Cyclodextrin-Free Posaconazole Injection for Peripheral IV Use
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Posaconazole has low solubility and requires cyclodextrin for formulation, leading to renal toxicity and vascular irritation, and its administration necessitates central venous access, which is cumbersome and risky.
Innovation Solution
A pharmaceutical composition comprising posaconazole, a good solvent, a stabilizer, a surfactant, and a nanocrystal inducer, without cyclodextrin, allowing for intravenous administration without central venous access and improved stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If cyclodextrin is used to improve posaconazole solubility, then solubility is improved, but renal toxicity increases
Solution Approach 1:
The patent removes cyclodextrin from the formulation entirely and replaces it with alternative solubilization strategies including co-solvents (polyethylene glycol, propylene glycol, ethanol) and surfactants (polysorbate 80, polyoxyl 35 castor oil), thereby eliminating the source of renal toxicity while maintaining posaconazole solubility
Solution Approach 2:
The patent changes the formulation parameters by adjusting pH to acidic range (pH 3-5 using citric acid or hydrochloric acid) and incorporating nanocrystal inducers to enhance posaconazole solubility without relying on cyclodextrin, thus avoiding renal toxicity while achieving adequate solubility for intravenous administration
2Quantity of substance
If low pH injection is used to dissolve posaconazole, then solubility is improved, but vascular irritation increases
Solution Approach 1:
The patent optimizes pH to a balanced range of 3-5 (rather than extremely low pH), and incorporates buffers (sodium citrate, disodium edetate) and surfactants to maintain solubility while reducing vascular irritation, allowing administration through peripheral veins rather than requiring central venous access
Solution Approach 2:
The patent introduces surfactants (polysorbate 80, polyoxyl 35 castor oil) and co-solvents as intermediary substances that facilitate posaconazole solubility and stability while reducing direct contact between the acidic drug solution and blood vessels, thereby minimizing vascular irritation
3Ease of operation
If central venous access is used for administration, then drug delivery is achieved, but patient comfort decreases and complications increase
Solution Approach 1:
The patent removes the requirement for central venous access by formulating posaconazole with improved solubility and reduced irritation properties through alternative solubilization strategies (co-solvents, surfactants, pH adjustment), enabling safe administration through peripheral intravenous routes and eliminating the risks associated with central line placement
Solution Approach 2:
The formulation incorporates stabilizers (sodium metabisulfite, α-tocopherol, ascorbyl palmitate) and buffers that maintain drug stability and reduce irritation without requiring special administration procedures or central venous access, allowing standard peripheral IV administration
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 formulation is stable, reduces renal toxicity risk, and can be administered via peripheral routes, enhancing patient comfort and safety while maintaining pharmacokinetic parameters.
Implementation Method 1
a good solvent
Implementation Method 2
a stabilizer
Implementation Method 3
a surfactant
Implementation Method 4
a nanocrystal inducer
Data Source
AI summary
The present disclosure relates to an in situ ready-to-use injection formulation of posaconazole free of cyclodextrin and derivatives of cyclodextrin, which can be formulated in situ as a nanosuspension injection of posaconazole by a simple dilution operation during clinical use. The formulation has no adverse effects on the renal function of patients, no extreme pH, and low vascular irritation, and can be administrated without the need for central venous cannulation during clinical use. The present disclosure also relates to a method for preparing the formulation and the use of the formulation in the treatment and prevention of fungal infections.