Development of antibiotic dry powder inhalers formulations for the treatment of respiratory bacterial infections: A comprehensive review

Abstract

Lower respiratory tract infections (LRTIs) constitute the fourth leading cause of mortality worldwide, resulting in over two million deaths annually. Bacterial pathogens are implicated in approximately 30 % of these fatalities. Dry powder inhalers (DPIs) facilitate the attainment of elevated pulmonary concentrations of antibiotics through targeted particle deposition at the site of infection, thereby optimizing local drug exposure while concurrently reducing systemic drug levels. Effective pulmonary drug delivery necessitates powders possessing optimal aerodynamic characteristics. Achieving such properties in dry powder inhalation particles is possible through diverse formulation strategies and advanced inhaler technologies. This targeted approach to drug delivery facilitates high-dose localized treatment while concurrently minimizing the potential for systemic adverse effects and the development of antibiotic resistance. This review outlines the global landscape of antibiotic DPIs, detailing marketed products and those in development. It highlights how particle-engineering and functional excipients address API constraints to enhance lung deposition. Future innovations are likely to focus on new delivery methods and strategic combinations, such as antibiotics combined with mucolytics or bacteriophages, to improve the treatment of drug-resistant respiratory infections.

Introduction

Lower respiratory tract infections (LRTIs) are the fourth leading cause of death globally, leading to over 2 million deaths annually [1]. Pulmonary infections caused by Gram-negative and Gram-positive bacteria may directly cause lung diseases such as tuberculosis and pneumonia, or induce severe complications in chronic diseases including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and non-CF bronchiectasis (NCFB) [2,3]. These diseases lead to reduced pulmonary function, impaired mucociliary clearance, and compromised immunity, predisposing patients to recurrent infections [4,5]. Management mainly relies on high-dose antibiotics administered systemically via oral or intravenous routes [6]. However, such approaches are associated with notable limitations: they often fail to achieve therapeutic drug concentrations at the pulmonary site of infection [7,8]. Furthermore, systemic regimens are frequently accompanied by dose-limiting toxicities and contribute to environmental contamination through the excretion of active antibiotic compounds [[9], [10], [11]]. Of greater concern, systemic drug delivery commonly results in pulmonary drug levels below the minimum inhibitory concentration (MIC) of target pathogens, leading to suboptimal clinical outcomes or outright treatment failure [12]. Sustained exposure to subinhibitory antibiotic concentrations not only promotes the emergence of bacterial resistance but also complicates subsequent therapeutic management and amplifies the overall healthcare burden [[13], [14], [15]]. Given that predominant bacterial etiologies often necessitate repeated high-dose systemic antibiotic courses, this cyclical pattern further exacerbates toxicity risks and accelerates the evolution of antimicrobial resistance, thereby escalating both clinical complexity and healthcare costs [11,16,17].

To address respiratory bacterial infections, novel therapeutic strategies and advanced pulmonary drug-delivery systems are being intensively investigated and clinically evaluated [18]. Dry-powder inhalable antibiotics achieve ultrahigh local drug exposure in the lungs that markedly exceeds systemic levels, thereby potentiating bactericidal activity, minimizing off-target toxicity, and attenuating the emergence of antimicrobial resistance [19]. Moreover, dry-powder formulations eliminate the need for propellants, provide rapid administration through portable devices, and exhibit superior chemical–physical stability [20], collectively enhancing patient adherence and quality of life [21] and offering an optimal platform for the long-term management of chronic pulmonary infections. In DPIs formulations, medication is released delivered as a respirable powder aerosol generated solely by the patient’s inspiratory through a purpose-designed device [22,23]. Most DPI systems enable reproducible unit-dose dispensing, high pulmonary deposition efficiency, superior chemical and physical stability, and an environmentally benign propellant-free design [24].

