ALI NOKHODCHI School of Life Sciences, University of Sussex, UK GARY P. MARTIN Institute of Pharmaceutical Science, King’s College London, UK

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• List of Contributors xiiiSeries Preface xviiPreface xix1. Lung Anatomy and Physiology and Their Implications for Pulmonary Drug Delivery 1Rahul K. Verma, Mariam Ibrahim, and Lucila Garcia-Contreras1.1 Introduction 21.2 Anatomy and Physiology of Lungs 21.2.1 Macro- and Microstructure of the Airways and Alveoli as It Pertains to Drug Delivery 21.2.2 Lung Surfactant 41.2.3 Pulmonary Blood Circulation 51.3 Mechanisms of Aerosol Deposition 51.3.1 Impaction 61.3.2 Sedimentation 61.3.3 Interception 61.3.4 Diffusion 71.4 Drug Absorption 71.4.1 Mechanisms of Drug Absorption from the Lungs 71.5 Physiological Factors Affecting the Therapeutic Effectiveness of Drugs Delivered by the Pulmonary Route 81.5.1 Airway Geometry 81.5.2 Inhalation Mode 81.5.3 Airflow Rate 91.5.4 Mechanism of Particle Clearance 91.5.5 Lung Receptors 101.5.6 Disease States 111.5.7 Effect of Age and Gender Difference 111.6 Computer Simulations to Describe Aerosol Deposition in Health and Disease 111.6.1 Semiempirical Models 121.6.2 Deterministic Models 121.6.3 Trumpet Models (One-Dimensional) 121.6.4 Stochastic, Asymmetric Generation Models 131.6.5 Computation Fluid Dynamics (CFD)-Based Model 131.7 Conclusions 13References 142. The Role of Functional Lung Imaging in the Improvement of Pulmonary Drug Delivery 19Andreas Fouras and Stephen Dubsky2.1 Introduction 192.1.1 Particle Deposition 202.1.2 Regional Action of Delivered Drug 222.1.3 The Role of Functional Lung Imaging in Pulmonary Drug Delivery 222.2 Established Functional Lung Imaging Technologies 232.2.1 Computed Tomography 232.2.2 Ventilation Measurement using 4DCT Registration-based Methods 242.2.3 Hyperpolarized Magnetic Resonance Imaging 242.2.4 Electrical Impedance Tomography 252.2.5 Nuclear Medical Imaging (PET/SPECT) 252.3 Emerging Technologies 262.3.1 Phase-contrast Imaging 262.3.2 Grating Interferometry 272.3.3 Propagation-based Phase-contrast Imaging 282.3.4 Functional Lung Imaging using Phase Contrast 282.3.5 Laboratory Propagation-based Phase-contrast Imaging 292.4 Conclusion 30References 313. Dry Powder Inhalation for Pulmonary Delivery: Recent Advances and Continuing Challenges 35Simone R. Carvalho, Alan B. Watts, Jay I. Peters, and Robert O. Williams III3.1 Introduction 363.2 Dry Powder Inhaler Devices 373.2.1 Overview 373.2.2 Recent Innovations in Dry Powder Inhaler Technology 393.3 New Developments in DPI Formulations and Delivery 433.3.1 Particle Surface Modification 433.3.2 Particle Engineering Technology for Pulmonary Delivery 443.4 Characterization Methods of Dry Powder Inhaler Formulations 503.5 Conclusion 52References 534. Pulmonary Drug Delivery to the Pediatric Population – A State-of-the-Art Review 63Marie-Pierre Flament4.1 Introduction 634.2 Patient Consideration 644.2.1 Anatomy and Physiology of Children’s Lungs 644.2.2 Nasal Versus Oral Inhalation 654.2.3 Patient-related Factors Influencing Aerosol Deposition 664.2.4 Age and Dosage Forms of Choice 674.3 Delivery Systems for the Pediatric Population 694.3.1 Nebulizers 694.3.2 Pressurized Metered Dose Inhalers 724.3.3 Dry Powder Inhalers 734.3.4 Interfaces 744.4 Recommendations 804.5 Conclusion 82References 825. Formulation Strategies for Pulmonary Delivery of Poorly Soluble Drugs 87Nathalie Wauthoz and Karim Amighi5.1 Introduction 885.1.1 In vivo Fate of Inhaled Poorly Water-soluble Drugs 895.1.2 The Pharmacokinetics of Inhaled Poorly Water-soluble Drugs Administered for Local and Systemic Action 925.1.3 Formulation Strategies for Pulmonary Delivery of Poorly Water-soluble Drugs 935.2 Co-solvents 935.3 Cyclodextrins 975.4 PEGylation 995.5 Reduction of Size to Micro-/Nanoparticles 1005.5.1 Nanocrystal Suspension 1015.5.2 Nanocrystals in a Hydrophilic Matrix System 1025.5.3 Nanoclusters 1035.6 Solid Dispersion/Amorphization 1035.7 Micelles 1065.8 Liposomes 1085.9 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 1105.10 Conclusion 111References 1146. Lipidic Micro- and Nano-Carriers for Pulmonary Drug Delivery – A State-of-the-Art Review 123Yahya Rahimpour, Hamed Hamishehkar, and Ali Nokhodchi6.1 Introduction 1246.2 Pulmonary Drug Delivery 1256.3 Liposomal Pulmonary Delivery 1266.4 Nebulization of Liposomes 1266.5 Liposomal Dry-powder Inhalers 1286.6 Solid Lipid Microparticles in Pulmonary Drug Delivery 1296.7 Solid Lipid Nanoparticles in Pulmonary Drug Delivery 1316.8 Nanostructured Lipid Carrier (NLC) in Pulmonary Drug Delivery 1336.9 Nanoemulsions in Pulmonary Drug Delivery 1346.10 