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1.
J Pharm Sci ; 101(1): 68-80, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21975852

RESUMO

The self-association of human interferon-α2b (hIFN-α2b), albinterferon-α2b (a recombinant protein with human serum albumin and hIFN-α2b peptides fused together in a single polypeptide chain), and Pegasys (PEGylated hIFN-α2a) was characterized by analytical ultracentrifugation analyses. By examining the apparent sedimentation coefficient distribution profiles of each protein at different concentrations, it was concluded that the above three proteins are self-associating in albinterferon-α2b formulation buffer. By model fitting of sedimentation data using SEDANAL software, the stoichiometry and equilibrium constants of the self-association of these proteins were characterized. The self-association of hIFN-α2b results in the formation of stable dimers, fast-reversible tetramers, octamers, and hexadecamers. In contrast, although both albinterferon-α2b and Pegasys are self-associated, their self-association stoichiometries are significantly different from that of hIFN-α2b. The self-association of albinterferon-α2b results in the formation of reversible dimers and trimers, whereas the self-association of Pegasys gives only reversible dimers. The self-association behaviors of hIFN-α2b and albinterferon-α2b involves attractive electrostatic forces, which can be suppressed to a negligible level in low pH (pH 4.0-4.5) and high salt concentration (400 mM NaCl) buffer, allowing quantification of their size variant contents by sedimentation velocity analysis.


Assuntos
Albuminas/química , Interferon-alfa/química , Polietilenoglicóis/química , Proteínas Recombinantes/química , Soluções Tampão , Humanos , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular , Concentração Osmolar , Sais , Eletricidade Estática , Ultracentrifugação/métodos
2.
J Pharm Sci ; 100(12): 5100-14, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21780119

RESUMO

Silicone oil is often used to decrease glide forces in prefilled syringes and cartridges, common primary container closures for biopharmaceutical products. Silicone oil has been linked to inducing protein aggregation (Diabet Med 1989;6:278; Diabet Care 1987;10:786-790), leading to patient safety and immunogenicity concerns. Because of the silicone oil application process (Biotech Adv 2007;25:318-324), silicone oil levels tend to vary between individual container closures. Various silicone oil levels were applied to a container closure prior to filling and lyophilization of an albumin and interferon alfa-2b fusion protein (albinterferon alfa-2b). Data demonstrated that high silicone oil levels in combination with intended and stress storage conditions had no impact on protein purity, higher order structure, stability trajectory, or biological activity. Subvisible particulate analysis (1-10 µm range) from active and placebo samples from siliconized glass barrels showed similar particle counts. Increases in solution turbidity readings for both active and placebo samples correlated well with increases in silicone oil levels, suggesting that the particles in solution are related to the presence of silicone oil and not large protein aggregates. Results from this study demonstrate that silicone oil is not always detrimental to proteins; nevertheless, assessing the impact of silicone oil on a product case-by-case basis is still recommended.


Assuntos
Albuminas/química , Antivirais/química , Excipientes/química , Interferon-alfa/química , Proteínas/química , Óleos de Silicone/química , Albuminas/administração & dosagem , Albuminas/análise , Albuminas/uso terapêutico , Animais , Antivirais/administração & dosagem , Antivirais/análise , Antivirais/uso terapêutico , Bovinos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Estabilidade de Medicamentos , Liofilização , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/análise , Interferon-alfa/uso terapêutico , Nefelometria e Turbidimetria , Transdução de Sinais/efeitos dos fármacos , Óleos de Silicone/análise , Estresse Mecânico , Fatores de Tempo
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