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In present studies, a hyponychium pathway (from ventral side of the nail plate) was investigated as a potential route of drug delivery into the nail apparatus using iontophoresis as an active physical method. In vitro transport studies were performed across the human nail plate using sodium fluorescein as a marker substrate for 24 h. After transport studies, the amount of sodium fluorescein extracted from an active diffusion area of the nail plate in case of iontophoresis was found to be ∼54-folds more to that of passive. The amount of sodium fluorescein retained in the peripheral area of the nail plate after application of iontophoresis was found to be ∼30-folds more relative to passive. Ex vivo transport studies were performed on excised human cadaver toe using terbinafine hydrochloride as a model drug for three days (8 h/day). The amount of terbinafine retained in the nail plate after application of iontophoresis (3.43 ± 1.34 µg/mg) was ∼20-folds more when compared with passive (0.17 ± 0.10 µg/mg). The amount of drug extracted from the nail bed and nail matrix was 1.73 ± 0.12 µg/mg and 0.55 ± 0.22 µg/mg, respectively. On the other hand, there was no detectable amount of terbinafine found in the nail bed and nail matrix in case of control (passive delivery). These studies show that the iontophoretic drug delivery through hyponychium region to other parts of the nail apparatus could be a potential way of onychomycosis treatment.

Itraconazole (ITR) is a potent antifungal drug. However, poor aqueous solubility limits its permeation ability across the human nail plate. Therefore, in this project, ITR was converted to hydrochloride salt (ITR-HCl) to improve its solubility and to render it amenable to iontophoresis. ITR-HCl was characterized by spectroscopic methods and antifungal efficacy was evaluated in comparison to the base. In vitro and ex vivo transport studies (passive and iontophoresis) were carried out across the porcine hoof membrane and excised human cadaver toe using two different protocols; continuous delivery of drug for 24 h and pulsed delivery of drug for 3 days (8 h/day). The antifungal efficacy of ITR-HCL was comparable to ITR. Iontophoresis was found to be more effective than passive mode of delivery of ITR-HCL. In both iontophoresis as well as passive mode of delivery, the pulsed protocol resulted in more ungual and trans-ungual delivery of drug than continuous protocol. ITR-HCL could be delivered into and across the nail plate by iontophoresis. Human cadaver toe appears to be a good model to investigate the ungual delivery of drugs.

Objective: The main objective of this study is to develop a safer non-invasive treatment for nail infections since the current treatment regimen has drawbacks like, incidence of systemic side-effects and higher cost. Proposed topical treatment on the other hand can drastically improve the situation, hence highly desirable. This work was undertaken with a hypothesis to develop a transungual microemulsion gel for topical treatment of onychomycosis., Methods: Benzyl alcohol and isopropyl myristate were used as oil, Pluronic F68 as surfactant and ethanol as co surfactant, in double-distilled water and loading itraconazole as the model antifungal drug. Pseudo-ternary phase diagram was developed by titrating different ratios of total oil and water with total surfactant, and Km ratio was fixed at 1:1. Microemulsion formulations were prepared based on the phase diagram and incorporated in gels by adding Carbopol 934P. Nail permeation enhancers like urea and salicylic acid were used to increase drug permeation through the nail plate. Parameters like drug loading, clarity, particle size distribution, drug entrapment efficiency (DEE), drug release profile, release kinetics and nail uptake were checked for the evaluation of the formulations., Results: Complete release of drug from the formulation varied from 60 to 120 min. The optimized formulation had DEE of 92.75%, complete drug release in 60 min and highest nail uptake of 0.386%/mm(2) (39 µg of drug) with 5% urea as nail permeation enhancer., Conclusion: The formulation may prove beneficial in safer treatment of onychomycosis.

Context: Onychomycosis is a common fungal infection of the nail plate and bed that affects up to 14% of the population and can have a substantial impact on the quality of life of those affected., Objective: This study compared the onychopharmacokinetics, nail absorption, nail distribution, and nail penetration of [(14)C]-ciclopirox dissolved in novel lipid diffusion enhancers with that of a commercial ciclopirox nail lacquer using the in vitro finite dose model., Materials and Methods: The penetration rate of ciclopirox was determined by applying doses of topical formulation twice daily to human nail plates for 11 d. Drug absorption was then measured by monitoring its rate of appearance in each nail layer and in the cotton pad/nail supporting bed., Results: After a multiple day treatment, cumulative concentrations of ciclopirox formulated with lipid enhancers in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of the commercial ciclopirox lacquer (p < 0.001) as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of the causative dermatophyte species., Conclusion: When formulated with lipid enhancers, the amount of ciclopirox in the ventral/intermediate layer and supporting bed dramatically exceed the inhibitory concentration of ciclopirox for the most common onychomycosis organisms. These results suggest that topical ciclopirox with lipid enhancers has the potential to be an effective topical treatment for onychomycosis, and the lipidic pathway of the nail can be utilized as a means of effective transungual delivery.