Conclusion and Perspectives 135References 1367. Chemical and Compositional Characterisation of Lactose as a Carrier in Dry Powder Inhalers 143Rim Jawad, Gary P. Martin and Paul G. Royall7.1 Introduction 1447.2 Production of Lactose 1457.3 Lactose: Chemical Forms, Solid-State Composition, Physicochemical Properties 1477.4 Epimerisation of Lactose 1507.5 Analysis of Lactose 1517.5.1 Powder X-ray Diffraction 1527.5.2 Nuclear Magnetic Resonance 1537.5.3 Infrared Spectroscopy 1567.5.4 Differential Scanning Calorimetry 1577.5.5 Polarimetry 1587.6 The Influence of the Chemical and Solid-State Composition of Lactose Carriers on the Aerosolisation of DPI Formulations 1597.7 Conclusions 163References 1638. Particle Engineering for Improved Pulmonary Drug Delivery Through Dry Powder Inhalers 171Waseem Kaialy and Ali Nokhodchi8.1 Introduction 1728.2 Dry Powder Inhalers 1728.3 Particle Engineering to Improve the Performance of DPIs 1728.3.1 Crystallization 1738.3.2 Spray-drying 1748.3.3 Spray-freeze-drying 1778.3.4 Supercritical Fluid Technology 1778.3.5 Pressure Swing Granulation (PSG) Technique 1788.4 Engineered Carrier Particles for Improved Pulmonary Drug Delivery from Dry Powder Inhalers 1788.5 Relationships between Physical Properties of Engineered Particles and Dry Powder Inhaler Performance 1828.5.1 Particle Size 1828.5.2 Flow Properties 1848.5.3 Particle Shape 1858.5.4 Particle Surface Texture 1878.5.5 Fine Particle Additives 1888.5.6 Surface Area 1888.6 Conclusions 189References 1899. Particle Surface Roughness – Its Characterisation and Impact on Dry Powder Inhaler Performance 199Bernice Mei Jin Tan, Celine Valeria Liew, Lai Wah Chan, and Paul Wan Sia Heng9.1 Introduction 2009.2 What is Surface Roughness? 2009.3 Measurement of Particle Surface Roughness 2029.3.1 General Factors to Consider During a Measurement 2029.3.2 Direct Methods to Profile or Visualise Surface Roughness 2049.3.3 Indirect Measurement of Surface Roughness 2069.4 Impact of Surface Roughness on Carrier Performance – Theoretical Considerations 2069.4.1 Mixing and Blend Stability 2069.4.2 Drug-carrying Capacity 2079.4.3 Drug Adhesion 2079.4.4 Drug Detachment 2089.4.5 Particle Arrangement in Ordered Mixtures After the Addition of Fine Excipient 2099.5 Particle Surface Modification 2109.5.1 Spray Drying 2109.5.2 Solution Phase Processing 2119.5.3 Crystallisation 2139.5.4 Sieving 2139.5.5 Fluid-bed Coating 2139.5.6 Dry Powder Coating 2139.6 Conclusion 215References 21510. Dissolution: A Critical Performance Characteristic of Inhaled Products? 223Ben Forbes, Nathalie Hauet Richer, and Francesca Buttini10.1 Introduction 22310.2 Dissolution of Inhaled Products 22410.2.1 Dissolution Rate 22410.2.2 Dissolution in the Lungs 22410.2.3 Case for Dissolution Testing 22510.2.4 Design of Dissolution Test Systems 22610.3 Particle Testing and Dissolution Media 22610.3.1 Particle Collection 22610.3.2 Dissolution Media 22910.4 Dissolution Test Apparatus 23010.4.1 USP Apparatus 1 (Basket) 23110.4.2 USP Apparatus 2 (Paddle) and USP Apparatus 5 (Paddle Over Disc) 23210.4.3 USP Apparatus 4 (Flow-Through Cell) 23210.4.4 Diffusion-Controlled Cell Systems (Franz Cell, Transwell, Dialysis) 23310.4.5 Methodological Considerations 23410.5 Data Analysis and Interpretation 23510.5.1 Modelling 23610.5.2 Comparing Dissolution Profiles (Model-independent Method for Comparison) 23710.6 Conclusions 237References 23811. Drug Delivery Strategies for Pulmonary Administration of Antibiotics 241Anna Giulia Balducci, Ruggero Bettini, Paolo Colombo, and Francesca Buttini11.1 Introduction 24211.2 Antibiotics Used for the Treatment of Pneumoniae 24311.3 Antibiotic Products for Inhalation Approved on the Market 24411.4 Nebulisation 24611.5 Antibiotic Dry Powders for Inhalation 25011.5.1 Tobramycin 25111.5.2 Capreomycin 25211.5.3 Gentamicin 25311.5.4 Ciprofloxacin 25411.5.5 Levofloxacin 25511.5.6 Colistimethate Sodium 25611.6 Device and Payload of Dose 25611.7 Conclusions 258References 25812. Molecular Targeted Therapy of Lung Cancer: Challenges and Promises 263Jaleh Barar, Yadollah Omidi, and Mark Gumbleton12.1 Introduction 26512.2 An Overview on Lung Cancer 26612.3 Molecular Features of Lung Cancer 26812.3.1 Tumor Microenvironment (TME) 26912.3.2 Tumor Angiogenesis 26912.3.3 Tumor Stromal Components 27012.3.4 Pharmacogenetic Markers: Cytochrome P450 27012.4 Targeted Therapy of Solid Tumors: How and What to Target? 