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The current study's objective was to formulate and evaluate a liposomal cream containing tolnaftate in order to improve the drug's bioavailability. Tolnaftate is a drug having low permeability which results in decreased drug absorption and so is the bioavailability. To overcome these problems tolnaftate is incorporated in liposomes. Liposome vesicular drug delivery system was preferred due to its greater solubility, permeability and bioavailability. It carries a substantial amount of drug which increased the drug's penetration. The liposomes were prepared using a variety of phospholipids, specifically soy lecithin and egg phosphatidylcholine in varying ratios. Liposomes were prepared by ethanol injection method and evaluated for morphology, percentage practical yield, percentage entrapment efficiency, drug content and invitro drug release study. The formulation with the best result according to the evaluation parameters was F2 with greater percentage drug entrapment, drug content and in-vitro drug release was considered to be optimized formulation and this F2 formulation was further evaluated by SEM, DSC and XRD. Liposomal cream was formulated using the optimized formulation. Spreadability, Viscocity, pH measurement and in-vitro drug release were evaluated for liposomal cream. Formulation F2 and optimized liposomal cream formulation showed in-vitro drug release of 92.44% and 77.48% respectively at the end of 8th hour. [ABSTRACT FROM AUTHOR]

Introduction: Topical antifungals for toenail onychomycosis must penetrate the nail to deliver an inhibitory concentration of free drug to the site of infection. In two ex vivo experiments, we tested the ability of topical antifungals to inhibit growth of Trichophyton rubrum and Trichophyton mentagrophytes, the most common causative fungi in toenail onychomycosis. Methods: Seven topical antifungals were tested: three U.S. Food and Drug Administration-approved products indicated for onychomycosis (ciclopirox 8% lacquer; efinaconazole 10% solution; tavaborole 5% solution) and four over-the-counter (OTC) products for fungal infections (tolnaftate 1% and/or undecylenic acid 25% solutions). The ability to inhibit fungal growth was tested in the presence and absence of keratin. Products were applied either to human cadaverous nails or keratin-free cellulose disks prior to placement on an agar plate (radius: 85 mm) seeded with a clinical isolate of T. rubrum or T. mentagrophytes. After incubation, the zone of inhibition (ZI), defined as the radius of the area of no fungal growth, was recorded. Results: In the nail penetration assay, average ZIs for efinaconazole (T. rubrum: 82.1 mm; T. mentagrophytes: 63.8 mm) were significantly greater than those for tavaborole (63.5 mm; 39.1 mm), ciclopirox (7.4 mm; 3.6 mm) and all OTC products (range: 10.5–34.2 mm against both species; all P < 0.001). In the cellulose disk diffusion assay, efinaconazole and tavaborole demonstrated maximal antifungal activity against both species (ZIs = 85 mm); average ZIs against T. rubrum and T. mentagrophytes were smaller for ciclopirox (59.0 and 55.7 mm, respectively) and OTC products (range: 31.2–57.8 mm and 25.7–47.7 mm, respectively). Conclusions: Among all antifungals tested, the ability to penetrate human toenails to inhibit growth of both T. rubrum and T. mentagrophytes was greatest for efinaconazole, followed by tavaborole. These results indicate superior transungual penetration of efinaconazole compared to the other antifungals, suggesting lower keratin binding in the nail. [ABSTRACT FROM AUTHOR]

Liquid chromatography-mass spectrometry (LC-MS) is a very sensitive technique for determining small concentrations of drugs in fixed dose combinations or even those deposited in skin layers. Therefore, an LC-MS method was applied for determining the drugs under investigation, namely, clioquinol (CLIO), tolnaftate (TOL), and betamethasone (BETA) in Quadriderm® cream and mixed lipid nanostructures (MLNs) prepared in laboratory in the presence of potential interferents, and was applied as a dermato-kinetic study in rat’s skin. The separation was achieved within 4.5 min by using C18 column as a stationary phase and the mobile phase used were 20% phase A composed of 0.1% formic acid (v/v) and 80% phase B composed of 0.1% formic acid in acetonitrile (v/v), coupled with triple quadrupole mass spectrometer. MLNs were prepared and characterized to be compared with the conventional commercially available Quadriderm® cream. The proposed method was accurate and precise with a linearity range of 0.2–20.0 µg·mL−1 for BETA, and 0.5–400.0 µg·mL−1 for CLIO and TOL and a better bioavailability of the new formulation was obtained ensuring the capability of the nanoparticles to accumulate the drugs within the skin layers. In conclusion, the LC-MS method was accurate and precise for the determination of the three drugs under investigation in cream dosage form and skin tissues.

