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| Practical Approaches to Protein Formulation Development | |
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| Introduction | |
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| Preparation for Formulation Development | |
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| Resource Requirements for Formulation Development | |
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| Useful Information for Designing Formulations | |
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| Preformulation Development | |
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| Characterization of Protein Pharmaceuticals | |
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| Accelerated Stability Studies | |
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| Developmentof Analytical Methods | |
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| Evaluation of the Significance of Problems | |
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| Formulation Development | |
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| Formulation Options for Protein Pharmaceuticals | |
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| Typical Protein Stability Problems: Causes and Solutions | |
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| Optimization of Formulation Variables | |
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| Necessary Studies for Formulation Development | |
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| Strategies to Overcome Difficult Formulation Problems | |
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| Formulation in Commercial Product Development | |
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| Critical Formulation Decisions During Pharmaceutical Development | |
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| Formulation for Early Preclinical and Clinical Studies | |
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| Commercial Formulation | |
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| Regulatory Issues in Formulation Development | |
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| List of Regulatory Documents | |
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| References | |
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| Recombinant Production of Native Proteins from Escherichia coli | |
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| Introduction | |
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| Distribution of Expressed Proteins | |
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| Cell Washing and Lysis | |
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| Purification of Soluble, Folded Proteins | |
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| Purification and Refolding of Soluble, Misfolded Proteins | |
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| Purification and Refolding of Proteins from Inclusion Bodies | |
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| Washing and Solubilization of Inclusion Bodies | |
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| Purification of Expressed Proteins from Inclusion Bodies | |
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| Refolding Mechanism | |
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| Disulfide Bond Formation | |
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| Removal of Denaturant | |
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| Effects of Tag Sequences | |
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| Effects of Excipients | |
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| Response Surface Methodology | |
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| High Pressure Disaggregation and Refolding | |
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| Methods to Analyze Folded Structures | |
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| Bioactivity | |
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| Binding to Receptors | |
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| Dilsulfide Bond Analysis | |
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| Spectroscopy | |
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| Conformational Stability | |
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| Limited Proteolysis | |
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| References | |
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| Physical Stabilization of Proteins in Aqueous Solution | |
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| Introduction | |
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| Overview of Physical Stability | |
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| Thermodynamic Control of Protein Stability | |
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| Kinetic Control of Protein Stability | |
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| Interactions of Excipients with Proteins | |
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| Preferentially Excluded Cosolvents | |
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| Buffers/Salts | |
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| Specific Binding of Ligands | |
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| Protein Self-Stabilization | |
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| Physical Factors Affecting Protein Stability | |
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| Temperature | |
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| Freeze-Thawing | |
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| Agitation and Exposure to Denaturing Interfaces | |
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| Pressure | |
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| Conclusions | |
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| Derivation of the Wyman Linkage Function and Application to the Timasheff Preferential Exclusion Mechanism | |
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| References | |
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| Effects of Conformation on the Chemical Stability of Pharmaceutically Relevant Polypeptides | |
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| Introduction | |
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| Relationship Between Structure and Deamidation Rates | |
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| Primary Structure Effects | |
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| Secondary Structure Effects | |
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| Tertiary Structure Effects | |
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| Summary of Structure Effects on Deamidation | |
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| Role of Structure in Protein Oxidation | |
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| Types of Oxidation Processes | |
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| Effects of Oxidation of Surface and Buried Methionines on Protein Structure | |
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| Limiting Solvent Accessibility of Residues | |
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| Conformational Control of Oxidation in Aqueous Solution | |
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| Structural Control of Oxidation in Lyophilized Products | |
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| Summary of Structural Control of Oxidation | |
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| Summary | |
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| References | |
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| Rational Design of Stable Lyophilized Protein Formulations: Theory and Practice | |
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| Introduction | |
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| Minimal Criteria for a Successful Lyophilized Formulation | |
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| Inhibition of Lyophilization-Induced Protein Unfolding | |
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| Storage at Temperatures Below Formulation Glass Transition Temperature | |
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| The Water Content is Relatively Low | |
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| A Strong, Elegant Cake Structure is Obtained | |
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| Steps Taken to Minimzie Specific Routes of Protein Chemical Degradation | |
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| Rational Design of Stable Lyophiilized Formulations | |
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| Choice of Buffer | |
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| Specific Ligands/pH that Optimizes Thermodynamic Stability of Protein | |
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| Trehalose or Sucrose to Inhibit Protein Unfolding and Provide Glassy Matrix | |
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| Bulking Agent (e.g., Mannitol, Glycine or Hydroxyethyl Starch) | |
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| Nonionic Surfactant to Inhibit Aggregation | |
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| Acknowledgments | |
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| References | |
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| Spray-Drying of Proteins | |
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| Introduction: Why Spray-Dry a Protein? | |
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| Developments in the Last 10 Years | |
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| The Practice of Spray-Drying Proteins | |
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| Type of Equipment | |
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| Spray-Drying Conditions | |
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| Influence of Formulation | |
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| Pure Proteins | |
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| Formulated Systems | |
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| Use of Added Surface Active Substances | |
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| Concluding Remarks | |
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| References | |
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| Surfactant-Protein Interactions | |
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| Introduction | |
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| Proteins and Surfactants at Surfaces | |
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| Protein-Surfactant Interactions in Solution | |
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| Surfactant Effects on Protein Assembly State | |
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| Surfactant Effects on Proteins During Freezing, Freeze-Drying and Reconstitution | |
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| Enzymatic Degradation of Non-Ionic Surfactants | |
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| Recommendations for Protein Formulation | |
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| References | |
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| High Throughout Formulation: Strategies for Rapid Development of Stable Protein Products | |
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| Introduction | |
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| Overall Structure of the HTF Approach | |
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| Role of an Established Decision Tree for Formulation Design | |
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| Constraints on a Pharmaceutically Acceptable Protein Formulation | |
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| Proper Choice of Dosage Form | |
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| Preformulation Studies | |
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| Proper Choice of Excipients | |
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| Estimates of Resources Needed for Formulation Development | |
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| Use of Software and Databases to Assist in the HTF Process | |
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| Essential Analytical Methods | |
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| Stability Protocols | |
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| Unified Strategy for HTF | |
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| References | |
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| Index | |