27112.4.1 EPR Effect: A Rational Approach for Passive Targeting 27212.4.2 Toward Long Circulating Anticancer Nanomedicines 27312.4.3 Active/Direct Targeting 27312.4.4 Overcoming Multidrug Resistance (MDR) 27312.4.5 Antibody-Mediated Targeting 27412.4.6 Aptamer-Mediated Targeted Therapy 27612.4.7 Folate Receptor-Mediated Targeted Therapy 27612.4.8 Transferrin-Mediated Targeted Therapy 27612.4.9 Targeted Photodynamic Therapy 27712.4.10 Multimodal Theranostics and Nanomedicines 27812.5 Final Remarks 278References 27913. Defining and Controlling Blend Evolution in Inhalation Powder Formulations using a Novel Colourimetric Method 285David Barling, David Morton, and Karen Hapgood13.1 Introduction 28613.1.1 Introduction to Blend Pigmentation 28713.1.2 Previous Work in the Use of Coloured Tracers to Assess Powder Blending 28813.1.3 Colour Tracer Properties and Approach to Blend Analysis 28813.2 Uses and Validation 29013.2.1 Assessment of Mixer Characteristics and Mixer Behaviour 29013.2.2 Quantification of Content Uniformity and Energy Input 29313.2.3 Detection and Quantification of Unintentional Milling during Mixing 29513.2.4 Robustness of Method with Tracer Concentration 29513.3 Comments on the Applied Suitability and Robustness in of the Tracer Method 29613.4 Conclusions 297Acknowledgements 297References 29714. Polymer-based Delivery Systems for the Pulmonary Delivery of Biopharmaceuticals 301Nitesh K. Kunda, Iman M. Alfagih, Imran Y. Saleem, and Gillian A. Hutcheon14.1 Introduction 30214.2 Pulmonary Delivery of Macromolecules 30214.3 Polymeric Delivery Systems 30314.3.1 Micelles 30414.3.2 Dendrimers 30514.3.3 Particles 30514.4 Preparation of Polymeric Nano/microparticles 30514.4.1 Emulsification Solvent Evaporation 30614.4.2 Emulsification Solvent Diffusion 30714.4.3 Salting Out 30714.5 Formulation of Nanoparticles as Dry Powders 30814.5.1 Freeze-drying 30814.5.2 Spray-drying 30914.5.3 Spray-freeze-drying 30914.5.4 Supercritical Fluid Drying 31014.6 Carrier Properties 31014.6.1 Size 31014.6.2 Morphology 31114.6.3 Surface Properties 31114.7 Toxicity of Polymeric Delivery Systems 31114.8 Pulmonary Delivery of Polymeric Particles 31214.9 Conclusions 313References 31315. Quality by Design: Concept for Product Development of Dry-powder Inhalers 321Al Sayyed Sallam, Sami Nazzal, Hatim S. AlKhatib, and Nabil Darwazeh15.1 Introduction 32215.2 Quality Target Product Profile (QTPP) 32415.3 Critical Quality Attributes (CQA) 32415.4 Quality Risk Management 32515.5 Design of Experiments 32615.6 Design Space 32815.7 Control Strategies 32815.8 Continual Improvement 32915.9 Process Analytical Technology/Application in DPI 32915.10 Particle Size 32915.11 Crystallinity and Polymorphism 33015.12 Scale-up and Blend Homogeneity 33115.13 Applying of QbD Principles to Analytical Methods 33115.14 Conclusion 332References 33216. Future Patient Requirements on Inhalation Devices: The Balance between Patient, Commercial, Regulatory and Technical Requirements 339Orest Lastow16.1 Introduction 34016.1.1 Inhaled Drug Delivery 34016.1.2 Patients 34016.2 Requirements 34116.2.1 Patient Requirements 34116.2.2 Technical Requirements 34316.2.3 Performance Requirements 34516.3 Requirement Specifications 34616.3.1 Requirement Hierarchy 34616.3.2 Developing the Requirements 34716.4 Product Development 35016.5 Conclusions 351References 352Index 353

ALI NOKHODCHI School of Life Sciences, University of Sussex, UK GARY P. MARTIN Institute of Pharmaceutical Science, King’s College London, UK

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• List of Contributors xiiiSeries Preface xviiPreface xix1. Lung Anatomy and Physiology and Their Implications for Pulmonary Drug Delivery 1Rahul K. Verma, Mariam Ibrahim, and Lucila Garcia-Contreras1.1 Introduction 21.2 Anatomy and Physiology of Lungs 21.2.1 Macro- and Microstructure of the Airways and Alveoli as It Pertains to Drug Delivery 21.2.2 Lung Surfactant 41.2.3 Pulmonary Blood Circulation 51.3 Mechanisms of Aerosol Deposition 51.3.1 Impaction 61.3.2 Sedimentation 61.3.3 Interception 61.3.4 Diffusion 71.4 Drug Absorption 71.4.1 Mechanisms of Drug Absorption from the Lungs 71.5 Physiological Factors Affecting the Therapeutic Effectiveness of Drugs Delivered by the Pulmonary Route 81.5.1 Airway Geometry 81.5.2 Inhalation Mode 81.5.3 Airflow Rate 91.5.4 Mechanism of Particle Clearance 91.5.5 Lung Receptors 101.5.6 Disease States 111.5.7 Effect of Age and Gender Difference 111.6 Computer Simulations to Describe Aerosol Deposition in Health and Disease 111.6.1 Semiempirical Models 121.6.2 Deterministic Models 121.6.3 Trumpet Models (One-Dimensional) 121.6.4 Stochastic, Asymmetric Generation Models 131.6.5 Computation Fluid Dynamics (CFD)-Based Model 131.7 Conclusions 13References 142. The Role of Functional Lung Imaging in the Improvement of Pulmonary Drug Delivery 19Andreas Fouras and Stephen Dubsky2.1 Introduction 