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      Clotrimazole-Loaded Mediterranean Essential Oils NLC: A Synergic Treatment of Candida Skin Infections

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          Abstract

          The increasing development of resistance of Candida species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (2 3 full factorial design) Mediterranean essential oil ( Rosmarinus officinalis, Lavandula x intermedia “Sumian”, Origanum vulgare subsp. hirtum) lipid nanoparticles for clotrimazole delivery, exploring the potential synergistic effects against Candida spp. Small sized nanoparticles (<100 nm) with a very broad size distribution (PDI < 0.15) and long-term stability were successfully prepared. Results of the in vitro biosafety on HaCaT (normal cell line) and A431 (tumoral cell line), allowed us to select Lavandula and Rosmarinus as anti-proliferative agents with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases. Results of calorimetric studies on biomembrane models, confirmed the potential antimicrobial activity of the selected oils due to their interaction with membrane permeabilization. Nanoparticles provided a prolonged in vitro release of clotrimazole. In vitro studies against Candida albicans, Candida krusei and Candida parapsilosis, showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming nanostructured lipid carriers (NLC) containing Mediterranean essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis.

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          Most cited references48

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          Two-step method for encapsulation of oregano essential oil in chitosan nanoparticles: preparation, characterization and in vitro release study.

          In this study, oregano essential oil (OEO) has been encapsulated in chitosan nanoparticles by a two-step method, i.e., oil-in-water emulsion and ionic gelation of chitosan with sodium tripolyphosphate (TPP). The success of OEO encapsulation was confirmed by Fourier transform infrared (FT-IR) spectroscopy, UV-vis spectrophotometry, thermogravimetric analysis (TGA) and X-ray diffraction (XRD) techniques. The obtained nanoparticles exhibited a regular distribution and spherical shape with size range of 40-80 nm as observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). As determined by TGA technique, the encapsulation efficiency (EE) and loading capacity (LC) of OEO-loaded chitosan nanoparticles were about 21-47% and 3-8%, respectively, when the initial OEO content was 0.1-0.8 g/g chitosan. In vitro release studies showed an initial burst effect and followed by a slow drug release.
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            Biological activities of lavender essential oil.

            Essential oils distilled from members of the genus Lavandula have been used both cosmetically and therapeutically for centuries with the most commonly used species being L. angustifolia, L. latifolia, L. stoechas and L. x intermedia. Although there is considerable anecdotal information about the biological activity of these oils much of this has not been substantiated by scientific or clinical evidence. Among the claims made for lavender oil are that is it antibacterial, antifungal, carminative (smooth muscle relaxing), sedative, antidepressive and effective for burns and insect bites. In this review we detail the current state of knowledge about the effect of lavender oils on psychological and physiological parameters and its use as an antimicrobial agent. Although the data are still inconclusive and often controversial, there does seem to be both scientific and clinical data that support the traditional uses of lavender. However, methodological and oil identification problems have severely hampered the evaluation of the therapeutic significance of much of the research on Lavandula spp. These issues need to be resolved before we have a true picture of the biological activities of lavender essential oil. Copyright 2002 John Wiley & Sons, Ltd.
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              Nanosuspensions: a promising drug delivery strategy.

              Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because of their versatile features and unique advantages. Techniques such as media milling and high-pressure homogenization have been used commercially for producing nanosuspensions. Recently, the engineering of nanosuspensions employing emulsions and microemulsions as templates has been addressed in the literature. The unique features of nanosuspensions have enabled their use in various dosage forms, including specialized delivery systems such as mucoadhesive hydrogels. Rapid strides have been made in the delivery of nanosuspensions by parenteral, peroral, ocular and pulmonary routes. Currently, efforts are being directed to extending their applications in site-specific drug delivery.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                13 May 2019
                May 2019
                : 11
                : 5
                : 231
                Affiliations
                [1 ]Laboratory of Drug Delivery Technology, Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125 Catania, Italy; teresa.musumeci@ 123456unict.it
                [2 ]Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), 3030-548 Coimbra, Portugal; mceuteixeira@ 123456ff.uc.pt
                [3 ]CNC—Center for Neurosciences and Cell Biology, University of Coimbra, 3030-548 Coimbra, Portugal; mcsousa@ 123456ci.uc.pt
                [4 ]Laboratory of Microbiology, Faculty of Pharmacy, University of Coimbra, 3030-548 Coimbra, Portugal
                [5 ]Department of Biology and Environment, University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, P-5001-801 Vila Real, Portugal; gomes.ma.carlos@ 123456gmail.com (C.M.-G.); amsilva@ 123456utad.pt (A.M.S.)
                [6 ]Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes e Alto Douro (UTAD), P-5001-801 Vila Real, Portugal
                [7 ]REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3030-548 Coimbra, Portugal
                Author notes
                [* ]Correspondence: ccarbone@ 123456unict.it (C.C.); ebsouto@ 123456ebsouto.pt (E.M.B.S.); Tel.: +39-095-738-4251 (C.C.)
                Author information
                https://orcid.org/0000-0003-3592-752X
                https://orcid.org/0000-0002-1564-3661
                https://orcid.org/0000-0002-7524-9914
                Article
                pharmaceutics-11-00231
                10.3390/pharmaceutics11050231
                6572383
                31085997
                4d1ecec7-536a-47d2-9b6c-6cdb742cf72b
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 April 2019
                : 09 May 2019
                Categories
                Article

                rosmarinus officinalis l.,lavandula x intermedia “sumian”,origanum vulgare subsp. hirtum,factorial design,stability,turbiscan,lumisizer,dsc,cytotoxicity,mic

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