Oral Delivery of Therapeutic Peptides and Proteins

Front Cover
Oral Delivery of Therapeutic Peptides and Proteins
Copyright Page
Contents
List of contributors
About the editors
Foreword
Preface
Acknowledgments
1. Landscape for oral delivery of peptides
	1.1 Introduction
	1.2 Barriers to oral delivery of peptides
	1.3 Strategies to improve the oral bioavailability of peptides
		1.3.1 Transient permeation enhancers
			1.3.1.1 Industrial development perspective of transient permeation enhancers
		1.3.2 Oral nanoparticles for peptide delivery
			1.3.2.1 Background and introduction
			1.3.2.2 Polymeric nanoparticles
			1.3.2.3 Inorganic nanoparticles
			1.3.2.4 Lipid-based nanoparticles
			1.3.2.5 Nanoparticle formulations to have reached clinical trials
			1.3.2.6 Industrial development perspective of oral nanoparticles for peptide delivery
		1.3.3 Transporter-mediated oral peptide drug delivery
			1.3.3.1 Molecular targeting of PepT1 to increase intestinal absorption
			1.3.3.2 Industrial development perspective of transporters
			1.3.3.3 Transporter-targeted nanoparticle delivery
			1.3.3.4 Industrial development perspective of transporter-targeted nanoparticles
		1.3.4 Ingestible injection devices
			1.3.4.1 Microneedles
			1.3.4.2 Jet capsules
			1.3.4.3 Industrial development perspective of ingestible injectable devices
	1.4 Progress versus an oral peptide target product profile
	Acknowledgments
	References
2. Design and synthesis of chemically modified peptides and proteins —critical considerations for oral delivery
	2.1 Introduction
	2.2 Enzymatic barriers to absorption of intact peptides and proteins
	2.3 Overcoming renal clearance of unmodified peptides
	2.4 Peptide design considerations to improve oral bioavailability
		2.4.1 Improving stability of peptide drugs in the GI tract
			2.4.1.1 Substitution of sequence liabilities
			2.4.1.2 Global modifications to improve metabolic stability
		2.4.2 Optimizing membrane permeability
		2.4.3 Disulfide bond surrogates
		2.4.4 Reducing elimination of peptide drugs in the circulation
	2.5 Rybelsus, an oral semaglutide formulation, a short case study
	2.6 Conclusions
	References
3. A biopharmaceutics perspective on oral peptide developability and drug delivery
	3.1 Introduction
	3.2 Lessons learned from small molecule developability
		3.2.1 Solubility
		3.2.2 Permeability
		3.2.3 Stability
		3.2.4 Ionization
		3.2.5 Inter- and intramolecular interactions
	3.3 Barriers to oral peptide delivery
		3.3.1 Biochemical barriers
		3.3.2 Cellular barrier
		3.3.3 Physicochemical properties of therapeutic peptides
	3.4 Chemistry approaches to oral peptide developability
		3.4.1 Amino acid sequence
		3.4.2 Peptide cyclization
		3.4.3 Hydrophobic modifications
		3.4.4 Nonnatural amino acids
		3.4.5 Examples of chemically modified peptide analogs
			i Somatostatin analogs
			ii GLP-1 analogs
	3.5 Formulation approaches for peptide developability
		3.5.1 Modulation of flux
		3.5.2 Enteric coatings
		3.5.3 Protease inhibitors
		3.5.4 Permeation enhancers
		3.5.5 Lipid-based formulations
		3.5.6 Novel transport-mediated uptake
	3.6 In silico and in vitro models
		3.6.1 In silico methods
		3.6.2 Characterization of peptide conformation and aggregation
		3.6.3 In vitro stability assessment
		3.6.4 In vitro permeability and flux measurements
	3.7 Outlook
		3.7.1 Reevaluating patient preferences
		3.7.2 Inter- and intraspecies variability
		3.7.3 Rationale design of a successful oral peptide product
	Acknowledgments
	References
4. Nanoparticle-assisted oral delivery of small and large peptides
	4.1 Introduction
	4.2 Insulin
	4.3 Cyclosporine
	4.4 Calcitonin
	4.5 Exenatide
	4.6 Future perspectives
	Acknowledgments
	References
5. Novel formulation approaches for gastrointestinal targeting: characterization and animal model considerations
	5.1 Introduction
	5.2 Oral route and human gastrointestinal anatomy (general physiological considerations for colonic drug delivery)
		5.2.1 Intraluminal pH of the human gastrointestinal tract
		5.2.2 Gastrointestinal motility
		5.2.3 Gastric emptying time, small intestine, and colonic transit time
	5.3 Formulation strategies for colon-targeted drug delivery
		5.3.1 Time-delayed systems
			5.3.1.1 Multiparticulate systems
			5.3.1.2 Capsules
			5.3.1.3 Tablets
		5.3.2 pH-dependent drug delivery systems
		5.3.3 Enzyme-sensitive drug delivery systems
			5.3.3.1 Polysaccharide-based systems
			5.3.3.2 Phloral technology
	5.4 Animal models for targeted oral formulations
		5.4.1 General considerations
			5.4.1.1 Use of anesthetic
			5.4.1.2 Circadian considerations
		5.4.2 Gastrointestinal considerations
			5.4.2.1 Gastrointestinal transit and forces
			5.4.2.2 Gastrointestinal pH and fluid composition
			5.4.2.3 Mucosal considerations
			5.4.2.4 Bacteria
	5.5 Conclusion
	References
6. CMC Considerations for conventional oral peptide formulations. Scale up and validation
	6.1 Introduction
