Pharmaceutical Nanotechnology E-Book

• Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
• Kategorie: Fachliteratur
• Serie: Nanotechnology Innovation & Applications
• Sprache: Englisch

Seitenzahl: 1558

Veröffentlichungsjahr: 2016

Beschreibung

With its focus on concrete methods and recent advances in applying nanotechnology to develop new drug therapies and medical diagnostics, this book provides an overall picture of the field, from the fundamentals of nanopharmacy with the characterisation and manufacturing methods to the role of nanoparticles and substances. Actual examples of utilization include drug development issues, translation to the clinic, market prospects, and industrial commercialization aspects. The applications described are taken from cancer treatment as well as other major therapeutic areas, such as infectious diseases and dermatology. An in-depth discussion on safety, regulatory, and societal aspects rounds off the book.
Written by a top team of editors and authors composed of the leading experts in Europe and the USA who have pioneered the field of nanopharmacy!

Leseprobe

Contents

Cover

Further Volumes of the Series “Nanotechnology Innovation & Applications”

Title Page

Copyright

Dedication

Series Editor Preface

About the Series Editor

Foreword

Industrial Requirement on Nanopharmacy Research

Introduction

Volume 1

Part One: Entry to the Nanopharmacy Revolution

Chapter 1: History: Potential, Challenges, and Future Development in Nanopharmaceutical Research and Industry

1.1 Nanopharmaceuticals in Cancer Therapy

1.2 Nanoparticles Actively Using the Host Machinery

1.3 Nanopharmaceuticals for Oral Administration and Long-Acting Injectable Therapy

1.4 Bridging Future Nanomedicines to Commercialization

1.5 Future Outlook

Acknowledgments

References

Chapter 2: Nanoscale Drugs: A Key to Revolutionary Progress in Pharmacy and Healthcare

2.1 Introduction

2.2 Nanopharmacy Concepts to Improve the Safety and Efficacy of Medicines

2.3 Technical Realization of Nanopharmaceuticals

2.4 Safety of Nanopharmaceuticals

2.5 Present and Future of Nanopharmacy

References

Chapter 3: The Emergence of Nanopharmacy: From Biology to Nanotechnology and Drug Molecules to Nanodrugs

3.1 Introduction

3.2 First Generation of Nanopharmaceuticals: From Drug Molecules to Nanodrugs

3.3 Conclusion

References

Chapter 4: Understanding and Characterizing Functional Properties of Nanoparticles

4.1 Introduction

4.2 The Approach to Characterization

References

Chapter 5: Omics-Based Nanopharmacy: Powerful Tools Toward Precision Medicine

5.1 Introduction

5.2 Precision Medicine

5.3 “OMICS” – New Era in Understanding Pathology

5.4 Nanomedicine

5.5 Future Outlook

Acknowledgments

References

Part Two: Fundamentals of Nanotechnology in Pharmacy

Chapter 6: Nanostructures in Drug Delivery

6.1 Introduction

6.2 Nanocarrier Classification

6.3 Drug Loading and Release

6.4 General Discussion and Conclusions

References

Chapter 7: Characterization Methods: Physical and Chemical Characterization Techniques

7.1 The Need for Nanomedicine-Specific Characterization

7.2 The Assay Cascade: From Basic Properties to Complex Interactions

7.3 Physicochemical Characterization of Pristine Nanoparticles

7.4 Characterization of Nanoparticles in the Biological Environment

7.5 Conclusions and Future Outlook

References

Chapter 8: Nanoparticle Characterization Methods: Applications of Synchrotron and Neutron Radiation

8.1 Advanced Characterization: Synchrotron Light and Neutron Sources

8.2 Application Examples

8.3 Going Beyond Characterization Using Synchrotron X-rays: Nanoparticles for Diagnostic and Therapeutic Approaches

8.4 Looking Ahead and Conclusions

Acknowledgments

References

Chapter 9: Overview of Techniques and Description of Established Processes

9.1 Introduction

9.2 Processing of Liquid Drug Carrier Formulations

9.3 Drug Nanoparticles and Process Chains to Solid Formulations

9.4 Industrial Status and Framework

9.5 Perspectives for Academia, Industry, and Regulatory Authorities

References

Chapter 10: Nanopharmacy: Exploratory Methods for Polymeric Materials

10.1 Introduction

10.2 Rationale for the Use of Polymers in Nanomedicines

10.3 Polymer Structures and Properties

10.4 Formulation of Copolymers into Micelles, Vesicles, and Nanoparticles

10.5 Conjugation of Polymers to Drugs and Proteins

10.6 Recent Advances in Polymer Synthesis for Therapeutic Applications

10.7 Controlled Radical Polymerization (CRP)

10.8 Concluding Remarks

References

Chapter 11: Overview and Presentation of Exploratory Methods for Manufacturing Nanoparticles/“Inorganic Materials”

11.1 Introduction

11.2 Gold NPs

11.3 Magnetic NPs

11.4 Metal Oxide NPs

11.5 Others (Silver, Quantum Dots, and Lanthanides)

11.6 Conclusion and Perspective

Acknowledgment

References

Chapter 12: Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations

12.1 Introduction

12.2 Presentation of Major Manufacturing Processes of Different Nanodrug Delivery Systems

12.3 Nanodrug Delivery Systems as Marketed Products

12.4 Particle/Vesicle Size Reduction Technologies

12.5 Process Development and Scale-Down/Scale-Up Strategy

12.6 Technological Concept for Manufacture of Drug Product for Human Use (GMP Unit)

12.7 Conclusion

References

Chapter 13: Occupational Safety and Health

13.1 Nanomaterials at the Workplace

13.2 Legal Aspects

13.3 Management of Uncertainty

13.4 Risks of Nanomaterials for Researchers and Workers

13.5 Prudent Practices and Proven Concepts for Controlling Risks

13.6 Instruction and Training

13.7 Summary

References

Volume 2

Part Three: Development of Nanopharmaceuticals

Chapter 14: Micro- and Nano-Tools in Drug Discovery

14.1 Introduction

14.2 General Concepts of Miniaturization

14.3 Micro- and Nanofabrication

14.4 Nanoformulation

14.5 Organ-on-a-Chip

References

Chapter 15: Computational Predictive Models for Nanomedicine

15.1 Introduction

15.2 Molecular Modeling in Nanomedicine

15.3 Computational Approaches for Predicting Nanotoxicology

15.4 Simulation of Nanoparticle Pharmacokinetics

15.5 Conclusion

References

Chapter 16: Drug Targeting in Nanomedicine and Nanopharmacy: A Systems Approach

16.1 Introduction

16.2 A Systems Approach to Drug Delivery and Drug Targeting

16.3 Current Nanomedicine Products

16.4 Transformation of a Discovery of Disease Target to a Therapeutic Product

16.5 The Role of Targeted Nanoformulations and a Systems Approach in Drug Development

16.6 Targeting Drugs to Sites of Action

16.7 A Size-Dependent Targeting to Tissues and Cells

16.8 Ligand–Receptor-Based Targeting: Active Drug Targeting

16.9 Conclusions and Future Prospects

References

Chapter 17: Nanoparticle Toxicity: General Overview and Insights Into Immunological Compatibility

