Skin Penetration Enhancers

Multiple factors influence the cutaneous absorption of drugs, cosmetics, and cosmeceuticals. To ameliorate wrinkles and aging skin, ingredients must provide dermal absorption to impart long-term effects. The pace at which absorption occurs relies on the particular ingredients in skin care preparations as well as skin temperature, strength of the skin barrier, and humidity levels. Penetration enhancers are added to skin care formulations to accelerate and improve cutaneous absorption of creams, gels, lotions, oils, and serums. The effectiveness of cosmetic and cosmeceutical delivery to the skin is increasingly of interest to cosmetic dermatologists striving to better match product recommendations with their patients’ skin types. To this end, practitioners must be able to identify the ingredients best known to act as penetration enhancers.

Leslie S. Baumann, MDHyaluronic acid, oleic acid, and dimethyl sulfoxide are good examples — particularly hyaluronic acid, which is an intrinsic component of the extracellular matrix of the skin with known anti-inflammatory, healing, and moisturizing activity. Also notable are glycerol and urea, two constituents of the natural moisturizing factor in the skin that have been shown to augment skin permeability in conditions of diminished hydration. Furthermore, some essential oils have been identified that facilitate the permeation of drugs through the skin. Enhancement of skin penetration capacity can be achieved chemically, physically (eg, via electrical voltage, microdermabrasion, microneedles, thermal ablation, and ultrasound), through a combination of these means, or through the use of suitable formulations. Overall, as Williams and Barry noted two decades ago, ideal penetration enhancers should work quickly, with predictable and reproducible actions; should exert no pharmacologic activity in the body; and should be nontoxic, nonirritating, and nonallergenic. This column will focus on the use of particular ingredients to improve the skin penetration capabilities of various skin formulations and other factors related to enhancing penetration into the stratum corneum.

Weight Matters

The 500 Dalton molecular weight rule for the skin penetration of chemical substances suggests that external compounds must fall below that weight threshold in order for the stratum corneum to allow passage; heavier molecules (such as peptides and growth factors) are unable to penetrate into the basal layer of the epidermis and the dermis. Notably, inflamed skin that impairs the barrier may permit the absorption of molecules slightly larger than 800 Da, including topically applied tacrolimus or ascomycin to treat atopic dermatitis.

Regulations on and Types of Penetration Enhancers

In 2021, Hu and He conducted a database search for articles on the transdermal/skin delivery of cosmetics between 1985 and 2020. They found that laws and regulations regarding the use of nanomaterials in cosmetics vary widely across countries. Although they cited several methods to improve and assess cosmetic delivery, they reported that there are no unified domestic or international laws and regulations guiding transdermal delivery assessment.

Significantly, they delineated the types of penetration enhancers available. Penetration enhancement can be achieved through these approaches:

• Chemical penetration enhancers (eg, surfactants such as propylene glycol and sodium lauryl sulfate; solvent-based substances such as urea, free fatty acids, sulfoxide, and nitrone; or oleic acid, nitrogen ketones, and the most common one, water)
• Nanodelivery systems
• Physical enhancement methods (eg, microdermabrasion, nonablative laser therapy, iontophoresis, and electroporation)
• Biochemical penetration enhancers (eg, amino acid derivatives, ceramides and their analogs, fatty acids, fatty acid esters, hyaluronic acid, glycerin, metabolic regulators, and osmotic peptides)
• Natural penetration enhancers (alkaloids, capsaicin, coumarins, herbal extracts, papain, saponins, terpenes, and various essential oils, including almond, Alpinia oxyphylla, basil, eucalyptus, niaouli, rosemary, and turpentine oils)

Unsaturated fatty acids absorb more readily into the skin than saturated fatty acids. The increased skin absorption associated with unsaturated fatty acids is ascribed to their structure, which is characterized by either one or more double bonds. The primary unsaturated fatty acids in skin care products are oleic, linoleic, palmitoleic, alpha-linolenic, and gamma-linolenic acids. Copious amounts of these fatty acids are found in several oils: olive (high in oleic), flaxseed (high in alpha-linolenic), grapeseed (high in linolenic), safflower (high in linoleic), and sunflower (high in linoleic).

