Organ Specific Drug Delivery and Targeting to the Lungs

Cover
Half Title
Series Page
Title Page
Copyright Page
Dedication
Table of Contents
Preface
Acknowledgments
About the Authors
List of Contributors
Section I In-Vitro and Ex-Vivo Methods
	Chapter 1 Estimating Clinically Relevant Measures of Inhaled Pharmaceutical Aerosol Performance with Advanced In Vitro and In Silico Methods
		1.1 Introduction
			1.1.1 Clinically Relevant Measures
			1.1.2 Pharmacopeial Measures of Inhaler Performance
			1.1.3 Defining Test Systems
		1.2 In Vitro Methods
			1.2.1 Airway Geometry
				1.2.1.1 Realistic and semi-realistic extrathoracic geometries
				1.2.1.2 Idealized extrathoracic geometries
				1.2.1.3 In vitro measures of thoracic deposition
			1.2.2 Inhalation Maneuver
				1.2.2.1 pMDIs and SMIs
				1.2.2.2 DPIs
				1.2.2.3 Nebulizers, spacers, valved holding chambers, and facemasks
			1.2.3 Hygroscopic Behavior
			1.2.4 Real-World Use
				1.2.4.1 pMDIs
				1.2.4.2 DPIs
				1.2.4.3 Inhaler orientation and other aspects of patient technique
		1.3 Deposition Models
			1.3.1 Extrathoracic Deposition
			1.3.2 Thoracic Deposition
		1.4 Pharmacokinetic Models
			1.4.1 Characterizing Disposition
				1.4.1.1 Modeling dissolution
				1.4.1.2 Solubility and permeability
				1.4.1.3 Lung-relevant dissolution testing
			1.4.2 Considering Health or Disease
		1.5 Moving Towards Clinical Relevance
		References
	Chapter 2 In Vitro Assessment of Drug Release, Dissolution, and Absorption in the Lung
		2.1 Introduction
		2.2 Factors Affecting Deposition and Bioavailability
			2.2.1 Factors Affecting Bioavailability
				2.2.1.1 Mucociliary clearance
				2.2.1.2 Alveolar clearance
				2.2.1.3 Enzymatic degradation
				2.2.1.4 Local vs systemic delivery
			2.2.2 Factors Affecting Deposition
				2.2.2.1 Formulation factors
				2.2.2.2 Physiological factors
		2.3 In Vitro Performance Testing for DPI Products
			2.3.1 Cascade Impactors
			2.3.2 Single-Stage Impactors
			2.3.3 Multi-Stage Impactors
		2.4 Drug Release
		2.5 In Vitro Dissolution
			2.5.1 Traditional Dissolution Studies
			2.5.2 Flow-Through Cell
			2.5.3 Membrane-Based Cell Systems
		2.6 Assessment of Absorption and Deposition of Formulation for Inhalation
			2.6.1 Calu-3 Cell Monolayer Model
			2.6.2 Human Alveolar Cell Monolayer Models
			2.6.3 Human Primary ALI-Cultured 3D Lung Cell Barrier Models
			2.6.4 Stem Cell-Derived Lung Epithelial Cells
			2.6.5 “Lung-on-a-Chip” Model
		2.7 Conclusion and Future Perspectives
		References
	Chapter 3 Lung-on-a-Chip and Lung Organoid Models
		3.1 Introduction
		3.2 Lung-on-a-Chip and Its Application in Drug Discovery and Development
			3.2.1 Prevalence of Pulmonary Diseases
			3.2.2 Establishment of Air-Liquid Interface Model
			3.2.3 Evolution in Lung-on-a-Chip Fabrication and Complexity
				3.2.3.1 Inception of microfluidics-based lung-on-a-chip model
				3.2.3.2 Challenges and further advancements in lung-on-a-chip fabrication, including 3D bioprinting
			3.2.4 Application of Lung-on-a-Chip in Modeling of Lung Cancer Growth
			3.2.5 Application of Lung-on-a-Chip in Modeling of Responses to Aerosolized Drugs and Nanoparticle Treatment
			3.2.6 Application of Lung-on-a-Chip in Modeling of Pulmonary Edema and Lung Inflammation
			3.2.7 Application of Lung-on-a-Chip in Modeling of Lung Infection and Identification of Antiviral Therapeutics
