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.

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.

Objective determination of the bioavailability of dermocorticoids--influence of the formulation.

In order to quantify the intensity of skin blanching and thus predict the bioavailability of topical corticoids, a physical device allowing the measurement of light reflected from skin without any contact between the probe and the skin was used (Leveque et al., 1984). Three series of experiments were carried out: firstly, to assess the vasoconstrictor potency of four corticoids; secondly, to show the influence of the vehicle on the bioavailability of the same drug under various galenic forms, such as fatty ointments or water in oil (W/O) and oil in water (O/W) creams; thirdly, to determine the reservoir effects, if any, of some of these formulations. The results confirm previous findings about the potency of hydrocortisone acetate, triamcinolone 17-acetonide, betamethasone 17-valerate, diflucortolone valerate and clobetasol 17-propionate.

[Biologic availability of diflucortolone-21-valerate in human skin]. / Verfügbarkeit von Diflucortolon-21-valerat in der menschlichen Haut.

The concentration of diflucortolone-21-valerate (DFV) in the different layers of human skin was investigated after topical application of Nerisona (0.1%) as a function of the formulation (fatty ointment, ointment and creme), of the duration of exposition and of the condition of the skin. From all galenic formulations DFV penetrated rapidly into the horny layer. Mean highest concentrations were determined 4 h after application with approx. 300 micrograms/ml (ca. 600 mumol/l) after treatment with fatty ointment and ointment and with approx. 500 micrograms/ml (ca. 1000 mumol/l) after treatment with the cream. The corticoid concentration decreased in the horny layer from distal to proximal by 1.5 to 2 decades. After application to damaged skin - as a model for diseased skin - the local corticoid concentrations in all skin layers were distinctly higher than after application to intact skin at all time points investigated. DFV penetrates selectively into the damaged skin. The systemic load caused by percutaneous absorption through intact skin is neglectable.