Evaluation of topical econazole nitrate formulations with potential for treating Raynaud's phenomenon.

The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud's phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase® cream, and F4_Lipoderm® Activemax™ Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10-20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2_HPMC dispersion could be further explored as a treatment option for RP.

A chitosan lactate/poloxamer 407-based matrix containing Eudragit RS microparticles for vaginal delivery of econazole: design and in vitro evaluation.

A matrix based on chitosan lactate and poloxamer 407 was evaluated as a delivery system for the vaginal administration of the antifungal drug econazole. The matrix was investigated both containing the pure drug and after introducing microparticles of Eudragit RS 100 containing econazole. Eudragit RS 100 microparticles were prepared using an emulsion-extraction method and dispersed in a solution containing chitosan lactate (2% w/w) and poloxamer 407 (1.7% w/w). The microparticles, obtained with a yield of 64% w/w and an encapsulation efficiency of 42% w/w, had a diameter of less than 2 µm and a drug loading of 13% w/w. The compressed matrices, characterized by DSC, swelling, erosion, release and mucoadhesion studies, had behaviours dependent on the relative amounts of the contained microparticles. The matrix without microparticles (MECN) showed zero-order release kinetics, with a maximum drug-release of 60% w/w, while those containing 50 or 75% w/w microparticles showed a diffusion controlled release up to 8 and 16 h, respectively, and a linear trend after those time intervals, caused by the erosion process, which allowed reaching a drug-release of approximately 100% w/w at 22 h. In in vitro experiments, the matrices were mucoadhesive and active in inhibiting the growth of Candida albicans 796.

A novel transdermal fomulation of 18ß-glycyrrhetic acid with lysine for improving bioavailability and efficacy.

The aim of this study was to develop a novel topical liposomal system entrapping 18ß-glycyrrhetic acid (GA) for the treatment of chronic allergic dermatitis. A novel liposomal system with molar ratios of GA to lysine from 1:1 to 1:3 was prepared by high-pressure homogenization. The liposomes at the optimized molar ratio of GA to lysine of 1:2 significantly improved GA loading (1.2%) and penetration in vitro. Liposomal gels containing GA 0.3, 0.6 and 0.9% were prepared to investigate the dosage effect on transdermal delivery and anti-inflammatory activity. In vivo pharmacokinetic studies were carried out by nonocclusive application of GA liposomal gels to ICR mouse ears. GA concentrations in skin and plasma increased proportionally with dose over the dose range of 0.3-0.9%. A 2,4-dinitrofluorobenzene-induced contact dermatitis mouse model was made up to evaluate the pharmacodynamics of GA liposomal gels. The liposomal gel with GA 0.9% showed a stronger anti-inflammatory activity than triamcinolone acetonide and econazole nitrate cream, while few side effects were observed in the present model. The topical administration of gel containing novel elastic liposomes of GA was safe and effective in the treatment of chronic allergic dermatitis.

Polymeric nanosponges as an alternative carrier for improved retention of econazole nitrate onto the skin through topical hydrogel formulation.

The present study was carried out to exploit the feasibility of using polymeric nanosponges as an alternative carrier for targeting econazole nitrate (EN) to the skin through topical hydrogel formulation. Nanosponges prepared by emulsion solvent diffusion method were evaluated for various physicochemical parameters and in vitro drug release. The nanosponges of EN were discrete free flowing nanosized particles with perforated orange peel like morphology as visualized by SEM. The nanosponge formulated using PVA:EC (3:2) displayed highest in vitro release after 12?h in phosphate buffer (pH 6.8) that fitted matrix model. Selected nanosponge was formulated as Carbopol 934 NF hydrogel using varying concentrations of permeation enhancers propylene glycol and N-methyl-2-pyrrolidone. The EN nanosponge-loaded hydrogels (F0?F7) were evaluated for pharmacotechnical properties and irritation studies on rat skin. On the basis of various evaluation parameters F7 with an equilibrium swelling of 0.944?g/g after 4?h, low firmness and high adhesiveness, a flux rate of 1540.2 (?g/cm(2).h) and that exhibited a controlled release of EN for 12?h was selected as best hydrogel. The DRS and DSC spectra of F7 confirmed stability of drug in the delivery system and absence of drug polymer interaction in nanosponges.

