Buffered Antibody Formulation for Thermal Stability
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Solution Overview
Problem
Current antibody formulations face challenges in maintaining thermal and colloidal stability, leading to aggregation and degradation, particularly due to high salt levels and pH imbalances, which affect the shelf storage and therapeutic efficacy of antibodies like adalimumab.
Innovation Solution
A buffered antibody formulation comprising 30 mg to 50 mg of an antibody with a specific amino acid sequence, 0.7 mM to 1.3 mM sodium acetate trihydrate, 200 mM to 206 mM mannitol, 16 mM to 22 mM glacial acetic acid, 24 mM to 28 mM sodium chloride, and 0.07% to 0.15% polysorbate 80, maintaining a pH of 5.1 to 5.3, which minimizes sodium chloride and optimizes buffer components for enhanced stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high salt levels are used in antibody formulations, then osmotic pressure and isotonicity are maintained, but thermal stability and colloidal stability deteriorate, leading to aggregation and degradation
Solution Approach 1:
The patent applies parameter changes by optimizing the sodium chloride concentration from typical high levels (e.g., 150 mM) down to a specific range of 15-30 mM, while simultaneously adjusting pH to 5.0-5.5 and incorporating mannitol (50-200 mM) as a stabilizing excipient. This combination of parameter modifications resolves the contradiction by maintaining formulation stability through pH and excipient control rather than relying on high salt concentrations.
2Stability of the object's composition
If pH is adjusted to optimize antibody stability, then conformational stability improves, but buffer capacity and pH control become more challenging
Solution Approach 1:
The patent employs a composite buffer system combining multiple components: acetate buffer (pH 4.5-5.0), phosphate buffer (pH 6.0-7.0), or citrate buffer (pH 3.0-4.0), along with mannitol and controlled sodium chloride. This composite approach allows the formulation to maintain conformational stability through optimized pH while the multiple buffer components work together to provide adequate buffer capacity and simplify pH control.
3Duration of action of stationary object
If buffer components are optimized for stability, then shelf storage life extends, but formulation complexity and manufacturing precision requirements increase
Solution Approach 1:
The patent establishes specific parameter ranges to balance shelf storage life with manufacturing feasibility: pH 5.0-5.5, sodium chloride 15-30 mM, mannitol 50-200 mM, and protein concentration 10-50 mg/mL. These defined ranges provide clear manufacturing targets that extend shelf storage life while avoiding excessive precision requirements, making the formulation practical for production.
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 stabilizes antibodies for long-term storage, reducing aggregation and degradation, and retains tumor necrosis factor alpha binding activity, ensuring therapeutic efficacy and improved patient acceptability by reducing injection-site reactions.
Implementation Method 1
a buffer comprising from 0.7 mM to 1.3 mM of an acetate salt, preferably sodium acetate trihydrate, from 200 mM to 206 mM of mannitol
Implementation Method 2
0.07%(v/v) to 0.15% (v/v) of non-ionic surfactant polysorbate 80
Implementation Method 3
a buffer comprising from 0.7 mM to 1.3 mM of an acetate salt, preferably sodium acetate trihydrate, from 16 mM to 22 mM of glacial acetic acid, and from 24 mM to 28 mM of sodium chloride, and 0.07%(v/v) to 0.15% (v/v) of non-ionic surfactant polysorbate 80, wherein the antibody formulation has a pH of from 5.1 to 5.3
Data Source
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AI summary
The invention provides buffered formulations of adalimumab. The formulations comprise a buffer comprising an acetate salt, mannitol, glacial acetic acid, sodium chloride, and polysorbate 80. The formulations have an acidic pH, and enhance the thermal, conformational and colloidal stability of antibodies, including the adalimumab antibody.