Biopharmaceutics: From Fundamentals to Industrial Practice (Advances in Pharmaceutical Technology)

Cover
Title Page
Copyright Page
Contents
List of Contributors
Chapter 1 An Introduction to Biopharmaceutics
	1.1 Introduction
	1.2 History of Biopharmaceutics
	1.3 Key Concepts and Definitions Used Within Biopharmaceutics
	1.4 The Role of Biopharmaceutics in Drug Development
	1.5 Conclusions
	References
Chapter 2 Basic Pharmacokinetics
	2.1 Introduction
	2.2 What is ‘Pharmacokinetics’?
	2.3 Pharmacokinetic Profile
	2.4 Bioavailability
	2.5 Drug Distribution
	2.6 Volume of Distribution
	2.7 Elimination
		2.7.1 Metabolism
		2.7.2 Excretion
	2.8 Elimination Half-Life (t½)
	2.9 Elimination Rate Constant
		2.9.1 Clearance
	2.10 Area Under the Curve (AUC)
	2.11 Bioequivalence
	2.12 Steady State
	2.13 Compartmental Concepts in Pharmacokinetics
	2.14 Concept of Linearity in Pharmacokinetics
	2.15 Conclusions
Chapter 3 Introduction to Biopharmaceutics Measures
	3.1 Introduction
	3.2 Solubility
	3.3 Dissolution
	3.4 Permeability
	3.5 Absorptive Flux
	3.6 Lipinsky’s Rule of 5
		3.6.1 Molecular Weight
		3.6.2 Lipophilicity
		3.6.3 Hydrogen Bond Donors/Acceptors
	References
Chapter 4 Solubility
	4.1 Definition of Solubility
	4.2 The Importance of Solubility in Biopharmaceutics
	4.3 What Level of Solubility Is Required?
	4.4 Solubility-Limited Absorption
	4.5 Methods to Assess Solubility
	4.6 Brief Overview of Forces Involved in Solubility
		4.6.1 van der Waals Interactions
		4.6.2 Hydrogen Bonding
		4.6.3 Ionic Interactions
	4.7 Solid-State Properties and Solubility
	4.8 pH and Drug Solubility
	4.9 Solvents
		4.9.1 Biorelevant Solubility
		4.9.2 Buffer System – Phosphate vs Bicarbonate
		4.9.3 Solubilisation by Surfactants
		4.9.4 Solubilisation During Digestion
		4.9.5 Excipients and Solubility
	4.10 Risk of Precipitation
	4.11 Solubility and Link to Lipophilicity
	4.12 Conclusions
	References
Chapter 5 Permeability
	5.1 Introduction
	5.2 Enzymes, Gut Wall Metabolism, Tissue Permeability and Transporters
		5.2.1 Enzymes
		5.2.2 Drug Transporters
		5.2.3 Efflux Transporters
		5.2.4 Transporters of Greatest Relevance to Oral Biopharmaceutics
		5.2.5 Regulatory Overview of Transporter Effects on Biopharmaceutics
		5.2.6 Regional Expression and Polymorphism of Intestinal Transporters and Impact of Drug Variability
	5.3 Applications and Limitations of Characterisation and Predictive Tools for Permeability Assessment
		5.3.1 In Silico Tools: Predictive Models for Permeability
		5.3.2 In Vitro Tools
		5.3.3 Ex Vivo Tools
		5.3.4 In Situ Tools
	5.4 In Vivo Tools
	5.5 Conclusion
	References
Chapter 6 Dissolution
	6.1 Introduction
	6.2 Purpose of Dissolution Testing
		6.2.1 Dissolution Versus Solubility
	6.3 History of Dissolution Testing
	6.4 Compendial (Pharmacopeial) Dissolution Apparatus
		6.4.1 USP1 and 2 Apparatus
		6.4.2 USP3 Apparatus
		6.4.3 USP4 Apparatus
		6.4.4 USP5 Apparatus
		6.4.5 USP6 Apparatus
		6.4.6 USP7 Apparatus
		6.4.7 Intrinsic Dissolution Rate (IDR) Apparatus
		6.4.8 Micro-dissolution Apparatus
	6.5 Dissolution Media Selection
		6.5.1 Biphasic Dissolution Media
	6.6 Dissolution Agitation Rates
	6.7 Reporting Dissolution Data
	6.8 In Vitro In Vivo Relationships and Correlations (IVIVR/IVIVC)
		6.8.1 Convolution and Deconvolution of Dissolution Data
	6.9 Evolution of Biorelevant Dissolution Testing
		6.9.1 Biorelevant Dissolution Media
		6.9.2 Dissolution Testing to Mimic GI Transit
		6.9.3 Dissolution Testing to Mimic Motility/Hydrodynamic Conditions
		6.9.4 Dissolution Testing to Incorporate Permeability
	6.10 Conclusions
	References
Chapter 7 Biopharmaceutics to Inform Candidate Drug Selection and Optimisation
	7.1 Introduction
	7.2 Oral Product Design Considerations During Early Development
	7.3 Biopharmaceutics in Drug Discovery
		7.3.1 Pre-Clinical Studies
	7.4 Biopharmaceutics Assessment
		7.4.1 Solubility
		7.4.2 Permeability
		7.4.3 Dissolution
		7.4.4 Biopharmaceutics Classification System
		7.4.5 Lipophilicity
		7.4.6 pKa
		7.4.7 Molecular Size
