Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole.

TRPV6 is a calcium-selective ion channel implicated in epithelial Ca2+ uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, including cancers. Here we combine cryo-EM, calcium imaging, and mutagenesis to explore molecular bases of human TRPV6 inhibition by the antifungal drug econazole and the universal ion channel blocker ruthenium red (RR). Econazole binds to an allosteric site at the channel's periphery, where it replaces a lipid. In contrast, RR inhibits TRPV6 by binding in the middle of the ion channel's selectivity filter and plugging its pore like a bottle cork. Despite different binding site locations, both inhibitors induce similar conformational changes in the channel resulting in closure of the gate formed by S6 helices bundle crossing. The uncovered molecular mechanisms of TRPV6 inhibition can guide the design of a new generation of clinically useful inhibitors.

Enantioselective determination of econazole in rat plasma and its application to a pharmacokinetic study.

Econazole is a widely used chiral antifungal drug. In this paper, an enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for determination of econazole enantiomers in rat plasma for the first time. After addition of the internal standard (IS) clotrimazole, plasma samples were extracted by liquid-liquid extraction with n-hexane:2-propanol (98.5:1.5, v/v). Baseline separation of the enantiomers was achieved on a Chiralpak® IC column (250 mm × 4.6 mm, 5 µm) using acetonitrile-ammonium acetate buffer (5 mM) (85:15, v/v) as mobile phase. The detection of the analytes was performed in multiple reaction monitoring (MRM) mode with positive electrospray ionization. Transitions of m/z 381.07 â†’ 124.92 and 276.78 â†’ 164.92 were monitored for econazole enantiomers and clotrimazole, respectively. The linear range was 0.20-50.00 ng/mL with the lower limit of quantification of 0.20 ng/mL for both econazole enantiomers in plasma. The intra-day and inter-day precisions were not exceeding 10.2% and the accuracies were within ±15.0%. The validated method was successfully applied to the stereoselective pharmacokinetic study of econazole enantiomers in rat plasma after transdermal administration of racemic econazole nitrate cream. Significant differences were observed in Cmax, AUC and CL/F of econazole enantiomers, indicating the enantioselective pharmacokinetic behavior of econazole in rats.

Antifungal activity of econazole nitrate/cyclodextrin complex: Effect of pH and formation of complex aggregates.

Econazole nitrate (ECN) is a weakly basic drug with very low aqueous solubility that hampers its permeation through biological membranes and results in low ECN bioavailability. Formation of drug/cyclodextrin (drug/CD) inclusion complexes is a formulation technology that can be applied to enhance drug solubility in aqueous media. The aim of this study was to determine the effect of CD complexation and pH adjustments on the ECN solubility. The ECN pH-solubility and ECN/CD phase-solubility profiles were determined. The solubility of ECN in aqueous acidic solutions containing α-cyclodextrin (αCD) was relatively high and much higher than in aqueous γ-cyclodextrin (γCD) solutions under same conditions. The complexation efficiency of the ECN/CD complex was relatively low for the unionized drug. Formation of ECN/CD inclusion complex was verified by proton nuclear magnetic resonance spectroscopy. Formation of ECN/CD complexes enhanced the drug stability during autoclaving. γCD complexes self-assembled to form nano- and microparticles whereas αCD complexes had negligible tendency to self-assemble. Formation of CD complex nano- and microparticles was investigated by dynamic light scattering and by drug permeation through semipermeable membranes of different molecular weight cut-off. The largest aggregate fraction was observed for the unionized ECN in aqueous pH 7.5 solution containing high CD concentration, that is 10% (w/v) CD. It was shown that in acidic solutions ECN/αCD can enhance the antifungal activity to filamentous fungi. This was associated with the increased ECN solubility and increase of readily available ECN molecules in aqueous αCD solutions.

Maltodextrin-modified graphene oxide for improved enantiomeric separation of six basic chiral drugs by open-tubular capillary electrochromatography.

