Transdermal drug delivery systems

Patch
REFERENCES
 Novel drug delivery systems, 2nd edition, by Y.W.
Chein page no.: 338 – 380.

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 Transdermal drug delivery system
• Definition:
Transdermal drug delivery is defined as a self
contained discrete dosage form, which when applied to
the intact skin, will deliver the drug at a controlled rate to
the systemic circulation.

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 POTENTIAL BENEFITS OF
TRANSDERMAL DRUG DELIVERY
(ADVANTAGES)
• Easy to use.
• Avoid GIT absorption problems for drugs.
• Avoids First Pass hepatic metabolism of drugs.
• More improved and convenient patient compliance.
• Rapid termination in case of toxicity is possible.
• Self medication is possible.
• Reduces frequency of dosing.
• Maintains therapeutic level for 1 to 7 days.
• Controlled delivery resulting in more reliable and
predictable blood levels.
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 DISADVANTAGES
• Daily dose of more than 10mg is not possible.
• Local irritation is a major problem.
• Drug requiring high blood levels are unsuitable.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Barrier function changes from person to person and within the
same person.
• Heat, cold, sweating (perspiring) and showering prevent the
patch from sticking to the surface of the skin for more than one
day. A new patch has to be applied daily.

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TDDSs may be constructed of a number of layers, including :

(a) an occlusive backing membrane to protect the system

from environmental entry and from loss of drug fromthe
system or moisture from the skin.

(b) A drug reservoir or matrix system to store and release the

drug at the skin site.

(c) a release liner, which is removed before application and

enables drug release.

(d) an adhesive layer to maintain contact with the skin after

application. Two types of adhesive layers, the
• peripheral adhesive and the face adhesive,
Basic components of Transdermal
drug delivery

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 BASIC COMPONENTS OF TRANSDERMAL
DRUG DELIVERY SYSTEM

COMPONENT OF TRANSDERMAL DEVICE INCLUDE:

1) POLYMER MATRIX
2) THE DRUG

3) PERMEATION ENHANCER

4) OTHER EXCEPIENTS

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 POLYMER MATRIX
Following criteria to be considered in selection a
polymer:

Molecular weight, physical of polymer must allow

diffusion of drug at desired rate.

 Polymer must be non-reactive, inert, non-toxic, easy

to manufacture, inexpensive.

 It should not decompose on storage of the device &

not deteriorate when large amount of active ingredient is
in corporated into it.

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 LIST OF POLYMERS USED
NATURAL POLYMERS:
Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,
Gums & Natural rubber

SYNTHETIC ELASTOMER POLYBUTADIENE:

Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle,
Butyl rubber, Styrene butadiene rubber.

SYNTHETIC POLYMER
Poly vinyl alcohol, Poly vinyl chloride, Polyethylene,
Poly propylene, Poly urea, PVP, Polymethacrylate
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 DRUG

For successful developing transdermal delivery, drug

should be chosen with great care physicochemical
properties
1. Mol. wt. less than 1000 Daltons
2. Affinity for both lipophilic & hydrophilic phase
3. Drug should have low melting point

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 Ideal molecular properties for drug
penetration

- A low molecular weight (generally less than 500 Daltons)

- An adequate solubility in oil and water
- A balanced partition coefficient
- A low melting point
- Potent drug (maximum 10 mg/day)
- Half life of drug should be short.
- Non irritant to skin.
- Drug prone to ‘first pass effect’ and which degrade in GIT are
ideal candidate.
 DRUG
Hormones
• Estradiol and progesterone
• Avoid hepatic metabolism

Cardiovascular drugs
• Hypertension and angina
• Betablockers : timolol, propranolol
• Hepatic metabolism of propranolol

Analgesics
• Control of chronic pain by transdermal therapy

Antihistamines
• Treatment of allergy E.X Chlorpheniramine
• Maintain histamine-receptor antagonism while reducing CNS side
effects such as drowsiness

Central nervous system drugs

• Physostigmine : cholinesterase inhibitors
• To inhibit breakdown of acetylcholine by 30 to 40% over 4days
 PERMEATION ENHANCERS

Optimization of Percutaneous Absorption:

• Vehicle or device to maximize drug partition into the skin
• Incorporate penetration enhancer into formulation\

 penetration enhancer are the agents which promote the skin

permeability by altering the skin as a barrier to the flux of desired
penetrant.

