Respiratory Delivery of Biologics, Nucleic Acids, and Vaccines (AAPS Introductions in the Pharmaceutical Sciences, 8)

Preface
Contents
About the Editors
Design Strategies of Dry Powders for Pulmonary Delivery of Pharmaceutical Peptides
	1 Introduction
	2 Factors Affecting Peptide Stability in Manufacturing Process
		2.1 pH
		2.2 Temperature
		2.3 Oxidative Stress
		2.4 Excipients
	3 Biological Barriers
	4 Production and Design of Peptide-Load Inhalable Particles for DPI
		4.1 Preparation Method
			4.1.1 Top-Down Method
			4.1.2 Bottom-Up Method
		4.2 Excipients to Enhance Stability of Peptides
	5 Pulmonary Delivery Strategies for Therapeutic Peptides
		5.1 Adjusting Mucodiffusiveness
		5.2 Stabilization by Chemical Modification and Derivatization
		5.3 Encapsulation into Micro/Nanocarrier Particles
	6 Conclusion
	References
Pulmonary Delivery of Antibody for the Treatment of Respiratory Diseases
	1 Introduction
	2 Stability of Antibodies During Aerosolization
		2.1 Aggregation as a Marker of Ab Stability
		2.2 Importance of the Device
		2.3 Importance of the Formulation
		2.4 Consequences of Antibody Instability During Aerosolization
	3 PK of Inhaled Ab
		3.1 Fate of Abs After They Deposit into the Pulmonary Tract
			3.1.1 Lung Absorption
			3.1.2 Lung Exposure
		3.2 Lung Clearance
			3.2.1 Mucociliary Barrier
			3.2.2 Surfactant Barrier
			3.2.3 Proteolytic Microenvironment
			3.2.4 Endogenous Catabolism
	4 Development of Inhaled Ab
		4.1 Inhaled Abs Used for the Treatment of Respiratory Infections
			4.1.1 ALX-0171 and Anti-RSV Ab
			4.1.2 Anti-influenza Abs
			4.1.3 Anti-SARS-CoV-2 Abs
			4.1.4 Anti-Pseudomonas aeruginosa Abs
		4.2 Inhaled Abs Used for the Treatment of Inflammatory Respiratory Diseases
			4.2.1 Inhaled Abs for the Treatment of Asthma
			4.2.2 Inhaled Abs for the Treatment of Acute Lung Injury
	5 Conclusion
	References
Dry Powder Formulation of Monoclonal Antibodies for Pulmonary Delivery
	1 Introduction and Background
	2 Manufacturing Process Overview
		2.1 Spray Drying
		2.2 Alternate Manufacturing Processes
	3 Formulation of Spray-Dried Inhaled MAbs
		3.1 Stabilizing Excipients
			3.1.1 Stabilizing Sugars
			3.1.2 Stabilizing Amino Acids
		3.2 Surface-Active Excipients
		3.3 Interaction of Spray-Drying Process and Formulation
		3.4 Spray-Drying Scale-Up
		3.5 Device and Packaging
	4 Preclinical and Clinical Case Studies
	5 Outlook and Conclusions
	References
Antimicrobial Peptides and Proteins for Inhalation
	1 Introduction to Antimicrobial Peptides and Proteins Inhalation Therapy
	2 Commercial and Off-Label Inhaled APPs
		2.1 Colistin
		2.2 Vancomycin
	3 Clinical Trial Stage Products
		3.1 Lactoferrin
	4 Research Stage Studies
		4.1 Strategies in Stabilizing and Enhancing Antimicrobial Peptides and Proteins for Inhalation
			4.1.1 Enantiomeric Optimization
			4.1.2 Dendrimer Synthesis
			4.1.3 Prodrug Peptides
			4.1.4 Peptide Sequence Optimization
			4.1.5 Use of Host Antimicrobial Capacity Enhancer APPs
			4.1.6 Inhalable Combination Formulations
		4.2 Strategies in Improving Aerosol Properties of APP Inhalation Formulations
			4.2.1 New Nebulizers for Biologics
			4.2.2 Spray Drying and Spray Freeze Drying
			4.2.3 Hydrogel
			4.2.4 Liposomal Formulation
			4.2.5 Nanoparticles
			4.2.6 Mesoporous Silica Particles
	5 Future Direction and Perspective
	References