Fungal keratitis (FK) is a devastating ocular disease that can cause corneal opacity and blindness if not treated effectively. Tolnaftate (TOL) is a selective fungicidal drug against Aspergillus spp. which are among the most common causes of mycotic keratitis. TOL is lipophilic drug with low water solubility and permeation which act as obstacles for its clinical ocular efficacy. Hence, this study aimed to statistically optimize a novel polymeric pseudorotaxanes (PSRs) containing TOL for enhancing its ocular permeability and antifungal effect. For achieving this goal, a full 31.22 factorial design was fashioned for preparing and optimizing TOL-PSRs using film hydration technique. Three formulation variables were studied: drug amount (X1), weight ratio of Pluronics to HPβCD (X2) and Pluronic system (X3). Entrapment efficiency percent (EE%) (Y1), particle size (PS) (Y2) and zeta potential (ZP) (Y3) were set as dependent variables. The selected optimal TOL-PSRs (PSR1) showed EE% of 71.55 ± 2.90%, PS of 237.05 ± 12.80 nm and ZP of −32.65 ± 0.92 mV. In addition, PSR1 was compared to conventional polymeric mixed micelles (PMMs) and both carriers significantly increased the drug flux and resulted in higher amount permeated per unit area in 8 h compared to drug suspension. The histopathological studies assured the safety of PSR1 for ocular use. The in vivo susceptibility testing using Aspergillus niger confirmed that PSR1 displayed sustained antifungal activity up to 24 h. The obtained results revealed the admirable potential of PSR1 to be used as novel nanocarriers for promoting TOL ocular delivery.

Simple and rapid stability indicating High Performance Liquid Chromatography-Photo Diode Array (HPLC-PDA) method was developed and validated for the estimation of tolnaftate in the presence of its forced degradation products. The method employed SunQSil C18 column (250 mm × 4.6 mm, 5 μm) as stationary phase and acetonitrile:water (85:15, v/v) as mobile phase. Retention time of tolnaftate was 6.9 min. Acid and alkali hydrolysis, oxidation, photo degradation and thermal degradation studies were carried out to evaluate the degradation behavior of tolnaftate. The developed and optimized method was validated as per International Conferences on Harmonization (ICH) guidelines. Limit of detection and limit of quantitation were found to be 0.092 and 0.276 μg/mL, respectively. Linearity was observed in a concentration range of 0.276–6 μg/mL with R2 = 0.9936. %Recovery was found to be between 98.28% and 100.71%. The developed and validated Reversed Phase-High Performance Liquid Chromatography (RP-HPLC) method was successfully applied for quantification of tolnaftate in in-house topical solution. Major base and oxidative degradation products were identified and characterized by liquid chromatography–electrospray ionization mass spectrometry. The probable mechanisms for the formation of degradation products were predicted based on the fragmentation pattern of degradation products. The in silico dermal penetration predictions and carcinogenicity of degradation products were evaluated by using QikProp and CarcinoPred-EL functionality. [ABSTRACT FROM AUTHOR]

