Biopharmaceutics: From Fundamentals to Industrial Practice

ISBN-13: 9781119678281 / Angielski / Twarda / 2021 / 320 str.

Hannah Batchelor

Spis treści

List of Contributors xvForeword xvii1 An Introduction to Biopharmaceutics 1Hannah Batchelor1.1 Introduction 11.2 History of Biopharmaceutics 11.3 Key Concepts and Definitions Used Within Biopharmaceutics 31.4 The Role of Biopharmaceutics in Drug Development 61.5 Conclusions 82 Basic Pharmacokinetics 9Hamid A. Merchant2.1 Introduction 92.2 What is 'Pharmacokinetics'? 92.3 Pharmacokinetic Profile 102.4 Bioavailability 122.5 Drug Distribution 132.6 Volume of Distribution 152.7 Elimination 162.7.1 Metabolism 162.7.2 Excretion 172.8 Elimination Half-Life (t½) 192.9 Elimination Rate Constant 202.9.1 Clearance 202.10 Area Under the Curve (AUC) 212.11 Bioequivalence 222.12 Steady State 232.13 Compartmental Concepts in Pharmacokinetics 242.14 Concept of Linearity in Pharmacokinetics 252.15 Conclusions 283 Introduction to Biopharmaceutics Measures 31Hannah Batchelor and Pavel Gershkovich3.1 Introduction 313.2 Solubility 313.3 Dissolution 333.4 Permeability 343.5 Absorptive Flux 353.6 Lipinsky's Rule of 5 353.6.1 Molecular Weight 363.6.2 Lipophilicity 363.6.3 Hydrogen Bond Donors/Acceptors 374 Solubility 39Hannah Batchelor4.1 Definition of Solubility 394.2 The Importance of Solubility in Biopharmaceutics 394.3 What Level of Solubility Is Required? 404.4 Solubility-Limited Absorption 414.5 Methods to Assess Solubility 414.6 Brief Overview of Forces Involved in Solubility 424.6.1 van der Waals Interactions 424.6.2 Hydrogen Bonding 424.6.3 Ionic Interactions 434.7 Solid-State Properties and Solubility 434.8 pH and Drug Solubility 434.9 Solvents 444.9.1 Biorelevant Solubility 454.9.2 Buffer System - Phosphate vs Bicarbonate 454.9.3 Solubilisation by Surfactants 454.9.4 Solubilisation During Digestion 474.9.5 Excipients and Solubility 474.10 Risk of Precipitation 484.11 Solubility and Link to Lipophilicity 494.12 Conclusions 495 Permeability 51Chris Roe and Vanessa Zann5.1 Introduction 515.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters 515.2.1 Enzymes 525.2.2 Drug Transporters 545.2.3 Efflux Transporters 555.2.4 Transporters of Greatest Relevance to Oral Biopharmaceutics 565.2.5 Regulatory Overview of Transporter Effects on Biopharmaceutics 585.2.6 Regional Expression and Polymorphism of Intestinal Transporters and Impact of Drug Variability 585.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment 595.3.1 In Silico Tools: Predictive Models for Permeability 595.3.2 in vitro Tools 605.3.2.1 PAMPA 605.3.2.2 Cell Lines 615.3.3 ex vivo Tools 635.3.3.1 Ussing Chambers 635.3.3.2 Everted Intestinal Sac/Ring 655.3.4 In Situ Tools 665.3.4.1 Closed-Loop Intestinal Perfusion 665.3.4.2 Single-Pass Intestinal Perfusion 665.3.4.3 Intestinal Perfusion with Venous Sampling 675.3.4.4 Vascularly Perfused Intestinal Models 675.4 in vivo Tools 675.5 Conclusion 696 Dissolution 75Hannah Batchelor and James Butler6.1 Introduction 756.2 Purpose of Dissolution Testing 756.2.1 Dissolution Versus Solubility 766.3 History of Dissolution Testing 776.4 Compendial (Pharmacopeial) Dissolution Apparatus 786.4.1 USP1 and 2 Apparatus 786.4.2 USP3 Apparatus 796.4.3 USP4 Apparatus 806.4.4 USP5 Apparatus 826.4.5 USP6 Apparatus 826.4.6 USP7 Apparatus 826.4.7 Intrinsic Dissolution Rate (IDR) Apparatus 836.4.8 Micro-dissolution Apparatus 836.5 Dissolution Media Selection 836.5.1 Biphasic Dissolution Media 846.6 Dissolution Agitation Rates 846.7 Reporting Dissolution Data 856.