Penetration enhancing effect of tetrahydrogeraniol on the percutaneous absorption of 5-fluorouracil from gels in excised rat skin.

Poly(acrylic acid) gels containing 5-fluorouracil (5-FU) and tetrahydrogeraniol (THG) were prepared and the effects of THG on 5-FU permeation across the excised rat skin were studied by in vitro methods. Experiments on in vitro permeation of 5-FU across the skin with vertical diffusion cells showed that addition of THG to the gels markedly enhanced the 5-FU permeability. Increasing the THG concentration in the gels to 8% proportionally increased the permeability of 5-FU. More than 12 h was required to reach a steady-state level of 5-FU after administration of 5-FU-THG gel topically. The permeability parameters such as flux, permeability coefficient and enhancement ratio were determined. The results indicated a maximum flux of 252.91+/-9.61 microgram/cm2 per h, and the enhancement ratio of 31.22+/-1.18 when the THG concentration was 8%. Synergistic effects of propylene glycol (PG) with THG were also investigated and a maximum flux of 256.81+/-9.15 microgram/cm2 per h, was obtained when the PG concentration was 5% and THG was 8%. The corresponding enhancement ratio was 31.71+/-1.13. These results suggest not only that THG would be very useful for increasing the skin permeability of 5-FU, but also that THG being a natural product might be useful for developing transdermal therapeutic systems for the delivery of practically unabsorbable drugs.

Synthesis and effect of two new penetration enhancers on the transdermal delivery of 5-fluorouracil through excised rat skin.

The tetrahydrogeraniol (THG) derivative, ethyl-(3,7-dimethyl octyl thio) acetate (EDOTA) was prepared by reacting tetrahydrogeranyl bromide (obtained by reaction of 40% hydrobromic acid and concentrated sulfuric acid) with ethyl 2-mercaptoacetate, while 3,7-dimethyl octyl propionate (DOP) was synthesized by a common esterification reaction by reacting THG with propionic acid in the presence of cyclohexane and concentrated sulfuric acid. The penetration-enhancing effect of the new enhancers were compared with THG and Azone in vitro using excised rat skin in modified Franz-type diffusion cells. 5-Fluorouracil (5-FU), a hydrophilic drug with poor skin permeability was used as a model permeant. Skin samples were pretreated with pure liquid enhancers for 12 h. 5-FU flux through the control and enhancer-treated skin increased linearly with its concentration in the receptor compartment. EDOTA and DOP interacted with the skin rapidly (< 2h), and the duration of action is at least 24 h. Significant differences were found in the flux values of 5-FU; EDOTA and DOP enhanced the permeability of the drug about 6-fold and 11-fold respectively. Increased partition coefficient and diffusion coefficient values were obtained by these enhancers. The results suggested that the amount of EDOTA and DOP in the skin, especially in the stratum corneum, may be related to their penetration-enhancing effect.