Terpenes have the potential for enhancing percutaneous dermal absorption of therapeutic proteins which cannot be delivered orally due to their unique pharmacokinetic characteristics and stability issues. 

Transdermal Absorption

Over the years, transdermal delivery has become one of the favored routes of delivering therapeutics. It offers several advantages over conventional delivery methods.

Transdermal delivery bypasses the first-pass effect sustains release of drugs over a period of time, and offers better patient compliance.

Dermal Products 

Transdermal patches containing hormones are being studied by scientists all over the world to exploit these advantages. Transdermal patch containing gestodene and ethinylestradiol is a convenient non-oral contraceptive which showed sustained release. 

Many cosmetic products available in the market contain various proteins, such as keratin and kinetin as the active ingredient.

Skin Barrier 

Due to the barrier functionality of top most layer of the skin, dermal delivery of protein/peptide based therapeutics has been problematic.The stratum corneum is made up of dead cells which mostly consisted of lipids and protein keratin. These cells have the dual ability to absorb water and avoid loss of moisture. A drug has to pass through the continuous layer of intracellular lipids and intercellular proteins to reach the systemic circulation via the skin. 

Permeation Enhancers

Several methods have been used to overcome the barrier property of skin to accelerate the flow of proteins/peptides across the skin.

One technique used to increase permeability through the skin is the use of chemical penetration enhancers. The method involves the reversible and transient perturbation of barrier integrity of stratum corneum by using terpenes 

Various terpenes are used to increase the permeability of drugs through the skin barrier into the blood circulation. These compounds are known as terpene penetration enhancers.

Generally, the smaller terpenes are found to be more active permeation enhancers and are reported to disrupt stratum corneum bilayer lipids. 

relatively large, long chain sesquiterpene such as nerolidol reinforces the bilayers possibly by orienting alongside the stratum corneum 

Hydrocarbon or nonpolar group containing terpenes such as Limonene provide better enhancement for lipophilic drugs than do polar terpenes. 

Conversely, terpenes containing polar groups such as menthol and 1,8-cineole provide better enhancement for hydrophilic drugs. 

Although nonaqueous solvents generally destabilize protein, some with low lipophilicity can have an opposite effect,

Lipophilicity is a desirable property for enhancing percutaneous absorption but may not be a favorable factor for preserving conformational stability and biological activity of a protein. 

Terpene Enhancement 

The percutaneous enhancement capacity of terpenes can be related to their structure and nature of permeation. Generally, terpenes with relatively greater lipophilicity provide better enhancement for lipophilic permeants while those with lower lipophilicity for hydrophilic permeants.

Terpene Data

There is limited data on terpene effect on stability and biological activity of proteins which must be understood to make delivery systems efficient and successful. 

Terpene Research

By researching the effects of nontoxic terpene-based skin penetration enhancers, such as fenchone, carveol, menthol, cymene, terpineol, limonene, eugenol, carvone, farnesol, geraniol, and verbenone, on the conformational stability we can have an understanding of the structural characteristics of terpenes optimal for use in a transdermal formulation of protein.