Transdermal drug delivery systemTransdermal drug delivery systemTransdermal drug delivery systemTransdermal drug delivery system

Transdermal Therapeutic Systems

vDiffusion of the medication (drug) through skin into

the systemic circulation for distribution and

therapeutic effect

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therapeutic effect

vMost TDD systems use passive delivery

13.1 Advantages of TTS’s

1. Eliminates oral absorption variables.

2. Eliminates first-pass metabolism

3. Provides controlled constant drug.

4. Can accommodate potent drugs

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4. Can accommodate potent drugs

5. Permits self-administration

6. Non-invasive (no needles or injections)

7. Improves patient compliance

8. Easy treatment termination

Limitations of TDD Systems

• Poor diffusion of large molecules• Skin irritation

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• Therapeutic indication• Desired drug delivery profile

- Dose level, duration, etc.• Skin adhesion profile• Application site

TDD System Design Factors

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• Application site• Ease of application• Patch size, shape, appearance, comfort• Wear period• Packaging• Patch disposal• Patch cost

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Process of transdermal permeation.

BASIC COMPONENTS OF TDDS1.Polymer matrix2.The drug 3.Permeation enhancers4.Other excipients

1.Polymer matrixIdeal polymer

٠MWT,and chemical functionality of the polymer should not affect the diffusivity of drug and its release

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٠stable٠non reactive٠easily manufactured٠easily fabricated into desired product٠inexpensive٠degaradation product must be non toxic or non antagonistic to the host٠ should retain its mechanical properties when the large amount of drug is

loaded in to it

Polymers used in TDDS• Natural polymers

– Cellulose derivatives– Zein– Gelatin– Shellac– Waxes– Proteins– Gums– Natural rubbers– starch

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• Synthetic elastomers--polybutadiene--hydrin rubber--polysiloxone--silicone rubber--nitrile--acrylonitrile--butyl rubber--styrene butadiene rubber--neoprine etc.

• Synthetic polymersPVA,PVC,PE,PP,Poly amide,Poly acrylate,Polyurea,PVP,PMMA,Epoxy etc.

2. Suitable drug candidate• Physico chemical properties of drug

– Should have MW less than 1000 daltons(500-1000)– Should have affinity for both lipophilic and hydrophilic phases– Should have low melting pont

• Biological properties of drug– Should be potent(less than 20mg)– Half life should be short

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– Half life should be short– Must not induce a cutaneous irritant or allergic response– Drugs which degrade in the GI tract or inactivated by hepatic

first pass effect are suitable candidate– Tolerance to the drug must not develop – Drugs which has to be administered for a longer period of time

can be formulated – Drugs which cause adverse effects to non target tissues can

also be formulated

3.PERMEATION ENHANCERS(to enhance stratum corneum permeability)

• SolventsIncreases penetration by swelling the polar pathway transport or fluidising lipidsEg.water,ethanol,methanol,DMS,homologs of methyl sulphoxide,dimethyl acetamide,and DMF,2-pyrrolidone,N-methyl,2-pyrrolidone,laurocapram,PG,glycerol,silicone fluids,isopropyl palmitate.

• SurfactantsEnhances the polar pathway transport of hydrophilic drugs

• Anionic surfactantsDioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc.

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Dioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc.• Non ionic surfactants

Pluronic F127,Pluronic F68,etc.• Bile salts

Sodium taurocholate,sodium deoxy cholate,sodium tauroglycocholate.• Binary systems

Propylene glucol-oleic acid and 1,4-butane diol-linoleic acid• Miscellaneous

Urea-hydrating and keratolytic agent,N,N-dimethyl-m-toluamide,calcium thioglycolate,anti cholinergic agents

• Potential permetion enhancersEuclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein

Permeability Coefficient Is the Critical Predictor of Transdermal Delivery

Transport = Flux = (mg/cm2/sec) = P x A x (Cd – Cr)

Permeability Coefficient = P = D x K (cm/sec) h

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Where A = Surface area of patchD = Diffusivity of drug in membrane (skin)K = Partition coefficient (patch/skin)C = Concentration in donor or receptor

