Factors Affecting Transdermal Drug Delivery System

1. pH
The pH of skin is normally acidic, ranging from pH 4 to pH 6 whereas the internal
environment has a near neutral pH which ranges from 7-9. Historically, it was thought that
acidic pH provides defensive mechanism against microbes. Recently it has been
demonstrated that it also helps in the effective functioning of the enzymes involved in
synthesis and maintenance of skin. The skin’s pH value is a product of water soluble
contents in the stratum corneum, secreted sweat and sebum and of eliminated
carbondioxide. The pH of skin is responsible for regulating permeability barrier and
ensures integrity and cohesion of stratum corneum. The pH of the skin can affect the
percutaneous penetration of the amount of unionized drug available for absorption.
According to the pH-partition hypothesis, only the unionized form of the drug can
permeate through the lipid barrier in significant. Factors affecting drug permeation
through the skin pH. The pH of skin is normally acidic, ranging from pH 4 to pH 6 whereas
the internal environment has a near neutral pH which ranges from 7-9. Historically, it was
thought that acidic pH provides defensive mechanism against microbes. Recently it has
been demonstrated that it also helps in the effective functioning of the enzymes involved in
synthesis and maintenance of skin. The skin’s pH value is a product of water soluble
contents in the stratum corneum, secreted sweat and sebum and of eliminated
carbondioxide. The pH of skin is responsible for regulating permeability barrier and
ensures integrity and cohesion of stratum corneum. The pH of the skin can affect the
percutaneous penetration of the amount of unionized drug available for absorption.
According to the pH-partition hypothesis, only the unionized form of the drug can
permeate through the lipid barrier in significant amount. If the formulation has very low or
a very high pH value then it may cause destruction of the skin.

2. Temperature
In theory a positive relation is anticipated between skin’s temperature and the percutaneous
penetration of the drug. The skin is more permeable when it is warmer. Heat is
identified to increase the kinetic energy of the proteins, lipids, and carbohydrate in the cell
membrane and of the drug molecule. This will increase the movement of drug to the
dermis but decrease the local delivery of drug. The studies have shown that the
temperature change of approximately 5°C is necessary to cause changes in the permeability
of the cell membrane

3. Molecular weight
The percutaneous absorption is inversely proportional to the molecular weight of the drug.
It may affect the diffusion coefficient of the respective drug. The preferred molecular
weight for transdermal drug delivery system of drug by passive diffusion is less than 500
Dalton however the rate of permeation may be increased by use of various penetration
enhancers

4. Partition coefficient
Log P or partition coefficient is essential to determine the distribution of drug within an
organism to exert its biological activity. Hydrophilic drugs are poorly absorbed when
applied topically, due to low partitioning through the lipid matrix of the stratum corneum.
Cutaneous blood flow rapidly clears the absorbed drug, which may result in low tissue
levels
5. Biotransformation of drug in skin
Abundant evidence has been provided for the presence of enzymes in the skin, including
the enzymes of the CYP family, which may cause biotransformation of drug entering the
cutaneous environment. This biotransformation may be synergistic, converting a prodrug
to an active metabolite, or it may decrease the bioavailability of the drug. Howerver it
must be noted that this biotransformation or cutaneous first-pass is less than that
observed in the liver.

6. Cutaneous microcirculation
Enhanced drug absorption, through increased tissue perfusion, depends on several factors
for instance the anatomy of the vessel plexuses in the skin. The organization of cutaneous
microcirculation has been described in two plexus of arterioles: an upper horizonatal
plexus located in the papillary dermis just below the epidermis, and a lower horizontal
plexus located in the deep dermis at the border of the underlying subcutaneous tissue.
Each plexus of arterioles gives rise to various networks of capillaries.

7. Hydration
The penetration rate of most of the drugs is increased by hydration of the stratum
corneum. It does so by opening up the compacted structure of horny layer of stratum
corneum thus enhancing the bioavailabilityof the drug. Impermeable films prevent surface
loss of water from the skin which increases the hydration of stratum corneum thereby
decreasing the diffusional path length. The flux across the skin is dependent on the
hydration of the skin, partitioning and transport across the stratum corneum and the
concentration gradient across the skin.

8. Age
According to the studies statistically there is only a slight increase in the number of cell
layers of the stratum corneum, mainly in males whereas there was a decrease in
cellular epidermis both in terms of thickness and number of cells. Skin surface pH
changes with age. Unbound water molecules, not bound to the proteins, found in the skin
increases with age which may delay the percutaneous penetration, especially of the
hydrophilic drug. The level of major lipids, especially ceramides, also decreases with age.

9. Gender
According to the studies statistically no difference has been observed in thickness or
number of cell layers of the stratum corneum. Although it was found that males have
thicker cellular epidermis as compared to women

10. Body site

According to the studies conducted the smallest number of cells in the stratum
corneum was found to be in genital areas and the largest number of cells was in the heels.
Sun exposure. The stratum corneum is thicker on the sun- exposed area as compared to
thinner stratum corneum on the sun-protected area.

11. Blood flow

The absorption of drug may be limited by the blood flow through the dermis. For
example, if a drug having vasoconstriction activity is given through any other route, it will
 significantly affect the blood flow through the skin and hence the drug clearance for
transdermal drug delivery system.

12. Skin condition

In atopic dermatitis the stratum corneum is less able to bind water, so the skin of AD patients
is dry, inelastic. Changed composition of intercellular lipids with increased cholesterol
levels and reduced level of ceramides significantly contribute to the reduction of barrier
function. The pH of the skin is also increased as compared to the healthy skin.

Shabbir et. Al., (2010). Formulation Considerations And Factors Affecting Transdermal
Drug Delivery System- A Review. Faculty of Pharmacy, The University of Lahore,
Lahore, Pakistan V2-(I9) PG(20-35)