Fungal keratitis (FK) is a devastating ocular disease that can cause corneal opacity and blindness if not treated effectively. Tolnaftate (TOL) is a selective fungicidal drug against Aspergillus spp. which are among the most common causes of mycotic keratitis. TOL is lipophilic drug with low water solubility and permeation which act as obstacles for its clinical ocular efficacy. Hence, this study aimed to statistically optimize a novel polymeric pseudorotaxanes (PSRs) containing TOL for enhancing its ocular permeability and antifungal effect. For achieving this goal, a full 31.22 factorial design was fashioned for preparing and optimizing TOL-PSRs using film hydration technique. Three formulation variables were studied: drug amount (X1), weight ratio of Pluronics to HPßCD (X2) and Pluronic system (X3). Entrapment efficiency percent (EE%) (Y1), particle size (PS) (Y2) and zeta potential (ZP) (Y3) were set as dependent variables. The selected optimal TOL-PSRs (PSR1) showed EE% of 71.55 ± 2.90%, PS of 237.05 ± 12.80 nm and ZP of -32.65 ± 0.92 mV. In addition, PSR1 was compared to conventional polymeric mixed micelles (PMMs) and both carriers significantly increased the drug flux and resulted in higher amount permeated per unit area in 8 h compared to drug suspension. The histopathological studies assured the safety of PSR1 for ocular use. The in vivo susceptibility testing using Aspergillus niger confirmed that PSR1 displayed sustained antifungal activity up to 24 h. The obtained results revealed the admirable potential of PSR1 to be used as novel nanocarriers for promoting TOL ocular delivery. [ABSTRACT FROM AUTHOR]

Tolnaftate (TOL) is a thiocarbamate fungicidal drug used topically in the form of creams and ointments. No ocular formulations of TOL are available for fungal keratitis (FK) treatment due to its poor water solubility and unique ocular barriers. Therefore, this study aimed at developing novel modified spanlastics by modulating spanlastics composition using different glycols for enhancing TOL ocular delivery. To achieve this goal, TOL basic spanlastics were prepared by ethanol injection method using a full 32 factorial design. By applying the desirability function, the optimal formula (BS6) was selected and used as a nucleus for preparing and optimizing TOL-cosolvent spanlastics according to the full 31.21 factorial design. The optimal formula (MS6) was prepared using 30% propylene glycol and showed entrapment efficiency percent (EE%) of 66.10 ± 0.57%, particle size (PS) of 231.20 ± 0.141 nm, and zeta potential (ZP) of −32.15 ± 0.07 mV. MS6 was compared to BS6 and both nanovesicles significantly increased the corneal permeation potential of TOL than drug suspension. Additionally, in vivo histopathological experiment was accomplished and confirmed the tolerability of MS6 for ocular use. The fungal susceptibility testing using Aspergillus niger confirmed that MS6 displayed more durable growth inhibition than drug suspension. Therefore, MS6 can be a promising option for enhanced TOL ocular delivery. [ABSTRACT FROM AUTHOR]

The aim was to formulate and evaluate glycerosomes as novel carrier for dermal (trans) drug delivery systems (tDDDS). Tolnaftate Loaded Glycerosomes were prepared by thin film hydration technique. The thin-film was hydrated using aqueous solution of glycerol (30 %v/v) against liposomes as control and were characterized. Glycerosome formulations were sphere-shaped with a mean diameter of 165.5 nm and narrow size distribution (P.I: 0.744). Zeta potential was –22.8mv indicating good stability. Tolnaftate loading capacity was found to be between 17.5±0.56 % and 91.32±0.57%. In-vitro permeation experiments showed an improved skin deposition and permeation of tolnaftate (5mg) when 30% glycerol, DSPC (100mg), cholesterol (25mg) content were used. Ex-vivo skin penetration studies showed an improved drug release than conventional liposomes and drug suspension. Skin irritancy studies on guinea pig showed no signs of toxicity. Glycerosomes must be an ideal novel transdermal drug delivery system for the effective delivery of tolnaftate. [ABSTRACT FROM AUTHOR]

Rosmarinus, tolnaftate, christianity, no-observed-effect level, superfund amendments and reauthorization act. [Extracted from the article]

Nanoemulsion has been identified as a promising delivery system for various drugs including Biopharmaceuticals. Nanoemulsion is heterogeneous system composed of one immiscible liquid dispersed as droplets within another liquid. Aim of the present study was to investigate the nanoemulgel as transdermal delivery system for poorly water soluble drug, Tolnaftate in order to overcome the troubles associated with its oral delivery. Different nanoemulsion components (Oil, Surfactant and Cosurfactant) were selected on the basis of solubility and emulsification ability. High pressure Homogenization techninique were used for the preparation of Nanoemulsion. Carbopol 934 was added as gel matrix to convert nanoemulsion into nanoemulgel. Drug loaded Nanoemulgels were characterized for particle size, SEM, Viscosity, Spreadability, Diffusion study using egg membrane, Nanoemulgel containing 3% Almond oil, 5.25% Tween 80, Proplene glycol as Cosurfactant, 1% drug, Water upto Quantity sufficient was concluded as optimized formulation (F1). [ABSTRACT FROM AUTHOR]

