Handbook of Lung Targeted Drug Delivery Systems : Recent Trends and Clinical Evidences

**__Handbook of Lung Targeted Drug Delivery Systems: Recent Trends and Clinical Evidences__** covers every aspect of the drug delivery to lungs, the physiology and pharmacology of the lung, modelling for lung delivery, drug devices focused on lung treatment, regulatory requirements, and recent trends in clinical applications. With the advent of nano sciences and significant development in the nano particulate drug delivery systems there has been a renewed interest in the lung as an absorption surface for various drugs. The emergence of the COVID-19 virus has brought lung and lung delivery systems into focus, this book covers new developments and research used to address the prevention and treatment of respiratory diseases. Written by well-known scientists with years of experience in the field this timely handbook is an excellent reference book for the scientists and industry professionals. Key Features: * Focuses particularly on the chemistry, clinical pharmacology, and biological developments in this field of research. * Presents comprehensive information on emerging nanotechnology applications in diagnosing and treating pulmonary diseases * Explores drug devices focused on lung treatment, regulatory requirements, and recent trends in clinical applications * Examines specific formulations targeted to pulmonary systems Cover Half Title Title Page Copyright Page Dedication Contents Editors List of Contributors Foreword Preface 1. Introduction to Lung Physiology from a Drug Delivery Perspective 1.1 Introduction 1.1.1 Brief Introduction to Nanotechnology and Nanoparticle Mediated Drug Delivery 1.1.2 The Inhalation Route 1.2 Anatomy and Physiology of Lungs 1.3 Nanoparticle-based Systems for Pulmonary Application 1.4 Treatment of Chronic Diseases Through the Pulmonary Route References 2. Introduction to Pharmacology of the Lung from a Drug Delivery Perspective 2.1 The Respiratory Tract: An Overview 2.1.1 The Conducting Zone 2.1.2 The Respiratory Zone 2.2 Respiratory Pathology 2.2.1 Asthma Overview 2.2.1.1 Classifications and Goals of Treatment 2.2.2 Chronic Bronchitis Overview 2.2.2.1 Chronic Bronchitis Goals of Treatment 2.2.3 Chronic Obstructive Pulmonary Disease (COPD) Overview 2.2.3.1 COPD Goals of Treatment 2.2.4 Cystic Fibrosis Overview 2.2.4.1 Cystic Fibrosis Goals of Treatment 2.3 Respiratory Drug Delivery Mechanisms 2.3.1 Therapeutic Administrations of Inhaled Medications 2.3.2 Inhaler Devices 2.3.2.1 Pressurized Metered Dose Inhaler 2.3.2.2 Dry Powder Inhaler 2.3.2.3 Respimat Soft Mist Inhaler 2.3.2.4 Nebulizers 2.3.4 Patient Education 2.4 Overview of Inhaled Therapies 2.4.1 β2 Adrenergic Agonists 2.4.1.1 β2 Adrenergic Agonists Subtypes: SABA and LABA 2.4.1.2 β2 Adrenergic Agonists Side Effects 2.4.2 Corticosteroids 2.4.2.1 Corticosteroids Side Effects 2.4.3 Anti-cholinergic Agents 2.4.3.1 Anti-cholinergic Side Effects 2.5 Overview of Oral Therapies 2.5.1 Mucolytics/Expectorants 2.5.1.1 Mucolytics/Expectorants Side Effects 2.5.2 Phosphodiesterase (PDE) Inhibitors 2.5.2.1 Phosphodiesterase (PDE) Inhibitor Side Effects 2.5.3 Macrolides 2.5.3.1 Macrolide Side Effects 2.5.4 Leukotriene Modifiers 2.5.4.1 Leukotriene Modifier Side Effects 2.6 Recommended Therapies for Asthma and COPD Management 2.6.1 Asthma 2.6.2 COPD 2.7 Systemic Drug Delivery via the Lungs References 3. Mechanism and Ways of Pulmonary Drug Administration 3.1 Introduction 3.2 Mechanisms of Drug Permeation into the Lungs 3.3 Deposition of Aerosol Particles in the Respiratory Airways 3.3.1 Mechanisms of Particle Deposition in the Respiratory Airways 3.3.1.1 Inertial Impaction 3.3.1.2 Sedimentation 3.3.1.3 Brownian Diffusion 3.3.2 Factors Affecting Particle Deposition 3.3.3 Effect of Particle Size 3.1 Respiratory Clearance of Inhaled Particles 3.4.1 Mucociliary Clearance 3.4.2 Alveolar Clearance 