Treatment Of Topical Fungal Infections Research Articles

Development of a nanoemulsion containing Lippia origanoides essential oil with antifungal activity by low energy method: from extraction to formulation

The essential oil of Lippia origanoides is of great pharmacological interest because of a wide variety of attributes, in particular its antifungal action. Due to its low solubility in aqueous media, high volatility, and a high propensity for physicochemical degradation, the search for nanostructured systems to promote the stability of this phytocomplex is necessary. Nanoemulsion is an alternative method to stabilize and preserve this type of active ingredient, especially when generated by a low energy method and using Syagrus coronata (licuri) oil as an active carrier and stabilizer of this nanostructure. The objective of the present investigation was to formulate a stable nanoemulsion with Lippia origanoides essential oil carried through licuri oil with antifungal action by the low energy method. For this, we began with the extraction of the essential oil and the phytochemical characterization obtaining the chemotype B of this Lippia (carvacrol: 49.12%). Then, using the pseudoternary phase diagram, the optimal ratio of the oil phase 6:4 (essential oil: Syagrus coronata oil) was established, adding 15% of surfactant (polysorbate 80) and 75% of the aqueous phase. Then, with the formulated nanoemulsion, the physical-chemical characterization and evaluation of preliminary and accelerated stability were carried out. In addition, cytotoxicity, Franz cell permeation and antifungal activity against dermatophytes were evaluated. A stable nanoemulsion was obtained by the low energy method with the characteristic appearance of a nanoemulsion and a characteristic odor of essential oil. The average size of the nanoparticles was around 167.5 nm, narrow PDI (<0.2 nm), zeta potential below -10.0 mV, acidic pH (5.1), average conductivity 134.4 μSm/cm, refractive index characteristic of a translucent system and low viscosity (<6.0 mPa.S). Regarding cytotoxicity, it proved to be safe at dosages below 90 μg/mL, efficient in terms of permeation (76.7% in 24h) and effective in terms of antifungal activity as it had a minimum inhibitory concentration between 234.4/156.3 μg /mL and 11.2/7.5 μg/mL against the tested dermatophytes. In view of the results, a nanoemulsion containing the essential oil of L. origanoides carried by the oil of Syagrus coronata was shown to be a potential product for the topical treatment of fungal infections like dermatophytosis.

Development and Evaluation of Voriconazole Loaded Invasomes Gel for Enhanced Antifungal Activity.

Although it has limited solubility and poor permeability to the skin, voriconazole (VRC) is a viable choice for the topical treatment of fungal infections. Owing to these constraints, treating the inflection requires several injections over an extended period. The goal of this work was to produce a VRC invasome gel with improved topical antifungal activity. The Box-Behnken design (BBD) program was utilized to optimize the IVS after it was created using the thin-film hydration process. The optimized invasome formulation through BBD has 159.9 nm of vesicle size, 68.58% of entrapment efficiency, and 23.5 mV of zeta potential. The spherical shape of the vesicle was revealed using scanning microscopy. According to FTIR spectra, the medication and polymers do not interact. The optimized invasomal VRC gel exhibited an optimum of 345 to 589 cp. Ex-vivo permeation studies of IG4 exhibited a higher flux of 0.168 as compared to pure voriconazole. An antimicrobial study was accepted to check the antimicrobial efficiency of voriconazole gel (IG4). The study confirmed a good zone of inhibition of the fungus infection (C. albicans). The voriconazole invasome’s potential diffusion and antibacterial efficacy are demonstrated here. Invasomal gel was found to be an effective carrier and a desirable strategy for improving the topical distribution of VRC to treat fungal infections.

Quality by design driven development of lipid nanoparticles for cutaneous targeting: a preliminary approach.

