Microwave-assisted microemulsion technique for production of miconazole nitrate- and econazole nitrate-loaded solid lipid nanoparticles.

The microwave-assisted production of solid lipid nanoparticles (SLNs) is a novel technique reported recently by our group. The small particle size, solid nature and use of physiologically well-tolerated lipid materials make SLNs an interesting and potentially efficacious drug carrier. The main purpose of this research work was to investigate the suitability of microwave-assisted microemulsion technique to encapsulate selected ionic drug substances such as miconazole nitrate and econazole nitrate. The microwave-produced SLNs had a small size (250-300nm), low polydispersity (<0.20), high encapsulation efficiency (72-87%) and loading capacity (3.6-4.3%). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies suggested reduced crystallinity of stearic acid in SLNs. The release studies demonstrated a slow, sustained but incomplete release of drugs (<60% after 24h) from microwave-produced SLNs. Data fitting of drug release data revealed that the release of both drugs from microwave-produced SLNs was governed by non-Fickian diffusion indicating that drug release was both diffusion- and dissolution- controlled. Anti-fungal efficacy of drug-loaded SLNs was evaluated on C. albicans. The cell viability studies showed that cytotoxicity of SLNs was concentration-dependent. These encouraging results suggest that the microwave-assisted procedure is suitable for encapsulation of ionic drugs and that microwave-produced SLNs can act as potential carriers of antifungal drugs.

Development of thermodynamically stable nanostructured lipid carrier system using central composite design for zero order permeation of econazole nitrate through epidermis.

The investigation was aimed at developing thermodynamically stable topical delivery system of nanostructured lipid carrier of econazole nitrate (EN) for the treatment of deep seated fungal infection by improving its permeability. Fifteen formulations (F1-F15) of nanostructured lipid carriers (NLCs) were prepared by solvent injection technique using central composite design and characterized for particle size and % entrapment efficiency. Closeness in the results, guided the selection of five NLC formulations which were formulated as hydrogels (G1-G5) using Carbopol 934. The permeation studies of gels demonstrated G3 with flux rate of 3.21 ± 0.03 µg/cm(2)/min (> target flux of 1.46 µg/cm(2)/min) as the best formulation that exhibited zero order permeation. The amount of drug/unit area demonstrated linear dependency on flux rate. Confocal laser scanning microscopy demonstrated penetration of rhodamine red till the stratum basale due to hydration of stratum corneum. Hydrogel G3 containing NLC formulation (F5) was selected as the optimized topical gel. TEM of F5 revealed spherical particles that presented low recrystallization index of 72.35%. Stability profile for 90 days revealed insignificant change (p < 0.05) in the particle size and zeta potential indicating substantial stability of the system. Thus, EN-loaded NLC indicated better permeability and thermodynamic stability as effective topical delivery system for deep seated fungal infection.

Asymmetric chemoenzymatic synthesis of miconazole and econazole enantiomers. The importance of chirality in their biological evaluation.

A simple and novel chemoenzymatic route has been applied for the first time in the synthesis of miconazole and econazole single enantiomers. Lipases and oxidoreductases have been tested in stereoselective processes; the best results were attained with oxidoreductases for the introduction of chirality in an adequate intermediate. The behaviors of a series of ketones and racemic alcohols in bioreductions and acetylation procedures, respectively, have been investigated; the best results were found with alcohol dehydrogenases A and T, which allowed the production of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol in enantiopure form under very mild reaction conditions. Final chemical modifications have been performed in order to isolate the target fungicides miconazole and econazole both as racemates and as single enantiomers. Biological evaluation of the racemates and single enantiomers has shown remarkable differences against the growth of several microorganisms; while (R)-miconazole seemed to account for most of the biological activity of racemic miconazole on all the strains tested, both enantiomers of econazole showed considerable biological activities. In this manner, (R)-econazole showed higher values against Candida krusei , while higher values were observed for (S)-econazole against Cryptococcus neoformans, Penicillium chrysogenum, and Aspergillus niger.

[Enantioselective synthesis and antifungal activity of optically active econazole and miconazole].

In an effort to investigate the relationship between stereochemistry and antifungal activity of the antimycotic agents, optically active econazole and miconazole were first enantioselectively synthesized. The key step was the enantioselective reduction of 2-chloro-1-(2,4-dichlorophenyl) ethanone catalyzed by chiral oxazaborolidine. Preliminary biological tests showed that (R)-(-)-econazole and (R)-(-)-miconazole were more active than the (S)-isomer and racemates against common pathogenic fungi such as Candida albicans, Trichophyton rubrum, T. gypseum, Microsporum lanosum and Aspergillus flavus in vitro.

[Antibacterial and antifungal agents. IV. Synthesis and antifungal activity of econazole analogs with pyrrole structure]. / Ricerche su agenti antibatterici ed antifungini. Nota IV--Sintesi ed attività antifungina di analoghi dell'econazolo a struttura pirrolica.

The synthesis of analogues of antifungal econazole with a pyrrole moiety starting from 1-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)ethanone and from 1-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)ethanol is described. Results of antimicrobial screening of the new derivatives in comparison with econazole are also reported.