Topical Treatment Of Onychomycosis Research Articles

Design, Synthesis, and Antifungal Activity of 3-Substituted-2(5H)-Oxaboroles.

Next generation antimicrobial therapeutics are desperately needed as new pathogens with multiple resistance mechanisms continually emerge. Two oxaboroles, tavaborole and crisaborole, were recently approved as topical treatments for onychomycosis and atopic dermatitis, respectively, warranting further studies into this privileged structural class. Herein, we report the antimicrobial properties of 3-substituted-2(5H)-oxaboroles, an unstudied family of medicinally relevant oxaboroles. Our results revealed minimum inhibitory concentrations as low as 6.25 and 5.20 μg/mL against fungal (e.g., Penicillium chrysogenum) and yeast (Saccharomyces cerevisiae) pathogens, respectively. These oxaboroles were nonhemolytic and nontoxic to rat myoblast cells (H9c2). Structure-activity relationship studies suggest that planarity is important for antimicrobial activity, possibly due to the effects of extended conjugation between the oxaborole and benzene rings.

New Formulation-Microporation Combination Approaches to Delivering Ciclopirox across Human Nails.

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients' adherence.

The Plant Defensin Ppdef1 Is a Novel Topical Treatment for Onychomycosis.

Onychomycosis, or fungal nail infection, causes not only pain and discomfort but can also have psychological and social consequences for the patient. Treatment of onychomycosis is complicated by the location of the infection under the nail plate, meaning that antifungal molecules must either penetrate the nail or be applied systemically. Currently, available treatments are limited by their poor nail penetration for topical products or their potential toxicity for systemic products. Plant defensins with potent antifungal activity have the potential to be safe and effective treatments for fungal infections in humans. The cystine-stabilized structure of plant defensins makes them stable to the extremes of pH and temperature as well as digestion by proteases. Here, we describe a novel plant defensin, Ppdef1, as a peptide for the treatment of fungal nail infections. Ppdef1 has potent, fungicidal activity against a range of human fungal pathogens, including Candida spp., Cryptococcus spp., dermatophytes, and non-dermatophytic moulds. In particular, Ppdef1 has excellent activity against dermatophytes that infect skin and nails, including the major etiological agent of onychomycosis Trichophyton rubrum. Ppdef1 also penetrates human nails rapidly and efficiently, making it an excellent candidate for a novel topical treatment of onychomycosis.

Performance of Two Extracts Derived from Propolis on Mature Biofilm Produced by Candida albicans.

Species of the Candida genus represent the third most common cause of onychomycosis, the most frequent and difficult to treat nail infection. Onychomycosis has been attributed to fungi organized in biofilm and some natural products have proved promising for its treatment. This study aimed to evaluate the antibiofilm activity of propolis extract (PE) and its by-product (WPE) on 7-day preformed biofilms produced by Candida albicans in polystyrene microplates, as well as in an ex vivo model on human nail fragments. The cytotoxicity and permeation capacity were also assessed. Firstly, multiple parameters were evaluated over 7 days to elucidate the dynamics of biofilm formation by C. albicans. The cell viability and total biomass did not vary much from the beginning; however, days 3 and 4 were crucial in terms of metabolic activity, which was significantly increased, and the levels of extracellular matrix components, wherein proteins and nucleic acids experienced an increase, but polysaccharide levels dropped. Architecturally, one-day biofilm showed a monolayer of organized cells (blastoconidia, hyphae, and pseudohyphae), while in the seven-day biofilm there was a three-dimensional well-structured and complex biofilm. This yeast was also able to form a biofilm on both surfaces of the nail, without an additional nutritional source. Both extracts showed excellent antibiofilm activity against the 7-day preformed biofilm and were not toxic to Vero cells at concentrations compatible with the antifungal and antibiofilm activities. Both extracts permeated the experimentally infected nail, with WPE being more efficient. The results of this study, taken together, reinforce the potential of these natural products, containing propolis, as a safe option for the topical treatment of onychomycosis.

Quality by Design Guided Development of Polymeric Nanospheres of Terbinafine Hydrochloride for Topical Treatment of Onychomycosis Using a Nano-Gel Formulation.