Laryngeal dyspnea in relation to an interaction between acenocoumarol and topical econazole lotion.

BACKGROUND: Bleeding is the most serious complication of oral anticoagulant therapy used for the prevention of thromboembolic complications. Drug-drug interactions are an important concern, as they may increase drug toxicity and, in the case of anticoagulant therapies, increase the risk of hemorrhage. CASE SUMMARY: An 84-year-old woman presented to the emergency department with a bilateral cervical hematoma and symptoms of upper-airway obstruction that had been increasing for 72 hours, with dyspnea and difficulty speaking developing in the previous 24 hours. Transnasal fiberoptic laryngoscopy revealed a significant laryngeal hematoma, as well as a hematoma on the floor of the mouth and in the tonsil area. Laboratory abnormalities included a prothrombin time < 10%, an international normalized ratio exceeding the laboratory limits, and an activated partial thromboplastin time >120 seconds. The patient had been receiving acenocoumarol 4 mg/d for 10 years for episodes of atrial fibrillation and recurrent deep venous thrombosis. Seventeen days earlier, she had received a prescription for topical econazole lotion 1% to be applied 3 times daily for 1 month to treat a dermatitis affecting 12% of the body surface. The patient was admitted to the intensive care unit for treatment of respiratory failure, where oxygen was delivered by face mask. The coagulation disorders were treated with prothrombin complex concentrate 30 IU/kg IV and vitamin K1 10 mg IV, and values normalized within 36 hours. Surgical evacuation of the laryngeal hematoma was not necessary. After 48 hours, improvement in the patient's respiratory symptoms allowed transfer to the ear, nose, and throat unit, where daily endoscopic examination was performed. Aspirin was substituted for acenocoumarol, and the patient returned home after 10 days without sequelae. Based on a Naranjo score of 7, this episode was probably related to an interaction between acenocoumarol and econazole. CONCLUSION: This report describes a case of a probable interaction between topical econazole lotion 1% and acenocoumarol that resulted in overanticoagulation and a life-threatening laryngeal hematoma in this elderly patient.

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.

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.

Novel drug delivery strategies for improving econazole antifungal action.

Econazole is a commonly used azole antifungal in clinical treatment of superficial fungal infections. It is generally used as conventional cream and gel preparations under the brand names of Spectazole (United States), Ecostatin (Canada), Pevaryl (Western Europe). Treatment efficiency of antifungal drugs depends on their penetration through target layers of skin at effective concentrations. Econazole's poor water solubility limits its bioavailability and antifungal effects. Therefore, formulation strategies have been examined for delivering econazole through targeted skin sites. The present overview focuses on novel nano-based formulation approaches used to improve econazole penetration through skin for treatment of superficial fungal infections.

Ocular supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) to enhance econazole nitrate bioavailability.

Econazole nitrate (ECO) is a poorly water soluble antifungal drug. Having low aqueous solubility affects negatively its use for ocular treatment. This work aimed to prepare ocular supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) of ECO employing hydroxypropyl methylcellulose as a precipitation inhibitor to improve the drug solubility by avoiding its precipitation after administration. Various oils, surfactants and co-surfactants were used to construct SNEDDS. The SNEDDS were evaluated for globule size, polydispersity index and their irritation potential using hen's egg test-chorioallantoic membrane (HET-CAM). The best SNEDDS was loaded with ECO and HPMC to prepare S-SNEDDS. In-vitro precipitation test of the S-SNEDDS was done to study the effect of the precipitation inhibitor. ECO permeation in rabbits' eyes from the selected S-SNEDDS (with and without HPMC) was evaluated. The results showed that SNEDDS-X consisting of 20% Capmul(®) MCM C10 as an oil, 60% Cremophor RH40(®) as a surfactant and 20% Transcutol(®) HP as co-surfactant possessed the lowest PDI value and a non-irritant effect on the CAM. The in-vitro precipitation test showed that the use of HPMC successfully sustained the supersaturated state by avoiding ECO precipitation. Higher Cmax, AUC0-8 and longer tmax confirm the development of a successful ECO-loaded S-SNEDDS.

