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prolonged occlusion. Sublingual dosage forms have been developed for nitroglycerin [87], ergotamine [88], nicotine [89], buprenorphine [90], methyl testosterone [87], and nifedipine [91]. Oxytocin, a small peptide, has been shown to cross the buccal mucosa [92]. Controlled release devices are also being developed for local applications, in particular, the release of antibiotics from fibers that are placed in periodontal pockets [93]. |
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Human oral mucosa is a stratified epithelium with specialized anatomical development. While the hard palate tends to have a cornified epithelial layer, the soft buccal mucosa is a nonkeratinized tissue (containing keratohyalin granules) with an average thickness of 580 microns [94]. Although certain rodents have a true stratum corneum in their buccal mucosa, no such layer exists in man. Compared to skin, there are a reduced number of Langerhans cells in the buccal mucosa, and these appear to process antigens in the same fashion as in the viable epidermis [95]. In contrast to dermal models, there is no validated model of local oral inflammation and sensitization, and a combination of buccal application and standard dermal animal models should be used to evaluate these issues. |
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The experimental paradigm of Beckett and Triggs [96] is the classical method for evaluating buccal absorption of drugs. With this method, a known concentration and volume of drug are kept in the subject's mouth for a fixed amount of time, spit out, and the drug absorption is calculated as the difference in the total amount of drug. In situ perfusion methods are also popular [97], but both methods have the same limitations: (a) absorption is not distinguished from metabolism and adsorption and (b) the solubility of the drug in water dominates the measurement. A result of this approach is the conclusion that unionized species dominate transport and that the flux follows the partition coefficient [98]. |
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The polar shunt pathway for buccal transport has been largely neglected until recently. Sodium diclofenac in its ionized form has been demonstrated to permeate buccal mucosa rapidly in humans and in dogs [98100]. Dipolar ions, i.e., angiotensin-converting enzyme inhibitors [101,102] and TRH [96,103] also permeate extensively. In these latter studies, permeation was calculated by comparison of the AUC from buccal devices containing saturated solutions in vivo to intravenous infusion or from in vitro methods, such as Ussing chambers. Permeation through buccal mucosa is orders of magnitude faster than through skin, but perhaps a factor of ten slower than through intestinal or nasal mucosa [98,104]. |
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Peptide and protein permeation through buccal mucosa has been reported based on pharmacodynamic measurements. The bioavailability of oxytocin administered transbucally was a few percent. Buccal tissue contains the typical aminopeptidases and degradation must be addressed [105,106]. Moreover, the extent of peptide permeation is unclear, and some histological studies indicate |
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