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1 354 FORMULATION AND DELIVERY OF PROTEINS AND PEPTIDES University of Colorado Health Sciences University of Kansas, 46 Center, 134,170 University of Wisconsin, 193 University of Colorado, 148 Subject Index Downloaded via on September 20, 2018 at 18:55:17 (UTC). See for options on how to legitimately share published articles. A Absorption spectroscopy, protein assessment, Activity, determination, 347 Additives, role in structure of dried proteins, Adrenocorticotrophic hormone, stability, Aerosol delivery, recombinant DNA derived human deoxyribonuclease I, Aerosol droplet size distribution, determination, 333, Aerosolized small molecular weight drugs, collection, 344 Aggregation, determination, 347 Alkyl hydroperoxide, role in protein oxidation, Analytical methods for protein assessment chemical degradation, chromatography, electrophoresis, 23,25-28 MS, primary structure analysis, protein alterations during formulation development, 23,24f requirements, 23 secondary and tertiary structure analysis, Analytical ultracentrifugation, protein assessment, Anhydrobiotic organisms, function, 223 Antibodies controlled intracranial delivery in rat, use for brain tumor treatment, 279 Antibody proteolytic fragments, use for brain tumor treatment, 279 Antigen delivery system, nanoparticles, Aqueous parenteral formulations, peptide stability, Asparagine residues, instability, Aspartic acid residues, instability, Β Basic fibroblast growth factor description, 85 disulfide nature of soluble multimers, 87,91/ fate in solution, heparin binding site, 94,95/ lyophilization effect on structure, 149,150/153 physiological state, 98 precipitate composition, 87,92r structure with precipitates, sulfated excipients vs. solution stability, 86-87,88-90/ vs. thermal stability, 86 Bioactive peptides and proteins, 242 Biodegradable injectable nanospheres composed of poly(ethylene glycol)- poly(lactic-a?-glycolic acid) copolymers, 267, Biodegradable polymers erosion,

2 INDEX 355 Biodegradable polymers Continued immunization, controlled-release devices, Bioerodible implants for parenteral administration of peptides and proteins, need, 292 Biopharmaceutical process development, progress, 1 Bound water, description, 8 C Capillary electrophoresis detection methods, 28 protein assessment, 27 size analysis, 28 Capillary isoelectric focusing, protein assessment, 28 Carbohydrate analysis, protein assessment, 33 α-casein, lyophilization effect on structure, 149,151/,153 Chemical degradation, protein assessment, Chemical instabilities, asparaginyl and aspartyl residues in model peptides, Chemical stability of peptides in aqueous parenteral formulations, See Peptide formulations Chromatofocusing, protein formulation and delivery system assessment, Chromatography, protein formulation and delivery system assessment, Circular dichroism spectroscopy, protein assessment, Clostridium botulinum neurotoxin type A applications, 193 Clostridium botulinum neurotoxin type A Continued description, 193 neurotoxin production, ,195/ recovery following lyophilization, Collapse temperature, definition, 121 Collection of nebulized proteins characterization, collection, 348,349f,350 experimental procedure, recovery, 348,349i,350 Concentration, determination, 347 Conformation of dried proteins, long-term stability effect, Conformational states, protein, See Protein conformational states Controlled intracranial delivery of antibodies in rat antibody distribution, 288/289 experimental procedure, matrix delivery, 283,284/ microsphere delivery, previous studies, 279 Controlled-release devices biodegradable injectable nanospheres composed of poly(ethylene glycol)- poly(lactic-c0-glycolic acid) copolymers, 267, biodegradable polymers for immunization, delivery of proteins and peptides from polymers, development, erosion of biodegradable polymers, examples of polymers, 243 problems, 243 protein delivery from polyanhydride microspheres, 264, ,268/270/ types, 243 Coomassie blue staining, protein detection after electrophoresis, 26 Cryoprotectant(s) description, 126

