Another article on transdermal delivery by Par Deus.
By: Par Deus
At present, the most common form of delivery for bodybuilding and sports supplementation is via the oral route. While this has the notable advantage of easy administration, it also has significant drawbacks -- namely poor bioavailabiltity due to hepatic metabolism (first pass) and the tendency to produce rapid blood level spikes (both high and low), leading to a need for high and/or frequent dosing, which can be both cost prohibitive and inconvenient.
In addition, some products would greatly benefit from targeted delivery to various body tissues, such as adipose tissue, in order to allow high dosing, while avoiding some of the side effects associated with systemic delivery and its subsequent distribution to the CNS (and various other tissues).
Many potentially promising supplements suffer from one or more of the above inadequacies, making their oral intake either less than optimal or a complete waste of time -- these include prohormones, andrenergic agents such as ephedrine and yohimbine, and flavones such as chrysin.
Problems
The pharmaceutical industry has encountered these same problems with various drugs, and, as such, there has been a wealth of research in the area. One of the methods most often utilized has been transdermal delivery -- meaning transport of therapeutic substances through the skin for systemic effect (1). Closely related is percutaneous delivery, which is transport into target tissues, with an attempt to AVOID systemic effects (1).
However, the skin provides an excellent barrier to the entry of foreign substances (toxins, microorganisms, etc.) into the body -- in fact , along with keeping water in, it evolved for exactly that purpose (2). Thus, it is not just a matter of rubbing a drug or supplement in and waiting for it to take effect. A drug and its delivery system must possess certain physiochemical properties in order to provide for efficient passage through the skin barrier.
Physically
Let us begin by taking a look at the physical make-up of the skin, so as to understand exactly how it produces this barrier, so that we may develop targeted strategies to defeat it.
The primary barrier for entry into the skin is the stratum corneum (SC), with transport occurring primarily through the intracellular regions -- sweat ducts and hair follicles are also paths of entry, but they are considered rather insignificant (1). These regions are made up highly ordered lipid bilayers, composed of various (non-polar) lipids -- ceramides, cholesterol, fatty acids, and triglycerides (3) -- stacked on top of each other, each bilayer separated from the others by a very thin water sheet associated with the lipid's polar head (4).
Diffusion through this area is hindered by hydrogen bonding, making polar (hydrophilic) substances particularly resistant to penetration. Conversely, it offers relatively little resistance to fairly non-polar (lipophilic) compounds (5). It has been suggested that a partition coefficient (Log P) of around 3 is ideal for penetration of skin (6).
Separate, "polar" pathways have been proposed to account for higher than predicted permeability shown by some polar substances (7). However, an alternate explanation was given by Pugh et. al., who showed the afore mentioned hydrogen bonding to be saturable, which would allow more efficient penetration once a certain threshold is reached (8).
Below the SC is the viable epidermis and the dermis. Because of its aqueous, hydrophilic nature, this region provides substantial resistance to the diffusion of lipophilic compounds (9, 10) and is perhaps even the rate-limiting step in their transport (11, 12). Polar compounds, on the other hand, traverse this area easily.
Ideal Situation
We can now begin to look at what the ideal drug for transdermal delivery would be, as well as what steps can be taken, via the delivery system, to manipulate the physical properties of the drug and the skin to improve efficiency of delivery.
Because substances must pass in the spaces between cells, drugs with low molecular weight are preferred (13). And, as mentioned earlier, it also helps if the drug possesses fairly good lipid solubility -- Log P of 3 or so (fortunately, androgens fit this description quite nicely). As Log P decreases, diffusion through intracellular lipids is hindered, as it increases diffusion through aqueous layers of both the epidermis and dermis, as well as those associate with the polar heads of the intracellular lipids, becomes rate limiting.
We cannot always guarantee that the substance we wish to deliver will fit the afore mentioned ideal -- and even if it does, we still do not get even close to our ideal delivery efficiency of 100%. Thus, an enormous amount of research has been conducted and a number of strategies/technologies have been developed to address this issue.
