TRANSDERMAL DRUG DELIVERYSYSTEM PRESENTED BY gandhi sonam m.
TRANSDERMAL DRUG DELIVERYSYSTEMDEFINITION: Transdermal therapeutic system are defined as self-contained discrete dosage form which when applied to the intactskin deliver the drugs, through the skin, at a controlled rate to thesystemic circulation. ORTransdermal drug delivery systems (TDDS) are systems thatutilize skin as a site for continuous drug administration into thesystemic circulation
ADVANTAGESTransdermal delivery can increase the therapeutic value of manydrugs by avoiding specification due to hepatic “First pass” effect,formation of metabolites that causes side effects, short half lifenecessitating frequent dosing etc.Self administration is possible with these system.The drug input can be terminated at any point of time by removingtransdermal patch.Allows effective use of drugs with short biological half-lifeAllow administration of drugs with narrow therapeutic windowProvides controlled plasma level of very potent drugsDrug input can be promptly interrupted when toxicity occurs
DISADVANTAGES:The barrier function of the skin changes from one site to another on thesame person or person to person and with age.Drug that require high blood levels cannot be administeredAdhesive may not adhere well to all types of skinDrug or drug formulation may cause skin irritation or sensitizationUncomfortable to wearMay not be economical.
Skin as site for drug administration epidermis- Dermis Hypodermis
PERMEATION THROUGH SKIN. mechanism of permeation can involve passage through the epidermisTheitself (transepidermal absorption) or diffusion shunts.TRANSEPIDRERMAL ABSORPTION It is now believe that the transdermal pathway is principallyresponsible for diffusion across the skin. The main resistance encounteredalong this pathway arises in the stratum corneum. Permeation by thetransepidermal route first involves partitioning into the stratumcorneum. Diffusion then takes place across this tissue.
Transdermal permeation (percutaneous absorption):• The passage of substance from the outside of the skin through its various layers into the bloodstream.• Transdermal permeation Drug Particles
Kinetics of transdermal permeation Knowledge of skin permeation kinetics is vital to the successfuldevelopment of transdermal therapeutic systems. Transdermalpermeation of a drug involves the following steps.Sorption by stratum corneum,Penetration of drug through viable epidermis,Uptake of the drug by capillary network in the dermal papillary layer.
Fundamentals of skin permeation Rate of permeation, dQ/dt, across a skin can be expressed as: dQ / dt = Ps (Cd - Cr) where dQ/dt – Rate of permeation Ps – Permeability coefficient Cd – Concentration in donor compartment Cr – Concentration in receptor compartment
.FACTORS AFFECTING TRANSDERMALPERMEABILITY The principle transport mechanism across mammalian skin is bypassive diffusion. The factors influencing and having differences intransdermal permeability of the stratum corneum can be classified into 3major category.1.Physico-chemical properties of penetrants (drug)2.Physico-chemical properties of drug delivery system.1.Physiological and pathological condition of skin.
Physico-chemical properties of penetrant molecule (drug) :Partition coefficient: Drugs possessing both water and lipid solubilityare favouraly absorbed through skin. Transdermal permeabilitycoefficient shows a linear dependency on partition coefficient. A liped /water partition of 1 or greater is generally required for optimaltransdermal permeability.pH condition: The extent of dissociation in case of ionic drugs andtheir transdermal permeability depends on the pH condition of skinsurface as well as of the drug delivery system. In case of ephedrine andscopolamine, the transdermal flux of the drug increases withincreasing pH up to approximately 1.2 higher than their respectivepKa values.
Physico-chemical properties of Drug Delivery System:Release Characteristics:The release characteristics of drug from delivery system can largelyaffect the transdermal permeation of drug molecules. The release of drug from the delivery vehicle depends on itsaffinity to the vehicle. The transdermal permeation rate increase as thedrug releases rate from the drug delivery system increases.
Composition of drug delivery system: (vehicle)Composition may not affect the rate of drug release, but affect thepermeability of the stratum corneum by means of hydration, mixingwith skin lipids.Eg: Salicylic acid and its methyesters, methyl salicylate is more lipophilicthen its parent acid and when applied to skin from fatty vehicle, theymethyl salicylate yielded a higher percutaneous absorption then salicylicacid.Incorporation of transdermal permeation:Like dymethyl sulphoxide, acetone, propylene glycol,tetradihydrofurfuryl alcohol, dimethyl sulphoxide etc in typicalformulation increases drug permeation.
Physiological & pathological condition of skin:Presence of hair follicle: Absorption is rapid where more hair folliclespresent eg: scalp.Thickness of stratum corneum: Absorption is low from region as foot andpalm.Trauma: cut inflammation, rashes, mild burn where stratum corneum isdestroyed, promote drug absorption.Hydration of skin: Soaking skin in H2O, plastic film, dressing promotehydration of skin and drug absorption increase.Age: Aged skin more prone to allergy and irritant effect, of topicallycontacted drug infant particularly concerned.
Grooming: the frequency and vigor with which one bathes andtype of soap that is used also contributes variability in drugabsorption.Chronic use of certain drug: long term use of keratolytics likesalicylic acid results in increased drug penetration.Skin temperature: increase temperature increase absorptionbecause of increase vasodilatation of skin vessels eg: 10 foldincrease skin permeation of aspirin and glucostroids was noticedwhen the environmental temperature increase from 10-51 C.
