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The in vivo effects of pharmaceutical excipients on gastrointestinal transit and drug absorption

Schulze, Julia Dorothee Regina; (2003) The in vivo effects of pharmaceutical excipients on gastrointestinal transit and drug absorption. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The objective of the project was to identify and characterize the in vivo effects of various pharmaceutical excipients, commonly employed as solubility enhancing agents, on gastrointestinal transit and drug absorption in humans and canines. Previous reports had indicated that high doses of the cosolvent polyethylene glycol 400 (PEG 400) accelerate the transit of oral liquid formulations through the small intestine leading to a reduction in drug bioavailability In human subjects, the effects of PEG 400 were investigated at amounts of 0, 1, 2.5 and 5g using the non-invasive technique of gamma scintigraphy combined with simultaneous assessment of pharmacokinetic data. The transit effect of PEG 400 was established to be dose-dependent, decreasing the small intestinal transit time of the administered liquid formulations even at concentrations as low as Ig. Surprisingly, a degree of dose-dependency of PEG 400 was also found with respect to the absorption of the model drug ranitidine. At higher concentrations the bioavailability of ranitidine was markedly reduced most likely due to shorter transit times since PEG 400 was shown not to affect passive drug diffusion. The absorption of ranitidine, however, was significantly increased in the presence of Ig PEG 400, potentially due to modulation of intestinal permeability. In separate scintigraphic studies the solubilizers propylene glycol, D-α-tocopheryl polyethylene 1000 succinate (VitE-TPGS), Labrasol® and Capmul® MCM were found not to affect small intestinal liquid transit but influenced the absorption of coadministered model drugs. The oral bioavailability of ampicillin was considerably reduced in the presence of propylene glycol, most likely as a result of the osmotic activity of the excipient, and Capmul® MCM, possibly via alterations in intestinal membrane function. VitE-TPGS was observed to increase the absorption of ranitidine by enhancing its permeation through the absorptive membrane. The results obtained in an in vivo scintigraphic study in four beagle dogs correlated well with findings from the human studies regarding gastrointestinal transit. Differences observed in drug absorption were most likely a result of interspecies differences in the permeability of the intestinal mucosa. These findings are expected to have ramifications for the use of these excipients in drug development and dosage form design.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The in vivo effects of pharmaceutical excipients on gastrointestinal transit and drug absorption
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10106294
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