Pharmaceutical Nanotechnology, 2 Volumes

Jean Cornier is presently consultant to several companies in the areas of life science, new technologies and business development. He obtained his PhD from the University of Caen, France, and a MSc degree in pharmaceutical medicine from the University of Duisburg-Essen, Germany. Since 1986 he has worked in the space industry as expert in Materials and Life Science research and projects, was participant in space commercialisation initiatives supported by the European and German space agencies as well as in several EU-funded projects in biotechnology and civil security research. Professor Arno Kwade is Head of the Center of Pharmaceutical Engineering and of the Institute of Particle Technology at the Technical University Braunschweig, Germany. After his PhD he worked nine years in industry as partner of a consulting firm for processing and handling of materials and as general manager of a medium-sized company active in materials processing. Professor Kwade is speaker of the European working party on comminution and classification and developed a course on nanomilling, taken by more than 1000 participants from different industries, among them many pharmaceutical companies. Professor Andrew Owen holds a personal Chair in Molecular and Clinical Pharmacology at the University of Liverpool, UK. He is also affiliated to the MRC Centre for Drug Safety Science and the Wolfson Centre for Personalised Medicine. He is Chair of the British Society for Nanomedicine, is co-inventor of several patents related to nanomedicines and has contributed to over 150 publications and book chapters. He is co-founder of University commercial start-ups, a Fellow of the Royal Society of Biology, a Fellow of the British Pharmacological Society and member of the steering committee for the Academy of Pharmaceutical Sciences Nanomedicine Focus Group. Marcel Van de Voorde has 40 years` experience in European Research Organisations including CERN-Geneva, European Commission, with 10 years at the Max Planck Institute in Stuttgart, Germany. For many years, he was involved in research and research strategies, policy and management, especially in European research institutions. He holds a Professorship at the University of Technology in Delft, the Netherlands, as well as multiple visiting professorships in Europe and worldwide. He holds a doctor honoris causa and various honorary Professorships.He is senator of the European Academy for Sciences and Arts, in Salzburg and Fellow of the World Academy for Sciences. He is a Fellow of various scientific societies and has been decorated by the Belgian King. He has authored of multiple scientific and technical publications and co-edited multiple books in the field of nanoscience and nanotechnology.

• Foreword XXVIIIndustrial Requirement on Nanopharmacy Research XXIXIntroduction XXXIVolume 1Part One Entry to the Nanopharmacy Revolution 11 History: Potential, Challenges, and Future Development in Nanopharmaceutical Research and Industry 3Albertina Ariën and Paul Stoffels1.1 Nanopharmaceuticals in Cancer Therapy 41.2 Nanoparticles Actively Using the Host Machinery 51.3 Nanopharmaceuticals for Oral Administration and Long-Acting Injectable Therapy 81.4 Bridging Future Nanomedicines to Commercialization 101.5 Future Outlook 11Acknowledgments 12References 122 Nanoscale Drugs: A Key to Revolutionary Progress in Pharmacy and Healthcare 17Simon Sebastian Raesch, Marina Poettler, Christoph Alexiou, and Claus-Michael Lehr2.1 Introduction 172.2 Nanopharmacy Concepts to Improve the Safety and Efficacy of Medicines 202.3 Technical Realization of Nanopharmaceuticals 302.4 Safety of Nanopharmaceuticals 342.5 Present and Future of Nanopharmacy 35References 373 The Emergence of Nanopharmacy: From Biology to Nanotechnology and Drug Molecules to Nanodrugs 43Marilena Hadjidemetriou, Zahraa