Fundamentals of Drug Delivery

Cover
Title Page
Copyright
Contents
Preface
List of Contributors
Part I Product Design, the Essence of Effective Therapeutics
	Chapter 1 Challenges and Innovations of Controlled Drug Delivery
		1.1 Background
		1.2 Parenteral Dosage Forms
			1.2.1 Intravenous Route (IV)
			1.2.2 Intramuscular Route (IM)
			1.2.3 Subcutaneous Route (SC)
			1.2.4 Other Parenteral Routes
		1.3 Oral Route and Delivery Systems
		1.4 Nasal Drug Delivery
		1.5 Pulmonary Drug Delivery
		1.6 Transdermal Drug Delivery
		1.7 Ocular Drug Delivery
		1.8 Drug Delivery System Development Process
		1.9 Conclusion
		References
	Chapter 2 Challenges in Design of Drug Delivery Systems
		2.1 Drug Properties to be Considered in Design of Controlled Release Products
		2.2 Physicochemical Factors that Need to be Considered in Design of CRDDS
			2.2.1 Dose Size
			2.2.2 Molecular Weight/Size
			2.2.3 Aqueous Solubility
			2.2.4 Lipid Solubility and Partition Coefficient
			2.2.5 Physicochemical Stability
		2.3 Biopharmaceutical Properties that Deserve Consideration in Design of Controlled Release Products
			2.3.1 Biological Half‐life
			2.3.2 Absorption
			2.3.3 Metabolism
			2.3.4 Presystemic Clearance
			2.3.5 Margin of Safety
			2.3.6 Adverse Effects
			2.3.7 Therapeutic Need
			2.3.8 Role of Circadian Rhythm
		2.4 Conclusion
		References
	Chapter 3 Drug Delivery of the Future (?)
		3.1 Introduction
		3.2 Therapeutic Indicators
		3.3 Drugs of the Future
		3.4 Delivering the Drugs of the Future
		3.5 A View to the Longer Term?
		3.6 Conclusion
		References
	Chapter 4 The Pharmaceutical Drug Development Process: Selecting a Suitable Drug Candidate
		4.1 The Oral Drug Candidate: How to Get There and Questions to Answer
		4.2 Challenges for Selecting a Topical Drug Candidate
		4.3 Percutaneous Flux as a Surrogate Measurement of Skin Tissue Concentration
		4.4 Learnings from Past Topical Drug Development of Factors Affecting Efficacy
		4.5 Dermal Pharmacokinetics/Pharmacodynamics
		4.6 Assessment of Systemic Exposure
		4.7 Screening Cascade Approach to Select a Dermal Drug Candidate
			4.7.1 Efficacy (Lack of Target Engagement)
			4.7.2 Developability
			4.7.3 Local Safety
			4.7.4 Systemic Safety
		4.8 Opportunities for Repurposing Molecules into Dermally Active Treatments for Cosmeceutical or Pharmaceutical Approaches
		4.9 Conclusion
		References
	Chapter 5 Preformulation and Physicochemical Characterization Underpinning the Development of Controlled Drug Delivery Systems
		5.1 When Is a Controlled Drug Delivery System Needed?
		5.2 Optimizing Drug Characteristics
		5.3 Defining the Product Profile
		5.4 Preformulation and Physicochemical Characterization Underpinning Development of CDD
			5.4.1 Feasibility and Risk Assessment
			5.4.2 Solubility and Dissolution Rate
			5.4.3 Permeability
			5.4.4 Drug and Drug Product Particle Sizes
			5.4.5 Solid‐State Chemistry
				5.4.5.1 Crystallinity and Polymorphism
				5.4.5.2 Salts
			5.4.6 Stability
			5.4.7 Excipient Compatibility
			5.4.8 Bulk Powder Properties
			5.4.9 Drug Metabolism and Pharmacokinetic Modeling
				5.4.9.1 Guiding the Design of CDD Dosage Forms
				5.4.9.2 Establishing In Vitro–In Vivo Correlation (IVIVC)
				5.4.9.3 Physiologically Based Pharmacokinetic (PBPK) Modeling Tools
		5.5 Conclusion
		References
	Chapter 6 Mathematical Models Describing Kinetics Associated with Controlled Drug Delivery Across Membranes
