Interaction between water and poly(vinylpyrrolidone) containing polyethylene glycol.

Information on the interaction between water and polymers is indispensable for manufacturing solid dispersion of a drug by hot-melt extrusion because this interaction affects various properties of the water-polymer mixtures, such as their viscoelastic properties. In this study, poly(vinylpyrrolidone) K30 (PVP) containing 0%, 10%, and 20% poly(ethylene glycol) 400 (PEG) was used as model amorphous polymers. The interaction of water with these polymers was assessed by the evaluation of the glass transition temperature (Tg), the point on the isotherm corresponding to the weight of sorbed water required to form a complete monolayer on the solid surface (apparent Wm), and the maximal amount of nonfreezing water, which were measured by differential scanning calorimetry and water sorption isotherms. In all of the systems with a water content below a certain water fraction (0.1 for PVP, 0.12 for PVP-PEG 10%, and 0.16 for PVP-PEG 20%), the Tg values were successfully predicted using theoretical equations, whereas the experimental Tg values were higher than predicted for those with a water content above these water fraction levels. In addition, these values of water fraction are similar to the apparent W(m) values determined using the Guggenheim-Anderson-DeBoer (GAB) equation (0.110, 0.117, and 0.147 weight fraction of water for PVP, PVP-PEG 10%, and PVP-PEG 20%, respectively). Nonfreezing water is detected above 0.47, 0.49, and 0.51 weight fraction of water for PVP, PVP-PEG 10%, and PVP-PEG 20%, respectively. Miscibility between water and PVP or PVP-PEG seems to change according to the water content in the system. All parameters increase with the concentration of PEG in the sample. This may be explained by the fact that PEG has a larger number of polymer repeating units, which may therefore interact with water more than PVP.

Characterization of mitomycin C-induced gastrointestinal damage. I. In situ recirculation experiment.

The effects of mitomycin C (MMC), an anti-tumor agent, on the intestinal absorption of various drugs in rats were investigated. Based on microscopic observations, preadministration of a single intravenous dose of MMC (3 mg/kg) caused serious degeneration of epithelial cells, villous atrophy, and mitotic arrest in crypts at 48 hr after pretreatment. At this time point, absorption of sulfanilamide, salicylic acid, cephalexin, and L-tryptophan was shown to be significantly decreased by means of an in situ recirculation technique. The histological changes and the decrease in absorption of sulfanilamide, a model for passively absorbed drugs, were shown to depend on the timing of MMC pretreatment. Maximal effects were observed 48 hr after dosing. The MMC-induced reduction in the absorption of drugs was not a result of differences between treated and control animals with respect to pH of the drug solution, binding of drugs with intraluminal macromolecules, or intestinal mucosal blood flow. The absorption of sulfanilamide from the small intestine in the in situ system correlated well with the wet weight of the small intestine regardless of pretreatment dose or route. This suggests that the change in absorptive surface area of the intestinal mucosa may play a major role in the MMC-induced decrease in absorption capacity of the intestine.

Characterization of mitomycin C-induced gastrointestinal damage. II. In vitro everted sac experiment.

The everted gut sac technique was employed to clarify the effects of preadministration of mitomycin C (MMC) on intestinal transport of various drugs. Loss of intestinal tissue weight and increase in mucosal-to-serosal fluxes of passively absorbed drugs were noted in the case of MMC pretreatment, although the extent of the latter effect varied according to the inherent absorbability of each drug. The maximal effect of MMC on intestinal tissue weight and transport of sulfanilamide, a model of a passively absorbed drug, was observed 48 hr after pretreatment. The increase in the transfer of sulfanilamide correlated well with the MMC-induced decrease in intestinal tissue weight. These phenomena may result from the shortened transfer distance from mucosal to serosal fluid and impaired barrier function of the intestinal mucosa. On the other hand, transport of actively absorbed 3-O-methyl-D-glucose was not influenced by MMC pretreatment, which could be explained by an increment in the passive permeation counterbalancing the decrement in the active permeation. The present study also suggested that the measurement of transport of drugs through everted gut sacs might be useful as a simple and qualitative index of gastrointestinal mucosal damage.

Immunological control of drug absorption from the gastrointestinal tract: the mechanism whereby intestinal anaphylaxis interferes with the intestinal absorption of bromthymol blue in the rat.

Rats were immunized intraperitoneally with ovalbumin and the disappearance of bromthymol blue (BTB) from the intestinal lumen, its accumulation in the tissue, and its net absorption were examined by means of an in-situ recirculation technique during local anaphylaxis. The disappearance of BTB from the intestinal lumen and its net absorption were significantly reduced, but there was no significant effect on its accumulation in the tissue. The pH value of the luminal solution and the perfusate volume were not influenced by intraluminal challenge with the antigen in ovalbumin-immunized rats. In addition, no significant effect was observed on intestinal permeability to BTB in the in-vitro everted sac technique. The intestinal blood flow, measured by a hydrogen clearance method, was not reduced significantly by the intraluminal exposure to antigen. There was enhanced Evans Blue leakage and mucus release in the perfusate after intraluminal challenge with ovalbumin in ovalbumin-immunized rats, but not in non-immunized rats. A significant increase of BTB binding with macromolecular substances in the perfusate was observed during the local anaphylaxis. These findings suggest that the decreased absorption of BTB is due to the interaction with the macromolecular substances in the perfusate during local anaphylaxis.

