Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines

424 Pages·2009·11.13 MB·English

Delivery Technologies
for Biopharmaceuticals
Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines
Edited by Lene Jorgensen and Hanne Mørck Nielsen
© 2009 John Wiley & Sons, Ltd. ISBN: 978-0-470-72338-8
Delivery Technologies
for Biopharmaceuticals
Peptides, Proteins, Nucleic Acids
and Vaccines
Editors
Lene Jorgensen
Faculty of Pharmaceutical Sciences
University of Copenhagen, Denmark
Hanne Mørck Nielsen
Faculty of Pharmaceutical Sciences
University of Copenhagen, Denmark
A John Wiley & Sons, Ltd., Publication
This edition fi rst published 2009
© 2009 John Wiley & Sons Ltd
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Library of Congress Cataloging-in-Publication Data
Delivery technologies for biopharmaceuticals : peptides, proteins, nucleic acids, and vaccines / editors, Lene Jorgensen,
Hanne Mørck Nielsen.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-470-72338-8 (cloth : alk. paper) 1. Drug delivery systems. 2. Drug carriers (Pharmacy) I. Jorgensen,
Lene. II. Nielsen, Hanne Mørck.
[DNLM: 1. Drug Delivery Systems–methods. 2. Biological Products. QV 785 D355 2009]
RS199.5.D45 2009
615′.6–dc22
2009025904
A catalogue record for this book is available from the British Library.
ISBN 9780470723388 (H/B)
Set in 10 on 12 pt Times by Toppan Best-set Premedia Limited
Printed and bound in Great Britain by CPI Antony Rowe Ltd, Chippenham, Wiltshire
Contents
Preface page xv
List of Contributors xvii
INTRODUCTION 1
1. Challenges in Delivery of Biopharmaceuticals; the Need for Advanced
Delivery Systems 3
Hanne Mørck Nielsen and Lene Jorgensen
1.1 Introduction 3
1.2 Overcoming Delivery Barriers 4
1.2.1 Stabilization 4
1.2.2 Enhancing Delivery 5
1.3 Drug Delivery Technologies and Excipients 5
1.4 Risks 6
1.5 Conclusion 7
References 7
DELIVERY OF BIOPHARMACEUTICALS 9
2. Novel Formulation Approaches for Peptide and Protein Injectables 11
Mingshi Yang and Sven Frokjaer
2.1 Introduction 11
2.2 Formulation Challenges 12
2.3 Chemical Modifi cation of Proteins and Peptides 13
2.3.1 PEGylation 13
2.3.2 Glycoengineering 15
2.3.3 Acylation 16
2.3.4 Amino Acid Substitution 17
2.3.5 Protein Fusion 17
2.4 Depot Delivery Systems 18
2.4.1 Micro- and Nanoparticulate Systems 18
2.4.2 In Situ Depot-Forming Systems 21
2.4.3 Implant Systems 21
vi Contents
2.5 Other Delivery Systems 22
2.5.1 Protein Crystallization and/or Precipitation 22
2.5.2 Injection Devices 22
2.6 Conclusions 23
References 23
3. Novel Non-Injectable Formulation Approaches of Peptides
and Proteins 29
Shirui Mao, Dongmei Cun and Yoshiaki Kawashima
3.1 Introduction 29
3.2 Intranasal Delivery of Peptide/Protein Drugs 30
3.2.1 Properties of Intranasal Delivery 30
3.2.2 Strategies to Enhance Intranasal Absorption 31
3.3 Pulmonary Delivery of Peptide/Protein Drugs 36
3.3.1 Properties of Pulmonary Delivery 36
3.3.2 Strategies to Enhance Pulmonary Delivery 36
3.4 Buccal Administration of Peptide/Protein Drugs 42