Fungal infections are the fourth common cause of infection affecting around 50 million populations across the globe. Dermatophytes contribute to the majority of superficial fungal infections. Clotrimazole (CTZ), an imidazole derivative is widely preferred for the treatment of topical fungal infections. Conventional topical formulations enable effective penetration of CTZ into the stratum corneum, however, its low solubility results in poor dermal bioavailability, and variable drug levels limit the efficacy. The aim was to increase dermal bioavailability and sustain drug release, thereby potentially enhancing drug retention and reducing its side effects. This work evaluated the CTZ loaded solid lipid nanoparticles (SLN) consisting of precirol and polysorbate-80 developed using high pressure homogenization and optimized with QbD approach. Prior to release studies, CTZ-SLNs were characterized by different analytical techniques. The laser diffractometry and field emission scanning electron microscopy indicated that SLNs were spherical in shape with mean diameter of 450 ± 3.45nm. DSC and XRD results revealed that the drug remained molecularly dispersed in the lipid matrix. The CTZ-SLNs showed no physicochemical instability during 6months of storage at different temperatures. Further, the Carbopol with its pseudoplastic behavior showed a crucial role in forming homogenous and stable network for imbibing the CTZ-SLN dispersion for effective retention in skin. As examined, in-vitro drug release was sustained up to 24h while ex-vivo skin retention and drug permeation studies showed the highest accumulation and lowest permeation with nanogel in comparison to pure drug and Candid® cream. Further, the in-vivo antifungal efficacy of nanogel suggested once-a-day application for 10days, supported by histopathological analysis for complete eradication infection. In summary, the findings suggest, that nanogel-loaded with CTZ-SLNs has great potential for the management of fungal infections caused by Candida albicans.

Optimizing novasomes: impact of oleic acid and co-surfactant ratio on posaconazole delivery: In vitro &amp; Ex vivo pharmacokinetic study

Background: Posaconazole, currently available as a solid oral dosage form, possesses erratic pharmacokinetics that complicate dosing regimens and increase the risk of adverse effects and drug interactions. Hence, innovative strategies, especially topical ones, are necessary to enhance the therapeutic profile and improve patient outcomes. Methodology: The regular 23 factorial design and the concentrations of Oleic acid: Span 80 (2:1) ratio, Cholesterol, and Tween 80 as independent variables were used for the formulation development. The preliminary effect was determined by dependent variables like vesicle size and entrapment efficiency; then the final optimized batch was loaded in 3 % w/w Carbopol gel. Result and Discussion: The optimized batch's vesicle size and entrapment efficiency were 193.34+14.84 nm and 90.03+0.11 %, respectively. These results were found statistically significant (ANOVA) in the trial version of Stat-Ease 360®. Other evaluation parameters like zeta potential and pH of all the formulations were also significant (p&lt;0.005). Conclusion: The optimized batch (NF7), when loaded with gel (NF7G-3), showed sustained release of Posaconazole up to 7 h in an In vitro diffusion study facilitated 87.14±0.11 % release confirming non-Fickian or Anomalous diffusion, interpreted from Korsmeyer Peppas (KKP) model. With the results from In vitro and Ex vivo pharmacokinetic release, the Posaconazole-loaded NF7G-3 Novasomal gel can exhibit potential formulation for the topical treatment of fungal infections. It will help significantly mitigate the negative effects of Posaconazole.

TOPICAL NANOEMULSION-BASED GEL OF ISOCONAZOLE NITRATE

This study aimed to make an o/wnanoemulsion of isoconazole the drugnitrate (ISN) for topical use. Low aqueous solubility is a characteristicfeature of the imidazole antifungal ISN. Therefore, ISN nanoemulsion would increase dispersibility and decreases skin resistance by enhancing the drug penetration to the first layers of skin (stratum corneum). The work included constructing the pseudo-ternary phase diagrams by using the aqueous titration method. The prepared o/w nanoemulsions were composed of oil, Smix (a mixture of surfactant and co-surfactant) and deionized water (DW). ISN nanoemulsions were subjected to characterization studies to choose the best formula. According to the characterization studies, the optimal formula, designated NE14 contains 1% ISN, 66% Smix ((1:3) tween60: propylene glycol:ethanol), 7% oleic acid, and 27% deionized water was reached. FormulaNE14 is characterized by having a polydispersity index of (0.146), pH (5.76), droplet size (84.6 nm), percent transmittance (98.8%), viscosity (80m Pa.s) and a high release of isoconazole propably due low viscosity. The droplet size of NE14 (84.6nm) was alsoconfirmed by an atomic force microscopy (AFM) research. The improved formula (ISN NE14) was found to be a promising nanoemulsion formula for enhancing the topical bioavailability of ISN and thus could increase its efficacy for the treatment of topical fungal infections.

