Main description:

An indispensable tool for those working at the front lines of new drug development 

The development of effective delivery systems is crucial to taking a drug from the discovery and development stages to successful clinical use. The advances of recent years in the pharmaceutical sciences, including from molecular biology and biotechnology, make the challenges of drug delivery higher and the need to train pharmaceutical scientists and students greater.

Continuing the legacy of its successful predecessor, the second edition of Drug Delivery gets readers quickly up to speed on both the principles and latest applications in the increasingly important field of drug delivery.

Contributions from leading international experts allows Drug Delivery to cover the entire field in a systematic yet concise way. It begins with an in–depth review of key fundamentals that include developability factors, physiochemical and biological barriers, drug delivery pathways, pharmacokinetics and pharmacodynamics, and regulations and intellectual property. The remainder of the book systematically examines a host of specific subjects, including:

Routes of drug administration
Approaches to improve delivery
Targeted drug delivery systems
Delivery of macromolecular drugs

Back cover:

An indispensable tool for those working at the front lines of new drug development 

The development of effective delivery systems is crucial to taking a drug from the discovery and development stages to successful clinical use. The advances of recent years in the pharmaceutical sciences, including from molecular biology and biotechnology, make the challenges of drug delivery higher and the need to train pharmaceutical scientists and students greater.

Continuing the legacy of its successful predecessor, the second edition of Drug Delivery gets readers quickly up to speed on both the principles and latest applications in the increasingly important field of drug delivery.

Contributions from leading international experts allows Drug Delivery to cover the entire field in a systematic yet concise way. It begins with an in–depth review of key fundamentals that include developability factors, physiochemical and biological barriers, drug delivery pathways, pharmacokinetics and pharmacodynamics, and regulations and intellectual property. The remainder of the book systematically examines a host of specific subjects, including:

Routes of drug administration
Approaches to improve delivery
Targeted drug delivery systems
Delivery of macromolecular drugs

Contents:

List of Contributors

Preface

1 Factors that impact the developability of drug candidates
Chao Han and Binghe Wang

1.1. Challenges facing the pharmaceutical industry

1.2. Factors that Impact Developability

1.3. Commercial goal

1.3.1. The Chemistry Efforts

1.3.2. Biotechnology in the Discovery of Medicine

1.3.3. Target Validation in Animal Models

1.3.4. Pharmacokinetics and Drug Metabolism

1.3.5. Preparation for Pharmaceutical Products

1.3.6. Remarks on Developability

1.4. Drug Delivery Factors that Impact Developability

References

2. Physiological, Biochemical, and Chemical Barriers to Oral Drug Delivery
Paul Kiptoo, Anna M. Calcagno, and Teruna J. Siahaan

2.1. Introduction

2.2. Physiological Barriers to Drug Delivery

2.2.1. Paracellular Pathway

2.2.2. Transcellular Pathway

2.3. Biochemical Barriers to Drug Delivery

2.3.1. Metabolizing Enzymes

2.3.2. Transporters and Efflux Pumps

2.4. Chemical Barriers to Drug Delivery

2.4.1. Hydrogen–Bonding Potential

2.4.2. Other Properties

2.5. Drug Modifications to Enhance Transport Across Biological Barriers

2.5.1. Prodrugs and Structural Modifications

2.5.2. Formulations

2.6. Conclusions

References

3 Physicochemical Properties, Formulation, and Drug Delivery
Dewey H. Barich, Mark T. Zell, and Eric J. Munson

3.1. Introduction

3.2. Physicochemical Properties

3.2.1. Solubility

3.2.2. Stability

3.3. Formulations

3.3.1. Processing steps

3.3.2. Influence of physicochemical properties on drugs in formulations

3.3.3. Other issues

3.4. Drug Delivery

3.4.1. Duration of Release

3.4.2. Site of Administration

3.4.3. Methods of Administration

3.5. Conclusion

References

4 Targeted Bioavailability: A Fresh Look at Pharmacokinetics and Pharmacodynamics Issues in Drug Discovery and Development
Christine Xu

