Safety assessment for nail cosmetics: Framework for the estimation of systemic exposure through the nail plate.

All cosmetics products, including nail care products, must be evaluated for their safety. The assessment of systemic exposure is a key component of the safety assessment. However, data on the exposure, especially via ungual route (nail plate) are limited. Based on the physicochemical properties of human nails and permeability data of topical onychomycosis drugs, the nail plate is considered a good barrier to chemicals. We examine factors impacting penetration of nail care ingredients through the nail plate, including properties of the nails of the ingredients and formulations. The molecular weight, vapor pressure, logP, water solubility, and keratin binding, as well as formulations properties e.g., polymerization of acrylate monomers are considered important factors affecting penetration. To estimate systemic exposure of nail care ingredients through the nail plate, a standardized framework is applied that quantifies the impacts of these properties on penetration with an adjustment factor for each of these influencing properties. All the adjustment factors are then consolidated to derive an integrated adjustment factor which can be used for calculation of the systemic exposure dose for the ingredient. Several case studies are presented to reflect how this framework can be used in the exposure assessment for nail cosmetic products.

Potential of Naftifine Application for Transungual Delivery.

Naftifine is used to treat fungal skin infections as it inhibits dermatophytes, which are the cause of onychomycosis. However, naftifine's ability to permeate the human nail barrier has not been investigated, thus, the antimycotic potential is not clearly established. This work aims to evaluate the effect of penetration enhancing factors on the accumulation of naftifine hydrochloride through human nail clippings. Naftifine polymeric nail lacquers with Eudragit RL100 were developed as a suitable delivery system. Low penetration of naftifine into nail has been determined as less than 10% of applied drug dose accumulated in the nail layers. Incorporation of thioglycolic acid into formulations resulted in increased accumulation of antifungal agent in the nail layers by 100% compared with a control group. Salicylic acid did not effect naftifine accumulation in the human nail. The permeation of naftifine through the nail increased by threefold when the thioglycolic acid-containing formulation was applied and the nail was pretreated with a fractional CO2 laser. Structural changes of the nail barrier, induced by fractional CO2 laser, were visualized by microscopy. The results suggest, that naftifine nail penetration could be significantly increased when physical and chemical enhancing factors are applied.

Efficiency of methylene blue-mediated photodynamic therapy vs intense pulsed light in the treatment of onychomycosis in the toenails.

BACKGROUND: Photodynamic therapy (PDT) or intense pulsed light (IPL) are efficient therapeutic methods in the treatment of superficial skin infections, and thus, they could be good options for onychomycosis treatment, the most common nail disorder. METHODS: Forty patients, affected with different diagnosed types of onychomycosis in nails of the first toe, were randomly divided into two groups of 20 patients to be treated by PDT or IPL. Nail plates were softened with urea 40% by occlusive dressing for 12 hours during 3-7 days before treatments. Then, eight sessions separated by an interval of 2 weeks of a PDT protocol mediated by methylene blue (MB) and red laser diode (Periowave® , λ = 670 nm, 200 mW) or an IPL protocol based on 10 pulses/cm2 (Dye-VL-F module, Alma Lasers, λ = 500-600 nm, 10 J) were applied. RESULTS: Both treatments reduced significantly the Onychomycosis Severity Index (OSI) (P < 0.05). In terms of complete cure: 70% (PDT) and 80% (IPL) of the patients reached it after 12 weeks post-treatment. No patient reported any adverse effects or complications, although in the IPL Group, some referred pain sensation during light irradiation and hematomas apparition. CONCLUSIONS: Photodynamic therapy and IPL were effective for onychomycosis cure of any etiology.

Liquid chromatography-tandem mass spectrometry is effective for analysis of ergosterol in fungal-infected nails.