17.1 Introduction

17.2 Systemic Toxicity

17.3 Pulmonary Toxicity

17.4 Cutaneous Toxicity

17.5 Immunotoxicity

17.6 Unintended Presence of Nanosized Materials in Pharmaceutical Formulations

17.7 Conclusion

Acknowledgments

References

Chapter 18: An Overview of Nanoparticle Biocompatibility for Their Use in Nanomedicine

18.1 Introduction

18.2 Nanomedicine

18.3 Biocompatibility of Nanoparticles for Medical Application

18.4 Summary

References

Chapter 19: Translation to the Clinic: Preclinical and Clinical Pharmacology Studies of Nanoparticles – The Translational Challenge

19.1 Introduction

19.2 Nanoparticle Formulations

19.3 Pharmacokinetic Characterization

19.4 Mononuclear Phagocyte System

19.5 Delivery of CMA in Tumor

19.6 Methods to Target Brain Tumors

19.7 Physical Characteristics

19.8 The Effect of MPS on CMA PK and PD

19.9 Age

19.10 Gender

19.11 Tissue and Organ Effects

19.12 Drug–Drug Interactions

19.13 Prior Treatment

19.14 Translational Challenges

19.15 Future Perspectives on PK and PD

References

Chapter 20: Regulatory Issues in Nanomedicines

20.1 Nanomedicines and the Pharmaceuticals Regulatory Framework in Europe

20.2 The European Medicines Agency and Nanomedicines

20.3 Is It Important to Define Nanomedicines?

20.4 Communicating About Nanomedicines

20.5 Liposomal Formulations: State of Play at the EMA

20.6 Nanosimilar Colloidal Intravenous Iron-Based Preparations

20.7 International Landscape and Convergence on Nanomedicines

20.8 Conclusions and Way Forward

References

Chapter 21: Social Studies of Nanopharmaceutical Research

21.1 Engaging with Ethical, Legal, and Social Implications of Nanoresearch

21.2 Nanopharmacy and the “Culture of Promise”

21.3 From “Science Meets Society” to Translation as a Social Process

21.4 Metaphors and Nanopharmacy

21.5 Nanopharmacy and “Personalized Medicine”

21.6 Concluding Remarks

References

Part Four: Pharmaceutical Applications of Nanomaterials

Chapter 22: Nanoparticles for Imaging and Imaging Nanoparticles: State of the Art and Current Prospects

22.1 Introduction

22.2 Conception of Nanotechnologies for Imaging

22.3 In Vivo Nanoparticle Imaging to Gain Insight into Nanomedicine Biodistribution and Stability

22.4 Translational Interest of Nanoparticles for Medical Imaging

22.5 Conclusion

References

Chapter 23: Nanoparticle-Based Physical Methods for Medical Treatments

23.1 Photothermal Therapy

23.2 Photodynamic Therapy

23.3 Magnetic Hyperthermia

23.4 Radiotherapy

23.5 Sonodynamic Therapy

23.6 Cryosurgery

23.7 Future Perspectives

References

Chapter 24: Nanodrugs in Medicine and Healthcare: Oral Delivery

24.1 General Aspects and Challenges of Oral Drug Delivery

24.2 Pure Drug Micronization as a Conceptual Preamble to More Complex Drug Delivery

24.3 Nanotechnology Platforms for Improved Oral Drug Delivery

24.4 Conclusive Remarks

Acknowledgments

References

Chapter 25: Steroidal Nanodrugs Based on Pegylated Nanoliposomes Remote Loaded with Amphipathic Weak Acids Steroid Prodrugs as Anti-Inflammatory Agents

25.1 A Short Relevant Background on Inflammatory and Autoimmune Diseases

25.2 Drug Delivery Systems (DDS) Based on Nanoparticles (NP) for the Treatment of Diseases That Involve Inflammation

25.3 Glucocorticosteroid as Anti-Inflammatory Agents

25.4 Steroidal Nanodrugs Based on Pegylated Nanoliposomes Remote Loaded with Amphipathic Weak Acids Steroid Prodrugs as Anti-Inflammatory Agents

25.5 Methods for Loading Drugs into Liposomes

25.6 Comparing Various Approaches Used for Formulating Liposomal GCs

25.7 The Use of Liposomes Loaded with Steroids as Anti-Inflammatory Agents: A Brief Historical Perspective

25.8 Lessons Learned from Experimental Animal Models of Diseases That Involve Inflammation

References

Chapter 26: Nanodrugs in Medicine and Healthcare: Pulmonary, Nasal and Ophthalmic Routes, and Vaccination