Tolnaftate, a classic antifungal compound, has been found to crystallize from 1:1 (v/v) acetone-water as large flat colorless needles in the centrosymmetric monoclinic space group P21/c. These crystals contain a 50:50 mixture of the (+ap,-sp,+ac,-ac) and (-ap,+sp,-ac,+ac) conformers. The bond lengths in the central CNOS unit are 1.3444 (19), 1.3556 (18) and 1.6567 (15) A À for C--N, C--O and C--S, respectively, and the CNOS and C3N moieties are flat and nearly coplanar with each other, consistent with the C--N bond possessing partial double-bond character. Tolnaftate and the four most closely related N,N-disubstituted thiocarbamates in the Cambridge Structural Database (CSD) all exist as E-conformational isomers in the solid state. Among these five compounds, tolnaftate is the only one in which the N-tolyl moiety is positioned trans to the S atom, i.e. the N-aryl substituent in each of the other compounds is positioned cis to their respective S atom. Notably, and more importantly, our experimental X-ray structure is unlike all prior theoretical models available for tolnaftate. The implication, either directly or indirectly, is that some of those theoretical models used in earlier studies to explain the spectroscopic properties of tolnaftate and to suggest which protein-ligand interactions are responsible for the binding of tolnaftate to squalene epoxidase are either inappropriate or structurally unreasonable, i.e. the results and conclusions from those prior studies are in need of critical reassessment. [ABSTRACT FROM AUTHOR]

Graphene “The novel carbon nano-trope” tailors auspicious platform for designing antimicrobial regimen by virtue of its conspicuous molecular interaction with the microorganism. In this work, Tolnaftate (Tf), an antifungal drug, was mingled with Graphene nanoplatelets (Gn) to develop composite (Tf-Gn) via the wet chemical route, embedded in a biocompatible polymeric blend of Eudragit RL100/Eudragit RS100 (EuRL100/EuRS100) and subjected to electrospinning to obtain nonwoven nanoengineered scaffolds (nanofibers) for enhanced anti-dermatophytic virtue. Pursuing cluster of optimization experiments, 20% w/v EuRL100/EuRS 100 was found to be adequate for formation of smooth, defect-free, and regular fibers. Field emission electron microscopy (FESEM) acknowledged zestfully fabrication of smooth, shiny, nano-range, and mesh-like architecture, comprising distinct pockets within their structure. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimeter (DSC) conceded formation of the composite Tf-Gn, its physical compatibility with polymers, and improved thermal behavior. Exceptional swelling capacity, significant hydrophilicity, and immense drug entrapment efficiency were obtained of nanofibers fabricated from 3:1 ratio of EuRL100/EuRS100 polymers blend owing to relatively higher permeability which gratified essential benchmark for fabrication of nanofibrous scaffold to alleviate fungal infections caused by dermatophytes. In vitro drug release interpreted controlled liberation of Tf in dissolution media, following Korsmeyer-Peppas model kinetics, and suggested a diffusion-based mechanism. Microdilution broth method was performed for in vitro antifungal efficacy against extremely devastating dermatophytes, i.e., anthropophilic Trichophyton rubrum and zoophilic Microsporum canis, exhibited preeminent growth inhibition against T.rubrum and scanty for M.canis. Findings revealed the superior antifungal activity of Tf-Gn-loaded nanofibers as compared to Tf-loaded nanofibers and recommended potential dressing materials for an effective regimen of dermatomycosis. [ABSTRACT FROM AUTHOR]

