Biomedical subjects
Publications and source records attributed to H Bechgaard.
The transit of pellets of different densities (0.94 and 1.96 g cm-3) through the gastrointestinal tract of ileostomy subjects has been followed using the technique of gamma scintigraphy. In contrast with earlier reported results, the transit of the pellets was not affected by particle density.
A concomitant meal did not affect the extent of bioavailability of indomethacin from a multiple-units controlled-release capsule formulation containing enteric-coated pellets, but the presence of food delayed absorption. When a capsule containing 75 mg indomethacin was administered after a 12 h fast, the mean peak drug concentrations in plasma of 2.7 micrograms/ml +/- 0.8 SD occurred at a mean time of 4.2 h (range 2-6 h). When this dose was administered with a substantial breakfast, the mean of the peak plasma concentration of 2.2 micrograms/ml +/- 1.0 SD occurred at 6.4 h (range 5-12 h). Secondary peak plasma drug concentrations, occurring at approximately 14 h after dosing, were more prominent and the times to reach the second peak more variable when the capsules were administered with food. Drug bioavailability after co-administration with food was 91% of that following administration after fasting. When the controlled-release capsule was administered during 3 days in a b.i.d. dosage regimen, drug bioavailability was 103% of that from a standard capsule administered q.i.d. The mean peak level after administration of the last dose of 50 mg as controlled-release capsules was 2.5 micrograms/ml +/- 1.1 SD and the means of peak levels after the penultimate and last doses of 25 mg as standard capsules were 2.0 micrograms/ml +/- 0.3 SD and 2.1 micrograms/ml +/- 0.7 SD, respectively. The controlled-release capsule formulation was a reliable and reproducible source of indomethacin when administered as repeated doses or with food.
The in vitro release of drugs from controlled-release dosage forms has been studied in terms of a diffusion model. The model has been applied to a pellet formulation containing propoxyphene hydrochloride. It is demonstrated that the model may be used to predict the drug release profile adequately, when the pellet size is changed and when the thickness of the coating is varied. The size distribution of pellets in an experiment may be too broad to justify a simulation with just one average pellet size. Therefore, the results for pellets of the same size are generalized to any size distribution of pellets in an experiment. This is only trivial if sink condition exists in the extraction medium, since under that condition, the release from each pellet type is independent of the releases from other pellet types. In that case, the total release may therefore be found as the sum of the individual releases. In the general case considered here, the releases are coupled.
Two multiple-units controlled-release indomethacin capsule formulations containing enteric-coated pellets were bioequivalent to a standard capsule formulation (taken as the reference) in respect of extent of bioavailability in a crossover study with normal human subjects. However, drug absorption from the enteric-coated pellet formulations was slower, when compared to that from the standard reference capsule. The standard reference capsule released 85% of its drug content in vitro during 10 min at pH 6.5 and 98% during 1 h at pH 7.5. On enteric-coated pellet capsule formulation (I) released 77% during 1 h at pH 6.5 and the other (II) released 10% during 1 h at pH 6.5. Release of drug from each capsule of enteric-coated pellets was complete during 1 h at pH 7.5. Although differences in areas under the plasma indomethacin concentration-time curves were not significantly different, the peak plasma levels and the times of their occurrence indicated that the absorption rates of indomethacin decreased in the order, reference formulation greater than pellet formulation I greater than pellet formulation II, which was the same rank order as that of their dissolution rates in vitro. The data indicated that multiple units controlled-release formulations represent a reliable and reproducible source of indomethacin, which by avoiding extremes of local or systemic drug concentrations also should be better tolerated by individuals susceptible to unwanted gastrointestinal and centrally-mediate side-effects.
The relative availability of potassium from a controlled-release multiple-units tablet (Kalinorm) and a single-unit tablet (Slow-K) were compared in 13 volunteers on a low potassium diet (less than 30 mmol), by observing changes in urinary potassium excretion after administration of a single dose of 32 mmol potassium, either with or without water loading. Irrespective of procedure, the two products had the same extent of availability. The use of water loading, and special precautions about the level of dietary potassium and its composition when studying urinary potassium excretion, are discussed. It is suggested that water loading should be avoided when investigating the rate of potassium excretion.
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Two types of controlled-release formulations of propoxyphene hydrochloride, one with a buffer system in the pellet core, were studied with regard to intra- and intersubject variations of Cmax and Tmax of propoxyphene as well as propoxyphene plus norpropoxyphene in 35 volunteers after administration of a single 150-mg dose. Statistically significant differences between the formulations in intrasubject variance were revealed, and the availability rate of the buffered product showed significantly better reproducibility, presumably due to the established low sensitivity of its release rate to the in vitro environment.
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The influence on transit time exerted by the density or diameter of pellets has been established in six ileostomy subjects. An increase in density from 1.0 to 1.6 significantly increased the average transit time of pellets in the small intestine. The average transit time for the light and heavy pellets being 7 and 25 h respectively. The diameter of pellets is of minor significance. The findings suggest the use of density as a means of modifying the period of absorption of controlled-release pellets.
By using the GI tube technique, niacin was shown to be equally well absorbed from the stomach and the upper small intestine. The maximum plasma niacin concentrations occurred 10-20 and 5-10 min, respectively, after instillation. Thus, the physiological prerequisites for a physically retarded niacin preparation were established.
1 In a single-blind, cross-over study fenfluramine in a daily dose of 120 mg was found to reduce the daily blood glucose level moderately in hospitalized obese diabetics treated with a 1200 calorie diabetic diet. 2 After 7 days of treatment, fenfluramine was found not to influence the intravenous glucose tolerance, the insulin response to intravenously administered glucose, or the growth hormone response to arginine. 3 No changes in blood levels of lactate, beta hydroxybutyrate, triglycerides or cholesterol were seen during fenfluramine treatment.
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