Ready-to-Inject Norepinephrine Compositions Without Antioxidants
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Solution Overview
Problem
Current norepinephrine formulations suffer from stability issues, including oxidative degradation and isomerization, and often contain antioxidants that can cause allergic reactions, necessitating the development of stable, antioxidant-free compositions with improved storage stability and reduced isomerization.
Innovation Solution
Aqueous acidic buffer formulations with a pH range of 3.7 to 4.3, containing a chelating agent and pharmaceutically acceptable salt, are used to prepare ready-to-inject norepinephrine compositions that are substantially free of antioxidants, ensuring less than 10% isomerization and less than 5% degradation over three months, even under elevated storage conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If norepinephrine is formulated with antioxidants to prevent oxidative degradation, then stability is improved, but allergic reactions and anaphylactic shock risk increase
Solution Approach 1:
The patent removes antioxidants (sulfites, metabisulfites) from the norepinephrine formulation entirely, extracting the harmful protective agent while maintaining stability through alternative means (proper pH control at 3.0-4.5, oxygen-free environment, and nitrogen atmosphere during storage)
Solution Approach 2:
The patent optimizes the pH parameter to 3.0-4.5 and controls oxygen concentration to create an environment that prevents oxidative degradation without requiring antioxidants, thereby eliminating the need for harmful substances while maintaining stability
2Duration of action of stationary object
If norepinephrine is stored at room temperature for extended periods, then convenience is improved, but degradation and isomerization increase
Solution Approach 1:
The patent performs preliminary stabilization by adjusting pH to 3.0-4.5 and removing oxygen before storage, creating conditions that prevent degradation and isomerization during extended room temperature storage without requiring refrigeration
Solution Approach 2:
The patent changes the pH parameter to 3.0-4.5 and controls oxygen concentration to create a stable environment that allows extended storage at room temperature while maintaining chemical stability and preventing isomerization
3Productivity
If concentrated norepinephrine formulations are used to reduce volume, then administration efficiency is improved, but dilution errors and microbial contamination risk increase
Solution Approach 1:
The patent provides ready-to-use stable formulations that can be stored for extended periods without degradation, eliminating the need for prolonged storage of concentrated solutions and reducing the risk of dilution errors and microbial contamination while maintaining administration efficiency
4Stability of the object's composition
If pH is reduced to prevent isomerization, then stability is improved, but patient comfort and safety worsen
Solution Approach 1:
The patent optimizes the pH parameter to 3.0-4.5, which is sufficiently low to prevent isomerization but not so low as to cause patient discomfort or safety issues, achieving a balance between stability and tolerability
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 exhibit enhanced stability, with less than 8% degradation and less than 10% isomerization, allowing for prolonged storage without antioxidants, and can withstand autoclaving without significant isomerization or degradation, thus eliminating microbial contamination and calculation errors.
Implementation Method 1
containing a chelating agent and pharmaceutically acceptable salt
Implementation Method 2
Aqueous acidic buffer formulations with a pH range of 3.7 to 4.3
Implementation Method 3
can withstand autoclaving without significant isomerization or degradation
Data Source
AI summary
The inventive subject matter is directed to compositions and methods for ready-to-inject norepinephrine compositions with improved stability. Most preferably, compositions presented herein are substantially antioxidant free and exhibit less than 10% isomerization of R-norepinephrine and exhibit less than 5% degradation of total norepinephrine.