Dihydroergotamine Injectable Formulation With pH-Controlled Impurity Reduction
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Solution Overview
Problem
Existing dihydroergotamine formulations suffer from high levels of impurities when stored at room temperature due to pH levels below 4.0, necessitating refrigerated storage and lacking a stable self-administrable form.
Innovation Solution
A parenteral unit dosage form with an aqueous solution of dihydroergotamine or its pharmaceutically acceptable salt, adjusted to a pH range of 4.1 to 4.9, packaged in an overwrap pouch with an optional oxygen scavenger, to minimize impurities I and II.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the pH of dihydroergotamine solution is maintained below 4.0, then the solution shows acceptable chemical stability, but high levels of isomeric and oxidative impurities are generated
Solution Approach 1:
The patent changes the pH parameter from below 4.0 to a higher range (4.0-5.0), which fundamentally alters the chemical environment to reduce impurity formation while maintaining stability. This parameter change resolves the contradiction by finding an optimal pH window that avoids both high impurity generation and instability.
Solution Approach 2:
The patent introduces antioxidants as intermediary substances that mediate between the dihydroergotamine and oxidative impurities. These antioxidants act as sacrificial agents that preferentially oxidize, thereby protecting the active ingredient from forming harmful impurities while maintaining solution stability.
2Reliability
If dihydroergotamine is formulated as an injectable product in sterile ampoules, then it provides effective migraine treatment, but it requires refrigerated storage and lacks self-administrable form
Solution Approach 1:
The patent changes the storage temperature parameter from refrigerated (2-8°C) to room temperature (20-25°C) by modifying the formulation pH and adding stabilizers. This allows the product to be stored under normal conditions without compromising stability, enabling self-administration.
Solution Approach 2:
The patent segments the treatment into single-use pre-filled syringes, each containing a predetermined dose. This eliminates the need for refrigeration of bulk solutions and allows patients to self-administer without complex storage requirements while maintaining treatment effectiveness.
3Ease of operation
If dihydroergotamine solution is stored at room temperature, then self-administration becomes feasible, but high levels of impurities are generated
Solution Approach 1:
The patent optimizes the pH parameter to a higher range (4.0-5.0) and controls ionic strength to create a chemical environment that minimizes impurity formation even at room temperature. This allows self-administration without generating harmful impurities.
Solution Approach 2:
The patent introduces antioxidants and chelating agents as intermediary substances that prevent oxidative and metal-catalyzed impurity formation during room temperature storage, enabling self-administration while maintaining low impurity levels.
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 maintains significantly lower impurity levels, allowing stable storage at room temperature without refrigeration, suitable for single-dose self-administration.
Implementation Method 1
The pH of the aqueous solution of this disclosure is such that it contains substantially lower amount of impurity of Formula I or impurity of Formula II as compared to aqueous solution having a pH of 4.0 or less
Implementation Method 2
packaged in an overwrap pouch with an optional oxygen scavenger, to minimize impurities I and II
Data Source
AI summary
A parenteral unit dosage form comprising an aqueous solution of dihydroergotamine or pharmaceutically acceptable salt thereof as a sole active ingredient, one or more pH adjusting agents, and optionally one or more co-solvents, wherein the pH of the aqueous solution is such that it contains substantially lower amount of impurity of Formula I and impurity of Formula II as compared to aqueous solution having a pH of 4.0 or less, when the parenteral unit dosage form is stored at 25° C. and 60% relative humidity for at least three months.