Buffered Antibody Formulation Stability
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Solution Overview
Problem
Current antibody formulations face challenges in maintaining thermal and colloidal stability, leading to aggregation and degradation, especially when stored at elevated temperatures or subjected to stress conditions, which affects their efficacy and shelf life.
Innovation Solution
A buffered antibody formulation comprising an antibody specifically binding to tumor necrosis factor alpha, with a buffer system including acetate or histidine salts, sorbitol, and polysorbate 80, optimized to maintain a pH of 5.1 to 5.3, minimizing sodium chloride and citrate or phosphate content, which enhances thermal and colloidal stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody formulations are used, then the formulation is simple and easy to manufacture, but the antibody undergoes aggregation and degradation under stress conditions
Solution Approach 1:
The patent optimizes buffer parameters including pH (5.0-6.0), ionic strength, and buffer composition (histidine, acetate, citrate) to enhance antibody stability. Specific concentration ranges are defined for each component to prevent aggregation while maintaining solubility and activity
Solution Approach 2:
The formulation uses a composite buffer system combining multiple components: histidine/acetate/citrate buffers, amino acids (arginine, glycine, proline), sugars (sucrose, trehalose, sorbitol), and surfactants (polysorbate 80, polysorbate 20). Each component contributes specific stabilizing functions that work synergistically
2Reliability
If the formulation contains high sodium chloride content, then the osmotic pressure is maintained, but the antibody aggregation increases under thermal stress
Solution Approach 1:
The patent reduces sodium chloride concentration to specific ranges (0-154 mM, preferably 0-50 mM) and compensates for osmotic pressure maintenance using alternative agents including amino acids (arginine 0-300 mM), sugars (sucrose 0-500 mM, trehalose 0-500 mM, sorbitol 0-500 mM), and buffer components (histidine 0-100 mM, acetate 0-100 mM, citrate 0-50 mM)
Solution Approach 2:
Alternative osmotic agents serve as intermediaries to maintain osmotic pressure without the aggregation-promoting effects of high sodium chloride. These agents include polyols (sorbitol, mannitol), sugars (sucrose, trehalose), and amino acids that provide osmotic support while stabilizing the antibody structure
3Reliability
If the formulation uses citrate or phosphate buffers, then the pH buffering capacity is sufficient, but the antibody thermal stability decreases
Solution Approach 1:
The patent optimizes buffer selection and concentration to enhance thermal stability. Histidine (0-100 mM), acetate (0-100 mM), and citrate (0-50 mM) are used at controlled concentrations within pH 5.0-6.0, where they provide adequate buffering capacity while minimizing thermal degradation and aggregation
Solution Approach 2:
The formulation creates different functional zones within the buffer system: histidine and acetate provide primary pH buffering and thermal stability, while citrate/phosphate provide secondary buffering capacity. Amino acids and sugars provide localized stabilization at the protein surface, and surfactants protect hydrophobic regions
4Duration of action of stationary object
If the antibody is stored at elevated temperatures, then the shelf life is extended without refrigeration, but the aggregation and degradation increase
Solution Approach 1:
The formulation includes stabilizing agents (sugars, amino acids, surfactants) that are pre-added to cushion against thermal stress before it occurs. These agents form protective complexes with the antibody and prevent aggregation pathways from initiating during temperature elevation
Solution Approach 2:
The formulation parameters are optimized for thermal stability including pH 5.0-6.0, specific concentrations of stabilizers (sucrose 0-500 mM, trehalose 0-500 mM, arginine 0-300 mM), and surfactants (polysorbate 80 0.01-1%). These parameters collectively raise the activation energy for aggregation reactions
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 formulation significantly reduces aggregation and degradation, maintaining the antibody's stability and efficacy over extended storage periods, even under stress conditions, ensuring therapeutic effectiveness.
Implementation Method 1
a buffer comprising from about 1 mM to about 30 mM of an acetate salt, from about 10 mM to about 30 mM of histidine and from about 0 mM to about 30 mM of arginine
Implementation Method 2
about 200 mM to about 206 mM of sorbitol
Implementation Method 3
about 200 mM to about 206 mM of sorbitol
Implementation Method 4
from about 0.07% (v/v) to about 0.15% (v/v) of a non-ionic surfactant such as polysorbate 80
Data Source
AI summary
The disclosure provides buffered formulations of adalimumab. The formulations comprise a buffer comprising an acetate salt, sorbitol, histidine and/or a histidine salt and optionally arginie and/or an arginine salt, and polysorbate 80. The formulations have an acidic pH, and enhance the thermal, conformational and colloidal stability of antibodies, including the adalimumab antibody.