BACKGROUND: Identification of onychomycosis is mainly based on clinical diagnosis with auxiliary diagnostic methods such as potassium hydroxide (KOH) microscopy, periodic acid-Schiff staining or fungal culture. However, each method is limited by its sensitivity and specificity. AIM: To develop a new test method using the common fungal end product, ergosterol, and investigate if it can be used as a new diagnostic tool. METHODS: We collected consecutive data from 20 participants with nail problems. Following clinical diagnosis, samples were taken for KOH microscopy and for mass spectrometry (MS) to check for the presence of ergosterol. RESULTS: Of the 20 cases collected, 7 were positive for fungal infection by MS. Four of these were already suspected to have onychomycosis, whereas one of the remaining three subjects was presumed to have dry nail and the other two to have onycholysis. The MS test seemed to be better at detecting combinations of nail conditions. Conversely, of the five patients clinically diagnosed as having onychomycosis, four had a positive MS result, whereas the fifth had negative results on both KOH and MS. Two other participants had a positive KOH test and were also found to have positive MS results. CONCLUSION: Detection of the presence of ergosterol by MS seems to be a useful tool for confirming onychomycosis. However, further studies are needed to verify the sensitivity and specificity of this MS method.

Understanding the formidable nail barrier: A review of the nail microstructure, composition and diseases.

The topical treatment of nail fungal infections has been a focal point of nail research in the past few decades as it offers a much safer and focused alternative to conventional oral therapy. Although the current focus remains on exploring the ways of enhancing permeation through the formidable nail barrier, the understanding of the nail microstructure and composition is far from complete. This article reviews our current understanding of the nail microstructure, composition and diseases. A few of the parameters affecting the nail permeability and potential causes of the recurrence of fungal nail infection are also discussed.

Antifungal ME1111 in vitro human onychopharmacokinetics.

This study determined ME1111 onychopharmacokinetics and possible topical antifungals' clinical efficacy in human great toenails using an in vitro finite dose model. ME1111 topical formulations in 1, 5, 10 or 15% for 3 days observation and 1, 5 or 10% for 14 days observation, respectively, were used to determine ME1111 penetration rate and transungual kinetics. ME1111 concentrations in the deeper nail (ventral/intermediate layers) and a cotton pad/nail bed, were several orders of magnitude greater than MIC90 and MFC90 for three major dermatophytes. ME1111 concentrations 3 days after a single and 14 days after multiple dosing of 10% formulation were 253 and 7991 µg/g nail, respectively, and superior to those of 8% ciclopirox control. ME1111 concentration (µg equivalent/cm3) in the cotton pad following 10% ME1111 multiple applications increased linearly throughout the 336 h experiment and was significantly greater than that of 8% ciclopirox. Flux rate of ME1111 averaged as 50.9 µg/cm3/day, which was ca. two orders of magnitude greater than the MIC90 values. The novel antifungal ME1111 penetrated well into human nail plate and its concentrations in the deeper nail and cotton pad after application of 10% formulation were significantly greater than those of ciclopirox.

Efinaconazole 10% and Tavaborole 5% Penetrate Across Poly-ureaurethane 16%: Results of In Vitro Release Testing and Clinical Implications of Onychodystrophy in Onychomycosis.