4.1. Introduction

4.2. Target bioavailability

4.3. Drug delivery trends and targets related to pharmacokinetics and pharmacodynamics

4.4. Pharmacokinetics (PK) – pharmacodynamics (PD) in drug discovery and development

4.5. Source of variability of drug response

4.6. Recent development and issues of bio–analytical methodology

4.7. Mechanistic PK–PD models

4.8. Summary

References

5 The Role of Transporters in Drug Delivery and Excretion
Marilyn E. Morris and Xiaowen Guan

5.1. Introduction

5.2. Drug Transport in absorption and excretion.

5.2.1. Intestinal transport

5.2.2. Hepatic Transport

5.2.3. Renal Transport

5.2.4. Blood–brain barrier transport

5.3. ABC (ATP–binding cassette) transporter family

5.3.1. P–glycoprotein (ABCB1)

5.3.2. Multidrug Resistance–associated Proteins (ABCC)

5.3.3. Breast Cancer Resistance Protein (ABCG2)

5.3.4. Other ABC transporters

5.4. SLC (solute carrier) transporter family

5.4.1. Organic Anion Transporting Polypeptides (SLCO)

5.4.2. Organic Anion Transporters (SLC22A)

5.4.3. Organic Cation Transporters (SLC22)

5.4.4. Multidrug and Toxin Extrusion Transporters (SLC47A)

5.4.5. Monocarboxylate Transporters (SLC16 and SLC5)

5.4.6. Peptide Transporters (SLC15A)

5.4.7. Other SLC transporters

5.5. Conclusions

References

6 Intracellular delivery and disposition of small molecular weight drugs
Jeffrey Krise

6.1 Introduction

6.2. The relationship between the intracellular distribution of a drug and its activity

6.3. The relationship between the intracellular distribution of a drug and its pharmacokinetic properties

6.4 Overview of approaches to study intracellular drug disposition

6.4.1 Fluorescence microscopy

6.4.2 Organelle isolation

6.4.3 Indirect methods

6.5 The accumulation of drugs in mitochondria, lysosomes and nuclei

6.5.1 Mitochondrial accumulation of drugs

6.5.2 Lysosomal accumulation of drugs

6.5.3 Nuclear accumulation of drugs

6.6 Summary and future directions

References

7 Cell Culture Models for Drug Transport Studies
Irina Kalashnikova, Norah Albekairi, Shariq Ali, Sanaalarab Al Enazy, and Erik Rytting

