Aflibercept Ophthalmic Composition for Stress Stability
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Solution Overview
Problem
Existing ophthalmic liquid compositions of aflibercept suffer from instability under various stressed conditions such as agitation, freezing and thawing, UV exposure, and high temperatures, leading to aggregation, fragmentation, and loss of therapeutic efficacy.
Innovation Solution
An ophthalmic liquid composition comprising aflibercept stabilized with a buffer containing sodium acetate or histidine, sugars like sucrose or trehalose, and a surfactant such as polysorbate, optimized for pH 5.3 to 6.2 and without sodium chloride, to maintain stability and activity under stressed conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If aflibercept is formulated in conventional ophthalmic liquid compositions, then it can be administered for treating ophthalmic diseases, but it undergoes physical and chemical deterioration under stressed conditions leading to aggregation and loss of activity
Solution Approach 1:
The patent optimizes specific formulation parameters including buffer pH (5.5-6.5), sugar concentration (5-20% w/v), and surfactant concentration (0.01-0.1% w/v) to enhance aflibercept stability. These parameter changes prevent oxidation, deamidation, isomerization, and polymerization that occur under stressed conditions such as agitation, freezing-thawing cycles, UV exposure, and high temperature storage.
Solution Approach 2:
The patent employs a composite formulation system combining multiple stabilizing agents: buffers (sodium phosphate, sodium acetate, or histidine), sugars (sucrose, trehalose, or a combination), and surfactants (polysorbate 20, polysorbate 80, or poloxamer 188). This composite approach provides synergistic protection against various degradation mechanisms including aggregation, fragmentation, and chemical modification of the protein.
2Stability of the object's composition
If stabilizers are added to prevent aggregation, then protein stability improves, but the formulation complexity increases
Solution Approach 1:
The patent selects stabilizing agents that perform multiple functions simultaneously. For example, sugars like sucrose and trehalose provide both steric stabilization to prevent aggregation and chemical protection against deamidation and oxidation. Buffers maintain pH stability while also protecting against acid- or base-catalyzed degradation. This multi-functionality reduces the need for additional specialized additives, thereby limiting formulation complexity while maintaining comprehensive protection.
Solution Approach 2:
The patent optimizes the concentration and type of each stabilizer based on its specific protective mechanism and interaction with aflibercept. Rather than using high concentrations of multiple different stabilizers, the formulation uses carefully controlled local concentrations of selected agents (e.g., 0.01-0.1% surfactant, 5-20% sugar) to provide targeted protection where needed most, minimizing unnecessary formulation complexity.
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 composition demonstrates enhanced stability against physical and chemical stress, minimizing aggregation and maintaining therapeutic activity over extended periods, suitable for intravitreal injection and treatment of ophthalmic diseases.
Implementation Method 1
a buffer containing sodium acetate or histidine
Implementation Method 2
a sugar including sucrose, trehalose or a combination thereof
Implementation Method 3
a surfactant
Data Source
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AI summary
The present invention relates to an ophthalmic liquid composition comprising: a therapeutically effective amount of aflibercept; a buffer containing sodium acetate or histidine; a sugar including sucrose, trehalose or a combination thereof; and a surfactant that is polysorbate or poloxamer, and a composition for stabilizing aflibercept. The ophthalmic liquid composition of the present invention is characterized by the excellent effect of imparting stability against stresses upon agitation, repeated freezing and thawing, ultraviolet (UV) exposure, and storage at a high temperature.