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

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 Ramucirumab
		27.2.3 Nintedanib
	27.3 Anti-angiogenics in Combination with Immunotherapy
	27.4 Bioassay Development in a Quest for Anti-VEGF Drugs
	27.5 The Regulations and Bioassays
	27.6 VEGF: The Fundamental Controller of Angiogenesis
	27.7 VEGF Family and Its Receptors
	27.8 Drugs Targeting VEGF or Its Receptors
	27.9 Global Sales of Anti-VEGF Drugs
	27.10 Bioassays Available for Anti-VEGF Drugs
		27.10.1 In Vivo Assays
			27.10.1.1 Chick Chorioallantoic Membrane Assay
			27.10.1.2 Hindlimb Ischemia Assay
			27.10.1.3 Chamber Assays
			27.10.1.4 Matrigel Plug Assay
			27.10.1.5 Corneal Angiogenesis Assay
		27.10.2 Ex Vivo (Organ Culture Assays)
			27.10.2.1 Aortic Ring Assay
			27.10.2.2 Porcine Carotid Artery Assay
			27.10.2.3 Chick Aortic Arch Assay
		27.10.3 Endothelial Cell-Based In Vitro Assays
			27.10.3.1 Endothelial Cell Proliferation Assay
			27.10.3.2 Endothelial Cell Migration Assay
			27.10.3.3 Endothelial Cell Tube Formation Assay
	27.11 Requirements for Cell Based Assay
	27.12 Engineering Cell Lines with Receptors for the Development of Cell-Based Bioassay
	Acknowledgments
	References
28. Emerging Applications of Nanoparticles for Lung Cancer Diagnosis and Therapy
	28.1 Introduction
	28.2 Classification of Lung Cancers
	28.3 Detection of Lung Cancer
	28.4 Treatments Available for Lung Cancer
	28.5 What Makes Treating Lung Cancer Difficult
	28.6 Emergence of Nanotechnology in Lung Cancer Treatment
		28.6.1 Advantages of Nanoparticles (37-49)
		28.6.2 Disadvantages of Nanoparticles
	28.7 Nanoparticles in the Treatment of Lung Cancer
	28.8 Nanoparticles in the Diagnosis of Lung Cancer
	28.9 Nano-theranostics
	28.10 Innovative Strategies Showed Promising Theranostic Applications in Treating Lung Cancer (35)
	28.11 Challenges of Nanoparticles in Cancer Treatment
	28.12 Conclusion
	References
29. Metallic Nanoparticles: Technology Overview and Drug Delivery Applications in Lung Cancer
	29.1 Introduction
	29.2 Characteristics of Metal Nanoparticles
	29.3 Different Types of Metal Nanoparticles, Synthesis and Preparation Methods
	29.4 Application of Metal Nanoparticles in Lung Cancer
	29.5 Conclusion
	References
30. Modeling of Pharmaceutical Aerosol Transport in the Targeted Region of Human Lung Airways Due to External Magnetic Field
