transdermal delivery systems2011

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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 associatedwith oral dosage)

First pass metabolism in the liver and GI tract isavoided

Reduced need for active administration (somepatches can last 7 days)

The patch is noninvasive and dosage can bestopped 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 (< 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.
http://en.wikipedia.org/wiki/Image:Skin.jpg


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http://en.wikipedia.org/wiki/Image:Skin.jpg


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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 thepatch 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 intoa 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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Film Backing

Drug/Adhesive Layer

Protective Liner (removed prior to use)

skin

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

of patch.


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Drug in Adhesive Patches Can Also Have

Additional Layers to Regulate Rate of DrugDelivery

Link
http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technology-solutions/transdermal-technologies/educational-resources/http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technology-solutions/transdermal-technologies/educational-resources/


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Reservoir Patches

The reservoir system has a drug layer thatis separate from the adhesive.


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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


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http://molinterv.aspetjournals.org/cgi/reprin

t/4/6/308

Article illustrating two types of patches can be found at:
http://molinterv.aspetjournals.org/cgi/reprint/4/6/308http://molinterv.aspetjournals.org/cgi/reprint/4/6/308http://molinterv.aspetjournals.org/cgi/reprint/4/6/308http://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 alsohave difficulties, this time associated with

their diffusion out of the stratum corneum.

The accepted range of logP values isbetween 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 asa 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 themuscarinic 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 electricalcurrent to promote flow of the drug

(usually charged) through the skin.


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I t h ti P t h


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Microneedles Patches

Microneedles patches are currently being

explored as mechanisms to deliver

vaccines and larger macromolecules.

T d l V i T h l


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Transdermal Vaccine Technology

LINK
http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technology-solutions/transdermal-technologies/educational-resources/http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technology-solutions/transdermal-technologies/educational-resources/


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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

A i d R di
http://purevax.us.merial.com/vetjet/animation.asphttp://purevax.us.merial.com/vetjet/animation.asp


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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. RecentAdvances in Transdermal Drug Delivery. Archives of

Pharmal Research (2010), 33(3): 339-351.

H k Q ti
http://www.nature.com/nbt/journal/v26/n11/abs/nbt.1504.htmlhttp://www.nature.com/nbt/journal/v26/n11/abs/nbt.1504.html


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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-adhesivepatch 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 functionalitiescapable 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 clinicaltrials.

6. Explain how transdermal delivery of vaccines might elucidate a

greater immune response than conventional methods.

transdermal delivery systems2011

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