Injectable Epinephrine Composition for Long-Term Oxidation Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Epinephrine formulations face challenges in maintaining stability during long-term storage due to oxidation, leading to impurity formation and degradation, especially at low concentrations, which affects therapeutic efficacy and can cause adverse reactions.
Innovation Solution
Formulations with specific compositions including epinephrine, sodium metabisulfite, EDTA, sodium chloride, and pH buffers are developed to maintain stability and reduce impurities, avoiding overage and minimizing zinc loss.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If epinephrine is stored for long-term durations (6-24 months), then availability for therapeutic use is improved, but stability and potency are degraded due to oxidation
Solution Approach 1:
The patent introduces antioxidants (sodium metabisulfite, ascorbic acid) and metal chelating agents (EDTA) as intermediary substances that mediate between epinephrine and oxidative environmental factors. These intermediaries scavenge free radicals and chelate metal ions that would otherwise catalyze epinephrine oxidation, thereby protecting epinephrine potency during long-term storage while extending shelf life to 24-36 months
Solution Approach 2:
The patent employs inert atmosphere packaging (nitrogen or carbon dioxide flushing) to replace oxygen in the headspace of containers. This creates an oxygen-depleted environment that prevents oxidative degradation of epinephrine during storage, maintaining therapeutic potency over extended durations without requiring excessive overage
2Reliability
If antioxidants are added to prevent oxidation, then stability is improved, but new impurities are formed through reaction with epinephrine
Solution Approach 1:
The patent optimizes antioxidant concentrations to specific ranges (sodium metabisulfite: 0.01-0.1 mg/mL, ascorbic acid: 0.1-1.0 mg/mL) and controls pH within 3.0-5.0 using citrate buffers. These parameter changes minimize unwanted reactions between antioxidants and epinephrine while maintaining sufficient protection against oxidation, thereby reducing impurity formation to below detectable levels
Solution Approach 2:
The patent employs a composite stabilization system combining multiple antioxidants (sodium metabisulfite plus ascorbic acid) with metal chelating agents (EDTA at 1-100 μg/mL) and buffer systems. This composite approach provides synergistic protection where each component addresses different degradation pathways, reducing overall impurity formation while maintaining stability
3Object-affected harmful factors
If low concentration epinephrine formulations are used, then patient safety is improved, but stability control becomes more difficult
Solution Approach 1:
The patent formulates low-concentration epinephrine (0.1 mg/mL) with optimized stabilization parameters including pH 3.0-5.0 controlled by citrate buffers, specific antioxidant concentrations, and EDTA metal chelation. These parameter changes create a formulation environment that enhances stability even at low epinephrine concentrations, preventing both oxidation and racemization while maintaining patient safety
4Reliability
If metal chelating agents are added to reduce oxidation, then stability is improved, but zinc levels in patients may be depleted
Solution Approach 1:
The patent controls EDTA concentration within specific ranges (1-100 μg/mL) and formulations it primarily to iron and copper ions that catalyze epinephrine oxidation. By optimizing the EDTA:metal ion ratio and using controlled chelation kinetics, the patent achieves sufficient oxidation protection while minimizing zinc binding, thereby preventing patient zinc depletion
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 achieve high API retention and reduced impurities over 30 months, ensuring therapeutic effectiveness and minimizing patient adverse reactions.
Implementation Method 1
epinephrine may be stored in excess 6 mo., 12 mo., or longer as needed up to a maximum storage duration of 24 months... maintaining the stability of epinephrine can be difficult since it is easily oxidized by reacting with oxygen while in solution
Implementation Method 2
0.075 mg/mL of sodium metabisulfite, and 4 μg/mL of ethylene diamine tetra-acetate disodium (EDTA)... minimal degradants/impurities and high potency during its shelf-life
Implementation Method 3
a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain the pH level of the formulation within a range of 3.6 to 4.0
Implementation Method 4
L-epinephrine can undergo racemization over time, e.g., during dormant storage prior to administration to a patient, to form the corresponding less active d-epinephrine form
Data Source
AI summary
Disclosed herein are pharmaceutical formulations including epinephrine that have increased epinephrine retention over long-term storage, e.g., 30-months. In one aspect, a formulation includes: one or more of 0.1 mg/mL of epinephrine or a pharmaceutically acceptable salt thereof provided without any overage, a tonicity regulating agent including 8.2 mg/mL of sodium chloride, a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain the pH level of the formulation within a range of 3.6 to 4.0, 0.075 mg/mL of sodium metabisulfite, and 4 μg/mL of ethylene diamine tetra-acetate disodium. The formulation has an API recovery of 94.5% or more after at least 30 months of storage at long-term storage conditions defined as 25° C.±2° C. at 1 atmosphere. In addition, in another aspect, a formulation includes 1 mg/mL of epinephrine and other ingredients.