Edaravone Liquid Composition for Solubility and Stability
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Solution Overview
Problem
Existing edaravone formulations face challenges with low solubility and stability in aqueous solutions, leading to degradation and poor oral bioavailability, which complicates administration for patients with ALS, particularly those with dysphagia, necessitating the development of stable, ready-to-use liquid compositions suitable for enteral administration.
Innovation Solution
The development of stable liquid pharmaceutical compositions of edaravone, comprising pharmaceutically acceptable solvents and excipients, including solubility enhancers, antioxidants, and crystallization inhibitors, to maintain edaravone in a solubilized state for extended periods, suitable for enteral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If edaravone is formulated as an aqueous solution, then it provides convenient liquid dosage form for enteral administration, but it exhibits poor stability due to rapid degradation in aqueous solutions
Solution Approach 1:
The patent uses non-aqueous solvents (polyethylene glycol, propylene glycol, glycerin) as intermediary substances to dissolve edaravone, avoiding direct contact with water that causes degradation. These solvents act as mediators that maintain solubility while preventing the hydrolysis and oxidation reactions that occur in aqueous environments.
Solution Approach 2:
The patent changes the chemical composition parameters of the formulation by replacing water with non-aqueous solvents and adjusting pH levels. This parameter change transforms the formulation from an unstable aqueous system to a stable non-aqueous system that prevents edaravone degradation while maintaining liquid dosage form advantages.
2Reliability
If edaravone is formulated as a solid form, then it maintains stability, but it is not user-friendly for patients with dysphagia and requires enteral or parenteral administration
Solution Approach 1:
The patent changes the physical state parameter from solid to liquid by using non-aqueous solvents that can dissolve edaravone at therapeutic concentrations. This transformation creates a liquid formulation that is easily administerable via oral or enteral routes while the non-aqueous composition maintains stability, thus resolving the contradiction between physical form and stability.
3Manufacturing precision
If edaravone is administered intravenously, then precise and comprehensive medication delivery is achieved, but it imposes added responsibilities and requires frequent hospital visits and caregiver assistance
Solution Approach 1:
The patent develops a liquid formulation using non-aqueous solvents as intermediaries that enables self-administration. The formulation acts as a mediator between the drug and the patient, allowing direct oral or enteral administration without requiring intravenous infrastructure, thus eliminating the need for hospital visits and caregiver assistance while maintaining dosing accuracy.
4Quantity of substance
If edaravone is formulated with high aqueous solubility, then oral bioavailability is improved, but degradation occurs rapidly due to the enol form and edaravone anion reacting with oxygen
Solution Approach 1:
The patent creates an inert chemical environment by using non-aqueous solvents that do not promote oxidation or hydrolysis. This inert environment prevents the edaravone anion from reacting with oxygen, thereby maintaining both solubility and stability without requiring high aqueous solubility that would accelerate degradation.
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 provide enhanced solubility and stability, ensuring edaravone remains effective for at least 3 months under various storage conditions, facilitating convenient oral or gastric administration and improving patient compliance.
Implementation Method 1
The edaravone anion becomes an edaravone radical when the anion donates an electron to oxygen. Thus, the electron reduction by the edaravone anion is the key step in edaravone degradation.
Implementation Method 2
The major hurdle to the development of an aqueous liquid formulation of edaravone is its low aqueous solubility, which is measured at 1.85 mg/mL.
Implementation Method 3
one or more pharmaceutically acceptable excipients selected from the group comprising of solubility enhancing agents, antioxidants, crystallization inhibitors, stabilizers, preservatives, flavoring agents, sweetening agents, thickening agents and mixtures thereof
Data Source
AI summary
The present invention relates to liquid pharmaceutical compositions of edaravone. More specifically, stable solutions of edaravone for enteral administration are provided, wherein the composition is stable for extended period of time. The present invention further relates to stable solutions of edaravone, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by edaravone.