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2. 2Contents1. Introduction2.Structure of skin3.Absorption mechanism4.History of patches5.Components of Transdermal Devices6.Types of Transdermal Patches7.Evaluation of TDDS8.Recent Advances9.Marketed preparations10.References

3. Transdermal Patch or Skin Patch is a medicatedadhesive patch that is placed on the skin to deliver atime released dose of medication through the skin andinto the bloodstream.The delivery rate is controlled by the skin or membranein the delivery system. 3

4. Advantages of TDDS1. Avoidance of presystemic metabolism.2. Reduced inter- & intra-patient variability.3. Maintained systemic drug level.4. Peak & Valley effect of oral or injectabletherapy is avoided.5. Extended duration of action.4

5. 6. Improved patient compliance.7. Drug input terminated by simple removal ofpatch.8. Reduced dosage related side-effects.5

6. Disadvantages of TDDSLimitations of TDDS are principally associatedwith the barrier function of skin.1. Method is limited only to potent drugmolecules.2. Physicochemical properties of drug shouldallow to be absorbed percutaneously.3. Molecular wt should be reasonable.6

7. 4. Solubility should be in both lipophilic andhydrophilic environments. Absence in eitherphase will preclude permeation.5. Drugs with short biological half-lives cannotbe delivered by TDDS.6. Drugs must not be locally irritating orsensitizing.7

8. The most extensive and readily accessible organ Covers a surface area of approximately 2 m2 Receives about one-third of the blood circulation.Composed of three tissue layers: Epidermis DermisSubcutaneous fat tissue or hypodermis.8

9. Fig: Structure of Skin9

10. Epidermis:Comprises of stratum corneum and stratum germinativum.Stratum corneum (10-15 m thick) is dry.Consists of blocks of cytoplasmic proteinmatrices(keratins) embedded in extracellular lipid.Corneocytes are arranged in an interlocking structure.Stratum corneum cells formed and continuouslyreplenished by slow upward migration of cells produced bybasal cell layers of Stratum germinativum.10

11. Stratum corneum lipids consists of ceramides and neutrallipids like free sterols , free fatty acids and triglycerides &phospholipids.Despite low phospholipid levels Stratum corneum lipidsform bilayers.All above points contribute to tightness and impermeabilitycharacteristics of intact skin.Molecules with molecular mass greater than 200-350 Da areinefficient to cross the intact skin.Removal of upper 3 epidermal layers results into water lossand an enhancement of the transdermal permeability.11

12. Dermis: Composes of network of collagen and elastic fibersembedded in mucopolysaccharide matrix.It provides physiological support for epidermis.Blood vessels approach the interface of 2 layers hence isnot considered significant barrier to inward drug permeationin vivo.Beneath the dermis fibrous tissue opens out and mergeswith the fat-containing subcutaneous tissue.12

13. Percuteneous Absorption & its MechanisticAspectsDesigning TDDS requires:1. Understanding permeation behavior of drug through skin.2. The flux through the skin into the systemic circulation.3. Mechanism of permeation.Route Relative surfacearea (%)Diffusionalpathlength ( m)Relative viscosityof ST (%)Transcellular 99.0 25 90-99Intercellular 0.7 350 1-10Transfollicular 0.1 200 0.113

14. 14Fig : Various routes of drug absorption

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16. 16 The stratum corneum limited skin permeation.For a systematically active drug to reach a target tissue remotefrom the site of drug administration on the skin surface, it mustposses physicochemical properties that facilitate the sorption ofdrug by the stratum corneum, the penetration of drug through theviable epidermis, and also the uptake of drug by microcirculation inthe dermal papillary layer.The rate of permeation dQ/dt across various layers of skin tissuecan be expressed mathematically asMechanism of Rate-Controlled Transdermal DrugDelivery

