Posaconazole IV Solution Stabilized by SBE-β-CD
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Solution Overview
Problem
Posaconazole has poor aqueous solubility and bioavailability, making it challenging to develop an intravenous formulation that is chemically and physically stable, which is essential for effective administration and treatment of fungal infections.
Innovation Solution
A pharmaceutical composition comprising posaconazole, sulfobutylether-β-cyclodextrin, and EDTA in an aqueous solution at a pH between 2.0 and 3.5, which significantly enhances the solubility and stability of posaconazole, preventing precipitation during administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If posaconazole is formulated as an intravenous solution, then bioavailability is improved and administration is simplified, but solubility and stability are insufficient due to poor aqueous solubility
Solution Approach 1:
The patent uses cyclodextrins as intermediary substances to form inclusion complexes with posaconazole. The cyclodextrin molecule acts as a mediator, with its hydrophobic cavity accommodating the posaconazole molecule while the hydrophilic exterior interacts with aqueous media, thereby solubilizing the poorly water-soluble drug for intravenous administration
Solution Approach 2:
The patent modifies the chemical structure of β-cyclodextrin by introducing sulfobutyl ether groups, transforming it into sulfobutylether-β-cyclodextrin (SBE-β-CD). This parameter change in the cyclodextrin structure significantly enhances its solubilizing capability and stability, enabling effective intravenous formulation of posaconazole
2Quantity of substance
If posaconazole is formulated at higher concentrations for effective dosing, then therapeutic efficacy is improved, but precipitation occurs during storage and administration
Solution Approach 1:
The patent creates a composite pharmaceutical system consisting of posaconazole incorporated within cyclodextrin inclusion complexes, combined with EDTA as a chelating agent. This composite formulation maintains high drug concentration (up to 4 mg/mL) while preventing precipitation through the synergistic stabilization provided by the cyclodextrin-positaconazole complex and EDTA
3Device complexity
If posaconazole is administered orally, then the formulation is simple, but bioavailability is poor and absorption is variable
Solution Approach 1:
The cyclodextrin inclusion complex acts as an intermediary that enhances the solubility and dissolution rate of posaconazole, thereby improving its bioavailability. The complex facilitates better interaction between the drug and the aqueous environment in the gastrointestinal tract, leading to more reliable and predictable absorption
Solution Approach 2:
The patent utilizes the phase transition properties of cyclodextrin inclusion complexes, which can form stable soluble complexes that enhance drug dissolution from the solid oral dosage form into the aqueous gastrointestinal environment, thereby improving bioavailability
Data Source
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AI summary
The present invention relates to aqueous solutions useful as pharmaceutical compositions of posaconazole for intravenous administration. These compositions include a solubilizing agent, such as a modified β-cyclodextrin in an acidified solution, which can also include a chelating agent such as disodium edetate (EDTA). In clinical trials, a 200 mg posaconazole dose of the selected composition was found to achieve acceptable pharmacokinetic properties.