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Penetration enhancement – molecular mechanisms in the skin

 

The components of cosmetics and dermatological preparations either remain on the surface of the skin when applied or they penetrate the skin barrier, the epidermis, the dermis or the circulation. The depth of penetration determines whether the desired receptor is reached and the desired effect occurs. The aim is to achieve maximum effectiveness quickly with the least possible loss of substance. We explain the molecular background.

 

The prerequisite for substances to work in the form of their individual molecules is their ability to penetrate the skin superficially. If they penetrate the skin transdermally, this is called permeation in contrast to penetration. Permeation can take place in various ways: intracellularly, intercellularly or via the hair follicles.
Penetration and penetration depth depend on the size and nature of the molecules. There are also substances that make it easier for active ingredient molecules to penetrate into or through the skin. These are known as penetration enhancers.
By the way, penetration enhancement is not only limited to the chemistry of the molecules, but can also be achieved physically, for example by ultrasound, radio frequency and iontophoresis.
In addition, there is a process that has received little attention to date – namely the upstream formation of smaller, faster penetrating metabolites, which are formed by skin flora and epidermal enzymes.

Bioavailability

Bioavailability is the percentage of molecules that – when applied to the skin – are actually available for an effect. Poor bioavailability and the associated poor penetration usually require high concentrations of active ingredients in a preparation. As a result, concentration-related side effects can occur in both topical medicinal products and cosmetics.
The release of an active substance from a preparation can occur quickly or slowly. Figure 1 shows a rapidly increasing and decreasing release with a pronounced concentration peak.


Fig. 1: Rapid release of an active ingredientFig. 1: Rapid release of an active ingredient

In other cases, lower penetration rates and nevertheless high bioavailabilities are found because either the matrix of the preparation and/or the skin barrier (depot effect) releases the active ingredient slowly but evenly into the skin over a longer period of time in a plateau shape (Figure 2).

Fig. 2: Plateau-shaped release of a substance Fig. 2: Plateau-shaped release of a substance

Plateau effects are particularly desirable in pharmaceuticals whose active ingredients cause irritation if they penetrate too quickly, which is the case, for example, in the treatment of psoriasis with dithranol (INN). In cosmetics, depot effects occur in anti-wrinkle preparations containing the active ingredient spilanthol (N-2-isobutyl-2,6,8-decatrienamide). In this case, the depot effect even leads to subsequent doses being lower than the initial dose.
Plateau effects can be achieved with lamellar preparations that contain cell membrane components such as phosphatidylcholine, while conventional O/W emulsions and liposomal dispersions tend to have short, high release. The latter have the advantage that they lack the undesirable wash-out effect1 of conventional emulsifiers.

Concentrations

Sometimes the concentrations are decisive in determining which effects occur. Alpha-hydroxy acids (AHAs) such as lactic acid contribute to the skin's water balance in low concentrations, while in high concentrations they lead to AHA acid peeling. A similar situation exists with urea, which is part of the NMF. In high concentrations it has a keratolytic effect.
The aim must normally be to reduce the dosage of active ingredients as far as possible by optimising penetration without losing their effectiveness in order to make the use of care products sustainable, i.e. economical, ecological, tolerable and without side effects. These conditions can best be achieved through physiological compositions2 which, like natural foods, are easily broken down and completely biodegraded by the body.
Liposomes are suitable for the rapid application of hydrophilic active ingredients and nanodispersions for lipophilic active ingredients. Both are aqueous products such as lotions, which can be adjusted to a higher consistency with thickening additives such as xanthan gum. In addition to the plateau-forming lamellar creams, completely biodegradable, water-free oleogels should also be mentioned. They are characterised by an even slower but extensive release of the preferably lipophilic active ingredients they contain.
There are situations in which a physiological active ingredient does not achieve the desired effect, even in high concentrations, because it does not penetrate. Free ascorbic acid (vitamin C) is such an example. As an antioxidant, it is unstable and does not reach the enzymes involved in collagen metabolism.
With phosphoric acid, however, it forms a synthetic ester (INCI: Ascorbyl Phosphate), which stimulates collagen synthesis in liposomal packaging even at a low dosage of around 1%. The oxidatively stable ester is broken down on the spot by enzymes (esterases) into the original components.
Another way to increase penetration is to apply two products to the skin one after the other. For example, azelaic acid can be applied to rosacea-prone skin in a liposomal dispersion of up to 1%, followed immediately by a barrier-stabilising cream. This principle corresponds to the extended corneotherapy of Prof. A. M. Kligman (Figure 3).

Figure 3: Application of liposomes and a barrier cream one after the other

Figure 3: Application of liposomes and a barrier cream one after the other

If the azelaic acid is processed together with phosphatidylcholine in an oleogel, this can also be used to treat rosacea without causing inflammation in the following days as is the case with fatty emulsions.