Dermatophytosis, topical fungal infection is the most common cause of skin bug in the world, generally underestimated and ignored. It is commonly caused by immensely mortifying and keratinophilic fungal eukaryotes which invade keratinized tissues and generate different tinea diseases in Mediterranean countries. We herein fabricated nanofibers/scaffolds embedded with thiocarbamate derivative topical antifungal tolnaftatefor the first time to target the complete elimination of dermatophyte at the site of infection. In this regard, variable combinations of biocompatible Eudragit grades (ERL100 and ERS100) were selected to provide better adhesion on the site of dermatophytosis, ample absorption of exudates during treatment, and customized controlled drug release. Surface topography analysis indicated that the fabricated nanofibers were regular and defect-free, comprising distinct pockets with nanoscaled diameters. Characterization and compatibility studies of tolnaftate, polymers, and their nanofibers were performed through ATR-FTIR, TGA, and PXRD. Remarkable hydrophilicity and an excellent swelling index were obtained from a 3:1 ratio of ERL100/ERS100 electrospun D3 nanofibers, which is an essential benchmark for the fabrication of nanofibrous scaffolds for alleviating dermatophytosis. In vitro drug release investigation revealed that a nonwoven nanomesh of nanofibers could control the rate of drug release for 8 h. A microdilution assay exhibited inhibition of more than 95% viable cells of Trichophyton rubrum for 96 h. However, Microsporum species rigidly restricted the effect of bioactive antifungal nanofibers and hence showed resistance. In vivo activity on Trichophyton rubrum infected Swiss albino mice revealed complete inhibition of fungal pathogens on successive applications of D3 nanofibers for 7 days. This investigation suggests potential uses of tolnaftate loaded polyacrylate nanofibers as dressing materials/scaffolds for effective management of dermatophytosis. [ABSTRACT FROM AUTHOR]

Background: Otomycosis is the superficial mycotic infection of the external ear canal which occurs as acute, subacute and chronic infection. It is the cause of 6.5% to 12.5% of external otitis. More than 62 species and 28 genera of fungi have been identified in patients with otomycosis among which the most common organisms are Aspergillus Niger and Candida Albicans. Recommended topical medications include steroids, anti-septic, acidic solutions, antifungal, and drying agents. The commonly recommended antifungal drugs are clotrimazole, amphotericin B, otosporin, and tolnaftate. This study aimed to identify two genera of fungus, and compare the efficacy of the treatment of clotrimazole and tolnaftate and the recurrence rate after the treatment. Methods: This was a clinical trial study conducted on 54 patients diagnosed with otomycosis (based on culture and smear with identification of the fungus genus and species). We compared the effect of clotrimazole and tolnaftate on the treatment and its recurrence on different types of fungus. Findings: After finishing the treatment course, 22 patients were improved in clotrimazole (81.5%); however, in the tolnaftate group, there were 21 improved patients (77.8%). Besides, Chi-square test showed no significant difference between the two groups (P = 0.99). Furthermore, out of 43 patients who have improved after the treatment, recurrence was seen in 15 of them (34.9%). Disease recurrence cases in the group treated with clotrimazole and tolnaftate were 8 and 7 patients respectively (36.4% vs. 33.3%). Although, the frequency distribution of disease recurrence was lower in the tolnaftate group, according to chi-square test, there was no significant difference between the two groups (P = 0.99). Conclusion: According to the results of this study and its comparison with other studies, both clotrimazole and tolnaftate had an appropriate impact on treating fungal infections of the ear. Given the non-improvement and recurrence cases, we should attempt to detect other therapeutic methods of otomycosis, and currently aspects such as financial and economic issues should be taken into account in choosing to use either of the drugs.