An electrochromatographic capillary was modified with graphene oxide (GO), and the coating was characterized by scanning electron microscopy, energy dispersive X-ray spectrometry, and Fourier transform infrared spectra. By utilizing maltodextrin (MD) as the chiral selector, the basic chiral drugs nefopam (NEF), amlodipine (AML), citalopram hydrobromide (CIT), econazole (ECO), ketoconazole (KET) and cetirizine hydrochloride (CET) can be enantiomerically separated on this CEC. Compared with an uncoated silica capillary, the resolutions are markedly improved (AML: 0.32 → 1.45; ECO: 0.55 → 1.89; KET: 0.88 → 4.77; CET: 0.81 → 2.46; NEF: 1.46 → 2.83; CIT: 1.77 → 4.38). Molecular modeling was applied to demonstrate the mechanism of enantioseparation, which showed a good agreement with the experimental results. Graphical abstractSchematic representation of the preparation of graphene oxide-modified capillary (GO@capillary) for enantioseparation of drug enantiomers. The monolayered GO was used as the coating of the GO@capillary. Then the capillary was applied to construct capillary electrochromatography system with maltodextrin for separation of basic chiral drugs.

Design and Characterization of Chitosan Nanoformulations for the Delivery of Antifungal Agents.

Among different Candida species triggering vaginal candidiasis, Candida albicans is the most predominant yeast. It is commonly treated using azole drugs such as Tioconazole (TIO) and Econazole (ECO). However, their low water solubility may affect their therapeutic efficiency. Therefore, the aim of this research was to produce a novel chitosan nanocapsule based delivery system comprising of TIO or ECO and to study their suitability in vaginal application. These systems were characterized by their physicochemical properties, encapsulation efficiency, in vitro release, storage stability, cytotoxicity, and in vitro biological activity. Both nanocapsules loaded with TIO (average hydrodynamic size of 146.8 ± 0.8 nm, zeta potential of +24.7 ± 1.1 mV) or ECO (average hydrodynamic size of 127.1 ± 1.5 nm, zeta potential of +33.0 ± 1.0 mV) showed excellent association efficiency (99% for TIO and 87% for ECO). The analysis of size, polydispersity index, and zeta potential of the systems at 4, 25, and 37 °C (over a period of two months) showed the stability of the systems. Finally, the developed nanosystems presented fungicidal activity against C. albicans at non-toxic concentrations (studied on model human skin cells). The results obtained from this study are the first step in the development of a pharmaceutical dosage form suitable for the treatment of vaginal candidiasis.

Transethosomes of Econazole Nitrate for Transdermal Delivery: Development, In-vitro Characterization, and Ex-vivo Assessment.

BACKGROUND: Transdermal drug delivery is an attractive approach for both local and systemic therapeutics of various diseases. Transdermal drug delivery systems show various advantages like reduction of local irritation, prevention of first-pass hepatic metabolism, and bioavailability enhancement of bioactive molecules over conventional drug delivery systems. OBJECTIVE: The main objective of the present research work was to develop and characterize (in-vitro and ex-vivo) econazole nitrate loaded transethosomes and their comparison with marketed cream of econazole nitrate [Ecoderm, Brown and Burk Pharmaceutical (Pvt.) Ltd., Bengaluru, India] for effective transdermal delivery. METHOD: Transethosomes loaded with econazole nitrate were developed by homogenization method and evaluated for entrapment (%), vesicular size, zeta potential, polydispersity index (PDI), and invitro drug release. Furthermore, optimized econazole nitrate loaded transethosomes were added to Carbopol 934 gel and this gel was evaluated for viscosity, pH, drug content, ex-vivo skin permeation and retention studies followed by in-vitro antifungal activity against C. albicans fungus. RESULTS: The optimized transethosomes loaded with econazole nitrate showed vesicle size of 159.3 ± 4.3 nm, entrapment efficiency about 78.3 ± 2.8%, acceptable colloidal properties like (zeta potential = -27.13 ± 0.33 mV, PDI = 0.244 ± 0.045), approximately 57.56 ± 2.33% drug release up to 24 h. Results of DSC analysis confirmed the encapsulation of econazole nitrate inside transethosomes. Optimized transethosomes showed drug release following zero order through diffusion mechanism. Transethosomal gel showed high drug content (92.35 ± 0.63%) and acceptable values of pH (5.68 ± 0.86) or viscosity (10390 ± 111 cPs). Transethosomal gel showed less ex-vivo skin penetration (17.53 ± 1.20%), high ex-vivo skin retention (38.75 ± 2.88%), and high in-vitro antifungal activity compared to the marketed cream of econazole nitrate. CONCLUSION: Therefore, it can be concluded that econazole nitrate loaded transethosomes are effective to deliver econazole nitrate transdermally in a controlled fashion for effective elimination of cutaneous candidiasis.

