Factors affecting short-term and long-term stabilities of proteins

Arakawa, Tsutomu; Prestrelski, Steven J.; Kenney, William C.; Carpenter, John F.

doi:10.1016/s0169-409x(00)00144-7

Cited by 446 publications

(276 citation statements)

References 98 publications

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“…69,[215][216][217] There are several other deleterious effects encountered during the freeze drying process, including ice formation, cold denaturation, and increased concentration, all of which must be countered with the use of appropriate stabilizer(s). [217][218][219][220][221][222][223][224] Furthermore, during storage, the suppression of various degradation processes, including deamidation, hydrolysis, and oxidation, requires the macromolecule to be restricted in mobility and limited in exposure to various media (including water and oxygen). Both can be accomplished with the use of amorphous, glass forming-excipients, such as trehalose.…”

Section: Proteins and Enzymesmentioning

confidence: 99%

Trehalose: Current Use and Future Applications

Ohtake

Wang²

2011

Journal of Pharmaceutical Sciences

393

261

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Section: Proteins and Enzymesmentioning

confidence: 99%

Trehalose: Current Use and Future Applications

Ohtake

Wang²

2011

Journal of Pharmaceutical Sciences

393

261

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“…Disaccharides (C 12 H 22 O 11 ) such as trehalose and sucrose are well-known for their high efficiencies in preserving biological molecules against thermal and dehydration stresses [1,2,3,4] and are accordingly widespreadly used in various industrial processes for the long-term conservation of therapeutic proteins, food and cosmetics [5,6,7]. However, the detailed molecular mechanisms underlying their bioprotecting abilities, and in particular the superior efficiency of trehalose, are still poorly understood [3].…”

Section: -Introductionmentioning

confidence: 99%

Slowing down of water dynamics in disaccharide aqueous solutions

Lerbret¹,

Affouard²,

Bordat³

et al. 2011

Journal of Non-Crystalline Solids

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The dynamics of water in aqueous solutions of three homologous disaccharides, namely trehalose, maltose and sucrose, has been analyzed by means of molecular dynamics simulations in the 0-66 wt % concentration range. The low-frequency vibrational densities of states (VDOS) of water were compared with the susceptibilities chi" of 0-40 wt % solutions of trehalose in D2O obtained from complementary Raman scattering experiments. Both reveal that sugars significantly stiffen the local environments experienced by water. Accordingly, its translational diffusion coefficient decreases when the sugar concentration increases, as a result of an increase of water-water hydrogen bonds lifetimes and of the corresponding activation energies. This induced slowing down of water dynamics, ascribed to the numerous hydrogen bonds that sugars form with water, is strongly amplified at concentrations above 40 wt % by the percolation of the hydrogen bond network of sugars, and may partially explain their well-known stabilizing effect on proteins in aqueous solutions.Comment: 14 pages, 4 figures, accepted in Journal of Non-Crystalline Solids (proceedings of the conference IDMRCS6

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“…1996; Arakawa et al 2001;Lins et al 2004). Among the various osmolytes in nature used to overcome deleterious environmental effects, one of the main benefits of trehalose is that it does not have internal hydrogen bonds, therefore allowing a more flexible formation of hydrogen bonds with the biomolecules.…”

mentioning

confidence: 99%

Spray-freeze-drying of nanosuspensions: the manufacture of insulin particles for needle-free ballistic powder delivery

Schiffter

Condliffe

Vonhoff

2010

J. R. Soc. Interface.

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The feasibility of preparing microparticles with high insulin loading suitable for needle-free ballistic drug delivery by spray-freeze-drying (SFD) was examined in this study. The aim was to manufacture dense, robust particles with a diameter of around 50 mm, a narrow size distribution and a high content of insulin. Atomization using ultrasound atomizers showed improved handling of small liquid quantities as well as narrower droplet size distributions over conventional two-fluid nozzle atomization. Insulin nanoparticles were produced by SFD from solutions with a low solid content (,10 mg ml 21 ) and subsequent ultra-turrax homogenization. To prepare particles for needle-free ballistic injection, the insulin nanoparticles were suspended in matrix formulations with a high excipient content (.300 mg ml 21) consisting of trehalose, mannitol, dextran (10 kDa) and dextran (150 kDa) (abbreviated to TMDD) in order to maximize particle robustness and density after SFD. With the increase in insulin content, the viscosity of the nanosuspensions increased. Liquid atomization was possible up to a maximum of 250 mg of nano-insulin suspended in a 1.0 g matrix. However, if a narrow size distribution with a good correlation between theoretical and measurable insulin content was desired, no more than 150 mg nano-insulin could be suspended per gram of matrix formulation. Particles were examined by laser light diffraction, scanning electron microscopy and tap density testing. Insulin stability was assessed using size exclusion chromatography (SEC), reverse phase chromatography and Fourier transform infrared (FTIR) spectroscopy. Densification of the particles could be achieved during primary drying if the product temperature (T prod ) exceeded the glass transition temperature of the freeze concentrate (T g 0 ) of 229.48C for TMDD (3 : 3 : 3 : 1) formulations. Particles showed a collapsed and wrinkled morphology owing to viscous flow of the freeze concentrate. With increasing insulin loading, the d (v, 0.5) of the SFD powders increased and particle size distributions got wider. Insulin showed a good stability during the particle formation process with a maximum decrease in insulin monomer of only 0.123 per cent after SFD. In accordance with the SEC data, FTIR analysis showed only a small increase in the intermolecular b-sheet of 0.4 per cent after SFD. The good physical stability of the polydisperse particles made them suitable for ballistic injection into tissue-mimicking agar hydrogels, showing a mean penetration depth of 251.3 + 114.7 mm.

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Factors affecting short-term and long-term stabilities of proteins

Cited by 446 publications

References 98 publications

Trehalose: Current Use and Future Applications

Trehalose: Current Use and Future Applications

Slowing down of water dynamics in disaccharide aqueous solutions

Spray-freeze-drying of nanosuspensions: the manufacture of insulin particles for needle-free ballistic powder delivery

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