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.

Isoconazole nitrate: a unique broad-spectrum antimicrobial azole effective in the treatment of dermatomycoses, both as monotherapy and in combination with corticosteroids.

Fungal skin infections, or dermatomycoses, are associated with a broad range of pathogens. Involvement of gram-positive bacteria is often suspected in dermatomycoses. Inflammation plays an important role in dermatomycoses, displaying a close association between frequent inflammation and reduced skin-related quality of life. Isoconazole nitrate (ISN) is a broad-spectrum antimicrobial agent with a highly effective antimycotic and gram-positive antibacterial activity, a rapid rate of absorption and low systemic exposure potential. ISN is effective against pathogens involved in dermatomycoses, with minimum inhibitory concentrations well below the concentration of ISN in skin and hair follicles. The combination of the corticosteroid diflucortolone valerate with ISN (Travocort) increases the local bioavailability of ISN. Compared with ISN monotherapy, Travocort has a faster onset of antimycotic action, faster relief of itch and other inflammatory symptoms, improved overall therapeutic benefits and earlier mycological cure rate. Travocort is effective in the treatment of inflammatory mycotic infections, and also in the eradication of accompanied gram-positive bacterial infections. The rapid improvement observed with Travocort treatment, combined with favourable safety and tolerability, results in higher patient satisfaction, and therefore, can be an effective tool to increase treatment adherence in patients with dermatomycoses accompanied by inflammatory signs and symptoms.

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.

6 alpha-Fluoro- and 6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione: synthesis and evaluation of activity and kinetics of their C-22 epimers.

It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. However, modification of the pharmacokinetics through structural alterations could provide steroids with a better therapeutic index than those currently used. Thus, new 16 alpha,17 alpha-acetals between butyraldehyde and 6 alpha-fluoro- or 6 alpha,9 alpha-difluoro-16 alpha-hydroxycortisol were synthesized and studied. Acetalization of the corresponding 16 alpha,17 alpha-diols or transacetalization of their 16 alpha,17 alpha-acetonides in dioxane produced mixtures of C-22 epimers, which were resolved by preparative chromatography. Alternatively, an efficient method was used to produce the 22R-epimer stereoselectively through performing the acetalization and transacetalization in a hydrocarbon with an inert material present. The C-22 configuration of (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione was unambiguously established by single crystal X-ray diffraction. The present compounds, especially the 22R-epimer just mentioned, bind to the rat thymus glucocorticoid receptor with high potency. The C-22 epimers of the 6 alpha,9 alpha-difluoro derivatives showed a 10-fold higher biotransformation rate than the budesonide 22R-epimer when incubated with human liver S9 subcellular fraction. The high receptor affinity in combination with the high biotransformation rate indicates that (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione may be an improved 16 alpha,17 alpha-acetal glucocorticosteroid for therapy of inflammatory diseases, in which the mucous membranes are involved, such as those in the intestinal tract as well in the respiratory tract.

Does salicylic acid increase the percutaneous absorption of diflucortolone-21-valerate?

The percutaneous absorption of diflucortolone-21-valerate (DFV) and its effect on the pituitary adrenal system were investigated during large skin area treatment (20 g ointment twice a day for 8 days) of two groups of healthy volunteers with Nerisona and Nerisalic ointment, respectively. Plasma levels of diflucortolone, cortisol and dehydroepiandrosterone (DHEA) were measured in both groups whereas plasma levels of salicylic acid were measured additionally in volunteers treated with Nerisalic. No differences, neither in percutaneous absorption of DFV nor in effects on cortisol and DHEA were found between the two treatment groups. There was a slight reduction in cortisol levels under both treatments, but the circadian rhythm was not disturbed. Mean salicylic acid plasma levels under high-dose topical Nerisalic treatment were about 50-fold below levels where toxicity may be expected.