Pulmonary Delivery of Nucleic Acids
	1 Introduction
	2 Nucleic Acid Therapeutics for Inhalation
		2.1 Antisense Oligonucleotide (ASO)
		2.2 MicroRNA (miRNA)
		2.3 Small Interfering RNA (SiRNA)
		2.4 Messenger RNA (mRNA)
		2.5 CRISPR/Cas
	3 Overcoming Lung Barriers to Nucleic Acids for Inhalation
		3.1 Noncellular Barriers
		3.2 Cellular Barriers
		3.3 Endosomal Escape: Intracellular Level
	4 Engineered Nanoplatforms for Nucleic Acid Inhalation: The Case of RNA-Based Therapeutics
		4.1 Lipid-Based Nanoplatforms
		4.2 Polymer-Based Nanoplatforms
		4.3 Hybrid Lipid/Polymer Nanoplatforms
		4.4 Bioinspired Nanoplatforms
		4.5 Inhaled mRNA Nanovaccines
	5 Development of Dosage Forms for Lung Delivery (Nebulization, pMDIs, DPIs)
	6 Summary and Outlook
	References
Intranasal and Inhaled Vaccines
	1 Background
	2 Principles of Intranasal and Inhaled Vaccines
		2.1 Tissue-Specific Mucosal Immune Response
		2.2 Common Mucosal Immune System
		2.3 Systemic Immunogenicity
	3 Social and Economic Benefits of Intranasal and Inhaled Vaccines
	4 Challenges and Limitations of Intranasal and Inhaled Vaccines
		4.1 Vaccine Adjuvants and Formulation Design
		4.2 Dose Variability and Administration Device
		4.3 Preclinical and Clinical Studies, and Inadequate Public Recognition
		4.4 Vaccine Manufacture
	5 Summary
	References
Respiratory Delivery of Probiotics to Improve Lung Health
	7.1 Microbiome of the Lungs
		7.1.1 Gut-Lung Axis
		7.1.2 Asthma and Differences in the Lung Microbiome
		7.1.3 Different Sampling Methods of the Lung Microbiome
		7.1.4 Geographical Differences
		7.1.5 Dysbiosis of the Lung Microbiome and Respiratory Diseases
	7.2 Effects of Probiotics on Respiratory Infections
		7.2.1 Possible Mechanisms of Probiotics Against Viral Infections
		7.2.2 Safety of Probiotics in the Human Respiratory Tract
	7.3 Intranasal Delivery of Probiotics
	7.4 Formulating Probiotics for Lung Delivery
	7.5 Conclusion
	References
Respiratory Delivery of Bacteriophages for the Treatment of Lung Infections
	8.1 Introduction
	8.2 Inhaled Phages Against MDR Pathogens
		8.2.1 Staphylococcus aureus
		8.2.2 Klebsiella pneumoniae
		8.2.3 Acinetobacter baumanni
		8.2.4 Pseudomonas aeruginosa
		8.2.5 Mycobacterium tuberculosis
	8.3 Phage Synergy
	8.4 Immune Responses Induced by Respiratory-Delivered Phages
	8.5 Formulations and Stability
		8.5.1 Liquid Aerosols
		8.5.2 Dry Powder Aerosols
	8.6 Future Directions
	References
Pharmacokinetics of Inhaled Medications – What Do We Know About Biological Macromolecules?
	1 Introduction
	2 Key Determinants of Pulmonary PK
		2.1 Pulmonary Physiology
		2.2 Pulmonary PK Processes: Absorption, Distribution, Metabolism and Elimination (ADME)
			2.2.1 Pulmonary Deposition
			2.2.2 Pulmonary Dissolution
			2.2.3 Absorption
			2.2.4 Distribution
			2.2.5 Metabolism
			2.2.6 Elimination
			2.2.7 Key Factors That Determine the PK of Inhaled Biological Macromolecules
		2.3 Animal-Based Inhalation Model for Clinical Development of Inhaled Biological Macromolecules
		2.4 Modeling and Simulation Tools
			2.4.1 Deposition Models
				Empirical Deposition Correlations Based on In Vivo Data
				Generational Deposition Models
			2.4.2 PK Models
				Physiologically-Based PK Models
					The GastroPlus™ Additional Dosage Routes Module
					PulmoSim™
				Data-Driven PK/PD Approaches
	3 Summary
	References
Index