Diflucortolone

Diflucortolone is a topically acting fluoridated corticosteroid which suppresses inflammation in inflammatory and allergic skin conditions and alleviates the subjective complaints such as itching, burning and pain.

Capillary dilatation, intercellular oedema and tissue infiltration regress; capillary proliferation is suppressed. This leads to fading of inflamed skin surfaces.

The diflucortolone product line contains as its active ingredient diflucortolone valerate, the 21-monoester of diflucortolone with valeric acid, in a concentration of 0.1%.

So that the diflucortolone formulations are able to exert their therapeutic antiproliferative and antiinflammatory effects in the skin, it is necessary for diflucortolone valerate to diffuse from the respective formulations into the living epidermis or upper corium. In-vitro penetration studies have shown that diflucortolone valerate quickly penetrates human skin from all galenic formulations.

The following highest substance levels were found in the horny layer 4 hours after application: approx. 300 g/ml (around 600 mol/ml) after treatment with fatty ointment and approx. 500 g/ml (around 1000 mol/ml) after application of the cream. The corticoid concentration falls in the horny layer from distally to proximally by around 1.5-2 powers of 10. After application to damaged skin – as the model for diseased skin – the local corticoid concentrations in the living skin were far higher at all time points studied than after application to intact skin.

Diflucortolone valerate is partially hydrolysed to diflucortolone while still in the skin. Diflucortolone binds even stronger to the corticoid receptor than the parent drug. Some of the corticosteroid applied to the skin is absorbed percutaneously and distributed in the organism; it then undergoes further metabolic breakdown before being eliminated.

The degree of percutaneous absorption and the resulting systemic load depend on a number of factors such as the nature of the vehicle, the exposure conditions (skin area dose, size of the treated area, duration of treatment), the nature of the treatment (open/occlusive), the condition of the skin barrier and the area of the body to be treated.

After simultaneous dermal application of the radioactively labelled cream, and fatty ointment to different fields of skin on the backs of six volunteers with healthy skin, the amounts of the applied dose absorbed within a mean period of exposure of 4 hours were approx. 0.2% via intact skin and approx. 0.4% via “stripped” skin. Extrapolated to a whole day, this results in a mean percutaneous absorption of approx. 1.2% in the case of an intact penetration barrier and of approx. 2.4% in the case of a removed barrier.

Following absorption, diflucortolone valerate is hydrolysed extremely quickly to diflucortolone and the corresponding fatty acid. In addition to diflucortolone, 11-keto-diflucortolone and two other metabolites were recovered in plasma. Diflucortolone is eliminated from plasma with a half-life of around 4-5 hours, all metabolites with a half-life of around 9 hours (half-lives were determined after i.v. administration), and excreted with urine and faeces in the proportion 75:25.

In systemic tolerance studies following repeated dermal and subcutaneous administration the effect of diflucortolone valerate was that of a typical glucocorticoid. It can be derived from these results that no side effects further to those which are typical of glucocorticoids are to be expected following therapeutic use of diflucortolone preparations under extreme conditions such as application over large areas and/or occlusion.

Specific embryotoxicity studies with diflucortolone valerate following subcutaneous and dermal administration led to results typical of glucocorticoids, i.e. following sufficiently high exposure embryolethal and/or teratogenic effects could be induced given the appropriate test systems. Since epidemiological studies have as yet given no indications of embryotoxic effects due to systemic glucocorticoid therapy, no embryotoxic effects are to be expected following the therapeutic use of diflucortolone preparations. However, taking animal-experimental results into consideration, particular care should be taken when prescribing diflucortolone.

In vitro investigations for detection of gene mutations in bacteria and mammalian cells as well as in vitro and in vivo examinations for detection of chromosome and gene mutations have not given any indications of a mutagenic potential of diflucortolone valerate.

Specific tumorigenicity studies have not been carried out with diflucortolone valerate. On the basis of the pharmacodynamic action pattern, the lack of evidence of a genotoxic potential, the structural properties and the results of chronic toxicity tests (no indication of proliferative changes), there is no suspicion of a tumorigenic potential of diflucortolone valerate. Since systemically effective immunosuppressive dosages will not be reached after dermal application of diflucortolone if used as directed, no influence on the occurrence of tumours is to be expected.

According to the results from local tolerance studies following repeated dermal administration, no dermal changes further to the side-effects already known for topical preparations containing glucocorticoids are to be expected from therapy with diflucortolone.