Transdermal vs. Topical Application of Cannabinoids

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von Dr. Jeremy Riggle, Ph.D.

What’s the difference…?

Many people often conflate the meanings of topical and transdermal, particularly when it comes to cannabinoid applications. It is an easy mistake to make, however, they differ in one important regard. The key difference lies in their final objective, as transdermal refers to the drug or medicine reaching the bloodstream where it will have a systemic effect, while topical refers to the drug or medicine acting locally. To further delineate the two: transdermal medicines are designed to act on the entire body via application to the skin, topical medicines are designed to act on the area of application, i.e. the location on the surface of the skin where the medicine was applied. Depending on the particular indication, both routes of administration have been shown to be effective forms for the application of many therapeutic drugs, including cannabinoids.

Transdermal

Transdermal drug delivery involves enabling the drug to traverse the multiple layers of the skin which is no simple task. The skin is one of the largest and most complex organs in the human body, composed of multiple layers with varying functions. Each of these layers contain differing physiochemical properties as well, further complicating transdermal drug delivery. Indeed, many factors need to be considered when attempting to design transdermal drug applications, these factors are discussed in greater detail below.

For Cannabinoid Therapy, there are obvious reasons why one would consider transdermal delivery. First of all, transdermal delivery avoids the risks associated with smoking any carbonaceous material. This is largely the reason why smoked cannabis will not likely ever be considered legitimate medicine by most regulatory bodies. Research has shown the presence of a number of known carcinogens in cannabis flower smoke (1) which are unavoidable artefacts of the pyrolysis process and happen with virtually all burned organic materials. Transdermal cannabinoid delivery also avoids first pass hepatic metabolism which occurs with orally administered cannabis. For example, first pass metabolism converts THC into its more bioactive and psychotropic metabolite, 11-OH-THC (2) which can lead to discomfort for the consumer and makes self-titration of the appropriate dose more complicated. Transdermal administration also provides a direct route for the drug to enter the blood stream, supplying whole body effects of the drug. It offers continual release of the drug over time, so dosing is less frequent than with other routes of administration. It is also more convenient and easy to use compared to other means of medicating. Finally, transdermal administration is discreet and allows patients more control over their preferred dose, while at the same time any negative outcomes from cannabinoid Therapy are being reduced. The biggest disadvantage of transdermal cannabinoid delivery is the same as for any transdermal drug, the difficulty of designing formulations to get the drug through the skin. Due to their typical routes of administration (smoking, vaping, oral, sublingual, buccal, etc.) which all have significant disadvantages and constraints, cannabinoids seem to be excellent candidates for transdermal drug delivery.

The skin is composed of three primary layers: the epidermis, the dermis, and the hypodermis. For transdermal drug delivery, the primary obstacle is presented by the epidermis, so we will restrict our discussion to this particular skin layer. Within the epidermis there are 5 sub-layers (from outermost to innermost): the Stratum corneum, the Stratum lucidum, the Stratum granulosum, the Stratum spinosum, and the Stratum basale. These layers are distinguished from each other based on their composition and accompanying physiochemical properties. The most challenging of the layers, from a drug delivery perspective, is the outermost one, i.e. the Stratum Corneum (SC). The SC is a 10- 40 μm thick layer composed of 15-20 layers of dead skin cells or corneocytes embedded in a lipid matrix composed of cholesterol, fatty acids and ceramides (3). It is often described as having a “brick and mortar” structure with the corneocytes representing the brick and the lipids representing the mortar. This layer is designed to prevent and control molecules entering or leaving the body, it protects the skin from chemical and mechanical injury, fights against infection and protects against

UV irradiation. As one could imagine, the SC works very good on all of these functions, but particularly effective at controlling which molecules enter and exit the body. For any transdermal drug, consideration has to be taken in terms of how to facilitate the movement of the drug through the SC, its associated “brick and mortar” structure and ultimately into the blood stream.

