1. 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.

2. Evidence of percutaneous drug absorption may be found through measurable blood levels of the drug, detectable excretion of the drug and/or its metabolites in the urine, and clinical response of the patient to the therapy.

3. The stratum corneum, being keratinized tissue, behaves as a semipermeable artificial membrane, and drug molecules penetrate by passive diffusion. It is the major rate-limiting barrier to transdermal drug transport.

4. Drugs penetrate through passive diffusion. The rate of drug movement across this layer depends on its concentration in the vehicle, iits aqueous solubility, and the oil–water partition coefficient between the stratum corneum and the vehicle. Substances with both aqueous and lipid solubility characteristics are good candidates for diffusion through the stratum corneum, epidermis, and dermis.

5. 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.

6. a. A chemical skin penetration enhancer increases skin permeability by reversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance.

b. Iontophoresis is delivery of a charged chemical compound across the skin membrane using an electrical field.

c. Sonophoresis, or high-frequency ultrasound, is also being studied as a means to enhance transdermal drug delivery. It is thought that high-frequency ultrasound can influence the integrity of the stratum corneum and thus affect its penetrability.

7. In vivo skin penetration studies may be undertaken for one or more of the following purposes:

1. To verify and quantify the cutaneous bioavailability of a topically applied drug

2. To verify and quantify the systemic bioavailability of a transdermal drug

3. To establish bioequivalence of different topical formulations of the same drug substance

4. To determine the incidence and degree of systemic toxicologic risk following topical application of a specific drug or drug product

5. To relate resultant blood levels of drug in human to systemic therapeutic effects

8. Materials in vitro skin penetration studies include limited use of human skin, animal skins, shed snake skin and Skin Equivalent Testkin.

9. Diffusion cell systems are employed in vitro to quantify the release rates of drugs from topical preparations. In these systems, skin membranes or synthetic membranes may be employed as barriers to the flow of drug and vehicle to simulate the biologic system.

10. TDDSs may be categorized into two types, monolithic and membrane-controlled systems. Monolithic systems incorporate a drug matrix layer between the backing and the frontal layers. The drug matrix layer is composed of a polymeric material in which the drug is dispersed. The polymer matrix controls the rate at which the drug is released for percutaneous absorption. Membrane-controlled transdermal systems are designed to contain a drug reservoir, or pouch, usually in liquid or gel form; a rate-controlling membrane; and backing, adhesive, and protecting layers.

11. TDDSs may be constructed of a number of layers, including (a) an occlusive backing membrane to protect the system from environmental entry and from loss of drug from the system or moisture from the skin; (b) a drug reservoir or matrix system to store and release the drug at the skin site; (c) a release liner, which is removed before application and enables drug release; and (d) an adhesive layer to maintain contact with the skin after application.

12. Included among the design objectives of TDDSs are the following:

1. Deliver the drug to the skin for percutaneous absorption at therapeutic levels at an optimal rate

2. Contain medicinal agents having the necessary physicochemical characteristics to release from the system and partition into the stratum corneum

3. Occlude the skin to ensure one-way flux of the drug into the stratum corneum

4. Have a therapeutic advantage over other dosage forms and drug delivery systems

5. Not irritate or sensitize the skin

6. Adhere well to the patient’s skin and have size, appearance, and site placement that encourage acceptance

13. Among the advantages of TDDSs are the following:

1. They can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity, and drug interactions with food, drink, and other orally administered drugs.

2. They can substitute for oral administration of medication when that route is unsuitable, as with vomiting and diarrhea.

3. They avoid the first-pass effect, that is, the initial pass of a drug substance through the systemic and portal circulation following gastrointestinal absorption, possibly avoiding the deactivation by digestive and liver enzymes.

4. They are noninvasive, avoiding the inconvenience of parenteral therapy.

5. They provide extended therapy with a single application, improving compliance over other dosage forms requiring more frequent dose administration.

6. The activity of drugs having a short halflife is extended through the reservoir of drug in the therapeutic delivery system and its controlled release.

7. Drug therapy may be terminated rapidly by removal of the application from the

surface of the skin.

8. They are easily and rapidly identified in emergencies (e.g., unresponsive, unconscious, or comatose patient) because of their physical presence, features, and identifying markings.

The disadvantages of TDDSs are as follows:

1. Only relatively potent drugs are suitable candidates for transdermal delivery because of the natural limits of drug entry imposed by the skin’s impermeability.

2. Some patients develop contact dermatitis at the site of application from one or more of the system components, necessitating discontinuation.

14.

A. Transdermal Scopolamine - Scopolamine, a belladonna alkaloid, is used to prevent travel-related motion sickness and the nausea and vomiting that result from the use of certain anesthetics and analgesics used in surgery.

B. Transdermal Nitroglycerin - Nitroglycerin is used widely in the prophylactic treatment of angina. It has a relatively low dose, short plasma half-life, high peak plasma levels, and inherent side effects when taken sublingually, a popular route.

C. Transdermal Clonidine - Clonidine lends itself to transdermal delivery because of its lipid solubility, high volume of distribution, and therapeutic effectiveness in low plasma concentrations. The TDDS provides controlled release of clonidine for 7 days.

D. Transdermal Nicotine - Nicotine TDDSs are used as adjuncts (e.g., along with counseling) in smoking cessation programs. They have been shown to be an effective aid in quitting smoking when used according to product-recommended strategies

E. Transdermal Estradiol - Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause, female hypogonadism, female castration, primary ovarian failure, and atrophic conditions caused by deficient endogenous estrogen production, such as atrophic vaginitis and kraurosis vulvae.

F. Transdermal Contraceptive System - a thin matrix-type transdermal contraceptive patch consisting of three layers, including a two-ply backing layer composed of beige flexible film of

low-density polyethylene and a polyester inner ply. The middle layer contains polyisobutylene and polybutene adhesive, crospovidone, nonwoven polyester fabric, and lauryl lactate as inactive components; the norelgestromin and ethinyl estradiol are in this layer. The third layer is the release liner that protects the adhesive layer during storage and is removed just prior to application

G. Transdermal Testosterone - The testosterone transdermal systems are available with various delivery rates as hormone replacement therapy in men who have an absence or deficiency of testosterone

H. Transdermal Methylphenidate - methylphenidate is indicated for attention deficit hyperactivity disorder in children. The advantage of the transdermal patch is that it can be applied in the morning 2 hours prior to the time the effect is needed, that is, at school, and removed later in the day after school earlier than the 9-hour limit.

15.

1. Percutaneous absorption may vary with the site of application. The preferred general application site is stated in the package insert for each product. The patient should be advised of the importance of using the recommended site and rotating locations within that site.

2. TDDSs should be applied to clean, dry skin that is relatively free of hair and not oily, irritated, inflamed, broken, or callused.

3. Use of skin lotion should be avoided at the application site because lotions affect skin hydration and can alter the partition coefficient between the drug and the skin.

4. TDDSs should not be physically altered by cutting (as in an attempt to reduce the dose) since this destroys the integrity of the system.

5. A TDDS should be removed from its protective package, with care not to tear or cut into the unit.

6. A TDDS should be placed at a site that will not subject it to being rubbed off by clothing or movement.

7. A TDDS should be worn for the full period stated in the product’s instructions.

8. The patient or caregiver should be instructed to cleanse the hands thoroughly before and after applying a TDDS.

9. If the patient exhibits sensitivity or intolerance to a TDDS or if undue skin irritation results, the patient should seek reevaluation.

10. Upon removal, a used TDDS should be folded in half with the adhesive layer together so that it cannot be reused.