Percutaneous delivery of econazole using microemulsion as vehicle: formulation, evaluation and vesicle-skin interaction.

This project was carried out to exploit the feasibility of using microemulsion (ME) as an alternative carrier for percutaneous delivery econazole nitrate (ECN) and elucidate the underlying mechanism of permeation enhancement. The ME was developed based on Labrafil M 1944 Cs as oil phase, Solutol HS15 and Span 80 as surfactants, Transcutol P as cosurfactant and water as aqueous phase. The solubility of ECN was firstly determined for screening the ingredients of the system. Pseudo-ternary phase diagrams were constructed to formulate ME and select surfactant and cosurfactant. Central composite design-response surface methodology (CCD-RSM) was utilized to optimize the formulation of ME. The ECN loaded ME was characterized in terms of morphology, particle size and size distribution, pH value, refractive index, viscosity and conductivity, and storage stability of the ECN loaded ME was assayed. Percutaneous permeation of ECN from ME in vitro through rat skin was investigated in comparison with PBS aqueous suspension (1%, w/w), and results showed that ME enhanced drug retention in the skin and permeation through the skin, the enhancement of ME on skin deposition was further visualized through fluorescent-labeled ME by confocal laser scanning microscope (CLSM). The action mechanism of ME on improving percutaneous delivery was studied by performing a pretreatment test. It can speculate that ME does not simply behave as enhancer but it also acts as drug carrier. Furthermore, ME-skin interaction was elucidated through transmission electron microscope (TEM), and attenuated total reflectance fourier-transform infrared (ATR-FTIR). TEM was performed to visualize the micro morphological change of skin. ATR-FTIR was carried out to investigate the molecular vibrations of the components of stratum corneum (SC). The results indicate that the ME system may be a promising vehicle for percutaneous delivery of ECN.

A prototype antifungal contact lens.

PURPOSE: To design a contact lens to treat and prevent fungal ocular infections. METHODS: Curved contact lenses were created by encapsulating econazole-impregnated poly(lactic-co-glycolic) acid (PLGA) films in poly(hydroxyethyl methacrylate) (pHEMA) by ultraviolet photopolymerization. Release studies were conducted in phosphate-buffered saline at 37°C with continuous shaking. The contact lenses and their release media were tested in an antifungal assay against Candida albicans. Cross sections of the pre- and postrelease contact lenses were characterized by scanning electron microscopy and by Raman spectroscopy. RESULTS: Econazole-eluting contact lenses provided extended antifungal activity against Candida albicans fungi. Fungicidal activity varied in duration and effectiveness depending on the mass of the econazole-PLGA film encapsulated in the contact lens. CONCLUSIONS: An econazole-eluting contact lens could be used as a treatment for fungal ocular infections.

In-situ gel formulations of econazole nitrate: preparation and in-vitro and in-vivo evaluation.

OBJECTIVES: This study describes the in-situ gelling of econazole nitrate containing thermosensitive polymers composed of poloxamer 407 and 188 as a novel treatment platform for vaginal candidiasis. METHODS: Aqueous thermosensitive formulations containing 1% of econazole nitrate and poloxamer 407 and/or 188 were prepared and their rheological, mechanical and drug-release properties determined at 20 ± 0.1°C and/or 37 ± 0.1°C. Based on their biologically suitable thermorheological properties, formulations containing the mixtures of poloxamer 407 and 188 in ratios of 15:15 (F1), 15:20 (F2) and 20:10 (F3) were chosen for comprehensive analysis. KEY FINDINGS: Formulations based on F3 exhibited typical gel-type mechanical spectra (G' > G″) at 37°C whereas formulations based on F1 and F2 exhibited properties akin to weakly cross-linked gels. Texture profile analysis demonstrated that F3 showed the highest cohesiveness, adhesiveness, hardness and compressibility. No statistically significant differences (P > 0.5) were observed in the release of econazole nitrate from the formulations at pH 4.5, which in all cases followed anomalous diffusion kinetics. Formulations based on 20% poloxamer 407:10% poloxamer 188 were chosen for in-vivo studies and were shown to be effective for the treatment of the vaginal candidiasis. Histopathologic evaluation also supported the effectiveness of the thermosensitive formulation administered intravaginally. CONCLUSION: By careful engineering of the rheological properties, in-situ thermosensitive gel formulations of econazole nitrate were prepared and were shown to be efficacious in the treatment of vaginal candidiasis.

