Tris Buffer Protein Formulation Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current protein formulations for intravitreal administration, such as those containing VEGF inhibitors, face challenges with stability, aggregation, and specific safety concerns due to inflammation and adverse reactions, requiring more precise osmolarity and particulation control.
Innovation Solution
Development of protein formulations comprising a VEGFR-Fc fusion protein with Tris as a buffering agent, along with stabilizers like sucrose and trehalose, and optionally surfactants like polysorbate, to maintain stability and reduce aggregation, suitable for intravitreal administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional protein formulations are used for intravitreal administration, then the formulation can be administered, but stability and aggregation control are insufficient
Solution Approach 1:
The patent changes the buffering agent parameter from conventional options to Tris specifically, and optimizes its concentration range (0.1-50 mM) to achieve both stability and reduced aggregation. This parameter optimization resolves the contradiction by finding the specific condition where both stability and aggregation control are simultaneously improved.
Solution Approach 2:
The formulation combines multiple components including the protein, Tris buffer, stabilizers (sucrose, trehalose), and surfactants (polysorbate) to create a composite system. This composite approach allows each component to contribute differently: Tris provides buffering and stability, stabilizers prevent aggregation, and surfactants reduce particulation, collectively resolving the contradiction between stability and aggregation control.
2Stability of the object's composition
If formulation components are added to improve stability, then stability increases, but osmolarity control becomes more difficult
Solution Approach 1:
The patent specifies precise concentration ranges for each component, particularly Tris (0.1-50 mM), stabilizers (5-50%), and surfactants (0.01-1%). These optimized parameters allow the formulation to achieve enhanced stability while maintaining osmolarity within the required intravitreal administration range, resolving the contradiction between stability improvement and osmolarity control.
3Reliability
If surfactants are added to reduce aggregation, then aggregation decreases, but particulation control becomes more challenging
Solution Approach 1:
The patent optimizes the surfactant concentration parameter within a specific range (0.01-1%, with preferred ranges of 0.01-0.5%). This optimized parameter allows sufficient surfactant to reduce aggregation effectively while preventing excessive surfactant that could cause unwanted particulation or other adverse effects, thus resolving the contradiction between aggregation reduction and particulation control.
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 formulations demonstrate increased stability and reduced aggregation, as shown by Size Exclusion Ultra High Performance Liquid Chromatography (SE-UHPLC), and meet the requirements for intravitreal administration with improved safety profiles.
Implementation Method 1
the formulation comprises Tris as a buffering agent. In some embodiments, the Tris concentration is from 0.1 mM to 50 mM, such as from 0.5 mM to 50 mM, from 1 mM to 50 mM, from 2.5 mM to 40 Mm, from 5 mM to 30 mM, or from 10 mM to 20 mM. The formulation can have a pH within the buffering capacity of Tris, such as a pH between 7.0 and 9.0.
Implementation Method 2
the formulation comprises a stabilizer, and optionally, a surfactant and/or a tonicity agent. In one embodiment, the formulation comprises two different stabilizers, such as two different sugars. In some embodiments, the formulation comprises sucrose and trehalose
Implementation Method 3
In one embodiment, the formulation comprises a surfactant, such as polysorbate 20, polysorbate 80, or Pluronic® F68
Data Source
AI summary
Protein formulations and methods of making and using such formulations are provided herein. The formulation can be an ophthalmic formulation, such as for intravitreal administration. In some embodiments, the formulation comprises a VEGFR-Fc fusion protein, such as aflibercept. In some embodiments, the formulation comprises a Tris buffer.