Econazole-releasing porous space maintainers for fungal periprosthetic joint infection.

While antibiotic-eluting polymethylmethacrylate space maintainers have shown efficacy in the treatment of bacterial periprosthetic joint infection and osteomyelitis, antifungal-eluting space maintainers are associated with greater limitations for treatment of fungal musculoskeletal infections including limited elution concentration and duration. In this study, we have designed a porous econazole-eluting space maintainer capable of greater inhibition of fungal growth than traditional solid space maintainers. The eluted econazole demonstrated bioactivity in a concentration-dependent manner against the most common species responsible for fungal periprosthetic joint infection as well as staphylococci. Lastly, these porous space maintainers retain compressive mechanical properties appropriate to maintain space before definitive repair of the joint or bony defect.

Fabrication of a drug delivery system that enhances antifungal drug corneal penetration.

Fungal keratitis (FK) remains a severe eye disease, and effective therapies are limited by drug shortages and critical ocular barriers. Despite the high antifungal potency and broad spectrum of econazole, its strong irritant and insolubility in water hinder its ocular application. We designed and fabricated a new drug delivery system based on a polymeric vector for the ocular antifungal application of econazole. This novel system integrates the advantages of its constituent units and exhibits superior comprehensive performance. Using the new system, drug content was significantly increased more than 600 folds. The results of in vivo and in vitro experiments demonstrated that the econazole-loaded formulation exhibited significantly enhanced corneal penetration after a single topical ocular administration, excellent antifungal activity, and good tolerance in rabbits. Drug concentrations and ocular relative bioavailability in the cornea were 59- and 29-time greater than those in the control group, respectively. Following the topical administration of one eye drop (50 µL of 0.3% w/v econazole) in fungus-infected rabbits, a high concentration of antimycotic drugs in the cornea and aqueous humor was sustained and effective for 4 h. The mechanism of corneal penetration was also explored using dual fluorescent labeling. This novel drug delivery system is a promising therapeutic approach for oculomycosis and could serve as a candidate strategy for use with various hydrophobic drugs to overcome barriers in the treatment of many other ocular diseases.

Mucoadhesive self-emulsifying delivery systems for ocular administration of econazole.

AIM: Development of mucoadhesive self-emulsifying drug delivery systems (SEDDS) providing a prolonged ocular residence time for poorly soluble active pharmaceutical ingredient. METHODS: l-Cysteine was covalently linked to 6-mercaptonicotinamide. The obtained ligand, Cysteine-6-mercaptonicotinamide (Cys-6-MNA) was attached to Eudragit® L100-55 via a carbodiimide mediated amide bond formation. The resulting entirely S-protected thiolated Eudragit® L100-55 was characterized regarding the degree of modification as well as stability toward oxidation in the presence of strong oxidizing agent (H2O2). The S-protected thiolated Eudragit® L100-55 was incorporated into SEDDS via hydrophobic ion pairing with benzalkonium chloride (BAK) in a concentration of 2% (m/m). S-protected thiolated Eudragit® L100-55-BAK ion pair SEDDS (S-protected thiolated EU-BAK SEDDS) were characterized regarding their physicochemical and mucoadhesive properties. Econazole nitrate (EN) was incorporated into SEDDS in concentration of 1% (m/m) and in vitro drug release was assessed. Furthermore, toxicity study was performed on procine corneas via resazurin assay. RESULTS: The entirely S-protected thiolated Eudragit® L100-55 exhibited 282 ±â€¯78.25 µmol of MNA per gram of polymer. Ellman's test confirmed no free thiol groups and stability study showed no significant increase in dynamic viscosity overtime. The droplet size of developed SEDDS in simulated lacrimal fluid was below 100 nm with polydispersity index below 0.3. S-protected thiolated EU-BAK SEDDS exhibited 2.5-fold higher mucoadhesive properties than blank SEDDS on ocular mucosa. S-protected thiolated EU-BAK SEDDS showed sustained EN release over period of 8 h and no pronounced corneal toxicity in 0.5% (m/v) concentration. CONCLUSION: Accordingly, these mucoadhesive SEDDS can be considered as promising ocular delivery system for EN.