BASIC COMPONENTS OF TRANSDERMAL DRUGDELIVERY SYSTEMS:The components of transdermal devices include:Polymer matrix or matricesThe drugPermeation enhancersOther excipients
Polymer matrix or matricesThe polymer controls the release of the drug from the device.Ideal properties of polymers for transdermal drug deliverysystem.The polymer should be stable, non-reactive with the drug,easily manufactured and fabricated into the desired product;and inexpensive.The polymer and its degradation products must be non-toxicor non-antagonistic to the host.The mechanical properties of the polymer should notdeteriorate excessively when large amounts of active agentare incorporated into it.
Possible useful polymers for transdermal devices are:Natural polymers:Synthetic Elastomers:Synthetic Polymers:
DrugDesired properties of drug for transdermal drug delivery systems arePhysicochemical properties,biological properitiespenetration enhancer are:The material should be pharmacologically inert.It should be non-toxic, non-irritating and non-allergenic.The action should be immediate and the effect shouldbe suitable and predictable.
Upon removal of the material, the skin should immediately andfully recover its normal barrier property.The enhancer should not cause loss of body fluids, electrolytes orother endogenous materials.It should be compatible with all drugs and excipients.The substance should be a good solvent for drugs.The material should be cosmetically acceptable (good spread abilityand skin ‘feel’).The chemical should formulate into all the variety of preparationsused topically.It should be odourless, tasteless, colourless and inexpensive
Solvents: Water is well-recognized in the dermatological field thatpromotes the topical pharmacological effect of a number drugs (e.g.,steroids). The mechanism of action is suggested to involve hydration ofkeratin and intracellular lipids however, recent infrared and x-rayexperiments show that increasing the hydration of stratum corneumdoes not increase lipid chain disorder or the interlamellar spacing.Alcohol and ethanol, in particular, have been proposed as effectivepermeation enhancers.Examples:Acetamide and derivatives, acetone, dimethyl acetamide, dimethylformamide, ethanol, ethanol / glycerol, polyethylene glycon, span-20,tween-80, etc.
electrodePassigcurrent patch Formationof microchanne l Release of drug
Evaluation of adhesive:Pressure sensitive adhesives are evaluated for followingproperties.Peel adhesion properties:- Peel adhesion is the force required to remove an adhesive coatingfrom a test substrate. It is important in transdermal device because theadhesive should not damage the skin on removal. peel adhesionproperties are affected by the molecules weight of the adhesive polymer,the type and amount of additives, and polymer composition.
• It is tested by measuring the force required to pull a single coated tape, applied to a substrate at a 1800C angle.• No residue on the substrate indicates adhesive failure which is desirable for transdermal devices.• Remnants on all substrate indicates ‘cohesive failure’ signifying a deficit of cohesive strength in the coating.
Shear Strength properties:• Shear strength is the measurement of cohesive strength of an adhesive polymer. Adequate strength means device will not slip on application and will not leave any residue on removal. It is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate, when a specified wt is hung from the tape which pulls the tape in a direction parallel to the plate.
In vitro drug release evaluation:1.In vitro permeation kinetics studies can be performed on hairlessmouse skin or human cadaver skin by using franz diffusion cell or tworeservoir diffusion cell.2.In two reservoir diffusion cells, sink conditions can be maintained.3.The permeation of nitroglycerins across human cadaver and hairlessmouse skin from different Transdermal Drug Delivery therapeuticsystem was compared for their kinetics.4.It was noted that the rates of skin permeation generated from theexcised skins of hairless mouse agree fairly with the date obtained fromhuman cadaver skin, suggesting that hairless mouse skin could be anacceptable animal modes for human skin permeation kinetics studies.
Franz diffusion cell• Franz diffusion cell and the keshary-chien (K-C) cell . the most widely used of these are the franz diffusion cell and the k-c cell . The K-C Diffusion has an effective receptor volume of 12ml and skin surface area 3.14cm2 .The receptor solution is stirred by a star-head magnate rotating at a constant speed of 600 rpm .
In-vivo evaluation:AnimAl model:In vivo animal models are preferred because considerable time andresource are required to carry out studies in human. Some of the animalare used to in vivo studies are mouse, rat, guinea pig, rabbit, hairlessmouse, hairless rat, hairless dog, cat, dog, miniature pig, pig, horse, goat,squirrel, monkey. Etc.
Human model:The final stage in the development of transdermal device involves thecollection of pharmacokinetic and pharmacodynamic data followingapplication of the device to human volunteers.Determination of absorption following topical administration requiresthe investigator to know the amount of radioactivity retained in thebody, or excreted by routs not monitored (assayed).This necessitates measurement of elimination following parenteral(ideally i.v.) administration of the compoundThe percentage of dose absorbed transdermally is then calculated as% dose absorbed =Total radioactivity excreted after topical administration Total radioactivity excreted after I.v administration .100
ConClusionTDDS offers number of advantages to patientTDDS offers scope for companies in terms of revenueImportantly, newer advances in transdermal technologyincluding microporation provides a means for deliveringproteins and peptides
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