26.1 Introduction

26.2 Different Routes of Administration

26.3 Different Types of Nanoparticles for Different Routes of Administration

26.4 Manufacturing Processes of Nanoparticles

26.5 Different Diseases Targeted Via Nanoparticle-Based Drug Delivery Systems

26.6 Challenges Faced in Formulation Development of Nanoparticle-Based Systems

References

Chapter 27: Neurodegenerative Diseases – Alzheimer's Disease

27.1 Introduction

27.2 Diagnosis

27.3 Therapy of Alzheimer's Disease

References

Part Five: The Nanopharmaceutical Market

Chapter 28: A Practical Guide to Translating Nanomedical Products

28.1 From the Laboratory to the Clinic: Overcoming the Valley of Death

28.2 Irreproducible Preclinical Research: A Bottleneck for Translation?

28.3 Protecting Inventions via Patents: The Cornerstone of Translation

28.4 Terminology and Nomenclature: Lost in Translation

28.5 Gaps in Regulatory Guidance

28.6 Conclusions and Outlook

28.7 Disclosures and Conflict of Interest

References

Chapter 29: Development and Commercialization of Nanocarrier-Based Drug Products

29.1 Drivers for New Medicines

29.2 Current Marketed Nanomedicines

29.3 Developing Nanomedicines

29.4 Commercialization of Nanomedicines

29.5 Conclusions

References

Chapter 30: Future Outlook of Nanopharmacy: Challenges and Opportunities

30.1 Matching the NC's Delivery Mode of Action (MoA) to the Tumor Type

30.2 Nonpredictive Animal Models

30.3 The Lack of Reliable Techniques that can Efficiently Characterize NCs and Measure their Stability in the Human Body

30.4 The Challenge of Scaling Up NCs

References

Index

End User License Agreement

List of Tables

Table 9.1

Table 9.2

Table 9.3

Table 9.4

Table 9.5

Table 9.6

Table 9.7

Table 9.8

Table 10.1

Table 11.1

Table 12.1

Table 12.2

Table 12.3

Table 15.1

Table 16.1

Table 20.1

Table 20.2

Table 20.3

Table 20.4

Table 22.1

Table 24.1

Table 24.2

Table 25.1

Table 25.2

Table 25.3

Table 25.4

Table 25.5

Table 26.1

Table 28.1

Table 28.2

Table 28.3

Table 28.4

Table 29.1

Table 29.2

Table 29.3

Table 29.4

List of Illustrations

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 2.6

Figure 2.7

Figure 2.8

Figure 3.1

Figure 3.2

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 5.1

Figure 6.1

Figure 6.2

Figure 6.3

Figure 7.1

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.5

Figure 9.1

Figure 9.2

Figure 9.3

Figure 9.4

Figure 9.5

Figure 9.6

Figure 9.7

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 10.11

Figure 10.12

Figure 10.13

Figure 10.14

Figure 10.15

Figure 10.16

Figure 10.17

Figure 10.18

Figure 11.1

Figure 11.2

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 12.5

Figure 12.6

Figure 12.7

Figure 12.8

Figure 12.9

Figure 12.10

Figure 12.11

Figure 12.12

Figure 12.13

Figure 12.14

Figure 12.15

Figure 12.16

Figure 12.17

Figure 12.18

Figure 12.19

Figure 12.20

Figure 12.21

Figure 12.22

Figure 12.23

Figure 12.24

Figure 12.25

Figure 12.26

Figure 12.27

Figure 12.28

Figure 12.29

Figure 12.30

Figure 12.31

Figure 12.32

Figure 12.33

Figure 12.34

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 13.6

Figure 13.7

Figure 13.8

Figure 13.9

Figure 14.1

Figure 14.2

Figure 14.3

Figure 14.4

Figure 14.5

Figure 14.6

Figure 14.7

Figure 14.8

Figure 14.9

Figure 14.10

Figure 14.11

Figure 14.12

Figure 14.13

Figure 14.14

Figure 14.15

Figure 15.1

Figure 15.2

Figure 15.3

Figure 15.4

Figure 16.1

Figure 16.2

Figure 16.3

Figure 17.1

Figure 17.2

Figure 18.1

Figure 18.2

Figure 19.1

Figure 19.2

Figure 19.3

Figure 19.4

Figure 19.5

Figure 19.6

Figure 19.7

Figure 19.8

Figure 19.9

Figure 19.10

Figure 19.11

Scheme 22.1

Figure 22.1

Figure 22.2

Scheme 22.2

Figure 22.3

Scheme 22.3

Figure 22.4

Figure 22.5

Scheme 22.4

Figure 22.6

Figure 23.1

Figure 23.2

Figure 23.3

Figure 23.4

Figure 23.5

Figure 23.6

Figure 24.1

Figure 25.1

Figure 25.2

Figure 25.3

Figure 28.1

Figure 28.2

Figure 28.3

Figure 28.4

Figure 28.5

Figure 29.1

Figure 29.2

Figure 29.3

Figure 29.4

Guide

Cover

Table of Contents

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Part 1

Chapter 1

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Further Volumes of the Series “Nanotechnology Innovation & Applications”

Axelos, M. A. V. and Van de Voorde, M. (eds.)

Nanotechnology in Agriculture and Food Science

2017

Print ISBN: 9783527339891

Fermon, C. and Van de Voorde, M. (eds.)

Nanomagnetism

Applications and Perspectives

2017

Print ISBN: 9783527339853

Mansfield, E., Kaiser, D. L., Fujita, D., Van de Voorde, M. (eds.)

Metrology and Standardization for Nanotechnology

Protocols and Industrial Innovations

2017

Print ISBN: 9783527340392

Meyrueis, P., Sakoda, K., Van de Voorde, M. (eds.)

Micro- and Nanophotonic Technologies

2017

Print ISBN: 9783527340378

Müller, B. and Van de Voorde, M. (eds.)

Nanoscience and Nanotechnology for Human Health

2017

Print ISBN: 9783527338603

Puers, R., Baldi, L., van Nooten, S. E., Van de Voorde, M. (eds.)

Nanoelectronics

Materials, Devices, Applications

2017

Print ISBN: 9783527340538

Raj, B., Van de Voorde, M., Mahajan, Y. (eds.)

Nanotechnology for Energy Sustainability

2017

Print ISBN: 9783527340149

Sels, B. and Van de Voorde, M. (eds.)

Nanotechnology in Catalysis

Applications in the Chemical Industry, Energy Development, and Environment Protection

2017

Print ISBN: 9783527339143

Edited by Jean Cornier, Andrew Owen, Arno Kwade, and Marcel Van de Voorde

Pharmaceutical Nanotechnology

Innovation and Production

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978-3-527-34054-5ePDF ISBN: 978-3-527-80067-4ePub ISBN: 978-3-527-80069-8Mobi ISBN: 978-3-527-80070-4oBook ISBN: 978-3-527-80068-1

Thanks to my wife for her patience with me spending many hours working on the book series through the nights and over weekends.The assistance of my son Marc Philip related to the complex and large computer files with many sophisticated scientific figures is also greatly appreciated.

Marcel Van de Voorde

Series Editor Preface

Since years, nanoscience and nanotechnology have become particularly an important technology areas worldwide. As a result, there are many universities that offer courses as well as degrees in nanotechnology. Many governments including European institutions and research agencies have vast nanotechnology programmes and many companies file nanotechnology-related patents to protect their innovations. In short, nanoscience is a hot topic!

Nanoscience started in the physics field with electronics as a forerunner, quickly followed by the chemical and pharmacy industries. Today, nanotechnology finds interests in all branches of research and industry worldwide. In addition, governments and consumers are also keen to follow the developments, particularly from a safety and security point of view.