3.5 Ways of Pulmonary Drug Administration 3.5.1 Pressurized Metered Dose Inhalers 3.5.2 Dry Powder Inhalers (DPIs) 3.5.3 Nebulizers 3.6 Conclusion References 4. Transepithelial Route of Drug Delivery through the Pulmonary System 4.1 Introduction 4.2 Macrostructure of Lungs 4.3 Drug Targeting: Anatomical Sites 4.3.1 Anatomical Barriers to Drug Flow 4.4 Drug Deposition: Mechanism 4.4.1 Physiological Factors Affecting Deposition 4.4.1.1 Effect of Diseased State on Drug Deposition 4.5 Levels of Clearance 4.5.1 The Mechanism to Overcome Pulmonary Clearance 4.6 Airway Cells, Pulmonary Circulation, and Receptors: Importance and Function 4.6.1 Airway Cells 4.6.2 Airway Receptors 4.6.3 Effect of Blood Circulation on Drug Delivery 4.7 Pulmonary Drug Delivery: Dissolution, Metabolism, Absorption, and Clearance 4.7.1 Pulmonary Dissolution 4.7.2 Pulmonary Absorption 4.7.3 Mucociliary Clearance 4.7.4 Pulmonary Retention 4.8 Affect of Lung Physiology and Pathophysiology on Drug Absorption 4.8.1 Pharmacokinetics of Nasal Drug Delivery 4.8.2 Pharmacokinetic Processes of Oral, Intravenous, and Inhalation Administration 4.9 Pulmonary Drug Delivery: Different Molecular Size 4.9.1 Smaller Molecules Used to Deliver Drugs through the Pulmonary Route 4.9.2 Large Microporous Molecules 4.9.3 Pulmonary Delivery of Large Peptides and High Molecular Weight Drugs 4.9.3.1 Insulin 4.9.3.2 Low Molecular Weight Heparins (LMWH) 4.10 Nanocarriers in Pulmonary Delivery of Drugs References 5. Understanding the Pharmacokinetics and Pharmacodynamics of Lung and Lung Drug Delivery 5.1 Introduction 5.2 Pharmacokinetics of the Lung and Lung Drug Delivery 5.2.1 Absorption of Drugs in the Lungs 5.2.2 Elimination of Drugs in the Lungs 5.3 Pharmacodynamics of Lung Drug Delivery: Recent Trends and Clinical Evidence 5.3.1 Inhaled Antibiotics 5.3.2 Hormones Administered through the Pulmonary Route 5.3.2.1 Inhaled Insulins 5.3.2.2 Inhaled Growth Hormone 5.3.3 Inhaled Corticosteroids References 6. Chronic Lung Diseases: Treatment, Challenges, and Solutions 6.1 Introduction 6.1.1 Types of Chronic Lung Diseases 6.1.1.1 Asthma 6.1.1.1.1 Pathophysiology 6.1.1.2 Chronic Bronchitis 6.1.1.2.1 Pathophysiology 6.1.1.3 Chronic Obstructive Pulmonary Disease (COPD) 6.1.1.3.1 Risk Factors 6.1.1.3.2 Pathophysiology 6.2 Different Treatment Strategies of Chronic Lung Diseases along with Their Pharmacology 6.2.1 Current Treatment Strategy for Lung Diseases 6.2.1.1 Treatment of Chronic Asthma (26–28) 6.2.1.2 Current Treatment Strategy of Bronchitis (29,30) 6.2.1.3 Current Treatment Strategy of COPD (31–34) 6.2.2 Bioactive Compounds 6.2.2.1 Bioactive Compounds for Treatment of Asthma (36,37) 6.2.2.2 Bioactive Compounds for Treatment of Chronic Bronchitis (38, 39) 6.2.2.3 Bioactive Compounds for Treatment of COPD (40, 41) 6.3 Conventional Drug Delivery Systems for Mitigating Chronic Lung Diseases 6.3.1 Material Based 6.3.1.1 Multifunctional Nanocarriers 6.3.1.2 Hydrogels 6.3.1.3 Micelle 6.3.1.4 Dendrimer 6.3.1.5 Liposomes 6.4.2 Administration Based 6.4.2.1 Pulmonary Drug Administration 6.4.2.2 Inhalation Delivery 6.4.2.3 Systematic Delivery 6.4.3 Different Drug Delivery Systems for Different Categories of Patients 6.4.3.1 Elderly Patients 6.4.3.2 Pregnant Patients 6.4.3.3 Obese Patients 6.4 Recent Development in Targeted Drug Delivery Systems for Mitigating Chronic Lung Diseases 6.5 Challenges and Solutions 6.5.1 Asthma 6.5.2 Bronchial Disorders 6.5.3 COPD 6.6 Future Prospects 6.7 Conclusion Acknowledgments References 7. Understanding of Lung Diseases with a Focus on Applications of Nano-particulate Drug Delivery Systems 7.1 Introduction 7.2 Lung Diseases: A Brief Insight 7.2.1 Obstructive Lung Disease (OLD) 7.2.2 Restrictive Lung Disease (RLD) 7.2.3 Pleural Lung Disease 7.2.4 Vascular Lung Disease 7.3 Management and Treatment of Lung Diseases 7.3.1 Pharmacological Approaches to Treating Lung Diseases 7.3.1.1 