How do creams permeate the skin?

Professor Richard Guy, Professor of Pharmaceutical Sciences at the University of Bath, helped James Tytko with the answer…

Richard - Thanks James. The truth is, water can penetrate the skin from inside-out (and outside-in, for that matter, but less so) by passive diffusion. The water concentration inside the body is about 50 molar; outside, it’s much less, meaning that there is a strong driving force for water to ‘escape' from the body especially as an adult body’s surface area is 1.5 to 2 m^2 (15,000 to 20,000 cm^2).

So, how can we exist on terra firma without having to continually drink lots of water?  The answer, as you point out, is the stratum corneum, a very thin but very effective barrier to water penetration. We say it looks like a ‘brick wall’ with keratin-filled corneocytes providing the bricks, and intercellular lipids, organised in multiple bilayers, the cement or mortar.  Transport of compounds across the skin appears to be constrained to the tortuous intercellular, lipid-filled pathway, making the passage of hydrophilic compounds like water, quite limited (but not zero).  

James - The result of this incredible bit of bioengineering is that the passive loss of water across the entire skin surface in a day (assuming that you are not exercising vigorously) is limited to about 500 mL or less. So how could we target therapies to traverse this almost watertight frontier?

Richard - Medications and cosmetic creams per se do not penetrate the skin, but the chemical constituents of which they are comprised do... but not all to the same extent.  Generally speaking, smaller molecules permeate better than bigger ones and very big ones (for example, collagen) do so negligibly in amounts that cannot be measured by available techniques.  A cream containing collagen may feel good when you rub it on but the collagen molecules therein “ain’t going nowhere” (so to speak!)  Chemicals that are more lipid-soluble than water permeate better but there’s a limit to how much lipid solubility you want for a chemical to cross the skin.  Super lipophilic ones might like being in the stratum corneum but they’ll never leave it.

So, while drugs and cosmetic actives with the optimal properties applied to the skin can be absorbed into the stratum corneum, epidermis, dermis, underlying tissue (the muscle, as Garth points out) and eventually the blood.  But the deeper you go, the less you’ll find in each successive layer or ‘compartment’.  So, a drug applied topically to elicit a pharmacological effect ‘centrally’ (think a patch containing nicotine where the site of action is the brain) has to be really potent and effective at very small doses.

Comments thus far assume that we are talking about intact, normal skin.  Using a microneedle patch creates ‘holes’ through the stratum corneum through which water-soluble compounds (and bigger ones) can penetrate much more easily.  Technology has been under serious study now for more than 20 years but - as yet - still no regulatory-approved medicinal product on the market.

Cosmetic companies care a lot about the uptake of the chemicals in their products, especially those used over large surface areas (lotions, sunscreens, etc.), when the amounts absorbed - even if small per cm^2 - can add up if the product is used every day or several times per day (also for products to be used on infants whose body surface-volume ratio is relatively high).  They pay a fair bit of attention to ensure that systemic effects are not induced.

James - So, Garth, water struggles to penetrate the skin due to the stratum corneum, a highly effective barrier made of keratin-filled cells and lipid layers. However, certain small, lipid-soluble drug and cosmetic molecules can diffuse through, though their penetration decreases with depth. Techniques like microneedles enhance absorption, but regulatory-approved medicinal products using this method are still in development.