Chitosan/sulfobutylether-ß-cyclodextrin nanoparticles as a potential approach for ocular drug delivery.

Development of efficient ocular delivery nanosystems remains a major challenge to achieve sustained therapeutic effect. The purpose of this work was to develop chitosan nanoparticles using sulfobutylether-ß-cyclodextrin (SBE-ß-CD) as polyanionic crosslinker and to investigate the potential of using those nanostructures as ocular drug delivery systems. Econazole nitrate (ECO) was chosen as model drug molecule. The influence of different process variables (chitosan molecular weight and the concentration of the two ionic agents) on particle size, polydispersity index, zeta potential, drug content, in vitro release and mucoadhesive properties was investigated. The results showed that the prepared nanoparticles were predominant spherical in shape having average particle diameter from 90 to 673 nm with positive zeta potential values from 22 to 33 mV and drug content values ranging from 13 to 45%. Drug release from optimized nanoparticles was controlled with approximately 50% of the original amount released over a 8h period. The release profile of nanoparticles followed a zero-order release kinetics. The optimized nanoparticles were tested for their use as ocular drug delivery systems on albino rabbits. The in vivo studies revealed that the prepared mucoadhesive nanoparticles had better ability in sustaining the antifungal effect of ECO than the ECO solution. Therefore, chitosan/SBE-ß-CD nanoparticles developed showed a promising carrier for controlled delivery of drug to the eye.

Inhibition of bone resorption by econazole in rat osteoclast-like cells through suppressing TRPV5.

Osteoclasts are primary bone resorption cells and intervention in osteoclast activation is considered an effective therapeutic approach to treatment of bone diseases involving osteoclasts. TRPV5 was detected in osteoclasts and it has been thought to take part in the transportation of the degraded calcium in the resorption lacuna, which is essential for bone resorption. The aim of the present study was to examine the effects of a modulator of calcium dynamics, econazole, on the expression of TRPV5 and bone resorption activity in rat osteoclast-like cells (OLCs). OLCs were obtained by co-culturing rat bone marrow cells with osteoblasts and then culturing with different concentrations of econazole (0.01, 0.1, 1.0, 10.0 µmol/L). Cell counting and staining protocols were used to determine whether econazole influenced the survival of OLCs. Expression of TRPV5 in response to econazole treatment was assessed by western blotting. Bone resorption activity of OLCs was determined by measuring the resorption area of dentin slices with a microscope and a digital image analysis system. Additionally, Ca(2+) inside OLCs was tested. We found that econazole inhibited expression of TRPV5 in a dose dependent manner while it had no influence on the survival of OLCs and it therefore inhibited bone resorption activity in rat OLCs. Ca(2+) inside OLCs increased, suggesting a limited compensatory mechanism to make up for inhibition of TRPV5 effects.

Polymer-lipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate.

