Antibody Liquid Formulation Buffers for Low Aggregation Storage
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Solution Overview
Problem
Highly-concentrated antibody-containing solutions form highly viscous solutions and aggregates during storage or freeze-thaw cycles, posing challenges for stable subcutaneous administration.
Innovation Solution
Utilizing histidine-aspartate or histidine-glutamate buffers, or tris(hydroxymethyl)aminomethane-aspartate or tris(hydroxymethyl)aminomethane-glutamate buffers, and arginine-aspartate or arginine-glutamate as stabilizers, to create stable antibody-containing formulations with reduced aggregation and viscosity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If antibody concentration is increased for subcutaneous injection, then dosage efficiency is improved, but viscosity increases making injection difficult
Solution Approach 1:
The patent changes the chemical parameters of the formulation by introducing specific excipients (histidine-aspartate buffer, polysorbate 80, and mannitol) to modify the physical properties of the antibody solution. These parameter changes enable high concentration (150-500 mg/mL) while maintaining acceptable viscosity and stability for subcutaneous injection
2Quantity of substance
If antibody concentration is increased, then dosage efficiency is improved, but aggregation and degradation occur during storage
Solution Approach 1:
The patent uses histidine-aspartate buffer as an intermediary substance that mediates between the antibody molecules, preventing direct intermolecular interactions that lead to aggregation. The buffer acts as a protective medium that maintains molecular spacing and electrostatic repulsion, thereby preserving formulation stability at high concentrations
Solution Approach 2:
The formulation employs a composite approach by combining multiple excipients (histidine-aspartate buffer system, polysorbate 80 surfactant, and mannitol osmotic agent) that work synergistically to prevent aggregation through different mechanisms, creating a stable high-concentration formulation
3Reliability
If lyophilization is used to stabilize formulations, then aggregation is reduced, but viscosity increases and handling becomes difficult
Solution Approach 1:
Instead of using lyophilization to achieve stability (solid state), the patent inverts the approach by developing a liquid formulation that achieves stability through careful selection of buffer composition and excipients. This allows the formulation to remain in liquid state while preventing aggregation, thereby maintaining ease of handling and injection
4Device complexity
If conventional buffers are used, then formulation is simple, but stabilization effect is insufficient at high concentrations
Solution Approach 1:
The patent modifies the buffer parameters by using histidine-aspartate instead of conventional histidine hydrochloride or acetate buffers. This parameter change in the counterion composition provides superior stabilization effect at high antibody concentrations while maintaining reasonable formulation complexity
Data Source
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AI summary
An objective of the present invention is to provide stable antibody-containing formulations which are suitable for subcutaneous administration and in which aggregation formation is suppressed during long-term storage. The present inventors discovered that a significant stabilization effect was achieved by using an acidic amino acid, aspartic acid or glutamic acid as a counter ion species in histidine buffer or tris(hydroxymethyl)aminomethane, specifically by using histidine-aspartate buffer or histidine-glutamate buffer, or tris(hydroxymethyl)aminomethane-aspartate or tris(hydroxymethyl)aminomethane-glutamate as a buffer. The present inventors also discovered that a significant stabilization effect was achieved by using an acidic amino acid, aspartic acid or glutamic acid, as a counter ion species to a basic amino acid such as arginine, specifically by using arginine-aspartate or arginine-glutamate.