Ciclopirox delivery into the human nail plate

Hui, Xiaoying; Wester, Ronald C.; Barbadillo, Sherry; Lee, Christine; Patel, Bhiku; Wortzmman, Mitchel; Gans, Eugene H.; Maibach, Howard I.

doi:10.1002/jps.20159

Cited by 46 publications

(37 citation statements)

References 3 publications

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“…To date, this is the only study on lateral diffusion which provides an insight on its effect on passive transungual permeation during in vitro studies. Longer lag-time and lower permeation flux values were observed in the transungual permeation of CPO through the nail dimension 9 mm×9 mm (81 mm 2 ). This indicates that a longer lag-time is obtained for a larger surface area of toenail using the same donor solution and same area of drug exposure.…”

Section: Discussionmentioning

confidence: 99%

“…The orifice diameter of the nail adapters is only 3 mm and therefore the constant area of drug exposure is 7.07 mm 2 . The nail piece with a measurement of 5 mm×5 mm (25 mm 2 ) helps to attain the smallest peripheral area while maintaining a leak proof seal within the nail adapter.…”

Section: Discussionmentioning

confidence: 99%

“…In the presence of lateral diffusion, the required driving force for transungual permeation is the high CPO concentration in the orifice and the periphery. As the size of the nail increases from 5 mm×5 mm (25 mm 2 ) to 7 mm×7 mm (49 mm 2 ) and finally to 9 mm×9 mm (81 mm 2 ), the concentration of CPO in the peripheral area of the nail drops significantly due to increased value of V n , resulting in decline in transungual permeation. The concentration drop may be caused by the gradient that forms between the treated area and the peripheral area of the nail.…”

Section: Discussionmentioning

confidence: 99%

“…The barrier properties of the nail plate and its thickness pose the greatest challenge towards permeation of any topically applied antifungal drug (1)(2)(3). One of the approaches to improve the passive transungual drug delivery is the use of chemical penetration enhancers.…”

Section: Introductionmentioning

confidence: 99%

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Lateral Drug Diffusion in Human Nails

et al. 2014

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Abstract. The main objective of the current work is to demonstrate the process of passive lateral diffusion in the human nail plate and its effect on the passive transungual permeation of antifungal drug ciclopirox olamine (CPO). A water soluble dye, methyl red sodium salt (MR) was used to visualize the process of lateral diffusion using a novel suspended nail experiment. The decline in concentration of CPO correlates with that of concentration of MR from the proximal to the distal end of the nail in suspended nail study. Three toenails each were trimmed to 5 mm×5 mm (25 mm 2 ), 7 mm×7 mm (49 mm 2 ), and 9 mm×9 mm (81 mm 2 ) to study the extent and effect of lateral diffusion of the CPO on its in vitro transungual permeation. The permeation flux of CPO decreased as the surface area of the toenail increased. There was a positive correlation between the concentrations of CPO and MR in the area of application and in the peripheral area of the toenails of the three surface areas, confirming the findings in the suspended nail experiment. Profound lateral diffusion of CPO was demonstrated and shown to reduce the in vitro passive transungual drug permeation and prolong the lag-time in human toenails. The study data implies that during passive in vitro transungual permeation experiments, the peripheral nail around the area of drug application has to be kept to a minimum, in order to get reliable data which mimics the in vivo situation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lateral Drug Diffusion in Human Nails

et al. 2014

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“…Topical onychomycosis therapy is challenged by the location of the fungal infection deep within the nail, the unique physicochemical properties of the nail (e.g., thickness and relatively compact construction), and low drug penetration (24). Enhanced drug delivery to the site of action may correlate with greater efficacy; thus, it is expected that drugs targeting the lower nail layers will be more effective in treating onychomycosis.…”

Section: Discussionmentioning

confidence: 99%

The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment

Sugiura

Sugimoto

Hosaka

et al. 2014

Antimicrob Agents Chemother

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Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.

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