For a drug to be considered a viable candidate for transdermal delivery it needs to meet a few specific criterias. The drug needs to be effective at low doses, up to 10 mg/day. Research has shown that as little as 0.002 mg/kg/ day of CBD is effective for reversing age related cognitive decline in the murine model (4). Although higher doses can be found in a number of products – sublingual and buccal tinctures, edibles, flowers, etc., the relatively poor bioavailability (5) via these routes mean that much less of the drug is actually therapeutically effective. Thus, cannabinoids meet this initial criterion. The drug must also have a relatively small molar mass, typically less than 500 μ (μ = atomic mass units). Cannabinoids are all ~314 μ, so again, they meet this second criterion as well. An ideal transdermal drug must also be moderately lipophilic, cannabinoids are moderate to highly lipophilic (Kow = 6000-9,440,000) which raises questions about the candidacy of these compounds as transdermal drugs. However, research has demonstrated that cannabinoids are not too lipophilic to be considered for transdermal delivery. A number of researchers have shown that they can indeed be delivered via transdermal applications (6-10).

To date, a number of drugs have been formulated and are available as transdermal drugs, including: clonidine, estradiol, ethinyl estradiol, fentanyl, granisetron, levonorgestrel, methylphenidate, nicotine, nitroglycerin, testosterone, norelgestromin, norethindron, oxybutynin, rivastigmine, rotigotine, to name a few. Thus, precedent has been set for delivering drugs through the skin. A question that often comes up with regard to transdermal drug delivery is “how long does it take for the drug to take effect?” The kinetics or absorption rate of transdermal drug delivery can be described by Fick’s law of diffusion, the equations are given below (11).

J = KpCvJ = (DKm/L)Cv

*where J = flux of the drug; Kp = permeabilitycoefficient; Cv = concentration of thedrug in the excipient; Km = partition coefficient;D = diffusion coefficient; and L = diffusionpath length.

There are a couple of key factors that dictate the rate at which the drug is absorbed. First of all, the length of the diffusion pathway (L) is inversely related to the rate, i.e. the longer the pathway, the slower the absorption rate. This factor can somewhat be controlled by where one applies the transdermal formulation: Thinner skin regions provide smaller L values and thus faster rates of absorption. The other major factor dictating absorption rate is the partition coefficient of the drug (Km), this represents the distribution of the drug between its formulation and the skin. In other words, Km in the equation above, represents how much of the drug is in the formulation vs. how much of the drug is in the skin, when equilibrium is reached.

A larger value of Km means there is more drug in the skin than in the formulation at equilibrium, thus larger values result in faster rates of absorption. Although this value is characteristic to each individual molecule, there are ways in which it can be modified to increase drug partitioning into the skin. This will be discussed below.

One paramount consideration of designing drugs for transdermal delivery is the choice of excipient or vehicle. This represents an important link between drug potency and therapeutic effectiveness. You can have very high drug potency in a transdermal formulation while at the same time having very low therapeutic effect. Thus, it is important to choose an appropriate and effective excipient, which will in turn have a substantial effect on the rate and extent of absorption of cannabinoids. Ultimately, the choice of excipient will influence Km from Fick’s law given above and can make this value smaller or larger. Larger Km values result in greater distribution of the drug into the skin and faster absorption rates. When deciding on an excipient, two factors need to be considered – the solubility of the drug in the excipient and the equilibrium distribution of the drug in the excipient vs. in the skin. Ideally, one would choose an excipient that demonstrates high solubility of the drug and is non-toxic. Determining the effect of the excipient on Km is a bit trickier and experiments must be performed to quantify this value following dissolution of the drug into the excipient.

In addition to choosing an appropriate and effective excipient, there are other means by which the skin can be modified to increase drug absorption. First of all, hydrated skin is much more effective for drug absorption, resulting in 5-10-fold increase in absorption rate (12). Other options can be divided into a couple of different categories. Those are chemical, biochemical and physical enhancement. Unlike the excipient, these approaches have little to do with the drug itself, but instead modify the SC to increase drug permeability. Chemical approaches include the addition of chemical permeation enhancers to the transdermal formulation. There are a number of permeation enhancers that have shown varying degrees of effectiveness. Categories include: solvents (alcohols, hydrocarbons, acids, amines, amides, esters, etc.), terpenoids, surfactants, lipids or fats, and sulfoxides (13).