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC) 866.8.1 Convolution and Deconvolution of Dissolution Data 876.9 Evolution of Biorelevant Dissolution Testing 886.9.1 Biorelevant Dissolution Media 886.9.2 Dissolution Testing to Mimic GI Transit 936.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions 946.9.4 Dissolution Testing to Incorporate Permeability 956.10 Conclusions 967 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation 103Linette Ruston7.1 Introduction 1037.2 Oral Product Design Considerations During Early Development 1037.3 Biopharmaceutics in Drug Discovery 1057.3.1 Pre-Clinical Studies 1067.4 Biopharmaceutics Assessment 1077.4.1 Solubility 1077.4.2 Permeability 1077.4.3 Dissolution 1087.4.4 Biopharmaceutics Classification System 1087.4.5 Lipophilicity 1097.4.6 pKa 1097.4.7 Molecular Size 1097.4.8 Crystallinity 1097.4.9 In Vivo Pre-Clinical Studies 1097.4.10 In Silico Modelling 1107.4.11 Human Absorption/Dose Prediction 1107.5 Output of Biopharmaceutics Assessment 1107.5.1 New Modalities/Complex Delivery Systems Within Early Development 1127.6 Influence/Optimise/Design Properties to Inform Formulation Development 1127.6.1 Fraction Absorbed Classification System 1137.7 Conclusion 1148 Biopharmaceutics Tools for Rational Formulation Design 117Panagiota Zarmpi, Mark McAllister, James Butler, and Nikoletta Fotaki8.1 Introduction 1178.2 Formulation Development to Optimise Drug Bioavailability 1188.3 Traditional Formulation Strategies 1198.3.1 Decision Making for Conventional or Enabling Formulations 1198.4 Decision Trees to Guide Formulation Development 1198.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS) 1198.4.2 Decision Trees Based on Developability Classification System (DCS) 1218.4.3 Expanded Decision Trees 1228.5 Computational Tools to Guide Formulation Strategies 1248.5.1 Statistical Tools 1248.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 1258.6 Decision- Making for Optimising Enabling Formulations 1258.7 Decision Trees for Enabled Formulations 1278.7.1 Statistical Tools 1288.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models 1288.8 System-Based Formulation Strategies 1288.8.1 Quality by Design 1288.8.2 Tools to Identify Quality Target Product Profile 1298.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM) 1318.9.1 Tools to Identify Quality Target Product Profile 1318.10 Conclusions 1329 Biopharmaceutic Classification System 139Hannah Batchelor and Talia Flanagan9.1 Description and History of the BCS 1399.2 BCS-Based Criteria for Solubility, Dissolution and Permeability 1399.3 BCS-Based Biowaivers 1419.4 Regulatory Development of BCS-Based Biowaivers 1429.5 International Harmonisation of BCS-Based Biowaiver Criteria - ICH M9 1439.5.1 Application of BCS-Based Biowaivers 1449.5.1.1 Drug Product Type 1449.5.1.2 Composition 1459.5.1.3 Dissolution Similarity 1459.6 BCS as a Development Tool 1469.6.1 Candidate Selection 1469.6.2 Solid Form Selection 1469.6.3 Product Development 1469.7 Beyond the BCS 1479.7.1 Biopharmaceutic Drug Disposition Classification System (BDDCS) 1489.7.2 Developability Classification System 1489.7.3 Fraction Absorbed Classification System 1489.7.4 BCS Applied to Special Populations 1499.8 Conclusions 14910 Regulatory Biopharmaceutics 153Shanoo Budhdeo, Paul A. Dickinson, and Talia Flanagan10.1 Introduction 15310.2 Clinical Bioequivalence Studies 15410.3 Design of Clinical Bioequivalence (BE) Studies 15610.4 Implication of Bioequivalence Metrics 15710.5 Bioequivalence Regulatory Guidelines 15910.6 Biowaivers 15910.7 Biopharmaceutics in Quality by Design 15910.8 Control of Drug Product and Clinically Relevant Specifications 16210.9 Establishing Clinically Relevant Dissolution Methods and Specifications 16210.