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Inhaled Treatment of Respiratory Infections, 2nd Edition
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Inhaled Treatment of Respiratory Infections, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 14932

Special Issue Editors

Dr. Philip Chi Lip Kwok

E-Mail Website
Guest Editor
Advanced Drug Delivery Group, Sydney Pharmacy School, Faculty of Medicine and Health, Pharmacy and Bank Building A15, The University of Sydney, Sydney, NSW 2006, Australia
Interests: pulmonary delivery; aerosols; inhalation; particle engineering; formulation; physicochemical characterisation; electrostatics
Special Issues, Collections and Topics in MDPI journals
Dr. Michael Yee Tak Chow

E-Mail Website
Guest Editor
Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, UK
Interests: bacteriophage; biopharmaceutics; gene delivery; inhalation; particle engineering; pulmonary drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Respiratory infections are conventionally treated with oral or intravenous antimicrobials (antibiotics, antifungals, antivirals). However, these routes of administration are not ideal because the required drugs are systemically delivered rather than being targeted to the respiratory tract. Higher doses may also be needed to achieve sufficiently high drug concentrations in the lungs, which may consequently cause more adverse effects. On the other hand, the drugs can be delivered efficiently into the airways as inhaled aerosols. Lower doses can then be used to attain relatively high local concentrations. There are specific challenges to the development of inhaled formulations, such as optimising their physicochemical stability and aerosol performance. In addition, antimicrobial resistance is an urgent global public health issue. Novel strategies are required to overcome these problems.

This Special Issue, Inhaled Treatment of Respiratory Infections—Volume II, will focus on recent advances in treating respiratory infections with inhaled formulations.

Dr. Philip Chi Lip Kwok
Dr. Michael Y. T. Chow
Guest Editors

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Keywords

  • respiratory infections
  • inhalation
  • aerosols
  • pulmonary drug delivery
  • antimicrobials

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Related Special Issue

Published Papers (7 papers)

