Etanercept Buffer System Stabilization Against Aggregation
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Solution Overview
Problem
Existing pharmaceutical compositions of Etanercept, a TNF receptor Fc fusion protein, face stability issues during long-term storage due to protein aggregation and degradation, particularly when using phosphate buffer with L-glycine as an anti-aggregating agent, which leads to reduced efficacy and immunogenicity.
Innovation Solution
A stable pharmaceutical composition is developed using a phosphate-citrate buffer system with L-glycine as the anti-aggregating agent, which demonstrates improved stability and reduced aggregation, maintaining Etanercept's activity for extended periods, suitable for long-term storage and administration in treating inflammatory disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If phosphate buffer with L-glycine is used as anti-aggregating agent, then aggregation is reduced, but protein degradation increases during long-term storage
Solution Approach 1:
The patent changes the buffer system parameters from simple phosphate buffer to a phosphate-citrate buffer combination, and optimizes the concentration of L-glycine anti-aggregating agent. This parameter modification resolves the contradiction by achieving both reduced aggregation and improved protein stability during long-term storage
Solution Approach 2:
The patent uses a composite buffer system combining phosphate buffer and citrate buffer instead of a single buffer component. This composite approach creates synergistic effects that simultaneously prevent aggregation and maintain protein stability, resolving the technical contradiction between reducing aggregation and preventing degradation
2Quantity of substance
If high concentration of Etanercept is used in composition, then therapeutic efficacy is improved, but aggregation tendency increases during storage
Solution Approach 1:
The patent introduces L-glycine as an intermediary anti-aggregating agent that mediates between the high concentration Etanercept molecules, preventing their direct interaction and aggregation. The optimized concentration of L-glycine in the phosphate-citrate buffer system effectively suppresses aggregation while maintaining high therapeutic protein concentration
3Object-generated harmful factors
If pH is adjusted to isoelectric point of protein, then solubility is reduced, but aggregation is minimized
Solution Approach 1:
The patent optimizes the pH parameter of the phosphate-citrate buffer system to achieve a balance where the protein remains sufficiently soluble while aggregation is minimized. The combined buffer system provides better pH control and buffering capacity, allowing operation near the isoelectric point without complete precipitation
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 exhibits enhanced stability with less than 5% high and low molecular weight impurities, maintaining approximately 90% of its activity after storage, compared to other buffer systems, ensuring effective treatment of conditions like rheumatoid arthritis and psoriasis with prolonged shelf life.
Implementation Method 1
A stable pharmaceutical composition is developed using a phosphate-citrate buffer system with L-glycine as the anti-aggregating agent, which demonstrates improved stability and reduced aggregation
Implementation Method 2
L-glycine as the anti-aggregating agent, which demonstrates improved stability and reduced aggregation, maintaining Etanercept's activity for extended periods
Data Source
AI summary
The present invention relates to the stable pharmaceutical compositions comprising tumor necrosis factor receptor Fc fusion protein (TNFR:Fc). More particularly, it relates to the stable pharmaceutical compositions comprising tumor necrosis factor receptor Fc fusion protein (TNFR:Fc), phosphate - citrate buffer. It also relates to the methods of manufacturing the composition, method of administration and kits containing the same.