CONTROLLED DELIVERY TO THE DEEP LUNGS: OPPORTUNITIES AND CHALLENGES

Background. Inhalation is unarguably the best way to achieve local drug accumulation in the lungs. Such a strategy is suitable for treating lung infections, being systemic antibiotic therapy affected by high dosages and, in some cases, lengthy treatments with high risks of toxic effects and low patient adherence. If properly tailored, such administration strategy could be of great efficacy considering the worldwide increased burden of bacterial resistance. Bacterial resistance is becoming a plague that urges novel approaches to enhance control and treatment. It is estimated that only in Europe one million resistant strains related deaths will be recorded by 2025. Here we discuss some of the approaches to achieve drug delivery to the deep lungs and related issues with a focus on their potential impact on pulmonary infection therapy. Increased evidences support inhalation as the only way to obtain high lung concentrations of multiple drugs at the desired pharmacological ratio, otherwise impossible to achieve through systemic administration. Moreover, cost increase compared to the oral route can be limited in light even of the market availability of cheap disposable devices. Based on the evidence that the search for novel and more potent, but often more toxic, drugs cannot be the only solution to fight bacterial resistance, we believe that a shift in the approaches to pulmonary infection treatment is needed and that such a change relies on the development of effective inhalation protocols. Methods and Results. We propose the hydrophobic strategy based on drug modification through ion pairing and complexation to improve inhalable drug penetration into tissues, intracellular activity and possible higher lung retention. A few examples include metal complexes and ion pairs of peptide and aminoglycoside drugs (capreomycin, amikacin, kanamycin) obtained with palladium, dehoxycholic acid (DCA) and oleic acid. Such compounds showed efficacy in vitro against M. tuberculosis and methicillin resistant S. aureus (MRSA) biofilms. Of course, such systems need to be shaped into respirable particles possessing the required aerodynamic properties and behavior. In this regard, we have developed spray-drying methods to produce consistently such preparations containing the modified drugs. This strategy may help to improve penetration of the delivered drugs even when pathophysiological modifications heavily impair access and deposition in damaged lung compartments. Conclusions. 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 ensure shorter bench-to-market time and repurposing of old actives. On the other side, delivery of drugs through inhalation can allow better control on infection and resistance development. The technology required to develop inhalation therapy is already available and the higher cost of production compared to oral systems could be balanced by higher efficacy. A global and concerted effort is however required to speed up innovation in this field.