This books series fills the gap between books that are available on various specific topics and the encyclopedias on nanoscience. This well-selected series of books consists of volumes that are all edited by experts in the field from all over the world and assemble top-class contributions. The topical scope of the book is broad, ranging from nanoelectronics and nanocatalysis to nanometrology. Common to all the books in the series is that they represent top-notch research and are highly application-oriented, innovative, and relevant for industry. Finally they collect a valuable source of information on safety aspects for governments, consumer agencies and the society.

The titles of the volumes in the series are as follows:

Human-related nanoscience and nanotechnology

Nanoscience and Nanotechnology for Human Health

Pharmaceutical Nanotechnology

Nanotechnology in Agriculture and Food Science

Nanoscience and nanotechnology in information and communication

Nanoelectronics

Micro- and Nanophotonic Technologies

Nanomagnetism: Perspectives and Applications

Nanoscience and nanotechnology in industry

Nanotechnology for Energy Sustainability

Metrology and Standardization of Nanomaterials

Nanotechnology in Catalysis: Applications in the Chemical Industry, Energy Development, and Environmental Protection

The book series appeals to a wide range of readers with backgrounds in physics, chemistry, biology, and medicine, from students at universities to scientists at institutes, in industrial companies and government agencies and ministries.

Ever since nanoscience was introduced many years ago, it has greatly changed our lives – and will continue to do so!

March 2016Marcel Van de Voorde

About the Series Editor

Marcel Van de Voorde, Prof. Dr. ir. Ing. Dr. h.c., has 40 years' experience in European Research Organisations, including CERN-Geneva and the European Commission, with 10 years at the Max Planck Institute for Metals Research, Stuttgart. For many years, he was involved in research and research strategies, policy, and management, especially in European research institutions.

He has been a member of many Research Councils and Governing Boards of research institutions across Europe, the United States, and Japan. In addition to his Professorship at the University of Technology in Delft, the Netherlands, he holds multiple visiting professorships in Europe and worldwide. He holds a doctor honoris causa and various honorary professorships.

He is a senator of the European Academy for Sciences and Arts, Salzburg, and Fellow of the World Academy for Sciences. He is a member of the Science Council of the French Senate/National Assembly in Paris. He has also provided executive advisory services to presidents, ministers of science policy, rectors of Universities, and CEOs of technology institutions, for example, to the president and CEO of IMEC, Technology Centre in Leuven, Belgium. He is also a Fellow of various scientific societies. He has been honored by the Belgian King and European authorities, for example, he received an award for European merits in Luxemburg given by the former President of the European Commission. He is author of multiple scientific and technical publications and has coedited multiple books, especially in the field of nanoscience and nanotechnology.

Foreword

Albert Einstein once remarked: “Look deep into nature, and then you will understand everything better.” Beginning with the idea that most people would not believe in, nanotechnology has allowed us – literally – to look deep into the functioning of biological mechanisms at molecular level and thereby define new pathways for diagnosis and treatment of human disease. The nanotechnology-based production of pharmaceuticals therefore has the potential to revolutionize the treatment of human disease, facilitate changes in future healthcare systems by enabling more personalized, predictive, preventive, regenerative, and even remote (tele)medicine, and has a major impact on the survival of the human race.

The book gives a thorough overview of the science and technology in the nanopharmacy spectrum worldwide, and it also clearly highlights the research requirements that Europe needs to undertake during the next decade if it is to achieve invaluable breakthroughs in this fascinating field of nanopharmacy – breakthroughs that will enable Europe to place itself among the top-ranking competitive industrial regions in the world.

This is because nanotechnologies provide the tools for analysis and manipulation of biological processes at the nanoscale, which is where diseases take root and progress. The result is an increasingly better understanding of the molecular biology of disease leading to new targets for more specific and earlier diagnostic and therapeutic strategies.

This publication – which gives me genuine pleasure to introduce to you – is perhaps the first time that Europe and the wider world have a unique opportunity. This is both to assess the current state of the art and to provide the larger nanomedicine community with new resources and strategies. It will make the best of European and international innovation so as to generate a highly competitive industrial sector. At the forefront is the very latest thinking in fundamental research, characterization and safety issues of nanotechnology as applied to the development of new drugs and treatments for medicine. This will help to meet the enormous challenge of bringing new innovative, safe, and cost-effective products to the patient in as short a time frame as possible. There is strong emphasis on patient needs and concerns, including personalized approaches that will make for new, efficient, and effective solutions for healthcare.

Applications of nanotechnology for healthcare perhaps best exemplify how interdisciplinary research is vital for future success. This is because all disciplines and their stakeholders are represented in this work: beginning with the laboratory-based scientists and including regulators, representatives from industry, and most important of all representatives from society at large. All play an equal part in delivering the appropriate benefits at the right time at the right price to the right patient.

Only collaborations, such as those represented in this publication, will bring new discoveries from science into products that generate greater economic value through more rapid societal use. It is literally the attention to such small details that can make this happen, for Albert Einstein also remarked: “Whoever is careless with the truth in small matters cannot be trusted with important matters.”1

This publication is a great initiative and will give an impetus to the entire nanopharmacy community in Europe. For this reason, I believe that this book should find a large distribution facilitating a broad debate between all policymaking bodies and research institutes in Europe.

Director-General, Publications Office,Rudolf Walter Strohmeier

European Commission, Luxembourg

Note

1.

2010, The Ultimate Quotable Einstein, Edited by Alice Calaprice, Section: On Humankind, Quote Page 187 and 188, Princeton University Press, Princeton, New Jersey.

Industrial Requirement on Nanopharmacy Research

Information on “nanotechnology” is proliferating within the scientific literature and media. In the field of pharmacy and medicine alone, the number of publications on nanotechnology has increased substantially over the past two decades. Searching the chemical database on CAS controlled terms for entries on “nano” in combination with medicine, pharmaceuticals, therapeutics, or formulations resulted in only eight publications in 1995. Since then the number of publications has jumped to 173 in 2005 and over 1400 in 2015. Therefore, nanotechnology in pharmacy became a very important field for academic and industrial research and development.

