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
ParDeus@avantlabs.com
This article appears courtesy of www.mindandmuscle.net
REFERENCES
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Par Deus
ParDeus@avantlabs.com
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