The association of isoconazole-diflucortolone in the treatment of pediatric tinea corporis.

BACKGROUND: Tinea corporis is a common mycotic infection in children. Staphylococcus aureus superinfections may be observed in atopic children with tinea corporis suffering from severe pruritus and consequent scratching. OBJECTIVE: From 2006 to 2011, we observed 288 children with mycologically proven tinea corporis. In 39 of them (13.5%) tinea corporis was superinfected by S. aureus: all these children were affected by atopic dermatitis. We interpreted these bacterial superinfections as the clinical result of scratching due to pruritus. METHODS: In 2012, we decided to treat all children with a single lesion of tinea corporis with a combination of 1% isoconazole nitrate and 0.1% diflucortolone valerate cream (one application/day for 5-7 days), followed by a treatment with isoconazole or clotrimazole or ciclopirox cream (two applications/day for two weeks). RESULTS: From 2012 to 2014, we observed 108 children with tinea corporis confirmed by mycological examinations. Clinical and mycological recovery was observed in 93 of them (86.1%). Only four of these children (3.7%) developed S. aureus superinfections. CONCLUSIONS: Our study in atopic children with tinea corporis superinfected by S. aureus confirms that a topical therapy with the association isoconazole-diflucortolone is useful and safe.

Nanostructured lipid carriers as semisolid topical delivery formulations for diflucortolone valerate.

CONTEXT: Topical treatment of skin disease needs to be strategic to ensure high drug concentration in the skin with minimum systemic absorption. OBJECTIVE: The aim of this study was to produce semisolid nanostructured lipid carrier (NLC) formulations, for topical delivery of the corticosteroid drug, diflucortolone valerate (DFV), with minimum systemic absorption. METHOD: NLC formulations were developed using a high shear homogenization combined with sonication, using Precirol® ATO5 or Tristearin® as the solid lipid, Capryol™ or isopropyl myristate as the liquid lipid and Poloxamer® 407 as surfactant. The present study addresses the influence of different formulations composition as solid lipid, liquid lipid types and concentrations on the physicochemical properties and drug release profile from NLCs. RESULTS AND DISCUSSION: DFV-loaded NLC formulations possessed average particle size ranging from 160.40 nm to 743.7 nm with narrow polydispersity index. The encapsulation efficiency was improved by adding the lipid-based surfactants (Labrasol® and Labrafil® M1944CS) to reach 68%. The drug release from the investigated NLC formulations showed a prolonged release up to 12 h. The dermatopharmacokinetic study revealed an improvement in drug deposition in the skin with the optimized DFV-loaded NLC formulation, in contrast to a commercial formulation. CONCLUSION: NLC provides a promising nanocarrier system that work as reservoir for targeting topical delivery of DFV.

Effective topical delivery systems for corticosteroids: dermatological and histological evaluations.

Atopic dermatitis (AD) is a chronic and relapsing skin disease with severe eczematous lesions. Long-term topical corticosteroid treatment can induce skin atrophy, hypopigmentation and transepidermal water loss (TEWL) increase. A new treatment approach was needed to reduce the risk by dermal targeting. For this purpose, Betamethasone valerate (BMV)/Diflucortolone valerate (DFV)-loaded liposomes (220-350 nm) were prepared and incorporated into chitosan gel to obtain adequate viscosity (∼13 000 cps). Drugs were localized in stratum corneum + epidermis of rat skin in ex-vivo permeation studies. The toxicity was assessed on human fibroblast cells. In point of in-vivo studies, pharmacodynamic responses, treatment efficacy and skin irritation were evaluated and compared with previously prepared nanoparticles. Liposome/nanoparticle in gel formulations produced higher paw edema inhibition in rats with respect to the commercial cream. Similar skin blanching effect with commercial creams was obtained via liposome in gels although they contain 10 times less drug. Dermatological scoring results, prognostic histological parameters and suppression of mast cell numbers showed higher treatment efficiency of liposome/nanoparticle in gel formulations in AD-induced rats. TEWL and erythema measurements confirmed these results. Overview of obtained results showed that liposomes might be an effective and safe carrier for corticosteroids in skin disease treatment.

Enhanced dermal delivery of diflucortolone valerate using lecithin/chitosan nanoparticles: in-vitro and in-vivo evaluations.