		6.1 Introduction
			6.1.1 General Description
			6.1.2 Governing Equations
				6.1.2.1 Differential Equations
				6.1.2.2 Dimensionless Differential Equations
				6.1.2.3 Initial and Boundary Conditions
			6.1.3 Other Derived Quantities
			6.1.4 Dimensionless Variables and Groups
		6.2 Model Solutions
			6.2.1 Type A Models – Well‐Stirred Vehicle on One Membrane
				6.2.1.1 Model A1
				6.2.1.2 Model A2
				6.2.1.3 Model A3
				6.2.1.4 Model A4
				6.2.1.5 Model A5
				6.2.1.6 Model A6
				6.2.1.7 Model A7
				6.2.1.8 Model A8
				6.2.1.9 Model A9
				6.2.1.10 Model A9a
				6.2.1.11 Model A9b
				6.2.1.12 Model A10
				6.2.1.13 Model A11
				6.2.1.14 Model A12
				6.2.1.15 Model A13
			6.2.2 Type B Models – Unstirred Semi‐infinite Vehicle on One Membrane
				6.2.2.1 Model B1
				6.2.2.2 Model B2
			6.2.3 Type C – Well Stirred Vehicle on Two Membranes in Series
				6.2.3.1 Model C1
		6.3 Solution Methods
			6.3.1 Separation of Variables Solutions
				6.3.1.1 Separating the Partial Differential Equation of N Independent Variables into N Ordinary Differential Equations
				6.3.1.2 Choosing the Sign (Positive or Negative) on the Separation Constant
				6.3.1.3 Finding the Constants of Integration and the Eigenvalues
				6.3.1.4 Superposition
				6.3.1.5 Finding the Remaining Constants of Integration
				6.3.1.6 Guidelines for Using Separation of Variable Methods to Solve Partial Differential Equations
				6.3.1.7 Methods for Making a Nonhomogeneous Partial Differential Equation or Nonhomogeneous Boundary Conditions Homogeneous
				6.3.1.8 Choosing the Index Starting Value on the Sum of All Solutions (i.e. should n = 1 or 0?)
			6.3.2 Laplace Transform Solutions
				6.3.2.1 Using Laplace Transforms to Determine Lag Times, Steady‐state Values and Other Derived Quantities
				6.3.2.2 Inversion of Laplace Transformed Functions to Time Domain Functions by Method of Residues
				6.3.2.3 Example A – Model A1
				6.3.2.4 Example B – Model A10
			6.3.3 Useful Identities
		References
	Chapter 7 Understanding Drug Delivery Outcomes: Progress in Microscopic Modeling of Skin Barrier Property, Permeation Pathway, Dermatopharmacokinetics, and Bioavailability
		7.1 Introduction
		7.2 Governing Equation
			7.2.1 Homogenized Model
			7.2.2 Microscopic Model
				7.2.2.1 Solute Diffusion in SC Lipid
				7.2.2.2 Solute Diffusion in SC Corneocytes
				7.2.2.3 Solute Diffusion in Appendages
			7.2.3 Numerical Methods
		7.3 Input Parameters
			7.3.1 SC Microstructure
			7.3.2 SC Lipid–Water Partition
			7.3.3 Diffusivity in SC Lipids
			7.3.4 Binding to Keratin
			7.3.5 Diffusivity in Corneocytes
			7.3.6 Solute Diffusivity and Partition in Sebum
		7.4 Application
			7.4.1 Steady‐State
			7.4.2 Dermatopharmacokinetics
			7.4.3 Systemic Pharmacokinetics
			7.4.4 Shunt Pathway
		7.5 Perspective
		References
	Chapter 8 Role of Membrane Transporters in Drug Disposition
		8.1 Introduction
		8.2 Distribution of Major Drug Transporters in Human Tissues
			8.2.1 Major Drug Transporters in the Intestine
				8.2.1.1 Drug Transporters Expressed in the Apical (Luminal) Membrane
				8.2.1.2 Drug Transporters Expressed in the Basolateral Membrane
				8.2.1.3 Expression of Drug Transporters in Different Intestinal Regions
			8.2.2 Major Drug Transporters in the Liver
				8.2.2.1 Drug Transporters Expressed in the Apical Membrane of Hepatocytes
