Cyclodextrin-based nanocarriers containing a synergic drug combination: a potential formulation for pulmonary administration of antitubercular drugs.

Tuberculosis (TB) remains a major global health problem. The use of ethionamide (ETH), a main second line drug, is associated to severe toxic side-effects due to its low therapeutic index. In this challenging context, "booster" molecules have been synthetized to increase the efficacy of ETH. However, the administration of ETH/booster pair is mostly hampered by the low solubility of these drugs and the tendency of ETH to crystallize. Here, ETH and a poorly water-soluble booster, so-called BDM43266, were simultaneously loaded in polymeric beta-cyclodextrin nanoparticles (pbetaCyD NPs) following a "green" protocol. The interaction of ETH and BDM43266 with pbetaCyD NPs was investigated by complementary techniques. Remarkably, the inclusion of ETH and BDM43266 pbetaCyD NPs led to an increase of their apparent solubility in water of 10- and 90-fold, respectively. Competition studies of ETH and BDM43266 for the CyD cavities of pbetaCyD NPs corroborated the fact that the drugs did not compete with each other, confirming the possibility to simultaneously co-incorporate them in NPs. The drug-loaded NP suspensions could be filtered through 0.22micron filters. Finally, the drug-loaded NPs were passed through a Microsprayer to evaluate the feasibility to administer pbetaCyD NPs by pulmonary route. Each spray delivered a constant amount of both drugs and the NPs were totally recovered after passage through the Microsprayer. These promising results pave the way for a future use of pbetaCyD NPs for the pulmonary delivery of the ETH/BDM43266 pair.