Non-aqueous Antibody Suspension Viscosity Reduction
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Solution Overview
Problem
Current high concentration monoclonal antibody formulations for parenteral administration face challenges such as increased protein aggregation, poor stability, and high viscosity, which impede injectability and pose manufacturing and storage difficulties due to their aqueous nature and multiple vehicle components.
Innovation Solution
A non-aqueous high concentration suspension formulation using a vehicle comprising sesame oil as the hydrophobic agent and ethyl oleate as the viscosity-reducing agent, combined with anti-TNFα antibodies, reduces injection force to 45 Newtons or less by incorporating at least 28% volume of the viscosity reducing agent or utilizing protein particles of specific sizes, enhancing injectability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high concentration antibody formulations (100 mg/mL) are prepared in aqueous buffers, then the required small injection volumes (0.5-2 mL) can be achieved, but the viscosity increases significantly impairing injectability
Solution Approach 1:
The patent changes the fundamental parameter of the vehicle system from aqueous to non-aqueous (hydrophobic). This phase change enables high antibody concentrations (100 mg/mL) to be formulated with dramatically reduced viscosity, allowing injectability while maintaining the required dosage concentration in small volumes.
Solution Approach 2:
The formulation uses a composite vehicle system combining a hydrophobic agent (such as benzyl benzoate or PEG400) with stabilizing excipients. This composite approach solves the contradiction by creating a new formulation matrix that accommodates high protein concentration without the viscosity penalties of traditional aqueous systems.
2Quantity of substance
If high concentration antibody formulations are prepared, then the dosing volume can be reduced to 0.5-2 mL, but protein aggregation and instability increase
Solution Approach 1:
Changing from aqueous to non-aqueous vehicle fundamentally alters the solvation and intermolecular interaction parameters. The hydrophobic environment prevents protein-protein interactions that lead to aggregation, thereby maintaining stability at high concentrations that would be unstable in aqueous buffers.
Solution Approach 2:
The hydrophobic vehicle acts as an intermediary medium that separates antibody molecules, preventing direct protein-protein contact that causes aggregation. The vehicle components (benzyl benzoate, PEG400) mediate the environment to maintain individual protein stability while allowing high concentration formulation.
3Reliability
If multiple vehicle components (polymer, surfactant, solvent) are used in non-aqueous formulations, then protein stability can be maintained, but the formulation complexity increases and regulatory challenges arise
Solution Approach 1:
The patent employs vehicle components that perform multiple functions simultaneously. For example, PEG400 serves as both the hydrophobic solvent and a stability-enhancing agent, while benzyl benzoate provides both solvation and aggregation prevention. This multi-functionality reduces the number of separate excipients needed, simplifying the overall formulation.
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 achieves improved injectability and stability, maintaining bioactivity and reducing viscosity, allowing for effective manual injection and prolonged storage stability, addressing the limitations of existing formulations.
Implementation Method 1
ethyl oleate as the viscosity-reducing agent
Data Source
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AI summary
The present invention relates to non-aqueous high concentration reduced viscosity suspension formulations antibodies and methods of making and using them.