Skin penetration enhancers: Improving skin absorption

The skin is the largest organ of the human body. The outermost layer, called the stratum corneum, consists of dead cells which form a protective barrier to keep the bad stuff (germs & chemicals) out and the good stuff (water) in the body.

The structure of human skin

When we apply skincare products (or medicated gels/creams/ointments), we generally want the active ingredients to be able to penetrate the stratum corneum and enter into the deeper layers of the skin to exert their effect.

How do molecules cross the stratum corneum?

1.  Intercellular route – Molecules pass through the spaces between the dead cells. This is the predominant route.
2. Transcellular route – Molecules directly pass through the dead cells. This is the path of greatest resistance as the molecules need to penetrate the cell membranes and cell contents of the dead skin cells.
3.  Transappendageal route – Through sweat glands or hair follicles. Since sweat glands and hair follicles occupy only 0.1% of the total human skin surface, the contribution of this route is considered to be small (although it is still important).

How molecules may cross the stratum corneum

Why is it difficult for molecules to cross the stratum corneum?

As mentioned earlier, the predominant route of transport of molecules across the stratum corneum is via the intercellular route. But the spaces in between the dead skin cells are not just empty space; these spaces are filled with lipids (cholesterol, ceramide & free fatty acids) which form the lamellar lipid bilayer. These lipids contain hydrophilic (water-loving) head groups and lipophilic (greasy, oil-loving) chains. So, in order to cross the stratum corneum, molecules must be able to cross the lamellar lipid bilayer.

Structure of the lamellar lipid bilayer

What are skin penetration enhancers?

Skin penetration enhancers are compounds that are added into the formulation of a product to enhance the delivery of its active ingredients across the skin barrier.

How do skin penetration enhancers work?

These substances work through various mechanisms:

1.  By interacting with the hydrophilic head groups of the lipids in the lamellar lipid bilayer – this disrupts the packing order of the lipids, making it easier for active ingredient to diffuse through. (e.g. propylene glycol)
2.  By interacting with the greasy chains of the bilayer lipids. This also disrupts the packing order of the lipids. (e.g. oleic acid)
3. By hydrating the skin (e.g. urea)

What are some of the commonly used/studied skin penetration enhancers?

1.       Alcohols

a)      Short chain alcohols (e.g. ethanol, isopropyl alcohol)

b)      Long chain alcohols (e.g. octanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol, oleyl alcohol, linoleyl alcohol, and linolenyl alcohol

2.       Fatty acid esters

-          Isopropyl myristate, ethyl oleate, glyceryl monolaurate, glyceryl mono-oleate, lauryl lactate, isopropyl palmitate, methyl oleate, oleyl oleate and sorbitan mono-oleate.

3.       Glycols

-          Propylene glycol

4.       Glycol ethers

-          Transcutol®

5.       Fatty acids

-          Oleic acid

6.       Sulphoxides

-          Dimethyl sulphoxide (seldom used due to skin irritating effects)

7.       Urea and derivatives

8.       Surfactants (e.g. Tween)

9.       Terpenes (found in essential oils)

References:

1.       Lane. Int J Pharm. 2013 Apr 15;447(1-2):12-21

2.       Trommer & Neubert. Skin Pharmacol Physiol. 2006;19(2):106-21

Parabens: Cause for concern?

Increasingly, cosmetics and skincare products are being advertised to be “paraben-free”. Today, I took a quick look at the ingredients in my shampoo, conditioner, body wash and some skin care products – no parabens in them, even though I haven’t been actively looking out for paraben-free products. But what are parabens, and why the concern over their use?

A simple Google search yielded many useful articles about parabens, and among them is an article from the FDA containing information to answer enquiries about the safety of parabens used in cosmetics.

To summarize, parabens are esters of p-hydroxybenzoic acid, and they are widely used as preservatives in cosmetics as well as in food and drugs. Methylparaben, propylparaben, and butylparaben are the most commonly used.

Chemical structure of parabens

So, why the health scare over parabens? All the websites I’ve visited quoted the famous 2004 study by Darbre, and here I quote from the FDA article:

“A study published in 2004 (Darbre, in the Journal of Applied Toxicology) detected parabens in breast tumors. The study also discussed this information in the context of the weak estrogen-like properties of parabens and the influence of estrogen on breast cancer. However, the study left several questions unanswered. For example, the study did not show that parabens cause cancer, or that they are harmful in any way, and the study did not look at possible paraben levels in normal tissue.”

But, the FDA also assures consumers that the estrogen-like activity of parabens (which could potentially be linked to cancers) is very, very low. Furthermore, parabens are used in very low levels in cosmetics. Presently, the FDA believes that there is no cause for concern over cosmetics containing parabens.