		7.4.8 Crystallinity
		7.4.9 in vivo Pre-Clinical Studies
		7.4.10 In Silico Modelling
		7.4.11 Human Absorption/Dose Prediction
	7.5 Output of Biopharmaceutics Assessment
		7.5.1 New Modalities/Complex Delivery Systems Within Early Development
	7.6 Influence/Optimise/Design Properties to Inform Formulation Development
		7.6.1 Fraction Absorbed Classification System
	7.7 Conclusion
	References
Chapter 8 Biopharmaceutics Tools for Rational Formulation Design
	8.1 Introduction
	8.2 Formulation Development to Optimise Drug Bioavailability
	8.3 Traditional Formulation Strategies
		8.3.1 Decision Making for Conventional or Enabling Formulations
	8.4 Decision Trees to Guide Formulation Development
		8.4.1 Decision Trees Based on Biopharmaceutics Classification System (BCS)
		8.4.2 Decision Trees Based on Developability Classification System (DCS)
		8.4.3 Expanded Decision Trees
	8.5 Computational Tools to Guide Formulation Strategies
		8.5.1 Statistical Tools
		8.5.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models
	8.6 Decision-Making for Optimising Enabling Formulations
	8.7 Decision Trees for Enabled Formulations
		8.7.1 Statistical Tools
		8.7.2 Physiologically Based Pharmacokinetic/Biopharmaceutics Models
	8.8 System-Based Formulation Strategies
		8.8.1 Quality by Design
		8.8.2 Tools to Identify Quality Target Product Profile
	8.9 Biopharmaceutics Risk Assessment Roadmap (BioRAM)
		8.9.1 Tools to Identify Quality Target Product Profile
	8.10 Conclusions
	References
Chapter 9 Biopharmaceutic Classification System
	9.1 Description and History of the BCS
	9.2 BCS-Based Criteria for Solubility, Dissolution and Permeability
	9.3 BCS-Based Biowaivers
	9.4 Regulatory Development of BCS-Based Biowaivers
	9.5 International Harmonisation of BCS-Based Biowaiver Criteria – ICH M9
		9.5.1 Application of BCS-Based Biowaivers
	9.6 BCS as a Development Tool
		9.6.1 Candidate Selection
		9.6.2 Solid Form Selection
		9.6.3 Product Development
	9.7 Beyond the BCS
		9.7.1 Biopharmaceutic Drug Disposition Classification System (BDDCS)
		9.7.2 Developability Classification System
		9.7.3 Fraction Absorbed Classification System
		9.7.4 BCS Applied to Special Populations
	9.8 Conclusions
	References
Chapter 10 Regulatory Biopharmaceutics
	10.1 Introduction
	10.2 Clinical Bioequivalence Studies
	10.3 Design of Clinical Bioequivalence (BE) Studies
	10.4 Implication of Bioequivalence Metrics
	10.5 Bioequivalence Regulatory Guidelines
	10.6 Biowaivers
	10.7 Biopharmaceutics in Quality by Design
	10.8 Control of Drug Product and Clinically Relevant Specifications
	10.9 Establishing Clinically Relevant Dissolution Methods and Specifications
	10.10 Application of In Silico Physiologically Based Biopharmaceutics Modelling (PBBM) to Develop Clinically Relevant Specifications
	10.11 Additional Considerations for Establishing Dissolution Methods and Specifications
	10.12 Common Technical Document (CTD)
	10.13 Other Routes of Administration and Locally Acting Drug Products
	10.14 Conclusion
	References
Chapter 11 Impact of Anatomy and Physiology
	11.1 Introduction
	11.2 Influence of GI Conditions on Pharmacokinetic Studies
	11.3 The Stomach
		11.3.1 Gastric Anatomy
		11.3.2 Gastric Motility and Mixing
		11.3.3 Gastric Emptying
		11.3.4 Gastric Fluid Volume
		11.3.5 Gastric Temperature
		11.3.6 Gastric Fluid Composition
	11.4 Small Intestine
		11.4.1 Small Intestinal Anatomy
		11.4.2 Small Intestinal Motility and Mixing
		11.4.3 Small Intestinal Transit Time
		11.4.4 Small Intestinal Volume
		11.4.5 Small Intestinal Fluid Composition
	11.5 The Colon/Large Intestine
		11.5.1 Large Intestine Anatomy
		11.5.2 Large Intestinal Motility and Mixing
		11.5.3 Large Intestinal Transit Time
		11.5.4 Large Intestinal Volume
		11.5.5 Large Intestinal Fluid Composition
		11.5.6 Impact of Microbiome on Oral Drug Delivery
	11.6 Conclusions
	References
Chapter 12 Integrating Biopharmaceutics to Predict Oral Absorption Using PBPK Modelling
	12.1 Introduction
	12.2 Mechanistic Models
	12.3 Solubility Inputs
