Chapter 11 TDDS

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 percuta- neous absorption of drug substances (1). 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, par- ticularly at sea.

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. With transdermal drug delivery, the blood concentra- tion needed to achieve therapeutic efficacy may be determined by comparative analysis of the patient’s response to drug blood levels. For transdermal drug delivery, it is considered ideal for the drug to migrate through the skin to the

underlying blood supply without buildup in the dermal layers (2). This is in direct contrast to the types of topical dosage forms discussed in the previous chapter, in which drug residence in the skin, the target organ, is desired.

As discussed in the previous chapter, the skin is composed of the stratum corneum (the outer layer), the living epidermis, and the dermis, which together provide the skin’s barrier layers to penetration by external agents (see Fig. 10.6). The film that covers the stratum corneum is composed of sebum and sweat, but because of its varied composition and lack of continuity, it is not a significant factor in drug penetration, nor are the hair follicles and sweat and sebaceous gland ducts, which constitute only a minor pro- portion of the skin’s surface.

Percutaneous absorption of a drug generally results from direct penetration of the drug through the stratum corneum, a 10- to 15-μm thick layer of flat, partially desiccated nonliving tissue (3, 4). The stratum corneum is composed

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OBJECTIVES

of approximately 40% protein (mainly keratin) and 40% water, with the balance being lipid, principally as triglycerides, free fatty acids, cho- lesterol, and phospholipids. The lipid content is concentrated in the extracellular phase of the stratum corneum and forms to a large extent the membrane surrounding the cells. Because a drug’s major route of penetration is through the intercellular channels, the lipid component is considered an important determinant in the first step of absorption (5). Once through the stratum corneum, drug molecules may pass through the deeper epidermal tissues and into the dermis. When the drug reaches the vascularized dermal layer, it becomes available for absorption into the general circulation.

The stratum corneum, being keratinized tis- sue, behaves as a semipermeable artificial mem- brane, and drug molecules penetrate by passive diffusion. It is the major rate-limiting barrier to transdermal drug transport (6). Over most of the body, the stratum corneum has 15 to 25 layers of flattened corneocytes with an overall thickness of about 10 μm (6). The rate of drug movement across this layer depends on its concentration in the vehicle, its aqueous solubility, and the oil– water partition coefficient between the stratum corneum and the vehicle (7). Substances with both aqueous and lipid solubility characteristics are good candidates for diffusion through the stratum corneum, epidermis, and dermis.

FACTORS AFFECTING PERCUTANEOUS ABSORPTION

Not all drug substances are suitable for trans- dermal delivery. Among the factors playing a part in percutaneous absorption are the physi- cal and chemical properties of the drug, includ- ing its molecular weight, solubility, partitioning coefficient and dissociation constant (pKa), the nature of the carrier vehicle, and the condition of the skin. Although general statements appli- cable to all possible combinations of drug, vehi- cle, and skin condition are difficult to draw, most research findings may be summarized as follows (2–11).

1. Drug concentration is an important factor. Generally, the amount of drug percutane- ously absorbed per unit of surface area per time interval increases with an increase in the concentration of the drug in the TDDS.

2. The larger the area of application (the larger the TDDS), the more drug is absorbed.

3. The drug should have a greater physicochem- ical 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. In essence, the aqueous solubility of a drug determines the concentration presented to the absorption site, and the partition coeffi- cient influences the rate of transport across the absorption site. Generally, drugs pene- trate the skin better in their unionized form. Nonpolar drugs tend to cross the cell barrier through the lipid-rich regions (transcellular route), whereas the polar drugs favor trans- port between cells (intercellular route) (6). For example, erythromycin base demon- strates better percutaneous absorption than erythromycin ethyl succinate.

4. 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.

5. Hydration of the skin generally favors percutaneous absorption. The TDDS acts as an occlusive moisture barrier through which sweat cannot pass, increasing skin hydration.

