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BEGINNERS GUIDE TO TRANSDERMAL DELIVERY
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CHEMO
Administrator
Submitted: April, 2003
SUMMARY
Transdermal dosing of various compounds has generated a lot of innovative ideas that have
revolutionized performance athletics. This dosing regime offers many advantages over oral forms
of delivery such as sustained release and higher availability especially with molecules that do not
have inherent hepatic resistance to breakdown. The choice to dose transdermally must be made
with considerations in mind such as choice of compound, dosing needs, and pharmacokinetics.
1. THE SKIN VIEWED AS A MEMBRANE
I. The skin is the most accessible organ in the body with the primary function of providing a
protective layer, temperature regulation, sensory input, and also water regulation. It is quite
large presenting almost 1.75 m2 in an average adult and containing roughly 1/3rd of the total
blood volume at any given time.
FIGURE 1.1 – Cross sectional view of the human skin.
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II. Transdermal dosing relies on successfully penetrating the skin and permeating the compound to
systemic circulation. The first step is negotiating the stratum corneum which is comprised of
protein and lipids (1, 2). There are other modes of absorption such as through hair follicles and
sweat glands but these are generally considered of little importance due to the small surface area
comparatively. Figure 1.1 accurately represents the relative thicknesses of the stratum corneum
to the rest of the skin. Although it is but a fraction of total skin thickness it presents the largest
challenge of crossing.
III. The skin can be modeled mathematically and the amount of absorbed material calculated for a
given time (3).
Cs = concentration of material in source
Cb = concentration of material in systemic circulation
a = Area for absorption through skin thickness d
K = Partition coefficient (through the SC)
M = Mass of drug diffusing in time t
D = Material’s diffusion coefficient
IV. Other factors that are not so easy to model are more numerous hence the inherent variation from
person to person. Steps can be taken to minimize this by addressing a few key areas and
considerations (4, 5, 6, 7).
i. Size of the molecule is critical as the trend holds smaller penetrates faster.
ii. Amount of material affects the concentration gradient and higher differences will support
better penetration.
iii. Most recipes will no doubt have various penetration enhancers with the action of each to
disrupt the SC layer. All enhancers are not created equal.
iv. Area of application plays a significant role in determining overall absorption. As a general
rule, the larger surface an area of application the higher the absorption.
v. Skin condition will affect both rate of absorption and actual net amount of flux. Factors here
are age, condition, and location.
vi. Skin temperature affects the vascular plexus blood flow and colder will decrease uptake.
This could possibly be used to delay the systemic release and aid in deeper penetration.
( ) t Cb Cs d
DKa m × - =
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2. PENETRATION ENHANCERS (PE’s)
I. The design and purpose of the enhancers are to temporarily decrease the efficient nature of the
stratum corneum. PE’s work by either disrupting the lipid layer or by interacting with intercellular
proteins. There are a few that work by both mechanisms such as DMSO and propylene glycol (8).
Figure 2.1 – Intercellular and Transcellular Structures
The first and second pictures in the series give a good indication of what will be involved with diffusing a
given compound across the skin. There are alternating bands of aqueous and lipid layers thereby
presenting a very difficult path.
Figure 2.2 – Table of Sorption Promoter (PE) Types
Most PE’s work by disrupting the organization of the lipid layer as
depicted in the second picture in the figure. Certain PE’s may
function in synergy when in combination such as Oleic Acid, Prop.
Glycol, IPM, Octyl Salicylate, and alcohol.
With so many choices which are the best ones?
This depends on several factors and includes availability,
mechanism of action, miscibility, and desired consistency.
Component Recommended Range
Isopropyl Myristate 15-30%
Isopropyl Palmitate 15-30%
Oleic Acid 10-15%
Octyl Salicylate 10-15%
DMSO 5-10%
Propylene Glycol 5-20%
Glycerol 5-10%
d-Limonene 10-20%
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3. GEL VERSUS SPRAY
This is a matter largely of personal choice as both are equally effective at transdermal absorption.
Some will find that there is some associated misting or overspray when using a liquid consistency
carrier system and this can only be solved by gelling or thickening. Others will not prefer the extra
steps in gelling the recipe so will tolerate the mist. The flexibility of transdermal formulation will allow
most any option in between.
I. Thickening agents
i. Carbomer family (934, 940, etc.)
These are very effective agents and relatively easy to work with providing you have the
ability to adjust the PH of the batches.
· Mix the water soluble ingredients (such as Prop. Glycol, Glycerol, i-prop alcohol,
etc.) with the Carbomer in the ratio of .5-1 gram per 240 mL (8 oz.)
· After COMPLETELY dissolving the Carbomer powder adjust the pH with
triethanolamine or similar to 7.0-7.4 and stir briskly.
· The batch will start to gel and will reach maximum action after 15 minutes or so.
· Slowly mix emulsifiers and allow to wet for 10 minutes.
· Add the oil soluble ingredients and mix well.
ii. Methyl Cellulose
· Mix the water soluble ingredients (such as Prop. Glycol, Glycerol, i-prop alcohol,
etc.) with the methyl cellulose in the ratio of .5-1 gram per 240 mL (8 oz.)
· After COMPLETELY dissolving the methyl cellulose powder adjust the pH with
triethanolamine or similar to 7.4-7.8 and stir briskly.
· The batch will start to gel and will reach maximum action after 15 minutes or so.
· Slowly mix emulsifiers and allow to wet for 10 minutes.
· Add the oil soluble ingredients and mix well.
Both of the thickening agents can be used at the same time with the recommendation being
.5 grams Carbomer 940 and .5 grams methyl cellulose. This has been found to provide
maximum gelling action.
II. Emulsifiers
These provide the ability to mix oil based ingredients with water soluble ingredients.
i. D-Limonene
· Useful emulsifier that can be used in the 5-20% range to great effect. Pleasant
citrus smell.
· Also lends to solvation for all types of molecules.
ii. PS-20
· Very powerful emulsifier that can be used in the 1-3% range.
If a gel is not desired the amount of emulsifier can be decreased to 1% PS-20 and 5% d-Limonene.
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REFERENCES:
1. Elias. Epidermal lipids, barrier function, and desquamation. J DERMATOLOGY
1983;80:44S-9S
2. Golden, McKie, and Potts. Role of stratum corneum lipid fluidity in transdermal flux. J
Pharm Sci 1987;76:25-8
3. Houk, Guy. Membrane models for skin penetration studies. Chem Rev 1988;88:455-71
4. Feldman, Maibach. Regional variation in percutaneous penetration of C-cortisol in man.
J Dermatol 1967;48:181-3
5. Elias. Lipids and the epidermal permeability barrier. Arch Derm Research 1981:270:95-1
6. Wiedmann. Influence of hydration on epidermal tissue. J Pharm Sci 1989;77:1037-41
7. Abraham, Chandra, Mitchell. The factors that influence skin penetration of solutes. J
Pharm Pharmacol 1995:47:8-16
8. Yamana. Propylene glycol/water co-solvent systems J Pahrm Pharmacol 1995;47:978-89
FIGURES:
1.1 Fox. Human Physiology, Fifth Edition 18:1.20 Brown Publishers 1996
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