Dermatophytosis, topical fungal infection is the most common cause of skin bug in the world, generally underestimated and ignored. It is commonly caused by immensely mortifying and keratinophilic fungal eukaryotes which invade keratinized tissues and generate different tinea diseases in Mediterranean countries. We herein fabricated nanofibers/scaffolds embedded with thiocarbamate derivative topical antifungal tolnaftatefor the first time to target the complete elimination of dermatophyte at the site of infection. In this regard, variable combinations of biocompatible Eudragit grades (ERL100 and ERS100) were selected to provide better adhesion on the site of dermatophytosis, ample absorption of exudates during treatment, and customized controlled drug release. Surface topography analysis indicated that the fabricated nanofibers were regular and defect-free, comprising distinct pockets with nanoscaled diameters. Characterization and compatibility studies of tolnaftate, polymers, and their nanofibers were performed through ATR-FTIR, TGA, and PXRD. Remarkable hydrophilicity and an excellent swelling index were obtained from a 3:1 ratio of ERL100/ERS100 electrospun D3 nanofibers, which is an essential benchmark for the fabrication of nanofibrous scaffolds for alleviating dermatophytosis. In vitro drug release investigation revealed that a nonwoven nanomesh of nanofibers could control the rate of drug release for 8 h. A microdilution assay exhibited inhibition of more than 95% viable cells of Trichophyton rubrum for 96 h. However, Microsporum species rigidly restricted the effect of bioactive antifungal nanofibers and hence showed resistance. In vivo activity on Trichophyton rubrum infected Swiss albino mice revealed complete inhibition of fungal pathogens on successive applications of D3 nanofibers for 7 days. This investigation suggests potential uses of tolnaftate loaded polyacrylate nanofibers as dressing materials/scaffolds for effective management of dermatophytosis.

Background: Otomycosis is the superficial mycotic infection of external ear canal which occurs as acute, subacute and chronic infection. It is the cause of 6.5 to 12.5 percent of external otitis. More than 62 species and 28 genera of fungi have been identified in patients with otomycosis among which the most common organisms are Aspergillus Niger and Candida Albicans. Recommended topical medications include steroids, anti-septic, acidic solutions, antifungal and drying agents. Among the antifungal, commonly recommended drugs are clotrimazole, amphotericin B, otosporin and tolnaftate. This study aimed to identify two genera of fungus and comparing the efficacy treatment of clotrimazole and tolnaftate and the recurrence rate after the treatment. Methods: This was a clinical trial study conducted on 54 patients diagnosed as proved otomycosis (based on culture and smear with identification of the fungus genus and species). We compared the effect of "clotrimazole and tolnaftate" on the treatment and its recurrence on types of fungus. Findings: After finishing the treatment course, 22 patients were improved in clotrimazole (81.5%); however, in the tolnaftate group, there were 21 improved patients (77.8%). Besides, Chi-square test showed no significant difference between the two groups (P = 0.99). Furthermore, out of 43 patients who have been improved after the treatment, recurrence was seen in 15 of them (34.9%). Disease recurrence cases in the group treated with clotrimazole and tolnaftate were 8 and 7 patients respectively (36.4% vs. 33.3%) and despite the frequency distribution of disease recurrence was lower in the tolnaftate group, according to Chi-square test, statistically there was no significant difference between the two groups (P = 0.99). Conclusion: According to the results of this study and its comparison with other studies, both clotrimazole and tolnaftate had an appropriate impact on treating era fungal infections and given to non-improvement and recurrence cases, we should attempt to detect other therapeutic methods of otomycosis, and currently therapeutic aspects such as financial and economic issues should be taken into account to use either of the drugs. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this work was to investigate the precipitation of a poorly water soluble drug (tolnaftate) from low, μM concentration solutions. This was to test the applicability of nanoparticle tracking analysis (NTA; the NanoSight instrument), with comparison to results from dynamic light scattering (DLS). Samples containing 30μM of tolnaftate, 1% dimethylsulfoxide (DMSO) (by volume) were prepared by mixing a concentrated DMSO stock solution and an aqueous buffer. The samples were then analysed over time either using the NanoSight instrument or by DLS. Obtaining meaningful results from the former required careful attention to instrument settings. From NTA there was initially a fairly narrow size distribution around 200nm, with concentration of around 4×108 nanoparticles/mL. Over 3h, the particles grew, with increasing polydispersity, and skewed distribution up to 800nm, whilst the concentration fell to around 1×108 particles/mL. DLS was consistent in showing the size increase, but could not detect the remaining smaller particles and polydispersity. Conclusions: The growth of particles of a poorly water soluble drug was successfully monitored using NTA, which gives additional information not offered by DLS. Nanoparticle precipitation at the concentrations used here is of relevance to high throughput screening in early drug discovery. [Copyright &y& Elsevier]