	12.4 Dissolution Inputs
		12.4.1 Fluid Dynamics and Dissolution
	12.5 Permeability Inputs
	12.6 Incorporation of Modelling and Simulation into Drug Development
		12.6.1 Understanding the Effect of Formulation Modifications on Drug Pharmacokinetics
		12.6.2 Model Verification/Validation
		12.6.3 Using Modelling to Understand Bioequivalence
	12.7 Conclusions
	References
Chapter 13 Special Populations
	13.1 Introduction
	13.2 Sex Differences in the Gastrointestinal Tract and Its Effect on Oral Drug Performance
	13.3 Ethnic Differences in the Gastrointestinal Tract
	13.4 Impact of Diet on Gastrointestinal Physiology
	13.5 Pregnancy and Its Effect on Gastrointestinal Physiology
	13.6 The Implication of Disease States on Gastrointestinal Physiology and Its Effect on Oral Drug Performance
	13.7 Diseases that Affect the Gastrointestinal Tract
		13.7.1 Irritable Bowel Syndrome
		13.7.2 Inflammatory Bowel Disease
		13.7.3 Celiac Disease
	13.8 Infections in the Gastrointestinal Tract
		13.8.1 Helicobacter pylori Infection
	13.9 Systemic Diseases that Alter GI Physiology and Function
		13.9.1 Cystic Fibrosis
		13.9.2 Parkinson’s Disease
		13.9.3 Diabetes
		13.9.4 HIV Infection
	13.10 Age-related Influences on Gastrointestinal Tract Physiology and Function
		13.10.1 Gastrointestinal Physiology and Function in Paediatrics
		13.10.2 Gastrointestinal Physiology and Function in Geriatrics
	13.11 Conclusion
	References
Chapter 14 Inhalation Biopharmaceutics
	14.1 Introduction
	14.2 Structure of the Lungs
		14.2.1 Basic Anatomy
		14.2.2 Epithelial Lining Fluid
		14.2.3 Epithelium
	14.3 Molecules, Inhalation Devices, Formulations
		14.3.1 Inhaled Molecules
		14.3.2 Inhalation Devices
		14.3.3 Inhaled Medicine Formulation
	14.4 Inhaled Drug Delivery and Models for Studying Inhalation Biopharmaceutics
		14.4.1 Dosimetry and Deposition
		14.4.2 Mucociliary Clearance
		14.4.3 Dissolution
		14.4.4 Lung Permeability, Absorption and Retention
		14.4.5 Metabolism
		14.4.6 Non-Clinical Inhalation Studies
		14.4.7 Mechanistic Computer Modelling
	14.5 Bioequivalence and an Inhalation Bioclassification System
	14.6 Conclusion
	References
Chapter 15 Biopharmaceutics of Injectable Formulations
	15.1 Introduction
	15.2 Subcutaneous Physiology and Absorption Mechanisms
		15.2.1 Physiology
		15.2.2 Absorption Mechanisms
	15.3 Intramuscular Physiology and Absorption Mechanisms
		15.3.1 Physiology
		15.3.2 Absorption Mechanisms
	15.4 In Vitro Performance and IVIVC
		15.4.1 In Silico Models
		15.4.2 Preclinical Models
	15.5 Bioequivalence of Injectable Formulations
	15.6 Summary
	References
Chapter 16 Biopharmaceutics of Topical and Transdermal Formulations
	16.1 Introduction
	16.2 Skin Structure
		16.2.1 Transport of Drugs Through Skin
		16.2.2 Skin Metabolism
	16.3 Active Pharmaceutical Ingredient Properties
	16.4 Topical and Transdermal Dosage Forms
	16.5 Measurement of In Vitro Drug Release
		16.5.1 Diffusion Cells
		16.5.2 Compendial Dissolution Apparatus
	16.6 Measurement of Skin Permeation
		16.6.1 Tape-Stripping ‘Dermatopharmacokinetics’ (DPK)
		16.6.2 Confocal Laser Scanning Microscopy (CLSM)
		16.6.3 Diffusion Cells Using Biorelevant Membranes to Model Permeation
		16.6.4 Dermal Microdialysis
		16.6.5 Skin Biopsy
		16.6.6 In Silico Models of Dermal Absorption
		16.6.7 Pre-Clinical Models
	16.7 Bioequivalence Testing of Topical/Transdermal Products
	16.8 Conclusions
	References
Chapter 17 Impact of the Microbiome onOral Biopharmaceutics
	17.1 Introduction
	17.2 Microbiome Distribution in the GI Tract
	17.3 Key Causes of Microbiome Variability
	17.4 Microbiome Influence on Key GI Parameters
		17.4.1 pH
		17.4.2 Bile Acid Concentration and Composition
		17.4.3 Drug Transporters
		17.4.4 Motility
		17.4.5 Hepatic Drug Metabolism
		17.4.6 Epithelial Permeability
	17.5 Enzymatic Degradation of Drugs by GI Microbiota
	17.6 Exploitation of the GI Microbiome for Drug Delivery
	17.7 Models of the GI Microbiome
		17.7.1 In Vitro Models
		17.7.2 In Silico Models
	17.8 Conclusion
	References
Index
EULA