Bronchodilators 7.3.1.1.1 Beta-2 Agonists 7.3.1.1.2 Anti-muscarinic Drugs 7.3.1.1.3 Methylxanthines 7.3.1.1.4 Combination Bronchodilator Therapy 7.3.1.2 Anti-Inflammatory Agents 7.3.1.2.1 Corticosteroids 7.3.1.2.2 Phosphodiesterase-4-Inhibitors (PDE4 Inhibitors) 7.3.1.2.3 Antibiotics 7.3.1.2.4 Leukotriene Modulators 7.3.1.2.5 Antioxidants 7.3.1.3 Vaccinations 7.3.1.4 Nicotine Replacement Therapy 7.3.2 Non-pharmacological Approach 7.3.2.1 Oxygen Therapy and Ventilatory Support 7.3.2.1.1 Oxygen Therapy 7.3.2.1.2 Ventilatory Support 7.3.2.2 Surgical Interventions 7.3.2.2.1 Lung Volume Reduction Surgery 7.3.2.2.2 Bullectomy 7.3.2.2.3 Lung Transplantation 7.3.2.2.4 Bronchoscopic Interventions 7.3.2.3 Education and Self-Management 7.3.2.4 Pulmonary Rehabilitation Programs 7.3.2.5 Exercise Training 7.3.2.6 Self-Management Education 7.3.2.7 Palliative Care 7.4 Application of Nano-Drug Delivery Systems in Lung Diseases 7.4.1 Characteristics of Pulmonary Nano-Drug Delivery 7.4.1.1 Pulmonary Distribution of Drug 7.4.1.2 Improved Solubility/Dissolution Rate 7.4.1.3 Sustained Release Properties 7.4.1.4 Delivery of Macromolecules 7.4.1.5 Internalization by Cells 7.4.2 Fate of Nanocarriers in the Lungs 7.4.3 Strategies to Overcome Clearance of Nanocarriers 7.4.4 Nano-Formulation for Drug Delivery to Lungs 7.4.4.1.1 Polymeric Nanoparticles 7.4.4.1.2 Antigenic Nanoparticles 7.4.4.1.3 Solid Lipid Nanoparticles 7.4.4.1.4 Depots 7.4.4.1.5 Pressure Sensitive Metered Dose Inhalers (pMDIs) 7.4.4.2 Vesicular Nano-Drug Delivery to Lungs 7.4.4.2.1 Liposomes 7.4.4.2.2 Nanoemulsions 7.4.4.3 Advantage of Particulate Drug Delivery to Lungs 7.5 Conclusion References 8. Model for Pharmaceutical aerosol transport through stenosis airway 8.1 Introduction 8.2 Numerical Method 8.3 Geometrical Development 8.4 Grid Generation and Validation 8.5 Results and Discussion 8.5.1 Effects of Aging Cases 8.5.1.1 Airflow Analysis 8.5.1.1.1 Velocity Profiles 8.5.1.1.2 Velocity Contours 8.5.1.2 Pressure Drop 8.5.1.2.1 Pressure Distribution 8.5.1.2.2 Pressure Contours 8.5.1.3 Wall Shear 8.5.1.4 Turbulent Intensity 8.5.1.5 Particle Transport 8.5.1.5.1 Deposition Efficiency 8.5.1.5.2 Deposition Fraction 8.5.2 Stenosis Cases 8.5.2.1 Airflow Analysis 8.5.2.1.1 Velocity Profiles 8.5.2.1.2 Velocity Contours 8.5.2.2 Pressure Drop 8.5.2.2.1 Pressure Drop 8.5.2.2.2 Pressure Contours 8.5.2.3 Wall Shear 8.5.2.4 Turbulence Intensity 8.5.2.5 Particle Transport 8.5.2.5.1 Deposition Efficiency 8.5.2.5.2 Deposition Fraction 8.6 Limitation of the Study 8.7 Conclusions References 9. Design of Efficient Dry Powder Inhalers 9.1 Introduction 9.1.2 Pressurized Metered Dose Inhaler (pMDI) 9.1.3 Dry Powder Inhaler (DPI) 9.2 Classification of DPI 9.3 DPI Design 9.3.1 Basic Principle of DPI Design 9.3.2 Improving Performance of DPI 9.3.3 DPI Performance Independent of Inhalation Flow Rate 9.3.4 Generic Drugs 9.4 Computational Modeling of DPI 9.4.1 Numerical Techniques used in DPI 9.4.2 Development of CFD Model 9.4.2.1 Mass Conservation 9.4.2.2 Conservation of Momentum 9.4.2.3 Turbulence Models 9.4.3 Coupling of CFD-DEM Model 9.4.4 Discrete Phase Modeling (DPM) 9.5 Pharmacological Aspects of DPI Design 9.5.1 Methods for Preparation of the Pharmaceutical Aerosol 9.5.2 Factors Affecting the Aerosol Performance 9.5.3 Aerodynamic Nature of Pharmaceutical Aerosol 9.5.4 Mechanism of Drug Deposition 9.5.5 Empirical Relationships for Drug Deposition 9.5.6 Formulation Challenge for Pulmonary Delivery of High Powder Dose 9.6 Various Factors Affecting DPI Performance 9.6.1 Device-related Factors 9.6.2 Powder-Related Factors 9.6.3 Patient-Related Factors 9.7 Future of DPI References 10. In Vivo Animal Models for Lung Targeted Drug Delivery Systems 10.1 Introduction 10.2 Coupled In Silico Platform: Computational Fluid Dynamics (CFD) and Physiologically Based Pharmacokinetic (PBPK) Modeling 10.3 Modeling and Simulation of