Non-equilibrium atmospheric pressure plasma as innovative method to crosslink and enhance mucoadhesion of econazole-loaded gelatin films for buccal drug delivery.

In this paper we developed an innovative, effective and rapid one-step approach to crosslink mucoadhesive gelatin films for buccal drug delivery. The method, which involves the application of non-equilibrium pressure plasma for 3 or 5 minutes/side, was compared with a classical approach based on the use of a chemical crosslinking agent, namely genipin. Econazole nitrate (ECN), an imidazole antifungal agent used for the treatment of skin infections and mucosal candidiasis, was selected as model drug. X-Ray Diffraction characterization performed on the drug-containing gelatin films revealed that ECN undergoes to a topotactic transformation into Econazole (EC) immediately after mixing with gelatin suggesting the occurrence of an acid-base reaction between drug and gelatin during film processing. Plasma treatment, as well as genipin crosslinking, did not provoke any further variation of EC structure. However, plasma exposure significantly improved films adhesiveness and allowed to reach mucoadhesive strength values more than double with respect to those obtained with genipin, ascribable to the presence of polar and hydrophilic groups on the plasma treated film's surface. A residence time of at least 48 h was obtained by properly selecting the plasma exposure times. These results, together with the in-vitro data showing retention of antifungal efficacy against a strain of Candida albicans, demonstrated that plasma treatment was a valid and rapid alternative, easy to scale-up, to chemical crosslinking methods for the production of highly mucoadhesive gelatin-based films.

Adsorption of Antifungal Drugs Inside Pristine and Functionalized Fullerenes and Nanotubes: DFT Investigation.

BACKGROUND: Econazole, sulconazole and tioconazole usage as antifungal agents is limited due to poor pharmacokinetic properties. Pristine and hydroxylated structures of the C240 fullerene and single walled carbon nanotube (SWCNT) were proposed as transporters of these imidazoles potentially enhancing their pharmacokinetics. METHODS: To assess possibility of creation of the endohedral complexes of the azoles and carbon nanostructures, their adsorption and interaction energies were calculated with the hybrid exchange-correlation density functional B97-1 and 6-31(d,p) basis set. Interactions within the transporter - drug complexes were investigated with the Atoms in Molecules (AIM) Theory and Reduced Density Gradient (RDG). RESULTS AND CONCLUSIONS: The adsorption energies of the studied azoles depend on type and surface modification of the transporter. Hydroxylation of the fullerene and nanotube surface makes an opportunity for chemisorption of the investigated antifungal drugs. The pristine and hydroxylated nanotube complexes exhibit thermodynamic stability. The complexes of the fullerenes are thermodynamically unstable but its kinetic stability could be significant thus allowing for the such structures to exist. The energetic instability would enhance liberation of the encapsulated molecule from the complex. It is advantageous in the context of drug release.

Improvement of the Ocular Bioavailability of Econazole Nitrate upon Complexation with Cyclodextrins.

