Aqueous High-Concentration Anti-VEGF Formulation for Low Aggregation
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Solution Overview
Problem
Existing formulations of high-concentration anti-VEGF antibodies suffer from instability, aggregation, and high levels of sub-visible particles, posing safety concerns and failing to meet regulatory standards for ophthalmic use.
Innovation Solution
Aqueous pharmaceutical compositions comprising anti-VEGF antibodies with stabilizers like sucrose or trehalose, buffers such as citrate or histidine, and surfactants like polysorbate 80, maintaining a pH of 6.3 to 7.3, to achieve low aggregation and undetectable degradation, suitable for long-term storage and ophthalmic administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high concentration of anti-VEGF antibody is formulated, then the volume for injection is reduced, but the formulation becomes unstable and aggregates during storage
Solution Approach 1:
The patent introduces multiple intermediary substances (excipients) including buffers (citrate, histidine, phosphate), surfactants (polysorbate 80, polysorbate 20), and stabilizers (human serum albumin, glycine) that mediate between the high-concentration antibody and the aqueous environment, preventing direct harmful interactions and maintaining stability at concentrations of 50-200 mg/ml
Solution Approach 2:
The patent systematically optimizes multiple formulation parameters including pH (adjusted to specific ranges using buffers), ionic strength, surfactant concentration, and stabilizer concentration to create a parameter space where high-concentration antibody remains stable. The buffered pH conditions and controlled ionic environment prevent aggregation while maintaining high antibody concentration
2Quantity of substance
If high concentration of anti-VEGF antibody is formulated, then the shelf life is shortened due to chemical and physical instabilities
Solution Approach 1:
The patent incorporates stabilizing excipients (human serum albumin, glycine, surfactants) that provide beforehand cushioning against degradation mechanisms. These substances are pre-formulated to prevent aggregation, oxidation, and deamidation before they can occur, thereby extending shelf life of high-concentration formulations to at least 18 months
Solution Approach 2:
The patent optimizes pH and ionic strength parameters to minimize chemical degradation rates. By maintaining pH within specific ranges using buffers and controlling ionic strength with salts, the formulation reduces the rate of deamidation and oxidation reactions, thereby extending shelf life while maintaining high antibody concentration
3Quantity of substance
If high concentration of anti-VEGF antibody is formulated, then aggregation increases leading to safety concerns, but reducing concentration increases injection volume
Solution Approach 1:
The patent uses surfactants (polysorbate 80, polysorbate 20) and stabilizing proteins (human serum albumin) as intermediary substances that adsorb to the antibody surface and prevent intermolecular aggregation. These intermediaries create a protective layer around each antibody molecule, eliminating direct antibody-antibody contact that would lead to aggregation even at high concentrations
Solution Approach 2:
The patent adjusts pH to specific ranges where the antibody carries a net charge that repels other antibody molecules, preventing aggregation. The buffered conditions maintain this charge state consistently, ensuring low aggregation levels while allowing high concentration formulation
4Quantity of substance
If high concentration of protein is formulated for ophthalmic use, then sub-visible particles increase exceeding regulatory limits, but lower concentration requires larger injection volume
Solution Approach 1:
The patent employs surfactants (polysorbate 80, polysorbate 20) as intermediary substances that prevent the formation of sub-visible particles by adsorbing to protein surfaces and preventing unwanted interactions. These surfactants act as protective intermediaries that maintain formulation clarity and meet USP particulate matter standards even at high protein concentrations
Solution Approach 2:
The patent optimizes pH and ionic strength parameters to minimize the formation of sub-visible particles. By maintaining pH within specific buffered ranges and controlling ionic strength, the formulation prevents protein aggregation into visible particles while allowing high concentration, thereby meeting regulatory particulate matter limits
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 compositions provide stable, high-concentration anti-VEGF formulations with low aggregation and sub-visible particles, meeting regulatory standards for up to 18 months at refrigerated storage, suitable for intravitreal injection or infusion.
Implementation Method 1
Aqueous pharmaceutical compositions comprising an anti-VEGF antibody, sucrose or trehalose, a citrate buffer, and polysorbate 80 as a surfactant
Implementation Method 2
polysorbate 80 as a surfactant
Implementation Method 3
a citrate buffer
Data Source
Figure 1
Figure 2A~2B
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AI summary
The present invention provides anti-VEGF antibodies formulated as high concentration, aqueous pharmaceutical compositions, suitable for an injection, preferably an intravitreal injection. The aqueous pharmaceutical compositions are useful for delivery of a high concentration of the antibody active ingredient to a patient without high levels of antibody aggregation and without a high level of sub-visible particulate matter. An aqueous composition of the invention comprises an antibody having a concentration of at least 50 mg/ml. An aqueous pharmaceutical composition of the invention includes a sugar, a buffering agent, and a surfactant.