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S.Brito Raj, M.PharmSri Venkateswara college of Pharmacy,RVS Nagar, Chittoor

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Definition: It is a self contained, discrete dosage form,

topically administered medicament in the form of

multilaminated adhesive patch that delivers a specific

dose of drug at a predetermined rate and controlled

rate, through skin to reach systemic circulation . Motion sickness, Angina, Hormonal therapy

Addiction for smokiness

Nicotine patch =The highest selling

Estrogen patches = menopausal symptoms

post-menopausal osteoporosis.

Nitroglycerin patches = angina

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cant used for all drugs

Skin rashes &

sensitization Bacterial & enzymatic

drug absorption under

patch

Complex tech

More cost Variation in absorption

efficiency

Difficult of adhesion to

certain skin

Permeability changes indiff. skin

By passes hepatic circulation ,ab.& mb

Drug with narrow therapeutic index.

Uniform drug level in plasma6-7 days the drug level in body

Avoid risks of inconvenience of IV

Used for drugs with short t

Increase BA and efficacy of drugReduce over & under dosing by

prolonged duration of action

Rapid termination by simple removal

of patch

Simple therapeutic regimen

Better patient compliance

Non invasive medication

Avoid problems in oral administration

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Drug dose should not be large ( 20 mg)

Drug should not have large molecular size (< 800 daltons)

Not for skin sensitizing and irritating drug

Not for drug metabolized in skin

Not for drug undergoes protein binding in skin

Should be both hydrophilic and lipophilic

MECHANISM

1. Rate of drug diffusion from the device

2. Rate of drug permeation through the stratum corneum

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Diffusion of drug from reservoir to the rate controlling

membrane.

Diffusion of drug from rate limiting membrane to stratum

corneum.

Sorption by stratum corneum

penetration through viable epidermis,dermis,subdermal tissue

Uptake of drug bycapillary network in the dermal papillary layer.

Effect on target organ

Mechanism of release: Passive diffusion

Diffusion controlled drug delivery through stratum corneum

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The drug permeation across the skin obeys Ficks first law

dm/dt=J=DC 0 P/hwhere

J= steady-state flux

D= diffusion coefficient of the drug in the stratum corneum

h= length or membrane thickness P= partial coefficient between the stratum corneum and the

vehicle

C0= applied drug concentration

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Drugs which undergo extensive first pass metabolism,

Drugs with narrow therapeutic window

Short half life t < 5 6 (non- compliance /frequent dosing)

Non ionic, of low molecular weight (less than 500 Daltons)

Physicochemical and biological compatible

Have adequate solubility in oil and water

A low melting point (less than 200 C)

Potent (dose in mg per day)

pH = 5 9

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t < 5 6 Should not stimulate an immune reaction in skin

Must not induce a cutaneous irritation

Must not induce a allergic response

It should penetrate the skin at any concentration

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Rivastigmine = Alzheimers And Parkinson Dementia

Rotigotine = Parkinson

Methylphenidate = Attention Deficit Hyperactive

Disorder

Selegiline = Depression

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Polymer matrix / Drug reservoir Drug

Permeation enhancers

Pressure sensitive adhesive (PSA)

Backing laminates

Crystal inhibitors

Release liner

Other excipients like plasticizers and solvents

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Biocompatibility and chemical compatibility with the drug

Natural Polymers: e.g. cellulose derivatives, zein, gelatin, shellac,

waxes, gums, natural rubber and chitosan

Synthetic Elastomers: e.g. polybutadiene, hydrin rubber,

polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene,

butylrubber.

Synthetic Polymers: e.g. PVA, PVC, polyethylene, polypropylene,

polyacrylate, polyamide, polyurea.

Matrix formers =Cross linked PEG, eudragits, EC, PVP, HPMC

Rate controlling membrane = EVA, silicon rubber, polyurethane

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Increase permeabilityof stratum corneum

To attain higher therapeutic levels

Mechanism:

Penetration enhancers interact with structural

components of stratum corneum i.e., proteins orlipids

TheyAlter the protein and lipid packaging of

stratum corneum, thus chemically modifying the

barrier functions leading to increased

permeability

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Maintaining intimate contact (transdermal system &skin

surface)

It should adhere with not more than applied finger pressure

Should not cause instabilityof the drug, penetration enhancer

The diffusing drug must not affect the adhesive

Physicochemically and biologically compatible

Exert a strong holding force

It should be removable from the smooth surfacewithout leavinga residue

Polyacrylates, polyisobutylene and silicon based adhesives

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While designing = consideration of chemical resistance of the

material is most important

Excipients compatibility

Chemical resistance is not there , lead to

= stiffness and high occlusivity to moisture vapour and air,

= causing patches to lift and irritate the skin during long wear

High flexibility

Good oxygen transmission

High moisture vapor transmission rate

Examples =vinyl, polyethylene and polyester films

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It is a primary packaging material

During storage the patch is covered by a protective liner Removed and discharged immediately before the application

of the patch to skin

Chemical inertness

Release liner

non-occlusive (e.g. paper fabric)

occlusive (e.g. polyethylene, polyvinylchloride)

release coating layer made up of silicon or teflon, polyesterfoil and metallized laminates

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Solvents = chloroform, methanol, acetone,

isopropanol and dichloromethane are used to

prepare drug reservoir.

