Pharmaceutical Formulation Development of Peptides and Proteins

Transcription

1 Pharmaceutical Formulation Development of Peptides and Proteins Edited by SVEN FROKJAER AND LARS HOVGAARD O* $L

2 List of figures,' page xi List of tables xiii Contributors xv Preface xvii 1 Peptide Synthesis 1 Bernard A. Moss 1.1 Introduction Chemical synthesis of peptides Solution and solid phase peptide synthesis Large-scale peptide synthesis Concluding remarks 10 References and additional sources 10 2 Basics in Recombinant DNA Technology 12 Nanni Din and Jan Engberg 2.1 Introduction General methods in gene technology DNA cloning tools Cloning of cdna PCR cloning and DNA database mining Expression of recombinant proteins Transcription, translation and protein modifications Choice of expression system Protein design Protein variants Protein chimeras Epitope display libraries 24

3 vi Contents 2.5 Recombinant protein therapeutics - status and future trends 25 References 27 3 Protein Purification 29 Lars Hovgaard, Lars Skriver and Sven Frokjaer 3.1 Introduction Fractionation strategies Initial fractionation step Intermediate purification step Final polishing step The finished product Protein stability in downstream processing Protein conformation stability Protein instability Essential process-related parameters 37 References 38 4 Peptide and Protein Characterization 41 Miroslav Baudys and Sung Wan Kim 4.1 Introduction Chromatography Reversed phase chromatography Hydrophobic interaction chromatography Ion-exchange chromatography Size-exclusion chromatography Electrophoresis Gel electrophoresis Two-dimensional gel electrophoresis 'Capillary electrophoresis Structural characterization Primary structure Mass spectrometry Secondary and tertiary structure Absorption and fluorescence spectroscopy Circular dichroism spectroscopy Infrared spectroscopy Other methods Conclusion 60 References 60 5 Chemical Pathways of Peptide and Protein Degradation 70 Chimanlall Goolcharran, Mehrnaz Khossravi and Ronald T. Borchardt 5.1 Introduction Hydrolytic pathways Deamidation of Asn and Gin residues Degradation of Asp residues 75

4 vii Degradation of N-terminal sequences containing penultimate Pro residues via diketopiperazine formation Oxidation pathways Autooxidation Metal-catalysed oxidation Photooxidation Strategies to prevent oxidation Other chemical pathways (3-Elimination reactions Disulphide exchange reactions Conclusion 85 References 86 6 Physical Stability of Proteins 89 Jens Brange 6.1 Introduction Protein structure Stabilizing interactions ' Role of water in structure and stability Protein destabilization (denaturation) Unfolding intermediates (molten globule) Temperature-induced changes Influence of ph Influence of pressure Aggregation and precipitation Mechanisms of aggregation Precipitation and fibrillation phenomena Factors influencing aggregation and precipitation Surface adsorption Solid phase stability Lyophilization-induced aggregation Stabilization of protein drugs Stabilization strategies 108 References Peptides and Proteins as Parenteral Suspensions: an Overview of Design, Development, and Manufacturing Considerations 113 Michael R. DeFelippis and Michael J. Akers 7.1 Introduction and scope Rationale for suspension development Types of suspensions and particle formation In situ particle formation Combination of particles and vehicle Excipient selection General requirements for suspension products Testing and optimization of chemical, physical, and microbiological properties 127

5 viii Contents Chemical properties Physical properties Microbiological properties 7.7 Techniques for characterizing and optimizing suspensions 7.8 Suspension manufacture Scale-up Manufacturing controls: special considerations for peptide and protein suspensions 7.9 Other related systems 7.10 Conclusions Acknowledgements References 8 Peptides and Proteins as Parenteral Solutions Michael J. Akers and Michael R. DeFelippis 8.1 Overview and introduction 8.2 Optimizing hydrolytic stability Buffers Ionic strength 8.3 Optimizing oxidative stability Antioxidants Chelating agents Inert gases Packaging and oxidation Other chemical stabilizers 8.4 Optimizing physical stability Denaturation Protein aggregation Adsorption Precipitation Surfactants Cyclodextrins Albumin Other physical complexing/stabilizing agents 8.5 Optimizing microbiological activity: antimicrobial preservatives (APs) 8.6 Osmolality (tonicity) agents 8.7 Packaging 8.8 Processing 8.9 Conclusion References Roles of Protein Conformation and Glassy State in the Storage Stability of Dried Protein Formulations 178 John F. Carpenter, Lotte Kreilgaard, S. Dean Allison and Theodore W. Randolph 9.1 Introduction Infrared spectroscopy to study protein secondary structure 180

6 ix 9.3 Physical factors affecting storage stability of dried protein formulations Summary and conclusions 186 Acknowledgements 186 References Peptide and Protein Drug Delivery Systems for Non-parenteral Routes of Administration 189 Mette Ingemann, Sven Frokjaer, Lars Hovgaard and Helle Brondsted 10.1 Introduction Non-parenteral routes of delivery for peptides and proteins Barriers to non-parenteral administration of peptides and proteins General approaches to bypass enzymatic and absorption barriers Formulation principles for peptides and proteins Entrapment and encapsulation Covalent binding Immobilized proteins intended for local effect in the GI tract - a case study Oral enzyme supplementation therapy - phenylalanine ammonia-lyase Future perspectives Summary 203 References Peptide and Protein Derivatives 206 Gitte Juel Friis 11.1 Introduction Imidazolidinone prodrugs Prodrugs of TRH Derivatives of desmopressin Derivatives of insulin Cyclic prodrugs Conclusions 214 References Chemical and Pharmaceutical Documentation 220 Karen Fich and Deirdre Mannion 12.1 Introduction Composition Method of manufacture Control of starting materials Active substances Excipients Packaging materials 226

7 12.5 Intermediate products Control tests on the finished product Stability Expert report 230 References 231 Index 232