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Rational Design of Stable Protein Formulations : Theory and Practice - John F. Carpenter

Rational Design of Stable Protein Formulations

Theory and Practice

By: John F. Carpenter (Editor), Mark C. Manning (Editor)

Hardcover Published: 30th April 2002
ISBN: 9780306467417
Number Of Pages: 206

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Recombinant proteins and polypeptides continue to be the most important class of biotechnology-derived agents in today's pharmaceutical industry. Over the past few years, our fundamental understanding of how proteins degrade and how stabilizing agents work has made it possible to approach formulation of protein pharmaceuticals from a much more rational point of view.

This book describes the current level of understanding of protein instability and the strategies for stabilizing proteins under a variety of stressful conditions.

Practical Approaches to Protein Formulation Development
Introductionp. 1
Preparation for Formulation Developmentp. 3
Resource Requirements for Formulation Developmentp. 3
Useful Information for Designing Formulationsp. 4
Preformulation Developmentp. 4
Characterization of Protein Pharmaceuticalsp. 5
Accelerated Stability Studiesp. 5
Developmentof Analytical Methodsp. 6
Evaluation of the Significance of Problemsp. 7
Formulation Developmentp. 10
Formulation Options for Protein Pharmaceuticalsp. 10
Typical Protein Stability Problems: Causes and Solutionsp. 13
Optimization of Formulation Variablesp. 13
Necessary Studies for Formulation Developmentp. 15
Strategies to Overcome Difficult Formulation Problemsp. 17
Formulation in Commercial Product Developmentp. 18
Critical Formulation Decisions During Pharmaceutical Developmentp. 18
Formulation for Early Preclinical and Clinical Studiesp. 19
Commercial Formulationp. 19
Regulatory Issues in Formulation Developmentp. 20
List of Regulatory Documentsp. 22
Referencesp. 23
Recombinant Production of Native Proteins from Escherichia coli
Introductionp. 27
Distribution of Expressed Proteinsp. 28
Cell Washing and Lysisp. 32
Purification of Soluble, Folded Proteinsp. 34
Purification and Refolding of Soluble, Misfolded Proteinsp. 35
Purification and Refolding of Proteins from Inclusion Bodiesp. 36
Washing and Solubilization of Inclusion Bodiesp. 36
Purification of Expressed Proteins from Inclusion Bodiesp. 36
Refolding Mechanismp. 38
Disulfide Bond Formationp. 41
Removal of Denaturantp. 41
Effects of Tag Sequencesp. 44
Effects of Excipientsp. 44
Response Surface Methodologyp. 47
High Pressure Disaggregation and Refoldingp. 48
Methods to Analyze Folded Structuresp. 48
Bioactivityp. 49
Binding to Receptorsp. 49
Dilsulfide Bond Analysisp. 50
Spectroscopyp. 50
Conformational Stabilityp. 51
Limited Proteolysisp. 51
Referencesp. 51
Physical Stabilization of Proteins in Aqueous Solution
Introductionp. 61
Overview of Physical Stabilityp. 62
Thermodynamic Control of Protein Stabilityp. 62
Kinetic Control of Protein Stabilityp. 63
Interactions of Excipients with Proteinsp. 65
Preferentially Excluded Cosolventsp. 66
Buffers/Saltsp. 67
Specific Binding of Ligandsp. 68
Protein Self-Stabilizationp. 69
Physical Factors Affecting Protein Stabilityp. 70
Temperaturep. 70
Freeze-Thawingp. 71
Agitation and Exposure to Denaturing Interfacesp. 71
Pressurep. 72
Conclusionsp. 73
Derivation of the Wyman Linkage Function and Application to the Timasheff Preferential Exclusion Mechanismp. 73
Referencesp. 78
Effects of Conformation on the Chemical Stability of Pharmaceutically Relevant Polypeptides
Introductionp. 85
Relationship Between Structure and Deamidation Ratesp. 86
Primary Structure Effectsp. 87
Secondary Structure Effectsp. 89
Tertiary Structure Effectsp. 91
Summary of Structure Effects on Deamidationp. 92
Role of Structure in Protein Oxidationp. 92
Types of Oxidation Processesp. 93
Effects of Oxidation of Surface and Buried Methionines on Protein Structurep. 95
Limiting Solvent Accessibility of Residuesp. 96
Conformational Control of Oxidation in Aqueous Solutionp. 97
Structural Control of Oxidation in Lyophilized Productsp. 99
Summary of Structural Control of Oxidationp. 100
Summaryp. 101
Referencesp. 101
Rational Design of Stable Lyophilized Protein Formulations: Theory and Practice
Introductionp. 109
Minimal Criteria for a Successful Lyophilized Formulationp. 111
Inhibition of Lyophilization-Induced Protein Unfoldingp. 112
Storage at Temperatures Below Formulation Glass Transition Temperaturep. 113
The Water Content is Relatively Lowp. 114
A Strong, Elegant Cake Structure is Obtainedp. 114
Steps Taken to Minimzie Specific Routes of Protein Chemical Degradationp. 116
Rational Design of Stable Lyophiilized Formulationsp. 117
Choice of Bufferp. 118
Specific Ligands/pH that Optimizes Thermodynamic Stability of Proteinp. 119
Trehalose or Sucrose to Inhibit Protein Unfolding and Provide Glassy Matrixp. 120
Bulking Agent (e.g., Mannitol, Glycine or Hydroxyethyl Starch)p. 126
Nonionic Surfactant to Inhibit Aggregationp. 127
Acknowledgmentsp. 127
Referencesp. 127
Spray-Drying of Proteins
Introduction: Why Spray-Dry a Protein?p. 135
Developments in the Last 10 Yearsp. 136
The Practice of Spray-Drying Proteinsp. 139
Type of Equipmentp. 139
Spray-Drying Conditionsp. 140
Influence of Formulationp. 147
Pure Proteinsp. 147
Formulated Systemsp. 149
Use of Added Surface Active Substancesp. 151
Concluding Remarksp. 156
Referencesp. 156
Surfactant-Protein Interactions
Introductionp. 159
Proteins and Surfactants at Surfacesp. 161
Protein-Surfactant Interactions in Solutionp. 166
Surfactant Effects on Protein Assembly Statep. 167
Surfactant Effects on Proteins During Freezing, Freeze-Drying and Reconstitutionp. 169
Enzymatic Degradation of Non-Ionic Surfactantsp. 170
Recommendations for Protein Formulationp. 170
Referencesp. 171
High Throughout Formulation: Strategies for Rapid Development of Stable Protein Products
Introductionp. 177
Overall Structure of the HTF Approachp. 179
Role of an Established Decision Tree for Formulation Designp. 181
Constraints on a Pharmaceutically Acceptable Protein Formulationp. 182
Proper Choice of Dosage Formp. 183
Preformulation Studiesp. 185
Proper Choice of Excipientsp. 186
Estimates of Resources Needed for Formulation Developmentp. 188
Use of Software and Databases to Assist in the HTF Processp. 189
Essential Analytical Methodsp. 191
Stability Protocolsp. 193
Unified Strategy for HTFp. 194
Referencesp. 195
Indexp. 199
Table of Contents provided by Syndetics. All Rights Reserved.

ISBN: 9780306467417
ISBN-10: 0306467410
Series: Pharmaceutical Biotechnology
Audience: General
Format: Hardcover
Language: English
Number Of Pages: 206
Published: 30th April 2002
Publisher: Springer Science+Business Media
Country of Publication: US
Dimensions (cm): 23.39 x 15.6  x 1.42
Weight (kg): 0.5

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