BACKGROUND: Poly-ureaurethane has been previously described for the management of dry, brittle, and in general, dystrophic nails. The polymer yields a waterproof, breathable barrier to protect the nail plate and prevent further damage to the nail, while regulating transonychial water loss (TOWL). Because nail dystrophy and dessication are contributing factors to onychomycosis, a barrier that protects the nail but also allows a topical antifungal to permeate its shield is potentially an advantageous combination. Oral antifungals such as terbinafine, itraconazole, and fluconazole, as well as the newer topical antifungals efinaconazole and tavaborole (although formulated to penetrate the nail unit and work with the porosity and inherent electrical charge of the nail plate), do not take into account nail damage that has been created from years of harboring a dermatophyte infection. Up to 50% of cases presumed to be onychomycosis are in fact onychodystrophy without fungal infection, and laboratory testing for fungus should be obtained prior to initiating antifungal treatment. Whether a nail has onychomycosis, or onychodystrophy due to other causes, barrier function and structural integrity are compromised in diseased nails, and should be addressed. A poly-ureaurethane barrier that protects against wetting/drying, fungal reservoirs, and microtrauma, followed by the addition of oral or topical antifungals after laboratory fungal confirmation may optimize outcomes in the treatment of onychomycosis.
OBJECTIVE: The purpose of this work was to determine through in vitro release testing (IVRT) whether poly-ureaurethane 16% allows for penetration of efinaconazole 10% or tavaborole 5%. Results could spur subsequent clinical studies which would have implications for the addition of an antifungal based on fungal confirmation, after addresssing the underlying nail dystrophy primarily.
METHODS: A vertical diffusion cell system was used to evaluate the ability of efinaconazole 10% and tavaborole 5% to penetrate across poly-ureaurethane 16%. The diffusion cells had a 1.0 cm2 surface area and approximately 8 mL receptor volume. Poly-ureaurethane 16% was applied to a 0.45 μm nylon membrane and allowed to dry before use. Efinaconazole 10% or tavaborole 5% was then applied to the poly-ureaurethane 16% coated membrane, and samples were pulled from the receptor chamber at various times. Reverse phase chromatography was then used to assess the penetration of each active ingredient across the membrane.
RESULTS: The flux and permeability of efinaconazole or tavaborole across poly-ureaurethane 16% were determined from efinaconazole 10% or tavaborole 5%, respectively. The flux and permeability of efinaconazole were determined to be 503.9 +/- 31.9 μg/cm2/hr and 14.0 +/- 0.9 nm/sec. The flux and permeability of tavaborole were determined to be 755.5 +/- 290.4 μg/cm2/hr and 42.0 +/- 16.1 nm/sec.
CONCLUSION: In addition to the treatment of onychoschizia, onychorrhexis, and other signs of severe dessication of the nail plate, a barrier that regulates TOWL should be considered in the management onychomycosis to address barrier dysfunction and to promote stabilization of the damaged nail. Previously published flux values across the nail are reported to be 1.4 μg/cm2/day for efinaconazole and 204 μg/cm2/day for tavaborole. These values are substantially lower than the herein determined flux for both molecules across poly-ureaurethane 16%. A comparison of the data suggests that poly-ureaurethane 16%, if used prior to efinaconazole or tavaborole, would not limit the ability of either active ingredient to access the nail, and therefore, would be unlikely to reduce their antifungal effect. Onychodystrophy is inherent in, and often precedes onychomycosis, and consideration should be given for initiation of treatment in the same sequence: stabilizing and protecting the nail plate barrier primarily, and subsequently adding oral or topical antifungals after laboratory confirmation. Future clinical studies will be needed to determine combination efficacy for in vivo use.

J Drugs Dermatol. 2016;15(9):1116-1120.

Iontophoresis for drug delivery into the nail apparatus: exploring hyponychium as the site of delivery.

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.

Human nail plate modifications induced by onychomycosis: implications for topical therapy.

PURPOSE: Through the characterisation of the human onchomycotic nail plate this study aimed to inform the design of new topical ungual formulations. METHODS: The mechanical properties of the human nail were characterised using a Lloyd tensile strength tester. The nail's density was determined via pycnometry and the nail's ultrastructure by electron microscopy. Raman spectroscopy analysed the keratin disulphide bonds within the nail and its permeability properties were assessed by quantifying water and rhodamine uptake. RESULTS: Chronic in vivo nail plate infection increased human nailplate thickness (healthy 0.49 ± 0.15 mm; diseased 1.20 ± 0.67 mm), but reduced its tensile strength (healthy 63.7 ± 13.4 MPa; diseased 41.7 ± 5.0 MPa) and density (healthy 1.34 ± 0.01 g/cm(3); diseased 1.29 ± 0.00 g/cm(3)). Onchomycosis caused cell-cell separation, without disrupting the nail disulfide bonds or desmosomes. The diseased and healthy nails showed equivalent water uptake profiles, but the rhodamine penetration was 4-fold higher in the diseased nails using a PBS vehicle and 3 -fold higher in an ethanol/PBS vehicle. CONCLUSIONS: Onchomycotic nails presented a thicker but more porous barrier, and its eroded intracellular matrix rendered the tissue more permeable to topically applied chemicals when an aqueous vehicle was used.

Ciclopirox delivery into the human nail plate using novel lipid diffusion enhancers.

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.

Development of microemulgel formulations with varied permeation enhancers for transungual delivery of luliconazole in onychomycosis management.

