Sesquiterpene Components of Volatile Oils as Skin Penetration Enhancers for the Hydrophilic Permeant 5-Fluorouracil

Abstract

Twelve sesquiterpene compounds, derived from natural volatile oils, were investigated as putative skin penetration enhancers for human skin. Pretreatment of epidermal membranes with sesquiterpene oils, or solid sesquiterpenes saturated in dimethyl isosorbide, increased the rate of absorption of the model hydrophilic permeant, 5-fluorouracil (5-FU). Enhancers with polar functional groups were generally more potent than pure hydrocarbons. Furthermore, enhancers with the least bunched structures were the most active. The largest effect was observed following pretreatment with nerolidol, which increased pseudo-steady-state 5-FU flux over 20-fold. Molecular modelling suggested that terpenes with structures suitable for alignment within lipid lamellae were the most potent enhancers. Sesquiterpene enhancers had long durations of action implying that they did not wash out of the skin easily. This study attempted to improve enhancer clearance by replacing the aqueous donor and receptor phases by ethanol:water (1:1) solutions. Ethanol increased the permeability coefficient for 5-FU 13-fold, demonstrating that, in aqueous solution, it is a moderately potent penetration enhancer. Sesquiterpene and ethanol enhancement effects were approximately additive. Sesquiterpene effects were almost fully maintained for at least 4.5 days following pretreatment, illustrating poor reversibility. Stratum corneum/water drug partitioning studies suggested that an important mechanism of action of the enhancers was to increase the apparent drug diffusivity in the stratum corneum. Increases in drug partitioning into the entire stratum corneum following enhancer pretreatment were relatively small. Diffusivity increases were directly related to overall rises in permeability. This study has shown that sesquiterpene compounds, which are of low toxicity and cutaneous irritancy, can promote 5-FU absorption across human skin. Sesquiterpene compounds, therefore, show promise as clinically-acceptable skin penetration enhancers.

Molluscicidal and Mosquitocidal Activities of the Essential oils of Thymus capitatus Hoff. et Link. and Marrubium vulgare L.

“…Sesquiterpenoids are credited with various biological actions. They may kill snails as well as snail egg masses via contact poisoning resulting in killing the early egg embryos 11 . These findings are in accordance with other studies that mentioned sesquiterpenes as promising skin penetration enhancers with specific P-glycoprotein modulators that can reverse cellular multidrug resistance by inhibiting the drug efflux process 26,34 .…”

Anti-inflammatory activity of essential oil from leaves ofMyrciaria tenellaandCalycorectes sellowianus

“…clove oil, cinnamon leaves, and copaiba balsam, all of which have been used as natural remedies and as fragrances. This compound is also known to have antimicrobial (Alma et al, 2003;Lourens et al, 2004), antioxidant (Lourens et al, 2004, Singh et al, 2006, anticarcinogenic (Kubo et al, 1996) and skin-penetration-enhancing properties (Cornwell & Barry, 1994). Essential oils containing this compound as a major component showed marked anti-inflammatory activity against carrageenan-and prostaglandin E 1 -induced edema in rats as well as anti-arthritic activity (Martin et al, 1993;Baricevic et al, 2001;Agarwal & Rangari, 2003).…”

Effect of Transdermally Delivered Aspirin on Blood Coagulation Parameters

“…A number of terpenes viz. menthol, 1-8-cineol, dlimonene, nerolidol, geraniol, thymol, cyminine, carvone, acetylterpineol, -bisabool have been shown to increase transdermal permeation rate of hydrophilic and lipophilic drugs [28,29].…”