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thiazide in rats due to prolonged gastric retention, in humans and dogs the effects were smaller. |
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Many studies of the oral delivery of proteins may be found in the controlled-release literature. There has yet to be any convincing data of intact oral absorption of a protein in vivo at sufficiently high bioavailabilities to be commercially viable and with sufficiently low intra- and intersubject variability in bioavailability to be safe. Many results are based on pharmacodynamic rather than pharmacokinetic results and are subject to considerable error. The combination of proteolysis and the macromolecular and hydrophilic nature of proteins minimize absorption from the GI tract. The use of carrier systems such as micelles or lipid vehicles [53] or proteinoids [54] may follow the flux of chylomicrons into the lymphatic system, but absorption from the lymphatics is poorly characterized. While enhancers may increase passive absorption across many regions of the GI tract [5558], such enhancement often depends on gross alterations of membrane properties that may also cause cellular lysis, inflammation, or at minimum, biochemical changes. When used in localized bursts, repair mechanisms may be able to handle such alterations. |
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Finally, proteins have been targeted to the colon, a region of lower proteolysis, to avoid proteolysis in the small intestine. However, the more thorough experiments still exhibit impractically low bioavailabilities. The colonic delivery systems use 3 basic approaches: (a) swelling upon sensing the pH change upon entering the colon, but this pH difference may be within the intersubject variation; (b) polymers that are subject to degradation by colonic bacteria; and (c) delayed release coatings or membranes that take advantage of the reproducibility of transit through the small intestine. The third approach has a faster development time in that conventional dosage forms may be modified without requiring new polymers with their extensive toxicological and processing requirements. A second more practical use of these colonic systems is for the niche of localized diagnosis and treatment of colonic diseases for which there are currently no convenient means of access. |
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A primary function of the skin is to protect the body from foreign insult and its three basic mechanisms of protection define the limitations of transdermal delivery: (a) the excellent barrier properties of the outermost layer, the stratum corneum, which is 1020 m thick and consists of keratinized epithelial cells joined by tight junctions, require the drug be very potent; (b) primary skin irritation, consisting of the local inflammatory trio of erythema, edema, and pain, that is initiated primarily by the cells surrounding the dermal vasculature just below the dermal-epidermal junction; and (c) after repeated insult, |
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