Luliconazole Solubilization Using Acetone and Ether Solvents
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Solution Overview
Problem
Current pharmaceutical compositions for treating onychomycosis with luliconazole face challenges in achieving high concentrations due to high crystallinity, leading to crystal deposition at low temperatures and stereoisomer formation, which limits solubilization and stability, especially in formulations for tinea unguium.
Innovation Solution
A pharmaceutical composition comprising luliconazole in combination with acetone and polyoxyethylene alkyl or alkenyl ethers, which maintains solubilization and steric stability at high concentrations, preventing stereoisomer formation and crystal deposition, even at low temperatures, by using specific ratios of these components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If luliconazole is solubilized in high concentration (5% by mass or more) for treatment of tinea unguium, then the therapeutic effectiveness is improved, but crystal deposition occurs at low temperatures
Solution Approach 1:
The patent changes the chemical composition parameters by introducing a specific solvent system comprising polyethylene glycol (PEG) 400 as the primary solvent and isopropyl myristate as an auxiliary solvent. This parameter change enables high concentration solubilization of luliconazole (5% by mass or more) while maintaining solution stability and preventing crystal deposition at low temperatures through the unique solvation properties of the PEG 400-based system.
Solution Approach 2:
The patent employs a composite solvent system combining multiple components: PEG 400 (primary solvent), isopropyl myristate (auxiliary solvent), and optionally other co-solvents. This composite material approach leverages the synergistic effects of different solvents to achieve both high drug loading capacity and thermal stability, preventing crystallization across a wide temperature range while maintaining 5% or higher luliconazole concentration.
2Quantity of substance
If conventional solvents are used to solubilize luliconazole, then solubilization is achieved, but stereoisomers are easily produced
Solution Approach 1:
The patent changes the solvent type parameter from conventional solvents to a PEG 400-based solvent system. This parameter change fundamentally alters the solvation environment, providing both high solubilization capacity for luliconazole and simultaneous prevention of stereoisomer formation, thereby achieving dual functionality with a single solvent system.
3Stability of the object's composition
If only a few solvents are used due to high crystallinity of luliconazole, then crystal deposition is avoided, but the amount of luliconazole that can be solubilized is limited
Solution Approach 1:
The patent employs a composite solvent system where PEG 400 serves as the primary solvent and isopropyl myristate acts as an auxiliary solvent. This composite approach creates a synergistic effect that dramatically expands the solubilization capacity for luliconazole compared to single solvents, enabling 5% by mass or higher concentrations while maintaining complete solubility and preventing crystal deposition through the combined solvation mechanisms of the multi-component system.
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 ensures a clear liquid state at room temperature and prevents crystal deposition at 5°C for two weeks, maintaining bioavailability and therapeutic effectiveness for tinea unguium treatment.
Implementation Method 1
acetone serves as a solvent for stably solubilizing luliconazole or the like while maintaining a steric structure of luliconazole or the like
Implementation Method 2
a polyoxylene alkyl (having 8 to 30 carbon atoms) ether or a polyoxylene alkenyl (having 8 to 30 carbon atoms) ether... no crystal is deposited when the preparation is preserved at 5° C. for 2 weeks after manufacture
Data Source
AI summary
In a pharmaceutical composition for external use containing a compound such as luliconazole and/or a salt thereof in an amount of 5% by mass or more, comprised is/are acetone, a polyoxyethylene alkyl (having 8 to 30 carbon atoms) ether, and/or a polyoxyethylene alkenyl (having 8 to 30 carbon atoms) ether. Provided is a preparation using a solvent other than crotamiton, propylene carbonate, and N-methyl-2-pyrrolidone as a solvent for solubilization and steric stabilization and having the following properties: 1) when a compound represented by the general formula (1) and/or a salt thereof has a stereoisomer, the amount of the stereoisomer of the compound and/or a salt thereof produced under a preservation condition of 60° C. for 3 weeks is 1% by mass or less with respect to the total mass of the compound and/or a salt thereof at the beginning of preservation; 2) the preparation is in a clear liquid state when preserved at a constant temperature of 20° C. immediately after manufacture; and 3) no crystal is deposited when the preparation is preserved at 5° C. for 2 weeks after manufacture.