			3.2.8 Application of Multi-Organ-Chip in Pharmacokinetics (PK) and Pharmacodynamics (PD) Modeling
			3.2.9 Application of Lung-on-a-Chip in Toxicology Studies
			3.2.10 Further Challenges and Future Directions in Lung-on-a-Chip Development
		3.3 Application of Lung Organoids in Disease Modeling and Drug Targeting
			3.3.1 Human Lung Organoids Derived from Primary Human Lung Epithelium Cells and Human Bronchioalveolar Stem Cells
			3.3.2 Application of Patient-Derived Lung Cancer Organoids in Testing and Screening Anticancer Drugs
			3.3.3 Application of Lung Organoids in Modeling Lung Infections and Antiviral Drugs
			3.3.4 Application of Lung Organoid in Toxicological Studies
		3.4 Concluding Remarks
		Competing Interests
		References
	Chapter 4 Interaction between Inhalable Nanomedicines and Pulmonary Surfactant
		4.1 Introduction
		4.2 Basic Information of Pulmonary Surfactant
			4.2.1 Physiological Functions
			4.2.2 Components
			4.2.3 Biosynthesis and Biodegradation
		4.3 Interaction between Inhalable Nanomedicines and Pulmonary Surfactant: A Biomolecular Corona-Associated Process
			4.3.1 Inevitableness of Nanomedicine-Pulmonary Surfactant Interaction
			4.3.2 Connection between the Interaction with Biomolecular Corona
			4.3.3 Categories of the Interaction
		4.4 The Impact of Interaction upon Nanomedicines
			4.4.1 Hydrophobicity
			4.4.2 Surface Charge
			4.4.3 Colloidal Stability
			4.4.4 Pulmonary Surfactant Layer Permeability
			4.4.5 Targeting Region
			4.4.6 Cellular Uptake
		4.5 The Impact of Interaction upon Pulmonary Surfactant
			4.5.1 Biosynthesis
			4.5.2 Components
			4.5.3 Surface Activity
		4.6 Characterization Methods for the Interaction
			4.6.1 Morphology
			4.6.2 Biomolecules Separation and Identification
			4.6.3 Conformational Change
			4.6.4 Surface Tension
			4.6.5 Kinetics and Thermodynamics
			4.6.6 In-silico Interaction Model
		4.7 Implications for Pulmonary Drug Delivery of Nanomedicines
			4.7.1 Impact of the Interaction on Drug Delivery
			4.7.2 Manipulation of the Interaction
			4.7.3 Application of Pulmonary Surfactant in Nanomedicine Design
		4.8 Concluding Remarks and Outlook
		4.9 Acknowledgment
		4.10 Appendices
			4.10.1 Representative Cases Summary of the Interaction
			4.10.2 Summary of Characterization Methods for the Interaction
		References
Section II Particle Design Understanding
	Chapter 5 Particle Engineering for Pulmonary Drug Delivery
		5.1 Introduction
		5.2 Interparticle Interactions in Aerosol-Based Delivery Systems
		5.3 Particle Properties and Interfaces
			5.3.1 Size
			5.3.2 Shape
			5.3.3 Solid-State Properties
			5.3.4 Surface Properties of Solids
				5.3.4.1 Surface energy
				5.3.4.2 Surface roughness
				5.3.4.3 Surface charge
				5.3.4.4 Surface moisture
		5.4 Particle Engineering Approaches
			5.4.1 Conventional Approaches
				5.4.1.1 Particle sizing
				5.4.1.2 Spray drying
				5.4.1.3 Crystallization
			5.4.2 Novel Advanced Approaches
				5.4.2.1 Supercritical fluid technologies
				5.4.2.2 Surface modification through dry coating
				5.4.2.3 Nanotechnology approaches
		5.5 Outlook and Future Perspectives
		References
	Chapter 6 Particle Architectonics for Pulmonary Drug Delivery
		6.1 Introduction
		6.2 Fate of Drug Particles in the Lung
		6.3 Down-Sizing of Solid Particles