Graphene Scaffolds: A Striking Approach to Combat Dermatophytosis.

Exclusive physicochemical and biological properties of carbon allotrope graphene have attracted the peer attention of researchers for the synthesis and development of newer topical remedies including films, scaffolds, microspheres, and hydrogels. Here, graphene nanoplatelets (GN) were embedded into a different ratio of polymeric ERL100/ERS100 solution and fabricated in the form of a scaffold through the electrospinning process. FTIR spectra displayed characteristic similar peaks present both in GN and GN-loaded scaffold owing to the compatibility of GN and polymeric mixture. XRD curve revealed a distinct GN peak at nearly 26° whereas from DSC/TGA thermal stability was observed between polymers and graphene nanoplatelets. FESEM images showed ultrathin architecture of GN-loaded scaffold in a range of 280 ± 90 nm. The fabricated scaffold exhibited hydrophilicity (contact angle 48.8 ± 2.8°) and desirable swelling index (646% in skin pH media) which were desired criteria for the scaffold for topical application. In vitro, antifungal activity was conducted through the broth microdilution method against different virulent dermatophytes i.e., Microsporum gypseum, M. canis, M. fulvum, and Trychophyton rubrum. For in vivo evaluation, T. rubrum inoculum was applied on the dorsal surface of each group of Swiss albino mice, and the degree and intensity of mycelial growth or erythema on skin surfaces was visually investigated. The study depicted complete signs of cure after 14 days of application of G3-loaded scaffold on the infected dorsal site. Hence graphene-loaded scaffold represented a possible alternative for the treatment of topical fungal infections caused by dermatophytes.

Recent progression in nanocarrier based techniques to address fungal infections and patent status in drug development process.

Fungal infections are becoming one of the most common diseases in recent years, especially when it comes about dealing skin infections. Different drugs are available commercially with antifungal activity for topical application and are effective for treatment of mild to moderate fungal infections. However they lack dermal bioavailability due to their poor penetrability, and less retention at the site thereby resulting in poor efficacy. The remaining systemic treatment options available so far may cause adverse drug effects and many other complications. In recent years nano carrier based formulations promised to overcome the limitations of the conventional topical dosage forms. Lipid based nano carriers and their importance for potential use in delivery of antifungal agents for the treatment of superficial fungal infections have been well discussed in this review article. It comprises of different nano lipid systems involved in treatment of topical fungal infections, effect of different polymers on their size, stability, and their mechanistic action behind skin penetration and dermal retention of drug into deeper epidermal layers is also highlighted to depict recent efforts of researchers in this context. Further, the addressing of the disease by novel drug delivery systems for the efficacious treatment, status of clinical trials, novel commercial formulations available for use in dermal drug delivery and patents claimed/granted in the respective field have been discussed in detail.

Development, Characterization and Evaluation of Phytosomal Gel of Curcumin for the Treatment of Topical Fungal Infection

An innovative approach to the delivery of phytoconstituents and plant extracts for therapeutic and cosmetic purposes constitutes a herbal medication delivery system. However, their bioavailability is low because of their high molecular size and low lipid solubility. Turmeric (Curcuma longa) and Curcuma xanthorrhiza oil contain the active component curcumin, also known as diferuloylmethane. This medication can kill or inhibit the growth of bacteria, fungi, viruses, and fungi, and it can reduce inflammation, lower blood sugar, and speed the healing of wounds. In this study, we created a phytosomal gel containing Curcumin and analyzed its efficacy. Anti-solvent precipitation was used to create Curcumin phytosomes in three separate batches with varying drug-to-soya lecithin ratios. Several tests, including those of yield, solubility, drug content, entrapment efficiency, and in vitro drug release, were conducted on phytosomal formulations. Based on a number of evaluation criteria, the formulation F1 was chosen as the optimal formulation to include into a gel basis of varying proportions utilizing carbopol 940 and PEG400 as polymers. This formulation contained drug extract: soya lecithin in the ratio 1:1. Maximum drug absorption (98.19%) was observed after 8 hours in the improved formulation (G2). 45 days of stability testing was conducted at 40oC ±20oC, 70±5%.RH The drug's potency, pH, dispersibility, extrudability, viscosity, or in-vitro diffusion profile all remained unchanged. The Curcumin phytosomal gel was found to have a superior diffusion and stability profile, making it an appealing vehicle for the delivery of the various phytoconstituents.

