EFFECT OF FORMULATIONS, SURFACTANTS, AND SOLVENTS UPON THE ORAL BIOAVAILABILITY OF POORLY SOLUBLE DRUGS IN THE BLOOD AND LYMPH

Solid dispersions of the poorly water soluble drug, phenytoin acid, in PEG 8000 were prepared. This dispersion was found to be bioequivalent (p > 0.05) in dogs after oral administration to the more soluble commercial prompt phenytoin sodium. In vitro dissolution results did not correlate with the pharmacokinetic parameters obtained in vivo.;The effects of solvents on the blood and lymph levels of C-14-phenytoin were determined as a function of time. The aqueous vehicles (water, 10% ethanol, and 10 mg/ml sodium oleate) resulted in significantly larger areas under the curves (AUC) for the blood and lymph than the oleaginous vehicles (10% emulsion, olive oil, or the 25 mg/ml sodium oleate). The oleaginous vehicles had a larger volume of collected lymph than the aqueous vehicles. This study strongly suggests that the test solution could significantly affect the blood or lymph radioactivity-time profiles, as well as the flow of lymphatic fluid, after oral administration.;Further investigation into the effect of sodium oleate concentration upon the blood radioactivity-time curves was studied at 0, 5, 10, 15, 25, and 50 mg/ml. The AUC from the 10 mg/ml treatment was significantly larger than the other treatments. An increase or decrease from the 10 mg/ml concentration resulted in a lower AUC indicating that there is an optimal sodium oleate concentration.;The results of the present investigation should be taken into consideraton in the design of drug delivery systems.;Absorption studies using the in situ rat gut technique were undertaken to determine the effects of Tween 80, Myrj 52, and PEG 8000 in dilute concentrations (10('-2) to 10('-6)M). The rate of C-14-pentobarbital disappearance and the percent cumulative water flux were inversely related to the concentration of the PEG 8000 or Myrj 52 solutions. The rate of drug disappearance was inversely related to the concentration of Tween 80, but a high percent cumulative water efflux was noted at all concentrations. Histological changes in the rat small intestine were observed through the use of lanthanum chloride as an extracellular marker.