7.1. Introduction

7.2. General Considerations

7.3. Intestinal Epithelium

7.3.1. The Intestinal Epithelial Barrier

7.3.2. Intestinal Epithelial Cell Culture Models

7.4. The Blood–Brain Barrier

7.4.1. The Blood–Brain Endothelial Barrier

7.4.2. Blood–Brain Barrier Cell Culture Models

7.5. Nasal and Pulmonary Epithelium

7.5.1. The Respiratory Airway Epithelial Barrier

7.5.2. The Nasal Epithelial Barrier and Cell Culture Models

7.5.3. The Airway Epithelial Barrier and Cell Culture Models

7.5.4. The Alveolar Epithelial Barrier and Cell Culture Models

7.6. The Ocular Epithelial and Endothelial Barriers

7.6.1. The Corneal and Retinal Barriers

7.6.2. Cell Culture Models of Ocular Epithelium and Endothelium

7.7. The Placental Barrier

7.7.1. The Syncytiotrophoblast Barrier

7.7.2. Trophoblast Cell Culture Models

7.8. The Renal Epithelium

7.8.1. The Renal Epithelial Barrier

7.8.2. Renal Epithelial Cell Culture Models

7.9. 3D In Vitro Models

7.10. Conclusions

References

8 Intellectual Property and Regulatory Issues in Drug Delivery Research
Wansheng Jerry Liu and Shahnam Sharareh

8.1. Introduction

8.2. Pharmaceutical Patents

8.3. Statutory Requirements for Obtaining a Patent

8.3.1. Patentable Subject Matter

8.3.2. Novelty

8.3.3. Non–Obviousness

8.4. Patent Procurement Strategies

8.5. Regulatory Regime

8.6. FDA Market Exclusivities

8.7. Regulatory and Patent Law Linkage

References

9 Presystemic and First–Pass Metabolism
Qingping Wang and Meng Li

9.1. INTRODUCTION

9.2. HEPATIC FIRST–PASS METABOLISM

9.2.1. HEPATIC ENZYMES

9.3. INTESTINAL FIRST–PASS METABOLISM

9.3.1. INTESTINAL ENZYMES

9.3.2. INTERPLAY OF INTESTINAL ENZYMES AND TRANSPORTERS

9.4. PREDICTION OF FIRST–PASS METABOLISM

9.4.1. IN VIVO ASSESSMENT OF FIRST–PASS METABOLISM

9.4.2. IN VITRO ASSESSMENT OF FIRST–PASS METABOLISM

9.4.3. IN VITRO–IN VIVO PREDICTION

9.4.4. IN SILICO APPROACH

9.5. STRATEGIES FOR OPTIMIZATION ORAL BIOAVAILABILITY

9.6. SUMMARY

References

10 Pulmonary Drug Delivery Pharmaceutical Chemistry and Aerosol Technology
Anthony J. Hickey

10.1. INTRODUCTION

10.2. AEROSOL TECHNOLOGY

10.2.1. Particle Production

10.2.2. Propellant Driven Metered Dose Inhalers (pMDIs)

10.2.3. Dry Powder Inhalers (DPIs)

10.2.4. Nebulizer

10.3. DISEASE THERAPY

10.3.1. Asthma

10.3.2. Emphysema

10.3.3. Cystic Fibrosis

10.3.4. Other Locally Acting Agents

10.3.5. Systemically Acting Agents

10.4. FORMULATION VARIABLES

10.4.1. Excipients

10.4.2. Interactions

10.4.3. Stability

10.5. Regulatory Considerations

10.6. FUTURE DEVELOPMENTS

10.7. CONCLUSION

References

11 Transdermal Delivery of Drugs Using Patches & Patchless Delivery Systems
Tannaz Ramezanli, Krizia Karry, Zheng Zhang, Kishore Shah, Bozena Michniak–Kohn