3.4.1 Properties of Buccal Delivery 42
3.4.2 Strategies to Improve Buccal Absorption 44
3.5 Oral Delivery of Peptide/Protein Drugs 47
3.5.1 Challenges of Oral Delivery 47
3.5.2 Strategies to Enhance Oral Absorption 48
3.6 Transdermal Delivery of Peptide/Protein Drugs 53
3.6.1 Properties of Transdermal Delivery 53
3.6.2 Strategies to Improve Transdermal Absorption of
Proteins/Peptides 53
3.7 Conclusions 56
References 57
4. Chemical Vectors for Delivery of Nucleic Acid-Based Drugs 69
Elizabeth A. Vasievich and Leaf Huang
4.1 Introduction 69
4.2 Barriers to Delivery of Nucleic Acids 70
4.2.1 Anatomical 70
4.2.2 Cellular 70
4.3 Major Classes of Delivery Vectors 71
4.3.1 Introduction 71
4.3.2 Cationic Lipids 71
4.3.3 Cationic Polymers 73
4.3.4 Cationic Dendrimers 74
4.3.5 Cell Penetrating Peptides (CPP) and DNA Mimics 75
4.3.6 Naked DNA 76
4.4 Targeted Delivery 76
4.4.1 Introduction 76
4.4.2 Targeting Solid Tumours and/or Metastasis 77
Contents vii
4.5 Triggered Release 79
4.5.1 Introduction 79
4.5.2 Proton Sponge Effect 80
4.5.3 Magnetofection™ (Magnetic Delivery) 80
4.5.4 Hyperthermic Delivery 81
4.5.5 Reductive Agents 82
4.5.6 Biotin–Avidin 82
4.5.7 Electrochemical 83
4.6 Recent Clinical Trials Using Naked and Chemically Complexed
Nucleic Acids 83
4.6.1 Introduction 83
4.6.2 Naked Nucleic Acids in Clinical Trials 83
4.6.3 Lipid-Based Nucleic Acid Carriers in Clinical Trials 85
4.6.4 Polymer-Based Nucleic Acid Carriers in Clinical Trials 86
4.7 Conclusion 86
References 87
5. Viral Technology for Delivery of Nucleic Acids 93
Shervin Bahrami and Finn Skou Pedersen
5.1 Introduction 93
5.2 Barriers and Topological Requirements to Cellular Entry 95
5.2.1 Enveloped Viruses and Membrane Fusion 95
5.2.2 Non-Enveloped Viruses 97
5.3 Routes of Administration 98
5.4 Delivery Vector Requirements 98
5.4.1 Targeting 98
5.4.2 Expression 100
5.4.3 Safety 101
5.5 Examples of Viral Delivery Technology 103
5.5.1 Retroviral and Lentiviral Vectors 103
5.5.2 Adenovirus Vectors 105
5.5.3 Adeno-Associated Virus Vectors 106
5.5.4 Mixed Delivery Systems 107
5.5.5 In Vitro Assembled Delivery Vehicles 108
5.6 Conclusion 108
References 109
6. The Innate Immune Responses, Adjuvants and Delivery Systems 113
S. Moein Moghimi
6.1 Introduction 113
6.2 Dendritic Cell Immunobiology 117
6.3 Antigen Capture 119
6.4 Particulate Antigen Delivery Systems 120
6.5 Signalling Receptors and the Role of Adjuvants 121
6.6 Conclusions 123
References 124
viii Contents
DELIVERY TECHNOLOGIES FOR BIOPHARMACEUTICALS 129
7. Lipid Nanoparticle-Based Systems for Delivery
of Biomacromolecule Therapeutics 131
Susana Martins, Domingos C. Ferreira and Eliana B. Souto
7.1 Introduction 131
7.2 Defi nitions and Properties of Solid Lipid Nanoparticles (SLNs) 133
7.3 Defi nitions and Properties of Lipid-Drug Conjugates (LDCs) 135
7.4 Administration, Delivery and Targeting 136
7.5 Toxicity and Safety 138
7.6 Applications for Biopharmaceuticals 139
7.6.1 Peptides and Proteins 139
7.6.2 Nucleic Acids 139