Molecular properties

In liposomal and nanodisperse carrier systems, including appropriately composed oleogels that contain the cell membrane component phosphatidylcholine (PC), the penetration enhancement is achieved physically. PC lowers the phase transition temperature of the less permeable lamellar skin barrier by fusion to such an extent that it can be more easily overcome by molecules carried along.
If these conditions are not met, only the diffusion of individual molecules is important. The following framework conditions apply to them:

  • With comparable molecule sizes, lipophilic substances penetrate and permeate more easily than hydrophilic substances.
  • Non-ionic molecules penetrate the skin more easily than ionic (salt-forming) molecules.
  • The effectiveness of the transdermal passage decreases with the thickness of the skin.
  • The mass of a penetrating molecule is limited to about M < 500 Da (Dalton).3

In addition to the aforementioned phosphatidylcholine and its special structure-forming properties, there are other individual substances whose presence increases the penetration of other components of a preparation. These include, among others:

  • Dicarboxylic acid esters, e.g. of adipic acid, serve as spreaders in dermal preparations.
  • Phthalic acid esters (plasticisers) – now largely banned in cosmetic and pharmaceutical products.
  • Unsaturated acids such as oleic and linoleic acid. Oleic acid is preferably used in pharmaceuticals due to its higher oxidation stability.
  • Ethoxylated alcohols (PEGs) such as oleth-5, oleth-10 or laureth-12.
  • Terpenes from essential oils ; depending on their structure, they permeate very well and are detectable in the circulatory system. Aromatherapy is based on this property.
  • Sulphur compounds: Short-chain representatives such as dimethyl sulphoxide (DMSO) permeate very well – recognisable by the later garlic-like smell of exhaled volatile dimethyl sulphide.
  • Amides such as urea, endocannabinoids such as palmitic acid ethanolamide (component of the stratum granulosum), D-panthenol.
  • Surfactants and emulsifiers, especially those with a high critical micelle formation concentration (CMC), disperse barrier components and thus damage the barrier. This makes the skin more permeable. In low concentrations, surfactant substances utilise the same principle to channel poorly soluble, nanodisperse solids through the skin. However, these systems have ultimately not become established in cosmetics or dermatology.

Microbiome of the skin

Cosmetic ingredients with a molar mass of > 500 Da are not absorbed as such. However, experience shows that many of them disappear from the skin surface after a certain period of time and become effective.
These include the triglycerides of plant oils, which are mainly broken down by lipases of the microbiome into glycerol and fatty acids such as oleic acid, linoleic acid and others. The unsaturated acids in turn have a penetration-enhancing effect as mentioned above, but are also broken down by oxidases and thus contribute to the low pH of the skin surface.
Another interesting example is hyaluronic acid, which is more easily broken down into its individual components, such as N-acetyl-glucosamine (NAG), the shorter the chain. As a substance with an amide structure (see above), NAG can penetrate the skin relatively easily. It may stimulate the endogenous synthesis of hyaluronic acid, which is responsible for the turgor.

Further procedures

In addition to the possibilities of physical penetration enhancement, dermal needling and mesoporation should also be mentioned, in which the obstacle of the skin barrier is overcome by perforation.
Similar are procedures to weaken or remove the skin barrier before applying a product by means of mechanical exfoliation with abrasive particles ("scrubbing"), microdermabrasion ("sandblasting") or water jets ("pressure wash"). Chemically, this is achieved by pre-treatment with fruit acids (cosmetics), trichloroacetic acid (dermatology) and enzymatic peels containing lipases and/or proteases.
Another option often used in cosmetic treatment and dermatology is the creation of occlusive conditions using hardening masks, packs, films and covering paraffins and waxes. Due to the blocked transepidermal water loss (TEWL), they lead to swelling, which in turn increases the permeability of the skin for cosmetic active ingredients and drugs.

Remark and References

1) When non-biodegradable emulsifiers from skin care products are reactivated during subsequent skin cleansing, they emulsify skin barrier components and wash them out.
2) H. Lautenschläger, Die Haut und ihre Pflege – Physiologie und Chemie im Einklang? Chemie in unserer Zeit 2021, 55 (5), 306-319
3) J. D. Bos, M. M. Meinardi, The 500 Dalton rule for the skin penetration of chemical compounds and drugs, 2000; 9 (3):165-9
4) U. K. Caliskan, M. M. Karakus, Essential Oils as Skin Permeation Boosters and Their Predicted Effect Mechanisms, Journal of Dermatology and Skin Science, Published on: November 24, 2020

Dr Hans Lautenschläger

 
Please note: The publication is based on the state of the art at the publishing date of the specialist journal.

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© Copyright Kosmetik Konzept KOKO GmbH & Co. KG, Leichlingen, www.dermaviduals.de
Revision: 06.01.2025
 
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published in
Medical
2024 (6), 20-23

 
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