17. 17Where,Cd = conc. of drug in donor phase.Cr = conc. of drug in the receptor phase.Ps = the overall permeability coefficient of the skin tissues to the drug.Ks/d = the partition coefficient for the interfacial partitioning of the drugmolecule from a TDD system onto the stratum corneum .Dss = the apparent diffusivity for the steady-state diffusion of the drugthrough the skin tissues.hs = overall thickness of the skin tissues for penetration.To achieve a constant rate of drug permeation one needs to maintain acondition in which the drug concentration on the surface of stratum corneumCd is consistently and substantially greater the drug concentration in the bodyCr, i.e. Cd >> Cr.So, if the magnitude of Cd value remains fairly constant throughout the courseof skin permeation, the rate of skin permeation should be constant.

18. 18To maintain Cd at a constant value, it is necessary to deliver the drug at a rate Rdthat is either constant or always greater than Ra the rate of skin absorption, i.e.Rd >>Ra. By making Rd greater than Ra the drug concentration on the skin surfaceCd is maintained at a level equal to or greater than the equilibrium solubility ofthe drug in the stratum corneum Cse , i.e. Cd > Cse.A maximum rate of skin permeation (dQ/dt)m can be expressed asMembrane limited drug release.In such systems the drug delivery is controlled by the use of rate-limitingmembrane. The bioavailability of the drug does not depend only on this, but alsoon its absorption through the stratum corneum, and its subsequent uptake intothe systemic circulation.

19. 19Historically, the Chinese medicated plaster can beviewed as the first development of transdermal drugdelivery; it is designed to bring medication into closecontact with the skin, so drug can be deliveredtransdermally.Medicated plasters were also very common in Japan asOTC dosage forms called Cataplasms, Salonpas.In Western countries Allocks porous plasters ofEngland and the ABC plaster of Germany.In the US 3 medicated plasters have been listed inthe official compendia since 40 yrs ago Belladonnaplaster, Mustard plaster, and Salicylic acid plaster.History of patches

20. 20Components of transdermal devicesThere are 2 basic types of transdermal dosing systems1. Those that control rate of drug delivery to skin2. Those that allow the skin to control the rate of drug absorption.The basic components of transdermal devices include: Polymer matrix Drug Penetration Enhancers Other Excipients Adhesive/Packaging

21. 21Polymer matrixPolymers used in TDDS should fulfill:1. Mol wt, physical & chemical characteristics must allow diffusionof drug.2. Should be chemically non-reactive (inert drug carrier).3. Must not decompose on storage.4. Polymer & its decomposed product should be nontoxic.5. Polymer must be easy to manufacture and fabricate .6. Cost should not be excessively high.Polymers used in TDDS are Poly-propylene Poly vinyl carbonate Cellulose acetate nitrate Polyacrylonitrle Ethylene vinyl acetate copolymer Polyethylene terephthalate Hydroxypropyl cellulose polyestersEthylene vinylacetatecopolymer

22. 22DrugChoice of drug is critical in successful development oftransdermal product.Important properties of drug that affect its diffusion include1. Molecular weight2. Chemical functionality3. Partition coefficient4. Skin metabolismSkin irritation & clinical need should also be considered.The drug should be non-irritating and non-allergic to humanskin.

23. 23Penetration enhancersSkin permeation enhancers are considered as integral part ofmost TDDDS.Penetration enhancers are classified into mainly 3 categories:1. Lipophilic solventse.g. Dimethyl sulfoxide2. Surface-active agentse.g. Sodium lauryl sulfate (SLS)3. Two component systemse.g. oleic acid and propylene glycol

24. 24Other excipientsSolvents such as:Chloroform,Methanol,Acetone,Isopropanol andDichloromethane are used to prepare drug reservoir.Plasticizers such as:Dibutylpthalate,Triethylcitrate,Polyethylene glycol andPropylene glycol are added to provide plasticity to thetransdermal patch.