Changes in D-glucose uptake by brush-border vesicles from small intestine of rats treated with mitomycin C.

The effect of mitomycin C pre-administration on the D-glucose transport system in the intestinal brush-border membrane of rat small intestine was examined by a rapid filtration technique. Forty-eight hours following the intravenous administration of mitomycin C, there were extensive and severe mucosal derangements. At this time point, membrane vesicles were prepared from the mitomycin-C-pretreated and control rats. Binding studies indicated that D-glucose entered into the intravesicular space of vesicles even in the case of mitomycin-C-pretreated rats. Vesicles obtained from both the mitomycin-C-pretreated and the control rats showed sodium-dependent uptake of D-glucose, but the initial uptake at 15 sec was significantly greater in control rats than in mitomycin-C-pretreated rats. Comparison of kinetic parameters of D-glucose transport indicated that Km was not significantly different between control and mitomycin-C pretreated rats. The pretreatment with mitomycin C decreased Vmax and increased the diffusional permeability to D-glucose considerably. These changes induced by mitomycin C seemed to derive not from a direct effect on mature enterocytes but from an indirect effect secondary to mitotic inhibition in the crypts.

Effect of temperature on intestinal transfer and tissue uptake of sulfanilamide and aminopropyron in vitro.

The effect of temperature on the transfer and the tissue uptake of sulfanilamide and aminopropyron, an aminopyrine derivative, was investigated using the everted and the non-everted sacs of rat intestine. The M (mucosa) to S (serosa) transfer of sulfanilamide was slightly faster than reverse S-to-M in the ileum at the temperatures studied. Decreased transfer and tissue uptake of sulfanilamide with decreasing temperature were observed using both ileal everted and non-everted sacs. On the contrary, the M-to-S transfer of aminopropyron was slower than the S-to-M transfer in the ileum. The tissue uptake of aminopropyron was almost constant at any temperature in the ileal non-everted sac experiments, while a decreased transfer of aminopropyron was observed with a decrease in temperature. Similar results, like aminopropyron in the ileum, were obtained in the experiments of aminopropyron and sulfanilamide using the colonic sacs. It is concluded that a close relationship may exist between the directional superiority in the transfer and the temperature independency of the tissue uptake.

Immunological control of drug absorption from the gastrointestinal tract: effect of local anaphylaxis on the intestinal absorption of low molecular weight drugs in the rat.

Intestinal absorption of various drugs was examined by means of in situ recirculation technique during local anaphylaxis. The antibody was determined by passive cutaneous anaphylaxis technique in rats immunized once or three times. The optimal condition of local anaphylaxis was determined by the leakage of Evans Blue. The most significant increase in leaks of the dye was observed by the intraluminal challenge with 400 mg of ovalbumin for 10 min in ovalbumin-immunized rats, and this condition was chosen as the optimal condition of local anaphylaxis. Under this condition, intestinal absorption of caffeine, phenylbutazone, and bromthymol blue (BTB) significantly decreased in ovalbumin-immunized rats compared with the control, whereas no significant effect was noted in the intestinal absorption of salicylic acid, quinine, pralidoxime iodide (2-PAM), tetracycline, and phenol red. In normal rats, no significant decrease was obtained in the intestinal absorption of caffeine, phenylbutazone, and BTB. On the other hand, the decreased absorption of BTB was not found in ovalbumin-immunized rats by the intraluminal challenge with bovine gamma-globulin. Furthermore, there was no significant change in the decreased absorption of BTB between rats immunized once and three times. The most effective condition for decreased BTB absorption was observed by the intraluminal challenge with 200 mg of ovalbumin for 10 min in ovalbumin-immunized rats, which almost correlated with the data of Evans Blue leakage. From these observations, it appears that the mucosal immune responses affect the intestinal absorption of low molecular weight drugs.

An assessment of gastric ulcers in vivo: enhancement of urinary recovery after oral administration of phenolsulfonphthalein in rats.

The permeability of gastric wall barrier to phenolsulfonphthalein (phenol red), a poorly absorbed drug, was examined as an index of an assessment of gastric mucosal damages in vivo. The urinary recovery after oral administration of phenol red and the ulcer index of the stomach were significantly increased in rats subjected to restraint and water immersion stress. Gastric absorption of phenol red, examined by means of in situ loop technique, was increased significantly in stressed rats. However, the urinary recovery of the dye after intravenous administration did not change in ulcerated rats compared with the control. These findings suggest that the increase in the urinary recovery of phenol red is due to the increased gastric absorption. The healing period of 12 d was enough to restore to control levels both the ulcer index and the urinary recovery of the dye. Both indices remained nearly at control level by the pretreatment with atropine sulfate. Good correlation between extent of gastric damage and urinary excretion of phenol red was obtained within single groups of animals. This method may be utilized as a simple and noninvasive screening test for an assessment of gastric mucosal damages in vivo.