Neutron activation based gamma scintigraphic evaluation of enteric-coated capsules for local treatment in colon.

The fate of two colon-specific formulations developed in our previous study was investigated using a gamma scintigraphic imaging method. The formulations contained paracetamol and samarium oxide (Sm2O3) and either microcrystalline cellulose (MCC) or hypromellose (HPMC K4M) as diluent and were coated with Eudragit S polymer. The gamma scintigraphic evaluation proved that the products remained intact in the stomach and the upper gastrointestinal tract. The gastric residence time was less that 1h. Three to four hours after administration the formulations had reached the ileo-caecal junction, i.e. the small intestine transit time was approximately 3h. The capsules disintegrated in the ileo-caecal junction or in the ascending colon. The capsules containing MCC released the marker momentarily, the capsules containing HPMC K4M gradually spreading it to the whole colon. The gamma images also verified that the HPMC gel disintegrates completely in 12-14 h. While comparing the results to those previously obtained from the bioavailability studies it could be concluded that it is possible to develop colon specific drug products that begin releasing the drug in the ileo-caecal junction or at the beginning of the ascending colon and spread the drug dose to a larger surface area by using enteric coats and hydrophilic polymers.

Are chitosan formulations mucoadhesive in the human small intestine? An evaluation based on gamma scintigraphy.

Rapid passage through the proximal intestine can result in the low bioavailability of a drug substance with site-specific absorption characteristics in the upper gastrointestinal tract. To overcome this, there is increasing interest in developing gastro-retentive formulations and/or formulations that linger in the proximal parts of the small intestine, e.g. by using mucoadhesive polymers as excipients in formulations. In our recent study, we used neutron activation-based gamma scintigraphy to evaluate the gastro-retentive properties of formulations containing chitosan (Mw 150 kDa) in man. At the same time, we had an opportunity to monitor the transit of the formulations (40 or 95% of chitosan) in the small intestine. Gamma scintigraphic investigations revealed that although the chitosan studied had exhibited marked mucoadhesive capacities in vitro, retention of the chitosan formulations in the upper gastrointestinal tract was not sufficiently reproducible and the duration of retention was relatively short. In 3 volunteers out of 10, the formulation adhered to the gastric mucosa (retention times varied from 1.25 to 2.5 h) and in two volunteers to the upper small intestine (approximate retention time 45 min). In one case, the formulation adhered to the oesophagus. The system failed to increase the bioavailability of furosemide, a drug site-specifically absorbed in the upper gastrointestinal tract. As far as the kind of formulation studied is concerned, preparation of a system that is site-specific to the stomach and/or the upper small intestine seems difficult if the proposed mechanism of action is mucoadhesion. The results suggest that other mechanisms of action should also be studied.

Neutron activation-based gamma scintigraphy in pharmacoscintigraphic evaluation of an Egalet constant-release drug delivery system.

This paper is a report from a pharmacoscintigraphic study with an Egalet constant-release system containing caffeine and natural abundance samarium oxide. First the formulation was tested in vitro to clarify integrity during irradiation in the nuclear reactor. Then six healthy male volunteers were enrolled into the in vivo study. The in vitro release of caffeine obeyed all the time linear zero-order kinetics. The in vivo release of radioactive Sm2O3 consisted of three consequent linear phases with different slopes. The release rate was fastest while the product was in the small intestine and slowest when the product was in the descending colon. In terms of the bioavailability of caffeine, the most important factor seemed to be the residence time in the ascending and transverse colon. A long residence time in these sections led to high AUC values for caffeine.

Gamma scintigraphic evaluation of the fate of hydroxypropyl methylcellulose capsules in the human gastrointestinal tract.

The fate (movement and disintegration) of hard novel hydroxypropyl methylcellulose (HPMC) two-piece capsules in the human gastrointestinal tract was investigated using a gamma scintigraphic imaging method. Two different prolonged-release formulations without an active ingredient were used. The capsules contained different viscosity grades of HPMC powder (HPMC K100 and HPMC K4M). The aim was to determine the main reason why the pharmacokinetic profiles of model drugs change when the diluent was changed to a higher viscosity grade. The results were compared with our previous pharmacokinetic studies with corresponding capsules containing metoclopramide hydrochloride or ibuprofen as a model drug. The first observation was that the HPMC capsules had a tendency to attach to the oesophagus. Therefore, it is recommended that the HPMC capsules as well as gelatine capsules be taken with a sufficient amount of water (150-200 ml) in an upright position and maintaining the upright position for several minutes. The viscosity grade of the HPMC did not affect the transit times of the capsules in the GI tract. The major differences between the two formulations were the complete disintegration times of the capsules and the spreading of the capsules to the large intestine. Most of the HPMC K100-based capsules were completely disintegrated during the 8h study, whereas the HPMC K4M-based capsules still exhibited plug formations in the large intestine. Also the HPMC K100-based capsules spread better to the ascending colon than the HPMC K4M-based capsules. The faster disintegration of the HPMC K100-based capsules explains the differences in the pharmacokinetic profiles of the model drugs between the HPMC K100- and K4M-based capsules in our previous studies. The main absorption site of the drugs from the capsules studied here is probably the large intestine when taken in a fasting state.

