This study was conducted to compare the luminal composition of the upper gastrointestinal tract in the fasted and fed states in humans, with a view toward designing in vitro studies to explain/predict food effects on dosage form performance. Twenty healthy human subjects received 250 mL water or 500 mL Ensure plus® (a complete nutrient drink) through a nasogastric tube and samples were aspirated from the gastric antrum or duodenum for a period up to 3.5 h, depending on location/fluid combination. Samples were analyzed for polyethylene glycol, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, and bile salts. Following Ensure plus® administration, gastric pH was elevated, buffer capacity ranged from 14 to 28 mmoL L−1 ΔpH−1 (vs. 7–18 mmol L−1 ΔpH−1), contents were hyperosmolar, gastric pepsin levels doubled, and surface tension was 30% lower than after administration of water. Post- and preprandial duodenal pH values were initially similar, but slowly decreased to 5.2 postprandially, whereas buffer capacity increased from 5.6 mmol L−1 ΔpH−1 (fasted) to 18–30 mmol L−1 ΔpH−1 (p 30%, bile salt levels were two to four times higher, luminal contents were hyperosmotic, and the presence of peptides and sugars was confirmed. This work shows that, in addition to already well characterized parameters (e.g., pH, and bile salt levels), significant differences in buffer capacity, surface tension, osmolality, and food components are observed pre-/postprandially. These differences should be reflected in test media to predict food effects on intralumenal performance of dosage forms.

Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies.

Intestinal adaptation (first of two parts). Structural, functional and cytokinetic changes.

Pharmaceutical solid oral dosage forms must undergo dissolution in the intestinal fluids of the gastrointestinal tract before they can be absorbed and reach the systemic circulation. Therefore, dissolution is a critical part of the drug-delivery process. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient as well as properties of the dosage form. Just as importantly, characteristics of the physiological environment such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamics can significantly impact dissolution and absorption. While significant progress has been made since 1970 when the first compendial dissolution test was introduced (USP apparatus 1), current dissolution testing does not take full advantage of the extensive physiologic information that is available. For quality control purposes, where the question is one of lot-to-lot consistency in performance, using nonphysiologic test conditions that ma...

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Physiological Parameters for Oral Delivery and in Vitro Testing

Restraint stress in biomedical research: A review

Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds.

The effects of Secretin (3.5 U/100 g) and Pentagastrin (25 μg/l00 g) on cell renewal in jejunal mucosa was studied in male Wistar rats. The labeling index (LI), mitotic index (MI), and histogram of the distribution of labeled cells were measured at 4-hour intervals during 24 h after intraperitoneal injection of hormones and compared with results obtained in control animals. DNA label was obtained by injection of tritiated thymidine (70 μCi/100 g) 30 min before sacrificing the animals. The proliferation of intestinal cells in rats was marked by a circadian rhythm with a nocturnal peak of DNA synthesis. After Pentagastrin, the LI remained high for 16,20, and 24 h after injection, during the time the control levels diminished in the circadian rhythm. The normal MI and the enlargement of the zone of proliferation support the hypothesis of a stimulating effect of gastrin on intestinal cell renewal. After Secretin, the LI peak of the cycle was suppressed and the MI decreased, indicating an inhibiting effect of Secretin on intestinal cell renewal. Secretin and gastrin act as trophic factors on intestinal mucosa and produce opposite effects on cell proliferation.

Influence of scretin and pentagastrin on the circadian rhythm of cell proliferation in the intestinal mucosa in rats.

While quantitative or immunological studies of sulfated glycoproteins have been carried out in the gastric juice, the actual origin of these molecules is far from being established; indeed sulfate is not detected histochemically in the normal gastric mucosa. Contamination by salivary glands and/or small glands in the pharynx, trachea and esophagus may be a cause of error. Some observations in patients throw light on the actual source of the SGP in gastric juice. In a patient treated for a melanoma, and receiving 3 injections of radiosulfate, the saliva contained a SGP of specific activity 685 000 dpm/mg. There was no histochemical or histoautoradiographical evidence of sulfate in fundic biopsies 6 and 24 h after the injection of the isotope. In 2 esophagectomized patients, there was no evidence of SGP in the juice obtained at gastrostomy, i.e. after interruption of the alimentary tract under the esophagogastric junction. At the same time SGP were present in the salivary secretions. The esophagogastric junction was examined in 2 specimens: a large amount of acidic glycoproteins was detected in the cardiac glands. Sulfate esters were detected mainly above the epithelial junction. Thus esophageal cardiac glands may be responsible for the presence of SGP in the gastric juice. Sulfate esters are also present in the submucosal glands of the thoracic esophagus. SGP in the gastric juice are not secreted by the normal gastric mucosa. Contamination by salivary SGP is more or less avoidable. The glands at the esophagogastric junction represent an unavoidable element of contamination.

Origin of the sulfated glycoproteins in human gastric secretions.

Pure sulphated glycoproteins may be isolated from human gastric and salivary secretions following proteolysis with pepsin and precipitation with cetylpyridinium chloride. The sulphated glycoproteins a

R. Lambert

Papers

Influence of scretin and pentagastrin on the circadian rhythm of cell proliferation in the intestinal mucosa in rats.

Origin of the sulfated glycoproteins in human gastric secretions.

Sulfated glycoproteins in human salivary and gastric secretions.

Relationship Between Hydrogen Ion and Pepsin Concentration in Human Gastric Secretion

A Study of the Mechanisms of Inhibition of Peptic Proteolysis by a Sulphated Polysaccharide