Plasticizers = dibutylpthalate, triethylcitrate,polyethylene glycol and propylene glycol are added

to provide plasticityto the transdermal patch

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TDDS

RESERVOIR OR

MEMBRANE

BY RATE

CONTROLMEMBRANE

SINGLE

RESERVOIR

MULTI RESERVOIR

WITHOUT RATECONTROLLING

MEMBRANE

ADHESIVE

ENCAPSULATED

DEVICE

HALLOW

CYLINDRICAL

RESERVOIR

SOLUBLE

MEMBRANES

MONOLITHIC OR

MATRIX

ADHESIVE

HYDROPHILIC

MICROPOROUS

MICROSEALED

RESERVOIR TYPE

PROTOPLASTIC

TYPE

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Classified into following types

Matrix type

Reservoir type

Membrane matrix hybrid Micro reservoir type

Drug in adhesive type

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Drug reservoir (drug +polymer HPMC,EC,PVP in a common solvent)

plasticizer +permeation enhancer

Medicated polymeric mixture

over the mercury horizontal surface

pour into molded rings (defined surface area , controlled thickness

elevated temperature solvent evaporation

Film formation

Mounted in occlusive base plate (drug impermeable backing)

Adhesive polymer (spread along the circumference of the film)

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Adhesive rim

Backing layer

Drug reservoir

Absorbent padOcclusivebaseplate

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Absence of dose dumping

Direct exposure of polymeric matrix to the skin

No interference of adhesive

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Solvent evaporation method or compression method.

The drug reservoir(homogenous dispersion )

(drug +viscous liquid medium ; silicon fluids)

Releasable solvent (e. g. ethanol)

Paste like suspension /gel /clear solution of drug

The drug reservoir (sandwiched) b/w rate controlling

membrane(nonporous, fluid filled micro pores- EVA, ethyl

cellulose, silicon rubber and polyurethane) and backing

laminate.

Duragesic, Estradem and Androderm

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It is a modification of reservoir type TDDS.

Drug reservoir : liquid formulation of the drug reservoir is

replaced with a solid polymer matrix (e.g. polyisobutylene)

Sandwiched

between rate controlling membrane and backing laminate.

Marketed preparations : Catapress and Transderm Scop.

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Drug reservoir (suspending drug solids + water miscible drug

solubilizer PEG)

homogenously dispersed lipophillic polymer

high shear mechanical force

Unleachable microscopic drug reservoirs (micro reservoirs)

Stabilized cross linking the polymer chains

Medicated polymer disc of a specific area and fixed thickness.

Occlusive base plate mounted between the medicated disc and

adhesive form backing prevents the loss of drug through the

backing membrane.

Nitrodisc

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Drug reservoir :The drug +excipients+ organic solvent + pressure

sensitive adhesivesolution(polysiloxanes, polyacrylates and

polyisobutylene)

mixed

cast as a thin film

dried to evaporate the solvents

adhesive matrix with drug

sandwiched

between release liner and backing layer.

Drug -in -adhesive patch may be single layer or multi layer

preferred for hydrophobic drugs as it is to be incorporated into

organic solvent based hydrophobic adhesive

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1. Physicochemical evaluation

2. In vitro evaluation

3. In vivo evaluationPhysicochemical Evaluation:

Thickness: The thickness of transdermal film is determined

at different points of the film by

traveling microscope dial gauge

screw gauge

Micrometer

Uniformity of weight: Weight variation =10 randomly selected patches

calculating the average weight

individual weight should not deviate significantly from the

average weight.

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Drug content determination:

An accurately weighed portion of film (100 mg)

dissolved in 100 mL solvent

shaken continuously for 24 hr in shaker incubator.

sonicated

Ultra sonicator

filtration

drug in solution is estimated spectrophotometrically

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10 patches are selected

content is determined for individual patches 9 out of 10 patches

=85% to 115%, one NLT 75% to 125%

pass the test

But if3 patches have content in the range of 75% to 125%,

20 patches

20 patches = 85% to 115%

pass the test.

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Patch are weighed individually

desiccators (cacl2) room temperature for 24 hr.