Nano-relevant techniques and applications are very diverse; they range from nanosized crystals of pharmaceutical drug substances to lipid carriers of submicrometer range, to functionalized particles for targeting, to particles for nucleotide or peptide delivery, among others. The abundance of technological options and possible applications appears to be overwhelming, and sometimes confusing. In this “gold rush” for an emerging key technology of the twenty-first century, it seems to be the right time to pause, take stock of the scientific basis for nanotechnology-enabled progress, and take a systematic and holistic view of emerging applications.

For these reasons, Pharmaceutical Nanotechnology starts by providing the reader with an understanding of the fundamental basic and applied sciences of nanotechnology in the context of pharmaceutical applications. This includes challenges associated with GMP manufacturing, scale-up, methods for characterization, and potential occupational and environmental safety issues. It is recognized that current and future applications of nanotechnology are at very different stages of maturity. Consequently, the book also provides the course of pharmaceutical drug development in a systematic manner. Opportunities and challenges are also addressed from the perspective of early discovery, preclinical and clinical development, to regulation and commercialization.

Throughout this journey, the reader will realize that nanotechnology is not a vague vision of a miracle technology that might come up in some distant future, but is already a reality in a substantial number of commercial products, including oral, dermatological, and parenteral treatments. On the other hand, the potential utility of nanotechnology in pharmacy is by far not fully exploited. New findings and concepts continue to emerge as is illustrated by over 320 new patent applications in the field of pharmaceutical and medical applications of nanotechnology in 2015 alone. Nanotechnology may play a crucial role in drug targeting and cellular delivery, oral and intravenous delivery of insoluble compounds, topical delivery to the lung, eye, and skin, diagnostic applications, and many other areas. The key to these new applications still lies in new research and sound science is still needed to elucidate mechanisms that underpin observed benefits. Despite the large number of publications, we still need a better and deeper understanding of the principles for preparation, characterization, and fate of nanoparticles in the body as well as in the environment.

Pharmaceutical nanotechnology still has the opportunity to avoid mistakes that have been made in the development and introduction of previous groundbreaking technologies. Researchers have previously been very enthusiastic about new opportunities, but the public were not brought on the journey, and sometimes unfounded worries about adverse effects are common. Therefore, Pharmaceutical Nanotechnology also addresses nanotoxicology and safety and ethical and societal aspects as integrated components of research and development of nanopharmaceutical products.

As demonstrated by the impressive list of contributors to this book, the challenges will hardly be met by a single inventor or institution. The topics are so diverse that they require multifunctional capabilities and collaborations in early laboratory research, pharmaceutical formulation, process engineering, material characterization, clinical evaluation and implementation, and regulatory and intellectual property considerations. Pharmaceutical Nanotechnology brings all these disciplines together to give a cross-cutting and in-depth review of this stimulating new field and is a very helpful basis for students and a base for academic research as well as provides industry with excellent innovation ideas. I wish the readers inspiring insights into the exciting field of the smallest particles.

Chief Scientist of Chemical & Pharmaceutical Development,Peter Serno

Bayer Pharma AG, Berlin

Head of Chemical & Pharmaceutical Development,Olaf Queckenberg

Bayer Pharma AG, Wuppertal

Introduction

Pharmaceutical Nanotechnology aims at applying nanotechnology to drug therapy of diseases and medical diagnostics. More exactly it involves the preparation and delivery of therapeutic substances in the molecular and nanometer size range to the expected site of action in the human body, reaching maximum efficacy while alleviating undesirable side effects at healthy organs and tissues. The importance of this emerging field of research and developments relies on the fact that nearly all present medicines exhibit poor pharmacokinetics and bioavailability characteristics, and instead of specifically concentrating and acting at their target sites they widely distribute within the body. Pharmaceutical Nanotechnology requires very specific knowledge on many topics such as drug formulation, drug delivery, route of administration, specific targeting, imaging, and diagnosis, and so on. Research in this field requires a multidisciplinary approach, involving pharmacists, material and chemical engineers, cellular biologists, and biophysicists as well as ICT specialists and medical specialists.

The goal of this unique book is to present an overall picture of the use of nanotechnology in pharmacy. It is designed to be a reference textbook on the application of nanotechnology in the development of nanostructures for therapeutic use. Focus is placed on the manufacturing and researching of candidate nanostructures as well as their translation into marketable medicines by industry. We also review the most interesting and promising developments in this emerging but fast developing field.

Following this brief introduction, Part One consists of Chapters 1–5 that give an entry to the Nanopharmacy revolution by addressing the history, potential, challenges, and most recent developments and applications of nanotechnology in pharmacy.

In Part Two, a systematic review of the fundamentals of nanopharmacy is performed with a description of the used nanostructures, their characterization methods, and a detailed overview of the preparation and manufacturing methods and issues. Established processes as well as new exploratory methods are separately reviewed and concrete actual examples of utilization given. All relevant aspects are being addressed including scale-up and occupational health.

Part Three reviews the various steps in the development of a new nanodrug. It includes the use of nanotools and models in drug discovery, drug targeting and design strategies, and nonclinical and clinical studies. Emphasis is laid on nanotoxicology and nanosafety aspects as well as regulatory issues for translation to the clinic of the most promising nanostructures. As the introduction of these new medicines may be controversial, ethical and societal aspects are also addressed in a specific chapter.

In Part Four, key medical applications of nanodrugs are reviewed. Diagnostics and imaging use and physical methods for treatment are first described. In the several following chapters and through the description of the various delivery routes in the body, main treatment areas such as cancer or infectious and neurodegenerative diseases are explained.

Finally, Part Five describes market prospects and industrial commercialization aspects with special focus on the commercial translation and its bottlenecks like the protection of intellectual property. Actual information about current commercialized products and market figures are also provided.

The chapters are written by leading researchers in pharmacy, biology, chemistry, physics, engineering, and medicine as well as law and social science from academia, industry, national/international laboratories, and government agencies in Europe, Israel, and the United States.

It is expected that this book will become a standard work for pharmacists and the pharmaceutical industry but also a database and a reference for scientists, researchers, and students, as well as for agencies, government, and regulatory authorities.

This book may bring inspiration for scientists, new ideas for drug developers, innovation in industry, and guidelines for toxicologists and finally will result in the establishment of guidelines for agencies and government authorities to establish safe rules in using this new promising technology. The book may result in breakthroughs in the pharmaceutical nanotechnology in such a way that medical doctors may cure life-threatening diseases such as cancer or infections with nanotechnology-based medicines, and thus in the welfare of the society.

