Polyethyleneimine Stabilized Antibody Formulations
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Solution Overview
Problem
Highly concentrated protein solutions, particularly antibody solutions, face significant challenges with protein aggregation, which can lead to unacceptable levels of high molecular weight species and insoluble aggregates during storage, making them unsuitable for therapeutic applications.
Innovation Solution
Incorporating a stabilizing amount of polyethyleneimine (PEI) into the aqueous solutions at a weight ratio of at least 20:1 with the antibody protein, effectively reducing aggregation, self-association, and viscosity increase, while maintaining the solution's isotonicity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the concentration of antibody protein is increased to at least 10 mg/mL, then the productivity and dosage convenience are improved, but the rate of aggregation and formation of high molecular weight species increases significantly
Solution Approach 1:
Polyethyleneimine acts as a mediating substance between the high concentration antibody molecules, preventing direct aggregation interactions. The PEI forms a protective environment around the antibody molecules, allowing high concentration formulation (≥10 mg/mL) while maintaining stability during storage and transport.
Solution Approach 2:
The invention changes the chemical environment parameters by introducing polyethyleneimine, which alters the local ionic strength, charge distribution, and molecular interactions in the solution. This parameter change enables the system to maintain stability at concentrations that would otherwise cause rapid aggregation.
2Reliability
If charged tonicity modifiers (e.g., sodium chloride) are added to control aggregation through ionic strength adjustment, then the aggregation rate is reduced, but the osmolarity becomes unacceptably high causing injection pain
Solution Approach 1:
Polyethyleneimine serves as an intermediary that controls aggregation through steric and electrostatic mechanisms rather than relying solely on ionic strength. This allows the formulation to maintain lower osmolarity while still preventing aggregation, thus avoiding injection pain.
Solution Approach 2:
The invention changes the mechanism of aggregation control from ionic strength-dependent (charged modifiers) to a combination of steric and electrostatic stabilization provided by PEI. This parameter change enables effective aggregation control at physiologically acceptable osmolarities.
3Object-affected harmful factors
If uncharged tonicity modifiers (e.g., sucrose, trehalose) are used to control aggregation, then the osmolarity is maintained at acceptable levels, but the aggregation control effectiveness is insufficient compared to charged modifiers
Solution Approach 1:
The invention creates a composite stabilization system combining polyethyleneimine with uncharged tonicity modifiers. The PEI provides primary aggregation control through charge-charge and steric interactions, while the uncharged modifiers contribute to osmotic balance and secondary stabilization, achieving both effective aggregation control and acceptable osmolarity.
Solution Approach 2:
The invention changes the dominant stabilization mechanism from weak steric stabilization by uncharged modifiers to strong electrostatic and steric stabilization by PEI. This parameter change enables uncharged modifiers to be used at lower concentrations while maintaining effective aggregation control and acceptable osmolarity.
4Reliability
If polyethyleneimine is added to reduce aggregation and self-association, then the solution stability and concentration are improved, but the viscosity may increase
Solution Approach 1:
The invention uses a controlled, sub-stabilizing amount of polyethyleneimine that provides sufficient aggregation control without excessive viscosity increase. By optimizing the PEI concentration to the minimum effective level, the formulation achieves stability while minimizing the viscosity penalty associated with higher PEI concentrations.
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 approach significantly reduces protein aggregation, maintains solution stability, and allows for higher concentration formulations suitable for subcutaneous or intramuscular injection, enhancing storage stability and reducing the formation of low molecular weight species.
Implementation Method 1
It is believed that in those cases where the rate of aggregation is lower in compositions of higher ionic strength than in compositions of lower ionic strength the key cause of aggregation is due to charge-charge interactions between the protein molecules.
Implementation Method 2
It is believed that two dominant types of non-covalent interactions drive the protein aggregation: (1) hydrophobic interactions between non-polar parts of the protein molecules, and (2) charge-charge interactions between charged regions of the protein molecules.
Data Source
AI summary
The present invention provides an aqueous solution comprising an antibody protein at a concentration of at least about 10 mg/m L and a stabilizing amount of polyethyleneimine.