Skin Penetration: An Overview

As I mentioned in my post last week, molecules don't penetrate or absorb the skin as easily as one would think. Consumers these days are a lot more conscious about what they put on their skin and are definitely a lot more skeptical. 

'Can this cream really get rid of my wrinkles? Can it really alter my DNA? Can it get rid of my acne?'

All of these questions require an understanding of how a molecule can reach its target skin layer.

skin penetration an overview

But first, let's start with a more in-depth look at the stratum corneum structure.


Figure 1. Stratum corneum structure. The yellow boxes represent corneocytes embedded in a matrix of interceullar lamellar lipids.

Figure 1. Stratum corneum structure. The yellow boxes represent corneocytes embedded in a matrix of interceullar lamellar lipids.

The stratum corneum is the first line of defense molecules encounter when trying to penetrate our skin.

As mentioned in last week's post, the stratum corneum is composed of dead keratinocytes called corneocytes. Corneocytes are filled with mostly keratin, but they also contain cytoplasm and molecules called natural moisturizing factors (NMF's). NMF's are hygroscopic agents in the cell that help to regulate the skin's moisture by attracting water toward the center of the cell.

Surrounding the corneocytes are covalently bound proteins and lipids. We call this layer of lipids the cornified cell envelope. The lipids of the corninfied cell envelope are free fatty acids and ceramides. Protein residues like glutamine and serine are also bound to the outside of the corneocyte. (1)

Corneocytes are embedded in a matrix of lipids which are organized in lamellar structures. These layers are composed of ceramides, cholesterol and free fatty acids. Corneodesmosomes (or just desmosomes) hold together the corneocytes in the stratum corneum.

The sebaceous gland coats the surface of the stratum corneum with a waxy substance called sebum, which consists of triglycerides, wax esters, squalene and metabolites of adipocytes (fat-producing cells). This helps to waterproof your skin, which also makes it harder for hydrophilic molecules to penetrate your skin.


There are three paths in which cosmetic ingredients can penetrate the skin: (2)


This is when the molecule passes between the corneocytes in the stratum corneum. Majority of topically applied molecules will permeate the skin via this route. In between the corneocytes are layers of lipids organized in a lamellar structure. Therefore, this route naturally tends to favor lipophilic molecules. In Figure 1 you can see that corneocytes are not packed into neat parallel rows. This means that the molecule must follow a tortuous path to get through the stratum corneum into the viable epidermis. 


In the intracellular route, the molecule passes through the lipid membranes and cytoplasm of the corneocytes in the stratum corneum. This path is difficult to pass through because it must first cross the lipophilic membrane of each cell, then the hydrophilic center of the cell, and then back out through the lipophilic membrane. This then tells us that a molecule must have both hydrophilic and lipophilic characteristics to be able to take this route of penetration. Molecules with hydrophilic and lipophilic character are called amphilic.


Although this route is not typical for molecules when penetrating the skin, it is still an important site of action for OTC actives which treat acne since it targets the hair follicle. Research has shown that steroid derivatives are keen on this route of penetration. Generally this pathway is difficult to study due to lack of animal models.


Lipophilic molecules tend to favor non-polar pathways while hydrophilic molecules tend to favor polar pathways. Why? If you remember back to your general chemistry class, you may recall the phrase "like-dissolves-like." The same concept applies here. Hydrophilic molecules tend to favor polar pathways due to dipole-dipole and hydrogen-bond interactions with other polar molecular entities in the pathway. Lipophilic molecules tend to favor the non-polar pathway since they are non-polar themselves. Thus they can mix and interact with non-polar environments using Van der Waals interactions. 

So which of the three routes are non-polar? Which are polar?

I would argue that the non-polar route can be attributed to all three routes of penetration. The intercellular route makes the most sense since it is made up of the lipid bilayers, and the intracellular route requires the molecule to have enough lipophilic character to cross through its cornified envelope in order to enter the inside of the cell. As for the transappendageal route, the hair is coated with oils from the sebaceous gland, making the pathway leading down the hair shaft more lipophilic.

Then which path is the polar path? Obviously the intracellular route also requires some hydrophilic character in order to transport through the the inside of the corneocyte, but interestingly enough another polar path of penetration is the intercellular route. 

Researchers have found small pockets of water called "pores" which exist between the corneocytes. It is not understood if these pores are localized to a certain location, but they are formed when the skin is damaged and water is collected in a certain area. Therefore, hydrophilic molecules can also pass through the skin via pores between the corneocytes. Similar to the intracellular route, molecules must have some lipophilic character to go through the lipid bilayers between the corneocytes to be able to reach these aqueous pores in the first place.(2)

You may be wondering at this point how molecules differentiate between which route to take.