Jean CornierAndrew OwenArno KwadeMarcel Van de Voorde

Part OneEntry to the Nanopharmacy Revolution

1History: Potential, Challenges, and Future Development in Nanopharmaceutical Research and Industry

Albertina Ariën1 and Paul Stoffels2

1Pharmaceutical Development and Manufacturing Sciences, Drug Product Development, Janssen Pharmaceutical Research & Development, Turnhoutseweg 30, Beerse, Belgium

2Chief Scientific Officer, Johnson & Johnson

Since the advent in 1906 of Dr. P. Erlich's magic bullets that would lookfor specific disease-causing agents in the human body, many therapies have been developed to increase the delivery of drugs to the target site. Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional drug therapy and aim to achieve both therapeutic and diagnostic functions in the same platform. These nanocarriers allow targeting of the medication to the site of action and release the drug in a controllable manner. Other features linked to nanopharmaceuticals are increased drug loading, increased bioavailability, enhanced efficacy, and increased safety. The nanocarriers are designed to be biocompatible and biodegradable.

A wide range of therapies are nowadays on the market or in late-stage development for the treatment of serious conditions such as cancer and infectious diseases [1,2]. Therapies include carriers of nanopharmaceuticals such as liposomes, lipid-based formulations such as solid lipid nanoparticles, nanocrystals, polymer-based nanoformulations, protein–drug conjugate nanoparticles, surfactant-based nanoformulations, metal-based nanoparticles such as iron oxide or gold nanoparticles, dendrimers, virosomes, and modified viruses.

The first product on the market employing nanotechnology was Doxil® that received US-FDA approval in 1995 for the treatment of AIDS-related Kaposi's sarcoma [3]. Doxil® are stealth liposomes encapsulating about 10 000 doxorubicin molecules [3,4]. Encapsulation minimizes side effects, such as cardiotoxicity, neutropenia, vomiting, myelosuppression, and alopecia, which are associated with high doses of free doxorubicin [5]. The incorporation of lipid and specifically cholesterol increases the bilayer cohesiveness and reduces leakage. The liposomes are designed by their size of approximately 100 nm and their pegylated surface to target to solid tumors via EPR effect (enhanced permeability and retention effect) and reduce toxicity to healthy tissues.

1.1 Nanopharmaceuticals in Cancer Therapy

Since, nanopharmaceuticals have become valuable arsenals in cancer therapy with enhancement of drug efficacy and decreased side effects. The efficiency of drug or gene delivery to a tumor site is dependent on the physicochemical properties of the delivery platform and a range of physiologically imposed design constraints, including clearance by the mononuclear phagocyte system and extravasation from circulation at the tumor site by the EPR effect.

The nanofeature of the pharmaceuticals contributes to enhanced solubility and chemical stability of the compounds along with potential protection from degradation by encapsulation into nanocarriers or coupling to synthetic polymers. Nanoparticle biodistribution and uptake by the reticuloendothelial system warranted the design of nanoparticles to evade rapid uptake such as lipid liposomes, albumin carriers, and PEGylation. PEGylation and conjugation to albumin respectively resulted in prolonged circulation and enhanced biodistribution of compounds, while the small size of nanopharmaceuticals led to improved tumor tissue accumulation [6].

Nanopharmaceuticals have improved biodistribution and targeting features as well as the potential of stimuli-sensitive microenvironments payload release. These collective features have led to the development of nanoparticle therapeutics of large antibody–drug conjugates (brentuximab vedotin and trastuzumab emtansine [6]) and small-molecule platforms such as liposomes (Doxil, DaunoXome, DepoCyt, Marqibo, Mepact, Myocet, Lipoplatin), polymeric nanoparticles (Eligard, Genexol, Opaxio, Zinostatin stimalamer), albumin nanoparticles (Abraxane), and metal-based nanoformulations (NanoTherm) [1,7].

Brentuximab vedotin and trastuzumab emtansine are antibody–drug conjugates (ADCs) with an anticancer drug conjugated to a targeting molecule. Brentuximab targets the protein CD30, a glycosylated phosphoprotein expressed by B cells, including B-cell lymphomas, some leukemias, and melanoma cancer stem cells [8–10]. Trastuzumab targets the human epidermal growth factor receptor 2 (HER2) overexpressed in HER2-positive breast cancer [11,12]. Monomethyl auristan E (MMAE) (brentuximab vedotin) and mertansine (trastuzumab emtansine) are too toxic to be used alone and hence coupling to a targeting antibody reduces toxic side effects. Several drug molecules are conjugated to each antibody via a valine–citrulline cleavable linker (brentuximab vedotin) or covalent linkage (trastuzumab emtansine) that is enzymatically degraded in endosomes following uptake. The relatively small number of approved ADCs highlights the difficulty in the development of nanotherapeutics to the clinic.

Since the introduction of Doxil on the market, many other liposomal formulations are developed [13]. More advanced liposomal carriers are designed to release their drug triggered by internal stimulus such as changes of pH or oxygen level or external stimulation such as local heating. Thermosensitive liposomes, such as ThermoDox, can release their payload in the tumor region with local heating owing to the gel-to-liquid crystalline phase change of the lipids at about 42 °C, a temperature that can be reached by local hyperthermia [13].

Another nanotherapeutic using temperature to induce tumor cell destruction or sensitization is NanoTherm, 15-nm-sized superparamagnetic iron oxide nanoparticles (SPION) coated with aminosilane. These nanoparticles are introduced directly in solid brain tumors and are exposed to a magnetic field that changes its polarity up to 100 000 times per second generating a local increase in temperature. Depending on the duration of exposure to the alternating magnetic field, the tumor cells may be destroyed or sensitized for further chemotherapy. Through the aminosilane coating, the nanoparticles remain localized, which allows repeated treatments [14].

Nanoparticle albumin-bound (nab™) technology is a nanotechnology-based drug delivery platform that exploits the natural properties of albumin to achieve a safe, solvent-free, efficient, and targeted drug delivery. Abraxane, or nab-paclitaxel, is a cremophor-free, albumin-bound 130-nm particle form of paclitaxel. The paclitaxel and albumin are not covalently linked but rather associated through hydrophobic interactions [15]. The particles of paclitaxel are in a noncrystalline, amorphous, readily bioavailable state, allowing for rapid drug release from the particles following intravenous administration. The albumin is thought to facilitate endothelial transcytosis and to play a role in preferential intratumoral accumulation of paclitaxel through its binding to SPARC (secreted protein acid and rich cysteine), a glycoprotein overexpressed in many tumors [15].