11.1. Introduction

11.2. Transdermal patch delivery systems

11.2.1. Definition and history of patches

11.2.2. Anatomy and Designs of Patches

11.3. Patchless transdermal drug delivery systems

11.3.1. First–generation systems

11.3.2. Second–generation systems

11.3.3. Third–generation systems

11.4. Recent advances in transdermal drug delivery

11.4.1. Frontier in transdermal drug delivery: Transcutaneous immunization via microneedle techniques

11.4.2. Patchless Transdermal Delivery: The PharmaDur® Virtual Patch

11.5. Summary

References

12 Prodrug Approaches to Drug Delivery
Longqin Hu

12.1. Introduction

12.2. Basic Concepts: definition and applications

12.2.1. Increasing lipophilicity to increase systemic bioavailability

12.2.2. Sustained–release prodrug systems

12.2.3. Improving gastrointestinal tolerance

12.2.4. Improving taste

12.2.5. Diminishing gastrointestinal absorption

12.2.6. Increasing water solubility

12.2.7. Tissue targeting and activation at the site of action

12.3. Prodrug design considerations

12.4. Prodrugs of various functional groups

12.4.1. Prodrugs of compounds containing COOH or OH

12.4.2. Prodrugs of compounds containing amides, imides, and other acidic NH

12.4.3. Prodrugs of Amines

12.4.4. Prodrugs for compounds containing carbonyl groups

12.5. Drug release and activation mechanisms

12.5.1. Cascade release facilitated by linear autodegradation reactions

12.5.2. Cascade release facilitated by intramolecular cyclization reactions

12.5.3. Cascade activation through intramolecular cyclization to from cyclic drugs

12.6. Prodrugs and intellectual property rights two court cases

References

13 Liposomes as Drug Delivery Vehicles
Guijun Wang

13.1. Introduction

13.2. Currently approved liposomal drugs in clinical applications

13.3. Conventional and stealth liposomes

13.4. Stimuli–responsive liposomes or triggered release liposomes

13.4.1. General mechanism of triggered–release

13.4.2. Thermo–sensitive liposomes

13.4.3. pH–sensitive liposomes

13.4.4. Photo–triggered liposomes

13.4.5. Triggered release controlled by enzymes

13.5. Targeted liposomal delivery

13.6. Hybrid liposome drug delivery system

13.7. Conclusions and future perspectives

References

14 Nanoparticles as Drug Delivery Vehicles
Dan Menasco and Qian Wang

14.1. Introduction

14.1.1. General DDV Properties

14.1.2. The DDV Core

14.1.3. DDV Targeting

14.1.4. DDV Size & Surface

14.2. Organic DDV s

14.2.1 Polymer Based Nanocarriers

14.2.2 Polymeric Micelles

14.2.3 Dendrimers

14.3. Inorganic DDV s

14.3.1. Mesoporous Silca Nanoparticles

14.3.2. Gold Nanoparticles

14.4. Conclusion

References

15 Evolution of Controlled Drug Delivery Systems
Krishnaveni Janaparedd, Bhaskara R. Jasti, and Xiaoling Li

15.1 Introduction

15.2 Biopharmaceutics and Pharmacokinetics

15.3 Material Science

15.4 Proteins, Peptides and Nucleic acids

15.5 Targeted drug delivery

15.6 Microelectronics and Microfabrication Technologies

15.7 Conclusion

References

16 Pathways for Drug Delivery to the Central Nervous System
Ngoc H. On, Vinith Yathindranath, ZhiZhi Sun, and Donald W. Miller

16.1. INTRODUCTION

16.1.1 Cellular Barriers to Drug Delivery in the CNS

16.1.2 General Approaches for Increasing Brain Penetration of Drugs

16.2. CIRCUMVENTING THE CNS BARRIERS

16.2.1 Intracerebraoventricular Injection (ICV)

16.2.2 Intracerebral Administration

16.2.3 Intranasal Delivery Route

16.3 TRANSIENT BBB DISRUPTION

16.3.1 Osmotic BBB Disruption

16.3.2 Pharmacological Disruption of the BBB

16.4 TRANSCELLULAR DELIVERY ROUTES

16.4.1. SLC Transport Systems in the BBB

16.4.2. ABC Transport Systems in the BBB

16.4.3 Vesicular Transport in the BBB

16.5 CONCLUSIONS

References

17 Metabolic Activation and Drug Targeting
Xiangming Guan

17.1 Introduction

17.2. Anticancer prodrugs and their biochemical basis

17.2.1. Tumor–activated anticancer prodrugs based on hypoxia

17.2.2. Tumor–activated prodrugs based on elevated peptidases or proteases

17.2.3. Tumor–activated prodrugs based on other enzymes with elevated activities at tumor sites

17.3. Antibody– and gene– directed enzyme prodrug therapy (ADEPT and GDEPT)

17.3.1. ADEPT

17.3.2. GDEPT

17.4. Summary

References

18 Targeted Delivery of Drugs to the Colon
Anil K. Philip and Sarah K. Zingales

18.1. Introduction

18.2. Microbially–triggered release

18.2.1. Azo–linked compounds

18.2.2. Amino acid conjugates

18.2.3. Sugar–derived prodrugs

18.3. pH–sensitive polymers for time–dependent release

18.4. Osmotic release

18.5. Pressure–controlled delivery

18.6. Nanoparticle approaches

18.7. Conclusion

References

19 Receptor–mediated Drug Delivery
Chris V. Galliford and Philip S. Low

19.1. Introduction

19.2. Selection of a Receptor for Drug Delivery

19.2.1. Specificity

19.2.2. Receptor Internalization/Recycling

19.3. Design of a Ligand–drug Conjugate

19.3.1. Linker Chemistry

19.3.2. Selection of Ligands

19.3.3. Selection of Therapeutic Drug

19.4. Folate–mediated Drug Delivery

19.4.1. Expression of Folate Receptors in Malignant Tissues

19.4.2. Expression of Folate Receptors in Normal Tissues

19.4.3. Applications of Folate–mediated Drug delivery

19.5. Conclusions

References

20 Protein and Peptide Conjugates for Targeting Therapeutics and Diagnostics to Specific Cells
Barlas Büyüktimkin, John Stewart Jr., Kayann Tabanor, Paul Kiptoo, and Teruna J. Siahaan

