Aflibercept Ophthalmic Composition Tonicity and pH Stabilization

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Solution Overview

Problem

Existing ophthalmic formulations containing aflibercept suffer from the formation of dimeric or multimeric impurities under stress and cold storage conditions, leading to reduced biological activity and potential side effects, particularly due to the use of ionic tonicity agents like NaCl.

Innovation Solution

An ophthalmic pharmaceutical composition with a pH range of 5.2 to 5.7, using a sodium acetate buffering agent and adjusting tonicity with sugar or sugar alcohols without ionic agents, thereby reducing the formation of dimeric and multimeric impurities and maintaining high biological activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If an ionic tonicity agent such as NaCl is used in the ophthalmic formulation, then the tonicity can be adjusted effectively, but dimeric or multimeric impurities are formed under stress and cold storage conditions

Engineering Contradiction:

Improvestability of afliberceptVSAvoidformation of dimeric or multimeric impurities

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent removes the ionic tonicity agent (NaCl) from the formulation to eliminate the harmful effect of impurity formation. This extraction of the problematic component resolves the contradiction by preventing dimeric and multimeric impurity formation while maintaining formulation stability through alternative means (sugar-based tonicity agents and optimized buffering system at pH 5.8-7.0)

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the pH parameter to an optimized range of 5.8-7.0 and replaces ionic tonicity agents with non-ionic alternatives (sugars and sugar alcohols). This parameter change strategy maintains the necessary tonicity and stability while eliminating the formation of harmful impurities, thus resolving the contradiction between reliability and harmful factors

Inventive Principle:

Principle #35Parameter changes

2Reliability

If the formulation is stored under accelerated or stress conditions, then the stability can be evaluated, but the stabilizing effect is markedly reduced and impurities increase

Engineering Contradiction:

Improvebiological activity of afliberceptVSAvoidformation of impurities under stress condition

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent employs a buffering system (phosphate or acetate buffer at pH 5.8-7.0) and protective agents (surfactants like polysorbate 20 or 80, and stabilizers like sucrose or trehalose) that provide beforehand cushioning against stress conditions. These components are pre-formulated to protect aflibercept from aggregation and degradation during accelerated or stress storage, maintaining biological activity while preventing impurity formation

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

3Ease of manufacture

If protein aggregation occurs, then insoluble microparticles are formed, but side effects such as immune reactions and reduced biological activity occur

Engineering Contradiction:

Improveformulation simplicityVSAvoidimmune reactions and reduced biological activity

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The patent introduces intermediary substances (surfactants like polysorbate 20 or 80, and stabilizers like sucrose or trehalose) that mediate between the protein and the formulation environment. These intermediaries prevent protein-protein interactions that lead to aggregation, thereby eliminating insoluble microparticle formation and associated harmful effects while maintaining formulation simplicity through well-established excipients

Inventive Principle:

Principle #24Intermediary (Mediator)

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 significantly reduces the formation of impurities and maintains high biological activity over time, making it suitable for prefilled syringes for intravitreal administration in treating ophthalmic diseases like wet age-related macular degeneration and diabetic macular edema.

Implementation Method 1

the pH is adjusted to pH 5.2 to 5.7 by using a specific buffering agent, which is sodium acetate

Methodology Applied

Scientific EffectBuffering:

Implementation Method 2

the tonicity is adjusted by controlling the amount of sugar or sugar alcohol without using an ionic tonicity agent such as NaCl

Methodology Applied

Scientific EffectOsmotic pressure: Osmotic Pressure

Data Source

PatentEP3452075B1Ophthalmic pharmaceutical composition

Publication Date: 2021.11.24 SAM CHUN DANG PHARM

Figure 1

AI summary

The present invention provides an ophthalmic pharmaceutical composition having a certain pH, comprising aflibercept as an active ingredient; an acetate salt buffering agent, wherein the ophthalmic pharmaceutical composition is free of an ionic tonicity agent. The ophthalmic pharmaceutical composition of the present invention can remarkably reduce the formation of dimeric and multimeric impurities and maintain the biological activity in a high level for a long time under the accelerated and stress conditions as well as under the cold storage condition.