WAYS AND MEANS FOR INHALED DRUG DELIVERY IN TB

Inhalation is unarguably the best way to achieve local drug accumulation in the lungs. Such strategy is suitable to treat lung infections especially TB, being systemic TB therapy affected by high dosages and lengthy treatments with high risks of toxic effects and low patient adherence. Here we discuss some of the strategies to achieve antiTB drug (ATD) pulmonary delivery useful for vaccination as well with a focus on their potential impact on TB therapy and market. Increased evidences support inhalation as the only way to obtain high lung concentrations of multiple ATD at the desired pharmacological ratio, otherwise impossible to achieve through systemic administration, with limited increased costs compared to the oral route, in light even of the availability of cheap disposable devices. Based on the evidence that the search for novel and more potent, but often more toxic, ATD cannot be the only solution to the TB problem, we believe that a shift in the approaches to TB treatment is needed and that such change relies on the development of effective inhalation protocols. In particular, we propose the hydrophobic strategy based on drug modification through ion pairing and complexation to improve inhalable drug penetration into tissues and intracellular activity. A few examples include metal complexes and ion pairs of second line peptide and aminoglycoside ATD (capreomycin, amikacin, kanamycin) obtained with palladium, dehoxycholic acid (DCA) and oleic acid. Moreover, vaccines and the microbiome strategy aimed at enhancing prevention and control of the infection and to limit the progression of the disease show some potential when delivered through inhalation in animal models. In addition, a few clinical trials are exploring safety and efficacy of such procedures. The proposed approaches provide multiple advantages. On the one side, the physical modification of the drugs is intrinsically advantageous compared to chemical synthesis of new compounds as it may grant shorter bench-to-market time and repurposing of old actives. On the other side, delivery of microbiomes and vaccines through inhalation can grant better control of TB infections and resistance development. The technology required to develop TB inhalation therapy is already available and the higher cost of production compared to oral systems is balanced by higher efficacy. A global and concertated effort is however required to speed up innovation in this field.