Mechanism for the enhancement effect of fatty acids on the percutaneous absorption of propranolol.
The effects of a series of fatty acids on the percutaneous absorption of propranolol (PL) through rabbit skin and the mechanism by which fatty acids facilitate the skin penetration of PL were examined in vitro and in vivo using a gel base. Lauric and myristic acids, at the fatty acid:PL molar ratio of 1:1 were the most potent agents in increasing the skin penetration, giving the largest penetration rate (Js) and penetration coefficient (Kp) of PL. The molar ratio of 2:1 also exerted a large enhancing effect, comparable to that with a molar ratio of 1:1. When the enhancing effects of lauric acid, its amide, and its methyl ester were compared, the free acid gave the highest Js and Kp values. The plasma PL concentrations were significantly higher and more sustained after a single percutaneous application of the formulation with lauric acid than those after the formulation without the acid. The mechanism for the enhancing effect was examined by measuring IR and 13C NMR spectra, the solubility in buffer, and the apparent partition coefficient of PL. Additionally, the penetration of PL and lauric acid, as co-penetrants, through rabbit skin and shed snake skin were evaluated. The IR spectra of the mixture of PL with lauric acid (molar ratio, 1:1) was characterized by an extreme shift of the CO peak. Comparison of the NMR spectra of PL, lauric acid, and the mixture suggested that the carbonyl group of lauric acid interacted with the amino and hydroxyl groups of PL, probably by charge interaction.(ABSTRACT TRUNCATED AT 250 WORDS)
Ogiso
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
Shintani
M
M
D000279:Administration, Cutaneous; D000818:Animals; D004357:Drug Synergism; D005227:Fatty Acids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007850:Lauric Acids / Q000378:metabolism; D008297:Male; D011433:Propranolol / Q000097:blood / Q000378:metabolism*; D011817:Rabbits; D012869:Skin Absorption
D005227:Fatty Acids; D007850:Lauric Acids; C030358:lauric acid; D011433:Propranolol