 Flux J across the skin can be given by J= D. dc/dx

D= diffusion coefficient
C= concentration
x=Spatial coordinate
 D is function of size, shape, flexibility of diffusing drug molecule

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 IDEAL CHARACTERISTIC OF
PENETRATION ENHANCERS
1) IT SHOULD BE INERT

2) NON-TOXIC, NON- IRRITATING

3) ACTION SHOULD BE IMMEDIATE& PREDICTABLE

4) SHOULD NOT CAUSE REMOVAL OF BODY FLUID

5) SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS

6) A SUITABLE SOLVENT FOR DRUG

7) SPREAD WELL ON THE SKIN

8) COSMETICALLY ACCEPTABLE

9) ODORLESS, TASTELESS, COLORLESS & CHEAP

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 SOLVENTS
The compounds increase penetration possibly by swelling the polar pathway
and fluidizing the lipid
e.g.. Methanol, ethanol, pyrolidiones, propylene glycol, glycerol etc..

SURFACTANTS
They enhance polar pathway transport of hydrophillic drugs
• ANIONIC SURFACTANTS :
Dioctyl sulpho succinate, SLS, decodemethyl sulphoxide
• NON -IONIC SURFACTANTS :
Pluronic F127, pluronic F58
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 The Theory for Activity of penetration
enhancers
 Interaction with the polar head groups of lipid via hydrogen and
ionic bonding

 Change in hydration sphere of lipids and affect the packing at

the head region

 Increase volume of the aqueous layer swelling and hydration

 Protein modification- open up the dense keratin structure and

make it more permeable

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 Backing membrane
They are flexible and provide a good bond to the drug
reservoir, prevent the drug from leaving the dosage form
through top.
It is an impermeable membrane that protects the product
during the use on the skin.
 Contains formulation throughout shelf-life and during
wear period
 Must be compatible with formulation (non adsorptive)
 Printable
E.g.: Metallic plastic laminate , plastic backing with
adsorbent pad adhesive foam pad.
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 Types of Transdermal Drug Delivery
Systems
• Technically, TDDSs may be categorized into two
types:
• Monolithic and
• Membrane-controlled systems.

• Monolithic systems incorporate a drug matrix layer

between the backing and the skin surface .

• The drug matrix layer is composed of a polymeric

material in which the drug is dispersed. The polymer
matrix controls the rate at which the drug is
released for percutaneous absorption.
• The matrix may be of two types, either with or without an
excess of drug with regard to its equilibrium solubility and
steady-state concentration gradient at the stratum corneum
.

• In types having no excess, drug is available to maintain the

saturation of the stratum corneum only as long as the level
of drug in the device exceeds the solubility limit of the
stratum corneum.

• As the concentration of drug in the device diminishes below

the skin’s saturation limit, the transport of drug from device
to skin declines .

• In systems with excess drug in the matrix, a drug reserve is

present to ensure continued saturation at the stratum
corneum. In these instances, the rate of drug decline is less
than in the type having no reserve.
• Membrane-controlled transdermal systems are
designed to contain a drug reservoir, or pouch,
usually in liquid or gel form; a rate-controlling
membrane; and backing, adhesive, and protecting
layers .
• Membrane-controlled systems have the advantage
over monolithic systems in that as long as the drug
solution in the reservoir remains saturated, the
release rate of drug through the controlling
membrane remains constant .

• In membrane systems, a small quantity of drug is

frequently placed in the adhesive layer to initiate
prompt drug absorption and pharmacotherapeutic
effects on skin placement.