Development and Evaluation of Nanoformulations Containing Timur Oil and Rosemary Oil for Treatment of Topical Fungal Infections.

The pervasiveness of fungal infections is an issue for skin health globally, and there are a reported 40 million cases in developed and developing countries. Novel drug delivery systems provide better therapeutic efficacy over conventional drug therapy due to their lower side effects and toxicity. Furthermore, combinations of essential oils can represent alternative therapies for fungal infections that are resistant to synthetic drugs. This study is aimed at developing Timur oil into a nanoemulgel and evaluating its antifungal effects. The development of the formulation involved the preparation of a nanoemulsion by the titration method, followed by its evaluation for various physicochemical properties. The antifungal activity of the nanoemulgel against Candida albicans was evaluated. The zone of inhibition was determined using the disk diffusion method. The results show that the developed nanoemulgel has a particle size of 139 ± 6.11 nm, a PDI of 0.309, and a zeta potential of -19.12 ± 2.73 mV. An in vitro drug release study showed a sustained release of 70 ± 0.289% of the drug over a period of 24 h. The % drug permeation across the skin was found to be 79.11 ± 0.319% over 24 h. However, the amount of drug retained in the skin was 56.45 µg/g. The flux for the nanoemulgel was found to be 94.947 µg/cm2/h, indicating a better permeability profile. The nanoemulgel formulation showed a zone of inhibition of 15 ± 2.45 mm, whereas the 1% ketoconazole cream (marketed preparation) exhibited a zone of inhibition of 13 ± 2.13 mm. The results of this study suggest that developed nanoemulgel containing Timur oil and rosemary oil has the potential to be used for treating topical fungal infections caused by Candida albicans.

Formulation and Evaluation of Niosomal Gel of Antifungal Luliconazole

Niosomes have potential applications in topical drug delivery system. Niosomes play an increasingly important role in drug delivery as they can reduce toxicity and modify pharmacokinetic and bio-availability. Topically applied niosomes can increase the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. It can act as drug containing reservoirs and the modification of the vesicular compositions or surface properties can adjust the drug release rate and the affinity for the target site. Luliconazole is a potential prescription candidate drug for the treatment of topical fungal infections. However, it has water solubility and skin permeability limitations. To overcome these limitations, a niosomal gel of luliconazole was formulated using Span 60, cholesterol and chloroform to improve its bioavailability and to reduce its toxicity. Niosomes were analyzed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) for morphological and spectral studies respectively. The formulations had ideal nanometric vesicle sizes, encapsulation efficiency (88.891% ± 0.0364%), Zeta potential (-40.1 mV), and storage instability was not observed. The sustained-release profile of niosomal gel was observed for up to 24 h. The highest R2 value was 0.913; the Higuchi model was considered the best fit model for the niosomal formulations. Based on the results, it can be concluded that niosomal luliconazole may enhance the activity of luliconazole against Candida albicans.&#x0D; Keywords: Luliconazole, Niosomes, Transdermal drug delivery, Antifungal drugs, Candida albicans

Development and characterization of itraconazole non-aqueous creams for the treatment of topical fungal infections

