Effect of limonene and related compounds on the percutaneous absorption of indomethacin

The promoting effect of cyclic monoterpenes present in essential oils on the percutaneous absorption of indomethacin (IMC) from gel ointments was investigated in rats. As compared Azone, drug absorption was markedly enhanced by the addition of d-limonene, which is the main component of orange or lemon oils. Similar activity was observed in the cases of the l- and dl-forms of limonene, p-menthane, alpha-terpinene or terpinolene. On the other hand, no effect was obtained when the additive had hydroxyl or carbonyl groups, or ether oxygen in its chemical structure. The effect of pretreatment of skin with d-limonene on subsequent percutaneous absorption of IMC was investigated in order to estimate the influence of d-limonene on the barrier properties of the skin. No effect was observed suggesting that d-limonene might reversible alter the skin structure as the barrier for the drug transport. The serum concentration of IMC increased proportionally when increasing amounts of ethanol were present in the formulation (gel ointment) containing d-limonene. Therefore, ethanol may act as the accelerating agent for the promoting activity of d-limonene.