The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers.

UNLABELLED: We report the safety, biodistribution, and internal radiation dosimetry of a new PET tracer, (18)F-AH111585, a peptide with a high affinity for the alpha(v)beta(3) integrin receptor involved in angiogenesis. METHODS: PET scans of 8 healthy volunteers were acquired at time points up to 4 h after a bolus injection of (18)F-AH111585. (18)F activity in whole blood and plasma and excreted urine were measured up to 4 h after injection. In vivo (18)F activities in up to 12 source regions were determined from quantitative analysis of the images. The cumulated activities subsequently calculated were then used to determine the internal radiation dosimetry, including the effective dose. RESULTS: Injection of (18)F-AH111585 was well tolerated in all subjects, with no serious or drug-related adverse events reported. The main route of (18)F excretion was renal (37%), and the 3 highest initial uptakes were by liver (15%); combined walls of the small, upper large, and lower large intestines (11%); and kidneys (9%). The 3 highest absorbed doses were received by the urinary bladder wall (124 microGy/MBq), kidneys (102 microGy/MBq), and cardiac wall (59 microGy/MBq). The effective dose was 26 microGy/MBq. CONCLUSION: (18)F-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common (18)F PET tracers.

Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems.

PURPOSE: Oral pH triggered drug delivery systems, for targeting to the lower gastrointestinal tract, show erratic behaviour in vivo. This study aimed to establish correlations between in situ gastrointestinal pH, transit time or feed status and the disintegration of pH-responsive dosage forms designed to dissolve above pH 7. METHODS: Tablets (radiolabelled with Technetium 99m) coated with Eudragit S were administered to eight healthy subjects in a three-way crossover study after an overnight fast. Food was administered either 30 min after (pre-feed) or 4 h after (fasted) tablet ingestion. Concurrently, a Bravo pH monitoring capsule (radiolabelled with Indium 111) was administered in a "freefall manner". In a third arm of the study tablets were given immediately after breakfast (fed). Transit was followed by gamma scintigraphy. RESULTS: Gastrointestinal pH showed variability between and within individuals but no differences were seen between pre-feed and fasted states. Three tablets failed to disintegrate in pre-feed and fed regimens and one in the fasted state; this has been tentatively linked to ileocaecal pH and ileoceacal junction residence time. CONCLUSIONS: In vivo performance of "pH-responsive" dosage forms is complex and influenced by a multitude of factors other than just in situ pH.

An investigation into the in vivo performance variability of pH responsive polymers for ileo-colonic drug delivery using gamma scintigraphy in humans.

Gastrointestinal performance of tablets coated with pH responsive acrylic polymers (Eudragit) was investigated in human volunteers. Tablet cores were coated with Eudragit S dissolved in ethanol (organic), Eudragit S aqueous dispersion (aqueous), or Eudragit FS aqueous dispersion. Eight fasted volunteers received the tablets in a two-way crossover design-treatment 1: Eudragit S (organic) and Eudragit FS coated tablets; treatment 2: Eudragit S (aqueous) and Eudragit FS coated tablets. Eudragit FS coated tablets were included in both treatments to assess its intra-subject performance. Tablets were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. Tablets coated with Eudragit S (aqueous) disintegrated in all volunteers mainly in the proximal to mid small intestine. Eudragit S (organic) tablets failed to disintegrate in three out of eight volunteers, while disintegration was in the ileo-caecal junction and ascending colon in all others. Eudragit FS coated tablets disintegrated in 14 out of the 16 administrations. The Eudragit FS coated tablets that did disintegrate exhibited consistent intra- and inter-subject performance, with the site of disintegration focused on the ileo-caecal junction and ascending colon. These in vivo results correlate better with our published in vitro dissolution data in physiological bicarbonate buffers compared to phosphate buffers.

Impact of formulation excipients on human intestinal transit.

The accelerating effect of polyethylene glycol 400 on small intestinal transit has been previously reported. The aim of this study was to investigate the influence of other solubility-enhancing excipient, propylene glycol, D-alpha-tocopheryl-polyethylene glycol-1,000 succinate (VitE-TPGS) and Capmul MCM, on human intestinal transit. A 5-g dose of each excipient was administered to seven healthy male subjects. Propylene glycol and VitE-TPGS were administered dissolved in 150 mL water. Capmul MCM was administered in the form of four 000 hard gelatin capsules to mask its taste and then given with 150 mL water. On a separate occasion, 150 mL water was administered as the control. Each formulation was radiolabelled with technetium-99 m to follow its transit using a gamma camera. The mean small intestinal transit times were 234, 207, 241 and 209 min for the control, propylene glycol, VitE-TPGS and Capmul MCM treatments, respectively. Although there were differences in the small intestinal transit times for the excipients investigated compared with the control, none of the results were statistically significant. Unlike polyethylene glycol 400 at the same dose of 5 g, the excipients tested (propylene glycol, VitE-TPGS and Capmul MCM) had little or no impact on small intestinal transit.