Itraconazole is a broad-spectrum triazole antifungal agent used to prevent and treat fungal infections. Itraconazole is commercially available as an oral and intravenous formulation; however, its administration via these routes is associated with various side effects, such as hepatotoxicity, peripheral neuropathy, cardiac dysrhythmia, and hearing loss. The objective of the current study was to prepare a stable non-aqueous topical cream loaded with itraconazole for prolonged drug contact, improved drug permeation and penetration into skin layers, and to prevent the side effects associated with other routes of administration for improved therapeutic outcomes. The developed creams were characterized for drug content, pH, texture analysis, rheology behavior, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, ex vivo drug permeation through human cadaver skin, and stability. The lead formulations were stable over three months (the last time-point tested) during refrigeration and room-temperature storage. The cream formulation developed with 15% w/w Transcutol® P improved itraconazole permeation and deposition through the skin by 8.4- and 8.2-fold, compared to the drug solution, respectively. Thus, itraconazole -loaded non-aqueous creams can serve as alternative drug delivery platforms for the treatment of fungal skin infections over oral/parenteral itraconazole formulations.

Green formulation, characterization, antifungal and biological safety evaluation of terbinafine HCl niosomes and niosomal gels manufactured by eco-friendly green method

Terbinafine (TER) is a promising candidate medication for the topical treatment of fungal infections. However, its solubility in water and skin permeability are limited. To overcome these limitations, a Terbinafine niosome and niosomal gel was developed. The impact of cholesterol:surfactants on terbinafine incorporated niosome (terbinasome) preparations was examined. Differential scanning calorimetry (DSC), photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy were used to assess the morphological features of terbinasome and the physicochemical characteristics of TER in terbinasome. The obtained results has shown that Chol enhanced the diameter of the terbinasome from 123.20 ± 2.86 to 701.93 ± 17.72 nm. The highest encapsulation of terbinafine was estimated to be around 66% due to the cholesterol:surfactants ratio in the terbinasome was 1:3 and 1:6. Additional examination has revealed that changes in the cholesterol:surfactants ratio can result in a change in the PDI value of between 0.421 ± 0.004 and 0.712 ± 0.011. The terbinasome gel was prepared and tested for pharmaceutical testing, including pH, viscosity, spreadability, and stability. The percentage of TER dissolution from terbinasome were determined more than 80% and showed quickest drug release. In a cutaneous permeability examination, the quantity of TER in the cutaneous layers and the receiver compartment were higher for the terbinasome gel than for the TER simple gel. The terbinasome's cell viability was around 90% (HFF cell line) and MTT experiment demonstrated that the terbinasome was not cytotoxic. The MIC of the terbinasome was lower than pure drug against Aspergillus, Fusarium, and Trichophyton. The terbinasomal gels were non-irritant (score < 2) in the cutaneous irritation examination performed on Wistar rats. The research suggests that the optimized terbinasome may be used as a nano-vesicle for TER drug administration, hence opening up new possibilities for the treatment of cutaneous infections.

In Vitro, Ex Vivo, and In Vivo Evaluation of Nanoparticle-Based Topical Formulation Against Candida albicans Infection.

Ketoconazole is commonly used in the treatment of topical fungal infections. The therapy requires frequent application for several weeks. Systemic side effects, allergic reactions, and prolonged treatment are often associated with non-compliance and therapy failure. Hence, we developed an optimized topical antifungal gel that can prolong the release of drug, reduce systemic absorption, enhance its therapeutic effect, and improve patient compliance. Ketoconazole-loaded PLGA nanoparticles were prepared by the emulsion/solvent evaporation method and were characterized with respect to colloidal properties, surface morphology, and drug entrapment efficiency. The optimized ketoconazole-loaded PLGA nanoparticles and commercially available silver nanoparticles were incorporated into a Carbopol 934P-NF gel base. This arrangement was characterized and compared with commercially available 2% ketoconazole cream to assess physical characteristics of the gel, in vitro drug release, ex vivo skin permeation and retention, and in vivo studies on Wister male albino rats. The results showed that polymeric PLGA nanoparticles were very effective in extending the release of ketoconazole in our optimized formulation. Nanoparticles were smooth, spherical in shape, and below 200 nm in size which is consistent with the data obtained from light scattering and SEM images. The ex vivo data showed that our gel formulation could strongly reduce drug permeation through the skin, and more than 60% of the drug was retained on the upper surface of the skin in contrast to 38.42% of the commercial cream. The in vivo studies showed that gel formulation could effectively treat the infection. This study demonstrates that our topical gel could be effective in sustaining the release of drug and suggests its potential use as a possible strategy to combat antifungal-resistant Candida albicans.

