High-Concentration Aflibercept Formulation for Stable Low-Volume Injection
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Solution Overview
Problem
Existing high concentration antibody and protein formulations, such as those containing vascular endothelial growth factor (VEGF) receptor fusion proteins, face challenges in maintaining pharmaceutically acceptable potency, stability, viscosity, and pH, leading to issues like protein aggregation and decreased efficacy.
Innovation Solution
Development of high concentration aflibercept formulations for intravitreal administration, including buffers, thermal stabilizers, and surfactants, with specific pH and viscosity ranges, to ensure stability and reduce injection volume.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If high concentration antibody formulations are used, then shorter injection times and smaller injection volumes are achieved, but protein aggregation and viscosity increase resulting in lower potency and stability
Solution Approach 1:
The patent applies parameter changes by systematically optimizing formulation conditions including pH (adjusted to specific ranges), ionic strength, excipient concentrations, and temperature. These parameter modifications enable the formulation to maintain protein stability at high concentrations while achieving reduced injection volumes, directly resolving the contradiction between concentration benefits and stability concerns
Solution Approach 2:
The patent employs intermediary substances (excipients such as buffers, surfactants, and stabilizing agents) that mediate between the high concentration requirement and protein stability. These intermediaries prevent protein aggregation and maintain solubility, allowing the formulation to achieve both high concentration (reduced injection time) and reliability (protein stability) simultaneously
2Productivity
If high concentration antibody formulations are used, then manufacturing and storage utility are improved, but protein aggregation increases resulting in lower manufacturing and storage stability
Solution Approach 1:
The patent applies preliminary action by incorporating stabilizing excipients and optimizing formulation conditions before the protein is subjected to manufacturing and storage conditions. This preventive approach ensures that protein aggregation is minimized during subsequent manufacturing processes and storage periods, maintaining both productivity benefits of high concentration and stability requirements
Solution Approach 2:
The patent utilizes parameter changes in formulation composition (adding specific excipients, adjusting pH, controlling ionic strength) to create a formulation environment that prevents protein aggregation during manufacturing and storage. This enables high concentration formulations to maintain both manufacturing efficiency and long-term storage stability
3Volume of moving object
If high concentration protein formulations are used, then injection volume is reduced, but viscosity increases making injection difficult
Solution Approach 1:
The patent applies parameter changes by optimizing formulation viscosity through pH adjustment, excipient selection, and concentration control. These modifications enable the formulation to achieve reduced injection volume while maintaining acceptable viscosity levels for easy injection, resolving the contradiction between volume reduction and injection ease
4Duration of action of stationary object
If high concentration antibody formulations are used, then frequency of administration is reduced, but protein aggregation increases resulting in lower overall potency
Solution Approach 1:
The patent employs intermediary excipients that prevent protein aggregation and maintain protein stability at high concentrations. These intermediaries ensure that the reduced administration frequency benefit is achieved without sacrificing potency, as the protein remains stable and active throughout the extended dosing interval
Data Source
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AI summary
The present invention provides ophthalmic formulations having high concentrations of vascular endothelial growth factor (VEGF) receptor fusion protein and high stability during storage. Methods for treating angiogenic eye disorders using the high concentration formulations are also provided.