Olive oil and clove oil-based nanoemulsion for topical delivery of terbinafine hydrochloride: in vitro and ex vivo evaluation.

In this article, formulation studies for terbinafine hydrochloride nanoemulsions, prepared by high-energy ultrasonication technique, are described. Pseudo-ternary phase diagram was constructed in order to find out the optimal ratios of oil and surfactant/co-solvent mixture for nanoemulsion production. Clove and olive oils were selected as oil phase. Based on the droplet size evaluation, maximum nanoemulsion region were determined for formulation development. Further characterization included polydispersity index (PDI), zeta potential, Fourier transform infrared (FT-IR) spectroscopy, morphology, pH, viscosity, refractive index, ex vivo skin permeation, skin irritation, and histopathological examination. Droplet sizes of optimized formulations were in colloidal range. PDI values below 0.35 indicated considerably homogeneous nanoemulsions. Zeta potential values were from 13.2 to 18.1 mV indicating good stability, which was also confirmed by dispersion stability studies. Ex vivo permeation studies revealed almost total skin permeation of terbinafine hydrochloride from the nanoemulsions (96-98%) in 6 hours whereas commercial product reached only 57% permeation at the same time. Maximum drug amounts were seen in epidermis and dermis layers. Skin irritation and histopathological examination demonstrated dermatologically safe formulations. In conclusion, olive oil and clove oil-based nanoemulsion systems have potential to serve as promising carriers for topical terbinafine hydrochloride delivery.

Determination of terbinafine in healthy Chinese human plasma using a simple and fast LC-MS/MS method and its application to a bioequivalence study.

A rapid, simple, and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was validated for the determination of terbinafine concentrations in the plasma of healthy Chinese subjects. Terbinafine-d7 was used as the internal standard (IS), and the acetonitrile protein precipitation method was selected. The processed samples were chromatographically separated with a C18 column. The mobile phases were 0.1% formic acid (FA) in water (A), and methanol (B), respectively, and the gradient elution program was used with a flow rate of 0.8 mL/min. Quantification was achieved by positive electrospray ionization containing multiple reaction monitoring (MRM) transitions of m/z 292.5 â†’ 141.1 for terbinafine and m/z 299.5 â†’ 148.1 for IS. The calibration curve range was 2.00-1200 ng/mL; the intra- and inter-batch precision (coefficient of variation, %CV) was <8.2%, with the accuracy deviation (relative error, %RE) of -6.5% to 10.2%. The selectivity, sensitivity, extraction recovery, matrix effect, dilution reliability, carryover, and stability were within the acceptable range. This method was successfully applied to a bioequivalence study that orally administered 125 mg of terbinafine hydrochloride tablets in 84 healthy Chinese subjects.

Effect of Different Nail Penetration Enhancers in Solid Lipid Nanoparticles Containing Terbinafine Hydrochloride for Treatment of Onychomycosis.

Onychomycosis is considered a stubborn nail fungal infection that does not respond to conventional topical antifungal treatments. This study aimed to develop and characterize novel solid lipid nanoparticles (SLNs) formulae containing terbinafine HCl (TFH) and loaded with different nail penetration enhancers (nPEs). Three (nPEs) N-acetyl-L-cysteine, thioglycolic acid, and thiourea were used. Characterization of the prepared formulae was done regarding particle size, zeta potential, polydispersity index (PDI), entrapment efficiency (EE%), physical stability, in vitro release study, infrared (FT-IR), and their morphological structures. The selected formulae and the marketed cream Lamifen® were compared in terms of their antifungal activity against Trichophyton rubrum as well as their nail hydration and their drug uptake by the nail clippers. Thiourea was the nPE of choice; formulae (N2 and N8), with thiourea, were considered the optimum TFH SLNs containing nPEs. They were selected for their optimum particle size of 426.3 ± 10.18 and 450.8 ± 11.45 nm as well as their highest EE% of 89.76 ± 1.25 and 90.35 ± 1.33, respectively. The in vitro microbiological screening of the antifungal activity of these two formulae showed significantly larger zones of inhibition in comparison with the marketed product. The ex vivo screening of the drug uptake of the two selected formulae was significantly higher than that of the marketed product. The nPE formulae present a very promising option as they showed optimum physicochemical characterization with high antifungal activity and high drug uptake as well as good nail hydration effect.

Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species.

1. Terbinafine (TBF), a common antifungal agent, has been associated with rare incidences of hepatotoxicity. It is hypothesized that bioactivation of TBF to reactive intermediates and subsequent binding to critical cellular proteins may contribute to this toxicity. In the present study, we have characterized the bioactivation pathways of TBF extensively in human, mouse, monkey, dog and rat liver microsomes and hepatocytes. 2. A total of twenty glutathione conjugates of TBF were identified in hepatocytes; thirteen of these conjugates were also detected in liver microsomes. To the best of our knowledge, only two of these conjugates have been reported previously. The conjugates were categorized into three groups based on their mechanism of formation: (a) alkene/alkyne oxidation followed by glutathione conjugation, with or without N-demethylation, (b) arene oxidation followed by glutathione conjugation, with or without N-demethylation, and (c) N-dealkylation followed by glutathione conjugation of the allylic aldehyde, alcohol and acid intermediates. 3. Differences were observed across species in the contributions of these pathways toward overall metabolic turnover. We conclude that, in addition to the glutathione conjugates known to form by Michael addition to the allylic aldehyde, there are other pathways involving the formation of arene oxides and alkene/alkyne epoxides that may be relevant to the discussion of TBF-mediated idiosyncratic drug reactions.