20.1. Introduction

20.2. Radiolabeled Antibodies for Cancer Treatment

20.3. Antibody Drug Conjugate (ADC)

20.3.1. Sites of Conjugation on MABS, Linkers, And Drugs

20.4. Non–Antibody–Based Protein–Drug Conjugates

20.5. Peptibody

20.6. Protein Conjugates for Diagnostics

20.7. Peptide–Drug Conjugates

20.8. Challenges in Analyzing Conjugates

20.9. Conclusions

References

21 Drug delivery to the lymphatic system
Qiuhong Yang and Laird Forrest

21.1. Introduction

21.2. Anatomy and physiology of the lymphatic system

21.2.1. Lymph

21.2.2. Lymphatic vessels

21.2.3. Lymph nodes

21.2.4. Lymph organs

21.3. Influence of physicochemical characteristics of drug carriers on lymphatic uptake and transport

21.3.1. Size

21.3.2. Surface charge

21.3.3. Hydrophobicity

21.4. Carriers for lymphatic drug delivery

21.4.1. Liposomes

21.4.2. Lipid–based emulsions and nanoparticles

21.4.3. Polymer–based carriers

21.5. Administration routes for lymphatic delivery

21.5.1. Intestinal

21.5.2. Pulmonary

21.5.3. Subcutaneous

21.5.4. Intraperitoneal

21.6. Lymphatic–targeting Vaccination

21.7. Conclusions

References

22 The Development of Cancer Theranostics: a New Emerging Tool towards Personalized Medicine
Hongying Su, Yun Zeng, Gang Liu, and Xiaoyuan Chen

22.1. Introduction

22.2. Imaging–Guided Drug Delivery and Therapy

22.3. Optical Imaging–Based Theranostics

22.3.1. NIR Fluorescence Imaging

22.3.2. Bioluminescence Imaging

22.3.3 Gold Nanoparticle as a Theranostics Platform

22.3. MRI–Based Theranostics

22.4. Nuclear Imaging–Based Theranostics

22.5. Ultrasound–Based Theranositic Platform

22.6. Multimodality Imaging–Based Theranostic Platform

22.6.1. PET/CT

22.6.2. MRI/Optical

22.6.3. MRI/PET

22.7. Conclusion and Future Perspectives

Acknowledgements

References

23 Intracellular delivery of proteins and peptides
Can Sarisozen and Vladimir P. Torchilin

23.1. Introduction

23.2. Intracellular Delivery Strategies of Peptides and Proteins

23.3. Concepts in Intracellular Peptide and Protein Delivery

23.3.1. Longevity in the Blood

23.3.2. Cellular Uptake Pathways

23.3.3. Endosomal Escape

23.4. Peptide and Protein Delivery to Lysosomes

23.5. Receptor–mediated intracellular delivery of peptides and proteins

23.5.1. Transferrin receptor–mediated delivery

23.5.2. Folate receptor–mediated delivery

23.6. Transmembrane delivery of peptides and proteins

23.6.1. Well studied classes of CPPs for peptide and protein delivery

23.6.2. Cellular uptake mechanisms of CPPs

23.6.3. CPP–mediated delivery of peptides and proteins

23.6.4. CPP–modified carriers for intracellular delivery of peptides and proteins

23.7. Conclusions

References

24 Vaccine Delivery: Current Routes of Administration and Novel Approaches
Neha Sahni, Yuan Cheng, C. Russell Middaugh, David B. Volkin

24.1. Introduction

24.2. Parenteral Administration of Vaccines

24.2.1 Currently available vaccines and devices for intramuscular and subcutaneous delivery

24.2.2 Currently available vaccines and devices for intradermal administration

24.2.3 Novel devices for parenteral injection

24.2.4 Novel formulations and delivery approaches for parenteral injection

24.3. Oral Delivery of Vaccines

24.3.1 Currently available orally administered vaccines

24.3.2 Novel formulations and delivery approaches for oral administration

24.4. Nasal and Aerosol Delivery of Vaccines

24.4.1 Currently available nasally administered vaccines

24.4.2 Novel devices and formulations for nasal administration

24.4.3 Devices and delivery systems for aerosol administration

24.5. Conclusions

References

25. Delivery of Genes and Oligonucleotides
Charles M. Roth

25.1. Introduction

25.2. Systemic Delivery Barriers

25.2.1. Viruses: Learning from Nature

25.2.2. Materials for Nucleic Acid Delivery

25.2.3. Characterization of Nanoparticles

25.2.4. Targeted Delivery of Nucleic Acids

25.3. Cellular Delivery Barriers

25.3.1. Endosomal Escape

25.3.2. Vector Unpackaging

25.4. Current and Future Approaches to Nucleic Acid Delivery

25.4.1. Vectors in the Clinic

25.4.2. Combinatorial Chemistry Approaches

25.4.3. Polymer–Lipid Nanocomposites

25.5. Summary and Future Directions

References

Index