	6.2 Chemistry, manufacturing, and controls
		6.2.1 Drug product considerations
			6.2.1.1 Drug formulation considerations
		6.2.2 Manufacturing process considerations
			6.2.2.1 Multiparticulates
			6.2.2.2 Capsules—granule or powder fill
			6.2.2.3 Tablets
			6.2.2.4 Process validation
		6.2.3 Quality control release testing, stability, and specifications
			6.2.3.1 Peptide drug substance testing
			6.2.3.2 Drug product testing
		6.2.4 Manufacturing facility considerations
			6.2.4.1 Facility design
			6.2.4.2 Facility qualification
			6.2.4.3 Facility operation and maintenance
	6.3 Typical challenges in chemistry, manufacturing, and controls
	References
7. Clinical translation of oral peptide delivery technologies
	7.1 Introduction
	7.2 Clinically translated oral peptides
		7.2.1 Salmon calcitonin
		7.2.2 Octreotide
		7.2.3 Parathyroid hormone
		7.2.4 Insulin
		7.2.5 Semaglutide
	7.3 Potential reasons for variable bioavailability in translational studies
		7.3.1 Variability in GI parameters between human subjects
			7.3.1.1 Surface area
			7.3.1.2 Motility and resulting exposure
			7.3.1.3 Intestinal permeability
			7.3.1.4 Absorption site transition time
			7.3.1.5 Gastric volume
			7.3.1.6 Gastric mucus
		7.3.2 Variability in intestinal and gastric pH
		7.3.3 Effects of gastric emptying
		7.3.4 Effect of food (meal and water intake)
		7.3.5 Effect of peptidases
	7.4 Future directions
	References
8. Regulatory aspects of oral peptide delivery
	8.1 Basis of regulation and regulatory framework
	8.2 Investigational studies under an IND
	8.3 Pre-IND meeting
	8.4 Investigational new drug application
	8.5 Chemistry, manufacturing, and controls regulatory requirements
		8.5.1 Drug substance
			8.5.1.1 Nomenclature
			8.5.1.2 Structure
			8.5.1.3 General properties
			8.5.1.4 Manufacturer(s)
			8.5.1.5 Description of the manufacturing process and process controls
			8.5.1.6 Control of materials
			8.5.1.7 Process validation
			8.5.1.8 Manufacturing process development
			8.5.1.9 Characterization of the drug substance
			8.5.1.10 Impurities
			8.5.1.11 Specifications
			8.5.1.12 Analytical procedures: description and validation
			8.5.1.13 Batch analyses
			8.5.1.14 Justification of specifications
			8.5.1.15 Reference standards
			8.5.1.16 Container closure system
			8.5.1.17 Stability
		8.5.2 Drug product
			8.5.2.1 Description and composition of the drug product
			8.5.2.2 Pharmaceutical development
			8.5.2.3 Manufacturer(s)
			8.5.2.4 Batch formula
			8.5.2.5 Description of the manufacturing process and process controls
			8.5.2.6 Control of critical steps and intermediates
			8.5.2.7 Process validation and evaluation
			8.5.2.8 Control of excipients
			8.5.2.9 Novel excipients
			8.5.2.10 Specifications
			8.5.2.11 Analytical procedures: description and validation
			8.5.2.12 Batch analyses
			8.5.2.13 Justification of specifications
			8.5.2.14 Reference standards
			8.5.2.15 Container closure system
			8.5.2.16 Stability
	8.6 Nonclinical requirements
	8.7 Pharmacology
	8.8 Pharmacokinetics
	8.9 Toxicology
		8.9.1 Safety pharmacology studies
		8.9.2 Toxicokinetic studies
		8.9.3 Acute toxicity studies
		8.9.4 Repeat-dose toxicity studies
		8.9.5 Immunogenicity studies
	8.10 Clinical requirements
	8.11 Drug–drug interactions
	8.12 Immunogenicity
	8.13 Regulatory affairs
	8.14 Regulatory meetings
	8.15 Marketing authorization
	8.16 Pre-NDA meeting
	8.17 NDA/MAA submission
		8.17.1 Module 1: administrative information
		8.17.2 Module 2: summaries
		8.17.3 Module 3: quality
		8.17.4 Drug substance
			8.17.4.1 General information
			8.17.4.2 Manufacture
			8.17.4.3 Characterization of the drug substance
			8.17.4.4 Control of the drug substance
			8.17.4.5 Reference standards
			8.17.4.6 Container closure system
			8.17.4.7 Stability
		8.17.5 Drug product
			8.17.5.1 Description and composition of the drug product
			8.17.5.2 Pharmaceutical development
				8.17.5.2.1 Components of the drug product
				8.17.5.2.2 Formulation development
				8.17.5.2.3 Manufacturing process development
				8.17.5.2.4 Container closure system
				8.17.5.2.5 Microbiological attributes
				8.17.5.2.6 Compatibility
			8.17.5.3 Manufacture
				8.17.5.3.1 Batch formula
				8.17.5.3.2 Description of manufacturing process and process controls
				8.17.5.3.3 Control of critical steps and intermediates
				8.17.5.3.4 Process validation and evaluation
			8.17.5.4 Control of excipients
			8.17.5.5 Control of drug product
				8.17.5.5.1 Specifications
				8.17.5.5.2 Analytical procedures: description and validation
				8.17.5.5.3 Batch analyses
			8.17.5.6 Characterization of impurities
			8.17.5.7 Justification of specifications
			8.17.5.8 Reference standards
			8.17.5.9 Container closure system
			8.17.5.10 Stability
		8.17.6 Module 4: nonclinical
		8.17.7 Module 5: clinical
	8.18 Drug–drug interactions
	8.19 Immunogenicity
	References
Index
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