Biopharmaceutical Performance in Lung Drug Delivery 10.4 Clinically Relevant Test Methods to Establish In Vitro Equivalence for Spacers and Valved Holding Chambers Used with Pressurized Metered Dose Inhalers (pMDIs) 10.5 Lipid Nanoparticles' Biocompatibility and Cellular Uptake in a 3D Human Lung Model 10.6 Designing In Vitro Bioequivalence Studies for Pressurized Metered Dose Inhalers with Spacer or Valved Holding Chamber Add-On Devices 10.7 International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences 10.8 In Vitro Evaluation of Aerosol Delivery by Different Nebulization Modes in Pediatric and Adult Mechanical Ventilators 10.9 Conclusion References 11. Advances in In Silico Study of Generic Orally Inhaled Drug Products 11.1 Introduction 11.2 Basic Consideration for Generic OIDPs 11.2.1 Formulation Considerations 11.2.2 Device Considerations 11.2.3 Requirement of BE for Generic OIDPs 11.3.1 CFD Modeling Techniques 11.3.2 In Silico Modeling of pMDIs 11.3.3 In Silico Modeling of DPIs 11.3.4 In Silico Modeling of SMIs 11.4 In Silico Modeling of Lung Deposition 11.4.1 Airway Geometry 11.4.2 CFD Modeling of Lung Deposition 11.4.3 CFD-PBPK Modeling 11.5 Summary and Perspectives References 12. Effect of Aerosol Devices and Administration Techniques on Drug Delivery in a Simulated Spontaneously Breathing Pediatric Tracheostomy Model 12.1 Introduction 12.2 Anatomical and Physiological Factors 12.3 Devices 12.4 Techniques 12.5 Pathological Considerations 12.6 Pharmalogical Considerations 12.7 Pediatric Considerations 12.8 Conclusion References 13. Pulmonary Drug Delivery: The Role of Polymeric Nanoparticles 13.1 Introduction 13.1.1 Pulmonary diseases 13.1.2 Anatomy and Physiology of the Respiratory System 13.1.3 Pulmonary Drug Delivery 13.1.3.1 Pulmonary Drug Delivery and the Treatment of Pulmonary Disorders 13.1.3.2 Challenges in Pulmonary Drug Delivery 13.1.4 Pulmonary Drug Deposition 13.1.4.1 Inertial Impaction 13.1.4.2 Sedimentation 13.1.4.3 Diffusion 13.1.4.4 The Physicochemical Properties of the Drug and Formulation 13.1.4.5 The Type of Delivery Device 13.1.5 Pulmonary Drug Delivery Devices 13.1.6 Methods of Formulation 13.1.6.1 Preparation of Particulate Matter 13.1.6.1.1 Spray Drying Technique 13.1.6.1.2 Supercritical Fluid Technology 13.1.6.1.3 Crystallization 13.1.6.1.4 Double Emulsion/Solvent Evaporation Technique 13.1.6.1.5 Particle Replication 13.2 Polymeric Nanoparticle Drug Delivery Systems 13.2.1 Types of Polymeric Nanoparticles 13.2.1.1 Lipid Polymer Hybrid Nanoparticles 13.2.1.2 Solid-Lipid Polymer Hybrid Nanoparticles 13.2.1.3 Functionalized Polymeric Nanoparticles 13.2.1.4 Polysaccharide Conjugated Polymeric Nanoparticles 13.2.1.5 Ligand-Based Polymeric Nanoparticles 13.2.1.6 Fluorescence Polymeric Nanoparticles 13.3 Applications of Polymer Nanoparticles in Pulmonary Drug Delivery 13.3.1 Modifications of Polymer Nanoparticle Pulmonary Drug Delivery Systems and Safety Evaluations for Better Performance 13.3.2 Progress in Safety Evaluations 13.4 Strategies, Approaches and Applications of Polymeric Nanoparticles in the Prevention and Treatment of Infectious Diseases 13.4.1 Pulmonary Infections 13.4.1.1 Advances in the Treatment of Pulmonary Viral Infections 13.4.1.2 Advances in the Treatment of Pulmonary Bacterial Infections 13.4.2 Advances in the Treatment of Pulmonary Diseases and Disorders 13.4.2.1 Lung Cancer 13.4.3 Advances in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease 13.4.4 Advances in the Treatment of Lung Fibrosis 13.4.5 Advances in the Treatment of Pulmonary Hypertension 13.5 Future Perspectives for Polymeric Nanoparticle Pulmonary Delivery of Therapeutic Agents in Emerging and Existing Lung Diseases 13.5.1 Prospects for Emerging Disease Therapy with Polymeric Nanoparticles References 14. Polymeric Nanoparticle-Based Drug-Gene Delivery for Lung Cancer 14.1 Introduction and Background 14.2 Nanoparticles for