Topical delivery systems containing clotrimazole for the management of candidiasis: effect of different excipients and enhanced antifungal activity of nanovesicles

WHO classified Candida albicans as one of the four critical priority fungi for public health worldwide in 2022. Conventional topical formulations commercially available for the treatment of cutaneous candidiasis are associated with low drug bioavailability at the infection site and the lack of a sustained therapeutic effect. The main objectives of this work were to develop new topical administration systems of clotrimazole (CLT) and study the influence of surfactants on the antifungal inhibitory efficacy. Therefore, the minimum concentration of CLT required to inhibit 50 % of growth (MIC₅₀) was determined, obtaining a value of approximately 15 ng/mL. A non-ionic emulsion type 1, Beeler base cream, hydrogel and liposomes containing CLT were designed, prepared, characterized and their antifungal activity against C. albicans was tested. CLT loaded liposomes were small in size (102 nm), homogeneous (polydispersity index = 0.3) and uncharged (+0.07 mV), showing higher antifungal activity against C. albicans than that of the commercially available cream Canesten®. Furthermore, the antifungal activity of CLT was reduced in combination with surfactants such as Tween-80/Span-80 or Brij-S10. Sodium lauryl sulphate showed a fungicidal effect that disappeared when formulated as part of the Beeler base cream.

2.1. Reagents

The following compounds were purchased from Acofarma (Madrid, Spain): clotrimazole, polyethylene glycol 400 (PEG 400), non-ionic self-emulsifying O/W base (Neo PCL® O/W), cetyl alcohol, white beeswax and glycerin. Sweet almond oil, butylhydroxytoluene (BHT), sodium lauryl sulfate (SLS), and carbopol 940 were obtained from Guinama (Valencia, Spain). Glucose, sabouraud dextrose agar (SDA), potassium chloride (KCl), sodium chloride (NaCl), acetonitrile (AcN) and methanol were obtained from VWR chemicals (Barcelona, ​​Spain). The reagents purchased from Sigma-Aldrich (Madrid, Spain) were potassium phosphate monobasic (KH₂PO₄), di-sodium hydrogen phosphate (Na₂HPO₄), sodium phosphate monobasic (NaH₂PO₄) dimethyl sulfoxide (DMSO), RPMI 1940, Brij-S10, Brij-35, propylene glycol, tryptone water, Tween-80 and Span-80. 4-Morpholinepropanesulfonic acid (MOPS) and glutamine were obtained from Alfa Aesar (Kandel, Germany) and sodium hydroxide (NaOH) from Scharlau (Barcelona, ​​Spain). Tween-60 and span-60 came from TCI (Tokyo Chemical Industry) and Canesten® was obtained from Bayer (Barcelona, ​​Spain). Phospholipon 90 G was provided by Lipoid GmbH (Ludwigshafen, Germany).

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Iris Usach, Paula Martínez-Álvarez, José-Esteban Peris, Topical delivery systems containing clotrimazole for the management of candidiasis: effect of different excipients and enhanced antifungal activity of nanovesicles, International Journal of Pharmaceutics, 2023, 123287, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2023.123287.