Transdermal flux predictions for selected selective oestrogen receptor modulators (SERMs): comparison with experimental results.
The aim of this work was to evaluate the feasibility of delivering transdermally a series of highly lipophilic compounds (log P ~4-7), comprising several selective oestrogen receptor modulators and a modified testosterone (danazol). The maximum fluxes of the drugs were predicted theoretically using the modified Potts & Guy algorithm (to determine the permeability coefficient (kp) from water) and the calculated aqueous solubilities. The correction provided by Cleek & Bunge took into account the contribution of the viable epidermal barrier to the skin permeation of highly lipophilic compounds. Experimental measurements of drug fluxes from saturated hydroalcoholic solutions were determined in vitro through excised pig skin. Overall, the predicted fluxes were in good general agreement (within a factor of 10) with the experimental results. Most of the experimental fluxes were greater than those predicted theoretically suggesting that the 70:30 v/v ethanol-water vehicle employed may have had a modest skin penetration enhancement effect. This investigation shows that the transdermal fluxes of highly lipophilic compounds can be reasonably predicted from first principles provided that the viable epidermis, underlying the stratum corneum, is included as a potentially important contributor to the skin's overall barrier function. Furthermore, the absolute values of the measured fluxes, when considered in parallel with previous clinical studies, indicate that it might be feasible to topically deliver a therapeutically useful amount of some of the compounds considered to treat cancerous breast tissue.
University of Bath, Department of Pharmacy & Pharmacology, Bath, UK; Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
Sevgi
S
Güngör
M Begoña
MB
Delgado-Charro
Valérie
V
Masini-Etévé
Russell O
RO
Potts
Richard H
RH
Guy
D000279:Administration, Cutaneous; D000465:Algorithms; D000818:Animals; D003613:Danazol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D004965:Estrogen Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008954:Models, Biological; D010539:Permeability; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine
D004965:Estrogen Antagonists; D020845:Selective Estrogen Receptor Modulators; D003613:Danazol
Breast cancer; Selective oestrogen receptor modulators; Skin flux prediction; Topical drug delivery; Transdermal drug delivery