Dantrolene Aqueous Composition Cyclodextrin Solubility
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Solution Overview
Problem
Current dantrolene formulations face challenges due to poor solubility in water, leading to cumbersome preparation, short shelf-life, and the need for large volumes for effective administration, along with instability at alkaline pH, which accelerates degradation.
Innovation Solution
An aqueous composition comprising dantrolene or its pharmaceutically acceptable salt combined with a cyclodextrin derivative at an alkaline pH (greater than 7), with a molar ratio of 1:2 to 1:30, enhancing solubility and stability, and a kit for rapid reconstitution of a stable injectable form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dantrolene is formulated in conventional aqueous solutions, then it can be administered intravenously, but the solubility is poor leading to precipitation and short shelf-life
Solution Approach 1:
The patent introduces cyclodextrin derivatives as intermediary molecules that form inclusion complexes with dantrolene. The cyclodextrin cavity accommodates the hydrophobic dantrolene molecule while the hydrophilic exterior maintains water solubility, effectively mediating between the incompatible requirements of solubility and stability
Solution Approach 2:
The patent modifies the chemical parameters of the formulation by using cyclodextrin derivatives with different substitution patterns (hydroxyethyl, hydroxypropyl, sulfobutyl groups) and controlling the pH to be greater than 7. This changes the solubility and stability parameters of the dantrolene formulation
2Quantity of substance
If dantrolene solution is prepared with conventional methods, then it can be administered, but large volumes are required to deliver efficacious doses
Solution Approach 1:
The cyclodextrin inclusion complexation dramatically increases the apparent solubility of dantrolene, enabling concentrations of 2.5-10 mg/ml to be achieved. This allows efficacious doses to be delivered in smaller, more manageable volumes suitable for intravenous administration
3Ease of operation
If dantrolene is stored as a powder requiring reconstitution, then shelf-life is extended, but preparation becomes cumbersome and time-consuming
Solution Approach 1:
The patent stabilizes the aqueous solution formulation with cyclodextrin derivatives, enabling the solution to be stored stably at room temperature for extended periods without requiring freeze-drying into powders. This eliminates the need for cumbersome reconstitution procedures while maintaining shelf-life
Solution Approach 2:
The cyclodextrin inclusion complexation and pH control (greater than 7) fundamentally change the stability parameters of dantrolene in aqueous solution, preventing precipitation and degradation that would otherwise require powder formulation for storage
4Reliability
If cyclodextrin is used at basic pH to enhance solubility, then storage stability improves, but degradation rate increases
Solution Approach 1:
The cyclodextrin derivative acts as a protective intermediary, encapsulating the dantrolene molecule within its cavity. This physical protection shields dantrolene from base-catalyzed hydrolysis even at pH greater than 7, allowing the solution to be stored stably without rapid 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 composition achieves increased storage stability, solubility, and rapid reconstitution, allowing for effective and efficient administration of dantrolene, addressing the limitations of existing formulations by providing a stable and easily preparable aqueous solution.
Implementation Method 1
Cyclodextrins may be used to enhance the solubility, stability and bioavailability of drugs
Implementation Method 2
dantrolene undergoes hydrolysis in alkaline solutions causing it to degrade via hydantoin ring opening
Data Source
AI summary
The present invention relates to an aqueous composition comprising either dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative wherein the pH of the aqueous composition is greater than 7. Further, the present invention relates to a powder obtained by drying the inventive composition as well as a kit comprising said inventive powder.