1. Transdermal drug delivery systems

2. Transdermal drug delivery systems (TDDSs) facilitate the passage of therapeutic quantities of drug substances through the skin and into the general circulation for their systemic effects.
In 1965, Stoughton first conceived of the percutaneous absorption of drug substances.
The first transdermal system, Transderm Scop (Baxter), was approved by the Food and Drug Administration (FDA) in 1979 for prevention of nausea and vomiting associated with travel, particularly at sea.

3. Routes of penetration
Simplified diagram of skin structure and routes of drug penetration,
(a) Macroroutes:
(1) via the sweat ducts;
(2) across the continuous stratum corneum;
(3) through the hair follicles with their
associated sebaceous glands,
(b) Representation of the stratum corneum membrane, illustrating two possible Microroutes for permeation ( Transcellular or Intercellular) across the continuous stratum corneum between these appendages

4. Routes of drug absorption through skin4

5. Skin appendages
Their fractional area available for absorption is small (about 0.1%) and this route usually does not contribute appreciably to the steady-state flux of a drug.
However, the route may be important for ions and large polar molecules that cross intact stratum corneum with difficulty.
For electrolytes and large molecules with low diffusion coefficients, such as polar steroids and antibiotics, and for some colloidal particles, the appendages may provide the main entry route.

6.  the slope = - P

7. Epidermal route
The epidermal barrier function resides mainly in the stratum corneum.
The corneocytes, consisting of hydrated keratin, are embedded in the in a complex lipid mixture of ceramides, fatty acids, cholesterol and cholesterol esters, formed into multiple bilayers.
Most molecules penetrating through the skin use this intercellular microroute.

8. FACTORS AFFECTING PERCUTANEOUS ABSORPTION
Not all drug substances are suitable for Transdermal delivery.
Among the factors playing a part in percutaneous absorption are the physical and chemical properties of the drug, including its molecular weight, solubility, partitioning coefficient and dissociation constant (pKa), the nature of the carrier vehicle, and the condition of the skin.

9. Physicochemical factors
Skin hydration.
Temperature and pH
Diffusion coefficient
Drug concentration
Partition coefficient
Molecular size and shape

10. Penetrate (Drug) concentration
Drug concentration is an important factor.
Generally, the amount of drug percutaneously absorbed per unit of surface area per time interval increases with an increase in the concentration of the drug in the TDDS.

11. Higher the concentration of the drug in vehicle faster the absorption.
At higher concentrations than solubility the excess solid drug will function as a reservoir and helps to maintain a constant drug constitution for prolonged period of time.

12. the area and time of application
The larger the area of application (the larger the TDDS), the more drug is absorbed.
Percutaneous absorption appears to be greater when the TDDS is applied to a site with a thin horny layer than with a thick one.
Generally, the longer the medicated application is permitted to remain in contact with the skin, the greater is the total drug absorption.

13. solubility of the drug in both lipid and water
The drug should have a greater physicochemical attraction to the skin than to the vehicle so that the drug will leave the vehicle in favor of the skin.
Some solubility of the drug in both lipid and water is thought to be essential for effective percutaneous absorption.
the aqueous solubility of a drug determines the concentration presented to the absorption site, and the partition coefficient influences the rate of transport across the absorption site.
release rate

14. Generally, drugs penetrate the skin better in their unionized form
Generally, drugs penetrate the skin better in their unionized form. Nonpolar drugs tend to cross the cell barrier through the lipid-rich regions ( Intercellular route),
whereas the polar drugs favor transport between cells (Transcellular route). For example, erythromycin base demonstrates better percutaneous absorption than does erythromycin ethyl succinate.

15. Drugs molecular weight
Drugs with molecular weights of 100 to 800 and adequate lipid and aqueous solubility can permeate skin.
The ideal molecular weight of a drug for Transdermal drug delivery is believed to be 400 or less.

16. Hydration of the skin
Hydration of the skin generally favors percutaneous absorption.
It can be achieved by covering skin with plastic sheeting, which leads to accumulation of sweat, condensed water vapors, increase hydration and increase porosity.
The TDDS acts as an occlusive moisture barrier through which sweat cannot pass, increasing skin hydration.

17. Temperature
The penetration rate of material through human skin can change tenfold for a large temperature variation, as the diffusion coefficient decreases as the temperature falls.
Clothing on most of the body would usually prevent wide fluctuations in temperature and penetration rates.
Occlusive vehicles increase skin temperature by a few degrees, but any consequent increased permeability is small compared to the effect of hydration.