6. Percutaneous absorption appears to be greater when the TDDS is applied to a site with a thin horny layer than with a thick one.

7. Generally, the longer the medicated application is permitted to remain in con- tact with the skin, the greater is the total drug absorption.

These general statements apply to skin in the normal state. Skin that is abraded or cut permits drugs to gain direct access to the subcutaneous tissues and the capillary network, defeating the function of the TDDS.

PERCUTANEOUS ABSORPTION ENHANCERS

There is great interest among pharmaceutical scientists to develop chemical permeation enhancers and physical methods that can increase percutaneous absorption of therapeutic agents.

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CHEMICAL ENHANCERS

By definition, a chemical skin penetration enhancer increases skin permeability by revers- ibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance (12). Among the altera- tions are increased hydration of the stratum corneum, a change in the structure of the lip- ids and lipoproteins in the intercellular chan- nels through solvent action or denaturation, or both (4, 13–17).

Some drugs have an inherent capacity to permeate the skin without chemical enhancers. However, when this is not the case, chemical permeation enhancers may render an other- wise impenetrable substance useful in trans- dermal drug delivery (17). More than 275 chemical compounds have been cited in the literature as skin penetration enhancers; they include acetone, azone, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, ethanol, oleic acid, polyethylene glycol, pro- pylene glycol, and sodium lauryl sulfate (13–15). The selection of a permeation enhancer should be based not only on its effi- cacy in enhancing skin permeation but also on its dermal toxicity (low) and its physicochemi- cal and biologic compatibility with the system’s other components (16).

IONTOPHORESIS AND SONOPHORESIS

In addition to chemical means, some physical methods are being used to enhance transdermal drug delivery and penetration, namely, iontophoresis and sonophoresis (6, 15, 18–23). 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 (18); dexamethasone; amino acids, peptides, and insulin (19, 20); verapamil (6); and propranolol (21). There is particular inter- est to develop alternative routes for delivery of biologically active peptides. At present, these agents are delivered by injection because of their rapid metabolism and poor absorption after oral delivery. They are also poorly absorbed by the transdermal route because of their large molecular size and ionic character and the gen- eral impenetrability of the skin (20). However,

iontophoresis-enhanced transdermal delivery has shown some promise as a means of peptide and protein administration.

Sonophoresis, or high-frequency ultrasound, is also being studied as a means to enhance transdermal drug delivery (22, 23). 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 integ- rity of the stratum corneum and thus affect its penetrability.

PERCUTANEOUS ABSORPTION MODELS

Skin permeability and percutaneous absorption have been the subject of numerous studies to define the underlying principles and to opti- mize transdermal drug delivery. Although many experimental methods and models have been used, they tend to fall into one of two catego- ries, in vivo or in vitro.

IN VIVO STUDIES

In vivo skin penetration studies may be undertaken for one or more of the following purposes (24):

1. To verify and quantify the cutaneous bioavail- ability of a topically applied drug

2. To verify and quantify the systemic bioavail- ability 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 topi- cal application of a specific drug or drug product

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

The most relevant studies are performed in humans; however, animal models may be used insofar as they may be effective as predictors of human response. Animal models include the weanling pig, rhesus monkey, and hairless mouse or rat (24, 25). Biologic samples used in drug penetration and drug absorption studies include skin sections, venous blood from the application site, blood from the systemic

CHAPTER 11 • TRANSDERMAL DRUG DELIVERY SYSTEMS 297 circulation, and excreta (urine, feces, and

expired air) (24–28).