Delivering Drugs and Genetic Materials in Cancer: Rationale and Need 14.3 Types of Nanoparticles Employed in Cancer Therapeutics 14.4 Polymeric Nanoparticles for Cancer Therapy 14.4.1 Dendrimers 14.4.2 Polymeric Magnetic Nanoparticles 14.4.3 Polymeric Micelles 14.4.4 Carbon Nanotubes (CNTs) 14.4.5 Quantum Dots (QDs) 14.4.6 Polymeric Nanoparticles Based on Natural Polymers-Drug Conjugates 14.4.7 Polymeric Nanoparticles from Synthetic Polymers 14.4.8 Polymersomes 14.4.9 PEG-Drug Conjugates 14.5 Inhalable and Pulmonary Nanoparticles for Lung Cancer 14.5.1 Polymeric NPs with Chemotherapeutic Agents by Inhalation 14.5.2 Pulmonary Gene Delivery by NPs 14.6 New Gene Delivery Platforms-Cell Penetrating Peptides (CPP) and CRISPR-Cas9 for Lung Cancer Therapy 14.7 An Overview of Targets for Polymeric NP in Lung Cancer Therapeutics 14.7.1 Passive Targeting 14.7.2 Active Targeting 14.7.2.1 Folate Receptors 14.7.2.2 Transferrin Receptors 14.7.2.3 Luteinizing Hormone Releasing Hormone (LHRH) Receptors 14.7.2.4 Epidermal Growth Factor Receptors (EGFRs) 14.7.2.5 CD44 Receptors 14.7.2.6 Integrin Receptors 14.7.2.7 Vascular Endothelial Growth Factor (VEGF) Receptor 14.8 Overcoming Drug Resistance by Tumor Cells 14.9 Polymeric Nanoparticle Aspects in Drug-Gene Delivery to Lung Cancer 14.10 Merits and Limitations of Polymeric NPs 14.11 Conclusion and Future Perspectives References 15. Inhalable Polymeric Nano-particulate Powders for Respiratory Delivery 15.1 Introduction 15.2 Challenges for Pulmonary Drug Delivery 15.2.1 Pulmonary Clearance Mechanisms 15.2.1.1 Mucociliary Clearance 15.2.1.2 Alveolar Macrophage Clearance 15.2.2 Enzymatic Degradation 15.2.3 Rapid Systemic Absorption 15.3 Significance of Particulate-based Pulmonary Drug Delivery 15.4 Transepithelial Transport of Drugs 15.5 Lung Compatibility of Formulation Excipients/Polymers 15.6 Fundamental Properties of Active Pharmaceutical Ingredient (API) Used by the Inhalation Route 15.7 Modes of Pulmonary Drug Administration 15.8 Mechanism of Deposition of a Particle in the Lungs 15.8.1 Gravitational Sedimentation 15.8.2 Inertial Impaction 15.8.3 Brownian Diffusion 15.8.4 Electrostatic Precipitation 15.8.5 Interception 15.9 Particle Clearance 15.10 Factors Affecting Drug Bioavailability via the Pulmonary Route 15.11 Devices for Pulmonary Delivery 15.11.1 Jet Nebulizers 15.11.2 Dry Powder Inhalers (DPI) 15.11.3 Metered Dose Inhalers (MDI) 15.12 Targeting Inhalable Polymeric Nanoparticles for Local Lung Delivery 15.13 Technical Issues of Nanoparticle Applications 15.14 Conclusion References 16. Recent Trends in Applications of Nano-Drug Delivery Systems 16.0 Recent Trends in Applications of Nano-Drug Delivery Systems 16.1 Nano-Drug Delivery Systems 16.1.1 Solid-Lipid Particulate Delivery System 16.1.2 Nano Structured Lipid Carriers 16.1.3 Nano-emulsions 16.1.4 Niosomes 16.1.5 Liposomes 16.1.6 Lipospheres 16.1.7 Polymeric Nanoparticles 16.1.8 Nanosuspension 16.1.9 Dendrimers 16.1.10 Carbon Nanotubes 16.1.11 Quantum Dots 16.1.12 Metal Nanoparticles 16.2 Applications of Nano-Drug Delivery Systems in the Management of Lung Diseases 16.2.1 Lung Diseases 16.2.1.1 Lung Airway Diseases 16.2.1.2 Lung Tissue Diseases 16.2.1.3 Lung Circulation Diseases 16.2.2.1 Asthma 16.2.2.2 Chronic Obstructive Pulmonary Disease (COPD) 16.2.2.3 Bronchioectasis 16.2.2.4 Acute Lower Respiratory Infections 16.2.2.5 Lung Cancer 16.2.2.6 Tuberculosis (TB) 16.2.2.7 Cystic Fibrosis 16.2.2.8 Pulmonary Fibrosis 16.2.2.9 Pulmonary Sarcoidosis 16.2.2.10 Pulmonary Hypertension 16.2.2.11 Noncardiogenic Pulmonary Edema 16.2.2.12 Pulmonary Embolism 16.3 Future Perspective References 17. Nanocarrier Systems for Lung Drug Delivery 17.1 Introduction 17.2 Barriers to Drug Absorption via Pulmonary Route 17.3 Conventional Strategies to Enhance Drug Absorption via the Pulmonary Route 17.4 Deposition and Clearance of Inhaled Particles 17.4.1 Deposition of