153 Shanoo Budhdeo, Paul A. Dickinson, and Talia Flanagan 10.1 Introduction 153 10.2 Clinical Bioequivalence Studies 154 10.3 Design of Clinical Bioequivalence (BE) Studies 156 10.4 Implication of Bioequivalence Metrics 157 10.5 Bioequivalence Regulatory Guidelines 159 10.6 Biowaivers 159 10.7 Biopharmaceutics in Quality by Design 159 10.8 Control of Drug Product and Clinically Relevant Specifications 162 10.9 Establishing Clinically Relevant Dissolution Methods and Specifications 162 10.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications 165 10.11 Additional Considerations for Establishing Dissolution Methods and Specifications 165 10.12 Common Technical Document (CTD) 166 10.13 Other Routes of Administration and Locally Acting Drug Products 167 10.14 Conclusion 168 11 Impact of Anatomy and Physiology 171 Francesca K. H. Gavins, Christine M. Madla, Sarah J. Trenfield, Laura E. McCoubrey, Abdul W. Basit, and Mark McAllister 11.1 Introduction 171 11.2 Influence of GI Conditions on Pharmacokinetic Studies 172 11.3 The Stomach 172 11.3.1 Gastric Anatomy 172 11.3.2 Gastric Motility and Mixing 174 11.3.3 Gastric Emptying 175 11.3.3.1 Gastric Fed State 176 11.3.4 Gastric Fluid Volume 176 11.3.5 Gastric Temperature 177 11.3.6 Gastric Fluid Composition 177 11.3.6.1 Gastric pH 177 11.3.6.2 Gastric Bile Salt Composition and Concentration 178 11.4 Small Intestine 178 11.4.1 Small Intestinal Anatomy 178 11.4.2 Small Intestinal Motility and Mixing 180 11.4.3 Small Intestinal Transit Time 180 11.4.4 Small Intestinal Volume 180 11.4.5 Small Intestinal Fluid Composition 181 11.4.5.1 Small Intestinal pH 182 11.4.5.2 Small Intestinal Buffer Capacity 182 11.4.5.3 Small Intestinal Surface Tension 182 11.4.5.4 Small Intestinal Osmolality 182 11.4.5.5 Bile Salt Composition and Concentration 183 11.5 The Colon/Large Intestine 183 11.5.1 Large Intestine Anatomy 184 11.5.2 Large Intestinal Motility and Mixing 184 11.5.3 Large Intestinal Transit Time 185 11.5.4 Large Intestinal Volume 185 11.5.5 Large Intestinal Fluid Composition 185 11.5.5.1 Large Intestinal pH 186 11.5.5.2 Large Intestinal Buffer Capacity 186 11.5.5.3 Large Intestinal Surface Tension 186 11.5.5.4 Large Intestinal Osmolality 186 11.5.5.5 Bile Salt Composition and Concentration 186 11.5.6 Impact of Microbiome on Oral Drug Delivery 187 11.6 Conclusions 188 12 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling 197 Konstantinos Stamatopoulos 12.1 Introduction 197 12.2 Mechanistic Models 198 12.3 Solubility Inputs 200 12.4 Dissolution Inputs 203 12.4.1 Fluid Dynamics and Dissolution 205 12.5 Permeability Inputs 206 12.6 Incorporation of Modelling and Simulation into Drug Development 208 12.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics 208 12.6.2 Model Verification/Validation 209 12.6.3 Using Modelling to Understand Bioequivalence 209 12.7 Conclusions 210 13 Special Populations 213 Christine M. Madla, Francesca K. H. Gavins, Sarah J. Trenfield, and Abdul W. Basit 13.1 Introduction 213 13.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance 213 13.3 Ethnic Differences in the Gastrointestinal Tract 216 13.4 Impact of Diet on Gastrointestinal Physiology 217 13.5 Pregnancy and Its Effect on Gastrointestinal Physiology 219 13.