Abstract: An indirect spectrofluorimetric method with high sensitivity and selectivity was developed for the determination of antifungal drug: tolnaftate (TNF), depending on the supramolecualr multirecognition interaction among the anionic surfactant sodium laurylsulfate (SLS), β-cyclodextrin (β-CD) and β-naphthol (ROH). The mechanism of the inclusion was studied and discussed by means of fluorescence spectrum, infra-red spectrograms and 1HNMR spectroscopy. Results showed that the naphthalene ring of ROH and the hydrophobic hydrocarbon chain of SLS were included into the β-CD''s cavity to form a ROH:SLS:β-CD ternary inclusion complex with stoichiometry of 1:1:1 at room temperature, which provided effective protection for the excited state of ROH. At λ ex/λ em =273/360nm, the fluorescence intensity was linear over a tolnaftate concentration range of 2.46×10−9 to 2.10×10−6 molL−1. The detection limit and relative standard deviation was 7.50×10−10 molL−1 and 1.4%, respectively. The interference of 31 foreign substances was slight. The proposed method had been successfully applied to the determination of tolnaftate in artificial mixed samples with almost quantitative recovery. [Copyright &y& Elsevier]

A dissolution apparatus was constructed to evaluate tolnaftate release from topical powders. It consisted of a mesh unit to support the powder, a receptor phase, and a sink. This report describes three parameters that were used to evaluate this technique. First, three different areas of contact were examined using 52-, 41-, or 30-µm mesh supports. Second, the effect of the pH on the dissolution rate was studied, using aqueous buffers of pH 3, 5, 7, or 8 as the receptor phase. Finally, different topical powder formulations containing different amounts of tolnaftate were tested. The results obtained showed that the percentage of tolnaftate released from topical powders increased at low pH levels and with the larger mesh support. The percentage released was greater in a starch-talc preparation than in a talc-only preparation. The mesh was replaced by a semipermeable membrane (2.5- to 4 nm pore size) to function as an in vitro model for intradermal diffusion. The results showed that a cream initially released more drug than powder formulations. [ABSTRACT FROM AUTHOR]

• Tolnaftate kills promastigote and amastigote forms of Leishmania sp. • Tolnaftate altered cell membrane and mitochondria of L. amazonensis. • Parasites treated with tolnaftate presented low levels of ergosterol. • Tolnaftate showed low cytotoxicity to macrophages. Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. The treatment of all forms of leishmaniasis relies on first-line drug, pentavalent antimonial, and in cases of drug failure, the second-line drug amphotericin B has been used. Besides the high toxicity of drugs, parasites can be resistant to antimonial in some areas of the World, making it necessary to perform further studies for the characterization of new antileishmanial agents. Thus, the aim of the present work was to evaluate the leishmanicidal activity of tolnaftate, a selective reversible and non-competitive inhibitor of the fungal enzyme squalene epoxidase, which is involved in the biosynthesis of ergosterol, essential to maintain membrane physiology in fungi as well as trypanosomatids. Tolnaftate eliminated promastigote forms of L. (L.) amazonensis, L. (V.) braziliensis and L. (L.) infantum (EC 50 ~ 10 μg/mL and SI ~ 20 for all leishmanial species), and intracellular amastigote forms of all studied species (EC 50 ~ 23 μg/mL in infections caused by dermatotropic species; and 11.7 μg/mL in infection caused by viscerotropic species) with high selectivity toward parasites [SI ~ 8 in infections caused by dermatotropic species and 17.4 for viscerotropic specie]. Promastigote forms of L. (L.) amazonensis treated with the EC 50 of tolnaftate displayed morphological and physiological changes in the mitochondria and cell membrane. Additionally, promastigote forms treated with tolnaftate EC 50 reduced the level of ergosterol by 5.6 times in comparison to the control parasites. Altogether, these results suggest that tolnaftate has leishmanicidal activity towards Leishmania sp., is selective, affects the cell membrane and mitochondria of parasites and, moreover, inhibits ergosterol production in L. (L.) amazonensis. [ABSTRACT FROM AUTHOR]