Luliconazole-loaded microemulgels containing different permeation enhancers were formulated for transungual drug delivery for the management of onychomycosis, onychomycosis, which affects nails. The physicochemical properties like droplet size, zeta potential, pH, viscosity, spreadability, extrudability, oil binding capacity, drug content, and microscopic study were evaluated. The Pseudo-ternary phase diagram was constructed for the formulation of microemulsions (MEs) by keeping the Km ratio constant at 3:1 and characterized for clarity, mean droplet size, zeta potential, viscosity, pH, transmittance, refractive index, and stability. The ME mean droplet size and zeta potential were found in the range of 38.78 to 171.4 nm, and 0.00 to - 6.6 mV, respectively. Prepared MEs were converted into microemulgel by adding a 2.5% gelling agent (Carbapol 934) in the external phase, and a drug release study was conducted. Formulation E3 showed better drug release and was chosen as the control. Four different penetration enhancers were added separately within E3 and further evaluated for pH, viscosity, spreadability, extrudability, oil binding capacity, drug content, microscopic study, Compatibility study, XRD, and DSC. A favorable docking score was observed between luliconazole and Lanosterol 14-alpha-demethylase. In-vitro cumulative drug release at the end of 24 h from E3-SS, containing sodium sulfide as a penetration enhancer, was found to be 94.70% and was 2 times more than the control formulation. Ex-vivo transungual permeation studies through cutting nail clippings were found to be in the range of 28.18 - 36.52 µg/mm2. The microemulgels tagged as E3, E3-SS, and E3-SL showed a significant zone of inhibition against Candida albicans and Aspergillus fumigatus as compared to the marketed formulation.

The diagnostic value of fungal fluorescence in onychomycosis.

BACKGROUND: Fluorescence of pathogenic fungi has been previously shown when hematoxylin and eosin-stained sections are examined under a fluorescent microscope. We hypothesize that this phenomenon could aid in the evaluation of nail specimens for onychomycosis. METHODS: Forty-eight routinely stained nail sections of periodic acid-Schiff (PAS)-positive onychomycosis, along with 23 PAS-negative control specimens with a clinical diagnosis of onychomycosis, were studied under a fluorescent microscope to determine the clinical usefulness of this technique. RESULTS: In most cases, fluorescence of fungal organisms was noted. Fungi were identified by their tubular or annular shapes with fluorescence surrounding them. The sensitivity and specificity of the method were 96 and 90%, respectively. In some cases, it was difficult to identify the fungi because of the relative paucity of organisms, weak fluorescence and high background fluorescence of eosinophilic nail keratin. CONCLUSIONS: We conclude that fluorescence microscopy can be used as a rapid screening tool for identification of fungi in nail specimens.

Therapeutic treatment strategies for the management of onychomycosis: a patent perspective.

INTRODUCTION: Onychomycosis, a multifactorial fungal infection of the nails, shows a global prevalence of about 5.5% and is responsible for 50% of all nail infections. To develop effective management strategies, it is necessary to understand the etiology, pathophysiology, and risk factors of onychomycosis. Oral route of drug delivery is one of the routes utilized to deliver anti-fungal agents, but, has its own limitations like longer duration of treatment, increased adverse effects, and potential for drug interaction. The ungual route has received greater attention due to its localized, non- invasive action and improved patient compliance. AREAS COVERED: This review comprehensively discusses conventional onychomycosis therapies and patented novel drug delivery systems for the management of onychomycosis including chemical permeation enhancers, non-particulate drug delivery systems, penetration enhancing devices etc., Databases such as PubMed, ResearchGate, and Google Patents were searched by using the keywords onychomycosis and trans-ungual drug delivery. EXPERT OPINION: Enormous research has been conducted and is still ongoing to find the best possible novel drug delivery system for onychomycosis management. Approaches like incorporation of herbal constituents in nano-formulations, inkjet printing, laser devices, iontophoretic techniques, etc. can be employed to make safe and effective drug delivery systems which are regulatory compliant.

Microemulsion-based gel of terbinafine for the treatment of onychomycosis: optimization of formulation using D-optimal design.