Inhaled Particles 17.4.2 Clearance of Inhaled Particles 17.5 Nanocarrier Systems for Pulmonary Delivery 17.5.1 Nanosuspensions 17.5.2 Liposomes 17.5.3 Polymeric Nanoparticles 17.5.4 Solid Lipid Nanoparticles 17.5.5 Nanomicelles 17.5.6 Microemulsion 17.5.7 Dendrimers 17.6 Enhancing Pulmonary Deposition of Nanocarrier Systems 17.6.1 Nanoparticle-in-Microparticles Formulations 17.6.2 Use of Mucoadhesive Polymers 17.6.3 Use of Active Targeting Approach 17.7 Toxicity Concerns with Inhalational Nanomedicines 17.8 Conclusion and Future Directions Acknowledgments References 18. Nanomedicine for the Management of Pulmonary Disorders 18.1 Introduction 18.2 Physicochemical Characterization for Nanoparticle-Based Systems 18.2.1 Dynamic Light Scattering 18.2.2 X-ray Diffraction 18.2.3 Scanning Electron Microscopy 18.2.4 Transmission Electron Microscopy 18.2.5 Zeta Potential Measurements 18.3 Criteria of Nano-formulations Intended for Pulmonary Delivery 18.3.1 Pulmonary Directed Nano-Drug Delivery Formulations 18.3.2 Particle Size and Materials 18.3.3 Particle Size and Deposition in Various Regions of the Respiratory System 18.3.4 Peptide Based Nano-formulation for Transportation of Pulmonary Drugs 18.3.5 Choice of Inhalation Device Depending Upon Diseased Condition 18.4 Pulmonary Infectious Diseases and Nanomedicinal Approach 18.4.1 Asthma 18.4.2 COPD 18.4.3 Tuberculosis 18.4.4 Lung Cancer 18.5 Regulation and Guidelines for Marketing 18.6 Safety Assessment of NPs 18.7 Conclusion References 19. Recent Approaches in Dendrimer-Based Pulmonary Drug Delivery 19.1 Introduction 19.2 Dendrimer Concept 19.2.1 General Features and Applicabilities 19.2.2 Structural Aspects 19.3 Dendrimer Syntheses 19.3.1 Classical Approaches 19.3.1.1 Divergent Approach 19.3.1.2 Convergent Approach 19.3.2 Accelerated Approaches 19.3.2.1 Double Exponential Growth Technique 19.3.2.2 Double-Stage Convergent Method 19.3.2.3 Branched Monomer Approach 19.4 Dendrimer Characteristics 19.4.1 Nanodimension 19.4.2 Monodispersity 19.4.3 Polyvalent Surface 19.4.4 High Solubilization Power 19.4.5 Low Viscosity 19.4.6 Wide Loading Capability 19.4.7 Altered Conformational Behavior 19.5 Dendrimer Applications in Medicine 19.6 Pulmonary Drug Delivery Devices 19.7 Dendrimers in Pulmonary Drug Delivery Applications 19.7.1 PAMAM Dendrimers 19.7.2 PEGylated Dendrimers 19.8 Dendrimer Toxicities and Countermeasure Strategies 19.9 Major Challenges 19.10 Current Clinical Status 19.11 Conclusion Conflicts of Interest References 20. Hybrid Lipid/Polymer Nanoparticles for Pulmonary Delivery of siRNA: Development and Fate Upon In Vitro Deposition on the Human Epithelial Airway Barrier 20.1 Introduction 20.1.1 Mechanism for Administration of Pulmonary siRNA Delivery 20.1.2 siRNA Delivery Barricades 20.1.3 Structural Components of Lipid Polymers Hybrid Nanoparticles and Their Arrangement Mechanism 20.2 RNA Interference Mechanism (RNAi) 20.2.1 Therapeutically Active Silencing of Gene with the Help of siRNA 20.3 General Method of Preparation for LPHNPs 20.3.1 Two-Step Method 20.3.1.1 Conventional Method 20.3.1.2 Non-conventional Method 20.3.1.2.1 Formulation Parameters Optimization 20.3.2 One-Step Method 20.3.3 Nano-precipitation 20.3.3.1 Optimization of Formulation Parameters in Nano-precipitation 20.3.4 Emulsification-Solvent Evaporation 20.3.4.1 Optimization in ESE 20.3.5 Manufacturing of DPPC/PLGA Hybrid NPs 20.4 Evaluation of Lipid Polymer Hybrid NPs Based siRNA Delivery 20.4.1 Evaluation by Size and Zeta Potential 20.4.2 Evaluation by Incorporating siRNA to the Interior of hNPs 20.4.3 Evaluation by SAXS Spectroscopy 20.4.4 Evaluation by In Vitro Interaction with Mucin 20.4.5 Evaluation by Particle Stability in Artificial Mucus 20.4.6 Evaluation by In Vitro Aerosol Performance 20.4.7 Evaluation by In Vitro Studies on Airway Triple Cell Cocultures 20.4.8 Evaluation by Nanoparticle Accumulation Effectiveness 20.4.9 