Composition for stabilizing protein and pharmaceutical formulation comprising the same
Inventors
Park, Soon Jae • Chung, Hye-Shin • Kim, Jin Hwan • Byun, Minsoo • Yeon, Ji Hyeon
Assignees
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Publication Number
US-9821059-B2
Publication Date
2017-11-21
Expiration Date
Abstract
The present invention relates to a composition for stabilizing TNFα-binding protein exhibiting physiological activity, and more specifically, to a composition for stabilizing protein including basic amino acid and sugar and/or ammonium salt, a pharmaceutical formulation including the same, and a method for stabilizing TNFα-binding protein. The formulation including basic amino acid; and sugar and/or ammonium salt according to the present invention effectively inhibits aggregation, denaturation and oxidation of TNFα-binding protein used for treating various diseases, for example, an anti-TNF-alpha antibody, such that the protein is capable of being preserved and stored for a long time, which is widely usable and effective in a medical field using TNFα-binding protein, for example, an anti-TNF-alpha antibody.
Core Innovation
The disclosure relates to a stabilized adalimumab composition comprising adalimumab, arginine, mannitol, ammonium sulfate, and citric acid. The composition is defined by specified concentration ranges for arginine, mannitol, and ammonium sulfate, together with citric acid, and is described as reducing denaturation, deamidation, oxidation, monomer loss, aggregates, and fragments.
In particular, the stabilization is described as inhibiting aggregation, denaturation, and oxidation to maintain long-term preservability and physiological activity. The disclosure also describes reduced C-terminal lysine variants (K0/K1/K2) and reduced acidic variants, with comparative behavior across pH and a reported stability range of about pH 5.7 to 6.3.
The same excipient set is additionally disclosed as a stabilizer system for a solution containing adalimumab. A method is described in which arginine, mannitol, ammonium sulfate, and citric acid are added to an adalimumab-containing solution while maintaining the specified concentration ranges for arginine, mannitol, and ammonium sulfate, for long-term storage while maintaining physiological activity.
Claims Coverage
The document provides two independent claims: one directed to a stabilized adalimumab composition and one directed to a method of stabilizing adalimumab by adding a defined excipient set. Each independent claim is characterized by a specific combination of inventive formulation features and quantitative concentration ranges.
Stabilized adalimumab composition with arginine, mannitol, ammonium sulfate, and citric acid
A stabilized adalimumab composition comprising adalimumab; arginine with a concentration of 50 to 100 mM; mannitol with a concentration of 1 to 2.5% (w/v); ammonium sulfate with a concentration of 40-65 mM; and citric acid.
Method of stabilizing adalimumab with arginine, mannitol, ammonium sulfate, and citric acid
A method of stabilizing adalimumab comprising adding arginine, mannitol, ammonium sulfate and citric acid to a solution containing adalimumab, wherein a concentration of arginine in the solution is 50 to 100 mM, a concentration of mannitol is 1 to 2.5% (w/v) and a concentration of ammonium sulfate is 40-65 mM.
Across the independent claims, the core inventive coverage is the defined excipient system for stabilizing adalimumab—arginine (50–100 mM), mannitol (1–2.5% w/v), ammonium sulfate (40–65 mM), and citric acid—either as a composition or as excipients added to an adalimumab-containing solution, with stabilization linked to reduced denaturation/deamidation/oxidation and reduced aggregation/fragment formation.
Stated Advantages
Inhibits aggregation, denaturation, and oxidation, thereby improving long-term preservability.
Maintains physiological activity over long-term storage.
Reduces denaturation/deamidation/oxidation and related quality changes such as variant-related changes and reduced monomer loss.
Reduces aggregates and fragments.
Documented Applications
Medical use as part of TNFα inhibitors, including medical/industrial applicability for storage and formulation of an anti-TNFα antibody (adalimumab).
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