18. PH condition
Only unionized molecules pass readily across lipid membranes. So when weak acids and bases dissociate to different degrees, depending on the pH and their pKa or pkb values. Thus, the proportion of unionized drug in the applied phase mainly determines the effective membrane gradient, and this fraction depends on pH.
Moderate pH is favorable because if solutions with high or low pH will result in destruction to the skin.
weak acids unionized molecules Low pH, Low pka
weak bases unionized molecules high pH, high pkb

19. Partition coefficient
Polar cosolvent mixtures, such as propylene glycol with water, may produce saturated drug solutions and so maximize the concentration gradient across the stratum corneum.
However, the partition coefficient of a drug between the membrane and the solvent mixture generally falls as the solubility in the solvent system rises.
Thus, these two factors - increase in solubility and decrease in the magnitude of the partition coefficient - may oppose each other in promoting flux through the membrane, when the system is not saturated.
Hence it is important not to over solubilize a drug if the aim is to promote penetration: the formulation should be at or near saturation.

20. Biological factors Skin condition. Skin age. Blood flow.
Regional skin sites.
Skin metabolism.

21. Skin condition
The intact, healthy skin is a strong barrier but many agents can damage it.
acids and alkalis injure barrier cells and thereby promote penetration, as do cuts, abrasions and dermatitis.
skins may lose their reactivity or 'harden' because of frequent contact with irritant chemicals.
Disease commonly alters skin condition; In diseases characterized by a defective stratum corneum ( e.g. psoriasis), percutaneous absorption usually increases.
permeability increases: the skin inflamed, with loss of stratum corneum and altered keratinization.
permeability decreases: the organ thickened, with corns, calluses and warts,

22. Skin age
It is often assumed that the skin of the young and the elderly is more permeable than adult tissue
Children are more susceptible to the toxic effects of drugs and chemicals, partly because of their greater surface area per unit body weight; thus potent topical steroids, boric acid and hexachlorophane have produced severe side-effects and death.

23. Regional skin sites Blood flow
an increased blood flow could reduce the amount of time a penetrant remains in the dermis, and also raise the concentration gradient across the skin ( Sink condition ) .
Regional skin sites
Variations in cutaneous permeability around the body depend on the thickness and nature of the stratum corneum and the density of skin appendages.

24. Skin metabolism
The skin metabolizes steroid hormones, and some other drugs.
Such metabolism may determine the therapeutic efficacy of topically applied compounds (particularly prodrugs)

25. The nature of the carrier vehicle :
A vehicle can influence absorption by its effect on physical state of drug and skin. Example greases, paraffin bases are more occlusive while water in oil bases are less. Humectants in bases will dehydrate the skin and decrease percutaneous absorption. 25

26. PERCUTANEOUS ABSORPTION ENHANCERS
Increase percutaneous absorption of therapeutic agents:
chemical permeation enhancers
physical methods

27. FACTORS AFFECTING TRANSDERMAL PERMEABILITY
Physico-chemical properties of drug delivery system
Release characteristic
Solubility of drug in vehicle determines the release rate.
Composition of drug delivery system
It not only effects the rate of drug release but also the permeability of STC by means of hydration mixing with skin lipids. Example methyl salicylate is more lipophilic than its parent acid (Salicylic acid). When applied to skin from fatty vehicle methylsalicylate yielded higher absorption. 27

28. CHEMICAL ENHANCERS
increases skin permeability by reversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusion resistance
Among the alterations are:
Increased hydration of the stratum corneum,
A change in the structure of the lipids and lipoproteins in the intercellular channels through solvent action or denaturation, or both

29. skin penetration enhancers
Water
Sulphoxides (especially dimethylsulphoxide) and their analogues
Pyrrolidones
Fatty acids and alcohols
Azone and its derivatives
Surfactants - anionic, cationic and non-ionic
Urea and its derivatives
Alcohols and glycols
Essential oils, terpenes and derivatives
Synergistic mixtures.

30. The selection of a permeation enhancer should be based on:
its efficacy in enhancing skin permeation
its dermal toxicity (low)
its physicochemical and biologic compatibility with the system’s other components

31. Physical methods Iontophoresis and Sonophoresis.
Iontophoresis is delivery of a charged chemical compound across the skin membrane using an electrical field.
A number of drugs have been the subject of iontophoretic studies; they include Lidocaine; dexamethasone; amino acids, peptides, and insulin ; Verapamil; and propranolol.
Sonophoresis, or high-frequency ultrasound,
Among the agents examined are hydrocortisone, lidocaine, and salicylic acid in such formulations as gels, creams, and lotions. It is thought that high frequency ultrasound can influence the integrity of the stratum corneum and thus affect its penetrability.

32. End of Lecture