Abstract
Long-term stability is critical in the successful development of pharmaceuticals, including macromolecular ones, such as proteins. Due to the relative instability of aqueous solutions of proteins, they are typically stored in a freeze-dried (lyophilized) state. However, proteins reversibly (and sometimes even irreversibly) denature upon lyophilization and consequently adopt conformations markedly distinct from the native ones. This phenomenon may profoundly affect deleterious processes in lyophilized proteins, e.g. moisture-induced aggregation, as illustrated in this review with bovine serum and recombinant human albumins.
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References
Ahern TJ, Manning MC, eds. (1992) Stability of Protein Pharmaceuticals. New York: Plenum Press.
Costantino HR, Langer R, Klibanov AM (1995) Aggregation of lyophilized pharmaceutical protein, recombinant human albumin: effect of moisture and stabilization by excipients. Bio/Technology 13: 493–496.
Desai UR, Osterhout JJ, Klibanov AM (1994) Protein structure in the lyophilized state: a hydrogen isotope exchange/NMR study with bovine pancreatic trypsin inhibitor. J. Am. Chem. Soc. 116: 9420–9422.
Griebenow K, Klibanov AM (1995) Lyophilization-induced reversible changes in the secondary structure of proteins. Proc. Natl. Acad. Sci. USA 92: 10969–10976.
He XM, Carter DC (1992) Atomic structure and chemistry of human serum albumin. Nature 358: 209–215.
Lai MC, Topp EM (1999) Solid-state stability of proteins and peptides. J. Pharm. Sci. 88: 489–500.
Liu WR, Langer R, Klibanov AM (1991) Moisture-induced aggregation of lyophilized proteins in the solid state. Biotechnol. Bioeng. 37: 177–184.
Peters Jr T (1996) All about Albumin. Biochemistry, Genetics and Medical Applications.San Diego: Academic Press.
Pikal MJ (1990a) Freeze-drying of proteins. Part I: Process design. BioPharm. 3(9): 18–27.
Pikal MJ (1990b) Freeze-drying of proteins. Part II: Formulation selection. BioPharm. 3(10): 26–30.
Prestegard JH (2001) High resolution NMR of biomolecules. In: Berthier C, Ljevy LP, Martinez G, eds. Lecture Notes in Physics, Vol. 595. Berlin: Springer-Verlag, pp. 426–434.
Robey FA, Tanaka T, Liu TY (1983) Isolation and characterization of two major serum proteins from the dogfish, Mustelus canis, Creactive protein and amyloid P component. J. Biol. Chem. 258: 3889–3894.
Rouhi AM (2002) Generics next wave: biopharmaceuticals. Chem. Eng. News 80(38): 61–65.
Schmidt TS (2002) Banking on structures. Bio-IT World 1(8): 227065–227068.
Shenoy B, Wang Y, Shan W, Margolin AL (2001) Stability of crystalline proteins. Biotechnol. Bioeng. 73: 358–369.
Shnaible V, Wefing S, Resemann A, Suckau D, Bulcker A, Wolf-Kulmmeth S, Hoffmann D (2002) Screening for disulfide bonds in proteins by MALDI in-source decay and LIFT-TOF/TOF-MS. Anal. Chem. 74: 4980–4988.
Struck MM (1994) Biopharmaceutical R&D success rates and development times. A new analysis provides benchmarks for the future. Bio/Technology 12: 674–677.
Torchinsky YM (1981) Sulfur in Proteins, Chapter 2. Oxford: Pergamon Press.
Wang W (2000) Lyophilization and development of solid protein pharmaceuticals. Int. J. Pharm. 203: 1–60.
Yeo S-D, Debenedetti PG, Patro SY, Przybycien TM (1994) Secondary structure characterization of microparticulate insulin powders J. Pharm. Sci. 83: 1651–1656.
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Klibanov, A.M., Schefiliti, J.A. On the relationship between conformation and stability in solid pharmaceutical protein formulations. Biotechnology Letters 26, 1103–1106 (2004). https://doi.org/10.1023/B:BILE.0000035520.47933.a6
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DOI: https://doi.org/10.1023/B:BILE.0000035520.47933.a6