The Equation
The following equation has been suggested to estimate delivery of a substance through the skin (14):
dQ/dT = (P.C.)Cv(DA/L)
Or, a bit more in English:
Rate of penetration [qQ/dT] = (Partition Coefficent between stratum corneum and vehicle [P.C.]) times ( The Concentration of drug in vehicle [Cv]) times ({average Diffusion [D] times Surface Area of application [A]} divided by {the effective Thickness of the skin barrier [L]})
We will now define the above terms as well as take a look at how we can manipulate them to increase the rate of penetration for a given substance. Obviously, some of them we will not be able to manipulate.
Simply Defined
Partition Coefficient (P.C.) -- For an individual substance, this is generally measured as the Octanol:Water ratio or Log P, and is a measure of a given substance's relative affinity for Octanol vs. Water. The higher it is, the more it tends to be attracted to Octanol and vice versa. To simplify, it is a measure of lipophilicity vs. hydrophilicity.
Obviously, if we are set on delivering a certain drug, this is a constant. However, in our situation, it is the P.C. between our drug in its vehicle and the skin that we are interested in, so some manipulation is possible. Due to solubility issues, which we will go into more later, our vehicle will not necessarily be water. It will often be a volatile solvent such as alcohol or acetone, both of which would actually reduce the effective ratio between the two. We are also interested in partitioning into the stratum corneum -- which is a bit more polar/hydrophilic -- rather than into Octanol (5).
This situation will have opposing effects on lipophilic and hydrophilic drugs. A reduction in the Log P will increase the P.C. for hydrophilic substances, and decrease it for lipophilic ones.
At this point, you may be wondering why, if increasing P.C. is a good thing, we would purposefully employ a solvent which will reduce it as our vehicle -- the answer is that the decrease in P.C. is going to be insignificant compared to the increase in diffusion we get from increasing solubility. This will be addressed further under the "Concentration" aspect of the equation.
Diffusion (D) -- This is the process by which a substance moves from one area to another. It is driven by thermal agitation and requires a concentration gradient. In other words, the area that a substance is going to have must a lower concentration of our drug than the area it is coming from. This is an issue of particular importance for lipophilic compounds (such as prohormones), that, in my opinion, has been overlooked in previously existing transdermal drug and supplement formulations.
Lipophilic substances diffuse easily through stratum corneum lipids, but have much more trouble with the aqueous layers below (the vice versa is true for hydrophilic substances). If transport slows too much in any layer of tissue -- be it stratum corneum, epidermis, or dermis -- diffusion slows, causing a buildup in the outer layers.
It is well documented that lipophilic compounds such as steroids have a high affinity for the stratum corneum, due to hydrogen bonding, attaching themselves and forming depots in the area (15, 16). This is fine under experimental conditions, where the drug is protected and will thus be free to slowly diffuse for several days. But, in the real world, skin (hint: the stratum corneum) is naturally shed, and people hopefully take showers, removing even more -- and taking your drug with it.
Thus, it of great importance to take into account diffusion through the epidermal and dermal regions, and a vehicle which could facilitate the diffusion of our drug through these regions would be a highly efficacious addition.
We would also like to maximize the rate of diffusion through the stratum corneum itself, not only for hydrophilic compounds, but lipophilic ones as well, which despite having good diffusion rates, are certainly far from ideal. The primary means of accomplishing this is through the use of various penetration enhancers (technically, what we have referred to as "vehicles", are penetration enhancers, but in this case I am referring specifically to enhancements which result from alterations in the physical structure of the stratum corneum -- whereas the vehicles primarily effect properties of the drug itself).
An ideal penetration enhancer will disrupt the barrier function of the skin without compromising its barrier effects on microorganism and toxins -- and without damaging cells (13). This has primarily been done through the use of chemical penetration enhancers.
There are two primary means by which chemical penetration enhancement occurs. The first is via lipid extraction -- it has been shown that the degree of drug penetration is proportional to % lipid extraction (3). Substances which fall into this category include Azone, isopropyl myristate, pyrrollidones, and terpenes (17). These perturb the water resistance function of the stratum corneum (18) -- and, as such, it will primarily enhance penetration of hydrophilic compounds. The efficacy of these substances is not typically linear with dosage (12) -- a certain concentration must be reached before significant extraction occurs -- meaning a thin layer will not really do a great deal.