Well, the article by FDA was written in October, 2007. Almost six years have passed now, so let’s take a look at the current perspective on parabens.

Parabens and breast cancer

After the 2004 study by Darbre, no other significant studies have tried to link parabens to breast cancer. A 2010 literature review concluded that there is no link between parabens and breast cancer.^[2]

Effect of parabens in men

Due to concerns about the estrogen-like activity of parabens, the effect of parabens on the male reproductive system has also been studied. However, animal studies in mice and rats have shown conflicting results on the reproductive effects of parabens. In humans, a study in men with fertility problems showed no correlation between sperm count/motility and paraben levels.^[3]

Paraben allergy

Though uncommon (in 0.5 to 3.5% of the population), parabens can cause allergies in some people. The allergic reaction usually appears as an eczema-like rash. Compared to other preservatives, the rates of paraben allergy are among the lowest.^[3]

The move away from paraben-containing products has led to the emergence of a wide range of alternative cosmetic products that paraben-allergic patients can turn to. However, replacing parabens with other preservatives may well lead to the placing on the market of products whose toxicity and allergenicity are not as well-documented.[4]

Current Government and Regulatory Control of Parabens^[3]

·       In the European Union (EU):  Parabens can be safely used in cosmetic products at concentrations of 0.4% for any individual paraben and 0.8% for total paraben concentrations.

·       In Denmark: In 2011, the use of parabens was banned in personal care products intended for children younger than 3 years of age.

·       In the United States: the Cosmetic Ingredient Review (CIR) has recommended the same maximum paraben concentrations as legislated by the EU. However, the CIR recommendations are only guidelines, not laws.

·       In Canada: Likewise, Health Canada agrees with the FDA and the CIR in regards to the safety of parabens and the adoption of maximum concentration guidelines. However, these are also recommendations, not laws.

Conclusion

From the current data available, it appears that parabens are still considered safe for use within the recommended limits. However, as a marketing strategy, many cosmetic and skincare companies are moving away from parabens and into more "natural" alternatives. With "natural" alternatives, there may be a higher risk of microbial contamination (germs!) and greater care must be taken to adhere to expiration dates. 

References:

1.      http://www.fda.gov/cosmetics/productandingredientsafety/selectedcosmeticingredients/ucm128042.htm

2.   Witorsch & Thomas. Crit Rev Toxicol. 2010 Nov;40 Suppl 3:1-30.

3.       Kirchhof & de Gannes. Skin Therapy Lett. 2013 Feb;18(2):5-7.

4.       Castelain & Castelain. Eur J Dermatol. 2012 Nov-Dec;22(6):723-7

Snail Creams - Do They Work?

Recently, snail creams have become a popular trend in Korean beauty products. They contain snail slime, which we all know as the gooey trail left behind by a snail as it moves along. (Eww!) Manufacturers claim that snail slime-containing products are able to improve acne, spots, blemishes, wrinkles, stretch marks and fine lines.

A garden snail

My dearie got me some samples of snail slime-containing products too! So, being curious as well as skeptical, I tried to search for any clinical or scientific trials which have been carried out to demonstrate the benefit of snail creams.

 

My own sample pack of snail secretion extract products

The first article that I came across was a very old article from 1982, by Iguchi et al..[1] Snail slime extract was collected from African giant snails (captured in Okinawa) and tested for antibacterial activity.  Indeed, the mucins (carbohydrate-conjugated proteins) present in the extract was found to possess antibacterial activity against a few different types of bacteria (both gram-positive and gram-negative).

The second article that I found was a report of a small clinical trial by Fabi et al..[2] In its introduction, the rationale behind the use of snail slime was explained. When snails are exposed to UV light or x-rays, they retract their tentacles and secrete a large amount of mucus as a defense mechanism. This mucus helps to repair the snail’s damaged skin in less than 48 hours. Maybe it can repair human skin too!

This trial was a 2-center, double-blind, randomized, 14-week study, with a sample size of 25 female patients with moderate to severe wrinkles around the eyes and mouth. The treatment used was an 8% emulsion and a 40% liquid serum containing snail secretion filtrate from Cryptomphalus aspersa (also known as Helix aspersa, or the common garden snail). The snail slime-containing emulsion & serum were applied to one side of the face, while a placebo emulsion & serum was applied to the other side. The result? The snail slime-treated side showed a trend towards greater improvement of wrinkling around the eyes compared to the placebo-treated side of the face. However, the difference was not statistically significant (probably owing to small sample size). Was the difference noticeable? At week 8 of using the products, patients reported an improvement in fine lines on the snail slime-treated side but did not report a difference in the overall quality of their skin.[2]

In the same article, a previous pilot trial by Tribó-Boixareu et al. was also mentioned. The pilot trial was a small nonrandomized, open-label study with 15 participants. The study had yielded promising results with improvement in sallowness, fine lines, deep wrinkles, elasticity, dryness and roughness of the skin.