IN VITRO STUDIES

Skin permeation may be tested in vitro using various skin tissues (human or animal whole skin, dermis, or epidermis) in a diffusion cell (29). In vitro penetration studies using human skin are limited because of difficulties of procurement, storage, expense, and variation in permeation (30). Excised animal skins may also vary in qual- ity and permeation. Animal skins are much more permeable than human skin. One alternative that has been shown to be effective is shed snakeskin (Elaphe obsoleta, black rat snake), which is nonliving, pure stratum corneum, hair- less, and similar to human skin but slightly less permeable (30, 31). Also, the product Living Skin Equivalent Testskin (Organogenesis, Inc.) was developed as an alternative for dermal absorption studies. The material is an organo- typic co-culture of human dermal fibroblasts in a collagen-containing matrix and a stratified epi- dermis composed of human epidermal keratino- cytes. The material may be used in cell culture studies or in standard diffusion cells.

Diffusion cell systems are employed in vitro to quantify the release rates of drugs from topi- cal preparations (32). 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. The typical diffusion cell has two chambers, one on each side of the test diffusion membrane (Figs. 11.1 to 11.3). A temperature-controlled solution of the drug is placed in one chamber and a receptor solution in the other chamber. When skin is used as the test membrane, it sepa- rates the two solutions. Drug diffusion through the skin may be determined by periodic sam- pling and assay of the drug content in the recep- tor solution. The skin may also be analyzed for drug content to show permeation rates and/or retention in the skin (29).

The United States Pharmacopeia (USP) describes the apparatus and procedure to deter- mine dissolution (release) of medication from a transdermal delivery system and provides an acceptance table to which the product must con- form to meet the monograph standard for a given article (33). Commercial systems use trans- dermal diffusion cells and automatic sampling DESIGN FEATURES

OF TRANSDERMAL DRUG DELIVERY SYSTEMS

TDDSs (also often called transdermal patches) are designed to support the passage of drug sub- stances from the surface of the skin through its various layers and into the systemic circulation. Examples of the configuration and composition of TDDSs are described in the text, presented in Table 11.1 and shown in Figures 11.4 to 11.7. Figures 11.8 to 11.10 depict the manufacture of TDDSs. Technically, 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 (Fig. 11.3). The drug–matrix layer is composed of a polymeric material in which the drug is dis- persed. The polymer matrix controls the rate at which the drug is released for percutaneous absorption. The matrix may be of two types, either with or without an excess of drug with

regard to its equilibrium solubility and steady-state concentration gradient at the stra- tum corneum (21, 35). In types having no excess, drug is available to maintain the saturation of the stratum corneum only as long as the level of drug in the device exceeds the solubility limit of the stratum corneum. As the concentration of drug in the device diminishes below the skin’s satura- tion limit, the transport of drug from device to skin declines (35). In systems with excess drug in the matrix, a drug reserve is present to ensure continued saturation at the stratum corneum. In these instances, the rate of drug decline is less than in the type having no reserve.

In the preparation of monolithic systems, the drug and the polymer are dissolved or blended together, cast as the matrix, and dried (21). The gelled matrix may be produced in sheet or cylin- drical form, with individual dosage units cut and assembled between the backing and frontal lay- ers. Most TDDSs are designed to contain an excess of drug and thus have drug-releasing capacity beyond the time frame recommended for replacement. This ensures continuous drug availability and absorption as used TDDSs are replaced on schedule with fresh ones.

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 (Fig. 11.5). Transderm- Nitro (Summit) and Transderm-Scop (Baxter) are examples of this technology. Membrane- controlled systems have the advantage over monolithic systems in that as long as the drug solution in the reservoir remains saturated, the release rate of drug through the controlling membrane remains constant (21, 22). In mem- brane systems, a small quantity of drug is fre- quently placed in the adhesive layer to initiate prompt drug absorption and pharmacotherapeu- tic effects on skin placement. Membrane-con- trolled systems may be prepared by precon- structing the delivery unit, filling the drug reservoir, and sealing or by lamination, a contin- uous process of construction, dosing, and sealing (Figs. 11.8 to 11.10).