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Research

18 pages, 5213 KiB  
Article
Lung Delivery of Lactose-Free Microparticles Loaded with Azithromycin for the Treatment of Bacterial Infections
by Gracia Molina, Dolores R. Serrano, María Auxiliadora Dea-Ayuela, Carmina Rodriguez, Elena González-Burgos and Brayan J. Anaya
Pharmaceutics 2025, 17(6), 770; https://doi.org/10.3390/pharmaceutics17060770 - 11 Jun 2025
Viewed by 550
Abstract
Background/Objectives: Respiratory bacterial infections remain a significant global health challenge, with effective drug delivery to the lungs being crucial for successful treatment. This study aimed to develop a lactose-free dry powder inhaler (DPI) formulation containing azithromycin (AZM) microparticles for enhanced pulmonary delivery. Methods: [...] Read more.
Background/Objectives: Respiratory bacterial infections remain a significant global health challenge, with effective drug delivery to the lungs being crucial for successful treatment. This study aimed to develop a lactose-free dry powder inhaler (DPI) formulation containing azithromycin (AZM) microparticles for enhanced pulmonary delivery. Methods: Using a quality-by-design approach, an optimized formulation (4% AZM, 20% leucine, and 76% mannitol) was achieved. Results: The formulation demonstrated excellent aerodynamic properties with a mass median aerodynamic diameter (MMAD) of 2.72 μm ± 0.01 μm and fine particle fraction (FPF) (<5 μm) of 65.42% ± 5.12%. AZM-loaded microparticles exhibited enhanced efficacy against Pseudomonas aeruginosa with a two-fold reduction in the minimum bactericidal concentration (7.81 μg/mL vs. 15.62 μg/mL) compared to unprocessed AZM, while maintaining activity against Streptococcus pneumoniae. AZM microparticles demonstrated good biocompatibility with red blood cells and bronchial epithelial cells at therapeutic concentrations. Conclusions: These findings establish a promising lactose-free antibiotic formulation for targeted pulmonary delivery with enhanced antimicrobial efficacy. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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22 pages, 1321 KiB  
Article
Assessment of Innovative Dry Powders for Inhalation of a Synergistic Combination Against Mycobacterium tuberculosis in Infected Macrophages and Mice
by Faustine Ravon, Emilie Berns, Isaline Lambert, Céline Rens, Pierre-Yves Adnet, Mehdi Kiass, Véronique Megalizzi, Cédric Delporte, Alain Baulard, Vanessa Mathys, Samira Boarbi, Nathalie Wauthoz and Véronique Fontaine
Pharmaceutics 2025, 17(6), 705; https://doi.org/10.3390/pharmaceutics17060705 - 27 May 2025
Viewed by 545
Abstract
Background/Objectives: In vitro, vancomycin (VAN) and tetrahydrolipstatin (THL) together have been shown to synergistically inhibit Mycobacterium tuberculosis (Mtb), the world’s most infectious killer. The poor oral bioavailability of VAN and THL and predominant tropism of Mtb infection to the lungs and alveolar macrophages [...] Read more.
Background/Objectives: In vitro, vancomycin (VAN) and tetrahydrolipstatin (THL) together have been shown to synergistically inhibit Mycobacterium tuberculosis (Mtb), the world’s most infectious killer. The poor oral bioavailability of VAN and THL and predominant tropism of Mtb infection to the lungs and alveolar macrophages make pulmonary administration highly attractive. This study aimed to develop and assess the efficacy of dry powders for inhalation of VAN microparticles embedded with THL. Methods: The dry powders produced by spray-drying, with or without hydrogenated castor oil (HCO), were characterized for their physicochemical properties among others by HPLC-DAD. The fast-screening impactor was used to determine powder aerodynamic properties, and VAN and THL releases were established from the paddle over disk method. Biological activities were assessed in a new M. bovis-infected macrophage model and in Mtb-infected mice. Results and Discussion: The addition of 25% HCO enables co-deposition (fine particle dose) at the desired weight ratio and co-releasing of VAN and THL in aqueous media. Microparticles with 0% to 50% HCO drastically reduced cytoplasmic Mycobacterium bovis survival (99.9% to 62.5%, respectively), with higher efficacy at low HCO concentration. Consequently, VAN/THL with or without 25% HCO was evaluated in Mtb-infected mice. Although no decrease in Mtb lung burden was observed after two weeks of administration, the endotracheal administration of VAN 500 mg/kg and THL 50 mg/kg with 25% HCO administrated three times during five days concomitantly with daily oral rifampicin (10 mg/kg) demonstrated 2-fold bacterial burden reduction compared to the group treated with RIF alone. Conclusions: HCO was crucial for obtaining a fine particle dose at the synergistic weight ratio (VAN/THL 10:1) and for releasing both drugs in aqueous media. With oral administration of the first-line rifampicin, the dry powder VAN/THL/25% HCO was able to exert a potential anti-tubercular effect in vivo in Mtb-infected mice after five days. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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16 pages, 2909 KiB  
Article
Development of Inhalable Bacteriophage Liposomes Against Pseudomonas aeruginosa
by Shruti S. Sawant, Maizbha Uddin Ahmed, Nathan-Gautham Gantala, Caitlin Chiu, Li Qu and Qi Zhou
Pharmaceutics 2025, 17(4), 405; https://doi.org/10.3390/pharmaceutics17040405 - 24 Mar 2025
Viewed by 964
Abstract
Background: Pseudomonas aeruginosa is one of the major pathogens that cause respiratory infections. The rise of antimicrobial resistance has prompted a need for alternatives to conventional antibiotics. Bacteriophages (phages), natural predators of bacteria, are gaining interest as an alternative therapeutic option against [...] Read more.
