Transdermal drug delivery systems

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 Learning Objec-ves
At the end of the lecture, you will be able to
• List the ideal proper<es of transdermal drug delivery
systems.
• Describe various pathways of percutaneous absorp<on.
• Describe factors that in?uence the rate of percutaneous
di@usion.
• Di@eren<ate various types of transdermal systems.

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 Introduc-on
• Many drugs are degraded in the intes<ne and liver.
• Many drugs are poorly absorbed.
• Some drugs may irritate the gastrointes<nal tract.
• Fluctua<on of the concentra<on of the drug in plasma.
• Many drugs need to be delivered in a very controlled manner.
• Con<nuous intravenous infusion at a programmed rate is a
superior mode of drug delivery since they bypass Frst-pass Advantage
metabolism and has constant, prolonged therapeu<cally
aar e@ec<ve drug level in the body.
• However, there are certain risks involved and therefore
s oxen
in necessitate hospitaliza<on of pa<ents, close medical
supervision, etc.

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Is there any alternative???????
 Transdermal Drug Delivery Systems (TDDS) Transcross
nermansuin

not
this topical

• The TDDS is deFned as a delivery device, which upon

applica<on on a suitable skin surface will be able to deliver
the drug to the systemic circula<on at a suLcient
concentra<on to ensure therapeu<c eLcacy.
• TDDS is designed to deliver drugs through the skin
(percutaneous absorp<on) to the general circula<on for
systemic e@ects. thisforsystemic iftargetskin istopical
absorption transdermal

• Target site: Generally, a site other than the skin.

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 Ideal TDDS
• Deliver the drug substance at a controlled rate to intact skin
for absorp<on into the systemic circula<on.
• Possess proper physicochemical characteris<cs to permit the
ready release of drug substance and facilitate its par<<on
from the delivery system into the stratum corneum.
• The patch should adhere well to the pa<ent skin and its
physical size should not be a deterrent to use.
• The system adhesive, vehicle, and ac<ve agents should be
non-sensi<zing and nonirritant as well.

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Transdermal delivery

Skin is designed to keep

substances outside the body

Strong barrier function

Increase in drug-transport
rate is required

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therthanbuca
second that
one fristpass
bypass metabolism

Advantages/Limita-ons
• Advantages
– Avoidance of ‘Frst-pass’ metabolism of drugs.
s so
– Reasonably constant dosage can so be maintained (as opposed to peaks
and valleys associated with oral dosage)
– Controls plasma levels of potent drugs.
– U<liza<on of drug with a short half-life and low therapeu<c index.
– Easy termina<on of drug delivery in case of toxicity.
– Reduc<on of dosing frequency and enhancement of pa<ent compliance.

• Limita<ons
– Higher molecular weight candidates (>500 Da) fail to penetrate the
stratum corneum.
– Drugs that cause skin sensi<za<on, and skin irrita<on.
– Drugs with very low par<<on coeLcients fail to reach the systemic eat
can neranatic

microgram
circula<on. ornano
gram
to
neversun
– Low skin permeability normally requires an enhancement approach.
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Drug plasma predic-on

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 Oral versus Transdermal
In humanstudyfind
datain ween

EE = Ethinyl Estradiol
much flucitation
No or variation Norelgestromin
History of TDDS

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 Skin as a site of drug delivery
• Skin is the largest organ in the body.
• Most extensive and readily accessible organ.
• In the adult, the skin has a total surface area of 2m2 and in most
places, it is no more than 2 mm in thickness.
• Mammalian skin is a mul<layer heterogeneous organ that forms
the external covering of the body. pH is 5.5. so
s.s n
inavearywitnpa
mn
anneiinsuin.me

• The drug must traverse three layers, the stratum corneum, the
epidermis, and the dermis.
• Anatomical Considera<ons
– The primary barrier to drug absorp<on is the stratum corneum
a
– Composed of dead kera<nocytes embedded in a lipid matrix,
through which most drugs are absorbed.
– Lipid matrix excreted by cells in the lower layer. maximise
im
– The basal layer consists of viable kera<nocytes.
– Dermis, vasculature and appendages
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I Bloodressele
 Anatomy of the skin
Hair follicle
Sebaceous gland
hardest
Stratum corneum
(0.8mm – 0.006mm)
any
here
exist
Epidermis
epidermis enter
dermis
IfDrug
pass

Dermis goInside
(3 – 5mm) no moon

Subcutaneous
tissue

Hair matrix
Endocrine sweat Basalepidermis AllInfectionwinexcithere get
there
energy

gland 13
 neraneoveino.name
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are

Dermal circula<on
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inn
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 Blood circula<on in skin
I vein

slowly andbecome
opening narrow
notdirectlyJointogether

Drugreach
surface
 Pathways of transdermal penetra-on
1. Through sweat ducts
2. Through Stratum Corneum
3. Transappendageal: via hair follicles, sebaceous and sweat glands

ononegiverapidabsorb
Secondonecan ofarug

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and
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atercan't
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Permeation through the stratum corneum