This research aimed to evaluate a new approach for the preparation of mucoadhesive microparticles and to design an innovative vaginal delivery systems for econazole nitrate (ECN) able to enhance the drug antifungal activity. Seven different formulations were prepared by spray-congealing: a lipid-hydrophilic matrix (Gelucire 53/10) was used as carrier and several mucoadhesive polymers such as chitosan, sodium carboxymethylcellulose and poloxamers (Lutrol F68 and F127) were added. All microparticles were characterized and compared for morphology, particle size, drug loading and solubility in simulated vaginal fluid, bioadhesion to mucosal tissue, dissolution behaviour and for their physicochemical properties. The antifungal activity of the microparticles against a strain of Candida albicans ATCC 10231 was also investigated. Non-aggregated microspheres with high yields (>90%, w/w) and with prevalent size in the range 100-355mum were obtained. Both poloxamers significantly (p<0.01) improved the solubility and in vitro bioavailability of the low solubility drug and the mucoadhesive strength. Poloxamers/Gelucire-based microparticles exhibited an inhibition effect on the C. albicans growth, suggesting their use as an effective treatment for vaginal candidiasis, with potential for reduced administration frequency. In conclusion the results demonstrated that spray-congealing technology can be considered a novel and solvent-free approach for the production of mucoadhesive microparticles for the vaginal delivery of ECN.

Econazole-polycarbophil, a new delivery system for topical therapy: microbiological and clinical results on vaginal candidiasis.

The aim of this study was to demonstrate that the addition of a bioadhesive polymer to econazole, which increases the duration of the active drug at the site of infection, leads to a greater frequency of negative culture after treatment and probably reduces the recurrence rate of vaginal candidiasis.180 women with vaginal candidiasis were treated with 150 mg vaginal ovules econazole nitrate with (group A) or without (group B) polycarbophil. After 3 days of treatment the negative culture of Candida albicans reached 98.6% in group A and 84.8% in B group, while the overall persistence (C. albicans, C. glabrata, C. krusei, and C. parapsilosis) was 5.6% and 30%, respectively. During a 60-day follow-up, only one case out of 85 (1.2%) in group A reported recurrence while in group B there were 6 out of 63 (9.5%) recurrences. We conclude that, since the women were treated with the same amount of econazole, the better clinical and microbiological results can be attributed to polycarbophil, as confirmed by a significant reduction of recurrences.

A parenteral econazole formulation using a novel micelle-to-liposome transfer method: in vitro characterization and tumor growth delay in a breast cancer xenograft model.

PURPOSE: The purpose of this study was to develop a parenteral liposomal formulation of econazole, a poorly water-soluble compound not previously available in an intravenous form. We are investigating econazole as an anticancer agent based on its unique mechanism of action to which cancer cells are preferentially sensitive. An intravenous formulation of econazole was desired for preclinical toxicity and efficacy studies of econazole. METHODS: Liposomal econazole was prepared using a novel micelle exchange technique to incorporate the drug into the lipid bilayer of pre-formed liposomes using a poly(ethylene) glycol-linked phospholipid, distearoyl phosphatidylethanolamine (DSPE-PEG). This method allowed for stable and efficient drug incorporation into DPPC and DMPC liposomes at a final drug:lipid ratio of 0.05 (w/w) and increased solubility in saline from <0.1 to 5 mg/ml. RESULTS: Stability over 14 days at 4 degrees C in buffer was demonstrated as well as in vitro plasma stability at 37 degrees C. Plasma elimination studies of micelle-loaded liposomal econazole showed a half-life of approximately 35 min and plasma AUC of 281 microg/ml min. In MCF-7 human breast cancer xenografts in Rag2M mice. Liposomal econazole did not induce significant hepatoxicity, renal toxity or weight loss compared to empty liposomes. Tumor growth was slightly delayed in liposomal econazole-treated mice, with approximately 10-day lag time to reach 300 mm(3) compared to vehicle controls. CONCLUSIONS: The micelle transfer method provided an efficient means of preparing liposomal econazole suitable for intravenous administration. Liposomal econazole was successfully administered to tumor bearing mice at 50 mg/kg, and no significant toxicities attributable to econazole were observed.

Control of Candida albicans murine vaginitis by topical administration of polycarbophil-econazole complex.

The complexation of econazole with the mucoadhesive polycarbophil was found to significantly improve the therapeutic benefit of the drug in the topical treatment of experimental vaginal candidiasis in mice, while no difference in the antimycotic activity exerted by econazole and polycarbophil-econazole could be detected in vitro.