Compared with alternative inhalation systems, DPIs offer a more rapid onset of action, compact portability [9], and minimal risk of microbial contamination owing to their simple, easily sanitized architecture—attributes that translate into high patient adherence and suitability for ambulatory care. In response to the increasing prevalence of bacterial respiratory infection, there is ongoing innovation in antibiotic dry powder inhalers (DPIs), characterized by progressively stringent specifications for emitted dose accuracy and pulmonary targeting efficiency [25]. Particle size is a critical determinant of the delivery efficiency of inhalation formulations and plays a significant role in the development of dry powder inhalation antibiotics. It is widely accepted that an aerodynamic diameter of particles between 0.5 and 5.0 μm is optimal for effective pulmonary delivery. Particles exceeding 5 μm predominantly deposit in the oropharynx and central airways, whereas particles smaller than 0.5 μm are significantly influenced by Brownian motion, leading to their diffusion and deposition on the airway surface. Due to their negligible inertial impact and limited diffusion efficiency, a substantial proportion of these smaller particles are exhaled shortly after inhalation [26]. In accordance with this fundamental requirement, the regulation of aerodynamic particle size can be attained through strategic advancements in both excipients and preparation methodologies. These methodologies encompass a variety of techniques, including but not limited to grinding [27], spray drying [[28], [29], [30]], spray freeze drying [31], recrystallization [32], inkjet printing, supercritical fluid processing [33], ultrasonic deposition crystallization [34], high-gravity controlled precipitation [35], hot melt extrusion [36], and 3D printing [37]. Furthermore, the incorporation of excipients such as lipids, amino acids, inorganic salts, and polymers facilitates the optimization of particle performance, thereby enhancing the ability to achieve the desired aerodynamic particle size [38,39]. Consequently, the selection of an appropriate platform for antibiotic dry powder necessitates a thorough evaluation of the physicochemical properties of the drug, the inherent advantages and limitations of each technique, and the requisite clinical performance characteristics [40].

However, eradicating deep-seated pulmonary infections caused by Pseudomonas aeruginosa or MRSA demands antibiotic doses that escalate to tens–even hundreds–of milligrams, posing a fundamental challenge to conventional DPI technology [41]. First, such high-dose delivery requires ultra-high drug loading, which exponentially increases powder cohesion, collapses flowability and reduces aerosolization efficiency. This directly compromises dose uniformity and lung deposition while promoting oropharyngeal and upper-airway impaction [42]. Second, the intrinsic irritancy of the antibiotic itself makes cough the most frequently reported adverse event during high-dose DPI therapy [[43], [44], [45]]. In patients with already compromised pulmonary function and sub-optimal inspiratory flow, the generated energy may be insufficient to de-agglomerate these highly cohesive powders, further amplifying upper-airway deposition and cough reflex, ultimately eroding tolerability and long-term adherence [43,46]. Addressing these intertwined issues therefore necessitates concurrent innovation in particle engineering (e.g., porous, low-density morphologies), force-control agents (e.g., magnesium stearate, L-leucine) and novel inhaler architectures capable of delivering elevated dispersion energy [[47], [48], [49]], with the dual objective of enhancing pulmonary deposition while simultaneously improving local tolerability to the DPI system.This article systematically reviews the research progress of antibiotic dry-powder inhalers in the treatment of respiratory bacterial infections. Starting from clinical needs, it comprehensively summarizes the formulation characteristics, technical challenges, and clinical application outcomes of marketed products, clinical-stage candidates, and pre-clinical drug candidates. The roles of different particle-engineering strategies, functional excipients, and novel delivery systems are analyzed in depth, aiming to provide a theoretical basis and formulation-design reference for the future development of antibiotic dry-powder inhalers that are highly efficient, stable, and exhibit good patient compliance.

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Mingjun Li, Min Zhao, Yaochen Deng, Zengming Wang, Hui Zhang, Conghui Li, Yi Cheng, Nan Liu, Shirui Mao, Aiping Zheng, Development of antibiotic dry powder inhalers formulations for the treatment of respiratory bacterial infections: A comprehensive review, Journal of Drug Delivery Science and Technology, Volume 117, 2026, 108041, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108041.

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