2 Pharmaceutical Biotechnology An Introduction for Pharmacists and Pharmaceutical Scientists Edited by DaanJ.A. Crommelin (Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands) and Robert D. Sindelar (Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, USA) harwood academic publishers Australia • Canada • China • France • Germany • India • Japan • Luxembourg • Malaysia The Netherlands • Russia • Singapore • Switzerland • Thailand • United Kingdom
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2 Pharmaceutical Biotechnology - GBVChapter 4: Formulation of Biotech Products, Including Biopharmaceutical Considerations 71 Daan J.A. Crommelin Introduction 71 Microbiological Considerations
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2Pharmaceutical BiotechnologyAn Introduction for Pharmacists andPharmaceutical Scientists
Edited by
DaanJ.A. Crommelin (Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands)
and
Robert D. Sindelar (Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, USA)
harwood academic publishersAustralia • Canada • China • France • Germany • India • Japan • Luxembourg • MalaysiaThe Netherlands • Russia • Singapore • Switzerland • Thailand • United Kingdom
Table of Contents
Preface XIX
Contributors xxi
Acknowledgements XXIII
Abbreviations XXV
Chapter i: Molecular Biotechnology 1Wiel P.M. Hoekstra and SjefC.M. Smeekens
Techniques for Characterizing Folding 39Protein Stability 40Analytical Techniques 41
Blotting Techniques 41Transfer of Proteins 41Detection Systems 41
Immunoassays 43ELISA 43
Electrophoresis 44Polyacrylamide Gel Electrophoresis 45Isoelectric Focusing 452-Dimensional Gel Electrophoresis 45Detection of Proteins within Polyacrylamide Gels 45Capillary Electrophoresis 45
Chromatography 46Size Exclusion Chromatography 46Reversed-Phase High Performance Liquid
Issues to Consider in Production and Purificationof Proteins 65N- and C-Terminal Heterogeneity 65Chemical Modification/Conformational Changes 66Glycosylation 66Proteolytic Processing 66Protein Inclusion Body Formation 66
References 67Self-Assessment Questions 70
Chapter 4: Formulation of Biotech Products, IncludingBiopharmaceutical Considerations 71Daan J.A. Crommelin
Excipients used in Parenteral Formulations ofBiotech Products 72Solubility Enhancers 72Anti-adsorption and Anti-aggregation Agents 72
CONTENTS
Buffer Components 73Preservatives and Anti-oxidants 73Osmotic Agents 74
Shelf Life of Protein Based Pharmaceuticals 74Freeze-Drying of Proteins 75Freezing 75Primary Drying 76Secondary Drying Stage 77Other Approaches to Stabilize Proteins 78
Delivery of Proteins: Routes of Administration andAbsorption Enhancement 78The Parenteral Route of Administration 78The Oral Route 79Alternative Routes of Administration 80Examples of Absorption Enhancing Effects 80
Delivery of Proteins: Approaches for Rate Controlled and
Target Site Specific Delivery by the Parenteral Route 82Approaches for Rate Controlled Delivery 84
Open Loop Systems: Mechanical Pumps 84Open Loop Systems: Osmotically Driven Systems 85Closed Loop Systems: Biosensor-Pump Combinations 86Protein Delivery by Self-Regulating Systems 86Protein Delivery by Microencapsulated Secretory Cells 87
Site Specific Delivery (Targeting) of Protein Drugs 88Anatomical, Physiological and Pathological Considerations
Relevant for Protein Targeting 89Soluble Carrier Systems for Targeted Delivery
of Proteins go(Monoclonal) Antibodies (MAh) as Targeted Therapeutic
Agents: Human and Humanized Antibodies goBispecijic Antibodies goImmunoconjugates: Combinations Between an Antibody
and an Active Compound goPotential Pitfalls in Tumor Targeting 91Colloidal Particulate Carrier Systems for Targeted Delivery
