1. Transdermal Drug Delivery Systems
Transdermal drug delivery system are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate.

2. Advantages of TTS
Avoid first-pass effect in intestine and the acidic environment of stomach
Transdermal systems are non-invasive and can be self-administered.
They can provide release of drug for long periods of time (up to one week) without dose dumping.
They can improve patient compliance since single application is administered for several days
Easy removal or termination of the device if needed
Avoid risks and inconvenience of IV therapy

3. Limitation of TTS
Drug may be metabolized by bacteria on skin surface since the hydration of skin can encourage bacterial growth
Enzymatic activity to certain drug by skin enzymes.
Molecular size is critical (max size is 400D).
The slow transport of drug across skin limit this approach for potent drugs (max conc. 20mg/day)
Skin pores may be blocked and cause problems because of long term appliaction

4. The skin site for transdermal drug administration
Skin is one of the most accessible organs of human body
It has an average surface area of 2 m2 and few millimeters in thickness
It also receives one third of circulating blood
Physiologically it serves as a barrier against physical and chemical attacks and protects the vital organs from microbial invasions
It is function as first line of defense of human body

5. Anatomy of human skin
Skin is a multilayered organ composed of three layers: epidermis, dermis and subcutaneous fat
Epidermis:
- The outerlayer of the skin, composed of multilayered stratified squamous epithelial cells.
- It is non vascular but contain amino acids.
- Epidermis has varying thickness ranging from very thin covering the eyelids to thickest on the palms and soles
- Normal epidermis is renewed as it is worn off
Epidermis composed of two main parts:
1 - Stratum corneum ( Horny layer)
2 - The viable epidermis (stratum germinativum)

7. 1. (Stratum corneum): The outermost layer of the epidermis
Composed of many layers of compact flattened dehydrated, keratinized cells in stratified layers
Cells have lost their nuclei and are inactive
Thickness is variable, dependent on abrasion and pressure, swells several folds in water
Cells are formed and replaced by migrating cells from stratum germinativum about every 2 weeks in adults
Composition: only 20% water, keratin, lipids
Stratum corneum requires min. of 10% moisture content to maintain softness and flexibility
Considered as the main barrier for percutaneous absorption

8. 2. (Startum germinativum):
Cells of the deepest layer of the epidermis that divide and migrate upwards, as these migrate, the cells loose their nucleus and give rise to the dead keratinized outmost layer of the skin ( Stratum corneum)
It is known as regenerative layer of the epidermis
Contains 70% water content
The germinativum zone to horny layer is made of three layers:
1. Stratum spinosum (pricky layer),
2. Stratum granulosum (granular layer) and
3. Stratum lucidum (clear layer)

9. 2. Dermis layer
Just below the epidermis
Composition: it is made of network of collagen fibers of uniform thickness
It gives the skin its elasticity
It is the vascular part of the skin, where it contains blood vessels, lymphatics and nerve endings
It is considered as the sink of the skin
It also contains skin appendages (sweat glands, sebaceuos glands and hair follicles)
3. Subcutaneous fat
Sheet of fat tissue attaching the dermis to underlying structures,
It provide mechanical cushion and thermal insulator

10. The skin appendages
Sweat glands: they aid in heat control and secrete sweat
Hair follicles: develop all over the skin except the red part of the lips, the palms and soles. One or more sebaceous glands, and some times sweat glands open into the follicle.
Sebaceous glands: most numerous on the face, forehead, in the ear. These produce sebum (principle components are glycerides, free fatty acids, cholesterol, cholesterol esters, wax esters and squalene).