				8.2.2.2 Drug Transporters Expressed in the Basolateral (Sinusoidal) Membrane of Hepatocytes
				8.2.2.3 Drug Transporters Expressed in the Bile Duct Epithelia (Cholangiocytes)
			8.2.3 Major Drug Transporters in the Kidney
				8.2.3.1 Drug Transporters Expressed in the Apical Membrane of Proximal Tubule Cells
				8.2.3.2 Drug Transporters Expressed in the Basolateral Membrane of Proximal Tubule Cells
			8.2.4 Major Drug Transporters in the Central Nervous System (CNS)
				8.2.4.1 Drug Transporters Expressed in the Capillary Endothelial Cells of BBB
				8.2.4.2 Drug Transporters Expressed in the Choroid Plexus Epithelial Cells of BCSFB
			8.2.5 Major Drug Transporters in Other Tissues
				8.2.5.1 Drug Transporters Expressed in Placenta Villi Epithelial Cells (Syncytiotrophoblasts)
				8.2.5.2 Drug Transporters Expressed in Mammary Glands
				8.2.5.3 Drug Transporters Expressed in the Blood–Testis‐Barrier (BTB)
		8.3 Role of Drug Transporters in Drug Disposition
			8.3.1 Role of P‐gp in Drug Disposition
			8.3.2 Role of BCRP in Drug Disposition
			8.3.3 Role of BSEP in Drug‐Induced Cholestatic Liver Injury
			8.3.4 Role of MRPs (MRP2, MRP3, and MRP4) in Drug Disposition
			8.3.5 Role of OATPs (OATP1B1, OATP1B3, and OATP2B1) in Drug Disposition
			8.3.6 Role of OATs (OAT1 and OAT3) in Drug Disposition
			8.3.7 Role of OCTs (OCT1 and OCT2)/MATEs (MATE1 and MATE2‐K) in Drug Disposition
		8.4 Closing Remarks
		References
Part II Challenges in Controlled Drug Delivery and Advanced Delivery Technologies
	Chapter 9 Advanced Drug Delivery Systems for Biologics
		9.1 Introduction
		9.2 Considerations in Biologics Product Development
			9.2.1 Challenges Specific to the Route of Administration
			9.2.2 Challenges Related to Parenteral Administration
			9.2.3 Optimization of Dosage Regimens
		9.3 Administration Routes for Biologics Delivery
			9.3.1 Parenteral Route
			9.3.2 Oral Route
			9.3.3 Buccal Route
			9.3.4 Sublingual Route
			9.3.5 Pulmonary Route
				9.3.5.1 Additional Concerns in Pulmonary Delivery
			9.3.6 Intranasal Route
			9.3.7 Trans(dermal) Delivery
				9.3.7.1 Gene Delivery
				9.3.7.2 Vaccine Delivery
				9.3.7.3 Protein Delivery
			9.3.8 Dermal Delivery of Growth Hormones
			9.3.9 Vaginal Route
		9.4 Conclusion
		References
	Chapter 10 Recent Advances in Cell‐Mediated Drug Delivery Systems for Nanomedicine and Imaging
		10.1 Introduction
		10.2 Cell Types and Modification for Therapeutic Agent Delivery
			10.2.1 Cell Types
				10.2.1.1 Blood Cells
				10.2.1.2 Stem Cells
				10.2.1.3 Antigen Presenting Cells (APCs)
				10.2.1.4 Cell Membranes
			10.2.2 Cargo Loading Methods
		10.3 Imaging and Tracking of Cell‐Based Delivery Systems
			10.3.1 MRI
			10.3.2 PET
			10.3.3 X‐Ray Imaging
			10.3.4 Multimodal Imaging Techniques
		10.4 Cell‐Mediated Drug Delivery Systems for Disease Treatment
			10.4.1 Cancer Therapy
			10.4.2 Immunotherapy
			10.4.3 Brain‐Related Diseases
			10.4.4 Inflammatory Diseases
			10.4.5 Theranostic Application
			10.4.6 Others
		10.5 The Mechanism of Cell‐Mediated Delivery Systems for the Cell Therapies
			10.5.1 Detoxification
			10.5.2 Adhesive Mechanism
			10.5.3 Homing Mechanism
		10.6 The Administration Approach of Cell‐Assist Drug Delivery System
		10.7 Clinical Application of Cell‐Based Delivery Systems
		10.8 Conclusion and Outlook
		References
	Chapter 11 Overcoming the Translational Gap – Nanotechnology in Dermal Drug Delivery