3 356 FORMULATION AND DELIVERY OF PROTEINS AND PEPTIDES Cryoprotectant(s) Continued of surimi lactitol, 207 lactulose, 207 nucleotides, 206 polydextrose, 206 sorbitol, 206 sucrose, 206 surfactants, 206 Cryoprotection experimental evidence for sodium lactate mechanism, mechanism in surimi, Cryostabilization, mechanism in surimi, Cryptobiotic organisms, function, 223 Cysteine, oxidation, Cystic fibrosis, D Deamidation determination, 347 peptide formulations, protein assessment, Degradation by oxygen, See Oxidation degradation of protein pharmaceuticals Degradation pathways, proteins and peptides, 5 Degree of supercooling, description, 121 Dehydration, importance of effect on protein structure, 148 Delivery proteins and peptides from polymers, controlled-release devices, therapeutics to lung by inhalation, concerns, 343 Delivery design depot systems, 9,11-14 future directions, 14,16 influencing factors, 14 pharmacokinetics effects, 14,15i Delivery design Continued routes, 8-9,10i steps, 8-15 Delivery efficiency, calculation, 333 Delivery formulation, drug development effect, 2-4 Delivery systems, analytical methods for assessment, Depot systems, delivery design, 9,11-14 Detection methods, capillary electrophoresis, 28 Development of formulation degradation pathways, 5,7i future directions, 14,16 influencing factors, 14 optimization conditions, 8 stability characterization, 8 steps, 4-5,6/ Diffusion-controlled protein release from nondegradable polymers, comparison to erosion of biodegradable polymers, 244 Diketopiperazine formation, peptide formulations, 107 Disulfide-linked oligomerization of basic fibroblast growth factor, sulfated compounds, Dried proteins additive effects on structure, conformation effect on long-term stability, preservation, rehydration, Driving force for sublimation, Drug development degradation pathways, 2 delivery formulation effect, 2-4 Drying, protein conformational states, Ε Electrophoresis, protein formulation and delivery system assessment, 23,25-28

4 INDEX 357 Electrospray ionization MS, protein assessment, Erosion of biodegradable polymers basic concept, 253 comparison to diffusion-controlled protein release from nondegradable polymers, 244 crystallinity changes, 250,252/ mechanisms, modeling, 250, monomer release, 250,252/ pattern, ph changes, 245,250,251/ polymer matrix representation, ,255/ polymer structures, ,251 quantitative evaluation of experimental results, reasons for study, 244 simulation, 254, / F Fibroblast growth factor, solution stability, Fluorescence spectroscopy, protein formulation and delivery assessment, 37 Formulation analytical methods for assessment, for delivery, drug development effect, 2-4 recombinant DNA derived human deoxyribonuclease I, Formulation development degradation pathways, 5,7i future directions, 14,16 influencing factors, 14 optimization conditions, 8 protein alterations, 23,24i stability characterization, 8 steps, 4-5,6/ Freeze-dried proteins, stress-specific stabilization, 164,166 Freeze-drying description, 120 multimeric enzyme stabilization by polymers, proteins formulation vs. stability, ,130/ residual moisture, 124,126 stabilization mechanism drying and storage, ,130/ freezing, storage stability, 126 stress-specific stabilization of proteins, Freeze-drying process freezing, ,125/ primary drying, secondary drying, 124,125/ Freezing mechanism for protein preservation, protein conformational states, stress induction, G Gel filtration chromatography, protein assessment, Granulocyte colony stimulating factor, lyophilization effect on structure, 149,152/153 H Histerelin, stability, 110 Human immunodeficiency virus (HIV), adjuvant effect, Hydration effect on protein structure and stability concept, 171

