High-Concentration Antibody Liquid Formulation with Arginine Stabilization
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Solution Overview
Problem
Existing antibody formulations for subcutaneous administration face challenges with high viscosity and degradation issues such as dimerization and deamidation during long-term storage, lacking sufficient stabilization methods.
Innovation Solution
A stable antibody-containing liquid formulation is achieved by incorporating arginine and optionally methionine as stabilizers, along with a histidine buffer, maintaining a pH range of 4 to 8 and viscosity between 2 to 15 mPa·s, preventing dimerization and deamidation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If a high concentration of antibody is used in liquid formulation for subcutaneous injection, then the dosing frequency can be reduced and formulation volume can be minimized, but the viscosity increases and dimerization and deamidation occur during storage
Solution Approach 1:
The patent introduces arginine as an intermediary substance that mediates between the high antibody concentration requirement and the stability requirement. Arginine acts as a stabilizer that prevents dimerization and deamidation of antibody molecules, allowing the formulation to maintain high concentration while preserving stability during storage
Solution Approach 2:
The patent changes the chemical composition parameters of the formulation by adding arginine at specific concentrations (50-1500 mM) and controlling pH (4-8). This parameter modification enables the formulation to achieve both high antibody concentration and stability, resolving the contradiction between concentration and stability
2Quantity of substance
If lyophilization-concentration technique is used to increase antibody concentration, then the formulation can be stored stably, but the viscosity increases due to cryoprotective agents and reconstitution is required
Solution Approach 1:
The patent extracts and eliminates the need for lyophilization and reconstitution steps from the formulation process. By using arginine-based stabilization in liquid form, the formulation achieves high concentration without requiring freeze-drying and reconstitution, thereby simplifying handling and improving ease of operation
Solution Approach 2:
The patent replaces the complex lyophilization system with a simple liquid formulation containing arginine. This disposable liquid formulation eliminates the need for reconstitution equipment and procedures, making the system more user-friendly and easier to operate
3Stability of the object's composition
If cryoprotective agents such as sugar are added during lyophilization, then the formulation can be stored stably, but the viscosity increases which is not preferred for subcutaneous injection
Solution Approach 1:
The patent uses arginine as an intermediary stabilizer that replaces the need for cryoprotective agents like sugar. Arginine prevents protein aggregation and maintains formulation stability without significantly increasing viscosity, thereby resolving the contradiction between stability and viscosity
Solution Approach 2:
The patent changes the stabilizing mechanism from cryoprotective agents (sugar) to amino acid-based stabilizers (arginine). This parameter change in the type of stabilizer maintains formulation stability while keeping viscosity at acceptable levels for subcutaneous injection
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 maintains stability for at least 6 months at 22-28°C, reducing dimerization and deamidation, allowing for subcutaneous administration without lyophilization and sugar addition.
Implementation Method 1
adding an amino acid, arginine or a salt thereof, as a stabilizer
Implementation Method 2
in which dimerization and deamidation during long-term storage are inhibited
Implementation Method 3
a histidine buffering agent
Implementation Method 4
maintaining a pH range of 4 to 8
Implementation Method 5
viscosity between 2 to 15 mPa·s
Data Source
AI summary
The problem to be solved is to provide a humanized anti-IL-6 receptor antibody MRA-containing formulation which is suitable for subcutaneous administration, wherein dimerization or deamidation is prevented during long-term storage. The present application is directed to a stable antibody-containing liquid formulation characterized by containing arginine and histidine buffer. A method of inhibiting deamidation or dimerization of such an antibody in a concentrated liquid formulation includes histidine buffer in the liquid formulation.