		6.4 Manipulation of Particle Morphology
		6.5 Miscibility of Spray-Dried Components
		6.6 Nanoparticle-Based Architectonics
		6.7 Lipid-Based Architectonics
		6.8 Excipients for Pulmonary Route
		6.9 Concluding Remarks
		References
	Chapter 7 Engineered Particles for Aerosolization and Lung Deposition
		7.1 Introduction
		7.2 Particle Size
		7.3 Morphologically Engineered Particles
			7.3.1 Elongated Particles
			7.3.2 Porous and Wrinkled Particles
			7.3.3 Spikey (Pollen-like) Particles
			7.3.4 Other Shaped Particles (PRINT Technology)
		7.4 Chemically Engineered Particles
			7.4.1 Co-Formulation with Hydrophobic Amino Acids
			7.4.2 Co-Formulation with Metal Stearates
			7.4.3 Co-Formulation of APIs
		7.5 Production Methods
			7.5.1 Methods Used in Commercial Inhalation Products
				7.5.1.1 Milling
				7.5.1.2 Spray drying
			7.5.2 Methods Used in Inhalation Powders under Development
				7.5.2.1 Spray freeze drying
				7.5.2.2 Other methods
				7.5.2.3 Newer technologies
		7.6 Characterization Techniques
			7.6.1 Particle Morphology and Roughness
				7.6.1.1 Specific surface area (SSA)
				7.6.1.2 Fractal dimension analysis
				7.6.1.3 Scanning electron microscopy (SEM)
				7.6.1.4 Laser diffraction
				7.6.1.5 Atomic force microscopy (AFM)
				7.6.1.6 White-light interferometry
			7.6.2 Chemical Composition and Distribution
				7.6.2.1 X-ray photoelectron spectroscopy (XPS)
				7.6.2.2 Time-of-flight secondary ion mass spectrometry (ToF-SIMS)
				7.6.2.3 AFM-based techniques
				7.6.2.4 Fourier transform infrared spectroscopy (FTIR)
			7.6.3 Electrostatic Charge
				7.6.3.1 Electrical low-pressure impaction (ELPI)
				7.6.3.2 Bipolar charge analyzer
			7.6.4 Other Commonly Used Bulk Characterization Methods
		7.7 Effect on Lung Deposition
		References
Section III Novel Technologies
	Chapter 8 Recent Advances in Inhalable Nanomedicine for Lung Cancer Therapy
		8.1 Cancer Epidemiology
		8.2 Treatment Strategies
		8.3 Challenges Facing Localized Drug Delivery
		8.4 Aerosol Drug Delivery Devices
		8.5 Applications of Inhalable Nanoparticle-Based Drug for Lung Cancer
			8.5.1 Inhalable Nebulized Nanosuspension
			8.5.2 Inhalable Protein Nanocomposites
			8.5.3 Inhalable Lipid Nanocomposites
			8.5.4 Inhalable Drug-Polymer Nano-Conjugates
			8.5.5 Inhalable Nano-in-Porous Microparticles
			8.5.6 Inhalable Flocculated Nano-Agglomerates
			8.5.7 Inhalable Mucoadhesive Nanoparticles
			8.5.8 Inhalable Hierarchical Multi-Stage Target Nanoparticles
			8.5.9 Inhalable Lung Surfactant-Mimic Nanocarriers
			8.5.10 Inhalable Gene Nanocarriers
			8.5.11 Inhalable Nano-Theranostics
		8.6 Challenges and Limitations
		8.7 Conclusion and Future Directions
		8.8 Financial and Competing Interest Disclosure
		References
	Chapter 9 Thin-Film Freeze-Drying Process for Versatile Particles for Inhalation Drug Delivery
		9.1 Introduction
		9.2 Applications of TFFD to Pulmonary Delivery
			9.2.1 Brittle-Matrix Powders Made by TFFD Are Suitable for Pulmonary Delivery via Nebulizers, Pressurized Metered Dose Inhalers, and Dry Powder Inhalers
				9.2.1.1 Inhaled drug delivery via nebulizers
				9.2.1.2 Inhaled drug delivery via pressurized metered dose inhalers (pMDI)
				9.2.1.3 Inhaled drug delivery via dry powder inhalers (DPI)
			9.2.2 Surface Texture Modification to Improve Aerosolization by Nanocrystalline Aggregates