 

Nope. Unfortunately, the effects of snail cream are not THIS pronounced.

But how does snail slime work? Brieva et al. set out to study the scientific basis for the regenerative properties of snail slime. They discovered that snail secretion:[3]

1.       Possesses antioxidant properties.  Snail secretion has multiple modes of action as an antioxidant: It possesses certain enzymatic (superoxide dismutase [SOD] & glutathione S-transferase [GST]) activities, which enables it to inactivate free radicals and reactive oxygen species which are already present. It is also able to scavenge free radicals, halting the chain reaction which produces more free radicals.

2.       Enhances the growth of fibroblasts (a type of cell that synthesizes the extracellular matrix and collagen, important for wound healing).

3.       Stimulates fibronectin secretion and assembly (also important in wound healing).

4.       Reduces the production of matrix metalloproteinase enzymes (Increased metalloproteinase expression has been associated with impaired wound healing and regeneration).

Fibroblasts

Am I convinced?

Based on the trial by Fabi et al., there seems to be some evidence to suggest that snail slime products may help to decrease the presence of wrinkles. Although the effect is not that pronounced, I think that many women (being the vain creatures that we are) would be willing to try these products out for even a modest benefit.

As for the skin healing and regenerative properties of snail slime, I think it’s really great that its benefits has been shown in vitro (i.e. in cells growing in petri dishes). But the big question is: Do these observations translate to real-life clinical benefits? How would the HUGE proteins in snail slime penetrate the skin barrier to exert their effect? Theoretically, it might work if applied on broken or inflamed skin. Some dermatologists may use laser to create tiny holes in the skin before applying snail cream, and this may work too. But on healthy, intact skin? I have my doubts.  

So, I will be conducting my own open-label trial, sample size = 1. I shall try out my snail slime products for a month (or until the product is finished), and if there is any improvement to my skin, I’ll make sure to update on this blog. ^_^
*Update: Click here for the results of my little trial of snail slime products!

References:

1. Iguchi et al., Comp Biochem Physiol A Comp Physiol. 1982;72(3):571-4.
2. Fabi et al., J Drugs Dermatol. 2013 Apr;12(4):453-7.
3. Brieva et al., Skin Pharmacol Physiol. 2008;21(1):15-22

Sunscreen

Many beauty products today contain sunscreen. Most BB creams and foundations come labelled with an SPF factor and PA grade. The ones which Dearie recently bought for me are no exception!

Some of my skincare products which contain sunscreen

And I’d say he bought them for me just in time! Because, is that an age spot developing on my left cheek??! Why?? I’m not even 30 yet! T_T

Age spot? T_T

I remember learning about sunscreens back when I was still an undergraduate student, but I couldn’t recall much of it anymore… Time to hit the books (or rather, internet) again! To my pleasant surprise, this exercise not only refreshed my memory but I discovered new information along the way. So, let me share with you what I’ve learnt. These information apply to sunscreen in general, not just in facial products.

Sunscreen is not a stand-alone protective measure against UV radiation. Remember to also use other sun-protection measures:

·       Avoid the sun at its hottest, i.e. between 10am to 4pm.

·       Wear protective clothing, i.e. long pants, long sleeves, sunglasses, and an umbrella or a wide-brimmed hat.

What is the difference between SPF and PA grade?

Firstly, a short introduction to UV radiation:

There are 2 types of UV rays that reach the earth’s surface: UVA (wavelength 320-400 nm) and UVB (wavelength 290-320 nm). UVB causes skin redness, inflammation and stinging – effects we can easily identify as sunburn. UVA penetrates into the deeper layers of the skin and may have greater destructive effects.

SPF = Sun Protection Factor. SPF mainly measures UVB protection.

Note: I used to think that SPF number corresponds to the length of time you can be exposed to sunlight without burning, e.g. if I would normally get a sunburn after 10 mins, an SPF 30 sunscreen would allow me to stay out 30 times longer (300 mins) before getting a sunburn. But, to my surprise, I found that this is not exactly accurate. Another piece of info: the relationship between SPF and UVB protection is not linear - a sunscreen with SPF 15 can filter 94% of UVB radiation, whereas SPF 30 provides >97% protection.

But let’s not get caught up with the details. The most important factor contributing to the efficacy of sunscreen is not really the SPF number, but whether or not we use it correctly – which I will talk about later below.

PA = Protection grade of UVA. This is the Japanese measurement of sun protection, and is not recognized by the FDA. The rating system ranges from + (lowest protection) to +++ (greatest protection).