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications 16510.11 Additional Considerations for Establishing Dissolution Methods and Specifications 16510.12 Common Technical Document (CTD) 16610.13 Other Routes of Administration and Locally Acting Drug Products 16710.14 Conclusion 16811 Impact of Anatomy and Physiology 171Francesca K. H. Gavins, Christine M. Madla, Sarah J. Trenfield, Laura E. McCoubrey, Abdul W. Basit, and Mark McAllister11.1 Introduction 17111.2 Influence of GI Conditions on Pharmacokinetic Studies 17211.3 The Stomach 17211.3.1 Gastric Anatomy 17211.3.2 Gastric Motility and Mixing 17411.3.3 Gastric Emptying 17511.3.3.1 Gastric Fed State 17611.3.4 Gastric Fluid Volume 17611.3.5 Gastric Temperature 17711.3.6 Gastric Fluid Composition 17711.3.6.1 Gastric pH 17711.3.6.2 Gastric Bile Salt Composition and Concentration 17811.4 Small Intestine 17811.4.1 Small Intestinal Anatomy 17811.4.2 Small Intestinal Motility and Mixing 18011.4.3 Small Intestinal Transit Time 18011.4.4 Small Intestinal Volume 18011.4.5 Small Intestinal Fluid Composition 18111.4.5.1 Small Intestinal pH 18211.4.5.2 Small Intestinal Buffer Capacity 18211.4.5.3 Small Intestinal Surface Tension 18211.4.5.4 Small Intestinal Osmolality 18211.4.5.5 Bile Salt Composition and Concentration 18311.5 The Colon/Large Intestine 18311.5.1 Large Intestine Anatomy 18411.5.2 Large Intestinal Motility and Mixing 18411.5.3 Large Intestinal Transit Time 18511.5.4 Large Intestinal Volume 18511.5.5 Large Intestinal Fluid Composition 18511.5.5.1 Large Intestinal pH 18611.5.5.2 Large Intestinal Buffer Capacity 18611.5.5.3 Large Intestinal Surface Tension 18611.5.5.4 Large Intestinal Osmolality 18611.5.5.5 Bile Salt Composition and Concentration 18611.5.6 Impact of Microbiome on Oral Drug Delivery 18711.6 Conclusions 18812 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling 197Konstantinos Stamatopoulos12.1 Introduction 19712.2 Mechanistic Models 19812.3 Solubility Inputs 20012.4 Dissolution Inputs 20312.4.1 Fluid Dynamics and Dissolution 20512.5 Permeability Inputs 20612.6 Incorporation of Modelling and Simulation into Drug Development 20812.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics 20812.6.2 Model Verification/Validation 20912.6.3 Using Modelling to Understand Bioequivalence 20912.7 Conclusions 21013 Special Populations 213Christine M. Madla, Francesca K. H. Gavins, Sarah J. Trenfield, and Abdul W. Basit13.1 Introduction 21313.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance 21313.3 Ethnic Differences in the Gastrointestinal Tract 21613.4 Impact of Diet on Gastrointestinal Physiology 21713.5 Pregnancy and Its Effect on Gastrointestinal Physiology 21913.