	30.1 Introduction
	30.2 Computational Domain and Mesh Generation
	30.3 Methodology
		30.3.1. Drag Force
		30.3.2. Magnetic Forces
	30.4 Grid Convergence Study
	30.5 Model Validation
	30.6 Results and Discussion
	30.7 Conclusions
	References
31. Phytochemicals and Biogenic Metallic Nanoparticles as Anti-cancer Agents in Lung Cancer
	31.1 Introduction
	31.1.1 Bacteria as a Biogenic Source for Metallic Nanoparticle Production
	31.1.2 Plants as a Biogenic Source for Metallic Nanoparticle Production
	31.1.3 Benefits of Biosynthesized Nanoparticles
	31.2 Biogenic Silver Nanoparticles (AgNP), Synthesis and Anti-cancer Activity
	31.3 Biogenic Gold Nanoparticles (AuNP), Synthesis and Anti-cancer Activity
	31.4 Biogenic Zinc Oxide (ZnONP), Synthesis and Anti-cancer Activity
	31.5 Biogenic Iron Oxide Nanoparticles (FeONP), Synthesis and Anti-cancer Activity
	31.6 Biogenic Cerium Oxide (CeONP), Synthesis and Anti-cancer Activity
	31.7 Conclusion
	References
32. Pulmonary Applications and Toxicity of Engineered Metallic Nanoparticles
	32.1 Introduction
	32.2 Pulmonary Applications of Engineered Metallic Nanoparticles
	32.3 Pulmonary Toxicity of Engineered Metallic Nanoparticles
	32.4 Conclusion
	References
33. Anti-cancer Activity of Eco-friendly Gold Nanoparticles against Lung and Liver Cancer Cells
	33.1 Introduction
	33.2 Gold Nanoparticles and Their General Properties
	33.3 Surface Modification of Gold Nanoparticles
	33.4 Gold Nanoparticle-Mediated Drug Delivery
	33.5 Advantages of Gold Nanoparticle-Mediated Drug Delivery
	33.6 Methods for the Synthesis of Gold Nanoparticles
	33.7 Clinical Applications of Gold Nanoparticles for Lung and Liver Cancer
	33.8 Conclusion
	References
34. Sub-chronic Inhalational Toxicity Studies for Gold Nanoparticles
	34.1 Introduction to Gold Nanoparticles
	34.2 History of Gold Nanoparticles
	34.3 Studies on Gold Nanoparticles and Their Therapeutic Uses
	34.4 Introduction to Metal Toxicity
	34.5 Types of Inhalational Toxicity Studies
	34.6 Sub-Chronic Inhalational Toxicity Studies According to Various Guidelines
		34.6.1 Sub-Chronic Inhalation Toxicity Guidelines According to OECD
		34.6.2 Sub-Chronic Toxicity Guidelines as per ICH
	34.7 Reported Gold Nanoparticle Inhalation Toxicity Studies
	34.8 Conclusion
	References
35. Single-Use Dry Powder Inhalers for Pulmonary Drug Delivery
	35.1 Introduction
	35.2 Classifications of Dry Powder Inhalers and Single-Use Disposable Devices
	35.3 Disposable Dry Powder Inhalers: Advantages
	35.4 Disposable Dry Powder Inhalers: Device Design and Formulation Development
	35.5 Single-Use Dry Powder Inhalation Devices
		35.5.1 MonoHaler
		35.5.2 TwinCaps®
		35.5.3 3M Conix™
		35.5.4 Twincer™
		35.5.5 DirectHaler™
		35.5.6 Aespironics DryPod
		35.5.7 Afrezza® Inhaler (MannKind Corp.)
		35.5.8 PuffHaler (Aktiv-Dry LLC)
		35.5.9 Perlamed™-BLISTair (Perlen Packaging)
		35.5.10 SOLO™ Inhaler (Manta Devices)
		35.5.11 Cyclops™
	35.6 Conclusions
	References
36. Lung Delivery of Nicotine for Smoking Cessation
	36.1 Introduction
	36.2 Adverse Health Effects of Smoking
		36.2.1 Smoking and Cardiovascular Diseases
		36.2.2 Smoking and Respiratory Diseases
		36.2.3 Smoking and Lung Cancer
	36.3 Mechanism of Nicotine Addiction
	36.4 Pharmacokinetic Considerations
