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for fabrication of a single chip, and the cost may then be comparable to passive transdermal delivery. An interesting alternative to iontophoresis is electroporation in which large reversible decreases in the impedance of skin are produced by brief, high-voltage pulses [84]. |
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All commercial transdermal systems to date use a generic drug, which allows for a new or more convenient therapy from its transdermal application. For these generics, pharmacokinetics and target plasma levels have been known at the inception of product development. The use of a generic allows a short feasibility phase of research, toxicology confined to the evaluation of local skin tolerability, a Phase I that typically includes 23 pharmacokinetic trials to optimize the performance of the dosage form in vivo, a pilot efficacy trial and the specified skin tolerability studies in Phase II, and 2 placebo-controlled, double-blind efficacy studies in Phase III. The final dosage form should be available for the start of Phase III. Large-scale adhesion and irritation trials may be part of Phase IV or in the actual Phase II trials. Such trials may be required as part of the European dossier. While improved patient compliance is typically a major advantage of transdermal dosage forms, surprisingly only one study with transdermal clonidine has been conducted [85]. |
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The incorporation of a new molecular entity into a patch or other novel drug delivery system must have an excellent therapeutic justification, because the overall probability of success of the project is the product of the probabilities of success for both the delivery system and the new chemical entity. There may be cases where this is justified. For example, PHNO, a dopamine autoreceptor agonist that was examined for Parkinson's disease was being developed first orally and then as a transdermal [86]. The side effects from oral delivery served to terminate both projects, yet there was greater than 90% first-pass metabolism orally. An alternative analysis prior to any clinical study would be to either develop only the transdermal patch or terminate the project at the research stage. |
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Buccal delivery offers many of the advantages of transdermal delivery, but may allow faster onset and is useful for a shorter duration, i.e., transdermal delivery is useful from 1 to 7 days while buccal delivery is typically from a few minutes to perhaps 12 hours. In contrast to the skin, the oral cavity is designed for some absorption and secretion, and consequently, the barrier properties and immunological activity are reduced as compared to the skin. Potential restrictions for the buccal route are its limited surface area, concerns of taste and comfort in a highly innervated area, the difficulties of adhesion to a mucosal surface for extended periods without the danger of swallowing or choking on a device, and potential bacterial growth or blockage of salivary glands associated with |
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