2. Definition: Transdermal drug delivery system can deliver the drugs through the skin portal to systemic circulation at a predetermined rate and maintain clinically the effective concentrations over a prolonged period of time.

3. Reasonably constant dosage can be maintained. First pass metabolism in the liver and GI tract is avoided Reduced need for drug readministration (some patches can last 7 days) Easy to apply, to remove, and to monitor Allows effective use of drugs with short biological half-life. Allow administration of drugs with narrow therapeutic window because drug levels are maintained within the therapeutic window for prolonged periods of time. Reduced inter and intra patient variability.

4. Drugs that require high blood levels cannot be administered limited only to potent molecules, those requiring a daily dose of 10mg or less. Transdermal administration is not a means to achieve rapid bolus type drug input. Adequate solubility of the drug in both lipophilic and aqueous environments, to reach dermal microcirculation and gain access to the systemic circulation. The molecular size of the drug should be reasonable to be absorbed percutaneously.

5. The drug must traverse three layers, the stratum cornium, the epidermis, and the dermis. Of these, the toughest barrier is the stratum corneum, which consists of 10-25 layers of keratinized cells.

6. Hydrophilic drugs permeates by Intercellular pathway drug molecule passes through the cells of the stratum corneum, As stratum corneum hydrates, water accumulates near the outer surface of the protein filaments Lipophilic drugs permeates by Transcellular mechanism. These molecules dissolve in and diffuse through the non- aqueous lipid matrix imbibed between the protein filaments

8. Penetration enhancement is the most critical factor in transdermal systems, so as to improve flux. Flux (J) can be defined as the amount (M) of material flowing through unit cross section (S) of a barrier in unit time (t). Flux can be given by: J=dM/S.dt. Each phase of the membrane have a diffusional resistance(R), which usually is the function of : thickness (hs) of the phase the permeant diffusion coefficient (Ds) within the phase the partition coefficient (Ks) between the membrane phase and external phase.

9. It can be expressed as: R=hs/Ds.Ks P=Ds.Ks/hs where P is permeability coefficient. The permeability coefficient is related to membrane flux (J) as given J=APs (Cp-Cr) where: Cp-Cr is the difference in permeant concentration across the membrane A is the area of application. Ps is permeability coefficient

10. 1- Prodrugs interactions The prodrug enhance transdermal delivery of drugs with unfavourable partition coefficients. involves addition of a pro-moiety (ester moiety) to increase partition coefficient and solubility to increase the transport of the drug in the stratum corneum. Upon reaching the viable epidermis, esterases enzyme release the active drug by hydrolysis thereby optimizing concentration in the epidermis

11. 2.Ion-pairs Charged drug molecules do not readily partition into or permeate through human skin. Formation of lipophilic ionpairs increase stratum corneum penetration of charged species. This strategy involves adding an oppositely charged species To the charged drug, forming an ion-pair in which the Charges are neutralized so that the complex can partition into And permeate through the stratum corneum. The ion-pair Then dissociates in the aqueous viable epidermis releasing The parent charged drug that can diffuse within the Epidermal and dermal tissues.

12. 3-Chemical permeation enhancers : Chemical permeation enhancers A substance that will increase the permeability of the epithelial barrier by modifying its structure also termed as accelerants or absorption promoters-can enhance drug flux. Ideal Penetration Enhancer Non-toxic, non-irritating, non- allergenic. Immediate onset of increased permeability. Immediate recovery of normal barrier properties upon removal (reversible). Physically and Chemically compatible with a wide range of drugs permeation enhancers include the following : 1. Sulphoxides 2. Alcohols 3. Polyols 4. Alkanes 5. Fatty acids 6. Esters 7. Amines and amides 8. Terpenes 9. Surface active agents

13. Basic components of TDDS : Drug Polymer matrix Penetration enhancers Rate controlling membrane Adhesive : Serves to bind the components of the patch to the skin e.g : Acrylic copolymers, polyisobutylene and polysiloxane. Release liner: Protects the drug during storage and is removed prior to use Backing membrane :Protects the patch from the outer environment. include water impermeable polymer e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins.