In summary, either the drug delivery device or the skin may serve as the rate-controlling mechanism. If the drug is delivered to the stra- tum corneum at a rate less than the absorption capacity, the device is the controlling factor; if the drug is delivered to the skin area to saturation, the skin is the controlling factor. Thus, the rate of drug transport in all TDDSs, monolithic and membrane, is controlled by either artificial or natural (skin) membranes.

TDDSs may be constructed of a number of layers, including (a) an occlusive backing mem- brane 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. Two types of adhesive layers, the peripheral adhesive and the face adhesive, can be used. The peripheral adhesive contains adhesive around the outer edge of the TDDS, usually in a wide strip surrounding the active drug portion. The face adhesive, which covers the entire face of the TDDS, is very com- mon. TDDSs are packaged in individual sealed packets to preserve and protect them until use. skin moisture and hydrate the site of application, enabling increased drug penetration. Preferred backing materials are approximately 2 to 3mm thick and have a low moisture vapor transmis- sion rate, less than about 20g/m2 in 24 hours (36). Transparent or pigmented films of polypro- pylene, polyethylene, and polyolefin are in use in TDDSs as backing liners.

The adhesive layer must be pressure sensitive, providing the ability to adhere to the skin with minimal pressure and remain in place for the intended period of wear. The adhesive should be nonirritating, allow easy peel-off after use, per- mit unimpeded drug flux to the skin, and be com- patible with all other system components. The adhesive material is usually safety tested for skin compatibility, including tests for irritation, sensi- tivity, and cytotoxicity (37). In some TDDSs, the adhesive layer contains the drug. Polybutyl acrylate is commonly used as the adhesive in TDDSs. The drug release membranes are commonly made of polyethylene, with microporous structures of vary- ing pore sizes to fit the desired specifications of the particular transdermal system.

Included among the design objectives of TDDSs are the following (2, 8, 35, 38, 39):

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

2. Contain medicinal agents having the neces- sary physicochemical characteristics to release from the system and partition into the stra- tum 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

ADVANTAGES AND DISADVANTAGES OF TDDSs

Among the advantages of TDDSs are the following:

1. They can avoid gastrointestinal drug absorp- tion 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, i.e., the initial pass of a drug substance through the systemic and portal circulation following gastrointesti- nal absorption, possibly avoiding the deacti- vation by digestive and liver enzymes.

4. They are noninvasive, avoiding the inconve- nience 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 half-life 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 emer- gencies (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 can- didates 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.

EXAMPLES OF TRANSDERMAL DRUG DELIVERY SYSTEMS

The following sections briefly describe some of the TDDSs in use. Table 11.1 describes the spe- cific design components of representative exam- ples of these systems.

TRANSDERMAL SCOPOLAMINE

As noted at the outset of this chapter, transder- mal scopolamine was the first TDDS to receive FDA approval. Scopolamine, a belladonna alka- loid, is used to prevent travel-related motion sickness and the nausea and vomiting that result from the use of certain anesthetics and analge- sics used in surgery.

The Transderm-Scop system is a circular flat patch 0.2mm thick and 2.5cm2 in area (40). It is a four-layer system described in Table 11.1. The TDDS contains 1.5mg of scopolamine and is designed to deliver approximately 1 mg of scopol- amine at an approximately constant rate to the systemic circulation over the 3-day lifetime of the system. An initial priming dose of 200μg of sco- polamine in the adhesive layer of the system satu- rates the skin binding sites and rapidly brings the plasma concentration to the required steady-state level. The continuous release of scopolamine through the rate-controlling microporous mem- brane maintains the plasma level constant. The rate of release is less than the skin’s capability for absorption, so the membrane, not the skin, con- trols the delivery of the drug into the circulation.

The patch is worn in a hairless area behind the ear (Fig. 11.10). Because of the small size of the patch, the system is unobtrusive, convenient, and well accepted by the patient. The TDDS is applied at least 4 hours before the antinausea effect is required. Only one disk should be worn at a time and may be kept in place for up to 3 days. If continued treatment is required, a fresh disk is placed behind the other ear and the other removed. The most common side effects are dry- ness of the mouth and drowsiness. Particularly in the geriatric population, use also may interfere with orientation, cognition, and memory. The TDDS is not intended for use in children and should be used with caution during pregnancy.

