Transdermal Delivery Systems

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Transdermal Delivery Systems
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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

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Oral versus Transdermal
EE Ethinyl Estradiol
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Limitations of Transdermal Delivery Systems

• Skin structure poses a barrier on the mw of the
  drug (lt 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.

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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.
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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.
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• 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.

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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.

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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

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Schematic Drawing of the Matrix
(Drug-in-Adhesive) type of patch.
Film Backing
Drug/Adhesive Layer
Protective Liner (removed prior to use)
skin
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Drug in Adhesive Patches Can Also Have Additional
Layers to Regulate Rate of Drug Delivery

• Link

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Reservoir Patches

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

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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
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Article illustrating two types of patches can be
found at

• http//molinterv.aspetjournals.org/cgi/reprint/4/6
  /308

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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.

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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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• 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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• Fentanyl
• Product Name Duragesic
• Used for Analgesia
• Type of Patch Drug-in-Adhesive
• Frequency of Application Weekly

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

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Lidoderm Patch

• Type of Patch Reservoir
• Frequency of Application Daily

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• Nicotine
• Product name Habitrol, Nicoderm CQ,
  Nicotrol, Prostep
• Used for Smoking cessation
• Frequency of administration Daily

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• 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

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• 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

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• Estradiol Norethindrone
• Product name CombiPatch
• Used for Hormone Replacement

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• 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

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

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• 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
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Iontophoretic Patches

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

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Iontophoretic Patches
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Iontophoretic Patches
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Microneedles Patches

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

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Transdermal Vaccine Technology
LINK
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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
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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.

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Homework Questions

• List the advantages of administering drugs via
  trandermal drug delivery systems, over
  administering medications orally.
• Use diagrams to illustrate the differences
  between a drug-in-adhesive patch and a reservoir
  patch
• 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.
• 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.
• Explain how second and third generation
  transdermal devices differ from first generation
  and provide examples of each that are in clinical
  trials.
• Explain how transdermal delivery of vaccines
  might elucidate a greater immune response than
  conventional methods.