Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations.
OBJECTIVE
Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally.


METHODS
Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted.


RESULTS
Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 microg x cm(-2) x h(-1) and 3.2 microg x cm(-2) x h(-1), respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation.


CONCLUSIONS
Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.
Funke
Adrian P
AP
Pharmaceutical Development, Schering AG, Berlin, Germany.
Schiller
Roman
R
Motzkus
Hans W
HW
Günther
Clemens
C
Müller
Rainer H
RH
Lipp
Ralph
R
D000277:Adjuvants, Pharmaceutic / Q000493:pharmacokinetics*; D000279:Administration, Cutaneous; D000818:Animals; D001692:Biological Transport; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004058:Diffusion; D004121:Dimethyl Sulfoxide / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007547:Isosorbide / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D007850:Lauric Acids / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D019946:Propylene Glycol / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D012997:Solvents / Q000493:pharmacokinetics*; D013457:Sulfur Compounds; D013997:Time Factors; D005466:Fluorocarbons
D000277:Adjuvants, Pharmaceutic; D004121:Dimethyl Sulfoxide; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D007547:Isosorbide; D007850:Lauric Acids; D019946:Propylene Glycol; D012997:Solvents; 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; C471034:11-fluoro-7-(5-(methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino)pentyl)estra-1,3,5(10)-triene-3,17-diol; C030358:lauric acid; C040079:2,5-dimethylisosorbide