The objective of this study was to prepare a suitable formulation for dermal delivery of diflucortolone valerate (DFV) that would maintain the localization in skin layers without any penetration and to optimize efficiency of DFV. Drug-loaded lecithin/chitosan nanoparticles with high entrapment efficiency (86.8%), were successfully prepared by ionic interaction technique. Sustained release of DFV was achieved without any initial burst release. Nanoparticles were also incorporated into chitosan gel at different ratios for preparing a more suitable formulation for topical drug delivery with adequate viscosity. In ex-vivo permeation studies, nanoparticles increased the accumulation of DFV especially in the stratum corneum + epidermis of rat skin without any significant permeation. Retention of DFV from nanoparticle in chitosan gel formulation (0.01%) was twofold higher than commercial cream, although it contained ten times less DFV. Nanoparticles in gel formulations produced significantly higher edema inhibition in rats compared with commercial cream in in-vivo studies. Skin blanching assay using a chromameter showed vasoconstriction similar to that of the commercial product. There were no barrier function changes upon application of nanoparticles. In-vitro and in-vivo results demonstrated that lecithin/chitosan nanoparticles in chitosan gel may be a promising carrier for dermal delivery of DFV in various skin disorders.

The advantages of topical combination therapy in the treatment of inflammatory dermatomycoses.

Dermatomycoses are contagious superficial fungal infections, which are highly prevalent in developed and developing countries. Caused by a range of Epidermophyton, Microsporum and Trichophyton species, dermatomycoses manifest on glabrous skin as 'ringworm', an annular scaly lesion with a variable inflammatory component. Itch is the chief subjective symptom, particularly in tinea cruris. Unless lesions are extensive or resistant to local therapy, dermatomycoses of glabrous skin are treated with topical antifungal agents, such as imidazoles and allylamines. Studies show, however, that the addition of a topical corticosteroid to imidazole therapy increases the bioavailability and prolongs the activity of the antimycotic, while rapidly reducing inflammatory symptoms. Travocort is a combination of 1% isoconazole nitrate (ISN), a broad-spectrum imidazole with established antimicrobial activity and antimycotic efficacy, and 0.1% diflucortolone valerate (DFV), a potent topical corticosteroid with low systemic absorption and therefore a low risk of systemic glucocorticoid side-effects. In randomised, double-blind controlled clinical trials, Travocort therapy showed a more rapid onset of action, faster relief of itch and other inflammatory symptoms, improved overall therapeutic benefits and better mycological cure rate during the first 2 weeks of treatment compared with ISN monotherapy. Travocort is well tolerated and, because of prolonged ISN retention in the skin, provides antifungal protection against reinfection for some weeks after therapy.

Synthesis and structure elucidation of potential 6-oxygenated metabolites of (22R)-6alpha,9alpha-difluoro-11beta,21-dihydroxy-1 6alpha,17alpha-propyl methylenedioxypregn-4-ene-3,20-dione, and related glucocorticosteroids.

(22R)-6alpha,9alpha-Difluoro-11beta,21-dihydroxy-16 alpha,17alpha-propylmethylenedioxypregn-4-ene-3,20-dione (rofleponide) is a synthetic glucocorticosteroid with high affinity for the rat thymus glucocorticoid receptor and a very high biotransformation rate demonstrated through incubation with a human liver S9 subcellular fraction. Because oxidation in the 6-position is an important metabolic pathway of glucocorticosteroids, the potential 6beta-hydroxy and 6-oxo metabolites of rofleponide were synthesized to be used as reference compounds. Three alternative routes were used to reach the 6-hydroxy compound: (a) a one-step procedure involving allylic oxidation of rofleponide by selenium dioxide, (b) selenium dioxide oxidation of the corresponding 1,4-diene followed by selective 1,2-hydrogenation using Wilkinson's catalyst, and (c) autoxidation of a 3-methoxypregna-3,5-diene derivative. All three routes proceeded stereospecifically. Routes (a) and (c) gave approximately the same overall yield of the 6beta-hydroxy epimer, whereas the overall yield from route (b) was much lower, primarily because of incomplete 1,2-hydrogenation. The 6-oxo compound was prepared through Pfitzner/Moffat oxidation of the 6-hydroxy compound. The stereochemistry of the 6-hydroxy substituent is discussed on the basis of 1H-NMR spectroscopy and supplementary 2D NOESY experiments.