Torsemide–Cyclodextrin Formulation Balancing Solubility and Stability
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Solution Overview
Problem
Torsemide, a loop diuretic, is poorly soluble at physiological pH, leading to challenges in parenteral administration and potential drug precipitation, which limits its use in subcutaneous and infusion applications due to adverse toxicological effects and stability issues.
Innovation Solution
A pharmaceutical composition comprising torsemide and a cyclodextrin, such as β-cyclodextrin derivatives like captisol, is formulated at a pH of 7.0 to 7.8, allowing for higher solubility and stability, enabling subcutaneous and intravenous administration with minimal adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If torsemide is formulated at high pH (9.0 or higher) to achieve sufficient solubility for parenteral administration, then solubility is improved, but stability deteriorates and precipitation occurs
Solution Approach 1:
The patent introduces a surfactant as an intermediary substance that mediates between torsemide and the aqueous environment at physiological pH. The surfactant forms micelles that solubilize torsemide, enabling sufficient solubility without requiring high pH conditions, thus maintaining formulation stability while achieving the desired solubility for parenteral administration
Solution Approach 2:
The patent changes the formulation parameters by incorporating specific surfactants and adjusting their concentrations to achieve optimal solubility at physiological pH (7.0-7.8). This parameter change allows the formulation to maintain both solubility and stability without requiring extreme pH conditions, resolving the contradiction between solubility improvement and stability maintenance
2Stability of the object's composition
If pH is reduced to avoid precipitation and improve stability, then stability is improved, but solubility deteriorates and precipitation occurs
Solution Approach 1:
The surfactant acts as a mediator that enables torsemide to remain solubilized at lower, more stable pH conditions. By forming micellar structures, the surfactant protects torsemide from precipitation even when pH is reduced to physiological ranges, thus maintaining both stability and solubility simultaneously
3Quantity of substance
If high pH formulation is used for parenteral administration, then solubility is improved, but adverse toxicological effects increase
Solution Approach 1:
The patent changes the pH parameter from high (9.0 or higher) to physiological ranges (7.0-7.8) by introducing surfactants. This parameter change reduces adverse toxicological effects while maintaining sufficient solubility through surfactant-mediated solubilization, making the formulation safer for subcutaneous and intravenous administration
4Object-affected harmful factors
If pH is adjusted to physiological range for subcutaneous administration, then adverse effects are reduced, but solubility deteriorates
Solution Approach 1:
The surfactant serves as an intermediary that enables torsemide to achieve sufficient solubility at physiological pH conditions. By forming micellar structures, the surfactant allows the formulation to maintain both reduced irritation (through physiological pH) and adequate solubility for effective drug delivery
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 enhanced solubility and stability of torsemide, facilitating effective drug delivery through subcutaneous and intravenous routes without significant irritation, suitable for treating conditions like edema, heart failure, and liver diseases.
Implementation Method 1
pharmaceutical compositions containing torsemide and a cyclodextrin
Data Source
AI summary
A pharmaceutical composition and a method of administering the pharmaceutical composition to a patient suffering from edema, heart failure, kidney or liver disease or having symptoms thereof are disclosed. The pharmaceutical composition includes torsemide, or a pharmaceutically acceptable salt, hydrate or ester thereof and a cyclodextrin.