This study determined the onychopharmacokinetics, nail absorption, distribution, and penetration of [¹⁴C]-terbinafine HCl in a new topical formulation into/through the human finger nail using the in vitro finite dose model. This study determined the penetration rate of terbinafine HCl from multiple doses of topical formulation applied daily for 14 days. Results showed that the total dose recovery (mass balance) was almost 100%. The concentration of terbinafine HCl in the deeper nail plate (ventral/intermediate layers) and the cotton-pad nail bed samples after the 14-day treatment were 613 ± 145 and (±S.D.) and 27 ± 1.2 µg/cm³ (or 1.9 ± 0.6 µg/cm³ daily) on average, respectively. In comparison with nail concentration data from the literature for other topical terbinatine formulations, our results show that higher amounts of terbinafine HCl reached the deep nail plate and/or the nail bed after a 14-day topical treatment with this topical formulation in vitro.

Topical therapy is desirable in treatment of nail diseases like onychomycosis (fungal infection of nail) and psoriasis. The topical treatment avoids the adverse effects associated with systemic therapy, thereby enhancing the patient compliance and reducing the treatment cost. However the effectiveness of the topical therapies has been limited due to the poor permeability of the nail plate to topically applied therapeutic agents. Research over the past one decade has been focused on improving the transungual permeability by means of chemical treatment, penetration enhancers, mechanical and physical methods. The present review is an attempt to discuss the different physical and chemical methods employed to increase the permeability of the nail plate. Minimally invasive electrically mediated techniques such as iontophoresis have gained success in facilitating the transungual delivery of actives. In addition drug transport across the nail plate has been improved by filing the dorsal surface of the nail plate prior to application of topical formulation. But attempts to improve the trans-nail permeation using transdermal chemical enhancers have failed so far. Attempts are on to search suitable physical enhancement techniques and chemical transungual enhancers in view to maximize the drug delivery across the nail plate.

Purpose: The objective of the present study was to assess the effect of pretreatment using chemical etchants on the delivery of terbinafine hydrochloride (TH) and 5-fluorouracil (5-FU) into and across the human nail plate., Methods: The TranScreen-N method was used to screen five potential etchants. Based on these results, the dorsal surface of nails was pretreated with chemical etchants, 1% or 10% (w/w) phosphoric acid (PA) or 10% (w/w) lactic acid (LA) gels, for a period of 60 seconds. The nail pretreated with a plain gel formulation (no PA or LA incorporated) was used as the control., Results: Despite the differences in physicochemical properties between TH (log P = 3.3) and 5-FU (log P = -0.83), the in vitro permeation as well as drug load of these drugs in the nail plate was enhanced because of pretreatment with the PA gels, whereas LA pretreatment failed to enhance the drug load and permeation. Optical microscopic and atomic force microscopy studies revealed that the PA enhanced the trans-ungual drug delivery by decreasing the keratin density of the dorsal layer of the nail plate and by microstructural alterations., Conclusions: This study demonstrated that pretreatment of the nail plate with PA (1% or 10%, w/w) for a short duration could be a potential method of improving the efficiency of topical monotherapy treatment for nail diseases.

The permeability of three imidazole antimycotics (miconazole nitrate, ketoconazole, and itraconazole) through the free edge of healthy human nail was evaluated in vitro using side-by-side diffusion cells. The influence of keratolytic substances (papain, urea, and salicylic acid) on the permeability of the antimycotics was also studied. The results suggested that the nail constituted an impermeable barrier for these antimycotics; it could be considered that the nail behaved as a hydrophilic gel membrane, through which drugs of low solubility could not permeate. The use of ethanol did not promote the passage of any of the antimycotic drugs. Although scanning electron microscopy indicated that the keratolytic substances had a significant effect on the nail surface (papain > salicylic acid > urea), the passage of the three antimycotics was not improved by pretreatment with salicylic acid alone (20% for 10 days), or by the application of the drug in a 40% urea solution. It was found that only the combined effects of papain (15% for 1 day) and salicylic acid (20% for 10 days) were capable of enhancing the permeability of the antimycotic.