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the speed of drug development can lead to immediate selection of conventional dosage forms. While the use of innovative approaches to drug delivery may have profound effects on the drug development process, the overall process and the probability of success may increase. A novel dosage form typically requires multiple Phase I or Phase IIa trials to research and optimize the dosage form, but Phase IIb and Phase III may be shorter, particularly if steady-state pharmacokinetics/pharmacodynamics in Phase IIa simplify the dose finding. This section serves as a guide to the novice in drug delivery to expand one's options and to understand its impact on development. |
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Any biological membrane in the human body is a potential portal for drug delivery. We elect to concentrate on the GI tract, transdermal, buccal, nasal, pulmonary, and parenteral delivery. Reviews including other routes such as vaginal, intrauterine, ocular, and rectal may be found elsewhere [21,22]. |
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Since oral delivery is the preferred route of drug delivery, problems in absorption, metabolism, or local tolerability define the rationale for other routes of delivery. Within the context of this review, 4 areas impinge on the drug development process: (a) the use of appropriate tools to screen absorption in the drug discovery process; (b) extended release dosage forms to lengthen the product life for short half-life drugs and the role of infusion studies in regions of the GI tract and scintigraphy in Phase I and IIa to define the dosage form; (c) niche therapies involving diseases of the local regions of the GI tract; and (d) oral peptide and protein delivery and whether this approach is realistic. |
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Transit through the GI tract may profoundly affect the performance of the dosage form. A median total transit time of 27.4 hours with a range of 5.1 to 38.3 hours was determined from the recovery of oral osmotic pumps [23]. Gastric emptying from the stomach with a pH of approximately 2 varies between 0.5 and 2 hours in the fasted state [24]. After feeding, larger dosage forms exit after the meal has emptied while small pellets empty with the meal [25,26]. Many factors may influence the gastric emptying time including caloric content, disease states, or various drugs. Transit through the small intestine is more reproducible and is typically 34 hours [27]. The values of pH in the duodenum and ileocecal junction are 5.8 ± 0.8 and 6.5 to 8.5, respectively [28], but the pH near the jejunal membrane may be 6.1 versus 7.2 in the bulk [29,30]. An increase in pH of 0.51.0 unit is typical of entry into the colon. Colonic transit is highly variable and is typically 1020 hours [31]. |
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Degradation of drugs may occur by hydrolysis in the stomach, by enzymatic digestion such as proteolysis in the small intestinal fluid, by metabolism in the gut wall, and by microorganisms in the colon. Extensive metabolism may also occur in the liver that is directly perfused by the portal blood supply leaving |
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