Al-Ahmady, Mariarosa Mazza, and Kostas Kostarelos3.1 Introduction 433.2 First Generation of Nanopharmaceuticals: From Drug Molecules to Nanodrugs 453.3 Conclusion 55References 564 Understanding and Characterizing Functional Properties of Nanoparticles 63Ester Polo, Valentina Castagnola, and Kenneth A. Dawson4.1 Introduction 634.2 The Approach to Characterization 70References 775 Omics-Based Nanopharmacy: Powerful Tools Toward Precision Medicine 81Daniel Rosenblum and Dan Peer5.1 Introduction 815.2 Precision Medicine 825.3 “OMICS” – New Era in Understanding Pathology 865.4 Nanomedicine 905.5 Future Outlook 93Acknowledgments 96References 96Part Two Fundamentals of Nanotechnology in Pharmacy 1016 Nanostructures in Drug Delivery 103Salma Nabil Tammam and Alf Lamprecht6.1 Introduction 1036.2 Nanocarrier Classification 1036.2.1 Inorganic Nanostructures 1046.3 Drug Loading and Release 1166.4 General Discussion and Conclusions 123References 1247 Characterization Methods: Physical and Chemical Characterization Techniques 135Sven Even F. Borgos7.1 The Need for Nanomedicine-Specific Characterization 1357.2 The Assay Cascade: From Basic Properties to Complex Interactions 1367.3 Physicochemical Characterization of Pristine Nanoparticles 1377.4 Characterization of Nanoparticles in the Biological Environment 1447.5 Conclusions and Future Outlook 149References 1508 Nanoparticle Characterization Methods: Applications of Synchrotron and Neutron Radiation 157Martha Brennich, Marité Cardenas, Hiram Castillo-Michel, Marine Cotte, V. Trevor Forsyth, Michael Haertlein, Simon A. J. Kimber, Geraldine Le Duc, Edward P. Mitchell, Adam Round, Murielle Salome, and Michael Sztucki8.1 Advanced Characterization: Synchrotron Light and Neutron Sources 1578.2 Application Examples 1598.3 Going Beyond Characterization Using Synchrotron X-rays: Nanoparticles for Diagnostic and Therapeutic pproaches 1688.4 Looking Ahead and Conclusions 169Acknowledgments 170References 1719 Overview of Techniques and Description of Established Processes 175Jan Henrik Finke, Michael Juhnke, Arno Kwade, and Heike Bunjes9.1 Introduction 1759.2 Processing of Liquid Drug Carrier Formulations 1769.3 Drug Nanoparticles and Process Chains to Solid Formulations 1929.4 Industrial Status and Framework 2159.5 Perspectives for Academia, Industry, and Regulatory Authorities 216References 21710 Nanopharmacy: Exploratory Methods for Polymeric Materials 231Kuldeep Bansal, Luana Sasso, Hiteshri Makwana, Sahar Awwad, Steve Brocchini, and Cameron Alexander10.1 Introduction 23110.2 Rationale for the Use of Polymers in Nanomedicines 23210.3 Polymer Structures and Properties 23410.4 Formulation of Copolymers into Micelles, Vesicles, and Nanoparticles 23610.5 Conjugation of Polymers to Drugs and Proteins 24010.6 Recent Advances in Polymer Synthesis for Therapeutic Applications 24810.7 Controlled Radical Polymerization (CRP) 25910.8 Concluding Remarks 260References 26111 Overview and Presentation of Exploratory Methods for Manufacturing Nanoparticles/“Inorganic Materials” 271Xavier Le Guevel11.1 Introduction 27111.2 Gold NPs 27211.3 Magnetic NPs 27911.4 Metal Oxide NPs 28211.5 Others (Silver, Quantum Dots, and Lanthanides) 28411.6 Conclusion and Perspective 285Acknowledgment 285References 28512 Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations 295Mostafa Nakach and Jean-René Authelin12.1 Introduction 29512.2 Presentation of Major Manufacturing Processes of Different Nanodrug Delivery Systems 29612.3 Nanodrug Delivery Systems as Marketed Products 30212.4 Particle/Vesicle Size Reduction Technologies 30212.5 Process Development and Scale-Down/Scale-Up Strategy 30812.6 Technological Concept for Manufacture of Drug Product for Human Use (GMP Unit) 32212.7 Conclusion 327References 32713 Occupational Safety and Health 331Thomas H. Brock13.1 Nanomaterials at the Workplace 33113.2 Legal Aspects 33513.3 