TRANSDERMAL DRUG

DELIVERY

Backing

Drug/Adhesive
Mix Release
Liner
 Transdermal Drug Delivery
The study of TDDS includes

• The structure of Human Skin

• Theoretical advantages of the transdermal route
• Optimization of percutaneous absorption
• Development of the transdermal therapeutic
system
• Examples of transdermal applications
• Evaluation
• Recent advances
 Transdermal Drug Delivery

Definition
Self contained,discrete dosage forms which,when
applied to the intact skin,deliver the drugs,through
the skin,at controlled rate to the systemic
circulation.

Transdermal permeation (percutaneous absorption)

The passage of substance from the outside of the
skin through its various layers into the
bloodstream.
 Transdermal Drug Delivery
Advantages
۞The system avoids the chemically hostile GI environment

۞ The system can delivers a steady infusion of a drug over an

extended period of time

۞increases the therapeutic value of many drugs

۞Can provide adequate absorption of certain drugs

۞Increased patient compliance

۞Avoids first-pass effect

۞Allows effective use of drugs with short biological half-life

۞Allow administration of drugs with narrow therapeutic windows

۞Provides controlled plasma levels of very potent drugs

۞Drug input can be promptly interrupted when toxicity occurs

۞Self administration is possible

Disadvantages of TDDS
۞Drug that require high blood levels cannot be administered

۞Adhesive may not adhere well to all types of skin

۞Drug or drug formulation may cause skin irritation or sensitization

۞Uncomfortable to wear

۞May not be economical

۞drugs must have desirable physico chemical properties for penetration through skin

۞Tdds is not possible if the drug dosage required for therapeutic value is more than 10mg/day

۞absorption variation at different sites of skin

۞skin metabolism

۞protein binding

۞high molecular size cannot be formulated(ideal 800-1000 daltons)

۞skin irritation

۞contact dermatitis
 The Structure of Human Skin
• Human skin
Epidermis is outer most layer of the skin and consists of several
layers like basal layer,prickle cell layer,granular layer and horny
layer or stratum corneum.
• Stratum corneum or horny layer
most important layer with respect to absorption
Rate-limiting barrier in the penetration process
•Dermis-rich in blood supply and is freely permeable to many solutes
• Transport mechanism
– Trans epidermal pathway across the horny layer (trans epithelial
absorption)
– Via the hair follicles and sweat glands (pilosebaceous absorption)
Trans epithelial absorption(99.5% of drug is absorbed)
absorption is enhanced by the following methods
1.innuction
2.iontophoresis
3.sonophoresis
4.magnetophoresis
5.penetration enhancers
Factors affecting epithelial absorption
1.thickness of horny layer
2.skin condition
3.hydration of the skin
4.skin temperature
5.chemical form of the drug and vehicle
Pilosebaceous absorption(0.5% of drug is absorbed)
Absorption through the hair follicles and sweat glands
 BASIC COMPONENTS OF TDDS
1.Polymer matrix
2.The drug
3.Permeation enhancers
4.Other excipients
1.Polymer matrix
Ideal polymer
٠MW,Tg,and chemical functionality of the polymer should not affect the
diffusivity of drug and its release
٠stable
٠non reactive
٠easily manufactured
٠easily fabricated into desired product
٠inexpensive
٠degaradation product must be non toxic or non antagonistic to the host
٠ 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
• Synthetic elastomers
--polybutadiene
--hydrin rubber
--polysiloxone
--silicone rubber
--nitrile
--acrylonitrile
--butyl rubber
--styrene butadiene rubber
--neoprine etc.
• Synthetic polymers
PVA,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(800-1000)
– Should have affinity for both lipophilic and hydrophilic phases
– Should have low melting pont
• Biological properties of drug
– Should be potent(less than 5mg)
– 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)
• Solvents
Increases penetration by swelling the polar pathway transport or fluidising lipids
Eg.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.
• Surfactants
Enhances the polar pathway transport of hydrophilic drugs
• Anionic surfactants
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 enhancers
Euclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein
 4.OTHER EXCIPIENTS
• Adhesives
Ideal 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
• Permeation of drug should not be affected
• Backing membrane
Ideal 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.
Process of transdermal permeation.
 Formulation of TDDS
1.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
 1.Membrane-moderated or permeation
controlledTDDS contd…
• Drug molecule are permitted to release through this rate controlling
membrane

