This study investigates physicochemical processes responsible for the biphasic transdermal flux profiles of melatonin in the presence of saturated fatty alcohols (SFAL) and unsaturated fatty alcohols (USFAL). The first phase melatonin flux (J1st) in the presence of USFAL enhancers increased with increase in the number of double bonds and reached a limiting value with two double bonds in the molecule. In case of SFAL enhancers, J1st increased with enhancer chain length and log formulation/skin partition coefficients (log Ps), which were calculated using the solubility parameters of various formulation components. But, melatonin flux in the second phase decreased with increase in the enhancer chain length and logP values. On the other hand, the transepidermal water loss (TEWL) from the SFAL treated skin increased drastically in the second phase and correlated with logP value of the enhancer. High TEWL value, indicative of a severely disrupted SC, may help the polar formulation components to accumulate in the SC. As a consequence, the SC polarity could change significantly and reduce the partitioning of lipophilic enhancer and/or melatonin in the second phase. This study demonstrated that an optimal level of barrier disruption enhances the transdermal permeation of drugs, whereas, a drastic barrier disruption impedes transdermal transport.
Bibliographical noteFunding Information:
The authors acknowledge the financial support provided by the NIH/NIGMS/MBRS 3S06GM008111-35S1; NIH/NCRR/RCMI G12RR03020; and NASA (Grant No. NCC 2-1005). The research assistance of the Department of Pharmaceutical Sciences, Auburn University is appreciated.
- Fatty alcohols
- Rat skin
- Solubility parameters
- Transdermal permeation