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Pharmaceuticals), an appetite suppressant, an elementary osmotic pump was designed to deliver 3.5 mg/h following a 20-mg bolus dose achieved by coating the semipermeable membrane with an immediate release fraction [47]. The plasma concentration of phenylpropanolamine remains at or above 60 ng/ml for 16 hours in contrast to the peaks associated with side effects from rapid-release dosage forms. |
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The push-pull OROS has a flexible impermeable partition spanning the interior of the semipermeable membrane and dividing the OROS into two compartments: (a) a drug compartment where the hole is present and (b) a compartment containing the osmotic agent. Procardia XL (marketed by Pfizer Inc.) delivers 20, 60, or 90 mg nifedipine, a calcium channel blocker, as a once-a-day dosage form [47]. It is an example of the use of a controlled-release dosage form to extend product life by using a patented dosage form to provide patent protection on a brand-name drug after the patent exclusivity on the chemical entity has expired (see below, Recent Successes). |
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The development of controlled-release oral dosage forms requires Phase I infusion studies in man in different regions of the GI tract, particularly duodenal and colonic infusions. Absorption or degradation from the colon may be a problem and needs to be examined. Inter- and intrasubject variation in absorption, particularly due to first-pass metabolism, may be characterized. Studies of transit recovering the osmotic pump [23], gamma scintigraphy [31], or Heidelberg capsules [28] can be helpful in understanding the performance of the dosage form. Differences in osmotic pressure in regions of the colon may necessitate compensation of the rate of drug delivery. However, it is likely that intersubject variation in GI transit may preclude designing release over too long a period. If diminished frequent side effects while maintaining efficacy is to be part of the labeling, pharmacokinetic/pharmacodynamic studies should be planned in Phase IIa. Minimal Phase III studies without Phase IIb would be a likely clinical program. |
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Extension of GI transit has been proposed for further decreasing the frequency of oral dosing. However, no such dosage forms are marketed, perhaps due to a lack of matching a therapeutic application of sufficient market potential to the technological possibilities. Dosage forms of various size or density have been investigated to delay gastric transit. Gastric transit has also been avoided by producing dosage forms that swell to become too large to pass through the pylorus. As the emptying time is typically within the range of emptying time for solids, these dosage forms have had limited success. A second approach is bioadhesion to soft mucosa or the mucus lining the GI tract [48,49]. Highly swollen hydrogels such as polyacrylic acid and carboxymethylcellulose may depend on entanglements and hydrogen bonding for this adhesion [50,51,52]. Sialic acid with its negative charge may also be important for mucoadhesion. While polycarbophil has been shown to double the bioavailability of chlor- |
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