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance 220 13.7 Diseases that Affect the Gastrointestinal Tract 220 13.7.1 Irritable Bowel Syndrome 220 13.7.2 Inflammatory Bowel Disease 221 13.7.3 Celiac Disease 223 13.8 Infections in the Gastrointestinal Tract 224 13.8.1 Helicobacter pylori Infection 224 13.9 Systemic Diseases that Alter GI Physiology and Function 224 13.9.1 Cystic Fibrosis 225 13.9.2 Parkinson's Disease 226 13.9.3 Diabetes 227 13.9.4 HIV Infection 229 13.10 Age-related Influences on Gastrointestinal Tract Physiology and Function 230 13.10.1 Gastrointestinal Physiology and Function in Paediatrics 230 13.10.2 Gastrointestinal Physiology and Function in Geriatrics 232 13.11 Conclusion 234 14 Inhalation Biopharmaceutics 249 Precious Akhuemokhan, Magda Swedrowska and Ben Forbes 14.1 Introduction 249 14.2 Structure of the Lungs 250 14.2.1 Basic Anatomy 250 14.2.2 Epithelial Lining Fluid 251 14.2.3 Epithelium 251 14.3 Molecules, Inhalation Devices, Formulations 252 14.3.1 Inhaled Molecules 252 14.3.2 Inhalation Devices 252 14.3.2.1 Nebulisers 252 14.3.2.2 Pressurised Metered-Dose Inhalers 253 14.3.2.3 Dry Powder Inhalers 253 14.3.2.4 'Soft Mist' Inhalers 253 14.3.3 Inhaled Medicine Formulation 253 14.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics 254 14.4.1 Dosimetry and Deposition 254 14.4.2 Mucociliary Clearance 256 14.4.3 Dissolution 256 14.4.4 Lung Permeability, Absorption and Retention 257 14.4.5 Metabolism 258 14.4.6 Non-Clinical Inhalation Studies 258 14.4.7 Mechanistic Computer Modelling 259 14.5 Bioequivalence and an Inhalation Bioclassification System 259 14.6 Conclusion 260 15 Biopharmaceutics of Injectable Formulations 263 Wang Wang Lee and Claire M. Patterson 15.1 Introduction 263 15.2 Subcutaneous Physiology and Absorption Mechanisms 266 15.2.1 Physiology 266 15.2.2 Absorption Mechanisms 266 15.3 Intramuscular Physiology and Absorption Mechanisms 268 15.3.1 Physiology 268 15.3.2 Absorption Mechanisms 269 15.4 In vitro Performance and IVIVC 269 15.4.1 In Silico Models 271 15.4.2 Preclinical Models 271 15.5 Bioequivalence of Injectable Formulations 271 15.6 Summary 272 16 Biopharmaceutics of Topical and Transdermal Formulations 275 Hannah Batchelor 16.1 Introduction 275 16.2 Skin Structure 275 16.2.1 Transport of Drugs Through Skin 276 16.2.2 Skin Metabolism 277 16.3 Active Pharmaceutical Ingredient Properties 277 16.4 Topical and Transdermal Dosage Forms 277 16.5 Measurement of Vitro Drug Release 278 16.5.1 Diffusion Cells 278 16.5.2 Compendial Dissolution Apparatus 279 16.6 Measurement of Skin Permeation 279 16.6.1 Tape-Stripping 'Dermatopharmacokinetics' (DPK) 279 16.6.2 Confocal Laser Scanning Microscopy (CLSM) 280 16.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation 280 16.6.3.1 Alternative Skin Substrates Used for Permeability Studies 280 16.6.4 Dermal Microdialysis 281 16.6.5 Skin Biopsy 281 16.6.6 In Silico Models of Dermal Absorption 281 16.6.7 Pre-Clinical Models 282 16.7 Bioequivalence Testing of Topical/Transdermal Products 282 16.8 Conclusions 283 17 Impact of the Microbiome on Oral Biopharmaceutics 287 Laura E. McCoubrey, Hannah Batchelor, Abdul W. Basit, Simon Gaisford, and Mine Orlu 17.1 Introduction 287 17.2 Microbiome Distribution in the GI Tract 288 17.3 Key Causes of Microbiome Variability 290 17.4 Microbiome Influence on Key GI Parameters 292 17.4.1 pH 292 17.4.2 Bile Acid Concentration and Composition 292 17.4.3 Drug Transporters 292 17.4.4 Motility 293 17.4.5 Hepatic Drug Metabolism 293 17.4.6 Epithelial Permeability 294 17.5 Enzymatic Degradation of Drugs by GI Microbiota 294 17.6 Exploitation of the GI Microbiome for Drug Delivery 295 17.7 Models of the GI Microbiome 295 17.7.1 In vitro Models 295 17.7.2 In Silico Models 299 17.8 Conclusion 299 Index 000

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