The films are weighed

The percent moisture content is calculated using following

Formula :

% Moisture content = Initial weight Final weight X 100

Final weight

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One strip is cut from the centre

Two from each side of patches.

The length of each strip is measured

Variation in length is measured by determining percent

constriction

Zero percent constriction is equivalent to 100 percent flatness.

% constriction = I1 I2 X 100

I1

I2 = Final length of each strip

I1 = Initial length of each strip

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Films are sandwiched separately bycorked linear iron plates.

One end of the films is kept fixed with the help of an iron screen

other end is connected to a freely movable thread over a pulley.

Theweights are added gradually to the pan .

A pointer on the thread is used to measure the elongation of the

filmTheweight just sufficient to break the film is noted..

Tensile strength= F/a.b (1+L/l)

F = force required to break; a = width & b = thickness;

L = length; l = elongation of film at break point

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Water vapor transmission studies (WVT):

WVT = W/ ST

W is the increase in weight in 24 h; S is area of film

exposed (cm2

); T is exposure time

Microscopic studies:

Distribution of drug and polymer in the film

By SEM.

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Quality of contact between the patch and the skin.

PSAs, which are defined as adhesives capable of bonding to

surfaceswith the application of light pressure. The adhesive

properties of a TDDS can be characterized by considering the

following factors:

Peel Adhesion properties: It is the force required to remove

adhesive coating from test substrate. It is tested by measuring

the force required to pull a single coated tape, applied to

substrate at 180 angle. The test is passed if there is no residue

on the substrate.

Tack properties: It is the ability of the polymer to adhere to

substratewith little contact pressure.

Tack is dependent on

molecular weight

composition of polymer

tackifying resins in polymer.

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Thumb tack test: The force required to remove thumb from

adhesive is a measure of tack.

Rolling ball test: This test involves measurement of the distance

that stainless steel ball travels along an upward facing adhesive. The

less tacky the adhesive, the further the ball will travel .

Quick stick (Peel tack) test: The peel force required breaking the

bond between an adhesive and substrate is measured bypulling

the tape away from the substrate at 90 at the speed of 12

inch/min.

Probe tack test: Force required to pull a probe away from an

adhesive at a fixed rate is recorded as tack.

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Shear strength properties or creep resistance : Shear

strength is the measurement of the cohesive strength of an

adhesive polymer i.e., device should not slip on application

determined bymeasuring the time it takes to pull an

adhesive coated tape off a stainless plate.

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In vitro release studies

Drug release mechanisms and kinetics, in vivo performance

Higuchi, First order, Zero order and Peppas and Korsenmeyer model

methods

The Paddle over Disc

The Cylinder modified USP Basket

The reciprocating disc

Diffusion Cells e.g. Franz Diffusion Cell and its modification

Keshary- Chien Cell

In vitro permeation studies

Franz diffusion cell or Keshary-chien diffusion cell

Then the amount of drug permeated per centimeter square at each

time interval is calculated

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Animal models &Human volunteers

Skin irritation studies

One group of animals ( control) was applied with marketed adhesive.

Transdermal systems (blank and drug loaded) were applied onto

nude skin of animals.

A0.8% v/v aqueous solution of formalinwas applied as standard

irritant The animals were applied with new patch/ formalin solution each

day up to 7 days

finally the application sites were graded according to a visual scoring

scale.

The erythema was as follows: 0 for none, 1 for slight, 2 for welldefined, 3 for moderate and 4 for scar formation.

The edema scale used was as follows: 0 for none, 1 for slight, 2 for

well defined, 3 for moderate and 4 for severe.

histological examination.

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Electrical enhancement method

Iontophorosis = it containes miniaturized, wireless dose

controller that connects directly to the integrated drug deliverysystem. Drug is applied under counter electrode in body by

applying current which repels the active substance and forces

into the skin. Used to treat skin cancer, psoriasis etc

Electroporation= application of current in millisecond and high

voltage (50-1000 volts). For large molecules (insulin and vacines)

Microporation : Microneedles (L-10-200m ,W-10-50m), pierce

stratum and increase permeability

Heat( 5): Increasing body fluid circulation drug solubility

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Heat( 5): Increasing body fluid circulation, drug solubility,

blood vessel wall permeability and rate limiting membrane

perm

Needless injection: Forcing compressed gas such as helium or

nitrogen through the nozzle through drug particles drug

particle

Medicated tattoos:very attractive , wetting with water and

binding to skin. for acetaminophen and vitamin c

Pressure waves:100Ps/sec generated byintense laser radiation

ex;caffeine

Sonophoresis :ultra sonic energy(20 100 KHz)

Magnetophorosis

Radiofrequency: Byhigh frequency AC 100 KHz that form heat

induced microchanells in the membrane

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