(S)-Ketorolac Lyophilized Powder Injection Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current formulations of ketorolac tromethamine injection, particularly those containing ethanol, face issues with stability, safety hazards due to precipitation and disulfiram reactions, and the use of propylene glycol or poloxamer 188 leads to adverse effects, while the racemic composition of ketorolac increases the risk of adverse effects and reduces efficacy.
Innovation Solution
A pharmaceutical composition of (S)-ketorolac is developed, including (S)-ketorolac or its pharmaceutically acceptable salts, a pH-adjusting agent, and excipients like mannitol or maltodextrin, formulated as a lyophilized powder injection to maintain optical purity and stability, avoiding organic solvents and inclusion compounds that cause irritation and hemolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If ethanol is used as a stabilizer in ketorolac tromethamine injection, then the injection can be stabilized, but white spots or crystals precipitate during long-term storage and disulfiram reaction occurs with cephalosporin antibiotics
Solution Approach 1:
The patent removes ethanol from the formulation entirely, extracting the harmful stabilizing agent that causes precipitation and disulfiram reactions, while replacing it with safe alternatives like polysorbate 80 and hydrophilic colloids that do not cause these adverse effects
Solution Approach 2:
The patent introduces polysorbate 80 and hydrophilic colloids as intermediary substances that serve as safe stabilizers and solvents, mediating the stability function previously performed by ethanol without causing the harmful effects associated with ethanol
2Stability of the object's composition
If propylene glycol is added to improve clarity, then white spots after sterilization are improved, but adverse stimulation occurs and related substances increase rapidly
Solution Approach 1:
The patent removes propylene glycol from the formulation, extracting the substance that causes adverse stimulation and rapid increase in related substances, while maintaining clarity through alternative safe excipients
Solution Approach 2:
The patent uses polysorbate 80 and hydrophilic colloids as temporary, safe excipients that perform their stabilizing function without causing long-term adverse effects or rapid degradation, unlike propylene glycol
3Stability of the object's composition
If cholesterol, oleic acid, or poloxamer 188 is used as a stabilizer, then clarity is improved, but hemolysis and sensitization occur
Solution Approach 1:
The patent removes cholesterol, oleic acid, and poloxamer 188 from the formulation, extracting the substances that cause hemolysis and sensitization, while replacing them with safe alternatives that maintain clarity without these adverse effects
Solution Approach 2:
The patent introduces polysorbate 80 and hydrophilic colloids as intermediary stabilizers that mediate the clarity function without causing hemolysis or sensitization, providing a safe alternative to the harmful stabilizers
4Productivity
If racemic ketorolac is used, then analgesic effect is achieved, but adverse effects increase and efficacy is reduced
Solution Approach 1:
The patent extracts and removes the harmful (R)-enantiomer from the racemic mixture, leaving only the active (S)-enantiomer, thereby eliminating adverse effects while maintaining analgesic efficacy
Solution Approach 2:
The patent applies local quality by selectively targeting and retaining only the beneficial (S)-enantiomer with analgesic properties while removing the harmful (R)-enantiomer, creating a formulation with improved safety profile
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 (S)-ketorolac lyophilized powder injection achieves enhanced optical stability, reduced dosage requirements, improved safety, and increased efficacy by maintaining optical purity and stability, while avoiding adverse effects associated with racemic ketorolac formulations.
Implementation Method 1
a pharmaceutical composition of (S)-ketorolac and preparation method therefor. (S)-ketorolac is an active optical isomer exerting drug efficacy in ketorolac tromethamine
Implementation Method 2
a pH-adjusting agent; and (3) a pharmaceutically acceptable excipient
Data Source
AI summary
Provided are a pharmaceutical composition of (S)-ketorolac and a preparation method therefor, which belong to the technical field of pharmaceutical preparations. The pharmaceutical composition includes (S)-ketorolac or a pharmaceutically acceptable salt thereof, a stabilizer, a pH-adjusting agent, and an excipient, and the dosage form of the pharmaceutical composition is preferably lyophilized powder injection. The lyophilized powder injection prepared herein has optical purity of an active ingredient greater than or equal to 95% after being stored under long-term stability test conditions for 6 months and optical purity of an active ingredient greater than or equal to 90% after being stored under accelerated stability test conditions for 6 months. The lyophilized powder injection has important use in the preparation of non-steroidal anti-inflammatory drugs with analgesic, anti-inflammatory, antipyretic effects.