Onychomycosis is fungal infection of toe nails or fingernails caused by a fungal microbe that invades the nail bed. It is the most common disease of the nails and constitutes about a half of all nail abnormalities and may affect toenails or fingernails, but toenail infections are particularly common. It occurs in about 10 percent of the adult population. The most common symptoms of fungal nail infection are thickening and discoloration of the nail. Treatment of onychomycosis is challenging because the infection is embedded in the nail making it difficult for the drug to diffuse to the site of infection. Onychomycosis is an opportunistic infection in people with compromised immune function and in those with diabetes, psoriasis, HIV/AIDS etc. Onychomycosis affects patients’ physical and psychological health and has a negative impact on overall quality of life. Oral administration of antifungal agents has been the mainstay in treatment of onychomycosis such as griseofulvin, terbinafine and itraconazole, but has limitations of systemic adverse events and drug interactions, whereas several drugs have been approved for topical administration but their efficacy is limited by the low permeability of the nail plate. This study evaluated the preformulation transungual permeability of econazole nitrate and formulation development of a transungual topical patch utilizing penetration enhancers in combination with econazole nitrate to optimize the delivery and penetration through the nail. The objectives of this project were to: 1) determine the critical factors for the in vitro transungual delivery of econazole nitrate, 2) design and develop a transungual formulation containing econazole nitrate and selection of the penetration enhancers, and 3) characterize the physical characteristics and functional properties of a novel transungual formulation. There were ten penetration enhancers being screened in this project according to the enhancement for saturation solubility, in vitro nail penetration and in vitro skin permeation and penetration of the antifungal drug econazole nitrate. Unlike transdermal drug delivery, the selection requirements for skin penetration enhancer were to increase drug accumulation in the epidermis and decrease the amount in the dermis to avoid unnecessary systermic absorption (Palliyil, et al. 2013). Thiourea (TU) improved the solubility and nail penetration of econazole nitrate. It also produced enhancement in the transungual diffusion of the drug. It was selected as the nail permeation enhancer and skin penetration enhancer for econazole nitrate. In the pH study, pH 5 ammonium phosphate buffer was the most effective pH for both enhancing the amount of drug in the nail and decreasing keratin binding. This resulted in increased accumulated of free drug in the target nail. In the formulation screening study, pressure sensitive adhesives (PSA), polyisobutylene, polysiloxane and polyacrylate classes of adhesives, were screened to develop a monolithic drug-in-adhesive type nail patch. Increasing the concentration of TU from 1% to 2.5% resulted in drug crystallization in the dry patch, therefore the concentration of 1% (w/w) TU was selected for all further screening. The concentration of econazole nitrate, propylene glycol and triethyl citrate were screened at 2.5%, 10% and 10% accordingly to ensure high drug release rate with no drug crystallization. The in vitro drug release rate of EN from the patch was improved with propylene glycol and hydrophobic plasticizer triethyl citrate. Polyvinylpyrrolidone was added to the patch formulation to lower the pH of the patch. This resulted in a greater concentration of ionized EN. The nail permeation and penetration of EN were studied in vitro using human cadaver toenails mounted in Franz diffusion cells. Thiourea, when formulated in the novel nail patch, was shown to deliver higher amount of EN into target tissues with a shorter permeation lag time compared to formulations which did not utilize thiourea. / Pharmaceutical Sciences

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Hypothèse: L’impression sur textile d’une formulation de microparticules lipidiques avec un principe actif (éconazole nitrate) permet de conserver ou d’améliorer son activité pharmaceutique ex vivo et in vitro. Méthode: Une formulation de microparticules d’éconazole nitrate (ECN) a été formulée par homogénéisation à haut cisaillement, puis imprimée sur un textile LayaTM par une méthode de sérigraphie. La taille des microparticules, la température de fusion des microparticules sur textile et la teneur en éconazole du tissu ont été déterminées. La stabilité de la formulation a été suivie pendant 4 mois à 25°C avec 65% humidité résiduelle (RH). L’activité in vitro des textiles pharmaceutiques a été mesurée et comparée à la formulation commerciale 1% éconazole nitrate (w/w) sur plusieurs espèces de champignons dont le C. albicans, C. glabrata, C. kefyr, C. luminisitae, T. mentagrophytes et T. rubrum. La thermosensibilité des formulations a été étudiée par des tests de diffusion in vitro en cellules de Franz. L’absorption cutanée de l’éconazole a été évaluée ex vivo sur la peau de cochon. Résultats: Les microparticules d’éconazole avaient des tailles de 3.5±0.1 μm. La température de fusion était de 34.8°C. La thermosensibilité a été déterminée par un relargage deux fois supérieur à 32°C comparés à 22°C sur 6 heures. Les textiles ont présenté une teneur stable pendant 4 mois. Les textiles d’ECN in vitro ont démontré une activité similaire à la formulation commerciale sur toutes ii espèces de Candida testées, ainsi qu’une bonne activité contre les dermatophytes. La diffusion sur peau de cochon a démontré une accumulation supérieure dans le stratum corneum de la formulation textile par rapport à la formulation Pevaryl® à 1% ECN. La thermo-sensibilité de la formulation a permis un relargage sélectif au contact de la peau, tout en assurant une bonne conservation à température ambiante. / Hypothesis: Textile imprinted with a formulation of microparticles of a drug (econazole nitrate) can maintain or improve its pharmaceutical activity ex vivo and in vitro. Methods: A formulation of econazole nitrate microparticles was made by high shear homogenization then printed on a LayaTM textile by screen-printing. The size of microparticles, melting temperature of microparticles on textile and econazole nitrate content were determined. The stability of the formulation was followed for 4 months at 25°C with 65% residual humidity (RH). The in vitro activity of pharmaceutical textiles was measured and compared to the commercial formulation econazole nitrate 1% (w/w) in several species of fungi including C. albicans, C. glabrata, C. kefyr, C. luminisitae, T. mentagrophytes and T. rubrum. Temperature sensitivity of the formulations was studied by in vitro tests in Franz diffusion cells. Dermal absorption of econazole nitrate was assessed ex vivo on pig skin. Results: Econazole microparticles were 3.5±0.1 μm in diameter. The melting temperature was 34.8°C. The thermosensitivity of the system was determined by a release test at 32°C compared to 22°C over 6 hours. Textiles showed stable levels for 4 months (97±0.3 μg/cm2). ECN textiles on in vitro tests showed similar activity to the commercial formulation on all Candida species tested, as well as good activity against dermatophytes. Ex vivo tests on pig skin showed a higher accumulation of ECN on the stratum corneum for textile formulation as compared to the Pevaryl® iv formulation. The thermo-sensitivity of the formulation permits a selective release in contact with the skin, while ensuring good storage at room temperature.