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the intestine prior to entering the systemic circulation. Gut wall or hepatic first-pass metabolism may lead to highly variable or poor absorption of drug into the systemic circulation. Metabolized or intact drug may also be recirculated into the small intestine after biliary excretion. |
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In spite of these complications, prediction of drug absorption from the GI tract has had some success. Simple models correlate oil solubility or melting point with absorption through a lipid membrane [32,33] with water solubility added to account for dissolution in the fluid [34]. More complex hydrodynamic models of flow through tubes may also be useful [35,36,37]. The use of these physical parameters with the models in combination with measurements of absorption in cell culture, such as CaCO2 [38], intestinal segments [39], or Ussing chambers can be invaluable screening tools when used as a guide to drug discovery to define structure/absorption/enzyme activity. The use of a physical model alone may particularly be in error for those ionized drugs that may be absorbed by active transport such as angiotensin-converting enzyme inhibitors and b-lactam antibiotics. While the models may not be definitive, the potential need for employing novel drug delivery or terminating projects may be highlighted early. |
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Oral controlled-release dosage forms may be designed to decrease the frequency of dosing by targeting a continuous delivery rate to the trough plasma levels resulting from steady-state dosing of the conventional dosage form. A variety of oral controlled-release dosage forms exist including microcapsules and coated pellets [40], ion exchange resins [41], hydrogels [42], and osmotic pumps [43]. Hydrogels may be reproducibly loaded with drug, designed to deliver over a wide range of delivery rates, and permit simple removal of monomers, initiators, stabilizers, and other species with unacceptable toxicological profiles. The cumulative release from a hydrogel is generally proportional to the square root of time, although there is extensive academic work on hydrogels that provide constant release. Such zero-order hydrogels release by such mechanisms as novel geometries [44], Case II diffusion [45], and dissolution-controlled systems [46]. When novel polymers are the basis of the controlled-release system, extensive toxicological studies are required and GMP scale-up and production issues are important. The uniqueness of the selection of these polymers should justify the time and cost. |
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Oral osmotic pumps (OROS) may be used to tailor the delivery rate to that of constant infusions. In practice, the limitations of drug solubilities and reasonable pressures are determined by the choice of membrane. Water diffuses down its activity gradient across a membrane impermeable to drug and exerts a constant pressure that forces the drug through a small hole. In the elementary osmotic pump, a semipermeable membrane, through which a delivery portal is drilled, surrounds a core of drug that may act as its own osmotic agent. In the case of Acutrim 16 hour steady-state control tablets (Ciba Consumer |
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