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The humanoid nail is considered an exceptional protective barrier that is formed mainly from keratin. Onychomycosis is the cause of 50% of nail infections that is generally caused by dermatophytes. Firstly, the infection was regarded as a cosmetic problem but because of the tenacious nature of onychomycosis and its relapses, these infections have attracted medical attention. The first line of therapy was the oral antifungal agents which were proven to be effective; nevertheless, they exhibited hepato-toxic side effects, alongside drug interactions. Following, the opportunity was shifted to the topical remedies, as onychomycosis is rather superficial, yet this route is hindered by the keratinized layers in the nail plate. A potential alternative to overcome the obstacle was applying different mechanical, physical, and chemical methods to boost the penetration of drugs through the nail plate. Unfortunately, these methods might be expensive, require an expert to be completed, or even be followed by pain or more serious side effects. Furthermore, topical formulations such as nail lacquers and patches do not provide enough sustaining effects. Recently, newer therapies such as nanovesicles, nanoparticles, and nanoemulsions have emerged for the treatment of onychomycosis that provided effective treatment with possibly no side effects. This review states the treatment strategies such as mechanical, physical, and chemical methods, and highlights various innovative dosage forms and nanosystems developed in the last 10 years with a focus on advanced findings regarding formulation systems. Furthermore, it demonstrates the natural bioactives and their formulation as nanosystems, and the most relevant clinical outcomes., (© 2023. The Author(s).)

Microneedles (MNs) are micron-scaled needles measuring 100 to 1000 μm that were initially explored for delivery of therapeutic agents across the skin. Considering the success in transcutaneous drug delivery, the application of microneedles has been extended to different tissues and organs. The review captures the application of microneedles to the oral mucosa, the eye, vagina, gastric mucosa, nail, scalp, and vascular tissues for delivery of vaccines, biologics, drugs, and diagnostic agents. The technology has created easy access to the poorly accessible segments of eye to facilitate delivery of monoclonal antibodies and therapeutic agents in management of neovascular disease. Microporation has been reported to drastically improve the drug delivery through the poorly permeable nail plate. Curved microneedles and spatially designed microneedle cuffs have been found to be capable of delivering stem cells and therapeutic macromolecules directly to the cardiac tissue and the vascular smooth muscle cells, respectively. Besides being minimally invasive and patient compliant, the technology has the potential to offer viable solutions to deliver drugs through impermeable barriers owing to the ability to penetrate several biological barriers. The technology has been successful to overcome the delivery hurdles and enable direct delivery of drug to the target sites, thus maximizing the efficacy thereby reducing the required dose. This review is an attempt to capture the non-dermatological applications of microneedles being explored and provides an insight on the future trends in the field of microneedle technology. Pictorial representation of different microneedle application., (© 2021. Controlled Release Society.)

Onychomycosis is a common fungal infection of the nails that mostly affects the elderly and athletes. Antifungal drug-like itraconazole is one of the therapeutic agents of choice for the topical treatment of onychomycosis. The current work aimed for the preparation and optimization of itraconazole-loaded nail lacquer formulation. Central composite design was employed; independent variables were polymer concentration (X 1 ) and thioglycolic acid (TGA) concentration (X 2 ). While the dependent variables were cumulative amount of drug permeated per unit area (CADP/A, Y 1 ), drying time (Y 2 ) and nonvolatile content (Y 3 ). The optimized formulation was characterized for various parameters including ex-vivo permeation study, confocal laser scanning microscopy (CLSM) and antifungal study. The optimized nail lacquer formulation (F7) exhibited CADP/A of 198.23 µg/cm 2 , drying time of 185 s and nonvolatile content of 97.23%. The scanning electron microscopy of goat hoof treated with optimized nail lacquer formulation demonstrated loosening of the structure and marked increase in surface roughness. The CLSM micrograph of goat hoof treated with optimized nail lacquer formulation demonstrated that the probe dye was eventually distributed and penetrated through the hoof. Bio-adhesiveness analysis showed that the prepared nail lacquer film has ample adhesiveness to be maintained on the nail plate surface for a sufficient time. In antifungal study, the optimized nail lacquer, and marketed gel exhibited a zone inhibition of 21 mm, and 10 mm against Candida albicans, respectively. The stability study showed that the optimized nail lacquer is stable at storage condition. The prepared nail lacquers have been shown to serve as a useful dosage form for the delivery of itraconazole across nail plate for controlling the problems associated with onychomycosis., Competing Interests: Conflicts of interestThe authors report no declarations of interest., (© King Abdulaziz City for Science and Technology 2021.)