In 2002, Touitou and colleagues reported that in their study of four penetration enhancers (oleic acid, propylene glycol, ethanol, and diethylene glycol monoethyl ether) for the treatment of the footpads of mice, 10% oleic acid yielded a sharp reduction in Langerhans cell density. A decrease in dendricity was also observed. Propylene glycol and diethylene glycol monoethyl ether had only mild, if any, impacts on Langerhans cells, with ethanol associated with statistically significant effects. Treatment with 10% oleic acid was also noted for creating pores on epidermal corneocyte surfaces in hairless rats. Such research has been borne out as oleic acid, the predominant fatty acid in olive oil, creates microscopic holes in the stratum corneum, thus accelerating absorption. This accounts for the status of olive oil as the oil that penetrates the skin deepest and most quickly, though it does not confer hydration. Coconut, almond, and tea tree oils may be preferable as penetration enhancers, depending on the skin type of patients.

Transdermal Drug Delivery

In 2020, Kovácik and colleagues published a review of the benefits and limitations of the use of penetration enhancers in transdermal drug delivery. While noting the difficulties in developing potent but safe enhancers, the investigators found that recent progress has yielded robust and safe enhancers and enhancer combinations.

Two years later, Li and colleagues characterized the use of polysaccharides derived from herbal, marine, and microbial sources as vehicles for transdermal drug delivery vs synthetic polymers. They noted that natural polysaccharides are biodegradable, more biocompatible, and nontoxic; confer antibacterial activity; and present advantages in targeting and making modifications. The researchers observed that adding polysaccharides to drug delivery vehicles (eg, hydrogels, films, microneedles, and tissue scaffolds) renders greater mechanical and tensile strength as well as swelling capabilities. They added that polysaccharides foster drug penetration because their charge and hydration enable them to interact with the skin.

Essential Oils as Penetration Enhancers

In 2017, Jiang and colleagues investigated the effectiveness of various oils (Angelica, Cyperus, chuanxiong, cinnamon, clove, and turpentine) in fostering skin penetration of ibuprofen across rat abdominal skin. Enhancement ratios were found to be significant in all tested oils (with cinnamon the strongest, followed by chuanxiong, Cyperus, turpentine, clove, and Angelica), and they afforded significantly greater penetration enhancement than azone, with lower associated cutaneous toxicity. The investigators concluded that essential oils can contribute to the cutaneous permeation of ibuprofen by interfering with rather than removing stratum corneum lipids.

In a review 2 years earlier, Herman and Herman discussed essential oils and their ingredients as skin penetration enhancers in transdermal drug delivery because these substances are quickly metabolized. They characterized the mechanisms of action of penetration as dissolving the structure between corneocytes in the stratum corneum, influencing and modifying the intercellular conditions of proteins, and enhancing the division or dispersal of a drug. They also identified  multiple essential oils (cajuput, anise, basil, black cumin, cardamom, chamomile, Chenopodium, citronella, clove, Eryngium bungei, eucalyptus, fennel, ginger, holy basil [tulsi], lavender, lilac, melissa, myrtle, niaouli, nutmeg, orange, peppermint, rosemary, sage, tea tree, thyme, turpentine, and ylang-ylang) that are effective in helping the delivery of a wide range of medications across the skin, such as aminophylline, benzoic acid, carvedilol, chlorhexidine digluconate, diclofenac sodium, estradiol, 5-fluorouracil , flurbiprofen, ibuprofen, indomethacin, ketoconazole, labetalol hydrochloride, nitrendipine, para-aminobenzoic acid, piroxicam, and trazodone hydrochloride.

Mixed with ethanol, menthol, or other kinds of alcohol, essential oils that are popular and known to augment the cutaneous absorption of other ingredients include anise, bisabolol (present in chamomile), cardamom, eucalyptus, niaouli, peppermint, sweet basil, and ylang-ylang. However, eucalyptus, peppermint, and tea tree oils can harm the skin by increasing the risk for irritation or provoking a skin allergy.

Conclusion

The weight of a molecule intended to induce some kind of healthy change to the skin through penetration definitely matters. Fortunately, several ingredients are available to accelerate penetration of substances that otherwise would not be able to permeate the skin barrier. Healthy stratum corneum is known to be resistant to penetration. Current research considers multiple factors in divining the optimal approaches and ingredients for enhancing the penetration of drugs, cosmetics, and cosmeceuticals into the skin.

Dr Baumann is a private-practice dermatologist, researcher, author, and entrepreneur in Miami, and a cosmetic dermatologist for Body+Beauty Labs. She founded the Division of Cosmetic Dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, Cosmetic Dermatology, was published in 2022.