Formulation of Tioconazole and Melaleuca alternifolia Essential Oil Pickering Emulsions for Onychomycosis Topical Treatment

Onychomycosis is a disease that affects many adults, whose treatment includes both oral and topical therapies with low cure rates. The topical therapy is less effective but causes fewer side effects. This is why the development of an effective, easy to apply formulation for topical treatment is of high importance. We have used a nanotechnological approach to formulate Pickering emulsions (PEs) with well-defined properties to achieve site-specific delivery for antifungal drug combination of tioconazole and Melaleuca alternifolia essential oil. Silica nanoparticles with tailored size and partially hydrophobic surface have been synthesized and used for the stabilization of PEs. In vitro diffusion studies have been performed to evaluate the drug delivery properties of PEs. Ethanolic solution (ES) and conventional emulsions (CE) have been used as reference drug formulations. The examination of the antifungal effect of PEs has been performed on Candida albicans and Trichophyton rubrum as main pathogens. In vitro microbiological experimental results suggest that PEs are better candidates for onychomycosis topical treatment than CE or ES of the examined drugs. The used drugs have shown a significant synergistic effect, and the combination with an effective drug delivery system can result in a promising drug form for the topical treatment of onychomycosis.

[1]  N. Papp,et al.  Cytotoxic Action of Artemisinin and Scopoletin on Planktonic Forms and on Biofilms of Candida Species , 2020, Molecules.

[2]  B. Kocsis,et al.  Preparation, characterisation and microbiological examination of Pickering nano-emulsions containing essential oils, and their effect on Streptococcus mutans biofilm treatment , 2019, Scientific Reports.

[3]  J. Morales,et al.  Silica-based nanosystems for therapeutic applications in the skin. , 2019, Nanomedicine.

[4]  D. Mercer,et al.  Improved Methods for Assessing Therapeutic Potential of Antifungal Agents against Dermatophytes and Their Application in the Development of NP213, a Novel Onychomycosis Therapy Candidate , 2019, Antimicrobial Agents and Chemotherapy.

[5]  A. Széchenyi,et al.  Preparation and in vitro diffusion study of essential oil Pickering emulsions stabilized by silica nanoparticles , 2018, Flavour and Fragrance Journal.

[6]  R. Coppola,et al.  Essential Oils and Antifungal Activity , 2017, Pharmaceuticals.

[7]  Yinghui Chen,et al.  An Overview of Pickering Emulsions: Solid-Particle Materials, Classification, Morphology, and Applications , 2017, Front. Pharmacol..

[8]  A. Tiwary,et al.  High failure rate of transungal drug delivery: need for new strategies. , 2017, Therapeutic delivery.

[9]  H. Maibach,et al.  Agache's Measuring the Skin , 2017 .

[10]  J. Wang,et al.  Antifungal modes of action of tea tree oil and its two characteristic components against Botrytis cinerea , 2015, Journal of applied microbiology.

[11]  J. H. T. Horst,et al.  Solubility determination from clear points upon solvent addition , 2015 .

[12]  Jun-Ho Kim,et al.  Evaluation of silica nanoparticle toxicity after topical exposure for 90 days , 2014, International journal of nanomedicine.

[13]  S. Jones,et al.  Human Nail Plate Modifications Induced by Onychomycosis: Implications for Topical Therapy , 2014, Pharmaceutical Research.

[14]  B. Sigurgeirsson,et al.  The prevalence of onychomycosis in the global population – A literature study , 2014, Journal of the European Academy of Dermatology and Venereology : JEADV.

[15]  J. Lear,et al.  British Association of Dermatologists' guidelines for the management of onychomycosis 2014 , 2014, The British journal of dermatology.

[16]  D. Monti,et al.  Ciclopirox vs amorolfine: in vitro penetration into and permeation through human healthy nails of commercial nail lacquers. , 2014, Journal of drugs in dermatology : JDD.

[17]  E. Elkady,et al.  Simultaneous HPLC and derivative spectrophotometry detrmination of tioconazole and benzyl alcohol in bulk and cream with tioconazole forced degradation study , 2014 .

[18]  Yves Chevalier,et al.  Emulsions stabilized with solid nanoparticles: Pickering emulsions , 2013 .

[19]  D. D. de Berker,et al.  Nail anatomy. , 2013, Clinics in dermatology.

[20]  S. N. Murthy,et al.  Ungual and Transungual drug delivery , 2012, Drug development and industrial pharmacy.

[21]  Kelly A. Smith,et al.  Effects of organic solvents on the barrier properties of human nail. , 2011, Journal of pharmaceutical sciences.

[22]  Lusiana,et al.  Keratin film made of human hair as a nail plate model for studying drug permeation. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[23]  S. Velaga,et al.  Hansen solubility parameter as a tool to predict cocrystal formation. , 2011, International journal of pharmaceutics.

[24]  I. Nielsen,et al.  Elucidating the bimodal acid-base behavior of the water-silica interface from first principles. , 2009, Journal of the American Chemical Society.

[25]  A. Rosato,et al.  In vitro synergic efficacy of the combination of Nystatin with the essential oils of Origanum vulgare and Pelargonium graveolens against some Candida species. , 2009, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[26]  Y. Chevalier,et al.  Topical delivery of lipophilic drugs from o/w Pickering emulsions. , 2009, International journal of pharmaceutics.