• A thin layer of silicone or poly acrylate adhesive may be applied to the

external surface of the rate controlling membrane to achieve intimate contact
of the TDDS and the skin surface

• Release rate of this TDDS depends upon the polymer

composition,permeability co efficient and thickness of the rate cotrolling
membrane and adhesive

• The intrinsic rate of drug release from this TDDS is calculated by the
following formula.1
CR
dQ/dt= --------------------
1/Pm+1/Pa
• 1.Membrane-moderated or permeation controlledTDDS contd…

Where
CR-con.of drug in the reservoir compartment
Pm-permeability co efficient of rate controlling polymeric
membrane
Pa- permeability co efficient of adhesive
For microporous membrane
Km/r. Dm
Pm = --------------------
hm
 
 
Ka/m. Da
Pa = --------------------
ha
Substituting these values in formula.1, it becomes

Km/r .Ka/m .Dm.Da

 
dQ/dt= ---------------------------------------------C R
 
Km/r. Dm.ha + Ka/m. Da. hm
 1.Membrane-moderated or permeation controlledTDDS contd…

Where
• Km/r --partition co-efficient of drug between membrane and reservoir
• Ka/m --partition co-efficient of drug between adhesive and membrane
• Dm --diffusion co-efficient of drug in the membrane
• Da -- diffusion co-efficient of drug in the adhesive
Example of this system are
1.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 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

• The cross sectional view of this system is shown in the following Fig.2
 2.Adhesive diffusion/dispersion-controlled TDDS contd…

• The rate of drug release in this system is defined by

Ka/r.Da
dQ/dt= -----------------CR
ha  

Where
Ka/r-partition co-efficient of drug bw adhesive layer and reservoir layer
Da-diffusion co-efficient of drug in the adhesive layer
ha-thickness of adhesive layer

Examples for this system

1.Iso sorbide dinitrate-releasing 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

• 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
 3.Matrix diffusion-controlled TDDS contd…

• the rate of drug release from this sytem is defined as

A Cp Dp
Dq/dt = [ ---------------------] 1/2
2t
where
A initial drug loading dose
Cp and Dp are solubility and diffusivity of drug in poymer matrix

the rate of drug release from this system at steady state is defined as

Q/t1/2= [(2A-Cp) Cp Dp] 1/2

 3.Matrix diffusion-controlled TDDS contd…

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
 4.Micro reservoir type/micro sealed dissolution-
controlled TDDS
Combination of the reservoir and matrix diffusion
Drug 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 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
4.Micro reservoir type/micro sealed dissolution-
controlled TDDS contd…
5.Drug reservoir gradient-controlled
TDDS
 Table 1 Transdermal Controlled-
Release Products and Devices
Drug Trade Name Type of Indication
Devices
Scopolamine Transderm- Reservoir Motion
Scop sickness
Nitroglycerine Transderm- Reservoir Angina
Nitro
Nitro-Dur Monolithic

Nitrodisc Monolithic

Estradiol Estraderm Reservoir and Hormone

ethanol treatment
enhancer
 Table 2 Transdermal Products
under Development
Drug Trade name Producer-Marketer

Minocycline Sunstar American Cyanamide,

Takeda
Estradiol+Nor Estracombi Ciba-Geigy, Alza
ethisterone TIS
DHEA Pharmedic

Fentanyl

Triamcinolone Whitby Pharm.

acetonide
 IX. Recent Advances
• Rolf
– Amphoteric enhancers : SLS, lauryl amine oxide, Azone
decylmethylsulfoxide, lauryl ethoxylate, octanol
• PSA (pressure sensitive adhesives)
– Adhesive matrix, multilaminated PSA matrix
– Adverse interaction between the drug, exicipents,
cosolvents and permeation enhancers in reservoir and
matrix-type system
– Silicone PSA : tack, adhesion, cohesive strength
– Polydimethylsioxane PSA : biocompatibility and high
permeability
• Actiderm (Bristol Myers Squibb)
– Path with no drug as occlusive dressing
– Placed over topically applied corticosterids to enhance
efficacy by promoting hydration of the stratum corneum
• Laminated reservoir system by Hercon
– Steady-state blood levels for extended periods
– Two or four layers, including a backing membrane, the
drug reservoir, a rate-controlling membrane, and an
adhesive
• Ketobemidone and carbonate ester prodrug
– Prodrug with isopropyl myristate, ethanol and ethanol-
water readily penetrate the skin
– Enzymatic conversion, high solubility of prodrug in
polar and apolar solvents
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