Propofol Aqueous Formulation Using Cyclodextrin Solubilization
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Solution Overview
Problem
Propofol emulsion products for anesthesia face issues such as injection site pain, allergic reactions, lipid overload, microbial contamination, and manufacturing difficulties, leading to recalls and a drug shortage, despite modifications like adding antimicrobial agents or altering pH.
Innovation Solution
An aqueous pharmaceutical formulation comprising propofol, sulfobutylether β-cyclodextrin, and citric acid at a pH of about 5.5, which reduces undesirable attributes and manufacturing challenges, and includes Captisol as a preferred sulfobutylether β-cyclodextrin, potentially with additional components like preservatives, antioxidants, or tonicity modifiers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If propofol is formulated in an oil-in-water emulsion to overcome poor water solubility, then propofol can be delivered intravenously, but injection site pain and allergic reactions occur due to fatty components
Solution Approach 1:
The patent uses sulfobutyl ether beta-cyclodextrin as a mediator to solubilize propofol in water. The cyclodextrin forms an inclusion complex with propofol, allowing the hydrophobic propofol molecule to be carried in aqueous solution without requiring fatty emulsion components, thereby eliminating injection site pain and allergic reactions while maintaining water deliverability
Solution Approach 2:
The patent changes the chemical environment by adjusting pH to 5.5 and using specific cyclodextrin derivatives, which alters the solubility parameters of propofol. This enables propofol to remain in solution at therapeutic concentrations without forming an oil-in-water emulsion, thus avoiding the harmful effects of fatty components
2Quantity of substance
If emulsion formulations are used to deliver propofol, then propofol can be administered intravenously, but microbial contamination risk increases due to difficulty in sterilization
Solution Approach 1:
The patent transforms the formulation from an oil-in-water emulsion to a clear aqueous solution by changing the solubilization mechanism. This parameter change allows the use of standard sterilization methods (autoclave or filtration) that are effective for aqueous solutions, thereby enabling reliable microbial contamination control while maintaining propofol deliverability
3Reliability
If antimicrobial agents are added to emulsion products to reduce microbial contamination, then microbial safety improves, but patient toxicity increases at high concentrations
Solution Approach 1:
The patent extracts and eliminates the need for antimicrobial agents by fundamentally changing the formulation from an emulsion that requires preservatives to a sterilizable aqueous solution. The cyclodextrin-based formulation allows standard sterilization, removing the harmful antimicrobial additives while maintaining microbial safety
Solution Approach 2:
The patent converts the inherent vulnerability of emulsions to microbial contamination into a benefit by using the aqueous cyclodextrin formulation's compatibility with sterilization methods. The formulation's water-based nature, which initially seemed to increase contamination risk, actually enables effective sterilization without requiring toxic preservatives
4Object-affected harmful factors
If pH of the emulsion is raised above pH 6.5 to reduce injection site pain, then pain relief improves, but the formulation becomes less stable and more prone to microbial growth
Solution Approach 1:
The patent optimizes the pH parameter to 5.5, which is slightly acidic rather than alkaline. This pH optimization, combined with the cyclodextrin solubilization system, achieves a balance where injection site pain is minimized while formulation stability and microbial resistance are maintained, avoiding the problems associated with higher pH values
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 provides stable, effective anesthesia or sedation with reduced dose variability, faster recovery, and lower blood concentration, minimizing allergic reactions and microbial growth, while being more compatible with IV equipment and requiring fewer dose adjustments compared to emulsion products.
Implementation Method 1
an aqueous pharmaceutical formulation comprising propofol, sulfobutylether β-cyclodextrin, and has a pH of about 5.5
Data Source
AI summary
Disclosed herein is an aqueous pharmaceutical formulation comprising about 10 mg/mL of propofol, 175 mg/mL of sulfobutylether β-cyclodextrin, a citric buffer, wherein the composition has a pH of about 5.5. Also disclosed is a method of inducing and maintaining anesthesia or sedation in a patient by administering the aqueous pharmaceutical formulation.