Nanopharmaceuticals have benefited from the concept of site-specific delivery. Active targeting of a nanoparticle is a way to minimize uptake in normal tissue and increase accumulation in a tumor. Active targeting can be achieved by linking, to the surface of the nanopharmaceuticals, molecules that bind specifically to surface membrane proteins that are upregulated in cancer cells [16]. These so-called targeting molecules are typically antibodies [17], antibody fragments [18], aptamers [19], or small molecules. Monoclonal IgG antibodies are widely used for protein recognition and targeting, since they have two epitope binding sites, high selectivity, and high binding affinity. Fab2 fragments of the antibodies retain both antigen-binding sites. Aptamers are folded single-strand oligonucleotides, usually 25–100 nucleotides in length (8–25 kDa) that bind to molecular targets [19]. Small molecules for targeting include peptides, growth factors, carbohydrates, ureas, and receptor ligands [20]. The interested reader is referred to Chapter 16 “Drug Targeting in Nanomedicine and Nanopharmacy: A Systems Approach” to read more on this topic.

1.2 Nanoparticles Actively Using the Host Machinery

Apart from cancer therapy, nanoparticles have become very valuable in vaccine therapy. Vaccine nanotechnology avant la lettre are the aluminum particles traditionally used as adjuvants, since most proteins are poorly immunogenic when administered alone. Strong adaptive immune responses to protein antigens typically require the antigen to be administered together with an adjuvant. Adsorption of the antigen on aluminum particles, either aluminum phosphate or aluminum hydroxide, transforms soluble antigens into particulate material. This form delays the release of the antigen and enhances the immune response by specifically activating macrophages and, additionally makes the antigen more prone to uptake by these antigen-presenting cells. Although used successfully since the 1930s, this approach does not work for every antigen, for example, tuberculosis and malaria. There is also some public concern regarding the ability of aluminum to translocate to the brain.

A more innovative approach to enhance the immune response is to integrate the antigen in liposomes. These virosomes consist of unilamellar phospholipid membrane nanovesicles incorporating virus-derived glycoproteins, 100–150 nm in diameter. The first commercial product based on this technology has been InflexalV®. The principle was to deliver influenza antigens within a nanostructure resembling a native influenza virus, but deprived of its genetic material and therefore of its in vivo replication capability. The preparation of virosomes [21,22] is based on virus dissolution, followed by a detergent removal procedure leading to the reconstitution of virus-like particles containing only the main virus antigens embedded in a lipid bilayer. Neither viral DNA nor core proteins are present in the final product. Properly formed virosomes retain the cell binding and membrane fusion properties of the native virus, mimicking the natural infection mechanism. This property, together with the particulate nature of virosomes, gives these structures the capability of triggering a broad immune response, involving both major histocompatibility complexes, MHC-I and MHC-II, while preventing the response against the structures themselves [23–25]. These nanoparticles are therefore considered an efficient delivery system, obsoleting the need for an extra adjuvant. Importantly, virosomes have a solid safety track record, as demonstrated during almost two decades of use. Due to versatility of this technology, flu vaccination was not the only application of this technology. The advantage of these reconstituted influenza virosomes is that the influenza glycoproteins embedded in the lipid bilayer activate macrophages and mediate membrane fusion and endocytosis. This leads to an accelerated cellular and humoral response [26,27]. The adjuvanting effect of influenza-derived virosomes was also exploited for the delivery of hepatitis A antigens (Epaxal®). Extensive clinical and postmarketing monitoring showed that Epaxal has an improved safety profile compared to an aluminum-adsorbed vaccine, while inducing a similar immune response. The difficulties with the stability of such virosomal structures have been recently overcome optimizing the formulation, allowing frozen as well as 4 °C long-term storage [28].

In contrast to these human-designed nanoparticles, Nature has provided us with surprisingly elegant nanopharmaceuticals, but only recently do we have the technology to unlock its potential. Millions of years of evolution have perfected viruses in their ability to infect host cells and express their viral genes. Although the viral replication materializes at the expense of the host cell, not all viruses are as pathogenic. For example, wild-type (wt) adenovirus typically causes only mild symptoms and is cleared by the immune system in healthy individuals. The relatively large icosahedral particles (about 80 nm) are proficient in transferring their linear double-stranded DNA to host cells. Scientists have taken advantage of this feature by deleting part of the viral genome (the E1 gene) and replacing it by a gene of choice. The resultant replication-deficient virus is a very efficient delivery device for any gene of interest, expressing high levels of the encoded protein. Originally explored for gene therapy purposes, it became soon apparent that E1-deleted adenoviruses coexpress low levels of viral proteins after cell transduction. This leads to an unexpectedly broad immune response, including local chemokine and cytokine responses. Transduced cells are rapidly cleared rendering the transgenic protein production transient. Although less suitable for gene therapy, this holds great promise for vaccination purposes. As opposed to one bolus injection of antigen in classical vaccines, recombinant adenoviruses use the cell machinery to produce the antigens in vivo over a period of a few weeks. This substantial but transient in vivo production supported by the immunogenic properties of adenoviruses lead to a robust and more balanced T- and B-cell immune response. Some infectious diseases that are unresponsive to traditional vaccines, such as Ebola or HIV, may finally be overcome using this technology [29–31]. In addition to prophylactic use, adenoviruses are currently also investigated for therapeutic use, for example in HPV infection, a major cause of cervical cancer. There are, however, two drawbacks that need to be addressed to use this next generation of vaccines to improve global health. First, one advantage of adenoviruses is also a potential problem. Its immunogenic character will lead to neutralizing antibodies against the vector requiring alternate vectors that show less preexisting immunity [32–34]. The second challenge is viral stability. Adenoviruses are sensitive to degradation during storage due to physical and chemical instability. Therefore, most adenoviruses are formulated as lyophilized products or as liquid formulations to be stored at −80 °C. However, recent advances have shown that with new and tailored formulations, it is possible to stabilize these complex biological structures to provide 2–3 year stability upon storage at 4 °C [35].