of Proteins g2Perspectives for Targeted Protein Delivery g$
References 95Self-Assessment Questions g8
Chapter 5: Pharmacokinetics and Pharmacodynamicsof Peptide and Protein Drugs 101
Rene Braeckman
Introduction 101Elimination of Protein Therapeutics 102
Proteolysis 102Renal Excretion and Metabolism 102Hepatic Metabolism 104Receptor-Mediated Elimination by Other Cells 104
Distribution of Protein Therapeutics 205
CONTENTS
Pharmacodynamics of Protein Therapeutics 106Direct Effects 107Indirect Effects 108PK/PD Link Models 108Indirect Effect Models 109Complex PK/PD Models 111Dose-Response and Concentration-Response Curves 111
Protein Binding of Protein Therapeutics 112Interspecies Scaling 124Heterogeneity of Protein Therapeutics 115Chemical Modifications of Protein Therapeutics 116Immunogenicity 117References 118Self-Assessment Questions 121
Chapter 6: Additional Biotechnology-Related Techniques 123Robert D. Sindelar
Introduction 123Polymerase Chain Reaction 123
Basic PCR Methodology 124Some Examples of Modified PCR and Related
Transgenic Animals 125Production of Transgenic Animals by DNA
Microinjection and Random Gene Addition 126Production of Transgenic Animals by Homologous
Recombination in Embryonic Stem Cells I2gProtein Production in Transgenic Animals I2gExamples of Transgenic Animal Models of Human
Disease in Drug Discovery and Development 131Knockout Mice 131Transgenic Animal Patents 131Genetic Ablation 132
Protein Engineering 132Production of Engineered Proteins 132Site-Directed Mutagenesis 132Enzyme Engineering 133Fusion Proteins 133Antibody Engineering 1343-D Structures of Engineered Proteins: Protein X-Ray
Crystallography, Nuclear Magnetic Resonance Spectroscopyand Protein Modeling 134Protein X-ray Crystallography 135Nuclear Magnetic Resonance (NMR) Spectroscopy 133Protein Modeling 136
Peptide Chemistry and Peptidomimetics 136Peptidomimetics 137"Pseudopeptide" Peptidomimetic Approach 138Conformationally-Constrained Peptides 138Rational Design of Peptidomimetics 139
CONTENTS
Nucleic Acid Technologies 140Oligonucleotides 142
Biochemistry 142Physiochemical Properties of Oligonucleotides 143Chemistry and Modifications 143
Antisense Technology and Triplex Technology 143Normal Cell Activity: DNA Makes RNA Makes Protein 143Rationale for Antisense Technology 144Therapeutic Antisense Molecules 143Triplex Technology 146
Glycobiology i4gBasic Principles of Glycobiology I4gGlycosylation and Biological Activity 150The Role of Glycosylation in Disease 151Cell Adhesion Molecules 151
Integrins 153Selectins 152
Biosensors 152The Impact of Biotechnology on Drug Discovery 154
Overview 154In Vitro Screening 154
Contributions of Biotechnology 154High-Throughput Screening (HTS) 154Combinatorial Chemistry 154
Introduction 167Ex Vivo versus In Vivo Gene Therapy 167
Ex Vivo Gene Therapy 167In Vivo Gene Therapy 167
Potential Target Diseases for Gene Therapy 167Inherited Disorders 167Cancer 168
Gene Transfer Methods 171Non-Viral Gene Transfer 171
Methods of Non-Viral Gene Transfer 171Application of Non-Viral Gene Transfer 171
CONTENTS
Gene Transfer Using Recombinant Viruses (Viral Vectors) 173General Requirements 173Retrovirus Vectors 173
Retrovirus Life Cycle 173Recombinant Retrovirus 174Application of Retroviral Vectors 175
Adenovirus Vectors 176Adenovirus Life Cycle 176Recombinant Adenoviruses 177Application of Adenoviral Vectors 178
Adeno-Associated Virus Vectors i7gReplication of Wild-Type AAV I7gRecombinant Adeno-Associated Virus 180Application of Adeno-Associated Viral Vectors 180
Clinical Studies 180Pharmaceutical Production and Regulation 181Concluding Remarks 181Further Reading 181References 182Self-Assessment Questions 183
