Terpenes are found in the essential oil. They are volatile, fragrant substances that are naturally occurring in many flowers and plants and their are natural substances which clinically acceptable enhancers because of their low toxicity and high medical activity.

Types of terpenes (isoprene units) (Nuanchan, 2006)(1)
– Monoterpenes (C10) : 2 isoprene units
– Diterpenes (C20) : 4 isoprene units
– Sesquiterpenes (C15) : 3 isoprene units

Other method may be classified according chemical groups such as alcohol terpenes, ketone terpenes, hydrocarbon terpenes  and oxide terpenes.


Cineole was the main component of the cyclic monoterpenes, followed by limonene, terpineol, and pinene. Cineole and limonene were mixed in a 2:1 ratio as a pretreatment vehicle, based on the composition ratio of these two major components in cardamom oil.


Type of Terpene
1. Alcohol terpenes
• Carvacrol
Carvacrol was used as an enhancer for propranolol hydrochloride through hairless mouse skin. The concentration of carvacrol used was in the range of 1, 5 and 10% in 40% ethanol. All concentrations of carvacrol enhanced the flux of propranolol hydrochloride. The fluxs were 156 μg/cm2/hr for 1%, 169 μg/cm2/hr for 5% and 188 μg/cm2/hr for 10% carvacrol, respectively. While at 1% carvacrol provided the longer lag time than other concentrations. The effect of carvacrol on the percutaneous absorption of azidothymidine (AZT) was investigated using two vehicle systems i.e.,IPA/water and PG/water. Five percentage of carvacrol in IPA/water (60:40) could enhance the flux of AZT at 38.0-fold. However, at a 10% carvacrol, the transport of AZT was significantly less than at 5%. When comparison was made between IPA/water and PG/water, carvacrol in the PG/water showed significantly decrease in the flux of AZT. Thus, the 5% carvacrol in IPA/water was effective for AZT.

• Menthol
The effect of menthol was studied in the vitro percutaneous absorption of tamoxifen (highly lipophilic drug) through porcine epidermis. Menthol at the concentration of 5% in combination with 50% ethanol could increase permeability of tamoxifen (ER=36.22) and the lag time of tamoxifen was significantly reduced as compared to control. The influence of menthol on the percutaneous absorption of ketoprofen formulations through the rat skin was investigated by in vitro study. The concentration of menthol was in range of 1, 3, 5, 7, and 10 % w/w. The flux of ketoprofen increased with an increase in menthol concentration and the maximum steady-state flux of ketoprofen was observed with 5 % menthol indicating that the value may be the optimal concentration for ketoprofen to attain the effective penetration capability.

• Thymol
Thymol (5%) was used to enhance the lipophilic drug (tamoxifen) through porcine epidermis. The result showed that thymol enhanced the permeation of tamoxifen with ER 42.52. The enhancing effect of thymol in the percutaneous permeation of piroxicam was investigated. Skin pretreatment with 5% thymol in 50% ethanol-water, the flux of piroxicam further increased which was significantly difference in comparison with 50% ethanol pretreatment.

• Geraniol
Geraniol (1%) was used to study the enhancement effect on hydrophilic drug, diclofenac sodium. The result showed that geraniol provided the highest increase in the flux of diclofenac sodium, which was 54.22 μg/cm2/hr (ER=18.97). Geraniol is an acyclic alcohol terpene. This compound had the structure suitable for disrupting the lipid packing of the SC because of the presence of
hydrocarbon tails besides a polar head group.

• Farnesol
Farnesol was investigated as skin penetration enhancer for human skin. Pretreatment of epidermal membrane with farnesol increased the rate of absorption of a model hydrophilic drug, 5-fluorouracil. Farnesol increased 5- fluorouracil flux 15-fold. Molecular modeling suggested that farnesol had the structure suitable for alignment within the lipid lamellae and disrupting lipid packing.

• Nerolidol
Nerolidol is a sesquiterpene, which derived from Careuva oil. Four model drugs were selected based on their lipophilicity denoted as log P. The enhancing effect of nerolidol was tested in vitro across full thickness hairless mouse skin with each of the drugs formulated in gel. Nerolidol provided the highest increase in ERflux of nicardipine hydrochloride at 135-fold, hydrocortisone at 33-fold, carbamazepine at 8-fold, and tamoxifen at 2-fold. Pretreatment of epidermal membranes with nerolidol increased the rate of absorption of 5-FU with ER 22.8. SC/water drug partition studies suggested that an important mechanism of action of nerolidol was to increase the apparent drug diffusivity in the SC.

