TRANSDERMAL DRUG DELIVERY

Drug/Adhesive Mix Release

Liner

Backing

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 DeliveryAdvantages ۞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)

http://upload.wikimedia.org/wikipedia/commons/3/34/Skin.jpg

Trans epithelial absorption(99.5% of drug is absorbed)

absorption is enhanced by the following methods1.innuction2.iontophoresis3.sonophoresis4.magnetophoresis5.penetration enhancersFactors affecting epithelial absorption1.thickness of horny layer2.skin condition3.hydration of the skin4.skin temperature5.chemical form of the drug and vehiclePilosebaceous 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 excipients1.Polymer matrixIdeal 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• 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• 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.

Process of transdermal permeation.

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

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= ---------------------------------------------CR

  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  

WhereKa/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 system1.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 DpDq/dt = [ ---------------------] 1/2

2t where

A initial drug loading doseCp 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 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 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

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

2. Estradiol di acetate releasing TDDS

3. Verapamil releasing TDDS

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 Devices

Indication

Scopolamine Transderm-Scop

Reservoir Motion sickness

Nitroglycerine Transderm-Nitro

Reservoir Angina

Nitro-Dur Monolithic

Nitrodisc Monolithic

Estradiol Estraderm Reservoir and ethanol enhancer

Hormone treatment

Table 2 Transdermal Products under Development

Drug Trade name Producer-Marketer

Minocycline Sunstar American Cyanamide, Takeda

Estradiol+Norethisterone

Estracombi TIS

Ciba-Geigy, Alza

DHEA Pharmedic

Fentanyl

Triamcinolone acetonide

Whitby Pharm.

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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