Transdermal drug delivery systems provide several advantages over oral administration, including maintaining consistent drug levels, avoiding first-pass metabolism, and not requiring active administration. There are two main types of patches - drug-in-adhesive patches where the drug is incorporated directly into the adhesive layer, and reservoir patches where the drug is contained separately from the adhesive. Limitations include the skin posing a barrier to larger drug molecules and low drug payloads, though these systems can still be commercially viable by maintaining drug levels over multiple days. Newer technologies like microneedles and iontophoresis aim to overcome limitations and expand the types of drugs that can be delivered transdermally.

1. Transdermal Delivery
Systems

2. 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

3. Oral versus Transdermal
EE = Ethinyl Estradiol

4. 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 largest daily dose of a drug from a patch is the
nicotine patch, with delivers a daily dose of only 21 mg.

6. 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.

7. 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.

8. • In the stratum corneum 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.

9. 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.

10. 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 multi-
layer.
• Sometimes referred to as the “matrix type
patch”

11. Film Backing
Drug/Adhesive Layer
Protective Liner (removed prior to use)
skin
Schematic Drawing of the Matrix (Drug-in-Adhesive) type
of patch.

12. Drug in Adhesive Patches Can Also Have
Additional Layers to Regulate Rate of Drug
Delivery
• Link

13. Reservoir Patches
• The reservoir system has a drug layer that
is separate from the adhesive.

14. Film Backing
Drug Layer
Protective Peel Strip (removed prior to use)
skin
Schematic Drawing of the Reservoir type of patch.
Rate-controlling Membrane
Contact Adhesive

15. • http://molinterv.aspetjournals.org/cgi/reprin
t/4/6/308
Article illustrating two types of patches can be found at:

16. 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.

17. 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

18. • Ethinylestradiol (EO) and norelgestromin (N)
• Product name = Ortho-Evra®
• Used for Contraception
• Type of patch = Drug-in-Adhesive
• Frequency of application = weekly

19. • Fentanyl
• Product Name = Duragesic®
• Used for: Analgesia
• Type of Patch = Drug-in-Adhesive
• Frequency of Application = Weekly

20. • Lidocaine
• Product Name = Lidoderm®
• Used for: analgesia of postherpetic neuralgia
(PHN), a painful condition caused by the
varicella zoster virus (herpes zoster = shingles)

21. Lidoderm Patch
• Type of Patch = Reservoir
• Frequency of Application = Daily

22. • Nicotine
• Product name = Habitrol®, Nicoderm –
CQ®, Nicotrol®, Prostep®
• Used for: Smoking cessation
• Frequency of administration = Daily

23. • 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

24. • 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

25. • Estradiol + Norethindrone
• Product name = CombiPatch®
• Used for: Hormone Replacement

26. • 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

27. • Scopolamine
• Works as competitive antagonist of acetylcholine
at the muscarinic receptor
• Product Name = Transderm Scop®
• Used for: Motion Sickness

28. • Testosterone
• Product Names = Androderm®, Testoderm TTS®,
Testoderm®
• Used for: Hypogonadism

29. • 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

30. Iontophoretic Patches
• Iontophoretic patches use a tiny electrical
current to promote flow of the drug
(usually charged) through the skin.

31. Iontophoretic Patches

32. Iontophoretic Patches

35. Microneedles Patches
• Microneedles patches are currently being
explored as mechanisms to deliver
vaccines and larger macromolecules.

36. Transdermal Vaccine Technology
LINK

37. The microneedle technology can result in more effective contact of the vaccine
with the antigen-presenting Langerhans cells
The needles can be fabricated to be long enough to penetrate the stratum
corneum, but short enough to not come into contact with nerve endings.
LINK

38. 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), 1261-
1268 Link
• Sieg, A.; Wascotte, V. Diagnostic and therapeutic
applications of iontophoresis. Journal of Drug Targeting,
(2009); 17(9): 690-700.
• Graduate Students Only: Subedi, R. K. et al. Recent
Advances in Transdermal Drug Delivery. Archives of
Pharmal Research (2010), 33(3): 339-351.

39. 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.