Management of Uncertainty 33613.4 Risks of Nanomaterials for Researchers and Workers 33613.5 Prudent Practices and Proven Concepts for Controlling Risks 33813.6 Instruction and Training 35113.7 Summary 352References 352Volume 2Part Three Development of Nanopharmaceuticals 35514 Micro- and Nano-Tools in Drug Discovery 357Andreas Dietzel, Monika Leester-Schädel, and Stephan Reichl14.1 Introduction 35714.2 General Concepts of Miniaturization 35714.3 Micro- and Nanofabrication 35914.4 Nanoformulation 36714.5 Organ-on-a-Chip 372References 37515 Computational Predictive Models for Nanomedicine 379Marco Siccardi, Alessandro Schipani, and Andrew Owen15.1 Introduction 37915.2 Molecular Modeling in Nanomedicine 38115.3 Computational Approaches for Predicting Nanotoxicology 38415.4 Simulation of Nanoparticle Pharmacokinetics 38615.5 Conclusion 395References 39716 Drug Targeting in Nanomedicine and Nanopharmacy: A Systems Approach 403Jingwei Shao, Lisa McConnachie, and Rodney J.Y. Ho16.1 Introduction 40316.2 A Systems Approach to Drug Delivery and Drug Targeting 40516.3 Current Nanomedicine Products 40716.4 Transformation of a Discovery of Disease Target to a Therapeutic Product 41016.5 The Role of Targeted Nanoformulations and a Systems Approach in Drug Development 41216.6 Targeting Drugs to Sites of Action 41316.7 A Size-Dependent Targeting to Tissues and Cells 41416.8 Ligand–Receptor-Based Targeting: Active Drug Targeting 41716.9 Conclusions and Future Prospects 421References 42217 Nanoparticle Toxicity: General Overview and Insights Into Immunological Compatibility 425Marina A. Dobrovolskaia17.1 Introduction 42517.2 Systemic Toxicity 42717.3 Pulmonary Toxicity 42817.4 Cutaneous Toxicity 43117.5 Immunotoxicity 43217.6 Unintended Presence of Nanosized Materials in Pharmaceutical Formulations 43417.7 Conclusion 435Acknowledgments 435References 43618 An Overview of Nanoparticle Biocompatibility for Their Use in Nanomedicine 443Matthew S.P. Boyles, Leagh G. Powell, Ali Kermanizadeh, Helinor J. Johnston, Barbara Rothen-Rutishauser, Vicki Stone, and Martin J.D. Clift18.1 Introduction 44318.2 Nanomedicine 44418.3 Biocompatibility of Nanoparticles for Medical Application 44518.4 Summary 458References 45919 Translation to the Clinic: Preclinical and Clinical Pharmacology Studies of Nanoparticles – The Translational Challenge 469Rachel Tyson, Leah Osae, Andrew J. Madden, and Andrew T. Lucas, and William C. Zamboni19.1 Introduction 46919.2 Nanoparticle Formulations 46919.3 Pharmacokinetic Characterization 47019.4 Mononuclear Phagocyte System 47019.5 Delivery of CMA in Tumor 47219.6 Methods to Target Brain Tumors 47519.7 Physical Characteristics 47719.8 The Effect of MPS on CMA PK and PD 48019.9 Age 48319.10 Gender 48619.11 Tissue and Organ Effects 48719.12 Drug–Drug Interactions 48819.13 Prior Treatment 48919.14 Translational Challenges 49019.15 Future Perspectives on PK and PD 491References 49220 Regulatory Issues in Nanomedicines 497Marisa Papaluca, Falk Ehmann, Ruben Pita, and Dolores Hernan20.1 Nanomedicines and the Pharmaceuticals Regulatory Framework in Europe 49720.2 The European Medicines Agency and Nanomedicines 49920.3 Is It Important to Define Nanomedicines? 50120.4 Communicating About Nanomedicines 50320.5 Liposomal Formulations: State of Play at the EMA 50420.6 Nanosimilar Colloidal Intravenous Iron-Based Preparations 51120.7 International Landscape and Convergence on Nanomedicines 51420.8 Conclusions and Way Forward 517References 51821 Social Studies of Nanopharmaceutical Research 521Michael Schillmeier21.1 Engaging with Ethical, Legal, and Social Implications of Nanoresearch 52121.2 Nanopharmacy and the “Culture of Promise” 52221.3 From “Science Meets Society” to Translation as a Social Process 52321.4 Metaphors and Nanopharmacy 52521.5 Nanopharmacy and “Personalized Medicine” 52621.6 Concluding Remarks 528References 529Part