Econazole nitrate (EC) is an active, imidazole antifungal agent. However, low aqueous solubility and dissolution rate of EC has discouraged its usage for the treatment of ophthalmic fungal infection. In this study, inclusion complexes of EC with cyclodextrins were prepared to enhance its solubility, dissolution, and ocular bioavailability. To achieve this goal, EC was complexed with ß-CyD/HP-ß-CyD using kneading, co-precipitation, and freeze-drying techniques. Phase-solubility studies were performed to investigate the complexes in the liquid form. Additionally, the complexes in the solid form were characterized with Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and transmission electron microscopy (TEM). Furthermore, different eye drops containing EC-CyD complexes were prepared using different polymers and then characterized regarding their drug contents, pH, viscosity, mucoadhesive strength, and in vitro release characteristics. The results showed that stable EC-CyD complexes were formed in 1:1 molar ratio as designated by BS-type diagram. Econazole nitrate water solubility was significantly increased in about three- and fourfold for ß-CyD and HP-ß-CyD, respectively. The results showed that the prepared complexes were spherical in shape having an average particle diameter from 110 to 288.33 nm with entrapment efficiency ranging from 64.24 to 95.27%. DSC investigations showed the formation of real inclusion complexes obtained with co-precipitation technique. From the in vitro studies, all eye drops containing co-precipitate complexes exhibited higher release rate than that of other complexes and followed the diffusion-controlled mechanism. In vivo study proved that eye drops containing EC-CyD complexes showed higher ocular bioavailability than EC alone which indicated by higher AUC, Cmax, and relative bioavailability values.

Econazole Nitrate Foam 1% Improves the Itch of Tinea Pedis.

Econazole nitrate topical foam, 1%, is indicated for the treatment of interdigital tinea pedis caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum in patients 12 years of age and older. The symptom of itch or pruritus was evaluated in two randomized, double-blind, parallel-group, vehicle-controlled, multicenter Phase III studies in which econazole foam was compared with foam vehicle in subjects with interdigital tinea pedis. A thin, uniform layer of study treatment was applied once daily to all clinically affected interdigital regions of both feet for four weeks. At baseline, at least 69% of all subjects had moderate to severe itch. Throughout the duration of both studies, numerically econazole foam was numerically superior to vehicle in achieving absence of itch. After the cessation of treatment, from day 29, itching continues to improve until day 43 in the active treatment group, whereas there is no evident continued improvement within the vehicle foam groups. At day 43, in the active treatment groups, 83% in Study 1 and 71% in Study 2 achieved complete absence of itching. Using less stringent criteria, for the econazole nitrate foam arm, achieving no itch or mild itch (0 or 1), in Study 1, 95% and 86.8% in Study 2 achieved this outcome. Tolerability of the products was excellent with few treatment-related adverse events. In summary, econazole foam decreased the burden of itch as early as day 8 in patients with interdigital tinea pedis, and this improvement continued after cessation of treatment.

J Drugs Dermatol. 2016;15(9):1111-1114.

Capillary electrophoretic enantioseparation of basic drugs using a new single-isomer cyclodextrin derivative and theoretical study of the chiral recognition mechanism.

A novel single-isomer cyclodextrin derivative, heptakis {2,6-di-O-[3-(1,3-dicarboxyl propylamino)-2-hydroxypropyl]}-ß-cyclodextrin (glutamic acid-ß-cyclodextrin) was synthesized and used as a chiral selector in capillary electrophoresis for the enantioseparation of 12 basic drugs, including terbutaline, clorprenaline, tulobuterol, clenbuterol, procaterol, carvedilol, econazole, miconazole, homatropine methyl bromide, brompheniramine, chlorpheniramine and pheniramine. The primary factors affecting separation efficiency, which include the background electrolyte pH, the concentration of glutamic acid-ß-cyclodextrin and phosphate buffer concentration, were investigated. Satisfactory enantioseparations were obtained using an uncoated fused-silica capillary of 50 cm (effective length 40 cm) × 50 µm id with 120 mM phosphate buffer (pH 2.5-4.0) containing 0.5-4.5 mM glutamic acid-ß-cyclodextrin as background electrolyte. A voltage of 20 kV was applied and the capillary temperature was kept at 20°C. The results proved that glutamic acid-ß-cyclodextrin was an effective chiral selector for studied 12 basic drugs. Moreover, the possible chiral recognition mechanism of brompheniramine, chlorpheniramine and pheniramine on glutamic acid-ß-cyclodextrin was investigated using the semi-empirical Parametric Method 3.

