title: Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage.
abstract: We characterised biological properties of novel formulations of two low-potency glucocorticosteroids, dexamethasone and hydrocortisone, which have an equivalent dose ratio of 1:50 in vasoconstriction tests. The rate of such carrier-mediated, mainly non-diffusive glucocorticosteroids transport with very deformable lipid vesicles (Transfersomes) through the skin, and the corresponding cutaneous drug biodistribution data, were complemented with the drug bio-efficacy studies. The minimum effective drug dose that reduces arachidonic acid-induced murine ear oedema by 50% was used as one bioactivity indicator. The minimum drug amount ensuring such an effect in mouse skin decreases appreciably when a corticosteroid is applied epicutaneously with very deformable vesicles rather than a lotion or a crème. Specifically, the minimum effective dose for hydrocortisone in very deformable carriers is 2-3 microg cm(-2) whereas for the crème- or lotion-like preparations at least 10 microg cm(-2) is required. Such three- to fivefold relative increase of hydrocortisone potency is accompanied by at least 13%, and more often >20%, absolute drug potency enhancement. The delivery of hydrocortisone with very deformable carriers moreover prolongs the suppression of the drug-induced oedema nearly 2-fold (to approximately 24 h per application). The effective dose of dexamethasone delivered with very deformable vesicles into murine skin is reduced >10 times compared with the crème- or lotion-based products. Specifically, less than 0.1 microg cm(-2) dexamethasone in very deformable vesicles suppresses the arachidonic acid-induced murine ear oedema >50%, on the average. Dexamethasone use on the skin in such vesicles extends the duration of drug action fourfold, compared with a commercial crème, i.e. to >48 h per application. Epicutaneous use of glucocorticosteroids in very deformable vesicles also diminishes such drug's abrasion sensitivity and may increase the general robustness of drug effect. Lower frequency of skin treatment, which ensures adequate biological response, is a result of this. Topical corticosteroid delivery with very deformable vesicles, Transfersomes, thus improves the therapeutic risk-benefit ratio, arguably due to better targeting into and longer drug presence in the skin.
authors.affiliation: Medizinische Biophysik, Technische Universität München, Ismaningerstr. 22, D-81675 München, Deutschland, E.U., Germany. cevc@idea-ag.de
authors.forename: Gregor
authors.initials: G
authors.lastname: Cevc
authors.forename: Gabriele
authors.initials: G
authors.lastname: Blume
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D002626:Chemistry, Pharmaceutical; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004427:Ear Diseases / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006854:Hydrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008081:Liposomes; D051379:Mice; D009824:Ointments; D012867:Skin / Q000187:drug effects; D013552:Swine; D014316:Tritium
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D008081:Liposomes; D009824:Ointments; D014316:Tritium; D016718:Arachidonic Acid; D003907:Dexamethasone; D006854:Hydrocortisone