Penetration of Cosmetics Into and Through the Stratum Corneum

One of the recurring debates in cosmetics development relates to the penetration of ingredients. How do manufacturers ensure optimal penetration for efficacy? What is the optimal penetration? How can water, lipophilic molecules, liposomes or nanoparticles penetrate through the stratum corneum (SC) and reach deep into the epidermis and below? This overview takes a somewhat different approach to the question of penetration by focusing on the SC, the first layer implicated by application of topical products to the skin. It also investigates how molecules are able to penetrate this outermost layer and stresses the fact that even if they penetrate no deeper, they play an essential role in skin health and youthfulness.

Stratum Corneum

To understand the dynamics of penetration, it is important to recall some biology basics. The SC is the outermost layer of the skin and consists of two distinct structural components: corneocytes and the intercellular lipid matrix. The corneocytes are differentiated keratinocytes, i.e., anucleated cells without intracellular organelles such as nuclei or mitochondria. They provide the structural support for the SC and act as a barrier against environmental aggressors. Corneodesmosomes interconnect corneocytes as desmosomes interconnect keratinocytes in the epidermis. Essential corneodesmosomal proteins include desmocollin and desmoglein. The gaps between intercellular lipids are how most hydrophilic and lipophilic molecules penetrate the SC.

The intercellular lipid matrix is located between corneocytes and is composed of ceramides, fatty acids, cholesterol and glucosylceramide derivatives. These lipids are synthetized by the keratinocytes in the upper layer of stratum granulosum. Covalent ester bonds between the ceramides of the intercellular lipid matrix and the structural proteins of corneocytes membrane create a dense network.1

Having revisited what the SC is, return now to the question at hand: How do molecules of different sizes and forms, which have different physicochemical properties, penetrate it?


The penetration of a substance through the skin depends on many parameters that can interact with one another, including biological factors such as skin condition and age, the site of application and skin hydration. Physicochemical factors, in particular those related to the substance itself, including the size of the molecules and their compatibility with the skin surface also play a role. There are various routes for molecules to passively diffuse through the SC: intercellular, trans- cellular, intrafollicular and the polar pores (see Figure 1). Only small molecules, meaning those whose molecular weight is below 500 Da, penetrate via these pathways.2 It should be noted that the vehicle carrying the active ingredients can also facilitate penetration through the SC. Vehicles may have a range of molecular interactions with the proteins and lipids of the SC to modify substance permeation and to improve dermal substance delivery.3

The intercellular pathway allows for the sinuous penetration of molecules between the corneocytes through the intercellular lipids. The gaps between the intercellular lipids measure between 6 and 13 nm,4 and this pathway is how most hydrophilic and lipophilic molecules penetrate the SC. Most skin penetration enhancers such as dimethylsulphoxide, glycols, surfactants and more, affect the intercellular lipid bilayers by reversibly decreasing the diffusional resistance.5

The transcellular pathway, on the other hand, involves corneodesmosomes that create bridges between cells and become sufficiently amphiphilic to enable the transport of molecules.6 Molecules that can integrate into the double phospholipid layer of the corneocyte membrane may therefore penetrate into the cells and be transported through them. Penetration by this pathway is slow, a characteristic that is offset by the significance of the surface involved.

The intrafollicular pathway enables penetration through hair follicles, which account for 1–2% of the total skin surface. Since the pilosebaceous follicles are located in the dermis within deep invaginations of the epidermis, they are able to carry molecules to the reticular dermis. Hair follicles do not have a highly developed SC, which facilitates penetration at this level. The intrafollicular pathway is used in particular by large molecules, which are typically highly insoluble.7 Moreover, the pilosebaceous follicles tend to scavenge lipophilic substances and sebum flow, which flows from the inside to the outside and counters the penetration of exogenous substances.

Finally, the polar pathway is a route composed of aqueous regions surrounded by polar lipids that create the walls of microchannels. These pores are present between cells and surrounded by polar lipids, which generate discontinuities in the organization of the lipids. This pathway is hydrophilic in nature, so substances such as sucrose, for example, penetrate into the epidermis via this route.8

Penetration of Water

The stratum corneum is impermeable except for a small quantity of water that is delivered by the epidermis into the SC. This water hydrates skin’s external layers, helps to maintain its flexibility, and enables enzymatic reactions and corneodesmolysis. The passage of water from the body through the skin and to the outside environment is called transepidermal water loss (TEWL). TEWL is influenced by the concentration of water in the epidermis, cellular integrity, relative humidity, diffusivity of water in the SC, and the thickness of the SC.

The ability of skin to maintain water depends on the arrangement of the corneocytes, the composition and structure of intercellular lipids, and the presence of natural moisturizing factors (NMFs). NMFs are made of water-soluble compounds that absorb water from the atmosphere. They are typically amino acids or other chemical substances that hold water and rehydrate the SC. NMFs are formed during epidermal differentiation and represent 10% of the corneocyte mass.9

Penetration of Lipophilic Molecules

Lipophilic molecules of low molecular mass enter the SC essentially via the intercellular pathway, i.e., between the corneocytes and through the intercellular lipids. These lipids provide epidermal differentiation, and consist of free or esterified sterols, free fatty acids, triglycerides and sphingolipids arranged in oriented bilayers that bind hydrophilic and lipophilic areas. The greater the concentration of cutaneous lipids in the bilayers, the slower the penetration speed of hydrophilic molecules. By increasing the fluidity of cutaneous lipids, penetration is facilitated.