192.1.1 Particle Deposition 202.1.2 Regional Action of Delivered Drug 222.1.3 The Role of Functional Lung Imaging in Pulmonary Drug Delivery 222.2 Established Functional Lung Imaging Technologies 232.2.1 Computed Tomography 232.2.2 Ventilation Measurement using 4DCT Registration-based Methods 242.2.3 Hyperpolarized Magnetic Resonance Imaging 242.2.4 Electrical Impedance Tomography 252.2.5 Nuclear Medical Imaging (PET/SPECT) 252.3 Emerging Technologies 262.3.1 Phase-contrast Imaging 262.3.2 Grating Interferometry 272.3.3 Propagation-based Phase-contrast Imaging 282.3.4 Functional Lung Imaging using Phase Contrast 282.3.5 Laboratory Propagation-based Phase-contrast Imaging 292.4 Conclusion 30References 313. Dry Powder Inhalation for Pulmonary Delivery: Recent Advances and Continuing Challenges 35Simone R. Carvalho, Alan B. Watts, Jay I. Peters, and Robert O. Williams III3.1 Introduction 363.2 Dry Powder Inhaler Devices 373.2.1 Overview 373.2.2 Recent Innovations in Dry Powder Inhaler Technology 393.3 New Developments in DPI Formulations and Delivery 433.3.1 Particle Surface Modification 433.3.2 Particle Engineering Technology for Pulmonary Delivery 443.4 Characterization Methods of Dry Powder Inhaler Formulations 503.5 Conclusion 52References 534. Pulmonary Drug Delivery to the Pediatric Population – A State-of-the-Art Review 63Marie-Pierre Flament4.1 Introduction 634.2 Patient Consideration 644.2.1 Anatomy and Physiology of Children’s Lungs 644.2.2 Nasal Versus Oral Inhalation 654.2.3 Patient-related Factors Influencing Aerosol Deposition 664.2.4 Age and Dosage Forms of Choice 674.3 Delivery Systems for the Pediatric Population 694.3.1 Nebulizers 694.3.2 Pressurized Metered Dose Inhalers 724.3.3 Dry Powder Inhalers 734.3.4 Interfaces 744.4 Recommendations 804.5 Conclusion 82References 825. Formulation Strategies for Pulmonary Delivery of Poorly Soluble Drugs 87Nathalie Wauthoz and Karim Amighi5.1 Introduction 885.1.1 In vivo Fate of Inhaled Poorly Water-soluble Drugs 895.1.2 The Pharmacokinetics of Inhaled Poorly Water-soluble Drugs Administered for Local and Systemic Action 925.1.3 Formulation Strategies for Pulmonary Delivery of Poorly Water-soluble Drugs 935.2 Co-solvents 935.3 Cyclodextrins 975.4 PEGylation 995.5 Reduction of Size to Micro-/Nanoparticles 1005.5.1 Nanocrystal Suspension 1015.5.2 Nanocrystals in a Hydrophilic Matrix System 1025.5.3 Nanoclusters 1035.6 Solid Dispersion/Amorphization 1035.7 Micelles 1065.8 Liposomes 1085.9 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 1105.10 Conclusion 111References 1146. Lipidic Micro- and Nano-Carriers for Pulmonary Drug Delivery – A State-of-the-Art Review 123Yahya Rahimpour, Hamed Hamishehkar, and Ali Nokhodchi6.1 Introduction 1246.2 Pulmonary Drug Delivery 1256.3 Liposomal Pulmonary Delivery 1266.4 Nebulization of Liposomes 1266.5 Liposomal Dry-powder Inhalers 1286.6 Solid Lipid Microparticles in Pulmonary Drug Delivery 1296.7 Solid Lipid Nanoparticles in Pulmonary Drug Delivery 1316.8 Nanostructured Lipid Carrier (NLC) in Pulmonary Drug Delivery 1336.9 Nanoemulsions in Pulmonary Drug Delivery 1346.10 Conclusion and Perspectives 135References 1367. Chemical and Compositional Characterisation of Lactose as a Carrier in Dry Powder Inhalers 143Rim Jawad, Gary P. Martin and Paul G. Royall7.1 Introduction 1447.2 Production of Lactose 1457.3 Lactose: Chemical Forms, Solid-State Composition, Physicochemical Properties 1477.4 Epimerisation of Lactose 1507.5 Analysis of Lactose 1517.5.1 Powder X-ray Diffraction 1527.5.2 Nuclear Magnetic Resonance 1537.5.3 Infrared Spectroscopy 1567.5.4 Differential Scanning Calorimetry 1577.5.5 Polarimetry 1587.6 The Influence of the Chemical and Solid-State Composition of Lactose Carriers on the Aerosolisation of DPI Formulations 1597.7 Conclusions 163References 1638. Particle Engineering for Improved Pulmonary Drug Delivery Through Dry Powder Inhalers 171Waseem Kaialy and Ali Nokhodchi8.1 Introduction 1728.2 Dry Powder Inhalers 1728.3 Particle Engineering to Improve the Performance of DPIs 1728.3.1 Crystallization 1738.3.2 Spray-drying 1748.3.3 Spray-freeze-drying 1778.3.4 Supercritical Fluid Technology 1778.3.5 Pressure Swing Granulation (PSG) Technique 1788.4 Engineered Carrier Particles for Improved Pulmonary Drug Delivery from Dry Powder Inhalers 1788.5 Relationships between Physical Properties of Engineered Particles and Dry Powder Inhaler Performance 1828.5.1 Particle Size 1828.5.2 Flow Properties 1848.5.3 Particle Shape 1858.5.4 Particle Surface Texture 1878.5.5 Fine Particle Additives 1888.5.6 Surface Area 1888.6 Conclusions 189References 1899. Particle Surface Roughness – Its Characterisation and Impact on Dry Powder Inhaler Performance 199Bernice Mei Jin Tan, Celine Valeria Liew, Lai Wah Chan, and Paul Wan Sia Heng9.1 Introduction 2009.2 What is Surface Roughness? 