Superficial fungal diseases of the skin and nails are an increasingly common occurrence globally, requiring effective topical treatment to avoid systemic adverse effects. Polymeric nanoparticles have demonstrated sustained and effective drug delivery in a variety of topical formulations. The aim of this project was to develop polymeric antifungal nanospheres containing terbinafine hydrochloride (TBH) to be loaded into a hydrogel formulation for topical nail drug delivery. A quality by design (QbD) approach was used to achieve optimized particles with the desired quality target product profile (QTPP). Polyvinyl alcohol (PVA) at 2% w/v and a drug to polymer ratio of 1:4, together with a robust set of processes and material attributes, resulted in nanoparticles of 108.7 nm with a polydispersity index (PDI) of 0.63, 57.43% recovery, and other desirable characteristics such as zeta potential (ZP), particle shape, aggregation, etc. The nanospheres were incorporated into a carbomer-based gel, and the delivery of TBH through this formulation was evaluated by means of in vitro drug release testing (IVRT) and ex vivo nail permeation study. The gel containing the TBH nanospheres demonstrated a slower and controlled drug release profile compared with the control gel, in addition to a more efficient delivery into the nail. These antifungal nanospheres can be utilized for topical therapy of a multitude of superficial fungal infections.

P111 A case of nail discoloration due to topical treatment of onychomycosis with luliconazole 5% nail solution

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMWe use efinaconazole 10% topical solution and luliconazole 5% nail solution for topical treatment of onychomycosis in Japan. We show a case of onychomycosis treated with nail debridement and topical luliconazole 5% nail solution to the nail and topical luliconazole 1% cream to the foot. A woman in her seventies with chronic urticaria had a nail spike color change on her left big toe (Fig. 1). We opened the spike lesions with a plastic nipper and KOH direct microscopic examination showed dermatophytoma. We treated with topical luliconazole cream on the toes and soles of the foot and 5% solution on the nail. Because of the summer season, she walked outside in sandals without socks during treatment and noticed the nail yellow color change (Fig. 2). We advised the patient to protect from sun light and not to walk outside without socks. Due to the report from the production company, the reason for nail color change to yellowish is photodegradation of luliconazole. After 1 year since first visit, the fungal infection of the big toe disappeared by our topical treatment. The nail yellow color change also disappeared. We recommended avoiding sunlight exposure on the treated nail during topical treatment of luliconazole 5% nail solution.

32994 Pezadeftide is a potent antifungal peptide with rapid fungicidial activity via a unique mechanism of action

Background: Fungal infections of skin, hair, and nails are extremely common and can be caused by a broad range of fungal pathogens including dermatophytes, yeasts, and nondermatophytic molds. Pezadeftide is a plant defensin peptide with potent fungicidal activity against a range of fungal pathogens that cause skin and nail infections, including Trichophyton spp., Candida spp, and a range of nondermatophytic molds. Pezadeftide is currently in development as a new topical treatment for onychomycosis. Methods: The activity of pezadeftide against a range of fungal pathogens was tested using the microbroth dilution method to determine the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC). Fluorescent dyes were employed to assess the effect of pezadeftide on various cellular components. To identify potential targets for pezadeftide, a yeast deletion library was screened for fitness in the presence of low concentrations of pezadeftide. Results: Pezadeftide has potent antifungal activity across a broad range of fungal pathogens that cause dermatophytic infections. Pezadeftide inhibits growth at low micromolar concentrations and is fungicidal at similar concentrations, suggesting that its primary mode-of-action is fungicidal. Pezadeftide rapidly enters fungal cells and causes a rapid mitochondrial response that results in hyperpolarization of the mitochondrial membrane. Fusion of the vacuoles and production of reactive oxygen species are observed prior to disruption of the plasma membrane and cell death. Conclusions: Pezadeftide is a potent, broad-spectrum antifungal with a fungicidal mode-of-action. It rapidly kills fungal cells via interaction with the mitochondria, hyperpolarisation of the mitochondrial membrane and production of reactive oxygen species.

Development and Validation of HPLC Method for Efinaconazole: Application to Human Nail Permeation Studies.

