In skin, drug permeation takes place by diffusionthrough different layers of skin as well as through hair follicles and sweatglands and the intrinsicphysicochemical propertiesof the drugs governs the flux of the molecules through these routes.  As discussed in previous section usually actsas a barrier for effective drug deliverybut other routes of systemic absorption arealso present. Differentpermeation routes are recognized in TDDS (Fig.): a) Intercellular; b)intra/transcellular; c) transappendegeal route.a)In paracellular/intercellular route mainly uncharged lipophilic drugs diffusethrough the lipid matrix present between cells of stratum corneum (SC).

  Stratum corneum is very thin, leastpermeable layer containing laminated compacted keratin filled corneocytes whichare formed by epidermal differentiation process and embedded in lipophilicmatrix. The lipids of SC are quite unique as they are deficient in phospholipids,composed of ceramide cholesterol and free fatty acids. They form continuous phasefrom skin surface to the base of SC. Despite bipolar phospholipids deficit SClipids are present as multi-laminellar sheets in skin and fatty acids have longchain saturated hydrocarbon hence forming gel phase membranes.  Other than unusual lipid composition, SCarchitecture also play pivotal role in its protective nature. Stratum corneumacts as a barrier due to complex tortuous structure created by zigzagcorneocytes arrangement which is 1000 times less permeable as compared to otherbiological membranes. In stratumcorneum, drug molecules partitioned itself intolipid bilayer followed by their diffusion to the inner side and in doing sothey travel through alternating lipid domains and aqueous layer.

 b)In intra/transcellular route drug passes all the way through the highlyhydrated keratinized corneocytes creating hydrophilic pathway and it ispreferred route for hydrophilic drugs. Herein, drugs partitioned into and diffuseall the way through keratinized corneocytes, intercellular lipid matrices andthe cytoplasm of the cells.  c)Transappendegeal/shunt route comprisesof delivery of drug through hair follicles, sebaceous glands and sweat glands.However, only 0.1% of the skin surface is covered by these appendages but stillit is the straight route for any drug to reach systemic circulation.  Otberg et al have reported the drug deliverythrough this route depends on follicular number, diameter of the opening andfollicular volume. They also calculated that forehead have 13.

7 mm2/cm2(i.e. 13.7% of the forehead surface area) surface area as the follicularinfundibula. The appendagesare continuous channels present across the SC either as pores or ducts e.g.sweat glands, oil glands, hair follicles.

 There are many factors that affect the drug transport through this routelike content and quantity of secretion hence it contributes very little inTDDS.