Background: Pseudomonas aeruginosa is one of the major pathogens that cause respiratory infections. The rise of antimicrobial resistance has prompted a need for alternatives to conventional antibiotics. Bacteriophages (phages), natural predators of bacteria, are gaining interest as an alternative therapeutic option against drug-resistant infections. However, phage viability can be lost during manufacturing and delivery. Recent studies show that phages can be taken up by lung epithelial cells, which makes fewer phages available for antibacterial action against extracellular bacteria P. aeruginosa in the airways. Methods: In this study, we encapsulated phages in liposomes using thin film hydration. The effect of processing conditions and phage loading titer on the phage encapsulation and viability was studied. The impact of nebulization on phage viability was tested using an air-jet nebulizer (PARI-LC Plus). Phage cellular uptake was evaluated using an in vitro H441 lung epithelial cell model, grown at the air–liquid interface. Results: Our results demonstrate favorable encapsulation (58 ± 6.02%) can be achieved with minimum loss in phage titer (0.64 ± 0.21 log) by using a low phage titer for hydration. The liposomal formulations exhibited controlled release of phages over 10 h. The formulation also reduced the loss of phage viability during nebulization from 1.55 ± 0.04 log (for phage suspension) to 1.08 ± 0.05 log (for phage liposomes). Encapsulation of phages in liposomes enabled a two-fold reduction in phage cellular uptake and longer extracellular phage retention in the human lung epithelial cell monolayer. Conclusions: Our results indicate that liposomal encapsulation favors phage protection and improves phage availability for antibacterial activity. These findings highlight the potential of liposomes for inhaled phage delivery. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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14 pages, 1736 KiB  
Article
Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin in Children with Cystic Fibrosis
by Anne M. Akkerman-Nijland, Paul Hagedoorn, Bart L. Rottier, Floris Grasmeijer, Henderik (Erik) W. Frijlink, Mathijs van Luin, E. ter Weijden, Peter J. Merkus, Daan J. Touw, Onno W. Akkerman and Gerard H. Koppelman
Pharmaceutics 2025, 17(3), 347; https://doi.org/10.3390/pharmaceutics17030347 - 7 Mar 2025
Cited by 1 | Viewed by 922
Abstract
Background: Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in persons with Cystic Fibrosis (CF). Nebulization with tobramycin or colistin is mostly applied but has a significant treatment burden. Dry powder (DP) inhalation may offer an attractive alternative. The aim [...] Read more.
Background: Pseudomonas aeruginosa (Pa) is the predominant pulmonary pathogen in persons with Cystic Fibrosis (CF). Nebulization with tobramycin or colistin is mostly applied but has a significant treatment burden. Dry powder (DP) inhalation may offer an attractive alternative. The aim of this study was to assess local tolerability and the systemic pharmacokinetic parameters of increasing doses of dry powder tobramycin. Methods: This was a local tolerability and pharmacokinetic evaluation pilot study DP tobramycin of three different doses inhaled through the Cyclops (30, 60, 120 mg) in ten persons with CF, aged 6–18 years, compared to nebulization of tobramycin solution. Results: Both nebulization of tobramycin in solution and inhalation of dry powder tobramycin were well tolerated. None of the participants showed a significant drop in FEV1 after inhalation. The only two adverse events were cough and bad taste in, respectively, 20% and 13% of all inhalations, compared to 10% cough and 60% bad taste with nebulization. Systemic tobramycin levels were not detected after 30 mg, detected only in 10% after 60 mg and in 30% after 120 mg, compared to 80% after nebulization. Conclusions: Inhalation of dry powder tobramycin using the Cyclops is well tolerated, with no significant drop in FEV1, and only mild adverse events of cough and bad taste. We found only a few detectable systemic tobramycin levels after inhalation of dry powder tobramycin. We recommend that future studies should focus on the relation between dose and inhaler resistance in different pediatric age groups. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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16 pages, 5063 KiB  
Article
Respiratory Delivery of Lacticaseibacillus rhamnosus GG by Vibrating-Mesh and Jet Nebulisation
by Alex Seungyeon Byun, Luis Vitetta, Hak-Kim Chan and Philip Chi Lip Kwok
Pharmaceutics 2024, 16(10), 1326; https://doi.org/10.3390/pharmaceutics16101326 - 14 Oct 2024
Viewed by 3109
Abstract
Background: The use of probiotic bacteria to improve lung health has been gaining interest. Although the oral delivery of probiotics and their effects are well documented, there is currently limited knowledge on the respiratory delivery of probiotics. Objectives: This study aimed to investigate [...] Read more.
Background: The use of probiotic bacteria to improve lung health has been gaining interest. Although the oral delivery of probiotics and their effects are well documented, there is currently limited knowledge on the respiratory delivery of probiotics. Objectives: This study aimed to investigate whether nebulisation is suitable for delivering Lacticaseibacillus rhamnosus GG (LGG) into the lungs for the potential treatment of bacterial pulmonary infections. Methods: It compared the dose output and aerosol performance of a vibrating-mesh nebuliser (VMN) and a jet nebuliser (JN) in nebulising LGG suspended in de Man Rogosa Sharpe (MRS) broth, phosphate-buffered saline (PBS), or normal saline (0.9% w/v sodium chloride in water). Results: The VMN consistently produced a higher output than the JN for all liquid media, indicating that VMN was more efficient. The fine-particle fractions of both nebulisers were comparable for a given medium. The highest fine-particle fraction was achieved with LGG suspended in MRS broth for both nebulisers (20.5 ± 2.8% for VMN; 18.7 ± 3.4% for JN). This suggests that the aerosol performance of nebulised probiotics may depend on the medium in which the probiotic bacteria were suspended. Conclusions: Therefore, this study demonstrated that the nebulisation efficiency of LGG depended on the nebuliser type and liquid medium of the probiotic suspension. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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18 pages, 8249 KiB  