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Factors inGuencing the rate of percutaneous diHusion
• Physiochemical Proper<es of the Drug
– Aqueous solubility - >1mg/mL
– Molecular size - <500 Daltons (g/mol)
– Stability & Binding ALnity
µ
– Lipophilicity & Par<<on CoeLcient (log P between 1-3)
– Mel<ng point - <200 ℃
– Composi<on type (solid, semisolid)
– Low required daily dose (<10 mg/day)
• Biological factors
– Skin condi<on: Integrity and thickness of the SC.
– Skin metabolism
– Blood ?ow
– Skin age (not signiFcantly)
• Other factors – Drug should not be an irritant to
the skin
– High potency – Drug should not s<mulate an
– Skin hydra<on immune reac<on in the skin
– Drug/skin binding
– Penetra<on enhancers
– Vehicle E@ects, surfactants, cosolvents, pH , concentra<on.
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 aat
e TDDS components
is
• Backing Layer: They prevent drug from leaving dosage form
through top.
– Polypropylene, polyethylene, polyoleFn (transparent or pigmented),
Polyethylene Terephthalate, polyurethane, PVC, Aluminium foil.
• Polymeric Controlling Membrane: Controls the release of the
drug from the reservoir in certain types of patches.
– HPC, polymethacrylates (Eudragit)
• Adhesive: Serves to bind the components
of the patch to the skin
– Polybutylacrylate, polyisobutylene and silicons.
• Drug Release Membranes (liner): Protects the drug during
storage and is removed prior to use.
– polyethylene (Pores)

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 Matrix transdermal patch membrane
wehaveserrated

• Commercial examples include:

– Habitol® (nico<ne)
These All Charge to
– Nitrodisc® (nitroglycerine)
– ProStep® (nico<ne) DIA Drug in
Adhesion

• Drug-in-adhesive matrix patch construction

• The drug in adhesive patch is a type of matrix type, where the drug is
incorporated directly into the adhesive.
• Commercial examples include:
– Monolithic DIA: Climara® (estradiol)
– Mul<laminate DIA: Nicoderm® (nico<ne)
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 Reservoir transdermal patch

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

the adhesive.
• Commercial examples include:
– Duragesic® (fentanyl, Janssen)
– Estraderm® (estradiol, Novar<s)
– Transderm-Nitro® (nitroglycerin, Novar<s)

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 ocluded

Applica-on
• Site
– Apply to clean, dry skin areas on the upper outer arm, abdomen,
bujock, or upper body where it will not be rubbed by <ght clothing
• Applica<on
– Must be worn for a full period
– Change the patch according to the instruc<on
– Remove the used patch before placing a new one
– Apply the patch to a di@erent area with each change to avoid skin
irrita<on
– Seek medical advice if the sensi<vity of intolerance is present
– If the patch falls o@, re-apply it or apply a new patch at the earliest
• Precau<ons
– Do not cut or damage the patch
– Do not use lo<ons, creams, oils, powders, or make-up at the patch
site
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 Products on the market, or in development include:

• Clonidine
• Works as an agonist of adrenaline at the presynap<c
a2 adrenergic
• Product name = Catapres-TTS®
• Type of Patch = Reservoir
• used to treat hypertension

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• Granisetron (Kytril or Sancuso)

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 • Ethinylestradiol and norelgestromin
• Product name = Ortho-Evra®
• Used for Contracep<on
• Type of patch = Drug-in-Adhesive
• Frequency of applica<on = weekly

OH
OH

H
H H

H H
H H
HO
HO
N

Ethinylestradiol (an estrogen) Norelgestromin (a progestin)

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 • Fentanyl
• Product Name = Duragesic®
• Used for: Analgesia
• Type of Patch = Drug-in-Adhesive
• Frequency of Applica<on = Weekly

Dose is very low

It useAftersurgery
O

N N

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• Lidocaine
• Product Name = Lidoderm®
• Used for: analgesia of postherpeu<c neuralgia (PHN),
a painful condi<on caused by the varicella zoster
virus (herpes zoster = shingles)

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 Lidoderm Patch

• Type of Patch = Reservoir

• Frequency of Applica<on = Daily

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• Nico<ne
• Product name = Habitrol®, Nicoderm – CQ®,
Nicotrol®, Prostep®
• Used for: Smoking cessa<on
• Frequency of administra<on = 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 administra<on = 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 applica<on = weekly

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

OH

H H

H H

Norethindrone

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• Oxybutynin
• Works as compe<<ve antagonist of the muscarinic
acetycholine receptor
• Product name = Oxytrol®
• Used for: Overac<ve bladder (an<spasmodic)
• Type of Patch: Drug-in-adhesive
• Frequency of applica<on = twice a week

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• Scopolamine
• Works as compe<<ve antagonist of acetylcholine at
the muscarinic receptor
• Product Name = Transderm Scop®
• Type of Patch: Reservoir
• Used for: Mo<on 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, iontophore<c.

Epinephrine acts as vasoconstrictor, thus prolonging the

duration of action of lidocaine (by delaying resorption) at the site

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 Iontophore<c Patches

useanothertechnicolorhydrophilic

top sopmelectrical
• Iontophore<c patches use a <ny electrical
current to promote ?ow of the drug (usually
charged) through the skin.
Ima
Itampine
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Iontophoretic Patches

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 References
• Ansel's Pharmaceu<cal Dosage Forms and Drug Delivery
Systems, Ansel H.C. Allen, L.V, Popovich N, Publisher;
Williams and Wilkins, Ed. 10th 2013.
• Targeted and Controlled Drug Delivery: Novel Carrier
Systems: Vyas S.P, Khar RK, Publisher; CBS Publishers &
Distributors. 2010.

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