Efinaconazole is the first azole derivative approved by FDA for the topical treatment of onychomycosis. The objective of present study was to develop and validate HPLC method for estimation of efinaconazole in ex vivo human nail permeation study samples. The chromatographic analysis was performed on a HPLC system equipped with diode array detector. The efinaconazole and internal standard (IS) were extracted from the human nail samples by using the protein precipitation method. The samples were injected on to 5 μm Polar C18 100Å, 4.6 mm × 150 mm column. The mobile phase consisted of 0.01 M potassium dihydrogen phosphate: acetonitrile (36:64) and eluent was monitored at 205 nm. The chromatographic separation of drug and analyte was achieved using isocratic elution at flow rate of 1 mL/min with a total run time of 15 min. The efinaconazole and IS were eluted at 6.4 ± 0.5 and 8.3 ± 0.5 min, respectively. The developed method was validated as per FDA guidelines, and the results met with acceptance criteria. The method developed was specific, and the analyte concentrations were linear at range of 50 to 10000 ng/mL (R2 ≥ 0.9981). The validated HPLC method was applied for quantifying efinaconazole in human nail permeation study samples. The permeation of efinaconazole was increased by twofolds with Labarfac CC (15135.4 ± 2233.9 ng/cm2) compared to formulations containing Transcutol P (6892.0 ± 557.6 ng/cm2) and Labrasol (7266.1 ± 790.6 ng/cm2). The study results demonstrate that developed efinaconazole HPLC method can be employed for formulation evaluation and clinical studies.

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.

The Success of Topical Treatment of Onychomycosis Seems to Be Influenced by Fungal Features.

Aim To evaluate the topical treatment of onychomycosis using a 10% hydroalcoholic propolis extract (PE) in two aleatorily chosen patients and analyze possible risk factors from hosts including some particularities of the isolated fungi that may justify the outcomes achieved. Materials and Methods A topical treatment, with PE, was started in two cases of toe onychomycosis due to T. rubrum. The in vitro PE antifungal activity against these isolates was confirmed. Moreover, the ability of the fungi to infect the human nail was evaluated also in an ex vivo study, analyzed by histopathology. Results Within four months, both patients showed evident improvement, but with different outcomes. The possible host-related risk factors justifying the poorer outcome in patient 1 include a longer duration time of onychomycosis (50 years). Some particularities in the T. rubrum strain isolated from this patient in relation to that found in patient 2 were observed: (1) the hypha morphology suggesting a major adaptation of the fungus to the host; (2) a 16 times greater propolis concentration was required in vitro; and (3) a faster ability to start a growth using the nail as the only nutritional source. Additionally, this isolate was more efficient in producing a biofilm on the nail surface. Conclusions A partial clinical and complete mycological cure for the two patients was achieved after four months of PE daily use. Despite a complete recovery, a different outcome was observed between both cases. A more persistent onychomycosis, added to greater fungal potential to produce biofilm on the nail, seems to influence greatly the success of a topical treatment with PE.

The invitro effect of nanoliposomal amphotericin B against two clinically important dermatophytes.

The present study aimed to investigate the antifungal activity of amphotericin B-loaded nanoliposomes against Trichophyton interdigitale and Trichophyton rubrum. Moreover, it was attempted to assess the obtained resistance invitro. In total, 29 archived clinical strains, namely, T. interdigitale (n = 16) and T. rubrum (n = 13), were included in this study. These strains were determined using a previous ITS1-ITS2 region sequence. Moreover, a liposomal formulation of amphotericin B was formulated by a thin-film hydration method. Particle size, polydispersity index (PdI), and zeta potential (ZP) were measured by a Zetasizer. Furthermore, physicochemical properties, such as appearance, aggregation of particles, particle size, PdI, and ZP, were determined at 0-, 1-, and 3-month intervals. A scanning electron microscope (SEM) was also used to examine nanoparticles structure. The minimum inhibitory concentration (MIC) of amphotericin B-loaded nanoliposomes, itraconazole, efinaconazole, terbinafine, and ciclopirox was determined according to the protocol of the broth microdilution method of CLSI M38-A2. The morphological changes of T. interdigitale and T. rubrum strains exposed to the amphotericin B-loaded nanoliposomes were observed using SEM. The amphotericin B-loaded nanoliposomes displayed a lower MIC compared to those of the amphotericin B and liposomes when used separately. Based on the results, amphotericin B-loaded nanoliposomes induced no drug resistance in any of the tested strains. Accordingly, amphotericin B-loaded nanoliposomes can be a potent antifungal for the topical treatment of onychomycosis. There was no invitro evidence regarding the resistance of the tested strains to amphotericin B-loaded nanoliposomes. This reflects that amphotericin B-loaded nanoliposomes have a low probability to induce drug resistance in dermatophyte species.