		11.1 Nanotechnology – Failure or Future in Drug Delivery?
		11.2 Identification of the Clinical Need
		11.3 Nanoparticle Design and Physicochemical Characterization
		11.4 Biomedical Studies
			11.4.1 Atopic Dermatitis
			11.4.2 Psoriasis
			11.4.3 Ichthyosis
			11.4.4 Wound Healing
			11.4.5 Infections
			11.4.6 Skin Cancer
			11.4.7 Alopecia Areata
		11.5 Approaches to Fill the Translational Gaps in Nanotechnology
		References
	Chapter 12 Theranostic Nanoparticles for Imaging and Targeted Drug Delivery to the Liver
		12.1 Introduction
		12.2 The Types of Theranostic NPs
			12.2.1 Lipid‐ and Polymer‐Based NPs
			12.2.2 Mesoporous Silica NPs
			12.2.3 Bio‐nanocapsules
			12.2.4 Iron Oxide NPs
		12.3 Mechanisms of NPs Targeting the Liver
			12.3.1 Passive Targeting to the Liver
			12.3.2 Active Targeting to the Liver
			12.3.3 Strategies for Combining Passive and Active Targeting
		12.4 NPs in Liver Target Imaging
			12.4.1 NP‐Based Contrast Agents in Liver MRI
			12.4.2 NP‐Based Contrast Agents in Liver CT Imaging
			12.4.3 NPs for Near‐Infrared Fluorescence Imaging in Liver
		12.5 NPs for Therapeutic and Drug Delivery in Liver Disease
			12.5.1 NP Delivery System in HCC
			12.5.2 NP Delivery System in Non‐tumoral Liver Disease
		12.6 Theranostic NPs in Liver Diseases
		12.7 Conclusions
		References
	Chapter 13 Toxicology and Safety of Nanoparticles in Drug Delivery System
		13.1 Introduction
		13.2 Lipid‐Based Nanocarrier: Liposomes
		13.3 Cellular Uptake Mechanism of Liposomes
		13.4 Biodistribution, Clearance and Toxicity of Liposomes
			13.4.1 Effect of Lipid Compositions on Liposome Distribution and Blood Circulation
			13.4.2 Effect of Surface Charge on Liposome Distribution and Blood Circulation
			13.4.3 Effect of Size on Liposome Distribution and Blood Circulation
		13.5 Application of Liposomes in Drug Delivery
		13.6 Inorganic Nanocarrier: Carbon Nanotubes
		13.7 Cellular Uptake Mechanism of Carbon Nanotubes
		13.8 Biodistribution, Clearance, and Toxicity of Carbon Nanotubes
		13.9 Application of Carbon Nanotubes in Drug Delivery
		13.10 Conclusion
		References
Part III Administrative Routes for Controlled Drug Delivery
	Chapter 14 Controlled Drug Delivery via the Ocular Route
		14.1 Introduction
		14.2 Physiology of the Eye
			14.2.1 Ocular Membranes; Conjunctiva, Cornea, and Sclera
			14.2.2 Internal Ocular Structures
			14.2.3 Anterior Chamber, Lens, and Vitreous Body
		14.3 Ocular Disorders
			14.3.1 Periocular Disorders
			14.3.2 Intraocular Disorders
		14.4 Controlled Drug Delivery Systems
			14.4.1 Formulation Strategies
			14.4.2 Mucoadhesive Systems
			14.4.3 Solution to Gel In Situ Gelling Systems
			14.4.4 Penetration Enhancers
			14.4.5 Contact Lenses and Ocular Inserts
			14.4.6 Intraocular Systems (Implants, Injectables, and Degradable Microparticles)
			14.4.7 Phonophoresis and Ionophoresis
			14.4.8 Topical Prodrugs
			14.4.9 Microneedle Systems
		14.5 Conclusions
		References
	Chapter 15 Controlled Drug Delivery via the Otic Route
		15.1 Introduction
		15.2 Anatomy and Physiology of the Otic Route
			15.2.1 Anatomy of the Otic Route
			15.2.2 Barriers Relevant to Inner Ear Drug Delivery
				15.2.2.1 Blood Labyrinth Barrier
				15.2.2.2 Round Window Membrane
				15.2.2.3 Oval Window
				15.2.2.4 Eustachian Tube
				15.2.2.5 Tympanic Membrane
		15.3 Controlled Drug Delivery Systems
			15.3.1 Intratympanic Administration
				15.3.1.1 Silverstein MicroWick
				15.3.1.2 Round Window Microcatheter (μCath)
				15.3.1.3 Gelfoam
				15.3.1.4 Seprapack
				15.3.1.5 Ozurdex as a RWM Implant
				15.3.1.6 Propel Steroid‐Eluting Stent
			15.3.2 Trans‐Oval Window Administration
			15.3.3 Intracochlear Administration
				15.3.3.1 Drug‐Eluting Cochlear Implants
