title: In-vitro release and transdermal fluxes of a highly lipophilic drug and of enhancers from matrix TDS.
abstract: Transdermal systems (TDS) are a well-known application form for small, moderately lipophilic molecules. The aim of this study was to investigate the possibility of applying a highly lipophilic drug, the antiestrogen AE (log P=5.82) transdermally by polyacrylate-based matrix TDS. For this purpose, two effects of both drug and enhancer concentration in TDS were investigated: in-vitro release and transdermal permeation of drug and enhancers. In the TDS investigated, in-vitro release as well as in-vitro permeation of AE through excised skin of hairless mice was found to be independent of concentrations of both drug and enhancers. The steady-state fluxes observed were low (about 50-100 ng cm(-2) h(-1)). But skin pretreatment with permeation enhancers resulted in a markedly enhanced permeability (1400 ng cm(-2) h(-1)). Therefore, the permeation of this highly lipophilic drug seems to be limited by the stratum corneum barrier function. In contrast, the transdermal permeation of the enhancers was dependent on the TDS composition. Increase in enhancer content resulted in a higher permeation of enhancers, whereas skin pretreatment did not. In conclusion, it was shown that the highly lipophilic antiestrogen can be administered transdermally by pretreating the skin with the fluid permeation enhancer combination propylene glycol-lauric acid (9+1) and then applying a matrix TDS.
authors.affiliation: Pharmaceutical Development, Schering AG, 13342, Berlin, Germany.
authors.forename: Adrian Peter
authors.initials: AP
authors.lastname: Funke
authors.forename: Clemens
authors.initials: C
authors.lastname: Günther
authors.forename: Rainer Helmut
authors.initials: RH
authors.lastname: Müller
authors.forename: Ralph
authors.initials: R
authors.lastname: Lipp
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007850:Lauric Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability; D019946:Propylene Glycol / Q000008:administration & dosage / Q000493:pharmacokinetics; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D012869:Skin Absorption; D013457:Sulfur Compounds; D005466:Fluorocarbons
chemical_list: D004958:Estradiol; D020847:Estrogen Receptor Modulators; D007850:Lauric Acids; D019946:Propylene Glycol; D013457:Sulfur Compounds; C466991:11-fluoro-7-(5-(methyl(3-((4,4,5,5,5-pentafluoropentyl)sulfanyl)propyl)amino)pentyl)estra-1,3,5(10)-triene-3,17-diol; D005466:Fluorocarbons; C030358:lauric acid