25. 25Adhesive and packaging:Adhesion of all transdermal devices to skin is an essentialrequirement.Pressure-sensitive polymeric adhesives are generally used.The adhesive system should posses following characteristics:1. Should not cause irritation, sensitization & imbalance to skin.2. Should adhere to skin strongly.3. Should resist to normal routine disturbances likebathing, abrasion and exercise.4. Should be easily removable.5. Should have intimate contact with the skin.

26. 26Pressure-sensitive adhesive:It is defined as a material that adheres to a substance when a lightpressure is applied and leaves no residue when removed.There are 3 different categories of adhesives:1. Butyl Rubberse.g. It is a copolymer of isobutylene & isoprene.2. Polyisobutylenesdiffer from butyl rubber in terminal unsaturation.used in polyolefin plaster surface.3. Butyl rubber and PolyisobutylenesCombination of above two.

27. 27Types of TransdermalPatchesPolymer Membrane Permeation ControlledTransdermal PatchPolymer Matrix Diffusion Controlled TransdermalPatchDrug Reservoir Gradient Controlled TransdermalPatchMicro reservoir Dissolution Controlled TransdermalPatch

28. 281. Polymer Membrane Permeation ControlledTransdermal PatchDrug reservoir - sandwiched between a drug impermeablebacking laminate and a rate-limiting polymeric membrane.The drug molecules are permitted to release only throughthe rate-controlling polymeric membrane.

29. 29 In the drug reservoir compartment the drug solids are :-dispersed homogeneously in a solid polymer matrix polyisobutylenesuspended in a unleachable, viscous liquid medium silicone fluiddissolved in a releasable solvent alkyl alcoholThe rate-controlling membrane can be either a microporous or anonporous membrane ethylene-vinyl acetate copolymer.On the external surface of the polymeric membrane a thin layer ofdrug-compatible, hypoallergenic pressure-sensitive adhesive polymermay be applied to provide intimate contact of the TDD system with theskin surface. These adhesives are usually based on silicones, acrylatesor polyisobutylene.Examples Scopolamine releasing TDD system Transderm-Scop system,Clonidine releasing TDD system Catapress-TSS system

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31. 312. Polymer Matrix Diffusion ControlledTransdermal Patch2 types of systems1. Drug-in-adhesive system2. Matrix-dispersion system1. Drug-in-adhesive system:Drug reservoir drug dispersed in hydrophilic or lipophilicpolymer matrixDrug reservoir is then mounted on a baseplate over which isthe drug-impermeable plastic backing with an absorbent pad.Adhesive rim surrounds the reservoir disc.

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33. 332. Matrix-dispersion systemDrug reservoir drug is directly dispersed in a pressure-sensitive adhesive polymer, e.g. polyacrylateThis is then coated onto a flat sheet of a drug-impermeablebacking laminate. Additionally Release liner is present.Examples Nitroglycerin releasing TDD system the Minitran systemIsosorbide dinitrate releasing TDD system Frandol tape.

34. 343. Drug Reservoir Gradient ControlledTransdermal PatchZero order releaseDrug reservoir drug loading level is varied in an incrementalmanner, forming a gradient of drug reservoir along theDiffusional path across the multilaminate adhesive layers.Example Nitroglycerinreleasing TDD systemthe Deposit system

35. 354. Micro reservoir Dissolution ControlledTransdermal PatchIt is a hybrid of the reservoir and matrix dispersion- typedrug delivery systems.Drug reservoir - formed by first suspending the drugsolids in an aq. solution of drug solubilizer, e.g.polyethylene glycol, and then homogeneously dispersingthe drug suspension, in a lipophilic polymer to formthousands of unleachable microscopic drug reservoirs.This thermodynamically unstable dispersion is quicklystabilized by immediately cross-linking the polymer chainsin situ. A TDD system is then produced by mounting themedicated disc at the centre of adhesive pad.

