S.Brito Raj, M.

Pharm Sri Venkateswara college of Pharmacy, RVS Nagar, Chittoor

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, Addiction for smokiness Nicotine patch Estrogen patches

Hormonal therapy

=The highest selling = menopausal symptoms post-menopausal osteoporosis.

Nitroglycerin patches = angina

By passes hepatic circulation Drug

,ab.& mb

with narrow therapeutic index. level in plasma level in body

Uniform drug

6-7 days the drug

Avoid risks of
Used

inconvenience of IV

for drugs with short t drug under dosing by action

Increase BA and efficacy of Reduce over &

prolonged duration of Rapid

termination by simple removal

of patch
Simple therapeutic regimen Better patient compliance Non

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 in diff. skin

invasive medication problems in oral administration

Avoid

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. 2.

Rate of drug diffusion from the device Rate of drug permeation through the stratum corneum

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 by capillary network in the dermal papillary layer. Effect on target organ Mechanism of release: Passive diffusion Diffusion controlled drug delivery through stratum corneum

The drug permeation across the skin obeys Ficks first law dm/dt=J=DC 0 P/h where 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

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 200C) Potent (dose in mg per day) pH = 5 9

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

Rivastigmine = Alzheimers And Parkinson Dementia

Rotigotine = Parkinson

Methylphenidate = Attention Deficit Hyperactive Disorder

Selegiline

= Depression

Polymer matrix / Drug reservoir Drug Permeation enhancers Pressure sensitive adhesive (PSA) Backing laminates Crystal inhibitors Release liner Other excipients like plasticizers and solvents

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

Increase permeability of stratum corneum To attain higher therapeutic levels

Mechanism:

Penetration enhancers interact with structural components of stratum corneum i.e., proteins or lipids They Alter the protein and lipid packaging of stratum corneum, thus chemically modifying the barrier functions leading to increased permeability

Maintaining intimate contact (transdermal system &skin surface)

It should adhere with not more than applied finger pressure Should not cause instability of 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 surface without leaving

a residue

Polyacrylates, polyisobutylene and silicon based adhesives

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

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, polyester

foil and metallized laminates

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 plasticity to the transdermal patch

BY RATE CONTROL MEMBRANE

SINGLE RESERVOIR

MULTI RESERVOIR RESERVOIR OR MEMBRANE TDDS MICROSEALED RESERVOIR TYPE WITHOUT RATE CONTROLLING MEMBRANE

ADHESIVE

ENCAPSULATED DEVICE HALLOW CYLINDRICAL RESERVOIR

PROTOPLASTIC TYPE ADHESIVE MONOLITHIC OR MATRIX HYDROPHILIC

SOLUBLE MEMBRANES

MICROPOROUS

Classified into following types Matrix type Reservoir type Membrane matrix hybrid Micro reservoir type Drug in adhesive type

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)

Occlusive baseplate

Backing layer Absorbent pad

Adhesive rim Drug reservoir

Absence of dose dumping Direct exposure of polymeric matrix to the skin No interference of adhesive

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

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.

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

Drug reservoir :The drug +excipients+ organic solvent + pressure sensitive adhesive solution(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

1.
2. 3.

Physicochemical evaluation
In vitro evaluation In vivo evaluation Thickness: The thickness of transdermal film is determined at different points of the film by

Physicochemical Evaluation:

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.

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

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 if 3 patches have content in the range of 75% to 125%, 20 patches 20 patches = 85% to 115% pass the test.

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

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

It gives the folding capacity of the films Repeatedly folding the film at the same place until it break.

Number of times the films could be folded at the same place without breaking is folding endurance value.

Films are sandwiched separately by corked 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.

The weights are added gradually to the pan .

A pointer on the thread is used to measure the elongation of the film The weight 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

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.

Quality of contact between the patch and the skin.

PSAs, which are defined as adhesives capable of bonding to surfaces with 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

substrate with little contact pressure.

Tack is dependent on

molecular weight composition of polymer

tackifying resins in polymer.

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 by pulling

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.

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 by measuring the time it takes to pull an adhesive coated tape off a stainless plate.

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

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. A 0.8% v/v aqueous solution of formalin was 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 well defined, 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.

Electrical enhancement method

Iontophorosis = it containes miniaturized, wireless dose controller that connects directly to the integrated drug delivery system. 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,

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 by intense laser radiation ex;caffeine

Sonophoresis :ultra sonic energy(20 100 KHz) Magnetophorosis Radiofrequency: By high frequency AC 100 KHz that form heat induced microchanells in the membrane