Evaluation by Cell Uptake Analysis 20.4.9.1 Evaluation by Cytotoxicity Assay 20.4.9.2 Evaluation by In Vitro Gene Silencing Effect 20.4.9.3 Evaluation by Western Blotting 20.5 Fate Upon In Vitro Deposition on Human Epithelial Barrier 20.5.1 Fate and Cytotoxicity of hNPs Aerosolized in TCCC 20.6 Applications of Lipid Polymer Hybrid Nanoparticles of siRNA Delivery in Various Clinical Conditions 20.6.1 Lipid-Polymer Hybrid Nanoparticles for Sustained siRNA Delivery and Gene Silencing in Treatment of Lung Cancer 20.6.1.1 Combinatorial of siRNA Delivery and Anti-cancer Drugs Delivery 20.6.2 Clinical Trials on Aerosolized siRNA Delivery Based Lipid Polymer Hybrid Nanoparticle 20.6.3 Delivery of siRNA as Nonviral Gene Therapy to the Lungs for Reducing Airway Inflammation 20.6.4 Delivery of Nebulized LPNHPs into Epithelial Cells of Bronchiole Possessing a Therapeutically Active siRNA Approach for Anti-inflammatory Properties and Fate Upon In Vitro Deposition 20.6.5 Potential of siRNA Delivery by Gene Therapy for Treating Cystic Fibrosis through LPNHPs 20.7 Conclusion References 21. Solid Lipid Nanoparticle-Based Drug Delivery for Lung Cancer 21.1 Introduction 21.1.1 Epidemiology 21.1.2 RisK Factors Leading to Lung Cancer 21.2 Current Management 21.2.1 Diagnosis 21.2.2 Standard of Care 21.3 Role of Nanocarriers in Treating Lung Cancer 21.4 Solid Lipid Nanoparticles as a Drug Delivery System for Treating Lung Cancer 21.5 Role of Solid Lipid Nanoparticles in Drug Delivery for Treatment of Lung Cancer 21.6 Ligand-Anchored Solid Lipid Nanoparticles 21.7 Solid Lipid Nanoparticles Administration by Pulmonary Drug Delivery System 21.7.1 Characterization of Dry Powders for Inhalation 21.7.1.1 In Vitro Aerodynamic Properties 21.7.1.2 Simulated Lung Deposition 21.8 Solid Lipid Nanoparticles for Gene Delivery 21.9 Role of Solid Lipid Nanoparticles in Combinatorial Drug Delivery 21.10 Stimuli Responsive Solid Lipid Nanoparticles 21.11 Solid Lipid Microparticles 21.12 Toxicological Evaluation of Solid Lipid Nanoparticles 21.13 Conclusion References 22. Lipid-Based Pulmonary Delivery System: A Review and Future Considerations of Formulation Strategies and Limitations 22.1 Introduction 22.2 Deposition in Pulmonary Circulatory System 22.3 Formulation Strategies 22.4 Device Selection 22.5 Patient Education 22.6 Lipid-Based Drug Delivery 22.6.1 Micro and Nano-Emulsions 22.6.2 Solid Lipid Nanoparticles 22.6.3 Liposomes 22.6.4 Micelle 22.7 Future Perspective References 23. Respirable Controlled Release Polymeric Colloidal Nanoparticles 23.1 Introduction 23.2 Effect of Particle Size on Distribution, Diffusion and Clearance after Lung Delivery 23.3 Surface Properties and Diffusion of the Drug from Nanoparticles 23.3.1 Polymer Nanoparticles in Controlled Release Pulmonary Drug Delivery System 23.3.2 PLGA/PLA for Lung Drug Delivery 23.3.3 Chitosan Polymer 23.3.4 CS Nanoparticles and Anti-tubercular/Anti-bacterial Drugs 23.3.5 Polymer Nanoparticles and Anti-Asthmatic Drugs 23.3.6 Anti-cancer Drugs 23.3.7 Pulmonary Delivery of Proteins/Peptides/Genes with Different Polymeric Nanoparticles 23.3.8 Pulmonary Delivery of Vaccines With Polymeric Nanoparticles 23.4 Conclusion and Future Directions References 24. Lung Clearance Kinetics of Liposomes and Solid Lipid Nanoparticles 24.1 Introduction 24.2 Anatomy and Physiology of Lungs 24.2.1 Lung Volumes and Capacities 24.2.2 Mechanism of Breathing 24.3 General Clearance Mechanism from Lungs 24.4 Clearance Kinetics of Liposome from Lungs 24.5 Clearance Kinetics of Solid Lipid Nanoparticles from Lungs 24.6 Conclusion References 25. Solid Lipid Nanoparticles for Sustained Pulmonary Delivery of Herbal Drugs for Lung Delivery: Preparation, Characterization, and In Vivo Evaluation 25.1 Introduction 25.2 The Respiratory System 25.3 Natural Compounds in Respiratory Diseases 25.3.1 Antiviral Natural Compounds 25.3.2 Natural Compounds Against