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance 22013.7 Diseases that Affect the Gastrointestinal Tract 22013.7.1 Irritable Bowel Syndrome 22013.7.2 Inflammatory Bowel Disease 22113.7.3 Celiac Disease 22313.8 Infections in the Gastrointestinal Tract 22413.8.1 Helicobacter pylori Infection 22413.9 Systemic Diseases that Alter GI Physiology and Function 22413.9.1 Cystic Fibrosis 22513.9.2 Parkinson's Disease 22613.9.3 Diabetes 22713.9.4 HIV Infection 22913.10 Age-related Influences on Gastrointestinal Tract Physiology and Function 23013.10.1 Gastrointestinal Physiology and Function in Paediatrics 23013.10.2 Gastrointestinal Physiology and Function in Geriatrics 23213.11 Conclusion 23414 Inhalation Biopharmaceutics 249Precious Akhuemokhan, Magda Swedrowska and Ben Forbes14.1 Introduction 24914.2 Structure of the Lungs 25014.2.1 Basic Anatomy 25014.2.2 Epithelial Lining Fluid 25114.2.3 Epithelium 25114.3 Molecules, Inhalation Devices, Formulations 25214.3.1 Inhaled Molecules 25214.3.2 Inhalation Devices 25214.3.2.1 Nebulisers 25214.3.2.2 Pressurised Metered-Dose Inhalers 25314.3.2.3 Dry Powder Inhalers 25314.3.2.4 'Soft Mist' Inhalers 25314.3.3 Inhaled Medicine Formulation 25314.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics 25414.4.1 Dosimetry and Deposition 25414.4.2 Mucociliary Clearance 25614.4.3 Dissolution 25614.4.4 Lung Permeability, Absorption and Retention 25714.4.5 Metabolism 25814.4.6 Non-Clinical Inhalation Studies 25814.4.7 Mechanistic Computer Modelling 25914.5 Bioequivalence and an Inhalation Bioclassification System 25914.6 Conclusion 26015 Biopharmaceutics of Injectable Formulations 263Wang Wang Lee and Claire M. Patterson15.1 Introduction 26315.2 Subcutaneous Physiology and Absorption Mechanisms 26615.2.1 Physiology 26615.2.2 Absorption Mechanisms 26615.3 Intramuscular Physiology and Absorption Mechanisms 26815.3.1 Physiology 26815.3.2 Absorption Mechanisms 26915.4 In vitro Performance and IVIVC 26915.4.1 In Silico Models 27115.4.2 Preclinical Models 27115.5 Bioequivalence of Injectable Formulations 27115.6 Summary 27216 Biopharmaceutics of Topical and Transdermal Formulations 275Hannah Batchelor16.1 Introduction 27516.2 Skin Structure 27516.2.1 Transport of Drugs Through Skin 27616.2.2 Skin Metabolism 27716.3 Active Pharmaceutical Ingredient Properties 27716.4 Topical and Transdermal Dosage Forms 27716.5 Measurement of Vitro Drug Release 27816.5.1 Diffusion Cells 27816.5.2 Compendial Dissolution Apparatus 27916.6 Measurement of Skin Permeation 27916.6.1 Tape-Stripping 'Dermatopharmacokinetics' (DPK) 27916.6.2 Confocal Laser Scanning Microscopy (CLSM) 28016.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation 28016.6.3.1 Alternative Skin Substrates Used for Permeability Studies 28016.6.4 Dermal Microdialysis 28116.6.5 Skin Biopsy 28116.6.6 In Silico Models of Dermal Absorption 28116.6.7 Pre-Clinical Models 28216.7 Bioequivalence Testing of Topical/Transdermal Products 28216.8 Conclusions 28317 Impact of the Microbiome on Oral Biopharmaceutics 287Laura E. McCoubrey, Hannah Batchelor, Abdul W. Basit, Simon Gaisford, and Mine Orlu17.1 Introduction 28717.2 Microbiome Distribution in the GI Tract 28817.3 Key Causes of Microbiome Variability 29017.4 Microbiome Influence on Key GI Parameters 29217.4.1 pH 29217.4.2 Bile Acid Concentration and Composition 29217.4.3 Drug Transporters 29217.4.4 Motility 29317.4.5 Hepatic Drug Metabolism 29317.4.6 Epithelial Permeability 29417.5 Enzymatic Degradation of Drugs by GI Microbiota 29417.6 Exploitation of the GI Microbiome for Drug Delivery 29517.7 Models of the GI Microbiome 29517.7.1 In vitro Models 29517.7.2 In Silico Models 29917.8 Conclusion 299Index 000

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Edited byHannah Batchelor, Strathclyde Institute of Pharmacy and Biomedical Sciences.