Application of central composite design for the optimization of itraconazole loaded nail lacquer formulation.

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 (X1) and thioglycolic acid (TGA) concentration (X2). While the dependent variables were cumulative amount of drug permeated per unit area (CADP/A, Y1), drying time (Y2) and nonvolatile content (Y3). 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 198.23µg/cm2, drying time of 185s 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 21mm, and 10mm 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.

In Vitro Resistance and Evolution of Resistance to Tavaborole in Trichophyton rubrum.

Tavaborole is currently used in the topical treatment of onychomycosis. In this study, we analyzed the in vitro emergence/evolution of resistance against tavaborole in Trichophyton rubrum When T. rubrum strains were propagated on media containing the MIC of tavaborole, spontaneous resistant mutants were isolated at a frequency of 10-8 The frequency was almost 100-fold higher following fungal growth in the presence of a subinhibitory tavaborole concentration (0.5-fold the MIC) for 10 transfers. All collected mutants showed similar 4- to 8-fold increases in the drug MIC. No cross-resistance to other antifungals was evident.

Formulation of Tioconazole and Melaleuca alternifolia Essential Oil Pickering Emulsions for Onychomycosis Topical Treatment.

Onychomycosis is a disease that affects many adults, whose treatment includes both oral and topical therapies with low cure rates. The topical therapy is less effective but causes fewer side effects. This is why the development of an effective, easy to apply formulation for topical treatment is of high importance. We have used a nanotechnological approach to formulate Pickering emulsions (PEs) with well-defined properties to achieve site-specific delivery for antifungal drug combination of tioconazole and Melaleuca alternifolia essential oil. Silica nanoparticles with tailored size and partially hydrophobic surface have been synthesized and used for the stabilization of PEs. In vitro diffusion studies have been performed to evaluate the drug delivery properties of PEs. Ethanolic solution (ES) and conventional emulsions (CE) have been used as reference drug formulations. The examination of the antifungal effect of PEs has been performed on Candida albicans and Trichophyton rubrum as main pathogens. In vitro microbiological experimental results suggest that PEs are better candidates for onychomycosis topical treatment than CE or ES of the examined drugs. The used drugs have shown a significant synergistic effect, and the combination with an effective drug delivery system can result in a promising drug form for the topical treatment of onychomycosis.

Study of the Antifungal Action of the Lacquer Based on the GABA Derivative of 2-Chloro-N-(9,10-Dioxo-9,10-Dihydroanthracen-1-yl)Acetamide

Onychomycosis is one of the most acute problems of modern medicine, which accounts for about 50% of all nail diseases. Fungi of dermatophytes of the genus Trichophyton are the most studied etiological factor of onychomycosis. Non-dermatophytes can also cause onychomycosis. Fungi of the genus Aspergillus is one of the main pathogens among the non-dermatophytes agents of onychomycosis. Antifungal nail lacquer is the most optimal dosage form for the topical treatment of onychomycosis. GABA derivative of 2-chloro-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)acetamide was used as a perspective antifungal agent in the form of lacquer. The antifungal action of the obtained lacquer containing compound 2 against fungus strain Aspergillus niger VKM F-1119 was compared with the known antifungal lacquer “Lamisil” containing terbinafine as the active agent. Investigation of the antifungal action was carried out at concentrations of 1%, 0.5%, and 0.1% of compound 2 and terbinafine using the diffusion in agar technic after 24 h and 72 h. It has been determined that derivative 2, as well as terbinafine at a concentration of 1%, caused fungicidal action after 24 h and fungicidal and fungistatic effect after 72 h.

