Human skin is a science and engineering marvel. Imagine developing a barrier that is able to keep water in, while simultaneously excreting it out. While we know that human skin is not totally impermeable (as it was believed to be for thousands of years), it is extremely water-resistant. This property is due to a uniquely structured layer of lipid molecules in the stratum corneum (the outermost layer of skin) that point in opposing directions and are stacked alternatingly on top of each other. This distinct structure prevents water from getting in (or out) regardless of direction, except for where it is supposed to (at the pores). This important trait helps keep harmful microorganisms out, protects our vital organs, and ensures that we aren’t perpetually leaking essential nutrients, but the same property that protects us also creates a challenge for the medical community. While ingestion is the most common route of administration for pharmaceuticals due to simplicity and convenience, it isn’t necessarily the most effective or safe. Not having to be metabolized by the liver and intestines, topically applied drugs are associated with fewer adverse events and may allow more efficient time release and direct targeted effects. But how do you get highly lipophilic substances (able to easily dissolve in fats, oils, and lipids) past that protective lipid layer in the stratum corneum?
The current answer is to combine these drugs with substances known as “penetration enhancers” that decrease the barrier resistance through a number of fascinatingly complex mechanisms. While effective, these compounds are not without their own spectrum of side effects. Some of the most popular penetration enhancers have been shown to induce concentration-dependent irritation, swelling, or even tissue ulceration. Due to their lipophilicity and host of skin health supporting properties, there has been growing interest in the use of terpene compounds (the dominant volatile aromatic compounds found in essential oils) for this purpose. To date the results are promising, but there is little consensus on their overall effectiveness and still valid concern about their safety.
There is no better example of the promise of transdermal application than nonsteroidal anti-inflammatory drugs (NSAIDs), a class of pharmaceutical whose primary aim is to reduce pain and other symptoms associated with inflammation. NSAIDs are some of the most popular medications, representing 5%–10% of all medications prescribed each year, and they come in various forms that provide their effects by inhibiting the activity of cyclooxygenase enzymes (COX). While generally used as a standalone (orally administered) compound, there is a growing concern for the risks—including elevated risk for acute renal failure and myocardial infarction—associated with chronic internal use of NSAIDs. Topically applied treatment for the discomforts of inflammatory-related issues could be both more effective (targeted and time-released) and safer, if modern science could figure out how to get lipophilic substances to infiltrate that lipid matrix in the outermost layers of our skin.
Known primarily by the name Celebrex, celecoxib was the first selective COX-2 inhibitor and is widely used to relieve symptoms associated with osteo and rheumatoid arthritis. As a COX-2 inhibitor, celecoxib works by reducing the production of prostaglandins, lipids made at the site of tissue damage that are intricately involved in the inflammatory response. Currently celecoxib is only available in one form, a capsule for ingestion, and research has shown that the risk for adverse effects is generally low compared to other NSAIDs. Nonetheless, regular use still poses a risk for toxicity (and various gastrointestinal and cardiovascular effects), so there is a growing interest in developing transdermal application models. Unfortunately, current transdermal applications, including some evaluating terpenes as penetration enhancers, have shown minimal absorption and distribution. But recent studies evaluating a new terpene-based penetration enhancer have shown promise.
Copaiba, the essential oil extracted from the resin of Copaifera trees, has become one of the most popular compounds in complementary and alternative medicine research. Most of the interest in copaiba is due to being the best known source of sesquiterpene beta-caryophyllene (BCP), a compound that has the unique ability to bind to cannabinoid 2 receptors (CB2R). What this means is that BCP, through modulation of the endocannabinoid system, not only has a host of skin-supporting properties but may have the potential to treat various pathologies, specifically neuro-inflammatory and neuropathic pain conditions. There is even recent clinical research that provided evidence that topical application of copaiba itself may ameliorate symptoms of rheumatoid arthritis. Among the latest research, little has examined the potential of copaiba as a cutaneous penetration enhancer, but due to its high lipophilicity and own anti-inflammatory properties, it could be a perfect complement to formulations including topical NSAIDs. And, a series of three recent studies have investigated this possibility, with fascinating results.
In the initial study, Quinones et al. investigated the permeability and retention of celecoxib in skin cells when applied with various concentrations (5%–50%) of copaiba essential oil. Results varied based upon concentration, but a formulation of 25% copaiba essential oil showed the most potential, exhibiting a 5.75 permeation enhancement ratio compared to the topical NSAID alone. In their second in vitro study, the results were confirmed, with the 25% copaiba concentration formulation showing superior cutaneous permeation and retention compared to controls, and doing so without any signs of skin irritation that are often associated with penetration enhancers. The researchers had several hypotheses to explain the outcomes, but noted that they were most interested in continuing the research by assessing whether there was a synergistic anti-inflammatory effect when combining the lipophilic NSAID and the essential oil. In the final study, they further evaluated this combination by comparing the anti-inflammatory effect of the 25% copaiba concentration formulation with a commercially available NSAID gel (diethylammonium diclofenac). As in the previous study, the copaiba/celecoxib formulation exhibited superior permeation and retention in the skin cells, but more importantly showed significantly improved suppression of all inflammatory parameters. The formulation showed an 89% improvement in protein extravasation (movement of white blood cells from the capillaries to affected tissue) and 77.51% improvement in edema formation (inflammation-related fluid retention) compared to celecoxib alone. Further testing showed that the copaiba/celecoxib formulation was also significantly more effective at suppressing inflammatory parameters than a combination the comparator. The researchers attributed the significantly improved effectiveness to the ability of copaiba to alter tissue morphology, specifically disrupting stratum corneum structure and increasing the formation of blood vessels at the site of irritation.
While this research, in isolation, only suggests that copaiba may improve the efficacy and safety of topical celecoxib, the possible implications are vast. For conventional medicine, the data suggests that copaiba may be the ideal transdermal penetration enhancer, not only improving absorption and systematic distribution of topically applied NSAIDs, but also synergistically working with the compounds to enhance the anti-inflammatory effects and reduce adverse reaction risk. For those into complementary and alternative therapies, as the richest source of BCP, copaiba offers all the possible benefits associated with topical cannabinoid use (pain regulation, localized anti-inflammatory activity, tissue remodeling, etc.) and may even improve the absorption of other lipophilic compounds (i.e. your favorite essential oils). While more research needs to be conducted regarding how copaiba is able to safely improve penetration and distribution of topically applied substances and the influence of the endocannabinoid system on our overall health, whether you are a medical professional or Joe Average just looking to deal with the discomforts of daily life, there appears to be scientifically-validated reasons to suggest that everything may be better with copaiba.
Dr. Damian Rodriguez is a health scientist and essential oil researcher. He holds a doctorate in health science, a master’s degree in exercise physiology, and countless professional certifications. He has spent most of his life researching nutrition, exercise, and the lifestyle behaviors associated with optimal health. Along with his passion for health, as someone who lives with Asperger’s Syndrome, he is also involved in bringing awareness to autism spectrum disorders.