			9.2.3 TFFD Production of Homogeneous Drug Particles in Powder
			9.2.4 Enhancement of Drug Absorption and Bioavailability in the Lungs Using TFFD Amorphous Drug Powders
			9.2.5 TFFD Application for Biologics as Dry Powders for Inhalation
		9.3 Processing Design Spaces of TFFD Process Influence the Properties of the Formulations
			9.3.1 Effect of Excipients on Physicochemical and Aerodynamic Properties of TFFD Powders
				9.3.1.1 Lactose
				9.3.1.2 Mannitol
				9.3.1.3 Trehalose
				9.3.1.4 Sucrose
				9.3.1.5 Leucine
			9.3.2 Solid Loading and Aerodynamic Properties of TFFD Formulations
			9.3.3 Drug Loading Affects Particle Morphology and Aerosolization
			9.3.4 Processing Temperature and Supercooling
			9.3.5 Effect of Solvents on Morphology and Aerosol Properties
		9.4 Delivery of TFFD powders to the lung as DPI relies on loading dose, device, and flow rates
			9.4.1 Loading Dose
			9.4.2 Device and Flow Rates
		9.5 Conclusion
		Conflicts of Interest
		References
	Chapter 10 Nanoparticles as Specific Drug Carriers
		10.1 Introduction
		10.2 Polymeric Nanoparticles
			10.2.1 Natural Polymers
			10.2.2 Synthetic Polymers
		10.3 Lipid Nanoparticles
		10.4 Cellulose Nanocrystals
		10.5 Carbon Nanoparticles
			10.5.1 Fullerene
			10.5.2 Nanodiamond
			10.5.3 Graphene
			10.5.4 Carbon Nanotube
			10.5.5 Final Considerations on the Use of Carbon Nanoparticles
		10.6 Inorganic Nanoparticles
			10.6.1 Silica Nanoparticles
			10.6.2 Calcium Phosphate Nanoparticles
		10.7 Metallic and Magnetic Nanoparticles
			10.7.1 Gold Nanoparticles
			10.7.2 Silver Nanoparticles
			10.7.3 Zinc Oxide Nanoparticles
			10.7.4 Magnetic Nanoparticles
		10.8 Conclusions and Future Perspectives
		Bibliography
Section IV Advancing Established Technologies
	Chapter 11 Surface Modification of Micronized Drug Particles for Aerosolization
		11.1 Introduction
		11.2 Mechanism of Particle Deposition in the Lungs
			11.2.1 Primary Mechanisms of Particle Deposition
				11.2.1.1 Inertial impaction
				11.2.1.2 Gravitational sedimentation
				11.2.1.3 Other deposition mechanisms
		11.3 Particle Engineering for Lung Delivery
			11.3.1 Sugar Carrier-Based Surface Engineering
			11.3.2 Amino Acid-Based Surface Engineering
			11.3.3 Cyclodextrin-Based Surface Engineering
			11.3.4 Miscellaneous
		11.4 Conclusions and Future Perspectives
		Conflict of Interest
		Acknowledgement
		References
	Chapter 12 Spray Dried Particles for Inhalation
		12.1 Introduction
		12.2 Spray Drying Technology
			12.2.1 Influence of Processing Parameters
				12.2.1.1 Inlet temperature
				12.2.1.2 Outlet temperature
				12.2.1.3 Feed concentration and viscosity
				12.2.1.4 Miscellaneous properties
		12.3 Spray Dried Particles for Inhalation
			12.3.1 Excipients
			12.3.2 Active Pharmaceutical Ingredients
			12.3.3 siRNA
			12.3.4 Vaccines
		12.4 Lab Scale vs Industrial Scale
		12.5 Inhalation Devices
		12.6 Commercial Products and Market
		12.7 Challenges and Future Perspectives
		12.8 Conclusions
		Acknowledgements
		References
	Chapter 13 Inhalation Aerosol Phospholipid Particles for Targeted Lung Delivery
		13.1 Introduction
		13.2 Lung Anatomy and Physiology
		13.3 Lung Lining Fluid and Endogenous Phospholipids
		13.4 Lung Surfactant Replacement Therapy
		13.5 Phospholipids in Inhalation Formulations
