Inhalable tobramycin EEG powder formulation for treating Pseudomonas aeruginosa-induced lung infection

Pulmonary delivery of antibiotics is an effective strategy in treating bacterial lung infection for cystic fibrosis patients, by achieving high local drug concentrations and reducing overall systemic exposure compared to systemic administration. However, the inherent anatomical lung defense mechanisms, formulation characteristics, and drug-device combination determine the treatment efficacy of the aerosol delivery approach. In this study, we prepared a new tobramycin (Tobi) dry powder aerosol using excipient enhanced growth (EEG) technology and evaluated the in vitro and in vivo aerosol performance.

We further established a Pseudomonas aeruginosa-induced lung infection rat model using an in-house designed novel liquid aerosolizer device. Notably, novel liquid aerosolizer yields comparable lung infection profiles despite administering 3-times lower P. aeruginosa CFU per rat in comparison to the conventional intratracheal administration. Dry powder insufflator (e.g. Penn-Century DP-4) to administer small powder masses to experimental animals is no longer commercially available. To address this gap, we developed a novel rat air-jet dry powder insufflator (Rat AJ DPI) that can emit 68–70 % of the loaded mass for 2 mg and 5 mg of Tobi-EEG powder formulations, achieving a high rat lung deposition efficiency of 79 % and 86 %, respectively.

Rat AJ DPI can achieve homogenous distribution of Tobi EEG powder formulations at both loaded mass (2 mg and 5 mg) over all five lung lobes in rats. We then demonstrated that Tobi EEG formulation delivered by Rat AJ DPI can significantly decrease CFU counts in both trachea and lung lobes at 2 mg (p < 0.05) and 5 mg (p < 0.001) loaded mass compared to the untreated P. aeruginosa-infected group. Tobi EEG powder formulation delivered by the novel Rat AJ DPI showed excellent efficiencies in substantially reducing the P. aeruginosa-induced lung infection in rats.

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Materials

Tobramycin base (Tobi) was purchased from ACROS Organics (Geel, Belgium). Pearlitol® PF-mannitol was donated by Roquette Pharma (Lestrem, France). Poloxamer 188 (Lutrol F68) was donated from BASF Corporation (Florham Park, NJ). L-leucine and all other reagents were purchased from Sigma-Aldrich Chemical Co. (St Louis, MO). The bioluminescent P. aeruginosa PAO1::p16Slux, a PAO1 strain tagged by chromosomal integration of p16Slux construction was obtained from Dr. Hugh Smyth’s lab, the University.

Rudra Pangeni, Surendra Poudel, Mohammad A.M. Momin, Dale Farkas, Caleb Dalton, Felicia Hall, Jason D. Kang, Phillip Hylemon, Worth Longest, Michael Hindle, Qingguo Xu, Inhalable tobramycin EEG powder formulation for treating Pseudomonas aeruginosa-induced lung infection, International Journal of Pharmaceutics, Volume 662, 2024, 124504, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124504.

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