Moisture-Resistant Co-Spray-Dried Netilmicin with l-Leucine as Dry Powder Inhalation for the Treatment of Respiratory Infections.

Yingtong Cui,Zhengwei Huang,Xuejuan Zhang,Ying Huang,Xin Pan,Ziyu Zhao,Guanlin Wang,Wen Wang,Shihao Cai,Chuanbin Wu,Hui Jing

doi:10.3390/pharmaceutics10040252

Yingtong Cui, Zhengwei Huang + Show 9 more

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https://doi.org/10.3390/pharmaceutics10040252

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Abstract

Netilmicin (NTM) is one of the first-line drugs for lower respiratory tract infections (LRTI) therapy, but its nephrotoxicity and ototoxicity caused by intravenous injection restrict its clinical application. Dry powder inhalation (DPI) is a popular local drug delivery system that is introduced as a solution. Due to the nature of NTM hygroscopicity that hinders its direct use through DPI, in this study, L-leucine (LL) was added into NTM dry powder to reduce its moisture absorption rate and improve its aerosolization performance. NTM DPIs were prepared using spray-drying with different LL proportions. The particle size, density, morphology, crystallinity, water content, hygroscopicity, antibacterial activity, in vitro aerosolization performance, and stability of each formulation were characterized. NTM DPIs were suitable for inhalation and amorphous with a corrugated surface. The analysis indicated that the water content and hygroscopicity were decreased with the addition of LL, whilst the antibacterial activity of NTM was maintained. The optimal formulation ND2 (NTM:LL = 30:1) showed high fine particle fraction values (85.14 ± 8.97%), which was 2.78-fold those of ND0 (100% NTM). It was stable after storage at 40 ± 2 °C, 75 ± 5% relative humidity (RH). The additional LL in NTM DPI successfully reduced the hygroscopicity and improved the aerosolization performance. NTM DPIs were proved to be a feasible and desirable approach for the treatment of LRTI.

Highlights

Lower respiratory tract infections (LRTI), mainly caused by Gram-negative (G−) bacteria of Pseudomonas aeruginosa (P. aeruginosa) or Gram-positive (G+) bacteria of Staphylococcus aureus (S. aureus), are frequently encountered in patients with cystic fibrosis or nosocomial pneumonias [1,2].Aminoglycoside antibiotic is considered an essential lower respiratory tract infections (LRTI) therapy due to its excellent solubility, wide antimicrobial spectrum, and strong antimicrobial ability
Netilmicin Sulfate was obtained from Beierka Biopharmaceutical Co., Ltd. (Wuhan, China)
LRTI are associated with a high mortality rate, and demand effective antibiotic treatment

Summary

Introduction

Lower respiratory tract infections (LRTI), mainly caused by Gram-negative (G−) bacteria of Pseudomonas aeruginosa (P. aeruginosa) or Gram-positive (G+) bacteria of Staphylococcus aureus (S. aureus), are frequently encountered in patients with cystic fibrosis or nosocomial pneumonias [1,2]. Aminoglycoside antibiotic is considered an essential LRTI therapy due to its excellent solubility, wide antimicrobial spectrum, and strong antimicrobial ability. Pha rmaceutics2018, 22of of antimicrobial spectrum, and strong antimicrobial ability. It is the first-line drug for G− drug for G.

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