EPSILON-AMINOCAPROIC ACID-ESTERS AS TRANSDERMAL PENETRATION ENHANCINGAGENTS

The synthesis of epsilon-aminocaproic acid esters is described. Two re presentative members from a group of five of the 1-alkyl homologues sy nthetized as flexible analogues of 1-alkylazacycloheptanone derivative s were evaluated in vitro for their effectiveness on the transport of theophylline through the excised human cadaver skin in comparison with Azone. The 1-octyl- and 1-dodecyl-epsilon-aminocaproic acid esters (O CEAC and DDEAC) show excellent penetration enhancement. Donor samples contained 2.5% theophylline and 1% enhancers tested in three different vehicles. Fluxes of theophylline were increased with OCEAC about 19 t imes from olive oil, 45 times from water, and about 38 times from wate r-propylene glycol (3:2) vehicle toward controls (with DDEAC about 17, 39, and 35 times, respectively) and they were markedly higher than Az one under the given conditions. Acute LD50's (i.p. in mice) of OCEAC ( DDEAC) were 245 mg/kg (352 mg/kg), with a slightly lower toxicity than Azone. OCEAC and DDEAC did not exhibit acute dermal irritation in viv o on rabbits at a 5% concentration in white petrolatum.