All of which have been found to alter the SC matrix to increase drug permeability to varying degrees. Biochemical methods utilize peptides to modify metabolic pathways to inhibit your body’s natural SC repair mechanism. At this point in time, this approach is relatively new and has not been used extensively. There are a number of different physical mechanisms in practice that increase the permeability of the SC. Many of these methods require the use of medical devices and have shown great potential for increasing the transdermal drug permeability. Stripping is a method that uses adhesive tape or cyanoacrylate glue to physically remove layers of the SC (14). This approach removes both corneocytes or the “bricks” of the SC as well as the lipid or “mortar” components. This significantly reduces the diffusion path length of the SC and increases drug permeability; however, it can also lead to inflammation of lower skin layers following multiple applications. Iontophoresis and electroporation are physical methods that use electricity to increase SC drug permeability. In the former, low currents are applied by an external electrode for minutes to hours to the skin which also has the drug applied. The current then forces the drug molecule across the SC and into the blood stream (15). But, there are a couple of disadvantages to this approach.

First of all, the drug in question must be charged (which cannabinoids are not) and it requires a specifically designed medical device, something that not everyone has access to. In electroporation, very high voltage (~100 V) is pulsed in micro to millisecond intervals on the skin leading to structural rearrangement of the components of the SC effectively creating pores in which the drug may pass. Again, the primary limitation to this approach is the fact that the drug must carry a charge, additionally, the pulsing voltage can cause pain and the drug must be hydrophilic, which cannabinoids again are not. Ultrasound is another physical technique that has been shown to increase SC permeability. In this method, ultrasound is used in the context of heating deep muscle tissue and has been shown to increase drug penetration (16). Ultrasound can also be used to initiate cavitation – the formation of submicroscopic defects in the SC structure, which also leads to increased drug permeability of the SC (17). While the physical mechanisms described above result in nano scale disruption of the SC and increased drug absorption, there are also mechanisms that create micro scale holes within the SC. In thermal ablation, micro to millisecond pulses of heat are applied to the skin which leads to micrometer sized holes in the SC allowing drugs to more efficiently pass through (18). Sandpaper abrasion and microdermabrasion are other methods that create micro scale pores in the SC (19). Finally, microneedles can be incorporated into transdermal applications, these create micro scale holes in the SC and increase drug delivery (20).

Although these physical methods have been used to good effect, they each come with their own associated disadvantages. Currently in the world of Cannabinoid Therapy, transdermal patches and transdermal gels or creams have been formulated and are available in many states where medical and/or recreational cannabis is legalized.

Topicals

An interesting fact about the skin that is underreported is that virtually all types of skin cells contain the primary components of the endocannabinoid system (eCS). In addition to cannabinoid receptor types 1 and 2 (CB1 and CB2), skin cells contain 2-arichidonylglycerol (2-AG) and arachidonylethanolamide (AEA – anandamide), which are naturally produced endocannabinoids. The enzymes responsible for endocannabinoid metabolism (i.e. the enzymes that synthesize and degrade 2-AG and AEA) have also been found in a number of skin cell types (21). So, the skin essentially contains its own version of the eCS and this system plays a very important role in skin pathophysiology.

The eCS in the skin reduces pain and inflammation following irritation, it contributes to epidermal cellular differentiation (i.e. the formation of specific skin cell types), mitigates symptoms of Psoriasis, reduces the size of melanoma and carcinoma tumor cells, alleviates Dermatitis and has shown promise as an anti-acne treatment (22).

Thus, topical cannabinoid therapy is a valid approach that has shown tremendous promise for the treatment of certain skin indications. In contrast to transdermal, topical cannabinoid application is a bit less complex due to the fact that the cannabinoids do not need to traverse the SC. Therefore, formulations can be concocted that do not need to consider how to facilitate movement of the drug through the SC.

In conclusion, transdermal and topical applications of cannabinoids are quite different from a drug design perspective. Both have shown great potential for systemic and local treatment of specific human health indications, and both are sure to develop further, as our understanding of cannabinoids and Cannabinoid Therapy increases.