Propofol Cyclodextrin Salt Complex for Injection Pain and Nephrotoxicity
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Solution Overview
Problem
Current propofol compositions for intravenous administration are painful due to free propofol, nephrotoxic from high cyclodextrin doses, and difficult to sterilize by filtration, requiring industrial-scale terminal sterilization and unsuitable emulsion globule sizes.
Innovation Solution
A pharmaceutical composition of propofol with an optimized amount of cyclodextrin and/or cyclodextrin derivative, using pharmaceutically acceptable salts to modify the solution's dielectric constant, pH, and osmolality, allowing for intravascular administration, reduced nephrotoxicity, and filtration sterilization without clogging filters.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If propofol is administered as a lipophilic-in-hydrophilic emulsion using soybean oil and phospholipids, then propofol can be delivered intravenously, but the injection remains painful due to free propofol within the emulsion
Solution Approach 1:
The patent introduces cyclodextrin as an intermediary substance that forms inclusion complexes with propofol. The cyclodextrin's hydrophilic exterior and lipophilic cavity allow it to solubilize propofol molecules, acting as a mediator between the lipophilic propofol and the aqueous injection medium, thereby eliminating free propofol that causes injection pain.
Solution Approach 2:
The patent changes the chemical environment by adjusting pH and adding salts to modify the dielectric constant of the aqueous solution. These parameter changes optimize the complexation between cyclodextrin and propofol, enhancing solubilization and reducing injection pain while maintaining formulation stability.
2Ease of operation
If high doses of cyclodextrin are used to complex propofol, then injection pain is reduced, but nephrotoxicity increases
Solution Approach 1:
The patent employs parameter changes by adjusting pH and ionic strength through salt addition to optimize the complexation efficiency between cyclodextrin and propofol. This enhancement of complexation stability allows reduction of cyclodextrin dosage while maintaining effective propofol solubilization and minimizing injection pain, thereby reducing nephrotoxicity risk.
Solution Approach 2:
The patent creates a composite formulation system consisting of cyclodextrin, propofol, salts, and buffer components. This composite approach allows synergistic interactions where salts and pH adjustment enhance complexation efficiency, enabling effective propofol delivery at lower cyclodextrin concentrations and thus reducing nephrotoxicity.
3Reliability
If terminal sterilisation is used to sterilize the emulsion, then sterility is achieved, but the preparation can only be carried out industrially in rotary mode
Solution Approach 1:
The patent changes the physical parameters of the formulation by optimizing pH, ionic strength, and cyclodextrin:propofol ratio to produce a stable aqueous complex solution. This formulation approach enables the product to withstand terminal sterilization processes (autoclaving or filtration) without compromising stability, thereby allowing both industrial and small-scale manufacturing with simplified procedures.
4Ease of manufacture
If the emulsion globules are made suitable for filtration, then sterilisation by filtration becomes possible, but the current globule size is unsuitable to pass through the filter
Solution Approach 1:
The patent transitions the formulation from an emulsion phase with large globules to a molecular complex phase where propofol is solubilized within cyclodextrin cavities. This phase transition results in a homogeneous aqueous solution with molecular-sized complexes that can readily pass through filtration membranes, enabling sterilization by filtration while maintaining sterility.
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 effectively complexes propofol, reducing injection pain, minimizing nephrotoxicity, and enabling simple, quick, and sterile preparation for intravenous use, maintaining stability and physiological compatibility.
Implementation Method 1
a pharmaceutical composition containing a complex of propofol and a water-soluble cyclodextrin
Implementation Method 2
using pharmaceutically acceptable salts to modify the solution's dielectric constant, pH, and osmolality
Implementation Method 3
enabling simple, quick, and sterile preparation for intravenous use, maintaining stability and physiological compatibility
Data Source
AI summary
The present invention relates to a pharmaceutical composition having propofol and at least one cyclodextrin and/or a cyclodextrin derivative. Characteristically, according to the invention, it further includes at least one pharmaceutically acceptable salt, with the exception of basic and/or acidic pharmaceutically acceptable salts.