		13.6 Phospholipid-Based Drug Delivery Systems
			13.6.1 Liposomes for Pulmonary Delivery
			13.6.2 Proliposomes for Pulmonary Delivery
		13.7 Engineering of Phospholipid Microparticulate Dry Powder Formulations
			13.7.1 Spray Drying
			13.7.2 Spray Freeze-Drying
			13.7.3 Freeze Drying
			13.7.4 Supercritical Anti-Solvent Technique
		13.8 Conclusion
		References
	Chapter 14 Nebulizers
		14.1 Introduction
		14.2 Conditions Treated with Nebulizer Therapy
		14.3 Operating Principles
			14.3.1 Jet Nebulizers
				14.3.1.1 Continuous output
				14.3.1.2 Breath-enhanced
				14.3.1.3 Breath-actuated
			14.3.2 Ultrasonic Nebulizers
			14.3.3 Mesh Nebulizers
		14.4 Smart Nebulizers
		14.5 Patient Factors Affecting Drug Delivery from Nebulizers
		14.6 Drug Delivery in Patients Receiving Ventilatory Support
			14.6.1 Heated High-Flow Nasal Cannula
			14.6.2 Noninvasive Mechanical Ventilation
			14.6.3 Tracheostomy
			14.6.4 Invasive Mechanical Ventilation
		14.7 Precautions for Use of Nebulizers in the Era of COVID-19
		14.8 Unmet Needs
		References
	Chapter 15 Protein and Peptide Delivery to the Lung via Inhalation
		15.1 Introduction
		15.2 Challenges in the Development of Protein Therapeutics for Pulmonary Delivery
			15.2.1 Airway Epithelium
			15.2.2 Alveolar Epithelium
			15.2.3 Mucociliary Clearance
			15.2.4 Dissolution Rate and Enzyme Degradation in the Lung Fluid
		15.3 Mechanism for Pulmonary Delivery
			15.3.1 Aerosol Deposition Mechanisms
				15.3.1.1 Impaction (inertial deposition)
				15.3.1.2 Sedimentation (gravitational deposition)
				15.3.1.3 Diffusion
				15.3.1.4 Interception
				15.3.1.5 Electrostatic precipitation
			15.3.2 Mechanism of Protein Release from Particles
				15.3.2.1 Diffusion-controlled release
				15.3.2.2 Solvent-controlled release
				15.3.2.3 Degradation-controlled release
				15.3.2.4 Permeation controlled release
				15.3.2.5 Stimuli-controlled release
			15.3.3 Manufacturing Techniques of Making Particulate Matter for Lung Delivery
				15.3.3.1 Nebulizers
				15.3.3.2 Pressurized metered-dose inhalers (pMDIs)
				15.3.3.3 Dry powder inhalers (DPIs)
				15.3.3.4 Soft mist inhaler (SMI)
			15.3.4 Types of Carriers Used for Pulmonary Delivery
				15.3.4.1 Lactose and other Sugars
				15.3.4.2 Lipids
				15.3.4.3 Biodegradable polymers
		15.4 Experimental Models for Testing Inhaled Particle Transport in Lung Airways
			15.4.1 Cell Culture Models
			15.4.2 Ex Vivo Isolated Perfused Lung Model
			15.4.3 Preclinical Model
		15.5 Peptide and Protein in Pulmonary Delivery
			15.5.1 Suitable Conditions for Pulmonary Delivery
				15.5.1.1 Diabetes mellitus
				15.5.1.2 Hormone disorder
				15.5.1.3 Osteoporosis
				15.5.1.4 Multiple sclerosis
			15.5.2 For Respiratory Diseases
				15.5.2.1 Infection for Viral Infections
				15.5.2.2 Cystic Fibrosis
			15.5.3 Immunotherapy
		15.6 Approaches to Enhance the Inhalation and Lung Deposition of Protein Therapeutics
		15.7 Concluding Remarks
		References
	Chapter 16 Exosomes-Based Drug Delivery for Lung Cancer Treatment
		16.1 Introduction
		16.2 Extracellular Vesicles
		16.3 Exosomes
			16.3.1 Exosomes as Drug Carrier
			16.3.2 Exosomes-Based Drug Delivery for Lung Cancer
		16.4 Challenges in Advancing Exosome-Based Therapeutics
		16.5 Conclusions
		Acknowledgements
		Conflict of interest
		References
Index