2009.3 Measurement of Particle Surface Roughness 2029.3.1 General Factors to Consider During a Measurement 2029.3.2 Direct Methods to Profile or Visualise Surface Roughness 2049.3.3 Indirect Measurement of Surface Roughness 2069.4 Impact of Surface Roughness on Carrier Performance – Theoretical Considerations 2069.4.1 Mixing and Blend Stability 2069.4.2 Drug-carrying Capacity 2079.4.3 Drug Adhesion 2079.4.4 Drug Detachment 2089.4.5 Particle Arrangement in Ordered Mixtures After the Addition of Fine Excipient 2099.5 Particle Surface Modification 2109.5.1 Spray Drying 2109.5.2 Solution Phase Processing 2119.5.3 Crystallisation 2139.5.4 Sieving 2139.5.5 Fluid-bed Coating 2139.5.6 Dry Powder Coating 2139.6 Conclusion 215References 21510. Dissolution: A Critical Performance Characteristic of Inhaled Products? 223Ben Forbes, Nathalie Hauet Richer, and Francesca Buttini10.1 Introduction 22310.2 Dissolution of Inhaled Products 22410.2.1 Dissolution Rate 22410.2.2 Dissolution in the Lungs 22410.2.3 Case for Dissolution Testing 22510.2.4 Design of Dissolution Test Systems 22610.3 Particle Testing and Dissolution Media 22610.3.1 Particle Collection 22610.3.2 Dissolution Media 22910.4 Dissolution Test Apparatus 23010.4.1 USP Apparatus 1 (Basket) 23110.4.2 USP Apparatus 2 (Paddle) and USP Apparatus 5 (Paddle Over Disc) 23210.4.3 USP Apparatus 4 (Flow-Through Cell) 23210.4.4 Diffusion-Controlled Cell Systems (Franz Cell, Transwell, Dialysis) 23310.4.5 Methodological Considerations 23410.5 Data Analysis and Interpretation 23510.5.1 Modelling 23610.5.2 Comparing Dissolution Profiles (Model-independent Method for Comparison) 23710.6 Conclusions 237References 23811. Drug Delivery Strategies for Pulmonary Administration of Antibiotics 241Anna Giulia Balducci, Ruggero Bettini, Paolo Colombo, and Francesca Buttini11.1 Introduction 24211.2 Antibiotics Used for the Treatment of Pneumoniae 24311.3 Antibiotic Products for Inhalation Approved on the Market 24411.4 Nebulisation 24611.5 Antibiotic Dry Powders for Inhalation 25011.5.1 Tobramycin 25111.5.2 Capreomycin 25211.5.3 Gentamicin 25311.5.4 Ciprofloxacin 25411.5.5 Levofloxacin 25511.5.6 Colistimethate Sodium 25611.6 Device and Payload of Dose 25611.7 Conclusions 258References 25812. Molecular Targeted Therapy of Lung Cancer: Challenges and Promises 263Jaleh Barar, Yadollah Omidi, and Mark Gumbleton12.1 Introduction 26512.2 An Overview on Lung Cancer 26612.3 Molecular Features of Lung Cancer 26812.3.1 Tumor Microenvironment (TME) 26912.3.2 Tumor Angiogenesis 26912.3.3 Tumor Stromal Components 27012.3.4 Pharmacogenetic Markers: Cytochrome P450 27012.4 Targeted Therapy of Solid Tumors: How and What to Target? 27112.4.1 EPR Effect: A Rational Approach for Passive Targeting 27212.4.2 Toward Long Circulating Anticancer Nanomedicines 27312.4.3 Active/Direct Targeting 27312.4.4 Overcoming Multidrug Resistance (MDR) 27312.4.5 Antibody-Mediated Targeting 27412.4.6 Aptamer-Mediated Targeted Therapy 27612.4.7 Folate Receptor-Mediated Targeted Therapy 27612.4.8 Transferrin-Mediated Targeted Therapy 27612.4.9 Targeted Photodynamic Therapy 27712.4.10 Multimodal Theranostics and Nanomedicines 27812.5 Final Remarks 278References 27913. Defining and Controlling Blend Evolution in Inhalation Powder Formulations using a Novel Colourimetric Method 285David Barling, David Morton, and Karen Hapgood13.1 Introduction 28613.1.1 Introduction to Blend Pigmentation 28713.1.2 Previous Work in the Use of Coloured Tracers to Assess Powder Blending 28813.1.3 Colour Tracer Properties and Approach to Blend Analysis 28813.2 Uses and Validation 29013.2.1 Assessment of Mixer Characteristics and Mixer Behaviour 29013.2.2 Quantification of Content Uniformity and Energy Input 29313.2.3 Detection and Quantification of Unintentional Milling during Mixing 29513.2.4 Robustness of Method with Tracer Concentration 29513.3 Comments on the Applied Suitability and Robustness in of the Tracer Method 29613.4 Conclusions 297Acknowledgements 297References 29714. Polymer-based Delivery Systems for the Pulmonary Delivery of Biopharmaceuticals 301Nitesh K. Kunda, Iman M. Alfagih, Imran Y. Saleem, and Gillian A. Hutcheon14.1 Introduction 30214.2 Pulmonary Delivery of Macromolecules 30214.3 Polymeric Delivery Systems 30314.3.1 Micelles 30414.3.2 Dendrimers 30514.3.3 Particles 30514.4 Preparation of Polymeric Nano/microparticles 30514.4.1 Emulsification Solvent Evaporation 30614.4.2 Emulsification Solvent Diffusion 30714.4.3 