(patch or skin)h = Thickness of membrane (skin)

4.OTHER EXCIPIENTS• AdhesivesIdeal properties• Should not irritate or sensitize the skin or affect normal functions of the skin• Should adhere to the skin aggressively• Should be easily removed• Should not leave an un washable residue on the skin• Should have an intimate contact with the skin • Should be compatible with the drug,excipients and permeation enhancers

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• Permeation of drug should not be affected• Backing membraneIdeal properties• Flexible and provide good bond to the drug reservoir• Prevent drug from leaving the dosage form• Should be impermeable• E.g.metallic plastic laminate,plastic backing with absorbent pad and

occlusive base plate,adhesive foam pad with occlusive base plate.

• Liner: Protects the drug during storage and is removed prior to use

• Drug• Adhesive: Serves to bind the components

of the patch to the skin• Membrane: Controls the release of the

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• Membrane: Controls the release of the drug from the reservoir in certain types of patches

• Backing: Protects the patch from the outer environment.

Formulation of TDDS1.Membrane-moderated or permeation controlled TDDS

• Drug reservoir(homogenous dispersion of drug with polymeric matrix or suspension of drug in un leachable viscous liquid medium such as silicone fluid) is encapsulated within drug impermeable metallic plastic laminate and a rate controlling polymeric membrane(ethylene vinyl acetate co polymer)

• The cross sectional view of this system is shown in the following Fig.1

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Reservoir Patches

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

Film Backing

Drug Layer

Schematic Drawing of the Reservoir type of patch.

Rate-controlling Membrane

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Protective Peel Strip (removed prior to use)

skin

Contact Adhesive

Example of this system are1.Nitro glycerin releasing TDDS (Transderm-

Nitro/ciba,USA)for once a day medication in angina pectoris

2.Scopolamine releasing TDDS (Transderm-Scop/ciba,USA)for 72 hrs.prophylaxis of motion sickness

3. Estradiol releasing TDDS (Estraderm/ciba)for treatment

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3. Estradiol releasing TDDS (Estraderm/ciba)for treatment of menopausal syndrome

4. Clonidine releasing TDDS (Catapres/Boehringer Ingelheim)for 7 day therapy of hyper tension

5. Prostaglandin-derivatives TDDS

2.Adhesive diffusion/dispersion-controlled TDDS

Drug reservoir• homogenous dispersion of drug with adhesive polymer(poly(isobutylene) or

poly acrylate)

• Then spreading of this medicated adhesive polymer on flat sheet of drug impermeable metallic plastic backing to form thin drug reservoir layer

• On top of the drug reservoir layer,thin layers of rate controlling adhesive polymer of specific permeability and constant thickness are applied to produce an adhesive diffusion/dispersion-controlled TDDS

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polymer of specific permeability and constant thickness are applied to produce an adhesive diffusion/dispersion-controlled TDDS

• The cross sectional view of this system is shown in the following Fig.2

Drug in Adhesive Patches

• A system in which the drug is incorporated directly into the adhesive, rather than into a separate layer. Usually used for smaller

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a 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”

Film Backing

Drug/Adhesive Layer

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

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Drug/Adhesive Layer

Protective Liner (removed prior to use)

skin

Examples for this system1.Iso sorbide dinitrate-releasing

TDDS

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TDDS 2.Verapamil releasing TDDS

• 3.Matrix diffusion-controlled TDDS

Drug reservoir

• homogenous dispersion of drug with hydrophilic or lipophilic polymer matrix by any one of the following methods

• Homogenous dispersion of finely ground drug particles with liquid polymer or highly viscous base polymer followed by cross linking of polymer chains

• Homogenous mixing of drug solid with rubbery polymer at an elevated temperature

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• Homogenous mixing of drug solid with rubbery polymer at an elevated temperature

• Dissolving the drug and polymer in a common solvent follwed by solvent evaporation in a mould at an elevated temperature or under vaccum.