		36.4.1 Acute Nicotine Treatment
		36.4.2 Chronic Nicotine Treatment
	36.5 Current Therapeutic Options for Smoking Addiction
		36.5.1 Nicotine Replacement Therapy (NRT)
		36.5.2 Non-nicotine Therapy
			36.5.2.1 Bupropion
			36.5.2.2 Varenicline
		36.5.3 Electronic Nicotine Delivery Device (E-cigarette)
	36.6 Pulmonary Delivery of Nicotine Inhalers
	36.7 Conclusions
	References
37. Formulation and Characterization of Dry Powder Inhalers for Pulmonary Drug Delivery
	37.1 Introduction
	37.2 History of Inhalation Therapy
	37.3 Advantages of Dry Powder Inhaler for Drug Delivery
	37.4 Aspects of DPI Design
	37.5 Formulation of Powders for Inhalation
	37.6 The Technical Design of DPI
		37.6.1 Dry Powder Inhalation Formulations
		37.6.2 Dose Measuring Systems
	37.7 Principles of Powder Dispersion
	37.8 DPI for High Dose Drugs
	37.9 The Technical Design of DPI Formulations
		37.9.1 Particle Preparation Techniques
			37.9.1.1 Spray Drying Techniques
			37.9.1.2 Spray-Freeze Drying
			37.9.1.3 Supercritical Fluid (SCF) Technologies
	37.10 Types of DPI Devices
		37.10.1 Single-Dose Devices
		37.10.2 Multiple-Unit Dose Devices
		37.10.3 Multi-dose Devices
	37.11 Challenges for Future Developments
		37.11.1 DPI Design
		37.11.2 Dry Powder Formulations
		37.11.3 Pulmonary Vaccination
		37.11.4 Special Patient Groups
		37.11.5 Target Sites for Inhaled Drugs
		37.11.6 Patient Compliance
	37.12 Conclusion for Ideal DPI Formulation
	Conflict of Interest
	References
38. Devices for Dry Powder Drug Delivery to the Lung
	38.1 Pulmonary Drug Delivery System
	38.1.1 Advantages of Pulmonary Drug Delivery System
	38.1.2 Mechanism of Drug Particle Deposition
	38.1.3 Drawbacks of Current Inhaler Devices
	38.2 Advancements in Pulmonary Delivery Devices
	38.2.1 Nebulizer
	38.2.2 Inhalers
		38.2.2.1 Dry Powder Inhaler
		38.2.2.2 Metered-Dose Inhaler
		38.2.2.3 Pressurized Metered-Dose Inhaler
	38.3 General Requirements for Pulmonary Delivery Devices
	38.4 Marketed Inhaler Technologies
		38.4.1 Technosphere® Insulin
		38.4.2 Exubera®
		38.4.3 AERx®
		38.4.4 GyroHaler®
		38.4.5 Pressair®
		38.4.6 Aspirair
		38.4.7 Neohaler®
		38.4.8 Respimat®
	38.5 Future Perspectives of Inhaler Devices for Lung Delivery
	References
39. Numerical Modeling of Agglomeration and De-agglomeration in Dry Powder Inhalers
	39.1 Introduction
	39.2 Numerical Modeling of Dry Powder Agglomeration and De-agglomeration
	39.3 Numerical Modeling for DPI Device Design and Evaluation
	39.4 Numerical Modeling of Particle Deposition in the Human Airway System
	References
40. Oronasal and Tracheostomy Delivery of Soft Mist and Pressurized Metered-Dose Inhalers with Valved Holding Chamber
	40.1 Introduction
		40.1.1 Oronasal Delivery
			40.1.1.1 Factors Affecting Oronasal Delivery
				40.1.1.1.1 Ineffective Breathing
				40.1.1.1.2 Impaired Mask Sealing
				40.1.1.1.3 Type of Pressure Support
				40.1.1.1.4 Humidity
				40.1.1.1.5 Physiological Conditions of Patients
		40.1.2 Tracheostomy Delivery
			40.1.2.1 Conditions Requiring Tracheostomy
				40.1.2.2 Airway Complications
				40.1.2.3 Lung Problems
				40.1.2.4 Other Complications
			40.1.2.2 Factors Affecting Tracheostomy Delivery
				40.1.2.2.1 The Internal Diameter of a Tracheostomy Tube
