Oral Delivery of Macromolecular Drugs (eBook)

Andreas Bernkop-Schnürch is the Dean of the Faculty of Chemistry and Pharmacy and Professor of Pharmaceutical Technology at the University of Innsbruck, Austria. His main interests focus on non-invasive drug delivery systems, multifunctional polymers such as thiomers, mucoadhesion and permeation enhancement. He is author of more than 200 original research and review articles and received the Research-Award of the City of Vienna (Vienna), EURAND-Award (Boston), Best of Biotech Award (Vienna), MBPW-Award (Munich), PHÖNIX Award (Mannheim), Houska-Award (Vienna) and Austrian-Nanoaward (Vienna). In addition, Andreas Bernkop-Schnürch is founder and owner of the following companies: ThioMatrix GmbH, Dr. K. Schnürch KG and Green River Polymers GmbH.

Oral Delivery of Macromolecular Drugs 2
Preface 5
Contents 8
Contributors 10
About the Editor 12
Enzymatic Barriers 13
1.1 Introduction 14
1.2 The Peptidases 16
1.3 The Nucleases 17
1.4 Other Enzymes 18
1.5 Where Are the Enzymes in the GI Tract? 19
1.5.1 The Stomach 20
1.5.2 The Lumen of the Small Intestine 20
1.5.2.1 Pancreatic Enzymes 20
1.5.2.2 Cellular Enzymes 22
1.6 Quantitative Aspects of Intestinal Enzymes: How Much and How Active? 24
1.7 The Colon 25
1.8 The Importance of In Vitro Testing 26
1.8.1 Strategies for In Vitro Testing of the Stability of Therapeutic Macromolecules and Macromolecular Formulations 27
1.9 Conclusions 29
References 29
Gastrointestinal Mucus Gel Barrier 32
2.1 Introduction 33
2.2 Mucin Structural Properties 34
2.2.1 Multi-domain Organization 34
2.2.1.1 Mucin (O-Glycosylated) Domains 35
2.2.1.2 CS-Domains 35
2.2.1.3 D-Domains 35
2.2.1.4 C- and CK-Domains 36
2.2.2 Glycosylation 36
2.2.2.1 O-Glycosylation 36
2.2.2.2 N-Glycosylation 37
2.2.2.3 C-Mannosylation 37
2.2.3 Oligomerization/Multimerization 38
2.2.4 Molecular Polydispersity 40
2.3 Mucin Biosynthesis and Intracellular Processing 41
2.3.1 Endoplasmic Reticulum 41
2.3.2 Golgi Complex 42
2.4 Mucin Intracellular Storage and Secretion 44
2.4.1 Mucin Granule 44
2.4.2 Mucin Granule Exocytosis 45
2.4.2.1 Regulatory Aspects 45
2.4.2.2 Biochemical/Biophysical Aspects 46
2.5 Mucin Extracellular Organization 47
2.5.1 Mucin Entanglements 47
2.5.2 Other Interchain Links 48
2.5.3 Mucinases 49
2.5.4 Emerging Notion 49
2.6 Other Mucus Components 51
2.7 Diffusion of Macromolecules in Mucus 51
2.7.1 Influence of Mesh Size 51
2.7.2 Influence of Other Factors 53
2.8 Conclusions 53
References 54
The Absorption Barrier 60
3.1 Introduction 60
3.2 Anatomy of the Digestive Tract 61
3.3 Barriers to Transcellular Absorption 63
3.3.1 Passive Diffusion 63
3.3.2 Transporter Systems 64
3.3.3 Pinocytosis 65
3.3.4 Transport by Caveolae 66
3.3.5 Efflux Systems 67
3.4 Barriers to Paracellular Absorption 68
3.4.1 The Tight Junctional Complex 68
3.4.2 Modulation of Intestinal Tight Junctions 70
References 72
Strategies to Overcome the Enzymatic Barrier 76
4.1 Introduction 77