The aim of the present investigation was to evaluate microemulsion as a vehicle for dermal drug delivery and to develop microemulsion-based gel of terbinafine for the treatment of onychomycosis. D-optimal mixture experimental design was adopted to optimize the amount of oil (X(1)), Smix (mixture of surfactant and cosurfactant; X(2)) and water (X(3)) in the microemulsion. The formulations were assessed for globule size (in nanometers; Y(1)) and solubility of drug in microemulsion (in milligrams per milliliter; Y(2)). The microemulsion containing 5.75% oil, 53.75% surfactant-cosurfactant mixture and 40.5% water was selected as the optimized batch. The globule size and solubility of the optimized batch were 18.14 nm and 43.71 mg/ml, respectively. Transmission electron microscopy showed that globules were spherical in shape. Drug containing microemulsion was converted into gel employing 0.75% w/w carbopol 934P. The optimized gel showed better penetration and retention in the human cadaver skin as compared to the commercial cream. The cumulative amount of terbinafine permeated after 12 h was 244.65 ± 18.43 µg cm(-2) which was three times more than the selected commercial cream. Terbinafine microemulsion in the gel form showed better activity against Candida albicans and Trichophyton rubrum than the commercial cream. It was concluded that drug-loaded gel could be a promising formulation for effective treatment of onychomycosis.

A drug-in-adhesive anti-onychomycotic nail patch: Influence of drug and adhesive nature on drug release, ungual permeation, in vivo residence in human and anti-fungal efficacy.

A nail patch is an attractive option for the topical treatment of onychomycosis, although no product is commercially available. We previously identified optimal nail patch formulations for two anti-onychomycotic drugs, based on their properties, as well as those of the other patch components. In this paper, our aim was to further investigate the potential of the patch formulations as topical nail medicines, in particular, whether the drug-in-adhesive patches release drug which then permeates into and through the nail plate and show anti-fungal efficacy, and whether and to what extent they remain adhered to the human nail plate in vivo when tested over 2 week durations. In addition, the influence of the drug (amorolfine HCl, ciclopirox olamine) and PSA (Duro-Tak 2852 or Duro-Tak 202A) on these parameters was determined. We found that both the nature of the drug and of the PSA influenced in vitro drug release. The nature of the drug, but not that of the PSA, influenced ungual drug permeation through human nail clippings, with considerably greater (almost double) permeation for ciclopirox olamine, the smaller and less lipophilic molecule. In vivo residence, tested with 3 out of the 4 patches, excluding the patch where ciclopirox olamine degraded with time, showed greater residence on toenails compared to fingernails reflecting their far lesser exposure to environmental stresses during daily activities. In vivo residence was enhanced when the patch was cut to the shape of the nail, was applied at bedtime, and when a clear colourless nail varnish was applied on top of the patch to 'seal' it into place on the nail. Comparison of the patches indicated greater residence of Duro-Tak 202A containing patches over those containing Duro-Tak 2852. Amorolfine HCl in Duro-Tak 202A based patch also showed antifungal efficacy in contrast to Duro-Tak 2852-based patch, and is particularly promising for further development as a potential toenail medicine, remaining almost fully adhered to toenails for at least two weeks.

Quantitative analysis of pathological nails using laser-induced breakdown spectroscopy (LIBS) technique.

Laser-induced breakdown spectroscopy (LIBS) has been used as a potential method for simultaneous measurement of the elements Ca, Na, and K, for normal and pathological nails. We compared the measured LIBS spectra of these elements for normal and pathological nails. The B²∑+ --> X²∑+ violet band emission spectrum of CN was used for the estimation of the transient temperature of the plasma plume and consequently of the sample surface considering thermodynamic equilibrium.

Hydrosoluble medicated nail lacquers: in vitro drug permeation and corresponding antimycotic activity.