• Membrane-controlled systems may be prepared by

preconstructing the delivery unit, filling the drug
reservoir,and sealing or by lamination, a continuous
process of construction, dosing, and sealing
FORMULATION APPROACHES
FOR DEVELOPMENT OF
TRANSDERMAL DRUG
DELIVERY SYSTEM

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1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM

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 1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
 The drug reservoir is sandwiched between a drug
impermeable backing laminate and a rate controlling
polymeric membrane.

 The drug molecules are permitted to release only through the

membrane.

 The drug reservoir compartment: The drug is:

1. Dispersed in solid polymer matrix (polyisobutylene)

2. Suspended in unleachable viscous liquid (silicone fluid) to

form paste like suspension.

3. Dissolved in a releasable solvent (alkyl alcohol) to form 24a

 The membrane:
 Microporous or non porous ploymeric (ethylene -
vinyl acetate copolymer).
 A thin layer of drug compatible, hypoallergenic
adhesive polymer e.g. Silicon or polyacrylet adhesive
may be applied to the external surface.
 Rate of drug release affect by varying the polymer
composition, permeability coefficient and thickness
of rate limiting membrane and adhesive.
 Accidental breakage of the rate controlling
membrane can result in dose dumping or a rapid
release of the entire drug content.
E.g.
 Nitroglycerine releasing trans dermal system for
once a day medication for angina
 Scopolamine-releasing transdermal system for 72
hr. prophylaxis of motion sickness.
 Clonidine releasing transdermal system for 7 day
therapy of hypertension.
 Estradiol-releasing transdermal system for
treatment of menopausal syndrome for 3-4 days.

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 The intrinsic rate of the drug release from this type
of drug delivery system is defined by

dq CR

dt
= 1/p + 1/p
m a

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Pm and pa respectively defined as….

pm km/r . Dm
=
hm

pa = ka/m . Da
ha

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 Where,

 Km/r and ka/m are the partition coefficient for the

interfacial partitioning of the drug from reservoir to
the membrane and from the membrane to adhesive
layer respectively.

 Dm and Da are diffusion coefficient and

 hm and ha are the thickness

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 Substituting the pm and pa equation in equation 1

dq km/r . Ka/m . Dm . Da
= cr
dt km/r. Dm. ha + ka/m . Da . hm

 Which define the intrinsic rate of drug release from a

membrane moderated drug delivery system.

 If the membrane is porous, porosity and tortuosity of

the membrane should be taken inconsideration. 30
2. POLYMER MATRIX DIFFUSION
CONTROLLED TDDS SYSTEM

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 The drug reservoir:
 Homogeneous dispersion of the drug solids in
hydrophilic or lipophilic polymer matrix, and the
medicated polymer is then molded into medicated
discs with defined surface area and thickness.
 Then mounted onto impermeable plastic backing.
 The adhesive polymer is applied to the
circumference of the patch.
 E.g. of this type of system is nitro-dur I and nitro-
dur II. for continuous transdermal fusion of
nitroglycerine at a daily dose of 0.5 mg/cm2 for
therapy of angina pectoris.

 Nitro dur II is modified version of I in which the

drug is dispersed in acrylic based polymer adhesive
with a resinous cross linking agent which result in
much thinner and more elegant patch.

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 The rate of drug release from this type of system is
defined as:

1/2
dq ACp Dp
=
dt 2t

 A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp
are the solubility and diffusivity of the drug polymer respectively.

 Since only the drug species dissolved in the polymer can release , Cp is equal to CR.

 At steady state, Q versus t1/2 drug release profile is obtained. (non zero order
release).
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3. ADHESIVE DISPERSION-TYPE
SYSTEM

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 e.g. of adhesive polymer is poly(isobutylene) or
poly(Acrylet) adhesive

 E.g. of this type of system is isosorbide dinitrate

releasing transdermal therapeutic system for once a
day medication of angina pectoris.

