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Procipient as a Skin Penetration Enhancer

Mechanism of Action Overview: DMSO as a Skin Penetration Enhancer

The Stratum Corneum (SC) provides a strong barrier to human skin and provides resistance against penetration and permeation of active ingredients and drugs. The “brick and mortar” model of skin dates to 1983. In this model, dead corneocytes act as “bricks” which are embedded in a highly ordered multilamellar lipid matrix, representing “mortar”. This hinders active ingredients as they work to overcome the SC. Because of these biological constraints, the ability to deliver drugs topically becomes limited or even nullified. Therefore, penetration enhancers may be employed in transdermal drug delivery systems to modify the structure of the stratum corneum reversibly to deliver an active ingredient drug through its rigid structure1.

Transdermal drug delivery (TDD) systems deliver drug substance in a predetermined and controlled rate from the skin to enable systemic circulation. There are several categories of transdermal drug delivery systems categorized as first, second and third generation methods, but the most commonly used TDD products are patches. Patches use a special backing membrane to control the release of drug and to protect the drug and other components from the environment. A high concentration of an active ingredient may be released into the circulatory system in low concentrations for a prolonged time. Many common patch TDD products deliver pain relievers (i.e. Lidocaine), therapeutic hormones Active Ingredients to manage dementia, and agents for smoking cessation2.

In order for a drug to penetrate the skin barrier and reach systemic concentrations, it is often coupled with DMSO. This helps to reversibly modify the skin’s structure, thereby increasing permeability.

Dimethyl sulfoxide (DMSO) is a one of the earliest and most popular permeation enhancers. It has been called a “universal solvent” in pharmaceutical sciences. It has a unique characteristic of hydrogen bonding with itself than with water. Apart from being a great penetration enhancer, DMSO also has an anti-inflammatory characteristic and has been applied alone topically to reduce inflammation. The penetration of DMSO is very rapid, with an interesting side effect: a mild garlic taste is sometimes experienced within seconds of treatment with DMSO. (2)  There are many published examples which discuss the medical use of DMSO in TDD formulations.  One recent example is a is a DMSO-based Hydrocortisone anti-inflammatory composition3.

Though the exact biomolecular path of DMSO penetration enhancement capabilities are unknown, many studies have investigated the important effect that DMSO may have on membrane structure and function. DMSO readily positions itself just beneath the lipid headgroups, thus reducing bilayer thickness, increasing headgroup area. This markedly reduces both the area compressibility modulus and the bending rigidity of the membrane, thus inducing water pore formation. The positioning of DMSO beneath the lipid head group forces movement within the lipid layer, resulting in the tails to compress and then to expand the neighboring lipids into a larger volume, creating a less dense bilayer. The overall effect of DMSO makes the bilayer “floppier” and results in more permeability4.

The effect of DMSO is multifold in the skin, including extraction of and interaction with SC lipids. Mueller et al published a study which evaluated a cocktail of lipids (ceramide, cholesterol and stearic acid) representing a simple model (bilayer, oligolayer and multilayer). This model system mimicked the lipid matrix of the SC using pharmaceutically relevant concentrations of DMSO. The results indicated that DMSO interacts with lipids in the skin and helps in permeation. The results showed that there is minimal to no change in hydrogen bonding in the lipid matrix. There was decrease in the size of liposome, supporting the previously established concept. An increase in lipid expansion of 30% was reported. The overall conclusion was that DMSO influences the dynamics and fluidity of the lipid bilayer, resulting in better penetration conditions for active ingredient1.

 

Namrata Matharoo

Student, Rutgers University

 

1Mueller, J.; Trapp, M.; Neubert, R.H.H., Chemistry and Physics of Lipids 2019, 225; 104816

2Malvey, S.; Venkateshwar Rao, J.; Muthu Arumugam, K., The Pharma Innovation Journal 2019, 8(1): 181-197

3Backer, J. Dimethyl Sulfoxide (DMSO) and hydrocortisone compositions and methods of use. US Patent Application 2020/0009157 A1, January 09, 2020.

4Notman, R.; Noro, M.; O’Malley, B.; Anwar, J., American Chemical Society 2006, 128, 43, 13982-13983

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