Four Pharmaceutical Applications of Nanomaterials 53322 Nanoparticles for Imaging and Imaging Nanoparticles: State of the Art and Current Prospects 535Thomas Maldiney and Nathalie Mignet22.1 Introduction 53522.2 Conception of Nanotechnologies for Imaging 53622.3 In Vivo Nanoparticle Imaging to Gain Insight into Nanomedicine Biodistribution and Stability 54422.4 Translational Interest of Nanoparticles for Medical Imaging 54822.5 Conclusion 553References 55323 Nanoparticle-Based Physical Methods for Medical Treatments 561Christine Ménager23.1 Photothermal Therapy 56123.2 Photodynamic Therapy 56523.3 Magnetic Hyperthermia 56723.4 Radiotherapy 57123.5 Sonodynamic Therapy 57223.6 Cryosurgery 57323.7 Future Perspectives 574References 57524 Nanodrugs in Medicine and Healthcare: Oral Delivery 579Alejandro Sosnik24.1 General Aspects and Challenges of Oral Drug Delivery 57924.2 Pure Drug Micronization as a Conceptual Preamble to More Complex Drug Delivery 58024.3 Nanotechnology Platforms for Improved Oral Drug Delivery 58124.4 Conclusive Remarks 591Acknowledgments 591References 59125 Steroidal Nanodrugs Based on Pegylated Nanoliposomes Remote Loaded with Amphipathic Weak Acids Steroid Prodrugs as Anti-Inflammatory Agents 603Keren Turjeman and Yechezkel Barenholz25.1 A Short Relevant Background on Inflammatory and Autoimmune Diseases 60325.2 Drug Delivery Systems (DDS) Based on Nanoparticles (NP) for the Treatment of Diseases That Involve Inflammation 60525.3 Glucocorticosteroid as Anti-Inflammatory Agents 60725.4 Steroidal Nanodrugs Based on Pegylated Nanoliposomes Remote Loaded with Amphipathic Weak Acids Steroid Prodrugs as Anti-Inflammatory Agents 60925.5 Methods for Loading Drugs into Liposomes 61025.6 Comparing Various Approaches Used for Formulating Liposomal GCs 61225.7 The Use of Liposomes Loaded with Steroids as Anti-Inflammatory Agents: A Brief Historical Perspective 61525.8 Lessons Learned from Experimental Animal Models of Diseases That Involve Inflammation 618References 62526 Nanodrugs in Medicine and Healthcare: Pulmonary, Nasal and Ophthalmic Routes, and Vaccination 633Christel C. Müller-Goymann and Mukta Paranjpe26.1 Introduction 63326.2 Different Routes of Administration 63426.3 Different Types of Nanoparticles for Different Routes of Administration 63826.4 Manufacturing Processes of Nanoparticles 63826.5 Different Diseases Targeted Via Nanoparticle-Based Drug Delivery Systems 64026.6 Challenges Faced in Formulation Development of Nanoparticle-Based Systems 641References 64227 Neurodegenerative Diseases – Alzheimer’s Disease 649Maria Gregori and Francesca Re27.1 Introduction 64927.2 Diagnosis 65027.3 Therapy of Alzheimer’s Disease 653References 656Part Five The Nanopharmaceutical Market 66128 A Practical Guide to Translating Nanomedical Products 663Raj Bawa28.1 From the Laboratory to the Clinic: Overcoming the Valley of Death 66628.2 Irreproducible Preclinical Research: A Bottleneck for Translation? 67328.3 Protecting Inventions via Patents: The Cornerstone of Translation 67828.4 Terminology and Nomenclature: Lost in Translation 68028.5 Gaps in Regulatory Guidance 68228.6 Conclusions and Outlook 68328.7 Disclosures and Conflict of Interest 694References 69429 Development and Commercialization of Nanocarrier-Based Drug Products 697Marianne Ashford29.1 Drivers for New Medicines 69729.2 Current Marketed Nanomedicines 69929.3 Developing Nanomedicines 70529.4 Commercialization of Nanomedicines 72229.5 Conclusions 732References 73230 Future Outlook of Nanopharmacy: Challenges and Opportunities 735Dan Peer and Marcel Van de Voorde30.1 Matching the NC’s Delivery Mode of Action (MoA) to the Tumor Type 73630.2 Nonpredictive Animal Models 73730.3 The Lack of Reliable Techniques that can Efficiently Characterize NCs and Measure their Stability in the Human Body 73730.4 The Challenge of Scaling Up NCs 738References 740Index 743