Chapter 8: Hematopoietic Growth Factors 185Jeanne Flynn and Allen W. Rosman
Introduction 185Definitions 185
Chemical Description 186Chemical Properties of G-CSF and GM-CSF 186Chemical Properties of Erythropoietin (EPO) 187Chemical Properties of Other Hematopoietic Growth Factors 188
Pharmacology 188In Vitro Activity 188In Vivo Activity 191
Cellular Sources and Stimuli for Release ig2Physiologic Role of G-CSF and GM-CSF ig2Physiologic Role of EPO ig2Physiologic Role of Other Hematopoietic Growth Factors ig3
Pharmaceutical Concerns 193Status and Source of Hematopoietic Growth Factors ig3Storage and Stability 193Pharmacokinetics 193Pharmacodynamics 196
Clinical and Practice Aspects ig8Established Uses 198
Interleukin-g through Interleukin-16 218Interleukin-iy 218
Commercially Available Interleukins 218Introduction: Interleukin-2 218Chemical Description of IL-2 218Pharmacology of IL-2 218
Indication 218Mechanism of Action 218Biotransformation 218Elimination 218
Pharmaceutical Concerns of IL-2 218Clinical and Practice Aspects of IL-2 219
Interferons 219a Interferon 2ig
Chemical Description of a Interferon Products 220Pharmacology 220
Absorption 220Time to Peak Concentration 220Biotransformation 220Onset of Action 220Time to Peak Effect 220
Pharmaceutical Concerns of a Interferons 220Clinical and Practice Aspects of a Interferons 221Side Effects of a Interferons 221
(3 Interferon 222
Chemical Description of P Interferon Product 222Pharmacology of p Interferon 222Pharmaceutical Concerns of P Interferon 222Clinical and Practice Aspects of p Interferon 222
CONTENTS
y Interferon 223Chemical Description of 7 Interferon Product 223Pharmacology of 7 Interferon 224
Absorption 224Time to Peak Plasma Concentration 224Peak Plasma Concentration 224
Pharmaceutical Concerns of 7 Interferon 224Clinical and Practice Aspects of 7 Interferon 224
References 224Self-Assessment Questions 226
Chapter 10: Insulin 22gJohn M. Beals and Paul M. Kovach
Introduction 22gChemical Description 22gPharmacology and Formulations 232
Introduction 241hGH Structure and Isohormones 241Pharmacology 241
Growth Hormone Secretion and Regulation 241Growth Hormone Biologic Actions 242hGH Receptor and Binding Proteins 242Molecular Endocrinology and Signal Transduction 242Dosing Schedules and Routes 242Pharmacokinetics and Metabolism 243
Protein Manufacture, Formulation and Stability 245Clinical Usage 247
Growth Hormone Deficiency/Idiopathic Short Staturein Children 247
Turner Syndrome 247
CONTENTS
Chronic Renal Insufficiency (CRI) 248Growth Hormone Deficient Adults and the Elderly 249Clinical Malnutrition and Wasting Syndromes 24gOther IndicationsSafety Concerns
Chapter 17: Dispensing Biotechnology ProductsHandling, Professional Education and Product Information 321Gary H. Smith and Peggy Piascik
Introduction 321Pharmacist Reluctance 321Types of Information Needed by Pharmacists 321Sources of Information for Pharmacists 322The Pharmacist and Handling of Biotech Drugs 322
Storage 323Temperature Requirements 323Storage in Dosing and Administration Devices 324Storage in IV Solutions 325Light Protection 326
Handling 326Mixing and Shaking 326Travel Requirements 327
Preparation 327Administration 327
Routes of Administration 328Filtration 328Flushing Solutions 328
Outpatient/Home Care Issues 328Patient Assessment and Education 328Monitoring 328
Reimbursement 32gEducational Materials
Professional ServicesEducational Materials for Health Professionals 32gEducational Materials for Patients 331
Toll-Free Access to Manufacturers' Services 331The Internet and Biotech Information 332