				40.1.2.2.2 The Inner Cannula of a Tracheostomy Tube
				40.1.2.2.3 Fenestration of a Tracheostomy Tube
				40.1.2.2.4 The Material Used to Manufacture a Tracheostomy Tube
				40.1.2.2.5 The Type of Aerosol Device
				40.1.2.2.6 Aerosol Drug Delivery Techniques
	40.2 Pressurized Metered Dose Inhalers (pMDIs)
		40.2.1 What is pMDI?
		40.2.2 Drugs Used
		40.2.3 Mechanism of Device
		40.2.4 Propellants Used in pMDI
		40.2.5 Methodology of Use
		40.2.6 Drug Deposition through pMDI
		40.2.7 Factors Affecting the Performance of pMDI
			40.2.7.1 Shaking the Canister
			40.2.7.2 Storage Temperature
			40.2.7.3 Nozzle Size and Cleanliness
			40.2.7.4 Timing of Actuation Intervals
			40.2.7.5 Priming
			40.2.7.6 Characteristics of the Patient
			40.2.7.7 Breathing Techniques
		40.2.8 Advantages of pMDIs
		40.2.9 Drawbacks of pMDIs
		40.2.10 BA-pMDI
			40.2.10.1 Advantages of BA-pMDIs
			40.2.10.2 Disadvantages of BA-pMDIs
		40.2.11 Spacers and Valved Holding Chambers
			40.2.11.1 Advantages
			40.2.11.2 Disadvantages
		40.2.12 Facemasks
	40.3 Soft Mist Inhalers (SMIs)
		40.3.1 What is an SMI?
		40.3.2 Why SMI?
		40.3.3 Drugs Delivered via SMI
		40.3.4 Mechanism of SMI
		40.3.5 Methodology to Use SMI
		40.3.6 Statistics
		40.3.7 Advantages of SMIs
		40.3.8 Disadvantages of SMIs
	40.4 Selection of Delivery Device
		40.4.1 Choice of Drug Device Combinations for Home Use
		40.4.2 Factors Affecting Choice of Aerosol Drug Delivery Device
			40.4.2.1 Patient-Related Factors
			40.4.2.2 Drug-Related Factors
			40.4.2.3 Device-Related Factors
			40.4.2.4 Environmental and Clinical Factors
			40.4.2.5 Cost and Reimbursement of Aerosol Devices
	40.5 Observations and Considerations
	40.6 Conclusion
	40.7 Summary
	References
41. Modeling for Biopharmaceutical Performance in Lung Drug Discovery
	41.1 Introduction
	41.2 Applications of Modeling and Simulation of Biopharmaceutical Performance Drug Delivery
		41.2.1 Modeling for Lung Studies or Lung Treatment
		41.2.2 Cellular Models to Study Lung Treatment
		41.2.3 Molecular Models for Lung Studies
	41.3 The Benefits of Modeling and Simulation
		41.3.1 In Vitro Models for Lung Studies
		41.3.2 In Vivo Models for Lung Performance
		41.3.3 Biopharmaceutical Simulations
	41.4 Future Usage
		41.4.1 Lung Cancer Models
		41.4.2 Lung Modeling Methods
		41.4.3 Growing Trend
	41.5 Conclusion
	References
42. Regulatory Consideration for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India
	42.1 Introduction
	42.2 Regulatory Considerations in the US (FDA)
		42.2.1 For Generic Inhalation Products
		42.2.2 In Vitro Studies
		42.2.3 Pharmacokinetic Study
		42.2.4 Pharmacodynamic study
		42.2.5 Other Recommendations
	42.3 Regulatory Consideration in EU
		42.3.1 Step 1: In Vitro Studies
		42.3.2 Step 2: Pharmacokinetic Study
		42.3.3 Step 3: Pharmacodynamic Studies
	42.4 Regulatory Consideration in Anvisa (Brazil)
		42.4.1 In Vitro Studies
		42.4.2 In Vivo Studies
		42.4.3 Pharmacokinetic Study
		42.4.4 Pharmacodynamic Study
	42.5 Regulatory Consideration in China
		42.5.1 In Vitro Study
		42.5.2 In Vivo Study
			42.5.2.1 Method 1: PK Study
			42.5.2.2 Method 2: PD + PK/EP
		42.5.3 For Category VI
	42.6 Regulatory Consideration in India
		42.6.1 For Reference Drug Approval in India