36. 36Example Nitroglycerin releasing TDD system Nitrodisc systemProgestin-estrogen releasing TDD system Transdermal contraceptive system

37. 37Evaluation of Transdermal Drug DeliverySystemsEvaluation of Adhesives1. Peel adhesion properties : Tested by measuring theforce required to pull single coated tape.2. Tack propertiesa) Thumb tack testb) Rolling ball tack testc) Quick-stick (or peel-tack) testd) Probe tack test3. Shear Strength Properties: Measurement of cohesivestrength of adhesive polymer.

38. 38Evaluation of Patches1. Interaction study2. Thickness of patch3. Weight uniformity4. Folding Endurance of patch5. % Moisture content6. % Moisture uptake7. Drug content8. Uniformity of unit dosage form test9. Skin irritation studies10. Stability studies

39. 39In-vitro drug release studies:Paddle over disc method is used.(USP apparatus V)In-vitro skin permeation studies:1. Keshery-Chien Diffusion Cell

40. 402. Franz diffusion cell

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42. 423. Valia Chien Diffusion Cell

43. 43Recent Advancements in TDD SystemsIontophoresis :- It can be defined as the facilitation of ionizable drugpermeation across the skin by an applied electrical potential, thedriving force of which may be simply visualized as electrostaticrepulsion. Technique involves application of small electric current(0.5mA/cm2)Example :- Piroxicam

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45. 45Sonophoresis :- It is the enhancement of migration of drug molecules through the skin byultrasonic energy. Mechanism of drug permeation involves disruption of stratum corneumlipids. The acoustic waves that reduce the resistance offered by stratumcorneum lie in the frequency range of 20 KHz to 20 MHz.Example :- Salicylic acid

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47. 47ElectroporationIt involves application of high voltage pulses to the skin whichinduces formation of transparent pores.High voltages of Direct Current 100 volts for few milliseconds areemployed.The technology has been successfully used to enhance skinpermeation of molecules differing in lipophilicity & size.Example :- metoprolol, lidocaine, tetracaine, etc

48. 48Marketed Preparations :- Scopolamine-releasing TDD system for 72 hrs prophylaxis ortreatment of motion-induced nausea (Transderm-Scop) Nitroglycerine-releasing TDD system (Deponit, Nitrodisc,Transderm-Nitro) and other isosorbide dinitrate-releasingTDD system for once-a-day medication of angina pectoris Clonidine-releasing TDD system for the weekly therapy ofhypertension (Catapres-TTS) Estradiol-releasing TDD system for the twice-a-weektreatment of postmenopausal syndromes (Estraderm) Fentanyl-releasing TDD system for the twice-a-weekanalgesic in cancer patients (Duragesic).

49. 491. Chien Y.W; Novel Drug Delivery System ; 2nd edition;volume 50; Informa healthcare; pg no 301-380.2. Jain N.K; Controlled and Novel Drug Delivery ; 1st edition;CBS Publishers; pg no 100-129.3. Wokovich Anna M. Transdermal drug delivery system(TDDS) adhesion as a critical safety, efficacy and qualityattribute European Journal of Pharmaceutics andBiopharmaceutics 64 (2006) 1-84. Mark Gibson; PHARMACEUTICAL PREFORMULATION ANDFORMULATION- A practical guide for candidate drugselection to commercial dosage form CRC press LLC 331-353.

50. 505. Keleb E, et al; Transdermal Drug Delivery System-Design and Evaluation; International Journal of Advancesin Pharmaceutical Sciences1 (2010) 201-211.6. Prabhakar V et al; Transdermal drug delivery system:Review; International Resarch Journal of Pharmacy 2012 3(5).7. Arunachalam. A. et al; Transdermal Drug DeliverySystem: A Review; Current Pharma Research vol 1, issue 1,Oct-Dec 2010.8. J. Ashok Kumar et al; Transdermal Drug DeliverySystem: A Overview; International Journal ofPharmaceutical Sciences Review and Research; Volume 3,Issue 2, July August 2010; Article 009

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