Mechanism of Action of Potent Boron-Containing Antifungals

Background:Boron is unusual to organic chemists, yet boron interacts greatly with organic biochemicals and has considerable bioactivity, especially as an antifungal and insecticide. The bestknown bioactive boron compounds are boric acid, its salt borax, and the closely related boronic acids. A newcomer is tavaborole (trade name Kerydin), recently developed and approved in 2014 for topical treatment of onychomycosis, a fungal infection of nails and the nail bed. It is timely to review the literature and explore the way in which these compounds may work.Methods:The focus of this review is to examine peer-reviewed literature relating to boric acid, boronic acid and tavaborole, the most bioactive boron-containing compounds, and the evidence for their proposed mechanism of antifungal action. In parallel with the literature, we have examined the fungistatic effects of boric acid on yeast.Results:All three compounds are reported to inhibit protein synthesis but their mechanism of action may differ. Chemistry studies indicate an interaction of boric acid with ribose and ribose-containing moieties such as NAD. In this review, we discuss the activity of boric acid and use both tavaborole and the boronic acids to exemplify the similar underlying mechanisms used. As there is a push to develop new antimicrobials, we demonstrate that boric acid’s fungistatic effect is alleviated with ribose, NAD and tryptophan.Conclusion:We speculate that boric acid inhibits yeast growth by disrupting tryptophan synthesis as well as downstream NAD, a rate limiting co-enzyme, essential for cellular function.

NP213 (Novexatin®): A unique therapy candidate for onychomycosis with a differentiated safety and efficacy profile.

NP213 (Novexatin®) is a novel antifungal peptide specifically designed for the topical treatment of onychomycosis. NP213 was designed using host defense peptides (HDP), essential components of the innate immune response to infection, as a template. NP213 is a water-soluble cyclic fungicidal peptide that effectively penetrates human nail. NP213 demonstrated a promising preclinical and clinical safety profile, with no evidence of systemic exposure following topical application to the skin and nails. NP213 was efficacious in two phase IIa human trials with 43.3% of patients having no fungi detectable by culture of fragments from NP213-treated nails after 180 days in the first study and likewise 56.5% of patients were culture negative for dermatophytes after 360 days in the second phase IIa study. In both trials, NP213 was applied daily for only 28 days in marked contrast to other topical onychomycosis treatments that require application for up to 52 weeks. Patient reported outcomes from the phase IIa studies were positive with participants recording an improved appearance of their nails after only 14 days of application. All fungi identified in these studies were Trichophyton spp. NP213 (Novexatin®) is a promising, highly differentiated peptide-based candidate for the topical treatment of onychomycosis, addressing the infectious cause and cosmetic issues of this very common condition.

Rational approach to choice of topical therapy of patients with onychomycosis

Objective — to increase the efficacy of treatment of patients with onychomycosis by appointing topical therapy with Onychocid® Emtrix complex.Materials and methods. The analysis of modern research on the prevalence of onychomycosis, features of clinical course and methods of treatment was conducted.Results and discussion. Onychomycoses are extremely widespread, long­lasting and have toxic and sensitizing action of fungal infection on the patient’s body. The incidence of onychomycoses increases with age, reaching a maximum in the elderly and old age. The drug of choice for topical treatment of onychomycosis is a complex drug Onychocid® Emtrix, which is characterized by efficiency and safety.Conclusions. Complex drug Onychocid® Emtrix is a drug of choice for topical treatment of patients with onychomycosis. It can be recommended as monotherapy for patients with concomitant somatic pathology.

Study of bases influence on the biopharmaceutical characteristics of the pastes for onychomycosis therapy