		42.6.2 For Reference Drug not Approved in India
		42.6.3 Process Consideration
		42.6.4 Summary of Regulatory Requirements for Approval of Generic Inhaled Drug Products
			42.6.4.1 In Vitro Study
			42.6.4.2 Pharmacokinetic Study
			42.6.4.3 Pharmacodynamic Study
			42.6.4.4 Qualitative and Quantitative Equivalence
			42.6.4.5 Lung Imaging
			42.6.4.6 Clinical End-Point Study
			42.6.4.7 Statistical Methods
	42.7 Conclusion
	Abbreviations
	References
43. Regulatory Perspectives and Concerns Related to Nanoparticle-Based Lung Delivery
	43.1 Introduction
		43.1.1 Pulmonary Drug Delivery
			43.1.1.1 Lung Anatomy
			43.1.1.2 Barriers in Pulmonary Drug Delivery
				43.1.1.2.1 Mechanical Barrier
				43.1.1.2.2 Chemical and Immunological Barriers
				43.1.1.2.3 Behavioral Barriers
			43.1.1.3 Pharmacodynamic Factors in Lung Delivery
			43.1.1.4 Pharmacokinetic (PK) Factors in Pulmonary Delivery
				43.1.1.4.1 Oral Bioavailabilty
				43.1.1.4.2 Systemic Clearance and Volume of Distribution
				43.1.1.4.3 Pulmonary Residence Time
		43.1.2 Nano-formulations in Pulmonary Delivery
			43.1.2.1 Nanoparticle Delivery for Pulmonary Application
				43.1.2.1.1 Solid Lipid Nanoparticles
				43.1.2.1.2 Polymeric Nanoparticles
				43.1.2.1.3 Liposomes and Niosomes
				43.1.2.1.4 Nano-emulsion
				43.1.2.1.5 Dendrimers
				43.1.2.1.6 Hydrogels
				43.1.2.1.7 Nanosuspension
		43.1.3 Current Trends
	43.2 Molecular Mechanism and Associated Pathways for Nano-particulate Lung Delivery
		43.2.1 Cancer
		43.2.2 Infectious Disease
		43.2.3 Asthma
		43.2.4 Chronic Obstructive Pulmonary Disease
	43.3 Regulation and Guidelines
		43.3.1 The European Union (EU)
		43.3.2 United Kingdom (UK)
		43.3.3 United States of America (USA)
		43.3.4 Canada
		43.3.5 Australia
		43.3.6 Japan
		43.3.7 The Republic of South Korea
		43.3.8 Taiwan
		43.3.9 Thailand
		43.3.10 China
		43.3.11 India
	43.4 Safety and Toxicity
		43.4.1 Preclinical Safety and Toxicity Assessment
		43.4.2 Clinical Safety and Toxicity Assessment
	43.5 Conclusion
	References
44. Clinical Controversies of Pediatric Aerosol Therapy
	44.1 Introduction
	44.2 Differences in Aerosol Drug Delivery — Adult versus Pediatric Patient Groups
	44.3 Considerations for Age-Appropriate Therapy
		44.3.1 Patient-Physician Factors
	44.4 Treatment Device Selection
		44.4.1 Metered-Dose Inhalers
		44.4.2 Dry Powder Inhalers
		44.4.3 Small-Volume Nebulizers
	44.5 Device Comparison
		44.5.1 Metered-Dose Inhaler
		44.5.2 Dry Powder Inhaler
		44.5.3 Small-Volume Nebulizers
	44.5.4 Difficulties with Aerosolized Device Treatment
	44.5.5 The "Universal" Design
	44.6 Controversies with Aerosol Therapy in Pediatrics
	44.7 Pediatric Models of Study
	44.8 Conclusion
	References
45. Drug Delivery Using Aerosols: Challenges and Advances in Neonatal Pediatric Subgroup
	45.1 Introduction
	45.2 Issues with Neonates: Different in Many Ways
	45.3 Considerations for Neonatal Aerosol Therapy: What Do We Need to Know?
	45.4 Challenges in Using Aerosol Medicines for Babies: In Baby Size
		45.4.1 Unique Cognitive Challenges
		45.4.2 Challenges during Aerosol Device Selection
		45.4.3 Challenges in Face Mask Design for Interface Selection
		45.4.4 Challenges in Dealing with Patient Preferences
		45.4.5 Challenges in Neonates for Device Synchronizing
