Mechanistic studies on effervescent-induced permeability enhancement

To determine the mechanism(s) by which effervescence induces penetration enhancement of a broad range of compounds ranging in size, structure, and other physiocochemical properties across rat and rabbit small intestinal epithelium. Effervescent induced penetration enhancement was investigated in vitro by utilization of a modified Ussing chamber diffusion cell apparatus and in vivo by single-pass intestinal perfusion. Carbon dioxide (CO2) bubbling directly onto rabbit ileum epithelium induced an increase in drug permeability. Mechanistic studies indicated that effects due to CO2 bubble evolution, such as increased drug dissolution rates, mucus thinning/stripping, and pH buffer effects did not contribute to increases in drug flux. Cellular enzyme (5'-ND and LDH) and total protein release assays did not indicate cell membrane perturbation and/or damage. CO2 bubbling induced a reduction in transepithelial electrical resistance (TEER) indicating epithelial disruption due to a structural change of the paracellular pathway. This was further substantiated by a MW dependence on paracellular marker flux. In addition, tissue recovery was relatively rapid, approximately 20 min. CO2 bubbling directly onto the intestinal epithelium induced enhanced drug permeability due to an alteration of the paracellular pathway. This, in addition to fluid flow and membrane hydrophobicity concepts, may account for observed increases in drug flux.