BACKGROUND: Two nail lacquers, containing ciclopirox (CPX) or amorolfine (MRF), based on water-insoluble polymers are currently considered mainstays of topical treatment of onychomycosis. The present study aimed at evaluating the antimycotic activity of a new water-soluble nail lacquer containing CPX (CPX/sol), easily removable by washing with water and applicable to periungual skin. OBJECTIVES: To compare transungual permeation of CPX with that of MRF in the same hydroxypropyl chitosan-based nail lacquer (MRF/sol) and with a nonwater-soluble reference (Loceryl); Galderma International, La Défense, France), and to evaluate the antimycotic activity of CPX/sol and Loceryl against the most common fungal strains that cause onychomycosis. Methods In vitro drug permeation experiments with CPX/sol, MRF/sol and Loceryl were carried out through bovine hoof slices. Experimental permeates from CPX/sol and Loceryl underwent in vitro susceptibility testing against clinical isolates of dermatophytes, moulds and yeast. Results MRF transungual flux from MRF/sol lacquer was significantly higher when compared with Loceryl. CPX was able to permeate hoof membranes more easily compared with MRF. CPX and MRF concentrations in the subungual fluids collected after application of CPX/sol or Loceryl were sufficient to inhibit fungal growth, with the exception of Candida parapsilosis. Smaller amounts of fluid containing CPX were required for complete inhibition of fungal growth. Efficacy index values were significantly higher for CPX/sol. Conclusions Application of the CPX/sol nail lacquer allows rapid nail penetration of CPX, providing CPX levels sufficient to inhibit fungal growth for a prolonged period of time (30 h) after application of lacquer dose. CPX/sol nail lacquer appeared superior to the market reference Loceryl in terms of both vehicle (hydroxypropyl chitosan) and active ingredient (CPX) as witnessed by its higher efficacy on all nail pathogens.

Application of conventional and microbeam synchrotron radiation x-ray fluorescence and absorption for the characterization of human nails.

The synchrotron radiation based spectroscopies X-ray fluorescence and X-ray absorption fine structure are used to detect illness-related changes in the elemental distribution and bonding environment of metals in human nails. The effective atomic number of a collection of nails is determined using two methods, the X-ray transmittance and the scattering method, and is found equal to 7.5 +/- 0.5. X-ray fluorescence maps of the elemental distributions, recorded with a lateral resolution of 5 microm, reveal that S, Ca and Zn are distributed homogeneously while Fe tends to cluster. In the Fe-rich clusters, which have a diameter in the range 15-30 microm, the Fe concentration is 10 times higher than in the matrix. The Zn K edge X-ray Absorption Fine Structure spectra reveal that Zn, in the nails from healthy donors and patients suffering from lung diseases, is four-fold coordinated with N and S and the Zn-N and Zn-S distances are equal to 2.03 A and 2.25 A, respectively. Finally the signature of various bonds in the C-, O- and N- K near edge X-ray absorption fine structure spectra is discussed.

Co-delivery of terbinafine hydrochloride and urea with an in situ film-forming system for nail targeting treatment.

Onychomycosis is a chronic nail disorder consisting of a fungal infection that causes physical and psychosocial discomfort to patients. However, its treatment remains challenging owing to the barrier of the highly keratinized nail plate and the short time that conventional formulations reside on nails. In this work, we developed an in situ film-forming system(IFFS) based on Eudragit® RLPO to co-deliver terbinafine hydrochloride (TBH) and urea, i.e., TBH-urea-RLPO IFFS, with the aim of overcoming the nail barrier, prolonging the residence time, and efficiently treating onychomycosis. The IFFS formulation formed a thin film with good appearance and adhesion upon application in situ. The physical states of TBH and urea in the film were evaluated with polarization microscopy and powder X-ray diffraction. TBH and urea were both amorphousmiscible components within the RLPO film. TBH release from TBH-urea-RLPO IFFS fitted to the Korsmeyer-Pappas model, and the cumulative release at 72 h was significantly higher than that from commercial preparations (Lamisil Pedisan® once). In vitro permeation of TBH from TBH-urea-RLPO IFFS through bovine hoof membranes was evaluated in comparison with the film containing TBH alone (TBH-RLPO) and commercial preparations. The retention and cumulative permeated amount of TBH were significantly enhanced for the TBH-urea-RLPO IFFS (170.80 ± 44.63 µg/cm2vs 75.49 ± 21.50 µg/cm2vs 60.25 ± 27.38 µg/cm2; 61.81 ± 16.09 µg/cm2vs 21.80 ± 11.56 µg/cm2vs 7.91 ± 1.03 µg/cm2, respectively), and the membranes treated with different formulations were observed with SEM and FTIR to identify the denaturing effect of urea on bovine hoof keratin. In vitro antifungal tests against Trichophyton rubrum,Microsporum canis, Fusarium, and Aspergillus fumigatus were cultured on Muller-Hinton agar; the findings indicated that TBH-urea-RLPO IFFS enhanced TBH antifungal activity. Overall, the results support that TBH-urea-RLPO IFFS is an efficient and promising approach for onychomycosis targeting treatment.