Epinephrine Formulation Stability via pH and Nitrogen Control

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Solution Overview

Problem

Existing pharmaceutical formulations of epinephrine suffer from racemization and oxidation, leading to reduced potency and safety issues due to the presence of impurities like d-epinephrine and adrenalone, and the use of sulfites as preservatives can cause allergic reactions in susceptible patients.

Innovation Solution

Development of preservative-free and sulfite-free pharmaceutical formulations of levorotatory-epinephrine with a higher 1-epinephrine content, using a manufacturing process that includes filtration, sterilization under inert nitrogen atmosphere, and a pH adjustment to 2.8-3.3 to minimize racemization and oxidation, resulting in a stable solution with reduced overage and impurities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If sulfites are used as preservatives in epinephrine formulations, then oxidation is prevented, but allergic reactions occur in susceptible patients

Engineering Contradiction:
Improveoxidation preventionVSAvoidallergic reactions
Core Design Contradiction:
ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent removes sulfites from the epinephrine formulation entirely, extracting the harmful preservative component while maintaining formulation stability through alternative means (pH adjustment to 2.8-3.3 and nitrogen atmosphere sterilization)

Inventive Principle:
Principle #2Taking out (Extraction)

2Quantity of substance

If existing epinephrine formulations are used, then d-epinephrine impurity is present, but potency is reduced due to racemization

Engineering Contradiction:
Improvetotal epinephrine contentVSAvoidpotency
Core Design Contradiction:
Quantity of substanceVSReliability

Solution Approach 1:

The patent changes the pH parameter of the formulation to 2.8-3.3, which creates optimal conditions for maintaining L-epinephrine stability and minimizing racemization to d-epinephrine, thereby preserving potency while maintaining total epinephrine content

Inventive Principle:
Principle #35Parameter changes

3Quantity of substance

If existing epinephrine formulations are used, then oxidation occurs, but purity is reduced due to adrenalone formation

Engineering Contradiction:
Improveepinephrine contentVSAvoidpurity
Core Design Contradiction:
Quantity of substanceVSReliability

Solution Approach 1:

The patent employs an inert nitrogen atmosphere during sterilization and storage to prevent oxidation of epinephrine to adrenalone, thereby maintaining high purity while preserving the active ingredient content

Inventive Principle:
Principle #39Inert atmosphere (Inert environment)

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 new formulations maintain high 1-epinephrine content and purity throughout their shelf-life, reducing the risk of adverse reactions and providing a safer, more potent epinephrine solution for medical use, including continuous intravenous infusion methods.

Implementation Method 1

sterilization under inert nitrogen atmosphere, and a pH adjustment to 2.8-3.3 to minimize racemization and oxidation

Methodology Applied
Scientific EffectOxidation prevention: Oxidation

Implementation Method 2

a pH adjustment to 2.8-3.3 to minimize racemization and oxidation

Methodology Applied
Scientific EffectRacemization prevention:

Data Source

PatentUS10039728B1More potent and less toxic formulations of epinephrine and methods of medical use
Publication Date: 2018.08.07 BELCHER PHARMACEUTICALS LLC

AI summary

The present invention provides pharmaceutical formulations of levorotatory-epinephrine, 1-epinephrine, more potent and less toxic than existing pharmaceutical formulations of epinephrine, along with methods of producing and using these pharmaceutical formulations of 1-epinephrine, including providing prefilled syringes of pharmaceutical formulations of 1-epinephrine and methods of using these prefilled syringes by treating patients with continuous intravenous infusion instead of bolus administration.