Furosemide–Cyclodextrin Compositions for Stable Parenteral Delivery
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Solution Overview
Problem
Furosemide's poor solubility and stability at physiological pH pose challenges for effective parenteral administration, particularly in subcutaneous and intravenous routes, limiting its use in certain clinical scenarios.
Innovation Solution
A pharmaceutical composition containing furosemide and a cyclodextrin, specifically a sulfobutyl ether derivative of β-cyclodextrin like captisol, which enhances solubility and stability at pH values from 7.0 to 8.5, allowing for subcutaneous and intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Volume of moving object
If the concentration of furosemide is increased to reduce administration volume, then the volume of administration is reduced, but precipitation occurs and formulation stability is impacted
Solution Approach 1:
A cyclodextrin compound is introduced as an intermediary substance that forms an inclusion complex with furosemide. The cyclodextrin's hydrophobic cavity encapsulates the furosemide molecule, enhancing its apparent solubility in aqueous physiological fluids at physiological pH without causing precipitation, thus allowing higher concentrations to be administered in smaller volumes while maintaining formulation stability.
Solution Approach 2:
The invention changes the physicochemical parameters of the furosemide formulation by adjusting pH to physiological ranges (6.5-8.5) and incorporating cyclodextrin compounds. This parameter modification allows furosemide to maintain solubility at higher concentrations without precipitation, resolving the contradiction between reducing administration volume and maintaining formulation stability.
2Quantity of substance
If the pH is reduced to improve solubility, then solubility is improved, but precipitation occurs
Solution Approach 1:
The cyclodextrin acts as a mediator that enables furosemide to remain soluble at physiological pH without requiring pH reduction. The inclusion complex formed between cyclodextrin and furosemide prevents precipitation that would otherwise occur at physiological pH, allowing the formulation to maintain both solubility and stability without extreme pH adjustments.
3Reliability
If a high pH formulation is used, then certain clinical uses are precluded or restricted, but furosemide stability is maintained
Solution Approach 1:
The invention modifies the pH parameter of the formulation to fall within the physiological range of 6.5-8.5, which is compatible with various administration routes including subcutaneous injection and intravenous infusion. This pH adjustment, combined with cyclodextrin incorporation, maintains furosemide stability while expanding adaptability to different clinical scenarios and administration methods.
4Ease of operation
If furosemide is administered orally for chronic treatment, then ease of administration is improved, but the onset is slow and duration is limited for acute conditions
Solution Approach 1:
The invention changes the physical state and solubility parameters of furosemide through cyclodextrin complexation, enabling parenteral administration forms that provide rapid onset for acute conditions while maintaining ease of administration. The enhanced solubility at physiological pH allows for convenient intravenous and subcutaneous formulations that act quickly when needed.
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 higher solubility and stability of furosemide, enabling effective drug delivery with minimal adverse effects, facilitating administration via subcutaneous infusion or injection, and intravenous use without precipitation.
Implementation Method 1
A pharmaceutical composition containing furosemide or a pharmaceutically acceptable form of the furosemide and a cyclodextrin... achieves higher solubility and stability of furosemide
Implementation Method 2
which enhances solubility and stability at pH values from 7.0 to 8.5, allowing for subcutaneous and intravenous administration... achieves higher solubility and stability of furosemide, enabling effective drug delivery with minimal adverse effects, facilitating administration via subcutaneous infusion or injection, and intravenous use without precipitation
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 furosemide, or a pharmaceutically acceptable salt, hydrate or ester thereof and a cyclodextrin.