The 500 Dalton rule for skin absorption of cosmetics

Skin absorption of cosmetics and skincare products: which factors affect it?

• Do cellulite creams (or any skincare cream) get absorbed? What is the optimum molecule size to penetrate skin?

• The 500 Dalton rule of cosmetic active ingredient absorption into the skin

• Most natural skincare active ingredients easily pass the 500 Dalton rule

• What is collagen’s dalton size? Do collagen and elastin fit to the 500 Dalton rule? Do they get absorbed into the skin?

• Do elastin and collagen peptides get absorbed?

• With a well-designed cream formulation, absorption is not a problem for the vast majority of natural actives

• Penetration enhancers further improve on the 500 Dalton rule

• The 500 Dalton rule for the skin penetration of chemical compounds and drugs

• Have a skin tightening/cellulite treatment in London with the experts

Do cellulite creams (or any skincare cream) get absorbed? What is the optimum molecule size to penetrate skin?

We analysed the subject of skincare active ingredient absorption in detail earlier. This article is about of one specific aspect of cosmetic active absorption: the 500 Dalton rule of cosmetic absorption.

The 500 Dalton rule of cosmetic active ingredient absorption into the skin

To simplify the understanding of cutaneous/transcutaneous (skin/through the skin) absorption, a general rule of a thumb was proposed by a group of scientists in 2000. The rule states that:

“Most compounds that must penetrate into/through the skin for pharmaceutical or cosmetic purposes must be of a molecular weight below 500 Da (Dalton)”

The scientists stated that almost all known pharmaceutical drugs proven to penetrate the skin under normal conditions are of 500 Da or smaller size.

However, since then it was shown that quite larger molecules, often above 1000 Da, can also penetrate into/through the skin, usually with the help of specially designed delivery molecules (penetration enhancers) or technologies (e.g ultrasound, radiofrequency, electroporation etc).

Most natural skincare active ingredients easily pass the 500 Dalton rule

In regard to cosmetics, most natural actives that are used in anti-ageing / anti-cellulite creams are of sizes below 500 Da, with some being of up to 700 Da molecular weight and extremely few being 1000 Da. Some examples of such actives, include:

• Caffeine, 194.19 Da (2.5x smaller than the upper size limit)

• Quercetin, 302.236 Da (1.6x smaller than the upper size limit)

• Ascorbyl glycoside, 338.265 Da (1.5x smaller than the upper size limit)

• Ascorbic acid, 176.12 Da (2.8x smaller than the upper size limit)

• Forskolin, 410.5 Da (1.2x smaller than the upper size limit)

• Asiatic acid, 488.70 Da (just below the upper size limit)

• Curcumin, 368.38 Da (1.4x smaller than the upper size limit)

• Retinol, 286.45 Da (1.7x smaller than the upper size limit)

What is collagen’s dalton size? Do collagen and elastin fit to the 500 Dalton rule? Do they get absorbed into the skin?

Collagen has a very high molecular weight of about 300kDa (i.e. 300,000 Dalton) and therefore is NOT absorbable by the skin.

Hydrolysed collagen is made up to 5-6 kDa fragments (i.e. 5,000-6,000 Dalton) and it is also NOT absorbable.

The same applies to elastin and hydrolysed, which have a molecular weight of 70kDa and 1000 Da, respectively.

Do elastin and collagen peptides get absorbed?

Collagen and elastin peptides, however, can have a low molecular weight and be absorbed quite effectively. For example:

• The anti-ageing pentapeptide KTTKS (lysine-threonine-threonine-lysine-serine, collagen fragment), has a MW of 563.64

• The anti-ageing hexapeptide VGVAPG (valine-glycine-valine-alanine-proline-glycine, elastin fragment), has a MW of 479.60

With a well-designed cream formulation, absorption is not a problem for the vast majority of natural actives

This list could go on and on and on, but the fact is that as far as skin formulations containing vitamins, antioxidants and similar anti-ageing compounds are concerned, absorption is not a problem.

Almost all of those actives are well below the 500 Dalton size and they do penetrate the skin - even more so if the design of the formulation is focused on absorption.

As we previously mentioned, not all products are designed for absorption: for example sunscreens should NOT be absorbed. On the other hand, most anti-ageing creams should be absorbed.

Some formulations, however, are just very badly designed.

Another issue is the low content of actives: if you have an active at 0.001% concentration, which is there just to decorate the label, why bother with enhanced absorption? Nothing will ever happen.

Penetration enhancers further improve on the 500 Dalton rule

The natural small molecules above can become even more easily absorbable if natural penetration enhancers are used in skincare creams (e.g. liposomes etc) or if specific technologies are used for aesthetic treatments (e.g. ultrasound, radiofrequency etc).

The 500 Dalton rule for the skin penetration of chemical compounds and drugs

• Research paper link: https://pubmed.ncbi.nlm.nih.gov/10839713

• Abstract: Human skin has unique properties of which functioning as a physicochemical barrier is one of the most apparent. The human integument is able to resist the penetration of many molecules. However, especially smaller molecules can surpass transcutaneously. They are able to go by the corneal layer, which is thought to form the main deterrent. We argue that the molecular weight (MW) of a compound must be under 500 Dalton to allow skin absorption. Larger molecules cannot pass the corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually all common contact allergens are under 500 Dalton, larger molecules are not known as contact sensitizers. They cannot penetrate and thus cannot act as allergens in man; 2) the most commonly used pharmacological agents applied in topical dermatotherapy are all under 500 Dalton; 3) all known topical drugs used in transdermal drug-delivery systems are under 500 Dalton. In addition, clinical experience with topical agents such as cyclosporine, tacrolimus and ascomycins gives further arguments for the reality of the 500 Dalton rule. For pharmaceutical development purposes, it seems logical to restrict the development of new innovative compounds to a MW of under 500 Dalton, when topical dermatological therapy or percutaneous systemic therapy or vaccination is the objective.

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