Ready-to-Inject Epinephrine Composition for Room-Temperature Stability
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Solution Overview
Problem
Current epinephrine formulations are unstable, leading to rapid degradation due to oxidation, isomerization, and microbial contamination, necessitating immediate use and posing risks of dilution errors and space inefficiency, especially at low concentrations.
Innovation Solution
Development of antioxidant-free, storage-stable epinephrine compositions with low concentrations, pH between 3.0 and 4.7, and metal ion chelators, packaged in polymeric containers with oxygen scavengers, allowing sterilization and extended shelf life without significant isomerization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If epinephrine is stored in aqueous solution at room temperature, then it is readily available for use, but it degrades rapidly through oxidation and isomerization
Solution Approach 1:
The patent uses nitrogen gas to displace oxygen from the headspace and dissolve oxygen from the aqueous solution, creating an inert atmosphere that prevents oxidation of epinephrine. This allows the solution to be stored at room temperature without rapid degradation, resolving the contradiction between availability and stability.
Solution Approach 2:
The patent introduces nitrogen gas as an intermediary substance that mediates between the epinephrine solution and atmospheric oxygen. The nitrogen acts as a physical barrier and oxygen scavenger, preventing direct contact between oxygen and epinephrine, thereby maintaining stability while allowing room temperature storage.
2Duration of action of stationary object
If concentrated epinephrine (1 mg/mL) is stored, then shelf life is extended, but dilution errors and microbial contamination risks increase
Solution Approach 1:
The patent changes the concentration parameter from concentrated (1 mg/mL) to low concentration (0.001-0.05 mg/mL) while simultaneously changing the oxygen environment parameter by introducing nitrogen gas. This dual parameter change allows low concentration solutions to achieve extended shelf life without the harmful effects of dilution errors and microbial contamination.
Solution Approach 2:
The patent creates a stable, ready-to-use low concentration formulation that can be stored for extended periods without special refrigeration requirements. This eliminates the need for frequent preparation and disposal of diluted solutions, reducing waste and improving efficiency.
3Reliability
If refrigerated storage is used for epinephrine solutions, then chemical stability is improved, but storage space requirements increase and availability decreases
Solution Approach 1:
By creating an inert nitrogen atmosphere in the container, the patent eliminates the need for refrigerated storage to maintain chemical stability. The solutions can be stored at room temperature without significant degradation, freeing up refrigerated storage space and improving availability.
Solution Approach 2:
The patent changes the storage temperature parameter from refrigerated (2-8°C) to room temperature (15-25°C) by simultaneously modifying the oxygen environment parameter through nitrogen gas introduction. This parameter change allows flexible storage options and improves accessibility.
4Reliability
If antioxidants are added to protect epinephrine from oxidation, then storage stability is improved, but severe allergic reactions may occur
Solution Approach 1:
Instead of using antioxidants that can cause allergic reactions, the patent converts the harmful effect of oxygen into a removable contaminant. By physically removing oxygen through nitrogen gas displacement and dissolution, the patent achieves stability without introducing potentially harmful chemical additives.
Solution Approach 2:
The patent uses nitrogen gas as an intermediary to prevent direct interaction between oxygen and epinephrine, avoiding the need for chemical antioxidants. This physical barrier approach maintains stability while eliminating the risk of allergic reactions from antioxidant additives.
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 compositions maintain stability for extended periods, enabling direct administration without dilution, reducing microbial risks and space requirements, while avoiding undesirable isomer formation and chemical degradation.
Implementation Method 1
Epinephrine in aqueous solution deteriorates rapidly on exposure to air or light (typically via auto-oxidation)
Implementation Method 2
The aqueous pharmaceutically acceptable carrier has dissolved oxygen in an amount of equal or less than about 2 ppm
Data Source
AI summary
A sterile storage stable ready-to-inject epinephrine composition contained within a flexible container and packaged within a secondary container, the composition including an aqueous pharmaceutically acceptable carrier containing epinephrine and a metal ion chelator, the epinephrine being present in a concentration of equal to or less than 0.07 mg/mL, substantially all of the epinephrine being an R-isomer, the composition having a pH of between 3.5-4.7, and the composition having, after storage of at least one month at 25° C., total impurities of equal or less than 0.7% and equal or less than 4% S-isomer content.