5 358 FORMULATION AND DELIVERY OF PROTEINS AND PEPTIDES Hydration effect on protein structure and stability Continued experimental procedure, ,173/ future perspectives, 190 O-D stretch region, protein bands, 184, spectral changes, 180,181/ sucrose bands, 184,185/ theory, 171, Hydrogen peroxide, role in protein oxidation, 67 Hydrolysis, peptide stability in aqueous parenteral formulations, Hydrophobic interaction chromatography, protein formulation and delivery system assessment, 32 Ice growth rate, description, 121 Influenza, adjuvant effect, 308,311 Instability asparagine residues in solid state, in solution, aspartic acid residues in solid state, in solution, Insulin delivery, poly(ortho esters), 294,296/297,298/ Intracranial controlled-release polymers, use for brain tumor treatment, 279 Ion-exchange chromatography, protein assessment, 29 IR spectroscopy, protein formulation and delivery system assessment, 38 Isoelectric focusing, protein formulation and delivery system assessment, Jet nebulizers, recombinant DNA derived human deoxyribonuclease I aerosol generation, 329 L Lactate dehydrogenase (LDH), preservation during freezing, Lactate dehydrogenase structure and activity recovery, stabilizer effect, 164,165/ Lactide-glycolide copolymer system, use as bioerodible implants, 292 Lactitol, cryoprotectant of surimi, 207 Lactulose, cryoprotectant of surimi, 207 Luteinizing hormone releasing hormone, stability, 110 Light scattering, protein formulation and delivery system assessment, Liposomes, use as depot systems for drug delivery, 12,14 Long-term stability, dried protein conformation effect, Lung, routes of drug administration, 322 Lyophilization real-time IR spectroscopic analysis of lysozyme, recovery of type A botulinal toxin, See also Freeze-drying Lyophilization effect on protein structure using FT IR spectroscopy additive effects, conformation effect on long-term stability, correlation of dehydration-induced structural and functional alterations, 155 examples of spectroscopic changes, poly-l-lysine, protein conformational states during freezing, drying, and rehydration, quantitative analysis, rehydration of dried protein, stress-specific stabilization of freeze-dried proteins, 164,166

6 INDEX 359 Lysozyme, real-time IR spectroscopic analysis during lyophilization, Lysozyme release, poly(ortho esters), M Mass balance, calculations, Mass spectrometer interfaces, protein assessment, 34 Mass spectrometry, protein formulation and delivery system assessment, Matrix-assisted laser desorption ionization MS, protein formulation and delivery assessment, 35 Methionine, oxidation, Monoclonal antibodies photosensitivity, properties, 72 Multimeric enzymes, stabilization by polymers during freeze-drying, Muramyl dipeptides, stability, Myofibrillar proteins, denaturation, 204 Myosin, 204 Ν Nafarelin release, poly(ortho esters), 294, / Nanoparticles adjuvant effect on HIV, on influenza, 308,311 body distribution, 307 definition, elimination, 307 example, 307 hydrophobicity vs. adjuvant effect, 308,310/ particle size vs. adjuvant effect, 308 Nanoparticles Continued physicochemical characterization, 308,309i preparation, 307 tolerance, Native electrophoresis, protein assessment, 23,25 Nebulization protein integrity effect, 343 recombinant DNA derived human deoxyribonulcease I stability effect, ,336 Nebulized proteins, collection, Nucleotides, cryoprotectant of surimi, 206 Ο Oligomerization of basic fibroblast growth factor, disulfide linked, sulfated compounds, Oxidation peptide formulations, protein assessment, Oxidation degradation of protein pharmaceuticals conditions, cysteine, methionine, reviews, 59 Ρ Parenteral formulations, aqueous, peptide stability, Peptide(s) degradation pathways, 5,7r delivery design, 8-15 delivery from polymers, controlled-release devices, enzymatic degradation by peptidases,

