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 largest daily dose of a drug from a patch is the

nicotine patch, with delivers a daily dose of only 21 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.

• 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.

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 multi-layer.

• Sometimes referred to as the “matrix type patch”

Film Backing

Drug/Adhesive Layer

Protective Liner (removed prior to use)

skin

Schematic Drawing of the Matrix (Drug-in-Adhesive) type of patch.

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.

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

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

Article illustrating two types of patches can be found at:

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 2 adrenergic

• Product name = Catapres-TTS®

• used to treat hypertension

• Ethinylestradiol (EO) and norelgestromin (N)• Product name = Ortho-Evra®

• Used for Contraception• Type of patch = Drug-in-Adhesive• Frequency of application = weekly

N

OH

H H

HO

H H

Norelgestromin (a progestin)

OH

H

H H

Ethinylestradiol (an estrogen)

HO

• Fentanyl• Product Name = Duragesic®

• Used for: Analgesia• Type of Patch = Drug-in-Adhesive• Frequency of Application = Weekly

N

O

N

• Lidocaine• Product Name = Lidoderm®

• Used for: analgesia of postherpetic neuralgia (PHN), a painful condition caused by the varicella zoster virus (herpes zoster = shingles)

Lidoderm Patch

• 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

O

OH

H H

H H

Norethindrone

• 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

• 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

LINK

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

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.

Homework Questions1. 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.