2. Ketone terpenes
• Carvone
Carvone (5%) increases the flux of hydrophilic and lipophilic drug. For example, carvone in combination with 50% ethanol could increase permeability of tamoxifen (ER=40.41) through porcine epidermis. Carvone did not affect the partitioning of tamoxifen into the SC in comparison with the control. The enhancement in the permeability coefficient by carvone was due to disruption of the SC lipids. Carvone also was used to study the enhancement effect on 5-FU. It was found that carvone provided ER of 91.62.

• Menthone, piperitone, and pulegone are used as penetration enhancers. In vitro permeation experiments of a model drug, 5-fluorouracil, on human epidermal membranes showed that these terpenes were effective in increasing the permeability coefficient of 5-fluorouracil approximately 37-fold for menthone, 29-fold for pipertone, and 20-fold for pulegone. The results of this study were compared with terpenes activities toward a model lipophilic drug, oestradiol. It was found that these terpenes were less effective as an enhancer for oestradiol. These terpenes did not affect the partitioning of 5-fluorouracil into the SC in comparison with the control.

3. Hydrocarbon terpenes
Limonene is found in various oils, particularly in oils of lemon, orange. It has been investigated as skin penetration enhancer for lipophilic drugs such as tamoxifen and ketoprofen. The flux of tamoxifen (lipophilic) was increased relative to 50% PG in water with increasing concentration of limonene (1, 2, 3 and 5%). The ER for 5% limonene in 50% PG was 25.25. The lag time was shorter than control. These lag times reflected an increase in the effective diffusion coefficient of tamoxifen. Thus, an increase in the permeability of tamoxifen through porcine epidermis by limonene was largely due to increasing the diffusivity of drug in the SC. In vitro transepidermal water loss (TEWL) findings suggested that limonene caused SC lipid extraction. Thus, an increase in SC lipid extraction led to an enhanced percutaneous absorption of tamoxifen. Results of skin damage also showed that the lower limonene concentrations (1,2 and 3%) induced skin damage that was reversible in comparison to the damage resulting from the higher concentration of 5%. Percutaneous absorption of ketoprofen was investigated from hydrogels containing 2% limonene through the rat abdominal skin. Percutaneous absorption was increased with limonene, but it also produced skin damage.

It has been investigated as skin penetration enhancer for hydrophilic drug, 5-fluorouracil. An in vitro permeation through human epidermis showed that limonene enhanced the flux of 5-FU. It increased the flux of 5-FU at 2.1-fold. Limonene showed the least effect on the transport of propranolol hydrichloride. Five percentages in combination with ethanol significantly increased the flux of propranolol hydrochloride at 2.80-fold through porcine epidermis. For diclofenac sodium, limonene enhanced the flux at 10.07 μg/cm2/hr and ER at 3.53. This indicates that limonene is the enhancer for the lipophilic drug.

4. Oxide terpenes
Percutaneous absorption-enhancing effects on the skin of hairless rat skin of cineole were investigated using three different model drugs (caffeine, hydrocortisone and triamcinolone acetonide). Cineole increased the flux of caffeine, whereas cineole did not affect the flux of hydrocortisone and triamcinolone acetonide when compared with controls. The enhancing effect of cineole in the percutaneous permeation of piroxicam through porcine ear was investigated. The results showed that 5% cineole in 50% ethanol increased the flux of piroxicam to 25.71 nmol/cm2/hr and ER at 1.98. Another study, using 5% cineole in 50% ethanol, showed the enhancement ratio of tamoxifen (high lipophilic) to be 36.22-fold. Percutaneous absorption of 5-FU (hydrophilic) was enhanced by cineole. It provided ER of 94.8 in human skin and 153.75 in pig skin.

Mechanism of action of terpenes
The steady-state transport of molecules through biological membranes is described as a solubility-diffusion process. The permeability coefficient (kp), relating the solute flux to the concentration gradient across the membrane, is expressed
mathematically in below equation.

kp = DK

Terpenes may act by altering the diffusion characteristics of the skin or by modifying the SC/vehicle partitioning behavior of the drug.

The SC lipids are composed mainly of ceramides, fatty acids, and cholesterols. These lipids are the principal barriers for transport of solute through the skin including drugs.

Treatment of SC with terpenes shifted the endothermic transition to a lower temperature. This indicated that the enhancers affected the lipid structure of SC. The enhancers may have caused a disturbance of the organized structure of the lipid matrix of the SC, producing an increase of the skin permeability, thus facilitating the penetration of drugs.

1. Nuanchan Issarapanichkit, 2006. Action of Terpenes as penetration enhancer on the skin permeation of Ketoprofen.