Antibody Formulation Stability via Histidine Buffering
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Solution Overview
Problem
Monoclonal antibodies in liquid pharmaceutical formulations are prone to degradation due to physical and chemical instabilities, leading to aggregate formation and loss of biological activity, which poses challenges in maintaining therapeutic effectiveness.
Innovation Solution
A stable formulation comprising 25-250 mg/ml antibodies, 10-30 mM buffering species, 1-15% polyol, 0.001-0.05% nonionic surfactant, and pH 5-7.5, with preferred use of Histidine as a buffer and trehalose as a lyoprotectant and cryoprotectant, inhibiting aggregate formation and maintaining biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are formulated in liquid pharmaceutical formulations, then they can be administered effectively, but they are prone to degradation and aggregate formation leading to loss of biological activity
Solution Approach 1:
The patent introduces intermediary substances (surfactants, polysorbates, and buffering agents) that mediate between the antibody molecules and the formulation environment. These intermediaries stabilize the antibody structure, prevent aggregation, and maintain biological activity by acting as protective agents against physical and chemical degradation during storage and administration.
Solution Approach 2:
The patent systematically changes formulation parameters including pH (optimized to 5-7.5), ionic strength, temperature, and the addition of stabilizing agents. By adjusting these parameters, the formulation maintains antibody stability and prevents degradation while preserving biological activity throughout the product shelf life.
2Productivity
If the antibody concentration is increased to improve therapeutic effectiveness, then dosing frequency can be reduced, but aggregate formation and degradation accelerate
Solution Approach 1:
At high antibody concentrations (25-250 mg/ml), the patent employs intermediary stabilizing agents that become critical for preventing aggregation. These intermediaries occupy spaces between antibody molecules and prevent harmful interactions, allowing high concentration formulations to maintain stability and prevent the acceleration of degradation that would otherwise occur.
Solution Approach 2:
The patent creates composite formulation systems combining antibody with multiple stabilizing components (surfactants, buffering agents, polysorbates). This composite approach allows the formulation to achieve high therapeutic concentration while the combined protective effects of multiple ingredients prevent aggregation and maintain stability.
3Reliability
If phosphate-based buffer is used for formulation, then it provides good buffering capacity, but acidic variant accumulation increases compared to Histidine-based formulations
Solution Approach 1:
The patent compares and optimizes buffer system parameters, specifically pH and buffering capacity. By switching from phosphate-based to Histidine-based buffering systems and optimizing pH to 5-7.5, the formulation maintains adequate buffering capacity while reducing acidic variant accumulation. This parameter optimization resolves the contradiction between buffering performance and degradation prevention.
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 aggregate formation and degradation, maintaining the biological activity of antibodies during storage and administration, with Histidine-based formulations showing improved stability and lower acidic variant accumulation compared to phosphate-based formulations.
Implementation Method 1
buffer providing pH 5 to pH 7.5
Implementation Method 2
0.001% to about 0.05% nonionic surfactant
Implementation Method 3
lyoprotectant and/or cryoprotectant
Implementation Method 4
lyoprotectant and/or cryoprotectant
Data Source
AI summary
A stable pharmaceutically formulation containing antibody, a buffer, a non-ionic surfactant, and a lyoprotectant/cryoprotectants. Also disclosed are associated methods for preparing, storing, and using such formulations.