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specific barrier layers to macromolecules, e.g., horseradish peroxidase [107]. Buccal tissue culture models are in development from hamster cheek pouch, a keratinized mucosa [108], and from canine mucosa [109], but the results are too early to evaluate. These models should permit careful evaluation of transport and biochemistry concurrently. Development of controlled-release buccal devices requires early and extensive in vitro and in vivo assessment of adhesion. |
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Nasal anatomy is designed to provide sizable resistance to air flow and to control the temperature and humidity of inhaled air. In an adult, the surface with an area of about 180 cm2 is lined with pseudostratified columnar epithelium. The blood perfuses the nasal cavity with a flow of 40 mL/cm for each 100 g tissue [110]. Nasal delivery is particularly convenient for local delivery of drugs, for treatment of allergic rhinitis and cold symptoms, and avoids hepatic metabolism. Trapped particles are removed by the mucociliary clearance with a mean turnover rate of 15 minutes [111]. Large particles have difficulty passing the nasal valve, a constriction. From in vitro studies of nasal mucosa in Ussing chambers, nasal mucosa is a leaky epithelium [112], and transport appears to be by parallel lipoidal and shunt pathways with oil and water solubilities and molecular weight providing an estimate of permeation [113]. While large proteins are not absorbed, small peptides such as the somatostatin analogs and oxytocin can show excellent bioavailabilities [114]. |
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Drugs may be administered intranasally as aerosols, powders, or small particulates. Sterility, stability, toxicology, and effects on delivery of adjuvants should be evaluated [115]. Design of an inhaler device is also a key to reproducible dosing. Plasticizers and other excipients in gaskets and seals may interact with the formulation, and their effects must be evaluated [116]. |
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Stability, bioavailability, and patient compliance may be substantially influenced by the actual device, and the device should be finalized by the latter stage of Phase II. For local delivery and potent drugs, accurate measurement of bioavailability is a concern, particularly for narrow therapeutic windows. Studies of the reproducibility of delivery within and among subjects are critical. |
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Screening of formulations may be performed in vitro. While the in situ rat perfusion model, in which inlet and outlet concentrations are measured, is the most popular model [117], sheep and primate models are to be preferred [118], although less convenient. |
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While the trachea and bronchi are lined with pseudostratified columnar epithelium, the bronchioles are lined with columnar ciliated epithelium, and in the alveoli, the barrier is a thin capillary membrane. While drug delivery to the |
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