Levcromakalim Ocular Formulation for Solubility and Shelf Stability
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Solution Overview
Problem
Cromakalim, particularly its (3S,4R)-stereoisomer levcromakalim, is poorly soluble in water and aqueous buffers, leading to challenges in topical ocular delivery for treating conditions like glaucoma due to insolubility and potential adverse effects, and existing formulations like CKLP1 are complex and costly.
Innovation Solution
A stable topical formulation of levcromakalim is developed using specific excipient combinations, avoiding covalent prodrugs and high-toxicity solvents, ensuring solubility and stability for at least 5 months, targeting the reduction of intraocular pressure through distal outflow resistance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If cromakalim is formulated in water or aqueous buffer, then it can be administered topically to the eye, but it crystallizes or precipitates from solution due to poor solubility
Solution Approach 1:
The patent uses cyclodextrins as intermediary molecules that form inclusion complexes with cromakalim. The cyclodextrin's hydrophilic exterior allows the complex to dissolve in aqueous ophthalmic formulations, while its hydrophobic interior cavity accommodates the lipophilic cromakalim molecule, preventing crystallization and maintaining solubility stability.
Solution Approach 2:
The invention creates a composite solubility system by combining cromakalim with cyclodextrin carriers. This composite approach allows the drug to maintain both water solubility (through the cyclodextrin exterior) and drug stability (through the protected inclusion complex), resolving the contradiction between ease of topical administration and compositional stability.
2Quantity of substance
If high concentration of DMSO is used to solubilize cromakalim, then solubility is improved, but toxicity increases making it unsuitable for ocular delivery
Solution Approach 1:
Cyclodextrins serve as non-toxic intermediary carriers that solubilize cromakalim through inclusion complexation. This eliminates the need for toxic high-concentration DMSO, as the cyclodextrin-water system provides adequate solubility at safe concentrations for ocular delivery while maintaining drug stability.
Solution Approach 2:
The invention changes the solubility mechanism from direct dissolution in toxic organic solvents like DMSO to inclusion complexation with biocompatible cyclodextrins. This parameter change in the solubilization approach allows achieving necessary cromakalim solubility without the harmful effects of high DMSO concentrations.
3Quantity of substance
If covalent prodrugs like CKLP1 are used to improve solubility, then water solubility increases, but formulation complexity and cost increase
Solution Approach 1:
Instead of creating complex covalent prodrugs, the patent uses cyclodextrins as simple non-covalent intermediary carriers. The inclusion complex formation is reversible and does not require chemical modification of the cromakalim structure, significantly reducing formulation complexity while achieving the desired water solubility enhancement.
Solution Approach 2:
The cyclodextrin carrier system is simpler and more cost-effective than covalent prodrug approaches. The inclusion complexes are stable during storage and administration but naturally dissociate to release active cromakalim at the target site, eliminating the need for complex enzymatic activation or metabolic conversion required by prodrugs.
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 within hours and maintains stability, providing a safe and tolerable profile for treating glaucoma, including normal tension glaucoma, without adverse events like hyperemia, and targets the fourth component of IOP regulation.
Implementation Method 1
Cromakalim placed in membrane patches from rabbit mesenteric arterial smooth muscle cells increases the open-state probability (Popen) of single KATP channels more than 9-fold in the presence of ATP
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
Implementation Method 3
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
An aqueous clear topical ocular solution of levcromakalim, or a pharmaceutically acceptable salt thereof, is provided in an effective therapeutic amount to treat the anterior portion of the human eye without the use of a covalent prodrug approach, a polymeric delivery system or a high level of toxic components, and with at least 4 months of shelf life stability, through the use of specifically discovered combinations of excipient components.