7.6.3 Vaccines 142
7.7 Conclusions 142
References 142
8. Dendrimers in Delivery of Biopharmaceuticals 149
Chandan Thomas and Fakhrul Ahsan
8.1 Introduction 149
8.1.1 Properties of Dendrimers as a Carrier System 150
8.2 Case I – Application of Dendrimers in Delivery of Large Molecular
Weight Drugs 153
8.3 Case II – Application of Dendrimers in Gene Delivery 155
8.3.1 Case IIA – Application of PAMAM-PLGA Microparticle
Conjugates in Gene Delivery 156
8.3.2 Case IIB – Application of Dendrimers in siRNA Delivery 158
8.4 Case III – Application of Dendrimers in Vaccine Delivery 162
8.5 Concluding Remarks 165
References 166
PEPTIDES AND PROTEINS 169
9. Modifi cation of Peptides and Proteins 171
Susanne Hostrup, Kasper Huus and Henrik Parshad
9.1 Introduction 171
9.2 PEGylated Peptides and Proteins 171
9.2.1 Methods 172
9.2.2 Conceptual Considerations on PEGylation 173
9.2.3 Pharmacokinetic Aspects 174
9.2.4 Pharmaceutical Aspects 175
9.2.5 PEGylated Proteins in Advanced Delivery Systems 177
9.3 Lipidization of Peptides and Proteins 177
9.3.1 Methods of Lipidization 177
9.3.2 Conceptual Considerations on Lipidization 178
Contents ix
9.3.3 Improved Pharmacokinetics 178
9.3.4 Improved Delivery via Non-Parenteral Delivery Routes 179
9.3.5 Pharmaceutical Aspects 180
9.3.6 Lipidization in Advanced Delivery Systems 181
9.4 Modifi cation of the Primary Structure of Peptides and Proteins 181
9.4.1 Strategies for Designing Protein Analogues 182
9.4.2 Advantages and Disadvantages 183
9.4.3 Pharmaceutical Aspects – General Principles for Improving
Protein Stability 183
9.4.4 Pharmacokinetic Aspects 185
9.4.5 Manipulating the Isoelectrical Point (pI) by Molecular
Engineering 185
9.5 General Considerations on Processing and Characterization 186
9.6 Conclusions 186
References 187
10. Nanocarriers for the Delivery of Peptides and Proteins 193
Kenneth Lundstrom
10.1 Introduction 193
10.2 Polymeric Nanoparticles 194
10.2.1 Lactic/Glycotide Polymers 194
10.2.2 Polycaprolactones 195
10.2.3 Polyphosphoesters 195
10.2.4 Polyanhydrides 196
10.2.5 Polyorthoesters 196
10.2.6 Block Copolymers with a Specifi c Emphasis on Medusa 197
10.2.7 Cross-Linked Dextran 198
10.3 In Situ Depot Forming Systems 199
10.3.1 Precipitation Systems 199
10.3.2 Thermal Gelling Systems 199
10.3.3 Cross-Linked Systems 200
10.3.4 Thermoplastic Semisolids 201
10.4 Conclusions 202
References 202
11. Polymer-Based Delivery Systems for Oral Delivery of Peptides
and Proteins 207
Bruno Sarmento, Domingos Ferreira and Teófi lo Vasconcelos
11.1 Introduction 207
11.2 Advances in Oral Protein Delivery 208
11.3 Intestinal Considerations for Protein Absorption 209
11.4 Polymer-Based Delivery Systems for Oral Delivery of Proteins 211
11.4.1 Hydrogels 211
11.4.2 Patches and Tablets 212
11.4.3 Microparticles 213
11.4.4 Nanoparticles 215
x Contents
11.5 Conclusions 219
References 220
12. Advanced Pulmonary Delivery of Peptides or Proteins Using
Polymeric Particles 227
Yu Seok Youn, Kang Choon Lee, You Han Bae, Kun Na and
