In skin, drug permeation takes place by diffusion
through different layers of skin as well as through hair follicles and sweat
glands and the intrinsic
physicochemical properties
of the drugs governs the flux of the molecules through these routes.  As discussed in previous section usually acts
as a barrier for effective drug delivery
but other routes of systemic absorption are
also present. Different
permeation routes are recognized in TDDS (Fig.): a) Intercellular; b)
intra/transcellular; c) transappendegeal route.a)
In paracellular/intercellular route mainly uncharged lipophilic drugs diffuse
through the lipid matrix present between cells of stratum corneum (SC).  Stratum corneum is very thin, least
permeable layer containing laminated compacted keratin filled corneocytes which
are formed by epidermal differentiation process and embedded in lipophilic
matrix. The lipids of SC are quite unique as they are deficient in phospholipids,
composed of ceramide cholesterol and free fatty acids. They form continuous phase
from skin surface to the base of SC. Despite bipolar phospholipids deficit SC
lipids are present as multi-laminellar sheets in skin and fatty acids have 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 zigzag
corneocytes arrangement which is 1000 times less permeable as compared to other
biological membranes. In stratum
corneum, drug molecules partitioned itself into
lipid bilayer followed by their diffusion to the inner side and in doing so
they travel through alternating lipid domains and aqueous layer.


In intra/transcellular route drug passes all the way through the highly
hydrated keratinized corneocytes creating hydrophilic pathway and it is
preferred route for hydrophilic drugs. Herein, drugs partitioned into and diffuse
all the way through keratinized corneocytes, intercellular lipid matrices and
the cytoplasm of the cells.


Transappendegeal/shunt route comprises
of 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 still
it is the straight route for any drug to reach systemic circulation.  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 have 13.7 mm2/cm2
(i.e. 13.7% of the forehead surface area) surface area as the follicular
infundibula. The 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