The objective of the present study was to prepare valencene (sesquiterpene) containing invasomes for itraconazole (ITZ) transungual delivery using central composite design. The phospholipid ( X 1 ) and valencene ( X 2 ) were selected as an independent variables, while vesicles size ( Y 1 ), entrapment efficiency ( Y 2 ) and in vitro drug release ( Y 3 ) were chosen as dependent variables. The antifungal activity of optimized formulation was screened against Trichophyton rubrum , a common causative onychomycosis pathogen, by cup plate method. The optimized ITZ-loaded invasomes formulation presented vesicles size of 176.8 ± 6.03 nm, entrapment efficiency of 83.21 ± 4.11% and in vitro drug release of 75.22 ± 5.03%. The ITZ-loaded invasomes gel formulation showed good homogeneity, pH 6.5  ±  0.23, viscosity 7.33  ±  0.67 Pa s and drug content 94.13 ± 1.13%. The spreadability and extrudability of developed ITZ-loaded invasomes gel were found to be 7.85 ± 0.24 gcm/s and 162 ± 2.74 g, respectively. The ITZ-loaded invasomes gel presented 71.11 ± 3.65% cumulative permeation of drug via goat hooves. The in vitro antifungal activity depicted that the ITZ-loaded invasomes gel and marketed preparation were presented zone of inhibition of 21.42 mm and 10.64 mm against T. rubrum respectively. Hence the prepared ITZ-loaded invasomes formulation could therefore be a promising topical dosage to mitigate the indications and hasten the cure for onychomycosis than conventional available therapies., Competing Interests: Conflict of interestThe authors report no declarations of interest., (© King Abdulaziz City for Science and Technology 2021.)

The present investigation focused on developing, optimizing, and evaluating a novel liposome-loaded nail lacquer formulation for increasing the transungual permeation flux of terbinafine HCl for efficient treatment of onychomycosis. A three-factor, three-level, Box-Behnken design was employed for optimizing process and formulation parameters of liposomal formulation. Liposomes were formulated by thin film hydration technique followed by sonication. Drug to lipid ratio, sonication amplitude, and sonication time were screened as independent variables while particle size, PDI, entrapment efficiency, and zeta potential were selected as quality attributes for liposomal formulation. Multiple regression analysis was employed to construct a second-order quadratic polynomial equation and contour plots. Design space (overlay plot) was generated to optimize a liposomal system, with software-suggested levels of independent variables that could be transformed to desired responses. The optimized liposome formulation was characterized and dispersed in nail lacquer which was further evaluated for different parameters. Results depicted that the optimized terbinafine HCl-loaded liposome formulation exhibited particle size of 182 nm, PDI of 0.175, zeta potential of -26.8 mV, and entrapment efficiency of 80%. Transungual permeability flux of terbinafine HCl through liposome-dispersed nail lacquer formulation was observed to be significantly higher in comparison to nail lacquer with a permeation enhancer. The developed formulation was also observed to be as efficient as pure drug dispersion in its antifungal activity. Thus, it was concluded that the developed formulation can serve as an efficient tool for enhancing the permeability of terbinafine HCl across human nail plate thereby improving its therapeutic efficiency.

Nail disorders are beyond cosmetic concern; besides discomfort in the performance of daily chores, they disturb patients psychologically and affect their quality of life. Fungal nail infection (onychomycosis) is the most prevalent nail-related disorder affecting a major population worldwide. Overcoming the impenetrable nail barrier is the toughest challenge for the development of efficacious topical ungual formulation. Sophisticated techniques such as iontophoresis and photodynamic therapy have been proven to improve transungual permeation. This article provides an updated and concise discussion regarding the conventional approach and upcoming novel approaches focused to alter the nail barrier. A comprehensive description regarding preformulation screening techniques for the identification of potential ungual enhancers is also described in this review while highlighting the current pitfalls for the development of ungual delivery.