[27]  Maria R R Silva,et al.  In vitro susceptibility testing of dermatophytes isolated in Goiania, Brazil, against five antifungal agents by broth microdilution method. , 2009, Revista do Instituto de Medicina Tropical de Sao Paulo.

[28]  H. Korting,et al.  Targeting virulence: a new paradigm for antifungals. , 2009, Drug discovery today.

[29]  Wei Yang,et al.  Drug delivery strategies for improved azole antifungal action , 2008, Expert opinion on drug delivery.

[30]  H. Maibach,et al.  In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. , 2007, Journal of pharmaceutical sciences.

[31]  D. A. Santos,et al.  In vitro activities of four antifungal drugs against Trichophyton rubrum isolates exhibiting resistance to fluconazole , 2007, Mycoses.

[32]  L. Estevinho,et al.  Antimicrobial activity and bioactive compounds of Portuguese wild edible mushrooms methanolic extracts , 2007 .

[33]  J. Kristl,et al.  An investigation into keratinolytic enzymes to enhance ungual drug delivery. , 2007, International journal of pharmaceutics.

[34]  Aditya K. Gupta,et al.  Therapies for onychomycosis: a review. , 2006, Dermatologic clinics.

[35]  G. Kardos,et al.  Efficacy of amphotericin B and flucytosine against fluconazole-resistant Candida inconspicua clinical isolates. , 2005, The Journal of antimicrobial chemotherapy.

[36]  M. Repka,et al.  Influence of human nail etching for the assessment of topical onychomycosis therapies. , 2004, International journal of pharmaceutics.

[37]  Michael D. Scherer,et al.  Scanning electron microscope imaging of onychomycosis. , 2004, Journal of the American Podiatric Medical Association.

[38]  T. Riley,et al.  Antifungal effects of Melaleuca alternifolia (tea tree) oil and its components on Candida albicans, Candida glabrata and Saccharomyces cerevisiae. , 2004, The Journal of antimicrobial chemotherapy.

[39]  M. Lahaye,et al.  Chemical structure and physico-chemical properties of agar , 1991, Hydrobiologia.

[40]  C. Madeira,et al.  Nail abrasion , 2003, Journal of Cosmetic Dermatology.

[41]  J. Pemán,et al.  Minimum fungicidal concentrations of amphotericin B for bloodstream Candida species. , 2003, Diagnostic microbiology and infectious disease.

[42]  Bernard P. Binks,et al.  Emulsions stabilised solely by colloidal particles , 2003 .

[43]  M. Canuto,et al.  Antifungal drug resistance to azoles and polyenes. , 2002 .

[44]  B. Binks Particles as surfactants—similarities and differences , 2002 .

[45]  M. Bohn,et al.  Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. , 2000, Journal of the American Academy of Dermatology.

[46]  B. Elewski,et al.  Onychomycosis: Pathogenesis, Diagnosis, and Management , 1998, Clinical Microbiology Reviews.

[47]  W. Hoven,et al.  Nail penetration of the antifungal agent oxiconazole after repeated topical application in healthy volunteers, and the effect of acetylcysteine , 1997 .

[48]  B. Lippold,et al.  In‐vitro Permeability of the Human Nail and of a Keratin Membrane from Bovine Hooves: Penetration of Chloramphenicol from Lipophilic Vehicles and a Nail Lacquer , 1997, The Journal of pharmacy and pharmacology.

[49]  P. Nenoff,et al.  Antifungal activity of the essential oil of Melaleuca alternifolia (tea tree oil) against pathogenic fungi in vitro. , 1996, Skin pharmacology : the official journal of the Skin Pharmacology Society.

[50]  Eric W. Smith,et al.  The selection and use of natural and synthetic membranes for in vitro diffusion experiments , 1994 .

[51]  R. Scher,et al.  Onychomycosis is more than a cosmetic problem , 1994, The British journal of dermatology.

[52]  F. Paycha,et al.  Measurement and clinical and pharmacokinetic implications of diffusion coefficients of antibiotics in tissues , 1989, Antimicrobial Agents and Chemotherapy.

[53]  R. Fromtling Overview of medically important antifungal azole derivatives , 1988, Clinical Microbiology Reviews.

[54]  U. Pfannenbecker,et al.  Validation of the red blood cell test system as in vitro assay for the rapid screening of irritation potential of surfactants. , 1987, Molecular toxicology.

[55]  G. Flynn,et al.  Physicochemical characterization of the human nail: permeation pattern for water and the homologous alcohols and differences with respect to the stratum corneum * , 1983, The Journal of pharmacy and pharmacology.

[56]  G. Stüttgen,et al.  Bioavailability, Skin‐and Nailpenetration of Topically Applied Antimycotics * , 1982, Mykosen.

[57]  M. Leeming,et al.  Antifungal Activity of Tioconazole (UK-20,349), a New Imidazole Derivative , 1979, Antimicrobial Agents and Chemotherapy.

[58]  W. Stöber,et al.  Controlled growth of monodisperse silica spheres in the micron size range , 1968 .