a) forehead surface area) surface area as

In paracellular/intercellular route mainly uncharged lipophilic drugs diffuse
through the lipid matrix present between cells of stratum corneum.  The stratum corneum is extremely thin least
permeable layer of the skin containing laminated compressed keratin filled
corneocytes which are formed by epidermal differentiation process and embedded
in lipophilic matrix. The lipids of SC are quite distinct as they lack
phospholipids, composed of ceramide cholesterol and free fatty acids and are
present as continuous phase from skin surface to the base of SC. Despite
bipolar phospholipids deficit SC lipids exist as multi-laminellar sheets and
fatty acids are made up of long chain saturated hydrocarbon hence forming gel
phase membranes.  Other than unusual
lipid composition, SC architecture also play pivotal role in its protective
nature. Stratum corneum
acts as a barrier due to complex tortuous structure created by staggered
corneocytes arrangement which make them 1000 times less permeable as compared
to other biological membranes. In stratum
drug molecules partitioned itself into lipid bilayer followed by their
diffusion to the inner side and in doing so they travel through alternating
domains of lipid and aqueous layer.


In intra/transcellular route drug passes through the highly hydrated
keratinized corneocytes creating hydrophilic pathway and it is suitable for
hydrophilic drugs. In this route drug partitioned into and diffuse not only
through keratinized corneocytes and intercellular lipid matrices but also
through the cytoplasm of the cells.

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Transappendegeal route comprises of delivery of drug
through hair follicles, sebaceous glands and sweat glands and also known as
shunt route. It is the shortest route for any drug to reach systemic
circulation, however these route occupies only 0.1% of total skin surface area
in general. The surface area provided by hair follicles varies from one
site to another in the same person. 
Otberg et al have reported the drug delivery through this route depends
on follicular number, diameter of the opening and follicular volume. They also
calculated 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 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 route like content and
quantity 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 are
discussed in the following section


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