Transdermals

Stability studies for devices applied directly to the skin for the purpose of continuously infusing a drug substance into the dermis through the epidermis should be examined for appearance, assay, degradation products, leakage, 

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I = injection T = tablet C = cream Tr = transdermal, continuous delivery, P = parenteral VC = vaginal cream VS = vaginal suppositories Ca = capsule. 

Fig. 45. Schematic of transdermal patch in which the rate of deUvery of dmg to the body is controlled by a polymer membrane. Such patches are used to...

Skin. The skin s unique molecular transport and barrier properties pose a challenge for transdermal dmg dehvery. Diffusion of dmgs through the stratum corneum, the outer layer primarily responsible for the skin s limited permeabUity, varies by dmg, by skin site, and among individuals. Until recently, virtuaUy aU dmgs appHed to skin were topical treatments. 

Passive transdermal dehvery systems on the market tend to be either matrix or membrane controUed. In matrix devices, the stmctural and molecular characteristics of the dmg-polymer matrix determine dmg release. Examples of polymer matrix-controUed diffusional systems for angina prophylaxis include Nitro-Dur and Nitrodisc, which provide transdermal dehvery of nitroglycerin [55-63-0], and Erandol, a tape that releases isosorbide dinitrate [87-33-2]. Matrix diffusional systems have been used for dehvering dmgs with a wide therapeutic index. 

Fig. 4. Schematic of transdermal therapeutic system in operation. The dmg diffuses through the intact skin into capillaries and is then carried into the...

Electrically assisted transdermal dmg deflvery, ie, electrotransport or iontophoresis, involves the three key transport processes of passive diffusion, electromigration, and electro osmosis. In passive diffusion, which plays a relatively small role in the transport of ionic compounds, the permeation rate of a compound is deterrnined by its diffusion coefficient and the concentration gradient. Electromigration is the transport of electrically charged ions in an electrical field, that is, the movement of anions and cations toward the anode and cathode, respectively. Electro osmosis is the volume flow of solvent through an electrically charged membrane or tissue in the presence of an appHed electrical field. As the solvent moves, it carries dissolved solutes. 

Eig. 6. Electrically assisted transdermal therapeutic system. Electrotransport faciUtates passage of dmgs (D ) through the skin and into adjacent tissue and... 

Euture electrotransport therapeutic systems will differ substantially from those just described. They will draw on advances in microelectronics and transdermal system technology to provide transdermal therapy for compounds with low passive permeation rates, patterned or pulsed dmg deHvery,... 

R. R. Burnette, Transdermal Drug Delivery Developmental Issues and Research Initiatives., Marcel Dekker, Inc., New York, 1989, pp. 247—291. 

Transdermal dmg dehvery is associated with a relatively long time lag before the onset of efficacy, and removal of the system is foUowed by a correspondingly extended fall in plasma concentration, which probably results from formation of a dmg depot in the skin that dissipates slowly. The time lag is approximately 3 to 5 h for many dmgs that have low binding in the skin (49—51), but may be considerably longer. In contrast, plasma dmg levels may be obtained between 2 and 5 min by the oral, buccal, or nasal routes. 

Despite the limitations imposed by the physiology of the skin, several marketed controUed release transdermal dmg dehvery systems are available in the United States for example, scopolamine [51-34-3] for the treatment of motion sickness, nitroglycerin [55-63-0] for angina, estradiol [50-28-2] for the rehef of postmenopausal symptoms and osteoporosis, clonidine [4205-90-7] for the treatment of hypertension, fentanyl [437-38-7] as an analgesic, and nicotine [54-11-5] as an aid to smoking cessation. These systems are designed to dehver dmg for periods of one to seven days. 

Nitroglycerin Delivery Systems. Transderm-Nitro, Nitro-dur, and Minitran are all transdermal therapeutic systems that dehver nitroglycerin [55-63-0] mol wt 227.09, at a continuous, controlled rate through intact skin for treatment of angina (95). 

Fig. 4. Cross-section of a reservoir type of transdermal dmg deUvery system. The backing material and heat seals at the periphery of the system prevent loss...

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