Advances in soft mist inhalers.

INTRODUCTION: Soft mist inhalers (SMIs) are propellant-free inhalers that utilize mechanical power to deliver single or multiple doses of inhalable drug aerosols in the form of a slow mist to patients. Compared to traditional inhalers, SMIs allow for a longer and slower release of aerosol with a smaller ballistic effect, leading to a limited loss in the oropharyngeal area, whilst requiring little coordination of actuation and inhalation by patients. Currently, the Respimat® is the only commercially available SMI, with several others in different stages of preclinical and clinical development. AREAS COVERED: The primary purpose of this review is to critically assess recent advances in SMIs for the delivery of inhaled therapeutics. EXPERT OPINION: Advanced particle formulations, such as nanoparticles which target specific areas of the lung, Biologics, such as vaccines, proteins, and antibodies (which are sensitive to aerosolization), are expected to be generally delivered by SMIs. Furthermore, repurposed drugs are expected to constitute a large share of future formulations to be delivered by SMIs. SMIs can also be employed for the delivery of formulations that target systemic diseases. Finally, digitalizing SMIs would improve patient adherence and provide clinicians with fundamental insights into patients' treatment progress.

Reducing Aerosol-Related Risk of Transmission in the Era of COVID-19: An Interim Guidance Endorsed by the International Society of Aerosols in Medicine.

National and international guidelines recommend droplet/airborne transmission and contact precautions for those caring for coronavirus disease 2019 (COVID-19) patients in ambulatory and acute care settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, an acute respiratory infectious agent, is primarily transmitted between people through respiratory droplets and contact routes. A recognized key to transmission of COVID-19, and droplet infections generally, is the dispersion of bioaerosols from the patient. Increased risk of transmission has been associated with aerosol generating procedures that include endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, turning the patient to the prone position, disconnecting the patient from the ventilator, noninvasive positive-pressure ventilation, tracheostomy, and cardiopulmonary resuscitation. The knowledge that COVID-19 subjects can be asymptomatic and still shed virus, producing infectious droplets during breathing, suggests that health care workers (HCWs) should assume every patient is potentially infectious during this pandemic. Taking actions to reduce risk of transmission to HCWs is, therefore, a vital consideration for safe delivery of all medical aerosols. Guidelines for use of personal protective equipment (glove, gowns, masks, shield, and/or powered air purifying respiratory) during high-risk procedures are essential and should be considered for use with lower risk procedures such as administration of uncontaminated medical aerosols. Bioaerosols generated by infected patients are a major source of transmission for SARS CoV-2, and other infectious agents. In contrast, therapeutic aerosols do not add to the risk of disease transmission unless contaminated by patients or HCWs.

Nebulised budesonide using a novel device in patients with oral steroid-dependent asthma.

This phase 2/3 randomised, parallel-group, placebo-controlled trial investigated oral corticosteroid (OCS)-sparing efficacy, safety and tolerability of nebulised budesonide (Bud) administered with a novel computer-controlled, compressor-driven inhalation system (AKITA) as add-on therapy to Global Initiative for Asthma step 5. Patients (18-65 years) with OCS-dependent asthma were randomised (2:1:1:1) to receive 18-week, twice-daily, double-blind treatment with AKITA inhaled corticosteroid (AICS)-Bud 1 mg, AICS-Bud 0.5 mg, AICS-placebo or open-label Bud 1 mg administered by conventional nebuliser (CN-Bud). OCS doses were tapered until week 14. 199 patients started treatment. More AICS-Bud 1 mg (80.0%) than placebo-treated (62.5%) patients had daily OCS doses reduced ≥50%, with clinical stability to week 18 (one-sided p=0.02; treatment difference: 17.5% (95% CI 0.1-34.9%), two-sided p=0.04). Mean±sd forced expiratory volume in 1 s improved (from baseline to week 18) for AICS-Bud 1 mg (239±460 mL, p<0.001) and AICS-Bud 0.5 mg (126±345 mL, p=0.01) but not placebo (93±419 mL, p=0.36) or CN-Bud (137±459 mL, p=0.18). Fewer AICS-Bud 1 mg-treated patients experienced asthma exacerbations (7.5%) compared with placebo (17.5%) or CN-Bud (22.5%). All treatments were well tolerated. Budesonide applied with AKITA allowed significant meaningful OCS reduction in OCS-dependent asthma patients while improving pulmonary function and maintaining exacerbation control.

The use of combined single photon emission computed tomography and X-ray computed tomography to assess the fate of inhaled aerosol.

BACKGROUND: Gamma camera imaging is widely used to assess pulmonary aerosol deposition. Conventional planar imaging provides limited information on its regional distribution. In this study, single photon emission computed tomography (SPECT) was used to describe deposition in three dimensions (3D) and combined with X-ray computed tomography (CT) to relate this to lung anatomy. Its performance was compared to planar imaging. METHODS: Ten SPECT/CT studies were performed on five healthy subjects following carefully controlled inhalation of radioaerosol from a nebulizer, using a variety of inhalation regimes. The 3D spatial distribution was assessed using a central-to-peripheral ratio (C/P) normalized to lung volume and for the right lung was compared to planar C/P analysis. The deposition by airway generation was calculated for each lung and the conducting airways deposition fraction compared to 24-h clearance. RESULTS: The 3D normalized C/P ratio correlated more closely with 24-h clearance than the 2D ratio for the right lung [coefficient of variation (COV), 9% compared to 15% p < 0.05]. Analysis of regional distribution was possible for both lungs in 3D but not in 2D due to overlap of the stomach on the left lung. The mean conducting airways deposition fraction from SPECT for both lungs was not significantly different from 24-h clearance (COV 18%). Both spatial and generational measures of central deposition were significantly higher for the left than for the right lung. CONCLUSIONS: Combined SPECT/CT enabled improved analysis of aerosol deposition from gamma camera imaging compared to planar imaging. 3D radionuclide imaging combined with anatomical information from CT and computer analysis is a useful approach for applications requiring regional information on deposition.

Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer.

Pulmonary alveolar proteinosis (PAP) is a rare condition characterized by the accumulation of lipoproteinaceous material within air spaces. Although whole lung lavage is the current standard of care, recent advances in our understanding of PAP pathophysiology suggest that the disorder may benefit from inhalation of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). The aim of this study was to determine the physical properties and bioactivity of rGM-CSF aerosolised by the highly efficient AKITA² APIXNEB® nebulizer system. The physical properties of aerosolised rGM-CSF were investigated in terms of droplet size, output and output rate by laser diffraction and gravimetrical analysis. Lung deposition was assessed using deposition modeling (ICRP). Molecular mass before and after aerosolisation was determined by SDS-PAGE, while the bioactivity of rGM-CSF was evaluated by measuring the GM-CSF-stimulated increase in pSTAT5 using mAM-hGM-R cells. Ninety-six % of the rGM-CSF filling dose was aerosolised with the Akita² Apixneb® nebulizer system. Particle size was highly reproducible, and the amount deposited within the lung was 80.35% of the delivered dose. The aerosolisation did not alter the molecular structure of rGM-CSF, nor its ability to stimulate the pSTAT5, which increased by 99.5%, similar to values for rGM-CSF prior to aerosolisation. We conclude that the highly efficient AKITA² APIXNEB® nebulizer system is likely to efficaciously deliver rGM-CSF to the airways of patients with autoimmune PAP.

The Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) in vitro system: design and experimental protocol.

The development of aerosol medicines typically involves numerous tests on animals, due to the lack of adequate in vitro models. A new in vitro method for testing pharmaceutical aerosol formulations on cell cultures was developed, consisting of an aerosolisation unit fitting a commercial dry powder inhaler (HandiHaler(c), Boehringer Ingelheim, Germany), an air-flow control unit (Akita(c), Activaero, Germany) and a custom-made sedimentation chamber. This chamber holds three Snapwell(c) inserts with monolayers of pulmonary epithelial cells. The whole set-up, referred to as the Pharmaceutical Aerosol Deposition Device On Cell Cultures (PADDOCC) system, aims to mimic the complete process of aerosol drug delivery, encompassing aerosol generation, aerosol deposition onto pulmonary epithelial cells and subsequent drug transport across this biological barrier, to facilitate the investigation of new aerosol formulations in the early stages of development. We describe here, the development of the design and the protocol for this device. By testing aerosol formulations of budesonide and salbutamol sulphate, respectively, reproducible deposition of aerosol particles on, and the integrity of, the pulmonary cell monolayer could be demonstrated.

Inhalative vaccination with pneumococcal polysaccharide in patients with chronic obstructive pulmonary disease.

In order to determine the feasibility of inhalative vaccination with polysaccharide antigen in patients with chronic obstructive pulmonary disease (COPD), we used controlled inhalation of a defined dose of Pneumovax in a randomized 3-arm study. The vaccine was either deposited in the alveoli (alveolar vaccination) or in the large airways (bronchial vaccination) and these were compared to standard intramuscular vaccination. Adverse effects were minor and never exceeded WHO grade 2. There was frequent cough, headache and shivering in the bronchial vaccination group, frequent fatigue only in the alveolar vaccination group and no frequent adverse effects in the intramuscular vaccination group. Specific serum IgG antibody was measured before and at 4 and 12 weeks after vaccination. At 12 weeks there was a greater than twofold rise in 7 out of 10 individuals in every vaccination group. Mean antibody levels of responders at 12 weeks were 278 mg/l for alveolar vaccination, 238 mg/l for bronchial vaccination and 737 mg/l for standard intramuscular vaccination. The data show that polysaccharide vaccine can be safely administered by controlled inhalation in COPD patients and that it can induce a rapid serum antibody response.

Inhalative vaccination with pneumococcal polysaccharide in healthy volunteers.

In order to determine the feasibility of inhalative vaccination with polysaccharide antigen, we used controlled inhalation of a defined dose of Pneumovax in a randomized 3-arm study. The vaccine was either deposited in the alveoli (alveolar vaccination) or in the large airways (bronchial vaccination) and this was compared to standard intra-muscular vaccination. Adverse effects were minor and never exceeded WHO grade 2. There was frequent cough in the inhalative groups and frequent local pain at the injection site in the intra-muscular group. Specific serum IgG antibody measured before, and 4 and 12 weeks after, vaccination showed a greater than 2-fold rise in 4 out of 10 individuals after alveolar vaccination and in 6 out of 10 individuals after bronchial vaccination as compared to 10 out of 10 in the intra-muscular vaccination group. Average antibody levels of responders at 12 weeks were 350 microg/ml for alveolar vaccination, 200 microg/ml for bronchial vaccination and 1010 microg/ml for standard intra-muscular vaccination. Analysis of antibodies for 9 specific serotypes showed a more than 3-fold rise to 7-9 of the serotypes in the intra-muscular group. In both the bronchial and the alveolar group, all subjects responded but this was restricted to 2-4 of the 9 serotypes. The data show that polysaccharide vaccine can be safely administered by controlled inhalation and that it can induce good, albeit lower, serum antibody responses.