Adalimumab Liquid Formulation Stability via Citrate Buffering
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Solution Overview
Problem
Current formulations of adalimumab for treating TNF-α-related autoimmune diseases are unstable due to inadequate inhibition of protein aggregation, precipitation, adsorption, osmotic pressure regulation, oxidation, and photo-oxidation, leading to variable product viability and safety concerns during storage and use.
Innovation Solution
A liquid pharmaceutical composition comprising adalimumab, a citrate buffering agent, and a sugar stabilizer, optionally with additional components, which maintains stability under stress conditions such as heat, light, and mechanical agitation, with a pH greater than or equal to 5.4 and minimal phosphate buffering agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple excipients are used to stabilize adalimumab, then protein stability is improved, but formulation complexity and processing burden increase
Solution Approach 1:
The patent removes Tween-80 surfactant from the formulation entirely, retaining only the essential excipients (mannitol, citric acid, sodium phosphate, sodium chloride) needed for stability. This extraction of unnecessary components reduces formulation complexity while maintaining adalimumab stability through the optimized core excipient system.
Solution Approach 2:
The patent makes mannitol serve multiple functions simultaneously: it acts as a stabilizer preventing protein aggregation, provides osmotic pressure regulation, and contributes to pH buffering capacity. This multi-functionality reduces the need for separate excipients, thereby simplifying the overall formulation while maintaining comprehensive protein protection.
2Reliability
If Tween-80 is added to inhibit aggregation and adsorption, then protein stability is improved, but oxidation risk increases
Solution Approach 1:
The patent eliminates Tween-80, which has the harmful side effect of promoting oxidation of double bonds in adalimumab. By removing this excipient, the formulation reduces oxidation risk while maintaining protein stability through alternative mechanisms provided by the remaining excipients, particularly mannitol and the buffered system.
3Duration of action of stationary object
If storage time is extended, then treatment flexibility is improved, but product degradation increases
Solution Approach 1:
The patent incorporates mannitol and a buffered system (citric acid and sodium phosphate) that proactively prevent protein degradation pathways before they can occur during storage. These excipients are pre-formulated to inhibit aggregation, maintain pH stability, and protect against oxidation, thereby extending the shelf life while maintaining adalimumab viability throughout the extended storage period.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The composition ensures a stable isoform profile and improved stability of adalimumab, reducing aggregation, fragmentation, and photo-oxidation, thereby enhancing the shelf life and clinical performance of the drug.
Implementation Method 1
a citrate buffering agent... wherein the composition... maintains stability under stress conditions... with a pH greater than or equal to 5.4
Implementation Method 2
a sugar stabilizer... reducing aggregation, fragmentation, and photo-oxidation
Implementation Method 3
Inadquate regulation of oxidation (a function supposedly served by mannitol and potentially undermined by Tween-80, which can promoted oxidation of double bonds)
Implementation Method 4
Inadquate inhibition of photo-oxidation... reducing aggregation, fragmentation, and photo-oxidation
Data Source
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AI summary
The present invention relates to novel liquid pharmaceutical compositions of adalimumab, which include adalimumab or a biosimilar thereof, a citrate buffering agent/system such as sodium citrate/citric acid, and a sugar stabiliser such as trehalose. 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.