11. Approaches to topical formulation
Surface treatment
Stratum corneum treatment
Skin appendages treatment: hyperhydrosis, Acne, Depilatories
Viable epidermis and dermis: psoriasis, anaesthetics, anti pruritics, Premalignant and malignant tumours
Systemic treatment

12. Fundamentals of skin penetration
Stratum corneum as skin permeation barrier
- The barrier can be viewed as three layers: stratum corneum (15 µm thick), viable epidermis (150 µm thick), the papillary layer of the dermis ( µm thick)
- The above structure is pierced in various places by two types of shunts: sweat glands and hair follicles

13. Routes for skin penetration
There are 3 potential entry routes of drug to the viable tissue (dermis):
1. Hair follicles and their associated sebaceous glands,
2. Via the sweat ducts, or
3. Across the continuous stratum corneum

14. Routes of Skin Penetration

15. Skin appendages
The average human skin contains hair follicles and sweat ducts per square centimeter
These only occupy 1% of the total cross sectional area of the skin.
Water soluble and large molecules can penetrate into the skin via these appendages at a faster rate than through the intact area of the stratum corneum
Skin appendages may act as shunts at short time period prior to steady state diffusion, nevertheless, very limited contribution in the overall profile of skin permeation

16. Epidermal route The main barrier is the stratum corneum
Molecules may penetrate either intercellularly or transcellularly.
Molecules partition into and diffuse through the network according to their polarity.
The intercellular route is rich in neutral lipids

18. The percutaneous absorption of drugs can be considered as a series of three steps:
Sorption of penetrant molecule onto the surface layers of stratum corneum
Diffusion through stratum corneum and the viable epidermis
At the papillary layer of dermis, the molecule is taken up by the capillaries for subsequent systemic absorption
The viable tissue layer and capillaries are relatively permeable and rapid.
The rate limiting step is often diffusion through stratum corneum.
In SC no active transport as the cells are dead, but only simple passive diffusion.

19. Factors influencing penetration
1. Biological Factors
Skin age
Site of application
State of the skin
Hydration of the skin
Ageing and environmental factors

20. 2.Physicochemical Factors
Drug/skin interactions: skin hydration, drug binding
Vehicle/skin interactions: vehicle effects on skin hydration, effect of temperature, penetration enhancers
Drug vehicle interactions

21. Evaluation of transdermal drug delivery systems
In vitro drug release kinetics
The release kinetics of drug from the TDDS technology can be evaluated using a two compartment diffusion cell assembly.
Cellophan membrane is mounted on a vertical diffusion cell such as Franz diffusion cell.
The skin permeation profile is followed by sampling the receptor solution at predetermined time intervals until steady state is reached.
In vitro skin permeation kinetics
The release and skin permeation kinetics of drug from the TDDS technology can be evaluated using a two compartment diffusion cell assembly.
Skin is mounted on a vertical Franz diffusion

23. In vivo studies
A. Animal models
B. Human studies

24. Approaches to enhance skin permeability
Physical approach
Stripping of stratum corneum: SC is considered as the main barrier for drug absorption, its removal enhances drug permeation.
Hydration of SC: SC can be hydrated and the dense structure of keratin opens up making permeation easier. SC can be hydrated by occlusion with water immiscible dressings
Iontophoresis: Iontophoresis passes a few milli-amperes of current to a few square centimeters of skin through the electrode placed in contact with the formulation, which facilitates drug delivery across the barrier.

25. 2. Chemical approach
Synthesis of lipophilic prodrugs: a drug with poor skin permeability may be chemically modified to a prodrug with improved skin permeation characteristics. After SC permeation, the prodrug is transformed by the metabolic processes within the skin tissue to regenerate the active drug.
E.g. ester type prodrugs of Estradiol

26. b.. Skin permeability promoters (absorption enhancers):
Are Substances that temporarily diminish the impermeability of the skin.
These should be safe and non toxic, pharmacologically inert, non irritating, non allergenic.
Their action must be immediate and once removed the skin should immediately and fully recover to its normal barrier properties.
The enhancement should not cause loss of body fluids, electrolytes or any endogenous material
The mechanism of action of various skin permeability promoters may be due to their activity on the lipophilic lipid matrix and/or hydrophilic protein gel in stratum corneum

27. Examples: Solvents: Alcohols Alkylmethylsulfoxide: DMSO, DMF, DMA
Azone,
Pyrrolidones (NMF): free fatty acids, urea
Surfactants(non-ionic SAA)
Others: Cyclodextrins, glycolate salts