Influence of MgAl-hydrotalcite on gastric absorption of BCS class IV drugs

Furosemide (FURO) is a BCS class IV drug preferentially absorbed in the gastric environment, site in which it shows the lowest solubility because of its weak acidic nature1. A previous study demonstrated that FURO intercalation into the lamellar inorganic matrix magnesium Aluminum Hydrotalcite (MgAl-HTlc), generating the nanocomposite MgAl-HTlc-FURO, improves its dissolution in acidic medium2. As the barriers to gastric absorption of drugs are represented by the mucus and the gastric mucosa, the influence of MgAl-HTlc on both biological structures has been evaluated. The mucus is a highly viscous and elastic gel which provides protection by pathogens, toxins, ultrafine particles, enzymatic injury and, in the case of the gastric mucosa, HCl of gastric fluid. However, various studies demonstrated that mucus can also represent a potential barrier to drug absorption3. At first FURO flux across the gastric mucus has been studied. With this aim an in vitro method has been developed, modifying the flow through diffusion cell apparatus 4 (F.U.XII Ed.) by introducing a cylindrical support mounted on the top of the dissolution chamber where the gastric mucus was placed. FURO sample (crystalline FURO, MgAl-HTlc-FURO or crystalline FURO/MgAl-HTlc physical mixture) was placed in the dissolution chamber and then gastric fluid with pepsin (F.U. XII Ed.) was pumped through the cell in order to simulate the flow of GI fluids through the mucus layer covering the gastric mucosa. The results highlighted that in presence of the nanocomposite MgAl-HTlc-FURO the drug flux is improved. After these first results it was interesting to evaluate the effect of MgAl-HTlc on gastric pH and then the possible modifications induced on mucus rheology. Thus, solutions of MgAl-HTlc in gastric fluid with pepsin (growing concentrations) have been put in contact with the gastric mucus and then, the obtained samples were submitted to rheological studies (viscometry and oscillation stress sweep measurements). Obtained data suggested that MgAl-HTlc is able to modify in a reversible manner the mucus structure reducing its viscosity as well as provoking an enlargement of mucus meshes network with following reduction of its compactness. These modifications are responsible for the improved drug flux across the gastric mucus observed for FURO samples in presence of MgAl-HTlc. Finally in vitro/ex vivo studies have been planned and performed in order to study FURO permeability across an artificial membrane and a biological membrane (gastric mucosa) mounted between the two chambers of a Side-Bi Side cell. From the obtained data resulted that the biological membrane (gastric mucosa) is the most suitable to perform permeation studies as its complex structure and chemical composition make it a tangible barrier to drug diffusion in comparison to artificial membrane. The test was performed on FURO alone and in presence of MgAl-HTlc and from Papp values of both samples resulted that the presence of the nanocomposite MgAl-HTlc-FURO enhances FURO Papp