Development and evaluation of inhalable imipenem dry powder for treating pulmonary P. aeruginosa infection.

Abstract

Pulmonary infections caused by P. aeruginosa (PA) remain a major clinical challenge due to biofilm formation, intrinsic resistance, and limited antibiotic penetration into lung tissues following systemic administration. Imipenem (IPM), a broad-spectrum carbapenem, requires high intravenous doses (500 mg every 6 h with cilastatin) to achieve therapeutic lung levels, leading to frequent dosing and systemic toxicity. Pulmonary delivery via dry powder for inhalation (DPI) offers a targeted alternative. However, formulation development is hindered by the chemical instability, specifically its susceptibility to thermal and hydrolytic degradation in the amorphous state. In this study, a high-dose, chemically stable IPM dry powder for inhalation (IPM-DPI) was developed by co-spray-drying IPM with L-leucine. The optimized 50:50 (w/w) IPM: L-leucine powder exhibited an initial IPM potency of ∼94% and low residual moisture content ( 95% of its initial IPM potency after 6 months at -20 °C, demonstrating improved stability associated with intermolecular interactions between leucine and IMP, with the semi-crystalline leucine phase forming a matrix around IMP molecules within the particle core. Overall, the developed IPM-DPI enables localized pulmonary delivery of imipenem, potentially eliminating the need for cilastatin and reducing systemic toxicity associated with parenteral therapy.

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