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sensitization, an immunological reaction in which recognition is initiated in the epidermis and is a systemic reaction. |
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Drugs must pass through the stratum corneum and epidermis to the blood vessels below the dermal-epidermal junction. The stratum corneum provides 9095% of the diffusional resistance in the skin. Transdermal drug delivery avoids first-pass metabolism, provides continuous delivery for short half-life drugs, may circumvent GI side effects, and may avoid poor GI absorption. |
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Permeation through skin of lipophilic drugs is a classical problem in ideal solution theory [59] and may be related to the solubility in oil [60] or the melting point of the permeant [59]. There is an exponential dependence of the flux on the molecular volume [32,61] through its diffusion constant. While skin permeation has been limited to lipophilic compounds, a number of recent studies indicate that polar and ionic compounds may also permeate skin [6264] and water solubility may also be important. |
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Enhancers to improve skin permeation have been a focal point of research [65]. Absorption of polar compounds may be enhanced by surfactants with hydrophilic head groups, or nonpolar and polar compounds when surfactants are combined with other solvents, such as diols or ethanol [65,66]. There is generally a correlation between the ability of a surfactant to improve skin permeation and skin irritation. Consequently, careful optimization of the formulation with respect to irritation and permeation may be required in the preclinical and early Phase I programs. Ethanol can increase the permeation of nonpolar species by increasing their solubility in the stratum corneum without altering their diffusion constants [6769]. Ethanol is the only solvent used in a commercial transdermal system where the relationship between drugs, estradiol and fentanyl, and the solvent has been characterized [6971]. |
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Skin tolerability is often a limiting factor in the feasibility of transdermal delivery. Primary irritation, either acutely after a single application or cumulatively after repeated application to the same site, must be characterized in preclinical and human studies. |
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For drugs that transport across skin at the same rate, irritation may correlate with the pKa of the drug [72,73]. The choice of site of application may affect the sensitivity to the irritant. For example, the incidence of irritation on the buttocks from alcohol-containing transdermal estradiol placebos is substantially reduced compared to the abdomen [74]. Site-to-site bioequivalence must be established. Sensitization is a systemic immune response with typically severe erythema, edema, generalized rash, etc. The classical example is poison ivy. Transdermal clonidine is the most studied transdermal sensitizer to date [75], but transdermal nicotine is also a sensitizer in a small percent of the population. Fortunately, individuals sensitized to the transdermal route for these two drugs almost always have not reacted to oral delivery of clonidine or smoking cigarettes containing nicotine. While guinea pig or mouse-ear- |
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