4.2 Formulations That Can Protect Drugs from Enzymatic Degradation 77
4.3 Chemical Modification 78
4.3.1 Modification of N and C Terminus 79
4.3.2 Replacement of Labile Amino Acids 79
4.3.3 PEGylation 80
4.4 Enzyme Inhibitors 81
4.4.1 Protease Inhibitors Which Are Not Based on Amino Acids 81
4.4.2 Protease Inhibitors Which Are Based on Amino Acids and Modified Amino Acids 82
4.4.3 Protease Inhibitors Which Are Based on Peptides and Modified Peptides 83
4.4.4 Protease Inhibitors Which Are Based on Polypeptides 84
4.4.5 Protease Inhibitors That Can Complex Ions 85
4.4.6 Protease Inhibitors Based on Multifunctional Mucoadhesive Polymers 86
4.4.6.1 Poly(acrylates) 87
4.4.6.2 Thiolated Polymers 87
4.4.6.3 Polymer-Enzyme Inhibitor Conjugates 88
4.5 Conclusion and Future Trends 91
References 91
Low Molecular Mass Permeation Enhancers in Oral Delivery of Macromolecular Drugs 95
5.1 Introduction 96
5.2 Transcellular Permeation Enhancers 97
5.2.1 Non-ionic Surfactants 97
5.2.2 Steroidal Detergents 97
5.2.3 N-Acetylated alpha-Amino Acids and N-Acetylated Non-alpha-Amino Acids 98
5.3 Paracellular Permeation Enhancers 99
5.3.1 Fatty Acids 99
5.3.2 Medium-Chain Mono- and Diglycerides 101
5.3.3 Acylcarnitines and Alkanoylcholines 101
5.3.4 Chelating Agents 102
5.3.5 Zonula Occludens Toxin 102
5.3.6 NO Donors 104
5.4 Oral Macromolecular Drug Delivery Systems Containing Low Molecular Mass Permeation Enhancers 104
5.5 Conclusion 106
References 107
Polymeric Permeation Enhancers 112
6.1 Introduction 113
6.2 Polyacrylates 113
6.2.1 Polyacrylates as Absorption Enhancers 114
6.3 Chitosan 116
6.3.1 Application, Mechanism and Safety Aspects 116
6.3.2 Chitosan as Absorption Enhancer of Hydrophilic Macromolecular Drugs 118
6.3.3 N,N,N,-Trimethyl Chitosan Hydrochloride (TMC) 119
6.3.3.1 Synthesis and Characterization of TMC 119
6.3.4 N-Trimethyl Chitosan as Absorption Enhancer of Peptide Drugs 120
6.3.5 Mono-carboxymethyl Chitosan (MCC) 122
6.4 Thiolated Polymers 125
6.4.1 Thiolated Polymers of Polyacrylates and Cellulose Derivatives 125
6.4.2 Thiolated Polymers of Chitosan 127
6.5 Conclusions 128
References 128
Strategies to Overcome Efflux Pumps 132
7.1 Introduction 132
7.2 Strategies to Overcome Efflux Pumps 133
7.2.1 Efflux Pump Inhibitors 133
7.2.1.1 Low Molecular Mass Inhibitors 135
7.2.1.2 Polymeric Inhibitors and Surfactants 137
Nonionic Polymers 137
Polyethylene Glycol (PEG) and PEGylation 137
d-Alpha-Tocopheryl Poly(Ethylene Glycol) Succinate 1000 (TPGS 1000) 138
Polysorbates (Tween) 138
PEG-8 Glyceryl Caprylate/Caprate (Labrasol) 138
POE Stearates (Myrj) and Alkyl-PEO Surfactants (Brij) 139
Poloxamers (Pluronics) 139
Ionic Polymers 139
Thiolated Polymers 140
7.2.2 Prodrug Modification 141
7.2.3 Antisense Targeting of Efflux Pumps 141
7.2.4 Avoiding Exposure to Intestinal Efflux Pumps 142
7.2.4.1 Enhanced Paracellular Transport 142
7.2.5 Absorption in the Upper Part of the Small Intestine 142
7.3 Conclusions 142
References 142
Multifunctional Polymeric Excipients in Oral Macromolecular Drug Delivery 146