The second mechanism is via disruption of the stratum corneum's highly ordered lipid bilayers. As we described earlier, it consists of lipophilic lipid regions, each separated by a thin layer of water. This aqueous layer is detrimental to the diffusion of lipophilic substances. Certain penetration enhancers such as unsaturated fatty acids, padimate O, and possibly isopropyl myristate and octyl salicylate, can disorder these bilayers, forming separate pools of oil within the stratum corneum's intracellular spaces, which lipophilic compounds can diffuse through much more freely (3,19,20). This would also be expected to help hydrophilic compounds, if aqueous pools were formed, and there is data suggesting both the capability of "straight through aqueous channels" (21), as well as enhancement with a combination of propylene glycol, which is hydrophilic, and unsaturated fatty acids (5).
Concentration (C) -- This is the amount of substance per unit volume of vehicle. In our case, the only part which we must be concerned with is that which is dissolved in the vehicle, as the penetration rate of undissolved substances is comparably insignificant (3). The importance of solubility is the reason a solvent carrier is typically used despite its reduction of P.C. For example, corticosterone's P.C. is reduced twofold by the addition of 50% ethanol to saline, but its solubility is increased 100 fold, giving a 40 fold penetration enhancement (3).
This solubility issue can become a problem if the vehicle evaporates before the drug has fully partitioned into skin, rendering it a useless precipitate (meaning it is left as a powder on the skin) -- an occurrence which has been reported both in the literature (3,5) and with real world use of existing transdermals. Thus, is is a good idea to also incorporate a small amount of a less volatile solvent such as fatty acids, terpenes, or isopropyl myristate into a transdermal formulation.
Surface Area (A) -- this should be rather straightforward. The larger the surface area of application, all else being equal, the greater the rate of penetration. Obviously, we can manipulate this to some extent.
Skin Thickness (L) -- again, fairly straightforward, the thicker the effective area of the skin barrier -- meaning the stratum corneum, the dermis and epidermis, the slower the rate of penetration. We cannot change our skin thickness, and though we can change the site of application, the areas with the thinnest skin, such as eyelids and scrotum, are areas we do not really want to use.
I think it should now be clear that, despite the claims of some, we can vastly improve the effectiveness of transdermals formulation with strategic manipulations of both the drug and the skin via the use of specific vehicles and chemical penetration enhancers. To see this applied to real world use of transdermal prohormones, take a look at this month's segment of Pimpology.
Before I conclude, I will also say a bit about "percutaneous delivery". As mentioned earlier, the goal of this is delivery of drug to target tissues, while AVOIDING systemic delivery as much as is possible (1). In the pharmaceutical realm, this has been pursued primarily for antibiotics and NSAIDS -- the former, to avoid destruction of systemic microflora (so-called "good bacteria"), and the latter to avoid hepatic recirculation, which is responsible for gastrointestinal problems (22,23).
In the supplement realm, this has tremendous applications for fat loss products such as yohimbine and EC, which ideally would reach fat cells in high doses, without the dangerous side effects of high central nervous system levels. This would allow us to achieve true "spot reduction". I will go into more detail on this, in my segment on LipoDerm-Y (our topical yohimbine) in next month's Pimpology column.
Conclusion
I believe transdermal delivery is the future of bodybuilding and sports supplementation. It has given us the most effective category of supplement to date -- the transdermal prohormone -- and it is only going to get better. Companies that have jumped on it early, such as Avant Labs, ErgoPharm, and Biotest, are way ahead of the game. However, "the future" may be fairly short-lived, as there are a number of technologies in their infancy, that have the possibility of blowing transdermals out of the water. That will be a subject we will look at at another time.
Questions and comments on this article can be sent to
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REFERENCES
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19. Mak VH, Potts RO, Guy RH Percutaneous penetration enhancement in vivo measured by attenuated total reflectance infrared spectroscopy. Pharm Res 1990 Aug;7(8):835-4
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