Formulation and evaluation of microemulsion containing miconazole nitrate

The aim of the present research is to formulate a microemulsion containing miconazole nitrate as it provides various advantages over conventional dosage form. It also put forward the idea for the formulation of microemulsion containing miconazole nitrate with the use of varying surfactant and co- surfactants with an objective to increase the better drug loading, high transparency, high thermodynamic stability, better bioavailability and ease of preparation. Miconazole nitrate is hydrophobic imidazole antifungal agent. The studies show that it is highly effective in the topical treatment of fungal infections. Due to the presence of both lipophilic and hydrophilic domains, a wide range of lipophilic and hydrophilic domains are incorporated in these systems.

Voriconazole nanoparticles-based film forming spray: An efficient approach for potential treatment of topical fungal infections

Voriconazole (VRC) is a broad-spectrum antifungal agent but possesses serious adverse effects systemically, which can be minimized by topical drug delivery. The goal of this project was to develop novel VRC-loaded polymeric nanoparticles to enhance the topical delivery in the form of film forming spray (FFS). The polymeric nanoparticles of VRC were prepared through Ionic gelation method and optimized using Design expert (free trial version 7) software. Optimized PNPs showed a spherical shape in nano-range. An extended release of VRC up to 24 h from the optimized formulation followed a diffusion-based mechanism at skin pH (5.5). Ex vivo permeability and skin retentivity test confirmed the deposition of VRC in skin layers. The final formulation showed potential antifungal activity against Candida albicans and Aspergillus flavus. Non-irritant nature of film forming spray (FFS) was confirmed through histological study on the rabbit's skin. Hence, VRC-PNPs based FFS could be a potential candidate for treating topical fungal infections.

FORMULATION DEVELOPMENT AND EVALUATION OF TRANSFERSOMES OF ECONAZOLE FOR EFFECTIVE FUNGAL TREATMENT

The aim of the present work is to formulate and characterize Econazole loaded transfersomal gel for antifungal activity. Econazole is a broad-spectrum imidazole antifungal agent that belongs to BCS Class II. Due to poor solubility, Econazole is incompletely absorbed after oral administration and bioavailability vary among individuals. Topical treatment of fungal infections is usually preferred, but the barrier is to cross stratum corneum, so formulating the drug in Transfersomes solved this problem. Prepared formulations of transfersomes were optimized on basis of vesicle size, shape, surface charge and entrapment efficiency. In order to predict and correlate the in vitro econazole permeation behavior from these transfersomes through semi-permeable membrane, it is necessary to fit into a suitable mathematical model. The in vitro drug permeation data from formulation F-12 containing econazole through semi-permeable membrane was evaluated kinetically by various mathematical models like zero-order, first-order, Higuchi, and Korsmeyer-Peppas Model. The results were obtained which showed that transfersomal gel was a promising candidate for transdermal delivery with targeted and prolonged release of a drug.

Development of novel biopolymer-based nanoparticles loaded cream for potential treatment of topical fungal infections

Objective Biodegradable polymers are extensively used due to their efficient safety profiles. The aim of the current study was to fabricate, evaluate, and characterize biodegradable, biocompatible fluconazole (FLZ) loaded chitosan (CHS) chondroitin sulfate (CS) nanoparticles (NPs) for topical delivery. Polymers utilized in the formulation not only served as a carrier system but also aided in fighting with complex etiology of the disease due to their innate antifungal activities. Methods NPs were prepared by the complex coacervation method, then were optimized for various parameters and subsequently loaded into a cream. Results Scanning electron microscopic (SEM) analysis showed spherical morphology of the NPs. Prepared NPs showed an average particle size in the range of 350–450 nm and an encapsulation efficiency (EE) of 86%. The polydispersity index (PDI) was found to be 0.148 that showed a uniform distribution of NPs. Fourier transform infrared (FTIR) spectroscopy confirmed the absence of any electrostatic interaction between ingredients. In vitro drug release analyses exhibited a sustained release of the drug and higher antifungal activity than free FLZ. Ex vivo permeability and drug distribution in different skin layers ensured a site-specific delivery of the FLZ-NPs. As compared with free FLZ and other control groups, the prepared NPs also exhibited significantly higher antifungal activity against Candida albicans (p < .01). Conclusion It was concluded from the results that the FLZ-NPs laden cream could be a potential candidate for topical and site-specific delivery of the drug cargo for the potential treatment of fungal infections.