8.1 Introduction 147
8.2 Multifunctional Polymers 148
8.2.1 Mucoadhesive Polymers 148
8.2.1.1 Non-covalent Binding Polymers 149
Anionic Mucoadhesive Polymers 149
Cationic Mucoadhesive Polymers 150
Non-ionic Mucoadhesive Polymers 150
8.2.1.2 Covalent Binding Polymers 150
8.2.2 Enzyme-Inhibiting Polymers 152
8.2.3 Permeation-Enhancing Polymers 155
8.2.4 Efflux Pump-Inhibiting Polymers 156
8.2.5 Polymers Providing Sustained/Delayed Release 156
8.2.5.1 Sustained Release 156
8.2.5.2 Delayed Release 157
8.3 Summary 158
References 159
Nano- and Microparticles in Oral Delivery of Macromolecular Drugs 162
9.1 Introduction 163
9.2 Preparation Methods 164
9.2.1 Different Methods 164
9.2.1.1 Dispersion of Preformed Polymers 164
9.2.1.2 Solvent Evaporation Method 164
9.2.1.3 Polymerization Methods 164
9.2.1.4 Emulsion Cross-Linked Nanoparticles 165
9.2.1.5 Coacervation/Precipitation 165
9.2.1.6 Ionic Gelation Method 165
9.2.2 Surface Modification 166
9.3 Properties of Micro- and Nanoparticles 166
9.3.1 Membrane-Passing Properties 166
9.3.2 Permeation-Enhancing Properties 167
9.3.3 Mucoadhesive Properties 167
9.3.4 Protective Properties 170
9.4 Proof of Concept 171
9.5 Conclusion 173
References 173
Liposome-Based Mucoadhesive Formulations for Oral Delivery of Macromolecules 177
10.1 Introduction 178
10.2 Oral Administration of Peptide Drugs with Mucoadhesive Liposomal Formulations 179
10.2.1 Mucoadhesive Dosage Forms 179
10.2.2 Mucoadhesive Liposomes 181
10.2.3 Mucoadhesive Polymer-Liposome Complexes 187
10.3 Absorption of Macromolecules with Liposomal Formulations 192
10.4 Pharmacological Action After Oral Administration of Liposomal Formulations 195
10.5 Conclusion 197
References 198
Strategies in Oral Immunization 202
11.1 Introduction 203
11.2 Gastrointestinal Anatomy 204
11.3 Oral Vaccination 205
11.3.1 Advantages and Disadvantages 205
11.3.2 Clinical and Pre-clinical Studies 206
11.4 Approaches and Different Oral Vaccine Delivery Systems 208
11.4.1 Recombinant Vaccines and Live Vector Vaccines 208
11.4.2 Virus-Like Particles 208
11.4.3 DNA Vaccines 209
11.4.4 Plant-Based Vaccines 209
11.4.5 Microcapsules 210
11.4.6 Liposomes, Adhesins, Saponins 211
11.4.7 Mucosal Adjuvants 211
11.4.8 Subunit Vaccines and Synthetic Peptides 212
11.4.9 Lipid-Based Vaccines 213
11.4.9.1 Monophosphoryl Lipid A 214
11.4.9.2 Bacterial Lipoprotein 215
11.4.9.3 Palmitoylated Peptides 217
11.4.9.4 The Lipid-Core Peptide System 217
11.4.10 Carbohydrate-Based Vaccines 218
11.4.10.1 Carbohydrates as Targeting Moieties 219
11.4.10.2 Carbohydrates as Carriers 220
11.5 Conclusion 221
References 222
Oral Delivery of Nucleic Acid Drugs 230
12.1 Introduction 231
12.2 Defining the Problems of Oral Administration 231
12.3 Type of Nucleic Acid Drugs 233
12.3.1 Plasmids 233
12.3.2 Aptamers 235
12.3.3 Antisense Oligonucleotides 235
12.3.4 Ribozymes 236
12.3.5 RNA Interference 236
12.4 Strategies 236
12.5 Conclusion 240
References 240
Index 244