Norepinephrine Formulation Stability via Citric Acid Buffering
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Solution Overview
Problem
Ready-to-inject norepinephrine formulations are unstable due to oxidation and racemization, requiring antioxidants that can cause allergic reactions and increase degradation, and existing stabilization methods are costly and complex, lacking storage stability and safety.
Innovation Solution
A container with a liquid phase containing norepinephrine and a buffering system of citric acid and its pharmaceutically acceptable salt, along with a tonicity agent, at a pH of 3.0 to 4.0, and a gas phase with an oxygen content of 0.2% or more, allowing for stable storage without antioxidants and under less stringent oxygen control.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If antioxidants are added to stabilize norepinephrine, then oxidation resistance is improved, but allergic reactions and degradation increase
Solution Approach 1:
The patent removes antioxidants from the norepinephrine formulation entirely, demonstrating that they are not necessary for stability. The formulation achieves oxidation resistance through optimized pH control (3.0-4.0) and absence of oxygen-sensitive components, proving that antioxidants can be extracted without compromising stability while eliminating their harmful side effects.
Solution Approach 2:
The patent converts the previously harmful effect of oxygen exposure into a beneficial demonstration of formulation robustness. By designing a formulation that remains stable even in the presence of oxygen and without antioxidants, the invention transforms what was considered a destabilizing factor into a proof of the formulation's superior stability profile.
2Stability of the object's composition
If oxygen content is reduced to stabilize norepinephrine, then oxidation is prevented, but manufacturing complexity and cost increase
Solution Approach 1:
The patent changes the pH parameter to the range of 3.0-4.0, which fundamentally alters the chemical stability profile of norepinephrine. This parameter change makes the formulation insensitive to oxygen content and antioxidant presence, allowing standard manufacturing processes without complex oxygen control systems while maintaining stability.
3Reliability
If strict oxygen exclusion is implemented, then norepinephrine stability is improved, but manufacturing cost and process complexity increase
Solution Approach 1:
The formulation is designed to be self-stabilizing through its pH buffer system and composition, eliminating the need for external oxygen exclusion measures. The norepinephrine remains stable through its own chemical properties at pH 3.0-4.0, making the system self-sufficient and removing complex manufacturing requirements.
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 formulation remains stable for over a year at room temperature, even in the presence of oxygen, providing a safe, cost-effective, and convenient ready-to-inject solution for medical emergencies.
Implementation Method 1
a buffering system consisting of citric acid and a pharmaceutically acceptable salt thereof, wherein the buffering system is present in a concentration in the range of from 1 mM to 30 mM; and wherein the liquid phase has a pH in the range of from about 3.0 to about 4.0
Data Source
AI summary
The present disclosure relates to a container comprising a liquid phase and a gas phase, wherein the liquid phase is a pharmaceutical composition comprising norepinephrine, or a pharmaceutically acceptable salt thereof, a buffering system consisting of citric acid and a pharmaceutically acceptable salt thereof, at least one tonicity agent, and water; and wherein the gas phase has an oxygen content of 0.2 % (V/V) or more based on the total volume of the gas phase; and a method of manufacturing the same.