Aqueous Levcromakalim Eye Drops for Solubility-Stable Glaucoma Delivery
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Solution Overview
Problem
Cromakalim, despite its strong biological activity, is poorly soluble in water and unsuitable for topical ocular administration due to insolubility issues, which has hindered its use in treating conditions like glaucoma.
Innovation Solution
A stable topical formulation of levcromakalim is developed, combining excipients such as Kolliphor, polysorbate, PVP, and poloxamer to create an aqueous solution that maintains solubility and stability for at least five months, allowing effective ocular delivery without the need for covalent prodrugs or high levels of toxic components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If cromakalim is formulated in water or aqueous buffer, then it can be suitable for topical ocular administration, but it crystallizes or precipitates from solution due to poor solubility
Solution Approach 1:
The patent employs solubility-enhancing excipients as intermediary substances that mediate between the poorly water-soluble cromakalim and the aqueous ocular environment. These excipients form soluble complexes or micelles that carry the drug through the aqueous medium without allowing crystallization, thus enabling topical ocular administration while maintaining solubility stability.
Solution Approach 2:
The patent modifies the physical-chemical parameters of the formulation by adjusting pH, ionic strength, and using co-solvents or surfactants to change the solubility characteristics of cromakalim. This allows the drug to remain in solution at therapeutic concentrations without precipitation, resolving the contradiction between aqueous formulation and solubility stability.
2Quantity of substance
If DMSO or other highly polar organic solvents are used to solubilize cromakalim, then solubility is improved, but these solvents are not preferred for in vivo delivery due to toxicity concerns
Solution Approach 1:
The patent uses biocompatible excipients as intermediaries that enable cromakalim solubilization without requiring toxic organic solvents like DMSO. These intermediaries bridge the gap between the hydrophobic drug and the hydrophilic ocular environment, achieving solubility enhancement while maintaining safety for in vivo delivery.
Solution Approach 2:
The patent changes the solubilization mechanism from direct dissolution in toxic organic solvents to indirect solubilization through excipient-mediated mechanisms such as micelle formation, complexation, or solubility enhancement at optimized pH levels. This parameter change eliminates toxicity while preserving solubility.
3Quantity of substance
If high concentration of cromakalim is administered to achieve therapeutic effect, then IOP lowering is maximized, but crystallization or precipitation occurs reducing formulation stability
Solution Approach 1:
The patent employs excipients as intermediaries that enable the formulation to achieve high therapeutic concentrations of cromakalim while preventing crystallization. These intermediaries maintain molecular dispersion of the drug at high concentrations through steric stabilization or complexation, thus achieving both high concentration and formulation stability.
Solution Approach 2:
The patent creates a composite formulation system where cromakalim is combined with multiple excipients that work synergistically to maintain solubility at high concentrations. This composite approach uses combinations of surfactants, co-solvents, and stabilizers to prevent precipitation while achieving therapeutic concentration levels.
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 effectively lowers intraocular pressure and treats glaucoma, including normal tension glaucoma, with a benign toxicology profile and no significant adverse events, targeting the reduction of episcleral venous pressure to maximize IOP lowering while maintaining vascular integrity.
Implementation Method 1
combining excipients such as Kolliphor, polysorbate, PVP, and poloxamer to create an aqueous solution that maintains solubility
Implementation Method 2
Cromakalim is soluble in highly polar 'universal' organic solvents such as DMSO (dimethyl sulfoxide), DMF (dimethyl formamide) or NMP (1-methylpyrrolidone) which are capable of hydrogen bonding interactions and hydrophobic interactions
Data Source
AI summary
Aqueous ocular topical pharmaceutical formulations are provided that deliver an effective amount of (lev)cromakalim or a pharmaceutically acceptable salt thereof to treat an anterior or a posterior ocular disorder that responds to (lev)cromakalim, including glaucoma.