Salting Out 30714.5 Formulation of Nanoparticles as Dry Powders 30814.5.1 Freeze-drying 30814.5.2 Spray-drying 30914.5.3 Spray-freeze-drying 30914.5.4 Supercritical Fluid Drying 31014.6 Carrier Properties 31014.6.1 Size 31014.6.2 Morphology 31114.6.3 Surface Properties 31114.7 Toxicity of Polymeric Delivery Systems 31114.8 Pulmonary Delivery of Polymeric Particles 31214.9 Conclusions 313References 31315. Quality by Design: Concept for Product Development of Dry-powder Inhalers 321Al Sayyed Sallam, Sami Nazzal, Hatim S. AlKhatib, and Nabil Darwazeh15.1 Introduction 32215.2 Quality Target Product Profile (QTPP) 32415.3 Critical Quality Attributes (CQA) 32415.4 Quality Risk Management 32515.5 Design of Experiments 32615.6 Design Space 32815.7 Control Strategies 32815.8 Continual Improvement 32915.9 Process Analytical Technology/Application in DPI 32915.10 Particle Size 32915.11 Crystallinity and Polymorphism 33015.12 Scale-up and Blend Homogeneity 33115.13 Applying of QbD Principles to Analytical Methods 33115.14 Conclusion 332References 33216. Future Patient Requirements on Inhalation Devices: The Balance between Patient, Commercial, Regulatory and Technical Requirements 339Orest Lastow16.1 Introduction 34016.1.1 Inhaled Drug Delivery 34016.1.2 Patients 34016.2 Requirements 34116.2.1 Patient Requirements 34116.2.2 Technical Requirements 34316.2.3 Performance Requirements 34516.3 Requirement Specifications 34616.3.1 Requirement Hierarchy 34616.3.2 Developing the Requirements 34716.4 Product Development 35016.5 Conclusions 351References 352Index 353

ALI NOKHODCHI School of Life Sciences, University of Sussex, UK GARY P. MARTIN Institute of Pharmaceutical Science, King’s College London, UK

Select Guide Rating

• List of Contributors xiiiSeries Preface xviiPreface xix1. Lung Anatomy and Physiology and Their Implications for Pulmonary Drug Delivery 1Rahul K. Verma, Mariam Ibrahim, and Lucila Garcia-Contreras1.1 Introduction 21.2 Anatomy and Physiology of Lungs 21.2.1 Macro- and Microstructure of the Airways and Alveoli as It Pertains to Drug Delivery 21.2.2 Lung Surfactant 41.2.3 Pulmonary Blood Circulation 51.3 Mechanisms of Aerosol Deposition 51.3.1 Impaction 61.3.2 Sedimentation 61.3.3 Interception 61.3.4 Diffusion 71.4 Drug Absorption 71.4.1 Mechanisms of Drug Absorption from the Lungs 71.5 Physiological Factors Affecting the Therapeutic Effectiveness of Drugs Delivered by the Pulmonary Route 81.5.1 Airway Geometry 81.5.2 Inhalation Mode 81.5.3 Airflow Rate 91.5.4 Mechanism of Particle Clearance 91.5.5 Lung Receptors 101.5.6 Disease States 111.5.7 Effect of Age and Gender Difference 111.6 Computer Simulations to Describe Aerosol Deposition in Health and Disease 111.6.1 Semiempirical Models 121.6.2 Deterministic Models 121.6.3 Trumpet Models (One-Dimensional) 121.6.4 Stochastic, Asymmetric Generation Models 131.6.5 Computation Fluid Dynamics (CFD)-Based Model 131.7 Conclusions 13References 142. The Role of Functional Lung Imaging in the Improvement of Pulmonary Drug Delivery 19Andreas Fouras and Stephen Dubsky2.1 Introduction 192.1.1 Particle Deposition 202.1.2 Regional Action of Delivered Drug 222.1.3 The Role of Functional Lung Imaging in Pulmonary Drug Delivery 222.2 Established Functional Lung Imaging Technologies 232.2.1 Computed Tomography 232.2.2 Ventilation Measurement using 4DCT Registration-based Methods 242.2.3 Hyperpolarized Magnetic Resonance Imaging 242.2.4 Electrical Impedance Tomography 252.2.5 Nuclear Medical Imaging (PET/SPECT) 252.3 Emerging Technologies 262.3.1 Phase-contrast Imaging 262.3.2 Grating Interferometry 272.3.3 Propagation-based Phase-contrast Imaging 282.3.4 Functional Lung Imaging using Phase Contrast 282.3.5 Laboratory Propagation-based Phase-contrast Imaging 292.4 Conclusion 30References 313. Dry Powder Inhalation for Pulmonary Delivery: Recent Advances and Continuing Challenges 35Simone R. Carvalho, Alan B. Watts, Jay I. Peters, and Robert O. Williams III3.1 Introduction 363.2 Dry Powder Inhaler Devices 373.2.1 Overview 373.2.2 Recent Innovations in Dry Powder Inhaler Technology 393.3 New Developments in DPI Formulations and Delivery 433.3.1 Particle Surface Modification 433.3.2 Particle Engineering Technology for Pulmonary Delivery 443.4 Characterization Methods of Dry Powder Inhaler Formulations 503.5 Conclusion 52References 534. Pulmonary Drug Delivery to the Pediatric Population – A State-of-the-Art Review 63Marie-Pierre Flament4.1 Introduction 634.2 Patient Consideration 644.2.1 Anatomy and Physiology of Children’s Lungs 644.2.2 Nasal Versus Oral Inhalation 654.2.3 Patient-related Factors Influencing Aerosol Deposition 664.2.4 Age and