Abstract
Poor solubility of new antifungal of 1,2,4-triazole class (S-119)—a structural analogue of fluconazole in aqueous media was estimated. The solubility improvement using different excipients: biopolymers (PEGs, PVP), surfactants (Brij S20, pluronic F-127) and cyclodextrins (α-CD, β-CD, 2-HP-β-CD, 6-O-Maltosyl-β-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. Additionally, 2-HP-β-CD and 6-O-Maltosyl-β-CD were proposed as promising solubilizers for S-119. According to the solubilization capacity and micelle/water partition coefficients in buffer pH 7.4 pluronic F-127 was shown to improve S-119 solubility better than Brij S20. Among biopolymers, the greatest increase in solubility was shown in PVP solutions (pH 7.4) at concentrations above 4 w/v%. Complex analysis of the driving forces of solubilization, micellization and complexation processes matched the solubility results and suggested pluronic F-127 and 6-O-Maltosyl-β-CD as the most effective solubilizing agents for S-119. The comparison of S-119 diffusion through the cellulose membrane and lipophilic PermeaPad barrier revealed a considerable effect of the lipid layer on the decrease in the permeability coefficient. According to the PermeaPad, S-119 was classified as a highly permeated substance. The addition of 1.5 w/v% CDs in donor solution moves it to low-medium permeability class.
Highlights
This work is aimed to increase the solubility of S-119, which was proposed as a novel potential drug compound for the prevention and treatment of fungi
The equilibrium solubility of S-119 was measured at several concentrations of polymers and cyclodextrins
At pH 7.4 the stability constants with all CDs belong to the optimal range of good potential bioavailability
Summary
Pathogenic fungi actively mutate and become increasingly resistant to the drugs used They are especially dangerous for people with weakened immunity, in particular, for those who have had a coronavirus infection and who have taken steroids and immunosuppressant for treatment [1]. Among them the triazole class compounds, exemplified by fluconazole, itraconazole, econazole, terconazole, butoconazole, tioconazole, voriconazole, posaconazole, ravuconazole are abundant [2] These drugs are active as the specific inhibitors of cytochrom P-450 enzyme lanosterol 14-αdemethylase [3], which determines the biosynthesis of ergosterol—the main structural component of the fungus cell membrane [4,5]. Fungi develop resistance to many drugs used Such an evolutionary process pushes the medical scientists to a constant searching for new antifungal molecules
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