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swelling models are generally predictive of sensitization, they did not predict the clonidine or nicotine response in man. Moreover, the classical 2-week maximization paradigm for testing sensitization in man was too short to indicate the magnitude of the response. A 4-week induction period or 2 repeated 2-week induction periods separated by a 2-week rest period may be more appropriate. In preclinical testing GLP primary irritation in rabbits and sensitization in guinea pigs are the usual studies to screen the local tolerability. Studies of irritation, sensitization, phototoxicity, photocontact allergenicity, and bacterial proliferation are standard Phase II studies for transdermal systems. These are short-term exaggerated studies to identify potential problems and do not impact on the time line for development. However, if a problem is identified, larger studies to identify the incidence and severity of the tolerability problem in use should be included in the Phase III program. |
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The design of transdermal systems falls into two basic types: membrane controlled and monolithic. Since the skin is rate controlling for all commercial systems except the alcohol-containing transdermal estradiol and transdermal clonidine systems, both membrane-controlled and monolithic systems exhibit zero-order release in vivo. The common elements of the current transdermal systems are a drug reservoir, a backing that is impermeable to the drug over the system's lifetime, an adhesive and release liner to attach the system to skin with minimal tolerability concerns, and appropriate pouching to achieve the desired shelf-life. Technical problems that commonly affect stability or process validation and production are the uniformity of laminated components from batch-to-batch, migration or loss of components throughout the system during storage, and crystallization of a drug contained in polymers in a metastable state. |
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Iontophoresis, or the use of electrical current to drive drugs across the skin has recently received much attention as a means of increasing skin permeation and for temporal variation in drug delivery [76,77]. Iontophoretic permeation appears to occur through rare negatively charged pores of 2025 Å radius with a surface charge of -0.05 C/m2 [78]. The existence of such pores creates the possibility of peptide delivery, and several in vitro and in vivo studies in man have been reported [79,80]. Current ranges need to be restricted to limit skin irritation, and at higher levels, pain [81,82]. The therapeutic applications are only in early clinical trials including an iontophoretic patient-controlled analgesic system for fentanyl and an antiemetic [83]. Until Phase III, clinical trials are research on the device as well as the therapy. Early trials must concentrate on obtaining information about the device, in vivo delivery, and pharmacokinetics and, therefore, must be capable of multiple measurements. As the trials progress, the device must become smaller, narrower in scope, more rugged, patient friendly, and comfortable. While cost may appear to be a factor, markets requiring tens to hundreds of millions of disposable systems/year allow |
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