Dosage Forms of Choice 674.3 Delivery Systems for the Pediatric Population 694.3.1 Nebulizers 694.3.2 Pressurized Metered Dose Inhalers 724.3.3 Dry Powder Inhalers 734.3.4 Interfaces 744.4 Recommendations 804.5 Conclusion 82References 825. Formulation Strategies for Pulmonary Delivery of Poorly Soluble Drugs 87Nathalie Wauthoz and Karim Amighi5.1 Introduction 885.1.1 In vivo Fate of Inhaled Poorly Water-soluble Drugs 895.1.2 The Pharmacokinetics of Inhaled Poorly Water-soluble Drugs Administered for Local and Systemic Action 925.1.3 Formulation Strategies for Pulmonary Delivery of Poorly Water-soluble Drugs 935.2 Co-solvents 935.3 Cyclodextrins 975.4 PEGylation 995.5 Reduction of Size to Micro-/Nanoparticles 1005.5.1 Nanocrystal Suspension 1015.5.2 Nanocrystals in a Hydrophilic Matrix System 1025.5.3 Nanoclusters 1035.6 Solid Dispersion/Amorphization 1035.7 Micelles 1065.8 Liposomes 1085.9 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 1105.10 Conclusion 111References 1146. Lipidic Micro- and Nano-Carriers for Pulmonary Drug Delivery – A State-of-the-Art Review 123Yahya Rahimpour, Hamed Hamishehkar, and Ali Nokhodchi6.1 Introduction 1246.2 Pulmonary Drug Delivery 1256.3 Liposomal Pulmonary Delivery 1266.4 Nebulization of Liposomes 1266.5 Liposomal Dry-powder Inhalers 1286.6 Solid Lipid Microparticles in Pulmonary Drug Delivery 1296.7 Solid Lipid Nanoparticles in Pulmonary Drug Delivery 1316.8 Nanostructured Lipid Carrier (NLC) in Pulmonary Drug Delivery 1336.9 Nanoemulsions in Pulmonary Drug Delivery 1346.10 Conclusion and Perspectives 135References 1367. Chemical and Compositional Characterisation of Lactose as a Carrier in Dry Powder Inhalers 143Rim Jawad, Gary P. Martin and Paul G. Royall7.1 Introduction 1447.2 Production of Lactose 1457.3 Lactose: Chemical Forms, Solid-State Composition, Physicochemical Properties 1477.4 Epimerisation of Lactose 1507.5 Analysis of Lactose 1517.5.1 Powder X-ray Diffraction 1527.5.2 Nuclear Magnetic Resonance 1537.5.3 Infrared Spectroscopy 1567.5.4 Differential Scanning Calorimetry 1577.5.5 Polarimetry 1587.6 The Influence of the Chemical and Solid-State Composition of Lactose Carriers on the Aerosolisation of DPI Formulations 1597.7 Conclusions 163References 1638. Particle Engineering for Improved Pulmonary Drug Delivery Through Dry Powder Inhalers 171Waseem Kaialy and Ali Nokhodchi8.1 Introduction 1728.2 Dry Powder Inhalers 1728.3 Particle Engineering to Improve the Performance of DPIs 1728.3.1 Crystallization 1738.3.2 Spray-drying 1748.3.3 Spray-freeze-drying 1778.3.4 Supercritical Fluid Technology 1778.3.5 Pressure Swing Granulation (PSG) Technique 1788.4 Engineered Carrier Particles for Improved Pulmonary Drug Delivery from Dry Powder Inhalers 1788.5 Relationships between Physical Properties of Engineered Particles and Dry Powder Inhaler Performance 1828.5.1 Particle Size 1828.5.2 Flow Properties 1848.5.3 Particle Shape 1858.5.4 Particle Surface Texture 1878.5.5 Fine Particle Additives 1888.5.6 Surface Area 1888.6 Conclusions 189References 1899. Particle Surface Roughness – Its Characterisation and Impact on Dry Powder Inhaler Performance 199Bernice Mei Jin Tan, Celine Valeria Liew, Lai Wah Chan, and Paul Wan Sia Heng9.1 Introduction 2009.2 What is Surface Roughness? 2009.3 Measurement of Particle Surface Roughness 2029.3.1 General Factors to Consider During a Measurement 2029.3.2 Direct Methods to Profile or Visualise Surface Roughness 2049.3.3 Indirect Measurement of Surface Roughness 2069.4 Impact of Surface Roughness on Carrier Performance – Theoretical Considerations 2069.4.1 Mixing and Blend Stability 2069.4.2 Drug-carrying Capacity 2079.4.3 Drug Adhesion 2079.4.4 Drug Detachment 2089.4.5 Particle Arrangement in Ordered Mixtures After the Addition of Fine Excipient 2099.5 Particle Surface Modification 2109.5.1 Spray Drying 2109.5.2 Solution Phase Processing 2119.5.3 Crystallisation 2139.5.4 Sieving 2139.5.5 Fluid-bed Coating 2139.5.6 Dry Powder Coating 2139.6 Conclusion 215References 21510. Dissolution: A Critical Performance Characteristic of Inhaled Products? 