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Transdermal Drug Delivery System- A Total View


About Authors:
Vinay Mishra, Shilpi Bhargava
Advance Institute of Biotech and Paramedical Sciences,
Kanpur

Introduction:
Delivering medicine to the general circulation through the skin is seen as a desirable alternative to taking it by mouth. Patientsoften forget to take their medicine, and even the most faithfullycompliant get tired of swallowing pills, especially if theymust take several each day. Additionally, bypassing the gastrointestinal(GI) tract would obviate the GI irritation that frequently occursand avoid partial first-pass inactivation by the liver. Further,steady absorption of drug over hours or days is usually preferableto the blood level spikes and troughs produced by oral dosageforms.1

From 1979, when the Food and Drug Administration approved the first transdermal drug delivery system (Transderm Scop® Patch), to the current transdermal delivery systems, there evolved a successful alternative to systemic drug delivery. Despite their relatively higher costs, transdermal delivery systems have proved advantageous for delivery of selected drugs, such as estrogens, testosterone, clonidine, nitroglycerin, scopolamine, fentanyl, and nicotine.
Transdermal therapeutic systems are defined as self contained, discrete dosages forms which when applied to the intact skin, deliver the drug, through the skin, at a controlled rate to the systemic circulation.Transdermal drug delivery systems, where applicable, offer several advantages over other conventional dosage forms.2

REFERENCE ID: PHARMATUTOR-ART-1183

Advantages:
Using TDDS, it is possible to achieve the following advantages:
1. Avoidance of the 'first pass effect'.
2. A stable and controlled blood level.
3. Comparable characteristics with intravenous infusion.
4. Termination of further administration, if necessary.
5. Long-term duration (ranging from a few hours to one week).
6. No interference with gastric and intestinal fluids.
7. Administration of drugs with:
          - A very short half-life
          - Narrow therapeutic window
          - Poor oral absorption
8. Improved patient compliance and reduced inter and intra-patient variability.
9. Self administration is possible.
10. Systems are non invasive.

Limitations:
Transdermal drug delivery systems have some limitations:
1. The drug must have some desirable physico-chemical properties for penetration through stratum corneum.
2. Skin irritation or contact dermatitis due to drug or exipients.
3. The barrier function of skin changes from one site to another on the same person, from person to person and with age. 6,8

Morphology Of skin:
Anatomically the skin has three major tissue layers- the epidermis, the dermis and the hypodermis.
The epidermis with its epithelium forms the surface layer of the body surface. It is a stratified squamous keratinized (horny) epithelium, and is in most areas of the body 0.1−0.2 mm thick. The cells divide constantly in the lowest cellular layers (collectively called germinative stratum, stratum germinale), the basal and prickle (or spinous) cell layers (stratum basale and stratum spinosum) (Fig.1a and 1b).

In this process, one daughter cell migrates to the surface, while the other divides again. As the cells migrate toward the surface to become cornified, they form granules (stratum granulosum).9

The major barrierwithin the skin is the stratum corneum, the top layer of theepidermis. The stratum corneum consists of keratinized, flattenedremnants of once actively dividing epidermal cells. Hygroscopic,but impermeable to water, it behaves as a tough, flexible membrane.The intercellular space is rich in lipids. The stratum corneumis about ten microns thick, but on the palms and soles it rangesup to 600 microns in thickness3.

Percutaneous absorption and kinetics of transdermal permeation:

Percutaneous absorption involves passive diffusion of substances through the skin. The mechanism of permeation can involve passage through the epidermis itself (transepidermal absorption) or diffusion through shunt particularly hair follicles and eccrine glands (transfollicular or shunt pathway absorption).

(A)Transepidermal absorption:
Transepidermal pathway is principally responsible for diffusion across skin. Permeation by the transepidermal route first involves partitioning into stratum corneum than diffusion takes place across this tissue. Most substances diffused across the stratum corneum via the intercellular lipoidal route.

(B)Transfollicular (shunt pathway) absorption: 
The skin’s appendages offer only secondary route for permeation.       Sebaceous and eccrine glands are the only appendages which are seriously considered as shunts bypassing the statum corneum.The follicular route remains an important route for percutaneous absorption since the  opening  of follicular pore, where the hair shaft exits the skin, is relatively large and sebum aids in diffusion of penetrants.

Transdermal permeation of a drug involves the following steps:
1. Sorption by stratum corneum
2. Penetration of drug through viable epidermis
3. Uptake of the drug by cappillary network in the dermal papillary layer

This permeation can be possible only if the drug possesses certain physicochemical properties.The rate of permeation across the skin (dQ/dt) is given by-

                                            dQ/dt=Ps(Cd-Cr)

where
Cd-the concentrations of skin penetrants in the donor   compartment(surface of stratum corneum)"
Cr - the concentrations of skin penetrants in receptor compartment (body)
Ps - overall permeability coefficient of the skin tissues to the penetrant.

                                           Ps=Ks.Dss / hs

where

Ks - partition coefficient

Dss - apparent diffusivity for steady state diffusion

hs - overall thickness of skin tissues.

A constant rate of drug permeation can be obtained only when Cd >> Cr i.e. the drug concentration at the surface of stratum corneum (Cd) is consistently and substantially greater than the drug concentration in the body-

                                           dQ/dt = Ps . Cd

When Cd >> Cs then maximum rate of skin permeation (dQ/dt)m

                                          (dQ/dt)m = Ps . Cs

The maximum rate of skin permeation depends on:

          -The skin permeability coefficient (Ps) and 

          -Equilibrium solubility in stratum corneum (Cs).

Thus skin permeation appears to be stratum corneum limited.6

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