Penetration of Liposomes

Liposomes are lipid vesicles that can be used as carriers for hydrophilic substances that are solubilized into aqueous domains, or lipophilic substances solubilized into lipidic membranes. These colloidal particles are formed as concentric bimolecular layers of phospholipids. Cholesterol may improve the bilayer characteristics of liposomes by increasing the microviscosity of the bilayer, reducing the permeability of the membrane to water-soluble molecules, or stabilizing the membrane and increasing the rigidity of the vesicle.10 Liposomes represent a method to enhance the permeation of substances through the skin.

There are five possible mechanisms for liposomes to penetrate and deliver into the SC.11 First, liposomes can penetrate independently into the skin, at which point they release the active substances. Also, they may be absorbed and then fused with the skin’s surface and constituents, changing the ultrastructure of the intercellular regions in the deeper layer of the SC. In turn, this decreases the impermeability of the SC and enhances the penetration of the encapsulated molecule.12

Liposomes may gravitate to the surface of the SC, resulting in a direct transfer of the encapsulated molecule from the liposome to the skin. Vesicles could also fuse and mix with the lipid matrix of the SC, increasing the distribution of molecules into the skin.13

In addition, liposomes can penetrate into the skin as an intact form. Although it is now generally accepted that conventional liposomes do not directly penetrate into the skin, this penetration mechanism has been described by Cevc et al. for deformable liposomes, also known as transfersomes.14 Due to the presence of a surfactant in their bilayer, these vesicles exhibit elastic properties that allow them to deform to pass between the cells of the SC, thus arriving intact into the epidermis. This penetration is made possible by the presence of a natural transepidermal water gradient, which is created by the hydrophilicity of phospholipids. Furthermore, these liposomes avoid dry environments and follow the gradient of moisture, moving into the deeper layers and more hydrated skin. Lastly, liposomes penetrate into the skin via cutaneous annexes such as hair follicles.15

Penetration of Nanoparticles

The penetration of nanoparticles occurs via two possible paths: intercellular and intrafollicular. Nanoparticles penetrate faster through the hair follicles than through routes in the SC. It was demonstrated, for example, that microparticules with an optimal size of around 1.5 µm showed 55% penetration into hair follicles.16 While the trans-follicular pathway plays a central role in studying the penetration of nano-particles,17 it is not yet clear whether nanoparticles penetrate into the hair follicles or are stored in the outer layer of these hair follicles.

Intelligent Targeting Capsules

Intelligent targeting capsules can be recognized by fibroblasts, melanocytes or adipocytes in order to deliver anti-aging, whitening or slimming actives directly to specific cells. Capsules are formed by a matrix of poly-(lactic-co-glycolic acid) PLGA with an outer polyvinyl alcohol (PVA) shell, with the addition of an N-pantothenic-peptide.18 A ligand is covalently bonded to the surface of the capsule. These ligands, consisting mostly of peptides, are recognized by receptors in the surface of the target cells, which are thus able to uptake the particle by endocytosis.

The particles are able to escape from the endosomal compartment, then degraded, and therefore able to deliver the active to the cytoplasm. Cruz has suggested that PLGA capsules used as intelligent targeting capsules increase the activity of the encapsulated active ingredients by concentrating them solely in the place where they can be biologically active. This is of further interest to personal care products for anti-aging, whitening, tanning and slimming benefits.19

Impact of the Vehicle

Cutaneous and percutaneous absorption can be enhanced by the formula vehicle, since delivery is influenced by interactions between the vehicle and skin. Specifically, the vehicle changes after topical application and during skin penetration. Skin components, i.e., intercellular lipids, may also be incorporated into components such as propylene glycol, a penetration enhancer, which evaporates after contact with the skin. Therefore, on a case-by-case basis, vehicles can be optimized, but the formulator must consider all such cases to master the complexity of the formula.3, 20 For more on these intricate interactions, see the article by Abbott.

Penetration Versus Protection

It is not clear yet whether the compounds found in cosmetic formulations truly penetration in vivo. While many researchers infer this means the formulations lack efficacy, this author proposes, rather, that the lack of penetration of a product’s active ingredients is not a negative characteristic. Indeed, these ingredients still possess the ability to protect the SC against environmental stress and damage.

While the SC constitutes only 10% of the entire skin, it contributes to more than 80% of the cutaneous barrier function. Thus, protection of the SC is of utmost relevance. For example, the use of antioxidant molecules in cosmetic products can help the SC regenerate and protect itself, in turn regenerating and protecting the underlying epidermis and dermis from the harmful effects of UV radiation and other environmental toxins.


The individual penetration of water, lipophilic molecules, liposomes and nanoparticles through the SC, as well as the function of the various transport pathways—intercellular, transcellular, intrafollicular and polar pores—are becoming better understood. Despite this progress, the penetration mechanisms of cosmetic formulations remain quite mysterious and deserve further research.

This overview presents current knowledge on the various pathways of penetration through the SC and suggests that even if cosmetic formulations penetrate no deeper, their efficacy may still be optimal. Indeed, the SC represents the barrier function of skin, and as such, must be protected from environmental assaults. By regenerating and protecting the SC, active cosmetic ingredients also protect the epidermis and dermis.


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