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Publication Number
US-11534403-B2
Publication Date
2022-12-27
Expiration Date
Abstract
The present invention relates to novel liquid pharmaceutical compositions of adalimumab, which include adalimumab or a biosimilar thereof, arginine and/or methionine, and a small polyol stabiliser such as glycerol. Such a combination of components furnishes formulations having a stability (e.g. on storage and when exposed to stress) which is comparable to or an improvement upon those known in the art, and with fewer ingredients. Such advances will help adalimumab treatments to become more widely available at lower cost, and prolong the viability of pre-loaded delivery devices (e.g. pre-filled syringes) to reduce unnecessary waste of the drug.
Core Innovation
The invention relates to liquid pharmaceutical compositions comprising adalimumab, including biosimilars, in combination with arginine and methionine, and a small polyol stabilizer selected from propylene glycol and glycerol. The compositions further include an acetate buffer system and a surfactant, with specified concentration ranges, an arginine:methionine molar ratio of 1:5 to 5:1, and a pH of 4.5 to 5.5.
The compositions are required to remain visually clear after 30° for 4 weeks as assessed using the 2.9.20 European Pharmacopoeia Monograph. The document describes the problem of providing liquid pharmaceutical compositions containing adalimumab that maintain stability and appearance under stress and storage conditions while addressing injection-related tolerability issues associated with painful injection.
The document describes an unexpected synergy between arginine and methionine, with further stabilization achieved by the addition of small polyols. The rationale is tied to improved formulation stability and suitability for higher antibody concentration and reduced injection pain, while maintaining compatibility with syringe/pen device use.
Claims Coverage
The independent claim covers a liquid pharmaceutical composition defined by specific concentration ranges for adalimumab, arginine, methionine, and a C2–C6 polyol, together with an acetate buffer system, a surfactant, a defined arginine:methionine molar ratio, and a pH and visual clarity requirement under specified conditions. Dependent claims refine formulation ranges and add acetate buffer constraints including basification of acetic acid and absence of sodium chloride generation.
Adalimumab liquid composition with arginine, methionine, and small polyol stabilizer
A liquid pharmaceutical composition comprising 75 mg/ml to 200 mg/ml adalimumab, 28.7 mM to 86.1 mM arginine, 16.7 mM to 50.2 mM methionine, and 50 mM to 200 mM propylene glycol or glycerol, having a pH of 4.5 to 5.5 and being visually clear after 30° for 4 weeks as assessed using the 2.9.20 European Pharmacopoeia Monograph.
Arginine:methionine molar ratio for formulation stability
The composition has an arginine:methionine molar ratio of 1:5 to 5:1.
Acetate buffer system with defined surfactant content
The composition includes 5 mM to 10 mM acetate and 0.1 mg/ml to 10 mg/ml of a surfactant.
Acetate buffer formed by basifying acetic acid
An acetate buffer system made by basifying acetic acid is included in the liquid pharmaceutical composition.
Acetate buffer formed without generating sodium chloride
An acetate buffer system is included that is made without generating sodium chloride.
The claimed inventive concept centers on a liquid adalimumab composition defined by specific arginine and methionine concentrations and arginine:methionine molar ratio, combined with a small polyol stabilizer, an acetate buffer system, and a surfactant, all constrained by a defined pH and visual clarity requirement.
Stated Advantages
Enables higher antibody concentration.
Reduced injection pain.
Comparable or improved stability versus commercial formulations.
Stability under stress testing including aggregation, fragmentation, deamidation/oxidation, sub-visible particle formation, and pH stability.
Maintains shelf-life at 2–8° C.
Syringe/pen device compatibility while maintaining visual clarity.
Documented Applications
Liquid pharmaceutical compositions for adalimumab, including biosimilars.
Use as a formulation compatible with syringe/pen device (pre-filled syringe/pen device compatibility).
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