• Medicated polymer is moulded in to desired surface area and controlled thickness

• This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing

• Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc

Example of this system are

1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key pharmaceuticals,USA)

2. Estradiol di acetate releasing TDDS

3. Verapamil releasing TDDS

The cross sectional view of this system is shown in the following Fig.3

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4.Micro reservoir type/micro sealed dissolution-controlled TDDS

Combination of the reservoir and matrix diffusionDrug reservoir•suspension of drug with aqueous solution of water soluble liquid polymer

•Homogenous dispersion of drug suspension in a lipophilic polymer(silicone elastomer)

•As a result discrete un leachable microscopic spheres of drug reservoir is formed which is stabilized by cross linking

•Medicated polymer is moulded in to desired surface area and controlled thickness and it is coated with

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•Medicated polymer is moulded in to desired surface area and controlled thickness and it is coated with a layer of bio compatible polymer to modify mechanism and rate of drug release

•This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing

•Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc

Example of this system are

1.Nitro glycerin releasing TDDS (Nitrodisc /searle,USA)

The cross sectional view of this system is shown in the following Fig.4

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Products on the market, or in development include:

• Clonidine• Works as an agonist of adrenaline at the

presynaptic α2 adrenergic • Product name = Catapres-TTS®

• used to treat hypertension

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• used to treat hypertension

• 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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OH

H

H H

Ethinylestradiol (an estrogen)

HO

• Fentanyl• Product Name = Duragesic®

• Used for: Analgesia• Type of Patch = Drug-in-Adhesive• Frequency of Application = Weekly

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N

O

N

• Lidocaine• Product Name = Lidoderm®

• Used for: analgesia of postheretic neuralgia (PHN), a painful condition caused by the varicella zoster virus (herpes zoster = shingles)

• Type of Patch = Reservoir• Frequency of Application = Daily

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• Frequency of Application = Daily

• 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 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 administration = Daily

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• Frequency of administration = Daily

• 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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O

OH

H H

H H

Norethindrone

• Oxybutynin• Works as competitive antagonist of the

muscarinic 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.

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Epinephrine acts as vasoconstrictor, thus prolonging the duration of action of lidocaine (by delaying resorption) at the site

Manufacturer Trade name Drug Strength available

Ciba

Estraderm Estradiol 25 µg, 50 µg, 100 µg

Transderm-Scop Scopolamine 1.5 mg

Transderm-Nitro Nitroglycerin 0.1 mg, 0.2 mg

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Janssen Duragesic Fentanyl 25 µg, 50 µg, 100 µg

Basel Habritol Nicotine 21 µg

Parke-Davis Nicotrol Nicotine 21 µg

Lederle Prostep Nicotine 21 µg

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TTS Available in market

Large scale mfg of TTS

üPhysical parameters üEvaluation of adhesiveüIn-vitro testingüIn-vivo assessmentüCutaneous metabolism

Evaluation Parameters

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üCutaneous metabolismüStability studiesüEvaluation of skin reactions.

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Thickness

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Weight variation

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Folding endurance

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Moisture content

% Moisture content = Initial weight – Final weight X 100

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% Moisture content = Initial weight – Final weight X 100Final weight

Moisture uptake

% moisture uptake = Final weight – Initial weight X 100

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Initial weight

Flatness

% constriction = I1 – I2 X 100I1

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I2 = Final length of each stripI1 = Initial length of each strip

Drug content

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Water Vapor Transmission studies

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Evaluation of adhesive

1} Peel adhesion propertiesIt is the force required to remove adhesive from test substrate.

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2} Tack properties

It is the ability of the polymer to adhere to substrate with little contact

pressure.

2.1} Thumb tack test

2.2} Rolling ball tack test

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2.2} Rolling ball tack test

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2.3}Quick-stick (or peel-tack) test

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2.4} Probe tack test

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3} Shear strength propertiesShear strength is the measurement of the cohesive strength of adhesive polymer.

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Tensile strength

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

F - the force required to breaka - width of film

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a - width of filmb - thickness of filmL - length of filml - elongation of film at break point

In-vitro testing

üThe Paddle over Disc

üThe Cylinder modified USP Basket

üThe reciprocating disc

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üDiffusion Cells e.g. Franz Diffusion Cell and its modification Keshary-

Chien Cell

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In-vitro testing

Importance

(1)Defining skin permeation kinetic studies using a diffusion cell system and cadaver skin during the drug

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diffusion cell system and cadaver skin during the drug development process.