TRANSDERMAL NITROGLYCERIN

A number of nitroglycerin-containing TDDSs have been developed, including Minitran

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(3M Pharmaceuticals), Nitro-Dur (Key), Transderm-Nitro (Summit), and Nitrodisc (Roberts). The design of each of these systems is briefly described in Table 11.1. Each of these products maintains nitroglycerin drug delivery for 24 hours after application. Tolerance, how- ever, is a major factor limiting the effectiveness of these systems when used continuously for more than 12 hours per day. Hence, an appropri- ate dosing schedule would include a daily “patch on” period of 12 to 14 hours and a “patch off” period of 10 to 12 hours.

Nitroglycerin is used widely in the prophylac- tic treatment of angina. It has a relatively low dose, short plasma half-life, high peak plasma levels, and inherent side effects when taken sub- lingually, a popular route. It is rapidly metabo- lized by the liver when taken orally; this first-pass effect is bypassed by the transdermal route.

The various nitroglycerin TDDSs control the rate of drug delivery through a membrane and/ or controlled release from the matrix or reser- voir. When a TDDS is applied to the skin, nitro- glycerin is absorbed continuously, resulting in active drug reaching the target organs (heart, extremities) before inactivation by the liver. Only a portion of the total nitroglycerin in the system is delivered over the usual 24-hour use period; the remainder serves as the thermodynamic energy source to release the drug and remains in the system. For example, in the Deponit TDDS, only 15% of the nitroglycerin content is deliv- ered after 12 hours of use (41).

The rate of drug release depends on the sys- tem. In the Transderm-Nitro system, nitroglyc- erin 0.02mg is delivered per hour for every square centimeter of patch, whereas in the Deponit system, each square centimeter deliv- ers approximately 0.013mg of nitroglycerin per hour (41, 42). Systems of various surface areas and nitroglycerin content are provided to accommo- date individual patients’ requirements. Because of different release rates, these systems cannot be used interchangeably by a patient.

The Nitro-Dur matrix is in a highly kinetic equilibrium state (43). Dissolved nitroglycerin molecules are constantly exchanging with adsorbed nitroglycerin molecules bound to the surfaces of the suspended lactose crystals. Suffi- cient nitroglycerin is adsorbed to the lactose in each matrix to maintain nitroglycerin in the fluid phase (aqueous glycerol) at a stable but saturated level (5mg nitroglycerin/cm2 matrix). When the

matrix is applied to the skin, nitroglycerin mole- cules migrate by diffusion from solution in the matrix to solution in the skin. To make up for the molecules lost to the body, the equilibrium in the matrix shifts such that more molecules of nitroglycerin leave the crystals than are adsorbed from solution. When balance is restored, the solution is again saturated. Thus, the crystals of lactose act as a reservoir of drug to maintain drug saturation in the fluid phase. The Nitro-Dur matrix in turn acts as a saturated reservoir for diffusive drug input through the skin (43).

Not all nitroglycerin systems have the same construction. For example, the Transderm-Nitro TDDS is a four-layer drug pouch system, as described in Table 11.1 and depicted in Figure 11.5, whereas the Deponit TDDS is a thin two- layer matrix system resembling that shown in Figure 11.7.

Patients should be given explicit instructions regarding the use of nitroglycerin transdermal systems. Generally, these TDDSs are placed on the chest, back, upper arms, or shoulders (Fig. 11.11). The site should be free of hair, clean, and dry so that the patch adheres with- out difficulty. The use of the extremities below the knee or elbow is discouraged, as are the areas that are abraded or have lesions or cuts. The patient should understand that physical such as in a sauna, may increase the absorption of nitroglycerin.

