Percutaneous penetration of ozagrel and the enhancement produced by saturated fatty acids.
The effects of a series of fatty acids on the percutaneous penetration of ozagrel (OZ), a selective thromboxane A2 synthetase inhibitor, through rat skin and the mechanism by which fatty acids enhance the skin penetration of OZ were examined in vitro. Lauric acid, at the fatty acid: OZ molar ratio of 2 : 1, was the most potent agent as far as increasing the skin penetration was concerned, with a flux 24-fold higher than that without fatty acid. A molar ratio of 3 : 1 also produced a large enhancing effect, comparable with that of a molar ratio of 2 : 1. When the gel formulation with lauric acid (molar ratio of 2 : 1) was applied to the skin for 6 h, the amount of drug penetrating into the skin was significantly increased compared with that after the formulations without lauric acid and with capric and palmitic acids. However, lauric acid did not change the apparent partition coefficient of OZ between n-heptane and phosphate buffer (pH 7.4). The 13C-NMR spectra of OZ was also unaffected by the addition of lauric acid, indicating that a complex or ion pair with lauric acid was not formed. A possible mechanism for the enhancing effect is the increased incorporation of lauric acid with OZ into the bulk lipid phase of the stratum corneum, where the fatty acid would act as a co-penetrant enhancing passage through the stratum corneum.
Ogiso
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Osaka, Japan. t-ogiso@phar.kindai.ac.jp
Koike
K
K
Iwaki
M
M
Tanino
T
T
Tanabe
G
G
Muraoka
O
O
D000279:Administration, Cutaneous; D000818:Animals; D002626:Chemistry, Pharmaceutical; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005227:Fatty Acids / Q000494:pharmacology*; D007850:Lauric Acids / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008689:Methacrylates / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007850:Lauric Acids; D008689:Methacrylates; C034364:ozagrel