Veltuzumab High Concentration Formulation pH Optimization
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Solution Overview
Problem
There is a need for high concentration liquid formulations of antibodies, particularly for veltuzumab, as existing methods struggle to stabilize and concentrate antibodies above 100 mg/mL due to viscosity issues and aggregation, which complicates administration and stability.
Innovation Solution
A method involving ultrafiltration and diafiltration to concentrate veltuzumab to 160-220 mg/mL, using a buffer solution with histidine, polysorbate 20, and sorbitol, maintaining a pH of 5.5±0.3, to stabilize the antibody and prevent aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If the concentration of antibody is increased to reduce administration volume, then the volume necessary for administration decreases, but the viscosity of the liquid formulation increases dramatically
Solution Approach 1:
The patent changes the pH parameter of the formulation to a specific range (5.0-6.5, preferably 5.5-6.0) to optimize the balance between antibody concentration and viscosity. This pH optimization allows achieving high concentrations (100-280 mg/mL) while maintaining acceptable viscosity levels for subcutaneous administration.
2Duration of action of moving object
If the concentration of antibody is increased to allow less frequent administration, then the frequency of administration decreases, but the tendency of proteins to form aggregates increases dramatically
Solution Approach 1:
The patent optimizes the pH parameter to a specific range (5.0-6.5) that minimizes aggregation tendency while enabling high antibody concentrations. This pH optimization stabilizes the antibody structure and prevents intermolecular aggregation, allowing concentrations up to 280 mg/mL without excessive aggregation.
Solution Approach 2:
The patent introduces surfactants (such as polysorbate 20 or polysorbate 80) as intermediary substances that adsorb to the antibody surface and prevent aggregation. These surfactants act as mediators that reduce intermolecular interactions, enabling high concentrations while maintaining stability.
3Ease of operation
If high concentration formulations are prepared to enable subcutaneous injection, then the route of administration becomes less invasive, but the formulation stability becomes more challenging
Solution Approach 1:
The patent optimizes multiple parameters simultaneously: pH (5.0-6.5), surfactant concentration (0.01-1.0%), and antibody concentration (100-280 mg/mL). This multi-parameter optimization creates a stable formulation that can be administered subcutaneously without aggregation or degradation.
Solution Approach 2:
The patent uses surfactants as intermediary substances that stabilize the high-concentration antibody formulation. These surfactants prevent aggregation and maintain physical stability, enabling subcutaneous administration of highly concentrated antibodies.
4Quantity of substance
If conventional ultrafiltration is used to concentrate antibodies, then the concentration increases, but aggregates form and stability is compromised
Solution Approach 1:
The patent performs preliminary buffer exchange to replace the original buffer with one optimized for stability (pH 5.0-6.5) before concentration. This preliminary action prevents aggregation during the subsequent ultrafiltration process by ensuring the antibody is in a stable conformational state.
Solution Approach 2:
The patent changes the buffer pH parameter to an optimized range (5.0-6.5) before concentration, which minimizes aggregation tendency during ultrafiltration. This parameter optimization allows achieving high concentrations while maintaining stability throughout the concentration process.
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
This method achieves a stable high concentration liquid formulation of veltuzumab, reducing aggregation and improving stability, allowing for more convenient and effective subcutaneous administration with enhanced patient convenience and reduced side effects.
Implementation Method 1
concentrating said solution by ultrafiltering said solution with an ultrafiltration membrane
Implementation Method 2
performing ultrafiltration/diafiltration (UF/DF) of the filtrate
Data Source
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AI summary
The present invention provides a method for preparation of a high concentration liquid formulation (HCLF) of an antibody or a fragment thereof. The present invention also relates to a method for stabilizing an anti-CD20 antibody or a fragment thereof in a liquid pharmaceutical formulation. Furthermore, the present invention relates to a liquid pharmaceutical formulation of a veltuzumab antibody or a fragment thereof comprising at least 155 mg/mL of a veltuzumab antibody or a fragment thereof.