TRANSDERMAL CLONIDINE

The first transdermal system for hypertension, Catapres TTS (clonidine transdermal therapeu- tic system, Boehringer Ingelheim), was marketed in 1985. Clonidine lends itself to transdermal delivery because of its lipid solubility, high vol- ume of distribution, and therapeutic effective- ness in low plasma concentrations. The TDDS provides controlled release of clonidine for 7 days. The product is a four-layer patch as described in Table 11.1.

Catapres TTS is available in several sizes, with the amount of drug released proportional to the patch size. To ensure constant release over the 7-day use period, the drug content is greater than the total amount of drug delivered. The energy of drug release derives from the concen- tration gradient between a saturated solution of drug in the TDDS and the much lower concen- tration prevailing in the skin. Clonidine flows in the direction of lower concentration at a con- stant rate controlled by a membrane (44).

The system is applied to a hairless area of intact skin on the upper outer arm or chest. After application, clonidine in the adhesive layer satu- rates the skin site. Then clonidine from the res- ervoir begins to flow through the rate-controlling membrane and the skin to the systemic circula- tion. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application. Application of a new system to a fresh skin site at weekly intervals maintains therapeutic plasma concentrations. If the patch is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly over several days. Over this period, blood pressure returns gradually to pre- treatment levels. If the patient has local skin irri- tation before 7 days of use, the system may be removed and replaced with a new one applied on a fresh skin site (44).

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 (45). In a blinded

study, users of nicotine TDDSs are more than twice as likely to quit smoking as individuals wear- ing a placebo patch (45). Example products include Nicoderm CQ (GlaxoSmithKline) and Nicotrol (McNeil Consumer Products).

The nicotine TDDSs provide sustained blood levels of nicotine as nicotine replacement ther- apy to help the patient establish and sustain remission from smoking (46). Motivation to quit smoking is enhanced through the reduction of withdrawal symptoms and by partially satisfying the nicotine craving and desired sensory feelings provided by smoking (46).

The commercially available patches contain 7 to 21 mg of nicotine for daily application dur- ing the course of treatment ranging from about 6 to 12 weeks. Different treatment regimens are used for light versus heavy smokers. Examples of nicotine TDDSs are described in Table 11.1. A nicotine TDDS usually is applied to the arm or upper front torso, with patients advised not to smoke when wearing the system. The TDDS is replaced daily, with sites alternated. Some of the nicotine replacement programs provide a gradual reduction in nicotine dosage (patch strength) during the treatment program. Used TDDSs should be discarded properly because the retained nicotine is poisonous to children and pets.

TRANSDERMAL ESTRADIOL

The estrogen estradiol has been developed for transdermal delivery. The Estraderm (Novartis) TDDS delivers 17β-estradiol through a rate- limiting membrane continuously upon applica- tion to intact skin (47). Two systems (10 or 20 cm2) provide delivery of 0.05 or 0.1 mg estra- diol per day. Estraderm is a four-layer TDDS as described in Table 11.1.

Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms associ- ated with menopause, female hypogonadism, female castration, primary ovarian failure, and atrophic conditions caused by deficient endoge- nous estrogen production, such as atrophic vagi- nitis and kraurosis vulvae.

Orally administered estradiol is rapidly metabolized by the liver to estrone and its conju- gates, giving rise to higher circulating levels of estrone than estradiol. In contrast, the skin metabolizes estradiol only to a small extent. Therefore, transdermal administration produces

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therapeutic serum levels of estradiol with lower circulating levels of estrone and estrone conju- gates than does oral therapy and requires a smaller total dose. Research has demonstrated that postmenopausal women receiving either transdermal or oral therapy will obtain the desired therapeutic effects, i.e., lower gonado- tropin levels, lower percentages of vaginal para- basal cells, decreased excretion of calcium, and lower ratio of calcium to creatinine, from both dosage forms. Studies have also demonstrated that systemic side effects from oral estrogens can be reduced by using the transdermal dosage form. Because estradiol has a short half-life (about 1 hour), transdermal administration allows a rapid decline in blood levels after the transdermal system is removed, as in a cycling regimen (47).

