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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

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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:

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

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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

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 Cornier
Andrew Owen
Arno Kwade
Marcel Van de Voorde

Part One
Entry to the Nanopharmacy Revolution