a) forehead surface area) surface area as

a)In paracellular/intercellular route mainly uncharged lipophilic drugs diffusethrough the lipid matrix present between cells of stratum corneum.  The stratum corneum is extremely thin leastpermeable layer of the skin containing laminated compressed keratin filledcorneocytes which are formed by epidermal differentiation process and embeddedin lipophilic matrix.

The lipids of SC are quite distinct as they lackphospholipids, composed of ceramide cholesterol and free fatty acids and arepresent as continuous phase from skin surface to the base of SC. Despitebipolar phospholipids deficit SC lipids exist as multi-laminellar sheets andfatty acids are made up of long chain saturated hydrocarbon hence forming gelphase membranes.  Other than unusuallipid composition, SC architecture also play pivotal role in its protectivenature. Stratum corneumacts as a barrier due to complex tortuous structure created by staggeredcorneocytes arrangement which make them 1000 times less permeable as comparedto other biological membranes. In stratumcorneum,drug molecules partitioned itself into lipid bilayer followed by theirdiffusion to the inner side and in doing so they travel through alternatingdomains of lipid and aqueous layer.  b)In intra/transcellular route drug passes through the highly hydratedkeratinized corneocytes creating hydrophilic pathway and it is suitable forhydrophilic drugs. In this route drug partitioned into and diffuse not onlythrough keratinized corneocytes and intercellular lipid matrices but alsothrough the cytoplasm of the cells.

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 c)Transappendegeal route comprises of delivery of drugthrough hair follicles, sebaceous glands and sweat glands and also known asshunt route. It is the shortest route for any drug to reach systemiccirculation, however these route occupies only 0.1% of total skin surface areain general. The surface area provided by hair follicles varies from onesite to another in the same person.

 Otberg et al have reported the drug delivery through this route dependson follicular number, diameter of the opening and follicular volume. They alsocalculated that forehead provide 13.7 mm2/cm2 (i.e. 13.

7%of the forehead surface area) surface area as the follicular infundibula. The skin appendages are continuous channels presentacross the SC either as pores or ducts e.g. sweat glands, oilglands, hair follicles.  There are manyfactors that affect the drug transport through this route like content andquantity of secretion hence it contributes very little in TDDS.

 Other than barrier like property of skin exterior,there are many factors which affect the delivery of the drug and they arediscussed in the following section

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