Nano Spray Drying Technique as a Novel Approach To Formulate Stable Econazole Nitrate Nanosuspension Formulations for Ocular Use.

The effect of using methyl-ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin as carriers for econazole nitrate nanoparticles prepared by nano spray dryer was explored in this work. Stabilizers, namely, poly(ethylene oxide), polyvinylpyrrolidone k30, poloxamer 407, Tween 80, and Cremophor EL, were used. The nano spray dried formulations revealed almost spherical particles with an average particle size values ranging from 121 to 1565 nm and zeta potential values ranging from -0.8 to -2.5 mV. The yield values for the obtained formulations reached 80%. The presence of the drug in the amorphous state within the nanosuspension matrix system significantly improved drug release compared to that for pure drug. Combination of hydroxypropyl-ß-cyclodextrin with Tween 80 achieved an important role for preserving the econazole nanosuspension from aggregation during storage for one year at room temperature as well as improving drug release from the nanosuspension. This selected formulation was suspended in chitosan HCl to increase drug release and bioavailability. The in vivo evaluation on albino rabbit's eyes demonstrated distinctly superior bioavailability of the selected formulation suspended in chitosan compared to its counterpart formulation suspended in buffer and crude drug suspension due to its mucoadhesive properties and nanosize. The nano spray dryer could serve as a one step technique toward formulating stable and effective nanosuspensions.

Econazole imprinted textiles with antifungal activity.

In this work, we propose pharmaceutical textiles imprinted with lipid microparticles of Econazole nitrate (ECN) as a mean to improve patient compliance while maintaining drug activity. Lipid microparticles were prepared and characterized by laser diffraction (3.5±0.1 µm). Using an optimized screen-printing method, microparticles were deposited on textiles, as observed by scanning electron microscopy. The drug content of textiles (97±3 µg/cm(2)) was reproducible and stable up to 4 months storage at 25 °C/65% Relative Humidity. Imprinted textiles exhibited a thermosensitive behavior, as witnessed by a fusion temperature of 34.8 °C, which enabled a larger drug release at 32 °C (temperature of the skin) than at room temperature. In vitro antifungal activity of ECN textiles was compared to commercial 1% (wt/wt) ECN cream Pevaryl®. ECN textiles maintained their antifungal activity against a broad range of Candida species as well as major dermatophyte species. In vivo, ECN textiles also preserved the antifungal efficacy of ECN on cutaneous candidiasis infection in mice. Ex vivo percutaneous absorption studies demonstrated that ECN released from pharmaceutical textiles concentrated more in the upper skin layers, where the fungal infections develop, as compared to dermal absorption of Pevaryl®. Overall, these results showed that this technology is promising to develop pharmaceutical garments textiles for the treatment of superficial fungal infections.

Pickering emulsions based on cyclodextrins: A smart solution for antifungal azole derivatives topical delivery.

Surfactants are usually used for the preparation of emulsions. Potential drawbacks on the human body or on the environment can be observed for some of them(e.g. skin irritation, hemolysis, protein denaturation, etc.). However, it is possible to use biocompatible emulsifiers such as native cyclodextrins (CDs). The mixture of oil (paraffin oil or isopropyl myristate), water and native CDs results in the formation of Pickering emulsions. The emulsion properties were investigated by ternary phase diagrams elaboration, multiple light scattering, optical and transmission microscopies. The results prove that these Pickering emulsions were very stable against coalescence due to the dense film format the oil/water interface. The rheological behavior has shown that these emulsions remain compatible for topical applications. This kind of emulsions (biocompatibility, stability and surfactant free) has been used to obtain sustainable formulations for antifungal econazole derivatives delivery. Our results prove that these new formulations are at least as active as commercially available formulations.