According to the European and American authors the onychomycosis prevalence in the world has amount from 8.0 % to 26.9 %. Topical treatment of onychomycosis in most cases is the only acceptable method of therapy mainly due to high safety. Etiotropic topical pharmacotherapy of this pathology is carried out by the dermatomicotic medicines – creams, ointments, gels, solutions. Nail polishes are the specific dosage forms for onychomycosis therapy. However antimycotic polish therapy is sufficiently effective only in case of treatment the surface white and distal-lateral form of onychomycosis, but just in case when less than 1/3 of nail plate is affected. Also wide application is limited to length of use (from 6 month to 1 year) and high therapy cost. According to above mentioned information, development of specific semisolid dosage form for onychomycosis therapy without removing the nail plate and allowing combination high efficacy of medical substances even in case of nail-bed affection, rational term of treatment and economical availability is rational. Presence of these effects may be reached by the way of combination in semisolid dosage form for appliication on the nail plate – the paste – substances with keratolytic and antimycotic action. At the same time use of acid combination as a keratolytic for pH decreasing in tissue of the nail plate and fungi growth inhibition and also providing with penetration of active components of paste for onychomycosis therapy. As a result of this development of semisolid dosage form for the topical treatment of onychomycosis with biologically active substances from the group of nonspecific antimycotics (2-mercaptobenzthiazol, chinozol) with broad spectrum of antimycotic, antibacterial activity and safety has a scientific and practical interest. The aim of this work is biopharmaceutical substantiation of optimal base for semisolid dosage form – paste for etiotropic therapy of onychomycosis. Materials and methods. As a device for developing pharmacotherapeutical preparation hydrofobic and emulsion bases resistant to combination with sufficiently aggressive keratolytics and described in literature were studied. As an active pharmaceutical ingredient for antimycotic paste 2-mercaptobenzthiazol and chinozol in concentration 10% and 10% accordingly for providing with the optimal level of antifungal activity were used. As keratolytic substances traditionally used for onycholysis: carbamide, mixture of salicylic and benzoic acids in concentration described in literature were used. At the same time chinozol shows keratolytic effect and in that capacity is used in formulations of chinozolo-salicylic, chinozolo-dimexidic and also carbamidic plasters for nails. The content of dry substances and plasticizers in formulations of onycholytic pastes was chosen taking into account the requirements of Ukrainian Pharmacopoea and normative document for this dosage form. Taking into account the advisability of high dispersion degree of medical substances in semisolid dosage forms for external use and physical-chemical properties of 2-mercaptobenzthiazol the latter was added in emulsion bases after preliminary dissolution in polyethylenoxyde 400 with heating. Keratolytics were added as a suspension in all bases. Investigations of scientifically substantiation of the base of paste for onychomycosis therapy were carried out according to plan of single-factor analysis of variance with repeated observations. For all selected compositions the releasing of active pharmaceutical ingredients (2-mercaptobenzthiazol and chinozol) from ointments were studied with equilibrium dialysis method by Kruvchinsky at the temperature 25.0 ± 0.5 °С (temperature on the surface of nail) through the semipermeable film “Kuprofan” in the Franz diffusion cell apparatus (producer PermeGear, Inc., USA). As a dialysis medium taking into account 2-mercaptobenzthiazol solubility was used solution containing methanol and water 1:1 and chinozol releasing was carried out into water. Concentration of active pharmaceutical substances released from experimental pastes after 2 hours was determined spectrophotometrically. Results . Carried out verification of average results of 2-mercaptobenzthiazol and chinozol releasing by the Dunkan’s multiple rank test allowed to build the preferred series of pastes base influence on the intensity of active pharmaceutical ingredients releasing. Obtained results showed the sighnificant advantage of the emulsion ointment base providing with optimal level of 2-mercaptobenzthiazol and chinozol releasing from experimental compositions of semisolid dosge forms for onychomycosis therapy. Conclusions . It was determined that sort of the base makes a sighnificant influence on 2-mercaptobenzthiazol and chinozol releasing from the antimycotic pastes for onychomycosis therapy. Variance analysis of results revealed that emulsion vehicle containing acid-resisting emulsifier provides with optimal 2-mercaptobenzthiazol and chinozol releasing.

Examining the Benefits of the Boron-Based Mechanism of Action and Physicochemical Properties of Tavaborole in the Treatment of Onychomycosis.

Onychomycosis is a fungal infection of the nail primarily caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. The topical-based treatment of onychomycosis remains a challenge because of the difficulty associated with penetrating the dense, protective structure of the keratinized nail plate. Tavaborole is a novel small-molecule antifungal agent recently approved in the United States for the topical treatment of toenail onychomycosis. The low molecular weight, slight water solubility, and boron chemistry of tavaborole maximize nail penetration after topical application, allowing for effective targeting of the infection in the nail bed. The efficacy of tavaborole is associated with its novel mechanism of action, whereby it inhibits the fungal leucyl-tRNA synthetase (LeuRS) enzyme. Because LeuRS is an essential component in fungal protein synthesis, inhibition of LeuRS ultimately leads to fungal cell death. Tavaborole is the first boron-based antifungal medication approved for the treatment of mild-to-moderate onychomycosis and presents patients with a new topical option. Previously, ciclopirox and efinaconazole were the only approved topical treatments for onychomycosis. This article details the properties that are at the core of the clinical benefits associated with tavaborole.