223Ben Forbes, Nathalie Hauet Richer, and Francesca Buttini10.1 Introduction 22310.2 Dissolution of Inhaled Products 22410.2.1 Dissolution Rate 22410.2.2 Dissolution in the Lungs 22410.2.3 Case for Dissolution Testing 22510.2.4 Design of Dissolution Test Systems 22610.3 Particle Testing and Dissolution Media 22610.3.1 Particle Collection 22610.3.2 Dissolution Media 22910.4 Dissolution Test Apparatus 23010.4.1 USP Apparatus 1 (Basket) 23110.4.2 USP Apparatus 2 (Paddle) and USP Apparatus 5 (Paddle Over Disc) 23210.4.3 USP Apparatus 4 (Flow-Through Cell) 23210.4.4 Diffusion-Controlled Cell Systems (Franz Cell, Transwell, Dialysis) 23310.4.5 Methodological Considerations 23410.5 Data Analysis and Interpretation 23510.5.1 Modelling 23610.5.2 Comparing Dissolution Profiles (Model-independent Method for Comparison) 23710.6 Conclusions 237References 23811. Drug Delivery Strategies for Pulmonary Administration of Antibiotics 241Anna Giulia Balducci, Ruggero Bettini, Paolo Colombo, and Francesca Buttini11.1 Introduction 24211.2 Antibiotics Used for the Treatment of Pneumoniae 24311.3 Antibiotic Products for Inhalation Approved on the Market 24411.4 Nebulisation 24611.5 Antibiotic Dry Powders for Inhalation 25011.5.1 Tobramycin 25111.5.2 Capreomycin 25211.5.3 Gentamicin 25311.5.4 Ciprofloxacin 25411.5.5 Levofloxacin 25511.5.6 Colistimethate Sodium 25611.6 Device and Payload of Dose 25611.7 Conclusions 258References 25812. Molecular Targeted Therapy of Lung Cancer: Challenges and Promises 263Jaleh Barar, Yadollah Omidi, and Mark Gumbleton12.1 Introduction 26512.2 An Overview on Lung Cancer 26612.3 Molecular Features of Lung Cancer 26812.3.1 Tumor Microenvironment (TME) 26912.3.2 Tumor Angiogenesis 26912.3.3 Tumor Stromal Components 27012.3.4 Pharmacogenetic Markers: Cytochrome P450 27012.4 Targeted Therapy of Solid Tumors: How and What to Target? 27112.4.1 EPR Effect: A Rational Approach for Passive Targeting 27212.4.2 Toward Long Circulating Anticancer Nanomedicines 27312.4.3 Active/Direct Targeting 27312.4.4 Overcoming Multidrug Resistance (MDR) 27312.4.5 Antibody-Mediated Targeting 27412.4.6 Aptamer-Mediated Targeted Therapy 27612.4.7 Folate Receptor-Mediated Targeted Therapy 27612.4.8 Transferrin-Mediated Targeted Therapy 27612.4.9 Targeted Photodynamic Therapy 27712.4.10 Multimodal Theranostics and Nanomedicines 27812.5 Final Remarks 278References 27913. Defining and Controlling Blend Evolution in Inhalation Powder Formulations using a Novel Colourimetric Method 285David Barling, David Morton, and Karen Hapgood13.1 Introduction 28613.1.1 Introduction to Blend Pigmentation 28713.1.2 Previous Work in the Use of Coloured Tracers to Assess Powder Blending 28813.1.3 Colour Tracer Properties and Approach to Blend Analysis 28813.2 Uses and Validation 29013.2.1 Assessment of Mixer Characteristics and Mixer Behaviour 29013.2.2 Quantification of Content Uniformity and Energy Input 29313.2.3 Detection and Quantification of Unintentional Milling during Mixing 29513.2.4 Robustness of Method with Tracer Concentration 29513.3 Comments on the Applied Suitability and Robustness in of the Tracer Method 29613.4 Conclusions 297Acknowledgements 297References 29714. Polymer-based Delivery Systems for the Pulmonary Delivery of Biopharmaceuticals 301Nitesh K. Kunda, Iman M. Alfagih, Imran Y. Saleem, and Gillian A. Hutcheon14.1 Introduction 30214.2 Pulmonary Delivery of Macromolecules 30214.3 Polymeric Delivery Systems 30314.3.1 Micelles 30414.3.2 Dendrimers 30514.3.3 Particles 30514.4 Preparation of Polymeric Nano/microparticles 30514.4.1 Emulsification Solvent Evaporation 30614.4.2 Emulsification Solvent Diffusion 30714.4.3 Salting Out 30714.5 Formulation of Nanoparticles as Dry Powders 30814.5.1 Freeze-drying 30814.5.2 Spray-drying 30914.5.3 Spray-freeze-drying 30914.5.4 Supercritical Fluid Drying 31014.6 Carrier Properties 31014.6.1 Size 31014.6.2 Morphology 31114.6.3 Surface Properties 31114.7 Toxicity of Polymeric Delivery Systems 31114.8 Pulmonary Delivery of Polymeric Particles 31214.9 Conclusions 313References 31315. Quality by Design: Concept for Product Development of Dry-powder Inhalers 321Al Sayyed Sallam, Sami Nazzal, Hatim S. AlKhatib, and Nabil Darwazeh15.1 Introduction 32215.2 Quality Target Product Profile (QTPP) 32415.3 Critical Quality Attributes (CQA) 32415.4 Quality Risk Management 32515.5 Design of Experiments 32615.6 Design Space 32815.7 Control Strategies 32815.8 Continual Improvement 32915.9 Process Analytical Technology/Application in DPI 32915.10 Particle Size 32915.11 Crystallinity and Polymorphism 33015.12 Scale-up and Blend Homogeneity 33115.13 Applying of QbD Principles to Analytical Methods 33115.14 Conclusion 332References 33216. Future Patient Requirements on Inhalation Devices: The Balance between Patient, Commercial, Regulatory and Technical Requirements 339Orest Lastow16.1 Introduction 34016.1.1 Inhaled Drug Delivery 34016.1.2 Patients 34016.2 Requirements 34116.2.1 Patient Requirements 34116.2.2 Technical Requirements 34316.2.3 Performance Requirements 34516.3 Requirement Specifications 34616.3.1 Requirement Hierarchy 34616.3.2 Developing the Requirements 34716.4 Product Development 35016.5 Conclusions 351References 352Index 353