Effect of d-limonene, alpha-pinene and cineole on in vitro transdermal human skin penetration of chlorpromazine and haloperidol.

The aim of this research is to carry out a comparative study of the ability to cross human skin of two neuroleptic drugs: chlorpromazine (CAS 50-53-3) and haloperidol (CAS 52-86-8), in the absence and in the presence of three terpenes (cineole, d-limonene and alpha-pinene) with the purpose of considering the possibility of improving their transdermal penetration profile. Franz diffusion cells were used, in conjunction with human skin as permeation membrane. The permeation parameters calculated were permeability constant (Kp), flux (J) and lag time (Tl) in the presence and in the absence of enhancers. None of the three enhancers assayed improved the penetration profile of chlorpromazine, and d-limonene even reduced the transdermal permeability (enhancement index, EI = 0.67) since its coefficient of relative activity was reduced, (Xr = 0.73). Cineole and d-limonene increased the permeation profile of haloperidol, giving EI values of 1.95 and 4.21, respectively, and leading to a fourfold increase in the flux value for both enhancers. alpha-Pinene did not modify the permeation profile of haloperidol. None of the three terpenes assayed had a significant effect on the lag time of chlorpromazine or haloperidol. In these experimental conditions the concentration values predicted at steady state of chlorpromazine formulated without enhancers are within the therapeutic range. In contrast, therapeutic levels of haloperidol cannot be predicted in the absence of enhancers such as d-limonene or cineole.