Article
Astodrimer Sodium Nasal Spray versus Placebo in Non-Hospitalised Patients with COVID-19: A Randomised, Double-Blinded, Placebo-Controlled Trial
by Stephen Winchester, Alex Castellarnau, Kashif Jabbar, Meera Nadir, Kapila Ranasinghe, Xavier Masramon, George R. Kinghorn, Isaac John and Jeremy R. A. Paull
Pharmaceutics 2024, 16(9), 1173; https://doi.org/10.3390/pharmaceutics16091173 - 6 Sep 2024
Cited by 1 | Viewed by 5211
Abstract
Background/Objectives: Dendrimer-based astodrimer sodium nasal spray was assessed for its ability to reduce SARS-CoV-2 load in outpatients with COVID-19, which remains a severe illness for vulnerable groups. Methods: This was a randomised, double-blind, placebo-controlled clinical investigation evaluating the efficacy of astodrimer nasal spray [...] Read more.
Background/Objectives: Dendrimer-based astodrimer sodium nasal spray was assessed for its ability to reduce SARS-CoV-2 load in outpatients with COVID-19, which remains a severe illness for vulnerable groups. Methods: This was a randomised, double-blind, placebo-controlled clinical investigation evaluating the efficacy of astodrimer nasal spray in reducing SARS-CoV-2 viral burden in the nasopharynx of outpatients with COVID-19. Non-hospitalised adults with SARS-CoV-2 infection were randomised 1:1 to astodrimer or placebo four times daily from Day 1 to Day 7. Nasopharyngeal swabs for SARS-CoV-2 load determination were self-obtained daily from Day 1 to Day 8. The primary endpoint was an area under the curve of SARS-CoV-2 RNA copies/mL through Day 8 (vAUCd1–8). The primary analysis population was the modified intent-to-treat population (mITT: all randomised participants exposed to the study treatment who had at least one post-baseline viral load determination). Safety analyses included all randomised participants exposed to the study treatment. Study registration: ISRCTN70449927; Results: 231 participants were recruited between 9 January and 20 September 2023. The safety population comprised 109 and 113 participants randomised to astodrimer and placebo, respectively, with 96 and 101 participants in the mITT. Astodrimer sodium nasal spray reduced the SARS-CoV-2 burden (vAUCd1–8) vs. placebo in non-hospitalised COVID-19 patients aged 16 years and over (−1.2 log10 copies/mL × Day). The reduction in SARS-CoV-2 load was statistically significant in those aged 45 years and older (−3.7, p = 0.017) and the effect increased in older age groups, including in those aged 65 years and older (−7.3, p = 0.005). Astodrimer sodium nasal spray increased the rate of viral clearance and helped alleviate some COVID-19 symptoms, especially loss of sense of smell. Overall, 31 participants (14%) had ≥1 adverse event (AE). Four AEs were deemed possibly related to treatment. Most AEs were of mild severity and occurred at similar rates in both treatment arms. Conclusions: Astodrimer nasal spray reduces viral burden and accelerates viral clearance, especially in older populations, and is well tolerated. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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15 pages, 11190 KiB  
Article
Tobramycin Reduces Pulmonary Toxicity of Polymyxin B via Inhibiting the Megalin-Mediated Drug Uptake in the Human Lung Epithelial Cells
by Maizbha Uddin Ahmed, Jian Li and Qi (Tony) Zhou
Pharmaceutics 2024, 16(3), 389; https://doi.org/10.3390/pharmaceutics16030389 - 12 Mar 2024
Cited by 3 | Viewed by 2412
Abstract
Accumulation of polymyxins in the lung epithelial cells can lead to increased mitochondrial oxidative stress and pulmonary toxicity. Aminoglycosides and polymyxins are used, via intravenous and pulmonary delivery, against multidrug-resistant Gram-negative pathogens. Our recent in vitro and animal studies demonstrated that the co-administration [...] Read more.
Accumulation of polymyxins in the lung epithelial cells can lead to increased mitochondrial oxidative stress and pulmonary toxicity. Aminoglycosides and polymyxins are used, via intravenous and pulmonary delivery, against multidrug-resistant Gram-negative pathogens. Our recent in vitro and animal studies demonstrated that the co-administration of polymyxins with aminoglycosides decreases polymyxin-induced pulmonary toxicity. The aim of this study was to investigate the in vitro transport and uptake of polymyxin B and tobramycin in human lung epithelial Calu-3 cells and the mechanism of reduced pulmonary toxicity resulting from this combination. Transport, intracellular localization, and accumulation of polymyxin B and tobramycin were investigated using doses of 30 mg/L polymyxin B, 70 mg/L tobramycin, and the combination of both. Adding tobramycin significantly (p < 0.05) decreased the polymyxin B-induced cytotoxicity in Calu-3 cells. The combination treatment significantly reduced the transport and uptake of polymyxin B and tobramycin in Calu-3 cells, compared to each drug alone, which supported the reduced pulmonary toxicity. We hypothesized that cellular uptake of polymyxin B and tobramycin shared a common transporter, megalin. We further investigated the megalin expression of Calu-3 cells using confocal microscopy and evaluated megalin activity using a megalin substrate, FITC-BSA, and a megalin inhibitor, sodium maleate. Both polymyxin B and tobramycin significantly inhibited FITC-BSA uptake by Calu-3 cells in a concentration-dependent manner. Sodium maleate substantially inhibited polymyxin B and tobramycin transport and cellular accumulation in the Calu-3 cell monolayer. Our study demonstrated that the significantly reduced uptake of polymyxin B and tobramycin in Calu-3 cells is attributed to the mechanism of action that determines that polymyxin B and tobramycin share a common transporter, megalin. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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