Miconazole-Urea in a Buccal Film as a New Trend for Treatment of Resistant Mouth Fungal White Patches

Abstract

A growing concern about Candida albicans is the emergence of high incidence of resistance against antifungal agents, which requires searching for new medications or improving the response to the existing members. The objective of this work was to evaluate the effectiveness of the miconazole in the absence and presence of urea, as a penetration enhancer, against C. albicans. In addition to, formulating both of them in a polymer film to be used topically for treatment of mouth fungal white patches caused by C. albicans. A synergistic effect was recorded between this imidazole and urea against the test strain. Miconazole MIC (32 mg/L) was dramatically reduced to 0.0625 mg/L following combination with urea. Transmission electron microscopy explained the mechanisms of action mediated by the test agents. Minimal fungicidal dose of miconazole combined with urea showed early apoptotic cells with condensed chromatin and small blebs. Cytoplasmic leakage and necrosis in some cells was observed at high fungicidal dose. Buccal bioadhesive films were prepared using increasing values of the drug MIC and urea. The physicochemical characters of the prepared films including; film weight, thickness, swelling index, drug content, folding endurance, surface pH, bioadhesion force and time and drug release kinetics, were studied. Microbiological evaluation of all prepared films showed an increase in the inhibition zone diameters for films containing increasing concentrations of both miconazole and urea in a concentration-dependent manner (30–40 mm) compared to miconazole alone (18 mm). Based on our results, the prepared films are promising for buccal administration of miconazole/urea showing synergistic effect for treatment of C. albicans infection.

Preparation, and Assessment of Antidermatophyte Activity of Miconazole–Urea Water-Soluble Film

“…The local film solubility curve model represented the absorption of solution from the moist infected area, which was considered the first step in the treatment resulting in dryness of the infected area, to some extent, and release of the active substances to penetrate the deeper skin layers exerting a localized effect. The chemical interaction between the drug and the film component could be expected as reported by Mady et al (2018). They proved the disappearance of all characteristic drug peaks under those of the film components following application of IR scan.…”

“…Furthermore, increasing the concentration of urea to 20 or 40% in combination with miconazole reduced only MIC dramatically to 0.001, while it did not affect the MFC (0.004 mg/L). Mady et al (2018) investigated the effect of miconazole/urea combination against resistant C. albicans and proved its effectivity in reducing MIC from 32 to 0.0625 µg/mL, resulting in a synergistic effect. Hultenby et al (2014) reported that 50% topical K101 nail solution composed of urea, propylene glycol, and lactic acid was effective against T. rubrum cells.…”

“…This effect might be attributed to two reasons: first, the amount of urea used was high compared to the film structure composition. Second, urea is a crystalline substance, which would be expected to increase the rigidity of the film (Al-Badr, 1972;Mady et al, 2018). To simulate the mechanism by which the inserted soluble film produce the antifungal effect, a special model was suggested.…”

“…Several studies have investigated the effect of different drugs, either synthetic or natural products, on T. rubrum, but there are no reports about the use of miconazole/urea combination against the test fungus (Smijs et al, 2008;Pereira et al, 2011;Kingsbury et al, 2012;Aala et al, 2014;Song et al, 2018). Interestingly, Mady et al (2018) developed novel buccal mucoadhesive patches against Candida albicans, which have the ability to attach to the buccal cavity, exerting a local effect on the infected site. In addition, the authors used urea in the prepared muco-adhesive patches, for the first time, which is a well-known penetration enhancer in the pharmaceutical technology to overcome the resistance of the pathogen.…”

K21 Compound, a Potent Antifungal Agent: Implications for the Treatment of Fluconazole-Resistant HIV-Associated Candida Species

“…Different approaches have identified effective combinations of natural compounds with marketed drugs (Prasad and Kapoor, 2005; Spitzer et al, 2017). Mady et al (2018) demonstrated synergistic activity between Miconazole and urea for treating C. albicans . Other examples include the use of novel compounds such as APX001A and APX2020 in combination with FCZ with a FICI of 0.37 (Shaw et al, 2018), calcium channel blockers such as amlodipine, nifedipine, bendipine, and flunarizine with FCZ with FICI <0.5 (Liu et al, 2016), licofelone and FCZ (Liu et al, 2017).…”