In reality, molecules topically applied to the skin will penetrate through all routes at the same time. Depending on their size and chemistry, the molecules will have a preference for the most optimal route of penetration.


Now let's actually think about the factors which play a role in what route of penetration a molecule will take:

  1. Concentration of the molecule in the formula
  2. The size of the molecule--the smaller it is (<500 Da), the better (3)
  3. The solubility of the molecule through the epidermis--balance of hydrophilic and lipophilic character
  4. The charge of the molecule--skin is negatively charged at physiological pH (~4.5), therefore it tends to attract cationic molecules
  5. The skin's health--affected by age, exposure to solvents, skin care routine, health condition, environmental factors
  6. Where the molecule is applied since the epidermis varies in thickness--for example, the skin on your face has a thinner stratum corneum than the soles of your feet; can also differentiate between races
  7. Moisture content of the skin
  8. Temperature of the skin--the warmer the skin, the more fluid the lipid barrier and easier for the molecule to flow through


We must understand that there is a difference when we talk about molecules penetrating or absorbing the skin. Personal Care Truth does a nice job in explaining this distinction which I will reiterate here. (4)

Penetration is when a molecule is applied to the skin and penetrates through to the bottom layer of the epidermis, the stratum basale. Remember that the epidermis is the top layer of the skin and does not have any vasculature for the molecule to be absorbed into the bloodstream. Thus, the molecule does not have an affect on any body systems. When a molecule is absorbed, this means that the molecule has reached the dermis where there is vasculature. 

Now just being absorbed in the bloodstream doesn't necessarily mean that the molecule is making biological changes to your body. If the molecule has any kind of reaction with your body, this would be considered making a biological change to your system. The molecule can also enter your bloodstream and either get excreted or accumulated. Accumulation, or bioaccumulation, can have detrimental affects. (5)

I surmise that most "actives" in your cosmetic products like plant extracts won't even be absorbed into the skin. A lot of times when developing cosmetic products with a marketing team, they can get pretty frustrated with you when you have to guide them through their copy to make sure they're not making any drug, or biological, claims. A huge struggle with using these "actives" in cosmetics is that since they most likely don't even penetrate into your skin, they have no real function in the product other than making the product appealing to consumers. 


In cosmetics, you can utilize skin penetration enhancers to disturb the barrier of the stratum corneum and deliver your product. Sometimes this can cause irritation to the skin, so formulators must be cautious of this when creating their product. To reduce irritation if you're using more than one enhancer in your formula, it's recommended you pick enhancers with different mechanisms.

Occlusive agents, esters, surfactants, solvents, enzymes, liposomes and ceramides are used as skin penetration enhancers. (2)


Occlusive agents act as a seal on the skin, which has been shown to increase penetration of ingredients. Ingredients like these include silicones, esters and fatty alcohols--essentially ingredients that cannot be easily washed off by water and leave a film on the skin. 


Esters like isopropyl myristate can also fluidize the lamellar bilayer of the intercellular lipids. This makes it easier for molecules to take the intercellular route since the bilayer physically will be easier to get through.


Surfactants and solvents help with skin penetration by solubilizing the intercellular lipids, affecting intercellular desmosomal connection and interfering with metabolic activity which maintains barrier homeostasis. As described in the previous blog post, surfactants in skin cleansers can also remove the oils on your skin, leaving it more permeable to hydrophilic ingredients. Propylene glycol is a common ingredient in cosmetics which doubles as a solvent and skin penetration enhancer.


Their main function is to affect the activity of enzymes which maintain barrier homeostasis. For example, a common target for this method is an enzyme which synthesizes the lipids in your stratum corneum. By inhibiting their synthesis, you can reduce the integrity of the barrier by decreasing the amount of lipids in the intercellular lamellar layer or the lipids on the cornified envelope of the corneocytes. Some topical enzymes can even trigger structural changes to the stratum corneum, consequently enhancing penetration.   


Liposomes can also be used to increase skin penetration. There has been conflicting research whether liposomes made from phospholipids or stratum corneum lipids are better for enhancing penetration.


Natural ceramides are already a prominent lipid found in the stratum corneum, so it's interesting that they can increase skin penetration when topically applied. However, research has shown that applying topical ceramides at certain concentrations can lead to an imbalance in lamellar organization of the intercellular lipids. Thus with a disturbed bilayer structure, the interceullar route of penetration is enhanced.


I hope this post was informative and comprehensive to new chemists and current ones. I'll see you in the next post.