	45.5 Considerations for Neonatal Aerosol Applications
		45.5.1 Air Flow Parameters
		45.5.2 Formulation
		45.5.3 Aerosol Particle Size
		45.5.4 Gastric Deposition and Impact on Upper Airways
	45.6 Aerosol Therapies Side Effects
	45.7 Improvements in Aerosol Therapies for Infants
	45.8 Limitations and Advances for Aerosol Delivery
	45.9 Conclusions
	Acknowledgments
	References
46. Safety and Toxicological Concerns Related to Nanoparticle-Based Lung Delivery
	46.1 Properties of Nanoparticles
	46.2 Clearance Mechanism of Nanoparticles from Lungs
		46.2.1 Enzymatic Degradation
		46.2.2 Pulmonary Clearance
		46.2.3 Rapid Systemic Absorption
	46.3 Surface-Modified Nanoparticles
	46.4 Pulmonary Drug Delivery
		46.4.1 Pulmonary Delivery of Nanoparticles Using Dry Powder Carriers
		46.4.2 Use of Nebulization for Pulmonary Delivery of Nanoparticle
		46.4.3 Magnetic Nanoparticles
		46.4.4 Delivering Nanoparticles Locally into the Lung
		46.4.5  Nanoparticle-Based Gene Delivery to Lungs
	46.5 Advantages of Nanoparticles in Lung Delivery
	46.6 Regulatory Concerns Related to Nanoparticles
	46.7 Safety Concerns Related to Nanoparticles
		46.7.1 Particle Size and Shape
		46.7.2 Biodegradability
		46.7.3 Surface Charge
		46.7.4 Disease State and Concentration at the Target Site
		46.7.5  Nanoparticle Interaction with Pulmonary Environment
	46.8 Toxicity of Inhaled Nanoparticles
		46.8.1 Toxicity of Inhaled Ultrafine Particles
		46.8.2 Toxicity of Polymeric Nanoparticles Used in Drug Delivery
	46.9 Conclusion and Future Perspectives
	References
47. Nanoparticle-Based Lung Drug Delivery: A Clinical Perspective
	47.1 Introduction
	47.2 In Vivo Behavior of Nanoparticles
	47.3 Drug Delivery System and Its Related Clinical Trials
		47.3.1  Polymer-Based Pulmonary Delivery
		47.3.2 Lipid Based Pulmonary Delivery
		47.3.3 Hybrid Lipid-Polymer Nanoparticles
		47.3.4  Dendrimers-Based Pulmonary Delivery
		47.3.5 Inorganic Nanocarrier-Based Pulmonary Delivery
	47.4 Factors Affecting the Toxicological Potential of Nanoparticles
		47.4.1 Shape and Structure
		47.4.2 Particle Size
		47.4.3 Surface Charge
		47.4.4 Biodegradability of the Nanoparticles
	47.5 Future Perspective and Concluding Remarks
	References
48. European Perspective on Orally Inhaled Products: In Vitro Requirements for a Biowaiver
	48.1 Introduction
	48.2 Regulatory Pathways in Europe
		48.2.1 Bioequivalence Requirements in the EU
			48.2.1.1 In Vitro Equivalence Testing
				48.2.1.1.1 Aerodynamic Particle Size Distribution
				48.2.1.1.2 Dose Content Uniformity
				48.2.1.1.3 Dissolution, Permeation, Particle Clearance, and Tissue Exposure
				48.2.1.1.4 In Vitro Dissolution
			48.2.1.2 Pharmacokinetics Approach
				48.2.1.2.1 Dose Selection
				48.2.1.2.2 Subject Selection
				48.2.1.2.3 Subject Training
				48.2.1.2.4 Other Factors
			48.2.1.3 Pharmacodynamics Approach
	48.3 Biowaiver for OIDP in the European Union
		48.3.1 Criteria 1
		48.3.2  Criteria 2
		48.3.3 Criteria 3
		48.3.4 Criteria 4
	48.4 Criteria for the In Vitro Comparison
	48.5 Case Studies of Orally Inhaled Drug Products
		48.5.1 Case Study of Glycopyrronium and Formoterol Fumarate
		48.5.2 Case Study of Fluticasone Furoate/Vilanterol DPI
	48.6 Summary
	References
Index