Eun Seong Lee
12.1 Introduction 227
12.2 Practical Issues in the Pulmonary Delivery of Peptides and Proteins 228
12.2.1 Physiological Features of the Lungs 228
12.2.2 Barriers to the Pulmonary Delivery of Peptides and Proteins 228
12.2.3 Factors Affecting the Pulmonary Delivery of Peptide and
Protein Particles 230
12.3 Polymeric Microparticles for Delivering Peptides and Proteins 231
12.4 Porous Microparticles 232
12.5 Polymeric Nanoparticles 237
12.6 Sustained or Controlled Release Issues in Polymeric Particle
Formulations 239
12.7 Stability Issues of Peptides and Proteins in Particles 240
12.8 Toxicity Issues of Inhaled Particles 240
12.9 Conclusions 240
References 241
NUCLEIC ACIDS 245
13. Polymer Microparticles for Nucleic Acid Delivery 247
Tim Pearce, Jared Hierman and Chun Wang
13.1 Introduction 247
13.2 Microparticles Based on Poly(Lactic-co-Glycolic Acids) (PLGA) 248
13.2.1 Overview 248
13.2.2 Design Parameters 248
13.2.3 General Strategies and Fabrication of Microparticles 251
13.2.4 Optimization of Microparticle Formulations 253
13.2.5 Combining Polycations with PLGA Microparticles 254
13.2.6 Current Applications 256
13.3 Other Types of Polymer Microparticles 257
13.3.1 Alginate 257
13.3.2 Chitosan 258
13.3.3 Hyaluronan (HA) 259
13.3.4 Macro-Albumin Aggregates (MAA) 260
13.3.5 Poly(D,L-Lactide-co-4-Hydroxy-L-Proline) (PLHP) 260
13.3.6 The Pluronics 261
13.3.7 Poly(Ortho Esters) (POEs) 262
13.3.8 Polyacrylamide 263
13.4 Conclusions 263
References 264
Contents xi
14. Pulmonary Delivery of Small Interfering RNA for Novel
Therapeutics 269
Qing Ge, David Evans, John J. Xu, Harry H. Yang and
Patrick Y. Lu
14.1 Introduction 269
14.2 RNA Interference: Mechanism of Action 270
14.3 Lung Physiology 270
14.4 Animal Models 272
14.5 siRNA Delivery to Treat Pulmonary Diseases 273
14.5.1 Challenges 273
14.5.2 Viral Versus Non-Viral Vectors 274
14.5.3 Airway siRNA Delivery 275
14.5.4 Intravenous siRNA Delivery 278
14.5.5 Other Delivery Methods 279
14.6 siRNA-Induced Infl ammatory Response 279
14.7 Case Studies 280
14.7.1 siRNA Therapeutics Against RSV and PIV Infection in
Mouse 280
14.7.2 siRNA Therapeutics for Treatment of SCV Infection in
Monkey 281
14.8 Faster Drug for Unknown Bugs 284
14.9 Conclusions 284
References 285
15. Lipid-Based Formulations for siRNA Delivery 291
Camilla Foged, Pieter Vader and Raymond M. Schiffelers
15.1 Introduction 291
15.2 Cationic Lipid-Based Delivery Systems for Nucleic
Acid-Based Drugs 292
15.2.1 Helper Lipids 293
15.2.2 Lipopolymers 294
15.2.3 Active Targeting 294
15.3 Neutral and Anionic Lipid-Based Drug Delivery Systems 296
15.4 Mechanisms of Internalization 296
15.5 Immune Activation 297
15.6 Conclusions 299
References 300
16. Cellular Bioavailability of Peptide Nucleic Acids (PNAs) Conjugated
to Cell Penetrating Peptides 305
Takehiko Shiraishi and Peter E. Nielsen
16.1 Introduction 305
16.2 Peptide Nucleic Acids (PNAs) 306
16.3 Cell Penetrating Peptides (CPPs) 306
16.4 Cellular Uptake Versus Bioavailability 307