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Open AccessArticle

Optimization of Innovative Three-Dimensionally-Structured Hybrid Vesicles to Improve the Cutaneous Delivery of Clotrimazole for the Treatment of Topical Candidiasis

1
Department Scienze della Vita e dell’Ambiente, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
2
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Burjassot, 46100 Valencia, Spain
3
Department of Surgical Science, University of Cagliari, Molecular Biology Service Lab (MBS), Via Ospedale 40, 09124 Cagliari, Italy
4
Biopharmaceutics and Pharmacokinetics Unit, Institute for Nanoscience and Nanotechnology, University of Barcelona, 08028 Barcelona, Spain
5
Department of Biochemistry and Molecular Biology A, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, 30080 Murcia, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceutics 2019, 11(6), 263; https://doi.org/10.3390/pharmaceutics11060263
Received: 7 May 2019 / Revised: 1 June 2019 / Accepted: 4 June 2019 / Published: 6 June 2019
New three-dimensionally-structured hybrid phospholipid vesicles, able to load clotrimazole in a high amount (10 mg/mL), were obtained for the first time in this work by significantly reducing the amount of water (≤10%), which was replaced with a mixture of glycerol and ethanol (≈90%). A pre-formulation study was carried out to evaluate the effect of both the composition of the hydrating medium and the concentration of the phospholipid on the physico-chemical properties of hybrid vesicles. Four different three-dimensionally-structured hybrid vesicles were selected as ideal systems for the topical application of clotrimazole. An extensive physico-chemical characterization performed using transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM), 31P-NMR, and small-angle X-ray scattering (SAXS) displayed the formation of small, multi-, and unilamellar vesicles very close to each other, and was capable of forming a three-dimensional network, which stabilized the dispersion. Additionally, the dilution of the dispersion with water reduced the interactions between vesicles, leading to the formation of single unilamellar vesicles. The evaluation of the in vitro percutaneous delivery of clotrimazole showed an improved drug deposition in the skin strata provided by the three-dimensionally-structured vesicles with respect to the commercial cream (Canesten®) used as a reference. Hybrid vesicles were highly biocompatible and showed a significant antifungal activity in vitro, greater than the commercial cream Canesten®. The antimycotic efficacy of formulations was confirmed by the reduced proliferation of the yeast cells at the site of infection in vivo. In light of these results, clotrimazole-loaded, three-dimensionally-structured hybrid vesicles appear to be one of the most innovative and promising formulations for the treatment of candidiasis infections. View Full-Text
Keywords: phospholipid vesicles; clotrimazole; co-solvents; skin delivery; fungal infections; Candida albicans phospholipid vesicles; clotrimazole; co-solvents; skin delivery; fungal infections; Candida albicans
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Manca, M.L.; Usach, I.; Peris, J.E.; Ibba, A.; Orrù, G.; Valenti, D.; Escribano-Ferrer, E.; Gomez-Fernandez, J.C.; Aranda, F.J.; Fadda, A.M.; Manconi, M. Optimization of Innovative Three-Dimensionally-Structured Hybrid Vesicles to Improve the Cutaneous Delivery of Clotrimazole for the Treatment of Topical Candidiasis. Pharmaceutics 2019, 11, 263.

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