(2) in vitro drug release kinetics, to be used for batch-to-batch release and as a compendial test.

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Preparation of skin for permeation studiesPreparation of skin for permeation studies

ll Intact Full thickness skinIntact Full thickness skinHair removal removal of subcutaneous Hair removal removal of subcutaneous

tissue dermis is cleaned with isopropyl tissue dermis is cleaned with isopropyl alcohol washed with water alcohol washed with water

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alcohol washed with water alcohol washed with water stored at stored at --2020°°CC

ll Separation of epidermis from full Separation of epidermis from full thickness skinthickness skin::

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K-C cell for permeation studies

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Effect of skin uptake metabolismEffect of skin uptake metabolism

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In-vivo assessment

1} Animal model

Mouse, hairless rat, hairless dog, hairless rhesus monkey,

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Mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig

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In-vivo assessment

2} Human model

Ø. Phase I clinical trials are conducted to determine mainly safety in volunteers.

ØPhase II clinical trials determine short term safety and mainly effectiveness

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in patients.

Ø Phase III trials indicate the safety and effectiveness in large number of patient population.

ØPhase IV trials at post marketing surveillance are done for marketed

patches to detect adverse drug reactions.

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Skin irritation studiesSkin irritation studies

ll Group I was served as normal, without Group I was served as normal, without any treatment.any treatment.

ll Group II, control, was applied with Group II, control, was applied with

Contact dermatitis

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ll Group II, control, was applied with Group II, control, was applied with marketed adhesive tape.marketed adhesive tape.

ll Group III Transdermal systems (blank)Group III Transdermal systems (blank)ll Group IV Transdermal systems (drug Group IV Transdermal systems (drug loaded)loaded)

ll Group V standard irritant .Group V standard irritant .

Evaluation of skin reactions.

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Stability studies

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Study Storage conditions Time period

Temperature Relative humidity

Long Term 25°C± 2°C 60%± 5% 12 months

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Long Term 25°C± 2°C OR

30°C± 2°C

60%± 5% OR

65%± 5%

12 months

Intermediate 30°C± 2°C 65%± 5% 6 months

Accelerated 40°C± 2°C 75%± 5% 6 months

APPLICATIONS

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APPLICATIONS

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The Past

• 3000 BC--Pharmaceuticals and plasters first recorded in Babylonia.

• 1500 BC--Plasters recorded in the Ebers Papyrus (Egypt).

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Papyrus (Egypt). • Plasters made by physicians or pharmacists at

the time of dispensing

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The Past

• Used for topical and deep tissues• Counterirritants, protective dressings, belladonna,

salicylic acid, flaxseed, mustard,

Plasters, Poultices and CeratesPlasters, Poultices and Cerates

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salicylic acid, flaxseed, mustard, • Adhered to skin with stiff ointments, waxes,

melted waxes and rubber resins, kaolin• Applied hot, could absorb water• Backings made of cloth or animal skin

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The Past: Adhesives

Example of plaster formula (1909)Rubber 20 gramsPetrolatum 20 gramsLead Plaster 960 grams

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Lead Plaster 960 gramsTo make, 1000 grams

Add any one of the following Belladonna Leaves,Oleoresin of Capsicum, Mercury, Opium, Soap

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The Past

The last 150 years:• Electrically assisted applications first occurred

in late 1800s and in early 1900s.• Rubber became available in the 1800s

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• Rubber became available in the 1800s• Nitroglycerin was applied topically as an

ointment for delivery to the bloodstream in the 1950 to present.

• Belladonna, capsicum, mustard and salicylic acid plasters

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The Present Day

• 1970-- Alza Research (US) began first development of the modern transdermal

• 1980-- Scopolamine first transdermal reached US

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US • 2002– Many Rx and non-RX products in US

market.• Transdermals deliver drugs from a few hours

up to 7 days.

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