Therapy is usually administered on a cycling schedule (3 weeks of therapy followed by 1 week without), especially in women who have not undergone a hysterectomy. The transdermal sys- tem is applied to a clean, dry area of the skin on the trunk of the body, either the abdomen or upper quadrant of the buttocks. The patch should not be applied to the waistline because tight clothing may damage or dislodge it.

The Vivelle (Novartis) and Climara (Berlex) estradiol TDDSs are two-layered matrix systems described in Table 11.1 and resembling that shown in Figure 11.7. The estradiol is contained in the adhesive layer (48, 49). These systems are used in the same general manner as Estraderm TDDS; however, some of these systems are applied every 7 days.

TRANSDERMAL CONTRACEPTIVE SYSTEM

The Ortho Evra (norelgestromin, ethinyl estra- diol; Ortho-McNeil) Transdermal System is a combination contraceptive patch with a contact surface area of 20 cm2; it contains 6 mg of norel- gestromin and 0.75mg of ethyl estradiol. It is released at a rate of norelgestromin 150μg and ethinyl estradiol 20μg into the blood stream every 24 hours.

The Ortho Evra is a thin matrix-type trans- dermal contraceptive patch consisting of three layers, including a two-ply backing layer com- posed of beige flexible film of low-density poly- ethylene 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. It is a trans- parent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle layer.

TRANSDERMAL TESTOSTERONE

The testosterone transdermal systems Testo- derm (Alza) and Androderm (Watson) are avail- able with various delivery rates as hormone replacement therapy in men who have an absence or deficiency of testosterone (50, 51).

The Testoderm TDDS is a two-layer system as described in Table 11.1. For optimal absorp- tion, it is applied to clean, dry scrotal skin that has been dry shaved. Scrotal skin is reported to be at least five times as permeable to testoster- one as other skin sites (50). The TDDS is placed on the scrotum by stretching the scrotal skin with one hand and pressing the adhesive side of the TDDS against the skin with the other hand, holding it in place for about 10 seconds. The TDDS is applied daily, usually in the morning to mimic endogenous testosterone release (52). Optimum serum levels are reached within 2 to 4 hours after application. The patch is worn 22 to 24 hours daily for 6 to 8 weeks.

The Androderm TDDS is designed to be applied nightly to a clean, dry, unabraided area of the skin of the back, abdomen, upper arms, or thighs. It should not be applied to the scrotum (51). The five-layer system is described in Table 11.1.

TRANSDERMAL METHYLPHENIDATE

Transdermal methylphenidate (Daytrana, Shire) is an adhesive-based matrix transdermal system applied to intact skin. The methylphenidate is dispersed in acrylic adhesive that is dispersed in a silicone adhesive. The composition per unit area is identical in all dosage strengths and the total dose delivered is dependent on the patch size and wear time. It is available as 10, 15, 20, and 30 mg patches nominally delivering the indi- cated dose over a 9-hour period. The 10-mg patch actually contains 27.5mg of the drug; the 15-mg patch contains 41.3mg; the 20-mg patch contains 55mg; and the 30-mg patch contains 82.5 mg of the drug. After 9 hours, the patch is to

be removed, folded in on itself (adhesive to adhesive), and appropriately discarded (52). There is a dose titration schedule which should be followed initially until the individualized final dosage and wear time are determined.

Usually, methylphenidate is indicated for attention deficit hyperactivity disorder in chil- dren. The advantage of the transdermal patch is that it can be applied in the morning two hours prior to the time the effect is needed, i.e., at school, and removed later in the day after school earlier than the 9-hour limit. This obviates the need for oral medication to be administered dur- ing the day and trips to the school nurse’s office.