				15.3.3.2 Microfluidic Reciprocating Reservoir
		15.4 Conclusions
		References
	Chapter 16 Controlled Drug Delivery via the Nasal Route
		16.1 Introduction
		16.2 Anatomy and Physiology of the Nose
		16.3 Absorption from the Nasal Cavity
			16.3.1 The Epithelial Barrier
			16.3.2 Absorption
		16.4 Mucus and Mucociliary Clearance
		16.5 Drug Delivery Systems
			16.5.1 Solutions and Suspensions
			16.5.2 Mucoadhesive Polymers
				16.5.2.1 In Situ Forming Nasal Gels
				16.5.2.2 Nasal Inserts
				16.5.2.3 Microspheres and Nanospheres
				16.5.2.4 Liposomes
				16.5.2.5 Microemulsions and Nanoemulsions
				16.5.2.6 Combination/Hybrid Products and Others
			16.5.3 The Nasal Route and the Blood–Brain Barrier
			16.5.4 The Nasal Route for Vaccinations
			16.5.5 In Vitro/in Vivo Models for Nasal Absorption
		16.6 Conclusion
		References
	Chapter 17 Controlled Drug Delivery via the Buccal and Sublingual Routes
		17.1 Introduction
		17.2 Buccal and Sublingual Physiology and Barriers to Drug Delivery
			17.2.1 Saliva and Mucus
			17.2.2 Buccal and Sublingual Epithelium and Permeation Barrier
		17.3 Controlled Drug Delivery Systems
			17.3.1 Tablets
			17.3.2 Films
			17.3.3 Gels, Ointments, and Liquid Formulations
			17.3.4 Spray
			17.3.5 Wafers
			17.3.6 Lozenges
			17.3.7 Advanced and Novel Drug Delivery Systems
		17.4 Functional Excipients Used in Controlled Release Systems to Enhance Buccal and Sublingual Drug Bioavailability
			17.4.1 Permeation Enhancers
			17.4.2 Mucoadhesive Polymers
		17.5 Conclusions
		Acknowledgments
		References
	Chapter 18 Controlled Drug Delivery via the Lung
		18.1 Introduction
		18.2 The Relevant Physiology of the Route Including the Barriers to Drug Delivery
		18.3 Controlled Drug Delivery Systems
			18.3.1 Formulations
				18.3.1.1 Dissolution Rate Controlled
				18.3.1.2 Sustained Release Systems
				18.3.1.3 Drug Complexes
				18.3.1.4 Drug–Receptor Binding
				18.3.1.5 Drug Conjugates
				18.3.1.6 Drug–Polymer Matrix Particles
				18.3.1.7 Large Porous Particles
				18.3.1.8 Nanosystems
			18.3.2 Devices
				18.3.2.1 Controlling Lung Deposition Patterns
				18.3.2.2 Nebulizers
				18.3.2.3 Dry Powder Inhalers
				18.3.2.4 Pressurized Metered‐Dose Inhalers
		18.4 Conclusions
		Acknowledgments
		References
	Chapter 19 Controlled Drug Delivery via the Vaginal and Rectal Routes
		19.1 Introduction
		19.2 Biological Features of the Vagina and Colorectum
			19.2.1 Vagina
			19.2.2 Colorectum
		19.3 Controlled Drug Delivery Systems
			19.3.1 Vaginal Route
				19.3.1.1 Conventional Dosage Forms
				19.3.1.2 Removable Drug Delivery Systems
				19.3.1.3 Nanotechnology‐based Drug Delivery Systems
			19.3.2 Rectal Route
				19.3.2.1 Dosage Forms
				19.3.2.2 Nanotechnology‐based Drug Delivery Systems
		19.4 Conclusions
		Acknowledgments
		References
	Chapter 20 Controlled Drug Delivery into and Through Skin
		20.1 Introduction
			20.1.1 Human Skin Structure and Function
				20.1.1.1 Biological Factors
				20.1.1.2 Skin as a Physical Barrier
			20.1.2 Drug Transport Through Skin
		20.2 Controlled Drug Delivery into and Through Skin
			20.2.1 Skin Barrier Modulation
				20.2.1.1 Penetration Enhancers
				20.2.1.2 Ablation
			20.2.2 Controlled Release Transdermal and Topical Systems
				20.2.2.1 Supersaturation
				20.2.2.2 Reservoir Formation
				20.2.2.3 Film Forming Systems
				20.2.2.4 Vesicles
				20.2.2.5 Particles
			20.2.3 Device‐Based Controlled Delivery
				20.2.3.1 Iontophoresis
				20.2.3.2 Sonophoresis
				20.2.3.3 Electroporation
				20.2.3.4 Microneedles
				20.2.3.5 Heat
				20.2.3.6 Other Devices
		20.3 Combination Approaches
		20.4 Conclusions
		References
Index
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