Gamma scintigraphic evaluation of the fate of microcrystalline chitosan granules in human stomach.

In several reports of in vitro studies it has been suggested that the mucoadhesive chitosans could be of value in preparing gastro-retentive formulations. The aim of this study was to obtain direct in vivo evidence of whether microcrystalline chitosan (MCCh) formulations acted as gastro-retentive systems in humans. Neutron-activation-based gamma scintigraphy was used to study gastric residence times of MCCh granules in healthy male volunteers. Possible effects of neutron irradiation on the properties of the MCCh granules were studied in advance, in vitro. In vivo gamma scintigraphic evaluations were carried out with the subjects in a fasted state, using granules containing 95% (F1) or 40% (F2) of MCCh of molecular weight 150 kDa. Reference formulation (F3) was lactose granules. The reference granules passed rapidly from the stomach (mean t50% 0.5+/-0.3 h (n=5)). MCCh in granules prolonged gastric residence times of the formulations in only a few cases (in one volunteer in the F1 group (n=4) and in two volunteers in the F2 group (n=5)). Maximum individual t50% values were 2.1 h (F1) and 2.3 h (F2). It was concluded that the in vivo mucoadhesion of MCCh formulations is erratic, and that the formulations studied are not reliable gastro-retentive drug delivery systems.

Scintigraphic verification of adherence of a chitosan formulation to the human oesophagus.

It is well known that adherence of a drug product, e.g. a gelatine capsule, to the oesophagus can cause oesophageal injury, which can be severe if the medicinal agent has corrosive properties. In a recent study we investigated by means of gamma scintigraphy whether chitosan granules dispensed in gelatine capsules had gastro-retentive properties. In one of ten volunteers the formulation lodged in the oesophagus. This case is reported here. The capsule adhered initially to the distal oesophagus. The capsule shell had started to disintegrate within 5 min, with some radioactivity detectable in the stomach. However, about two thirds of the radioactivity remained detectable in the oesophageal region for 1.75 h. This could be explained on the basis that there had been adherence not only of the gelatine shell but also of chitosan granules to the oesophageal mucosa. In evaluating potential for causing oesophageal injury it is not enough to consider only the mucoadhesive properties of the outermost layer of a drug product, because the filler may also have such properties. When new excipient materials are introduced, evaluation of their mucoadhesive tendencies is important.

Orally administered targeted recombinant Beta-lactamase prevents ampicillin-induced selective pressure on the gut microbiota: a novel approach to reducing antimicrobial resistance.

Antibiotics that are excreted into the intestinal tract promote antibiotic resistance by exerting selective pressure on the gut microbiota. Using a beagle dog model, we show that an orally administered targeted recombinant beta-lactamase enzyme eliminates the portion of parenteral ampicillin that is excreted into the small intestine, preventing ampicillin-induced changes to the fecal microbiota without affecting ampicillin levels in serum. In dogs receiving ampicillin, significant disruption of the fecal microbiota and the emergence of ampicillin-resistant Escherichia coli and TEM genes were observed, whereas in dogs treated with ampicillin in combination with an oral beta-lactamase, these did not occur. These results suggest a new strategy for reducing antimicrobial resistance in humans.

Oral administration of beta-lactamase preserves colonization resistance of piperacillin-treated mice.

We hypothesized that orally administered, recombinant class A beta-lactamase would inactivate the portion of parenteral piperacillin excreted into the intestinal tract, preserving colonization resistance of mice against nosocomial pathogens. Subcutaneous piperacillin or piperacillin plus oral beta-lactamase were administered 24 and 12 h before orogastric inoculation of piperacillin-resistant pathogens. Oral administration of beta-lactamase reduced piperacillin-associated alteration of the indigenous microflora and prevented overgrowth of pathogens.

Enzymic degradation of a beta-lactam antibiotic, ampicillin, in the gut: a novel treatment modality.

Antibiotics can cause severe alterations in the gut microflora and promote diarrhoea and overgrowth of pathogenic bacteria. The present study investigated the potency of targeted recombinant beta-lactamase (TRBL) to degrade a beta-lactam antibiotic in the jejunum of fistula-operated beagles. We used different peroral doses of purified beta-lactamase (PenP) of Bacillus licheniformis in enteric-coated pellets together with intravenous ampicillin. Serum and jejunal samples were collected for ampicillin and beta-lactamase analysis. A dose-response effect of TRBL on ampicillin concentrations in the jejunal samples could be observed. The highest doses applied decreased the jejunal ampicillin concentrations to undetectable levels. In the serum samples, the ampicillin concentrations were not affected by the beta-lactamase dose used. Our results indicate that it may be possible to evolve a targeted treatment to degrade beta-lactam antibiotics intestinally and, thus, decrease antibiotic-induced adverse effects on the gut microflora.