14. Transdermal patches Iontophoresis Microneedles High velocity jet injectors

15. Advantages of skin patch: Easy to apply and to remove. Avoids liver (“first pass” effect) Improves patient compliance Disadvantages of skin patch: Can irritate skin Adhesive bond may fail Sometimes slow to take an effect Transdermal patches

16. Transdermal matrix system : Rate controlling factors include: Drug concentration in polymer matrix Chemical nature of polymer matrix Geometry of device Polymers: PVP, Ethylene vinylacetate, polypropylene. Initially the drug is released rapidly, then rate declines as matrix Is depleted. Advantages: Sleeker and thinner daily or multiple-day Applications. Appropriate for drugs that penetrate readily and/or have low dosage requirements.

17. Film Backing Drug suspension/semisolid matrix skin Schematic Drawing of the Matrix patch. Protective Liner (removed prior to use) Adhesive Layer

18. Transdermal reservoir system : Rate controlling factors include: Membrane thickness Membrane permeability Polymers: Cellulosic esters, polyamides or PVC. Advantages: Used when matrix systems cannot penetrate skin Used when drugs require significant penetration enhancement and/or high dosage levels.

19. Reservoir Patches The reservoir system has a drug layer that is separate from the adhesive.

20. Schematic Drawing of the Reservoir type of patch. Film Backing Drug Layer skin Rate-controlling Membrane Contact Adhesive Protective Liner (removed prior to use)

21. Drug-in-Adhesive Single-layer Drug-in-Adhesive The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing Multi-layer Drug-in-Adhesive is similar to the single-layer system in that adhesive layers are also responsible for the releasing of the drug. One of the layers is for immediate release of the drug and other layer is for control release of drug from the reservoir. The multi-layer system is different however that it adds another layer of drug-in- adhesive, usually separated by a membrane.

22. Rate controlling factors include: Thickness of adhesive layer Polymers: crosslinked gelatin, lecithin Advantages: A system in which the drug is incorporated directly into the adhesive, rather than into a separate layer. Usually used for smaller molecular weight compounds.

23. Iontophoretic patches use a tiny electrical current run through a drug containing electrode in contact with the skin to promote flow of the drug (usually charged) through the skin. The most popular electrodes are based on the silver/silver chloride redox couple. Three main mechanisms enhance molecular transport: 1.Electro-repulsion Charged species which driven primarily from the driving electrode. 2.Flow of electric current may increase the permeability of skin 3.Electro osmosis affect uncharged molecules and large polar peptides. Limitations: Hair follicle damage is possible.

24. Mechanism is based on the physical phenomenon that “like charges repel and opposite charges attract”. The drugs are forced Across the skin by simple electronic repulsion of similar charges. Thus, anionic drugs Can cross the skin by using a negatively charged electrode. Similarly, cationic drugs enter the skin when a positively charged electrode is used. While delivering a negatively charged drug across skin, it is placed between the negative electrode (cathode), and the skin. The drug ion is then attracted through the skin towards the positive electrode (anode) by the electromotive force provided by the cell. In case of positively charged drug, it is placed between the positive electrode (Anode), and the skin. Once the drug has passed through the outer barrier layer of skin, it reaches to its site of action by rapidly going into the circulation. The mechanism of iontophoresis

26. The system fires solid particles (20–100µm) through stratum corneum into lower skin layers, using a supersonic shock wave of helium gas. Intraject is a development of the vaccine gun designed to deliver liquids through skin without using needles. Advantages : Pain-free delivery — particles are too small to trigger pain receptors on the skin. Improved efficacy and bioavailability. Targeting to a specific tissue, such as a vaccine delivered to epidermal cells. Accurate dosing and Overcomes needle phobia. Safety — the device avoids skin damage or infection from needles or splash back of body fluids.

28. A device containing 400 solid or hollow silicon needles, approximately 150 μm in length, that penetrate through the stratum corneum into the upper epidermis When a current is passed through the PCB heater the composite heat up and expands into the liquid reservoir, consequently ejecting through the hollow microneedles. Advanteges: Microneedles patches are currently being explored as mechanisms to deliver vaccines and larger macromolecules. Pain-free delivery — microneedles are too small to trigger pain receptors on the skin.