Gastrointestinal Tracking and Gastric Emptying of Coated Capsules in Rats with or without Sedation Using CT imaging

Abstract

Following oral administration, gastric emptying is often a rate-limiting step in the absorption of drugs and is dependent on both physiological and pharmaceutical factors. To guide translation into humans, small animal imaging during pre-clinical studies has been increasingly used to localise the gastrointestinal transit of solid dosage forms. In contrast to humans, however, anaesthesia is usually required for effective imaging in animals which may have unintended effects on intestinal physiology. This study evaluated the effect of anaesthesia and capsule size on the gastric emptying rate of coated capsules in rats. Computed tomography (CT) imaging was used to track and locate the capsules through the gastrointestinal tract. Two commercial gelatine mini-capsules (size 9 and 9h) were filled with barium sulphate (contrast agent) and coated using Eudragit L. Under the effect of anaesthesia, none of the capsules emptied from the stomach. In non-anaesthetised rats, most of the size 9 capsules did not empty from the stomach, whereas the majority of the smaller size 9h capsules successfully emptied from the stomach and moved into the intestine. This study demonstrates that even with capsules designed to empty from the stomach in rats, the gastric emptying of such solid oral dosage forms is not guaranteed. In addition, the use of anaesthesia was found to abolish gastric emptying of both capsule sizes. The work herein further highlights the utility of CT imaging for the effective visualisation and location of solid dosage forms in the intestinal tract of rats without the use of anaesthesia.

X-ray Imaging for Gastrointestinal Tracking of Microscale Oral Drug Delivery Devices

“…39 Recently, CT scanning of anesthetized and non-anesthetized rats, orally administered with millimetersized gelatin capsules filled with BaSO 4 , was used to investigate how sedation affects GI transit. 40 However, there have not yet been performed any X-ray imaging studies with microscale oral drug delivery devices. Only millimeter-sized devices have previously been investigated and tracked in detail with X-ray imaging.…”

Effect of Food and an Animal’s Sex on P-Glycoprotein Expression and Luminal Fluids in the Gastrointestinal Tract of Wistar Rats

“…Rats are one of the most commonly used pre-clinical animal models in oral drug development due to their low cost, ease of handling, and, more importantly, the similarities between their GI tract and those of humans [14][15][16][17]. Our group has previously found a sex difference in the bioavailability of a P-gp substrate ranitidine after administration with the excipient poly(ethylene glycol) (PEG) 400 in humans [18] and rats [19,20].…”

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

“…Several advanced, preferably noninvasive and real-time, imaging technologies have been adopted to overcome this hurdle, but further progress is still required. Magnetic resonance (MR), contrast-enhanced MR, computed tomography (CT) and nuclear imaging, capsule endoscopy, 3D endoscope imaging, high-resolution electrical mapping, and electrogastrogram have been used to visualize the gut lumen (patho)-physiology and gain insight into the in vivo behavior of drug/formulation in preclinical species, healthy humans, and patients. − Furthermore, systematic exploration of the capabilities of molecular dynamics (MD) simulations, synchrotron small-angle X-ray scattering, coherent anti-Stokes Raman spectroscopy, and surface plasmon resonance would promote understanding of membrane transport, drug-colloidal structures interactions, lipid imaging at the molecular level, drug or excipient release, disposition, and intracellular concentrations. ,,, Thus, a plethora of opportunities not only for GI imaging but also for the development of data analysis and in silico tools, which will be interacting or even be integrated into PBPK models, is foreseen.…”