7 360 FORMULATION AND DELIVERY OF PROTEINS AND PEPTIDES Peptide(s) Continued formulation development, 4-8,14,16 Peptide aggregation effect, peptide formulations, 101 Peptide and protein delivery systems polyanhydrides, poly(ortho esters), Peptide and protein drug formulations, See Protein and peptide drug formulations Peptide mapping, protein formulation and delivery system assessment, Peptide formulations deamidation, diketopiperazine formation, 107 factors affecting degradation rates, 102 formulation stability of drugs, hydrolysis, in vivo vs. in vitro effects, 101 influencing factors, 101 model peptides, 102 oxidation, peptide aggregation effect, 101 previous studies, 100 pyroglutamic acid formation, racemization, 106 reactive functional groups, 111,112* surface adsorption effect, 101 Pharmaceutical formulations, goal of stability at room temperature, 222 Pharmaceuticals from proteins, oxidation degradation, Pharmacokinetics, drug delivery effect, 14,15* Phosphofructokinase, preservation during freezing, Photosensitivity of monoclonal immunoglobulin G experimental procedure, factors affecting fluorescence decrease, 81,83 fluorescence excited state lifetimes of Trp residues, 81 Photosensitivity of monoclonal immunoglobulin G Continued N-formylkynurenine formation, 78,79/ kinetics of Trp loss, 76,78 photoinduced spectral changes, 74-76,77/ photosensitive Trp population location, 81,82/ solvent exposure of Trp residues, 78,80/81 Polyanhydride(s) copolymer synthesis, 302,303/ hydrolysis, 302 protein release rates, 303,304/ structure from oleic and sebacic acid dimers, synthesis, 302 Polyanhydride microspheres, protein delivery, 264,266-68,270 Polydextrose, cryoprotectant of surimi, 206 Poly(ethylene glycol)-poly(lactic-co glycolic acid) copolymers, controlledrelease devices, 267, Poly(lactic acid), use as depot systems for drug delivery, 9,12,13* Poly(lactic-co-glycolic acid), use as depot systems for drug delivery, 9,12,13* Poly(lactic-c6>-glycolic acid)-poly(ethylene glycol) copolymers, controlled-release devices, 267, Poly-L-lysine lyophilization effect on structure, stabilizer effect, Polymers delivery of proteins and peptides, controlled-release devices, multimeric enzyme stabilization during freeze-drying, Poly(methyl methacrylate) adjuvant effect on HIV, on influenza, 308,311

8 INDEX 361 Poly(methyl methacrylate) Continued advantages for use as adjuvant, 307 body distribution, 307 elimination, 307 hydrophobicity vs. adjuvant effect, 308,310/ particle size vs. adjuvant effect, 308 physicochemical characterization, 308,309i preparation, 307 tolerance, Poly(ortho esters) lysozyme release, structurally distinct families, 293 surface hydrolysis, 293 synthesis, ,297,299 use in nafarelin release, 294, / in self-modified insulin delivery, 294,296/297,298/ Polypeptides exogenous factors affecting chemical instability, 46 solution and solid-state chemical instabilities of asparaginyl and aspartyl residues, use as therapeutic agents, 46 Primary brain tumor, treatment methods, Primary drying, freeze-drying process, Primary sequences, prediction of peptide formulations, 100 Primary structure analysis, protein assessment, Protein(s) degradation pathways, 5,7i delivery design, 8-15 delivery from polymers, controlled-release devices, formulation development, 4-8,14,16 freeze-drying, nebulized, collection, Protein(s) Continued stress-specific stabilization during freeze-drying, Protein alterations, formulation development, 23,24i Protein and peptide delivery systems, See Peptide and protein delivery systems Protein and peptide drug formulations design and production development, 1-2 See also Drug development Protein chromatography in reversed-phase high-performance liquid chromatography, protein formulation and delivery system assessment, Protein conformational states drying, freezing, rehydration, Protein delivery, polyanhydride microspheres, 264, ,270 Protein detection after electrophoresis, methods, Protein formulation(s), need for stability, 134 Protein s, analytical methods for assessment, Protein pharmaceuticals, oxidation degradation, Protein preservation mechanism during freezing, water replacement hypothesis, Protein stability, hydration effect, Protein stabilization by trehalose advantages, 223 brown coloration development, 231,232/ experimental evidence, Maillard reaction(s) in dried protein formulations, 227,230/ schematic representation, 227,229/ mechanism of action, , / nonenzymatic browning, 227,228/