Coronavirus 25.3.3 Natural Compounds Against the Influenza Virus 25.3.4 Anti-inflammatory and Anti-asthmatic Compounds 25.3.5 Anti-cancer Compounds 25.3.6 Saikosaponins in Lung Diseases 25.4 Solid Lipid Nanoparticles for Pulmonary Deliver 25.5 Methods for Preparation of Solid Lipid Nanoparticles 25.5.1 High Shear Homogenization 25.5.2 Hot Homogenization 25.5.3 Cold Homogenization 25.5.4 Solid Lipid Nanoparticles Prepared by Solvent Evaporation 25.5.5 Microemulsion Based Technique 25.5.6 Microwave-Assisted Microemulsion Technique 25.5.7 Ultrasonication 25.5.8 Double Emulsion Method 25.5.9 Solvent Diffusion Method 25.5.10 Using Supercritical Fluid Method 25.5.11 Membrane Contactor Method 25.5.12 Coacervation Technique 25.5.13 Phase Inversion Temperature Technique 25.5.14 Spray Drying Method 25.6 Critical Parameters of Pulmonary Delivery 25.6.1 Structural Composition 26.6.2 Biocompatibility 25.6.3 Particle Size and Shape 25.6.4 Surface Properties of the Particles 25.6.5 Isotonicity and pH Value 25.6.6 Ligands for Targeting of Solid Lipid Nanoparticles 25.6.7 Pulmonary Delivery Tools 25.6.8 Patient Related Factors 25.7 Characterization 25.7.1 Surface Morphology, Particle Size, and Size Distribution 25.7.2 Transmission Electron Microscopy 25.7.3 Scanning Electron Microscopy 25.7.4 Dynamic Correlation Spectroscopy 25.7.5 Laser Diffraction Spectroscopy 25.7.6 Acoustic Methods 25.7.7 Surface Charge 25.7.8 Nuclear Magnetic Resonance 25.7.9 Crystallinity and Polymorphism 25.7.10 Differential Scanning Calorimetry 25.7.11 X-ray Diffraction 25.7.12 Determination of Process Yield and Moisture Content 25.7.13 Flow Properties of Solid Lipid Nanoparticles 25.7.13.1 Angle of Repose 25.7.13.2 Bulk and Tapped Density 25.7.14 Drug Content and Entrapment Efficiency 25.7.14.1 UV Spectroscopy 25.7.14.2 High Performance Liquid Chromatography 25.7.14.3 High Performance Thin Layer Chromatography 25.7.15 In Vitro Aerosol Dispersion Performance 25.7.16 In Vitro Activity Study 25.8 Pulmonary Delivery Strategies 25.9 Pharmacokinetics of Pulmonary Delivery 25.10 Pulmonary Disposition 25.11 Elimination of Solid Lipid Nanoparticles 25.12 Sterilization of Solid Lipid Nanoparticle Formulations 25.13 Storage Challenges For Solid Lipid Nanoparticle Products 25.14 In Vivo Models for the Study of Lung Diseases 25.14.1 Animal Models of Asthma 25.14.2 Bacterial Lung Infection Models 25.14.3 Influenza Models 25.14.4 Mouse Influenza Model 25.14.5 Ferret Influenza Model 25.14.6 Lipopolysaccharide-Induced Pulmonary Neutrophilia Model 25.14.7 Mouse Model 25.14.8 Rat Model 25.14.9 Pulmonary Fibrosis Model 25.14.9.1 Mouse and Rat Model of Bleomycin-Induced Lung Fibrosis 25.14.10 Pulmonary Cancer Model 25.14.11 Mouse Models for Non Small Cell Lung Cancer 25.14.12 Mouse Models for Squamous Cell Carcinomas 25.14.13 Mouse Models for Small Cell Lung Cancer 25.15 Conclusion Conflict of Interest References 26. Improved Solid Lipid Nano-formulations for Pulmonary Delivery of Paclitaxel for Lung Cancer Therapy 26.1 Introduction: Lung Cancer 26.2 Pulmonary Drug Delivery for Lung Cancer by Inhalation 26.3 Solid Lipid Nanoparticles for Lung Cancer Therapy 26.3.1 Lipid-Based Nanocarriers 26.3.2 Solid Lipid Nano-Vectors for Lung Cancer 26.4 Paclitaxel for Lung Cancer Therapy 26.4.1 Paclitaxel, Its Mechanisms and Drug Resistance 26.4.2 Improved Anti-angiogenic Efficacy of Paclitaxel through Newly Established Pharmaceutical Formulations 26.5 Chitosan and Its Derivatives in Lung Cancer Therapy 26.5.1 Chitosan-Based Delivery Systems in Lung Cancer Therapy 26.6 Folate-Decorated Nano Systems for Lung Cancer Therapy 26.7 Conclusion, Recommendation, and Future Prospects References 27. Anti-angiogenic Therapy for Lung Cancer: Focus on Bioassay Development in a Quest for Anti-VEGF Drugs 27.1 Introduction 27.2 Anti-angiogenic Therapy in NSCLC and Approved Anti-angiogenic Agents 27.2.1 Bevacizumab 27.2.2 Ramucirum