 It is used for the administration of verapamil.

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 The rate of drug release in this system is defined by:

dQ ka/r . Da
= cr
dt ha

where,

Ka/r is partition coefficient for the interfacial partitioning

of the drug from the reservoir layer to adhesive layer.

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4. GRADIENT CONTROLLED TDDS

Drug – impermeable metallic

plastic laminate

}
R11 Drug reservoir
R2 gradient layers
R1>R2>R3
R3

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 The rate of drug release from this drug reservoir
gradient controlled system is given by:
dQ ka/r . Ds
= h (t) A (ha)
dt a

 Thickness of the adhesive layer for drug molecules to

diffuse through increases with time h(t)

E.g. Nitroglycerine TDD patch

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 To overcome the non zero order release, the drug
loading level in the reservoir is varied incrementally.

 The thickness of the diffusional path increases with

time, to compensate for this, the drug loading level
in the multilaminate adhesive layer is increased
 Deponit system: nitroglycerin releasing TDDS.
 5. MICRORESERVIOR TYPE OR
MICROSEALED DISSOLUTION CONTROLLED
SYSTEM

rim

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 Hybrid of reservoir and matrix dispersion type.

 The drug is suspended in aqueous solution of water

miscible drug solubilizer, then dispersing the drug
suspension in a lipophilic polymer by shear mechanical
force to form thousands of microscopic drug reservoirs.

 The medicated disc is then mounted at the center of an

adhesive pad.
 It is successfully utilized in the preparation of nitro-disc, a
nitroglycerine releasing trans dermal therapeutic system
used in angina pectoris.

 This system followed zero order release of drug without the

danger of dose dumping.
 ADVANCED RESEARCHES
MICROARRAY NEEDLE
 Advanced micro-needle Patch transdermal system
allowing continuous delivery through the skin of
proteins and water-soluble drugs.

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 ADVANCED RESEARCHES
• The device create painlessly micropores in the S.C.
known as microstructered arrays or microneedles.
• These devices have about 400 microneedles.
• The solid silicone needles (coated with drug) or
hollow metal needles (filled with drug solution)
penetrate the horny layer without breaking it or
stimulating nerves in deeper tissues.
• Flux increase up to 1,00,000 fold are reported.

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MICRONEEDLE ARRAY

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 MICRO TRANS

Applications :
 Delivery of large proteins, fragile antibodies, and
hormones.
 Delivery of small molecules, particularly those
with difficulty diffusing through skin layers.
 Delivery of vaccines, both conventional and DNA-
based.
 Fluid sensing of glucose, hormones, blood gases,
and therapeutic drug levels.

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Liposomes and vehicles

Liposome are colloidal particles formed as concentric

bimolecular layers that are capable of encapsulating
drugs.

There are many examples of cosmetic products in which the

active ingredients are encapsulated in vesicles. These include
humectants such as glycerol and urea, sunscreening and
tanning agents, enzymes, etc. Phosphatidylcholine from soybean
or egg yolk is the most common composition although many
other potential ingredients have been evaluated .

Cholesterol added to the composition tends to stabilize the

structure thereby generating more rigid liposomes.
Solid lipid nanoparticles
Solid lipid nanoparticles (SLN) have recently been
investigated as carriers for enhanced skin delivery of
sunscreens, vitamins A and E, triptolide and
glucocorticoids.

It is thought their enhanced skin penetration is primarily

due to an increase in skin hydration caused by the
occlusive film formed on the skin surface
 Find an appropriate place to put the
patch
 Choose a dry, unbroken, non-hairy part of your skin.
The buttocks, lower abdomen, lower back, and upper
arm (outer part) are good choices. If the area you choose
has body hair, clip (do not shave) the hair close to the
skin with scissors.
 the area is clean. If there is any oil or powder (from bath
products, for example), the patch may not stick properly.
 Attach the adhesive side of the patch to skin in the
chosen area.

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Find an appropriate place to put the
patch

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