OTHER TRANSDERMAL THERAPEUTIC SYSTEMS

Other transdermal therapeutic systems include the Oxytrol (oxybutynin chloride transdermal system, Watson) and additional drugs under study for use in TDDSs include diltiazem, iso- sorbide dinitrate, propranolol, nifedipine, mepin- dolol, and verapamil, cardiovascular agents; levonorgestrel with estradiol for hormonal con- traception; physostigmine and xanomeline for Alzheimer disease therapy; naltrexone and meth- adone for substance addiction; buspirone for anxiety; bupropion for smoking cessation; and papaverine for male impotence.

GENERAL CLINICAL CONSIDERATIONS IN THE USE OF TDDSs

The patient should be advised of the following general guidelines along with product-specific instructions in the use of TDDSs (53, 54).

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. Rotating locations is impor- tant to allow the skin beneath a patch to regain its normal permeability after being occluded and to prevent skin irritation. Skin sites may be reused after a week.

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

or moist skin can accelerate drug perme- ation beyond the intended rate. Oily skin can impair adhesion of the patch. If hair is present at the intended site, it should be carefully cut; it should not be wet-shaved nor should a depilatory agent be used, since the latter can remove the outermost layers of the stratum corneum and affect the rate and extent of drug permeation.

3. Use of skin lotion should be avoided at the application site because lotions affect skin hydration and can alter the partition coeffi- cient 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 pro- tective package, with care not to tear or cut into the unit. The protective backing should be removed to expose the adhesive layer with care not to touch the adhesive surface (which sometimes contains drug) to the fin- gertips. The TDDS should be pressed firmly against the skin site with the heel of the hand for about 10 seconds to ensure uni- form contact and adhesion.

6. A TDDS should be placed at a site that will not subject it to being rubbed off by clothing or movement (as the belt line). TDDSs gen- erally may be left on when showering, bathing, or swimming. Should a TDDS pre- maturely dislodge, an attempt may be made to reapply it or it may be replaced with a fresh system, the replacement being worn for a full period before it is replaced.

7. A TDDS should be worn for the full period stated in the product’s instructions. Follow- ing that period, it should be removed and replaced with a fresh system as directed.

8. The patient or caregiver should be instructed to cleanse the hands thoroughly before and after applying a TDDS. Care should be taken not to rub the eyes or touch the mouth during handling of the system.

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

10. Uponremoval,ausedTDDSshouldbefolded in half with the adhesive layer together so that it cannot be reused. The used patch, which contains residual drug, should be placed in the replacement patch’s pouch and discarded in a manner safe to children and pets.

CHAPTER 11 • TRANSDERMAL DRUG DELIVERY SYSTEMS 307

308 SECTION IV • SEMISOLID DOSAGE FORMS AND TRANSDERMAL SYSTEMS

PATCHES (NOT SYSTEMS)

The Lidoderm (lidocaine) 5% patch consists of an adhesive material containing 5% lidocaine, which is applied to a nonwoven polyester felt backing and covered with a PET film release liner. The release liner is removed just prior to application. The patch is 10 cm × 14 cm and each patch contains 700 mg of lidocaine in an aqueous base. The base contains dihydroxyaluminum aminoacetate, disodium edentate, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylpara- ben, sodium carboxymethylcellulose, sodium

polyacrylate, D-sorbitol, tartaric acid, and urea. This product is indicated to treat postherpetic neuralgia. The patch is applied to intact skin to cover the most painful area. Depending upon the directions for use, the patient can apply up to three patches, only once for up to 12 hours within a 24-hour period. This patch may be cut with scissors into a smaller size prior to the removal of the release liner. The patient should wash his/her hands prior to and after handling the lidocaine patch and should avoid eye contact. After removal, the patch should be immediately disposed of, and in such a way to avoid accidental exposure to children and animals.