A comparative study using novel quadruple divisor and mean centering of ratio spectra spectrophotometric methods was developed for resolution of five- component mixture of Tolnaftate, β -naphthol (Tolnaftate alkaline degradation product and its toxic impurity), methyl(m-tolyl)carbamic acid (Tolnaftate alkaline degradation product), N -methyl-m-toluidine (Tolnaftate toxic impurity) and methyl paraben (as a preservative). For the novel quadruple divisor method, each component in the quinary mixture was determined by dividing the quinary mixture spectrum by a sum of standard spectrum of equal concentration of the other four components as a quadruple divisor. First derivative of each ratio spectra was then obtained which allowed selective determination of each component without interference from other components in the mixture. The second method was mean centering of ratio spectra that depended on utilizing the mean centered ratio spectra in four successive steps leading to enhancement of the signal to noise ratio. The absorption spectra of the five studied components were recorded in the wavelength range of 210–350 nm. The mean centered fourth ratio spectra amplitudes for each component were used for its determination. The developed methods were successfully applied for determination of laboratory prepared quinary mixtures to ensure method's specificity, then, were further applied on Tinea Cure® cream where no interference from excipients. For the first time, Tolnaftate was determined along with its toxic impurity; β -naphthol, that could be absorbed by the skin, causing systemic toxic effects, unlike Tolnaftate that poorly absorbed, indicating the significance of this work. The proposed methods were statistically compared with each other and with the reference method. Furthermore, ICH guidelines were followed for their validation. Unlabelled Image • Alkaline degradation of Tolnaftate and synthesis of its impurity D. • IR, H1NMR and mass tools for structural elucidation of degradates and impurity. • Development of novel quadruple divisor and mean centering ratio spectra methods. • Determination of Tolnaftate, degradation products, impurity and Methyl paraben • Tracing toxic impurities; B-naphthol and N -methyl-m-toluidine with high sensitivity [ABSTRACT FROM AUTHOR]

Tolnaftate, a thionoester anti‐fungal drug, was subjected to alkaline hydrolysis to produce methyl(m‐tolyl)carbamic acid and β‐naphthol (tolnaftate impurity A). N‐Methyl‐m‐toluidine, tolnaftate impurity D, was synthesized and structurally elucidated along with tolnaftate alkaline degradation products using IR, H1NMR and MS. Two stability‐indicating HPTLC and RP‐HPLC methods were developed and validated, for the first time, for determination of tolnaftate, its alkaline degradation products and toxic impurities in the presence of methyl paraben, as a preservative in Tinea Cure® cream. The proposed HPTLC method depended on separation of the studied components on TLC silica gel F254 plates using hexane–glacial acetic acid (8:2, v/v) as a developing system and scanning wavelength of 230 nm. The proposed RP‐HPLC method was based on separation of the five components on an Eclipse plus C18 column. The mobile phase used was acetonitrile–water containing 1% ammonium formate (40:60, v/v), with a flow rate of 1 mL/min and detection wavelength of 230 nm. The proposed methods allowed the assay of tolnaftate toxic impurities, β‐naphthol and N‐methyl‐m‐toluidine, down to 2%, allowing tracing of β‐naphthol that could be absorbed by the skin causing systemic toxic effects, unlike tolnaftate, indicating the high significance of such determination. International Conference on Harmonization guidelines were followed for validation. [ABSTRACT FROM AUTHOR]

Abstract A simple, accurate, rapid and sensitive visible spectrophotometric method has been developed for the determination of tolnaftate in pure and pharmaceutical preparations. The method is based on the reaction of tolnaftate with potassium permanganate in alkaline medium to form a bluish green colored product with an absorption maximum at 610 nm. Beer’s law was obeyed in the range of 5-60 µg/25ml with a molar absorbitivity of 5.379×104 L.mol.-1.cm-1. The optimum conditions for all color development were described and the proposed method has been successfully applied for the determination of tolnaftate in pharmaceutical preparations. A statistical comparison of these results with those of official method using (t and F) values at 95% confidence level, The calculated t- and F- values did not exceed the theoretical values indicating that there was no significant differences between the precision of the proposed and official method. So that the proposed method can be used as a routine quality control for determination of tolnaftate in pure form and in pharmaceutical formulations.The common excipients and additives did not interfere in the proposed method.