9 362 FORMULATION AND DELIVERY OF PROTEINS AND PEPTIDES Protein stabilization by trehalose Continued residual activity in alkaline phosphatase samples, 227,230/,231 residual sugar contents of samples, 231,233* residual water content effect on chemical reactions, 237,238/ therapeutic peptide glucagon analysis, 231, /237 Protein-stabilizer interactions during freezing and drying, See Stabilizer-protein interactions during freezing and drying Protein structure additive effects, dehydration effect, 148 hydration effect, Pulmonary route of drug administration, advantages, Pyroglutamic acid formation, peptide formulations, Racemization, peptide stability in aqueous parenteral formulations, 106 Rat, controlled intracranial delivery of antibodies, Real-time IR spectroscopic analysis of lysozyme during lyophilization advantages, hydration effect on structure and stability, role in lysozyme lyophilization, Recombinant DNA derived human deoxyribonuclease I aerosol collection, 331 aerosol generation by jet nebulizer, 329 calcium in formulation, 323,324/325,326/ characterization of aerosols, 333, Recombinant DNA derived human deoxyribonuclease I Continued collection, degradation route, , isotonic formulation without buffer salts, 323,324/ nebulization process stability effect, ,336 vs. activity, 331,332*,333 vs. aggregation, 331,332* vs. conformation, 333,334/336/ vs. stability, 331,332* stability, 325,328/329,330/ Recombinant human proteins, delivery to lung, 343 Recovery of type A botulinal toxin following lyophilization aggregation effect, 197,198*, 199,202 deamidation effect, excipient effect, 197* experimental procedure, 194, freezing effect, 197 process parameter effect, 199 salt concentration effect, 197,199,201 stability vs. temperature, 202 toxin inactivation mechanisms, 199,200/ Rehydration dried proteins, protein conformational states, stabilizer effect, 164 Relaxin, stability, 111 Reversed-phase chromatography, protein assessment, 30 Routes, delivery design, 8-9,10* Secondary drying, freeze-drying process, 124,125/ Secondary structure analysis, methods, Sequencing, protein formulation and delivery system assessment, 32-33

10 INDEX 363 Silver staining, protein detection after electrophoresis, Size analysis, capillary electrophoresis, 28 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, protein formulation and delivery system assessment, 25 Sodium lactate, cryoprotection mechanism, Solid-state chemical instabilities, asparaginyl and aspartyl residues in model peptides, Solution chemical instabilities, asparaginyl and aspartyl residues in model peptides, Sorbitol, cryoprotectant of surimi, 206 Stability at room temperature, goal for pharmaceutical formulations, 222 of peptides in aqueous parenteral formulations, See Peptide formulations of proteins, hydration effect, Stabilization during freeze-drying, stress specific, description, multimeric enzymes by polymers during freeze-drying, of proteins and peptides in lyophilized state, theories, 8 of proteins by trehalose, See Protein stabilization by trehalose Stabilizer(s) LDH structure and activity recovery effect, 164,165/ poly-l-lysine effect, rehydration effect, 164 Stabilizer-protein interactions during freezing and drying multimeric enzyme stabilization by polymers during freeze-drying, protein preservation mechanism during freezing, Stabilizer-protein interactions during freezing and drying Continued stress-specific protein stabilization during freeze-drying, water replacement hypothesis, Stress-specific stabilization during freeze-drying, description, freeze-dried proteins, 164,166 Structure of proteins additive effect, dehydration effect, 148 hydration effect, Sulfated compounds for disulfide-linked oligomerization of basic fibroblast growth factor basic fibroblast growth factor precipitate composition, 87,92r basic fibroblast growth factor structure with precipitates, disulfide nature of soluble basic fibroblast growth factor multimers, 87,91/ fate of basic fibroblast growth factor in solution, heparin binding site, 94,95/96 physiological state of basic fibroblast growth factor, 98 solution stability effect, 86-87, 88-90/ thermal stability effect, 86r Surface adsorption effect, peptide formulations, 101 Surfactants, cryoprotectant of surimi, 206 Surimi consumption, 204,206 cryoprotectants, experimental evidence for sodium lactate cryoprotection, manufacture, 204,205/ mechanisms of cryoprotection and cryostabilization,

11 364 FORMULATION AND DELIVERY OF PROTEINS AND PEPTIDES Τ Tertiary structure analysis, methods, Trehalose, chemistry of protein stabilization, Tryptophan residues, photooxidation products, 72 Two-dimensional gel electrophoresis, protein formulation and delivery system assessment, 26 V Vitrification hypothesis, 131,132/ W Water replacement hypothesis description, 8 development, evidence, Water-soluble hypothesis, description, ,130/131 Production: Meg Marshall Indexing: Deborah H. Steiner Acquisition: Anne Wilson Cover design: Tana Powell Printed and bound by Maple Press, York, PA