In the world of skincare, very few companies actually test the penetration of their products. The reason for this is usually very simple: cost. It’s extremely expensive to test your products, just as it is needlessly expensive to have products pushed through the FDA (example: we only have 16 FDA-approved sunscreen filters, with 8 being actively used, despite many countries having many more). Because of this, there are very few products on the market today that have been truly tested for their ability to penetrate the skin, and if so, how deeply they penetrate the skin. Brands owned by pharmaceutical companies tend to be the most well-tested for their absorption, distribution, metabolism, and excretion (ADME).
This is fine for some products, such as sunscreen, which you do not want to penetrate the skin anyway (sunscreen must form a barrier on top of the skin to effectively protect you from UV, for instance). However, it can be a bit trickier when you are considering products that claim to be active or anti-aging ingredients, such as retinol, or ones that advertise various molecular weights to their products (such as hyaluronic acid).
There are several factors that can change or inhibit penetration of a product. The first, and perhaps the most obvious, is the molecular weight. The 500 Dalton Rule gets the most attention regarding this, and perhaps for good reason. In 2000, an article was published in “Experimental Dermatology” titled “The 500 Dalton Rule for the skin penetration of chemical compounds and drugs.” The abstract is as follows:
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. (Source)
500 Daltons is essentially a measurement of molecular weight. For perspective, water is 18 Daltons, while hyaluronic acid can vary from 5,000 to 20,000 Daltons. Here are others:
|Molecular Weight of Common Skincare Ingredients (Source)|
Ingredients that are smaller than 1000 Daltons can penetrate the skin, with 500 Daltons being the golden rule for products that can penetrate through the lipids between corneocytes and into the deeper layers of skin. Molecules around 400 Daltons can enter cells, while those less than 100 can enter the blood stream.
However, it is important to keep in mind that the penetration of your products does not occur in a vacuum. Just because caprylic/capric triglycerides have a molecular weight of 408 does not mean that they are penetrating your skin cells. In fact, many ingredients only remain on top of the skin, among the very top layers of the stratum corneum. This is because there are a variety of factors that can effect penetration, namely other ingredients.
The cosmetic chemist and author of “The 500 Dalton Rule of Dermal Penetration and Cosmetic Science,” Amanda Foxon-Hill, explains this by using testosterone patches as an example:
Testosterone patches are a good example of an active that is less than 500 Daltons (testosterone is 288 Daltons) and that is able to penetrate the skin this way. Here is some information I found online about a Testosterone patch called Androderm.
Each Androderm® 2.5 mg/day Transdermal Patch contains 12.2 milligrams of testosterone and delivers 2.5 milligrams of testosterone over 24 hours.
Looking at this we see that only around 20% of the available Testosterone is absorbed in the 24 hours. It is available in packs of 60 patches.
Each Androderm® 5 mg/day Transdermal Patch contains 24.3 milligrams of testosterone and delivers approximately 5 milligrams of testosterone over 24 hours.
It is available in packs of 30 patches. Other ingredients in the gel reservoir include:
- purified water,
- glycerol monoleate,
- methyl laurate,
- carbomer copolymer (type B)
- sodium hydroxide.
The adhesive substance is laminate AR-7584.
So this is a gel type base with the Testosterone suspended or emulsified into it (I’m not entirely sure exactly where it sits as I haven’t thought about it for long enough but anyway…). The base would be designed to facilitate the release of the Testosterone through the skin. Often an excess of active on the outside of the cell helps to force some of it through the cell, this may be why only 20% of the available testosterone gets through. If you think of it as like a crowd situation where the momentum of the crowd behind you pushes you along, it’s the same scenario here.
While the author admits that testosterone patches are not a perfect analog to cosmetics – the target destination for testosterone in Androderm is the blood stream, which is not the target location for cosmetics – it demonstrates the effects of the solvents on how the active ingredient (testosterone) is taken in by the skin. In cosmetics, for instance, alcohol is frequently used to remove or break down the barrier of the stratum corneum so that products may penetrate deeper. This can occassionally lead to more irritation in some products, as other ingredients penetrate slightly deeper than intended. Tape stripping, dermabrasion, and chemical peels are all used to the same effect.
Many other things can effect penetration of products into the skin. Those things include:
- Absorption channels (follicles, pores, glands)
- Solubility (lipophilic or hydrophilic)
- Polarity (negatively or positively charged molecules)
- Sound waves (ultrasound)
- Mild electric currents (iontophoresis)
That last one brings me to hyaluronic acid (HA), which is frequently marketed based on it’s molecular weights. My beloved HadaLabo products, for instance, advertise five different molecular weights of hyaluronic acid. As I said before, hyaluronic acid is usually a pretty large weight – somewhere between 5,000 and 20,000 Daltons. This puts the lowest weight HA close to elastin (collagen is heavier than low weight HA) that is in our dermis, but it does not end up in our dermis. Instead, it frequently acts as a delivery system for other ingredients. According to Ms. Foxon-Hill:
Hyaluronic acid works as an osmotic delivery system that can push water-soluble actives deeper into the skin by forming a highly hydrated reservoir on the surface of the skin. The main difference between the low and regular weight HA is in how thick it can get when you hydrate it and how it feels on the skin. Both work well as osmotic pumps. This situation would be quite different if we were looking at injecting HA as a dermal filler.
In short, it frequently does not matter the size of your hyaluronic acid because both are achieving the same goal due to their equal inability to penetrate the skin. Exceptions are some skin conditions, such as sebhorrheic dermatitis, which may do better with smaller sizes of HA. (Source)
This is important, however, when you are choosing active ingredients. For instance, I mentioned above that collagen is heavier than the lowest weight HA, which is roughly 5,000 Daltons. This explains why topical collagen only serves to form a smooth, emollient base on the skin, but is not an effective anti-aging ingredient for topical products. On the flip side, it explains why tretinoin is such an effective anti-aging ingredient and not recommended for pregnant women (roughly 5-8% of topical tretinoin ends up in the bloodstream [Source]).
Peptides are perhaps another ingredient that comes up frequently when discussing what products can truly penetrate the skin, with argirelene (889 Daltons) and matrixyl (578 Daltons) being the two chief synthetics designed to improve the look of the skin by inciting a cell to produce collagen and other proteins. However, there is not a large body of evidence around these ingredients yet, and it is important to look at the vehicle of the finished product rather than simply the peptide itself.
To sum up, when you’re considering a product, especially one that is designed for anti-aging or cell-communication, it is imperative to consider not only the weight of the product, but also the vehicle of delivery.