Microneedles loaded with lipid nanocarriers for local treatment of vulvovaginal candidiasis

Abstract

Vaginal yeast infections, such as vulvovaginal candidiasis (VVC), affect nearly three out of four women worldwide. Re-occurrence is frequent and requires repeated treatments with oral, antifungal medications at high doses. Prolonged treatments contribute to development of resistant fungal strains and the risk of systemic adverse effects. Vaginal drug delivery can overcome several of the disadvantages associated with oral drug administration.

However, current dosage forms, such as vaginal creams and gels, are rapidly expelled from the vaginal tract and require daily dosing to assure therapeutic outcome, thus jeopardizing patient compliance. Therefore, we developed rapidly dissolving microneedle arrays for local, vaginal delivery of antifungal drugs. Clotrimazole, a poorly water-soluble antifungal agent, was formulated in lipid-based nanocarriers (LNCs) and incorporated in the tips of microneedles. The antifungal activity was then tested against the most common VVC fungal strains, C. albicans and C. glabrata, using an in vitro disk diffusion assay and an explant model from bovine vaginal tissue.

Antifungal activity increased when the LNCs were incorporated in the microneedles. Notably, the LNC-loaded microneedles inhibited fungal growth at a 10-fold lower drug dose than a commercial clotrimazole cream. Finally, a device prototype was manufactured, based on an intravaginal ring with multiple microneedle arrays on its surface. Local vaginal drug delivery using such microneedle-based devices could enable more effective treatment strategies for VVC.

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Materials

Labrasol, Capryol 90 and Labrafac lipophile WL 1349 were kindly provided by Gattefossé (Lyon, France). Lipoid S100 (>94% phosphatidylcholine) was provided by Lipoid GmbH, Ludwigshafen, Germany. Clotrimazole (≥99%), cellulose acetate filters (0.45 µm, Sartorius), and dialysis membrane (molecular weight cutoff 12-14 kDa) were obtained from VWR, Stockholm, Sweden. Sulforhodamine B, Tween 80, sodium acetate, ammonium acetate, acetonitrile (>99.9%), methanol (>99.9%), Mueller-Hinton agar, potato dextrose, glucose, agar, polyvinyl alcohol (PVA; 87-89% hydrolyzed, MW 13-23 kDa, Sigma-Aldrich), poly methyl methacrylate (PMMA; MW ~120 kDa, Sigma-Aldrich) and paraformaldehyde were obtained from Merck (Darmstadt, Germany). Canesten cream 1% (Bayer AB, Solna, Sweden) was procured from a local Swedish pharmacy and bovine vaginal tissue from a local abattoir (Lövsta kött AB, Uppsala, Sweden). Clinical isolates of C. albicans (U251) were obtained as samples from a previous study [22] and C. glabrata (44136) was obtained from CCUG, Gothenburg, Sweden. The vaginal epithelial cell line VK2/E6E7 was obtained from ATCC, Teddington, UK. A cell viability assay (CellTiter-Fluor, G6081) was purchased from Promega (Nacka, Sweden). TTP tissue culture, 96-well plates, polyethylene glycol 400 and benzyl alcohol were purchased from Sigma-Aldrich, Solna, Sweden. Artificial cervicovaginal mucus was obtained from Bac3gel, Porto Salvo, Portugal. Calcofluor White and Concovalin Texas red were obtained from ThermoFisher, Uppsala, Sweden.

Udayakumar P, Škalko-Basnet N, Salas Cotaquispe CF, Hemmingsen LM, Sotiriou G, Du J, et al. Microneedles loaded with lipid nanocarriers for local treatment of vulvovaginal candidiasis. ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-fj3gp This content is a preprint and has not been peer-reviewed.