Transdermal Delivery
Systems
Advantages of Transdermal
Delivery Systems
• Reasonably constant dosage can be maintained
(as opposed to peaks and valleys associated
with oral dosage)
• First pass metabolism in the liver and GI tract is
avoided
• Reduced need for active administration (some
patches can last 7 days)
• The patch is noninvasive and dosage can be
stopped by removal
• Easy to apply and to monitor
Oral versus Transdermal
EE = Ethinyl Estradiol
Limitations of Transdermal Delivery
Systems
• Skin structure poses a barrier on the mw
of the drug (< 500 Da)
• Usually reserved for drugs which are
extremely potent (thus requiring a dosage
of only a few mg).
The drug must traverse three layers, the stratum cornium, the epidermis, and
the dermis.
Of these, the toughest barrier is the stratum corneum, which consists of 10-25
layers of keratinized cells.
The stratum corneum is the outermost layer of the epidermis and is
composed mainly of dead cells that lack nuclei.
These are sloughed off during the day and replaced by new cells from the
stratum germinativum.
There is a high proportion of keratin, an insoluble protein, with a high
proportion of disulfide bridges (from cysteine), and also a high level of glycine
and alanine residues that allow strong H-bonds to neighboring amino acids.
Types of patches: definitions
• Liner: Protects the drug during storage and is
removed prior to use
• Drug
• Adhesive: Serves to bind the components of the
patch to the skin
• Membrane: Controls the release of the drug
from the reservoir in certain types of patches
• Backing: Protects the patch from the outer
environment.
Drug in Adhesive
Patches
• A system in which the drug is incorporated
directly into the adhesive, rather than into
a separate layer. Usually used for smaller
molecular weight compounds.
• These can be either a single layer or multilayer.
• Sometimes referred to as the “matrix type
patch”
Schematic Drawing of the Matrix (Drug-in-Adhesive) type
of patch.
Film Backing
Drug/Adhesive Layer
Protective Liner (removed prior to use)
skin
Drug in Adhesive Patches Can Also Have
Additional Layers to Regulate Rate of Drug
Delivery
• Link
Reservoir Patches
• The reservoir system has a drug layer that
is separate from the adhesive.
Schematic Drawing of the Reservoir type of patch.
Film Backing
Drug Layer
Rate-controlling Membrane
Contact Adhesive
Protective Peel Strip (removed prior to use)
skin
Article illustrating two types of patches can be found at:
• http://molinterv.aspetjournals.org/cgi/reprin
t/4/6/308
What kind of drugs can be
incorporated into a patch?
• Compounds with low logP will not diffuse
into skin lipids
• However, compounds with high logP also
have difficulties, this time associated with
their diffusion out of the stratum corneum.
• The accepted range of logP values is
between 1 and 3.
Products on the market, or in development include:
• Clonidine
• Works as an agonist of adrenaline at the
presynaptic a2 adrenergic
• Product name = Catapres-TTS®
• used to treat hypertension
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•
•
•
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Ethinylestradiol (EO) and norelgestromin (N)
Product name = Ortho-Evra®
Used for Contraception
Type of patch = Drug-in-Adhesive
Frequency of application = weekly
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•
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•
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Fentanyl
Product Name = Duragesic®
Used for: Analgesia
Type of Patch = Drug-in-Adhesive
Frequency of Application = Weekly
• Lidocaine
• Product Name = Lidoderm®
• Used for: analgesia of postheretic neuralgia
(PHN), a painful condition caused by the
varicella zoster virus (herpes zoster = shingles)
• Type of Patch = Reservoir
• Frequency of Application = Daily
• Nicotine
• Product name = Habitrol®, Nicoderm –
CQ®, Nicotrol®, Prostep®
• Used for: Smoking cessation
• Frequency of administration = Daily
• Nitroglycerin
• Works by producing nitric oxide (NO), which then acts as
a vasodilator
• Product Names = Nitro-Dur®, Transderm-Nitro®
• Used for: Angina
• Type of Patch = Nitro-Dur is Drug-in-adhesive
Nitrodisc is reservoir
• Frequency of administration = Daily
• Estradiol
• Product Name = Alora®, Climara®, Esclim®,
Estraderm®, FemPatch®, Vivelle®, Vivelle-DOT®
• Used for: Hormone replacement
• Type of Patch: Drug-in-adhesive
• Frequency of application = weekly
• Estradiol + Norethindrone
• Product name = CombiPatch®
• Used for: Hormone Replacement
• Oxybutynin
• Works as competitive antagonist of the
muscarinic acetycholine receptor
• Product name = Oxytrol®
• Used for: Overactive bladder (antispasmodic)
• Type of Patch: Drug-in-adhesive
• Frequency of application = twice a week
• Scopolamine
• Works as competitive antagonist of acetylcholine
at the muscarinic receptor
• Product Name = Transderm Scop®
• Used for: Motion Sickness
• Testosterone
• Product Names = Androderm®, Testoderm
TTS®, Testoderm®
• Used for: Hypogonadism
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Lidocaine + Epinephrine
Product name = Lidosite
Used for: Dermal anesthesia
Type of Patch = Reservoir,
iontophoretic.
Epinephrine acts as vasoconstrictor, thus prolonging the
duration of action of lidocaine (by delaying resorption) at the site
Iontophoretic Patches
• Iontophoretic patches use a tiny electrical
current to promote flow of the drug
(usually charged) through the skin.
Iontophoretic Patches
Iontophoretic Patches
Microneedles Patches
• Microneedles patches are currently being
explored as mechanisms to deliver
vaccines and larger macromolecules.
Transdermal Vaccine Technology
Assigned Reading
• Scheindlin Stanley Transdermal drug delivery: PAST,
PRESENT, FUTURE. Molecular interventions (2004),
4(6), 308-12 (see link in presentation).
• Prausnitz, Mark R.; Langer, Robert. Transdermal drug
delivery. Nature Biotechnology (2008), 26(11), 12611268 Link
• Dixit Nitin; Bali Vikas; Baboota Sanjula; Ahuja Alka; Ali
Javed Iontophoresis - an approach for controlled drug
delivery: a review. Current drug delivery (2007), 4(1),
1-10 Link
Homework Questions
1. List the advantages of administering drugs via trandermal drug
delivery systems, over administering medications orally.
2. Use diagrams to illustrate the differences between a drug-in-adhesive
patch and a reservoir patch
3. List the limitations on the types of drugs which can be administered by
first-generation transdermal delivery systems. Explain why much of
the drug is wasted, and how this is commercially feasible.
4. Draw the structures of the following drugs and circle the functionalities
capable of ionization at biological pH. Redraw each structure,
showing the predominant charge state at pH = 7.4 (blood pH):
Fentanyl, Lidocaine.
5. Explain how second and third generation transdermal devices differ
from first generation and provide examples of each that are in clinical
trials.
6. Explain how transdermal delivery of vaccines might elucidate a
greater immune response than conventional methods.