aFGF Formulation Stabilization via Citrate Buffer
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Solution Overview
Problem
Current formulations of acidic fibroblast growth factor (aFGF), particularly the variant ES135, face stability issues due to precipitation and deamidation, limiting storage temperature and requiring costly cold chain shipments, with existing stabilizers like high concentrations of NaCl causing adverse effects.
Innovation Solution
Incorporating a citrate buffer, specifically citric acid or isocitric acid, into the pharmaceutical composition to improve stability, allowing for a wider range of storage temperatures and preventing protein precipitation and deamidation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If phosphate buffer is used in the formulation, then the formulation can be maintained at neutral pH, but the drug substance precipitates at room temperature leading to decreased protein concentration and purity
Solution Approach 1:
The patent changes the buffer system from phosphate to citrate, which fundamentally alters the chemical environment. Citrate buffer prevents precipitation and deamidation of aFGF at room temperature, while maintaining appropriate pH levels, thus resolving the stability issue without compromising protein integrity
Solution Approach 2:
Citrate acts as an intermediary substance that mediates between the aFGF protein and the formulation environment. It provides stabilization through specific interactions that prevent unwanted chemical reactions (precipitation and deamidation) while maintaining protein solubility and activity
2Stability of the object's composition
If high concentration of NaCl is used to slow down precipitation, then precipitation is reduced, but adverse effects occur due to high osmolality and limited stability requiring -20°C storage
Solution Approach 1:
The patent changes the stabilizing mechanism from ionic strength adjustment (NaCl) to pH-controlled stabilization (citrate buffer). This parameter change allows stabilization at physiological osmolality levels, avoiding adverse effects while maintaining room temperature stability
Solution Approach 2:
The patent converts the harmful effect of pH sensitivity into a beneficial stabilization mechanism. By using citrate buffer to control pH, the formulation gains stability without requiring high salt concentrations that cause osmolality-related adverse effects
3Stability of the object's composition
If high concentration of NaCl is used in the formulation, then precipitation is slowed down, but deamidation of ES135 increases rapidly at room temperature
Solution Approach 1:
The patent changes from salt-based stabilization (NaCl) to pH-based stabilization (citrate buffer). This parameter change simultaneously addresses both precipitation and deamidation issues, as citrate buffer maintains optimal pH that prevents deamidation while providing precipitation resistance
Solution Approach 2:
Citrate buffer serves as an intermediary that prevents deamidation through pH control. It creates a chemical environment that is unfavorable for deamidation reactions while also providing precipitation resistance, thus protecting protein integrity
4Stability of the object's composition
If strict cold chain storage at -70°C is implemented, then long term stability is maintained, but high-cost cold chain shipment is required
Solution Approach 1:
The patent changes the storage temperature parameter from -70°C to room temperature through the use of citrate buffer. This parameter change maintains protein stability without requiring expensive cold chain infrastructure and shipment, significantly improving commercial viability
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 citrate buffer significantly enhances the stability of aFGF formulations, preventing precipitation and deamidation, enabling storage at higher temperatures without adverse effects, thus improving commercial viability.
Implementation Method 1
a citrate buffer comprising a citric acid compound provides an efficacy in improving the stability of pharmaceutical compositions comprising aFGF
Implementation Method 2
the citrate buffer significantly enhances the stability of aFGF formulations, preventing precipitation
Implementation Method 3
the liquid formulation has a pH value within the range of pH 5.8 to pH 7.0
Implementation Method 4
preventing protein precipitation and deamidation
Data Source
AI summary
A stabilized aPGF composition or a method for stabilization of the pharmaceutical composition comprising aFGF are provided. The composition comprises aPGF, a citric acid compound and other excipients. The method for improving stability of aPGF in the form of a liquid formulation or a lyophilized formulation so as to increase storage stability is also provided.