Halloysite nanotubes as tools to improve the actual challenge of fixed doses combinations in tuberculosis treatment.

Halloysite nanotubes (HLNTs) were used as nanocarriers of the tuberculostatic agent isoniazid (INH), a BCS (Biopharmaceutics Classification System) class III drug. Self-assembling nanohybrids (INH-loaded HLNTs) with an average outer diameter of 90 nm and polydispersity index of 0.7 approximately, were obtained by spontaneous adsorption of INH molecules to HLNTs powder in aqueous medium. The nanohybrids were aimed to improve oral drug bioavailability and reduce physicochemical incompatibility of INH with other concomitantly administered tuberculostatic agents. In vitro drug release from INH-loaded HLNTs was successfully fitted to a diffusive kinetic law founded on the adsorption-desorption equilibrium between drug molecules in solution and solid inorganic excipients. INH-loaded HLNTs showed good in vitro biocompatibility toward Caco-2 cells at the concentrations studied (up to 1233 μg/mL), with improved cell proliferation. Permeability tests showed that INH transport across Caco-2 cellular membranes was greatly enhanced and fluorescent microscopy confirmed that the drug encapsulated into nanohybrid was effectively internalized by the cells. INH-loaded HLNTs enhanced stability of the drug in presence of other tuberculostatic agents, both in binary and quaternary combinations. It has been demonstrated that simple interaction between INH with HLNTs leads to drug permeability and stability improvements that could greatly facilitate the design of multiple drug dosage forms, an actual challenge in oral treatment of tuberculosis.