Synthetic Derivatives of Ciclopirox are Effective Inhibitors of Cryptococcus neoformans.

Opportunistic fungal infections caused by Cryptococcus neoformans are a significant source of mortality in immunocompromised patients. They are challenging to treat because of a limited number of antifungal drugs, and novel and more effective anticryptococcal therapies are needed. Ciclopirox olamine, a N-hydroxypyridone, has been in use as an approved therapeutic agent for the treatment of topical fungal infections for more than two decades. It is a fungicide, with broad activity across multiple fungal species. We synthesized 10 N-hydroxypyridone derivatives to develop an initial structure–activity understanding relative to efficacy as a starting point for the development of systemic antifungals. We screened the derivatives for antifungal activity against C. neoformans and Cryptococcus gattii and counter-screened for specificity in Candida albicans and two Malassezia species. Eight of the ten show inhibition at 1–3 μM concentration (0.17–0.42 μg per mL) in both Cryptococcus species and in C. albicans, but poor activity in the Malassezia species. In C. neoformans, the N-hydroxypyridones are fungicides, are not antagonistic with either fluconazole or amphotericin B, and are synergistic with multiple inhibitors of the mitochondrial electron transport chain. They appear to function primarily by chelating iron within the active site of iron-dependent enzymes. This preliminary structure–activity relationship points to the need for a lipophilic functional group at position six of the N-hydroxypyridone ring and identifies positions four and six as sites where further substitution may be tolerated. These molecules provide a clear starting point for future optimization for efficacy and target identification.

Solubility enhancement, formulation development and antifungal activity of luliconazole niosomal gel-based system

Luliconazole is a potential prescription candidate drug for the treatment of topical fungal infections. However, it has water solubility and skin permeability limitations. To overcome these limitations, a niosomal gel of luliconazole was formulated using Span 60, cholesterol, and chloroform to improve its bioavailability and to reduce its toxicity. Niosomes were analyzed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) for morphological and spectral studies respectively. The formulations had ideal nanometric vesicle sizes, encapsulation efficiency (88.891% ± 0.0364%), Zeta potential (−40.1 mV), and storage instability was not observed. The sustained-release profile of niosomal gel was observed for up to 24 h. The highest R2 value was 0.913; the Higuchi model was considered the best fit model for the niosomal formulations. Cytotoxicity studies confirmed the biocompatibility of the niosomal gel of luliconazole. Based on the results, it can be concluded that niosomal luliconazole may enhance the activity of luliconazole against Candida albicans (C. albicans).

Soft Malleable Vesicles: versatile carriers for efficient topical delivery of fungal therapeutics.

Fungal infections have become a subject of great concern and the incidence of fungal infections is increasing, presenting an enormous challenge to healthcare professionals. Since most of the fungal infections are occurring over the skin, the treatment option of these infections always involves topical application. However, in topical delivery drug reaches into systemic circulation through different barriers of skin. Nevertheless, due to the low permeability, skin restricts the movement of many drugs. Hence, a delivery system is required, which deliver the medicament into the skin layers or through the skin and into the systemic circulation. Ethosomes or Soft malleable vesicles are the novel lipid vesicular carrier that offer improved skin permeability and efficient delivery due to their structure and composition. They contain high concentration of ethanol, which increases the fluidity of the skin. Therefore, in the present paper, we have explored the utility of ethosomal systems in the topical treatment of fungal infections. Structure, compositions types, mechanism and techniques of preparation of ethosome also discussed in the paper.