Besides PA grade (commonly used in Asian products), product labels in other countries use different ways to indicate UVA protection. In the US, the FDA requires delineating “broad-spectrum” and sun protection factor (SPF) information on the label of sunscreens which protect against both UVA and UVB. In the European Union, the UVA logo is used.

FDA requirement for "broad spectrum" to be displayed on label

EU UVA logo

When you choose a sunblock, make sure to select one that confers both UVA and UVB protection!

What is the active ingredient in sunscreen?

There are 2 main types of active ingredients:

·       Physical sunscreens – these are particles such as zinc oxide and titanium oxide which physically reflect UV radiation. Very similar to wearing clothes to block the sunlight! The downside, though, is that the texture of these products can be pasty and clumpy. They may also leave a white residue on the skin. However, with advances in nanotechnology, these particles can now be processed to be really, really small so that they no longer cause these problems.

·       Chemical sunscreens – these are organic compounds which absorb UV radiation. Different active ingredients absorb UV radiation at different wavelengths, so it is not uncommon to see several active ingredients blended together in the same product in order to achieve broad-spectrum coverage.

What is the correct way to use sunscreen?

·       Apply a generous amount of sunscreen to dry skin 30 minutes before sun exposure.

·       Apply sunscreen to all skin surfaces that will be exposed to sun, e.g. face, ears, hands, arms and lips. If you don't have much hair on your head, apply sunscreen to the top of your head or wear a hat.

·       Reapply sunscreen every 2 hours, and immediately after swimming or heavy sweating.

·       Be aware that sand, water, snow and concrete reflect sunlight, making it all the more important to use sunscreen.

·       UV light can pass through clouds, so use sunscreen even when it's cloudy.

What is the incorrect way to use sunscreen?

The use of sunscreen to enhance tanning and deliberately prolong exposure to the sun is an abuse of the product and may actually increase the risk of skin cancer. A common misperception is that sunscreens decrease the risk of sunburns and therefore, it’s OK to stay out in the sun for a long time. But this could increase the risk of skin cancers and cause photoaging (e.g. wrinkles, sunspots).

What can sunscreen protect me against?

·       Sunburn (Yep, that’s a no-brainer.)

·       Immunosuppression. Yes, that’s right. UV radiation can suppress our immune system, and this can contribute to the development of skin cancers. Quite scary, huh? Thankfully, research shows that broad-spectrum sunscreens do protect against immunosuppression.

·       Skin damage such as solar elastosis (thickened, dry, wrinkled skin) and decreased skin elasticity. Interestingly, sunscreens are still beneficial even at lower levels of UV exposure which do not cause sunburn.

·       Some types of skin cancers. Sunscreens can help prevent the formation of squamous cell carcinoma and actinic keratosis (thick, scaly patches of skin which can potentially progress to squamous cell carcinoma). However, there is no strong evidence that they also prevent other types of skin cancers such as basal cell carcinoma and melanoma.

Are there any harmful side-effects of sunscreen?

·       Although rare, there are people who develop allergies to some chemical sunscreens.

·       Some chemical sunscreens may be absorbed through the skin into the bloodstream. (This is less of a concern with non-soluble sunscreens such as zinc oxide & titanium oxide.) Could it potentially cause harm in the body? Some animal studies suggest that selected sunscreens may alter hormone levels. However, such effects have not been shown in humans.

·       Are nanoparticles of zinc oxide and titanium oxide small enough to be absorbed by the skin? Worry not, many studies have shown that they do not penetrate the skin.

If sunscreens may cause harm, should I still use them?

UV radiation has long been known to cause skin damage and even cancers. These harmful effects can be prevented by taking sun-protective measures including staying out of the sun, wearing protective clothing and using sunscreen. There may be some concerns about product safety of sunscreens, but it is definitely reassuring to know that each active ingredient has to pass a very stringent safety evaluation before their approval in the EU, US and Japan. With the very favourable risk-benefit profile of sunscreens, I would definitely recommend their use.

Of course, if you develop an allergic reaction, stop using the product immediately. See a doctor, especially if the allergic reaction is severe.

If I were pregnant or breastfeeding, I might choose to be kiasi (Singlish for “afraid to die”) and use physical sunscreens instead of chemical ones - just for the peace of mind that the sunscreen will not be absorbed into my body and passed to the baby.

References:

1.       Mayoclinic

2.       Jou PC, Feldman RJ, Tomecki KJ. Cleve Clin J Med. 2012 Jun;79(6):427-36

3.       Krause et al., Int J Androl. 2012 Jun;35(3):424-36

4.       Lodén et al., Br J Dermatol. 2011 Aug;165(2):255-62.