In recent years, significant progress has also been made in the field of viral gene therapy. After a few vector-related adverse events in the past, more suitable vectors have been further optimized for gene transfer applications. A wide range of target tissue is now in scope (e.g., muscle, liver, eye, salivary glands, and joint) and almost 1900 clinical trials [36] are ongoing in fields like cancer (e.g., gynecological and lung), neurological disorders (e.g., Alzheimer's), inflammatory diseases (e.g., rheumatoid arthritis), monogenic disorders (e.g., hemophilia A and B), ocular disorders (e.g., macular degeneration), and diabetes. A vector that appears to be particularly promising is adeno-associated virus (AAV). The first gene therapy product approved by the EMA in 2012 for lipoprotein lipase deficiency used this vector [37]. Originally discovered as a contaminant in adenovirus batches, AAV is now widely acknowledged for application in gene therapy. AAV is small compared to adenovirus, also nonenveloped but a single-stranded DNA virus from the family of parvoviruses. They are nontoxic and nonpathogenic in humans. The key advantage of recombinant AAV, replication incompetent, is that the absence of viral gene expression minimizes host immune responses. This allows stable gene transfer and long-term transgene expression. Using specific AAV serotypes allows tailoring of the tropism to the target organ. Further optimization can be done using tissue-specific promoters and codon-optimized transgenes. Difficulties with cumbersome AAV production and purification techniques have been overcome [38–40], but a point of concern remains the physically small transgene packaging capacity in AAVs limiting its use to relatively small genes. Recently, also RNA molecules and oligonucleotides based on RNA interference have proven their potential in gene therapy applications [41]. Liposomes incorporating nucleic acids or virus vector-mediated gene therapy can be used to downregulate specific cellular protein expression through RNA interference or microRNA production.

1.3 Nanopharmaceuticals for Oral Administration and Long-Acting Injectable Therapy

Although most research and commercial nanoparticles are administered parenterally, nanoparticles also have proven to enable oral drug delivery by increasing oral bioavailability. In recent years, advances in drug discovery and combinatorial chemistry have led to many potential drug candidates that can be characterized by poor aqueous solubility and hence low bioavailability [42]. Because of the large increase in surface area at smaller particle sizes, the dissolution rate and solubility of nanoparticulate drugs are significantly increased as described by respectively the Noyes–Whitney and Ostwald–Freundlich equations [42,43].

Particle size reduction techniques for small molecule APIs (active pharmaceutical ingredients) can be classified as “top-down” or “bottom-up” processes. Top-down processes are characterized by the milling of coarse particles into smaller particles, usually to a size range of 200–500 nm. Bottom-up nanoparticles are generated by controlled crystallization of a supersaturated solution. The most widely used top-down technique is wet media milling [44]. In this technique, drug crystals are reduced in particle size through the combination of high-energy shear and impact forces of the milling beads on the coarse drug particles. The nanoparticles that are generated are stabilized in the liquid phase by polymers or surfactants. The technology is proven to be scalable from discovery scale using as little as 10 mg API up to commercial manufacture [45]. Another technique that is frequently used to generate nanoparticles is high-pressure homogenization [46]. The nanoparticle suspensions that are formed can easily be further processed using techniques such as spray-drying, freeze-drying, or granulation to form solid oral tablets or fill into capsules [44]. The interested reader can learn more about particle size reduction techniques in Chapter 9 “Overview of Techniques and Description of Established Processes” and Chapter 12 “Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations”.

Multiple products, such as rapamycin, fenofibrate, aprepitant, and megasterol acetate, are on the market using the NanoCrystal® technology or the DissoCube® technology. The benefit of these nanoproducts over their conventional counterparts is that the dose can be significantly reduced and/or the food effect is much less pronounced [47]. The interested reader can learn more about oral applications of nanodrugs in Chapter 24 “Nanodrugs in Medicine and Healthcare: Oral Delivery.”

Nanosuspension generated by particle-size reduction can also be used for parenteral applications to promote long-acting injectable therapies and enhance the amount of drug that can be administered. This approach is already frequently used in preclinical studies but commercial and clinical applications remain limited [42,48]. The only commercial application currently is paliperidone palmitate injectable formulation (Invega Sustenna) that is a slow-release intramuscular injectable formulation for the treatment of patients with schizophrenia [49]. This therapy offers the opportunity of improved adherence and simplified medication regimen over the oral therapy that needs to be dosed daily. Although no longer nanoparticles, Invega Trinza uses the same technology to obtain particles showing a 3 month sustained release profile, further improving patient's quality of life. A number of other nanoparticles are currently under clinical evaluation such as thymectacin (Theralux, Celmed) and a combination therapy of cabotegravir (GlaxoSmithKline) and Rilpivirine (Janssen). The combination therapy of the two long-acting HIV therapies that are dosed every 4 or 8 weeks has shown to be comparable in maintaining viral suppression rates to a three-drug oral therapy of cabotegravir and two nucleoside reverse transcriptase inhibitors (ViiV Healthcare) [50]. This therapy offers great opportunities in developing countries where distribution and procurement of drugs is precarious and where adherence to daily oral therapy remains strikingly low for many reasons such as stigma against HIV. Data from studies in nonhuman primates have also shown great potential of the long-acting therapy in the prevention of HIV and may present a useful alternative for HIV preexposure prophylaxis (PrEP) [51].

Long-acting injectable formulations do not only lead to improved patient comfort but also have the potential to increase therapeutic compliance and efficacy even when patients cannot autonomously or reliably take their medication (e.g., due to disability/morbidity) or have limited access to medication such as in developing countries. The controlled release rate translates into lower variability in plasma drug concentrations, often reducing adverse effects, which in turn contributes to better clinical outcome. This is especially relevant for the treatment of chronic viral or bacterial infections in developing countries such as HIV, tuberculosis, malaria, and dengue. The failure to maintain minimal inhibitory concentrations could rapidly lead to incomplete viral suppression and ultimately drug resistance [52].

1.4 Bridging Future Nanomedicines to Commercialization

A lot of nanotherapeutics have already gained market access worldwide. Although for nanopharmacy to show its full potential in healthcare industry, a number of challenges remain to be addressed:

Stabilization of nanotherapeutics remains challenging. Further understanding on the principles governing physical stability of these colloidal drugs and prevention of specific degradation routes, for example, by formulation, remains to be elucidated.

The scale-up and manufacturing of nanotherapeutics remains variable. Process control is challenging and concerns related to the unpredictable impact of small variations to chemistry, manufacturing, and control (CMC) on the

in vivo

faith of the nanodrugs require tight controls of physicochemical properties of individual drug batches. Well-defined analytical tools that allow the full characterization of the nanoparticles' safety, efficacy, and quality need further development. Existing

in vitro

techniques have limitations in a way that

in vitro in vivo

correlation (IVIVC) cannot be performed easily and extensive bioequivalence testing is still needed. It would be great if novel

in vitro

methods become available that are straightforward to use and are predictive of the

in vivo