Amidated pectin-based wafers for econazole buccal delivery: formulation optimization and antimicrobial efficacy estimation.

Combinations of low-methoxy amidated pectin (LMAP) and carboxymethylcellulose (CMC) were used to develop a lyophilized wafer formulation, aimed to obtain prolonged residence and controlled release of econazole nitrate (ECN) in the oral cavity. Ternary ECN/sulphobutylether-ß-cyclodextrin/citric acid complex, resulted as the most efficient system against selected Candida strains, was loaded into this formulation. The final product with the desired and predicted quality was developed by an experimental design strategy. The experimental values of mucoadhesion strength (28.37 ± 0.04 mg/cm(2)) and residence time (88.1 ± 0.1 min) obtained for the optimized wafer formulation were very close to the predicted ones, thus demonstrating the actual reliability and usefulness of the assumed model in the preparation of buccal wafers. The optimized formulation provided a constant ECN in situ release of 5mg/h and was efficacious against selected Candida strains in vitro. This clearly proved its potential as a novel effective delivery system for the therapy of oral candidiasis.

Antifungal efficiency of miconazole and econazole and the interaction with transport protein: a comparative study.

CONTEXT: Miconazole (MIZ) and econazole (ECZ) are clinically used as antifungal drugs. OBJECTIVE: The drug effect and binding property with transport protein human serum albumin of MIZ and ECZ were studied. MATERIALS AND METHODS: The antifungal efficiency was investigated by microdiluting drug solutions from 0 to 48 µmol L(-1) through microcalorimetry and voltammetry studies. Transmission electron microscopy was used for morphological observations of C. albicans. The interaction with HSA was studied by electrochemical methods, fluorescence spectrometry, electron microscopy, and molecular simulation. RESULTS: IC50 of MIZ and ECZ for C. albicans were obtained as 19.72 and 29.90 µmol L(-1). Binding constants of MIZ and ECZ with HSA of 2.36 × 10(4) L mol(-1) and 3.73 × 10(4) L mol(-1) were obtained. After adding MIZ solution of 12 and 40 µmol L(-1), the peak currents increased to 4.887 and 6.024 µA. The peak currents of C. albicans in the presence of 20 and 48 µmol L(-1) ECZ were 4.701 and 5.544 µA. The docking scores for MIZ and ECZ of the best binding conformation in site I and site II were 5.60, 4.79, 5.63, and 5.85. DISCUSSION AND CONCLUSION: Strong inhibition to the metabolism of C. albicans and destructive effect was proved for both drugs. The lower IC50, growth rate constant of C. albicans, and higher peak current, reveal stronger antifungal activity of MIZ. Both drugs show an efficient quenching effect to intrinsic fluorescence residues of protein. MIZ mainly binds on site I while ECZ on site II. Molecular modeling experiments give further insight of the binding mechanism.

Evaluation of chitosan based vaginal bioadhesive gel formulations for antifungal drugs.

The aim of the present study was to evaluate chitosan as a vaginal mucoadhesive gel base for econazole nitrate and miconazole nitrate. To this aim, different types of chitosan with different molecular masses and viscosity properties [low molecular mass chitosan (viscosity: 20,000 mPa s), medium molecular mass chitosan (viscosity: 200,000 mPa s), high molecular mass chitosan (viscosity: 800,000 mPa s)] have been used. First, rheological studies were conducted on chitosan gels. Mechanical, syringeability and mucoadhesive properties of chitosan gels were determined. Release profiles of econazole nitrate and miconazole nitrate from chitosan gels were obtained and evaluated kinetically. In addition, anticandidal activities of formulations were determined. Finally, vaginal retention of chitosan gels in rats was evaluated by in vivo distribution studies. Based on the results, it can be concluded that gels prepared with medium molecular mass chitosan might be effectively used for different antifungal agents in the treatment of vaginal candidiosis, since it has high mucoadhesiveness, suitable mechanical and release properties with good vaginal retention.